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Best Advice: Anytime you are able to talk about an Algorithm for these questions is

the better than having a PhD in that topic ;)

-By using the algorithms it gives you the main points the professors want to hear

good to know:
 Q79 - under this Q i have copy pasted part from kovačs book that explains

how thermoregulatory center works ***the real answer to this q can be found

under q.80 and 83

 Q.84- I have provided you with the answer from kovačs book which in my

opinion is not good enough so I would recommend reading first few pages of

ch4 in pathology

 q86- I didnt write about about particular immunodef. so you should read ch 4

for more info on specific ones.

 Small fixes and corrections: NB (MSE class of 2020)

1. Homeostatic Mechanism Dysfunction and the Range of Physiological Value Oscillation.

Homeostasis: Maintenance of nearly constant conditions in the internal environment. Organs and
tissues work synonymously to help maintain these relatively constant conditions. The body has key
variables that must be kept within a particular operating range if the body is to remain healthy, i.e
blood pressure and blood glucose concentration.
These important regulated variables are monitored and adjusted by control systems in physiology.
A control system consists of (I) an input signal, (II) controller, programmed to respond to
certain input signals, (III) an output signal.
In addition, all systems are involved. For example, Respiratory system- main gas exchanger
in the body, Circulatory System- bodies main delivery system, Gastrointestinal Tract- bodies main
nutrient absorber, Liver- performs main metabolic functions such as changing molecules to active or
inactive forms.


When you drink a large volume of water, the dilution of your extracellular fluid triggers a
mechanism that causes your kidneys to remove excess water and protect your cells from dilution.

Taking a look at the homeostatic circuit we can conclude the following:

 Regulated Value: Change of some normally regulated value in the body
 Sensor: This change is registered by a sensor
 Integrator: This receives information registered by the sensor
 Effector: Counteracts or amplifies the change (Negative or Positive Feedback Loops)

Negative Feedback Loops are very important homeostatic mechanisms and are the most abundant
when compared to Positive Feedback Loops. If a variable in the body is in excess or deficient, there
is a control mechanism that initiates a negative feedback. This consists of a series of changes that
will return the variable back to its normal mean value, resulting in the maintenance of homeostasis.
In general, NFLs (not national football league ;)) stabilize the variable being regulated and
thus aid the system in maintaining homeostasis, i.e. when the body senses that there is enough of a
certain type of molecule it will remove the stimulus causing the formation of that molecule. The
response loop has then been shut off.

Positive Feedback Loops are when the response reinforces the stimulus rather than decreasing or
removing it. This causes the variable to be regulated far beyond its normal value, causing the
system to temporarily lose control. Naturally, this may seem like just a pathological mechanism,
however, there are some important physiological situations in which PFLs are useful. For example,
uterine contractions during child birth.

Baby drops lower in uterus to initiate labour → Cervical stretch → oxytocin release →uterine
contractions →push baby against cervix → further cervical stretch

This occurs until an outside event or intervention stops the response loop. In this case it would be
the delivery of the baby.
Plurimodal Regulation: Regulation of values in an organism is often controlled by multiple
independent homeostatic mechanisms.
Assessment of normal values vs their fluctuations is based on statistical analysis of an adequate
population of a determined ethnic group, age and gender. Normal values in some groups may
actually be pathological in other groups.

2.Adaptation, Principles of Integral Body Reactivity.

In general, Adaptation is any change in function, structure or behaviour by which a species or

individual improves its chance of survival in a specific environment.

According to this definition of adaptation we can see a clear picture of evolution being a huge part
of this.
Forms of adaptation on the macroscopic level:
 Species and Group Adaptation
 Cultural Adaptation
 Individual Adaptation
1. Inherited adaptation mechanisms
2.Aquired mechanism of adaptation

Species and Group Adaptation: This is the classical Natural Selection form of adaptation where
certain characteristics have been either evolutionary preserved or altered among certain groups and
species. These MUST have been proven to be advantageous for survival in order to be considered
adaptations. (Sickle cell anemia trait in areas of malaria)

Sickle cell anemia is a recessive genetic disease. Red blood cells are misshapen, crescents
instead of discs, preventing enough oxygen from being delivered to all parts of the body. According
to the “Natural Selection” theory, we would assume that this is rare. However, it is not and it is
more prevalent amongst people of African Descent in areas of high incidences of Malaria.
Since the sickle cell mutation seemed to protect individuals against Malaria, it was retained
for individuals living in those high Malarial incidence areas even though sickle cell anemia is a
disease in itself.
Taking a look at now some descendants living in areas with low Malarial incidences, sickle
cell anemia becomes more of a problem rather than an advantage. However, we know that it takes
thousands of years for populations to adapt to new environments and for natural selection to occur.

Cultural Adaptation: This has to do with adaptations of society to life conditions based on
collective knowledge and civilization (i.e medicine). It is the process of adjusting health messages
to the intended audience by incorporating their cultural heritage, language and ethnicity.
Sometimes it means finding the right word.
On other occasions, it is about finding cultural equivalents so that the information is accurate
but is also relevant and understandable to a different cultural audience.

Individual Adaptation:
(I) Inherited Adaptation Mechanisms

These types of adaptations have to do with environmental factors on an individual, that takes place
on all levels in the body. For example, Hypertrophy, Atrophy, Hyperplasia, Metaplasia etc.
However, these individual adaptations may not always be an advantage. For example,
Hypersensitivity disorders such as allergies.

(II) Aquired Mechanism of Adaptation

By understanding and learning from experiences, an individual can adapt to certain environmental
conditions externally. For example, at colder temperatures it is known to wear warmer clothes to
keep the body temperature normal.
A concept known as “psychosocial adaptation” is referred to when patients are faced with a
chronic disease or disability often face significant obstacles which they need to overcome. These
patients are often forced to adapt to stress, trauma, grief, changes to self-image and uncertainty.
Patients who achieve psychosocial adaptation posses certain traits which help them cope.
One study showed that psychosocial adaptation to cancer was related to a patients ego strength,
concluding that the patients who possessed a strong ego, or strong sense of self, used better coping
strategies to deal with their cancer.

3. Reactivity, anabolism, catabolism and Constitution.

Reactivity : is the functional-dynamic ability of an organism to react to a particular stimulus. The

capacity of an organism to react in a qualitative and quantitative manner to a stimulus.

There are 3 important factors when discussing reactivity.

 Environment
 Genotype (inherited traits)
 Phenotype (expressed characteristics that depend on genotype and environment)

Reactivity varies amongst age groups. For example, when considering the Babinski reflex, it is
considered to be physiological until the second year of life. Afterwards it is considered to be a
pathological condition.
In older age groups, reactivity is slower and weakens due to the slow-down of metabolic
processes and physiological functions. For example, the function of the immune system is known
to decline in the elderly. This change is considered to be a primary immunological change in the
elderly since it is an age-dependent intrinsic decline of immune responsiveness observed in
otherwise healthy individuals. As we know, decreased immune reactivity is not only age related.
So if we encounter this with an underlying disease or other various environmental factors, it is
considered to be a secondary immunological change. Most can be influenced by therapeutic
measures, whereas primary immunodeficiencies of the elderly cannot, or only to a very minor

Anabolism: Constructive metabolism; the synthesis in living organisms of more complex substance
from simple ones (as opposed to catabolism). Anabiosis (from the Greek to return to life): A state
of suspended animation under adverse environmental conditions.

Catabolism: The breakdown of complex molecules in living organisms to form simpler ones
together with the release of energy. Catabiosis (from the Greek “kata”-reverse and “biosis”-way of
life): The organic process of growing older and showing the effects of increasing age.

Constitution: defined as the persons functional and morphological features and qualities of the
human body. A persons physical state with regard to vitality, health and strength.
 Leptosomal (vata type): Tall, skinny, narrow thorax, thin and long neck, bird-like facial
 Pyknic (kapha type): Bulky, wide thorax, relatively narrow shoulders, short neck, wide face.
 Athletic (pitta type): Strong skeleton, firm muscle and wide shoulders compared to pelvis.

Most people have a mix of all three constitutional body types. Some of these body types have
increased risks in developing certain diseases.
For example, Leptosomic types are more prone to develop peptic ulcers and arterial hypotension.
The Pyknic type experience heavy digestions and gain weight easily. They experience diseases
such as atherosclerosis, diabetes and gout. Lastly, the athletic types experience exhaustion and
circulation impairment. They have tendencies towards inflammations, rheumatism, acne and gum

4. Assessment of Systemic Function

When assessing functional systems, all levels of the organism must be considered (macromolecular,
cellular, etc). This estimates the capacity of the system to perform a certain function and the state
the organism is in.

 Assessment of dynamic balance (steady state): When there is a change in gradient or

functional organization of the system that will disturb the steady state. However, the body
usually has homeostatic mechanisms that maintain the steady state whenever there is a
nonfunctional, or potentially destructive change in the body.
 Assessment of the patients Reactivity: Here there are two things to consider.
 Sufficiency- normal ability to respond to stress.
 Insufficiency (failure)- qualitative and quantitative reduction of the reactivity of the
organism below normal levels. The subtypes of this insufficiency are:
 Latent (hidden) - Usual symptoms are not yet manifested. There is only moderate, if any,
reduced reactivity. However, the compensatory mechanisms are sufficient to maintain
almost normal reactivity. Remember: (NO SIGNS, NO SYMPTOMS). Example, Herpes
 Manifested - This means that the insufficiency becomes apparent through the appearance of
symptoms. There is great reduction of reactivity, regardless of the compensatory
mechanisms, which become insufficient.

Assessment of reactivity is not all the same for all organ systems. Generally, specific organ systems
have different ways of assessing disturbances of reactivity. For example the Glasgow Coma Scale is
a neurological scale that aims to give a reliable, objective way of recording the conscious state of a
person for initial as well as subsequent assessment. A patient is assessed against the criteria of the
scale, and the resulting points give a patient score between 3. (indicating deep unconsciousness) and
either 14 (original scale) or 15 (the more widely used modified scale)

Glasgow Coma Scale: Grading disturbances in consciousness

5. Pathophysiology of Stress and Systemic Organism Reaction to Injury

Any threat to homeostasis puts the body in a state of stress. Compensatory mechanisms, again, take
place to readjust whatever has altered the body balance. If the disturbing factor is not of the usual
kind (i.e. bacterial pathogen, etc) but rather stress, the body secretes certain stress hormones to take
care of the situation. This process is called Fight or Flight via the stimulation of the sympathetic

Stressful conditions stimulate the hypothalamus to secrete ARH (adrenocorticotrophic releasing

hormone). This hormone then goes on to stimulate the pituitary gland that is below the
hypothalamus to secrete ACTH (Adrenocorticotrophic hormone). This hormone then stimulates the
adrenal glands to secrete the stress hormones, Adrenaline and Cortisol.

The Functional Adjustments made or biological effects of stress:

 Diversion of the blood from less vital to more vital organs
 Increase in heart rate to supply more blood quickly
 Increase in blood pressure to supply blood efficiently
 Increase in the respiratory rate to get more oxygen from the atmosphere
 Breakdown of glycogen stores in liver and muscle to get more glucose
 Formation of more glucose from non-carb substances

Cushings Syndrome and Cushings Disease are examples of when this response becomes pathologic.
Remember!!! Cushings Disease and Syndrome are clinically almost identical. However, the
difference is that Cushings Disease is when there is a micro-adenoma related to the pituitary,
whereas Syndrome is any other Cortisol increasing tumor outside the pituitary (i.e. adrenal glands,
small cell tumor of the lung.
This disorder is an example of negative feedback, since the excess cortisol sends a message to the
gland to stop secretion of ACTH. However, the tumor does not respond to negative feedback and
therefore cortisol increase does not cease.

Canon: introduced the term homeostasis, named the response “fight or flight”, emphasizing the
adrenergic effects.

Syle: introduced the concept of stress and distinguishes 3 phases: alarm, adaptation, and exhaustion.
 Alarm: corresponds to fight or flight and is a response to acute stressor effect.
 Adaptation: adjustment of homeostatic mechanism that render the organism resistant to the
 Exhaustion: organism weakens and becomes susceptible to various disorders. For example,
chronic fatigue syndrome, myocardial infarction.

6. Etiological Factors and Mechanisms of Pathogenesis

Pathogenesis: is the biological mechanism of a disease that leads to the diseased state.

CAUSE: initiator of the pathological process

MECHANISM: responsible for the development of the pathological process

ETIOLOGY: branch of pathophysiology that studies causes of various pathologic processes.

Factors- are either endogenous or exogenous.

ARNDT-SCHULZOV LAW: For every substance, small-intermediate doses stimulate, strong-

moderate doses inhibit, large doses paralyze/kill.

Preconditioning: In smaller doses, brings the organism to a desired state with protection from
subsequent exposure. (i.e. vaccines)

Radiation Hormesis: is a hypothesis that low doses of ionizing radiation have a protective effect
and stimulate immune and inflammatory resistance.

Specificity of etiological factors: Depends on if their effect is strictly bound to one target tissue or
they exhibit organotropism.

Development of a pathological process: chain of events in which the consequence of one reaction is
the cause of the next reaction. Think of Dominos.

Analysis of etiology and pathogenesis: examining the interaction of the etiological factor and the
organism. To understand the disease, requires VERTICAL ANALYSIS of disorders on hierarchal
levels of organization. For example, primary structure of proteins is determined by genetic code but
subsequent modifications depend on surroundings and may alter conformation physiologically or
pathophysiologically. This dysfunctional protein can cause problems at the cellular level which can
then manifest widely throughout the organism in various tissues. This analysis has been well
demonstrated in CYSTIC FIBROSIS.

Time Factors in Pathogenesis: development of pathological processes as a function of time allows

for proper selection of diagnostic procedures, prognosis and treatment.

Functional Dynamic Networks: Method of systematic biology that analyzes genome, and its
connections as well as its expression of how variations and exogenous factors influence the system

All together > PATHOGENESIS

Cause(etiology)+mechanism= pathogenesis

7. Hereditary, Environment and Pathological Process

(robbins environmental chapter charts as well as genetic disease chapter)

Hereditary: due to genes

Phenylketonuria: Look at the algorithm for this example. It will be very helpful during oral :)

Other examples are Galactosemia, lysosomal storage diseases and other genetic diseases (review P1
chapter examples).

Environmental: due to surroundings

Infectious diseases such as TB are important. Previously known as consumption. Symptoms are
chronic cough with blood-tinged sputum, fever, night sweats, and weight loss. Infection begins
with mycobacteria reachng the pulmonary alveoli, where they invade and replicate within
endosome of alveolar macrophages. Since the bacteria has a thick waxy capsule, this protects it
from the macrophages enzymes. Therefore eventually the macrophage itself will be destroyed due
to replication of the mycobacterium.
GHON FOCUS: is the primary site of infection in the lungs.
SIMON FOCUS:TB in the lungs occuring via infection from the blood stream.

Granulomatous inflammatory disease. Macrophages, T-lymph, B-lymph and fibroblasts aggregate

to form granulomas with lymphocytes surrounding the infected macrophages.

Chemical Substances: (List in environmental chapter of robbins) Some examples are Vinyl
Chloride causing liver angiogenesis.
Benzene causing Leukemias
CCL4 affecting the CNS.

Lack of nutrition:
Kwashiorkor (visceral protein deficiency) and Marasmus (somatic protein deficiency)
Vitamin deficiencies

Nutritional Excess:

8. DISEASE (General factors, development, outcome)

Entity with specific etiology and pathogenesis with molecular cell and tissue defects along with a
clinical picture. Basically, a disordered or incorrectly functioning organ, part, structure or system of
the body resulting from the effect of genetic or developmental errors, infection, poisons, nutritional
deficiency or imbalance toxicity, or unfavorable environmental factors; illness, sickness, ailment.

Factors that are involved in formation of DISEASE:

 Etiological
 Factors in which the organism is exposed to internally
 Environmental Conditions.

Characteristics of disease:
 Acute
 Chronic
 Degenerative

Several Degrees of Disease:

 Subclinical
 Mild
 Moderate
 Severe
 Terminal
Phases of Illness:
 Introductory
 Disease expression
 Disease regression (exacerbation of symptoms and of illness)
 Recovery phase

Outcome of Disease:
 complete recovery
 consequence of disease
 acute disease can become chronic (review robbins)
 remission (disappearance of symptoms)
 relapse (early appearance)

9. Disorder of DNA Structure and Function

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other
organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell
nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the
mitochondria (where it is called mitochondrial DNA or mtDNA).

5 types of DNA changes include:

1.Oxidation: ROS cause damage to the DNA strand. Remember how ROS are formed because it is a
common side question (review Page 38-39 in Robbins)

2.Alkylation: is the transfer of an alkyl group from one molecule to another. Alkylating agents are a
class of antineoplastic or anticancer drugs which act by inhibiting the transcription of DNA into
RNA and thereby stopping the protein synthesis. Alkylating agents substitute alkyl groups for
hydrogen atoms on DNA, resulting in the formation of cross links within the DNA chain and
thereby resulting in cytotoxic, mutagenic, and carcinogenic effects. This action occurs in all cells,
but alkylating agents have their primary effect on rapidly dividing cells which do not have time for
DNA repair. Cancer cells are among the most affected because they are among the most rapidly
dividing cells. Eg. Nitrogen mustards, nitrosoureas, triazenes.
3.Hydrolysis: Involves the reaction of breaking of a bond in a molecule using water. Mainly occurs
between an ion and water molecules and often changes the pH of a solution. Examples are,
Deamination which is the removal of an amine group from a molecule. The enzymes that catalyze
this reaction are called deaminases. This process primarily takes place in the liver, however
glutamate is also deaminated in the kidneys. There is also Oxidative deamination occuring under
aerobic conditions in all tissues but especially the liver. During this process, an amino acid is
converted into the corresponding keto acid by the removal of the amine functional group as
ammonia and the amine functional group is replaced by the ketone group. The ammonia eventually
goes into the urea cycle. Depurination of DNA is the result of a loss of a purine from the DNA
backbone. Finally Depyrimidination which is self-explanatory.

4. Dimerization: Cross-linkage between adjacent cytosine and thymine bases that creates
pyrimidine dimers.
5. Mismatch of bases: Due to errors in DNA replication where the wrong base is added in the new
forming DNA strand or a DNA base is skipped over or mistakenly inserted. (Review Robbins 234-
235, this will help expand on this question)

There are several causes that affect DNA structure formation. These can be either endogenous or

Endogenous: Most important to considered are ROS formed as metabolic byproducts and
replication errors during cell division. Some carcinogens act directly on the target DNA. However,
most are converted to their damaging metabolically reactive form by the processes (cytochrome P-
450 > production of a ROS causing DNA damage) It would be useful to refer back to some toxic
drugs you learned in pharmacology and give a more specific example. Look back to all the
cytochrom P-450 related drugs. Eg. Bisphosphonates

Exogenous: UV rays, Gamma-rays, x-rays, xenobiotics etc. Review page 271 in Robbins for a
more detailed description. Also, viruses and plant toxins as well as temperature.

10. Disorders of DNA Repair

DNA repair system is important in maintaining genetic stability. Diminished capacity for DNA
repair is associated with a variety of Human Diseases.

Examples include : Ataxia telangiectasia, Bloom Syndrome, Fanconi’s anemia, Werner Syndrome,
and Xeroderma Pigmentosum. (it would be wise to know at least two in greater detail to expand on
the question)
Multiple pathways are available for DNA repair using enzymes that act upon different kind of

 1st pathway is BASE EXCISION REPAIR (really cute video)

DNA glycosylase removes the desaminated nucleotide. AP endonuclease comes in along with DNA
polymerase and DNA Ligase. DNA polymerase fills the gap with the correct nucleotide and DNA
ligase seals it.

 2nd pathway is NUCLEOTIDE EXCISION REPAIR (not as cute but informative :P )

3rd mechanism occurs when both strands of the double helix are broken.

REPAIR BY RECOMBINATION: This is a type of genetic recombination in which nucleotide
sequences are exchanged between two similar or identical molecules of DNA. Widely used by cells
to accurately repair harmful breaks that occur on both strands of DNA, a.k.a double-strand breaks.

Also, damage to DNA generates signals that block cell cycle progression. Review Robbins page

RB genes, ATM protein, p53, RAS, ABL and/or BCR-ABL are all very good topics to discuss
during this question. Remember some of the diseases associated with them.


Disorder can occur if there is:

 change in nucleotide sequence (mutations)
 or if someone else's DNA enters the cell
Mutations are consequences of DNA damage that are not repaired. Types of mutation:

1. according to cell mutation presence

 constitutional- contained in zigote and all other cells(proven in all tissue types)
 acquired/somatic- DNA change acquired during life; transffered to daughter cells
2. according to size of DNA change
 point mutation- replacement of a single base nucleotide with another nucleotide of
the genetic material; also includes insertions or deletions of a single base pair
 gene remodeling
 chromosome mutation
3.according to change in DNA information contents
 sense mutation-gives rise to a different codon which is transcribed as a
“synonymous” codon and the same AA is incorporated into the growing polypeptide
as would have been incorporated by original, non-mutated codon; the protein
remains unchanged
 missense mutation- single nucleotide change results in a codon that codes for a
different AA (sickle cell disease)
 nonsense mutation- mutation in a sequence of DNA that results in a premature stop
codon; formation nonfunctional protein product (thalassemia as an example)
 frameshift mutation- caused by insertion or deletion of a number of nucleotides in a
DNA sequence that is not divisible by three; they will cause the reading of the
codons after the mutation to code for different amino acids. The frameshift mutation
will also alter the first stop codon ("UAA", "UGA" or "UAG") encountered in the
sequence. The polypeptide being created could be abnormally short or abnormally
long, and will most likely not be functional. (Tay-Sachs disease, cystic fibrosis)
4. according to mechanism of development
 spontaneous mutation

 induced mutation
 dynamic mutation (Huntington's disease)
5. according to phenotype
 nosogenic*- cause protein dysfunction (PKU)
 silent
6. according to the functional behavior of mutant protein
 loss of function/negative- afunctional or hypofunctional protein
 gain of function mutation- change the gene product such that it gains a new and
abnormal function


Karyotype is a term used for complete set of chromosomes in a certain species. Karyotype of
diploid human cell (2n) has 23 chromosomal pairs.
Disorders of the chromosome structure and number occur relatively often and we call them
chromosomal aberrations.
 Numerical abnormalities
 Polyploidy – numerical change in a whole set of chromosomes; may occur due to abnormal
cell division; usually results in spontaneous abortion; polyploid cell can be triploid(3n),
 Aneuploidy - any deviation from an exact multiple of the haploid number of chromosomes,
whether fewer or more
 Monosomy (2n-1) – lack of one chromosome of the normal complment; monosomy
of the sex chromosome (45,X) causes Turner syndrome
 Trisomy (2n+1) – presence of three copies, instead of the normal two, of a particular
chromosome; trisomy 21(Down sy),trisomy 18 (Edwards sy), trisomy 13(Patau sy);
trisomy of the sex chromosome is also possible such as 47 XXY (Klinefelter sy)
 Tetrasomy (2n+2) – presence of four copies of chromosome
 Pentasomy (2n+3) - presence of five copies of chromosome
 Structural abnormalities
 Deletion – loss of a portion of chromosome; examples: cri-du-chat, Wilms tumor
 Translocation – transfer of a part of one chromosome to another chromosome;
ch.granulocytic leukemia (Philadelphia chromosom) as an example
 Inversion – when there are two interstitial breaks in a chromosome, and the segment
reunites after a complete turnaround
 Isochromosomes result when the centomere divides horizontally rather than
vertically. One of the two arms of the chromosome is then lost, the remaining arm is
duplicated, resulting in a chromosome with two short arms only or two long arms
 A ring chromosome is a variant of a deletion. After loss of segments from each end
of chromosome, the arms unite to form a ring.

Gene expression is the process by which genetic instructions are used to synthesize gene products.
These products are usually proteins, which go on to perform essential functions as enzymes,
hormones and receptors, for example. Genes that do not code for proteins such as ribosomal RNA
or transfer RNA code for functional RNA products. -short video on gene expression and

regulation) Regulation of gene expression is a complex process in which a mistake at any level can
lead to cell dysfunction. Disorders of gene expression can involve:
 disorders of DNA structure
 mutations in regulatory circuits
 DNA remodeling
 epigenetic disorders
 DNA methylation (example: in hepatocellular CA methylation of α-fetoprotein gene is
decreased that is way α-fetoprotein appears in plasma which is an important diagnostic
sign). DNA methylation disorders participate in pathogenesis of malignant tumors
because hypermethylation inactivates antioncogenes and hypomethylation activates
 covalent modification of histones (acetylation, methylation, phosphorylation)
 chromatin condesation
 disorders of the general transcription factors- failure of RNA polymerase II and TATA box
 disorders of the specific transcription factors – may contribute to control of both initiation
and elongation; typically bind cofactors which are proteiun complexes that contribute to
activation (coactivators) and repression (corepressors) but do not have DNA binding
properties on their own.
 disorders of signaling molecules: for example
NF-κB (Nuclear factor κB ) is found in cytoplasm bound to inhibition molecule I- κB. Many
excitatory messages, acting through different receptors, stimulate separation of I- κB from NF- κB ;
NF- κB then gets into the nucleus, binds and activates excitatory genes. Activated genes determine
synthesis of proteins that are involved in local inflammation and organism response to injury and
 RNA interference- process in which RNA molecules inhibit gene expression. In human cells
microRNA binds to mRNA in cytoplasm and blocks translation or causes mRNA
degradation.By inhibition of inhibitor mRNA can also stimulate gene expression.

MicroRNA gene 1 gene 2 **MicroRNA inhibits expression of gene 1 that normally

inhibits gene 2; in this way microRNA indirectly, by inhibiting
X the inhibitor, stimulates expression of gene 2
Legend: X-inhibition; Δ- stimulation


Transcription is the first step of gene expression, in which a particular segment of DNA is copied
into RNA by the enzyme RNA polymerase. Transcription proceeds in the following general steps:
One or more sigma factor protein binds to the RNA polymerase holoenzyme, allowing it to
bind to promoter DNA.
RNA polymerase creates a transcription bubble, which separates the two strands of the DNA
helix. This is done by breaking the hydrogen bonds between complementary DNA nucleotides.
RNA polymerase adds matching RNA nucleotides to the complementary nucleotides of one
DNA strand.
RNA sugar-phosphate backbone forms with assistance from RNA polymerase to form an RNA
Hydrogen bonds of the untwisted RNA-DNA helix break, freeing the newly synthesized RNA
If the cell has a nucleus, the RNA may be further processed. This may include
polyadenylation,capping, and splicing.
The RNA may remain in the nucleus or exit to the cytoplasm through the nuclear pore
Transcription disorder can occur as a consequence of action of different inhibitors. One example of
such an inhibitor is α-amanitin, toxin found in several species of the Amanita genus of mushrooms,
one being the death cap (Amanita phalloides), that specificlly inhibits RNA polymerase II causing
inhibition of mRNA synthesis. Tissues that are very sensitive to this poison are: liver, kidney and
mucous membranes of digestive system. Symptoms(severe diarrhea, ac.liver insufficiency,ac.renal
insufficiency) are evident 6 to 24 hours after ingestion.
Translation is the second part of protein biosynthesis. Translation happens in four stages: activation,
initiation,elongation and termination. It proceedes in following steps:
Amino acids are brought to ribosomes and assembled into proteins. In the activation stage, the
correct amino acid isocovalently bonded to the correct transfer RNA (tRNA). When the tRNA is
connected to an amino acid, it is "charged".
Initiation is when the small part of the ribosome connects to 5' end of the mRNA with the help
of initiation factor(IF).
Elongation is when the amino acids brought by the "charged" tRNAs are connected to each
other to form a polypeptide.
Termination of the polypeptide happens when site A of the ribosome meets a stop codon(UAA,
UAG, or UGA). There is no tRNA that matches that codon, so no tRNA can connect to it. This
breaks the polypeptide off the ribosome.
Most common translation disorders are protein biosynthesis disorders;they inhibit initiation of
translation through cell hypoenergosis and lack of amino acids. Often they serve as an adaptation
mechanisam for cell survival in adverse conditions. For example in viral infection interferon will
inhibit protein biosynthesis and by that it will disable further viral replication.
For a short while translation disorders will not affect transcription but with time pathologic
process in one of those two will also cause pathology in the other. When a cell is in inadequate
metabolic conditions due to lack of different growth factors or insulin, rate of RNA synthesis
decreases (transcription), protein synthesis decreases (translation); this leades to disaggregation of
polyribosomes and it also decreases synthesis of: nucleic acids, amino acids, glucose. This
complicated metabolic response is called negative pleotypic response. If you add lacking growth
factors than the response is reversed and it is called positive pleotypic response.


Mendelian disorders result from mutations in a single gene that has a large effect. Every individual
is a carrier of between five or eight potentially deleterious mutations; 80% are inherited (familial)
while the remainder represent de novo mutations.
 Whether a given mutation will have an adverse outcome is influenced by compensatory
genes and environmental factors.
 Some autosomal mutations produce partial expression in heterozygotes and full expression
only in homozygotes (sickle cell disease).
 Mendelian traits can be dominant, recessive or codominant, the later referring to full
expression of both alleles in a heterozygote.
 Penetrance refers to the percentage of individuals who carry a particular gene and also
express the trait.
 Variable expressivity refers to variation in the effect caused by particular mutation; thus
manifestations of neurofibromatosis type I range from brown macules to skin tumors to
skeletal deformities.
 Pleiotropism refers to multiple possible end effects of a single mutant gene;thus in sickle
cell disease, the mutant hemoglobin causes hemolysis and anemia, as well as vascular
occlusion leading to spleenic infarction and bone necrosis.
 Genetic heterogeneity refers to multiple different mutations leading to the same outcome;
thus different autosomal recessive mutations can cause childhood deafness.
Single gene disorders:
1. Autosomal dominant disorders – manifest in heterozygous state and have the following features:
 Disease is usually also present in a parent. When both parents of the affected individual are
normal, a de novo germ cell mutation is suggested; this happens more commonly in the
sperm of older fathers.
 Clinical features are modified by penetrance and expressivity.
 Clinical onset is often later than in autosomal recessive disorders.
 Most autosomal dominant mutations are loss of function mutations, that is, they result in
either reduced production of a gene product or reduced activity of a protein.
Mutations in a key structural protein(collagen), especially if the mutation is a part of multimer, can
interfere with the function of the normal gene product(i.e., by affecting folding), thereby leading to
dominant negative effects.
Mutations of components in complex metabolic pathways subject to feedback inhibition (e.g., LDL
receptor) are often autosomal dominant.
Mutations in enzymes are usually not autosomal dominant since even loss of 50% activity can be
 Gain of function autosomal dominant mutations are less common; they cause disease by
endowing a gene product with toxic properties or by increasing a normal activity.
 e.g. spherocytosis, osteogenesis imperfecta
 Autosomal recessive disorders include most inborn errors of metabolism. General features:
 The expression of disease features tend to be more uniform.
 Complete penetrance is common.
 Onset is frequently early in life.
 De novo mutations are rarely detected clinically until several generations have passed
and a heterozygote-heterozygote mating has occurred.
 Enzymes rather than structural proteins are more commonly affected.
 e.g. galactosemia, lysosomal storage diseases
 X-linked disorders
All sex linked disorders are X-linked and most are recessive. They are fully expressed in males,
because mutant genes on the X chromosome do not have a Y chromosome counterpart (affected
males are hemizygous for the X-linked mutant gene). Heterzygote females usually do not express
the disease due to paired normal X allele; however, random X inactivation in a population of cells
can lead to a variable phenotype. X-linked dominant conditions are rare; affected women express
the disease and transmit it to 50% of their sons and daughters,while affected men express the
disease and transmit it to 100% of their daughters and none of their sons.


Tab:Pathogenesis of hereditary metabolic disorders- expression on 5 levels
Level of expression Disorder caused by mutation Example
I. on the gene level modified sequence of nucleotides Mutation of β-globin gene:
in a DNA molecule , gene deletion GAG(Glu) GTG(Val)
, gene duplication , insertion, point
mutation ...

II. level of the gene product- disorder of structure, function or Replacement of glutamine for
protein quantity of the gene product which valine at the 6th position of β-
is a protein with many different globin chain of hemoglobin; the
functions end result is HbS

III. level of metabolic function of slowing of enzymatic HbS in deoxygenated state turns
cells and tissues reactions,defects in receptors and into microfilaments that causes
transport systems defrormation in erythrocyte
membrane (sickle cell disease)
IV. level of clinical phenotype clinical picture clinical picture of hemolytic
anemia with sickle cells disease
V .levels of heritability(genetic) mode of inheritance recessive inheritance

Enzyme defects and their consequences:

Mutations can result in the synthesis of defective enzyme (reduced activity) or reduced synthesis of
normal enzyme. The outcome is a metabolic block with:
 accumulation of substrate that is toxic (e.g. phenylalanine in PKU)
 decreased amount of an end product necessary for normal function (e.g.melanin in albinism)
 decreased metabolism of a tissue damaging substrate (e.g. neutrophil elastase in α1-
antitrypsin deficincy)
Pathogenesis of hereditary enzimopathies: A) normal function; B) consequences of enzyme
mutation. Decrease in catalytic functions of enzyme can cause lack of product, accumulation of
substrate ( this can block other enzymes, disturbe transport through cell membrane) can activate
secondary,in healthy persons, inactive metabolic pathways or it can accumulate in lysosomes.

A) normal function

Secondary inactive
metabolic pathway
secondary product
B)gene mutation

(lysosomal storage disease) LACK OF

Lysosomal storage diseases result from a genetic deficiency of functional lysosomal enzymes or
other proteins essential for their activity. They are classified on the basis of bichemical nature of the
accumulated metabolite. The tissues affected and resultant clinical features depend on where the
material to be degraded is normally located and in which sites it is typically catabolized. Since
macrophages re particularly rich in lysosomes and are responsible for degradation of several
substrate, organs with abundat macrophages (liver and spleen) are often affected.
Tay-Sachs disease
Results from mutation in α-subunit of the hexoaminidase enzyme complex; it is the most common
of the three GM2 -gangliosidoses resulting from lysosomal GM2 -ganglioside accumulation.It is the
most common in Jews of Eastern European origin.Antenatal diagnosis and carrier detection are
possible by DNA probe analysis and enzyme assays on cells obtained from amniocentesis. Because
neurons are rich in gangliosides, they are the cell type most severely affected;thus typical clinical
features are motor and mental deterioration commencing at abouth 6months of age and blindness
and death by age 2 to 3 years.
Niemann-Pick diseases, types A and B
Disorders associated with sphingomyelin deficiency.Sphingomyelin accumulation is most
prominent in mononuclear phagocytes, but it can also affect neurons. Acid sphingomyelinase is an
imprinted gene that is preferentially expressed from the maternal chromosome due to paternal gene
epigenetic silencing.
Type A is more common.It is a severe infantile form of the disease that is clinically manifest
at birth.Death typically occurs within 3 years. Affected cells are engorged with numerous small
vacuoles that impart cytoplasmic foaminess.
Diffuse neuronal involvement, leading eventually to cell death and CNS atrophy; a retinal,
cherry-red spot is seen in roughly half of the patients. Extreme accumulation of lipids in
mononuclear phagocytes,yielding massive hepatosplenomegaly and lymphadenopathy with bone
marrow infiltration. Visceral involvment mainly affecting gut and lungs.
Niemann-Pick disease,type C
Most common of all types.Occurs due to mutations in either NPC1(95%) or NPC2, coding
for proteins involved in cholesterol transport from lysosomes to the cytosol.Cholesterol and
gangliosides are both accumulated, and patients can present with hydrops fetalis,neonatal hepatitis,
or (most commonly) progressive neurologic degeneration beginning in childhood with
ataxia,dystonia, and psychomotor regression.
Gaucher disease
Refers to a cluster of autosomal recessive disorders involving mutations leeading to
diminished glucocerebrosidase activity.Cleavage of ceramide (derived from cell membranes of
senescent leukocytes and RBCs as well as from turnover of brain gangliosides) is impaired.
Glucocerebroside accumulation occurs in mononuclear phagocytes and ,in some forms, the CNS.
Type I (chronic, non-neuronopathic form) is the most common form and it occurs in
adults;there are reduced, but detectable, levels of enzyme activity.Although there is no brain
involvement,patients have massive splenomegaly and lymphadenopathy, and marrow involvement
leads to bone erosions that can cause pathologic fractures.Pancytopenia or thrombocytopenia result
from hypersplenism.
Type II is the acute neuronopathic form affecting infants.It is associated with
hepatosplenomegaly, but progressive CNS deterioration predominates with death at young age.
Type III is intermediate with systemic involvement of macrophages, as well as progressive
neurologic disease begining in adolescence.
Group of disorders resulting from inherited deficiencies of enzymes that degrade
glycosaminoglycans (abundant in the ECM of connective tissues).Accumulated substrates include
heparan sulfate,dermatan sulfate, keratan sulfate, and chondroitin sulfate. Several MPS clinical
variants are known; all forms are progressive and are characterized by:
 coarse facial features
 hepatosplenomegaly
 corneal clouding
 valve and subendothelial arterial thickening
 joint stiffness
 mental retardation
They result from hereditary deficiencies in the synthesis or catabolism of glycogen;
disorders may be restricted to specific tissues or can be systematic. They are divide into three major
 Hepatic form is due to deficincies in enzymes that primarily influence liver glycogen
catabolism; these are characterized by hypoglycemia and hepatic glycogen accumulation.
The prototype is von Gierke disease (type I) due to glucose-6-phosphatase deficiency, which
converts glucose 6-phosphate to glucose.
 Myopathic form is characterized by deficincies of enzymes that fuel glycolysis in striated
muscles.Thesee characteristically present with muscle weakness and cramping after exercise
without exrcise-induced rises in blood lactate;skeletal muscles show glycogen accumulation.
McArdle disease is du to deficient muscle phosphorylase.
 Miscellaneous forms are associated with α-glucosidase deficiency or lack of branching
enzyme;typically these lead to glycogen overload in many organs and early death.Pompe
disease results from deficiency of the lysosomal enzyme acid maltase ( α-
glucosidase).Cardiac involvement is most prominent in tthis disorder.

In this autosomal recessive disease, lack of homogentisic oxidase blocks the metabolism of
phenylalanine,leading to homogentisic acid (alcapton) accumulation. Excessive homogentisic acid
leads to:
 urinary excretion,imparting a black color if allowed to stand
 ochronosis, a blue-black pigmentation of the ears,nose and cheeks resulting from binding of
homogentisic acid to connective tissue
 arthropathy associated with deposition in articular cartilage; affected cartilage (typically
vertebral column,knee, shoulders and hips) loses resilience and is readily eroded.
PKU is an autosomal recessive disease, most commonly associated with bi-allelic mutations of the
gene encoding phenylalanine hyddroxylase(PAH) an enzyme that irreversibly converts
phenylalanine to tyrosine.Disease severity correlates with the loss of enzyme activity and the
associated increase in phenylalanine levels. Although normal at birth, affected infants exhibit rising
plasma phenylalanine within the first few weeks of life,followed by impaired vrain development
and mentll retardation. Screening for elevated phenylalanine metabolite in urine allows early
diagnosis;subsequent phenylalanine dietary restriction prevents most clinical
sequelae.Phenylalanine and its metabolites are teratogenic- infants born to PKU mothers with high
phenylalanine levels are microcephalic and mentally retarded.


Channelopathies are diseases caused by disturbed function of ion channel subunits or the proteins
that regulate them.These diseases may be either congenital (often resulting from a mutation or
mutations in the encoding genes) or acquired (often resulting from autoimmune attack on an ion
Cystic fibrosis is an autosomal recessive disorder that affects epithelial cell ion transport and causes
abnormal fluid secretion in exocrine glands, as well as in respiratory, gastrointestinal and
reproductive mucosa. It is the most common lethal genetic disease affecting Caucasian
populations.Heterozygote carriers also have a higher incidence of respiratory and pancreatic
pathology relative to the general population.
The CF associated gene: normal structure and function:
 The gen mutated in CF encodes the cystic fibrosis transmembrane regulator (CFTR) protein
– a chloride channel; activation of the channel occurs via agonist induced increases in
intracellular cAMP, fillowed by protein kinase A activation and CFTR phosphorylation.
 CFTR regulates other ion channels and cellular processes. Although CF mutations
specifically affect the CFTR, disease manifestations are related to the interactions of CFTR
with other ion channels and cellular processes.These include potassium,sodium, gap
junction channels, as well as ATP transport and mucus secretion.
 CFTR association with the epithelial sodium channel (ENaC) has the most pathophysiologic
relevance to CF. ENaC is an apical membrane protein in exocrine epithelium that is
rsponsible for sodium transport.
 CFTR functions are tissue specific.

 CFTR mediates bicarbonate transport.
The CF gene:mutational spectra and genotype-phenotype correlation
At least 1300 disease-causing mutations of CFTR have been identified.The most common is a
three-nucleotide deletion coding for phenylalanine at position 508 (ΔF508); this results in defective
intracellular CFTR processing with degradation before it reaches the cell surface.Patients
homozygous for the ΔF508 mutation have virtual absence of CFTR function; they present with
severe clinical disease (classic CF), including early pancreatic insufficiency and various degrees of
pulmonary damage.Patients with other combinations may present with features of atypical or
variant CF,including isolated chronic pancreatitis,late-onset ch.pulmonary disease,or infertility only.

Variable features of CF depending on affected epithelium:

 Pancreas: Abnormalities occur in 85% to 90% of patients ranging from mucus accumulation
in small ducts with mild dilation to total atrophy of the exocrine pancreas.Absence of
pancreatic exocrine secretions impairs fat absorption, and the resulting avitaminosis partly
explains ductal squamous metaplasia.
 Intestine:Thick viscous plugs of mucus (meconium ileus) can cause smal bowel obstruction.
 Liver: Bile canalicular plugging by mucinous material results in diffuse hepatic cirrhosis.
 Salivary glands: progressive duct dilation,ductal squamous metaplasia,glandular atrophy.
 Lungs:Involved in most cases and are the most serious complication of CF.Mucus cell
hyperplasia and viscous secretions block and dilate bronchioles.Superimposed infections
and pulmonary abscesses are common.
 Male genital tract: Azoospermia and infertility occur in 95% of male patients surviving to
adulthood,frequently with congenital abscence of the vas deferens.

Diseases due to mutation of proteins:
Osteogenesis imperfecta ( brittle bone disease, or "Lobstein syndrome") is a congenital bone
disorder characterized by brittle bones that are prone to fracture. People with OI are born with
defective connective tissue, or without the ability to make it, usually because of a deficiency of type
I collagen. Eight types of OI can be distinguished. Most cases are caused by mutations in the
COL1A1 and COL1A2 genes. Collagen is of normal quality but is produced in insufficient
Bones fracture easily
Slight spinal curvature
Loose joints
Poor muscle tone
Discoloration of the sclera, usually giving them a blue-gray color. The blue-gray color of the sclera
is due to the underlying choroidal veins which show through. This is due to the sclera being thinner
than normal because of the defective Type I collagen not forming correctly.
Early loss of hearing in some children
Slight protrusion of the eyes
Life expectancy is slightly reduced compared to the general population due to the possibility of
fatal bone fractures and complications related to OI Type I such as basilar invagination.

An autosomal dominant disorder resulting from (mostly missense) mutations in the fibrillin-1-gene.
Fibrillin is a glycoprotein component of microfibrils that provides a scaffold for the deposition of
elastin; it is especially abundant in the connective tissues of the aorta,ligaments and ciliary zonules
that support the eye lens.Mostly affects the skeletal,ocular and cardiovascular systems. Abnormal
fibrillin results in defective microfibril assembly resulting in reduced elasticity, as well as reduced
sequestration of TGF-β;excess TGF- β reduces normal vascular smooth muscle development and
matrix production.
Skeletal changes: tall stature with exceptionally long extremities,arachnodactyly,laxity of joint
ligaments,hyperextensibility,dolichocephaly(long head) with frontal bossing and prominent
supraorbital ridges,spinal deformities
Ocular changes:bilateral dislocation of lenses,increased axial length of the globe giving rise to
retinal detachments
Cardiovascular changes: mitral valve prolapse, aortic cystic medial degeneration causing aorrtic
ring dilation and valvular incompentence
Group of disorders caused by defects in collagen synthesis.Major manifestations
involve:hyperextensible skin vulnerable to trauma,wound healing is markedly
impaired,hypermobile joints prone to dislocation, rupture of colon and large arteries,ocular fragility
with corneal rupture and retinal detachment,diaphragmatic hernias.


Disorders of cell membrane can be either heritable or acquired.

 Changes in the expression of selectins,integrins and other adhesion molecules that are
involved at the level of intracellular contacts in all the processes which are changing the
interaction between cells(atherosclerosis,inflammation and immune processes,metastasis
of malignant tumors).Dysfunction of these systems are reflected in specific syndromes
such as Syndrome of Neutrophil Dysfunction(syndrome CD11/CD18 deficiency in
which adhesion processes are dysfunctional as well as chemotaxis and phagocytosis).
 Maintenance of transmembrane electrolyte concetration differences in the cell is an
important physiologic phenomena underlying the numerous functions of cells and
tissues, as well as signal transmission in the nerves, sensory excitation,excitation of
muscle contraction and ejection of cytoplasmic granules.Maintenance of depends on the
active transport of electrolytes, permeability of selective and nonselective channels, and
permeability of membrane. For example, disorders of potassium channels participate in
Hereditary Hyperinsulinemic Hypoglycemia in newborns and in the long QT-interval
syndrome.Sodium channel disorders occur in Hyperkalemic periodic skeletal muscle
paralysis, and long QT syndrome.
 Abnormalities of cell membrane reduce flexibility of RBCs with consequent faster
removal from the bloodstream and shorter lifespan. It can also lead to reduced resistance
to osmotic load and more or less pronounced anemia. For example, Hereditary
Spherocytosi occurs due to lack of spectrin and decreased lipid content in the membrane.
Such cells are more leaky for sodium causing compensatory increase in glucose
metabolism in order to ensure sufficient quantities of ATP and to correct electrolyte
imbalances.Consequences are: longer retention of spherocytes in the spleen,energy
shortage due to relative lack of glucose and electrolyte disorder leading to decreased
functional flexibility(plasticity) of erythrocytes making them more prone to

 Disorders caused by endogenous factors
▪ Breakdown of lateral connections with loss of functional polarity (basal and apical
part of the cell) is seen in hypoenergosis,in big increase of intraluminal
pressure(ileus), and in effects of bacterial enzymes and toxins.
▪ In oxidative phosphorylation 2-4% of oxygen, in physiologic conditions, is reduced
to free oxygen radicals.Radicals react with endogenous molecules, changing their
structure.Multiple unsaturated fatty acids in membrane phospholipids react with free
radicals resulting in process called lipid peroxidation.This reaction can occur in both
hypoxic and hyperoxic conditions due to excess of electron donors or acceptors.
Lipid peroxidation changes microenviroment of membrane proteins resulting in
changes in enzymatic function or changes in transmembrane channels. It can
potentially lead to formation of lipid channels and increse in ionic permeability.
Degradation products of this reaction are responsive to amino groups on the side of
proteins,for example they block sulfhydryl groups that are most commonly in the
active center of enzymes.Normally organism has various antioxidants that protect
membranes from destruction by oxygen radicals.Natural antioxidants: α-tocopherol,
steroid hormones,vit. C,ubiquinone,aliphatic alcohols, glutatione peroxidase.
▪ Membrane perforation results in communication between intracellular and
extracellular space enabling free ion diffusion and disappearance of electrochemical

and concetration gradients.It is an effective mechanism of of cellular
destruction,used by immune system in executive phase. Once complement system is
activated, its components C5b,C6,C7,C8 and C9 spontaneously create amphiphile
(both hydro -phobic and -philic) molecular complex that is placed into the membrane
making a tunnel that connects intracellular and extracellular space. Cytotoxic cells (
CD8 lymphocytes,NK cells) destroy target cells using membrane attack/perforin
complex.When they recognize target cell they release perforin which polymerizes
into perforin complex. Perforin complex creates pores on the membrane of target
cells.Through created pores big intracellular molecules attract water, which causes
cellular edema and finally its complete disintegration.
▪ In hyperuremic conditions,uric acid is crystallized,forming spiny crystals of mono-
sodium urate.Crystals are endocytosed by phagocytes leading to possible weakening
of lysosomal membrane and clinical presentation of gout.

 Disorders by external factors

▪ There are cell membrane molecules that serve as receptors for certain biological
factors and their products. Tissue distribution of receptors explains histotropism of
intracellular germs.By entry of germ into the cell,conditions for their multiplication
and colonization of tissues are created. TAB 4.5.
▪ Some physiological molecules of the membrane serve as receptors for toxins in the
body that are formed by disintegration of germs(endotoxins) or or active secretion of
toxins from living organisms in distant foci (exotoxins). TAB4.6


 Disorders of mitochondrial structure and function

Mitochondria are cell's energy generators.Damage to the mitochondrial function reduces energy
production.When it drops to energy threshold (the critical level necessary for cell function) the
disturbances of cell function are seen.
 Disorders of DNA,ribosomes and mitochondria division
Mitochondria contain from 2 to 10 of their own mitochondrial DNA(ring like DNA). It contains 13
genes for polypeptide enzymes needed for oxydative phosphorylation. MtDNA damage can be
inherited or acquired.Inherited MtDNA damage causes inherited mitochondrial disease.These rare
syndromes are caused by various tissue damages. Tissue damage follows tissue sensitivity to energy
shortage that depends on their energy threshold.The most common are damages to the optic
nerve(blindness) and CNS (epileptic spasm,movement disorders,neurogenic muscle weakness)
followed by skeletal muscle,heart muscle,pancreatic islets of Langerhans, kidney and liver. The
most common signs of inherited mitochondrial diseases occur after age of 20 years and deteriorate
with age. In severe cases of mitochondrial disease signs are evident soon after birth
(hypoventilation,lactic acidosis,signs of serious CNS damageand heart disorders, so patient die as
infants. Mothers transmit mitochondrial diseases, but both male and female offspring is equally

affected.Mitochondriial diseases are not inherited by Mendel's law.
Acquired MtDNA damages primarily occur due to effects of free oxygen radicals.This effect is
bigger than in the nucleus on nDNA because in mitochondria there is no system that repairs
MtDNA damages. The production of free oxygen radicals increases when the oxydative
phosphorylation is disrupted due to hereditary or acquired MtDNA damages, hypoxia or toxic
effects. Since free oxygen radicals damage the MtDNA, and MtDNA damage increases increases
formation of free oxygen radicals,pathogenic vicious circle is closed which eventually leads to
damage of oxidative phosphorylation, reduction in energy production and organe damage.
Mitochondrial ribosomes are also like MtDNA similar to bacterial ribosomes considering their
structure and function.Due to that similarity they are sensitive to antibiotics (chloramphenicol).
Lack of mitosis or fusion of mitochondria leads to formation of large mitochondria,
megamitochondria.Seen in alcoholic liver damage and in renal tubular necrosis.In these conditions
total mass of mitochondria remains unchanged.In organ hypertrophy there is an increase in number
and size of the mitochondria(heart hypertrophy). On the contrary, in poor nutritional conditions the
number of mitochondria increases again when conditions improve.

 Cellular energy charge and mitochondrial function

Energy production disorders in mitochondria are associated with many pathological
processes.Oxidative phosphorylation in mitochondria is regulated by the action of ATP and ADP.
ATP inhibits while ADP enhances oxidation.The final effect depends on the ATP and ADP ratio or,
more accurately on the cellular energy charge(E):
The higher the energy charge, the lower the activity of the mitochondria to create ATP. This form of
mitochondrial function control is called respiratory or acceptor control.
Cytosolic Ca2+ concetration regulates mitochondrial function.Ca2+ enters mitochondria driven by
electrochemical gradient of H+, the same one that is phosphorylation initiator. The passage of Ca2+
through the mitochondrial membrane stimulates synthesis of ATP. When concetration of Ca 2+ rises
above 1 micro mol/liter pores in the mitochondrial membrane are formed. The appearance of pores
causes an increase in mitochondrial membrane permeability with consequent functional
changes(mitochondrial permeability transition).Increased permeability of mitochondrial inner
membrane destroys H+ electrochemical gradient with consequent decoupling of oxidative
phosphorylation and lack of ATP.Due to incomplete reduction of oxygen , the formation of
superoxide anion increases, from which secondary free oxygen radicals arise.Ca 2+ and proteins with
MR less than 1.5kD diffuse through the pores of mitochondria into cytosol, and the water enters the
mitochondria.Among the proteins that come out of mitochondria are initiators of apoptosis.Ca 2+ is
not the only factor of mitochondrial permeability transition; free fatty acids, acyl carnitine, acyl
CoA stimulate formation of pores.ADP and ATP stimulate their closing. Bcl-2 prrotein closes the
pores and thus suppresses the apoptosis. Reversibility of mitochondrial permeability transition
depends on the duration of this condition.
 Lysosome function disorder
Organells that contain acid hydrolase enzymes that function as intracellular digestive system. The
most typical lysosomal enzymes are: acid phosphatase,beta-glucuronidase, N-acetyl-beta-
glucosaminidase, cathepsin,aryl sulfatase and deoxyribonuclease. Granules in the
polymorphonuclear leukocytes are the most typical example of lysosomes.
Lysosomes are important in the regulation of hormone activity: when there is excess of hormones
lysosomes partly autolyse them, and when the hormones are needed such activity stops. They also
have an important role in bone resorption; phagocytosis of microorganisms; removal of old
erythrocytes,leukocytes and platelets from bloodstream; reabsorption of proteins in renal proximal
tubule... Lysosome function depends on:endocytotic cellular activity,phagosome fusion with
lysosome,lysosomal enzyme membrane permeability,presence of specific lysosomes,accumulation
of disintegrated material.
1.Endocytotic cellular activity
The strongest endocytotic activity have macrophages, polymorphonuclear
leukocytes,intestinal epithelial cells and renal proximal tubule cells. Lack of opsonins in some
hypoglobulinemic states will have as a consequence reduction of endocytotic activity of
polymorphonuclear leukocytes.
Increased endocytotic activity of smooth muscle cells of blood vessels and macrophages,
with an increased level of lipids in the body, is associated with development of atheromatous
The extreme endocytotic activity of the epithelial cells of renal proximal tubule leads to the
accumulation of some heavy metals such as cadmium. Nephrotoxicity of most antibiotics is
associated with their accumulation in renal proximal tubules; the great affinity of this compounds to
some lysosomal enzymes reduces normal catabolic function of renal lysosome.
2.Phagosome fusion with lysosome
In some infectious diseases cause of disease interferes with normal phagocytosis
(toxoplasma,listeria,tuberculosis).They are phagocyted but withinn them they produce compounds
that prevent phagosome-lysosome fusion, so they remain alive in phagosome.
Chédiak-Higashi syndrome, an inherited disease that manifests itself in childhood, in which
secondary lysososme can not be formed allowing bacteria to freely reproduce causing early death in
such patients.
3.Lysosomal membrane permeability and enyzme activation
Labilisators are substances that increase lysosomal membrane permeability;such as
hormones, biogenic amines,bacterial toxins,carcinogenes,hypoxia. Stabilisators reduce the
permeability of lysosomal membrane and stabilize it (cortisol, antihistamines, antirheumatic drugs).
An example of pathogenic importance of lysosomes is seen in synovitis caused by uric aacid
microcrystals. Phagocytosis of
Crystallisation of amorphous crystals and
Hyperuricemic fluid urates ac.inflammation

Local decrease of Lactate hyperproduction and

PH lysosome membrane damage

Some microorganisms(streptococci) after phagocytosis release membranolysing toxins(streptolysin)

that break down the secondary lysosomal membrane and damage the host cell.
Photosensitization is associated with accumulation of photosensitive compounds (porphyrins,
polybenzene hydrocarbons,acridine color) in lysosomes.These substances absorbe light energy
leading to development of photo-oxydation reactions whose products labilise lysosomal membrane.
X-rays and γ-rays also labilise membrane in irradiated persons and this contributes to development
of ac.inflammation.
4.Inadequacy of specific lysosomal membranes
Exampes: Pompe disease,Gaucher disease, Tay-Sachs disease
5.Accumulation of substances in lysosomes
When the concetration of iron in blood is increased, it binds to apoferritin,and produces
ferritin; this assembly is resistant to lysosomal enzymes and accumulates in lysosomes. When iron
is needed it separates from ferrritin and as a soluble forms enters the blood so it can be
used.Sometimes, however, liver lysosomes accumulate abnormal amounts ferritin and and poorly
soluble hemosiderin, which leads to hemochromatosis and hemosiderosis.
More examples: anthracosis(deposition of coal dust in the lungs), lipofuscin in old cells,Wilsons
disease(copper accumulation)
 Dysfunction of cell nucleus
Two forms of chromatin can be distinguished: euchromatin and heterochromatin.Euchromatin is
less dense,active in RNA synthesis.Chromatin condesation and decrease in RNA synthesis occurs in
hypoxic cells.I n lethally damaged cells chromation is condensed more(pyknosis)and than under the
influence of enzymes it is cleaved(karyorrhexis) and degradede(karyolysis).
 Dysfunction of polyribosomes
Causes slowing of protein biosynthesis.Change in the functional distribution of ribosomes, in which
the number of unprogrammed polyribosomes increases,and the number of ribosomes associated
with mRNA decreases causes polyribosomes to decrease in size.
 Dysfunction of endoplasmic reticulum
Deaggregation of polyribosomes on the RER.Another common form of damage is when the tubules
are spread due to the accumulation of electrolytes and water because of disturbances in cell
permeability and cell transport.If posttranslation modification is disturbed unfinished polypeptides
can be: excreted,proteolytically degraded or they can accumulate in tubules.

Abnormal protein in endoplasmic reticulum

Abnormal Proteolytic
Overload with abnormal proteins
protein export degradation

Autophagy Inhibition of Block of growth Apoptosis Activation of

protein proliferation and NF-κB
synthesis differantiation



General respose patterns:
 Hypoenergosis directly causes hypofunction and afunction of organs, can trigger
apoptosis and necrosis of the cell.
 Oxidative stress,hyperthermia and ionizing radiation trigger inflammation,repair
mechanisms and catabolic reaction. In unfavorable conditions cells increase the
synthesis of heat shock proteins. With consumption of ATP HSP repair errorson the new
cellular proteins or support their rapid degradation.
 Greater cell membrane damage directly causes cell death while minor damage of the
membrane causes disturbance in elecrolyte balance and development of hypoexcitability
or hyperexcitability.
 In function overloads cells affected will increase in mass and functional capacity
(unilateral nephrectomy causes hypertrophy of contralateral kidney). If the physiological
load is reduced (immobilization of limbs)within a few days tissue atrophy can be seen.
 When osmolality of extracellular fluid changes, affected cells will synthesize
endogenous osmolitically active particles. For larger hyperosmolarity in cells catabolic
reactions are initiated.

Cellular damage due to lack of oxygen:

Hypoxia is the most frequent cause of cell damage. The cell instantly adapts to acute
hypoxia by changing enzyme activity. Oxidative phosphorylation inside the cells stops after just
twenty seconds of acute hypoxia. Anaerobic glycolysis is initiated at the same time as only source
of energy; but it is able to generate only 10% of the energy generated by oxidative
phosphorylation.Simuntaneously accumulation of metabolites inhibits anaerobic glycolysis and
results in deficiency of ATP.
Reparable structural damages:
The first processes damaged in hypoxic cell are energy dependant transport systems that
maintain electrolyte homeostasis.Calcium,sodium and water are accumulated within the cell and
potassium is lost from it.The energy deficiency inhibits protein biosynthesis and causes
deaggregation of polyribosomes.
The mitochondria undergo permeability transition because Ca2+ enters mitochondria and
induces formation of pores within membrane. If normal oxygenation is restored they will start to
generate ATP,pores will be close and mitochondrial functions repaired.However, re-establishment of
circulation after ischemia and new arrival of oxygen can damage cells that endured hypoxia.
Irreparable structural damages:
Occur when ischemia and hypoxia last longer.The point of no return is determined by the
state of mitochondria. They become swollen if permeability transition is irreversible and the
consequences of increased permeability ( oxidative phosphorylation uncoupling,increased
production of superoxide anion,leakage of Ca2+ and proteins) negatively affects various cellular
The loss of electrolyte homeostasis,especially uncontrolled increase of cytosolic Ca2+is the
cause of irreversible alterations during hypoenergosis.ATP deficiency reduces the activity of Ca2+
transporters on both ER and cellular membrane so that removal of Ca2+ is slowed down and
maintenance of low cytosolic Ca2+ is impaired.The reduced activity activity of Na/K transporter
further minimizes cellular removal of Ca2+ by increasin intracellular levels of Na+ and thus making
Na/Ca exchange difficult.
Activation of phospholipase C initiates phosphoinositol 2nd messenger. DAG and IP3
produced in that pathway increase cytosolic Ca2+ by affecting cellular membrane and ER transports
mechanisms.Ca2+ that accumulated in the mitochondria durinn initial,reversible phase of cell damge
now leaks out through pores into the cytosol.
Ca-calmodulin complex activates phospholipases (A1 and A2)which then tear fatty acids off
the membrane (including the arachidonic acid) resulting in defects in cellular and organelle
membranes. The release of arachidonic acid stimulates it's further metabolism by cyclooxygenation
and lipooxygenation which then produce free oxygen radicals.
Ca-calmodulin complex activates a protease that disassembles enzyme xanthine-
dehydrogenase at a specific position and converts it to xanthine-oxidase which is the terminal
enzyme in degradation of purine bases (oxidases hypoxanthine to xanthine and finally to uric acid).
Endothelial cells are particularly rich with this enzyme. Healthy cells contain the majority of this
enzyme's activity in a form of xanthine-dehydrogenase that transfers electrons and hydrogen onto
NAD during the oxidation of hypoxanthine to xanthine. In hypoxic cells xanthine dehydrogenase is
converted to xanthine oxidase by proteolysis.Then,during oxidation, it transfers electrons onto
molecular oxygen and superoxide anion O2- is formed. Superoxide anion is converted to hydrogen
peroxide in the presence of Fe2+ in traces. The latter is finally converted to free hydroxyl radical.
Ca2+-calmodulin complex stimulates the activity of NO synthase in endothelial and nerve cells.
Increased amount of NO obtains a cytotoxic effect by transforming to peroxynitrite anion and
further by producin OH-.

Once circulation is re-established and oxygen enters the cells,metabolic alterations in cells
that occur during hypoxia can cause production of greater amount of oxygen free radicals which
then induce postischemic or reperfusion injuy. Hypoxia also reduces the activity of enzymes which
protect the cell from free oxygen radicals. These enzymes are superoxide dismutase,catalase and
glutathion reductase.Therefore, hypoxia creates conditions necessary for development of oxidative
stress(condition in which production of oxygen free radicals is greater than their degradation).
Initial changes are seen on endothelial cells as expression of adhesion molecules on their
membranes.Oxygen free radicals that are produced during hypoxia in reversibly damaged cells act
as messenger molecules and they stimulate activation of NF-ĸB.Consequentially they increase
expression of adhesion molecules on endothelial cell membranes. Leukocytes get into hypoxic
tissue when circulation is restored and adhere onto endothelial cell membranes with the help of
adhesion molecules. Leukocyte activation then releases a great amount of oxygen free radicals.
Oxygen free radicals can damage all cellular parts. They disturb many functions of cell
membrane and organelles by peroxiding unsaturated fatty acids inside membranes. They can also
reduce enzyme activity and depolymerase polysaccharides by oxidizing sulfhydryl groups or
hydroxylate nucleic acid bases and break polynucleotide chains. In such a way oxygen free
radicalscan directly or indirectly damage all cellular formations and irreparably damage the whole
cell which recived oxygen after hypoxia.

22. Pathogenesis of Cell Death. Natural Cell-Killing Mechanisms

It is important to recall that the cells first try and adapt to the damaging stimulus in order to
preserve functionality. However, if the stimulus is too strong and/or cannot be removed then the
cells will either undergo apoptosis or necrosis.

Two types of cell death: Apoptosis and Necrosis

Apoptosis is a pathway of cell death in which cells activate enzymes that degrade the cells’ own
nuclear DNA and nuclear and cytoplasmic proteins. (Robbins page 18-22).

Key players to remember and elaborate on:

Extrinsic pathways and Intrinsic pathway (Robbins page 20 figure 1-22)

Bcl-1 family ( Bax and Bak )
Unfolded protein response and ER Stress (Robbins page 22 figure 1-24)
Alzheimer, Huntington and Parkinsons
 Mitochondrial pathway of apoptosis (Robbins 1-23)
Cytochrome C together with co-factors activate caspase 9 which activates the caspase cascade
and leads to nuclear fragmentation
Describe what happens with nucleus

Necrosis is the type of cell death that is associated with loss of membrane integrity and leakage of
cellular contents culminating in dissolution of cells, largely resulting from degradative action of
enzymes on lethally injured cells. (Robbins page 9-11)

Key factors to remember and elaborate on:

 The cell swelling, cytoplasmic and nuclear changes ( Robbins page 9 morphology)
 Types of necrosis (Robbins page 10-11 morphology)
 Fibrinoid necrosis example is polyarteritis nodosa (type III immune Hypersensitivity
 Caseous Necrosis vs Non-caseating. Tuberculousis is caseating and was formerly known as

A few other important pieces of information to keep in mind are what cause cell injury when
discussing these types of cell death. ROS is a very important player in this section. Robbins page
12-16 will come in handy when needing to discuss in further detail about the processes and where
they occur. MITOCHONDRIA is a favorable topic in the exam.


Natural killer cells are lymphocytes that are a component of innate immunity, fighting intracellular

Functions are:
 Cell Killing- kills viruses, microbes etc
 Secretion of Cytokines- produce IFN-y to activate macrophages, granzymes (are proteases
that degrade proteins in the cell membrane, which also leads to the loss of cell contents and
hence cell death), perforin (form a channel through the membrane and the cell contents are
 Participate in Fas-FasL mediated Apoptosis

NK cells are the major effector lymphocyte of innate immunity found in all the primary and
secondary immune compartments as well as various mucosal tissues. Through their ability to induce
direct cytotoxicity of target cells and produce pro-
inflammatory cytokines such as interferon-gamma, NK
cells are critically involved in the immune surveillance
of tumors and microbial infections. The major
mechanism that regulates NK cell contact-dependent
functions (such as cytotoxicity and recognition of
targets) is the relative contribution of inhibitory and
activating receptors that bind to cognate ligands. NK
cells have many receptors that recognize their cognate
(You do not need to memorize these, it is just to show you how diverse they are and nonspecific)
Next we will take a look at the molecular pathways leading to NK cell recognition of intrinsic
cellular stress. Oncogenic transformation and viral infection can activate intrinsic cellular
responses to stress. This includes the activation of the DNA-damage response, senescence, tumour
suppressors and the presentation and/or release of HSPs that, in turn, can activate NK cells through
various receptor ligand interactions.

The role of NK cells during immunogenic cell death induced by cancer therapy

NK cells provide an important primary defense mechanism against stressed cells. This is due to
their ability to respond rapidly to the up-regulation of multiple activating ligands. Although
frequently documented on stressed cells, the mechanisms that govern the regulation of NK cell-
activating ligand expression have only recently become apparent, particularly in the context of
cancer. These mechanisms include multiple intrinsic cellular responses, such as the activation of the
DNA-damage response, senescence, the activation of tumor suppressors and oncogenes, and the
sensing of deregulated cell proliferation. Indeed, many forms of chemo- and radiotherapy that are
currently used in the clinic that aim to engage these intrinsic cellular responses have been shown to
require the immune system, including NK cells for their full efficacy.

Possible diseases associated with defective NK function

23.Etiopathogenetic Role of Apoptosis

Growth factors, are defined as polypeptides that stimulate cell proliferation. They are major growth-
regulatory molecules for cells. These are naturally occurring substances capable of stimulating
cellular growth, proliferation, healing and cellular differentiation. Usually they are proteins or
steroid hormones. They are important for regulating a variety of cellular processes.

Some examples are: EGF, FGF, TGF-alpha, PDGF, etc

When cells are deprived of growth factors, or the cell’s DNA or proteins are damaged beyond
repair, the cell kills itself by apoptosis.
Apoptosis is triggered via Physiologic Situations or Pathologic Situations.

Physiologic Situations: Normal phenomenon that serves to eliminate cells that are no longer
needed. Also they help maintain a steady number of various cell populations in tissues. It is
important in the following situations:

 Programmed destruction of cells during embryogenesis (if this does not happen,
remember syndactyly)
 Menstrual Cycle
 Cell loss in proliferating cell populations (skin, intestinal mucosa)

 Death of cells that have served their purpose, example Neutrophils in an acute
inflammatory response.
 Elimination of potentially harmful set of self-reactive lymphocytes
 Cell death by cytotoxic T lymphocytes

Pathologic Conditions: Elimination of cells that are genetically altered or injured beyond repair
without eliciting a severe host reaction.

 DNA damage: Review types of DNA damage from previous questions

 Accumulation of Misfolded proteins: Caused by mutations in genes or proteins damaged by
ROS. Excessive accumulation of these proteins in the ER leads to ER stress
 Cell injury in certain infections: particulary viral infections either by the virus itself or the
host immune system.
 Pathologic atrophy in parenchymal organs: after duct obstruction, such as in pancreas,
parotid gland, and kidney.

24.Disorders of Energy Metabolism. Futile Metabolism

Metabolism is the process your body uses to get or make energy from the food you eat. Food is
made up of proteins, carbohydrates, and fats. Chemicals in your digestive system break the food
parts down into sugars and acids, your body's fuel. Your body can use this fuel right away, or it can
store the energy in your body tissues, such as your liver, muscles, and body fat.

A metabolic disorder occurs when abnormal chemical reactions in your body disrupt this process.
When this happens, you might have too much of some substances or too little of other ones that you
need to stay healthy.


Autosomal Recessive Deficiency of any of the enzymes involved in GLYCOGEN SYNTHESIS or
DEGRADATION can result in excessive accumulation of glycogen or some abnormal form of
glycogen in various tissues.

Many different types of Glycogen Storage Diseases exist, some worthy of note are:

 TYPE ONE: VON GIERKE DISEASE : This is known as the hepatic type. The enzyme
deficiency is GLUCOSE-6-PHOSPHATASE. Hepatomegaly due to storage of glycogen or
some abnormal form of glycogen in various tissues. Common clinical features are described
in Robbins on page 233 table 6-5

 TYPE TWO: POMPE DISEASE: This is known as generalized glycogenosis. The enzyme
deficiency here is ACID MALTASE aka LYSOSOMAL GLUCOSIDASE. Accumulation of
normally structured glycogen in most tissues. Massive Cardiomegaly.

Glycogen is stored in the muscles and there is associated muscle weakness due to impaired
energy production. Painful cramps with strenuous exercise along with myoglobinuria are
some of the clinical features of this type.


This is an autosomal recessive disorder of amino acid metabolism. It is caused by a lack of the
enzyme phenylalanine hydroxylase, which results in the inability to metabolize phenylalanine.

Review Robbins page 227-228 as well as Color Atlas of Pathophysiology Thieme page 260
Also discuss the algorithm on Phenylketonuria

*side note* most of the diseases discussed in robbins from 228 are good examples.

The Futile Cycle, is also referred to as the substrate cycle

This occurs when two metabolic pathways run simultaneously in opposite directions and have no
overall effect other than to dissipate energy in the form of heat. (not the greatest video but helps)

25.Hypoxia and Cyanosis

Hypoxia is characterized as lack of O2 in tissues and in turn causes hypoxic hypoenergosis.

Types of Hypoxia:
 Hypoxemic hypoxia
-decreased OXYGENATION of the blood in lungs that leads to low partial pressure of O2 in
the arterial blood.
-decrease PO2 gradient caused by high altitudes, abnormal pulmonary functions, respiratory
obstructions etc.

 Hematopathic (or hypemic) hypoxia

-decreased ability of blood to TRANSPORT O2.

For example: Anemias- decreased concentration of Hb results in decreased oxygen-carrying

capacity of the blood.
Hemoglobinopathies (innate or acquired):
-CO poisoning (You can discuss the CO poisoning algorithm here)
-Alkalosis: shifts dissociation curve to the left (Acute Respiratory alkalosis algorithm here)
-Acidosis: shifts dissociation curve to the right
-2,3 DPG (hypoxia promotes its synthesis): allosteric regulation of Hb, shifts curve to the right.

 Circulatory (or stagnant) Hypoxia
-Due to SLOWED BLOOD FLOW: general (heart failure) and local (ischemia)


 SUPPLY: supply of O2 not good enough to maintain the basic metabolism
 DEMAND: supply of O2 not good enough when the needs increase (Recall physical
exercise when the muscles switch to anaerobic metabolism to produce lactate)

 Histotoxic Hypoxia
-Occurs when there is a NORMAL DELIVERY OF O2 but the TISSUES ARE UNABLE
Major cause is cyanide poisoning, however, any agent that decreases cellular respiration such as
narcotics, alcohol, acetone etc can also be a cause of this type of hypoxia.

Four Major Stages of Hypoxia:

Indifferent- person may be unaware in the beginning. The eye unable to adapt to dark and
colour may be one of the first signs.
Compensatory- The respiration rate may rise along with the heart rate and BP to try and
“compensate” for the onset of hypoxia
Disturbance- Obvious symptoms begin now. Numbness, tingling, may vary from person to
Critical- Loss of consciousness, coma and death

Cyanosis: Blue skin and mucosa due to increase concentration in small blood vessels. Two
different types of Cyanosis.
 Central Cyanosis: General. The cause is hypoxemia or hematopathy
 Peripheral Cyanosis: Slowed blood flow or peripheral vasoconstriction

26.Biochemical and Subcellular Effects of Hypoxia

(Review any algorithms that deal with Hypoxia as a main component, for example CO poisoning)

-Decreases in ATP/ADP and increases NADH/NAD

-Aerobic metabolism shifts to Anaerobic metabolism
-Glycolysis becomes the only source of getting energy. However, eventually it will become packed
with products such as lactate and NADH
-Lactate is unable to be moved out by
Cori Cycle. This accumulation of lactate
can lead to metabolic acidosis.

The Cori Cycle ----------

27.Compensatory Mechanisms in Hypoxia

(Use the CO poisoning, or any other algorithm to help you discuss these mechanisms)

Some examples of these compensatory mechanisms are:

 HYPERVENTILATION: stimulation of chemoreceptors. Hyperventilation occurs only if

the hypoxia is not caused by some severe lung disease. Respiratory alkalosis can develop.
(bring in the Acute respiratory alkalosis algorithm here)


erythropoietin. In severe hypoxia, erythrocytosis is so significant that it increases
VISCOSITY of the blood. Therefore the peripheral resistance increases which in turn
decreases cardiac minute volume and worsens hypoxia.


vasoconstriction. The blood gets redirected to well perfused areas in the lung, which
increases the total area involved in gaseous exchange.
-Vasodilation will decrease BP.
-Vasoconstriction of aortic arch and carotid increases heart rate which increases cardiac
outpu and increases supply to the brain and, to a lesser extent, to tissues.

Increases dissociation of O2 from Hb in periphery. This is one of the main mechanisms in
circulatory hypoxias.

28.Dysenzymatic Hypoenergosis

Inherited or acquired mutational enzymatic hits involved in several biochemical pathways

(glycolysis, Beta oxidation, TCA cycle, Oxidative Phosphorylation, Transmembrane transport,
Mitochondrial Oxidative Decarboxylation)

Glycolysis- Inherited enzymatic mutations (involving muscle or erythrocyte enzymopathies)

 Muscle: enzymatic defect (6-phosphofructokinase) results in decreased muscle VII
which leads to pain and cramps after physical exertion similar to ischemia (cladicatio
intermittens). Spasm in the results from lack of ATP which is needed to return
calcium from sarcoplasm back into the sarcoplasmic reticulum.
 Erythrocyte: contain no mitochondria so they rely on glycolysis as a sole source for
energy. (i.e. membrane pump activation). Enzymatic defect pyruvate kinase stunts
glycolysis which decreases ATP production. This then decreases Na/K pump activity
and creates electrolyte imbalance. This causes H2O influx which leads to hemolysis
and essentially anemia.
Mitochondria- Inherited or acquired enzymatic effect
Inherited: acyl-CoA dehydrogenase mutation leads to defective Beta oxidation of Fatty Acids.

Beta Oxidation of Fatty Acids Overview

With a defect in this pathway, we can encounter encephalopathy and then death often due to viral
infection (Reye’s syndrome)

-With a decrease in Beta Oxidation, energy needs are taken over by glycolysis and therefore there is
no disease unless the organism is subjected to decreased glycolysis, as in STARVATION. During
starvation the body uses ketone bodies as energy source, but due to enzymopathy within BETA
OXIDATION the organism cannot supplement energy demand with Ketone Bodies.

Acquired Mutational hits due to damage to Mitochondrial DNA would either decrease
Cofactors or stimulate overactivity of inhibitor enzymes.
Causes can be:
- Toxic exposure: Cyanide poisoning which blocks cyto-c oxidase and thus ETC. The
ultimate results is Oxidative Uncoupling.
(review page 20 and 21 in Robbins to see all the molecules involved, those are good to list
out during exam)

3. Thyroid Hormones: Hyperthyroidism causes decrease energy metabolism efficiency that

will lead to uncoupling and increase of futile cycles. (refer back to question 24 of the

4. Cofactors are needed for biochemical pathways. Without them the pathway stops.
Examples are:

(Review page 302-303 table 7-9 in Robbins)

- Vitamin B1 - Thiamine = pyruvate dehydrogenase

The thiamine–dependent enzymes pyruvate dehydrogenase (PDH) and a–ketoglutarate
dehydrogenase (α–KGDH) participate in the metabolism of glucose through two biochemical
reactions, glycolysis and the citric acid cycle. The main function of these two sets of reactions is to
generate adenosine triphosphate (ATP), which provides energy for the cells. Reduced PDH and α–
KGDH activity resulting from thiamine deficiency can lead to less ATP synthesis, which in turn can
contribute to cell damage and even cell death. In addition, PDH is needed to produce the
neurotransmitter acetylcholine and to generate myelin, a compound that forms a sheath around the
extensions (i.e., axons) of many neurons, thereby ensuring proper neuronal functioning. The citric
acid cycle and α–KGDH play a role in maintaining the levels of the neurotransmitters glutamate,
gamma–aminobutyric acid (GABA), and aspartate, as well as in protein synthesis.

Also review Thiamine deficiency on page 281 in relation to Alcohol abuse in Robbins.

Other examples of important Cofactors are:

- Vitamin B2 - Riboflavin = FAD

- Niacin = NADH

29.Substrate Hypoenergosis

In general, you need materials (substrate) to build a product (energy). Without those materials you
cannot survive.

For example: Decrease in glucose (during starvation, lack of insulin, insulin resistance (diabetes),
hypophosphatemia) decreases the availability
for energy production which leads to a
decrease in ATP.

The body adapts to lack of glucose by

gluconeogenesis, ketogenesis, and fatty acid
utilization. If the lack of glucose is too severe
for adaptation mechanisms, then the body will
go into hypoenergosis.

Some pathways to elaborate on since they like

hearing about molecules :P

Glycolysis vs. Gluconeogenesis: -----

Ketogenesis Pathway:

Starvation: Review Protein Energy Malnutrition in Robbins on Pages 294-295

Also refer to Algorithm dealing with starvation problem 13

Starvation is mainly a decrease in nutrients. The most common culprit is GLUCOSE
When there is lack of glucose there are a few mechanisms in which the body will try and help cope
with the matter.
-Liver: Gluconeogenesis to form glucose. Beta Oxidation to form ketone bodies. Ketone Bodies is
what the body forms when there is, lack of glucose. It is due to the break down of fat instead of
glucose for energy.

Some ketone bodies are:

1. Acetone
2. Acetoacetate
3. Beta-hydroxybutyrate

These can build up in the blood (ketosis) and then spill over into the urine (ketonuria). The body
can also rid itself of acetone through the lungs giving the breath a fruity odor. Ketone bodies are
extremely important during starvation for the heart and skeletal muscle.

Fat: Lipolysis (main energy source in muscles is fatty acids and KB)
Main hormones during starvation: GLUCAGON, CATECHOLAMINES, CORTISOL, AND

Prolonged starvation: decrease insulin secretion leads to decrease influx glucose into cells,
decreased glycolysis which leads to increased glucagon and eventually increased gluconeogenesis
and glycolysis.

1. Fatty Tissue: the hormone activity increases the amount of Fatty acid utilization for muscles
and myocardium and also production of KB.
2. Carnitin-acyl-transferase 1 is key enzyme for Fatty Acid Oxidation- enzyme transports CoA
through inner mitochondrial membrane - enzyme depends on carnitine (stimulatory,
glucagon increase carnitine) and Malonyl CoA (inhibitory).
3. Brain and muscle need ketone bodies to function during insufficiency of carbohydrate
4. Ketosis develops due to limited glycolysis and insufficient usage of carbohydrates (this is
not just for starvation but also hypoglycemia (iatrogenic), Diabetes Mellitus.

Alanine: most important substrate for Gluconeogenesis

Breakdown of proteins for Gluconeogenesis is the main cause of death in starvation
Hypoglycemia-> hypoenergosis disrupts brain function, if prolonged leads to hypoglycemic coma.
This also leads to:
-increase us of FA acids
-increase production of KB -> ketoacidosis

In kids: decrease muscle mass

less amount of alanine available for gluconeogenesis-> faster onset ketoacidosis also can
develop from vomiting, diarrhea, gluco. dysfunction
Ethanol Poisoning: Oxidation of ethanol -> acetylaldehyde -> acetate

During ethanol poisoning increases in pyruvate creates lactate -> lactic acidosis develops. Since
alcoholics are not likely to eat well they tend to develop hypoglycemia.

Diabetes Mellitus:
-decrease insulin (and glycogen used up) -> not only increase KB but also decrease the muscle
ability to use them at a faster rate therefore you have a excess of KB -> life threatening
-otherwise the situation is similar to starvation but different cause

30.Hypoenergosis of the Specific Tissues

Review Algorithm Problem 25 on Hypoenergosis

-uses 25% glucose (majority of energy is for function 10% is used to keep function, 20%
O2, and 15% Heart minute volume.)
-Does not have big storage for glucose so anything that impedes blood flow will yield
substrate insufficiency, not to mention hypoxia (irreversible damage can happen within 4-5 min)
-hypoxia damages capillary endotel -> increase permeability -> risk for brain edema
-Any metabolic dysfunction (i.e. ketoacidosis, liver damage, uremia) -> decrease energy
metabolism -> hypoenergosis/coma

-need for O2 -> increase blood flow through coronaries if malfunction (atherosclerosis) ->
hypoxia of myocardium
-depending on the hearts ability to adapt and the extent of the neg. stimulus there are
different degrees of injury from Pectoris major to MI
-ischemia -> anaerobic metabolism used for energy -> accumulation of lactic, loss of
phosphate -> pain, decrease permeability/contraction, arrythmis, Vent Fib
-Chronic Hypoxia -> heart better able to adapt but develop hypertrophy, dilation, fibrosis

-Most of the energy used from active transport
-Acute ischemia, kidney react by constricting afferent arterioles -> acute kidney

-Hypoxia in lungs causes vasoconstriction or arterioles -> decrease PO2 in alveoli
-Cor Pulmonal, pulmonary hypertension

-Centrolobular necrosis due to the anatomic arrangement of blood flow through the liver
there is a watershed region from the periphery to the center of the Liver Lobule

-Hypoenergosis -> muscle spasm (inorder for muscle to relax Ca needs to return to
sacroplasmic ret. via Ca pump which needs ATP to function)
31.Carbohydrate Metabolism Disorders

Carbohydrates are sugars, which are simple or complex Sucrose is made of two simple sugars
(glucose and fructose) Lactose is made of (glucose and galactose).
Both sucrose and lactores must be broken down into their component sugars by enzymes before the
body can absorb and make use of them.
If an enzyme needed to process a certain sugar is missing, the sugar can accumulate in the body
causing problems:

-Lactose Intolerance
-Fructose Intolerance
-Glycogen Storage Disease
-Diabetes Mellitus

* Galactosemia: Review page 228 in Robbins

Definition: High Blood level of Galactose
Cause: inherited lack of Galactose-1-phosphate uridyltransferase which is needed for metabolizing
galactose into glucose.

Clinical Features: due to milk ingestion

1. Vomiting
2. Diarrhea
3. Jaundice
4. Kidney impairment for amino acid transport if there is accumulation of galactose and
galactose 1-phosphate resulting in aminoaciduria
5. Hepatomegally
6. Cataracts
7. Nonspecific alterations in the CNS
8. White blood cell function is affected and can develop serious infections such as E coli sepsis

Treatment: Removal of galactose from diet at least for first two years of life. Even with proper
treatment, children generally have speech problems and lower IQ levels than their siblings. Girls
has nonfunctional ovaries while boys have normal testicular function.
Diagnosis: Detectable by assay of the transferase in leukocytes and erythrocytes.

*Lactose Intolerance: Lactose intolerance means the body cannot easily digest lactose, a type of
natural sugar found in milk and dairy products. This is not the same thing as a food allergy to milk.

When lactose moves through the large intestine (colon) without being properly digested, it can
cause uncomfortable symptoms such as gas, belly pain, and bloating. Some people who have
lactose intolerance cannot digest any milk products. Others can eat or drink small amounts of milk
products or certain types of milk products without problems.

1. Primary Lactose Intolerance: Environmentally induced when weaning a child in non-dairy
consuming societies
2. Secondary Lactose Intolerance: Environmentally induced when there are certain
gastrointestinal diseases involved, including exposure to intestinal parasites such as Giardia.
Gastroenteritis is also another important one to consider and is generally caused by
3. Congenital Lactase Deficiency: Autosomal Recessive Disorder which prevents enzymatic
production of lactase. Present at birth and diagnosed in early infancy.

Diagnosis: The intestingal function is challenged by ingesting more dairy than can be readily
digested. Clinical symptoms appear within 30 minutes.
An important thing to note is to be able to distinguish lactose intolerance from milk allergy. Milk
allergy is an abnormal immune response to usually milk proteins. (review Hypersensitivity type I in
Robbins page 111 and discuss this in further detail to redirect the question)

*Glycogen Storage Diseases: Review in Robbins Page 232-233

Algorithm Problem 14: McArdles disease

Glycogen is made of many glucose molecules linked together. The sugar glucose is the body’s
main source of energy for the muscles (including the heart) and the brain. ANy glucose that is not
immediately used for energy is held in reserve in the liver, muscles, and kidneys in the form of
glycogen and released when needed by the body.

GLUCOSE-6-PHOSPHATE to GLYCOGEN metabolism impairment:

-Type I (Von Gierke’s Disease-Hepatic Type) -> Glucose-6-phosphatase enzyme deficiency

GLYCOGEN to FRUCTOSE-6-PHOSPHATE metabolism impairment

-Type II (Pompe’s Disease-General Type but more related to cardiomegaly because it is most
prominent) -> Lysosomal Acid Maltase decifiency
-Type V (McArdle’s Disease- Myopathic Type) -> Muscle Glycogen Phosphorylase deficiency


Hyperglycemia can be a serious problem if you don't treat it, so it's important to treat as soon as you
detect it. If you fail to treat hyperglycemia, a condition called ketoacidosis (diabetic coma) could
occur. Ketoacidosis develops when your body doesn't have enough insulin. Without insulin, your
body can't use glucose for fuel, so your body breaks down fats to use for energy.
When your body breaks down fats, waste products called ketones are produced. Your body cannot
tolerate large amounts of ketones and will try to get rid of them through the urine. Unfortunately,
the body cannot release all the ketones and they build up in your blood, which can lead to
Ketoacidosis is life-threatening and needs immediate treatment.

Symptoms include:
1 Shortness of breath
2 Breath that smells fruity
3 Nausea and vomiting
4 Very dry mouth

The signs and symptoms of hyperglycemia include the following:

 High blood glucose
 High levels of sugar in the urine
 Frequent urination
 Increased thirst

Normal glucose levels are between 4 and 6mmol/L. With excessive glucose in the blood circulating
there can be a number of problems that can arise.

Diabetes Mellitus:
Chronic Hyperglycemia is the defining characteristic of the disease. This type is caused by low
insulin levels, which reduces the transport of glucose across cell membranes therefore causing high
blood glucose levels.
Review Diabetes Algorithm Problem 20.

Diabetes Mellitus is classified in 3 different types depending on its cause and course: Type 1, Type
2 and Gestational. (Review Robbins Page 743-750)

This question can also be answered in connection with Question 33.

There are times when the blood sugar levels become very high or has been high for a long time, in
such cases, there are a few additional symptoms:

-Recurrent infections such as vaginal yeast infections, groin rash or ecternal ear infections
(swimmers ear)
-Kussmaul Hyperventilation
-Impairment of cognitive function, along with increased sadness and anxiety
-Increased confusion or drowsiness

From The Book of Kovac:

Diabetic Ketoacidosis:

Insulin Deficiency is characterized by decreased utilization of glucose and mobilization of

free FA from the fat tissue. Fatty acids reach the liver, the site of their conversion into ketoacids:
acetoacetic and Beta-hydroxybutyric.
Ketoacid production can increase up to approximately 7mmol/min. However, ketoacidosis is
not precipitates solely by increased production of acids, but by decreased utilization of ketoacids in
the muscle tissues as well.
In physiological pH ranges, these acids are completely dissociated and therefore increase
concentration of H+ ions and deplete buffering capacities. This potentially causes severe acidemia.
Diabetic Ketoacidosis is accompanied by dehydration (OSMOTIC DIURESIS) and
hyperventilation as a respiratory compensation of metabolic acidemia. Due to K+ outflux from
cells, its plasmic concentration remains normal or even slightly increases despire the loss of the
total K+ quantity from the body. Hyperglycemia can be minimal is acidemia was preceded by
prolonged starvation.


We can differ between two types of diabetes mellitus:
1.In type I (insulin-dependent diabetes mellitus, previously called juvenile diabetes) there is an
absolute lack of insulin, so that the patient needs an external supply of insulin. The condition is
caused by a lesion in the beta cells of the pancreas, as a rule produced by an autoimmune
mechanism that may, in certain circumstances, have been triggered by a viral infection.

2.Type II (non-insulin-dependent diabetes mellitus is by far the most common form of diabetes.
Here,too,genetic disposition is important. However, there is a relative insulin deficiency: the
patients are not necessarily dependent on an exogenous supply of insulin. Insulin release can be
normal or even increased,but the target organs have a diminished sensitivity to insulin. Most of the
patients with type II diabetes are overweight. The obesity is the result of a genetic disposition,large
intake of food,and too little physical activity.The imbalance between energy supply and
expenditure increases the concentration of fatty acids in the blood. This in turn reduces glucose
utilization in muscle and fatty tissues. The result is a resistance to insulin, forcing an increase of
insulin release.The resulting down-regulation of the receptors further raises insulin resistance.
Obesity is an important trigger, but not the sole cause of type II diabetes. More important is the
already existing genetic disposition to reduced insulin sensitivity.

The first symptom of DM is hyperglycemia that occurs in begining after intake of food rich in
carbs, but afterwards it is also seen in starvation (fasting glucose increased). When glucose
concetration in blood reaches kidney reabsorption threshold, glucose will appear in urine
(glucosuria) and it will cause osmotic diuresis. Increased concetration of plasma and osmotic
diuresis cause both cellular and extracellular dehydration. Polyuria, polydipsia and polyphagia are
clinical symptoms of DM.

When lack of insulin causes reduction in the utilization of carbohydrates for energy purposes fat
metabolism will also be disturbed. Insulin inhibits hormon sensitive lipase that glucagon
stimulates.So lack of insulin and glucagon increase are causing increased lipolysis in fat tissue and
increased β-oxidation of free fatty acids in liver. Increased β-oxidation causes formation of acetyl-
CoA in to big amount (not all can be used in TCA cycle). That results with condensation of 2 acetyl-
CoAs into: 1) acetoacetic acid, 2) β-hydroxy-butiric acid, 3) aceton. Lack of insulin on the other
hand causes decreased utilization of ketone bodies in muscles which will result in metabolic
acidosis. Acidosis will cause stimulation of resulting in Kussmal's breathing.

Acidosis causes H+ exchange for K+ ion which will lead to accumulation of K+ in extracellular
space. But because of increased diuresis and dehydration K+ will also be lost by urine. In that case
K+ concentration in extracellular space may be increased but total concentration of K+ is decreased.
Complications development in DM:


Hypoglycemia is determined by decreased glucose concetration in blood. Clinical symptoms

usually occur when concentration is 2,5 mmol/L or less.
Symptoms caused by hypoglycemia can be separated into two different groups:
 First group of symptoms occurs when blood glucose concentration suddenly decreases due
to adrenalin release as a contra-regulation hormon. Those symptoms are: pallor,sweating,
shivering, palpitation,fear and aggitation.
 Second group is connected with CNS- brain hypoenergosis. Symptoms pertaining to this
group are: dizziness,headache, blurred vision, confusion and coma.
According to mechanism of development we can divide them into induced and spontaneous
 Induced hypoglycemia
 caused by applying external insulin or oral hypoglycemic drugs
Most common cause of hypoglycemia is inappropriately high insulin or hypoglycemic drug dosage.
By determining C-peptide concetration we can distinguish endogenous hyperinsulinism from
egzogenous. In endogenous hyperinsulinism C-peptide concentration is increased.
 caused by alcohol consumption
It will occur only when alcohol consumption is combined with prolonged starvation (12-72hours)
because glycogen storage in liver will be used up by then and alcohol will inhibit gluconeogenesis.
 post-absorptive reactive hypoglycemia
It occurs 3-5 hours after a meal rich in carbs.There is increased but also delayed insulin release.
This includes also hypoglycemia seen in "dumping syndrome" after gastric resection,gastrectomy
and gastrojejunostomy; they occur 1-3h after a meal rich in carbs because sudden gastric emptying
and fast glucose reabsorption in small intestine which will increase blood glucose and insulin
 induced by leucin
Occur together with leucin insensitivity; usually in kids up to 6 years of life.
 Spontaneous hypoglycemia : occurs after starvation of several hours to 1-2 days. It can be
caused by reduced entry of glucose into the blood or increased glucose consumption.
 Reduced entry of glucose in blood
 Lack of hormones that directly or indirectly stimulate gluconeogenesis or glycogenolysis.
(hypopituitarism due to lack of ACTH; Addison disease due to lack of cortisol).
 Hereditary lack of enzymes needed for gluconeogenesis or glycogenolysis (lack of glucose-6-
 Lack of substrate for gluconeogenesis (alanine)
 acquired liver disease (hepatitis, liver congestion)
 Increased glucose consumption
▪ hyperinsulinism due to insulinoma
▪ hypoglycemia with normal insulin concentration in blood followed by growth
of bog mesodermal tumors
▪ hypoglycemia in cahexia



Lipoproteins are made of lipids and proteins (apoproteins); they are formed because lipids
are not water soluble by it self so lipoproteins enable their transport by blood. Disorders of
lipoprotein metabolism occur due to change in their synthesis or catabolism. Egzogenous and
endogenous lipids are metabolised in the organism in two ways.
Egzogenous lipids (triglycerides and cholesterol from food) in epithelial cells of small
intestine together with apoproteins form chilomicrones that are transported by lymph into the blood
and then into the capillaries of fat and muscle tissue. Lipoprotein lipase (LPL) activated by apo CII
cuses trigliceride hydrolyzes. Released free fatty acids and monoglicerides pass through
endothelium ; they are stored in fat cells; in muscle cells they serve as energy source. Residual
particles of chilomicrones are degraded in liver. Colesterol formed during catabolism will be partly
turned into bile acids, partly it is excreted unchanged into bile, and partly gets into the bloodstream
as VLDL.
Endogenous lipids are synthesized in liver after meal rich in carbs and they are main part of
VLDL. Carbs in liver are transformed into fatty acids that after esterification combine with glycerol
forming triglycerides. VLDL from liver gets into the capillaries where triglycerides are hydrolyzed
and all that remains is IDL from which all apoproteins (except apoB) are transformed into HDL.
Remaining IDL (without apo) is partly degraded in bloodstream but most part of it is converted into
LDL. LDL attaches to specific receptors (specific for apoB100) on the cells of most tissues and
enters the cell as main cholesterol transporter.
Cholesterol esters are hydrolyzed in cells by lysosomal cholesterol esterase. Free cholesterol
is used for synthesis of cell membrane, and as an forrunner of steroid hormones and bile acids.
Free cholesterol in cell inhibits synthesis and diminishes activity of 3-
hydroxymethylglutaryl-CoA-reductase that catalyses formation of mevalonic acid (choesterol
harbinger). Meaning that free egzogenous cholesterol will inhibit synthesis of endogenous
cholesterol, and it also decreases synthesis of LDL receptors( limiting entry of cholesterol into the
cell); it also increases esterification ( stimulates activity of acyl-CoA-cholesterol-acyl-transferase).
Depending on the cause, disorders of lipoprotein metabolism can be divided:

1.Primary hyperlipoproteinemia
a)Hereditary hypercholesterolemia
Caused by gene muation responsible for synthesis of LDL receptors resulting in increased
concentration of LDL and cholesterol in plasma. Due to diminished entry of cholesterol into the cell
activity of HMG-CoA-reductase will increase as well as cholesterol synthesis.
Because of increased LDL concetration in bloodstream those particles will enter arterial
vessel wall leading to development of premature and severe atherosclerosis in heterozygotes.
Homozygotes will die from consequences of atherosclerosis (MI) before 20th birthday. Deposition
of cholesterol esters from LDL into macrophages leads to formation of foamy cells. Together with
extracellularly placed cholesterol cristals those cells form xanthomas.
b) Familial defective apolipoprotein B100
 LDL that has mutated apoB100 weakly binds normal LDL receptors.
c)Hereditary lack of lipoprotein lipase
d)Hereditary lack of apolipoprotein CII
e)Hereditary disbetalipoproteinemia
f)Hereditary hypertriglyceridemia
 Manifested in puberty or early adulthood
 autosomal dominant
 disturbance in ability to catabolise triglycerides from VLDL, resulting in increased concetration
of both
g)Familial combined hyperlipidemia
h)Familial hyperalfalipoproteinemia

2.Secondary hyperlipoproteinemia
Can occur as a side effect of some disease or as a consequence of taking certain medication.
a) Increased production of lipoprotein particles
 Diabetes mellitus – increased formation of VLDL. Lack of insulin increases effectivness of
hormon dependant lipase and release of FA from adipose tissue. That will result in triglyceride
excess in liver which are then secreted via VLDL in blood resulting in hypertriglyceridemia.
 Alcohol – increased formation of NADH stimulates synthesis of FFA in liver; their abundance is
esterified to triglycerides that will partly accumulate in liver( fatty liver) and another part will be
released into blood via VLDL resulting in hypertriglyceridemia.
 Obesity – increased synthesis of VLDL due to increased amount of FFA( formed due to
increased lipolysis as a consequence of increased insulin resistency) and incresed inflow of
glucose and glycerol; in obese people synthesis of cholesterol is increased and HDL is
 Oral contraceptives – increased secretion of VLDL, but also incresed catabolism resulting in
mild total triglyceride increase.
b) Reduced degradation of lipoprotein particles
 Uremia and prolonged untreated diabetes – decrease in activity of lipoprotein lipase
causes decreased catabolism of VLDL and chilomicrones which results in
 Hypothireosis – decreased catabolism of IDL and LDL ( tyroxin is important for
synthesis of LDL receptors)
c)combination of increased formation and decreased degradation
 nephrotic syndrom – hypolbuminemia stimulates synthesis of apolipoproteins in
liver with simultaneous reduction in catabolism of VLDL and LDL


Most important risk factors for development of atherosclerosis are hypercholesterolemia and
increased LDL. Other risk factors are low HDL,hypertension,DM,obesity, smoking,
hyperhomocysteinemia, hyperfibrinogenemia,low physical activity,stress.
Process of atherosclerosis begins as a response to endothelial damage that stimulates
formation of free oxygen radicals. Radicals participate in activation of transcription factors(NF-ĸB)
that stimulate expression of adhesion molecules(VCAM) on endothelial cell membranes resulting in
monocyte and T lymphocyte adherence to endothelium. Simultaneously LDL penetrates into
endothelium where it is oxidized and as such it causes cytotoxic damage to endothelium; it
stimulates endothelial cells to secrete cytokines and chemokines involved in leukocyte migration,
monocyte migration and differentiation into macrophages. Macrophages have receptors specific for
oxidized LDL; accumulation of LDL results in foamy macrophages. Oxidized LDL stimulates
macrophages to secrete cytokines such as IL-1,IL-6,PDGF,TNF-α, TNF-β. Cytokines stimulates
endothelial cells to secrete adhesion molecules on their membranes resulting in additional
adherence of monocytes and stimulates proliferation of smooth muscle cells of the media.
In damaged endothelim synthesis of prostacycline (inhibitor of thrombocyte aggregation) is
decreased and synthesis of thromboxane (stimulates aggregation) is increased.Individual is prone to
development of microthrombi.
Smoking causes agglutination of thrombocytes and it decreases fibrinolytic activity so it has
a negative effect at this stage of development of atherosclerosis.
PDGF released from thrombocytes together with LDL and some hormones (insulin,
angiotensin II) stimulates migration of smooth muscle cells from media into intima and their
HDL inhibits effectss of LDL, and it works as a "cleaner" of blood vessels ( it binds
cholesterol from atherosclerotic clusters. HDL also has antiinflammatory and antithrombotic effects.
Stages of atherosclerosis: fatty spot →fatty streak→intermediary lesion→atheroma
(fibrotic cap+necrotic core) →atherosclerotic plaque
Complication of atherosclerosis:
Large elastic arteries (e.g., aorta, carotid, and iliac arteries) and large and medium-sized
muscular arteries (e.g., coronary, renal, and popliteal arteries) are the vessels most commonly
involved by atherosclerosis. Accordingly, atherosclerosis is most likely to present with signs and
symptoms related to ischemia in the heart, brain, kidneys, and lower extremities.Myocardial
infarction (heart attack), cerebral infarction (stroke), aortic aneurysms,and peripheral vascular
disease (gangrene of extremities) are the major clinical consequences of atherosclerosis.
The principal pathophysiologic outcomes depend on the size of the affected vessel, the size
and stability of the plaques, and the degree to which plaques disrupt the vessel wall:
 Occlusion of smaller vessels can compromise tissue perfusion.
 Plaque rupture can expose atherosclerotic debris, leading to acute (and frequently
catastrophic) vascular thrombosis or (with shedding of debris) distal embolization.
 Destruction of the underlying vessel wall can lead to aneurysm formation, with secondary
rupture and/or thrombosis.
 Dissection-pressurized blood gains entry to the arterial wall through a surface defect and
then pushes apart the underlying layers.


Obesity can be explained as excess body fat that endangers health. It is associated with
art.hypertension, hyperlipidemia,DM type2, atherosclerosis and some malignant tumors. By WHO
standards it is determined by BMI higher than 30 kg/m2. BMI= weight(kg)/height(m2)
Causes of obesity:
 From energetic point of view obesity is a consequence of positive energy balance ( E
intake is higher than E utilization)
 damage to the satiety center (tumor)
 psychological, social factors (sedentery lifestyle)
 mutation of the gene for leptin
 reduced heat response to food ( energy used up on intake and metabolism of food)
 ↑lipoprotein lipase (facilitates fat uptake and storage in adipose tissue; it will not
drop down after weight loss)
 secondary obesity such as in: hypothireosis,hypopituitarism, cushing`s,insulinoma
Pathophysiological consequences of obesity:
 ↑ insulin secretion due to reduced insulin sensitivity
 risk factor for development of de novo DM in adults; causes worsening of existing DM
 ↑synthesis of cholesterol(especially in adipose tissue) and its metabolism( resulting in
increased secretion by bile and increased susceptibility of bile stones
 ↑ synthesis and secretion of VLDL due to ↑metabolism of FFA leading to
 ↑risk for atherosclerosis
 women: oligomenorrhea,amenorrhea,hirsutism,changes in LH,FSH,GRH
 men:↑conversion of androgens into estrogen in adipose tissue; testosterone levels are normal
 prone to development of endometrial carcinoma and breast cancer
 hypogonadism is not observed because ↓ concetration of steroid binding globulins
 ↑secretion of steroids from adrenal cortex and their excretion via urine
 hypoventilation (Pickwick sy), polycythemia, pulmonary hypertension,cor pulmonale,
changes on joints and spine


Proteins are in constant metabolic flux in the organism. Average protien half life is 80 days.
Daily 300g of proteins is degraded in human organism. When anabolism and catabolism of proteins
are balanced the same amount is synthesized as it is degaded.
Protein synthesis is part of gene expression and it takes place on polyribosomes. Proteins
are degraded by proteolytic enzymes (part of proteosomes and/or lysosomes).
 Nitrogen balance:
Shows the relationship between anabolism and catabolism of proteins. Nitrogen balance is the
difference between nitrogen entering the body through proteins from food and nitrogen excreated
from organism as carbamide and other nitrogen compounds in urine,sweat and feces. When
anabolism is higher than catabolism than we have positive nitogen balance. When catabolism is
higher than anabolism we have negative nitrogen balance. Nitrogen balance is positive during
growth and development, pregnancy, muscle hypertrophy. It is balanced from end of growth until
old age. Nitrogen balance is negative in old age, starvation, in states of increased catabolism such as
severe infections and injuries and also when protein loss can not be compensated by increased
anabolism of proteins.
 Hormonal disorders:
Relationship between anabolism and catabolism changes during changes in hormonal secretion that
affect protein metabolism (insulin,growth hormone, somatomedin C (IGF-I),
triiodothyronine,cortisol,androgens and estrogens).
 Insulin stimulates entry of AA into the cells and biosynthesis of proteins; decreses
catabolism of proteins and desamination of AA. It has a strong anabolic effect
especially in muscles.
 GH and IGF-I stimulate entry of AA into the cells and biosynthesis of proteins
 Triiodothyronine in physiological concentrations stimulates synthesis and degradation
of proteins. Concetrations bigger than physiological stimulates catabolism.
 Glucocorticoids stimulate catabolism of proteins in muscles, in lymphatic and
connective tissue. They stimulate anabolism in liver.
 Diabetes mellitus - ↑ proteinn catabolism in muscles, ↑ AA utilization for
gluconeogenesis in liver. In severe DM person can develop negative nitrogen balance
with loss of muscle mass.
 Cushing's syndrome – loss of muscle mass, osteoporosis, striae, slow wound healing
due to catabolic effects of cortisol
 Hyperthyroidism – loss of muscle mass
 Hypothyroidism – reduced formation of muscle mass
 Nitrogen excretion disorders:
Daily needs and submission of proteins from food are reduced in disorders that lead to
retention of ammonia and carbamide(urea). Those are severe liver insufficiency with portal
encefalopathy, hereditary disorder of enzymes involved in urea cycle, renal insufficiency.
Ammonia and carbamides are accumulated so it is necessary to decrease their production.
Except ammonia formed by desamination of AA in liver, part of ammonia is formed in gut by
desamination of glutamine and from urea which is excreted into large intestine where it is
broken down by bacterial urease. Ammonium than gets into the liver where it is used for
amination of keto acids or detoxification of urea (removal of ammonia through urea cycle). This
process is weakened in liver insufficiency; due to portal hypertension part of blood bypasses
liver by anastomoses.
In uremia - ↓ excretion of urea in urine, ↑ circulating urea and ammonia between intestine and
liver,↑ synthesis of nonessential AA in liver. By limiting proteins in food, giving keto acids (
they will form essential AA in liver by amination) to the patient we can reduce formation of


Protein deficiency in organism occurs when synthesis is lower than degradation, which
means whenever nitrogen balance is negative. Reduced protein synthesis can be a consequence of
lower intake or disturbed utilization of AA. Loss of protein can be immediate or direct (when
proteins are lost from the body)and indirect or metabolic(when catabolism is higher than synthesis).
1. Decreased protein synthesis – disorders that due to reduced protein synthesis reduce the
amount of protein in the whole organism
 Decreased AA intake – caused by decreased amount of proteins in food (starvation, protein-
caloric malnutrition) or incomplete absorption in gut.
 Decresed amount of proteins in food
o general starvation – lack of all nutrients
o lack of carbs suppresses insulin secretion, anabolic effects of insulin are diminished
resulting in protein catabolism in muscles
o released AA are used in liver for gluconeogenesis and synthesis of plasma proteins
o hypoproteinemia will develop quite late
o children can develop marasmus
o malnutrition – lack of proteins
o -carbs stimulate secretion of insulin; protein catabolism in muscles is not so pronounced
o -less AA are released resulting in reduced synthesis of plasma proteins
o -hypoproteinemia develops rapidly
o -kids can develop kwashiorkor
o can be seen in alcoholics and patients on parenteral nutrition

b) Disorder of AA absorption
Even though pepsin from gastric juice and proteolytic enzymes from pancreas are
involved into protein digestion, severe disorders of AA absorption occur only when large portions
of small intestine are damaged.
II.Reduced utilization of AA -liver bufferes fluctuations in influx of AA(dependent on the
rhythm of eating) and permanently supplies the body with AA and plasma proteins
-liver insufficiency results in: protein and AA disturbances, hypoalbuminemia(↓synthesis,
loss of albumin by lymph in ascites), ↓ of coagulation factors
III. Immobilization
After limb immobilization muscles become atrophic and bones osteoporotic. That is a consequence
of metabolic protein loss because of slow anabolism and rapid catabolism of proteins.
2.Protein loss
 Immediate (direct) protein loss
-bleeding, loss of plasma proteins through damaged skin (burns,wounds),ascites, nephrotic
syndrome(↑ glomerular membrane permeability leads to ↑ protein filtration), gastroenteropathies
with protein loss(hypoproteinemia and hypoalbuminemia)
Gastroenteropathies with protein loss
1.Mucosal damage with 2.Mucosal damage without 3.Pressure increase in 4.Irregularities in
ulceration ulceration lymphatic vessels lymphatic system structure
Gastric carcinoma Gluten enteropathy Lymphoma Primary lymphangiectasis
Chron's disease Hyperplasia of gastric Whipple's disease
Colon cancer Allergic gastroenteropathy Cardiac decompensation
Ulcerative colitis Constrictive pericarditis

II.Metabolic (indirect) protein loss

Synthesis of new proteins can't compensate for amount of degraded proteins (↑↑catabolism,
↓anabolism). This occurs in states in which catabolic reaction is stimulated by injury or infection
(sepsis- ac.phase response), cahexia( loss of plasma and blood due to tissue damage caused by
malignant tumors), endocrinopathies with increased hormonal catabolic effects.

Protein deficincy affects integrity and tissue function followed by decreased concetration of plasma
proteins. Due to metabolic adaptations proteins are not lost equally from all tissues (30g of tissue
proteins=1g of plasma proteins lost).

State in which person lacks one or more nutritients. According to ethiology we can divide
malnutrition into primary (insufficient food intake) and secondary (consequence of certain disease
that causes reduced absorption,increased loss,decreased utilization or increased need for nutritients).
 Primary malnutrition – starvation
Seen in impoverished countries. We may differ between acute and chronic malnutrition. Depending
on the type of nutritients missing we distinguish general malnutrition and protein(caloric)
malnutrition. The latter group belongs to chronic malnutrition common in children ( marsasmus,
1. Acute starvation
Sudden discontinuation of food intake resulting from willing refusal, acute lack of nutritients,
inability to consume food due to upper GI damage or malignant tumor (obstruction). Death is a final
consequence of starvation. Survival time depends on several different factors. In adult man average
survival time is 40 – 50 days. Clinically we can differ several stages of acute starvation:
irritability,depression, metabolic breakdown followed by amplification of metabolic rate of reaction
resulting in tissue protein utilization.
Metabolic and endocrine consequences of acute starvation:
 glycogen from liver and muscles is used first, followed by fats and proteins
 glucose needed for brain function is obtained from proteins by gluconeogenesis
 lipids are degraded to ketone bodies – main cell energy source
 weight loss as a consequence of fats and protein utilization

 proteins- mostly used in initial and final stage of starvation ( between those two phases
gluconeogenesis is reduced so is protein consumption)
 basal metabolism ↓ due to ↓ secretion of thyroid hormones, hypothermia (↓ heat production)
 ↓ insulin – brain can use up more glucose
 ↑ GH,corticosteroids,glucagon – spare glucose and proteins, stimulate utilization of FA
 ↑ ketone bodies – metabolic acidosis
 ↑ β-hydrobutyric acid – uric acid excretion by kidneys is disrupted leading to ureate
accumulation and gout
 ↓ K,Mg,P – due to muscle catabolism and their ↑ renal excretion
 cardiac output, arterial pressure and glomerular filtration are ↓

2.Chronic starvation
a) General chronic starvation
Also called general malnutrition; it occurs as a consequence of total caloric lack.
Most commonly occurs as a primary disease (insufficient intake) or as a secondary disease
(inappropriate utilization,increased loss or increased nutritient consumption). Particularly
vulnerable are preschool kids,pregnant women and sick people.
Metabolic and endocrine consequences seen in chronic starvation:
 glucose is obtained from gluconeogenesis
 tissues are starting to use FFA for energy purposes
 brain starts to use keton bodies
 there is NO negative nitrogen balance only negative total calorie balance
 hypoproteinemia, hypoalbuminemia, ↓ plasma colloid osmotic pressure – edema
 ↓ GFR
 atrophy of intestinal villi
 ↓ conc. of digestive enzymes
 endocrine disorders involve: hypophysis, thyroid, pancreas, ovaries, testicles
 ↓ specific and nonspecific immunity; atrophy of lymphatic tissue
 kids - growth retardation
 hypovitaminosis – skin changes
 osteoporosis, osteomalacia – deformations and spontaneous fractures

b)Starvation in pregnant women and its effects on fetus
 pregnant women: malnutrition in pregnant women can affect growth and development of
fetus; ↑ anabolism,↓ blood glucose,↑ carbamide conc. in blood, ↑ carbamide excretion, ↑
catabolism of proteins used for gluconeogenesis,↑ FFA utilization, ketone body production,
smaller placenta, placental infarction and/or calcifications, ↑ formation of human placental
lactogen( spares glucose for fetus, stimulates lipolysis), ↓ estrogen and progesterone in
plasma (fetal growth retardation)
 fetus: growth retardation, loss of subcutaneous fat tissue, hypoglycemia
 Chronic malnutrition with protein deficit- Kwashiorkor

Disease of the first child when the second one is born. Kid becomes hypoproteinemic because of
diet low in proteins. Carbs from food stimulate insulin secretion (different than in general
starvation). Anabolic effects of insulin are slowing down protein catabolism in muscles. On the
other hand there is not enough AA for protein synthesis.Hypoalbuminemia and ↓ colloid osmotic
pressure contribute to development of edema. Degradation and atrophy of muscles, mucous
membranes and parenchymal organs also favors edema development. Lack of proteins with
sufficient amount of carbohydrates causes liver enlargement and fatty changes.This results
primarily from disorders of lipoprotein synthesis during protein starvation (lipoproteins are
necessary for the mobilization of fats from the liver). Insulin secretion supports synthesis and
storage of fast, so they are well preserved. However when protein deficit is accompanied with
energy lack there will not be any liver changes (nor enlargement nor fatty changes). Mucosal
atrophy of digestive system and pancreas causes decreased synthesis of digestive enzymes;
digestion and absorption are disturbed resulting with diarrhea.
Other symptoms of kwashiorkor: skin changes (depigmentation, ulcerations, cornification),
skeletal muscle atrophy, decreased resistancy to infections, nervous disorders (apathy, irritability),
anemia,hypoplasia of the bone marrow, hypovitaminosis.

d) Chronic malnutrition with calorie deficiency - Marasmus

Primarily affects children aged 1-2 years, which along with a calorie deficient diet live in
unsanitary conditions and have frequent gastroenteritis. Main signs of marasmus are general
starvation with total atrophy of fat tissue. There is no edema nor skin changes; growth is not
disturbed. Because of frequent diarrhea large amounts of bicarbonates are lost which leads to
development of metabolic acidosis. Protein concetration in plasma is normal, K and Mg
concetrations are low. These children are often anemic.
e) Anorexia nervosa
Psychosomatic disorder similar to a general starvation, characterized by aversion to food,
which leads to extreme weight loss and amenorrhea. Most commonly affects women between 10-30
years of age. Very often begins in obese girls that are on restriction diet.
In later stages of disease edema together with extreme weight loss can develop. Clinical
picture of general chronic starvation starts to develop. Anorexia nervosa differs from it by the

normal development of breast and normal hairiness and the absence of skin lesions.
 II.Secondary malnutrition
 Malabsorption and maldigestion:
a) insufficient secretion in gut (gastric atrophy with achlorhydria, gastric resection)
b)increased gut motility (ulcerative colitis, dysentery,gastroenteritis with diarrhea)
c)reduction of resorption surfaces (bowel resection, diseases of small intestine)
d)other malabsorptions (hypovitaminosis, sprue)
 Increased nutrition loss (burns,kidney diseases,bleeding,lactation)
 Increased nutritional need (↑ physical activity,pregnancy, fever, hyperthyroidism)
 Disturbed utilization and storage of nutrients (liver diseases, DM, GI tumors)
Consequences of primary and secondary malnutrition - CAHEXIA
Condition of extreme malnutrition and physical and metabolic exhaustion due to severe illness (
malignant tumors, TB;endocrine diseases, radiation, old age). Loss of body mass primarily due to
increased catabolism. Pathogenesis of cahexia depends on release of inflammatory cytokines (
TNF-α, IL-1,IL-6). They cause: catabolic reactions, hypermetabolism, insulin resistency, stress
response, anorexia with malnutrition, depression with fatigue).


In order to maintain optimum physiological and anatomical unity of the organism many
essential substances must be administered with food because they can not be synthesized in the
body. With minerals, it is estimated that there are 23 essential organic compound (9 amino acids,
some unsaturated fatty acids and 13 vitamins).
A. Mechanisms leading to lack of specific metabolic substances (SMS)
Lack of specific metabolic substances in food
 poverty, vegetarianism, old age, restriction diet
 leads to primary starvation
Digestive system dysfunction
 decreased intake of SMS (loss of apetite) or disturbed absorption or both
Transport disorder of specific metabolic substances
 After absorption some minerals and vitamins bind to proteins and thus are transferred
to the tissues.
 Lack of carrier can be result of gene disorder.
 Loss of transferrin that carries iron can cause anemia, which is resistant to treatment
with iron.
Utilization disorder of specific metabolic substances
 To enable SMS to be used they have to be activated,transported and they have to
enter the target cell.
 Vitamins are activated in liver and kidney so any damage to those tissues (molecular
activation disorder) will result in hypovitaminosis.
 Xenobiotics can change activity of SMS (hydrazin effects pyridoxin activation – B6
Increased consumption of specific metabolic substances
 during intense tissue and cell growth and development
 growth,pregnancy, fever, physical exercise,hyperthyroidism
Increased loss of specific metabolic substances
 gut,kidney,sweat (normal excretion)
 bleeding, vomiting, burns
B. Development of disorders caused by lack of SMS (5 stages)
 Nitrogen balance
 mismatch between supply (↓) and demand (↑)
 negative nitrogen balance worsens over time → disorder development
 Tissue depletion
 usage of SMS from tissues
 Biochemical disorders
 after exhaustion of reservers real SMS shortage is observed
 iron lack limits hemoglobin synthesis; lack of ascorbic acid limits collagen synthesis
 Functional disorders
 thiamine deficiency disrupts the function of the cardiovascular and nervous system
(heart failure, weakening of deep tendon reflexes, muscle weakness, neuropathy);
recovery after thiamine administration is very fast
 Structural damage to the organism
 lack of iron,pyridoxine, cobalamin, folate and cobalt
 iron deficiency causes formation of small erythrocytes with low amount of hemoglobin
(microcytic anemia)

Hypovitaminosis can be caused by:
 lack of vitamines in diet
 functional disorder of gastrointestinal system
 transport and utilization disorder
 increased loss
Intestinal absorption of vitamines depends on their solubility; according which we can differentiate:
water soluble (B and C) and lipid soluble (A,D,E,K) vitamines.

B1 hypovitaminosis (thiamine deficiency)

 active absorption in upper part of small intestine
 about 80% is found as thiamine-diphosphate (muscles), synthesized in liver, excreated via
kidneys as thiamine
 daily need for thiamine depends on type and amount of food, physical activity
 connected with ch.alcoholism (alcoholics eat less and alcohol disturbes absorption of
 disorders due to lack of thiamine are a consequence of disturbed energy metabolism ( tissues
that are affected the most are the ones that use carbs as an energy source – muscles and
nervous tissue)
 metabolic disorder (hypoenergosis)→vasodilation ( ↑ stroke volume and heart rate),
myocardial hypertrophy, heart failure, dyspnea, lower leg edema (warm and well
perfused)→ wet beriberi
 peripheral neuropathy (dry beriberi)→ reduced sensory, motor and reflex functions of lower
legs, degenerated and demyelinated nerve fibers, orthostatic hypotension with syncope
 Wernick's encephalopathy → dysfunction of eye muscles (nystagmus and paresis), ataxia,
confusion (changes in thalamus, hypothalamus and cerebellum)
 Korsakoff 's psychosis →irreversible damage to posterior medial thalamic nuclei

B2 hypovitaminosis (riboflavin deficiency)

 absorbed in upper part of small intestine through special transport mechanism
 free in plasma; found only in small concentration in tissues
 central component of the cofactors FAD and FMN and as such required for a variety of
flavoprotein enzyme reactions including activation of other vitamins
 involved in metabolism of: carbs,fats, proteins and nucleic acids
 excreted via kidneys as riboflavin (can't be stored)
 ↓ FMN and FAD lead to ↓ oxidation-reduction processes
 skin changes,stomatitis including painful red tongue with sore throat, chapped and fissured
lips (cheilosis), and inflammation of the corners of the mouth;eyes can become itchy,
watery, bloodshot and sensitive to light.
 Due to interference with iron absorption, riboflavin deficiency results in an anemia with
normal cell size and normal hemoglobin content (normochromic normocytic anemia)
B3 hypovitaminosis (niacin deficiency)
 absorbed in small intestine
 tryptophan as a source of niacin
 NAD and NADP (coenzymes)
 Pellagra - "the three Ds": diarrhea,dermatitis and dementia
 DG is established by decreased excretion of niacin and tryptophane metabolites via urine,
decreased concetraation of NAD and NADP in RBCs
B6 hypovitaminosis (pyridoxine deficiency)
 absorbed in upper part of small intestine
 effective as pyridoxal phosphate (very active)
 pyridoxine metabolismis disturbed by alcohol and hydrazines
 usually it is destroyed during food preparation or by antagonists in the organism
 skin changes,stomatitis, microcytic anemia (small RBCs but normal MCV), peripheral
 DG: EEG changes (generalized spikes), ↑ oxalate in urine(stones)
B9 hypovitaminosis (folic acid deficiency)
 absorbed in upper part of jejunum
 increased need in states of hypermatabolism, pregnancy and alcoholism
 reserves are sufficient for 3 to 6 months
 synthesis of DNA is disturbed→ megaloblasts are formed (megaloblastic anemia)
 changes are first seen in hematopoetic(megaloblastic anemia) and digestive systems
B12 hypovitaminosis (cobalamine deficiency)
 occurs due to lack of vit in food, utilization disorder or decreased absorption
 key role in the normal functioning of the brain and nervous system, and for the formation of
 animal product, only bacterias can produce it
 90% of reserves are in the liver ( hypovitaminosis is evident after 10 years)
 causes: lack of vit in food, gasterectomy (↓intrinsic factor), ↓ pancreatic proteases (limited
binding to IF due to ↓ separation of vit and cobalofilin), Zollinger- Ellison's syndrome, blind
loop syndrome (normal bacterial flora proliferation causes significant derangement to the
normal physiological processes of digestion and absorption), disorders of the ileum
(resection,disease or lack of receptors for IF-B12 complex), disorders of IF secretion
(hematopoietic, gastrointestinal, neurologic disorders,megaloblasts, disturbed DNA
 pernicious anemia- loss of gastric parietal cells or autoantibodies against IF or parietal cells,
↓ absorption of vitamines or minerales
 subacute combined degeneration of spinal cord
 parasthesia,weakness and spasticity→ synthesis of non-physiological fatty acids and their
implementation into myelin and nerve cell membranes
Vit.C hypovitaminosis
 decreased intake, decreased absorption (diarrhea)
 absorbed in jejunum
 scurvy- collagen synthesis disorder ( capillary wall weakness, bleeding,poor wound healing,
gum disease, loosening of teeth,anemia, ↓ iron release from feritin
Biotin hypovitaminosis
 absorbed in small intestine
 deficiency of biotin rarely causes hypovitaminosis
 dry scaly dermatitis,fatigue, myalgia,nausea, EKG changes
 can arise due to various inborn genetic errors that affect the activity of biotin-related
Pantoteic acid hypovitaminosis
 80% of reserves in form of CoA
 excreted via kidneys after degradation of CoA
 fatigue,nausea,headache, vomiting, abdominal cramps
Vit.A hypovitaminosis
 in presence of oxygen it easily oxidizes into inactive form
 it won't be absorbed if absoption of fat is disturbed
 reserves are sufficient for a year
 night blindness (↓ rodopsin - ↓ photosensitivity of molecules), xerophtalmia(dry eye)
Vit.K hypovitaminosis
 stored in liver, deficiency is evident within 3 weeks
 occurs due to disturbed absorption or due to destroyed intestinal flora
 coagulation disorders- bleeding tendency

Vit. D hypovitaminosis
 absorbed in small intestine
 decreased bioavailability of 1,25(OH)2D3-due to lack of vit.D or formation disorder of
 ↓intake in kids, ↓sun exposure, ↓ fat absorption in gut
 consequences of vit. D deficiency: ↓ absorption of calcium and phosphorus in small bowel
 rickets in kids, osteomalacia in adults

44.Disorders of Trace Elements Metabolism

Review Page 303 of Robbins table 7-10

Major Trace Elements are:

-Iron (Page 42 and 270 Thieme book)
-Magnesium (Page 136 Thieme)

-Zinc : Interacts with a wide range of organic ligand and has a role in the metabolism of RNA and
DNA, signal transduction and gene expression (Zinc Metalloproteinases). It also regulates
apoptosis and can modulate brain excitability.

Deficiency results in :
Hair loss
Skin lesions
wasting of body tissues

Eyesight, taste, smell and memory are also connected with Zinc.
Just like Zinc deficiency can be harmful, so can excess zinc. Excessive absorption of zinc
suppresses copper and iron absorption.

(Read thieme Pages 24 and 164)

-Iodine (page 302 Thieme)

-Copper: (Thieme Page 272)

Copper is distributed widely in the body and occurs in live, muscle and bone. It is found in
a variety of enzymes such as cytochrome- c oxidase ( here you can mention where cytochrome-c is
found and its significance in regards to cell injury Chapter One in Robbins)

Copper is also used in ETC transport.

45.Disorders of Osmolality and Hydration of the Organism

Review Algorithm Problem 38

Important things to review are:


Baroreceptors transmit changes in blood pressure to

the brain

Blood pressure is constantly monitored by your

body and adjusted constantly to meet the needs of your body. This monitoring is performed by
baroreceptors. Baroreceptors are special receptors that detect changes in your blood pressure.
Baroreceptors are found within the walls of your blood vessels. The aorta and the carotid sinus
contain important baroreceptors which constantly monitor blood pressure fluctuations. These
baroreceptors transmit their data to the central nervous system, and more specifically, to the cardio
regulatory center of the medulla oblongata.

Review Guyton for more detailed description on Baroreceptors. It is a common discussion in oral


ADH (antidiuretic hormone): A peptide molecule that is released by the pituitary gland at the base
of the brain after being made nearby (in the hypothalamus). ADH has an antidiuretic action that
prevents the production of dilute urine (and so is antidiuretic).
A syndrome of inappropriate secretion of ADH may occur in association with oat-cell lung cancer,
pancreatic cancer, prostate cancer, and Hodgkin's disease as well as a number of other disorders.
The inappropriate secretion of ADH results in the inability to put out dilute urine, perturbs fluid
(and electrolyte) balance, and causes nausea, vomiting, muscle cramps, confusion and convulsions.
ADH also can stimulate contraction of arteries and capillaries. ADH is also known as vasopressin.

*Thieme Page 132


Review Algorithm Hypovolemic Shock.


Fluid volume excess, or hypervolemia, occurs from an increase in total body sodium content and an
increase in total body water. This fluid excess usually results from compromised regulatory
mechanisms for sodium and water as seen in congestive heart failure (CHF), kidney failure, and
liver failure. It may also be caused by excessive intake of sodium from foods, intravenous (IV)
solutions, medications, or diagnostic contrast dyes. Hypervolemia may be an acute or chronic
condition managed in the hospital, outpatient center, or home setting. The therapeutic goal is to treat
the underlying disorder and return the extracellular fluid compartment to normal. Treatment consists
of fluid and sodium restriction, and the use of diuretics. For acute cases dialysis may be required.

Related Factors
• Excessive fluid intake
• Excessive sodium intake
• Renal insufficiency or failure
• Steroid therapy
• Low protein intake or malnutrition
• Decreased cardiac output; chronic or acute heart disease
• Head injury
• Liver disease
• Severe stress
• Hormonal disturbances

Defining Characteristics
• Weight gain
• Edema
• Bounding pulses
• Shortness of breath; orthopnea
• Pulmonary congestion on x-ray
• Abnormal breath sounds: crackles (rales)
• Change in respiratory pattern
• Third heart sound S3
• Intake greater than output
• Decreased hemoglobin or hematocrit
• Increased blood pressure
• Increased central venous pressure (CVP)
• Increased pulmonary artery pressure (PAP)
• Jugular vein distention
• Change in mental status (lethargy or confusion)
• Oliguria
• Specific gravity changes
• Azotemia
• Change in electrolytes
• Restlessness and anxiety

46.Imbalance of Na+ Contents within the Organism


Hyponatremia is a condition that occurs when the level of sodium in your blood is
abnormally low. Sodium is an electrolyte, and it helps regulate the amount of water that's in and
around your cells.
In hyponatremia, one or more factors — ranging from an underlying medical condition to
drinking too much water during endurance sports — causes the sodium in your body to become
diluted. When this happens, your body's water levels rise, and your cells begin to swell. This
swelling can cause many health problems, from mild to life-threatening.
Hyponatremia treatment is aimed at resolving the underlying condition. Depending on the
cause of hyponatremia, you may simply need to cut back on how much you drink. In other cases of
hyponatremia, you may need intravenous fluids and medications.
Hyponatremia signs and symptoms may include:

• Nausea and vomiting

• Headache
• Confusion
• Loss of energy and fatigue
• Restlessness and irritability
• Muscle weakness, spasms or cramps
• Seizures
• Coma


Hypernatremia results when there is a net water loss or a sodium gain and reflects too little water in
relation to total body sodium and potassium. In a simplified view the serum sodium concentration
(Na+) can be seen as a function of the total exchangeable sodium and potassium in the body and the
total body water.The formula is expressed below:

Na+ = Na+ total body + K+ total body/total body water

Consequently, hypernatremia can only develop as a result of either a loss of free water or a gain of
sodium or a combination of both. Hypernatremia by definition is a state of hyperosmolality, because
sodium is the dominant extracellular cation and solute.
Thirst is the body’s mechanism to increase water consumption in response to detected deficits in
body fluid. As with AVP secretion, thirst is mediated by an increase in effective plasma osmolality
of only 2-3%. Thirst is thought to be mediated by osmoreceptors located in the anteroventral
hypothalamus. The osmotic thirst threshold averages approximately 288-295 mOsm/kg. This
mechanism is so effective that even in pathologic states in which patients are unable to concentrate
their urine (diabetes insipidus) and excrete excessive amounts of urine (10-15 L/d), hypernatremia
does not develop because thirst is stimulated and body fluid osmolality is maintained at the expense
of profound secondary polydipsia.
Developing hypernatremia is virtually impossible if the thirst response is intact and water available.
Thus, sustained hypernatremia can occur only when the thirst mechanism is impaired and water
intake does not increase in response to hyperosmolality or when water ingestion is restricted.

Review Diabetes Insipidus Algorithm to expand on this question

Thieme Page 132

47.General Principles of Water and Electrolyte Homeostasis Imbalance

Review Algorithm Problem 25
Thieme Page 132

This is something good to talk about at this point. It is also a favorite topic during oral exams.

• Water Balance and ECF Osmolality

◦ To remain properly hydrated, water intake must equal water output
◦ Water intake sources
■ Ingested fluid (60%) and solid food (30%)
■ Metabolic water or water of oxidation (10%)
◦ Water output
■ Urine (60%) and feces (4%)
■ Insensible losses (28%), sweat (8%)
◦ Increases in plasma osmolality trigger thirst and release of antidiuretic hormone
• Regulation of Water - Homeostasis
◦ Intake - Hypothalamic Thirst Center
■ Thirst is quenched as soon as we begin to drink water
■ Feedback signals that inhibit the thirst centers include:
■ Moistening of the mucosa of the mouth and throat

■ Activation of stomach and intestinal stretch receptors
◦ Influence and Regulation of ADH
■ Water reabsorption in collecting ducts is proportional to ADH release
■ Low ADH levels produce dilute urine and reduced volume of body fluids
■ High ADH levels produce concentrated urine
■ Hypothalamic osmoreceptors trigger or inhibit ADH release
■ Factors that specifically trigger ADH release include prolonged fever;
excessive sweating, vomiting, or diarrhea; severe blood loss; and traumatic
Sodium in Fluid and Electrolyte Balance
• Sodium holds a central position in fluid and electrolyte balance
• Sodium salts:
◦ Account for 90-95% of all solutes in the ECF
◦ Contribute 280 mOsm of the total 300 mOsm ECF solute concentration
• Sodium is the single most abundant cation in the ECF
• Sodium is the only cation exerting significant osmotic pressure
• The role of sodium in controlling ECF volume and water distribution in the body is a result of:
◦ Sodium being the only cation to exert significant osmotic pressure
◦ Sodium ions leaking into cells and being pumped out against their electrochemical
• Sodium concentration in the ECF normally remains stable
• Changes in plasma sodium levels affect:
◦ Plasma volume, blood pressure
◦ ICF and interstitial fluid volumes
• Renal acid-base control mechanisms are coupled to sodium ion transport
• Regulation of Sodium Balance:
◦ Aldosterone
■ The renin-angiotensin mechanism triggers the release of aldosterone
■ This is mediated by juxtaglomerular apparatus, which releases renin in
response to:
■ Sympathetic nervous system stimulation
■ Decreased filtrate osmolality
■ Decreased stretch due to decreased blood pressure
■ Renin catalyzes the production of angiotensin II, which prompts aldosterone
■ Adrenal cortical cells are directly stimulated to release aldosterone by
elevated K+ levels in the ECF
■ Aldosterone brings about its effects (diminished urine output and increased
blood volume) slowly
◦ Cardiovascular System Baroreceptors
■ Baroreceptors alert the brain of increases in blood volume (hence increased
blood pressure)
■ Sympathetic nervous system impulses to the kidneys decline
■ Afferent arterioles dilate
■ Glomerular filtration rate rises
■ Sodium and water output increase
■ This phenomenon, called pressure diuresis, decreases blood pressure
■ Drops in systemic blood pressure lead to opposite actions and systemic blood
pressure increases
■ Since sodium ion concentration determines fluid volume, baroreceptors can
be viewed as "sodium receptors"
◦ Atrial Natriuretic Peptide (ANP)
■ Reduces blood pressure and blood volume by inhibiting:
■ Events that promote vasoconstriction
■ Na+ and water retention
■ Is released in the heart atria as a response to stretch (elevated blood pressure)
■ Has potent diuretic and natriuretic effects
■ Promotes excretion of sodium and water
■ Inhibits angiotensin II production
◦ Influence of Other Hormones on Sodium Balance
■ Estrogens:
■ Enhance NaCl reabsorption by renal tubules
■ May cause water retention during menstrual cycles
■ Are responsible for edema during pregnancy
■ Progesterone:
■ Decreases sodium reabsorption
■ Acts as a diuretic, promoting sodium and water loss
■ Glucocorticoids - enhance reabsorption of sodium and promote edema

48. Disorders of Fluid Movements Through Capillary Membrane. Types of Edema

Fluid movement through capillary membrane is determined by Starling Forces:

The four Starling Forces can be broken into two hydrostatic pressures and two osmotic forces
(sometimes called colloid osmotic pressures, or COP) shown at right. Each of these forces will
cause either filtration or reabsorption.
Starling Forces—Hydrostatic Pressures

The capillary (blood) hydrostatic pressure (or Pc for short) is the pressure on the fluid forcing it
outward on the walls of the capillaries. This pressure is roughly 35 mmHg at the arterial end of the
capillary and 15 mmHg at the venous end of the capillary causing filtration. Recall that resistance
causes this decrease in pressure along the capillary.
The interstitial-fluid hydrostatic pressure (or PIF for short) is the pressure from the fluid in the
interstitial compartment pushing back on the capillary. This pressure varies from organ to organ,

varying from –6 mmHg (in subcutaneous tissue) to +6 mmHg (in the brain and kidneys). Here we
will assume that there is no hydrostatic pressure in the interstitial fluid.

Starling Forces—Osmotic Forces

The two remaining Starling Forces, called osmotic forces (or colloid osmotic pressures—COP),
cause fluid to move into an area due to osmosis. The osmotic forces at right are caused by the
presence of large proteins in the plasma (generally albumin) and in the interstitial fluid. These
large proteins are unable to move across the capillary and will, consequently, cause osmosis.
The osmotic force of plasma proteins (or P) will draw fluid back into the capillary, causing
reabsorption. Since the plasma contains a lot of proteins, this force is high at 28 mmHg.
The osmotic force of proteins in the interstitial space (or IF) will pull fluid out of the capillary,
causing filtration. Since the interstitial fluid contains little proteins, this force is low—around 3

Edema: Pathologic accumulation of fluid beneath the skin, or in one or more cavities of the body.
Review Thieme Page 250

Two Classifications:
1.Intracellular-> Addisons Disease (Lack of pump, increased Na+ intracellular)
Review Algorithm 37: Addisons disease

2.Extracellular-> Hemodynamic due to Pc increase (heart Failure)

-> Oncodynamic (hypoproteinemia in liver failure, diarrhea, nephrotic syndrome,
Review Algorithm for Nephrotic Syndrome or Algorithm on Burns

Localized or Generalized Edema is also something to consider:

1. Localized: Hydroperitoneum for instance (cirrhosis)
Review Algorithm on Liver Cirrhosis
2. Generalized: Anasarca

49. Mechanisms of Edema Development in Specific System Dysfunctions

Best to talk about the algorithms and review Question 48. Here you can elaborate more in detail on
a specific disease whether it is Cirrhosis, Nephrotic Syndrome, Addisons.

Inflammation is also a key point to discuss here. Review Robbins Page 31-34 as well as Thieme
Page 250

50. Disorder of K+ Metabolism

Regulation of Potassium Balance

• Relative ICF-ECF potassium ion concentration affects a cell's resting membrane potential
◦ Excessive ECF potassium decreases membrane potential
◦ Too little K+ causes hyperpolarization and non-responsiveness
• Hyperkalemia and hypokalemia can:
◦ Disrupt electrical conduction in the heart
◦ Lead to sudden death
• Hydrogen ions shift in and out of cells
◦ Leads to corresponding shifts in potassium in the opposite direction
◦ Interferes with activity of excitable cells
• Influence of Aldosterone
◦ Aldosterone stimulates potassium ion secretion by principal cells
◦ In cortical collecting ducts, for each Na+ reabsorbed, a K+ is secreted
◦ Increased K+ in the ECF around the adrenal cortex causes:
◦ Release of aldosterone -->Potassium secretion
◦ Potassium controls its own ECF concentration via feedback regulation of aldosterone

Liddle Syndrome: rare autosomal dominant disorder characterized by severe hypertension and
hypokalemia. Caused by unrestrained Na reabsorption in the distal nephron due to one of several
mutations found in genes encoding for epithelial Na channel subunits. High reabsorption of Na
results in both hypertension and renal wasting.

Renal K wasting: can also be caused by numerous congenital and acquired renal tubular diseases
such as renal tubular acidosis and FANCONI SYNDROME. This unusual syndrome resulting in
renal wasting of K, glucose, phosphate, uric acid and amino acid.
Hypokalemia is diagnosed on the basis of plasma or serum K level of <3.5 mEq/L
(Review Thieme Page 134)

51. Disorders of Ca2+ Metabolism

Regulation of Calcium
• Ionic calcium in ECF is important for:
◦ Blood clotting
◦ Cell membrane permeability
◦ Secretory behavior
• Hypocalcemia: Increases excitability, causes muscle tetany
• Hypercalcemia: inhibits neurons and muscle cells; cause heart arrhythmias
• Calcium balance is controlled by parathyroid hormone and calcitonin
◦ PTH promotes increase in calcium levels by targeting:
■ Bones - PTH activates osteoclasts to break down bone matrix
■ Small intestine - PTH enhances intestinal absorption of calcium
■ Kidneys - PTH enhances calcium reabsorption and decreases phosphate
■ Calcium reabsorption and phosphate excretion go hand in hand
◦ Influence of Calcitonin
■ Released in response to rising blood calcium levels
■ Calcitonin is a PTH antagonist, but its contribution to calcium and phosphate
homeostasis is minor to negligible
52. Imbalance of Magnesium and Phosphate Metabolism

Conditions of Magnesium Imbalance

Hypomagnesemia, too little magnesium in the blood stream, may occur because of many
reasons. Some have to do with dietary deficiencies, inability of the intestine to absorb the chemical,
or due to increased excretion.
Common causes of low magnesium include alcoholism and its associated malnutrition,
chronic diarrhea, and medications like diuretics (water pills used to control high blood pressure).
More than half of hospitalized patients in ICUs may become magnesium deficient.

Symptoms involve the heart with rhythm abnormalities, muscles with weakness and cramps,
and the nervous system, potentially causing confusion, hallucinations, and seizures.
Hypermagnesemia describes too much magnesium in the blood stream and most often
occurs in patients with kidney function problems in which the excretion of magnesium is limited.
Since the absorption and excretion of magnesium is linked to other electrolytes, other
diseases may be associated with high magnesium levels, including diabetic ketoacidosis, adrenal
insufficiency, and hyperparathyroidism. Hypermagnesemia is often associated with hypocalcemia
(low calcium) and hyperkalemia (high potassium).

Hypomagesemia is plasma Mg concentraion of <1.4mEq/L.

Hypermagnesemia is plasma Mg concentration of >2.1mEq/L.

Conditions of Phosphate Imbalance

• Hyperphosphatemia: Too much phosphate. Causes include: broken bones; kidney disease;
intestinal obstructions; hypoparathyroidism.
• Hypophosphatemia: Too little phosphate. Causes include: hypomagnesemia; hypokalemia;
severe burns; traumatic injuries; chronic alcoholism; kidney disease; hypothyroidism;
malnutrition; prolonged diuretic use.

Review page 142 in Thieme.

Discuss Algorithm: Postemenopausal Osteoporosis
Robbins page768-773

53. Pathophysiological Factors of the Acid-Base Imbalances

• Introduction to Acids and Bases

◦ Strong acids - all their H+ is dissociated completely in water
◦ Weak acids - dissociate partially in water and are efficient at preventing pH changes
◦ Strong bases - dissociate easily in water and quickly tie up H+
◦ Weak bases - accept H+ more slowly (e.g., HCO3¯ and NH3)
◦ Normal pH of body fluids
■ Arterial blood is 7.4
■ Venous blood and interstitial fluid is 7.35
■ Intracellular fluid is 7.0
◦ Alkalosis or alkalemia - arterial blood pH rises above 7.45
◦ Acidosis or acidemia - arterial pH drops below 7.35 (physiological acidosis)
• Sources of Hydrogen Ions - Most hydrogen ions originate from cellular metabolism
◦ Breakdown of phosphorus-containing proteins releases phosphoric acid into the ECF
◦ Anaerobic respiration of glucose produces lactic acid
◦ Fat metabolism yields organic acids and ketone bodies
◦ Transporting carbon dioxide as bicarbonate releases hydrogen ions
• Hydrogen Ion Regulation
◦ Concentration of hydrogen ions is regulated sequentially by:
■ Chemical buffer systems - act within seconds
■ Physiological buffer systems
■ The respiratory center in the brain stem - acts within 1-3 minutes
■ Renal mechanisms - require hours to days to effect pH changes

*Review Algorithm Problem 33

54. Respiratory Acidosis and Alkalosis

Review Respiratory Alkalosis Algorithm as well as Acidosis Algorithm
Thieme Page 94 and Page 98

Respiratory Acidosis and Alkalosis

• Result from failure of the respiratory system to balance pH
• PCO2 is the single most important indicator of respiratory inadequacy
• PCO2 levels - normal PCO2 fluctuates between 35 and 45 mm Hg
◦ Values above 45 mm Hg signal respiratory acidosis
◦ Values below 35 mm Hg indicate respiratory alkalosis
• Respiratory acidosis is the most common cause of acid-base imbalance
Occurs when a person breathes shallowly, or gas exchange is hampered by diseases such as
pneumonia, cystic fibrosis, or emphysema

 ↓ HCO-3 , ↓pH, ↓Pa CO2
 causes: ↓ H+ secretion (uremia, tubular acidosis), ↑H+ formation (ketosis: insulin lack,
starvation, alcohol consumption), base loss(diarrhea), acid intake
 ↑H+ occurs slowly allowing full respiratory response
 compensation: through peripheral chemoreceptors(hyperventilation-Kussmal's breathing),
changes in pH of cerebrospinal fluid
 within 2 hours kidneys will reabsorbe all bicarbonates; 3 to 5 days after secretion of NH4
will increase which will allow bigger H+ excretion
 concetration of bicarbonates will decreae because they will be used up as buffers
Hyperchloremic metabolic acidosis
 when renal excretion of H+ is disturbed or when anions(bicarbonates) are lost; to maintain
electrochemical equilibrium chlorides are retained
 kidney function disorders - interstitial nephritis with azotemia, hydronephrosis, renal tubular
acidosis- due to disorder in bicarbonate absorption (proximal type) or H+ disorder (distal
 gastrointestinal causes: diarrhea, loss of alkali in the stool
Metabolic acidosis with anion gap
 increased formation or accumulation of anions of non-volatile acids
 uremic metabolic acidosis- accumulation of phosphates,sulphates and urates; ↓NH4
formation and ↓bicarbonate reabsorption- exhausted buffer capacity
 diabetic ketoacidosis
 alcohol induced ketoacidosis
 L-lactacidemia
 salicylic acid intoxication
Combined metabolic acidosis
 D-lactacidemia- intestinal bacteria degrade carbs into D-lactate that mamals can't metabolize

 ↑HCO-3 , ↑pH, ↑PaCO2, hypokalemia
 causes:loss of acid or ↑ reabsorption of bicarbonates, kidneys and stomach can synthesize as
much bicarbonates needed to cause alkalosis(CO2→H2CO3), vomiting(loss of fluid
→secundary hyperaldosteronism,alkalosis)
 primary metabolic alkalosis: as compensation ↑PaCO2
 metabolic alkalosis dependent on salt (vomiting,diuretics)-chlorides used as therapy(NaCl)
 metabolic alkalosis independent on salt- NaCl can't be used, KCl used instead; e.g. alkalosis
with increased secretion of mineralocorticoides (↑extracellular fluid volume)
 constriction alkalosis-↓ECF volume (sweating,urination)→ aldosteron→ constriction→
bicarbonate reabsorption→metabolic alkalosis
 loss of hydrochloric acid due to vomiting→ ↑bicarbonate conc in plasma→metabolic
alkalosis (↑bicarbonate conc in plasma is very big causing big loss of sodium bicarbonate
via urine→↓ECF volume→renin,aldosterone→ ↑ Na + reabsorption,↑K+ and H+

Maximal enzymatic activity when pH is optimal; any change in pH causes decreased enzymatic
 Acidosis: ↑K+, ↑Ca 2+,↓Hb affinity for oxygen(Bohr's effect), vasoconstriction in
lungs, vasodilation in brain,↓ affinity of albumin for bilirubin→toxicity
 Alkalosis: ↑NH4+→toxicity, disturbes Crebs cycle,↓K+,↑ Hb affinity for oxygen
 effects on cardiovascular system:
a) Acidosis: ↓ heart contractility (H+ and Ca2+ are competing for troponin C),
vasoconstriction in lungs, vasodilation in brain;
- ↓affinity of albumin for Ca2+→↑Ca 2+ (good for the heart), ↑adrenalin
- ↑K+ -arrhythmias, fibrillations
-↑ intracranial pressure→headache,sleepiness,stupor,coma
Pathogenetic role of local acid-base disorders:
 hyperchlorhydria (increased secretion of HCl in gastric juice)surpasses buffering
system; causes peptic disease,maldigestion,reflux esophagitis
 inhibition of carbon anhydrase by certain drugs causes carbonaturia, urine
alkalization and polyuria
 tissue acidosis causes hypofunction, pain,fatigue


Endocrinopathies are diseases that result from disorders of endocrine glands (hormone
imbalances). They can be differentiated between hypofunctioning and hyperfunctioning
Glandular endocrinopathies involve disturbances in endocrine glands and/or their regulation
mechanisms. If the disturbances do not involve endocrine glands or their regulation mechanisms
then we call them extraglandular endocrinopathies. Glandular endocrinopathies may occur due to
disturbances in the gland that secretes a specific hormone (primary endocrinopathy) or due to
disorder in a system that monitors the activity of these glands (secondary endocrinopathy - due to
pituitary disturbances; tertiary endocrinopathy - due to hypothalamus disturbances).
In hypofunctional gland primary hormone secretion can be normal but hormonal reserves
are low causing signs of hypofunction to show during increased load. That kind or endocrinopathies
are called hidden or latent. Endocrinopathies in which consequences of hormonal disturbances are
seen throught the disease are called expressed or manifested.
Causes of endocrinopathies:
1.loss of endocrine compensation due to overthrow of reactive norms
-despite normal reactivity expected endocrine compensation is lost
-e.g. in moderate hypovolemia organism will compensate with hypercatecholaminemia,
hypercortisolemia, hyperaldosteronism. But in hypovolemic shock when loss of volume is too big
all of those mechanisms become ineffective.
2.neurovegetative regulation disorders are reflected in numerous endocrinopathic deviations.
-ch.stress(hypotestosteronemia),psychosomatic diseases
3.congenital and acquired genetic disorders of hormones,receptors, signaling systems
4.lack of basic and specific metabolic substances
-malnutrition,ch.starvation,pituitary infarction (Sheehan's disease)-panhypopituitarism,
hemorhagic infarction of adrenals(Waterhouse-Friderichsen syndrome)
5.inflammatory, immune and infectious processes in glandular tissue that disrupt endocrine function
by toxic effects,destruction of parenchyma and tissue fibrosis
6.tumors: - uncontrolled hormone production, ectopic peptide hormone production, compression of
endocrine glands due to expansive tumor growth
7.aging and degenerative processes causing endocrine changes
8.biotransformationdisorders of hormones and pharmacological substances
Increased hormonal secretion:
 increased hormone secretion in the gland

◦ gland that normally secretes hormones begins to excrete them in increased

quantity (because of independent secretion caused by hyperplasia, neoplasia) or
disorders of the feedback control loop that regulates the secretion of the hormone
(hyperthyroidism, Cushing's disease, acromegaly)
 ectopic hormone secretion
 tumors of non-endocrine origin can secrete hormones or substances that act as normal
hormones ( Cushing's syndrome seen in patients with bronchial carcinoma that secretes
 different pathophysiological mechanisms
a) gene depression - in the malignant cells previously inactive genes, that normally control
the creation of certain hormones in the endocrine glands, can be activated so that the corresponding
hormone begins to secrete ectopically. Only polypeptide hormones can be secreted this way.
b)cell hybridization -tumors that secrete ectopic hormones are formed by connecting
neoplastic non-endocrine cells with endocrine cells
Decreased hormone secretion:
Caused by: infection,necrosis, therapeutical procedures(radiation,surgery), immunological disorders
(Hashimoto disease), tumors...


Endocrine gland functions normally, hormonal secretion and transport are not affected but

there is no response from target tissue. This is called hormone insensitivity or hormone resistance.
Hormone concetration in plasma is normal or increased with simultaneous lack of hormone effect.
Hormone insensitivity can be caused by :
 lack of hormone activation in the target tissue
 receptor disorders or disorders of postreceptor effective mechanisms in the cell
 creating antibodies to hormones or hormone receptors
 lack of target cells
Congenital receptor disorders:
 gene mutation for androgen receptors →male pseudohermaphroditism ( mutation causes lack of
androgen receptors seen as complete testicular feminization, XY chromosome, testicles are
contained in abdominal cavity( secreating increased concetration of testosterone), external
genitalia of female)
 male hermaphroditism can also occur due to gene mutation of 5-α-reductase (enzyme that
converts testosterone into active dihydrotestosterone( active form of androgens in most
 gene mutation of Gs α receptor subunit for PTH →pseudohypoparathyroidism- insensitivity to
PTH; increased concetration of PTH in plasma with hypocalcemia and hyperphosphatemia
Acquired hormone receptor disorders:
 regulatory effects of hormones

◦ increased secretion of thyroid hormones in hyperthyroidosis causes stimulation

of β-adrenergic receptors resulting in increased heart rate and increased
minute volume

◦ increased secretion of GH in acromegaly stimulates prolactin receptors and

causes galactorrhea in women
 metabolic disorders can affect target tissue response on hormones

◦ in ketoacidosis there is a decreased affinity of insulin receptors resulting in

decreased tissue sensitivity to insulin
 autoimmune diseases (antibodies against hormone receptors) -the effect of the
antibody may be stimulating (as in Graves' disease) or blocking (as in myasthenia
 somatic mutations in tumors may affect hormone receptors


Secretion of most hormones are affected directly or indirectly by their final products or
metabolic effects. Activity of most hormonal systems is regulated by negative and positive feedback
loops. Physiologically negative feeddback loops are more common. Feedback mechanisms have
certain set point that can be changed in conditions such as stress and neuroendocrine diseases.
Disorders of hypothalamus-hypophysis-target gland system:
 primary endocrinopathy - target gland as a culprit
 secondary endocrinopathy – hypophysis as a culprit
 tertiary endocrinopathy – hypothalamus as a culprit

Cushing's syndrome as an example of all three types of endocrinopathies:

 primary endocrinopathy – adrenal gland neoplasia causes increased secretion of cortisol
 secondary endocrinopathy – increased cortisol secretion associated with hyperplasia of
adrenal cortex that occured as a consequence of increased secretion of ACTH from
 tertiary endocrinopathy – increased secretion of CRH from hypothalamus stimulates
adenohypophysis that causes stimulation of adrenals as a consequence
Hormone secretion disorders caused by homeostasis imbalance:
Homeostasis imbalance affects hormone secretion that is not regulated by hypothalamus or
hypophysis. Hormones that are not under their control are insulin, glucagon,PTH,ADH, aldosterone
and certain gastrointestinal hormones. Their concetration is regulated by blood concetration of
specific substances ( glucose,calcium, and also by concetration and volume of blood). In the
primary endocrinopathy disorder occurs in the endocrine gland while in secondary endocrinopathy
it occurs due to disorders of homeostatic mechanisms. Example:
 primary aldosteronism (Conn's syndrome) – increased aldosterone secretion due to
tumor or adrenal cortex hyperplasia
 secondary aldosteronism – increased aldosterone secretion as a consequence of
stimuli originating outside of adrenals, most common stimulus is decreased renal
blood flow
The pituitary gland, along with the hypothalamus, plays a critical role in the regulation of
most other endocrine glands. It is composed of two morphologically and functionally distinct
 adenohypophysis (80% of pituitary) – hypothalamic factors carried to the anterior pituitary
by a portal circulation influence hormone production by the five basic anterior lobe cell
types: somatotrophs(growth hormone), lactotrophs(prolactin), corticotrophs (ACTH,
POMC, MSH, endorphins and lipotropin), thyrotrophs(TSH), gonadotrophs (FSH,LH)
 neurohypophysis- comprises modifiedd glial cells and axonal processes extending from
hypothalamus, oxytocin and ADH synthesized by the hypothalamus are stored in the axon
Disorders of adenohypophysis:
 Hypopituitarism – lack of hormones secreated by adenohypophysis (
panhypopituitarism – all anterior lobe hormones are lacking; monotropic
hypopituitarism- only one specific hormone is lacking).
Primary hypopituitarism occurs when a disorder affect hypophysis itself. Most common causes are
vascular disorders(postpartum pituitary gland necrosis,vasculitis,aneurysms), tumors, infections
(TB,syphilis, meningitis),surgeries,radiation,metabolic disorders, etc.
Secondary hypopituitarism occurs due to disorders at a higher level (hypophyseal stalk,
hypothalamus, other parts of the brain).
Clinical signs of hypopituitarism are seen when 70-75% of adenohypophysis is destroyed.
 Consequences of hypopituitarism in children:
 Pituitary nanosomy (dwarfism) – caused by any condition that interferes with
GH formation and activation; low conc of GH in blood
 Laron syndrome (dwarfism) – significant increase of GH in the blood but low
con of IGF-1; most probable cause is insensitivity of liver cells to GH
 Pituitary infantilism – lack of GH and other hormones of adenohypophysis;
stunted growth and poor development of secondary sexual characteristics
 Consequences of hypopituitarism in adults:
 Secondary hypogonadism – lack of FSH and LH; women – secondary
ammenorrhea with decreased estrogen activity,atrophy of: brest,vaginal
mucosa and uterus; men-secondary testicular atrophy (loss of libido,potency
and muscle tonus)
 Secondary adrenal hypofunction similar to Addison's disease – lack of
 Secondary hypothyroidism- lack of TSH, causes stunted growth in kids that
does not improve after GH administration
 lack of prolactine – absence of lactation after delivery; seen in Sheean's
syndrome (postpartum pituitary gland necrosis caused by hemorrhagic
 Excessive secretion of pituitary hormones:
 Hyperprolactinemia – Disruption in hypothalamic-pituitary axis results in
increased prolactin secretion due to loss of inhibition ( prolactin secretion is
normally inhibitedd by dopamin). Most common causes are adenomas and
prolactinomas. Women- galactorrhea,decreased ovarian function,anovulatory
cycle,oligomenorrhea,amenorrhea. Men- loss libido and potency,hypogonadism
and galactorrhea are rarely seen.
 Increased secretion of GH :
 Gigantism – increased GH secretion before closure of the epiphyseal
 Acromegaly - increased GH secretion in adults; linera growth is normal,
enlargement of the hands and feet, protrusion of the lower jaw, overgrowth of
facial bones, cardiomegaly,hypertrophic
arthropathy,visceromegaly,neuropathy, blood glucose conc tends to rise and
insulin secretion increases to compensate for the GH-induced insulin
resistance (GH is diabetogenic)
 Increased conc of ACTH Cushing' disease ( take a look at the algorithm #40)
Disorders of neurohypophysis:
 Diabetes insipidus – condition characterized by excessive thirst (polydipsia) and excretion
of large amounts of severly dilute urine (hypo-osmolal polyuria).
 Neurogenic diabetes insipidus, more commonly known as central diabetes insipidus,
occurs due to the lack of ADH production in the hypothalamus.The underlying causes
of central DI can include vascular problems, autoimmune diseases, infections, some
drugs, surgery, head trauma, benign or metastatic pituitary-hypothalmic tumor
(particularly originating from breast and lung), although 50% of cases are found to be
 Nephrogenic diabetes insipidus occurs due to ADH receptor dysfunction in the kidneys.
 Syndrome of inappropriate ADH secretion - is characterized by excessive release of ADH
from the neurohypophysis or another source. The result is often dilutional hyponatremia in
which the plasma sodium levels are lowered and total body fluid is increased. It was
originally described in people with small cell carcinoma of the lung, but it can be caused by
a number of underlying medical conditions. ADH activity effectively dilutes the blood
(decreasing the concentrations of solutes such as sodium), causing hyponatremia ; this is
compounded by the fact that the body responds to water retention by decreasing aldosterone,
thus allowing even more sodium wasting. For this reason, a high urinary sodium excretion
will be seen.


 increased concetration of thyroid hormones due to hyperactivity of the gland
 causes: glandular disease, increased and uncontrolled secretion of TSH or TRH,
trophoblastic tumor(secretes TSH), Graves disease
 increased blood conc of T3 and T4 (↑T3 > ↑T4 )
 T3 hyperthyroidism - ↑T3 with normal conc of T4 ; caused by iodine deficiency
 T4 hyperthyroidism - ↑T4 with normal conc of T3 ; seen in people with
ch.diseases and in elderly people;due to decreased peripheral conversion of T4
into T3
 pathophysiological changes: ↑ energy utilization,↑ oxygen consumption, ↑heat
production, ↑food intake, ↑ glucose absorption from gut, ↑gluconeogenesis,
↑glucose utilization in muscle and fat tissue, ↓glycogen reserves in liver, ↑protein
anabolism, ↑↑protein catabolism, ↑FFA in blood,↑cholesterol and triglycerides

synthesis (but their conc ↓ in plasma due to ↑↑utilization), ↑ sympathetic tone (
thyroid hormones ↑ number of β adrenergic receptors- ↑ heart rate, ↑ minute
volume and ↑ stroke volume, ↓TPR - ↑systolic pressure and ↓diastolic pressure),
moist and warm skin,tremor, muscle weakness, myopathy
Graves disease
 most common form of hyperthyroidism
 diffusley enlarged thyroid, ↑hormone secretion, exophtalamus, pretibial edema,
↓conc of TSH in blood
 TSI (thyroid stimilating immunoglobulins) found in blood – IgG type of Ig, act as
autoantibodies against TSH receptors ( bounds to TSH receptor and activates it
mimicking TSH)
Multinodular toxic goiter and toxic adenoma
 independent on TSH, ↑hormone secretion that causes thyrotoxicosis
 autonomy of one or more areas of the gland
Hypothyroidism - insufficient production of thyroid hormones
Primary hypothyroidism
 consequence of thyroid disease itself
 ↓ thyroid hormone secretion, ↑TSH secretion (resulting in hypertrophy,
hyperplasia and goiter as a compensation but when that fails hypothyroidism
 most common primary hypothyroidism is Hashimoto disease)
Secondary (pituitary) hypothyroidism
 gland itself is normal but there is ↓ TSH secretion from pituitary
 usually occurs due to pituitary tumor, surgery or radiation
 TRH administration is not curative
Tertiary (hypothalamic) hypothyroidism
 occurs due to disturbances in the hypothalamus and consequent lack of TRH
 low or normal TSH conc, low conc of thyroid hormones
 TRH administration is curative
Hypothyroidism in adults (mixedema)
 skin changes, pitting edema
 slower degradation of mucopolysaccharides in intercellular space
 possible jaundice due to accumulation of carotenoids
 slow metabolism, hypothermia, dry and cold skin, slow mental reaction, serous
effusions, constipation, hypercholesterolemia

Cretinism and juvenile hypothyroidism
 signs of hypothyroidism can exist at birth, but are most often seen in the first
months of life
 growth retardation, mental retardation, cretenism

Disorders of adrenal cortex
 Hyperfunctions of adrenal cortex
 Cushing's syndrome/ disease
 ↑cortisol secretion due to bilateral adrenal hyperplasia caused by ↑ACTH
secretion from pituitary (Cushing's disease);adenoma or carcinoma of adrenals,
prolonged use of glucocorticoides (Cushing's syndrome)
 Cushing's disease -↑cortisol, androgens and mineralocorticoides
(desoxycorticosterone); androgens are on periphery converted into
testosterone and dihydrotestosterone causing hirsutism,acne and amenorrhea
in women
 ectopic secretion of ACTH from non-endocrine tumors (mostly bronchial
carcinoma) - ACTH and cortisol levels are much higher then in Cushing's
disease; lipotropin (β-LPH) is also increased; ACTH and β-LPH stimulate
melanin synthesis causing skin hyperpigmentation, hypertension,
hypokalemia, ↓ renin plasma activity
 Cushing's syndrome - ↑cortisol secretion and ↓ ACTH secretion, atrophy of
zona fasciculata and zona reticularis;
↑cortisol,mineralocorticoides,glucocorticoides, androgens; cortisol ↑
gluconeogenesis, hyperglycemia, ↓ glucose tolerance – possible DM; ↑
protein catabolism results in release of AA that are partly used up in
gluconeogenesis and partly excreted via urine (negative nitrogen balance);
muscle weakness and atrophy;appearance of striae on the abdomen,breast and
thighs (collagen weakness); ecchymoses and purpura (due to lose of
perivascular connective tissue blood vessels are fragile and prone to bleeding),
slow wound healing ( cortisol inhibits collagen and fibronectin synthesis),
buffalo hump, moon face, centripetal obesity, prone to infections(cortisol
weakens immunoreactivity and silences inflammatory response), osteoporosis
(inhibits osteoblastic activity and increases bone resorption, inhibits calcium
 Hyperaldosteronism
 Primary aldosteronism ( Conn's syndrome)
1. ↑ aldosterone secretion most commonly due to tumor or
hyperplasia of zona glomerulosa

2. causes increased renal sodium ion exchange for potassium
and hydrogen resulting in hypokalemia, metabolic acidosis
and mild or moderate hypertension
3. hypokalemia and metabolic acidosis lead to muscle
weakness, paresthesia, paralysis and tetany
4. due to ↑ aldosterone and ↑ECF volume plasma renin
activity is low
5. no edema
 Secondary aldosteronism
1. ↑ aldosterone secretion due to extrarenal causes and renin-
angiotensin-aldosterone system activation
2. The most common underlying disorder is reduced plasma
volume and/or decreased renal blood flow which promotes
increased secretion of renin
3. physiological phenomenon in pregnancy and in luteal
phase of menstrual cycle
 Excessive secretion of androgens (adrenogenital syndrome)
 Congenital adrenal hyperplasia
1. occurs due gene mutation and consequent shortage of one
or more enzymes required for the synthesis of steroid
hormones ( lack of C-21 hydrxylase)
2. low cortisol conc in plasma and high ACTH conc (
stimulates cortisol secretion that results in adrenal
hyperplasia, stimulates androgen production)
 Adrenogenital syndrome in adults
1. virilization
2. excess of androgen hormones in adult women causes
hirsutism, acne, breast atrophy, enlarged clitoris and
 Hypofunction of the adrenal cortex (↓ steroid hormone secretion)
 Primary hypofunction of the adrenal cortex (Addison disease)
 clinical signs of insufficiency are observed when more than 90%
of both adrenal cortices are destroyed
 at the begining of the disease stress response is decreased
 acute adrenal crisis can develop
 lack of mineralocorticoides: insufficient reabsorption of sodium in
renal tubules, potassium retention, ↓plasma volume,hyponatriemia,
hyperkalemia,metabolic acidosis; hypovolemia can cause prerenal
azotemia,orthostatic hypotension and shock
 cortisol lack: loss of appetite and body weight, morning
hypoglycemia, GI disorders, skin hyperpigmentation
 Secondary hypofunction of the adrenal cortex
 lack of ACTH resulting in decreased glucocorticoide secretion
 atrophy of zona fasciculata and reticularis
 ↓ cortisol, aldosterone levels are within range ( hyponatriemia will
develop anyway, no hyperkalemia)
 hyponatriemia results from ↓ cortisol and ↑ ADH
 prolonged glucocorticoide treatment inhibits ACTH and CRF
secretion resulting in adrenal atrophy due to lack of endogenous


 Primary hyperparathyroidosis

◦ disorder that affects one or more parathyroid glands (↑PTH secretion)

◦ PTH is secreted when there is a high conc of ionizing calcium in plasma

◦ commonly caused by adenoma and primary hyperplasia of parathyroid glands

◦ when renal function is normal ↑PTH causes ↑ calcium conc, normal or ↓ conc of
phosphate and hypercalciuria

◦ hypercalcemia→polyuria, nephrocalcinosis,nephrolithiasis, loss of renal function

◦ ↑PTH→↑ osteoclast activity, progressive loss of calcium from bones, demineralization,

compensatory ↑ osteoblast activity
 Secondary hyperparathyroidism

◦ any factor that decreases blood conc of ionizing calcium stimulates PTH secretion

◦ in vit D hypovitaminosis secondary hyperparathyroidism is not only a consequence of

decreased calcium conc but it also results from low 1,25(OH)2D3 that usually decreases
gene transcription for PTH

◦ seen in adults with osteomalacia and kids with rickets

 Tertiary hyperparathyroidism

◦ state of excessive secretion of PTH after a long period of secondary hyperparathyroidism

and resulting in a high blood calcium level
◦ It reflects development of autonomous (unregulated) parathyroid function following a
period of persistent parathyroid stimulation.
 Pseudohyperparathyroidism

◦ ectopic secretion of PTH

 Primary hypoparathyroidism

◦ due to removal or damage of parathyroid glands during surgery, autoimmune disease

◦ low plasma ionizing calcium(tetany), high plasma conc of phosphates

 Secondary hypoparathyroidism

◦ occurs when hypercalcemia inhibits PTH secretion

◦ high con of ionizing calcium in blood and low PTH conc

 Pseudohypoparathyroidism

◦ target tissue insensitivity to PTH

◦ hypocalcemia, hyperphosphatemia, parathyroid hyperplasia, high PTH conc

◦ short stature, short neck, adiposity,mental retardation, short metatarsal and metacarpal

 Testicles

◦ Hypogonadism
▪ primary (testicular disorder) or secondary ( disorder of hypophysis-hypothalamus
 Hypergonadotropic (primary) hypogonadism
◦ ↑gonadotropin secretion, testicular hormones are not secreted and
negative feedback loop is not functional
◦ is a condition which is characterized by hypogonadism due to an impaired
response of the gonads to the gonadotropins,FSH,LH and in turn a lack of
sex steroid production and elevated gonadotropin levels (as an attempt of
compensation by the body).
◦ may present as either congenitall or acquired, but the majority of cases
are of the former nature
 Hypogonadotropic (secondary) hypogonadism
◦ condition which is characterized by hypogonadism due to an impaired
secretion of gonadotropins,including FSH and LH, by the pituitary, and in

turn decreased gonadotropin levels and a resultant lack of sex steroid
◦ Hypergonadism
▪ condition where there is a hyperfunction of the gonads
▪ precocious puberty - caused by abnormally high levels of testosteron or estrogen
▪ it may be caused by a tumor, which can be malignant but mostly it is benign,
anabolic steroids may also be a major cause of high androgen and/or estrogen
functional activity
▪ Symptoms of the condition may include precocious puberty, rapid growth in
adolescents, high libido,acne, excessive hairiness
 Ovaries

◦ Ovarian hypofunction (hypogonadism)

▪ menstrual cycle disorder in women of reproductive age (primary amenorrhea-

woman never had her period; secondary amenorrhea - woman who has been
having normal menstrual cycles stops getting her periods for 6 months or longer)

▪ primary ovarian insufficiency is associated with ↑conc of gonadotropins in

 Chronic anovulation without estrogen
◦ estrogen is not produced or it is produced in very small quantity
◦ it can occur due to big emotional and psychological stress
◦ LH and FSH are not secreted, endometrial atrophy
 Chronic anovulation with estrogen
◦ estrogen is produced but it is not secreted cyclically
◦ seen in polycystic ovary syndrome ( infertility,hirsutism,obesity,
amenorrhea,oligomenorrhea) – PCOS is actually hyperfunctional disorder
◦ Ovarian hyperfunction (hypergonadism)
 Primary ovarian hyperfunction
◦ due to ovarian tumors that secrete estrogen
◦ pseudopubertas praecox
◦ ↑ estrogen conc, ↓ gonadotropin conc
 Secondary ovarian hyperfunction
◦ ↑ gonadotropin conc
◦ precocious puberty

66. Pathophysiological Significance of Biogenic Amines

Biogenic amines are organic bases with low molecular weight and are synthesized by microbial,
vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw
material or are generated by microbial decarboxylation of amino acid’s.

Classical monoamines
• Histamine - a substance derived from the amino acid histidine that acts as a neurotransmitter
mediating arousal and attention, as well as a pro-inflammatory signal released from mast
cells in response to allergic reactions or tissue damage. Histamine is also an important
stimulant of HCl secretion by the stomach through histamine H2 receptors.
• Serotonin - a central nervous system neurotransmitter derived from the amino acid tryptophan
involved in regulating mood, sleep, appetite, and sexuality.
• The three catecholamine neurotransmitters:
• Norepinephrine (noradrenaline) - a neurotransmitter involved in sleep and
wakefulness, attention, and feeding behavior, as well as a stress hormone released by
the adrenal glands that regulates the sympathetic nervous system.
• Epinephrine (adrenaline) - an adrenal stress hormone, as well as a neurotransmitter
present at lower levels in the brain.
• Dopamine - a neurotransmitter involved in motivation, reward, addiction, behavioral
reinforcement, and coordination of bodily movement.

Review Robbins Page 45 Table 2-5

Review Thieme Page 316

67. Pathophysiological Significance of Plasmin-Kinin System and Complement

Review Robbins Page 83-86

Thieme Page 64

68. Pathophysiological Significance of Prostaglandins and Leukotrienes

Oxidative metabolism of arachidonic acid is increased in inflamed tissues. There are two
principal enzyme pathways of arachidonic acid oxygenation involved in inflammatory processes,
the cyclo-oxygenase which produces prostaglandins (PGs) and the 5-lipoxygenase which produces
leukotrienes (LTs).

Of the various cyclooxygenase products formed during inflammation, PGE2 and

prostacyelin are the most important. These products are both potent vasodilator and hyperalgesic
agents and since they have been detected at sites of inflammation it is believed that they contribute
to the erythema, oedema and pain which are characteristic of the inflammatory response.
Prostaglandin E2 is also a powerful pyrogenic substance. The selective inhibition of cyclo-
oxygenase by non-steroid aspirin-like drugs explains the anti-inflammatory, analgesic and anti-
pyretic activity of this class of drug.

Of the leukotrienes, LTB4 is the strongest candidate as an inflammatory mediator. It is one of
the most potent leukotactic substances known and its presence in inflamed tissues could represent a
local control mechanism for the accumulation of inflammatory leukocytes. It is possible that
inhibitors of the synthesis of leukotrienes could be useful therapeutic agents.

These metabolites of arachidonic acid facilitate many functions in the immune system.

Review Robbins page 46-47

Thieme 318

69. Disorder of the Renin-Angiotensin System

The importance of this system is maintenance of cardiovascular homeostasis and the control of
composition and volume of bodily fluid renin-angiotensinogen.

Renin,enzyme secreted by the kidney (juxtaglomerular cells during reduction of blood volume) that
is part of a physiological system that regulates blood pressure. In the blood, renin acts on a protein
known as angiotensinogen, resulting in the release of angiotensin I. Angiotensin I is cleaved by
angiotensin-converting enzyme, splitting off two amino acids from the 10-amino-acid chain of
angiotensin I, to form angiotensin II. The resultant angiotensin II octapeptide (previously called
hypertensin, or angiotonin) acts via receptors to constrict arterioles, causing a rise in both systolic
and diastolic blood pressure. Angiotensin II is one of the most active vasoconstrictors known; on a
weight basis it is significantly more potent than norepinephrine. It also increases the secretion of
cortisol and aldosterone by a direct action on the adrenal cortex.

Tumours of the juxtamedullary system are accompanied by malignant hypertension and electrolyte
changes in the composition of bodily fluids

Review Electrolyte imbalance algorithm to help expand on the question Problem 25

Angiotensin II (Ang II) raises blood pressure (BP) by a number of actions, the most important ones
being vasoconstriction, sympathetic nervous stimulation, increased aldosterone biosynthesis and
renal actions. Other Ang II actions include induction of growth, cell migration, and mitosis of
vascular smooth muscle cells, increased synthesis of collagen type I and III in fibroblasts, leading to
thickening of the vascular wall and myocardium, and fibrosis. These actions are mediated by type 1
Ang II receptors (AT1), and may be blocked by losartan, a specific blocker of AT1 receptors. In
particular, studies employing losartan have shown that Ang II is an important contributor to BP
regulation and plays a significant role in hypertension and in the pathophysiology of vascular
damage during the course of hypertension. Ang II is also involved in the process of atherosclerosis
and in remodelling and repair processes of the myocardium following myocardial infarction.
Finally, increased Ang II is an important part of neurohumoral activation in heart failure.

This is the most important factor in this system. Along with everything said before, it encourages
- gluconeogenesis and glyconeolysis
- Increased thirst and stimulates production of ADH and ACTH
- Disease in kidney parenchyma associated with hypertension
- Increased aldosterone release (secondary) associated with kidney artery stenosis or liver
fibrosis (edematous state)

70. Growth Factor and Cytokine Role in the Pathophysiological Processes

In Regards to Growth Factor

Review Robbins Growth Factor deprivation page 20-22

Review Robbins RB Gene Page 182-184
Robbins Page 62 Growth Factor Chart**
Thieme Page 16

In Regards to Cytokines

Review Robbins Page 48

Understand that Cytokines are key players in the role of Inflammation, angiogenesis and targeted
immune reactions.

Robbins chart page 53 : Role of Mediators in Different Reactions of Inflammation

Robbins Diagram page 54 and 55

Autocrine Signalling cytokine (IL-2) is when a cell secretes a chemical messenger (autocrine agent)
that binds to autocrine receptors on that same cell, leading to changes in the cell.

Example: T cell is induced to mature by binding to a peptide:MHC complex on a professional

antigen-presenting cell and by the B7:CD28 costimulatory signal. Upon activation, "low-affinity"
IL-2 receptors are replaced by "high-affinity" IL-2 receptors consisting of α, β, and γ chains. The
cell then releases IL-2, which binds to its own new IL-2 receptors, causing self-stimulation and
ultimately a monoclonal population of T cells. These T cells can then go on to perform effector
functions such as macrophage activation, B cell activation, and cell-mediated cytoxicity.

Another example is for growth of a tumour. This can cause even more damaging effects.

Paracrine Signalling: Is cell-cell communication in which a cell produces a signal to induce changes
in NEARBY cells, altering the behaviour or differentiation of those cells.

Example would be the FGF family. Angiogenesis and fribroplasia help the survival of tumours.

This chart is also helpful when needing to remember which cells secrete which GF and Cytokines

Of Importance as well to remember because it is a frequently asked question :

71. Disorders of Gastrointestinal Hormones and Neuropeptides

stimulates secretion of gastric acid and pepsin, and weakly stimulates secretion of pancreatic
enzymes and gallbladder contraction.
-Important mediator of peptic ulcers and duodenal ulcers (hypersecretion of HCL)

Review Algorithm for Zollinger-Ellison Syndrome (Peptic Ulcer Disease) Problem 538

Greek chole, "bile"; cysto, "sac"; kinin, "move" ;)

Therefore move the bile-sac (gallbladder) is a peptide hormone of the gastrointestinal system
responsible for stimulating the digestion of fat and protein.

1. Secretin: increase secretion of water and bicarbonate from pancreas
2. Gastric Inhibitor Polypeptide (GIP): inhibits gastric acid secretion and mobility of the
3. Vasoactive Intestinal Polypeptide (VIP): relaxes smooth muscles of blood vessels, acting
like secretin, GIP and glucagon


Review Robbins Page 49

1. Somatostatin: Inhibits growth hormones, HCL, insulin, glucagon, pancreatic secretion of

bicarbonate, water and enzymes; Concentration increased in patients with tumours of delta
cells (increased somatostatin).
-Mild Diabetes
-Malabsoprtion Syndrome

2. BOMBESIN: Gastrin-Releasing Peptide, Lowers Temperature

3. Neurotensin: Lowers temperature
4. Substance P
5. Endogenous Peptides

72.Pathophysiological Significance of Nitric-Monoxide and Free Oxygen Radicals

Review Robbins Page 13, 14, 15, 17 (add reperfusion Injury explanation)
How ROS are formed and aounterbalanced!!!

Nitric Monoxide Monoxide

Important in the regulation of blood vessel tone (vasodilation, limits vasoconstriction effects,
reduces thrombocyte aggregation)
Endothelial damage caused by reduced NO creation (emergence of ischemic damage)
Important effect in the pathogenesis of septic shock
*Review Algorithm on Sepsis

Contain and unpaired electron in outer electron shell
Resulting from:
Incomplete reduction of O2
Catalyzed reactions of enzymes or metals
Radiolysis of small molecules
Intermediate products from metabolism of exogenous and endogenous molecules and also in
platelet activation
***Neutrophils produce free oxygen radicals by NAPH-oxidase and MPO in oxidative explosion
*Review Robbins Page 37-39

Algorithm on Aging could be a good one to give an example of what happens when there is
increased ROS and decreased Antioxidant production.

Important to discuss the effects of

1. Antioxidants:
Vitamins C, A, E
Co-enzyme Q
Thiol molecules
Catabolic Peptides

2. Enzyme Reactions:
Superoxide-dismutase, catalase

Review Robbins Page 14-16

73.Etiology and Classification of Neurovegetative Disorders

From the Book of Kovac

Neurovegetative System, which lays emphasis upon the role of the system in initiation, exaltation,
and acceleration of vital functions.

Visceral Nervous System: emphasizes a dominant role in regulation of abdominal organs

Autonomous Nervous System: lays Stess upon predominant absence of individuals voluntary
GREEK: Autocracy, autonomous management

Neurovegetative System: through appropriate activity levels, this system coordinates independent
functions, thereby becoming a crucial bond between bodily homeostasis and integral organismic

A diagrammatic illustration of the role of the two arms of the autonomic nervous system.

Note that in general the actions of the sympathetic nervous system are illustrated as being in the
opposite direction to that of the parasympathetic nervous system. Not shown here but discussed
below is the CNS regulation of the immune system via the vagal cholinergic anti-inflammatory
pathway adding yet another dimension to the role of the autonomic nervous system in survival of
the organism.

74.Disorders of Circadian Rhythm. Sleep-wake Pattern Disorders

Circadian rhythms are physical, mental and behavioral changes that follow a roughly 24-hour
cycle, responding primarily to light and darkness in an organism's environment. They are found in
most living things, including animals, plants and many tiny microbes.

RAS: Reticular Activating System: outgoing stimulating fibers originating from the interactive
relationships of aminergic (wakefulness) and cholinergic (sleeping) activities

Increase of RAS activity increases brain activity and the reduction of RAS, decreases brain activity.

Suprachiasmatic Nucleus: Circadian controller of RAS rhythm


There are three phases of non-REM sleep. Each stage can last from 5 to 15 minutes. You go through
all three phases before reaching REM sleep.

Stage 1: Your eyes are closed, but it's easy to wake you up. This phase may last for 5 to 10 minutes.

Stage 2: You are in light sleep. Your heart rate slows and your body temperature drops. Your body is
getting ready for deep sleep.

Stage 3: This is the deep sleep stage. It's harder to rouse you during this stage, and if someone woke
you up, you would feel disoriented for a few minutes.
During the deep stages of NREM sleep, the body repairs and regrows tissues, builds bone and
muscle, and strengthens the immune system.

As you get older, you sleep more lightly and get less deep sleep. Aging is also linked to shorter time
spans of sleep, although studies show you still need as much sleep as when you were younger.

Stage 4: Usually, REM sleep happens 90 minutes after you fall asleep. The first period of REM
typically lasts 10 minutes. Each of your later REM stages gets longer, and the final one may last up
to an hour. Your heart rate and breathing quickens.
You can have intense dreams during REM sleep, since your brain is more active.

Sleep apnea is a serious sleep disorder that occurs when a person's breathing is interrupted during
sleep. People with untreated sleep apnea stop breathing repeatedly during their sleep, sometimes
hundreds of times. This means the brain -- and the rest of the body -- may not get enough oxygen.
There are two types of sleep apnea:
1 Obstructive sleep apnea (OSA): The more common of the two forms of apnea, it is caused by a
blockage of the airway, usually when the soft tissue in the back of the throat collapses
during sleep.
2 Central sleep apnea: Unlike OSA, the airway is not blocked, but the brain fails to signal the
muscles to breathe, due to instability in the respiratory control center.
Book of Kovac: Hypersomnia, Narcolepsy, Parasomnia, Somnambulism

Hypersomnia: State of excessive sleeping which appears in connection of organic neurologic, and
psychiatric illnesses (Narcolepsia- extreme sleepiness during day time of the REM type)

Hyposomnia and Insomnia- Insomnia is a sleep disorder that is characterized by difficulty falling
and/or staying asleep. People with insomnia have one or more of the following symptoms:
1 Difficulty falling asleep
2 Waking up often during the night and having trouble going back to sleep
3 Waking up too early in the morning
4 Feeling tired upon waking

Parasomnia: Parasomnias are a category of sleep disorders that involve abnormal movements,
behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between
sleep stages, or during arousal from sleep. Most parasomnias are dissociated sleep states which are
partial arousals during the transitions between wakefulness and NREM sleep, or wakefulness and
REM sleep.

Example: from Kovac book is Sleep-related epilepsy, in the form of tonic-clonic convulsions
appears in NREM-sleep or is related to the awakening. When epilepsy appears in sleep, it is
followed by prolonged period of REM-sleep.

1. Sleep terror is the most disruptive arousal disorder since it may involve loud screams and panic;
in extreme cases, it may result in bodily harm or property damage by running about or hitting walls.
All attempts to console the individual are futile and may prolong or intensify the victim’s confused
state. Usually the victim experiences amnesia after the event but it may not be complete amnesia.
Up to 3% of adults suffer from sleep terrors and exhibited behavior of this parasomnia can range
from mild to extremely violent. This is very prevalent in those who suffer violent post-traumatic
stress disorder (P.T.S.D.) They typically occur in stage 3 sleep.

2. Bruxism is a common sleep disorder where the individual grinds their teeth during sleep. This
can cause sleep disruption for the individual and also the bed partner. Grinding can wear and
fracture the teeth, and also cause severe jaw pain. This can lead to migraines, teeth impairment,
temporomandibular joint disorder, and other complications. Many are not aware of their teeth
grinding. Teeth grinding may be caused by stress and anxiety; it could also be caused by a non
typical bite, or missing teeth. Bruxism can sometimes be managed by being fitted with a night
guard. It is advisable to see a Licensed Dentist, Orthodontist, or Oral Surgeon for proper fitting of
the right device(s).

3. Sleepwalking has a prevalence of 1-17% in childhood, with the most frequent occurrences around
the age of eleven to twelve. About 4% of adults experience somnambulism. Normal sleep cycles
include states varying from drowsiness all the way to deep sleep. Every time an individual sleeps,
he or she goes through various sequences of non-REM and REM sleep. Anxiety and fatigue are
usually connected with sleepwalking. For adults, alcohol, sedatives, medications, medical
conditions and mental disorders are all associated with sleepwalking. Sleep walking may involve
sitting up and looking awake when the individual is actually asleep, and getting up and walking
around, moving items or undressing themselves. They will also be confused when waking up or
opening their eyes during sleep. Some individuals also talk while in their sleep, saying meaningless
words and even having arguments with people who are not there.

Somnambulism: A sleeper gets up and walks in the deepest stage of sleep (REM) with enuresis
(urinary incontinence) appearing in stage four of sleep as well.

Sleep/Awakeness Rhythm synchronization disorders in relation to altered day/night environmental

conditions occur with rapid time zone change. In these conditions, lack of coordination of the
internal clock with daylight and night succession leads to fatigue, irritability, somnolence with
difficulties falling asleep- JET-LAG (Time zone change syndrome).
75. Neurovegetative factors in complex conditions

Book of Kovac

The true role of neurovegetative disorder (etiological, etiopathogenetic or compensatory) in these

conditions predominately remain unexplained

Psychosomatic Illnesses: designates complex conditions where mental processes contribute to or

cause functional pathogenetic alterations in body organs, without clearly noticeable
pathoanatomical alterations.

1. Hysterical Syndrome: speechlessness, Bulimia Nervosa, Anorexia Nervosa, Irritable Colon,

Migraine Headaches.
-Also accompanied by dysphagia and sensation of “a lump in the throat” and other paralytic
phenomena. Pathoanatomnical substrate cannot be demonstrated at the time despite severe
2. Loss of Function (Hypothermia- Algorithm)
3. Increase in Functions (Tachycardia, Bradycardia)
4. Chronic Fatigue Syndrome
5. Acute and Chronic stress can contribute to peptic ulcer disease and arterial hypertension
6. Severe forms of tetanus are accompanied by development of Secondary Pandysautonomia
with motor spastic disorders. The toxin that is involved is clostridium tetani.
7. Chronic Fatigue Syndrome: represents a borderline condition of pathophysiological
reactivity where fatigue predominates a basic symptom and diagnosis is based upon
exclusion of potentially related diseases and syndromes.

76.Organ System Dysfunction in Autonomous Innervation Disorders

1. Primary: Consequence of developing disturbances and functional inter-relations within the

neurovegetative system.
a) CENTRAL: Parkinsons Disease (Thieme 334, 354) (Robbins Page 839), Cerebral and
extrapyramidal syndromes, olivopontocerebellar atrophy syndrome
b) PERIPHERAL: Raynaud Syndrome (Robbins 355) (Thieme 258), Hirschprung Disease
(Robbins page 573) (Thieme 168), orthostatic hypertension, autonomic paralysis syndrome
(loss of self-regulation)

2. Secondary: Structural functional disturbances of the neurovegetative system in connection

with other pathogenetic processes which occur in the neurovegetative system

a) Peripheral: due to energetic damages (ischemia, infarct, hypoglycemia), tumour expansions,

loss of continuity in transferring parts of the system, metabolic toxic processes, autoimmune
processes, infective diseases.
Algorithm on myocardial Infarction could be a good idea to discuss here.

We can differentiate between physiological (adaptive) pain and pathological pain.
Physiological pain arises when organism tries to adapt to painful stimuli.Pain that occurs due to
damage of pain perception and consequent disturbances in the processing of pain sensation is
pathological pain.
According to pain pathogenesis we could differentiate 4 groups of pain:
 Nociceptive pain - adaptive pain that occurs due to stimulation of nociceptors by
mechanical force, heat,cold or chemical agents without tissue damage.
 Neuroplastic (inflammatory) pain – pain caused by tissue injury and inflammation
 tissue injury and inflammation are causing significant chemical changes in the
microenvironment of nociceptors
 injured cells release hydrogen and potassium ions,ATP
 inflammatory cells release prostaglandins,leukotrienes,histamine, bradykinin,
cytokines and chemokines...
 hydrogen,ATP and bradykinin act as nociceptor activators
 bradykinin and prostaglandins act as nociceptor sensitisers(↓nociceptor
 sensitized nociceptors actively participate in the creation of an inflammatory
microenvironment by releasing neuropeptides with proinflammatory actions
(substance P, neural growth factor-NGF, calcitonin gene related peptide-CGRP)
 neuropeptides cause vasodilation, ↑capillary permeability→edema, ↑ pian
sensation →neurogenic inflammation
 leukocytes release endogenous opioids that bind to peripheral terminals of
nociceptors resulting in analgesia
 Peripheral sensitization- associated with ac.inflammation, stimulated with
 Central sensitization
 Neuropathic pain – consequence of nervous system damage; pathologic pain
 Peripheral mechanisms of neuropathic pain - changes that occur during injury
of the nociceptive fibers affect both damaged fibers and adjacent undamaged
neurons which then become abnormally sensitive and can spontaneously
 Central mechanisms of neuropathic pain - increased excitability and
spontaneous activity of peripheral nociceptive neurons injured and
uninjured); loss of central inhibition of pain sensation
 Functional pain


 According to pain quality we can distinguish:

 Pulsating pain
a) occurs simultaneously with pulse stroke with resulting increase in hyperdynamic
 Pricking pain
a) superficial, short lasting,sharp pain
b) very well localized
 Cutting pain
a) characteristic for hollow organ penetration in peritonitis
 dull pain
a) arises from joints,bones and muscles
 spasmodic pain
a) occurs during enlargement of hollow organs, muscle stretching
 burning pain
a) arises from mucosal damage

According to pain localization we differentiate:

 Visceral pain
◦ occurs due to stimulation of free nerve terminals in visceral organs
◦ poorly localized, often reffered
◦ accompanied by signs of sympathetic stimulation (more often)
◦ most common causes: hypoxia, inflammation, stretching of muscle wall, serosa
or tunica
◦ outbursts of pain sensation due to the strong contraction of hollow organs during
inflammation or obstruction are called colics
 Parietal pain
◦ occurs as a consequence of internal organ damage (organs with serous
◦ sharp pain, sometimes perceived as burning or dull pain
◦ most sensitve are: liver capsule, parietal pleura,bronchi
 Reffered pain
◦ is pain perceived at a location other than the site of the painful stimulus
◦ this occurs because the branches of visceral pain fibers and fibers that transmit
pain impulses from the skin are connected to the same neurons-viscerosomatic
◦ such pain is reflected on the surface of the body that does not correspond to
topographic position of that organ


Heat is constantly produced in the body through the basal metabolism, thermogenic
hormone stimulated metabolism(catecholamines,thyroid hormones), muscular activity and specific
dynamic effects of ingested nutritients. Heat production and regulation is tightly regulated by
powerful thermoregulatory mechanisms thus maintaining body temp within narrow limits. Daily
temp rhythm involves physiological nocturnal decline of 0.5-0.7 °C in relation to the daily temp.
Temp homeostasis is maintained by regulated changes in tissue heat production and by
regulation of heat transfer between the organism and its enviroment. Hypothalamic
thermoregulatory center is functionally divided into the thermolytic and thermogenic area.
Thermolytic part is anatomically located in the anterior hypothalamus and thermogenic area in
posterior. Thermoregulatory center integrates inbound information from cutaneous thermosensitive
neurons and thermosensitive neurons from anterior hypothalamus to produce corresponding efferent
pathways and signals. Efferent information pattern of the thermolytic area induces cutaneous
vasodilatation,perspiration and reduces metabolic turnover rate. Thermogenic stimulation represents
a pattern of simultaneous increase in metabolic heat production,stimulation of mechanical shivering
and reduced heat dissipation due to cutaneous vasoconstriction.
Perspiration represents the main mechanism of heat dissipation in high ambient temp,
elimination of sweat from the body surface in such conditions represents an aggravating
circumstance.Likewise, if ambient air humidity increases sweating becomes an inefficient
mechanism, due to ceased sweat evaporation. Therefore, high enviromental temp with high air
humidity produce conditions favoring heat stroke development.
Physiologically temp set point in the healthy organism is 36.6-36.8°C. Thermoregulatory
center stimulates cutaneous vasodilatation and sweating even at temp 37.0-37.2°C, while
vasoconstriction ensues at 36.0°C and thermogenesis (by metabolic rate acceleration at first;
followed by shivering) is being stimulated at temp below 36.0°C.
Hypothermia markedly decelerates metabolism while hyperthermia accelerates metabolic
rate.Extreme hypothermia and hyperthermia are followed by denaturation of proteins therefore
potentially causing irreversible changes to the organism.Temp point of physiological irreversibility
is approximately 43.7°C.

Hyperthermia is a state of elevated body temp in homeotherms. It can result from
thermoregulatory center set-point increase to a higher level,as in fever, or from a disordered
relationship between heat production and heat release from the organism.
 Hyperthermia due to excessive ambient temp
 In hyperthermia caused by external factors, major role is played by elevated enviromental
temp and all of conditions which impair body temp release, such as dysfunction of sweat
glands or increased air humidity. Thermoregulatory center thermostat (set-point) does not
change in the process(stays on the normothermic level). When thermoregulatory function is
impaired due to hyperthermia thermoregulatory mechanisms fail and further detoriate the
initial disorder.
 Heat exhaustion
 It can be provoked by moderate dehydration and salt loss.Symptoms include
tiredness,hypotension and elevated body temp. In non-acclimatized individuals
excessive perspiration can lead to profound dehydration.Fluid loss directly affects the
thermoregulatory center by adjusting hypothalamic thermostat on the febrile level.; fluid
loss will reduce further sweating. Both events will result in body temp increase.
Peripheral vasodilatation ensues as a compensatory reaction and along with dehydration
increases tendency towards hemodynamic shock. Acclimatization significantly reduces
salt loss.
 Heat convulsions/cramps
 Beside high ambient temp important role in pathogenesis of convulsions is played by the
muscle work.
 Strong activation of thermoregulatory mechanisms causes intense perspiration with
consequential fluid and salt loss. Loss of salt from extracellular fluid decreases osmotic
pressure thus causing cell swelling.
 Intracellular edema in the CNS lowers the excitability threshold, potentially resulting in
convulsions which additionally increase body temp.
 It is prophylactically very important to substitute salt along with fluid loss.
 Heat stroke
 the most serious condition that can proceed from disturbed thermoregulatory
 when hypothalamus overheats due to elevated ambient temp thermoregulatory center
gets damaged resulting in impaired regulation of heat production and release
(uncontrolled hyperthermia)
 sweat glands cease to function
 hyperthermic state develops at 42-44°C
 elevated body temp accelerates metabolic processes resulting in increased heat
production (viscious circle)
 predominantly damages brain cells; hepatic,renal and cutaneous cells are also affected
 petechial bleeding,parenchymal degeneration,,anxiety, restlessness, dry warm hot and
red skin,syncope,delirium,convulsions,coma
 death ensues due to respiratory and vasomotor failure
 caution is necessary during cooling procedure in order to avoid vasoconstriction
 survivors sometimes suffer from permanent damage in the form of dementia, motor and
sensory deficits
 Sunstroke
 cumulative effect of generalized hyperthermia and local irradiation by infrared rays upon
unprotected occipital head area
 thermic rays cause vasodilatation and increased vascular permeability in meningial
membranes and brain, potentially resulting in edema and bleeding
 clinically characterized by hyperthermia,unconsciousness, ocasionally coma with
potentially lethal outcome
 Thermogenic anhidrosis: appears in acclimatized individuals, follows after sweat gland
excretory duct obstruction
Fever is a state of increased body temp in homeotherms. Thermoregulatory center set point
is tuned to a higher level accompained with increased heat production and decreased heat release.
Increased body temp requests big increase of additional heat production within a short time which is
metabolically very demanding. Upon termination of the fever heat is released and profuse sweating
Fever predominantly accompanies infectious diseases but can also appear in allergies,
physical and chemical injuries of the organism. Can be caused by various factors, commonly named
exogenous pyrogens.Apart from them it can be caused by microorganisms and endogenous
processes in the organism.
Fever predominantly develops due to endogenous pyrogen effect on the thermoregulatory
center. Endogenous pyrogens (IL-1,IL-6,TNF-α) are produced in cells either spontaneously or upon
stimulation by exogenous pyrogens. IL-1,IL-6 and TNF-α affect thermoregulatory center in

hypothalamus. IL-1 and TNF-α induce protein catabolism in muscles, induce prostaglandin E2
synthesis in the thermoregulatory center (adjusting thermoregulator sensitivity onto higher set
Type of fever Molecular and cellular mechanism in fever development
 Components or secretions of exogenous organisms stimulate
production and release of IL-1 in monocyte lineage and neutrophil
cells in the organism, which shift thermoregulatory set point to a
higher level,mediated by prostaglandins E1 and E2. This mechanism
is common to multitude of intracellular,extracellular microbes and
parasites. Quantty of excreted endogenous pyrogens reflects a degree
of stimulation and clinical properties of fever. (e.g. fever periodicity
in malaria)
 Variety of noninfectious conditions which commonly manifest by in
vivo formation of antigen-antibody complexes.Phagocytozed
INFLAMMATORY ASEPTIC complexes induce secretion of ndogenous pyrogens in macrophages.
(non-infectious)  associated with serum sickness, post-transfusion reactions and
autoimmune diseases( rheumatoid fever, rheumatoid arthritis) and
granulomatous disorders (sarcoidosis, Chron)
 Certain tumor cells directly secrete endogenous pyrogens thus
causing fever(Hodgkin and non-Hodgkin lymphoma)
 remanents of necrotic tumor cells cause secretion of IL-1 in
macrophages and thereby fever
 Decay and resorption of tissues in the organism cause fever by
monocyte stimulation and secretion of endogenous pyrogens. Such
RESORPTIVE conditions are seen in surgical procedures, cytostatic
therapy,ionizing radiation, massive tissue infarcts and spontaneous
tissue necrosis.
 Thermoregulatory center dysfunction due to pathological changes in
the hypothalamus, and also due to certain psychiatric disorders without
DYSREGULATORY any pathoanatomical substrate (encephalitis,tumor,hemorrhage,
anorexia nervosa). Integrative function of the thermoregulatory center
is impaired
 Medical procedures and patient management ocacsionally result in
fever (vaccination,TCAs,methyldopa,bleomycin,anticholinergic,
MEDICAMENTOUS (iatrogenic)
interferonsympathomimetic overdose, hyperosmolar fluid

FIG.14-7 schematically describes pathogenetic stages in development of fever.Endogenous

pyrogen effect increases thermoregulatory center set pointwhile the actual body temp at the moment
is below that newly adjusted value which strongly stimulates thermogenic mechanisms.
Described stage of body temp increase is reffered to as the stadium incrementi.Case of
sudden temp increase can be accompanied by shivering (chills).It can not be ameliorated by warm
blankets since the reaction is caused directly from the thermoregulatory center and not by
stimulation of surface thermoreceptors.
When body temp reaches the set level defined by the thermoregulatory system, balance
between heat production and dissipation arises ( on the higher level than in normothermia). That
stage is called stadium acmes/fastigum (peek).
In the third stage, stadium decrementi (weakening,decrease) effect of causative factor that
has increased thermoregulatory center set point stops affecting it. Level of the hermoregulatory
center adjustment has been restored into the normothermic range,therefore activating mechanisms
for increased heat loss.
Temp decrease can be gradual (lysis) or sudden(crisis). Vasodilation enables agumented
conduction, convection and heat radiation while abundant perspiration enables water evaporation
from the body surface.

***Don't forget the table from the previous question with pathogenic types of fever

With respect to body temp alterations, we distinguish several types of clinical fever:
 Febris continua (continuous,constant fever)
◦ oscillations between morning and noctural temp are less than 1ºC
◦ miliary TB, pneumococcal pneumonia, abdominal typhus
 Febris remittens (recurrent fever)
◦ daily oscillations exceed 1ºC but without afebrile periods
◦ bronchopneumonia,sepsis
 Febris intermittens (intermittent fever)
◦ daily oscillations exceed 1ºC; daily temp minimum is 37ºC
◦ alternate periods of afebrile and febrile values
◦ septic conditions or malaria where periods of chills and shivering coincide with parasitic
developmental cycle
 Subfebrile fevers
◦ hyperthermias with body temp of approximately 37.5ºC

Hypothermia is a state of decreased body temp in homeothermic organism. It can develop
acidentally or as a result of some pathological process in the organism.HYpothermia can result from
intentional inhibition of thermoregulatory mechanisms followed by exposure to low temp (artificial
 Accidental hypothermia
 It develops in absence of prior thermoregulatory center impairment usually with
low enviromental temp.
 It is mostly seen in neglected newborns due to relatively large body surface area
in relation to their mass, poor development of subcutaneous fatty tissue and weak
muscles.It can also develop in immobilized adults, drug users, alcoholics,
unconcious individuals and in young adults as a consequence of winter sport
 distinct form is immersion hypothermia- shipwreck, sinking through the ice
 develops due to increased heat conduction
 Induced hypothermia
 results from exposing homeotherms to low temp
 cooling can be superficial or deep(internal)
 in superficial cooling organism is exposed to cold air, immersed in icy water or
wrapped in ice
 deep cooling is achived by cooling blood through extracorporeal circulation by
administration of cold solutions into the body cavities
 Pharmacological substances can attain pharmacological blockage which causes
arest of thermoregulatory mechanisms.Together with low ambient temp body
temp will drop significantly.That condition is called pharmacological
hibernation. In clinical operative conditions hypothermia of 20ºC or less can be
applied (metabolic rate reduces for approximately four times). Such hypothermic
organism more easily endures hypoxic conditions.
 Effects of hypothermia on body functions:
 Ambient temp decrease in homeothermic organisms induces a chain of reactions
following Arndt-Shultz law (weak stimuli enhance,moderate stimuli inhibit,
strong stimuli arrest function). In humans temp decrease up to 35ºC enhance
physiological functions; at temp range between 30-35ºC functions are inhibited;
while temp range of 25-30ºC represents a critical zone for normal course of vital
 On the cellular level central hypothermia induces overexpression of cellular
stress proteins, stimulates apoptosis and necrosis in some cells. Overexpression
of stress proteins mostly provides a protective role; while cell death contributes
to functional loss in hypothermic syndrome.
 If thermoregulatory mechanisms have not been altered artificially or by
pathological process homeothermic organisms that have been exposed to cold
experience three phases:phase of maximal metabolism,phasse of minimal
resistance or passivity and the paralytic phase.
 Phase of maximal metabolism – at the onset of body temp decrease all
neuroendocrine defense mechanisms are being strongly activated. This phase is
also called active contra-reaction (characterized by maximal thermogenic
metabolic effect due to activation of hypothalamus-pituitary and sympathetic
system). Catecholamines and thyroxin accelerate metabolic processes
accompained by increased cardiovascular and respiratory activity (increased
stroke volume,improved organ perfusion,increased respiratory rate) with
coldness polyuria.Glycogen hepatic reserves are mobilized yet patient has
hypoglycemia as a reflection of increased glucose utilization.
 Phase of minimal resistance – characterized by passivity of defense mechanisms.
It develops after initial phase in case of further body temp decrease. At
approximately 34ºC hypothalamus partially loses its thermoregulatory capacity;
below 30ºC its regulatory function ceases. During this phase energy need of the
organism is on its lowest point and oxygen consumption is decreased – this
phenomenon is called temp coefficient inversion.
 Paralytic phase -exceeded energy demand causes functional disorders (critical
hypothermic conditions – critical temp)
 Hypothermia causes denaturation of tissue and serum proteins resulting in
increased plasma viscosity and hematocrit, reduced tissue perfusion. Since
hypothermia shifts hemoglobin dissociation curve to the left (affinity increases)
oxygen release in hypoperfused organism additionally decreases.
 Temp at which particular function stops is called physiological zero of that
 definite cause of death can be CNS arrest with inability of oxygen utilization,
respiratory center failure,cerebral edema, ventricular fibrillation or disorders of
microcirculation. Increased viscosity, hemoconcetration and intravascular
erythrocyte aggregation render tissue perfusion inappropriate thus contributing to
development of acidosis.

Immune reaction is a dominant and the strongest line of organism defense from disease. It
encompases the capacity of antibody and lymphocyte production that specifically attack invading
agents. Besides specificity of recognition of non-self, the difference between specific and non-
specific defense mechanisms lies in capability of the specific ones to "remember" antigen
encounter and to react strongly against it in the following contact.
Specific immune reaction has a physiological capacity for clonal proliferation, biological
recollection of preceding events and agumented capability of focuded response in repetitive
reactions (increased antibody and receptor affinity, accelerated response rate and quantitative
amplification of a reaction). Such nature of the immune reactivity provides a powerful protective
defense mechanism. During infections and infestations microorganisms multiply in body
compartments thus forming a mass which soon renders unspecific defense inefficient enabling
foreign pathogens to spread to other body compartments and tissues. Since MO divide rapidly their
growth in body compartments become exponential in favorable conditions; at the same time that
agumented mass gains additional virulence. Specific immune reaction has a task to inhibit their
growth and eliminate them from the body through its self-expansion directed against dominant MO
antigens. By mnestic (memorized) microbial recollection in repeated encounter the strength of host
selective response eliminates MO even in subclinical course of potential infections therefore the
host does not manifest disease. This phenomenon underlies powerful mechanisms in vaccination.
According to molecular-cellular mechanisms of reactivity immune response can be divided

into innate and adaptive immunoreactivity. Adaptive immunity has high specificity for recognition
of minimal antigenic differences while innate specificity stays limited to several generic groups of
microbial components( structural components in common to numerous MO). Both types of
immunity synergize with inflammatory reaction mechanisms through mutual cytokines.
Innate immunity encompasses numerous cellular and molecular mechanisms with the
capacity of exponential response amplification and recognition of MO components.These microbial
components are of the polysaccharide or lipopolysaccharide composition. Amplified reactivity is
achived through the hepatocyte acute-phase response, complement amplification and recruitment of
monocyte and granulocyte lineage cells. Neither αβ T lymphocytes, B lymphocytes nor antibodies
participate in the innate immunity. Primary biological role of such form of immunity is to reduce
MO quantity and toxic derivatives in a short period of time.
The basis of acquired immunity underlies complex lymphocyte activation, differention and
recirculation predominantly directed against protein antigens. Reaction inatiation requires immune
processing and immune presentation associated with HLA molecules while receptor specificity is
formed through recombination and somatic mutations of the original V,D and J genes. Beside
receptor signal a prerequisite for activation is interaction through another signal pathway
(CD28:B7) between lymphocytes and antigen presenting cells. In the first encounter with new
antigen (primary immunization) recognition processes, cellular recruitment and tissue infiltration,
cell division and differentiation occur in several days time (4-10 days). Acquired immunity has a
capacity of biological memory for specific antigen determinants as a basis of more permanent
protection and vaccination against particular MO. Acquired immunity recognizes microbial
antigens (as does innate), other exogenous antigens, antigens of own altered tissue and tumor
antigens. Very high specificity of acquired immunity manifests in recognition of differences in one
aminoacid or hapten modification inside residues of endogenous proteins.


Recognition of appertaining immunogenic complex by immune presenting cells stimulates
CD4+ αβ T lymphocytes on proliferation and differentiation. Multiplication produces clones of
identical lymphocytes which stimulate differentiation in humoral and effector arm of adaptive
immunity through intracellular contacts and secreted cytokines. According to the cytokines
secreted, helper effect can be divided into two functional patterns: Th1 (T helper) pattern which
includes cytokines IL-2,TNF-α, INF-γ and Th2 pattern comprised of IL-4,IL-5,IL-6,IL-10,IL-13.
Th1 pattern is sometimes referred to as type I response and Th2 as type II response. Cytokine
dichotomy has profound functional repercussion to the biological nature of immune reactivity and
pathogenetic mechanisms in a significant group of disorders. Fig.15-6 schematically represents
differentiation effects of two helper patterns. In a physiological immune response, protective
adaptive immunity is principally attained by Th1 type reactivity pattern, with production of
protective antibodies and cytotoxic T lypmhocytes. Accordingly in such mode of reactivity
vaccination achives its protective role. Fig.15-6 shows isotypic switch to IgE antibodies in B
lymphocytes, as a result of Th2 helper effect, which contributes to development of IgE
hypergammaglobulinemia. Cytokines IL-4,IL-5, IL-10 contribute to increased eosinophil count in
tissues and eosinophilia, with concomitantly increased mastocyte quantity. These cellular and
humoral alterations are in common to a vast group of atopic disorders. Pathogenesis of these
disorders involves prevalence of the helper Th2 type pattern.
Although a certain degree of Th2 response activity is important for Blymphocyte
differentiation, there is active reciprocal inhibition between the two helper patterns. IFN-γ directly
inhibits CD4+ T lymphocytes of the Th2 response.Conversely,IL-4 cytokine of the Th2 type
response directly inhibits Th1 type response. In response to new immunogenic complex, helper
lymphocytes compete for prevalence of "their" mode of reactivity. Fig.15-7 schematically
represents that regulatory interrelation.In primary contact with an immunogenic complex CD4+ αβ
T lymphocytes are directed by the microenviroment towards one of the reactivity modes. In case of
IL-12 domination in the microenviroment,differentiation towards Th1 response will ensue, with
resulting development of protective immunity. In case of microenviromental prevalence of IL-4 or
IL-10 αβ T lymphocytes will be directed towards Th2 type of helper pattern. Shift towards Th1
response prevails in the healthy organism.

Minor or greater partial dysfunction and the complete loss of specific immune reactions
manifest in particular immunodeficiency syndromes.These syndromes regularly comprise
susceptibility for infections, states of incomplete curation and ocasionally more frequent appearance
of neoplastic disorders, as components of their own pathogenesis and clinical picture. In general
symptoms and signs of idsease are defined by a degree of deficiency and specificity of the
insufficient segment in specific immune reaction.
According to the dominant pathogenic process in immune cell linage, immunodeficiencies
can be categorized as humoral, cellular or combined. Cellular immunodeficiency designates
nosogenous T lymphocyte dysfunctions manifest on any cell subtype (CD4+,CD8+,helper
lymphocytes) while the term humoral immunodeficiency designates not only serum disorders but B
lymphocyte dysfunction as well.
Primary immunodeficiencies- (ocassionaly referred to as congenital) are qualitative and
quantitative immune response disorders due to genetic and developmental impairment of B and T
lymphocytes.Such disorders selectively affect particular immune tissues and cells.
Secondary immunodeficiencies - (also reffered to as adaptive or acquired) are syndromes
occuring due to independent pathogenetic processes in other tissues that cause specific immunity


Autoimmunity is a state of organism failure to distuinguish slef from non-self; it exchanges
own for the foreign in the process and directs immune reactivity against it. One should discern
autoimmunity from autoimmune disease. Autoimmunity implies signs of immune recognition and
reactivity against self antigens (e.g.presence of autoantibodies) while autoimmune disease
represents a pathological condition initiated by an autoimmune process.
All autoimmune diseases are Th1 type, with effector arm mediated by cytotoxic autoreactive
CD8+ Tlymphocytes, autoantibodies,cytokine and other mediator mechanisms (complement
activation,stimulated inflammatory activity...). Destruction of own parenchymatous cells induces
secondary inflammatory processes and fibrosis, which contribute to diminished reactivity of
functional systems(latent and manifest insufficiency).
Mechanisms of autoimmunity:
The state of self tolerance or unreactivity to own antigens is normally being maintained in
the organism. Disruption of that tolerance designates onset of autoimmunity. Tolerance is usually
maintained on the basis of elimination or inactivation of lymphocyte clones specific to self
antigens.Phenomenon of reactivity to one's own therefore designates appearance or activation of
autoreactive lymphocytes.Such undesired activation can result from multiple mechanisms.

1.Absence of immune tolerance:

Lymphocyte tolerance to antigens of one's own organism develops due to a constant release of body
antigens into circulation where they inhibit newly synthesized lymphocytes specific to themselves.
It is not known why T lymphocytes are so much more sensitive to stimuli that induce immune
tolerance as opposed to B lymphocytes. The difference is nicely ilustrated by the following
example: in an appropriate experimental system T lymphocyte tolerance can be induced in 24 hours,
however it takes 15 to 20 days to develop B lymphocyte tolerance in the same system.In addition, T
lymphocyte tolerance lasts for 100 days while B lymphocyte tolerance is only short lasting. Even
when induced by high antigen doses, B lymphocyte tolerance is only transient and seldom
complete. In a normal organism, numerous autoantigens circulate through bodily fluids in very low
concetrations. These are thyroglobulin,protein hormones and various soluble membrane antigens. In
such low conc they maintain only T lymphocyte but no B lymphocyte anergy. The obstacle for
development of autoimmunity against majority of body antigens is not in B lymphocytes since
autoreactive B lymphocytes normally persist, but in autoreactive T lymphocytes that are either
absent or inactivated beyond detection in normal conditions. However, that withal means that any
kind of B lymphocyte activation through helper T lymphocytes could result in B lymphocyte-
mediated autoimmunity. Evasion of unreactive T lymphocytes in mechanisms of autoimmunity is
based on renowned fact that in reaction to a certain antigen, T and B lymphocytes cooperate in a
way that T lymphocytes recognize carrier epitope on that antigen while B lymphocyte detect
hapten epitope. Antibodies are produced against the hapten part of that antigen. Autoantibody
production against epitopes of one's own organism is based on T lymphocyte activation by a foreign
carrier that has for any reason bound to a certain self epitope-hapten. Foreign carrier activates
specific T lymphocytes while they activate (preexisting) B lymphocytes specific to epitopes of
own organism.

2.Autoantigen change
Autoantigen damage can alter antigen structure of certain molecules and enable T lymphocyte
stimulation.It is also possible that partial degradation reveals certain epitopes usually not accessible
to T lymphocytes, that would consequentialy stimulate pre-existent yet inactive T lymphocyte
clones that carry receptors for such epitopes. That mechanism of autoimmunity is attributed by
appearance of rheumatoid factor-like antiglobulin in many types of infections and initiation of
Goodpasture's syndrome. Target autoantigens are considered to be incompletely degraded or altered
Ig produced in reaction against infectious agents.

3.Immunoregulatory disorders
Animal experiments indicate that autoimmunity can arise from disordered regulation of immune
response. Cytokine mediated feedback control loops are formed between Th1 and Th2
lymphocytes. For example, through secretion of IL-4 and IL-10 cytokines, Th2 lymphocytes
repress Th1 lymphocyte activity and vice versa – Th1 lymphocytes mediated by INF-γ and IL-12
suppress Th2 lymphocyte activity.That is way appropriate immune response depends upon the
balance between activities of these two lymphocyte subtypes, although other cells participate in
immune regulation as well, through secretion of their cytokines.

88. Immune Hypersensitivity

Review Robbins (page 109-120) Dont forget to look at the charts!

Review Thieme (56-59)

See some charts to help put it all together (next page):

89. Immuno-Pathogenetic role of HLA system. Immune relations in pregnancy

Review Robbins Page 100-103, Thieme Page 60

Graft Rejection:Any cell displaying some other HLA type is “non-self” and is an invader resulting
in the rejection of the tissue baring those cells. Because of the importance of HLA in
transplantation, the HLA loci are among the most frequently typed by serology or PCR relative to
any other autosomal alleles.

In Autoimmunity: HLA types are inherited, and some of them are connected with autoimmune
disorders and others diseases
1. SLE (Robbins 125)
2. Type I Diabetes
3. Sjorgren’s Syndrome (Robbins 131)
4. Celiac Diseases (Robbins 578)
5. Ankylosing Spondylitis
Immune tolerance in pregnancy or gestational/maternal immune tolerance is the absence of a
maternal immune response against the fetus and placenta,which thus may be viewed as unusually
successful allografts, since they genetically differ from the mother. In the same way, many cases of
spontaneous abortion may be described in the same way as maternal transplant rejection. It is
studied within the field of reproductive immunology.

Placental transfer of maternal IgG antibodies to the fetus is an important mechanism that provides
protection to the infant while his/her humoral response is inefficient. IgG is the only antibody class
that significantly crosses the human placenta. This crossing is mediated by FcRn expressed on
syncytiotrophoblast cells. There is evidence that IgG transfer depends on the following: (i) maternal
levels of total IgG and specific antibodies, (ii) gestational age, (iii) placental integrity, (iv) IgG
subclass, and (v) nature of antigen, being more intense for thymus-dependent ones. These features
represent the basis for maternal immunization strategies aimed at protecting newborns against
neonatal and infantile infectious diseases. In some situations, such as mothers with primary
immunodeficiencies, exogenous IgG acquired by intravenous immunoglobulin therapy crosses the
placenta in similar patterns to endogenous immunoglobulins and may also protect the offspring
from infections in early life. Inversely, harmful autoantibodies may cross the placenta and cause
transitory autoimmune disease in the neonate.

The Eutherian Fetoembryonic Defense System(eu-FEDS) is a hypothetical model describing a

method by which immune systems are capable of recognizing additional states of relatedness like
“own species” such as is observed in maternal tolerance of a related fetus.

Implied Immunopathogenic Mechanisms in Pregnancy: Reccurrent spontaneous miscarriage-

reduced ability to turn on the Th2 response and enhanced Th1 response which causes increased
rejection risk of embryo by the pregnant woman.

90.Tissue Transplantation Reactions and Graft Rejection

Robbins Page 135-139

Book of Kovac:
Tissue and Organ Transplantation: are effective treament options for patients suffering from chronic
failure of tissues, organs or organ systems.

Successful Transplantation holds several advantages over conservatively treated patients. These
include better quality of life, more independence and improved lifespan.
ALLOREACTIVITY/ALLOIMMUNITY: is a condition in which the body gains immunity from
another individual of the same species against its own cells.
Alloimmunity should not be confused with AUTOimmunity, in which the bodys immune
system attacks its own cells, without being provoked or influence by sustances or cells from another
member of the same species.
Antigen: any substance that is antibody generating and or is recognized by the immune
Alloantigen/Isoantigen: is an antigenic substance present in some members of a species and
capable of stimulating antibody production in those members of the same species that lack it.
Examples: MHC, HLA

“BYSTANDER LEUKOCYTE EFFECT”: Mixture of cells in a transplant, whereby some carry

class I antigens and others class II, is going to cause strong reaction and rapid rejection. It has been
demonstrated that leukocyte presence in an organ transplant (renal) facilitates rejection of that
organ. Leaukocytes are very rich in class II alloantigens (unlikely kidney), so these leukocyte
antigens augment reaction against renal class I alloantigens through stimulation of host helper T

HVGR: Host versus graft reaction: Foreign HLA molecule allomorphs on transplant cells become
target molecules of the host immune response

GVHR: Graft versus host reaction: transferred immunocompetent graft cells attack the host.

91.Pathophysiology of the Acute Inflammatory Reaction

Kovac's book:

General properties of local inflammation are described by classical signs and symptoms of

Latin: inflammatio and in Greek (latinized phlogosis) [haha -.-’ ]

This phenomena originates from the potent oxidative metabolism with the inflamed tissue, in
neutrophils and macrophages. (Review Robbins Oxidative Metabolism, ROS chapter 2)

Basic Reactive Pattern of Acute Local Inflammation:

1. Infiltration with proinflammatory mechanisms and their stimulation

2. activation of biochemical amplifying proinflammatory mechanisms
3. alterations in vascular permeability and resistance
4. more or less altered tissue architecture with changed function of the inflammed tissue

Cellular Inflammatory Dynamics: Granulocyte infiltration dominates for the first ten days, among
which neutrophil tissue infiltration prevails. During the second week of inflammation, share of
monocyte lineage and lumphocytes increases, designating development of the specific immune
response, while increased proportion of fibroblasts and endothelial cells designates healing
processes. Vascular endothelium acively participates in the process of neutorphilic infiltration
guided by local chemotactic factors with increased quantity and activation of key adhesion

Review Chapter 2 in Robbins

92.Etiology of the Inflammation

Book of Kovac:
Many causes of inflammation exist in the world that can be separated into two main groups:

Exogenous Noxae:
1. Infection/Infestation
2. Ionization Radiation
3. UV radiation
4. Thermal Radiation
5. Mechanical Trauma
6. Chemical Noxae
7. Iatrogenic Noxae
8. Foreign Bodies

Algorithm on Burns is also a good one.

Endogenous Noxae:
1. Necrotic cell death
2. Immune Reaction
3. Tissue Ischemia
4. Increased endogenous production of radicals
5. Obstruction of Hollow Organs
6. Neurogenic Inflammation
7. Excess of endogenous substances and Metabolites
8. Disorders of body compartments

Chapters 1 and 2 of Robbins.

93. Mechanism of the Vascular and Cellular Reaction

Review Robbins Chapter 2

Steps in Inflammation

Vascular changes: Fluid Leakage

More Vascular changes

ProInflammatory Factors and AntiInflammatory Factors

Formation of Prostaglandins and Leukotrienes are good to explain here as well.
Previous questions can also be used here.
Histamine role
Serotonin Role
Nitric Oxide

94.Chemical Mediators of the Acute Inflammatory Reaction

Same as previous question (Robbins Chapter 2 is a big chapter for many questions)

95.Relationship Between Pro-Inflammatory and Anti-Inflammatory Processes

Protease Inhibitors: are plasmic proteins which quantitatively constitute the third largest
functional group of plasma proteins, following albumin and immunoglobulins. All of these
constitute acute phase proteins. Protease inhibitors base their plurispecificity on a common
structural motif in a critical inhibitory part of the molecule. Inhibition is based on stechiometric,
almost permanent binding of inhibitor to the enzyme followed by annihilating enzymatic effect on

Deficiency of certain protease inhibitors:

-alpha 1- antitripsin deficiency (A1AT-deficiency): due to increased activity of neutrophil elastase,

elastin degradation in tissue structure gradually results in pulmonary emphysema. Some forms of
mutated inhibitor precipitate in hepatocytes cause liver cirrhosis.
-Anticytokines: are a group of soluble proteins with specific affinity for particular cytokines,
referred to as cytokine binding proteins. They belong to Immunoglobulins and soluble cellular
receptors for certain cytokines.
Activation of apoptosis in proinflammatory cells decreases severity of inflammation.
Hypercortisolemia acts as a direct activator of apoptosis in lymphocytes and esosinophils, thereby
acting in immunosuppressive and anti-inflammatory manner. Accordingly, hypoenergosis, hypoxia,
TNF-alpha, IL-4, IL-10 can cause apoptosis. Potential contribution of these processes to the anti-
inflammatory action has only partially been investigated.

-Antiendotoxins: have high affinity for LPS and lipid A. Responsible for their binding-mediated
elimination from the ECS.

-Antioxidant Systems: Vitamins A, K, C, E. Reduce Oxidative stress

96.Integral Acute-Phase Response and Multiple Organ Failure

Kovac's Book

Acute phase response proceeds according to a general stress response pattern; from such point of
view we can observe systemic adaptive reactions as a phase of general adaptation or general
adaptation syndrome (GAS)

Acute Phase Response Involves:

1. Acute phase response of the central nervous system
2. hepatic acute phase response
3. fever
4. catabolic reaction
5. acceleration of energy metabolism
6. secondary alterations in particular functional systems

The central role in initiation of acute phase response is played by cytokines TNF-alpha, IL-1, IL-6

Central nervous system accordingly rearranges its own efferent humoral information which
involves hyperprolactinemia, hypercorticoliberinemia, hypervasopressinemia,
hypercorticotropinemia, hypogonadotropinemia.

Acute phase response of the central nervous system directly causes patients behavioural changes,
like sensation of illness, reduced work readiness, reduced work efficacy, sensation of exhaustion
and prostration, accompanied by reduced food intake.

The book has some diagrams relating to stress so algorithm on stress may be useful as well as
cushings syndrome (cortisol=stress hormone)


Stress response and acute phase response to tissue injury (trauma) or infection represent a sum of
interconnected systemic reactions which enable healing in the injured area, elimination of infective
agents and integral organismic recovery.
Numerous cytokine-mediated reactions also possess positive Feedback Mechanisms which increase
production of numerous proinflammatory mediators. This possibility is also present on the
molecular regulatory level controlling production of proinflammatory cytokines and other proinflam

SIRS (systemic inflammatory response): Inflammatory processes loose their biological

purposefulness and processes become predom. noxious. Inflammation turns into a horror
autotoxicus, which in clinical manifestation represents a very severe condition with frequently
lethal outcome.

Algorithm of Sepsis is good here.

Algorithm of Hypovolemic Shock as well

MODS: previously known as multiple organ failure (MOF), is altered organ function in an acutely
ill patient requiring medical intervention to achieve homeostasis.

97. Pathophysiology of the Chronic Inflammation and Fibrosis. Healing Processes

Dominated by fibroblasts, endothelial cells, monocytes and lymphocytes that form the histological
image of granulations or granuloma.

1. Persistency of noxa
2. Lack or deficiency of anti-inflammatory processes
3. Primarily diffuse noxious noxa (radiation)
4. Abnormal stimulation of certain inflammatory elements (eosinophils)
5. Persistence of autoimmune (Rheumatologic Disorders) or alloreactive processes (GVHD)
Robbins Page 53-56
Robbins Page 69-72

Basically all of chapter 2 is important.

98.Basic Disorders in the Hemodynamic Shock

Algorithm of Cardiogenic circulatory shock (Problem 67).

The clinical definition of cardiogenic shock is decreased cardiac output and evidence of tissue
hypoxia in the presence of adequate intravascular volume. Cardiogenic shock is the leading cause of
death in acute MI, with mortality rates of up to 70-90% .

Signs and symptoms

The diagnosis of cardiogenic shock can sometimes be made at the bedside by observing the
• Hypotension
• Absence of hypovolemia
• Clinical signs of poor tissue perfusion (ie, oliguria, cyanosis, cool extremities, altered

Findings on physical examination include the following:

• Skin is usually ashen or cyanotic and cool; extremities are mottled
• Peripheral pulses are rapid and faint and may be irregular if arrhythmias are present
• Jugular venous distention and crackles in the lungs are usually (but not always) present;
peripheral edema also may be present
• Heart sounds are usually distant, and third and fourth heart sounds may be present
• The pulse pressure may be low, and patients are usually tachycardic
• Patients show signs of hypoperfusion, such as altered mental status and decreased urine output
• Ultimately, patients develop systemic hypotension (ie, systolic blood pressure below 90 mm
Hg or a decrease in mean blood pressure by 30 mm Hg)


Circulatory shock can occur as a result of three pathogenetically diverse groups of
disorders:loss of cardiac function, loss of tonic adaptability of the vascular tree with maintained
anatomical integrity and by compensable loss of blood volume. Therefore we discern
cardiogenic,vasohypotonic and hypovolemic shock. Each results in reduced AV pressure gradient
through redduced arterial, agumented venous pressure or alterations in both pressures
simultaneously. Measurments of these pressures (arterial,venous,pulmonary,arteriolar) are crucial in
assessment of the clinical state of the patient.

Cardiogenic shock
It occurs in conditions of sudden decline in cardiac work thus producing insufficient arteriovenous
pressure gradient. Alterations in myocardium,cardiac valves, pericardium and great blood vessels
could directly or indirectly reduce mechanical cardiac workload, up to the clinical manifestation of
shock. That condition displays significantly decreased surface area of the cardiac workload curve
while resulting AV pressure gradient produces systemic tissue hypoperfusion according to the
Q(flow)=ΔP/R(resistance). All types of cardiogenic shock menifest as extensive cardiac output
decrease with venous preload increase.
Decreased heart muscle contractility, diastolic dysfunction or asynchronous work of cardiac areas
result in loss of a sufficient AV gradient. Due to insufficient production of the AV pressure gradient
adaptive mechanisms become less efficient thus accelerating natural disease course towards
multisystem failure and death.

Vasohypotonic shock
It pathogenetically represent irregular vascular adaptation to the containing volume therefore causin
loss of AV pressure gradient despite normal cardiac function and maintained volume of blood.
Cardiac output(CO) increase results from increased venous return due to the lowered peripheral
resistance. Despite increased CO arterial pressure is low and venous increased. Contents of blood
within veins simultaneously increase due to tonus reduction.Both mechanisms, systemic resistance
decrease and decreased blood vessel tonus act directly against adaptive vasomotor
responses,thereby reducing their efficiacy.
Neurogenic,septic and anaphylactic shock reduce tonic vascular adaptability through diverse

Hypovolemic shock
It results from the loss of circulating blood below vascular system adaptability.Volume decrease
exceeding approximately 35% (below 36-39ml/kg of body mass) causes vascular inability to adapt
even with maximal contraction of its muscular layer; therefore even venous pressures decrease
below normal.


The basic property of circulatory shock is multiple organ system failure.Circulatory shock
manifestation on certain organs reflects the common pathogenesis of shock.Due to retarded blood
flow(especially in microvasculature),increased hematocrit, erythrocyte aggregation and activation
of coagulation system(as in septic shock) as well as accumulation of thrombocytes on sites of
damaged capillary endothelium coagulation system is being activated which manifests in
disseminated intravascular coagulation. That kind of coagulation leads to consumptive
coagulopathy which manifests as bleeding into tissues.Depending on the stage of shock
pathoanatomical picture will involve all forms of bleeding and coagulation.The kidney undergoes
prerenal acute failure which can propagate towards the chronic failure due to cell loss. Cerebral
dysfunction manifests in consciousness impairment, ranging from somnolence to coma. Cell death
ensues from prolonged cerebral hypoenergosis and can selectivly result in permanent loss of
function in telencephalic areas (also called decerebration). Following circulatory restoration patients
almost regularly display short term memory loss for events just preceding and accompanying shock
development.The amnestic condition results from hypoenergosis. Decompensated stage of
circulatory shock manifests as strong vasoconstriction in lungs as a response to hypoxemia and
endothelial damage thus causing noncardiogenic pulmonary edema (ARDS). Pathoanatomical

picture shows edema,atelectatic alveoli, numerous microvascular microthrombi and bleeding –
called shock lungs. Gastric and intestinal mucosa rapidly develops hypoenergosis even in the
compensated stage due to circulatory centralization.Therefore superficial damage in the form of
hemorrhagic ulcers can develop quickly.Intravascular coagulation can result in necrosis of the
entire intestinal wall. Due to centralization of the circulation liver losses majority of its blood flow.
Liver dysfunction is followed by necrosis that develops first in centrilobular hepatocytes.


Compensated stage:
Maintenance of the AV pressure gradient stands under powerful regulation of multiple
homeostatic mechanisms.Their response ensures compensated stage of circulatory shock, whereby
organ function is being maintained by utilization of the functional hemodynamic reserve.
Homeostatic mechanisms are being activated even with minimal volume and pressure deflections in
circulation. Distribution of adrenergic receptors in the vasculature and the heart, momentary
catecholamine concetration in plasma as well as sympathetic-parasympathetic vascular and heart
innervation define a pattern of hemodynamic effects. Strong sympathetic response of the vasomotor
center on AV pressure gradient declines which is manifested as coordinated pattern of circulatory
centralization. Accompanying catecholamine release from the adrenal medulla can increase for 30-
300 times whereby noradrenaline response surpasses the adrenalin one. Increased venous tonus
decreases venous volume of blood and thereby increases venous return (stroke volume) and
shortens duration of blood flow through the veins. Both mechanisms contribute to the AV pressure
gradient correction. Simultaneously, sympathetic vascular stimulation decreases flow through the
skin, intestines and the kidney due to marked (low-tonicity vessels) or moderate (high tonicity
vessels) increase in resistance. That "exclusion" of the circulatory irrigation segment enables more
focused cardiac output redistribution. Redirection of circulation is a powerful mechanism in AV
pressure gradient repair. Therefore in compensate state summed response maintains circulatory
pressure gradient in order to maintain almost optimal flow through high tonic vessels(heart,brain)
by autoregulation. The kidney despite reduced flow maintains optimal glomerular filtration rate
with increased salt and water reabsorption.That sort of negative homeostatic feedback loop has its
own response capacity.
Endocrine response of the organism is being initiated simultaneously as a response to the
AV pressure gradient drop.Endocrine glandular responses augument compensatory response of the
vasomotor center by metabolic effects and direct regulation of fluid osmolality and vascular tonus.
Irreversible decrement in AV pressure gradient leads towards significant metabolic derangements
and tissue dysfunction representing decompensated stage of circulatory shock.Further deterioration
of hypoenergosis intracellularly causes individual cell death in tissues. Cell loss, accumulated tissue
metabolites(adenosine,acidosis,degradation tissue peptides) and agumented hypoenergosis turn
numerous regulatory mechanisms into positive feedback loops.At certain moment the condition will
become irreversible with loss of function of target organs which manifest in gradual multisystem

Decompensated stage:
Crucial event in development of decompensated stage liesin altered behaviour of the
arteriolo-capillary-venular tree.Capillary system is a web-like parallel complex.Flow through such
complex has its preferential pathways(the shortest;ones with lowest resistance) and secondary
pathways used for blood flow in states of increased metabolic demand.In physiological conditions
capillaries contain around 5% of blood volume and majority of that blood flows through the shortest
paths. Physiological transition of erythrocytes through the capillaries lasts for 3 seconds on
average.In circulatory shock development microvascular system gradually alters its behaviour
which can be classified into three stages.Due to resulting deceleration of the entire circulation,
decompensated stage of shock is sometimes (in septic shock) also called hypokinetic stage.
Every positive feedback loop of independant mechanisms potentiates AV pressure gradient
reduction.Concomitantly with events in microcirculatory wall, intraluminal erythrocyte aggregation
increases due to stasis while endothelial damage(individual cell death) initiates disseminated
intravascular coagulation.Both processes increase blood viscosity which increases resistance to
microvascular flow.


Mechanisms of coma development can be pathological or metabolic-toxic:
 caused by pathological processes in the brain or meninges
 most sensitive areas are: tegmentum(brain steam), lateral hypothalamus, dopaminergic
and noradrenergic neurons
 all processes that can cause damage to any component of activation center(system):
encephalitis,meningitis,brain edema,tumor,concussion,hematoma
 metabolic(toxic) mechanisms of coma development
 they occur due to metabolic disorders affecting organism and consequently brain
 hypoenergosis,excitability disturbances and neurotransmitter disturbances are some of
those mechanisms
Stages of consciousness impairment:
People who do not respond quickly with information about their name,
location, and the time are considered "obtuse" or "confused". A confused
Disoriented; person may be bewildered, disoriented, and have difficulty following
Confused impaired thinking instructions.The person may have slow thinking and possible memory
and responses time loss. This could be caused by sleep deprivation, malnutrition,
allergies, environmental pollution, drugs (prescription and
nonprescription), and infection.
Some scales have "delirious" below this level, in which a person may be
Delirious hallucinations,
restless or agitated and exhibit a marked deficit in attention.
A somnolent person shows excessive drowsiness and responds to stimuli
Somnolent Sleepy
only with incoherent mumbles or disorganized movements.
alertness; slowed In obtundation, a person has a decreased interest in their surroundings,
psychomotor slowed responses, and sleepiness.
Stuporous Sleep-like state (not People with an even lower level of consciousness, stupor, only respond
unconscious) ; by grimacing or drawing away from painful stimuli.
Cannot be aroused;
Comatose people do not even make this response to stimuli, have no
Comatose no response to
corneal or gag reflex, and they may have no pupillary response to light.


A) Coma caused by pathological processes in brain or meninges
1.diffuse process:encephalitis,meningitis
2.localized processes- focal symptoms
a) circulatory disorders-bleeding,thrombosis,hematomas
b)expansive processes-apsces,tumor,hematomas
B)coma caused by metabolic/toxic effects
1.Hypoenergosis – coma caused by hypoenergosis is often reversible because brain uses
80% of energy for its function and 20 % for structure maintenance. Hypoenergosis can be caused
by: hypoxia,hypoglicemia and by deficit of metabolic cofactors.
a)hypoxic coma
 sudden stop of blood flow causes coma after 8-10seconds and irreversible
damage occurs after 4-5minutes
 occurs in hypoxic encephalopathy (hypoenergosis)
b)hypoglicemic coma
 glucose level in blood is below 1.5mmol/L
 irreversible damage affter 90min
c)coma caused by deficit of metabolic cofactors
 hypovitaminosis- lack of thymine/niacin
2.Organ system disorders
a)cardiovascular system causes hypoxic coma
b)hypercapnic coma
 CO2 has narcotic effect, it decreases sensitivity
 the main stimulator is hypoxia (MUST NOT BE TREATED WITH
 it is reversible
c)hepatic coma
 due to increased amount of NH3,GABA,fatty acids and aminoacid
 development of hypoenergosis, formation of false neurotransmitters and
decreased degradation of them leads to direct neuron damage
d)uremic coma
 occurs in renal failure
 urea inhibits Na/K ATPase
e)endocrine system

 coma in diabetic ketoacidosis
 hyperosmolar coma in diabetics(neuronal dehydration due to ↑ glucose conc)
 myxedema coma(in hypothyroidosis)
 coma in hyperparathyroidism
3.Disorders of extracellular fluid composition
a)acidosis – vasodilatation and edema-coma due to brain damage
c)hyperosmolarity-dehydration of neurons
d)hypoosmolarity-cell edema
e)hypercalcemia-neuronal depression
e)poisons- ethanol and barbiturates when combined can cause coma
4.Termoregulatory disorders
a)hypertermia- heat stroke or heat exhaustion
b)hypothermia-temp below 25ºC causes coma


 hypoglycemia
 conc of glucose below 1.5 mmol/L
 hypoenergosis
 dizziness, lightheadedness, blurred vision, slow mental activity, confusion, coma
 reversible coma - if hypoenergosis last for short period of time
 irreversible coma - prolonged hypoenergosis(more than 90min), brain starts using up
lipids and proteins
 hypoxic coma (cardiovascular system)
 PaO2 below 3.3 kPa – brain ischemia- hypoxic coma
 ↓minute volume and plasma volume
 hypercapnic coma(lungs)
 CO2 has narcotic effect, it decreases sensitivity
 vasodilation in brain -increased intracranial pressure
 the main stimulator is hypoxia (MUST NOT BE TREATED WITH OXYGEN)
 it is reversible
 hepatic coma(liver)
 due to increased amount of NH3,GABA,fatty acids and aminoacid metabolites
 development of hypoenergosis, formation of false neurotransmitters and decreased
degradation of them leads to direct neuron damage
 uremic coma(kidney)
 occurs in renal failure
 urea inhibits Na/K ATPase
 acidosis, hypotonicity,hypophosphatemia, secondary hyperparathyroidism
 endocrine system
 coma in diabetic ketoacidosis( ketone bodies,neuronal dehydration,hypovolemia,electrolite
disturbance, cardiogenic shock)
 hyperosmolar coma in diabetics without ketoacidosis(neuronal dehydration due to ↑ glucose
 myxedema coma(in hypothyroidosis, letargy,psychomotor slowness)
 coma in hyperparathyroidism( Calcium is above 4 mmol/L)
 Addisons disease(coma due to hypovolemia and hypoglycemia)


a) acidosis – vasodilatation and brain edema-coma due to brain damage
b) alkalosis-vasoconstriction-ischemia-hypoenergosis
c) hyperosmolarity- high extracellular conc of Na +, dehydration of neurons; in acute
hyperosmolarity consciousness impairment occurs sooner then in chronic hyperosmolarity (brain
adaptation to higher conc); osmolality >320-330mmol/kg-confussion; >360-350mmol/kg-coma
d) hypoosmolarity-water intoxication, hyponatremia, cell edema, intracellular Na +<120mmol/L-
somnolence-coma; brain tries to addapt by decreasing potassium levels
e) hypercalcemia-neuronal depression( high Mg and Ca conc')

Syncope is a sudden, short-term, reversible loss of consciousness due to cerebral ischemia.
1.heart disorders
 rhythm disorders- decreased brain supply, decreased minute volume; Gerbec-
Morgagni-Adams-Stokes syndrome-refers to a sudden, transient episode of syncope,
occasionally featuring seizures. Prior to an attack, a patient may become pale, their
heart rhythm experiences a temporary pause, and collapse may follow. Normal
periods of unconsciousness last approximately thirty seconds; if seizures are present,
they will consist of twitching after 15–20 seconds. Breathing continues normally
throughout the attack, and so on recovery the patient becomes flushed as the heart
rapidly pumps the oxygenated blood from the pulmonary beds into a systemic
circulation which has become dilated due to hypoxia.
 SA pain – SA block – asystole- coma
 complete AV block- depends on the length of asystole( how much time is needed for
subordinate center to get in charge)
 partial block and atrial fibrilation
 ventricular fibrilation- blood is not pumped out-syncope
 drugs(digitalis, antiarrhytmics,beta blockers)
 valvular disorder,thromb,ischemia,hampered venous return
 paroxismal tachycardia
2.circulatory syncope
 carotid sinus hypersensitivity – transient bradycardia ,asystole (head turning,stiff collar)
 compression of vertebral artery or subclavia
 orthostatic syncope-prolonged standing, getting up suddenly
 vasovagal syncope
3.changes in blood composition
 hyperventilation: *hypercapnia, hypoxia- vasoconstriction in brain, increased resistance
* res.alkalosis, decreased Ca conc-cramps
4.other causes:

 hypoglycemia, decreased Ca2+, neurological disorders (epilepsy,injuries)


Fetal growth is closely linked with the growth and development of placenta which makes
anatomical and functional group entity called fetoplacental unit.Damages that span into
fetoplacental unit primarily affect placenta and immediately after affect fetus or act indirectly by
disrupting placental functions.Development and growth of the placenta differs in the first four fifths
of pregnancy in relation to development and growth in the last quintile.

Physiology of fetal life:

The fetus is developed on the basis of its growth potential and of the way how nutritients and
oxygen pass to conceptus from mother through placenta and umbilical cord. Growth potential is
determined by heritage,child's sex,enzymes,receptors and hormonal secretion. Insulin is the most
important fetal hormone which stimulates glycogenesis,lypogenesis and aminoacid incorporation.
Level of fetal growth hormone is not representing actual level of fetal growth even tho its levels are
increased at the end of pregnancy.Thyroid hormone has no effect on fetal growth; the conc of PTH
and 1,25(OH)2D3 are small; calcitonin and 24,25(OH)2D3 are increased and they stimulate cartilage
synthesis and incorporation calcium in bones.Androgens have limited effect on fetal growth.They
are more abundant in male fetus.Concetration of somatomedin in the blood of the fetus is relatively
low and its conc increases with advancing pregnancy.The increase in weigh during last four weeks
of pregnancy slows down; after birth the weight gain is uniform. The result of normal heritage and
adequate inflow of nutritients and oxygen as well as unchanged hemochorial membranes will be
exemplary fetal growth which is linear from 28th to 36th week of pregnancy.

Disorders of fetal mass:

Fetal hypotrophy-birth of a child that is below 10 percentile for a given gestational age.The
most common cause of fetal hypotrophy is insufficient food intake in mother or reduced blood flow
in the uterus and placenta.Has a few times higher risk of perinatal mortality in children and it can
result in many complications.Postnatal development can also be slowed down.Slowing of the
growth may be symmetrical (fetal weight and height are equally reduced as well as head
circumference; effect of noxa starts before 34th week of pregnancy) and asymmetric (weight
reduction but normal height and head circumference;effect of noxa starts after 34th week of
pregnancy).With prolonged fasting not only fetal weight is reduced but also mass of several
organs(adrenal glands,lungs, kidneys,spleen and in particular liver which is poor in glycogen). Such
infants develop hypoglycemia.

Fetal hypertrophy – excessive fetal growth explained as birth of the child that weights more than 90
percentile for a given gestational age.Excessive fetal growth occurs in pregnant women with
excessive weight gain in pregnancy which is almost exclusively caused by excessive eating during
pregnancy and in women with primary or gestational diabetes. In both groups of pregnant women
with diabetes there is a permanent (primary DM) or postprandial(gestational DM) hyperglicemia
which increases transfer of glucose from mother to fetus. Fetal hyperglycemia is a stimulus for fetal

Teratogenicity -denotes deviation from normal development of the embryo and fetus.Failures of
development or malformations can manifest in many forms.The most severe form is called a freak
or monster; much milder are abnormalities of certain organs, parts of organs and organ systems. If
the malformation occurs due to hereditary factors in the stage of gametes or in early begining of
development it is called the primary or real malformation. Malformations occuring in the later
stages of development are called disruption, dysplasia and deformities.
Gametopathies are hereditary; they may manifest as chromosomal changes (aneuploidy-
Turner syndrome, polyploidy-Down syndrome,Patau sy, Edwards sy) or can occur on
subchromosomal levels(genopathies-development anomalies and metabolic disorders such as cystic
fibrosis,hemophila A, Duchennemuscular dystrophy). So far mentioned malformations are of
primary type.
Malformations occuring in later stages of development: gametes are genotypicaly normal,
zygote begins normal development but subsequently could experience damage(radiation,chemical
agents, drugs,deficient oxygenation of embryo,maternal disease). Anomalies that occured during
embryogenesis (first 12th weeks after conception) are called disruptions.Dysplasia is milder
anomaly and occurs later in the course of intrauterine life after completing embryogenesis.
Deformations are changes in the shape or position of the body caused by uterine factors.
The most sensitive stages of development are embryogenesis and organogenesis.Fetal
damage is less dependent on type of noxa and more on the duration of the damage and gestational
age at the time of noxious stimuli.For example the rubella virus damages eyes,ears,heart and CNS
only during the first 16 to 20 weeks of gestation.


A) Disorders of sex differentiation

Sexual development consists of three processes that follow one after the other. These are
creation of genetic, gonadal and phenotypic sex. Genetic sex is determined by the type and number
of chromosomes therefore by default at the time of fertilization.
Gonadal sex development is determinedsequence of events in which the genetic record
determines whether the undetermined sex glands develop into testis or ovary. A gene from a sex
determining region Y (SRY) plays an important role in the development of testicular glands and
mutations in this gene cause a 46XY gonadal dysgenesis. Other genes located on the autosomes
and on the X chromosome also affect the development of testes.These are the Wilms tumor
suppressor gene (WT1) whose mutations cause Denys-Drash syndrome ( bilateral Wilms
tumor,diffuse mesanglial sclerosis of the kidney and 46XY gonadal dysgenesis).
Phenotypic sex development is a consequence of the immediate effects of the sexually
differentiated gonads. Internal sex organs are created from two grounds:Müller and Wolff's
channels. In men Müller channels wither and from the Wolff channels epididymis,vas deferens and
seminal vesicles are formed. In women Wolff channels wither and from Müller's channels fallopian
tubes, uterus and upper third of vagina are formed. Internal sex organs in each of the sexes develop
from different backgrounds. In contrast, external genitalia are created from the common base:
urogenital tubercle from which the glans penis or clitoris arise,urogenital folds from which the
corpus penis or labia minora arise and urogenital protrusions from which the scrotum or labia
majora arise.
 Classification of intersex conditions
We have divided the disorders of sex differentiation a condition of intersex into four groups:
 Chromosomal or gonadal disorders – this group of patients was primarily characterized
by the possibility that a person may develop both Müller and Wolff's channels.
Depending on the type of disorder sexual glands of these patients showed various
degrees of gonadal epithelial development, disorders of endocrine secretion and not so
rare malignant tumors.
 Masculinisation of genetic females (female pseudo-hermaphroditism) develops in
patients with karyotype 46XX. They have normally developed ovaries and organs
arising from Müller channels but their external sex organs are masculine.These condition
occurs when female fetus is exposed intrauterinely to the influence of high concetrations
of androgens. Increased androgen conc can be of maternal or fetal origin. Most common
cause of virilisation is congenital adrenal hyperplasia (due to impaired activity of 21-
hydroxylase and 11-hydroxylase). It is a hereditary disease in which there is an increased
ACTH secretion because of blockage of enzyme needed in the synthesis of cortisol
which then causes hypersecretion of adrenal androgens.
 Incomplete masculinisation of genetic males (male pseudo-hermaphroditism)develops in
patients with 46XY karyogram they have the external genitalia of both sexes, patient
may have internal sex organs corresponding to both male and female, although only
existing gonads are testis. It is a heterogenous group of patients with large phenotypic
differences: from individuals with apparently normal female genitalia to men with a
slightly proununced hypospadiasis. The most common causes of it are disturbances in
the development of testosterone, the conversion of testosterone to dihydro-testosterone, a
deficit or disorder of structure and function of the androgen receptor and disorders in
development or response to Müllerian inhibiting factor.
 Abnormalitiesin the development of sexual organs can be found in general disorder of
embryogenesis.For example these are epispadias glans,penoscrotal transposition and
slotted penis paired with exstrophyof the bladder, or penile agenesis paired with
unslotted anus.
B)Disorders of sexual development
Puberty and phenomena associated with it are a combination of many anatomical and
physiological changes that include acceleration of somatic growth and development, maturation of
gonads and the development of secondary sexual characteristics.
The hypothalamus and pituitary gland in children have a very low threshold of sensitivity to
inhibitory action of sex hormones. Minimum conc of sex hormones in pre-pubertal age is sufficient
to stop the secretion of gonadotropin releasing hormone and gonadotropines themselves. Over the
years hypothalamus and pituitary gland are becoming less sensitive to the suppressive effects of sex
steroids. In early puberty excessive secretion of GnRH and gonadotropins cause an increase in
gonads, increased synthesis of sex steroids, development of secondary sexual characteristics,
accelerated growth and bone maturation. This whole process is called "maturation" of the
hypothalamic-pituitary areas (known as gonadostate).
 Premature puberty
Under precocious puberty we understand the appearance of secondary sexual signs before 8.5 years
in girls and 9.5 years in boys. Precocious puberty can be real or fake.
 Real precocious puberty (pubertas praecox vera) fully resembles the physiological
pubertal development.It is always isosexual and it is accompanied by increased sex
glands and development of secondary sexual signs.It is marked by an increased secretion
of gonadotropins and sex hormones. In the girls the first sign of premature sexual
development is breast enlargement while in boys its testicular enlargement.Growth and
bone maturation are accelerated.Closure of epiphyseal plates occurs earlier resulting in
short stature(150-155cm).
 In the false premature puberty (praecox pubertas spuria,pseudopubertas praecox) child
develops secondary sexual characteristics but without gonadal development.Can be
isosexual (premature development of secondary sexual signs in accordance with the
child's sex) or heterosexual (premature development of secondary sexual signs not in
accordance with the child's sex so the boy develops female sexual signs and vice versa).
Marked with increased level of sex hormones and low level of gonadotropins. The most
common cause is congenital adrenal hyperplasia or adrenogenital syndrome.
 Delayed puberty
Pubertas tarda is a condition when secondary sexual characteristics don't develop before 14-14.5
years in girls and 15-15.5 years in boys. Delayed puberty is accompanied with growth lag. It is
most likely that it occurs due to a physiological lag of hypothalamic-pituitary-gonadal axis
maturation. Adrenal androgen conc in plasma, which plays a role in maturation and activation of
hypothalamic-pituitary-gonadal axis, is low with respect to chronological and bone age.

110.Growth Impairment

Short Stature (nanism)

1. Genetically conditioned
- Retardation of growth (short constitution) and sexual Development in children ( Example,
Turner Syndrome and Klinefelters.
-Nanism (dwarfism) primordial or genetic, extreme short stature visible at birth

2. Diseases of organs and other diseases:

-Disease of the heart, kidneys and bones
- Chromosomal abnormalities (down and turners)
- Malnutrition
- Psychological

3. Hormonal Disorders
-GH deficiency (hypopituitarism, isolated deficiency, peripheral lack of sensitivity)
-Hypothyroidism (late bones maturation, growth retardation, mental retardation)

3. Gigantism (Hypersecretion of GH during childhood), Acromegaly (hypersecretion after

closure of epiphysial plate),
4. Overproduction of sex hormones- increased growth, earlier closure of epiphysial plates,
resulting in a dwarf-like growth
5. Sexual Hormone Deficiency- late closure of epiphysial plate and prolonged period of growth

111.Pathophysiology of the Aging Process

ALGORITHM ON AGING! and then discuss also ROS types and their antioxidants to help expand
on the topic. Use previous questions to help with this one :)

112. Chemical and Physical Carcinogenesis

A)Chemical Carcinogenesis:
1. Environmental Factors (xenobiotics) : nitrosamines, aflatoxin B
2. Metabolic Endogenous Substances : Free Radicals

-Primary carcinogens

Reaction of carcinogens with cellular components:

-Chemical damage of DNA
-Inactivation of repair mechanism
-malignancy is a multistep process in which there is accumulation of various gene mutations

B) Physical Carcinogenesis:
1. Ionizing Radiation (ROS)
2. UV rays

Review Robbins Page 169-177

113.Biological Carcinogenesis

Pick 2- 3 and be able to discuss them in a bit more detail.

1. Viruses:
a) EBV: Burkitt’s Lymphoma, Hodgkin Disease, nasopharingeal Carcinoma
b) HPV: Cervical Cancer (CIN I, II, III)
c) HBV: Hepatocellular carcinoma
d) HTVL: T cell leukemia and somatic cell leukemia

2. Oncogenes and AntiOncogenes

RAS is an example of Proto-oncogene.
Review Robbins: Page 179

114.Cellular Oncogenes

An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated
or expressed at high levels.
Most normal cells will undergo a programmed form of rapid cell death (apoptosis) when
critical functions are altered. Activated oncogenes can cause those cells designated for apoptosis to
survive and proliferate instead. Most oncogenes require an additional step, such as mutations in
another gene, or environmental factors, such as viral infection, to cause cancer.

A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased
expression. The resultant protein encoded by an oncogene is termed oncoprotein. Proto-oncogenes
code for proteins that help to regulate cell growth and differentiation. Proto-oncogenes are often
involved in signal transduction and execution of mitogenic signals, usually through their protein
products. Upon activation, a proto-oncogene (or its product) becomes a tumor-inducing agent, an

Examples of proto-oncogenes include RAS, WNT, MYC, ERK, and TRK. The MYC gene is
implicated in Burkitt's Lymphoma, which starts when a chromosomal translocation moves an
enhancer sequence within the vicinity of the MYC gene. The MYC gene codes for widely used
transcription factors. When the enhancer sequence is wrongly placed, these transcription factors are
produced at much higher rates. Another example of an oncogene is the Bcr-Abl gene found on the
Philadelphia Chromosome, a piece of genetic material seen in Chronic Myelogenous Leukemia
caused by the translocation of pieces from chromosomes 9 and 22. Bcr-Abl codes for a receptor
tyrosine kinase, which is constitutively active, leading to uncontrolled cell proliferation.

Bcr-Abl: Review Robbins Page 179-180

Rb: Review also in Robbins Page 185

115.Genome Instability and Cell Cycle Oncogenesis

Review Robbins Page 180-187

Rb Cell Cycle example!

Genomic instability is broadly classified into microsatellite instability (MIN) associated with
mutator phenotype, and chromosome instability (CIN) recognized by gross chromosomal

The sources of genome instability have only recently begun to be elucidated. A high frequency of
externally caused DNA damage can be one source of genome instability since DNA damages can
cause inaccurate translesion synthesis past the damages or errors in repair, leading to mutation.
Another source of genome instability may be epigenetic or mutational reductions in expression of
DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very frequent,
occurring on average more than 60,000 times a day in the genomes of human cells, any reduced
DNA repair is likely an important source of genome instability.

In cancer, genome instability can occur prior to or as a consequence of transformation. Genome

instability can refer to the accumulation of extra copies of DNA or chromosomes, chromosomal
translocations, chromosomal inversions, chromosome deletions, single-strand breaks in DNA,
double-strand breaks in DNA, the intercalation of foreign substances into the DNA double helix, or
any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the
misexpression of genes. Situations of genome instability (as well as aneuploidy) are common in
cancer cells, and they are considered a "hallmark" for these cells.
The unpredictable nature of these events are also a main contributor to the heterogeneity
observed between tumour cells.
It is currently accepted that sporadic tumors (non-familial ones) are originated due to the
accumulation of several genetic errors.
An average cancer of the breast or colon can have about 60 to 70 protein altering mutations,
of which about 3 or 4 may be “driver” mutations, and the remaining ones may be “passenger”
mutations. Any genetic or epigenetic lesion increasing the mutation rate will have as a consequence
an increase in the acquisition of new mutations, increasing then the probability to develop a tumor.
During the process of tumorogenesis, it is known that diploid cells acquire mutations in
genes responsible for maintaining genome integrity (caretaker genes), as well as in genes that are
directly controlling cellular proliferation (gatekeeper genes). Genetic instability can originate due to
deficiencies in DNA repair, or due to loss or gain of chromosomes, or due to large scale
chromosomal reorganizations. Losing genetic stability will favour tumor development, because it
favours the generation of mutants that can be selected by the environment.

116.Etiopathogenetic factors in Malignant Transformation

Malignant transformation is the process by which cells acquire the properties of cancer. This may
occur as a primary process in normal tissue, or secondarily as malignant degeneration of a
previously existing benign tumor.

There are many causes of primary malignant transformation, or tumorigenesis. The
underlying commonality is genetic mutation either by inheritance or more commonly by acquiring
mutations in one's DNA over time. Although malignant transformation may occur because of
changes within the cell, it can be induced by inorganic toxic substances such as cadmium or arsenite
and organics such as tobacco-specific nitrosamines. It is also thought that some malignant
transformations are due to viruses such as the Epstein-Barr virus, although this is currently
restricted to just a few cancer types. A more common cancer associated with viral infection is
cervical cancer, which has been linked to the human papilloma virus.
Malignant transformation of cells in a benign tumor may be detected by pathologic examination of
tissues. Often the clinical signs and symptoms are suggestive of a malignant tumor. The physician,
during the medical history examination, can find that there have been changes in size or patient
sensation and, upon direct examination, that there has been a change in the lesion itself.

Main Players:
1. Genetic Factors are involved
2. Environmental Factors (80-90%)

Use Previous Questions to help expand :)

117.Biological Properties of the Malignant Cell

Inside the Original Tumor: Four of the Six “Hallmarks”

Four of the six hallmarks of cancer occur inside the cell: We discussed the cell cycle earlier to
provide the needed background of how normal cells work to help you understand the changes that
occur in cancer cell biology.
• Self-sufficiency in growth signals - Describes the observation that tumor cells grow even when
they are not getting a message to grow.
• Insensitivity to anti-growth signals - They do not pay attention to the stop signs, which means
the cell ignores messages telling it to stop growing.
• Evading apoptosis - A cancer cell learns to evade apoptosis (normally programmed cell death),
leading to the accumulation of damaged cells. It ignores the signals telling it that it is time to
• Limitless replicative potential - Most mammalian cells can replicate (make an exact copy of
themselves). Virtually all malignant cancer cells gain an ability to maintain their telomeres
(ends of the chromosome), conferring "limitless replicative potential" and eventually
picking up more and more mutations.
Mutations in certain genes have been discovered that promote these four processes. There is no
single mutation that is able to create all six hallmarks of cancer. It requires many different mutations
that accumulate over time to cause cancer.

Outside The Original Tumor: The Final Two “Hallmarks”

Without an adequate blood supply to bring in needed nutrients, a tumor cannot continue to grow.
Scientists have found that tumor cells send out signals that encourage the growth of new blood
vessels surrounding the tumor.

Increasing research has been devoted to processes beyond the inside of the tumor. These processes
have also been recognized to be key to the natural history of cancer:
• Sustained angiogenesis (creation of blood supply)
Since cancer cells cannot survive without nutrients or at distances of more than 100 microns
(~diameter of a strand of human hair) from a blood supply, they must initiate the formation of new
blood vessels to support their growth via the process of "sustained angiogenesis".

• Tissue invasion (to nearby tissue) & metastases (to distant organs)

Some primary tumor cells acquire the ability to undergo "invasion and metastasis" whereby they
leave their original location and move into the surrounding tissue. They eventually travel to distant

sites in the body, forming new colonies and secondary tumors. It is almost always this metastases,
rather than the primary tumor, which causes ultimate death.

The new metastatic colonies resemble cells from their site of origin
and disrupt the functioning of the host organ.
Metastatic breast cancer in the lungs is still breast cancer, not lung

Review Robbins Page 178, 206(oncofetal proteins)

118. Tumor Growth Kinetics

In Tumor, cells are not created more abundantly than in normal tissue. It is the loss of cells that is
Mass and growth rate is dependent upon the % of cells in the cell cycle, the duration of the cell
cycle and the checkpoints as well as cells not in the cell cycle. (Review previous questions)

The rate of growth depends upon the cell renewal and loss
The doubling time of the tumour is the time needed to double the number of tumour cells
(exponential growth)

119.Tumor to Host Relationship

Can answer this question along the same lines as Question 117.

Immunological response to the tumour:

1. Cytotoxic Lymphocytes CD8- recognize tumour antigens with HLA I
2. NK cells are activated by absence of HLA I
3. Antitumour antibodies- activate complement

All of these mechanisms lead to death of tumour cells and promote a local inflammatory response.
The cells that participate create free radicals and NO which can destroy tumour cells.

Paraneoplastic Syndromes:
-Increased Body temperature
-Thrombotic states
-Hormone imbalances, ectopic hormone productions

Review in Robbins

120.Mechanical Injury and Wound Healing Mechanism

Receptors will convert a part of mechanical energy into tissue energy, usually into heat.
Elasticity is a physical property which describes the opposition of a body to change size and shape

HOOKS LAW: The extension of a spring is in direct proportion with the load added to it as long as
this load does not exceed the elastic limit.

Outside these parameters, plastic changes occur (bone fractures)

Excessive Mechanical Forces:

Abrasion, Amputation, Bleeding, Wounds, Ruptures, Herniation, Sprain

Robbins Environmental chapter

Excessive Mechanical Forces damages tissue:

Frank killing of cells
Disruption of local Vasculature
Disruption of Innervation

Wounds can be divided into zones

Zone of dead biological material
Zone of relative Ischemia
Zone of active Collagen Synthesis
Zone of resorption

Cell infiltration leads to the formulation of GRANULATION TISSUE

-Robbins chapter Two wound healing.


Gunshot wounds (vulnera sclopetaria) are usually deep tissue damages which affect many organ
systems. Superficial entrance (and exit) wounds often are not in correlation with internal damage.
Gunshot grain losses part of energy which manifests as deceleration as it passes through air or
water. Kinetic energy of grain is lost in destruction of tissue in direct collision,warming of tissue
and blast work.Blast work represents short-term elevation of tissue pressure in immediate range of

gunshot grain passing trail.It manifests with high oscillating changesof pressure which forms
temporary cavity. This cavity forms and disappearsin 0.1-0.4miliseconds.Final cavity, bullet canal,
is smaller in volume and size from the temporary cavity. Size of the temporary canal and bullet
cavity are dependant on kinetic energy of the bullet upon entry.
High energy shots have higher energy transfer in deeper tissue layers far from the entry
wound.They are causing bigger damage to the tissue as well as larger temporary and bullet canals
compared with low energy shots.In high energy shots changes in bullet trajectory can sometimes
happen resulting in irregular bullet canals in tissue. In shot with entrance and exit wound injury is
bigger at the exit wound.
GSW sometimes affect organs which leads to direct pathogenetic mechanisms that can cause
death. Damage of the larger vesselsleads to hypovolemia and cardiogenic shock.GSW to the torax
can cause pneumothorax and wounds to the respiratory system can cause asphyxia which is seen as
global respiratory insufficiency.Shots to the spinal cord are causing motoric and sensory deficit of
the distal parts of the body(quadriplegia,paraplegia). Damage of the intestinal tract leads to sepsis
and causes septic shock. All GSW can cause bacterial infrection( they are regularly contaminated).


In car accidents, in ruins and in war injuries large crush injuries of the torso and limbs are
accounted. After release of external mechanical pressure crush tissue starts unique pathognomonic
reaction which causes renal injury and vascular shock, called crush syndrome.
While tissue is under external pressure ischemia,metabolic acidosis, hematoma and cellular
destruction take place. At the same time in the other body parts hemodynamic functions are
maintained.Few hours after external pressure is eliminated intense swelling and traumatic edema
are formed. Traumatic edema is of angiomural,lymphodynamic,hemodynamic and oncodynamic
type. Several minutes after elimination of external pressure muscles that are wrapped in fascia swell
due to increase in pressure. Venous flow is stopped enhancing the edema and afterwards arterial
flow stops causing ischemia. That hemodynamic separation in crushed tissue (tissue compartment
syndrome) causes enormous fluid accumulation and sudden hypovolemia.
The transport of substances in the body is also diverted.Muscular and other cells have been
destroyed.During rhabdomyolysis large amounts of myoglobin are released which can cause
myoglobinemia and myoglobinuria.Myoglobin in the tubules of the nephrone produces myoglobin
cillinders and that can lead to the blockage of the nephrone lumen.
Plasma calcium is deposited in damaged tissue resulting in hypocalcemia.
Potassium,phosphate and purines are release from destoyed cells resulting in hyperkalemia,
hyperphosphatemia and hyperuricemia.Lactic acid which is which is released during that process
and produced in the ischemic tissue causes lactic acidosis.The activity of intracellular enzymes
(creatine-kinase, lactate-dehydrogenase,aspartate-aminotransferase)in the blood also increases.
Large areas of damaged endothelium cause platelet accumulation, scattered blood clotting within
the vessels and consequent thrombocytopenia.
Hemodynamic shock develops from hypovolemia,hyperkalemic toxic effects on the heart,
vasohypotonic mechanisms in damaged tissue mass and neurogenic mechanisms of pain. The
organism triggers a stress response to pain and the development of hemodynamic shock. Both of
them are increased by the secretion of ACTH and cortisol, hyperventilation and hyperaldosteronism
are also initiated which can lead to metabolic and volume adjustments.

The explosion
During the explosion of the matter the bursted particles are drifting apart at high speed.Regardless
of the amount of energy released with each explosion-the released energy is reflected through the
thermal effects in the immediate vicinity of the explosion,through the deposit of the energy on
shards of the surrounding structures and through the blast shock wave. The blast shock wave is
expanding radially from the explosion in the concentric circles and it consists of displacement and
vacuum phase.
Pathogenetically the most important shock wave is the one passing through air then water
and solid substances. Shock wave's mechanical force causes transient pressure on the body surface
and pathological changesinside the body.During air shock wave alveolar and and capillary
endothelium ruptures with risk of air embolism.Depending on the severity it can cause ruptured
eardrum,ossicular dislocation or the inner membrane rupture. During water shock wave internal
injuries of abdominal organs commonly occur. Shock wave that spreads through solids is
transferred to the bones that are in contact with medium of wave propagation causing their
numerous fractures.

The tissue effect in the vibrational field depends on its mass (inertia),elasticity and friction.The
contributions of these properties in vibration of the tissues are called mass reactance,elastic and
frictional reactance. Mass reactance increases with frequency while elastice reactance decreaes. At
given frequency two reactancts are reversed and the tissue flickers with greater amplitude or begins
to resonate with the source of vibration.Since the resonance frequency of the tissues and organs are
low vibrations transmitted from the enviroment are absorbed and interfere with normal tissue
function.Vibration syndrome and diarrhea are clinical examples of absorbed vibrational energy

Acceleration and decceleration

Gravity is acting on every tissue in body at rest which is in equilibrium with the supporting forces
of bone and muscular system so that resultant force equals zero (no acceleration). Acting on the
body force causes change of speed (acceleration,deceleration) by size inversly proportional to the
size of the body weight.
During air and space flights acceleration and deceleration forces appear which exceed the
gravity.Size of such forces is expressed as a multiple value of gravity.Considering the longitudinal
axis of the human body force vector can be parallel,transverse or under some angle between them.
If the force is acting longitudinally and has the same direction as gravity hydrostatic pressure in the
blood increases in direction of force.For example, if the force equals 5G hydrostatic pressure in
veins of the feet will be five times larger than normal value. The return of the blood to the heart is
obstructed causing upper body ischemia.At even higher forces(more than 20G)blood vessels rupture
and bones break because the load exceeded their elasticity.
If the direction of longitudinal forces is opposite to the direction of gravity (negative G)
there is anti-hydrostatic effect with hyperemia and potential hemorrhage of upper body vessels.
Transvers loads are much better tolerated.
Kinetosis(motion sickness)
Collective name for vegetative nervous system disorders primary caused by a special motion of the
body (air-,sea-,car- sickness).During this rides irregularly repeated motions occur.Although the
body(especially neck)somewhat neutralize this movements they nevertheless permanently stimulate
utricular receptors and semicircular canals.Stimulation of vegetative nervous system results in
nausea,,vomiting,pallor and sweating.

Reduced atmospheric pressure

Human body is exposed to low air pressure in higher altitudes and in aviation.Partial pressure of
oxygen is decreasing proportionally to reduction in atmospheric pressure. However reduction of
PO2 in the alveolar air is higher than in atmospheric air on the account water vapor and CO2 content
in the alveolar air.To ensure an optimal oxidative metabolism the organism has developed a series
of adaptive mechanisms(↑vital capacity,↑residual volume,↑FRC this ↑breathing capacity per unit of
time and diffusion surface for gas exchange).The vaule of FEV1/FVC decreases which is a result of
a relatively high resistance to gasp.
The total oxygen diffusion increaes : due to an increase in the diffusion surface,because the
hyperventilationensures the maintenance of alveolo-capillaryy oxygen gradient and because the
reactive erythrocytosis reduces diffusion distance for oxygen.The number of RBCs in blood
increases because hypoxia stimulates erythropoeitin secretion in kidney.Strongly stimulated bone
marrow produces more RBCs so the hematocrit increases to 0.60-0.65 and the Hb conc to 200g/L.
Hemoglobin dissociation curve shifts to the right.At the level of peripheral tissues new capillaries
are produced due to reactive angiogenesis which reduces the vessels-cell distance and facilitates
oxygen diffusion.

Elevated atmospheric pressure

At high atmospheric pressure greater amount of gas is dissolved in saline solution.When this gases
are inert as helium and nitrogen their increased content does not disturb the life processes in cells.If
there is a large quantity this syndrome of dissolved oxygen poisioning with it occurs. At the
molecular level is on of the partial reduction of molecular oxygen manifestations(formation of
ROS) due to hyperoxia in the cell. We are exposed to high atmospheric pressure when
diving.Special problem is sudden decompression-sudden exit from areas of high pressure to an area
of lower pressure.While a men is in an area with high atmospheric pressure a significant amount of
metabolically inert nitrogen dissolves in the body fluids.Rapid decrease of external pressurecauses
the release of excess nitrogen in the form of bubbles in the tissues and body cavities.Decompression
sickness syndrome can include a wide range of symptoms from light pain through gas bubble
embolism and death.

Acustic injury
Acoustic trauma is an injury to the inner ear that is often caused by exposure to a high decibel noise.
This injury can be related to a single very loud noise or by exposure to a lower decibel noise over a
long period of time. Some injuries to the head can cause acoustic trauma if the eardrum is ruptured,
or if other injuries to the inner ear occur.The eardrum protects the middle and inner ear. It also
transmits signals to the brain by way of small vibrations. Acoustic trauma can damage the way that
these vibrations are handled, causing hearing loss. Sound moving into the inner ear can cause what
doctors sometimes call a “threshold shift,” which can trigger hearing loss.One of the most important
symptoms that can signal the onset of acoustic trauma is called tinnitus. Tinnitus is a type of injury
to the ear that causes a buzzing or ringing sound. Those with slight to moderate tinnitus will most
often be aware of this symptom when they are in a silent environment. While tinnitus can be caused
by drug use, changes to blood vessels, or other factors, it is often a precursor to acoustic trauma
when it is caused by exposure to loud noises. Tinnitus can be persistent or chronic, where long-term
tinnitus is a good reason to suspect acoustic trauma.

Increased body temp(over 45ºC)causes changes to the skin ,epidermis and even deeper layers.The
severity of the change depends on the temp and on the duration of exposure.In order for bulla to be
formed on the surface of the skin takes 2.5 times longer than is needed for erythema development.
Burns are classified into three degrees:
I degree:only epidermis is damaged; it appears as visible skin redness(erythema),healing is
complete after approximately 7 days without any consequences
II degree: - II A degree (the superficial dermalburn) denotes damage to different layers of epidermis
or dermis. The skin is unequally red or pink ,painful,moist with the presence of bullae.Because only
superficial parts of the dermis are affected the healing process is complete after 10-14 days.Certain
pigmentation changes remain on the skin surface for some time after healing but eventually they
-If a deeper layer of dermis is affected the burnt surface is red or brown which than
classifies the injury as a II.B or as a deep dermal burn.The healing process lasts for 40 days after
which a scar is usually formed.The dermis can also be damaged due to infection; in such case the
burn is classified as III degree burn.
III degree: extends through entire dermis, it can also extend to subcutaneous tissue,muscle and
bone.The damaged skin is white/gray to dark brown, dry and insensitive.A skin graft is used to
cover the area after removing all damaged tissue.
Burns can also be differentiated into burns with partial skin loss(superficial) and into burns
with complete skin loss (deep).The first type is analogue to I and II degree whereas the second type
is analogue to III degree. The exact depth of the burn can be determined 48 hours after the injury.

Injuries caused by cold

Fingers,nose and earlobes are most commonly affected.All tissues are not equally susceptible to
cold.Nerves and striated muscles are very sensitive unlike the skin,fascia and connectiv e tissue.The
least sensitive are cortical parts of bones and tendons.Blood vessels contract as a rection to coldness
to preserve body temp but at the sam time periphery is prone to damage because reduced blood flow
also contributes to tissue cooling. After tissue warming vasodilation with capillary stasis occurs and
blood flow is redirected to arterio-venous anastomosis.This causes edema which retracts within 24
hours.Skin shows intracellular vacuole in epidermis with necrosis.Nerve response to moderate
coldness is lost along with muscular weakness or palsy.Longer exposure of nerves to coldness
causes edema of nerve fibers and degeneration of myelin envelope and axons. The most severe
damage of muscular cells is coagulation necrosis which develops shortly after local exposure to
lower temp. Changes in tissue are classified as:
grade I:edema,redness,insensitivity of the skin without billae on the surface
grade II:bullae formation on partially damaged skin
grade III:enire thickness of skin is damaged with partially damaged subcutis
grade IV:enire thickness of skin is damaged along with deeper structures (muscles,bones)

Of all physical caused injuries those caused by electricity are most dependent on physical
laws. It means that the severity of injury will depend on well known factors:type of electricity,
electrical charge,intensity of current,current density,body electric resistance and transitive
resistance, electricity flow through body and readiness for electric shock as well as time of exposure
to electricity.
Effect of electricity is electro-specific in sense of interfering with membrane potentials
(heart,brain,muscles) and electro-thermic in sense of creating heat.
 Effects on heart and blood flow
Short term exposure of heart to low voltage can momentarily cause cardiac arest but soon after heart
function returns with irregularity in rhythm, dyspnea and angina like pain. Higher voltages or longer
exposure can cause ventricular fibrilation or asystole. Besides voltage and exposure time effect of
electricity on heart depends on phase of heart cycle in which heart is affected.Especially vulnerable
phases are the top of T-wave in ECG.
 Effects on nervous system
High current passing through brain causes immediate loss of consciousness, convulsions or paralysis followed by retrograde amnesia,confusion,headache,drowsiness and asymmetric
neurological symptoms.Voltages greater than 1000V usually cause coma leading to death.Due to
strong thermal effects the brain can sometimes be literally cooked. Pathological-anatomical findings
are not characteristic for electrical injury but rather for hypoxia due to respiratory and circulatory
arrest and for small meningeal artery spasms. Evidence of brainn edema together with scattered
bleeding foci,encephalomalacia, demyelination,perivascular necrosis and ganglion cell degeneration
are found. High current passing through the spinal cord causes asymmetric neurological symptoms,
weakness and limb paresthesia.Peripheral nerves are rarely damaged primarily but rather
secondarily due to severe burns, muscle rupture or movements of bones and joint fragments.
 Effects on skin
The skin is the organ most frequently in contact with electric current.Skin injuries caused by
electricity may present in various forms- from slight burns to carbonization.The rapid conversion of
electrical energy into heat is the main cause of damage so the injuries are similar to burns.The
injury may affect only the epidermis or also the corium and deeper tissues including bones.
 Effects on other organs
In the lungs electric shock causes edema,emphysema,petechial hemorrhages,focal necrosis and
inflammation.Bones and joints are usually damaged.Thermall effects are particularly strong in limb
joints because electrical current condensation in that area.Joint and bone necrosis have been
described even bone melting and burning.Being on the current path the ear can be damaged in any
part(hemorrhage,necrosis,inflammation,eardrum perforation) leading to a permanent or temporary
hearing loss.Burns can effect eyelids,conjuctiva and cornes. Corneal and lens blurring are possible
(cataracta electrica).Kidney failure occurs secondarily due to high voltage and extensive burns. The
digestive system,the pancreas and the liver function are usually not impaired.Endocrine and
sympathetic system injuries manifest only with delayed symptoms such as attacks of sweating,skin
dehydration, pigmentolysis, hair loss,menstrual disturbances, temporary glycosuria and polyuria,
rapid weight loss or gain,diabetes insipidus,hyperthyroidism.


The biological effect of different radiation types depends on physical characteristics of
beams itselves and their degree of absorption.The temporal and spatial dimension and the
distribution of total radiation dose absorbed should also be taken into consideration. Only a narrow
spectrum of visible light (400-780nm) is actually noticable by our eye.
Usually the electromagnetic waves from 1nm to 1μm in length are included in the so called
optical radiation including ultraviolet rays,visible light and infrared rays.
 Ultraviolet rays
 electromagnetic radiation that is just below visible spectrum according to wave length
measurments (below 400nm)
 it is divided into three parts:
 UV-A – long waves so called black light
 UV-B – medium waves, waves that cause tanning
 UV-C – short waves,bactericidal effects
 absorbed UV rays cause cascade of photochemical reactions, most important of which
are the ones causing protein and nucleic acid degradation (dimers of thyamine and other
pyrimidines are formed; repair starts immediately)
 UV light is good for human health (photochemical synthesis of vit.D and increased
synthesis of skin pigment) but only to a certain limit. Specific UV-wave lengths
penetrate deep into skin and that partly depends on amount of skin pigment.Vascular
reaction of the skin to the UV waves is based on vascular , increased blood flow and
increased vascular permeability. UV waves affects the skin cell growth: first 24 hours
after the exposure cell growth stops and after 72 hours number of mitosis
increases.Chronic exposure to UV waves causes skin thickening which ca lead to actinic
keratosis and skin carcinoma.
 Eyes are also exposed to UV waves.Most of those waves are absorbed by retina and the
rest by ocular lens.Only in the eye without ocular lens those waves can damage retina.
2-24 hours after intensive UV exposure photokeratitis and conjuctivitis can occur which
is seen as redness of the eye,photophobia and blepharospasm(snow blindness).Long
term exposure to the UV light can cause formation of cataracts.
 Visible light
 Pathological effect of visible light is seen as skin damage called photosensibilisation.
Photosensibilisation is caused by photon absorbing molecules which are after
absorption transformed into active state that starts chemical reactions which can cause
tissue damage. Tissue damage can be a consequence of direct damage by photon
products or these products can be allergens that cause allergic reaction and tissue
 Endogenous photosensitive matters are different porfirins which absorbe visible light

and start photosensible reactions who's end product is oxygen.IN porfirias those
molecules are causing serious skin damage.
 Infrared waves
 includes lengths from 0.78-1000μm and is divided to three biologicaly important parts
 most sources of visible and UV light emit some of the infrared light too
 infrared light is a consequence of atom spin in every body with temp above absolute
 the eye has many defense mechanisms against natural sources of heat rays beacause they
also radiate the visible spectrum; foe example blinking moisturizes cornea and prevents
it from overheating.Industrial sources can overheat some parts of the eye because they
don't trigger defense reactions. In extreme cases inflammation of conjuctiva, burns of
cornea and overheating of iris (which absorbes infrared light more due to its pigment)
can occur.If professional exposure lasts for years and with inadequate protection blurs
near posterior lens wall develop and sometimes even cataract.
 Skin of light tanned people absorbes stronger rays while skin of dark tanned people
absorbs more rays. However wave lenght of 1.2μm equally penetrates light and dark
skin; about 50% of heat radiation penetrates to depth of 0.8mm(the dermis affecting
nerve endings and capillaries).Intense infrared light causes erythema,edema and
bullaeon the skin. Skin heated to 46-47ºC is severly damaged(denaturation) and when
temp rises to 70ºC most of enzyme systems in skin decompose.Excessive and prolonged
heating with infrared light can cause shronic rhinitis and laryngitis and also general
hyperplasia of respiratory mucosa.In those circumstances reduction of immunoreactivity
and decreased sperm count are also noticed.
 Effects of laser light
 Distress caused by laser radiation depends on wave lenght,focusing of beams, strenght of
source,time of exposure...Laser devices can be harmless with low energy in visible
spectrum area(where defense reaction is possible); they can be of moderate risk when
directly looking at the source or reflection from mirror; and finally they can be very
powerful igniting objects or burning skin even when radiation is diffuse.
 Several mechanisms participate in laser-caused damage.The initial physical effect of
that radiation includes heat,thermo-acustic or photochemical effect.Due to tissue
heating,denaturation of proteins occurs and sudden conc of energy in small volume can
cause boiling of tissue fluid and steam that develops can damage cells. Steam production
is especially dangerous becase of pressure increase in closed space (eye,skull). Elastic or
thermo-acustic wave is a side effect of sudden heat expansion, this transient wave can
lacerate tissue and eject ,many tissue fragments from impact point. Photochemical
reactions are result of activated molecules which have absorbed quanta of energy.
 Effects of microwaves and ultrafrequency radiowaves
 IN organism exposed to microwaves and high frequency radiowaves electric and
magnetic field are induced.Absorbed energy excites molecules,causing them to rotate
which heats up tissues.With increase in wave frequency tissue electrical conductivity is
also increased and dielectrical constant is decreased.Tissue and organs with higher
amount of water(brain,muscles,skin) have relatively high dielectric constant
 Exposure of animals to microwaves and high frequency radiowaves causes patho-

physiological changes that depend on many factors such as type,strenght and duration of
radiation. Local exposure causes mainly functional disorders and morphological changes
consequences of which can even lead to death by hyperthermia.Only waves of higher
intensity cause mutagenic and genetic effects, embryonic and post-natal development
disorders, damage of germinative epithelium of testicles,activation of hypothalamus-
pituitary axis.
 There are data that show the functional disorders of the cardiovascular system after
exposure to microwaves (prolonged atrio-ventricular conducting
stimuli,bradycardia,blood pressure changes).
 Hematologic disorders have also been described. When the radiation intensity is strong
enough(acute exposure) reticulocytosis and lymphopenia develop with disappearance of
eosinophilia.But when it comes to chronic exposure to microwave radiation of lower
intensity then the opposite reaction occurs(lymphocytosis and eosinophilia).


 electromagnetic waves such as gamma and x-rays and cosmic rays
 the corpuscular ionizing radiation include the alpha rays(helium nuclei),beta rays
(electrons), protons and neutrons
 the interaction of radiation with matter in different ways leads to the creation of
larger or smaller number of ion pairs- biological effects depend on that as well as on
 LET(linear energy transfer) is the amount of ionizing radiation energy absorbed per
unit distance traveled.The x,beta and gamma rays belong to the low LET radiation
while alpha particles,protons and neurons are considerd as a part of high LET.Hence
the difference in their relative biological effectivness(RBD: x,beta,gamma=1, protons
and secondary fast neurons=10, alpha particles and heavyions=20).Physico-chemical
events after the absorption of ionizing radiation begin the process of excitation and
ionization which ultimately leads to significant biological effects.
 The interaction of photon radiation and tissue is specified by the energy of photons
and atoms in structure of tissues that accept the energy. Because the most common
atoms in living tissue are carbon,oxygen,nitrogen and hydrogen it is obvious that
most of the absorbed energy is reflected due to the Compton effect.In this effect
photon changes direction.Such acceptance of energy causes the ejection of
electrons(ionization),the spin change and termination of covalent connection.Pair
formation occurs at very high photon energies.
 Initial changes on the level of atoms and molecules occur very shortly after radiation
while much longer time is needed for manifestation of biochemical and
morphological cell damage.
 Given that most tissues contain a large percentage of water (about 75%) under the
action of radiation there will be a substantial number of water radiolysis
products..Besides more or less stable ions there are also very reactive free radicals.
Released electron can react with water creating the so called aquatised electron
which is loosely connected with the surrounding water molecules.It is this electron
and hydroxy radical which are the most reactive with biologicaly important
 The cells show a special sensitivity to radiation in different parts of the cell cycle.
The highest sensitivity is in G2 and M phase.
 Like the phase of the cycle local factors also determine tissue sensitivity to ionizing
radiation.Increased oxygen partial pressure enhances tissue radiation sensitivity.This
effect is interpreted by increased local conc of toxic oxygen free radicals in such
conditions.The effect of tissue oxygenation degree to tissue radiation sensitivity is
important in radiation therapy of tumor diseases.
 0.05 Sv is the dose considered maximum permissable radiation dose to professional
personnel.Nevertheless it is important to stick to the theory of linear relation between
absorbed radiation dose and tumor or leukemia occurence probability.
 External irradiation can be acute (single irradiation of the whole body or some body
part) or chronic (divided into multiple individual doses over time).Pathophysiologic
response of tissue is proportional to the dose absorbed but varies according to tissue
type,its weight, radiation quality factor and dose rate. Rapidly absorbed radiation
causes bigger damage.
 Pathogenesis and damage severity in a case of internal irradiation by incorporated
radionucleoides depends on 4 factors:
 radionucleoide and its compounds solubility in body fluids; this determines
the possibility and degree of resorption
 radionucleoide organotrophic (histotrophic) properties which define the
(non)existence of "critical" organ or place of effect.
 Type and energy of radionucleoide radiation; it determines ionization density
and the amount of damage
 period of radionucleoide's disappearance from the organism (effective half-
life); this depends on certain radionucleoide's half-time of radioactive decay
(physical half-life) and on the half-time of its excretionfrom the
organism(biological half-life), regardless of radioactivity.
 Most dangerous are radionucleoides that emit alpha particles
(radium,polonium, plutonium and most of transplutonium elements).
 In contact with skin radionucleoides that emit beta-rays(electrons) provoke a
local inflammation so called beta-dermatitis.
 Local irradiation can occur willingly in a case of radiotherapy of tumors or skin
diseases.There is also a possibility of unwilling local exposure. The most exposed
part of tissue soon presents with erythema and symptoms of 2nd or 3rd degree burns
(swelling, pain,bullae, wet dermatitis, skin necrosis).Necrosis will appear in deeper
tissues especially in intima of blood vessels if local irradiation has been very intense
(tens of Gy). Deep ulcers can develop as well as ischemia,infection and sepsis. The
affected limbs often have to be amputated.
 Total body irradiation (panirradiation) simultaneously affect all tissues that are sensitive to
ionizing radiation. Hematologic disorders will be expressed already after low or moderate
dose of irradiation due to impairment of bone marrow stem cells and direct destruction of
lymphocytes.Lymphopenia is the earliest sign detectable in peripheral blood and it can be
used as a valuble indicator to estimate severity of radiation injury.

Rapidly absorbed dose of radiation with relatively short exposure time results in acute
radiation disease. Before complete clinical picture of the disease is developed prodromal
nausea,vomiting and diarrhea appear.This phase is followed by latency period with no visible signs
of disease but with blood picture alterations. Usually ends after 2 months with recovery or death.
Hematopoietic syndrome causes death if bone marrow is not transplanted. Death occurs at doses
greater than 10 Gy before hematopoietic tissue failure due to haemorrhagic enterocolitis and
pneumonia (radiation pneumonitis). Peracute course (> 50 Gy) appears next to a picture of the
cerebral syndrome with neurological and cardiovascular outbursts. If there is a mechanical or
thermal injury together with acute irradiation syndrome mutual deterioration syndrome will
develop- on the first place is maintenance of the basic life functions. There are compounds
(aminothiols) that reduce the effects of acute radiation (if they are administrated before irradiation)
by neutralizing free radicals.
Chronic radiation sickness can develop as a consequence of ac.radiation sickness or as a
consequence of permanent or fractioned radiation of organism with low speed doses or due to
incorporation of radionucleoides.
 Milder form-reversible functional disorders(neurovegetative distony)
 Moderate form- subjective difficulties with objective signs (astenic syndrome and
focal neurological disorders accompanied with signs of increased intracranial
 Severe form- cerebral disorders (diffuse encephalomyelitis with increased
permeability of small blood vessels),severe dysfunction of hematopoiesis, chronic
affinity to sepsis, osteo-algic (vertebrogenic algic) syndrome with unbearable limb
pain is developed


Xenobiotics are substances foreign to organism.Most common xenobiotics in humans are:
natural substances (micotoxins,alcohol),pharmacological substances (drugs,narcotics,contrast
agents), food additives, enviromental and technological substances of mineral origin (pollutants,
detergents), insecticides,herbicides,cosmetics...
Xenobiotics that can cause structural and/or functional cell damage are called poisons.
Toxicology is branch of pharmacology that studies their properties.The effects of xenobiotics on
organism depend on the form of exposure,dosage, biotransformation and excretion as well as on
healing properties of the organism.

Xenobiotics intake and its distribution in the organism

Contact with skin or moucose membranes (respiratory and digestive system) can cause local
reaction (inflammation,necrosis,neoplasia) or if the substance is absorbed systemic toxicity
develops. System toxicity can be caused by direct effect of noxae or after its biotransformation.
Contact with noxae can occur subcutaneously, intramuscularly, peritoneally and intravenously. We
can differ between acute toxicity (adverse effects seen after one time exposure) and toxicity due to
repeated exposure (short-term repeated exposure→exposed to effects of noxae during <5% of life;
subchronic→5-20%;chronic→most of lifetime).
Noxae can be absorbed by: passive diffusion(most common), facilitated diffusion, active
transport, phagocytosis and pinocytosis. Absorption depends on bioavailability of the substance in
question. Substances that are activated in liver express greater toxicity if taken peros while
substances that liver detoxifies are less toxic when given peros. If however dose is too high even
then ac.toxicity will manifest because detoxifying ability of the liver will be exceeded. So the
overall effect is dose-dependant but also time dependent.
After absorption into the bloodstream xenobiotics circulate partly free and partly bind to
proteins or blood cells. The degree of binding and factors that affect balance in its free form decide
on availability of noxae for metabolism, storage and excretion. If affinity to bind less perfused
tissue (fat) is high or if the substance is polar (low lipid solubility) the rate of distribution of that
substance is low. Tissue binding (depending on affinity and flow) can cause high level of conc
gradient (tissue/plasma) and slow release of noxae into blood even after cessation of external
Lipophilic substances(chlorinated hydrocarbons) will accumulate in adipose tissue, divalent
heavy metals(lead, strontium) are deposited in bones instead of calcium, and arsenic will be
deposited in keratin(hair,nails).

Dose-effect relationship of xenobiotics

According to so called hit-theory only one molecule of substance is sufficient to cause
adverse effect if found at the right time in the right place.This concept is particularly supported by
mutagenesis and carcinogenesis.
The presumption is that xenobiotic conc must cross the threshold below which homestatic
mechanisms can prevent its deterimental effects. It is known that some substances in small conc are
essential for the human body(arsenic,selenium) but are toxic in greater amount. Acute toxicity is
usually determined on animals and it is expressed as mean lethal dose (LD50) for a particular route
of intake. LD50 is the dose that kills 50% of tested animals.In the same way mean effective dose
(ED50) is established. ED50 represents the obvious signs of intoxication in 50% of exposed animals.
The amount of substance that in a man will not cause side effects even after long permanent
exposure is very difficult to determine. For this purpose doses without adverse effects ( NOAEL- no
observed adverse effect level) have to be determined on experimental animals.

Polar molecules are soluble in water and excreated through urine and bile, they do not show
tendency to accumulate in the body. Nonpolar (hydrophobic) molecules are lipophilic so they can
enter the cell and fatty tissue; they show tendency to accumulate in the body.
Biotransformation serves as protection against accumulation of nonpolar molecules by
increasing their polarity(↑excretion at the same time).Metabolic conversion and excretion are two
basic ways to remove xenobiotics from the body.
Metabolic conversion:
1.Detoxification – decreases toxicity and increases solubility of xenobiotics
 non-synthetic reactions (1st degree reaction)-oxidation,reduction,hydrolysis
 synthetic reactions (2nd degree reaction)- bioactive substance binds to some
endogenous compounds; conjugation,acetylation, methylation
 considering the place of detoxification we differ between microsomal (endoplasmic
reticulum) and non-microsomal (mitochondria,cytosol,plasma)detoxification. Liver
is the most important organ for biotransformation but not the only one. Microsomal
detoxification is a process that depends on many specific enzymes related to smooth
endoplasmic reticulum majority of which are oxidases commonly called
polysubstratum monooxidases. They are also often called P-450 enzymes because
they contain cytochrome P-450. Reactions that require CP-450 also require
molecular oxygen and NADPH. The expression of microsomal enzyme can be
significantly inducced with many different substances (enzyme induction) that is also
followed with proliferation of endoplasmic reticulum. The best known compounds
that can induce microsomal enzymes are phenobarbital and chlorinated
hydrocarbons. There is also a huge number of substances that can suppress activity
of microsomal enzymes of which the most important is carbon disulfide that is often
present in the air as pollutant.
2.Bioactivation – metabolic activation of xenobiotic compounds into toxic,reactive compounds
In most cases toxic metabolites are created in reactions that are catalyzed by P-450 monooxygenase
but there also examples of toxicity intensified by synthetic reactions. So called "lethal synthesis"
happens if foreign substance (with structure similar to those of regular substrate) is incorporated in
biochemical pathway and metabolized into toxic product.Typical example is fluorineacetic acid by
itself non-toxic but as fluorineacetyl-CoA it is incorporated in Crebs cycle and it creates
fluorinecitric acid together with oxaloacetate. Fluorinecitrate blocks Crebs cycle because it
interferes with transmission of OH-groups from citrate to isocitrate. Microsomal liver enzymes
cause metabolic activation of carbon tetrachloride which results in hepatotoxic 3-chlorine-methyl-
peroxy-radicals. Acetyl-amino-fluorene through N-hydroxylation is converted into far more
carcenogenic N-hydroxy-acetyl-amine. Furthermore many chemical substances that are
carcinogenic are not active in their original forms until they are biotransformed. Oxidative
desulfurisation of parathion creates paraoxon,strong inhibitor of cholinesterase.

The factors that modify xenobiotic biotransformation

 Genetic variations are significant in synthesis of certain enzymes that are important and
irreplaceable for detoxification of certain molecules. Decreased activity of acetyl-CoA
transferase in liver is connected with increased toxicity of some medications. In persons that are
"slow acetylators" prolonged use of tuberculostatic isoniazid more often causes toxic
 Sex is also an important factor that can have effect on detoxification of certain xenobiotics. For
instance organophosphorous pesticide parathion is less toxic to male than female rats.
 Age of the organism is also very important.Newborns activity of microsomal enzymes and
enzymes responsible for conjugation is very small and this is the reason why many chemical
substances are far more dangerous for newborns than they are for older population groups. On
the other hand substances that undergo bioactivation (such as carbon tetrachloride) are less toxic
to newborns.
 Chronic inflammation and degradation of parenchyma (liver cirrhosis) will also decrease
detoxification potential of liver as well as many enviromental factors that cause stress.
 Biotransformation has its own capacity which may be affected. Capacity increases by induction
of biotransformation enzymes (monooxigenase, glucuronyl transferase, γ-glutamyl transferase)
and by reducing competition of xenobiotics for active sites. This causes complex interactions,
eg. in chronic alcoholics microsomal system is induced even when they are not drinking so they
are resistant to many xenobiotics but if they consume alcohol sensitivity to xenobiotics is

Excretion of xenobiotics-in the original form or via a conjugate or metabolite

The most important way of excretion is by urine. Others are: bile, feces, breath, saliva,
sweat, deposition in hair and nails, in the milk.
The rate of removal depends on the ability of separation of substances from bloodstream-
clearance (the volume of blood per unit of time is being relieved of the presence of certain
substances), and the removal of metabolism or excretion. It also depends on the distribution of
substances between the blood and tissues (the release rate in the circulation). The degree of removal
(ER) = (difference of conc. in an artery and a vein) / conc. in an artery. When the ER is high blood
flow changes will not affect its performance, and when the ER is low change will depend on time-
slowing of the flow will increase ER. The clearance is also relatively constant and independent of
the blood flow.


The effect may be non-specific (causing inflammation, necrosis) and specific (reaction with
only one kind of molecules). Basic mechanisms of action of xenobiotics on the body are:
1.Impairments of cell energy production
 Substances acting as uncouplers of oxidative phosphorylation (eg.2,3-dinitrophenol
(DNP)) hinder the creation of energy-rich phosphate compounds and the energy is
released as heat. The clinical picture is similar to hyperthyroidism (major feature
being hyperthermia). Due to the large useless release of energy DNP was used as an
agent for weight loss.
 Cyanide – is covalently linked to trivalent iron in the cytochrome C oxidase, leading
to its inhibition that disables electron transmission and utilization of oxygen
(hemoglobin saturation is not disturbed so there is no cyanosis) .It is treated in a way
that divalent iron converts into trivalent iron that binds cyanide achieving liberation
of Fe as part of cytochrome and thus enable electron transport.
2.Oxygen transport disorders
 Carbon monoxide - is bound to Fe in the hemoglobin (210 x higher afnitet than
oxygen) to form carboxyhemoglobin
 Nitrites - the oxidation of iron in hemoglobin and methemoglobin formation (as well
as carboxyhemoglobin it can not carry oxygen) which leads to tissue hypoxia.
 Clastogenic effects - changes in the structure of chromosomes
 mutagenicity - chemical DNA damage due to direct transformation of a base,
installation of abnormal base analog , alkylation/arylation of purine and pyrimidine
 Important etiological factors of teratogenicity and carcinogenesis
4.Protein synthesis disorders
 α-amanitin (poison from Amanita phalloides mushroom) and alkylating compounds
(nitrosamines, cytostatics) are inhibiting transcription
 inhibition of translation initiation (mycotoxins-secondary metabolites of mold)
 stop the elongation of the polypeptide chain (diphtheria toxin and ricin from castor
oil seeds)
 heavy metals (mercury,cadmium) at high concentrations cause disintegration of
 xenobiotics that increase the amount of free radicals also interfere with protein

5.Inhibition of enzymes
 due to the substrate accumulation
 due to the lack of the reaction product - inhibition of acetylcholinesterase (degrades
acetylcholine) by anticholinesterase. Anticholinesterases are applied as pesticides in
public health. There are two main groups:
◦ esters of phosphoric acid so called organophosphorous compounds (irreversible
effect if part of the enzyme is cleaved(aging)
◦ esters of carbamic acid so called carbamates (reversible - acylated enzyme reacts
with the water and can be fully reactivated)
◦ The acylation reaction depends on the temperature; reaction rate constant
depends on inhibitor. Knowing the rate constant of acylation and reactivation as
well as rate of aging we can estimate anticholinesterase activity.
◦ Except organophosphorus insecticides aging is characteristic of poison gases
(sarin). Clinically most evident sign of intoxication are seizures that rapidly
progress to status epilepticus and damage the brain. Central neurotoxic effect
rises frrom accumulation of acetylcholine and permanent stimulation of
muscarinic receptor. But far more important role has excessive liberation of
glutamate which in high concentrations is directly neurotoxic (becoming a major
◦ trivalent arsenic binds to sulfhydryl groups of proteins which causes the
inhibition of enzymes containing SH groups.Inhibition of pyruvate -
dehydrogenase and phosphatase increase concentration of pyruvate and decrease
tissue breathing. (Lewisit = poison containing arsenic)
6.Receptor function impairment
 The effect on the hormone receptors and neurotransmitter receptors can be:
 agonistic
 antagonistic
 example: α-bungarotoxin (acetylcholine receptors); dioxin (receptors for steroid hormones)
= has one of the strongest immunosuppressive, carcinogenic andteratogenic effects.
7.Disorders of membrane permeability
 lysosomal membrane destabilizers - bee poison - liberates histamine
 disrupted activity of ion channels and membrane ion pumps - eg. insecticides from the
group of chlorinated hydrocarbons (DDT) which prevent closing of the door for sodium
8.Formation of free radicals
 Numerous substances especially quinones can stimulate reduction .Those substances
are reduced by taking an electron from NADPH. Newly reduced compound returns
to its original state when oxidized by molecular oxygen, leading to the formation of
superoxide anion.Superoxide anion can trigger carcinogenesis, cause DNA
mutations, damage membrane by lipid peroxidation, inactivate enzymes.Glutathione
peroxidase, catalase, superoxide dismutase and vitamins A, C, E provide protection
from it.
 Free radicals are created by
 anthracycline anti-cancer drugs
 carbon tetrachloride-activates hepatic P450 enzyme into trichloromethyl and
trichloromethyl peroxyl radicals. The result is centrolobullar necrosis.
 Paraquat (pneumotoxic herbicide) -swallowing causes damage to the lining of the
mouth, esophagus, nausea and vomiting, diarrhea and reduced renal function (if
the doses are not hugesymptoms dissapear rapidly). After several days
pronounced signs of lung damage and often destructive lung edema can be
observed. This occurs because paraquat is pilled up in the lungs (it is attracted
by oxygen). It is reduced by cellular reductase which leads to lack NADPH.
Reduced form of paraquat gives electron to oxygen and thus produce superoxide
anion. Lack of NADPH and superoxide anions lead to cell damage.

132.Pathophysiological Mechanisms of Infective Diseases

Infections all start out as inflammation and the body develops long term protection in the long run
usually. Often it is a synergistic effect.
Clinically Important Diseases can be divided into:
1. Acute or subacute course. Where there is inflammation and immunologic reaction but it is
cleared and healed without compromise.
2. Permanent or Chronic stimulus that is not removed. Chronic Infectious Diseases
(Tuberculosis)- here you can talk about caseating necrosis and other factors of TB
a) Percutaneous Toxic Syndrome
b) Sepcific Toxic Syndromes
c) Acute Infective Illness
d) SIRS, Sepsis, MODS, MOFS
e) Chronic infective Diseases (TB)
f) Autoimmunity
g) Immunoinsufficiency
h) Viral oncogenesis (HPV, EBV)

Here you can use Algorithm on sepsis or AIDS would also be a good one.

133.Haematological and Metabolic Changes Caused by Activities of Infectious Factors

1. Changes in the Blood
a) Changes in blood plasma
-plasmatic protein
I. changes in mutual relations between albumin and globulin
II. acute infection the concentration of albumin is reduced and increased by the liver
III. Chronic infections, the concentration of alpha-globulin is elevated

b) Sedimentation of erythrocyte- accelerated

I. When infection lasts longer than a few weeks “CHRONIC ANEMIA” infectious stage
II. In acute infection Hemolytic Anemia (ALGORITHM)
III. Destruction of bone marrow by infection “ aplastic anemia” develops

c) Leukocytes
I. Most of acute bacterial infections are accompanied with leukocytosis (increase in the
number of neutrophil granulocytes)
II. some infections (Measles, infective mono) are followed by neutropenia
III. Viruses cause LYMPHOCYTES

d) Blood Coagulation Disorders

-Changes in platelet- thrombocytopenia
-Disseminated intravascular coagulation (DIC)
I. uncontrolled activation of blood clotting in larger areas of blood bypass (triggers infectious
II. Microplatelets are deposited in small blood vessels and block blood flow
III. clotting factors are drained and risk of bleeding is increased

2. Metabolic Changes
a) Increased catabolism of protein
b) changes in electrolyte and water transport (ALGORITHM)
c) Increased concentration of total plasmatic lipids

Septic Collapse: Changes first occur in peripheral-> MOFS

Oxidation of glucose is disrupted- blocks entry of pyruvate into krebs cycle, breaking creation and
energy consumption.


134.Pathogenetic Mechanisms of PRION and Degenerative Diseases

Review Robbins Page 831-832


Prion disease represents a group of conditions that affect the nervous system in humans and
animals. In people, these conditions impair brain function, causing changes in memory, personality,
and behavior; a decline in intellectual function (dementia); and abnormal movements, particularly
difficulty with coordinating movements (ataxia). The signs and symptoms of prion disease typically
begin in adulthood and worsen with time, leading to death within a few months to several years.

Kuru is a very rare disease. It is caused by an infectious protein found in contaminated human brain
Kuru is found among people from New Guinea who practiced a form of cannibalism in which they
ate the brains of dead people as part of a funeral ritual. This practice stopped in 1960, but cases of
kuru were reported for many years afterward because the disease has a long incubation period. The
incubation period is the time it takes for symptoms to appear after being exposed to the agent that
causes disease.

Kuru causes brain and nervous system changes similar to Creutzfeldt-Jakob disease. Similar
diseases appear in cows as bovine spongiform encephalopathy (BSE), also called mad cow disease.

Symptoms of kuru include:
• Arm and leg pain
• Coordination problems that become severe
• Difficulty walking
• Headache
• Swallowing difficulty
• Tremors and muscle jerks
Difficulty swallowing and being unable to feed oneself can lead to malnutrition or starvation.

Creutzfeldt-Jakob disease (CJD)

-is a form of brain damage that leads to a rapid decrease of movement and mental function.

CJD is caused by a protein called a prion. A prion causes normal proteins to fold abnormally. This
affects other proteins' ability to function.

CJD is very rare. It occurs in about 1 out of every 1 million people. There are several types of CJD.
It can be grouped into sporadic, familial, or acquired types.

The classic types of CJD are:

• Sporadic CJD makes up most cases. It occurs for no known reason. The average age at which
it starts is 65.
• Familial CJD occurs when a person inherits the abnormal prion from a parent (this form of
CJD is rare).
• Acquired CJD includes variant CJD (vCJD), the form related to mad cow disease; and
iatrogenic CJD, in which the disease is sometimes passed through a blood product
transfusion, transplant, or contaminated surgical instruments.

Variant CJD is caused by eating infected meat. The infection that causes the disease in cows is
believed to be the same one that causes vCJD in humans.

CJD may be related to several other diseases caused by prions, including:

• Chronic wasting disease (found in deer)
• Kuru (seen in New Guinea women who ate the brains of dead relatives as part of a funeral
• Scrapie (found in sheep)
• Other very rare inherited human diseases, such as Gerstmann-Straussler-Scheinker disease and
fatal familial insomnia

• Blurred vision (sometimes)
• Changes in gait (walking)
• Confusion, Disorientation
• Hallucinations (seeing things that aren't there)
• Lack of coordination (for example, stumbling and falling)
• Muscle stiffness
• Muscle twitching
• Nervous, jumpy feelings
• Personality changes
• Sleepiness
• Sudden jerky movements or seizures
• Trouble speaking
• Dementia that gets worse quickly over a few weeks or months

CJD is rarely confused with other types of dementia (such as Alzheimer's disease) because the
symptoms get worse much more quickly in CJD.

135. Immunological Alterations in Infections

- Skin and Mucosa
- macrophages
- alternative way of activation complement
- lymph nodes
- monocytes and neutrophils in the blood
- reticuloendothelin cell system in the liver
- humorous (Extracellular bacteria) and cellular (intracellular bacteria) Immune Mechanisms

- skin and visible epithelia
- macrophages
- Cytotoxic T lymphocytes, NK cells

- nonspecific phagocytes (macrophages)
- IgE antibodies
- Eosinophils **

- cells
- antibodies

Here you can basically just talk about the way different cells work and kill off offending agents.
Talk about inflammation. Basically anyway that you can include “inflammation, oxidative
metabolism, ROS, Stress, Sepsis, Shock” is a good direction to go into :) It may seem repetitive, but
there are a few topics the prof is really into and you will notice that he will try and gear you towards
them anyways.

136.Pathophysiology of Septic and Toxic Collapse (see what I mean? :))


Sepsis: THIEME PAGE 246

Sepsis is a potentially life-threatening complication of an infection. Sepsis occurs when chemicals

released into the bloodstream to fight the infection trigger inflammatory responses throughout the
body. This inflammation can trigger a cascade of changes that can damage multiple organ systems,
causing them to fail.

If sepsis progresses to septic shock, blood pressure drops dramatically, which may lead to death.
Anyone can develop sepsis, but it's most common and most dangerous in older adults or those with
weakened immune systems. Early treatment of sepsis, usually with antibiotics and large amounts of
intravenous fluids, improves chances for survival.

To be diagnosed with sepsis, you must exhibit at least two of the following symptoms:
• Body temperature above 101 F (38.3 C) or below 96.8 F (36 C)
• Heart rate higher than 90 beats a minute
• Respiratory rate higher than 20 breaths a minute
• Probable or confirmed infection
Severe sepsis
Your diagnosis will be upgraded to severe sepsis if you also exhibit at least one of the following
signs and symptoms, which indicate an organ may be failing:
• Significantly decreased urine output
• Abrupt change in mental status
• Decrease in platelet count
• Difficulty breathing
• Abnormal heart pumping function
• Abdominal pain

Septic Shock:

To be diagnosed with septic shock, you must have the signs and symptoms of severe sepsis — plus
extremely low blood pressure that doesn't adequately respond to simple fluid replacement.

Toxic Collapse: Except for the basic pathogenesis, septic collapse includes the effects of
SUPERANTIGEN (exotoxins acting like not-specific mitogenic-triggers 5-10% of all T-
lymphocytes- cause strong Th1 secretion of cytokines)

137.Outcome of Infection

1. Factors that determine outcome of Infections

A)Infectious Germs:
- Their resistance to phagocytosis
- Changes in surface antigens (viral proteins capable of binding to normal cell components)
- Anergy (smallpox, leprosy, TB miliar)

B) Host
- genetic characteristics
- age
- nourishment
- other host diseases (diabetes, alcoholic cirrhosis, malignant tumours, insufficient adrenal
glands, splenectomy)
- host with suppressed immune system (ALGORITHM ON CUSHINGS SYNDROME can
help explain increased risk of infection)

2. While Recovering
- incubation
- initial period
- period of developed disease
- period of regression (withdrawal disease)- deterioration of illness
- period of healing (convalescence)- reappearance of illness

3. Permanent Infection
- Carrier (HBV, HPV)
- Chronic Infectious Diseases (TB, Leprosy, Syphilis)
- Latent Infection (varicella-zoster, Typhoid)

138.Disorders of Collagen Structure and Function

Collagen is a protein made up of amino-acids, which are in turn built of carbon, oxygen and
hydrogen. Collagen contains specific amino acids – Glycine, Proline, Hydroxyproline and Arginine.
Collagen makes up approximately 30% of the proteins within the body. These are tough and strong
structures found all over the body: in bones, tendons and ligaments.

Where is collagen found?

In nature, collagen is found exclusively in animals, especially in the flesh and connective tissues of
mammals. Collagen is a part of the connective tissue that in the skin helps in firmness, suppleness
and constant renewal of skin cells. Collagen is vital for skin elasticity.
Ligaments are another type of connective tissue that attach two bones and consequently hold the
joints together. Tendons are similar but different type of tissue that attach the muscles to the bones.
All of these tissues, the bones, ligaments, tendons and the skeletal muscles themselves, are made up
of proteins. One of the most predominant proteins is called collagen.

What does collagen do?

Collagen helps to give strength to various structures of the body and also protects structures like the
skin by preventing absorption and spreading of pathogenic substances, environmental toxins, micro
- organisms and cancerous cells. Collagen protein is the cement that holds everything together.

Collagen is also present in all the smooth muscle tissues, blood vessels digestive tract, heart,
gallbladder, kidneys and bladder holding the cells and tissues together. Collagen is even the major
component of the hair and nails.

Aging and collagen

With age, collagen production slows and the cells structures weaken. The skin gets thinner and is
easier to damage, hair gets lifeless, skin sags and wrinkles, tendons and ligaments become less
elastic, joints get stiff etc.

Structure of collagen
Collagen microscopically occurs in elongated fibrils. It is mostly found in fibrous tissues such as
tendon, ligament and skin, and is also abundant in cornea, bone, blood vessels, cartilage,
intervertebral disc and the digestive tract.
In muscle tissue, collagen serves as a major component of endomysium.1 to 2% of the muscles are
formed of collagen and around 6% of the total weight of muscles is formed of collagen.

Collagen occurs in many places throughout the body. Over 90% of the collagen in the body,
however, is type I.

So far, 28 types of collagen have been identified and described. They can be divided into several
groups according to the structure they form:
• Fibrillar (Type I, II, III, V, XI)
• Short chain (Type VIII, X)
• Basement membrane (Type IV) [NONFIBRILLAR COLLAGEN]
• Other (Type VI, VII, XIII)

The five most common types are:

• Type I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of
• Type II: cartilage (main collagenous component of cartilage)
• Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
• Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
• Type V: cell surfaces, hair and placenta

Review Robbins page 220-221

Marfan and Ehlers-Danlos Syndromes

Osteogenesis Imperfecta (ALGORITHM)

139.Metabolic Disorders of the Skeletal System

1. OSTEOMALACIA and RICKETS: Review Robbins Page 298-301

2. OSTEOPOROSIS: (ALGORITHM) you can also mention that cushings disease/syndrome

predisposes an individual to osteoporosis.

There typically are no symptoms in the early stages of bone loss. But once bones have been
weakened by osteoporosis, you may have signs and symptoms that include:
• Back pain, caused by a fractured or collapsed vertebra
• Loss of height over time
• A stooped posture
• A bone fracture that occurs much more easily than expected

Two types:

a) Essential or Idiopathic (cause not known)

-postemenopausal (ALGORITHM)- lack of estrogen causes an increase in osteoclast
activity. Activation of IL-1, IL-6, TNF-alpha. Reduction of apoptosis. Shortened life-span
of osteoclasts. Reduces level of calcium. More frequent fractures in the pectoral spine and

b) Secondary (consequence of pre-existing disease (CUSHINGS) or drug)

Juvenile osteoporosis: in children before puberty, spontaneous healing

PAGET’S DISEASE: Osteitis deformans

-chronic disorder that typically results in enlarged and deformed bones

*Review Robbins Page 770-771

140.Anemias- General Pathogenesis and Consequences

Anemia is strictly defined as a decrease in red blood cell (RBC) mass. The function of the RBC is to
deliver oxygen from the lungs to the tissues and carbon dioxide from the tissues to the lungs. This is
accomplished by using hemoglobin (Hb), a tetramer protein composed of heme and globin. Anemia
impairs the body’s ability for gas exchange by decreasing the number of RBCs transporting oxygen
and carbon dioxide.

The most serious complications of severe anemia arise from tissue hypoxia. Shock, hypotension, or
coronary and pulmonary insufficiency can occur. This is more common in older individuals with
underlying pulmonary and cardiovascular disease.

The physiologic response to anemia varies according to acuity and the type of insult. Gradual onset
may allow for compensatory mechanisms to take place. With anemia due to acute blood loss, a
reduction in oxygen-carrying capacity occurs along with a decrease in intravascular volume, with
resultant hypoxia and hypovolemia. Hypovolemia leads to hypotension, which is detected by stretch
receptors in the carotid bulb, aortic arch, heart, and lungs.
These receptors transmit impulses along afferent fibers of the vagus and glossopharyngeal
nerves to the medulla oblongata, cerebral cortex, and pituitary gland.
In the medulla, sympathetic outflow is enhanced, while parasympathetic activity is
diminished. Increased sympathetic outflow leads to norepinephrine release from sympathetic nerve
endings and discharge of epinephrine and norepinephrine from the adrenal medulla.

Sympathetic connection to the hypothalamic nuclei increases antidiuretic hormone (ADH) secretion
from the pituitary gland. ADH increases free water reabsorption in the distal collecting tubules. In
response to decreased renal perfusion, juxtaglomerular cells in the afferent arterioles release renin
into the renal circulation, leading to increased angiotensin I, which is converted by angiotensin-
converting enzyme (ACE) to angiotensin II.

Angiotensin II has a potent pressor effect on arteriolar smooth muscle. Angiotensin II also
stimulates the zona glomerulosa of the adrenal cortex to produce aldosterone. Aldosterone increases
sodium reabsorption from the proximal tubules of the kidney, thus increasing intravascular volume.
The primary effect of the sympathetic nervous system is to maintain perfusion to the tissues
by increasing systemic vascular resistance (SVR). The augmented venous tone increases the preload
and, hence, the end-diastolic volume, which increases stroke volume. Therefore, stroke volume,
heart rate, and SVR all are maximized by the sympathetic nervous system. Oxygen delivery is
enhanced by the increased blood flow.

In states of hypovolemic hypoxia, the increased venous tone due to sympathetic discharge is
thought to dominate the vasodilator effects of hypoxia. Counterregulatory hormones (eg, glucagon,
epinephrine, cortisol) are thought to shift intracellular water to the intravascular space, perhaps
because of the resultant hyperglycemia.

CONSEQUENCES: Reduced Tissue Oxygenation

SHIFT OF Hb-O dissociation curve to the right : because of increased concentrations of 2,3-DPG

Redistribution of Blood:
-Reduced total peripheral resistance due to reduced viscosity
-increased venous flow

141.Disorders of Erythropoiesis and Erythrocyte Maturation

MEGALOBLASTIC ANEMIA: folate and B12 deficiency Anemia: ALGORITHM!

Thieme Page 34, 38

IRON DEFICIENCY ANEMIA: Robbins Page 420-421


Aplastic anemia is a condition that occurs when your body stops producing enough new blood cells.
Aplastic anemia leaves you feeling fatigued and with a higher risk of infections and uncontrolled
A rare and serious condition, aplastic anemia can develop at any age. Aplastic anemia may occur
suddenly, or it can occur slowly and get worse over a long period of time. Treatment for aplastic
anemia may include medications, blood transfusions or a stem cell transplant.

Aplastic anemia develops when damage occurs to your bone marrow, slowing or shutting down the
production of new blood cells. Bone marrow is a red, spongy material inside your bones that
produces stem cells, which give rise to other cells. Stem cells in the bone marrow produce blood
cells — red cells, white cells and platelets. In aplastic anemia, the bone marrow is described in
medical terms as aplastic or hypoplastic — meaning that it's empty (aplastic) or contains very few
blood cells (hypoplastic).
Factors that can temporarily or permanently injure bone marrow and affect blood cell production
• Radiation and chemotherapy treatments. While these cancer-fighting therapies kill cancer
cells, they can also damage healthy cells, including stem cells in bone marrow. Aplastic
anemia can be a temporary side effect of these treatments.
• Exposure to toxic chemicals. Exposure to toxic chemicals, such as some used in pesticides
and insecticides, may cause aplastic anemia. Exposure to benzene — an ingredient in
gasoline — also has been linked to aplastic anemia. This type of anemia may get better on
its own if you avoid repeated exposure to the chemicals that caused your initial illness.
• Use of certain drugs. Some medications, such as those used to treat rheumatoid arthritis and
some antibiotics, can cause aplastic anemia.
• Autoimmune disorders. An autoimmune disorder, in which your immune system begins
attacking healthy cells, may involve stem cells in your bone marrow.
• A viral infection. Viral infections that affect bone marrow may play a role in the development
of aplastic anemia in some people. Viruses that have been linked to the development of
aplastic anemia include hepatitis, Epstein-Barr, cytomegalovirus, parvovirus B19 and HIV.
• Pregnancy. Aplastic anemia that occurs in pregnancy may be related to an autoimmune
problem — your immune system may attack your bone marrow during pregnancy.

142.Disorders of Hemoglobin Synthesis and Structure

Hemoglobin is produced by genes that control the expression of the hemoglobin protein. Defects in
these genes can produce abnormal hemoglobins and anemia, which are conditions termed
"hemoglobinopathies". Abnormal hemoglobins appear in one of three basic circumstances:
 Structural defects in the hemoglobin molecule. Alterations in the gene for one of the two
hemoglobin subunit chains, alpha (a) or beta (b), are called mutations. Often, mutations
change a single amino acid building block in the subunit. Most commonly the change is
innocuous, perturbing neither the structure nor function of the hemoglobin molecule.
Occasionally, alteration of a single amino acid dramatically disturbs the behavior of the
hemoglobin molecule and produces a disease state. Sickle hemoglobin exemplifies this
 Diminished production of one of the two subunits of the hemoglobin molecule. Mutations that
produce this condition are termed "thalassemias." Equal numbers of hemoglobin alpha and
beta chains are necessary for normal function. Hemoglobin chain imbalance damages and
destroys red cells thereby producing anemia. Although there is a dearth of the affected
hemoglobin subunit, with most thalassemias the few subunits synthesized are structurally

 Abnormal associations of otherwise normal subunits. A single subunit of the alpha chain (from
the a-globin locus) and a single subunit from the b-globin locus combine to produce a
normal hemoglobin dimer. With severe a-thalassemia, the b-globin subunits begin to
associate into groups of four (tetramers) due to the paucity of potential a-chain partners.
These tetramers of b-globin subunits are functionally inactive and do not transport oxygen.
No comparable tetramers of alpha globin subunits form with severe beta-thalassemia. Alpha
subunits are rapidly degraded in the absence of a partner from the beta-globin gene cluster
(gamma, delta, beta globin subunits).

Types of hemoglobins
There are hundreds of hemoglobin variants that involve involve genes both from the alpha and beta
gene clusters. The list below touches on some of the more common and important hemoglobin
Normal Hemoglobins
• Hemoglobin A. This is the designation for the normal hemoglobin that exists after birth.
Hemoglobin A is a tetramer with two alpha chains and two beta chains (a2b2).
• Hemoglobin A2. This is a minor component of the hemoglobin found in red cells after birth
and consists of two alpha chains and two delta chains (a2d2). Hemoglobin A2 generally
comprises less than 3% of the total red cell hemoglobin.
• Hemoglobin F. Hemoglobin F is the predominant hemoglobin during fetal development. The
molecule is a tetramer of two alpha chains and two gamma chains (a2g2).
The genes for hemoglobin F and hemoglobin A are closely related, existing in the same gene cluster
on chromosome 11. Hemoglobin F production falls dramatically after birth, although some people
continue to produce small amounts of hemoglobin F for their entire lives.

Thalassemia: Mutations from loss of one or both alpha chains or one or both beta chains of the Hb
The thalassemias are a group of disorders in which the normal hemoglobin protein is produced in
lower amounts than usual. The genes are defective in the amount of hemoglobin they produce, but
that which they produce (generally) is normal. The thalassemias are a complex group of disorders
because of the genetics of hemoglobin production and the structure of the hemoglobin molecule.

Hemoglobin SC disease: Mutation arises in the beta chain of the Hb causing malformation
- Patients with hemoglobin SC disease inherit a gene for hemoglobin S from one parent, and a gene
for hemoglobin C from the other. Hemoglobin C interacts with hemoglobin S to produce some of
the abnormalities seen in patients with sickle cell disease.

On average, patients with hemoglobin SC disease have milder symptoms than do those with
sickle cell disease. This is only an average, however. Some people with hemoglobin SC disease
have a condition equal in severity to that of any patient with sickle cell disease. A number other
syndromes exist that involve a hemoglobin S compound heterozyous state. They are less common
than hemoglobin SC disease, however.
Ironically, hemoglobin SC disease is often a much more severe condition than is
homozygous hemoglobin C disease. The expression of a single hemoglobin S gene normally
produces no problem (i.e., sickle cell trait). The hemoglobin C molecule disturbs the red cell
metabolism only slightly. However, the disturbance is enough to allow the deleterious effects of the
hemoglobin S to be manifested.

Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of RBCs,
either in the blood vessels (intravascular hemolysis) or elsewhere in the human body
(extravascular). It has numerous possible causes, ranging from relatively harmless to life-
threatening. The general classification of hemolytic anemia is either inherited or acquired.
Treatment depends on the cause and nature of the breakdown.
Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness
of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of
particular long-term complications, such as gallstones and pulmonary hypertension.
Hemolytic anemia involves the following:
 Abnormal and accelerated destruction of red cells and, in some anemias, their precursors
 Increased breakdown of hemoglobin, which may result in:
 increased bilirubin level (mainly indirect-reacting) with jaundice
 increased fecal and urinary urobilinogen
 Hemoglobinemia,methemoglobinemia,hemoglobinuria and hemosiderinuria(where there
is significant intravascular hemolysis).
 Bone marrow compensatory reaction:
 Erythroid hyperplasia with accelerated production of red cells, reflected by
reticulocytosis, and slight macrocytosis in peripheral blood
 Expansion of bone marrow in infants and children with severe chronic hemolysis -
changes in bone configuration visible on X-ray
 The balance between red cell destruction and marrow compensation determines the
severity of anemias.
Hemolytic anemias are divided into 2 groups:
A) corpuscular hemolytic anemia (the cause is related to the RBC itself):
 erythrocyte membrane disorders
a) damage in proteins of cytoskeleton that are reflected as changes in shape
b) e.g. spherocytosis with small spherical erythrocytes
 defective RBC metabolism
a) e.g. lack of glucose-6-phosphate dehydrogenase (X-linked , G6PD converts
glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting
enzyme of this metabolic pathway that supplies reducing energy to cells by

maintaining the level of the reduced form of the coenzyme NADPH. The
NADPH in turn maintains the supply of reduced glutathione in the cells that is
used to mop up free radicals that cause oxidative damage.The G6PD / NADPH
pathway is the only source of reduced glutathione in red blood cells.
b) e.g. piruvat- kinase deficiency (autosomal recessive; erythrocyte life is shortened
because ATP is not produced in the last stage of glycolysis).
c) e.g. methemoglobinemia (hereditary -lack of the enzyme methemoglobin
reductase; acquired - caused by toxic action of chemical substances and drugs
that oxidize Fe 2+ to Fe 3+).
B)extracorpuscular (autoimmune) hemolytic anemia
 Acquired anemia caused by autoantibodies against erythrocyte antigens.
 Autoantibodies can be warm (IgG, react at 37 ° C) and cold (IgM, react at lower
temperatures). The erythrocytes that are bound to the autoantibodies are
phagocytosed or lysed(complement).
 e.g. fetal erythroblastosis is an alloimmune condition that develops in a fetus, when
the IgG molecules produced by the mother pass through the placenta. Among these
antibodies are some which attack the RBCs in the fetal circulation. The red blood
cells are broken down and the fetus can develop reticulocytosis and anemia. This
fetal disease ranges from mild to very severe, and fetal death from heart failure
(hydrops fetalis) can occur. When the disease is moderate or severe, many
erythroblasts are present in the fetal blood.
 Immune-mediated causes could include transient factors as in Mycoplasma
pneumoniae infection (cold agglutinin disease) or permanent factors as in
autoimmune diseases like autoimmune hemolytic anemia (itself more common in
diseases such as SLE, rheumatoid arthritis,Hodgkin's lymphoma and chronic
lymphocytic leukemia).
◦ Paroxysmal nocturnal hemoglobinuria(PNH), sometimes referred to as
Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening
disease of the blood characterized by complement-induced intravascular hemolytic
◦ Any of the causes of hypersplenism(increased activity of the spleen), such as
portal hypertension.
◦ Acquired hemolytic anemia is also encountered in burns and as a result of certain
◦ Lead poisoning resulting from the environment causes non-immune hemolytic
◦ Runners can suffer hemolytic anemia due to "footstrike hemolysis", owing to the
destruction of red blood cells in feet at foot impact.
◦ Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients,
and severe hemolytic anemia occurs in 3%


Polycythemia is a pathological condition in which there is an increased number of all blood
cells. Erythrocytosis is a pathological condition in which only erythrocytes are increased.
Erythrocytosis may be:
a)ABSOLUTE (increased production of red blood cells)
They are called secondary when resulting from excessive secretion of erythropoietin in conditions
of hypoxia (reduced oxygen saturation of hemoglobin, decreased capacity of the blood to carry
b)RELATIVE (plasma volume is reduced and the total mass of red blood cells is normal)
The most common cause is dehydration, which occurs due to heavy urination after taking diuretics,
due to excessive sweating, vomiting or diarrhea.

Polycythemia vera is a disease in which multiplication of stem cells in the bone marrow is
increased and as well as outside bone marrow (eg, spleen). Neoplastic proliferation of myelopoietic
cells in the bone marrow being the cause of the disease. The reduced concentration of
erythropoietin due to the inhibitory action of increased red cell mass on renal factor. In the
peripheral blood of patients with polycythemia number of erythrocytes can be 12x10 12 / L, the
hemoglobin concentration of 250 g / L and 80% hematocrit. With the increased number of red blood
cells, there is a leukocytosis and thrombocytosis; platelets often exhibit morphological and
functional irregularities and this is particularly evident in a reduced ability of clot retraction. In
30% of cases the disease develops into myelofibrosis, and 15% in acute myeloid leukemia.


Leukocytes make cellular basis of the inflammatory and immune response. The increase in
the number of leukocytes in peripheral blood (> 10x109 / L) is called leukocytosis, and a decrease in
the number of leukocytes in peripheral blood (<3.5x109 / L) is called leukopenia.
We can talk about the quantity and function disorder of immunocytes (lymphocytes and
plasma cells), and about the quantity and function disorder of phagocytes (granulocytes and

A) immune cells - their number and function in the body usually changes due to the impact
of antigens from the environment; it is manifested as lymphadenopathy, splenomegaly, presence of
plasmocytes, plasmoblasts and lymphoblasts in the blood.
When the number of lymphocytes is lower than 1-1.5x109 / L we are talking about
lymphocytopenia which usually occurs due to reduced production and increased destruction of
lymphocytes. The increased loss of cells can occur due to leakage of lymph or X-ray radiation.
Patients with AIDS gradually develop selective CD4 + lymphocytopenia due to cytotropism of HIV
virus to these cells.
When the number of lymphocytes in adults is greater than 5x109 / L lymphocytosis is diagnosed;
most commonly develops in adrenal insufficiency, viral infections, lymphoproliferative diseases, in
non-Hodgink's and Hodgink's lymphoma, ALL, CLL.

B) Phagocytes have receptors for the Fc fragment of immunoglobulin and C3 complement

component which greatly facilitate phagocytosis.
 Granulocytopenia (granulocyte count is less than 3x109 / L) develops in megaloblastic
anemia and in conditions with increased destruction of the granulocytes in the blood. It can
be seen before other forms of cytopenia because these cells have a short life span and small
 Agranulocytosis is the ultimate form of reduction in the number of granulocytes, when
immature granulocytes appear in the blood.
 Granulocytosis(granulocyte count greater than 1x1010 / L) may occur due to an acute
infection, injury or emotional stress. When granulocyte count exceeds 3x1010 / L leukemoid
reaction is apparent.
 Eosinophilia (increased number of eosinophils) occurs in helminth infestations and allergic
 Eosinopaenia (reduced number of eosinophils) occurs with increased secretion of cortisol
and corticosteroid treatment. Functional disorders of granulocytes with their normal number
cause reduced resistance to infection.
2. monocytes – macrophages
 Monocytosis- increased number of monocytes over 5x107 / L and it is usually caused by
bacterial infections, protozoa and rickettsiae.
 Monocytosis can be found in lymphoma, chronic myelomonocytic leukemia and chronic
granulocytic leukemia .
 In chronic infections number of macrophages in the tissues increases, which can cause
splenomegaly and lymphadenopathy.

Leukemias are a group of heterogeneous neoplastic disorders of white blood cells. Based on
their origin, myeloid or lymphoid, they can be divided into two types. Leukemias traditionally have
been designated as acute or chronic, based on their untreated course. Acute leukemias usually
present as hemorrhage, anemia, infection, or infiltration of organs.Many patients with chronic
leukemias are asymptomatic. Other patients present with splenomegaly, fever, weight loss, malaise,
frequent infections, bleeding, thrombosis, or lymphadenopathy. Some chronic leukemias enter a
blast phase where the clinical manifestations are similar to the acute leukemias.
Chronic myelogenous leukemia(CML) is characterized by an uncontrolled proliferation of
granulocytes. An accompanying proliferation of erythroid cells and megakaryocytes is usually
present. Many patients are asymptomatic but may present with splenomegaly, weight loss, malaise,
bleeding, or thrombosis.
Chronic lymphocytic leukemia(CLL) represents a monoclonal expansion of lymphocytes. In
95% of cases, CLL is a predominantly malignant clonal disorder of B lymphocytes. The remainder
is secondary to a T-cell clone. The neoplastic cell is a hypoproliferative, immunologically
incompetent small lymphocyte. There is primary involvement of the bone marrow and secondary
release into the peripheral blood. The recirculating lymphocytes selectively infiltrate the lymph
nodes, the spleen, and the liver. Most patients are asymptomatic at diagnosis. As the disease
progresses, lymphadenopathy, splenomegaly, and hepatomegaly develop. A secondary immune
deficiency with hypogammaglobulinemia exists. A study by Wang et al found that when they
studied the landscape of somatic mutations in chronic lymphocytic leukemia, pre-mRNA splicing
was an important cellular process.

Acute lymphocytic leukemia (ALL) is a malignant clonal disorder of the bone marrow

lymphopoietic precursor cells. In ALL, progressive medullary and extramedullary accumulations of
lymphoblasts are present that lack the potential for differentiation and maturation. An inhibition of
the normal development of hematopoietic cell elements occurs. The clinical presentation is
dominated by progressive weakness and fatigue secondary to anemia, infection secondary to
leukopenia, and bleeding secondary to thrombocytopenia. When 50% of the bone marrow is
replaced, then peripheral blood cytopenias are observed.

Acute myelogenous leukemia (AML) is a group of neoplastic disorders of the hematopoietic

precursor cells of the bone marrow. AML is subdivided by the French-American-British system into
6 categories depending on the morphology. AML is not a disorder of rapidly proliferating neoplastic
cells. The time for one cell division is prolonged with respect to that of normal bone marrow blast
cells. A failure of maturation of the neoplastic cell clone exists. The bone marrow is gradually
replaced by blast cells. Therefore, the most important complications are progressive anemia,
leukopenia, and thrombocytopenia.


In leukemias, a clone of malignant cells may arise at any stage of maturation, that is, in the
lymphoid, myeloid, or pluripotential stage. The cause for this clonal expansion is poorly understood
in most cases, but it appears to involve some rearrangement of the DNA. External factors, such as
alkylating drugs, ionizing radiation, and chemicals, and internal factors, such as chromosomal
abnormalities, lead to DNA changes.

Chromosomal rearrangements may alter the structure or regulation of cellular oncogenes.

For instance, in the B-cell lymphocytic leukemias, chromosomal translocations may put the genes
that normally regulate heavy and light chain immunoglobulin synthesis next to the genes that
regulate normal cellular activation and proliferation. This results in proliferation of lymphoblasts.
As the population of cells expands, the bone marrow starts to fail. Pancytopenia is typical and
results in part from the physical replacement of normal marrow elements by the immature cells. In
addition, the abnormal cells may secrete factors that inhibit normal hematopoiesis.

As the bone marrow becomes replaced, the abnormal cells spill into the circulation and
infiltrate other organs, such as the liver, the spleen, and the eye. The ocular manifestations may be
secondary to direct infiltration of the leukemic cells, as a result of abnormal systemic hematological
parameters, opportunistic infections, or iatrogenic complications arising from chemotherapy.


Thrombophilia (sometimes hypercoagulability or a prothrombotic state) is an abnormality of

blood coagulation that increases the risk of thrombosis.Such abnormalities can be identified in 50%
of people who have an episode of thrombosis (such as deep vein thrombosis in the leg) that was not
provoked by other causes. A significant proportion of the population has a detectable abnormality,
but most of these only develop thrombosis in the presence of an additional risk factor.

There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis
may be an indication for long-term preventative anticoagulation.The first major form of
thrombophilia, antithrombin deficiency, was identified in 1965, while the most common
abnormalities (including factor V Leiden) were described in the 1990s.

The most common conditions associated with thrombophilia are DVT and pulmonary
embolism (PE), which are referred to collectively as venous thromboembolism (VTE). DVT usually
occurs in the legs, and is characterized by pain, swelling and redness of the limb. It may lead to
long-term swelling and heaviness due to damage to valves in the veins.The clot may also break off
and migrate (embolize) to arteries in the lungs. Depending on the size and the location of the clot,
this may lead to sudden-on set shortness of breath,chest pain,palpitations and may be complicated
by collapse, shock and cardiac arrest.

Thrombophilia can be congenital or acquired.Congenital thrombophilia refers to inborn

conditions (and usually hereditary, in which case "hereditary thrombophilia" may be used) that
increase the tendency to develop thrombosis, while, on the other hand, acquired thrombophilia
refers to conditions that arise later in life.
Congenital thrombophilia
The most common types of congenital thrombophilia are those that arise as a result of
overactivity of coagulation factors. They are relatively mild, and are therefore classified as "type II"
defects.The most common ones are factor V Leiden and prothrombin overactivity.
The rare forms of congenital thrombophilia are typically caused by a deficiency of natural
anticoagulants. They are classified as "type I" and are more severe in their propensity to cause
thrombosis.The main ones are antithrombin III deficiency, protein C deficiency and protein S
Acquired thrombophilia
A number of acquired conditions augment the risk of thrombosis. A prominent example is
antiphospholipid syndrome which is caused by antibodies against constituents of the cell
membrane, particularly lupus anticoagulant (first found in people with the disease systemic lupus
erythematosus but often detected in people without the disease), anti-cardiolipin antibodies, and
anti-β2-glycoprotein 1 antibodies; it is therefore regarded as an autoimmune disease. In some cases
antiphospholipid syndrome can cause arterial as well as venous thrombosis. It is also more strongly
associated with miscarriage, and can cause a number of other symptoms (such as livedo reticularis
of the skin and migraine).
Heparin-induced thrombocytopenia (HIT) occurs as an immune system reaction against the
anticoagulant drug heparin.Though it is named for associated low platelet counts, HIT is strongly
associated with risk of venous and arterial thrombosis.
Paroxysmal nocturnal hemoglobinuria(PNH) is a rare condition resulting from acquired
alterations in the PIGA gene, which plays a role in the protection of blood cells from the
complement system. PNH increases the risk of venous thrombosis but is also associated with
hemolytic anemia.
Hematologic conditions associated with sluggish blood flow can increase risk for
thrombosis. For example,sickle-cell disease (caused by mutations of hemoglobin) is regarded as a
mild prothrombotic state induced by impaired flow.Similarly,myeloproliferative disorders, in which
the bone marrow produces too many blood cells, predispose to thrombosis, particularly in
polycythemia vera (excess red blood cells) and essential thrombocytosis (excess platelets).
Cancer, particularly when metastatic (spread to other places in the body), is a recognised risk
factor for thrombosis.A number of mechanisms have been proposed, such as activation of the
coagulation system by cancer cells or secretion of procoagulant substances. Furthermore, particular
cancer treatments (such as the use of central venous catheters for chemotherapy) may increase the
risk of thrombosis further.
Nephrotic syndrome, in which protein from the bloodstream is released into the urine due to
kidney diseases, can predispose to thrombosis;this is particularly the case in more severe cases (as
indicated by blood levels of albumin below 25g/l) and if the syndrome is caused by the condition
membranous nephropathy.
Inflammatory bowel disease(ulcerative colitis and Crohn's disease) predispose to
thrombosis, particularly when the disease is active.
Pregnancy is associated with an increased risk of thrombosis. This probably results from a
physiological hypercoagulability in pregnancy that protects against postpartum hemorrhage.
The female hormone estrogen, when used in the combined oral contraceptive pill and in
perimenopausal hormone replacement therapy, has been associated with a two- to sixfold increased
risk of venous thrombosis. The risk depends on the type of hormones used, the dose of estrogen,
and the presence of other thrombophilic risk factors.
Obesity has long been regarded as a risk factor for venous thrombosis. It more than doubles
the risk in numerous studies, particularly in combination with the use of oral contraceptives or in
the period after surgery. Various coagulation abnormalities have been described in the obese.
Plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, is present in higher levels in people
with obesity. Obese people also have larger numbers of circulating microvesicles (fragments of
damaged cells) that bear tissue factor.Platelet aggregation may be increased, and there are higher
levels of coagulation proteins such as von Willebrand factor, fibrinogen,factor VII and factor VIII.
Obesity also increases the risk of recurrence after an initial episode of thrombosis.


Disorders of plasma clotting factors can be divided into:
a) hereditary disorders
 most important is hemophilia A
 lack of factor VIII
 transferred in plasma as a complex with vWF, which is important in the adhesion of
 X-linked (men are affected, women are carriers)
 Hemophilia B
 caused by lack of factor IX, due to defective synthesis of fibrinogen blood can not clot.
 Von Willebrand disease
 caused by a lack of VWF; characterized by a prolonged bleeding time and dysfunction
of factor VIII
b) Acquired disorders
 may be caused by:

◦ liver disease(causing deficiency of coagulation factors due to reduced


◦ vitamin K deficiency (it is necessary for the final part of the synthesis of
prothrombin and factors VII, IX and X in the liver)

◦ the presence of various inhibitors (in which are not normally present in blood)

▪ autoimmunity to coagulation factors, mainly to factor VIII

▪ too big consumption of certain factors (lysis of fibrinogen- mostly due to

liver failure, various tumors, and disseminated intravascular coagulation)

Disorders that cause bleeding tendency :
 disorders of the blood vessels:
 Hereditary:
 eg. Rendu-Osler-Weber disease or hereditary hemorrhagic telangiectasia, which affects
the arterioles, capillaries and venules. Their walls become thin and incapable of
contraction .
 Ehlers-Danlos syndrome which is characterized by disorders of collagen and connective
tissue as well as a decrease in skin resistance to stimuli.
 Acquired:

▪ usually occur due to hypersensitivity to bacteria or medication, and may be the

result of non-allergic events, e.g. scurvy

▪ they occur in the course of systemic lupus erythematosus in which vasculitis occurs
and causes damage of blood vessels
 platelet function disorders:
 quantitative

▪ including a reduced number of platelets (thrombocytopenia) due to reduced platelet

production,increased platelet degradation or increased allocation of platelets

▪ increased platelet count (thrombocytosis) which occurs due to disturbances in the

bone marrow
 qualitative

▪ platelet count in peripheral blood is normal but their functional qualities are
 disorders of plasma coagultion factors:

 hereditary

▪ eg. hemophilia A is caused by a lack of factor VIII; Hemophilia B is caused

by a lack of factor IX; Von Willebrand disease characterized by prolonged
bleeding time and platelet function disorder and disorder of fibrinogen
synthesis (blood does not clot)
 acquired

▪ caused by liver disease, vitamin K deficiency, the presence of different

inhibitors or excessive consumption of certain factors

Plasma proteins are a heterogeneous group with different backgrounds and functions and their
disorders can be:
 Quantitative disorders
 Total protein concentration in plasma is 60-80 g / L

▪ we divide them according to their physical and chemical properties (different

electrical charges cause different electrophoretic mobility of the protein and by
function (e.g. complement)
 albumin-largest concentration in the plasma, alpha- 1 globulins, alpha-2
globulins, beta-globulins and gamma-globulins
 Hyperproteinemia may arise due to: increased synthesis of immunoglobulins
(less often a consequence of malignant conversion of plasma cells (myeloma),
often resulting from overproduction of normal plasma cells in some connective
tissue diseases, chronic inflammation, particularly in active chronic hepatitis),
 Hypoproteinemia due to reduction of oncotic pressure causes edema; caused by:
increased loss of protein (burns, nephrotic syndrome, gastrointestinal disease),
increased catabolism (infection, injury, surgery, thyrotoxicosis, Cushing),
decreased synthesis (liver diseases such as hepatitis and diseases of the digestive
tract such as malnutrition and malabsorption), false hypoproteinemia (during
pregnancy and in the parenteral fluid compensation)
 Qualitative disorders
 Dysproteinemia
 disorders of the protein content of the blood
 most of the time globulins are increased and albumins are decreased
 occurs in:
 acute diseases where acute phase protein changes are manifested after
injury, tissue necrosis or acute inflammation and infection (IL-1, IL-6,
 chronic diseases (advanced tumors and later stages of chronic

* albumins- largest concentration in the plasma, its disturbances significantly affect con of other
* alpha-globulins- elevated in chronic inflammation and tissue disorders, in nephrotic syndrome due
to abundance of lipoproteins, as well as in diseases with necrosis and cell multiplication
* beta globulins- in hyperlipidemia, severe obstructive jaundice or nephrotic syndrom
*gamma globulins (immunoglobulins)- chronic inflammation and immune response to antigens
 Paraproteinemia
 paraproteins - monoclonal proteins that do not function as antibodies
(electrophoretic display as a narrow spike, resulting in the duplication of a
single clone of plasma cells which produce only one type of antibody). We
divide them into:
 benign monoclonal gammopathy
 presence of IgG, IgA, IgD, IgE but without symptoms of the disease
 present with amyloidosis, autoimmune diseases and chronic
 malignant monoclonal gammopathy
 IgM tumor cells produce a lot of IgM, which are large so we are
talking about IgM macroglobulinemia
 Waldenstrom's disease-hyperviscosity symptoms caused by
paraprotein; IgM paraprotein may have activity of rheumatoid factor
 hemolytic anemia can occur as a symptom of paraproteinemia
 Multiple myeloma- cause of malignant monoclonal gammopathy
(overflowing plasma cells damage skeleton and produce IgG, IgA,
IgD and IgE, or light chains of protein) if:
1. paraprotein levels are increased
2. synthesis of normal immunoglobulin is stopped
3. noticeable Bence-Jones proteinuria
4. bone marrow biopsy showing increased number of plasma
5. osteolytic damage on X-rays
Properties of pathological proteins:
Hyperviscosity syndrome - increased viscosity due to increased amounts of protein interferes
with blood flow in the brain (sudden confusion), fingers, kidneys, eyes (dilated venuoles, a lot
of bleeding),signs of heart failure
Cryoglobulinemia - occurs due presence of cryoglobulin (proteins that accumulate in the cold,
and melt in a warm (usually immunoglobulins and can be simple, monoclonal and mixed), often
do not cause symptoms, but can cause skin ulcers and gangrene, Raynaud's phenomenon (in the
cold fingers are pale then cyanotic and red )
Cold agglutinin disease-antibodies that cause hemolysis after cold exposure (rare in infectious
mononucleosis or atypical pneumonia, often in lymphosarcoma and macroglobulinemia)
Bence-Jones proteinemia - light chains are constructed in of monomers or dimers. Monomers
are filtered through the glomeruli, reabsorbed in the proximal tubules, and the excess is excreted
in the urine. When they pass through the distal and collecting tubules they can form dimers and
percipitate damaging transmission mechanisms in the cell membrane; they also release
lysosomal enzymes. Due to the high concentration of light chains and the metal salts in the
tubules and changes in the pH of urine Tamm-Horafallov mucoproteinsare precipitated forming
cylinders which together with the rest of the decomposed cells clogs up the tubules which can
lead to chronic renal failure. It is demonstrated by the heat coagulation test (after heating of
acidified urine to 40°-60° C proteins precipitate and then are redissolved at 90°C)
Amyloidosis - amyloid is a protein that is deposited in tissues and interferes with their
function. It has two components: AA protein important for secondary amyloidosis and AL
amyloid made from immunoglobulin light chains characteristic of primary amyloidosis
(associated with diseases of plasma cells)
Other- paraprotein may react with calcium or clotting factors or coated platelets disturbing
normal clotting

Can arise primarily due to disability of spleen (developmental defects) or secondary to diseases that
cause its atrophy or increase.
Agenesis of the spleen is rare but can be found along with heart defects and situs inversus viscerus a
condition called Ivermak's syndrome. The red blood cells have the shape of the target (target cells)
with Howell-Jolly's bodies in the cytoplasm. About 80% of children die within the first year due to
heart failure or severe bacterial infections. Similar changes are seen with sickle-cell anemia in
which due to defective red blood cells spleen eventually becomes atrophic. Splenomegaly can
occur due to :
 reticular hyperplasia
 infectious diseases with erythropoiesis such as thalassemia, osteopetrosis
 lymphoproliferative disease with portal hypertension
 Gaucher and Niemann-Pick disease
 infection, tumors

Hypersplenism is a splenomegaly with increased spleen function -increase in retaining and
destroying blood cells leading anemia, leukopenia and thrombocytopenia and reactive hyperplasia
of hematopoietic tissue in the bone marrow. Symptomes: paleness,fatigue (anemia), recurrent
bacterial infections (neutropenia) and bleeding tendency (thrombocytopenia).
Banti's syndrome (chronic congestive splenomegly) – occurs because of the increased
pressure in the portal circulation in liver cirrhosis resulting in a stagnation of blood in the spleen.
Results in anemia, leukopenia, thrombocytopenia, splenomegaly and consequent bleeding from
varicose veins of the esophagus and stomach. After a while spleen becomes fibrose and
splenectomy is performed.
Splenectomy is done because of the risk of bleeding. It is done in patients with spleen
rupture, cysts, tumors or vascular anomalies of the spleen, spherocytic anemia, autoimmune
hemolytic anemia and idiopathic thrombocytopenic purpura. It reduces the degradation of blood
cells in the spleen, but increases the risk of serious bacterial infections, sepsis and meningitis, which
occur a year or two after splenectomy (in adults it can occur even after 20 years). The risk is higher
in younger people.


The work of the myocardium depends on the relaxation of the heart that allows the diastolic filling
and contraction which ejects stroke volume. Functional units are the sarcomeres (contractility)
consisting of actin, myosin, troponin and tropomyosin. Contractility is affected by mutual relations
of these proteins, the amount of ATP and the ion levels (Ca 2+ and H +).
Contraction encourages the entry of Na + in to the sarcoplasm leading up to the entry of Ca 2+
through the membrane, but also from sarcoplasmic reticulum. Ca2+ bindse with troponin C, which
causes the conformational changes that reduce the inhibitory effect of troponin I on the interaction
of actin and myosin. Troponin T change is transmitted to tropomyosin which leads to the discovery
of the reactive sites on actin for the interaction with myosin.Actin activates myosine ATPase awhich
leads to conformational changes of myosin whose head is now bound to ADP allowing it to bend
and cross-link with the actin. Actin slides between myosin molecules and reduces sarcomere.
Relaxation occurs when calcium pump, which consumes energy from ATP, transports the Ca 2+
from sarcoplasm into the sarcoplasmic reticulum leading to conformational changes of troponin and
tropomyosin and returns them their inhibitory effect.
Factors affecting activity of the myocardium are:
 tonic contractility control (long term monitoring)

◦ myosine ATPase →affects the speed of actin and myosin respons ; an adjustment that
increases or decreases the activity, allows the weakened heart to do the same work but
slowly with the same consumption of ATP as a normal heart (P = W / t)

◦ heart with less power does the same work as normal heart in the longer amount of time

154.Heart Valve Dysfunction

 Mitral Stenosis
 Mitral Insufficiency
 Aortic Stenosis: Robbins Page 389 (ALGORITHM PROBLEM 106), Thieme 212
 Aortic Insufficiency (ALGORITHM PROBLEM 105)

1. Mitral Stenosis: Mitral stenosis is a disorder in which the mitral valve does not fully open. This
restricts the flow of blood.

Blood that flows between different chambers of your heart must flow through a valve. The valve
between the two chambers on the left side of your heart is called the mitral valve. It opens up
enough so that blood can flow from the upper chamber of your heart (left atria) to the lower
chamber (left ventricle). It then closes, keeping blood from flowing backwards.
Mitral stenosis means that the valve cannot open enough. As a result, less blood flows to the body.
The upper heart chamber swells as pressure builds up. Blood and fluid may then collect in the lung
tissue (pulmonary edema), making it hard to breathe.
In adults, mitral stenosis occurs most often in people who have had rheumatic fever. This is a
disease that can develop after an illness with strep throat that was not properly treated.
The valve problems develop 5 - 10 years or more after having rheumatic fever. Symptoms may not
show up for even longer. Rheumatic fever is becoming rare in the United States because strep
infections are most often treated. This has made mitral stenosis less common.
Rarely, other factors can cause mitral stenosis in adults. These include:
• Calcium deposits forming around the mitral valve
• Radiation treatment to the chest
• Some medications
Children may be born with mitral stenosis (congenital) or other birth defects involving the heart that
cause mitral stenosis. Often, there are other heart defects present along with the mitral stenosis.
Mitral stenosis may run in families.

2.Mitral Insufficiency: Mitral regurgitation is a disorder in which the mitral valve on the left side of
the heart does not close properly. Regurgitation means leaking from a valve that does not close all
the way.

Mitral regurgitation is the most common type of heart valve disorder.

Blood that flows between different chambers of your heart must flow through a valve. The valve
between the two chambers on the left side of your heart is called the mitral valve

When the mitral valve doesn't close all the way, blood flows backward into the upper heart chamber
(atrium) from the lower chamber as it contracts. This cuts down on the amount of blood that flows
to the rest of the body. As a result, the heart may try to pump harder. This may lead to congestive
heart failure.
Mitral regurgitation may begin suddenly. This often occurs after a heart attack. When the
regurgitation does not go away, it becomes long-term (chronic).
Many other diseases or problems can weaken or damage the valve or the heart tissue around the
valve. You are at risk for mitral valve regurgitation if you have:
 Coronary heart disease and high blood pressure
 Infection of the heart valves
 Mitral valve prolapse (MVP)
 Rare conditions, such as untreated syphilis or marfan syndrome
 Rheumatic heart disease. This is a complication of untreated strep throat that is
becoming less common.
 Swelling of the left lower heart chamber

3.Aortic Stenosis: The aorta is the main artery that carries blood
out of the heart to the rest of the body. Blood flows out of the
heart and into the aorta through the aortic valve. In aortic
stenosis, the aortic valve does not open fully. This decreases
blood flow from the heart.

As the aortic valve narrows, the left ventricle has to work harder to pump blood out through the
valve. To do this extra work, the muscles in the ventricle walls become thicker. This can lead to
chest pain.
As the pressure continues to rise, blood may back up into the lungs. Severe aortic stenosis can limit
the amount of blood that reaches the brain and the rest of the body.
Aortic stenosis may be present from birth (congenital), but most often it develops later in life.
Children with aortic stenosis may have other conditions present from birth.
Aortic stenosis mainly occurs due to the buildup of calcium deposits that narrow the valve. This is
called calcific aortic stenosis. The problem mostly affects older people.
Calcification of the valve happens sooner in people who are born with abnormal aortic or bicuspid
valves. In rare cases, calcification can develop more quickly when a person has received chest
radiation (such as for cancer treatment).
Another cause is rheumatic fever. This condition can develop after strep throat or scarlet fever.
Valve problems do not develop for 5 - 10 years or longer after rheumatic fever occurs. Rheumatic
fever is becoming rarer in the United States.
Aortic stenosis occurs in about 2% of people over 65 years of age. It occurs more often in men than
in women.

4.Aortic Insufficiency: Aortic insufficiency is a heart valve disease in which the aortic valve does not
close tightly. This allows blood to flow from the aorta (the largest blood vessel) into the left
ventricle (a chamber of the heart).

Any condition that prevents the aortic valve from closing completely can cause this problem. When
the valve doesn't close all the way, a small amount of blood comes back each time the heart beats.
This makes the heart have to work harder to force out enough blood. The left lower chamber of the
heart widens (dilates) and the heart beats very strongly (bounding pulse). Over time, the heart
becomes less able to supply enough blood to the body.
In the past, rheumatic fever was the main cause of aortic insufficiency. The use of antibiotics to treat
strep infections has made rheumatic fever less common. Therefore, aortic insufficiency is more
commonly due to other causes. These include:
 Congenital (present at birth) valve problems, such as bicuspid valve
 Endocarditis
 High blood pressure
 Marfan syndrome
 Reiter syndrome (also known as reactive arthritis)
 Syphilis
 Systemic lupus erythematosus
 Aortic Dissection
 Ankylosing Spondylitis

Aortic insufficiency is most common in men between the ages of 30 and 60.

155.Cardiac Preload Dysfunction

Overall, the changes in cardiac function associated with heart failure result in a decrease in cardiac
output. This results from a decline in stroke volume that is due to systolic dysfunction, diastolic
dysfunction, or a combination of the two. Briefly, systolic dysfunction results from a loss of
intrinsic inotropy (contractility), most likely due to alterations in signal transduction mechanisms
responsible for regulating inotropy. Systolic dysfunction can also result from the loss of viable,
contracting muscle as occurs following acute myocardial infarction. Diastolic dysfunction refers to
the diastolic properties of the ventricle and occurs when the ventricle becomes less compliant (i.e.,
"stiffer"), which impairs ventricular filling. Both systolic and diastolic dysfunction result in a higher
ventricular end-diastolic pressure, which serves as a compensatory mechanism by utilizing the
Frank-Starling mechanism to augment stroke volume. In some types of heart failure (e.g., dilated
cardiomyopathy), the ventricle dilates as preload pressures increase in order to to recruit the Frank-
Starling mechanism in an attempt to maintain normal stroke volumes.

Blood Volume
In heart failure, there is a compensatory increase in blood volume that serves to increase ventricular
preload and thereby enhance stroke volume by the Frank-Starling mechanism. Blood volume is
augmented by a number of factors.
Reduced renal perfusion results in decreased urine output and retention of fluid.
Furthermore, a combination of reduced renal perfusion and sympathetic activation of the kidneys
stimulates the release of renin, thereby activating the renin-angiotensin system. This, in turn,
enhances aldosterone secretion. There is also an increase in circulating arginine vasopressin
(antidiuretic hormone) that contributes to renal retention of water.
The final outcome of humoral activation is an increase in renal reabsorption of sodium and
water. The resultant increase in blood volume helps to maintain cardiac output; however, the
increased volume can be deleterious because it raises venous pressures, which can lead to
pulmonary and systemic edema. When edema occurs in the lungs, this can result in exertional
dyspnea (shortness of breath during exertion).
Therefore, most patients in heart failure are treated with diuretic drugs to reduce blood
volume and venous pressures in order to reduce edema.


Cardiac Tamponade: Result of compression of a heart filled with fluid (transudate, exudate, blood)
in the intrapericardial sac under increased pressure which leads to decreased venous filling and
increased resistance to diastolic ventricular filling.

The normal pericardium is composed of 2 layers: the tough fibrous parietal pericardium and the
smooth visceral pericardium. Usually, approximately 50 mL of fluid (plasma ultrafiltrate) is present
in the intrapericardial space to minimize friction during cardiac motion.
Acute and subacute forms of pericarditis (which may or may not be symptomatic) may deposit
fibrin, which, in turn, can evoke a pericardial effusion. This often leads to pericardial organization,
chronic fibrotic scarring, and calcification, most often involving the parietal pericardium (see
Constrictive-Effusive Pericarditis for visceral pericardial disease).
In constrictive pericarditis, the easily distensible, thin parietal and visceral pericardial linings
become inflamed, thickened, and fused. Because of these changes, the potential space between the
linings is obliterated, and the ventricle loses distensibility. Venous return to the heart becomes
limited, and ventricular filling is reduced, with associated inability to maintain adequate preload.
Filling pressures of the heart tend to become equal in both the ventricles and the atria.
Since the myocardium is unaffected, early ventricular filling during the first third of diastole is
unimpeded. After early diastole, the stiff pericardium affects flow and hemodynamics. Accordingly,
the ventricular pressure initially decreases rapidly (producing a steep y descent on right atrial
pressure waveform tracings) and then increases abruptly to a level that is sustained until systole (the
“dip-and-plateau waveform” or “square root sign” seen on right or left ventricular pressure
waveform tracings).
The preservation of myocardial function in early diastole aids in distinguishing constrictive
pericarditis from restrictive cardiomyopathy. Systolic function is rarely affected until late in the
course of the disease, presumably secondary to infiltrative processes that affect the myocardium,
atrophy, or scarring or fibrosis of the myocardium from the overlying adjacent pericardial disease.

156.Cardiac Arrhythmias

Regardless of the specific arrhythmia, the pathogenesis of the arrhythmias falls into one of three
basic mechanisms: enhanced or suppressed automaticity, triggered activity, or re-entry.
Automaticity is a natural property of all myocytes. Ischemia, scarring, electrolyte
disturbances, medications, advancing age, and other factors may suppress or enhance automaticity
in various areas. Suppression of automaticity of the sinoatrial (SA) node can result in sinus node
dysfunction and in sick sinus syndrome (SSS), which is still the most common indication for
permanent pacemaker implantation. In contrast to suppressed automaticity, enhanced automaticity
can result in multiple arrhythmias, both atrial and ventricular. Triggered activity occurs when early
afterdepolarizations and delayed afterdepolarizations initiate spontaneous multiple depolarizations,
precipitating ventricular arrhythmias. Examples include torsades de pointes and ventricular
arrhythmias caused by digitalis toxicity. Probably the most common mechanism of
arrhythmogenesis results from re-entry. Requisites for re-entry include bidirectional conduction and
unidirectional block. Micro level re-entry occurs with VT from conduction around the scar of
myocardial infarction (MI), and macro level re-entry occurs via conduction through (Wolff-
Parkinson-White [WPW] syndrome) concealed accessory pathways.

Arrhythmias may be caused by many different factors, including:
 A heart attack that's occurring right now
 Scarring of heart tissue from a prior heart attack
 Changes to your heart's structure, such as from cardiomyopathy
 Blocked arteries in your heart (coronary artery disease)
 High blood pressure
 Diabetes
 Overactive thyroid gland (hyperthyroidism)
 Underactive thyroid gland (hypothyroidism)
 Smoking
 Drinking too much alcohol or caffeine
 Drug abuse
 Stress
 Certain prescription medications
 Certain dietary supplements and herbal treatments
 Electrical shock
 Air pollution

**Remember/Find as many causes as possible, I was asked to list a lot**



157.Impairment of the Heart Electrical Impulse Generation and Conduction

The normal electrical conduction in the heart allows the impulse that is generated by the sinoatrial
node (SA node) of the heart to be propagated to (and stimulate) the cardiac muscle (myocardium).
The myocardium contracts after stimulation. It is the ordered stimulation of the myocardium during
the cardiac cycle that allows efficient contraction of the heart, thereby allowing blood to be pumped
throughout the body.

Cardiac muscle has some similarities to neurons and skeletal muscle, as well as important unique
properties. Like a neuron, a given myocardial cell has a negative membrane potential when at rest.
Stimulation above a threshold value induces the opening of voltage-gated ion channels and a flood
of cations into the cell. The positively charged ions entering the cell cause the depolarization
characteristic of an action potential. Like skeletal muscle, depolarization causes the opening of
voltage-gated calcium channels and release of Ca2+ from the t-tubules. This influx of calcium causes
calcium-induced calcium release from the sarcoplasmic reticulum, and free Ca2+ causes muscle
contraction. After a delay, Potassium channels reopen and the resulting flow of K+ out of the cell
causes repolarization to the resting state.
Note that there are important physiological differences between nodal cells and ventricular
cells; the specific differences in ion channels and mechanisms of polarization give rise to unique
properties of SA node cells, most important, the spontaneous depolarizations necessary for the SA
node's pacemaker activity.

Review in Guyton the Conduction of the heart and mention “In Guyton it says.....” :)

1. Impairment in generating impulses:

- Cells in the SA node depolarize less automatic tissues before they have a chance to
depolarize spontaneously to the threshold potential-natural conduction center.
- Changes in speed of spontaneous diastolic depol. = stimulus generation disruption
- Changes in resting potential
- changes in potential threshold

Failure of conducting center can be a result of:

a) non appearance of impulse
b) an aggravated or impossible conduction of impulses to neighboring tissues

2. Impairment in spreading of impulses:

Fast action potentials

0. phase massive inflow of Na+ into cell

1. phase activation of Na+ entry and immediate outflow of K+
2. phase entry of Ca2+ and outflow of K+
3. Phase outflow of K+
4. Phase ionic balance is established

Slow action potentials (SA and AV node) Ca2+ is the main carrier of depolarization

 phase inflow of Ca2+ into cell

 phase outflow of K+
 Phase ionic balance is established

Circus movements : ‘re-entry’ of the impulse into a muscle that has already been excited can occur.
- pathway is too long (dilated hearts) (ALGORITHM: HYPERTROPHY)
- pathway remains constant but the velocity of conduction becomes decreased (blockage of purkinje
system, ischemia of muscle or high potassium levels) ( ALGORITHM ISCHEMIC HEART

3. Complex Disorders of generating and spreading impulses

Myocardial Ischemia (ALGORITHM) or increased concentration of catecholamines affect

appearance of ectopic stimulus.

Extra Systole- caused by a disturbed automacity or by a repeated stimulus

158. Ischemic Myocardial Damage

Algorithm Ischemic Heart disease (problem 100)

Hypoxia: decreased O2 in blood
Coronary Insufficiency: imbalance between availability and requirement of blood flow (oxygen)
Ischemia : Algorithm, Review Robbins Page 377-381
Myocardial infarction here use algorithm problem 96
ANGINA PECTORIS: Review Robbins Page 376

159.Consequences of the Ischemic Myocardial Damage

1. Disorders of the function and Hemodynamic myocardial damage:

- disorders of regional contractility
- asynergy: disorder of the sequence of contraction of individual parts of the ventricular wall
- Hypokinesis: diminishing of systolic shortening of contractile elements
- paradoxal systolic bulging of the noncontractile ischemic part
- Cardiogenic Collapse: If nonischemic myocard cannot compensate for a functional disorder
in a part that is involved by ischemia or by infarct.
- Dramatic decrease in minute volume and hypotension

-acute demanding ischemia slows the diastolic filling by slowing the isovolumic relaxation
Chronic ischemia causes myocardial fibrosis and by that decreases its passive compliance.
Therefore there is stronger atrial contraction that is needed and the development of pumonic
congestion (edema is possible)
-you can discuss Pulmonary edema algorithm here problem 110

Electrophysiologic Consequences:

-decreased efficacy of Na-K pump in the cell membrane

-switching to anaerobic metabolism with decreased pH (acidosis)

-changes in lipid and protein content in the sarcolemma, changes in permeability and content of
ECF which leads to amplitude and duration of action potential being changed and the tendency to
spontaneous diastolic depolarization increase.

Action Potential Changes:

1. early phase: uneven spread of AP in acute ischemic myocard with developed re-entry circles
(ventricullar fibrillation)
2. polymorphic ventricular disturbances of the rhythm (ventricular tachycardia)
3. tendancy of different forms of tachyarrhythmia and fibrillation (late arrhythmia's): Here you
can shift the question and talk about cardiac arrhythmia’s :)

160.Pathophysiology of Congenital Heart Defects

Changes in direction of blood flow or disturbances in blood flow

1. Anomalies without pathological connection
2. Anomalies with left-right shunt
3. Anomalies with right-left shunt

A cardiac shunt is a pattern of blood flow in the heart that deviates from the normal circuit of the
circulatory system. It may be described as right-left, left-right or bidirectional, or as systemic-to-
pulmonary or pulmonary-to-systemic. The direction may be controlled by left and/or right heart
pressure, a biological or artificial heart valve or both. The presence of a shunt may also affect left
and/or right heart pressure either beneficially or detrimentally.

The most common congenital heart defects (CHDs) which cause shunting are atrial septal defects
(ASD), patent foramen ovale (PFO), ventricular septal defects (VSD), and patent ductus arteriosi
(PDA). In isolation, these defects may be asymptomatic, or they may produce symptoms which can
range from mild to severe, and which can either have an acute or a delayed onset. However, these
shunts are often present in combination with other defects; in these cases, they may still be
asymptomatic, mild or severe, acute or delayed, but they may also work to counteract the negative
symptoms caused by another defect (as with d-Transposition of the great arteries).

Right-to Left Shunt

Tetralogy of Fallot (TOF) is a congenital heart defect which is
classically understood to involve four anatomical
abnormalities of the heart (although only three of them are
always present). It is the most common cyanotic heart defect,
and the most common cause of blue baby syndrome. TOF is
usually a right-to-left shunt, in which higher resistance to right
ventricular outflow results in more severe cyanosis symptoms.

Eisenmenger’s syndrome: Right  Left shunt

Eisenmenger syndrome refers to any untreated congenital cardiac

defect with intracardiac communication that leads to pulmonary
hypertension, reversal of flow, and cyanosis.The previous left-to-
right shunt is converted into a right-to-left shunt secondary to
elevated pulmonary artery pressures and associated pulmonary
vascular disease.

Lesions in Eisenmenger syndrome, such as large septal defects, are

characterized by high pulmonary pressure and/or a high pulmonary flow state. Development of the
syndrome represents a point at which pulmonary hypertension is irreversible and is an indication
that the cardiac lesion is likely inoperable.

161. Heart Functional Overload

La Place’s Law: T= (PxR)/(2h)

T= tension
P= Pressure
h= thickness of wall

Types of Overload:

1. Pressure (systolic, compensated) - Increases

the tension of the myocardium during
contraction of the heart:
-Hypertension and valvular stenosis
- Volume of myofibrils is more increased than the mitochondria
- Provokes less compliance of the myocardium- force needed to develop a higher ventricular
pressure is arranged on a larger amount of sarcomeres (compensatory mechanism)

2. Volume (diastolic)- increases the tension of the myocardium during stretching

-abnormal shunts and valvular regurgitation
- determine the length of myofibrils before contraction
- dilatation causes shifts of sarcomeres which are distributed serially
- The number of sarcomeres is increased without lengthening of individual sarcomeres

162. Dynamics and Consequences of the Cardiac Hypertrophy

Algorithm Problem 99 Cardiac Hypertrophy

163. Pathogenesis of the Cardiac Insufficiency

Cardiac insufficiency is a medical term that refers to a type of heart failure in which the heart is not
able to pump enough blood throughout the body. The most common causes of the condition are
chronic hypertension, inflammation of heart tissue, and high cholesterol. A person may experience
chronic insufficiency, in which symptoms of fatigue, cough, and shortness of breath persist over
time, or acute cardiac insufficiency, where severe chest pain and breathing problems come about

Signs and symptoms of heart failure include the following:

• Exertional dyspnea and/or dyspnea at rest
• Orthopnea
• Acute pulmonary edema
• Chest pain/pressure and palpitations
• Tachycardia
• Fatigue and weakness
• Nocturia and oliguria
• Anorexia, weight loss, nausea
• Exophthalmos and/or visible pulsation of eyes
• Distention of neck veins
• Weak, rapid, and thready pulse
• Rales, wheezing

The pathophysiologic cycle of heart failure is initiated by myocardial failure that accompanies a
reduction in myocardial contractility secondary to ischemic or myopathic heart disease. Reduction
in cardiac output and oxygen delivery to the tissues is followed by vasoconstriction that raises
systemic vascular resistance to preserve systemic arterial pressure while maintaining regional O2
availability. As a consequence, however, impedance to left ventricular ejection is increased, creating
an additional hemodynamic burden for the failing heart. A vicious cycle ensues. Hemodynamic
features of acute cardiac failure include decreases in cardiac output and mixed venous O2
saturation, together with increases in left ventricular filling pressure and systemic resistance. If
hypotension is present with failure, there is a markedly decreased cardiac output or an inappropriate
increase in systemic resistance. If acidosis is also present with hypotension and failure, cardiac
output is severely decreased and lactic acid is increased. A major objective of medical therapy in
acute heart failure is to enhance ventricular emptying, thereby increasing cardiac output and O2
delivery while decreasing left ventricular filling pressure, pulmonary venous pressure and vascular

164. Compensatory Mechanisms in Heart Insufficiency

1. Frank-Starling Mechanism:
- striking increase in volume when increasing the diastolic filling and pressure
- Increase venous inflows (various mechanisms) increases the diastolic filling volume
- Depends on myocardial contractility

-> Hypertrophys and Dilation Myocardial
-Does not increase the length of sarcomere (saves the reserves that exist on the basis of
Frank-Starling Mechanism)
- Reduce the difference due to the increase in heart myocardial mass and increased amounts
of binders in the heart tissue

2. Retention Sodium and Water:

-Redcution of the effective arterial volume causes the state of pre-renal kidney failure and
leads to increased reabsorption of salt and water
-Increased venous inflow and thus minute volume

3. Adaptation Hypoxemia:
-Hypoxia stimulates the synthesis of 2,3-DPG which reduces the affinity of hemoglobin for
oxygen and thus increase the release of oxygen in tissue capillaries that demonstrate an
increase in arterio-venous differences in oxygen content
- The release of O2 stimulating effect and slow blood flow and tissue acidosis


The basic hemodynamic disturbance in congestive heart failure is its inability to increase stroke
volume as much as volume and pressure are increased at the end of diastole.That leads to a
reduction of effective arterial volume(EAV).Decrease in EAV stimulates compensatory
mechanisms which further burdenes the heart.Vasoconstriction of arterioles exacerbates the
pressure overload; venoconstriction and retention of sodium and water deteriorates volume
load.This disturbs the equilibrium between the elevated diastolic pressure(volume) and stroke
volume manifested by reduction of the ejection fraction.Heart starts to decompensate.Main disorder
due to loss of dynamic balance is the elevation of diastolic filling pressure and reduction of EAV.
Because of reduced flow through the kidneys glomerular filtration rate is reduced but filtration
fraction is increased because of the prevailing constriction of efferent arteriole. In severe
decompensation due to a further reduction in EAV afferent arteriole gets contracted.So state of
pre-prerenal failure becomes prerenal failure (prerenal azotemia). Decreased EAV and increased
secretion of angitensin II (increases the sense of thirst) stimulate the secretion of ADH. Resulting in
sodium and water retention which increases the volume of extracellular fluid and that is a
prerequisite for the development of edema. Increase in extracellular fluid volume increases the
systemic filling pressure thus increasing pulmonary or systemic venous pressure- pulmonary or
systemic stasis develops.That increased venous pressure increases the hydrostatic pressure in
capillaries and enhance the filtration of fluids in intracellular space.This also leads to the
development of edema. Decompensation disturbs the functioning of the whole organism. It affects
every organ differently:
Decreased flow causes hypoxia.Consequences being mental disorders,confusion and consciousness
disorders of varying degrees.
 Possibility for physical activity is reduced. Manifested by wheezing and dyspnea on
exertion.In left sided decompensation dyspnea increases in the supine position, because it
increases the flow of blood from the legs and splanchnic flow in the right atrium and
ventricle and thus the delay in the lung circulation.As soon as patient sits dyspnea is
relieved (orthopnea) .With a stasis in lung circulation interstitial and then alveolar edema
 Due to reduced renal perfusion prerenal azotemia develops. In initial phase the
concentration of urea increases. When afferent arteriole get constricticted glomerular
filtration rate decreases so the amount of creatinine in plasma increases.
4.Digestive system
 Due to delays in the mesenteric veins and lymphatic congestion malabsorption
develops, along with the loss of protein through the intestinal
membrane(transudation).Development of hypoproteinemia exacerbates edema.
Circulation disorders can lead to a gut infarction.
 Hepatomegaly develops because of venous and lymphatic congestion.That disrupts
the liver function and increases the concentration of free and conjugated bilirubin
(jaundice). Aldosteronedegradation is decreased and that with the increased
concentration of aldosterone in the blood enhances its effect.
 Decreased flow and hypoxia in muscle cause weakness and rapid fatigue, thus
limiting physical activity.


Cardiac output is equal to the product of stroke volume and heart rate. At rest it is about 5-6
L/min, and in relation to the body surface area (cardiac index) in 95% of patients it is between 2.8
and 4.2 L/min/m2. Values less than 2.5 L/min/m2 are pathological, and in shock they are lower than
2 L/min/m2. Physiological increases during pregnancy, and during exertional heat (due to
vasodilation in the skin), and short-term decreases when standing up (distribution of blood in the
veins with a reduction in venous).
1.Venous return disorders
Stroke volume depends on the venous filling of the heart (preload), systolic and diastolic function
of the heart, resistance (pressure, subsequently load, afterload) and the size of the ventricles.
 Volume overload
Depends on the venous return, the function of the right ventricle, the resistance in the pulmonary
circulation and changes in the mitral valve. Increased venous return causes an increase in blood
volume and pressure in the ventricles during diastole. This increases the length of myofibrils at the
end of diastole, but only up to certain limits.
 Reduction in minute and stroke volume
Because of the blood loss(hemorrhage, dehydration or sunburn) MV and SV are reduced, but only
after exhaustion of compensatory mechanisms (sympathicus and tachycardia).Hypovolemic shock
can develop due to tonus disturbances of small blood vessels in the periphery and accumulation of
blood. Expiration, tension pneumothorax and plugging on a respirator with positive pressure
reduces the intrathoracic volume of blood and the venous return, and therefore the MV and SV.
Reduced pressure on the skeletal muscle veins, anesthesia, certain medications (nitroglicerin) and
simpatholytics dilate veins and reduce the venous return.

 Increase in minute and stroke volume
Inspiration decreases the intrathoracic pressure, increases the intrathoracic blood volume,
venous return and MV.Transfusion increases venous return, arterial pressure and MV but
nervous reflexes return those values to normal fastly.Venous return is increased by all
conditions with reduced peripheral resistance, such as:
- anemia, fever (MV increases by increasing the metabolic needs of the blood), ductus
arteriosus persistens,hyperthyroidism
1. a) increased metabolism in the tissues causes vasodilation and reduces peripheral
2. b) increased heat release causes vasodilation in the skin
3. c) thyroid hormones by direct action on myocardium increase heart rate and
myocardial contractility
4. d)the impact of sympatoadrenal system on the heart and increased sensitivity of
myocardium to catecholamines
▪ Systemic arteriovenous fistula
 reduces peripheral resistance and increases the heart rate, MV and SV
▪ Hyperkinetic syndrome
 usually occurs in younger people
 marked by an increased MV,elevated systolic and normal mean blood
pressure and decreased peripheral resistance.
 (Probably occurs due to sympathetic stimulation, and can be successfully
treated by blocking the beta-adrenergic receptors)
▪ lack of thiamine(B1)- Beriberi
 MV increases probably due to damaged sympathetic nuclei, which may
decrease peripheral resistance.
 It also has slowed the conversion of pyruvate into acetyl CoA, which
limits the energy metabolism.
▪ Paget's disease - manifold increase in blood flow of the affected limb
(increased blood supply and many small arterio-venous fistulas)
▪ Liver disease (cirrhosis and viral hepatitis)
 because of the multitude of AV fistulas in cirrhotic liver, mesenteric and
pulmonary circulation
 peripheral vasodilatation that develops due to decreased inactivation of
estrogen and vasodilating substances and hypoxemia that develops
because of AV fistulas in the lungs
 less often collaterals between the lung and portal vein
▪ in patients with carcinoid syndrome peripheral resistance is reduced and the
secretion of serotonin directly increases myocardial contractility
MV is also increased in patients with: acute glomerulonephritis (due to retention of salt and
water), in chronic hemodialysis, uremia and hypermetabolic state, in chronic obstructive pulmonary
disease (due to hypoxemia and fever which accompanies an infection), with polycythemia vera (due
hypervolemia), in extremely obese individuals.

 Pressure overload
Pressure overload of the left ventricle depends on the size of the ventricul and its arterial pressure,
indirectly it depends on arteriolar tonus, elasticity of the aorta and large arteries and blood viscosity.
According to Laplace law bigger ventricle will have a bigger tension than smaller ventricle even if
the pressure is equal. Increased pressure load (aortic stenosis, reflex vasoconstriction) reduces SV
and reduced pressure load increases the SV. Increased pressure load with a decrease in MV is found
in arterial hypertension and aortic stenosis.
 Systolic heart function
Contractility of the heart is affected by sympathicus (cutback heart MV), catecholamines from
blood, heart rate and rhythm, drugs with inotropic effect, hypoxia, ischemia, acidosis, loss of
contractile tissue or changes in the myocardium. The states of heart failure poor myocardial
contractility limits MV (drugs with positive inotropic effect increase MV (in a healthy heart they do
 Diastolic heart function
Diastolic acceptance of venous return is a fundamental diastolic function of the heart. It is
determined by the time and ventricular relaxation and contraction of the atria. Diastolic filling of the
left ventricle is reduced in ishemic, hypertrophic and decompensated myocardium,mitral stenosis
(usually due to hypertrophy and coronary artery disease), defects in heart valves, cardiomyopathies
and pericardial diseases. Diastolic dysfunction of the left ventricle causes an increase in filling
pressure, which is transmitted to the pulmonary capillary pressure (reflected in the early appearance
of dyspnea on exertion). In significant cardiac decompensation MV is decreased already at a rest, it
is accompanied with peripheral vasoconstriction.
2.Disorders of heart rate regulation
The increase in frequency is important for increase of the MV during activity for people who are
not accustomed to the effort(people with sedentary life style), and in sports- men/women it is more
important to increase contractility and stroke volume. MV in healthy heart starts to decrease with
tachycardia higher than 170-180/min (in the elderly and in diseased greater than 120 / min).
Increased freq. reduces the phase of diastole and coronary flow (which is mainly diastolic). The
increase in cardiac freq. slightly increases contractility (Bowditch phenomenon- autoregulation
method by which myocardial contractility increases with an increase in heart rate. Also known as
the Treppe phenomenon, Treppe effect or staircase effect ) but with a significant tachycardia and
shortening of the systole contractility may weaken. Inability to increase the MV with increasing
freq. is expressed in conditions with limited SV (aortic or mitral stenosis). Increase in frequency
may be lost in the AV-block, diseases of sinus node, application of pacemaker or beta-blockers.
Frequent extrasystoles can reduce SV. Ventricular fibrillation, asystole, and extreme bradycardia
may cause cardiogenic shock.


Normal blood pressure levels in adults are 120/85 mmHg. According to the cause hypertension can
be essential (of unknown origin) or secondary (consequence of a particular pathogenetic disorders).
High normal blood pressure is 130-139 / 85-89 mm Hg
stage I hypertension-mild; 140-159 / 90-99 mmHg
stage II hypertension-moderate; 160-179 / 100-109 mmHg
stage III hypertension-heavy; ≥180 / 110 mmHg .
Arterial hypertension is important in the development of heart disease, peripheral vascular disease
and kidney disease. In many patients with hypertension, there is thickening of the left ventricle
(concentric hypertrophy) resulting in difficult diastolic filling possible only with increased pressure
in the ventricle which is then transmitted to the pulmonary circulation. At the end systolic function
of the left ventricule may cave in (contractility), and the cavity itself increasingly expands
(eccentric hypertrophy);more often seen in obese people.


Essential hypertension is a group of diverse disorders that can cause an increase in arterial pressure
by variety of pathogenic mechanism.70-80% of people have family history of hypertension that
usually occurs around 30th-50th year of life. The major environmental factors(risk factors) which
are associated with the occurrence of essential hypertension are: excessive intake of salt (it seems
that the effect of salt is associated with a lack of calcium and potassium), increaed food intake and
reduced physical activity (causing obesity and consequently insulin resistance primarily in skeletal
muscles and hyperinsulinemia. Insulin insensitivity decreases activity of Na-K pump. In obese
people concentration of free fatty acids has increased and that increases peripheral resistance and
vasoconstrictor effects of catecholamines, reducing the vasodilatory effects of NO), psychosocial
factors (stress, lifestyle, over-eating, eating salty food, reduced physical activity and alcoholism.

Hypertension occurs because stress increases sympathetic activity and increased consumption of
salt / as a result of stress / increases vasoconstrictor response of arterioles.There are is a number of
nervous mechanisms such as the: disorder of the central regulation of sympathetic activity
(psychosocial factors can act through telencephalic structures on the vasomotor center activity
which is also affected by the afferent impulses from the periphery and angiotensin), adrenaline
action of blood (released in stress; it acts on beta-receptors and increases the release of
noradrenaline) and α and β receptors mismatch (predominance of α- receptors with vasoconstrictor
action over β-receptors with vasodilating action causes an increase in peripheral resistance). In the
development of essential hypertension when increase of MV prevails over increasing peripheral
resistance β-receptors prevail, whereas in the maintenance phase of hypertension α-receptors are
predominant). Patients with essential hypertension maintain the balance of sodium with higher
blood pressure, and this does not increase the volume of extracellular fluid. Renin activity is often
increased in younger hypertensive patients with increased cardiac output and higher levels of
norepinephrine and low renin activity is more common in elderly hypertensive patients with
increased peripheral resistance. Disturbances in the transfer of Na and K through the cell membrane
could cause increased intracellular concentration of Na and the consequential increase in
intracellular Ca2 + content (increased smooth muscle excitability). In younger people with unstable
or mild hypertension (intermittent) we often found moderate increase in MV, cardiac freq increase
and SV increase.

In the first phase (development phase) there is a normal peripheral resistance and increased
adrenergic stimulation, sympathetic predominance over parasympathetic nervous system. In the
second phase (maintenance phase) peripheral resistance is increased initially because of adrenergic
vasoconstriction and functional changes, and later due to changes in the wall of blood vessels.
Increased content of Na and K in the wall of blood vessels and increased sensitivity to
norepinephrine and angiotensin results in development of hypertrophy and decreased lumen of the
vessels with the consequent increase in the resistance which is most pronounced in the kidney. With
the increase in peripheral resistance: cardiac output, heart freq. and myocardial contractility are
decreased, and signs of increased sympathetic activity disappears. Obese people have special
features: large output, increased blood volume in circulation and normal peripheral resistance.


Kidney hypertensions:
Hypertension in kidney disease is caused by: disruption of volume and regulation of renin. It
is divided into renal hypertension in the narrow sense (a consequence of the kidney disease) and
renovascular hypertension. Arterial hypertension with acute glomerulonephritis result from
increased extracellular volume, increased volume of circulating blood and cardiac output, while
peripheral resistance remains unchanged.
Hypertension with pregnancy nephropathy is characterized by a high renin activity due to
increased production of renin in the liver.
In patients with chronic glomerulonephritis or nephroangiosclerosis due to defective renin
secretion hypertension develops.It can not be treated by hemodialysis or suppressed by drugs.
In patients with advanced renal failure salt retaining is the most important factor for
hypertension development.It can be treated with hemodialysis and can be suppressed by drugs.
Hypertension in uremia is often referred to as renal hypertension which implies the loss of
salt and water.Loss of vasodepressive substances, particularly prostaglandins. (Can occur after
bilateral nephrectomy because vasodepressive substances are synthesized in the interstitial renal
Renovascular hypertension is a result of narrowing of the renal artery or some of its larger
branches leading to kidney ischemia.By nephrectomy of such kidney normotension can be
established only if contralateral kidney did not developed vascular changes.In assessing whether it
is necessary to remove the renal artery stenosis it is necessary to determine renin activity in both
renal veins, if the ratio of the renin activity (ischemic/contralateral kidney) is equal to or greater
than 1.5 that indicates the pathogenic narrowing.

Endocrine hypertensions:
Pheochromocytoma-characterized by hypertension which can be permanent or in spikes. After
surgery there is a risk of sudden onset of hypotension and shock.
Primary hyperaldosteronism (Conn's syndrome) - hypokalemia, hypernatremia, arterial
hypertension with increased cardiac output, increased peripheral resistance, renin secretion is
Cushing's disease/syndrome - an increased production of cortisol probably results in increased
synthesis of angiotensinogen with the retention of salt and water.
Acromegaly-due to the effects of growth hormone Na is retained and extracellular volume increases.
Hypertension in cardiovascular diseases:
Atherosclerosis of large arteries causes an increase in systolic with normal or reduced
diastolic blood pressure (due to reduced ductility).
Coarctation of aorta causes systolic hypertension.
In aortic regurgitation,ductus arteriosus or arteriovenous fistula left ventricle is under
volume overload and because of the draining of blood into the system with significantly lower
pressure (from the left ventricle into the pulmonary trunk or veins) diastolic blood pressure is low.
In the conditions that cause bradycardia, systolic pressure is elevated due to increased stroke
volume, and diastolic is low because of the long diastole.
Sometimes cardiac decompensation can be accompanied with initial milder hypertension
due to delays in the venous part of the circulatory system.
Neurogenic hypertension- due to encephalitis or polio
Oral contraceptives- estrogen stimulates the renin angiotensin system and consequently
leads to an increase in blood pressure
Malignant hypertension-occurs in patients who have prolonged essential or secondary
hypertension Manifests as changes in the eye background, hypertensive encephalopathy, and
hemolytic anemia (due to microthrombosis at the damaged endothelium of small arteries and
arterioles-erythrocytes fall apart passing through them).


Arterial hypotension is the state with a systolic pressure of less than 13.3 or 14.7 kPa.
Hypotension at standing is orthostatic hypotension or postural. According to the etiology it can be
divided into primary (essential) and secondary (symptomatic) hypotension.
The primary (essential) hypotension is not caused by a certain disease.
 orthostatic syndrome-hypotension when standing up, the result of a marked MV
decrease Shift of the blood (half a liter or a little more) to the lower parts of the
body thereby reducing the filling pressure of the right ventricle as well as stroke and
minute volume. In several seconds arterioles constrict due to the influence of
sympathetic system and adrenalin is released locally.That increases peripheral
resistance and blood pressure, but extravasation of plasma volume arises! The
reduction in stroke volume (due to reduced venous filling of the heart) is followed
with increase in heart frequency.In hyperdiastolic (hyperadrenergic) form an
increase in the peripheral resistance that compensates for reduced MV is noted so
that lowers only systolic pressure with a pronounced increase in heart freq.In
hypodiastolic (hypoadrenergic) form there is no strong constriction of the arterioles
and the diastolic pressure is significantly decreased (heart freq. does not increase).
 vasovagal reaction -occurs when standing up or standing position. Characterized
with a marked reduction in MV and a decrease in peripheral resistance with
hypotension and decreased oxygen utilization.Even tho before syncope person often
has rapid heartbeat, with syncope bradycardia is a characteristic finding.
 constitutional hypotension -patients have permanent low pressure, that they do not
experience as a health problem, because it is likely that that pressure is a
physiological variant of normal.
Secondary (symptomatic) hypotension is caused by other diseases.
 Addison's disease – Na loss that consequently leads to hypovolemia.
 Hypothyroidism - reduced MV
 insufficiency of adenohypophysis - lack of ACTH and TSH cause hypofunction of the adrenal
gland and thyroid gland
 heart failure - cardiogenic shock
 mitral and aortic stenosis - limited ability to increase MV necessary to maintain blood pressure
(due to stenosis!), characteristic symptom is syncope!
 aortic arch syndrome - stenosis at the starting point of the great arteries, hypotension of the
affected area.
 Chronic idiopathic orthostatic hypotension in elderly people, when getting up, lack of
compensatory tachycardia and sweating, with frequent syncope and disorder of sphincter
 Valsalva experiment- strong cough decreases venous return to the heart with the possible
occurrence of syncope.
 In pregnant women, in developed legs varices or loss of muscle pump function orthostatic
hypotension can occur


Palpation of the arterial pulse is obligatory part of every clinical examination and allows us
to assess whether the patient has a cardiac or peripheral vascular disease. Pulsation of the carotid
tell us about what is going on near the aortic valve and provide the best insight into the quality of
the pulse.
Pulse is rarely completely regular.Sinus arrhythmia is normal at any age, but is more
common in children and young people. The exhalation increases left ventricular filling and stroke
volume and thus the systolic pressureincreases which can stimulate baroreceptors and vagus causing
reflex bradycardia. It is important to differentiate between the rhythm that is irregular and sinus
arrhytmmia. Pulse may appear as a regularly irregular (as extrasystoles!) and as irregular
irregularity (absolute arrhythmia due to atrial fibrillation).
The duration of the diastole in atrial fibrillation varies. During short diastole there will not
be enough time to replenish the left ventricle, stroke volume will be small, and the pulse wave will
not reach the radial artery and therefore we will not be able to feel the pulse on the radial artery.
This is called deficiency pulse.
Pulse pressure (the amplitude of the pulse wave) is the difference between the highest
systolic and diastolic blood pressure measured at any point in the peripheral arterial system.Pulse
pressure is low in states with low SV (stroke volume), in states with reduced emptying of the left
ventricle (mitral and aortic stenosis) and at increased peripheral resistance (relaxation of the left
ventricle). Bigger SV, higher systolic blood pressure, decreased elasticity of the arterial wall will
cause an increase in pulse pressure.Pulse pressure disorders can be divided into hypokinetic and
When analyzing the shape of the pulse pressure curve we should distinguish anacrotic wave
(seen in the first part of the systole) and dicrotic wave (occurs in another part of systole,
immediately after incisure-2nd heart sound, closing of aortic valve!).
Differential pulse-means unequal (asynchronous) pulse between the radial and femoral
artery on the same side of the body.Pulse decrease on one of the arteries indicates a local
obstruction of blood flow, usually due to atherosclerosis.
Pulsus alternans- occurs due to changes in the contractile power of myocardium, a sign of
the left ventriclar failure.
Pulsus bigeminus-appears as two successive pulse beats separated with a pause. Regular
exchange of early ectopic contractions with regular ventricular contraction.
Pulsus parvus et tardus-developed in close valvular stenosis.Occurs due to low SV (parvus)
and delayed peaking due to prolonged ejection time (tardus).
Pulsus altus et celer (Corrigan pulse) -it is a wave with a high systolic and low diastolic
blood pressure and usually occurs in aortic insufficiency.SV in aortic insufficiency is significantly
increased, but on the contrary the diastolic pressure in the aorta is rapidly lowered due to the
outflow of blood to the periphery and rapid venous return of left ventricle.That is why we have
systolic and diastolic pulse collapse (collapsing pulse). Corrigan pulse is therefore characteristic of
aortic insufficiency, and sometimes you can see capillary pulsations on the mucosa and nail base.
Collapsing pulse is characteristic for chronic mitral insufficiency it also occurs in other states with
large SV such as the opening of ventricular septum, complete AV block, bigger AV fistula, ductus
arteriosus persistens ...
Double pulse (pulsus bisferiens) - 2 waves in systole, typically occurring in obstructive
cardiomyopathy and can be the first guideline for the correct diagnosis.
Paradoxical pulse-characteristic in the cardiac tamponade, which means reinforcing the
physiological systolic blood pressure decrease more than 1.3kPa in inspire.


Optimal values of PaO2 are from 9.3-14.7 kPa and gradually decrease with age. Normal
range of PaCO2 is 4.8-5.9 kPa.
Hypoxemia may occur due to 5 reasons:
 hypoventilation
 diffusion disorder
 ventilation/perfusion mismatch
 right-left appendage
 inhalation of air with low partial pressure of oxygen.
Hypoventilation as one of the most common causes of hypoxemia is defined as a condition
in which the alveolar spaces are not filled with enough fresh air.Therefore oxygenation of blood in
the pulmonary capillaries is disturbed as well as the removal of carbon dioxide.
Hypercapnia is the basic feature of alveolar space hypoventilation (real or global
hypoventilation).Regional or partial hypoventilation exists when hypoventilation affects only
certain areas of lungs. Real alveolar hypoventilation occurs extremely rarely.
Hypercapnia leads to respiratory acidosis.Respiratory center sensitivity adjusts to a higher
PCO2 and the center becomes insensitive to hypercapnia! The only stimulus to respiration in these
circumstances is stimulation of peripheral receptors with hypoxemia.That is way such patients
should not suddenly get oxygen because they would lose the only remaining stimulus for breathing.
Limited amounts of oxygen needed!
Hypoxemia causes vasoconstriction of pulmonary blood vessels and consequent failure of
the right heart!

Hyperventilation occurs in the state of fear, in metabolic acidosis,in hypoxia.
Hyperventilation is a state in which ventilated alveolar area is greater than that required for
removal of metabolically generated CO2. Hypocapnia and respiratory alkalosis are developed.
Alkalosis increases the capacity of plasma proteins for binding of Ca2+, and will therefore cause
hypocalcaemia.Such patients complain of numbness and tingling in the arms, legs, lips, and tongue.
In hyperventilation blood flow to the brain decreases due to vasoconstriction of cerebral
Obstructive lung diseases are bronchial asthma, chronic bronchitis and pulmonary
emphysema. It is believed that pathoanatomical disorder starts at the level of the small airways.
They can occur due to endogenous or exogenous factors.

Endobronchial obstruction - important role of mucus hypersecretion and increase in its

viscosity, mucosal edema of the respiratory tract or bronchial muscle spasm (which can be
successfully controlled by applying the therapeutic beta-2 agonist of adrenergic receptors).
There are three fundamental disorder of the airways in the bronchial asthma.Those are
obstruction, inflammation and hyperactivity of airways.Main disorder in most patients is the
hypersensitivity type 1 (antibody IgE). Leading to increased retention of the substance P because its
inactivation is decreased due to damage of epithelial cells (damage results from a variety of
inflammatory factors that are released by degranulation of mast cells). Stimuli that come to the beta
2 adrenergic receptors increase the intracellular concentration of cAMP resulting in the relaxation
of bronchial smooth muscle and termination of the liberation of anaphylactic reaction
mediators.Conversely, if you stimulate alpha adrenergic or cholinergic receptors that results in
reduction of cAMP and cGMP increase, leading to the increased activity of the bronchial muscles
and increased anaphylactic response.

Egzobronhal obstruction -when the elasticity of the lungs are reduced leading to increased lung
compliance, volume of air in the lungs increases with the occurrence of emphysema and bronchial
compression. Due to the compression of the bronchi bronchial cavity becomes narrower and
resistance to air flow increases (especially at the end of inhalation)! Mechanisms responsible for
cleaning of the lungs are damaged. The result is obstructive pulmonary emphysema! Greater
obstruction causes intrapleural pressure at end of inspiration to become more negative, while at the
end of expire approaches the atmospheric pressure (even become positive).That positive pressure
reduces the venous return, thereby reducing the SV of the heart. When positive intrapleural pressure
becomes higher than intrabronchial pressure at the site proximal to the point of equal pressure
additional obstruction may occur which plays a major role in reducing tolerance to physical

Restrictive lung diseases are a category of extrapulmonary, pleural, or parenchymal respiratory

diseases that restrict lung expansion,resulting in a decreased lung volume, an increased work of
breathing, and inadequate ventilation and/or oxygenation. Pulmonary function test demonstrates a
decrease in the forced vital capacity.
In disorders that are intrinsic to the lung parenchyma, the underlying process is usually pulmonary
fibrosis (scarring of the lung). As the disease progresses, the normal lung tissue is gradually
replaced by scar tissue interspersed with pockets of air. This can lead to parts of the lung having a
honeycomb-like appearance.The main symptoms are shortness of breath and cough.
In restrictive lung disease, both forced expiratory volume in one second (FEV1) and forced vital
capacity(FVC) are reduced, however, the decline in FVC is more than that of FEV1, resulting in a
higher than 80% FEV1/FVC ratio. In obstructive lung disease however, FEV1 is reduced while

FVC remains stable, consequentially depicting a lower FEV1/FVC ratio.]
One definition requires a total lung capacity which is 80% or less of the expected value.
Restrictive lung diseases may be due to specific causes which can be intrinsic to the parenchyma of
the lung, or extrinsic to it.
Pneumoconiosis caused by long-term exposure to dusts, especially in mining. For
example Asbestosis.
 Radiation fibrosis, usually from the radiation given for cancer treatment.
 Certain drugs such as amiodarone,bleomycin and methotrexate.
 As a consequence of another disease such as rheumatoid arthritis.
 Hypersensitivity pneumonitis due to an allergic reaction to inhaled particles.
 Acute respiratory distress syndrome(ARDS), a severe lung condition occurring in
response to a critical illness or injury.
 Infant respiratory distress syndrome due to a deficiency of surfactant in the lungs of
a baby born prematurely.
Many cases of restrictive lung disease are idiopathic. Still, there is generally pulmonary fibrosis.
Examples are:
 Idiopathic pulmonary fibrosis
 Idiopathic interstitial pneumonia, of which there are several types
 Sarcoidosis
 Eosinophilic pneumonia
 Lymphangioleiomyomatosis
 Pulmonary Langerhans' cell histiocytosis
 Pulmonary alveolar proteinosis
Conditions specifically affecting the interstitium are called interstitial lung diseases.
 Nonmuscular diseases of the upper thorax such as kyphosis, pectus carinatum and
pectus excavatum.
 Diseases restricting lower thoracic/abdominal volume (e.g.obesity,diaphragmatic
hernia, or the presence of ascites).
 Pleural thickening.


In respiratory physiology, the ventilation/perfusion ratio (V/Q ratio) is a measurement used
to assess the efficiency and adequacy of the matching of two variables:
 "V" –ventilation– the air that reaches the alveoli
 "Q" –perfusion– the blood that reaches the alveoli
VQ Ratio can therefore be defined as: the ratio of the amount of air reaching the alveoli to the
amount of blood reaching the alveoli. These two variables, V & Q, constitute the main determinants
of the blood oxygen (O2) and carbon dioxide (CO2) concentration.
The V/Q ratio can be measured with a ventilation/perfusion scan.
A V/Q mismatch can cause a type 1 respiratory failure.
Ideally, the oxygen provided via ventilation would be just enough to saturate the blood fully.
In the typical adult, 1 litre of blood can hold about 200 mL of oxygen; 1 litre of dry air has about
210 mL of oxygen. Therefore, under these conditions, the ideal ventilation perfusion ratio would be
about 1.05. If one were to consider humidified air (with less oxygen), then the ideal v/q ratio would
be in the vicinity of 1.0, thus leading to concept of ventilation-perfusion equality or ventilation-
perfusion matching. This matching may be assessed in the lung as a whole, or in individual or in
sub-groups of gas-exchanging units in the lung. On the other side Ventilation-perfusion mismatch is
the term used when the ventilation and the perfusion of a gas exchanging unit are not matched.
The actual values in the lung vary depending on the position within the lung. If taken as a whole,
the typical value is approximately 0.8.
Because the lung is centered vertically around the heart, part of the lung is superior to the heart, and
part is inferior. This has a major impact on the V/Q ratio:
apex of lung – higher
base of lung – lower
In a subject standing in orthostatic position (upright) the apex of the lung shows higher V/Q
ratio, while at the base of the lung the ratio is lower but nearer to the optimal value for reaching
adequate blood oxygen concentrations. The main reason for lower V/Q ratios at the base is that both
ventilation and perfusion increase when going from the apex to the base, but Q does it more
strongly thus lowering the V/Q ratio. The principal factor involved in the genesis of V/Q
dishomogeneity between the apex and the base of the lung is gravity (this is why V/Q ratios change
in positions other than the orthostatic one).
Gravity and lung’s weight act on ventilation by increasing pleural pressure at the base
(making it less negative) and thus reducing the alveolar volume. The lowest part of the lung in
relation to gravity is called the dependent region. At the dependent region smaller volumes mean the
alveoli are more compliant(more distensible) and so capable of wider oxygen exchanges with the
external environment. The apex, though showing a higher oxygen partial pressure, ventilates less
efficiently since its compliance is lower and so smaller volumes are exchanged.
The impact of gravity on pulmonary perfusion expresses itself as the hydrostatic pressure of the
blood passing through the branches of the pulmonary artery in order to reach the apical and basal
district of the lung, acting respectively against or synergistically with the pressure developed by the
right ventricle. Thus at the apex of the lung the resulting pressure can be insufficient for developing
a flow (which can be sustained only by the negative pressure generated by venous flow towards the
left atrium) or even for preventing the collapse of the vascular structures surrounding the alveoli,
while the base of the lung shows an intense flow due to the higher resulting pressure.
Extreme alterations of V/Q
An area with perfusion but no ventilation (and thus a V/Q of zero) is termed "shunt."
An area with ventilation but no perfusion (and thus a V/Q undefined though approaching
infinity) is termed "dead space".
Of note, few conditions constitute "pure" shunt or dead space as they would be incompatible with
life, and thus the term V/Q mismatch is more appropriate for conditions in between these two
 A lower V/Q ratio (with respect to the expected value for a particular lung area in a defined
position) impairs pulmonary gas exchange and is a cause of low arterial partial pressure of
oxygen (paO2). Excretion of carbon dioxide is also impaired, but a rise in the arterial partial
pressure of carbon dioxide (paCO2) is very uncommon because this leads to respiratory
stimulation and the resultant increase in alveolar ventilation returns paCO2 to within the
normal range. These abnormal phenomena are usually seen inchronic
bronchitis,asthma,hepatopulmonary syndrome, and acute pulmonary edema.
 A high V/Q ratio decreases PACO2 and increases PAO2. This finding is typically associated
with pulmonary embolism(where blood circulation is impaired by an embolus). Ventilation
is wasted, as it fails to oxygenate any blood. A high V/Q can also be observed in emphysema
as a maladaptive ventilatory overwork of the undamaged lung parenchyma. Arterial pO2
will decrease as a result due to lack of re-oxygenation.


Although the diffusion of respiratory gases is affected by lung ventilation (changing their
partial pressure in the alveolar space), in the narrow sense of the term gas diffusion disorders
include disorders arising from changes in respiratory membrane (extended diffusion path, reducing
the diffusion surface).
1.respiratory membrane thickening (alveolar-capillary block)
 diffuse interstitial pulmonary fibrosis
 interstitial pneumonia
 pneumoconiosis
 Reduction of alveolar space (decreased alveolar surface where the gas exchange takes place)
 pulmonary edema
 pneumonia
 tuberculosis
 Reduction of capillary diffusion surface (the most important and the most common cause of
the mismatch)
 pulmonary emphysema
 pulmonary embolism
 disease of pulmonary blood vessels
Disorder of diffusion in the lungs more easily produces hypoxemia (due to short contact of blood
and alveoli) than hypercapnia because carbon dioxide is 20 times more soluble than oxygen.

176. Conditions that Alter Partial Oxygen Pressure and CO2 Levels in Blood

Thickening of the Alveolar-Capillary Membrane:

-diffuse interstitial lung fibrosis
hamman rich syndrome (idiopathic pulmonary fibrosis) ROBBINS PAGE 472
allergic alveolitis
sarcoidosis: ROBBINS p. 478

carcinoma of alveolar wall cells

Reduced Alveolar Space:

-Pulmonary Edema (ALGORITHM Problem 110)
Pneumonia ROBBINS PAGE 487
Bronchial, alveolar carcinoma

Reduced capillary surface:

-Pulmonary emphysema ROBBINS PAGE 463
Pulmonary blood vessels disease
Pumonary emboli ROBBINS PAGE 482

177. Imbalance of Fluid Distribution and Pulmonary Circulation

Pulmonary Edema: ALGORITHM PROBLEM 110

Pulmonary edema is often caused by congestive heart failure. When the heart is not able to pump
efficiently, blood can back up into the veins that take blood through the lungs.
As the pressure in these blood vessels increases, fluid is pushed into the air spaces (alveoli) in the
lungs. This fluid reduces normal oxygen movement through the lungs. These two factors combine
to cause shortness of breath.

Congestive heart failure that leads to pulmonary edema may be

caused by:
• Heart attack, or any disease of the heart that weakens or
stiffens the heart muscle (cardiomyopathy)
• Leaking or narrowed heart valves (mitral or aortic valves)
• Sudden, severe high blood pressure (hypertension)
• Lymph Flow obstruction or damage

Symptoms of pulmonary edema may include:

• Coughing up blood or bloody froth
• Difficulty breathing when lying down (orthopnea)
• Feeling of "air hunger" or "drowning" (This feeling is called "paroxysmal nocturnal dyspnea"
if it causes you to wake up and try to catch your breath.)
• Grunting, gurgling, or wheezing sounds with breathing
• Problems speaking in full sentences because of shortness of breath

CARDIOGENIC PULMONARY EDEMA: Hemodynamic edema due to increase in pulmonary

capillary pressure

Causes are :
- increase in pressure in the left atrium
- increase in pressure at the end of left ventricular diastole
- occlusion in the pulmonary veins


impairment of the lung functions, the gas exchange, increase in breathing work, hypoxemia and
Seen in:
- Mitral stenosis
- congestive heart failure (Algorithm)
- heart failure

NONCARDIOGENIC PULMONARY EDEM: Caused by increase in permeability of the

pulmonary capillar membran

Causes are:
Neurogenic pulmonary edema
pulmonary edema in renal failure and/or fluid overload
Negative-Pressure Pulmonary edema

Caused by vasoconstriction and/or thickening of the alveolar capillary leads to increased pulmonary
capillary pressure and resulting in a pulmonary edema.
Causes are:
cor pulmonale
left to right shunt

178. Respiratory Rhythm Disorder

Cheyne-Stroke Breathing
is an abnormal pattern of breathing characterized by progressively deeper and sometimes faster
breathing, followed by a gradual decrease that results in a temporary stop in breathing called an
apnea. The pattern repeats, with each cycle usually taking 30 seconds to 2 minutes. It is an
oscillation of ventilation between apnea and hyperpnea with a crescendo-diminuendo pattern, and is
associated with changing serum partial pressures of oxygen and carbon dioxide.
Cheyne–Stokes respiration and periodic breathing are the two regions on a spectrum of severity of
oscillatory tidal volume. The distinction lies in what is observed at the trough of ventilation:
Cheyne–Stokes respiration involves apnea (since apnea is a prominent feature in their original
description) while periodic breathing involves hypopnea (abnormally small but not absent breaths).

Due to: Brain damage or prolonged time in circulation of blood from lungs to brain in left heart
Hyperventilation of alveolar spaces leads to hypocapnia


is a sleep disorder characterized by pauses in breathing or instances of shallow or infrequent

breathing during sleep. Each pause in breathing, called an apnea, can last for several seconds to
several minutes, and may occur, by definition, at least 5 times in an hour. Similarly, each
abnormally shallow breathing event is called a hypopnea. Sleep apnea is classified as a dyssomnia,
meaning abnormal behavior or psychological events occur during sleep. When breathing is paused,
carbon dioxide builds up in the bloodstream. Chemoreceptors in the blood stream note the high
carbon dioxide levels. The brain is signaled to wake the person sleeping and breathe in air.
Breathing normally will restore oxygen levels and the person will fall asleep again.


Obesity leads to loss of elasticity of chest and abdomen leading to a decrease of lung permeability.
This leads to an increase in breathing work, hypoventilation and functional right-left shunt.
Decrease of vital capacity, total lung capacity and functional residual volume is another result
- severe hypoxemia
- mild to moderate hypercapnia
- respiratory acidosis

179. Pathogenesis of Respiratory Insufficiency

Respiratory failure is inadequate gas exchange by the respiratory system, with the result that levels
of arterial oxygen, carbon dioxide or both cannot be maintained within their normal ranges. A drop
in blood oxygenation is known as hypoxemia; a rise in arterial carbon dioxide levels is called
hypercapnia. The normal partial pressure reference values are: oxygen PaO2 more than 80 mmHg
(11 kPa), and carbon dioxide PaCO2 lesser than 45mmHg (6.0 kPa). Classification into type I or
type II relates to the absence or presence of hypercapnia respectively.
Type 1
-> respiratory failure is defined as a low level of oxygen in the blood (hypoxemia) without an
increased level of carbon dioxide in the blood (hypercapnia), and indeed the PaCO2 may be normal
or low. It is typically caused by a ventilation/perfusion (V/Q) mismatch; the volume of air flowing
in and out of the lungs is not matched with the flow of blood to the lungs.

This type of respiratory failure is caused by conditions that affect oxygenation such as:
• Low ambient oxygen (e.g. at high altitude)
• Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to
absorb it, e.g. pulmonary embolism)

• Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle activity,
e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory failure if
• Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g. in
pneumonia or ARDS)
• Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, e.g.
right-to-left shunt)

Type 2: hypoxemia with hypercapnia

Type 2 respiratory failure is caused by inadequate alveolar ventilation; both oxygen and carbon
dioxide are affected. Defined as the buildup of carbon dioxide levels (PaCO2) that has been
generated by the body but cannot be eliminated. The underlying causes include:
• Increased airways resistance (chronic obstructive pulmonary disease, asthma, suffocation)
• Reduced breathing effort (drug effects, brain stem lesion, extreme obesity)
• A decrease in the area of the lung available for gas exchange (such as in chronic bronchitis)
• Neuromuscular problems (Guillain-Barré syndrome,motor neuron disease)
• Deformed (kyphoscoliosis), rigid (ankylosing spondylitis), or flail chest.

180. Interrelation Between Pulmonary and the Other Organs Dysfunctions

Systemic Consequence of pulmonary disease:

1. Hypoxemia
-Cardiovascular: dilatation of peripheral blood vessels, increased skeletal muscle of ventricle
- Erythrocyte: increase of blood viscosity
- physical stress
- CNS disturbance
- liver damage
- ulcer
- loss of appetite
- club fingers and hypertrophy
- pulmonary osteorthropathy

2. Hypercapnia
- peripheral vasodilation and hypotonia
- Dilation of brain vessels and increased blood flow in CNS (CO2 narcosis)

Pulmonary Symptom of Systemic Disease:

1. Cardiogenic Disease-> Pulmonary edema (ALGORITHM)
2. Liver Cirrhosis- chronic hyperventilation, hypocapnic, hypoxemic and respiratory alkalosis
3. CNS Disease- Cheyne-strokes

181.Impairment of Renal Blood Flow

Common cause of Renal Failure is :

Liver disease
Heart failure
renal artery stenosis

Before total failure there is compensatory phase:

- Decrease resistance in kidney
- Increase plasma filtration
- increase osmotic pressure in peritubilar capillaries -> increase reabsoption

When all compensatory mechanisms are overcome, failure develops:

Increase in plasma concentration of nitrogen compounds
increase in ECF volume
oliguria with concentrated urine

Pre-renal failure is reversible if there is no ischemic acute tubular necrosis

182. Impairment of Glomerular Function

Renal failure, also known as kidney failure or renal insufficiency, is a medical condition in which
the kidneys fail to adequately filter waste products from the blood. [1] The two main forms are acute
kidney injury, which is often reversible with adequate treatment, and chronic kidney disease, which
is often not reversible. In both cases, there is usually an underlying cause.
Renal failure is mainly determined by a decrease in glomerular filtration rate, the rate at which
blood is filtered in the glomeruli of the kidney. This is detected by a decrease in or absence of urine
production or determination of waste products (creatinine or urea) in the blood. Depending on the
cause, hematuria (blood loss in the urine) and proteinuria (protein loss in the urine) may be noted.
In renal failure, there may be problems with increased fluid in the body (leading to swelling),
increased acid levels, raised levels of potassium, decreased levels of calcium, increased levels of
phosphate, and in later stages anemia. Bone health may also be affected. Long-term kidney
problems are associated with an increased risk of cardiovascular disease

Glomerulopathies are due to:

-Immune complex accumulation (ALGORITHM SERUM SICKNESS)
Antibodies developed against glomerular basement membrane (GOODPASTURE ALGORITHM)
-Sclerosis within glom or matrix proliferation
decrease of macro glom. filtration (NEPHRITIC SYNDROMe ALGORITHM) or increase of
glomerular capillary waller (Nephrotic syndrome)

Nephritic syndrome:
-hematuria with dysmophilic red blood cells
-dysuria, azotemia

Nephrotic syndrome:
-Massive proteinuria
-generalized edema

183. Nephrotic Syndrome

Nephrotic syndrome is a group of symptoms that include protein in the urine, low blood protein
levels, high cholesterol levels, high triglyceride levels, and swelling.


Nephrotic syndrome is caused by different disorders that damage the kidneys. This damage leads to
the release of too much protein in the urine.
The most common cause in children is minimal change disease. Membranous glomerulonephritis is
the most common cause in adults.

The renal glomerulus filters the blood that arrives at the kidney. It is formed of capillaries with
small pores that allow small molecules to pass through that have a molecular weight of less than
40,000 Daltons, but not larger macromolecules such as proteins.

In nephrotic syndrome, the glomeruli are affected by an inflammation or a hyalinization (the

formation of a homogenous crystalline material within cells) that allows proteins such as albumin,
antithrombin or the immunoglobulins to pass through the cell membrane and appear in urine.

Albumin is the main protein in the blood that is able to maintain an oncotic pressure, which
prevents the leakage of fluid into the extracellular medium and the subsequent formation of edemas.

As a response to hypoproteinemia the liver commences a compensatory mechanism involving the

synthesis of proteins, such as alpha-2 macroglobulin and lipoproteins. An increase in the latter can
cause the hyperlipidemia associated with this syndrome.

184. General Disorders of Tubular Function

Primary: Acute Tubular Necrosis, Pyelonephritis

Secondary: Consequence of glomerulopathy

-Loss of Urine Concentration acidity and excretion of acids

ATN: Acute Tubular Necrosis

-due to hypoperfusion (hypotension due to sepsis)
-local necrosis along tubulars with GMB damage
-most are cells of proximal tubules (increase of ATP utillization)

-Due to Toxins (antibiotics, metals)
-Basal Membrane Preservation

Tubulointerstitial disease due to drugs can cause ATN, hypersensitivity reaction and cell damage.
-Hypersensitivity can be caused by some antibiotics and diuretics that are bound to proteins of
tubular cells and cause immunological reactions
-Analgesic cellular nephropathy is caused by analgesics that damage kidneys by making ROS and
inhibiting protein synthesis

Tubulointerstitial disease caused by inflammation

- acute pyelonephritis:
- ascending bacterial infection of pyelonephron and kidney
- sudden with strong controvertebral pain, dysuria and fever
- complications: chronic inflammation, pyelonephron abcess, necrotic papillitis

Uric Acid Nephropathy:

Overproduction of uric acid occurs primarily when tissue breakdown is accelerated. Acute uric acid
nephropathy is the term applied to the development of acute oligoanuric renal failure caused by
renal tubular obstruction by urate and uric acid crystals. This is observed almost exclusively in the
setting of malignancy, especially leukemia and lymphoma, in which rapid cell turnover or cell lysis
occurs from chemotherapeutic agents or radiation therapy.
The release of intracellular nucleotides leads to severe hyperuricemia. When urate is filtered at
exceedingly high concentrations from the plasma and is further concentrated through the course of
the tubular system, with the pH becoming progressively more acidic, uric acid precipitation and
obstruction in the tubules, collecting ducts, and even pelves and ureters may result.

Crystal deposition causes increased tubular pressure, increased intrarenal pressure, and extrinsic
compression of the small-diameter renal venous network. This causes an increase in renal vascular
resistance and a fall in renal blood flow. The elevated tubular pressure and decreased renal blood
flow cause a decline in glomerular filtration and can result in acute renal failure.

185. Disorders of Specific Tubular Functions

Pseuohipoaldosteronism: Hypovolemia, Hypercalcemia due to insensitivity of tubular cells to


Barettes Syndrome: Mutaion of gene for Na+/K+/Cl- transporter in thick ascending loop
Hypovolemia and compensated hyperaldosterone.

Nephrologic Diabetes Insipidus: Kidneys are insensitive to ADH

Proximal Renal Tubular Acidosis: Decrease Bicarbonate reabsorption leading to metabolic acidosis

Distal Renal Tubular Acidosis: Normal Bicarbonate reabsorption, decreased ability of acidification
of urine in distal tubule leading to high pH of urine. This leads to nephrocalcinosis

Fanconi Syndrome: Proximal Tubule cell disorder. Decrease absorption of substances (electrolytes
and nutrients into the blood)

186. Pathophysiology of the Acute Renal Insufficiency

Pre-renal failure
Intrinsic Renal failure

The driving force for glomerular filtration is the pressure gradient from the glomerulus to the
Bowman space. Glomerular pressure depends primarily on renal blood flow (RBF) and is controlled
by the combined resistances of renal afferent and efferent arterioles. Regardless of the cause of AKI,
reductions in RBF represent a common pathologic pathway for decreasing glomerular filtration rate
(GFR). The etiology of AKI consists of 3 main mechanisms: prerenal, intrinsic, and obstructive.
In prerenal failure, GFR is depressed by compromised renal perfusion. Tubular and glomerular
function remain normal.
Intrinsic renal failure includes diseases of the kidney itself, predominantly affecting the
glomerulus or tubule, which are associated with the release of renal afferent vasoconstrictors.
Ischemic renal injury is the most common cause of intrinsic renal failure. Patients with chronic
kidney disease may also present with superimposed AKI from prerenal failure and obstruction, as
well as intrinsic renal disease.
Obstruction of the urinary tract initially causes an increase in tubular pressure, which
decreases the filtration driving force. This pressure gradient soon equalizes, and maintenance of a
depressed GFR then depends on renal efferent vasoconstriction.

Nephrotic Syndrome: Damage to the filtering mechanism of the glomerulus

Nephritic Syndrome: Inflammation (hypertension-hematuria-proteinuria are signs)
- The causes of the latter syndrome are post infectious glomerulopathies (strep)
- IgA nephropathy
- Membranoproliferative Glomerulonephritis
You can also state that acute renal failure may lead to chronic renal failure and start discussing
Algorithm Problem 113


Chronic kidney disease (CKD) is a common condition that is more prevalent in the elderly
population. Usually CKD in younger patients is associated with loss of kidney function, but of
patients over 65 years of age with CKD, 30% do not have progressive disease with loss of kidney
function over time.CKD is associated with an increased risk of cardiovascular disease and chronic
renal failure. Kidney disease is the ninth leading cause of death in the United
States.Hyperparathyroidism is one of the pathologic manifestations of CKD.
Signs and symptoms
Patients with CKD stages 1-3 (GFR >30 mL/min/1.73 m²) are generally asymptomatic. Typically, it
is not until stages 4-5 (GFR < 30 mL/min/1.73 m²) that endocrine/metabolic derangements or
disturbances in water or electrolyte balance become clinically manifest.

Signs of metabolic acidosis in stage 5 CKD include the following:

Protein-energy malnutrition
Loss of lean body mass
Muscle weakness
Signs of alterations in the way the kidneys are handling salt and water in stage 5 include the

 Peripheral edema
 Pulmonary edema
 Hypertension
Anemia in CKD is associated with the following:

 Fatigue
 Reduced exercise capacity
 Impaired cognitive and immune function
 Reduced quality of life
 Development of cardiovascular disease
 New onset of heart failure or the development of more severe heart failure
 Increased cardiovascular mortality
Other manifestations of uremia in end-stage renal disease (ESRD), many of which are more likely
in patients who are being inadequately dialyzed, include the following:

 Pericarditis: Can be complicated by cardiac tamponade, possibly resulting in death if

 Encephalopathy: Can progress to coma and death
 Peripheral neuropathy, usually asymptomatic
 Restless leg syndrome
 Gastrointestinal symptoms: Anorexia, nausea, vomiting, diarrhea
 Skin manifestations: Dry skin, pruritus, ecchymosis
 Fatigue, increased somnolence, failure to thrive
 Malnutrition
 Erectile dysfunction, decreased libido, amenorrhea
 Platelet dysfunction with tendency to bleed
Screen adult patients with CKD for depressive symptoms; self-report scales at initiation of dialysis
therapy reveal that 45% of these patients have such symptoms, albeit with a somatic emphasis.


A normal kidney contains approximately 1 million nephrons, each of which contributes to the total

glomerular filtration rate (GFR). In the face of renal injury (regardless of the etiology), the kidney
has an innate ability to maintain GFR, despite progressive destruction of nephrons, as the remaining
healthy nephrons manifest hyperfiltration and compensatory hypertrophy. This nephron adaptability
allows for continued normal clearance of plasma solutes. Plasma levels of substances such as urea
and creatinine start to show measurable increases only after total GFR has decreased to 50%.

The plasma creatinine value will approximately double with a 50% reduction in GFR. For example,
a rise in plasma creatinine from a baseline value of 0.6 mg/dL to 1.2 mg/dL in a patient, although
still within the adult reference range, actually represents a loss of 50% of functioning nephron mass.

The hyperfiltration and hypertrophy of residual nephrons, although beneficial for the reasons noted,
has been hypothesized to represent a major cause of progressive renal dysfunction. The increased
glomerular capillary pressure may damage the capillaries, leading initially to secondary focal and
segmental glomerulosclerosis (FSGS) and eventually to global glomerulosclerosis. This hypothesis
is supported by studies of five-sixths nephrectomized rats, which develop lesions identical to those
observed in humans with chronic kidney disease (CKD).

Factors other than the underlying disease process and glomerular hypertension that may cause
progressive renal injury include the following:

 Systemic hypertension
 Nephrotoxins (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], intravenous
contrast media)
 Decreased perfusion (eg, from severe dehydration or episodes of shock)
 Proteinuria (in addition to being a marker of CKD)
 Hyperlipidemia
 Hyperphosphatemia with calcium phosphate deposition
 Smoking
 Uncontrolled diabetes

Childhood renal function and CKD in children

In children, the GFR increases with age and is calculated with specific equations that are different
than those for adults. Adjusted for body surface area, the GFR reaches adult levels by age 2-3 years.

Aspects of pediatric kidney function and the measure of creatinine are informative not only for
children but also for adults. For example, it is important to realize that creatinine is derived from
muscle and, therefore, that children and smaller individuals have lower creatinine levels
independent of the GFR. Consequently, laboratory reports that do not supply appropriate pediatric
normal ranges are misleading. The same is true for individuals who have low muscle mass for other
reasons, such as malnutrition, cachexia, or amputation.

Another important note for childhood CKD is that physicians caring for children must be aware of
normal blood pressure levels by age, sex, and height. Prompt recognition of hypertension at any age
is important, because it may be caused by primary renal disease.

Fortunately, CKD during childhood is rare and is usually the result of congenital defects, such as
posterior urethral valves or dysplastic kidney malformations. Another common cause is FSGS.
Genetic kidney diseases are also frequently manifested in childhood CKD. Advances in pediatric
nephrology have enabled great leaps in survival for pediatric CKD and end-stage renal disease
(ESRD), including for children who need dialysis or transplantation.

Aging and renal function

The biologic process of aging initiates various structural and functional changes within the
kidney.Renal mass progressively declines with advancing age, and glomerulosclerosis leads to a
decrease in renal weight. Histologic examination is notable for a decrease in glomerular number of
as much as 30-50% by age 70 years. The GFR peaks during the third decade of life at
approximately 120 mL/min/1.73 m2; it then undergoes an annual mean decline of approximately 1
mL/min/y/1.73 m2, reaching a mean value of 70 mL/min/1.73 m2 at age 70 years.

Ischemic obsolescence of cortical glomeruli is predominant, with relative sparing of the renal
medulla. Juxtamedullary glomeruli see a shunting of blood from afferent to efferent arterioles,
resulting in redistribution of blood flow favoring the renal medulla. These anatomic and functional
changes in renal vasculature appear to contribute to an age-related decrease in renal blood flow.

Renal hemodynamic measurements in aged humans and animals suggest that altered functional
response of the renal vasculature may be an underlying factor in diminished renal blood flow and
increased filtration noted with progressive renal aging. The vasodilatory response is blunted in the
elderly when compared to younger patients.

However, the vasoconstrictor response to intrarenal angiotensin is identical in young and older
human subjects. A blunted vasodilatory capacity with appropriate vasoconstrictor response may
indicate that the aged kidney is in a state of vasodilatation to compensate for the underlying
sclerotic damage.

Given the histologic evidence for nephronal senescence with age, a decline in the GFR is expected.
However, a wide variation in the rate of GFR decline is reported because of measurement methods,
race, gender, genetic variance, and other risk factors for renal dysfunction.

Most cases of CKD are acquired rather than inherited, although CKD in a child is more likely to
have a genetic or inherited cause. Well-described genetic syndromes associated with CKD include
autosomal dominant polycystic kidney disease(ADPKD) and Alport syndrome. Other examples of
specific single-gene or few-gene mutations associated with CKD include Dent disease,
nephronophthisis, and atypical hemolytic uremic syndrome (HUS).

The ability to maintain potassium excretion at near-normal levels is generally maintained in CKD,
as long as aldosterone secretion and distal flow are maintained. Another defense against potassium
retention in patients with CKD is increased potassium excretion in the gastrointestinal tract, which
also is under control of aldosterone.

Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73 m², at
which point the kidneys have decreased ability to excrete potassium. Hyperkalemia can be observed
sooner in patients who ingest a potassium-rich diet or have low serum aldosterone levels. Common
sources of low aldosterone levels are diabetes mellitus and the use of ACE inhibitors, NSAIDs, or

Hyperkalemia in CKD can be aggravated by an extracellular shift of potassium, such as occurs in

the setting of acidemia or from lack of insulin.

Hypokalemia is uncommon but can develop in patients with very poor intake of potassium,
gastrointestinal or urinary loss of potassium, or diarrhea or in patients who use diuretics.

Metabolic acidosis
Metabolic acidosis often is a mixture of normal anion gap and increased anion gap; the latter is
observed generally with stage 5 CKD but with the anion gap generally not higher than 20 mEq/L. In
CKD, the kidneys are unable to produce enough ammonia in the proximal tubules to excrete the
endogenous acid into the urine in the form of ammonium. In stage 5 CKD, accumulation of
phosphates, sulfates, and other organic anions are the cause of the increase in anion gap.

Metabolic acidosis has been shown to have deleterious effects on protein balance, leading to the

 Negative nitrogen balance

 Increased protein degradation
 Increased essential amino acid oxidation
 Reduced albumin synthesis
 Lack of adaptation to a low-protein diet
Hence, metabolic acidosis is associated with protein-energy malnutrition, loss of lean body mass,
and muscle weakness. The mechanism for reducing protein may include effects on adenosine
triphosphate (ATP)–dependent ubiquitin proteasomes and increased activity of branched-chain keto
acid dehydrogenases.

Metabolic acidosis also leads to an increase in fibrosis and rapid progression of kidney disease, by
causing an increase in ammoniagenesis to enhance hydrogen excretion.

In addition, metabolic acidosis is a factor in the development of renal osteodystrophy, because bone
acts as a buffer for excess acid, with resultant loss of mineral. Acidosis may interfere with vitamin
D metabolism, and patients who are persistently more acidotic are more likely to have osteomalacia
or low-turnover bone disease.

Salt- and water-handling abnormalities

Salt and water handling by the kidney is altered in CKD. Extracellular volume expansion and total-
body volume overload results from failure of sodium and free-water excretion. This generally
becomes clinically manifested when the GFR falls to less than 10-15 mL/min/1.73 m², when
compensatory mechanisms have become exhausted.

As kidney function declines further, sodium retention and extracellular volume expansion lead to
peripheral edema and, not uncommonly, pulmonary edema and hypertension. At a higher GFR,
excess sodium and water intake could result in a similar picture if the ingested amounts of sodium
and water exceed the available potential for compensatory excretion.
Tubulointerstitial renal diseases represent the minority of cases of CKD. However, it is important to
note that such diseases often cause fluid loss rather than overload. Thus, despite moderate or severe
reductions in GFR, tubulointerstitial renal diseases may manifest first as polyuria and volume
depletion, with inability to concentrate the urine. These symptoms may be subtle and require close
attention to be recognized. Volume overload occurs only when GFR reduction becomes very severe.

Normochromic normocytic anemia principally develops from decreased renal synthesis of
erythropoietin, the hormone responsible for bone marrow stimulation for red blood cell (RBC)
production. The anemia starts early in the course of the disease and becomes more severe as, with
the shrinking availability of viable renal mass, the GFR progressively decreases.

Using data from the National Health and Nutrition Examination Survey (NHANES), Stauffer and
Fan found that anemia was twice as prevalent in people with CKD (15.4%) as in the general
population (7.6%). The prevalence of anemia increased with stage of CKD, from 8.4% at stage 1 to
53.4% at stage 5.

No reticulocyte response occurs. RBC survival is decreased, and bleeding tendency is increased
from the uremia-induced platelet dysfunction. Other causes of anemia in CKD include the

 Chronic blood loss: Uremia-induced platelet dysfunction enhances bleeding tendency

 Secondary hyperparathyroidism
 Inflammation
 Nutritional deficiency
 Accumulation of inhibitors of erythropoiesis
Bone disease
Renal bone disease is a common complication of CKD. It results in skeletal complications (eg,
abnormality of bone turnover, mineralization, linear growth) and extraskeletal complications (eg,
vascular or soft-tissue calcification).

Different types of bone disease occur with CKD, as follows:

 High-turnover bone disease from high parathyroid hormone (PTH) levels

 Low-turnover bone disease (adynamic bone disease)
 Defective mineralization (osteomalacia)
 Mixed disease
 Beta-2-microglobulin–associated bone disease
Bone disease in children is similar but occurs during growth. Therefore, children with CKD are at
risk for short stature, bone curvature, and poor mineralization (“renal rickets” is the equivalent term
for adult osteomalacia).

CKD–mineral and bone disorder (CKD-MBD) involves biochemical abnormalities related to bone
metabolism. CKD-MBD may result from alteration in levels of serum phosphorus, PTH, vitamin D,
and alkaline phosphatase.

Secondary hyperparathyroidism develops in CKD because of the following factors:

 Hyperphosphatemia
 Hypocalcemia
 Decreased renal synthesis of 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D, or
 Intrinsic alteration in the parathyroid glands, which gives rise to increased PTH secretion
and increased parathyroid growth
 Skeletal resistance to PTH
Calcium and calcitriol are primary feedback inhibitors; hyperphosphatemia is a stimulus to PTH
synthesis and secretion.

Hyperphosphatemia and hypocalcemia

Phosphate retention begins in early CKD; when the GFR falls, less phosphate is filtered and
excreted, but because of increased PTH secretion, which increases renal excretion, serum levels do
not rise initially. As the GFR falls toward CKD stages 4-5, hyperphosphatemia develops from the
inability of the kidneys to excrete the excess dietary intake.

Hyperphosphatemia suppresses the renal hydroxylation of inactive 25-hydroxyvitamin D to

calcitriol, so serum calcitriol levels are low when the GFR is less than 30 mL/min/1.73 m².
Increased phosphate concentration also effects PTH concentration by its direct effect on the
parathyroid glands (posttranscriptional effect).

Hypocalcemia develops primarily from decreased intestinal calcium absorption because of low
plasma calcitriol levels. It also possibly results from increased calcium-phosphate binding, caused
by elevated serum phosphate levels.

Increased PTH secretion

Low serum calcitriol levels, hypocalcemia, and hyperphosphatemia have all been demonstrated to
independently trigger PTH synthesis and secretion. As these stimuli persist in CKD, particularly in
the more advanced stages, PTH secretion becomes maladaptive, and the parathyroid glands, which
initially hypertrophy, become hyperplastic. The persistently elevated PTH levels exacerbate
hyperphosphatemia from bone resorption of phosphate.

Skeletal manifestations

If serum levels of PTH remain elevated, a high ̶ bone turnover lesion, known as osteitis fibrosa,
develops. This is one of several bone lesions, which as a group are commonly known as renal
osteodystrophy and which develop in patients with severe CKD. Osteitis fibrosa is common in
patients with ESRD.

The prevalence of adynamic bone disease in the United States has increased, and it has been
described before the initiation of dialysis in some cases. The pathogenesis of adynamic bone disease
is not well defined, but several factors may contribute, including high calcium load, use of vitamin
D sterols, increasing age, previous corticosteroid therapy, peritoneal dialysis, and increased level of
N-terminally truncated PTH fragments.

Low-turnover osteomalacia in the setting of CKD is associated with aluminum accumulation. It is

markedly less common than high-turnover bone disease.

Another form of bone disease is dialysis-related amyloidosis, which is now uncommon in the era of
improved dialysis membranes. This condition occurs from beta-2-microglobulin accumulation in
patients who have required chronic dialysis for at least 8-10 years. It manifests with cysts at the
ends of long bones.


Polyuria is a condition usually defined as excessive or abnormally large production or passage of

urine (greater than 2.5 or 3 L over 24 hours in adults). Frequent urination is sometimes included by
definition, but is nonetheless usually an accompanying symptom. Increased production and passage
of urine may also be termed diuresis.

Polyuria often appears in conjunction with polydipsia(increased thirst), though it is possible to have
one without the other, and the latter may be a cause or an effect.Psychogenic polydipsia may lead to
polyuria.Polyuria is physiologically normal in some circumstances, such as cold diuresis,altitude
diuresis, and after drinking large amounts of fluids.

The most common cause of polyuria in both adults and children is uncontrolled diabetes mellitus,
causing an osmotic diuresis. In the absence of diabetes mellitus, the most common causes are
excessive secretion of aldosterone due to adrenal cortical tumor,primary polydipsia (excessive fluid
drinking),central diabetes insipidus and nephrogenic diabetes insipidus.
Polyuria may also be due to various chemical substances (diuretics,caffeine,ethanol). It may also
occur after supraventricular tachycardias, during an onset of atrial fibrillation, childbirth, and the
removal of an obstruction within the urinary tract. Diuresis is restrained by antidiuretics such as
vasopressin,angiotensin II and aldosterone.
Cold diuresis is the occurrence of increased urine production on exposure to cold, which also
partially explains immersion diuresis.
High-altitude diuresis occurs at altitudes above 10,000 feet (3,000m) and is a desirable indicator of
adaptation to high altitudes. Mountaineers who are adapting well to high altitudes experience this
type of diuresis. Persons who produce less urine even in the presence of adequate fluid intake are
probably not adapting well to altitude.
In case of absence of Antidiuretic Hormone, the Distal convoluted tubule(DCT) and the Collecting
duct is impermeable to water. As a result, water is not re-absorbed in the kidney. Therefore, large
amount of water is lost with urine. This condition is called as Diabetes insipidus.

Oliguria is the low output of urine.In humans, it is clinically classified as an output more than 100
ml/day but less than 400ml/day.The decreased output of urine may be a sign ofdehydration,kidney
failure,hypovolemic shock, HHNS hyperosmolar Hyperglycemic Nonketotic Syndrome,multiple
organ dysfunction syndrome,urinary obstruction/urinary retention,DKA,pre-eclampsia, and urinary
tract infections, among other conditions.
The most extreme type of oliguria is called anuria, which represents an absence of urine, clinically
classified as below 50ml/day.
Oliguria is defined as a urine output that is less than 1 mL/kg/h in infants,less than 0.5 mL/kg/h in
children,and less than 400 mL or 500 mL per 24h in adults - this equals 17 or 21 mL/hour. For
example, in an adult weighing 70 kg it equals 0.24 or 0.3 mL/hour/kg. Alternatively, however, the
value of 0.5 mL/kg/h is commonly used to define oliguria in adults as well.
Olig- (or oligo-) is a Greek prefix meaning small or few.
Anuria is defined as less than 50mL urine output per day.

The pathophysiologic mechanisms causing oliguria can be categorized globally in three different
 Prerenal: in response to hypoperfusion of the kidney (e.g. as a result of dehydration
by poor oral intake,cardiogenic shock,diarrhea,G6PD deficiency, massive bleeding
or sepsis)
 Renal: due to kidney damage (severe hypoperfusion,rhabdomyolysis,medication)
 Postrenal: as a consequence of obstruction of the urine flow (e.g. enlarged prostate,
tumour compression urinary outflow, expanding hematoma or fluid collection)

Postoperative oliguria
Patients usually have decrease in urine output after a major operation that may be a normal
physiological response to:
 fluid/ blood loss – decreased glomerular filtration rate secondary to hypovolemia and/or
 response of adrenal cortex to stress -increase in aldosterone(Na and water retention) and
antidiuretic hormone (ADH) release


Proteinuria is the daily excretion of protein in the urine in amounts greater than 150 mg (10-
15mg albumin). Massive Proteinuria is a condition in which the secretion is greater than 3.5 grams
of protein per day. The amount of protein in the urine depends on the size of the glomerular
filtration rate and the concentration of protein in the plasma. Glomerular proteinuria occur due to
glomerular cells damage resulting in release of lysosomal neuraminidase, an enzyme that cleaves
the negatively charged sialic acid molecule which facilitates the transmembrane passage of albumin
and other proteins of low molecular weight - selective proteinuria.
Major defects that affect entire basement membrane cause loss of albumin and larger
proteins - non-selective proteinuria. Tubular proteinuria arise due to tubular lesions so tubules no
longer absorb any small protein that is filtered in glomeruli. Overflow proteinuria occur in normal
renal function, because kidney is swamped by large amount small proteins, which occurs in
conditions such as hemoglobinuria, plasmacytoma (abnormal Ig secretion with plenty of free light
chains in urine which are called Bence- Jones proteins). Other proteinuria resulting from: muscle
work, fever, congestive heart failure or when levels of angiotensin II and catecholamines are

Anuria means nonpassage of urine,in practice is defined as passage of less than 100 milliliters of
urine in a day. Anuria is often caused by failure in the function of kidneys. It may also occur
because of some severe obstruction like kidney stones or tumours. It may occur with end stage renal
disease. It is a more extreme reduction thanoliguria, sometimes called anuresis.

Failure of kidney function, which can have multiple causes including medications or toxins (e.g.,
antifreeze, cephalosporins, ACEIs); diabetes; high blood pressure. Stones or tumours in the urinary
tract can also cause it by creating an obstruction to urinary flow. High blood calcium, oxalate, or
uric acid, can contribute to the risk of stone formation. In males, an enlarged prostate gland is a
common cause of obstructive anuria.
Acute anuria, where the decline in urine production occurs quickly, is usually a sign of obstruction
or acute renal failure. Acute renal failure can be caused by factors not related to the kidney, such as
heart failure,mercury poisoning, infection, and other conditions that cause the kidney to be deprived
of blood flow.

Anuria itself is a symptom, not a disease. It is often associated with other symptoms of kidney
failure, such as lack of appetite, weakness, nausea and vomiting. These are mostly the result of
buildup of toxins in the blood which would normally be removed by healthy kidneys.

Treatment is dependent on the underlying cause of this symptom. The most easily treatable cause is
obstruction of urine flow, which is often solved by insertion of a urinary catheter into the urinary
bladder. Mannitol is a medicine that is used to increase the amount of water removed from the
blood and thus improve the blood flow to the kidneys. However, mannitol is contraindicated in
anuria secondary to renal disease, severe dehydration, intracranial bleeding (except during
craniotomy), severe pulmonary congestion, or pulmonary edema. Dextrose and Dobutamine are
both used to increase blood flow to the kidney and act within 30 to 60 minutes.

A kidney stone, also known as a renal calculus or nephrolith, is a solid piece of material which
formed in the kidneys from minerals in the urine.Kidney stones typically leave the body in the urine
stream, and a small stone may pass without causing symptoms.If stones grow to sufficient size
(usually at least 3 millimeters) they can cause blockage of the ureter. This leads to pain, most
commonly beginning in the flank or lower back and often radiating to the groin. This pain is often
known as renal colic and typically comes in waves lasting 20 to 60 minutes. Other associated
symptoms include: nausea,vomiting,fever,blood in the urine,pus in the urine, and painful urination.
Blockage of the ureter can cause decreased kidney function and dilation of the kidney.
Most stones form due to a combination of genetics and environmental factors.Risk factors include
being overweight, certain foods, some medications, and not drinking enough fluids.The diagnosis is

usually based on symptoms, urine testing, and medical imaging.Blood tests may also be
useful.Urinary stones are typically classified by their location in the kidney
(nephrolithiasis),ureter(ureterolithiasis), or bladder (cystolithiasis), or by their chemical
composition(calcium-containing,struvite, uric acid, or other compounds).
In those who have previously had stones, prevention is recommended by drinking fluids such that
more than two liters of urine is produced per day. If this is not effective enough,thiazide diuretic,
citrate or allopurinol may be taken. It is recommended that soft drinks containing phosphoric acid
(typically colas) be avoided.When a stone causes no symptoms, no treatment is needed. For stones
which are causing symptoms, pain control is usually the first measure, using medications such as
nonsteroidal anti-inflammatory drugs or opioids. More severe cases may require procedures. For
example, some stones can be shattered into smaller fragments using extracorporeal shock wave
lithotripsy. Others require cystoscopic procedures.
In the United States about 9% of the population has had a kidney stone.Slightly more men are
affected than 2013 kidney stones resulted in about 15,000 deaths globally.

Signs and symptoms

Diagram showing the typical location of renal colic, below the rib
cage to just above the pelvis
The hallmark of a stone that obstructs the ureter or renal pelvis is
excruciating, intermittent pain that radiates from the flank to the groin
or to the inner thigh.This pain, known as renal colic, is often described
as one of the strongest pain sensations known.Renal colic caused by
kidney stones is commonly accompanied by urinary urgency,
restlessness, hematuria, sweating, nausea, and vomiting. It typically comes in waves lasting 20 to 60
minutes caused by peristaltic contractions of the ureter as it attempts to expel the stone.The
embryological link between the urinary tract, the genital system, and the gastrointestinal tract is the
basis of the radiation of pain to the gonads, as well as the nausea and vomiting that are also
common in urolithiasis. Postrenal azotemia and hydronephrosis can be observed following the
obstruction of urine flow through one or both ureters.Pain in the lower left quadrant can sometimes
be confused with diverticulitis because the sigmoid colon overlaps the ureter and the exact location
of the pain may be difficult to isolate due to the close proximity of these two structures.


Swallowing disorders
Dysphagia is a condition which is characterized by a sense of heavy passage of food through
the mouth, pharynx and esophagus. Different from:
odynophagia - painful swallowing,
aphagia - the impossibility of passing the ingested food ,
globus hystericus - feeling of lump in the throat.
The pathogenesis of dysphagia can be divided into mechanical and functional (motorical).
Mechanical is caused by obstacles in the way of passing food. Functional are the result of
neuromuscular disorders. According to the placement of the disorder we differentiate oropharyngeal
(generally a result of CNS diseases or generalized muscle disease) and esophageal dysphagia
(resulting from achalasia (cardiospasm) or hiatus hernia). The consequences of long-term dysphagia
are malnutrition and aspiration of food into the respiratory system.
Achalasia is a disease of the esophagus with the abnormal or absent esophageal
peristalsis.Occurs due to damage or lack of ganglion cells in myenteric plexus of smooth muscle
resulting in gastroesophageal sphincter relaxation.
Reflux of gastric contents - the return of gastric contents into the esophagus mostly because
of weakened tension of lower esophageal sphincter. Gastric content contains 10,000 to 100,000
times the concentration of H + ions , resulting in chronic inflammation or ulcers.


Two main disorders: motoric disorders and mucosal function disorder which are linked to
one another.
Motoric disorders may be organic or functional with the final result always being
decelerated or accelerated gastric emptying. Accelerated discharge occurs rarely, e.g. after surgical
intervention such as subtotal gastrectomy, vagotomy and pyloroplasty. The most common cause of
aggravated discharge is duodenal or gastric ulcer (organic causes) while the functional causes are:
acute: diabetic ketoacidosis, hypokalemia and chronic: neurosyphilis. The most common are
metabolic and electrolyte disorders,infection and abdominal lesions.
Gastric emptying disorders lead to accumulation of gastric contents and vomiting. They can
be so severe leading to the enlargement of the stomach which can contain 10 liters of liquid.
Because of vomiting dehydration occurs with hyponatremia, hypokalemia and alkalosis.
Disorders affecting function of the stomach:increased secretory function or reduced mucosa-ulcer;
reduced secretory function - atrophy of the stomach.


Peptic ulcer disease encompasses gastric, duodenal, and esophageal ulcers, with common
etiologies of Helicobacter pylori infection, NSAID use, and stress-related mucosal damage. Due to
the more invasive involvement of the gastric muscularis mucosa, PUD differs from the more
superficial acid-related disorders such as erosions and gastritis.Peptic ulcers are typically named for
their anatomical location, such as gastric or duodenal ulcers, and increased gastric acid is the
primary cause. For the purpose of this article, only etiologies of H. pyloriand NSAID-induced PUD
will be discussed. In addition to these etiologies, other controversial environmental risk factors
including cigarette smoking, psychological stress, caffeine intake, and alcohol ingestion may
increase the risk for the development of PUD.

The disease process of PUD is multifactorial based on etiology and risk factors. Ulcers may
occur with hypersecretion of hydrochloric acid and pepsin, causing an imbalance between gastric
luminal factors and degradation in the defensive function of the gastric mucosal barrier. Mucosal
defenses include mucus, secretion of bicarbonate, mucosal blood flow, and epithelial cell defense.
When acid and pepsin invade a weakened area of the mucosal barrier, histamine is released.
Histamine will stimulate parietal cells to secrete more acid. With the continuation of this vicious
cycle, erosion occurs to form the ulcer.

Although over 50% of the population has chronic H.pylori infection, only 5% to 10% develop
ulcers.H.pylori Is a pH-sensitive bacterium that can infiltrate the gastric mucosal layer to reside in a
neutral-pH environment. Acutely, the infection or colonization may ironically produce a
hypochlorhydric environment. It is thought that this protective mechanism for the organism occurs
due to the increase of urease, which hydrolyzes urea and converts it to ammonia and carbon
dioxide.H pylori contributes to mucosal injury by multiple mechanisms

Ulcers induced by nonselective NSAIDs can occur due to a topical irritation of the gastric
epithelial cells and reduced protective prostaglandin synthesis.Due to their pharmacologic
properties, many acidic NSAIDs cause alterations in the hydrophobic mucosal gel layer. The topical
irritation may be the first insult to injury; however, inhibition of cyclooxygenase (COX) is the
greatest concern. NSAIDs inhibit the rate-limiting enzyme in the conversion of arachidonic acid to
prostaglandins. COX-2 exists throughout the body, producing prostaglandins associated with
inflammation and pain, whereas COX-1 is located in the stomach, kidney, intestines, and platelets.
Isoforms COX-1 and COX-2 are inhibited by nonselective NSAIDs. As a result of COX-1
inhibition, adverse effects such as ulcers or GI bleeds may occur.


The major complications of H pylori–associated and NSAID-induced ulcers include UGI

hemorrhage, gastric or duodenal perforation, stricture at the ulcer site, and gastric outlet
obstruction.NSAIDs are responsible for a four-fold increased risk of ulcer complications among
users compared to nonusers.Patients at risk for ulcer complications are those with a history of ulcers
or ulcer complications, advanced age, comorbidities,H pylori infection, use of high-dose NSAIDs,
and concomitant use of corticosteroids, aspirin, or anticoagulants.Elderly patients are particularly
susceptible to PUD complications because they may present atypically or with a painless ulcer, and
also because NSAID use has risen among this population.

UGI bleeding represents the most common and severe complication of peptic ulcers, with 28% to
59% of all episodes attributed to PUD.The mortality rate from peptic ulcer bleeding is 5% to 10%
worldwide.Peptic ulcer bleeding is managed through supportive care, proton pump inhibitor (PPI)
treatment, and endoscopic hemostasis. Surgical interventions are typically reserved for endoscopic
treatment failure. Perforation and obstruction related to peptic ulcers occur less frequently than
hemorrhage and often require surgical intervention.Of concern is the relationship between H.pylori
and gastric cancer. The International Agency for Research on Cancer and the World Health
Organization (WHO) have classified H.pylori as a definite carcinogen.Thus, treatment and
eradication of H.pylori should be considered in infected persons.

Clinical Presentation

The most common presenting symptom of patients with PUD is epigastric pain.Stomach pain upon
food intake is suggestive of a gastric ulcer, while presentation of a duodenal ulcer includes pain
occurring 2 to 5 hours after eating or on an empty stomach and nocturnal pain. It is relieved by food
intake, antacids, or antisecretory therapy.Chronic ulcers may be asymptomatic and are often
NSAID-induced, with UGI bleeding or perforation being the first clinical manifestation.Patients
presenting with alarm symptoms should be suspected of having complications of PUD and referred
for endoscopic evaluation.


Disorders of the digestive processes that occur in the intestinal lumen depend on the composition
and secretion of bile and pancreatic juice, but they can be influenced by impaired function of the
stomachas well.
1. The impact of gastric dysfunction on digestion
 high concentration of hydrochloric acid in the small intestine causes malabsorption
 due to the action of hydrochloric acid pancreatic enzymes are inactivated (especially
lipases) and bile salts precipitate directly damaging the intestinal mucosa, resulting in
impaired digestion and absorption of lipids - steatorrhea
 disturbed function of the stomach may in other ways affect the digestion:
 resection of the stomach by Billroth I - food bypasses the duodenum or rapidly
passes through the intestine and can not cause the secretion of cholecystokinin and
secretin which leads to pancreatic insufficiency
 post-gastrectomy hypoglycemia - linked with Billroth type II
 a) early dumping syndrome - 5 to 30 min. after a meal rich in carbohydrates
cramps, nausea and sometimes vomiting appear
 b) late dumping syndrome - is the result of reactive hypoglycemia and
hypersecretion of insulin, hyperglycemia is a consequence of sudden
carbohydrate absorption in the jejunum because of failed dosing
 blind loop syndrome - increases the number of bacteria in a "blind" intestinal
gyrus because it is out of order or because passage of chyme through it is very
slow, examples are resection Billroth II and interior intestinal fistula
2. Enzyme lack
 majority of the enzyme performing the final digestion in the intestinal lumen are
pancreatic enzymes- lipase, protease, amylase
 all diseases that damage the function of the exocrine pancreas (chronic pancreatitis,
cystic fibrosis, pancreatic cancer) lead to a deficiency of the enzymes with the
significantly reduced secretion
3. Disturbance of the bile salts
a) with disorder of bile salts excretion from the liver cells or with bile duct
occlusion bile and bile salts are not excreted into the duodenum
b) in blind loop syndrome amplified bacteria cause deconjugation and
dehydroxilation of bile salts, produced bile acids are absorbed by diffusion
through the intestinal wall and partly precipitated from solution therefore they do
not work in the intestinal contents which leads to reduced fat emulsification and
creation of mycelium
◦ lypolysis takes place despite that fact but fatty acids and triglycerides are
absorbed slowly
◦ consequence: reduced steatorrhea and reduced absorption of cholesterol and of
fat soluble vitamins

Main role of the small intestine is:

a) a final digestion (specific enzymes)

b) absorption (transport proteins) of the food- allowed due to specific build of the mucous
membranes and motility (parasympathetic stimulates sympathetic slows down),increased flow of
blood and lymph

1.General absorption disorders

When the pathological process have reduced total absorption surface of the intestine or it has
damaged more than one intestinal function (blood circulation, mobility), the consequence is the
absorbing disturbance of more than one substance. In every disease consequence is the same -
general malabsorption.

 short bowel syndrome- large part of the intestine is "excluded" (non-functional)

◦ in acute and chronic conditions -disturbed intestinal motility and absorption →

diarrhea causing loss of fat and bile salts (unabsorbed substance)

◦ gluten enteropathy (celiac disease, non-tropical sprue)- chronic disorder of the digestive
tract that results in an inability to tolerate gliadin, the alcohol-soluble fraction of gluten.
Gluten is a protein commonly found in wheat, rye, and barley.When patients with celiac
sprue ingest gliadin, an immunologically mediated inflammatory response occurs that
damages the mucosa of their intestines, resulting in maldigestion and malabsorption of
food nutrients.

◦ Crohn's disease or regional enteritis is a chronic granulomatous inflammation of

unknown origin that affects parts of the small and large intestine, and sometimes the
esophagus.Often bowel fistula arises between intestines and "blind loop" syndrome
develops.Because of disease severity and heavy bleeding sometimes therapeutic resection
is performed so that a syndrome of "short bowel" develops. Patient often has

◦ Diseases of the cardiovascular and lymphatic system-typical representatives are

constrictive pericarditis, atrial septum opening, primary cardiomyopathy, congestive heart
disease.They damage the absorption function in 2 ways: -slowing the blood flow slows
down the flow of lymph → wall edema and fluid transudation in intestinal lumen→
difficult absorption. Circulatory stasis→relative hypoxia, slowing of energy dependent
and slowing bowel mobility.Symptoms are:loss of appetite, cramps, bloating and nausea.

2.Selective absorption disorders
Hereditary and acquired deficiencies such as lack ofdigestive enzymes, disorders of digestion and
absorption of amino acids, hexoses, vitamin B12, etc.Two typical examples are:
1. lactase deficiency
 intolerance to milk, lactose in the small intestine can not be broken down into glucose and
 accelerated peristalsis,diarrhea and malabsorption
 fat absorption disorder
◦ dependent on dysfunction of different mechanisms:
▪ disorder of pancreatic lipase so there is no degradation of triglycerides
▪ disorder of bile salts essential for the formation of mycelium
▪ esterification disorder in mucosal cells thereby creating lipoproteins
◦ disorder dependent on only one of the enumerated mechanisms is called


A defect in the processing and enzymatic splitting within the gastrointestinal tract is called
maldigestion; a disorder of absorption is called malabsorption. As both of them are closely
intertwined, they are grouped together here as malabsorption (in the wider sense). Malabsorption
may affect the three energy carriers of food,i.e.,fats,proteins,and carbohydrates, as well as vitamins,
iron, calcium, magnesium, and trace elements, for example, zinc. Malabsorption of the
enterohepatically circulating bile salts is also clinically significant.

The respective site of absorption of these substances is determined by: 1) the number and duration
of preceding steps of processing and splitting; and 2) the provision in the intestinal segments of
specific mechanisms of absorption. Thus, monosaccharides such as glucose and galactose can be
absorbed at the beginning of the duodenum; disaccharides must first be split by the enzymes of the
brush border; polysaccharides (just like proteins and fats) must first come into contact with
pancreatic juice, with the result that they may not be absorbed until they reach the jejunum. Rapid
emptying of the stomach can mean that the place of absorption is moved distally , i.e. intestinal
segments which lie further downstream can take over absorption that, in the long term,can lead to a
change in the mucosa.The ileum,for example, may take on jejunum-like properties. This is not
possible with substances for which only the terminal ileum possesses specific absorption
mechanisms (cobalamine,bilesalts). Normal digestion and absorption consists of the following serial
steps: 1. Mechanical processing of food (chewing,distal gastric peristalsis); 2. Luminal
digestion (gastric,intestinal, and pancreatic juices;bile); 3. Mucosal digestion by enzymes of the
brush border; 4. Absorption by the mucosal epithelium; 5. Processing in the mucosal cell;6.
Transportation into blood and lymph, through which the absorbed substances reach the liver and the
systemic circulation,respectively. The causes of malabsorption can affect all these steps!

After gastric resection and/or vagotomy, the stimulation of enteral hormone secretion(CCK, e.g.)is
reduced and the synchronization of chyme apportioning with pancreatic secretion, gallbladder
emptying, and choleresis is disturbed. Furthermore, passage through the small intestine is
accelerated and the pH in the duodenal lumen is too acidic, so that the digestive process may be
greatly disturbed (enzyme inactivation, bile salt precipitation). A gastrinoma (Zollinger–Ellison
syndrome) can cause malabsorption for the same reason.Pancreatic diseases, for example, chronic
pancreatitis, carcinoma of the pancreas, cystic fibrosis, or resection of the pancreas may lead to
malabsorption due to a lack of important enzymes (lipase, colipase, trypsin, chymotrypsin,
amylase,etc.)as well as of HCO3– which is necessary for buffering acidic chyme.Atrophic gastritis
with achlorhydria will firstly diminish gastric digestion and secondly favor colonization of the
small intestine with bacteria. This may also be caused by stasis in the small intestine due to
diverticulosis or a small-intestine shunt (blind loop syndrome). The bacteria deconjugate bile salts
and split the binding between cobalamine and intrinsic factor. The resulting cobalamine
malabsorption leads to cobalamine deficiency, as does a reduced intake (strictly vegetarian diet; it is
true also for breast fed infants of such mothers, because their milk also lacks cobalamine), intrinsic
factor deficiency (achlorhydria), lack of enzymatic liberation of cobalamine from its binding with
other proteins (high gastric pH, trypsin deficiency), or resection of the terminal ileum, the site of
absorption of thecobalamine–intrinsic factor complex.


The consequences of malabsorption are reflected in virtually all organs and organ
systems.Pathophysiological consequences and symptomatology are very different, depending on the
pathological process that caused malabsorption and whether the disorder is general or specific.
General absorption disorder → malnutrition → weight loss, vitamin deficiency →
malabsorption and diarrhea follow, they occur due to many reasons (↑ osmolar conc of intestinal
content due to unabsorbed substances, increased secretion of water and electrolytes) → water,
electrolytes and nutrients are lost→ acidosis, hypokalemia, dehydration and hypovolemia→
reduced circulation pressure→hypoxia of intestinal mucosa and further deterioration of absorption
Malabsorption can cause complex disorders of Ca2+ metabolism(hypocalcaemia, bone
demineralization and osteomalacia) and disorders of bone tissue structure (loss bone matrix-
Anemia in malabsorption syndrome is caused by decreased absorption of Fe, vit.B12 and folic acid.
Anemia also arises due to loss of blood due to bleeding, or as a result of impaired coagulation due
to decreased absorption vit.K


Pancreas produces and secretes more than 20 different enzymes, which are activated only in
the duodenum. Disruption of exocrine function of the pancreas may be activation of enzymes in the
pancreatic tissue with subsequent autodigestion of the pancreas and pancreatitis.
 Acute pancreatitis
Factors that cause acute pancreatitis are mostly alcohol and gallstones. The way they trigger
enzymes in the pancreatic tissue is not clear but probably it is a mechanism that initially triggeres a
small amount of trypsin, which then activates other proteolytic enzime.
Initial damage could affect major pancreatic duct (bile salts,ethanol) which is normally
impermeable to enzymes. Activated proteolytic enzymes destroy proteins, elastase breaks
connective tissue of blood vessels, and phospholipase lyse cell membrane.Resulting in

inflammatory reaction.When necrosis and bleeding are present as well then we talk about
hemorrhagic pancreatitis (the most severe form).
After the enzymes have destroyed pancreas they leak into the extracellular fluid and
blood.Increase in amylase levels in the plasma and urine is a reliable sign. Potasium also leaks out
of the cell leading to hyperkalemia. However, if the patient vomits then it results in consequential
hypokalemia.Calcium gets into the necrotic tissue leading to hypocalcaemia (bad prognostic sign!).
There's also a development of circulatory shock that causes hypoxia and functional disorders of
many organs that leads to renal ischemia that causes renal insufficiency, and in lungs leads to
noncardiogenic edema.
 Chronic pancreatitis
Chronic pancreatitis develops as a result of repeated acute inflammations or as a long-term
chronic inflammation caused by the same factors as acute pancreatitis.Tissue collapses, and when
the amount of enzymes decreases below 10% (not sufficient for the digestion) it is reflected with
steatorrhea and in more severe forms the disorder of protein digestion is apparent. Destruction of
Langerhans cells causes secondary diabetes.


Constipation is a condition in which the patient has fewer than three stools a week
throughperiod of several months.Severe constipation with the absence of spontaneous defecation is
called opstipation.It all depends on your lifestyle and diet. There are three main mechanisms of
constipation development:
1.) Slow movement of the colon or even its complete absence
◦ etiology of the disorder:
▪ intestinal smooth muscle - disease of smooth muscle reduces propulsive power
resulting in prolonged feces retention and increased absorption leading to hard
 cholinergic and adrenergic fibers of the autonomic nervous system - lack of innervation
prevents peristalsis and causes constipation, typical of Hirschsprung's disease
2.) Metabolic and hormonal disorders
 hypothyroidosis, hypokalemia and hypercalcemia
3.) Psychogenic or habitual constipation
 most common form of constippation
 appears very early, mainly because of emotional problems between parents
and child
 Reflex arch, which begins by stretching the walls of the rectum and ends its
contraction and dilation of the inner and outer sphincter, may be willingly
disabled by external sphincter contraction .This is how rectum adjusts to
bigger amount of stool. Because of defecation suppression over time
defecation reflex diminishes and habitual constipation develops . When
constipation lasts for a long time and has a particularly severe form, the colon
is widespread and results in megacolon. Colon can be expanded so much that
it may cause perforation (life-threatening).


Diarrhea is the condition of having at least three loose or liquid bowel movements each day.
It often lasts for a few days and can result in dehydration due to fluid loss( more than 200ml/24h).
We differ several types of diarrhea:
 Osmotic diarrhea occurs when too much water is drawn into the bowels. If a person drinks
solutions with excessive sugar or excessive salt, these can draw water from the body into the
bowel and cause osmotic diarrhea.Osmotic diarrhea can also be the result of maldigestion
(e.g., pancreatic disease or Coeliac disease), in which the nutrients are left in the lumen to
pull in water. Or it can be caused by osmotic laxatives(which work to alleviate constipation
by drawing water into the bowels). In healthy individuals, too much magnesium or vit.C or
undigested lactose can produce osmotic diarrhea and distention of the bowel. A person who
halactose intolerance can have difficulty absorbing lactose after an extraordinarily high
intake of dairy products. In persons who have fructose malabsorption, excess fructose intake
can also cause diarrhea. High-fructose foods that also have a high glucose content are more
absorbable and less likely to cause diarrhea. Sugar alcohols such as sorbitol (often found in
sugar-free foods) are difficult for the body to absorb and, in large amounts, may lead to
osmotic diarrhea.In most of these cases, osmotic diarrhea stops when offending agent (e.g.
milk, sorbitol) is stopped.
 Secretory diarrhea means that there is an increase in the active secretion, or there is an
inhibition of absorption. There is little to no structural damage. The most common cause of
this type of diarrhea is a cholera toxin that stimulates the secretion of anions, especially
chloride ions. Therefore, to maintain a charge balance in the lumen, sodium is carried with
it, along with water. In this type of diarrhea intestinal fluid secretion is isotonic even during
fasting.It continues even when there is no oral food intake.
 Exudative diarrhea occurs with the presence of blood and pus in the stool. This occurs with
inflammatory bowel diseases, such as Crohn's disease or ulcerative colitis, and other severe
infections such as E. Coli or other forms of food poisoning.
 Inflammatory diarrhea occurs when there is damage to the mucosal lining or brush border,
which leads to a passive loss of protein-rich fluids and a decreased ability to absorb these
lost fluids. Features of all three of the other types of diarrhea can be found in this type of
diarrhea. It can be caused by bacterial infections, viral infections, parasitic infections, or
autoimmune problems such as inflammatory bowel diseases. It can also be caused by
tuberculosis, colon cancer, and enteritis.
 Motoric diarrhea-we talk about it when diarrhea causes rapid motoric activity of the small
and large intestine which markedly reduces retention, and this results in incomplete
apsorption .Motoric diarrhea caused by two groups of disorders:
a) disorders related to increased secretion of substances-VIP, serotonin, calcitonin , thyroid
hormones and prostaglandins, all of these diseases are caused and secretory diarrhea
b)disorders associated with abnormal activity of the autonomic nervous system,
primarily parasympathetic stimulation posterior-vagal motor nuclei, intramural intestinal
plexus neuropathy
Diarrhea due to incomplete absorption of the electrolyte is very rarely seen in isolation,it is
an example of innate chloridorea. Chloride concentration in the stool is high, and bicarbonate
low because they were replaced in the distal ileum and colon
CONSEQUENCES of diarrhea:
loss of water and electrolytes, malabsorption, loss of bicarbonates which disturbs acid-base
in secretory diarrhea water and electrolytes are lost equally resulting in isotonic dehydration,
this condition causes hypotension and shock which can lead to death if you do not make up for
fluid lost
osmotic diarrhea patient loses more water than electrolytes which causes dehydration and
hypernatremia, osmolality of extracellular fluid becomes greater (water shift-thirst)
bigger diarrhea can be compensated through renal function
 final result depends on the lost volume of extracellular fluid,loss of electrolytes and renal
function and the frequent vomiting
loss of K+, bicarbonate and anions of organic acids through stool leads to development of
hyperchloraemic acidosis
when kidney tries to compensate, due to the activation of the renin-angiotensin-aldosterone
system, more K+ and H+ is excreted in exchange for Na+ constrictive alkalosis may develop

Ileus is a disruption of the normal propulsive ability of the gastrointestinal tract. We
differentiate between mechanical and functional ileus.
 Mechanical ileus
◦ develops when there are mechanical faults in passing through the intestine
◦ divided into: a) obstructive-when only the intestinal lumen is closed (tumors, gallstones)
b) strangulation-when blood flow is also distracted (e.g. the gut wall and
associated mesentery get caught in hernia)
2.)Functional ileus
1. a consequence of the neuromuscular disorder.
2. Divided into:
1. a) paralytic ileus or adynamic
1. when peristalisis is reduced or absent
2. the most common form of intestinal obstruction
3. consequence of the increased sympathetic activity or electrolyte imbalance,
particularly hypokalemia
4. appears in any disorder,ischemia, surgical procedure
2. b) spastic ileus or dynamic
1. intestinal spasm interrupts the passage of content
2. it is very rare and occurs in porphyria, and heavy metals poisoning like lead
and sometimes in uremia
The consequences of ileus:
1.)Ileus→ block in the intestinal lumen→ pressure increase in lumenu→ increased secretion and
decreased absorption→ electrolyte and water loss →dehydration, hipovolemija→ acute
renal failure and cardiogenic shock
2.)at strangulative ileus ischemia and bowel necrosis develop → bacteria accumulation at the sight
→ peritonitis and sepsis


The basic pathophysiology of all forms of liver disease represents failures of the numerous and
complex hepatic metabolic functions. Although there is some variability in basic pathophysiology
from one type of liver disease to another, all forms of liver disease can reasonably be called hepatic
failure. The signs and symptoms, the natural history, and the rationale of treatment for all forms of
liver disease derives from certain relatively simple basic pathophysiologic concepts.
It should be made clear at the outset that jaundice, an obvious physical sign, sometimes represents
problems other than liver disease and is by no means synonymous with it. There are other, far more
important and more complex metabolic problems associated with liver disease so that the problem
of jaundice will be dealt with only briefly in this minicourse. The liver plays several complex roles
in amino acid metabolism, protein synthesis, carbohydrate metabolism and lipid metabolism. It is
also the site of manufacture of a number of blood coagulation proteins.
The basic derangements of hepatic failure will be discussed first. These will then be applied to the
most common forms of liver disease, acute hepatitis and cirrhosis.

Defects in Amino Acid Metabolism

The liver is the most important single organ involved in amino acid metabolism. Amino acids are
delivered to the liver either from the gut or from the general circulation. In the liver there are two
major processes in the metabolism of amino acids:oxydative deamination and transamination.
Oxydative deaminiation is a process by which the amino radical is removed from the amino acid
thus converting it into two products: a keto acid and ammonia.
The ammonia from these deamination reactions is transformed, in the liver, to urea by combination
with CO2.
Since oxydative deamination results in the production of ammonia,any impairment of the above
function results in a diminution of the blood urea nitrogen level(BUN) and an increase in the
amount of circulating ammonia. Elevated serum ammonia levels can become extremely toxic,
especially to the brain, often leading to a state called hepatic coma.
The ketoacid produced by deamination can follow several metabolic pathways:
 1. It can be modified and cycled through the Krebs cycle, producing energy in the form
of ATP.
 2. It can be converted (depending on the structure of the amino acid from which it was
derived) into glycogen or fatty acids, or it can be transaminated.
 3. It can be transaminated whereby the amino radical from another amino acid is
transferred to it, thus converting it back to its original form and leaving another kind of keto
acid which itself can then undergo any of the above three steps.
Amino acid metabolism is controlled primarily by the hepatocyte, one of the three types of cells in
the liver. In widespread, advanced hepatic parenchymal disease, or in severe acute hepatic failure,
as can happen in severe acute hepatitis of any form, this particular hepatocyte failure results in a
severe derangement of amino acid metabolism and thus of ammonia and urea levels.

Defects in Protein Synthesis
Two of the liver's cell types, the hepatocyte and the Kupffer cell, are responsible for synthesizing
many kinds of proteins. The hepatocyte synthesizes albumin and some immune globulins. The
Kupffer cells, which line the hepatic sinusoids, and which are a part of the socalled
reticuloendothelial system, synthesize several kinds of immune globulins. Since the functions of
both of these kinds of cells can be impaired in either chronic diffuse liver disease or in severe acute
liver disease, a diminution of the levels of circulating albumin and of the immune globulins often
appears in liver disease. Since impaired amino acid metabolism may also be found in liver disease,
protein synthesis may be doubly impaired because of a decreased availability of amino acids and
because of direct impairment of the synthetic processes themselves in the hepatocyte and in the
Kupffer cell.
Defects in protein synthesis are responsible for some of the more protean manifestations of severe
diffuse chronic liver disease and of severe acute liver disease. These will be discussed in later
Defects in Carbohydrate Metabolism
The hepatocyte actively stores glucose by converting it to the longchain starch, glycogen. Glycogen
can then be later broken down to release glucose into the general circulation. The factors that
control thisinsulin, epinephrine, growth hormone (STH), glucagon and the thyroid hormonestend to
counterbalance each other so that the hepatocytes store glycogen as the blood sugar rises and break
it back down into glucose as blood sugar level falls. Again, this is a critical function, an impairment
of which produces some of the more serious manifestations of liver disease hyperglycemia and
hypoglycemia. In fact, patients with severe liver disease often have glucose tolerance curves very
much like those seen in diabetes mellitus. That is to say, with food ingestion, they tend to become
hyperglycemic because the hepatocytes cannot store glycogen while, as dietary intake is decreased
or absent, the hepatocytes are not well able to mobilize glucose from what little stored glycogen
there is, and so these patients have episodes of hypoglycemia. This phenomenon is sometimes
called "hepatic diabetes."
Defects in Lipid Metabolism
The liver has an extremely complex role in lipid metabolism, very little of which will be discussed
here. In the diseased liver, there are two prime manifestations of liver failure with regard to lipid
metabolism. The first of these is the deposition of triglycerides within the organ itself. This is the
basic mechanism of socalled "fatty liver," which develops most often as a result of chronic
alcoholism. The second prime feature of disordered hepatic lipid metabolism is a diminution in the
rate of synthesis of cholesterol. In fact, a decrease below the normal level of serum cholesterol is
often found in advanced diffuse liver disease or in severe acute liver disease.
Impaired Production of Clotting Factors
Fibrinogen, prothrombin, Factors V, VII, and X are all produced in the liver, and impairment of their
production leads to coagulation defects. In fact, production of clotting factors is so exquisitely
affected in liver disease that the measurement of prothrombin time is a very sensitive indicator of
the progress of acute hepatitis. For example, in the patient profoundly ill with severe acute hepatitis
with a circulating bilirubin level 20 times normal, measurement of the bilirubin and observation of
jaundice become far less reliable indicators than the prothrombin time.
Impairment of Detoxification Functions
The liver is responsible for detoxifying, by chemical modification, many substances that enter it.
This includes substances drained from the gut, many kinds of drugs, and circulating hormones.
Some substances are converted to water soluble salts or esters and are excreted in the bile. Others
are chemically modified and released into the general circulation for renal excretion. Sometimes,
toxic substances are modified, released into the bile, excreted into the gut, reabsorbed from the gut
in their modified form, and later find their way to the kidneys for renal excretion.
The two classic examples of the liver's role in detoxification are the effect of phenobarbital on the
liver and estrogen degradation by the liver. It has been observed that the chronic ingestion of
phenobarbital results in an increase in the amount of hepatocytic endoplasmic reticulum,
presumably indicating a response to the presence of a toxic substance. Estrogen degradation, or lack
of it, is best demonstrated in the alcoholic male who, unable to modify and excrete his circulating
estrogens, develops gynecomastia,telangiectasis (e.g. spider angiomata) and other signs of
Alcohol is not the only drug that is toxic to the liver. Many kinds of drugs in wide use are
hepatotoxic and, since these hepatotoxic drugs may have to be degraded for excretion by an already
diseased liver, their use in advanced or in severe acute liver disease must be approached with
caution. The list of drugs that require caution for this reason is enormous.

Mechanisms of Hepatic Failure in Acute Hepatitis

The basic problem in acute hepatitis is a widespread inflammatory reaction throughout the liver.
This results in edema and congestion, and these compromise hepatic function. Kupffer cell
functions are impaired. Hepatocyte functions are impaired. Formation and excretion of bile is
impaired. In every case, all of the basic pathophysiologic mechanisms already discussed become
operative. In other words, every case of acute hepatitis represents acute hepatic failure with all of its
attendant interruptions of normal physiologic functions. The pathologic changes (tissue changes)
that occur within the liver itself include hepatocyte necrosis, hyperplasia of the Rupffer cells, and
some microscopic anatomic changes. As the liver becomes edematous and engorged, bile canaliculi
become obstructed, and bile stasis develops. This undoubtedly contributes further to degeneration of
liver tissue.
Most of the basic pathophysiologic problems in infectious hepatitis are transitory. They disappear
after the infection has cleared and after hepatic anatomy returns to normal. In a more severe
infection with extreme, widespread acute inflammation and edema, there may be some residual
impairment of hepatic function.
The Mechanisms of Cirrhosis
Over the years, the term "cirrhosis" has been used to label a wide variety of patterns of chronic
diffuse parenchymal liver disease. The single common denominator among all forms of "cirrhosis"
is the presence of widespread microscopic, hepatic anatomic changes.
There are many causes of cirrhosis. Certainly the most common kind of chronic diffuse
parenchymal liver disease is that seen in alcoholism. This form of cirrhosis, which is also called
alcoholic cirrhosis, portal cirrhosis, fatty cirrhosis and Laennec's cirrhosis, is believed to be

primarily the result of ethanol's direct effect on normal hepatocyte lipid metabolism. The presence
of ethanol in the hepatocyte impairs the usual lipid metabolic pathways within the hepatocyte and
results in the deposition of fat throughout the organ. There is also scattered fine scarring that
follows patchy necrosis; this results in diffuse hepatic fibrosis. Histologically, the pattern of
cirrhosis found by liver biopsy in patients with a history of alcoholism is quite variable. In some
cases there may be a great deal of fatty change and very little fibrosis; in others, there may be very
little fatty change and a great deal of fibrosis. Since fibrosis is the result of parenchymal necrosis,
there must be the necessary antecedent necrosis and, this, too, is also often found by biopsy.
Alcohol probably accounts for ninetyfive percent of all cirrhosis. The remaining small percentage of
cases develop from various metabolic abnormalities. Socalled "biliary cirrhosis," which occurs
almost exclusively in middleaged women, for example, is believed to be produced by an
autoimmune abnormality that results in necrosis of bile ducts. This leads to bile stasis which, in
turn, leads to further necrotic changes, further duct damage, further bile stasis, and so on. This same
vicious cycle may develop in a person who suffers a severe episode of acute infectious hepatitis that
produces widespread scarring and obstructive ductal changes.
All forms of cirrhosis tend to be progressive. This should not be taken as an iron rule, however, lest
the clinician be tempted to pass a sentence of hepatic doom on every patient with alcoholic liver
disease, a history of hepatitis, or primary or secondary biliary cirrhosis.
Since any kind of cirrhosis involves widespread diffuse parenchymal disease, there is usually some
impairment of every kind of hepatic function. Again, this should not be taken as an unchallengable
axiom because, as can be demonstrated by biopsy, the actual pattern of histologic changes is quite
variable. Nevertheless, there does tend to be impairment of many kinds of hepatic function,
including impaired amino acid metabolism, impaired storage and release of glycogen, impaired
lipid metabolism, some impairment of formation of coagulation factors, and some impairment of
the liver's ability to modify and excrete toxic substances (including drugs).
One should bear in mind that most patients with acute infectious hepatitis do not slip into this cyclic
pattern of hepatic damage, bile stasis, further damage and selfperpetuating, progressive, cirrhotic
changes. This pattern is seen most often in patients with noninfectious diffuse liver disease, most
often alcoholinduced Laennec's cirrhosis.
Jaundice and Bilirubin
Bilirubin, a yellow pigment, is one of several products of hemoglobin breakdown. Since
hemoglobin synthesis and breakdown are continuous processes, small amounts of bilirubin (and
other products of hemoglobin breakdown) are released into the general circulation continuously.
Many kinds of cells can, given enough time, modify bilirubin chemically so that it can be excreted.
The hepatocyte, though, is the prime bilirubin processor, and so hepatocyte impairment results in
disordered bilirubin metabolism.
In its original form, bilirubin is fatsoluble, not watersoluble. A hepatocyte enzyme,glucuronyl
transferase, modifies bilirubin as it arrives at the liver, and converts it to a watersoluble compound.
This process is called bilirubin conjugation because one of the steps involved is the attachment of
bilirubin to another molecule. The conjugated bilirubin is then excreted into the bile and is released
into the gut. Impairment of any of these steps results in distribution of bilirubinunconjugated,
conjugated, or boththroughout the body. The unconjugated bilirubin, which is fatsoluble,

accumulates in fatty tissues, most notably the skin, where the presence of this yellow pigment
produces jaundice. If exeretion of watersoluble, conjugated bilirubin is impaired, jaundice may also
Most bilirubin is produced by RBC breakdown in the spleen. Some, about 1520X of the total, is
produced by destruction of RBC precursors in the marrow.
Jaundice indicates one of four problems:
 1. increased RBC breakdown
 2. failure of hepatocyte conjugation
 3. failure of hepatocyte excretion of conjugated bilirubin into the bile canaliculi
 4. extrahepatic obstruction
In liver disease, problems 2 and 3 usually occur together.
Portal Hypertension
As widespread, diffuse parenchymal liver disease progresses, there is loss of the hepatic vascular
bed and an increase in fibrotic tissue scattered throughout the organ. If these anatomic changes
progress beyond a certain point, there is, eventually, definite impairment of blood flow through the
liver. Since the liver receives twothirds of its blood supply from the hepatic portal vein and onethird
from the hepatic artery, circulatory impairment through the liver results primarily in an increase in
venous pressure in the portal drainage system. This direct increase in hydrostatic pressure in the
portal system, which drains the entire G.I. tract, results in an increase in hydrostatic pressure in all
of the G.I. tract's venous drainage system. This increase in pressure is called portal hypertension. If
venous pressure in the gut drainage system is raised high enough, hydrostatic pressure overcomes
intravascular osmotic pressure and fluid begins to seep out of the gut capillary bed and into the
peritoneal space (ascites). At the same time, the G.I. tract itself, because of impaired venous
drainage, becomes somewhat edematous, and this results in impairment of gastrointestinal function.
That is the basis for the nonhepatic gastrointestinal signs and symptoms that develop in advanced
cirrhosis. The amount of fluid that accumulates in the peritoneal space may be enormous.
Because there is impairment of venous drainage in advanced cirrhosis, there is a natural tendency
for venous drainage from the G.I. tract to flow through alternate channels. The most conspicuous of
these in advanced liver disease is the umbilical venous system which connects the portal system
with the systemic circulation. An increase in pressure in the umbilical veins results in the dilation of
veins on the abdominal wall, producing the socalled "caput medusae" sometimes seen in
faradvanced cirrhosis.
An increase in portal venous pressure also results in two common problems that are a direct result
of portal hypertension. One of these is hemorrhoids, which are actually varices of the hemorrhoidal
veins. Hemorrhoids certainly develop often in patients who do not have cirrhosis but they are also a
rather common finding in patients who do. Similarly, esophageal varices develop in these
patientsand for the same reason. Both of these phenomena are a direct result of increased portal
venous pressure. Hemorrhoids tend to be more of a nuisance than a threat, but esophageal varices,
which can, and often do hemorrhage massively, can be lifethreatening.
All of the basic pathophysiologic mechanisms of both infectious hepatitis and cirrhosis can be
classed in two major categories: those that are the result of impairment of hepatocellular and
Kupffer cell functions, and those that derive from impairment of hepatic circulation in advanced

204.Hepatic Metabolic Function Impairment

Carbohydrate Metabolic Disorder:

- impaired removal of glucose from blood
- decreased glucose synthesis due to lack of hepatic enzyme (VON GIERKE DISEASE lack
of glucose-6-phosphate) ROBBINS

Fatty Acid Metabolism Disorder:

- accumulation of triglycerides in cytoplasm of liver cells
- increased lipolysis (diabetics and individual fasting), Increased concentration of
glucocorticoids (CUSHINGS ALGORITHM), decreased synthesis of apoproteins
(Kwashikior), Alcohol consumption

Protein Metabolism Disorder:

- Hypoalbuminemia
- Decreased clotting factor production - factors VII, IX, X
- Vitamin K deficiency- fibrinogen, factors V, XI, XII, and plasminogen
- Amino acid disbalance- decreased concentrations of valine, leucine and isoleucine,
increased concentrations of tyrosine, tryptophan and methionine

Xenobiotic biotransformation:
- not sufficiently water soluble to be eliminated in urine, left with ROS, can be carcinogenic

Hormone Degradation:
- Degeneration of steroid with reduction and glucoronidisation, insulin and glucose with
proteolysis and T3, T4 with deiodination
- Estrogen and progesterone can increase risk of bile stones

Ethanol Metabolism:
- Hypoglycemia
- Fatty Liver change and hyperlipidemia
- secondary hyperuricemia
- liver hypoxia, affacted cytochrome P450 system

205.Pathogenesis of Jaundice

Jaundice is a yellowing of the skin, nail beds and whites of the eyes that is caused by a build-up of
bilirubin in the body’s tissues. The condition is divided into three forms, depending on what has
caused the bilirubin to accumulate. The different types of jaundice are described below.

• Pre-hepatic jaundice– Here, the bilirubin level is disrupted prior to transportation of blood to
the liver. Examples of conditions that cause this type of jaundice are hemolytic anemia and
sickle cell disease.
• Hepatocellular jaundice – Here, the disrupted bilirubin is caused by disease in the liver and
examples of conditions that cause this include liver cirrhosis and Gilbert’s syndrome.
• Post-hepatic jaundice or obstructive jaundice – Here, bile and therefore the bilirubin contained
inside, is obstructed and prevented from draining into the digestive system from the
gallbladder. Examples of factors that may cause this are tumors and gallstones.

Mechanisms of hyperbilirubinemia

Hyperbilirubinemia may involve predominantly unconjugated or conjugated bilirubin.

Unconjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:

 Increased production
 Decreased hepatic uptake
 Decreased conjugation

Conjugated hyperbilirubinemia is most often caused by ≥ 1 of the following:

Dysfunction of hepatocytes (hepatocellular dysfunction)
Slowing of bile egress from the liver (intrahepatic cholestasis)
Obstruction of extrahepatic bile flow (extrahepatic cholestasis)

206.Enteropathic bile salt recirculation disturbances

- Bile salts develop in hepatocytes from cholesterol

- 90% are reabsorbed in terminal ileum and return to live by enterohepatic circulation
- Increase of bile acids results in skin purities

Bile acid malabsorption, known also as Bile acid diarrhea, is a cause of several gut-related
problems, the main one being chronic diarrhea. It has also been called Bile acid-induced diarrhea,
Cholerheic or Choleretic enteropathy and Bile salt malabsorption. It can result from malabsorption
secondary to gastro-intestinal disease, or be a primary disorder, associated with excessive bile acid
production. Treatment with bile acid sequestrants is often effective.

Enterohepatic circulation of bile salts

Bile acids (also called bile salts) are produced in the liver, secreted into the biliary system, stored in
the gall-bladder and are released after meals stimulated by cholecystokinin. They are important for
the digestion and absorption of fats (lipids) in the small intestine. Usually over 95% of the bile acids
are absorbed in the terminal ileum and are taken up by the liver and resecreted. This enterohepatic
circulation of bile acids takes place 4-6 times in 24 hours and usually less than 0.5g /24h of bile
acids enter the large intestine. When larger amounts of bile acids enter the large intestine, they
stimulate water secretion and intestinal motility in the colon, which causes symptoms of chronic
207.Mechanism of Gallstone Formation
THIEME page 178
Gallstone pathogenesis must be briefly considered to facilitate the presentation of risk factors.
Cholesterol gallstones, composed predominantly of cholesterol crystals, result from abnormalities in
cholesterol metabolism.
Many abnormalities have been considered to be responsible for cholesterol gallstone formation.
The first and essential requirement is bile supersaturation in cholesterol. The per cent
saturation of the cholesterol in bile is determined by the molar ratio of the three major biliary lipids:
cholesterol, bile acids, and phospholipids. Cholesterol supersaturation, the essential requirement for
cholesterol gallstone formation, might occur via excessive cholesterol biosynthesis (increased 3-
hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase activity), which is the main
lithogenic mechanism (that is, in obese persons). A reduced acyl-CoA cholesterol acyltransferase
(ACAT) activity, inhibiting cholesterol esterification, leads to an increased excretion of free
cholesterol into the bile. In the non-obese, excessive cholesterol secretion could result from
defective conversion of cholesterol to bile acids, due to a low or relatively low activity of
cholesterol 7α hydroxylase, the rate limiting enzyme for bile acid biosynthesis (and cholesterol
elimination). Finally, interruption of the enterohepatic circulation of bile acids could increase bile
saturation. Temporary interruption of the enterohepatic bile acid circulation during overnight fasting
leads to a higher cholesterol/phospholipid ratio in the vesicles secreted by the liver.

The second abnormality is enhanced nucleation of

cholesterol crystals. Mucin and its congeners, the major
proteins, act as matrix molecules to hold cholesterol
crystal aggregates together to form a stone.

There also must be sufficient time for nucleation to occur,

for crystals to form and grow to microliths, and for
microliths to aggregate to form gallstones, hence
gallbladder stasis is a contributing factor to gallstone formation. During overnight fasting, the
gallbladder does not empty so that hours of storage occur in all individuals.

It should be the sum of these three factors that determines when gallstones form. If bile is highly
supersaturated, hypernucleation and stasis might be modest. Conversely, if bile were only slightly
supersaturated, hypernucleation or prolonged stasis might result in gallstone formation.

Intestinal hypomotility has been recently recognised as a fourth primary factor in cholesterol
lithogenesis. Having a longer exposure to intestinal micro-organisms, primary bile salts are in
greater proportion deconjugated and dehydroxylated to more hydrophobic secondary bile salts. An
increased proportion of the secondary bile acid deoxycholate, a potent down regulator of the rate
limiting enzyme for bile acid biosynthesis, enhances cholesterol hypersecretion into bile.


208. Impairment of Hepatic Blood Flow

Hepatic Portal vein brings blood to liver from gut, portal venous system branches extensively
within the liver and branches rejoin to form hepatic vein which joins inferior vena cava.

Divided into prehepatic (portal vein), intrahepatic (portal venous system within liver itself) and
posthepatic (hepatic vein)

Portal Hypertension
- Prehepatic vein can be thrombosed
- intrahepatic vein: any liver disease that causes cirrhosis can cause changes in vascular
system leading to portal hypertension (ALGORITHM)
- posthepatic: hepatic vein can be thrombosed (Budd-Chiari Syndrome): resistance to flow in
hepatic vein/IVC system can increase portal pressure (Right heart failure, restrictive
cardiomyopathy, constrictive pericarditis)

Causes include: Liver Cirrhosis (ALGORITHM), schistosomiasis, sarcoidosis, constrictive


Major Clinical Consequences:

- Sinusoidal hypertension (drives fluid into space of Disse, promoted by hypoalbuminemia)
- Leakage of hepatic lymph into peritoneal cavity (reflected in protein rich ascetic fluid)
- REnal retention of Na+ and H2O (due to secondary aldosteronism)

Formation of portosystemic venous shunts

- Veins around and within rectum (haemorrhoids), cardioesophageal junction (esophagogastric
varices), retroperitoneum and falciform ligament of liver (periumbilical and abdominal wall
- Congestive Splenomegaly
- Haptic Encephalopathy


Disorders of salt and water transport occur in many liver disease, mostly in cirrhosis.
Basically, pathogenesis of transport and distribution of liquid in compensated and decompensated
stage of liver failure are differentiated.
Compensated stage- postsinusoidal block increases intrasinusoidal pressure to which
intrahepatic receptors react. The resultant increase in sympathetic over intrarenal mechanisms cause
an increase in extracellular volume and partly compensates the dynamics of blood flow in the liver.
Decompensated stage- hypoalbuminemia leads to the formation of visceral edema, and
ascites. False neurotransmitters contribute to peripheral vasodilatation, which by means of
baroreceptor mechanisms increases sympathetic activity with consequential narrowing of vessels in
the renal cortex (endotoxins of gram-negative bacteria lead to vasoconstriction, as well as
endothelin which is increasingly produced in cirrhotic liver) and retention of salt and water.
Progression of disease deteriorates more liver tissue, reducing inactivation of aldosterone and ADH.
In the decompensated stage of cirrhosis numerous positive feedback loops are established. Loss of
protein in ascites boosts oncodynamic mechanisms, secondary aldosteronism increases sodium and
water retention.Hypovolemia enhances the sequestration of fluid in intracellular space (edema), and
the virtual body cavities.
Ascites is a common complication of advanced liver cirrhosis. The pathogenesis involves
hemodynamic mechanism in sinusoids and splanhnic capillaries (consequently to postsinusoidal
block and portal hypertension), oncodynamic mechanism (consequently hypoproteinaemia).
Consequently lymh production is increased. Because of portal hypertension and hypoalbuminemia
that occurs due to the loss of albumin and reduction in their synthesis in cirrhotic liver retained
sodium and water do not remain in the circulation rather they escape into the interstices and the
free abdominal cavity, which exacerbates the disorder. Secondary aldosteronism also exacerbates
the condition (the development intractable ascites unresponsive to treatment).


Function disorders of the nervous system
The main and most important disorder is hepatic encephalopathy. Marked by tension,
irritability or apathy, uncontrolled behavior, mental confusion, and severe neuromuscular
discrepancy and severe trembling. Advanced disorder leads to hepatic coma and death.
Two main factors: hepatocyte damage and portal hypertension because of collateral flow
most of the blood bypasses the liver and toxic substances enter the brain. A key role in its creation
have ammonia, mercaptans (formed by metabolism of methionine) and fatty acids and some AA
(methionine, phenylalanine, tyrosine).Hypoxia, hypoglycaemia and electrolyte imbalance contribute
to the disorder.
In the brain, ammonia acts to α-ketoglutaric acid to form glutamic acid and glutamine.
Ammonia steals substrates from Krebs cycle and reduces the formation of energy in the brain; and
inhibiting the activity of neural Na-K ATPase and changing transmembrane gradients necessary for
normal neuronal activity. It disturbes the repolarization and leads to encephalopathy.
Disorders of renal function
Hepatorenal syndrome, a form of kidney failure with characteristics prerenal kidney failure,
renal vasoconstriction of blood vessels with a consequent reduction in glomerular filtration,
retention of salt and water, azotemia and oliguria. Cardiac output is not reduced, it is increased with
decreased peripheral resistance and arterial pressure.Compensatory neurohumoral systems that are
activated in order to remedy the disturbance of volume homeostasis, as well as substances that the
sick liver secretes or can not break down cause vasoconstriction. Renal vasodilator ability is
reduced during the disorder.Due to that the patient does not respond to any treatment and may die of
kidney failure, although the kidneys are morphologically normal.
Changes in blood
The main haematological consequence of the disorder is blood clotting. Factors dependent
on vitamin K may be missing due to reduced absorption of vitamins or in the normal amounts of
vit.K due to acute and chronic diseases protein synthesis is impaired.
The concentration of fibrinogen in the plasma can be reduced because of reduced synthesis
or because chemically modified fibrinogen is formed. Another reason for the decreased conc. of
fibrinogen may be its consumption in the DIC (disseminated intravascular coagulation).Due to
bleeding from the gastrointestinal tract microcytic hypochromic anemia appears; due to decreased
intake of folic acid makrocytic anemia accompanied by leukopenia or thrombocytopenia develop.
As a result of acute viral hepatitasa (especially hep.A) aplastic anemia may develop.
Endocrine disorders
Hypogonadism in males and females, the disappearance of secondary male sexual
characteristics, loss of libido, impotence and signs of feminization in men are common in patients
with chronic liver disease, particularly alcoholic cirrhosis (still occurs reduced spermatogenesis,
decreased synthesis of testosterone). The most striking changes caused by estrogen are
gynecomastia and spider angiomas on the skin, telangiectasia and erythema of palms.
Decreased catabolism of cortisol and aldosterone, increased secretion of growth hormone.
Decreased catabolism of thyroid hormones. Reduced conversion of T4 to T3; T3 concentration in
plasma is reduced; T4 and TSH and rT3 are increased. Patients are euthyreotic.
Insulin, glucagon and glucose: hyperinsulinemia and hyperglucagonemia because the liver
destroys 50% of the insulin secreted in the pancreatic vein, and it inactivates glucagon. The increase
in blood glucagon leads to insulin resistance. Besides the liver removes 50% of the absorbed
glucose so patient has hyperglycemia.
Disorders of the cardiovascular system
In decompensated cirrhotics cardiac output is increased due to increased blood volume and
reduced pressure of oxygen in arterial blood.
Alcoholic cardiomyopathy follows alcoholic cirrhosis.