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ACQUIRED IMMUNODEFICIENCY SYNDROME 1

- caused by theretrovirus human immunodeficiency virus
(HIV)
- characterizedby profound suppression of T-cell–
mediated immunity leading to opportunistic infections,
secondary neoplasms, and neurologic disorders.
- males are affected frequently than females
HIV transmission
1. SEXUAL CONTACT—> virus is carried in semen and vaginal
secretions (as free virus and within infected lymphocytes and
enters the host via mucosal abrasions (rectal, oral, vaginal) or
direct mucosal cell contact—>transmission occurs by direct
inoculation into the bloodstream, or infection of host
mucosal dendritic cells or CD4+ T cells—>transmission is
enhanced by concurrent sexually transmitted diseases,
either by causing increased mucosal ulceration or by
increasing numbers of virus containing inflammatory cells in
genital fluids
the protease, as well as the retroviral
polymerase.
MECHANISM OF INFECTION
- by binding of CD4 by theviral gp120, followed by entry into
cell by fusion, which requires gp41 and coreceptorsCCR5 (β-
chemokine receptor 5) and CXCR4 (α-chemokine receptor).
DX: HIV+ and has CD4 count <200 cells/mL
HIV-positive and has an AIDS-defining disease
CDC recommends initial testing with an Ag/Ab
combination immunoassay, followed by confirmatory
HIV1/HIV2 Ab differentiation immunoassay—> if
confirmatory test is (-)—> test with HIV1 nucleic acid is done
Tx: antiretroviral, reverse transcriptase inhibitors, protease
inhibitors, and prophylaxis for opportunistic infections based
on CD4 count

2. PARENT INCOCULATION—> IV drugs users with recipients Clinical Manifestation:

of blood product concentrates (e.g hemophilliacs; blood
transfusion; accidental needle stick; anti-retroviral
therapypost-exposure reducesthe risk an additional eight-
fold.
3. VERTICAL TRANSMISSION—> mother to fetus/newborns:
through transplacental during delivery through infected birth
canal ingestion of breastmilk
- risk is increased with high viral load and
chorioamnionitis
a. acute phase—> viremia with reduction in CD4
count, mononucleosis-like viral symptoms and
lymphadenopathy, andseroconversion.
b. latent phase—>asymptomatic or persistent
generalizedlymphadenopathy with continued viral
replication in the lymph nodesand spleen, low level of virus in
the blood, and minor opportunistic
infectionsincluding oral thrush (candidiasis) and herpes
zoster. The average duration of latent phase is 10 years

Major Risk groups: c. Progression to AIDS—>reduction of CD4 countto

-homosexual/bisexual/ heterosexual contact <200 cells/mL, which is accompanied by reemergence
- IV drug users of viremia anddevelopment of AIDS-defining diseases,
- hemophilliacs possibly to eventual death.
- Component recepient
Etiology

PROPERTIES OF HIV
1. enveloped RNA retrovirus that contains reverse
transcriptase
2. lipid envelope= studded with 2 viral glycoproteins
(gp120 and gp 41); both critical
for HIV infection
3. core proteins= capsid protein 24 nucleocapsidprotein
p7/p9 two copies of genomic RNA three
viralenzymes: protease, integrase, and
reverse transcriptase
4. viral genome= gag, pol,and, envgenes; the gag and
pol gene products are synthesized as a
largerprecursor protein that must be
proteolytically processed.Components of
antiviral therapy are thus directed against
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ACUTE RESPIRATORY DISTRESS SYNDROME 1

- “diffuse alveolar damage”
- noncardiogenic pulmonary edema resulting from
acute alveolar capillary damage
- due to direct injury to the lungs or sytemic diseases
causes:
A. g(-) sepsis > 40% of cases
B. gastric aspiration >30% of cases
C. severe trauma with shock >20% cases
D. diffuse pulmonary infections—> SARS, hanta virus
E. other causes: heroin, smoke inhalation, acute
pancreatitis, cardiopulmonary bypass, disseminated
intravascular coagulation, amniotic fluid embolism
and fat embolism
pathogenesis:
a. acute damage occurs in alveolar capillary walls
and epithelial cells
b. alveolar macrophages and other cells release
cytokines
-neutrophils transmigrate into the alveoli through
pulmonary capillaries
-capillary damage causes leakage of a protein-rich
exudate producing hyaline membranes
-neutrophils damage type 1 and type 2
pneumocytes—> decrease in surfactant—> causes
atelectasis with intrapulmonary shunting
c. Late findings
-repair by type 2 pneumocytes
- progressive interstitial fibrosis (restrictive
lung disease)
laboratory findings:
A. severe hypoxemia NOT responsive to O2 therapy—>
PaO2 <50mmHg
B. b. pulmonary artery wedge pressure < 18 mmhg if >
18mmhg—> cardiogenic pulmonary edema
C. respiraotry acidosis or normal PaCO2
D. increased A-a gradient due to:
- intrapulmonary shunting related to atelectasis
- diffusion abnormalities related to hyaline
membranes, alveolar infiltrate
ex. chest X-ray
- bilateral interstitial infiltrates initially (lung opacity-
WHITE OUT)
- progresses to widespread alveolar consolidation
with air bronchograms (80%)
Gross Examination:
- lungs affected are heavy, stiff and noncompliant
Microscopic :
- intraalveolar edema
- hyaline membranes line the alveolar spaces
- resolving cases—> type 2 pneumocytes
proliferation—> interstitial inflammation—> fibrosis
Treatment:
- treat underlying cause
- hemodynamic monitoring
- mechanical ventilation
- Nitric oxide inhalation, corticosteroids

clinical findings: Prognosis:

- dyspnea/tachypnea - poor prognosis 40% mortality rate
- late inspiratory crackles

ALPORT SYNDROME 1
 hematuria-nephropathy deafness
 hemorrhagic familial nephritis
 hereditary deafness and nephropathy
 hereditary nephritis
 hereditary nephritis with sensory deafness
genetic condition characterized by kidney disease
(glomerulonephritis), hearing loss, and eye abnormalities.
Mutations in the COL4A3, COL4A4, and COL4A5 (85%) - X-
linked recessive pattern
Defect in making of type IV collagen
prevents the kidneys from properly filtering the
blood and allows blood and protein to pass into the urine.
Gradual scarring of the kidneys occurs, eventually leading to
kidney failure in many people with Alport syndrome.

 hematuria DX:
 proteinuria FEATURE
 kidney biopsies - absence of the type IV collagen
 end-stage renal disease (ESRD).
 Immunohistochemistry or immunofluorescence
Male = Female  kidney transplant found that they had somewhat
increased life expectancy
1 in 50,000 newborns.
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Currently, there is no specific treatment for Alport
syndrome.
AMYOTROPHIC LATERAL SCLEROSIS 1
 motor neurone disease (MND)
 Lou Gehrig's disease
- disease which causes the
death of neurons controlling voluntary muscles
characterized by
 fasciculations (muscle twitches) in the arm,
leg, shoulder, or tongue
 muscle cramps
 tight and stiff muscles (spasticity)
 muscle weakness affecting an arm, a leg,
neck or diaphragm.
 slurred and nasal speech
 difficulty chewing or swallowing.
This results in difficulty speaking, swallowing, and
eventually breathing
The cause is not known in 90% to 95% of cases.
Inherited – 5-10%
AUTOIMMUNE DISEASE 1
Autoimmunity= immune reactions against self antigens;
results from the loss of self-tolerance
Autoantibodies= can be found in the serum of apparently
normal individuals, particularly in older age groups;
sometimes produced after damage to tissues and may serve a
physiologic role in the removal of tissue breakdown products
Pathologic autoimmunity requirements:
1) presence of an immune reaction specific for some
self antigen or self tissue
2) evidence that such a reaction is not secondary to
tissue damage but is of primary pathogenic
significance
3) absence of another well-defined cause of the disease
Clinical manifestations:
 extremely varied
 Organ-specific disease= directed against a single
organ or tissue
o type 1 DM- autoreactive T cells and
antibodies are specific for β cells of the
pancreatic islets
The goal is to treatthe symptoms and help slow the
progression of kidney disease.
This may include: ACE inhibitor or ARB medicines
(medications to control high blood pressure
MC – 55-75
Male > Female
Caucasians, Non-Hispanics
No one test can provide a definitive diagnosis of
ALS. However, the presence of upper and lower motor
neuron symptoms strongly suggests the presence of the
disease.
Electromyography (EMG), a special recording technique that
detects electrical activity of muscle fibers, can help diagnose
ALS.
Nerve conduction study (NCS), which measures electrical
activity of the nerves and muscles by assessing the nerve’s
ability to send a signal along the nerve or to the muscle.
The outlook for ALS is poor, with most patients dying of it,
typically from respiratory failure.
Statistics show that half of those with ALS live at least three
years after diagnosis, 25 percent at least five years, and up
to 10 percent 10 years or more.
Treatment: No cure
o multiple sclerosis-autoreactive T cells
react against CNS myelin
 Systemic/generalized disease= autoimmune
reactions are against widespread antigens
o SLE- diversity of antibodies directed
against DNA, platelets, red cells, and
protein-phospholipid complexes result in
widespread lesions throughout the body
 Goodpasture syndrome=falls in the middle of the
spectrum; antibodies to basement membranes of
lung and kidney induce lesions in these organs
General features:
 tend to be chronic, sometimes with relapses and
remissions, and the damage is often progressive
 clinical and pathologic manifestations are
determined by the nature of the underlying
immune response
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BACTERIAL ENDOCARDITIS 1
Infective Endocarditis (IE)is microbial infection of the heart
valves or the mural endocardium that leads to the
formation of vegetations composed of thrombotic debris
and organisms, often associated with destruction of the
underlying cardiac tissues.
Classification: reflects range of the disease severity and
tempo
 Acute IE=caused by infection of a previously
normal heart valve by a highly virulent organism
(S. aureus) that rapidly produces necrotizing and
destructive lesions. Difficult to cure with antibiotics
alone, and usually require surgery. Death can
ensue within days to weeks despite appropriate
treatment.
 Subacute IE= characterized by organisms with
lower virulence (viridans streptococci) that cause
insidious infections of deformed valves with
overall less destruction.Protracted course of
weeks to months, and cures can be achieved
with antibiotics.
Causative agents:
o Streptococcus viridans, affecting native but
previously damaged or otherwise abnormal valves
o S. aureus, infect either healthy or deformed
valves; among intravenous drug abusers
o HACEK group (Haemophilus, Actinobacillus,
Cardiobacterium, Eikenella, and Kingella)
o S. epidermidis, causes prosthetic valve endocarditis
o Gram-negative bacilli
o Fungi
Morphology:
 Classic hallmark: Vegetations on heart valves
(friable, bulky, potentially destructive lesions
containing fibrin, inflammatory cells, and bacteria or
other organisms
 Most common sites: aortic and mitral valves; right
heart valves (IV drug abusers)
 Single or multiple; may involve more than one valve
 Occasionally erode into the underlying myocardium
and produce a ring abscess
 Subacute= less valvular destruction than those of
acute endocarditis; exhibit granulation tissue at
their bases indicative of healing
Clinical features:
 stormy onset with rapidly developing fever, chills,
weakness, and lassitude.
 most consistent sign= fever, but can be slight or
absent, particularly in older adults (with may be
nonspecific fatigue, loss of weight, and a flulike
syndrome)
 Murmurs = in left-sided IE (90%)
 Duke criteria= facilitate evaluation of individuals
with suspected IE
Complications:
 generally begin within the first few weeks of
onset
 Glomerulonephritis
 common clinical manifestations of long-standing
IE— microthrombo emboli, Janeway lesions, Osler
nodes, and Roth spots
Earlie diagnosis and effective treatment has nearly
eliminated these manifestations

BACTERIAL VAGINOSIS 1
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Candidia: common in pregnant, Diabetics, and

undergoing antibiotic therapy

These may cause premature labor or abortion if it

ascends into utero

BONE TUMOR 4
1. Osteoid osteoma: <2cm, benign c. Likes to metastasize to the lung via the blood
a. Younger men, 20 y.o or younger d. has a chondroblastic and an osteoblastic version
b. Likes appendicular skeleton esp. face ;) depending on the morphology of the structured
c. Nocturnal pain reliever by ASPIRIN or steroids formed by the cells 
d. Thick rind of reactive bone cortical bone
e. Tx: radiofrequency ablation
2. Osteoblastoma: >2cm, benign
a. Likes post. spine
b. Pain unresponsive to aspirin
c. Tumor doesn’t induce marked bony reactive
d. Tx: curettage/excision en bloc
e. Malignant transformation is rare for both of these
guys 6. EWING:
3. Osteochondroma: AKA: Exostosis
a. Cartilage tumors
b. Grow from metaphysis near growth plate (which is
why usually diagnosed in adolescents)
c. Sessile w/ short stalks a.
b. Have the youngest average age of presentation
d. Slow growing but can be painful if impinges a
c. MC Primary bone tumor in children (2nd is
nerve
osteosarcoma)
e. Benign hyaline cartilage cap
d. Geographic necrosis prominent w/ dense
f. Progress to chondrosarcoma
cellularity

g.
4. Giant cell: multinucleated osteoclast-type giant cells
a. According to doc pete: (F>M)
b. Tx: curettage
c. Likes to metastasize to the lungs

Note: I didn’t bring my notes from Doc peter’s class so please nalang
5. Osteosarcoma ko co-relate 
a. “Sun rays” appearance in the x-ray References: Cotran and USMLE 
b. If around the knee: distal femur and prox. Tibia
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CARCINOID TUMOR 3
1. Carcinoid Tumor -minimal pleomorphism
-arise from diffuse components of endocrine system. -rare: anaplasia, mitotic activity and necrosis
-also called-well differentiated neuroendocrine tumors
-most are found in GI tract and more than 40% occur in small Immunohistochemical Stain:
intestine. (+) endocrine granule marker (synaptophysin and
2nd most common: Tracheobronchial tree and lungs chromogranin A)
Incidence: 6th decade but appear at any age
-symptoms are determined by hormones produced Most impt. Prognostic factor for GI carcinoid tumors is
-Tumors produce gastrin cause Zollinger Ellison Syndrome location.
while ileal tumors cause carcinoid syndrme
-Carcinoid Syndrome: occur <10% caused by 1.Foregut Carcinoid Tumors
vasoactivesubstances secreted by tumor into systemic -rarely metastasize
circulation Location: Stomach,Duodenum proximal to ligament of Treitz,
esophagus
Clinical Features: Mgt: Resesction
1. Cutaneous Flushing
2.Sweating 2. Midgut Carcinoid Tumors
3. Bronchospasm -often multiple and aggressive
4.Colicky Abdominal -greater depth of invasion, and increased size
6. Right sided cardiac valvular fibrosis - presence of necrosis and mitoses are assoc. with worse
outcome
Gx: Location: jejunum, ileum
-Yellow-tan in color, very firm
-Intramural or submucosal masses create polypoid lesions 3. Hindgut Carcinoid Tumors
-At All GI sites they are intact or ulcerated , in intestines they -incidentally discovered
invade deeply to mesentery -rare, >2cm , always benign
Location: appendix, colorectal
Mx: comosed of islands, trabeculae, strands, glands or sheets -Rectal Carcinoids: uncommon, produce polypeptide
uniform cells with scant pink granular cytoplasm and round hormones and when symptomatic present with abdl. pain
oval stippled nucleus and weight loss.

CARDIAC FUNCTION TESTS 2

Cardiac Function Test - Note: serial determination every 3-4 hours must be
Enzymes: done over 12 -16 hour period
• Creatinine Phosphokinase (CPK)
• Lactic Dehydrogenase (LDH) Serum Glutamic Oxaloacetate Transaminase (SGOT)
• Serum Glutamic Oxaloacetate Transaminase - Also known as Aspartate Aminotransaminase (AST).
(SGOT) - Is elevated after the first 12 hours of Acute
Acute Phase Reactants Myocardial Infarction (AMI).
• Troponin T (TnT) - Peak is at 24 hours post AMI.
• Troponin I (TnI) - Returns back to normal within 48 hours.
• C reactive protein (CRP)
There are three (3) isoenzymes: Lactate Dehydrogenase (LDH)
• CPK 1 (BB)- increased in brain abnormalities - Is elevated after the first 24 hours of Acute
• CPK 2 (MB)- cardio-specific Myocardial Infarction (AMI).
• CPK 3 (MM)- increased in muscular disorders - Peak is at 48 hours post AMI.
- Returns back to normal within 12 days.
Creatinine Phosphokinase
- Is elevated after the first 4-6 hours of There are five (5) isoenzymes:
• LDH 1 (cardio-specific)
Acute Myocardial Infarction (AMI) • LDH2(most numerous)
- Peak is at 12 hours post AMI. • LDH3(pulmonary)
- Returns back to normal within 24 hours. • LDH 4
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• LDH 5 • Troponin T
• Troponin I
In Acute Myocardial Infarction (AMI) there is LDH • C reactive protein (CRP)
flipped ratio.
• LDH 1 is increased when there is myocardial damage. Troponin T (TnT)
• Therefore: LDH 1 > LDH 2. - Elevated after a few hours of chest pain
• Example: Normal LDH 1 LDH 2 ratio = < 1 - Maybe elevated in patients with renal disease

• Given: LDH 1 = 1.0 Troponin I (TnI)

LDH 2 = 2.0 • Increased 4-8 hours after onset of chest pain
• Normal formula = LDH 1 = 1 = 0.5 • Peaks at 12-16 hours
LDH 2 2 • Remains elevated for 5-9 days
• Normal formula = LDH 1 = 2 = 0.5 • Values above 1.5 ng/dL is positive for AMI
LDH 2 4 • Cardiospecific
-More specific than CPK-MB
• LDH 1 is increased when there is myocardial damage.
• C reactive protein (CRP)
• Therefore: LDH 1 > LDH 2 - Diagnosis of Congestive Heart Failure (CHF)
• LDH 1 = 6 =3.0
LDH 2 2 B- type Natriuretic Peptide (BNP)
• - definitive test for CHF
• Therefore LDH 1 LDH 2 ratio is increased in AMI - also increased in arrhythmia and stroke
- excellent marker for early heart failure
Other parameters used to detect AMI:

CARDIAC TUMORS 1
Primary Tumors  Hemodynamic Impairment
Benign  Flow obstruction of venous drainage or across
-Myxomas atrioventricular valves
-Fibromas  Obstruction is usually progressive
-Lipomas  Intermittent obstruction can cause syncope or
-Papillary Fibroelastosis sudden death in 1/4 to 1/2 of patients
-Rhabdomyomas  Embolism
Malignant  Occurs in 30 to 40% of left atrial myxomas and
-Angiosarcoma over 50% of left ventricular myxomas
-Rhabdomayosarcoma  About 50% of emboli will affect the CNS
 Right-sided tumors have a lower frequency of
Metastatic tumor 5% of px with cancer embolism
 Constitutional Symptoms
Benign  Include fever, weight loss, clubbing, Raynaud’s
Cardiac Myxomas myalgias/arthralgias, hemolytic anemia
 Most common primary tumor in adults  Laboratory test may reveal elevated IgM or
 90% location is left atria IgA globulins, ESR, and C-reactive protein
 Almost always occur single, but rarely be multiple  Familial Myxoma (Carney Syndrome)
 Size range of <1cm-10cm  Familial occurence in 10% of patients
 Sessile or pedunculated  Usuallly found in young men, more often
 Globular hard masses to soft-translucent papillary or multiple and less common in left atrium
villous lesions having a gelatinous appearance
 Composed of stellate or globular myxoma cells, Lipomas
endothelial cells, smooth muscle cells and  Well-encapsulated tumor, usually found incidentally
undifferentiated form  Most commonly occur in atrial septum as part of
 Cells are embedded within an abundant acid lipomatous hypertrophy of the interatrial septum; right
mucopolysaccharide ground substance atrium; and left ventricle
 Covered on the surface by endothelium  May occur in the subendocardium, subepicardium, or
 Clinical Manifestation within myocardium
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 Well demarcated, generally encapsulated mass of  Tumors may be unresectable at surgery

mature fat cells  About 50% of survivors will eventually develop tuberous
sclerosis
Papillary Fibroelastoma
 Usually incidental lesions
 Generally located on valves Malignant
 Right-sided valves in children Angiosarcoma
 Left-sided valves in adults  Most frequent cardiac sarcoma
 Hairlike projection up to 1cm, covered by endothelium  Usually occur on the right side of the heart of the heart
 Core of myxoid connective tissue, with smooth muscle or in the percardium
cells and fibroblasts  Variegated, hemorrhagic mass
 Symptoms usually occur when the tumor is large enough
Rhabdomyoma to obstruct blood flow through the heart which causes
 Most frequent primary tumor of the heart in infants and heart failure
children  A piece breaks off the tumor and embolizes
 Over 90% present before age 15, usually in the first few  Prognosis is poor, as most patient have distant
days of life metastases at presentation
 Frequently discovered in the first year of life due to  Adjuvant therapy may have some role
obstruction of a valvular orifice or cardiac chamber
 Maybe left or right sided gray white ventricular wall
mass Metastatic Carcinoma
 Large, rounded or polygonal cells, rich in glycogen  Most common neoplastic process involving the heart
 Contain myofibrils  Most frequently metastasize to pericardium, then
 Presence of spider cells myocardium, and endocardium
 Cause cardiac failure from obstruction of conduction
pathways and ventricular tachycardia

CARDIOMYOPATHY 1
Cardiomyopathy - Nutritional
 Heart disease resulting from a primary abnormality and - Other metabolic or immunologic derangement
localized in the myocardium  Genetic: 20 to 30% with family history
 Categories: - Autosomal Dominant, Autosomal Recessive, and X-
Dilated Cardiomyopathy (DCM) linked inheritance
Hypertrophic Cardiomyopathy (HCM) o Deletion in mitochondrial genes
Restrictive Cardiomyopathy (RCM) o Mutation in the gene for dystrophin
o Mutation in genes encoding for enzymes for β
Dilated Cardiomyopathy fatty acid oxidation
- Most common - 90% of cases Morphology
- Occur at any age; commonly 20-60years old - Heart is usually heavy (2-3x the normal)
- Slow progressive congestive heart failure - Large and flabby with four - chamber dilation
- a.k.a Congestive Cardiomyopathy - Wall thinning
Causes: - Mild to moderate focal endocardial thickening
Unknown - Mural thrombi may be seen
 Viral Myocarditis - Microscopically non specific; 25% with significant
- Coxsackie alterations
- Other enteroviruses - Myocyte hypertrophy
 Alcoholic Toxicity - Attenuated and stretched myocyte
- Direct toxicity of metabolites (acetaldehyde) - Interstitial and endocardial fibrosis
- Secondary nutritional disturbance (e.g. Thiamine
Deficiency - Beri Beri) Basic Physiologic Abnormal
 Drug Toxicity - Cardiomyopathy -> Impaired contractility -> systolic
- Doxorubuxin (adriamycin) dysfunction -> signs and symptoms of congestive heart
 Pregnancy failure
- Pregnancy - associated hypertension
- Volume Overload Clinical Features and Prognosis
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- Presents as slow progressive CHF

- End Stage
o Ejection fractioin <25%
o 50% die in 2 years
o 2% survive longer than 5 years
- Death usually due to progressive cardiac failure or
arrhythmia; embolism may occur
- Management
o Symptomatic and supportive
o Cardiac transplantation

Hypertrophic Cardiomyopathy
- a.k.a idiopathic hypertrophic subaortic stenosis or
hypertrophic obstructive cardiomypathy
- Usually seen in young adults
Causes:
 Genetic
- 1/2 familial
- Autosomal dominant pattern of transmission
 Unknown
Morphology
- Marked cardiomegaly
- Massive myocardial hypertrophy usually without
ventricular dilation
- Asymmetric septal hypertrophy
o Disproportionate thickening of the
ventricular septum relative to the left
ventricle free wall ( with a ratio of septum
to free wall > 1:3)
- 10% concentric and symmetrical
- Left ventricular cavity is compressed
o Banana-like configuration by bulging of the
ventricular septum into the lumen
Clinical Features and Prognosis
Major Clinical Problems
1. Atrial fibrillation with mural thrombus formaation ->
embolization
2. Infective endocarditis on the mitral valve
3. Intractable cardiac failure
4. Sudden death - common cause of unexplained death in
young athletes
 Clinical and morphologic features are markedly
heterogenous
- Many are stable over many year of observation
- Some may improve
- 403Arg -> Gla mutation in the β-myosin heavy chain
yields severe disease and sudden death
 Treatment is usually medical that enhances ventricular
relaxation

Histologic Hallmarks Restrictive Cardiomyopathy

 Extensive myocyte hypertrophy Ø Rarest Form
 Haphazard disarray of bundle of myocytes “helter- Causes
skelter myocyte disarray” 1. Idiopathic
 Interstitial and replacement fibrosis 2. Associated with disease affecting the myocardium
- Radiation fibrosis
 Abnormal thick -walled vessels
- Amyloidosis
- Metastatic tumor
Pathogenesis
- Inborn errors of metabolism
 Mutation of any of the four genes that encode proteins
Classification (Braunwald)
of the cardiac contractile elements (sarcomeres: β-
1. Myocardial
myosin heavy chain, troponin T, α-tropomyosin, and
- Noninfiltrative - e.g. Tumors
myosin-binding protein C)
- Infiltrative - e.g. Amyloidosis
2. Endomyocardial
Basic Physiologic Abnormality
- Endomyocardial fibrosis
- Loeffler endocarditis
- Endocardial fibroelastosis
Morphology
Ø Venricles are approximately normal in size or slightly
enlarged
Ø Ventricular cavities are not usually dilated
Ø Myocardium is firm
Ø Bi-atrial dilation is commonly observed
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Ø Patchy or diffuse interstitial fibrosis
Ø Maybe minimal to extensive
Basic Physiologic Abnormality
Heart -> Decreased ventricular compliance -> restricted
ventricular filling during diastole -> decrease cardiac output
Endomyocardial Fibrosis
Ø Typically in children; young adults in africa
Ø Etiology is unknown
Morphology
Ø Ventricular subendocardial fibrosis from the apex to
inflow tracts of one or both ventricles
Ø Often with mural thrombi formation
Ø AV valves maybe involved
Loeffler Endocarditis
Functional Pattern Left Ventricular Ejection
Fraction
Dilated <40%
Hypertrophic 50-80% Impaired compliance (diastolic Idiopathic, Genetic; Friedreich
Restrictive 45-90%
CELLULAR ADAPTATIONS AND CELL DEATH 2
Adaptations are reversible changes in the size, number,
phenotype, metabolic activity, or functions of cells in
response to change in their environment
1. Hypertrophy refers to an increase in the size of cells,
that results in an increase in the size of the affected
organ. Mechanisms of Hypertrophy Hypertrophy is
the result of increased production of cellular
proteins.
2. Hyperplasia is defined as an increase in the number
of cells in an organ or tissue in response to a
stimulus. Hyperplasia is all result of growth factor –
driven proliferation of mature cells and, in some
cases, by increased output of new cells from tissue
stem cells. Physiologic hyperplasia due to the action
of hormones or growth factors occurs in several
circumstances: when there is a need to increase
functional capacity of hormone sensitive organs;
when there is need for compensatory increase after
damage or resection. Pathologic Hyperplasia most
forms of pathologic hyperplasia are caused by
excessive or inappropriate actions of hormones a
growth factors acting on target cells.
Morphology
Ø Endomyocardial fibrosis with large mural thrombi
Maybe associated with:
Ø Peripheral eosinophilia
Ø Eosinophilic infiltration of multiple organs
Ø Rapidly fatal course
Endocardial Fibroelastasis
Ø Uncommon
Ø Seen in the first 2years of life; rarely in adults
Often associated with congenital cardiac anomalies
Ø Unknown Etiology
Morphology
Ø Diffuse fibroelastic thickening of the mural left
endocardium
Mechanism of Heart Failure Causes
Impaired contractility Idiopathic; Alcohol, Peripartum,
(systolic dysfunction) Genetic, Hemochromatosis,
Chronic anemia, doxorubucin,
sarcoidosis
dysfunction ) ataxia, storage disease, infants of
diabetic mothers
Impaired compliance Idiopathic; amyloidosis; radiation-
(Diastolic Dysfunction) induced
3. Atrophy is defined as a reduction in the size of an
organ or tissue due to a decrease in cell size and
number. Atrophy results from decreased protein
synthesis and increased protein degradation in cells.
Protein synthesis decreases because of reduced
metabolic activity. The degradation of cellular
proteins occurs mainly by the ubiquitinproteasome
pathway.
4. Metaplasia is a reversible change in which one
differentiated cell type (epithelial or mesenchymal)
is placed by another cell type. Metaplasia does not
result from a change in the phenotype of an already
differentiated cell type; instead it is the result of a
reprogramming of stem cells that are known to exist
in normal tissues, or or undifferentiated
mesenchymal cells present in connective tissues.
Morphologic Alterations in Injured Cells and Tissues
 Reversible cell Injury: Cellular swelling, fatty
change, plasma membrane blebbing and loss of
microvilli, mitochondrial swelling, dilation of the
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ER, eosinophilia (due to decreased cytoplasmic
RNA)
 Necrosis: increased eosinophilia; nuclear
shrinkage fragmentation, and dissolution;
breakdown myelin figures; leakage and
enzymatic digestion of cellular contents
CLOTTING TEST 2
COMMON WARTS 1
 Verrucae - are squamo proliferative disorders
caused by human papilloma viruses causing
acanthosis and hyperkeratosis
o Transmission of disease usually involves
direct contact between individuals or
autoinoculation. Verrucae are generally
self-limited, regressing spontaneously
within 6 months to 2 years.
 Verruca vulgaris (HPV 2 & 7) is
the most common type of
wart. The lesions of verruca
vulgaris occur anywhere but
CONN SYNDROME 1
CONN SYNDROME (Primary Hyperaldosteronism)
- autonomous overproduction of aldosterone, with
resultant suppression of the reninangiotensin
system and decreased plasma renin activity.
- Blood pressure elevation is the most common
manifestation of primary hyperaldosteronism,
which is caused by one of three mechanisms:
a) Bilateral idiopathic hyperaldosteronism (IHA)
- most common underlying cause of primary
hyperaldosteronism. Characterised by bilateral
 Patterns of tissue necrosis: under different
conditions, necrosis in tissues may assume
specific
 patterns: coagulative, liquefactive, gangrenous,
caseous, fat, and fibrinoid
most frequently on the
hands, particularly on the
dorsal surfaces and
periungual areas, where they
appear as gray-white to tan,
flat to convex, 0.1- to 1-cm
papules with a rough,
pebble-like surface.
 Histologic features- verrucous or
papillomatous epidermal
hyperplasia, with koilocytes
present.
nodular hyperplasia. They are older and to
have less severe hypertension than those
presenting with adrenal neoplasms.
b) Adrenocortical neoplasm - either an
aldosterone-producing adenoma (the most
common cause) or, rarely, an adrenocortical
carcinoma. 35% of cases, primary
hyperaldosteronism is caused by a solitary
aldosterone-secreting adenoma, a condition
referred to as Conn syndrome.
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c) Glucocorticoid-remediable hyperaldosteronism hyperaldosteronism.

- an uncommon cause of primary familial

CROHN DISEASE 2
 Characterized by recurring episodes of inflammation
of any part of the gastrointestinal tract, from the
mouth to the anus.
o Most commonly found at the terminal
ileum, ileocecal valve, and cecum.
 microscopic skip lesions.
 Can actually occur anywhere in the
GI tract
 SI = 40%
 SI + colon = 30%
 This inflammation is transmural and can result in
strictures, microperforations, and fistulae. The
inflammation may not be contiguous and thus can
produce skip lesions throughout the bowel.
 ‘Skip Lesions’ is the differentiating characteristic
from ulcerative colitis
 Histologically, Crohn's disease can have transmural
lymphoid aggregates, non-necrotizing granulomas,
fissuring, or

 ulcer  serpentine ulcers (oriented along the axis of

the bowel)  sparing of interspersed mucosa 
results in cobblestone appearance (depression of
normal mucosa)
 Fissures  extend deeply to become fistula tracts 
thickened and rubbery intestinal wall  stricture
formation mesenteric fat frequently extends
around the serosal surface (creeping fat) for
extensive transmural disease o May further result into:
 Microscopically, there would be abundant  Iron deficiency anemia colonic
neutrophils within a crypt (crypt abscesses) disease
o This results in ulceration due to destruction  Extensive small bowel diseaseloss
of the crypt infiltrated of serum protein and
o You will observe a patchy appearance and hypoalbuminemia
distortion of mucosal architecture  Malabsorption of V. B12 and bile
 Epithelial Metaplasia salts
o Pseudopyloric metaplasia  Fibrosing strictures are common and require surgical
 Due to chronic relapsing injury resection
 Takes form of gastric antral-  Fistulae
appearing glands o Develop between loops of bowel
o Paneth cell metaplasia o Involves Urinary B., vagina and abdominal
 Left colon or perianal skin
 Nonceseating granulomas  Extraintestinal manifestations
o Hallmark o Uveitis
 Clinical o Migratory polyarthritis
o Mild diarrhea, fever, and abdominal pain o Sacroiliitis
o May mimic appendicitis or bowel o Ankylosing spondylitis
perforation o Erythema nodosum
o Reactivation may occur due to physical and o Clubbing of the fingertips
emotional stress, diet, and cigarette o Pericholangits& 1o sclerosis cholangitis
smoking  Anti-TNF antibodies are used for treating Crohn
disease
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CROUP SYNDROME 1
CROUP SYNDROME
 Is a common, primarily pediatric viral respiratory
tract illness.
 a.k.a
o acute laryngotracheitis
o acute laryngotracheobronchitis
 most common etiology for hoarseness, cough and
onset of acute stridor in febrile children
 On physical
o A seal-like barking cough
o Inspiratory stridor
o A variable degree of respiratory distress
 Morbidity
o Secondary to narrowing of the larynx and
CYANOTIC/ACYANOTIC HEART DISEASE 1
SHUNTS
 Left to right shunts (Acyanotic Heart Disease)
 Causes pressure overload to the right side of the
heart resulting to secondary pulmonary
hypertension and right ventricular hypertrophy.
 Late cyanosis happens when there is overriding
pressures.
 Right to left left shunts (cyanotic heart disease)
 Carries unoxygenated blood to the general
circulation. They permit emboli from the venous
system to paradoxically lodge in the systemic
circulation.
LEFT TO RIGHT SHUNTS
 Atrial Septal Defect
 Ventricular Septal Defect
 Patent Ductus Arteriosus
Atrial Septal Defect
 Abnormal opening in the atrial septum.
trachea at the subglottic region
‘Steeple or pencil sign’ of the proximal trachea
 The most common viral etiologies are parainfluenza
viruses (type 1,2 & 3)
 The primary entry points are the nose and
nasopharynx and eventually spreads to the larynx
and trachea
o Inflammation and edema of the subglottic
larynx and trachea, especially near the
cricoid cartilage (most clinically significant)
 Allows free communication of blood between atria.
 Most common congenital cardiac anomaly in adults.
 ASD 3 categories:
 Primum type: represents 5% of ASD and assoc
with Down Syndrome. It occurs low in the atrial
septum
 Secundum type: represents majority (90%) of
ASD and occurs in the foramen ovale
 Sinus venosus type: 5% of ASD, occurs near the
superior vena cava
 Pathophysiology:
 Oxygenated high pressure blood flow from left
atrium to right atrium causing chronic increased
pressure in the right side of the heart.
 Patients are acyanotic until late in adult life
when significant pulmonary hypertension
develops, and right-sided hyperthropy induce
right to left shunt → late cyanosis
Ventricular Septal Defect
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 Abnormal communication in the ventricular septum
 Allows free communication between the right
atrium and left ventricles
 Most common congenital cardiac anomaly.
 2 types: membranous and muscular type
 frequently assoc with other anomalies such as
Tetralogy of Fallot
 Clinical presentation: depends on the size of the
defect
 Small to medium defects are at risk for infective
endocarditis
 Spontaneously close → CHF
 Pathophysiology similar to ASD
Patent Ductus Arteriosus
 In the fetus, the ductus arteriosus connects and
conveys blood from pulmonary artery to the aorta.
 Physiologically closes during 1st 2 days of life
otherwise, it becomes permanent.
 In 85-90% of cases it occurs an isolated defect.
 The size varies upto 1cm in diameter.
 Initially asymptomatic, but later develops a
machinery like murmur especially when pulmonary
hypertension and right ventricular hypertrophy sets
in.
 Produces late cyanosis.
RIGHT TO LEFT SHUNTS
 Tetralogy of Fallot
 Transposition of the Great Vessels
 Truncus Arteriosus
Tetralogy of Fallot
 Aorta originates from the right ventricle not the left,
or overrides the septum, receiving blood from both
the ventricles.
DERMATOMYOSITIS 1
 Female dominant disease with an increased
incidence in Black population
 Primarily occurs in persons aged 40-60 years
 Increased ridk of malignant neoplasms (15-20%)
particularly lung and bladder cancer, and non-
hodgkin malignant lymphoma.
Clinical findings
 Symmetrical, proximal muscle weakness (with or
without pain) in both the upper and lower
extremities, trunk, shoulders, and hips.
 Cutaneous findings are key.
 Gottron’s papules
 Stenosed pulmonary artery with less than normal
amounts of blood passing to the lungs; instead it
passes to gthe aorta.
 Blood from the left ventricle passes to the VSD then
to the overriding aorta.
 Aorta has a high pressure so the right heart pumps
harder and therefore the musculature is well-
developed → enlarged ventricle
 Abnormal dynamics: shunting of the blood past the
lungs without its becoming oxygenated.
 As much as 75% of venous blood returning to the
heart pass directly from the right ventricle to the
overriding aorta.
 Major cause of cyanosis in babies → blue babies
 With severe pulmonary stenosis, survival warrants a
PDA
Transposition of the Great Vessels
 Survival depends on the presence of a PDA, VSD,
ASD
 Prognosis depends on the degree of tissue hypoxia
and the ability of the right ventricle to maintain the
aortic flow.
 Untreated patients die within months after birth.
Truncus Arteriosus
 Developmental failure of the aorta and pulmonary
artery to separate.
 Results in an infundibular VSD with a single vessel
receiving blood from both ventricles.
 Associated with other cardiac defects
 Early cyanosis is evident due to right to left shunt
 Prognosis is poor
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DIABETES INSIPIDUS 1 and DIABETES MELLITUS 2

Diabetes Insipidus (DI) is a condition characterized by large
amounts of dilute urine and increased thirst. Complications
may include dehydration or seizures.
 Central (CDI) is due to a lack of the
hormone vasopressin (ADH). This can be due to damage to
the hypothalamus or pituitary gland, or genetics.
 Nephrogenic (NDI) occurs when the kidneys fail to
respond properly to adequate supply of ADH.
Diabetes Type I
Other names IDDM, Juvenile Onset
Defect Absence of insulin
Ketoacidosis Present
Treatment Insulin
 Gestational DI occurs only during pregnancy.
Diabetes Mellitus (DM) is a group of metabolic disorders in
which there are high blood sugar levels over a prolonged
period. Symptoms of high blood sugar include polyuria,
polydipsia and polyphagia.
Type II
NIDDM, Adult Onset
Receptor sensitivity
Not present
Sulfonylureas

Diagnostic Criteriafor DM:

 RPG ≥ 200mg/dL Glucose Monitoring:
 FPG ≥ 126mg/dL  Daily – FBS, RBS
 2-Hr PG ≥ 200mg/dL  Weekly – Fructosamine (q2w)
 Monthly - HbA1C (q3m)
Glucose Metabolism Tests:
 2-Hr Post Prandial – 8hrs fasting, 75g of oral glucose, Gestational DM (GDM) is hyperglycemia during pregnancy:
blood glucose testing after 2hrs  ~4% of pregnant women; 60% become diabetic in next
 OGTT – 75g of oral glucose, blood and urine samples at 30, 16yrs
60, 120 and 180mins
Neonatal DM presents with blood glucose between 245 and
Impaired Glucose Tolerance: 2300mg/dL:
 FBS >100mg/dL but <126mg/dL  Detected at fourth day; met acidosis usually present;
 2-Hr, OGTT >140mg/dL but <200mg/dL postmaturity and low birth weight
Primary Tumors of Pancreas:
Cell Type Hormone Secreted Tumor
A cell Glucagon Glucagonoma
B cell Insulin Insulinoma
D cell Gastrin Gastrinoma
Somatostatin Somatostatinoma
H cell Vasoactive Intestinal Polypeptide Vipoma
HPP cell Human Pancreatic Polypeptide HPP-secreting tumor (very rare)

DUCHENNE MUSCULAR DYSTROPHY 1

Epidemiology: Characteristic traits
X-linked recessive Shoulders and arms are held back awkwardly when
Incidence 1:3500 male births walking
MOST COMMON CHILDHOOD MUSCULAR Sway back
DYSTROPHY Weak butt muscles
Knees may bend back to take weight
Pathogenesis Thick lower leg muscles
A. Absence of dystrophin Tight heel core (contracture)
B. Due to frameshift mutation Belly sticks out due to weak belly muscles
Thin, weak thighs
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Poor balance
Weak muscles in front of leg cause “feet drop” and Diagnosis
tip toe contracture - Muscle biopsy
Laboratory Findings - Electromyography (EMG)
- increased serum creatine at birth - DNA testing
- decreased serum creatine in later stages

General Timeline of Duchenne

Walking problems --> Wheel chair -Skeletal deforrmity --> Very limited use of arms --> Ventilation at night -->
Ventilation 24hrs --> Death

EMPHYSEMA 1
- is a type of Chronic Obsructive Pulmonary Disease (COPD) - Purse Lip Breathing
(irreversible obstruction airflow out of lungs) - Dyspnea
- known as PINK PUFFER - Hyperresonance on Chest Percussion
- permanent enlargement of all or part of the respiratory unit - Orthopneic
- abnormal and permanent enlargement of the airspaces distal - Barrel Chest
to the terminal bronshioles that is accompanied by - Exertional Dyspnea
destruction of the airspace walls, without obvious fibrosis - Prolonged Expiratory Time
- Speaks in Short Jerky sentences
Etiology - Anxious
a. Smoking cigarettes is the most common cause - Use of Accessory muscles to breathe
b. Alpha 1 antitrypsin (AAT) deficiency - Thin Appearance

Characteristics: Types of Emphysema

- Increased CO2 Retention (Pink) 1. Centrilobular (smoking)
- Minimal Cyanosis 2. Panacinar (AAT deficiency)
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ENDOMETRIOSIS 1 and ENVIRONMENTAL DISORDERS 1
Endometriosis
 Non-neoplastic endometrium-like glands/stroma outside
endometrial cavity.
 Most common sites are ovary (frequently bilateral), pelvis,
peritoneum.
 In ovary, appears as endometrioma (blood-filled
“chocolate cysts”).
 Cause: retrograde flow, metaplastic transformation of
multipotent cells, transportation of endometrial tissue via
lymphatic system.
 Characterized by cyclic pelvic pain, bleeding,
dysmenorrhea, dyspareunia, dyschezia (pain with
defecation), infertility; normal-sized uterus.
 Treatment: NSAIDs, OCPs, progestins, GnRH agonists,
danazol, laparoscopic removal.
 Under the influence of ovarian hormones and therefore
undergo cyclic menstrual changes with periodic bleeding,
but they have no means of sloughing externally like
normal endometrial lining.
 Exhibiting marked activation of inflammatory cascades
and increased stromal aromatase activity (and thus
estrogen production).
Morphology
• Grossly: Endometriosis manifests as red-blue to yellow-
brown mucosal or serosal nodules. Extensive disease can be
marked by organizing hemorrhage and fibrosis.
• Microscopically: Foci classically exhibit endometrial glands
and stroma, with or without hemosiderin.
Endometriosis primarily affects women during their
reproductive years (10% of all women are
affected).Uncommonly, malignancy can develop from the
ectopic foci.
I. Chemical Injury
-Tobacco use
Most preventable cause of death worldwide
Nicotine: addictive component in tobacco
Cotinine is the most important metabolite of nicotine;
used for screening
Nicotine patch used to Rx ulcerative colitis
Carcinogens: polycyclic hydrocarbons, phenol,
nitrosamine
Tar contains carcinogenic agents
Smokeless tobacco: addictive; ↑risk for oral
squamous cancer
Passive smoke: ↑risk of respiratory/middle ear
infections in children; risk for lung cancer; CAD
-Alcohol abuse
Alcohol MC recreational drug
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Stomach/liver metabolize alcohol; stomach/small
bowel reabsorb alcohol by diffusion
Enzymes metabolizing alcohol: alcohol
dehydrogenase (from Cytosol of the liver), CYP2E1
(MEOS), catalase (from Peroxisomes)
ADH: rate-limiting enzyme in alcohol metabolism
Conversion of acetaldehyde by acetaldehyde
dehydrogenase to acetic acid occurs in the
mitochondria.
Women at risk for acute/chronic alcohol
complications; ↓alcohol dehydrogenase
NADH enhances pyruvate conversion to lactate →
↓pyruvate → fasting hypoglycemia
↑Anion gap metabolic acidosis: lactic acid, β-OHB
acid
Lactic acid/β-OHB → hyperuricemia (potential for
gout); hypertriglyceridemia
Alcohol liver disease: AST > ALT; ↑GGT
-Other drugs of abuse
CNS effects of long-term drug abuse: a. Damage to
neurotransmitter receptor sites b. Risk for cerebral
atrophy (e.g., alcohol abuse)
Complications of intravenous drug use (IVDU):
a. Hepatitis C recently surpassed hepatitis B as the
most common hepatitis due to IVDU.
b. Human immunodeficiency virus infection
c. Infective endocarditis (tricuspid/aortic valves) -
Most often caused by Staphylococcus aureus
d. Tetanus - Complication of “skin popping” using a
dirty needle
-Adverse effects of therapeutic drug use
Acetaminophen: chemical hepatitis; renal papillary
necrosis
Aspirin: tinnitus, vertigo, tachypnea
Both acetaminophen and aspirin toxicity may cause
fulminant hepatitis
Unopposed estrogen: Adenocarcinoma
endometrium/breast; Venous thromboembolism;
intrahepatic cholestasis; Myocardial infarction/stroke
OCP: MCC hypertension in young women →
↑angiotensinogen → ↑ATII;risk for breast
adenocarcinoma, cervical SCC, folic acid deficiency
(macrocytic anemia), hepatic adenoma causing
intraperitoneal hemorrhage
II. Physical Injury
A. Mechanical injury
-skin wounds
Contusion: blunt force injury to blood vessels
with blood leaking into tissue
Abrasion: superficial excoriation of epidermis
Laceration: jagged tear with intact bridging
vessels/nerves/ connective tissue
Incision: wound with sharp margins; severed
blood vessels
- Gunshot wounds
Contact wound: stellate-shaped; fouling (soot +
gunpowder)
Intermediate-range wound: powder tattooing
around entrance site
Long-range wound: no powder tattooing
Exit wounds: larger than entrance wound
- Motor vehicle accidents (MVAs)
MCC death ages 1 to 44 years
Frequently alcohol-related
-Shaken baby syndrome: >50% deaths from child
abuse
Infants <1 year old
Characteristic signs: Retinal hemorrhages (key
finding, can be the only sign, Multiple fractures of
long bones, Subdural hematomas
B. Thermal injury
- Burns
MC site for burn is upper extremities
Common denominator in burns is
proteindenaturation
Center of burn has irreversible coagulation
necrosis
Zone of ischemia has reduction in dermal
microcirculation
Sources for skin regeneration: basal layer of cells
at margins; dermal skin appendages
1st degree burn: limited to epidermis
2nd degree superficial: extends into papillary
dermis; partial-thickness burn
2nd degree deep: extends into reticular dermis;
partial-thickness burn
3rd degree burn: extends through
epidermis/dermis;full-thickness; Scarring is
inevitable.
4th degree burn: extends thru skin, subcutaneous
fat, muscle/bone
Complications: Hypovolemic shock, Sepsis due to
Pseudomonas aeruginosa, Curling ulcers,
Hypermetabolic syndrome, CO and cyanide
poisoning
- Major heat syndrome: classic heatstroke
Clinical Presentation: Core body temp >40° C
(104° F); skin hot/dry; mental status abnormal;
CNS dysfunction
Predisposing factors: high ambient temperature;
poor, elderly without air-conditioning
- Major heat syndrome: exertional heatstroke (EHS)
Clinical Presentation: Core body temp >40° C
(104° F); profuse sweating; severe CNS
dysfunction
Predisposing factors: athletes/military recruits;
endogenous heat production overrides cooling
mechanisms
- Frostbite:tissue exposed to temperature <0° C; ice
crystallization of tissue; stasis of blood flow
Most common freezing injury to tissue
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Trench foot/immersion foot: nonfreezing injury;
exposure to wet cold
Chilblain: nonfreezing injury; exposure to dry cold
C. Electrical injury
-Current is the main determinant of damage to tissue.
-AC 3× more dangerous that DC at same voltage
-AC induces tetanic contractions (hold on to electricity
source); DC induces single muscle spasm (throws
away)
-Cardiorespiratory arrest MCC death from lightening
injury
D. Drowning
-Cause of death
(1) Most often relates to asphyxia caused by
laryngospasm and closure of the glottis,leading to
hypoxemia and combined respiratory and
metabolic acidosis
(2) Tonicity of the water (fresh water versus salt
water) does not appear to play a significant role
as a cause of death in drowning, because not all
drowning victims have water in their lungs.
-Diving reflex occurs in water that is colder than 20° C
(70° F); characteristics include:
(1) Bradycardia
(2) Peripheral vasoconstriction(shunts blood to
more vital areas)
(3) Blood shifting (shift of blood to the thoracic
cavity to prevent lung collapse)
(4) A longer survival without O2 in both conscious
and unconscious people
-Near drowning—survival following asphyxia
secondary to submersion
-Wet drowning—aspiration of water occurred during
the event
-Immersion syndrome—sudden death after
submersion in very cold water, most likely due to a
vagally mediated asystolic cardiac arrest
-Dry drowning—asphyxia caused by intense
laryngospasm without aspiration
E. High altitude injury
-Hypoxemia stimulates the peripheral
chemoreceptors, which increases the respiratoryrate
and causes respiratory alkalosis.
• Decrease in alveolar Pco2 causes a corresponding
increase in alveolar Po2, which slightly increases the
arterial Po2.
GERM CELL TUMORS 1
In the 15- to 34-year age group, testicular germ cell tumors
constitute the most common tumor of men and cause
approximately 10% of all cancer deaths.
- Risk Factors:
 Environmental factors – Play a role in testicular germ
cell tumors. Associated with a spectrum of disorders
collectively known as testicular dysgenesis
-Respiratory alkalosis increases glycolysis by activating
phosphofructokinase (PFK), the rate-limiting reaction
of glycolysis.
• Results in an increased synthesis of 2,3-
bisphosphoglycerate (2,3-BPG), which shifts the O2-
binding curve (OBC) to the right, causing increased
delivery of oxygen to tissue
-Acute mountain sickness (AMS) Usually occurs at
elevations >8000 feet (>2440 m)
Clinical findings: Headache (most common), Fatigue,
dizziness, anorexia, nausea, insomnia
-High altitude pulmonary edema (HAPE)More
common above 14,500 feet (4420 m). Clinical
findings: Noncardiogenic pulmonary edema with
increased protein (exudate)
-Acute cerebral edema, or high altitude cerebral
edema (HACE). More common above 12,000 feet
(3658 m). Clinical findings:ataxia, stupor, coma
-Common treatment: immediate descent
III. Radiation Injury
A. Ionizing radiation injury
-Most radiosensitive tissues (highest mitotic activity)
include:
(1) Lymphoid tissue (most sensitive)
(2) Bone marrow
(3) Mucosa of the gastrointestinal tract and germinal
tissue
-Cancers caused by radiation
a. Acute leukemia (most common; refer to Chapter
13)
b. Papillary carcinoma of the thyroid (refer to Chapter
23)
c. Osteogenic sarcoma
B. Nonionizing radiation injury
-Ultraviolet light B (UVB) is most damaging to the
skin.
-General effects of UVB light injury
(1) Sunburn
(2) Actinic (solar) keratosis - Precursor of SCC
(2%–5% of cases)
(3) Corneal burns from skiing
-Cancers associated with UVB light injury
(1) Basal cell carcinoma (BCC; most common)
(2) SCC
(3) Malignant melanoma
syndrome(TDS). Components of this syndrome
include cryptorchidism, hypospadias, and poor sperm
quality.
 Genetic factors – there is a strong familial
predisposition associated with the development of
testicular germ cell tumors. The relative risk of these
tumors is four times higher than normal in fathers
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and sons of affected patients and is 8 to 10 times
higher in brothers.
Classification:
Seminomatous tumors – are composed of cells that resemble
primordial or early gonocytes
Nonseminomatous tumors – may be composed of
undifferentiated cells that resemble embryonic stem cells, as
in the case of embryonal carcinoma, but the malignant cells
may also differentiate along other lineages, generating yolk sac
tumors, choriocarcinomas and teratomas.
Seminomas – are the most common type of germ cell tumor,
making up about 50% of these tumors. Peak incidence at 3rd
decade of life and never occur in infants.
- Identical tumor arises in the ovary, where it is called
dysgerminoma (Chapter 22). Seminomascontain
isochromosome 12p and express OCT3/4 and NANOG.
Approximately 25% of thesetumors have KIT activating
mutations.
- Gx: bulky mass, ten times the size of normal testis. Has
homogenous, gray-white, lobulated cut surface devoid of
hemorrhage or necrosis. Tunica albuginea is not
penetrated.
- Mx: sheets of uniform cells divided into poorly
demarcated lobules. Cells are large and round to
polyhedral and has distinct cell membrane clear or
watery-appearing cytoplasm; and a large, central nucleus
with one or two prominent nucleoli.
Spermatocytic Seminoma –rare, slow-growing germ cell tumor
predominantly affecting older men. Because it is a slow-
growing tumor that does not produce metastases, the
prognosis is excellent.
- Gx:soft, pale gray, cut surface that sometimes reveal
mucoid cysts.
- Mx: Spermatocytic seminomas contain three cell
populations, all intermixed: (1) medium-sized cells, the
most numerous, containing a round nucleus and
eosinophilic cytoplasm; (2) smaller cells with a narrow rim
of eosinophilic cytoplasm resembling secondary
spermatocytes; and (3) scattered giant cells, either
uninucleate or multinucleate.Chromatin in some
intermediate-sized cells is similar to that seen in the
meiotic phase of nonneoplastic spermatocytes (spireme
chromatin).
Embryonal carcinomas– occur mostly in the 20 to 30-year age
group. These tumors are more aggressive than seminomas.
- Smaller than seminoma and do not replace the entire
testis. Histologically the cells grow in alveolar or tubular
patterns, sometimes with papillary convolutions. More
undifferentiated lesions may display sheets of cells.
Yolk Sac Tumor– also known as endodermal sinus tumor, yolk
sac tumor is ofinterest because it is the most common
testicular tumor ininfants and children up to 3 years of age. In
this age group,it has a very good prognosis.
- Nonencapsulated and have a homogeneous, yellow-white,
mucinous appearance.
- Composed of a lacelike (reticular) network of medium-
sized cuboidal or flattened cells. In addition, papillary
structures, solid cords of cells, and a multitude of other
less common patterns may be found. In approximately
50% of tumors, structures resembling endodermal sinuses
(Schiller-Duval bodies) may be seen.
Choriocarcinoma– isa highly malignant form of
testiculartumor. In its “pure” form, choriocarcinoma is rare,
constituting less than 1% of all germ cell tumors.
- No testicular enlargement and are detected only as a
small palpable nodule. Typically,these tumors are small,
rarely larger than 5 cm in diameter. Hemorrhage and
necrosis are extremely common.
Teratoma– refers to testicular tumors havingvarious cellular or
organoid components reminiscent of thenormal derivatives of
more than one germ layer. They mayoccur at any age from
infancy to adult life.
- Are usually large, ranging from 5 to 10 cm in diameter.
Because they are composed of various tissues, the gross
appearance is heterogeneous with solid, sometimes
cartilaginous, and cystic areas.
- Composed of a heterogeneous, helter-skelter collection of
differentiated cells or organoid structures, such as neural
tissue, muscle bundles, islands of cartilage, clusters of
squamous epithelium, structures reminiscent of thyroid
gland, bronchial or bronchiolar epithelium, and bits of
intestinal wall or brain substance, all embedded in a
fibrous or myxoid stroma.
Sertoli Cell Tumors– most Sertoli cell tumors are hormonally
silent and presentas a testicular mass. These neoplasms
appear as firm, smallnodules with a homogeneous gray-white
to yellow cutsurface. Histologically the tumor cells are
arranged in distinctivetrabeculae that tend to form cordlike
structuresand tubules. Most sertoli cell tumors are benign,
butapproximately 10% pursue a malignant course.
Gonadoblastoma– are rare neoplasms comprised of amixture
of germ cells and gonadal stromal elementsthat usually arise in
gonads with some form of testiculardysgenesis (discussed
earlier). In some cases, thegerm cell component becomes
malignant, giving rise toseminoma.
Testicular Lymphoma– aggressive non–Hodgkin lymphomas
account for 5% oftesticular neoplasms, and are the most
common form oftesticular neoplasms in men older than age 60
years.Although an uncommon tumor of the testis, testicular
lymphomais included here because affected patients
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maypresent with only a testicular mass, mimicking other,
morecommon, testicular tumors.
Germ Cell Tumor (Female)
- 15-20% of all ovarian cancer
Teratomas
A. Mature (Benign) Teratoma
- Most are cystic; aka Dermoid cyst
- Almost always lined by skin structures
- In young women of active reproductive years
- Gx:
 Bilateral in 10-15%; unilocular cyst containing hair
and sebaceous material
 Common to find tooth structure and areas of Ca2
- Mx:
 Thin walled, lined by epidermis with hair follicles,
sebaceous glands, and other skin adnexal elements
 Structures originating from other germ cell layers
(cartilage, bone, thyroid, neural tissue)
 1% undergo malignant transformation;mc: SQCA,
others are thyroid CA and ,melanoma
B. Monodermal or Specialized Teratoma
- Rare grp of tumors
- Mc: Struma ovarii and Carcinoid; usually unilateral
- Straumaovarii – composed entirely of mature thyroid
tissue; may be functionalhyperthyroidism
- Ovarian carcinoid – may arise from intestinal tissue; may
be functional (>7cm)produce 5-
hydroxytryptamine;metastatic intestinal carcinoid usually
bilateral
C. Immature Malignant Teratomas
- Rare tumors; embryonal or immature fetal tissue
- Found in prepubertal adolescent and young women; mean
age: 18 y/o
- Gx: bulky tumor; still see components of the mature
counterpart
- Mx:
 immature neuroepithelium, cartilage, bone, muscle
and other element
 Grow rapidly; penetrate capsule local or distant
spread
 Good prognosis
Dysgerminoma
- 2% of ovarian CA’s; 50% of malignant germ cell tumors
- Female counterpart of testicular seminoma
GI TUMOR 1
Gastric Polyp - developas a result of epithelial or stromal cell
hyperplasia, inflammation, ectopia, or neoplasia
- May occur in childhood; 75% in 20-30 y/o
- NO endocrine function
- Expresses OCT3, OCT4 and NANOG (transcription factors);
KIT gene mutations
- Gx: 80-90% unilateral tumor: barely visible nodules to
masses filling virtually entire body
 Solid yellow-white to gray pink surface
 Often soft and fleshy appearance
- Mx: composed of large vesicular cells with clear cytoplasm
and centrally placed nuclei
 Tc: grow in sheet and cords separated by scant
fibrous stroma (infiltrated by mature lymphocyte)
 All are malignant tumors; only 1/3 is aggressive
 96% cure rate when limited to ovary; highly
responsive to chemotherapy even for tumors
extending beyond ovary; overall survival is high (80%)
Yolk Sac Tumor
- Aka Endodermal Sinus Tumor
- 2nd mc malignant tumor and germ cell origin
- Derived from malignant germ cell differentiating along the
extraembryonic yolk sac lineage
- Elaborate α-fetoprotein
- Characteristic feature:glomerulus-like structure
composed of a central by enveloped by tc within a space
also lined by tumor cells
 IC and EC hyaline drop[lets are seen; stained positive
for α-fetoprotein by peroxidase
 Mostly in children and young women; abdominal pain
and rapidly growing pelvic mass; unilateral
- Tx: surgery + chemotherapy (80% SR)
Choriocarcinoma
- Similar to yolk sac tumor; extraembryonic differentiation
of malignant germ cell
- Usually in associated with other germ cell tumors; pure
chorioCA is extremely rare
- Aggressive; hematogenous spread- lung, liver, bone and
other site (at the time of Dx)
- Secrete inc levels of BHCG
- Unresponsive to chemomtx thus fatal
Other Germ Cell Tumors
- Embryonal CA – highly malignant
- Polyembryoma – embryomoid bodies
- Mixed Germ Cell Tumors
Inflammatory and Hyperplastic Polyp
- 75% of all gastric polyp
- Chronic gastritis initiates injury and reactive hyperplasia
causes growth
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- if associated with H. pylori gastritis, polyps may regress
after bacterial eradication
- Mx: polyp frequently are multiple; ovoid in shape; less
than 1cm; covered by smooth surface
 Polyp have irregular, cystically dilated, and elongated
foveolar glands; lamina propria edematous; variable
degrees of acute and chronic inflame; and surface
erosion may be present
 Hyperplastic polyp Mx: marked foveolar hyperplasia,
myxoidstroma with dilated tortuous glands, larger
polyp prominent erosion covered with fibrino-
purulent material, and often areas of edematous
stroma and oddly shaped glands
Fundic Gland Polyp
- Occur in persons with Familial Adenomatous Polyposis
(FAP) with APC gene mutation
- Pathogenesis:
Use of PPI’s→Reduced acidity→ increased gastrin
secretion glandular hyperplasia
 Ssx:fundic gland polyp may be asymptomatic or
associated with nausea and vomiting or epigastric
pain
 Mx: often are multiple and composed of cystically
dilated, irregular glands lined by flattened parietal cell
and chief cells.
Gastric Adenoma
- 10% of all gastric polyps; usually 50-60 y/o; males 3x >
females
- Almost always occur on a background of chronic gastritis
with atrophy and intestinal metaplasia
- Risk for development of adenocarcinoma elevated with
lesions > 2 cm
- Mx:
 Most commonly located in the antrum, typically
composed of intestinal-type columnar epithelium.
 All exhibit epithelial dysplasia (low or high grade)
 Both grades = enlargement, elongation,
hyperchromasia of epithelial cell nuclei, epithelial
crowding and pseudostratification; villous/tubular or
both.
 High grade dysplasia is characterized by more severe
cytologic atypia and irregular architecture, including
glandular budding and gland-within-gland, or
cribriform structures.
Gastric Adenocarcinoma
- Most common type (>90% of all gastric cancers)
- The cancer is often at advanced stages when clinical
manifestations (weight loss, anorexia, altered bowel
habits, anemia, and hemorrhage trigger diagnostic
evaluation)
- Risk factors:
 H. pylori induced – most common etiologic agent
 Tobacco use and excessive alcohol consumption
 Condition with multifocal mucosal atrophy and
intestinal metaplasia
 EBV infection = 10% of gastric adenocarcinoma
 Obesity
 Familial gastric cancer = mutations in CDH1 gene
 Mutations in APC genes
 Partial gastrectomies for PUD leads to slightly higher
risk of developing cancer in the residual gastric stump
as a result of hypochloridia, bile reflux, and chronic
gastritis
- Mx: roughly linear, longitudinally oriented, superficial
tear/laceration
 Range in length from mm to cm
 Usually across the gastro-esophageal junction
- Tx: do not generally require surgical intervention; healing
tends to be rapid and complete
- Boerhaave syndrome – repeated episodes of severe
retching and vomiting, typically in a middle-aged man with
recent excessive dietary and alcohol intake.
 Characterized by transmural esophageal rupture, and
mediastinitis (communication between the esophagus
and the pleural cavity)
Barrett Esophagus
- Complication of chronic GERD (10%)
- Characterized by gastric or intestinal metaplasia within
the normal esophageal squamous mucosa
- Greatest concern: increased risk of esophageal
adenocarcinoma (0.2-1.0%); incidence increases with
duration of symptons
- Mx: residual smooth, normal pale squamous (esophageal)
mucosa proximally, interfaces with tongues or patches of
metaplastic red to light brown, velvety, columnar mucosa
extending upward from the gastroesophageal junction
- Genetic mutational changes and inflammation –
contribute to neoplastic progression
- Dx: endoscopy and biopsy
- SSx: usually propted by GERD symptoms
- Tx options:
 Surgical resection (esophagectomy)
 Photodynamic therapy (photosensitizing drugs + light
to kill cancer cells)
 Laser ablation
 Endoscopic mucosectomy
Esophageal Tumors
- Adenocarcinoma (mostly distal in location)
- Squamous cell carcinoma (more common; middle 3rd of
esophagus)
- SSX: pain or difficulty in swallowing, progressive weight
loss, chest pain, or vomiting.
- Adenocarcinoma – arises in background of long-standing
GERD and Barrett esophagus with dysplasia
 Risk of adenocarcinoma is increased by tobacco use,
obesity, and previous radiation therapy.
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 Conversely, reduced adenocarcinoma risk is
associated with diets rich in fresh fruits and
vegetables
- Squamous cell carcinoma
 Risk factors:
 Alcohol and tobacco use
 Caustic injury
 Achalasia
 Middle 3rd – mediastinal, paratracheal,
tracheobronchial LN
STOMACH
Gastric Primary Lymphoma
- Common in stomach; nearly 5% of all gastric malignancies
- Most common: extranodal marginal zone b cell
lymphomas (MALTomas)
- Diffuse large B cell lymphoma – 2nd most common
Carcinoid Tumor
- Arise from neuroendocrine organs
- Majority are found in GI tract, and >40% occur in the small
intestine. The tracheobronchial tree and lungs are the
next most commonly affected
- Gastric carcinoids: associated with endocrine cell
hyperplasia, chronic atrophic gastritis, and Zollinger-
Ellison syndrome.
 Most current WHO classification describes tumor
grades basing on mitotic activity and fraction of cells
immunohistochemically positive for Ki67, a mitotic
marker
 High grade neuroendocrine tumors (neuroendocrine
carcinoma) frequently display necrosis and most
common in jejunum.
 Mx: often form a submucosal nodule composed of
tumor cells embedded in dense fibrous tissue.
 Chromatin texture, with fine and coarse
clumps (“salt and pepper” pattern)
 SSx: carcinoid syndrome caused by vasoactive
substances (serotonin &kallikrein) secreted by the
tumor:
 Cutaneous flushing
 Sweating
 Bronchospasm
 Colicky abdominal pain
 Diarrhea
 Right sided cardiac valvular fibrosis
 Px: the most important prognostic factor for GI
carcinoid tumors is location
 Plummer-Vinson syndrome
 Frequent consumption of hot beverages
 Radiation therapy to the mediastinum
 Nutritional deficiencies
 Mutagenic compounds
 HPV 16 infection
 Sites of metastases:
 Upper 3rd of esophagus favor cervical LN
 Lower 3rd – gastric and celiac LN
 Foregut carcinoid tumor: rarely
metastasize and generally cured by
resection
 Midgut carcinoid tumor: arise in
jejunum and ileum often are multiple
and tend to be aggressive
 Hindgut carcinoids (appendix and
colorectum): incidental
 Rectal carcinoid tumors: produce
polypeptide hormones and may
manifest with abdominal pain and
weight loss; only occasionally
metastasize.
Gastrointestinal Stromal Tumor
- Most common mesenchymal tumor of the abdomen and
>50% occur in the stomach
- Pathogenesis:
 75-80% have oncogenic, gain-of-function mutations
of the gene encoding the tyrosine kinase c-KIT, which
is the receptor for stem cell factor
 GISTs arise from the interstitial cells of Cajal in the
muscularispropria, “pacemaker cells” for gut
peristalsis
- Mx:
 Solitary, well-circumscribed, fleshy, submucosal mass
 Metastases: multiple nodules in the liver; spread
outside of the abdomen is uncommon
 GISTs can be composed of thin, elongated spindle
cells or plumper epitheloid cells
 Diagnostic marker is c-KIT (detectable in 95% of these
tumors)
- SSx: related to mass effects or mucosal ulceration
- Px: correlates with tumor size, mitotic index, and location
 Recurrence or metastasis common for mitotically
active tumors larger than 10 cm
- Tx: complete surgical resection for localized gastric GIST.
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Patients with unresectable, recurrent, or metastatic disease

often respond to Imatinib, an inhibitor of the tyrosine kinase
activity of c-KIT, though some are becoming resistant

Colonic Polyps and Neoplastic Disease

Inflammatory Polyps - forms from Solitary Rectal Ulcer Syndrome

- clinical triad of rectal bleeding, mucus discharge, and reactive inflammatory polyp of the anterior
rectal wall

Hamartomatous Polyps - disorganized, tumor-like growths composed of mature cell types normally present at the site at
which the polyp develops

A.Juvenile Polyp - most common type of hamartomatous polyp

- vast majority occur in children younger than 5 years of age
- located in the rectum and most manifest with rectal bleeding
- usually solitary (Syndrome of Juvenile Polyposis 3-100 polyps)
- pedunculated, smooth-surface, reddish lesions <3 cm with cystic spaces on cut sections
- spaces are dilated glands filled with mucin and inflammatory debris

B. Peutz-Jeghers Syndrome - rare autosomal dominant disorder

- multiple gastointestinalhamartomatous polyps and mucocutaneous hyperpigmentation
- Intestinal polyps are most common in the small intestine
-Polyps are large and pedunculated with a lobulated contour
- Histologic: arborizing network of connectiive tissue, smooth muscle, lamina propria, and glands
lined by normal-appearing intestinal epithelium

C. Hyperplastic Polyps
- common epithelial proliferations in sixth and seventh decades of life
- result from decreased epithelial cells turnover and delayed shedding of surface epithelial cells,
leading to a “pileup” of goblet cells.
- smooth, nodular protrusions often on the crests of mucosal folds
- frequently multiple, particularly in the sigmoid colon and rectum
- composed of crowding mature goblet and absorptive cells creating serrated surface architecture
(morphologic hallmark)

Adenoma - colonic adenomas = benign polyps that give rise to a majority of colorectal adenocarcinoma
- range from small, often pedunculated polyps to large sessile lesions
- present in nearly 50% pf adults living in the Western world beginning age 50
- frequently has risen in Asia as Western diets and lifestyles become more common
- classified as (1) tubular, (2) tubulovillous, (3) villous on the basis of their architecture
- Sessile serrated adenomas = serrated architecture present throughout the full length of the glands,
including the crypt base, associated with crypt dilation, and lateral growth

Familial Adenomatous - autosomal dominant disorder in teenage years

Polyposis (FAP) - caused by mutations of the adenomatous polyposis coli (APC) gene
- 100 polyps (necessary) to several thousand polyps may be present
- Tx: Prophylactic colectomy is standard therapy for persons carrying APC mutations

Hereditary Nonpolyposis - also known as Lynch Syndrome

Colorectal Cancer (HNPCC)
- familial clustering of cancers at several sites including the coloretum, endometrium, stomach,
ovary, uterus, brain, small bowel, hepatobiliary tract, and skin
- Colon cancers occur at younger ages and often are located in the right colon
- HNPCC is caused by inherited germ line mutations in MSH2 or MLH1 genes that encode proteins
responsible for the detection, excision, and repair of errors that occur during DNA replication
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Adenocarcinoma - most common type of malignancy of the colon

- By contrast, the small intestine, which accounts for 75% of the overall length of the GI tract, is an
uncommon site for benign and malignant tumors.
Epidemiology: a. Colorectal adenocarcinoma related deaths, second to lung cancer
b. Dietary factors associated with increased colorectal cancer rates are: low intake of
unabsorbable vegetable fiber; high intake of refined carbs, high meat, and fat.
- Some studies show that some NSAIDs cause polyp regression and promote epithelial proliferation,
in response to injury

*Daily Protein Requirement: 2-4 oz of lean meat enogh for a day

*Cellulose fibers: important in normal passage of wastes

SSx: fatigue and weakness (IDA from occult bleeding, changes in bowel habits, or cramping
abdominal discomfort)
Prognostic factors: depth of invasion and the presence or absence of lymph node metastases
- Liver is the most common site of metastatic lesions
- Dukes and Kirklinfrom the core of the TNM (Tumor-node-metastasis) Classification

Mx = Gross: Tumors in large-caliber cecum and ascending colon = polypoid, exophytic masses, and
rarely cause obstruction
- Carcinomas in the distal colon: annular lesions that poduce “napkin ring” constrictions and
luminal narrowing, causing obstruction

Histologic: composed of dysplastic tall columnar epithelial cells in glandular formations

Tumors of Appendix

Carcinoid Tumor - most common tumor of the appendix

- usually discovered incidentally at the time of surgery or on examination of a resected
appendix
- frequently involves the distal tip of the appendix (2 to 3 cm)
- nodal metastases infrequent, distant spread rare

Conventional adenomas or non-

mucin-producing
adenocarcinomas

Mucocele - dilated appendix filled with mucin

- inspissated mucin from an obstructed appendix or a consequence of mucinous
cystadenoma or cystadenocarcinoma
- advanced cases: the abdome fills with tenacious, semi-solid mucin,
“pseudomyxomaperitonei”
- ultimately fatal

Pancreatic Neoplasms

1. Cystic Neoplasms 5-50%

A. Serous Cystadenomas - composed of glycogen-rich cuboidal cells surrounding small cyts containing clear, straw-colored fluid
- seventh decade of life; non-specific abdominal pain; female-to-male ration is 2:1; almsot uniformly
benign
-surgical resection is curative in majority
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B. Mucinous Cystic Neoplasm - 95% in women, usually in body or tail of pancreas

- painless, slow-growing cystic spaces filled with thick, tenacious mucin, lined by columnar mucinous
epithelium, stroma resembling that of the ovary
- low-grade, moderate, or severe dysplasia; one-third associated with an invasive adenocarcinoma
- Distal pancreatectomy for nonivasive cysts typically is curative.

C. Intraductal Papillary Mucinous - mucin-producing intraductal neoplasms

Neoplasms (IPMNs)
- more frequently in men than in women
- more frequently involve the head of the pancreas
- arise in the main pancreatic ducts, or one of major branch ducts
- lack the cellular stroma seen in mucinous cystic neoplasms
- also harbor various grades of dysplasia
- 2/3 harbor oncogenic mutations associated with invasive adenoCA

D. Pancreatic Carcinoma - Infiltrating Ductal AdenoCA of the pancreas

- 4th leading cause of CA death in US
- it carries one of the highest mortality rates

Pathogenesis
- The strongest environmental influence = smoking, which doubes the risk
- Chronic pancreatitis now considered an enabler of malignancy
- 60% of pancreatic head; 15% of body; 5% tails; 20% diffuse

Two characteristic features:

1.highly early invasiveness = peripancreatic tissues extensively
2.elicits an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and
extracellular matrix (desmoplastic response) = obstructs the bile duct

50% of cases = jaundice

Carcinomas of body anf tail remain silent for some time.
Distant metastases = liver, lungs, and bones

Mx
- hard, gray-white, stellate, poorly defined masses ductal adenoCA secreting mucin
- abortive tubular structures or cell clusters and exhibiting an aggressive, deeply infiltrative growth
pattern
- dense stromal fibrosis accompanies tumor invasion
- perineural and lymphatic invasion within and beyond the organ

SSx
- pain + obstructive jaundice
- weight loss, anorexia, and generalized malaise and weakness
- migratory thrombophlebitis (Trousseau syndrome) 10% of patients, attributablle to the elaboration
of platelet-aggregating factor and pro-coagulants from the tumor or its necrotic products

The clinical course of pancreatic CA is rapidly progressive and distressingly brief.

Tumor markers (Serum Carcinoembryonic and CA19-9antigens) elevated

GOOD PASTURE SYNDROME 1

Goodpasture syndrome is an uncommon autoimmune disease
in which kidney and lung injury are caused by circulating
autoantibodies againstthe noncollagenous domain of the α3
chain of collagen IV. Whenonly renal disease is caused by
thisantibody, it is called antiglomerular basementmembrane
disease.Goodpasture syndrome designates the 40% to 60% of
patients who develop pulmonary hemorrhage in addition to
renal disease. The antibodies initiate inflammatory destruction
of thebasement membrane in renal glomeruli and pulmonary
alveoli,givingrisetorapidlyprogressiveglomerulonephritis
andnecrotizing hemorrhagic interstitial pneumonitis
Pathogenesis:
I. Production of antibodies against basement
membrane (anti-GBM antibodies), which result in
damage of the lunes and the kidney.
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II. Goodpasture antigen is the noncollagenous
component of type IV collagen.
Morphology:
 Lungs are heavy, with areas of red-brown
consolidation.
 Focal necrosis of alveolar walls associatedwithintra-
alveolarhemorrhages often containhemosiderin-laden
macrophages.
 Fibrous thickening of the septae, hypertrophy of
type II pneumocytes, and organization of blood in
alveolar spaces.
 Immunofluorescence: diagnostic linear deposits of
immunoglobulins (IgG) and complement (C3) are
GUILLAINE BARRE SYNDROME 2
• Guillain-Barré Syndrome (Acute Inflammatory
Demyelinating Polyneuropathy)is ademyelinating
peripheral neuropathy that maylead to life-
threatening respiratory paralysis.The disease is
characterized clinically by weakness beginning in the
distal limbs that rapidly advances to affect proximal
muscle function(“ascending paralysis”). Histologic
features are inflammation and demyelination of
spinal nerve roots and peripheral nerves
(radiculoneuropathy). It is considered the most
common acute peripheral neuropathy and most
common cause of flaccid paralysis.
Pathogenesis:
I. Most cases, is thought to be an acute-onset immune-
mediated demyelinating neuropathy.
II. 2/3 of cases are preceded by an acute, influenza-like
illness
III. Common preceeding infections: Campylobacter
jejuni, Cytomegalovirus, Epstein-Barr virus, and
Mycoplasma pneumoniae, or prior vaccination, have
significant epidemiologic associations with Guillain-
Barré syndrome
IV. There is an autoimmune attack on myelin of the
peripheral sensory & motor nervespredominantly
mediated by lymphocytes or macrophages
V. Cytoplasmic processes of macrophages penetrate the
basement membrane of Schwann cells & extend
between the myelin lamellae
VI. Myelin sheath is stripped away from the axon
Morphology:
HEMATOLOGIC EXAMINATIONS 1
Complete Blood Count (CBC)
The CBC is a basic screening test and is one of the most
frequently ordered laboratory procedures. The findings in the
seen by immunofluorescence studies along the
glomerular basement membranes
Clinical Features:
 Males > Females
Majority are active smokers
 Peak incidence: Ages 20-40
 Pulmonary involvement typically precedes the renal
disease
 Presents with pulmonary hemorrhage and recurrent
hemoptysis
 Most develop Rapidly Progressive Glomerulonephritis
 The most common cause of death is uremia.
 The dominant histopathologic finding is inflammation
of peripheral nervesmanifested as perivenular
and endoneurial infiltration by lymphocytes,
macrophages, and a few plasma cells.
 Segmental demyelination affecting peripheral
nerves is the most prominent lesion.
Clinical Features:
 Dominated by ascending paralysis and areflexia.
 Deep tendon reflexes disappear early in the process
 Nerve conduction velocities are slowed because of
multifocal destruction of myelin segment in many
axons within a nerve.
 Cerebrospinal fluid (CSF) protein levels are elevated
due to inflammation and altered permeability of the
micro circulation within the spinal roots as they
traverse thesubarachnoid space
Diagnosis:
 Lumbar puncture
 Electromyography (EMG) or nerve conduction study
(NC)
Treatments:
 Plasmapheresis
 to filter antibodies out of the blood
system
 IV immunoglobulin (IVIG)
 to neutralize antibodies
 Mechanical ventilation
CBC give valuable diagnostic information about the
hematologic and other body systems, prognosis, response to
treatment, and recovery. The CBC consists of a series of tests
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that determine number, variety, percentage, concentrations,
and quality of blood cells:
1. White blood cell count (WBC): leukocytes fight infection
2. Differential white blood cell count (Diff): specific
patterns of WBC
3. Red blood cell count (RBC): red blood cells carry O 2
from lungs to blood tissues and CO 2 from tissue to
lungs
4. Hematocrit (Hct): measures RBC mass
5. Hemoglobin (Hb): main component of RBCs and
transports O 2 and CO 2
6. Red blood cell indices: calculated values of size and Hb
content of RBCs; important in anemia evaluations
7. Mean corpuscular volume (MCV)
8. Mean corpuscular hemoglobin concentration (MCHC)
9. Mean corpuscular hemoglobin (MCH)
10. Stained red cell examination (film or peripheral blood
smear)
11. Platelet count (often included in CBC): thrombocytes
are necessary for clotting and control of bleeding
12. Red blood cell distribution width (RDW): indicates
degree variability and abnormal cell size
13. Mean platelet volume (MPV): index of platelet
production
*Note: Each of these tests in the CBC will be discussed in the
later sections of this Pathology review material (in the Red
blood cell tests)
Additional Tests:
1. Reticulocyte Count
A reticulocyte —young, immature, nonnucleated
RBC—contains reticular material (RNA) that stainsgray-blue.
Reticulum is present in newly released blood cells for 1 to 2
days before the cell reachesits full mature state. Normally, a
small number of these cells are found in circulating blood.
For thereticulocyte count to be meaningful, it must be
viewed in relation to the total number of
erythrocytes(absolute reticulocyte count =% reticulocytes x
erythrocyte count).The reticulocyte count is used to
differentiate anemias caused by bone marrow failure
fromthose caused by hemorrhage or hemolysis (destruction
of RBCs), to check the effectiveness oftreatment in
pernicious anemia and folate and iron deficiency, to assess
the recovery of bonemarrow function in aplastic anemia,
and to determine the effects of radioactive substances
onexposed workers.
Normal
Adults: 0.5%–1.5% of total erythrocytes (women may be
slightly higher)
Newborns: 3%–6% of total erythrocytes (drops to adult levels
in 1–2 months)
Clinical Implications
A. Increased reticulocyte count (reticulocytosis) means that
increased RBC production is occurring as the bone
marrow replaces cells lost or prematurely destroyed.
Identification of reticulocytosismay lead to the
recognition of an otherwise occult disease, such as
hidden chronic hemorrhage or unrecognized hemolysis
(e.g., sickle cell anemia, thalassemia). Increased levels
are observed in the following:
a. Hemolytic anemia
i. Immune hemolytic anemia
ii. Primary RBC membrane problems
iii. Hemoglobinopathic and sickle cell disease
iv. RBC enzyme deficits
v. Malaria
b. After hemorrhage (3 to 4 days)
c. After treatment of anemias
i. An increased reticulocyte count may be
used as an index of the effectiveness of
treatment.
ii. After adequate doses of iron in iron-
deficiency anemia, the rise in reticulocytes
may exceed 20%.
iii. There is a proportional increase when
pernicious anemia is treated by
transfusion or
iv. vitamin B 12 therapy.
B. Decreased reticulocyte count means that bone
marrow is not producing enough erythrocytes;
thisoccurs in:
o Untreated iron-deficiency anemia
o Aplastic anemia (a persistent deficiency of
reticulocytes suggests a poor prognosis)
o Untreated pernicious anemia
o Anemia of chronic disease
o Radiation therapy
o Endocrine problems
o Tumor in marrow (bone marrow failure)
o Myelodysplastic syndromes
o Alcoholism
2. Erythrocyte Sedimentation Rate
The erythrocyte sedimentation rate (ESR) is ordered
with othertests to detect and monitor the course of
inflammatory conditionssuch as, rheumatoid arthritis,
infections, or certain malignancies.It is also useful in the
diagnosis of temporal arteritisand polymyalgia
rheumatica.15 The ESR, however, is not a specifictest for
inflammatory diseases and is elevated in manyother
conditions such as plasma cell myeloma,
pregnancy,anemia, and older age. It is also prone to
technical errors thatcan falsely elevate or decrease the
sedimentation rate. Becauseof its low specificity and
sensitivity, the ESR is not recommendedas a screening test
to detect inflammatory conditionsin asymptomatic
individuals.15 Other tests for inflammation,such as the C-
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reactive protein level, may be a more predictableand
reliable alternative to monitor inflammation.
Normal
Men: 0–15 mm/hr (over age 50 years: 0–20 mm/hr)
Women: 0–20 mm/hr (over age 50 years: 0–30 mm/hr)
Newborn: 0–2 mm/hr
Children: 0–10 mm/hr
3. Iron (Fe), Total Iron-Binding Capacity (TIBC),and
Transferrin Tests
Iron is necessary for the production of Hb. Iron is
contained in several components. Transferrin(also called
siderophilin), a transport protein largely synthesized by the
liver, regulates ironabsorption. High levels of transferrin
relate to the ability of the body to deal with infections.
Totaliron-binding capacity (TIBC) correlates with serum
transferrin, but the relation is not linear. Aserum iron test
without a TIBC and transferrin determination has very
limited value except incases of iron poisoning. Transferrin
saturation is a better index of iron saturation; it is
evaluatedas follows:
Transferrin saturation % =(Serum iron x 100)
TIBC
The combined results of transferrin, iron, and TIBC tests
are helpful in the differential diagnosisof anemia, in
assessment of iron-deficiency anemia, and in the
evaluation of thalassemia, sideroblasticanemia, and
hemochromatosis
4. Bleeding Time (Ivy Method; Template Bleeding Time)
Bleeding time measures the primary phase of hemostasis:
the interaction of the platelet with the blood vessel wall and
the formation of a hemostatic plug. Bleeding time is the best
single screening test for platelet function disorders and is one
of the primary screening tests for coagulation disorders. This
test is of value in detecting vascular abnormalities and platelet
abnormalities or deficiencies. It is not recommendedfor
routine presurgical workup. A small stab wound is made in
either the earlobe or the forearm; the bleeding time (the
amount of time it takes to form a clot) is recorded. The
duration of bleeding from a punctured capillary depends on
the quantity and quality of platelets and the ability of the
blood vessel wall to constrict. The principal use of this test
today is in the diagnosis of von Willebrand’s disease, an
inherited defective molecule of factor VIII and a type of
pseudohemophilia. It has been established that aspirin may
cause abnormal bleeding in some normal persons, but the
bleeding time test has not proved consistently valuable in
identifying such persons.
Reference Values
Normal
3–10 minutes in most laboratories
Duke method (earlobe): 5 minutes (not recommended—not
very reproducible with a wide range of
normal values)
Ivy method (forearm with template): 25–90 minutes
Mielke’s method (Surgicut):
Adults: 1–7 minutes
Teens: 3.0–8 minutes
Children: 2.5–13 minutes
Clinical Implications
1) Bleeding time is prolonged when the level of platelets
is decreased or when platelets are
qualitativelyabnormal:
o Thrombocytopenia (platelet count _ 80 _ 10
3 /mm 3 )
o Platelet dysfunction syndromes
o Decrease or abnormality in plasma factors
(e.g., von Willebrand’s factor, fibrinogen)
o Abnormalities in the walls of the small blood
vessels, vascular disease
o Advanced renal failure
o Severe liver disease
o Leukemia, other myeloproliferative diseases
o Scurvy
o DIC disease (owing to the presence of FDPs)
2) In von Willebrand’s disease, bleeding time can be
variable; it will definitely be prolonged if aspirin is
taken before testing (aspirin tolerance test).
3) A single prolonged bleeding time does not prove the
existence of hemorrhagic disease. Because a larger
vessel can be punctured, the puncture should be
repeated on an alternate body site, and the two
values obtained should be averaged.
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4) Bleeding time is normal in the presence of
coagulation disorders other than platelet dysfunction,
vascular disease, or von Willebrand’s disease.
5) Aspirin therapy (antiplatelet function therapy): when
thrombus formation is thought to be mediatedby
platelet activation, the patient frequently is given
agents to interrupt normal platelet function, which
may be monitored by bleeding times or platelet
HEMOLYTIC UREMIC SYNDROME 1
 The term thrombotic microangiopathyencompasses a
spectrum of clinical syndromes that includes thrombotic
thrombocytopenic purpura (TTP) and hemolytic-uremic
syndrome (HUS).
 HUS and TTP are caused by diverse insults that lead to the
excessive activation of platelets, which deposit as thrombi
in capillaries and arterioles in various tissue beds, including
those of the kidney
 Widespread “consumption” of platelets leads to
thrombocytopenia, and the resulting thrombi create flow
abnormalities that shear red cells, producing a
microangiopathic hemolytic anemia. Of even greater
aggregation studies. Aspirin is the most commonly
used inhibitor; it inhibits platelet adhesion or
“stickiness.”
Sources:
a. Rodak’s Hematology
b. A Manual of Laboratory and Diagnostic Tests by
Fischbach and Dunning
importance, the thrombi produce microvascular occlusions
that cause tissue ischemia and organ dysfunction.
Classifications:
1. Typical HUS (synonyms: epidemic, classic, diarrhea-
positive)
 can occur at any age, but children and older adults
are at highest risk
 Most cases occur following intestinal infection with
strains of E. coli (the most common being O157:H7)
that produce Shiga-like toxins, so-called because
they resemble those made by Shigelladysenteriae,
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 Less commonly caused by other agents like
Shigelladysenteriae
 Epidemics have been traced to various sources, most
commonly the ingestion of contaminated ground
meat (as in hamburgers), but also drinking water,
raw milk, and person-to-person transmission.
 Following a prodrome of influenza-like or diarrheal
symptoms, there is a sudden onset of bleeding
manifestations (especially hematemesis and
melena), severe oliguria, and hematuria, associated
with microangiopathic hemolytic anemia,
thrombocytopenia, and (in some patients)
prominent neurologic changes.
 Hypertension is present in about half the patients.
2. Atypical HUS (synonyms: non-epidemic, diarrhea-
negative), associated with:
 Occurs mainly in adults except for patients with
genetic mutations in complement regulatory
proteins who develop HUS at any age
 Inherited mutations of complement-regulatory
proteins, most commonly Factor H, which breaks
down the alternative pathway C3 convertase and
protects cells from damage by uncontrolled
complement activation
 A small number of patients have mutations in two
other proteins that regulate complement,
HEPATIC TUMORS 1
Malignant:
1. HCC-most common hepatic carcinoma
- male preponderance 3:1 compared to female
- common tumor in Asia and Africa
- main cause: chronic hepa B and C,alcoholic
cirrhosis,nonalcoholic fatty liver dse,hemochromatosis
- in western pop (90%) from cirrhotic liver and from
hepatitis C epidemic
complement Factor I and CD46 (membrane cofactor
protein)
 Diverse acquired causes of endothelial injury,
including: antiphospholipid antibodies;
complications of pregnancy and oral contraceptives;
vascular renal diseases such as scleroderma and
hypertension; chemotherapeutic and
immunosuppressive drugs; and radiation
 Roughly half of affected individuals have a course
marked by multiple relapses and progression to end-
stage renal disease.
The remaining cases of atypical HUS arise in association with a
variety of miscellaneous conditions or exposures. These
include:
• The antiphospholipid syndrome, either primary or
secondary to SLE (lupus anticoagulant)
• Complications of pregnancy or the postpartum period,
so-called postpartum renal failure is a form of HUS that
usually occurs after an uneventful pregnancy, 1 day to
several months after delivery. The condition has a grave
prognosis, although recovery can occur in milder cases.
• Vascular diseases affecting the kidney, such as systemic
sclerosis and malignant hypertension.
• Chemotherapeutic and immunosuppressive drugs, such
as mitomycin, cyclosporine, cisplatin, gemcitabine, and
antagonists of VEGF.
• Irradiation of the kidney.
- in Asia (50%) from non-cirrhotic, usually through HBV
transmitted vertically
- chronic inflam is caused by viral hepa,activation of IL-
6/jak stat pathway
- unifocal/mutifocal/ diffusely infiltrative,tend to invade
blood vessels
- tx: surgery or ablation with good outcomes
2. cholangiocarcinoma-second m.c. primary malignant
tumor after HCC
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- malignancy of biliary tree arising from bile ducts
within and outside the liver
- endemic in areas where liver flukes such as
opistorchis and clonorchis are endemic
- chronic inflam dses of bile ducts are also risk factors
- may arise from extrahepatic forms including perihilar
Klatskin tumor (50-60%), distal tumors from
common bile duct (20-30%)or intrahepatic bile ducts
(10%)
- uniformly poor prognosis if intrahepatic due to late
detection
HEREDITARY SPHEROCYTOSIS 1
Hereditary spherocytosis
- inherited disorder caused by intrinsic defects in rbc
membrane skeleton that render red cells
spheroid,less deformable and vulnerable to splenic
sequestration and destruction
- prevalence is highest in northern Europe
- caused by diverse mutation that lead to insufficiency
of membrane skeletal components (usually
ankyrin,band3,spectrin or band 4.2)
- lifespan of affected rbc decreases from normal 120
days to 10-20days
Pathophysiology: primary membrane skeletal defect>
decrease membrane stability>membrane loss> decrease
HYPERPARATHYROIDISM 1
• Primary hyperparathyroidism: an autonomous
overproduction of parathyroid hormone (PTH), usually
resulting from an adenoma or hyperplasia of parathyroid
tissue
• Secondary hyperparathyroidism: compensatory
hypersecretion of PTH in response to prolonged hypocalcemia,
most commonly from chronic renal failure
• Tertiary hyperparathyroidism: persistent hypersecretion of
PTH even after the cause of prolonged hypocalcemia is
corrected, for example after renal transplant
Primary hyperparathyroidism is one of the most common
endocrine disorders, and it is an important cause of
hypercalcemia. The frequency of the various
parathyroidlesions underlying the hyperfunction is as follows:
• Adenoma: 85% to 95%
• Primary hyperplasia (diffuse or nodular): 5% to 10%
• Parathyroid carcinoma: ~1%
Primary hyperparathyroidism is usually a disease of adults and
is more common in women than in men by a ratio of nearly
4:1.
3. hepatoblastoma-most common tumor of early
childhood
- rarely occur over the age of 3yrs.
- due to activation of WNT signalling pathway
- assoc with familial adenomatos
polyposis,beckwith-wiedemann syndrome
tx: surgery,chemo
Metastasis: involvement of the liver by metastatic malignancy
is far more common than primary hepatic neoplasia.
surface to volume ratio (spherocytosis) and decrease
deformability>splenic trapping>erythrostasis (decrease
glucose and ph)> phagocytosis and extravascular hemolysis
Morphology:spherocytosis (small,dark-
staining/hyperchromicrbc lacking central pallor)
Diagnosis: family history,hematologicfindings,rbc abnormally
sensitive to osmotic lysis when incubated in hypotonic salt
solution,increasedmchc due to dehydration of rbc
Clin features: anemia,splenomegaly,jaundice
Tx: transfusion and splenectomy
There are two molecular defects that have an established role
in the development of sporadic adenomas:
• Cyclin D1 gene inversions leading to overexpression of cyclin
D1, a major regulator of the cell cycle.
• MEN1 mutations: Approximately 20% to 30% of sporadic
parathyroid tumors have mutations in both copies of the
MEN1 gene, a tumor suppressor gene on chromosome 11q13.
Clinical Course.
Primary hyperparathyroidism may be
(1) asymptomatic and identified on routine blood
chemistry profile,
(2) associated with the classic clinical manifestations of
primary hyperparathyroidism.
Signs and Symptoms:
Primary hyperparathyroidism is associated with “painful
bones, renal stones, abdominal groans, and psychic moans.”
• Bone disease and bone pain secondary to fractures of bones
weakened by osteoporosis or osteitisfibrosacystica.
• Nephrolithiasis (renal stones) in 20% of newly diagnosed
patients, with attendant pain and obstructive uropathy.
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Chronic renal insufficiency and abnormalities in renal function
lead to polyuria and secondary polydipsia.
• Gastrointestinal disturbances, including constipation,
nausea, peptic ulcers, pancreatitis, and gallstones.
• Central nervous system alterations, including depression,
lethargy, and eventually seizures.
• Neuromuscular abnormalities, including weakness and
fatigue.
• Cardiac manifestations, including aortic or mitral valve
calcifications (or both).
Laboratory findings
a. Increased serum PTH, increased calcium, decreased
phosphorus
 Intact serum PTH is the best initial screening test.
b. Normal anion gap metabolic acidosis
 Due to decreased proximal tubule reclamation of
bicarbonate
 Type II renal tubular acidosis
c. Chloride/phosphorus ratio >33
 Ratio <29 excludes primary HPTH.
d. Decreased serum 1,25-(OH)2D
 Hypercalcemia decreases synthesis of 1-α-
hydroxylase in the proximal renal tubule.
 Protective effect so that serum calcium is not too
high.
e. Electrocardiogram shows shortening of QT interval.
Localization of adenoma
• Technetium-99m-sestamibi radionuclide scan
Treatment
a. Surgical removal of the adenoma
b. Treatment of hypercalcemia
(1) IV hydration with normal saline followed by IV
furosemide
• Most common therapy
(2) Bisphosphonates
(3) Cinacalcet directly lowers PTH levels
• Increases the calcium-sensing receptor to
extracellular calcium
Secondary Hyperparathyroidism
 Secondary hyperparathyroidism is caused by any condition
that gives rise to chronic hypocalcemia, which in turn leads
to compensatory overactivity of the parathyroid glands.
 Renal failure is by far the most common causeof secondary
hyperparathyroidism, although several otherdiseases,
including inadequate dietary intake of calcium,steatorrhea,
and vitamin D deficiency, may also cause thisdisorder.
 Chronic renal insufficiency is associatedwith decreased
phosphate excretion, which in turnresults in
hyperphosphatemia. The elevated serum phosphatelevels
directly depress serum calcium levels and thereby stimulate
parathyroid gland activity.
 In addition, loss of renal substance reduces the availability
of α-1- hydroxylase necessary for the synthesis of the
active form of vitamin D, which in turn reduces intestinal
absorption of calcium. Because vitamin D has suppressive
effects on parathyroid growth and PTH secretion, its
relative deficiency compounds the hyperparathyroidism in
renal failure.
 May develop tertiary hyperparathyroidism
a. Glands become autonomous regardless of the calcium
level.
b. This may bring the serum calcium into a normal or
increased range.
Clinical Course.
 The clinical features of secondary hyperparathyroidism
are usually dominated by the inciting chronic renal failure.
 Secondary hyperparathyroidism perse is usually not as
severe or as prolonged as primary hyperparathyroidism,
hence the skeletal abnormalities (referred to as renal
osteodystrophy) tend to be milder.
 The vascular calcification associated with secondary
hyperparathyroidism may occasionally result in significant
ischemic damage to skin and other organs, a process
sometimes referred to as calciphylaxis.
 Patients with secondary hyperparathyroidism often
respond to dietary vitamin D supplementation, as well as
phosphate binders, which decrease the prevailing
hyperphosphatemia.
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IGA NEPHROPATHY 1
characterized by the presence of prominent IgA deposits in
the mesangial regions and recurrent hematuria, is the most
common type of glomerulonephritis worldwide. The disease
can be suspected by light microscopic examination, but the
diagnosis is made only by the detection of glomerular IgA
deposition. Mild proteinuria is usually present, and the
nephrotic syndrome may occasionally develop. Rarely,
patients may present with crescentic RPGN.
Associated with Celiac Sprue and Henoch-Schonlein purpura
Secondary IgA nephropathy-occurs in patients with liver and
intestinal diseases (defective hepatobiliary clearance of IgA
complexes)
Epidemiology
i. Most common cause of glomerulonephritis in the world
ii. Common in France, Japan, Italy and Austria
iii. Affects older children and young adults (mostly males)
Clinical features
i. Hematuria
 With gross hematuria after an infection ofthe
respiratory or, less commonly, gastrointestinal or
urinary tract
 hematuria typically lasts for several days and then
subsides, only to return every few months
 30% to 40% have only microscopic hematuria, with or
without proteinuria
ii. Predominantly nephritic
 5% to 10% develop acute nephritic syndrome,
including some with rapidly progressive
glomerulonephritis.
iii. Slow progression to chronic renal failure occursin 15%
to 40% of cases over a period of 20 years
iv. Onset inold age
INFECTIOUS DISEASES 1
- Germs, or microbes, are found everywhere - in the
air, soil, and water. There are also germs on your skin
and in your body. Many of them are harmless, and
some can even be helpful. But some of them can
make you sick. Infectious diseases are diseases that
are caused by germs.
There are many different ways that you can get an infectious
disease:
 Through direct contact with a person who is sick. This includes
kissing, touching, sneezing, coughing, and sexual contact.
Pregnant mothers can also pass some germs along to their
babies.
 heavy proteinuria, hypertension, and the extent of
glomerulosclerosis on biopsy are clues to an
increasedrisk of progression.
v. Recurrence of IgA deposits in transplanted kidneys is
frequent, and in approximately 15% of those with
recurrent IgA deposits, the disease runs the same slowly
progressive course as that of primary IgAnephropathy.
Pathogenesis
 The mechanism is unknown. There is a possible
entrapment of circulating immune complexes with
activation of the alternate complement pathway.
There is also a possible genetic predisposition
Light microscopy- Variable,Normal or mesangial proliferation
Immunofluorescence: mesangial deposits of IgA and C3often
with C3 and properdin and lesser amounts of IgG or IgM . Early
complement components are usually absent. (The deposited
IgA and IgAcontaining immune complexes activate the
complement system via the alternate pathway, and hence the
presenceof C3 and the absence of C1q and C4 in glomeruli are
typical of this disorder.)
Electron microscopy: mesangial immune complex deposits;
Capillary wall deposits if present, are usually sparse
 Through indirect contact, when you touch something that has
germs on it. For example, you could get germs if someone who
is sick touched a door handle, and then you touch it.
 Through insect or animal bites
 Through contaminated food, water, soil, or plants
There are four main kinds of germs:
1. Bacteria - one-celled germs that multiply quickly. They
may give off toxins, which are harmful chemicals that
can make you sick. Strep throat and urinary tract
infections are common bacterial infections.
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2. Viruses - tiny capsules that contain genetic material.
They invade your cells so that they can multiply. This
can kill, damage, or change the cells and make you
sick. Viral infections include HIV/AIDS and
the common cold.
3. Fungi - primitive plant-like organisms such as
mushrooms, mold, mildew, and yeasts. Athlete's
foot is a common fungal infection.
4. Parasites - animals or plants that survive by living on
or in other living things. Malaria is an infection caused
by a parasite.
Infectious diseases can cause many different symptoms. Some
are so mild that you may not even notice any symptoms, while
others can be life-threatening. There are treatments for some
infectious diseases, but for others, such as some viruses, you
can only treat your symptoms. You can take steps to prevent
many infectious diseases:
 Get vaccinated
 Wash your hands often
 Pay attention to food safety
 Avoid contact with wild animals
 Practice safe sex
 Don't share items such as toothbrushes, combs, and straws
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INFLAMMATION 3
Characteristics of Inflammation:  Tumor
 Rubor (redness) Mediated by Prostaglandin E2 and Brdykinin
 Dolor (pain)  Dolor
 Calor (heat) Sequential Vascular Events in Al
 Tumor (swelling)  Vasoconstriction of arterioles
 Functio laesa (loss of function)  Due to a neurogenic reflex that lasts only a few
Acute Chronic seconds
Cells  Vasodilation of arterioles
- Neutrophil - Mononuclear cells  Histamine and other vasodilators relax vascular
- Eosinophil - Fibroblast smooth muscle, causing increased blood flow.
 Increased blood flow due to vasodilation of
Hallmarks None arterioles increases hydrostatic pressure (HP) in
- Blood vessel venule lumens.
proliferation  Increased permeability of venules
- Fibrosis  Histamine and other mediators contract
- Granuloma endothelial cells in venules, producing
endothelial gaps exposing bare basement
Course Resolution -Scarring membrane.
Abscess - Amyloidosis  Transudates (fluid low in proteins and cells) move
formation through the intact venular basement membrane
into instertial tissue because of the increased HP.
Histamine – mediated  Swelling of tissue (tumor, edema)
 Rubor
 Calor
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 Net outflow of fluid from venule surpasses the  Reduced blood flow eventually occurs because of
capacity of lymphatics to remove fluid; hence, outflow of fluid into the interstitial tissue and
there is swelling of tissue. increased uptake of fluid by lyphatics.
 Reduced blood flow
Chemical Mediators in AI

Mediator Sources Functions

Arachidonic Acid Metabolites

Prostaglandins Macrophages, endothelial cells platelets PGE2: vasodilation, pain, fever,

PGH2: major precursor of PGs and thromboxanes PGE1: vasodilation, inhibition of platelet
aggregation

Thromboxane A2 Platelets converted from PHG2 by thromboxane Vasoconstriction, platelet aggregation

synthase

Leukotienes (LTs) Leukocytes LTB4: chemotaxis and activation of

Converted from arachidonic acid by
lipoxygenase-mediated hydroxylation
neutrophil adhesion molecules
LTC4, LTD4, LTE4: vasoconstriction, increase
venular permeability, bronchoconstriction
Zeleuton inhibits 5- lipoxygenase: decrease
synthesis LTB4, LTC4, LTD4, LTE4

Mediator Sources Functions

Arachidonic Acid Metabolites

IL-1, TNF Macrophages (main source), Initiate PGE2 synthesis in the anterior hypothalamus, leading to
monocytes, dendritic cells, production of fever
endothelial cells Activate endothelial cell adhesion molecules
TNF is a promoter of apoptosis
IL-6 Primary cytokine responsible for increased liver synthesis of
acute phase reactants (APRs),such as ferritin, coagulation factors,
(e.g., fibrinogen), and C-reactive protein

IL-8 Chemotaxis

Histamine Mast cells (primary cell), Vasodilation, increased venular permeability

platelets, enterochromaffin cells
Nitric Oxide (NO) Macrophages, endothelial cells free Vasolidation, bactericidal
radical gas released during
conversion of arginine to citrulline
by NO synthase

INTUSSUSCEPTION 1
 Occurs when a segment of the intestine,
constricted by a wave of peristalsis, telescopes
into the immediately distal segment.
 Once trapped, the invaginated segment is
propelled by peristalsis and pulls the mesentery
along. Untreated intussusception may progress
to intestinal obstruction, compression of
mesenteric vessels, and infarction.
 Intussusception is the most common cause of
intestinal obstruction in children younger than 2
years of age. In these idiopathic cases there is
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usually no underlying anatomic defect and the

patient is otherwise healthy.
 Other cases have been associated with viral
infection and rotavirus vaccines, perhaps due to
reactive hyperplasia of Peyer patches and other
mucosa-associated lymphoid tissue which can act
as the leading edge of the intussusception.
 Intussusception is rare in older children and
adults, and is generally caused by an intraluminal
mass or tumor that serves as the initiating point
of traction (Fig. 17-23B). Contrast enemas can be
used both diagnostically and therapeutically for
idiopathic intussusception in infants and young
children, in whom air enemas may also
effectively reduce the intussusception.
 However, surgical intervention is necessary when
a mass is present, as is generally the case in older
children and adults.

IRRITABLE BOWEL SYNDROME 1

 (IBS) is characterized by chronic, relapsing abdominal pain, bloating, and changes in bowel habits without obvious gross
or histologic pathology. The pathogenesis of IBS is not defined, but includes contributions by psychologic stressors, diet,
the gut microbiome, abnormal GI motility, and increased enteric sensory responses to gastrointestinal stimu
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LEUKEMIA 1
LEUKEMIA features insufficiency & fever
Generalized neoplastic Enlargement of Lymph node; Splenomegaly
proliferation or Variable leukocytes count: (+) Prostation (+) Malaise
accumulation of Leukocytosis >50-300x109/L Rapidly progressive course
leukocytes, with or without Leukocytosis 50,000 – 300,000/cumm
involvement of the >90% of all non-erythroid cells are blasts
peripheral organs. Clonal, recurring t(8;21)(q22;q22)
Primarily involved the Decreased LAP/NAP score cytogenic abnormalities inv(116)(p13q22)
blood and bone marrow Diagnosis (Regardless of the blast t((16;16)(p13;q22)
percentage) t(15;17)(q22;q12)
Composed of fused lysosomal
Classification Acute Leukemia Chronic Leukemia (+) Auer rods granules seen in the
Rapid & cytoplasm
Insidious 5-year survival
progressive
Onset
Several days to rate for AML – M3 & M4e have higher
Min. of 1 to 2 years Prognosis children response rate and greater
months
improved by survival rate
Course when
<6 months 2-6 years 50%
untreated
Age All ages Adult
Elevated Lower proliferative
AML – M0 >30% Type I
proliferative rates rates, with greater
(Minimally >20% (+) CD13, CD33 &/or CD14
with predominance proportion of mature
Proliferative Differentiated) <3% (+) Myeloperoxidase& Sudan black
of blasts cells
states
Mild to severe AML – M1 >30% Type I
Mild anemia and (Without (+) CD13, CD14, CD11b, CD33, & HLA-DR
anemia and
thrombocytopenia Maturation) t(9;22) Philadelphia chromosome, +8, -5 &
thrombocytopenia
Organomegaly Mild Prominent -7
>3% (+) MPO& Sudan black
(-) NAS & PAS
Cytologic Natural course Auer rods infrequent
features Acute Chronic AML – M2 Most common type (20-40%)
Chronic (With >30% Type I, II, III
Lymphoid or Acute Lymphocytic Maturation) >10% of non-erythroid cells are
Lymphocytic
Lymphocytic Leukemia (ALL) promyelocytes or more mature granulocytes
Leukemia (CLL)
Myeloid, Chronic <20% Monocytic lineage
Acute Myelogenous (+) CD13, CD33, HLA-DR; (-) CD14 &
Myelocytic, or Myelogenous
Leukemia (AML) CD11b
Granulocytic Leukemia (CML)
T(8;21), 8+, -5, -7
>3% (+) MPO& Sudan black B
Risk Factors AML – M3 >30% Type I, II, III
Down Syndrome Benzene Exposure Tobacco smoking Majority of abnormal promyelocytes with
Ionizing numerous primary type granules
Retrovirus infection Pesticide exposure
radiation (+) CD13, CD3; (-) HLA-DR
t(15;17)
>85% (+) MPO& Sudan black B
Acute(>20% of blasts in the bone marrow) Chronic (+) Auer rods, frequent & often multiple
Myeloid Lymphoid Associated with DIC & Hemorrhage
M1 Myeloblastic L1 AML – M4 >30% Type I, II
Myeloblastic with >30% Myeloblasts, Monoblasts,
M2 L2
differentiation Promonocytes
M3 Promyelocytic L3 Burkitt’s t(4;11), t(9;11), 8+ & -7
M4 Myelomonocytic M4e,>5% Eosinophils are increased in
M5 Monocytic number & associated with abnormalities of
M6 Erythroleukemia chromosome 16
M7 Megakaryocytic CAE (-) Eosinophils, (+) Abnormal
eosinophils of M4e
>20% (+) MPO, Sudan black B&Non-
French-American-British (FAB) Classfication specific esterase
Morphology of cells Cytochemical reactions or High serum lysozyme (3x normal)
serum lysozyme levels A peripheral monocytosis of >5 x10/L in
All blast have central nuclei with fine uncondensed chromatin M2 marrow and >20% NSE + marrow blasts
and prominent nuclei AML – M5 >30% Myeloblasts, Monoblasts,
Type I Blast Lack cytoplasmic granules Promonocytes
Type II Blast Small number if primary (azurophilic) M5a, poorly differentiated > 80% of
granules nonerythroid nucleated cells are monoblasts
Type III Blast More abundant azurophilic granules M5b, differentiated Promonocytes
Acute Myeloid Leukemia (AML) predominates
<1; Mid-40s; Rare in childhood & t(9;11), 8+, -5, -7; abnormalities of 11q
Most common (M5a)
>60 adolescent
<20% (+) Myeloperoxidase &Sudan black
Clinical Granulocytic Ulceration of mucous membrane
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> 80% (+)α- naphthyl acetate esterase (α- Most common malignancy in childhood & adolescent
NAE), (+) α- naphthyl butyrate esteras (α- Proliferation of lymphoblast in the bone marrow
NBE) Commonly in the peripheral blood & other organs are
AML – M6 Di – Guglielmo’s Syndrome involved
Erythroleukemia Anemia – usually normocytic Leukocyte >100 x 109/L
>50% Erythroblasts Predominant cell is
>30% Type I, II, III Frequent nucleated red cells
lymphoblast
(+) Glycophorin A Hematopoietic cells are fat
Thrombocytopenia is the
8+, -5, del (5q), & -7 are replaced by diffuse
rule
(+) NSE, (-) MPO, (+) PAS infiltration of lymphoblasts
AML – M7 >30% Myeloblasts&Megakaryocytes (+) TdT
20% Moderately / (+) Acid
t(1;22), M7 in infants phosphatase
(+) Glycoprotein GP Ib& GP IIb / IIIa T cell CD2, CD3, CD4, CD5, CD7, CD8
(+) PPO B cell CD19, CD22, CD79
May be accompanied by atypical Lymphoblast Small, round to oval nuclei with coarse
megakaryocytes; Marrow is often fibrotic chromatin
Nuclei, small & inconspicuous
Cytoplasm, sparse in volume & basophilic,
Prognostic Factors without granules
Factors Favorable Unfavorable (-) Auer rods
Age <45 years <2 years, > 60 years L1 Blasts are small & uneven in size
Leukocytosis <25 x 109/L > 100 x 109/L Very fine homogenous, with deeply staining
CNS involvement Absent Present regular nuclei
Response to therapy Rapid Delayed/incomplete Nuclei are obscured
Auer rods Present Absent Cytoplasm is scanty, moderate basophilia
M2, M3, L2 13% Children 35% Adult
FAB type M5, M6, M7
M4EO Somewhat large & varied morphology
CD2 or Indented irregular nuclei, with nucleoli
Cell markers CD13, CD14, CD33
CD19 Cytoplasm & nuclei have small vacuoles
-7; del(7q), - Can sometimes be confused with myeloid or
t(15;17), 5;del(5q),11q23 monocyctic cells
t(8;21) abnormalities; 3q21 & L3 2% Children 2% Adult
Cytogenetics
inv(16)del 3q26 abnormalities, Large
(16q) Complex karyotypic Nuclear chromatin is relatively delicate,
abnormalities finely stippled with 1 or 3 nucleoli
(+) Cytoplasmic & Nuclear vacuoles

Acute Lymphoblastic Leukemia (ALL)

LIPID FUNCTION TEST 1

LIPIDS / FATS Triacylglycerol (Adipose tissue)
C-H bonds Primary sources of fuel (Neutral Fat) 150–199 Borderline high  Metabolized to FA
Provide stability to cell membrane Insoluble in blood & water, bur → energy →
& allow for transmembrane soluble in organic solvents 200–499 High TAG insulation
transport (chloroform & ether)  ≥200 risk for CAD
Require special transport Very high TAG because of
Major lipids: Phospholipids, C, atherogenic VLDL
mechanism (LPP) for circulation in (Acute &
TAG, Fat soluble vitamins (ADEK) >500 remnants
the blood recurrent
*Ch Cholesterol, TAG Triglycerides, LPP Lipoprotein, CM Chylomicrons, Apo Apolipoprotein
pancreatitis)  Either plasma or
serum
 Important sources
of energy
Reference Fatty Acids 9–15
 Substance for
Lipids value Remarks Notes
gluconeogenesis
(mg/dL)
40 Cut-off level
 In the lungs,
Phospholipid High risk for
produced by Type II HDL <35
(Conjugated 150–380 CHD
pneumocytes
Lipid) >60 Protective
(Surfactant)
 Evaluate the risk of <100 Optimal
<200 Desirable Atherosclerosis, MI, Near/Above
100–129
CA occlusions optional
LDL
Cholesterol /  Increases with 130–159 Borderline high
3-hydroxy-5, 200–239 Borderline high age,↑2mg/dL/year 160–189 High
6-cholestene) at 50 – 60 ≥ 190 Very high
 Instruct on usual
Hypochole-
≥240 diet 2 weeks prior to
steremia testing
Lipoproteins
Triglyceride / <150 Normal  Main storage lipid
Large macromolecular complexes of lipids with specialized proteins
known as Apo
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Main purpose is to transport TAG &Ch to sites of energy storage & Minor Lipoproteins
utilization Intermediate Density Product of VLDL catabolism – VLDL
Keep the lipids solubility in the circulation Lipoprotein (IDL) remnant
Aid in the solubilization of the lipids, interact with Apo B-100
Apolipoproteins
specific cell-surface receptors Lipoprotein (a) / LP (a) Similar to LDL
Maintain the structural integrity of the LPP complex “Sinking pre-β LPP”
↑ levels may indicate premature
coronary heart disease & stroke
Major Lipoproteins Independent risk factor for
Chylomicrons (CM) Largest&least dense Atherosclerosis
Produced in the intestine from dietary fat Apo B-100 & Apo (a)
Completely cleared within 6–9 hours post <20 – 1500 mg/L or more
prandial
Transports exogenous/dietary TAG to liver,
muscles&fat deposits Specimen Requirement
90% TAG (Non-fasting plasma) +1-2% protein Sample collected using serum separator tubes
Apo B–48, Apo A–1, Apo C & Apo E Plasma or serum is used
Density <0.95 kg/L EDTA is preferred anticoagulant
Very Low Density Secreted in the liver
Lipoprotein / Pre- Transport endogenousTAG from liver to
Beta Lipoprotein muscle, fat deposits, & peripheral tissues Patient Preparation
(VLDL) Prolonged consumption of high fat diet leads to Fasting 12–14 hours NPO
elevated TAG in the VLDL particles TAG & LDL-C
65% TAG (Fasting plasma) + 6-10% protein + Non-fasting TC & HDL-C, CM
16 C Concentration of LDL-C & HDL-C
Diet
Apo B-100, Apo C & Apo E decline temporarily after eating
Density0.95–1.006 kg/L Posture Sitting position for 5 minutes before
High Density Smallest &most dense (5-12nm) sampling to prevent hyperconcentration
Lipoprotein / Alpha Produce in the liver&intestine Standing decreases 10% LPP
Lipoprotein (HDL) concentrations due to transfer of water
Transport excess Ch from the tissues & return it
“Good Cholesterol” to the liver (Reverse cholesterol transport) to the vascular system & dilutes
nondiffusable plasma constituents
Maintains the equilibrium of Ch in peripheral
cells
Transports effectively the lipids to the liver and
Recommendation
more cardioprotective
Initial screening (≥20): Total C, HDL-C, LDL-C & TAG
Its phospholipid content is more important
Testing should be repeated at least once every 5 years
30% phospholipid + 45-50% protein + 20% Ch
LPP measurements be made no sooner than 8 weeks after any form of
Apo A-I, Apo A-II, Apo C
trauma or acute viral infection, & 3 – 4 months after childbirth
Density 1.063–1.21 kg/L
Low Density Synthesized in the liver
Lipoprotein / Beta Major end product from the catabolism of VLDL Notes
Lipoprotein (LDL) 50% of the total LLP in plasma Intake of alcohol & drugs
“Bad Cholesterol” Major source of cholesterol for tissues High HDL-C (Phenytoin, RIF, Estrogen) &
Transports C to the peripheral tissues – it Exercise
carries most of the circulating Ch& transport Ch Physical inactivity, Obesity,
to hepatic & extrahepatic tissues High CHO diet & intake of
Most Ch-rich LPP &most atherogenic Low HDL-C drugs (Beta blockers,
Primary target of CE lowering therapy Progesterone, Anabolic
Primary marker for CHD risk steroids)
50% CE + 18% Protein & Phospholipid Apo-B containing LPP (LDL, VLDL, CM) is to deliver Ch& TAG
Apo B–100 & Apo E to various tissues
Density 1.019 – 1.063 kg/L

LIVER CIRRHOSIS 1
 Lack of portal triads
Types  Surrounded by strands of fibrosis
 Micronodular (Laennec): if less than 3mm  Compressed sinusoids and central venules
 Macronodular: if 3mm or more
Etiology:
Definition:  Alcoholic liver disease (most common)
 Irreversible diffuse fibrosis of the liver with formation  Postnecrotic cirrhosis (HBV,HCV)
of regenerative nodules  Autoimmune disease
 Wilson Disease
Histologic features:  a1–antitrypsin deficiency
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 galactosemia 2. Synthetic function: monitored by measuring the levels of

albumin and coagulation factors (PT and aPTT)
Complications: 3. Excretory function: assessed by measuring the levels of
 Hepatic failure bilirubin
 Hypoalbuminemia 4. Integrity of liver cells: assessed by measuring the liver
 Hepatic encephalopathy enzymes
5. Storage function: assessed by using different serum iron test
LIVER FUNCTION TEST: Dr. Casio 6. Detoxification of blood: monitored by measuring the levels
1. Carbohydrate metabolic function: assessed by measuring the of excreted drug and foreign compounds
Random Blood Sugar

LIVER FUNCTION TESTS 2

LIVER FUNCTION TEST: DR. PSA  Parasites
Jaundice Bilirubin + diazotized sulfanilic acid= azobilirubin (purple color)
 can be detected clinically when the total serum
bilirubin rises higher that 2-3 mg/dl (34-51umol/L) Liver Enzymology
 NV: 0.5-1.3 mg/dl  Alanine Aminotransferase (ALT)
 Formerly known as Seum Glutamic Pyruvate
Conversion factor from conventional unit to SI unit of Bilirubin Transaminase (SGPT)
 1mg/dl=17.1  If increase is massive (e.g>100 units) indicative of
viral hepatitis
Kernicterus  Alkaline Phosphatase (ALP)
 When values of bilirubin exceeds 20mg/dl and will  Marked increased in obstructive liver disease
cross the BBB, and be deposited in the brain leading to  May also be increased in primary bone tumors
seizures.  Placental ALP (Regan isoenzyme)
 Physiologic increase: pregnancy, healing fracture,
Computation for Bilirubin growing children
 TB= Total bilirubin  Gamma Glutamyl-Transferase (GGT)
 DB= Direct bilirubin [water-soluble]  Marker increased in alcoholism
 IB= Indirect Bilirubin [water-insoluble]
 TB= DB+IB Prothrombin Time (PT)
 most sensitive hematologic test associated with liver
Causes of Hyperbilirubinemia function
 Pre-hepatic  extrinsic
 Hepatic
 Post-hepatic Liver Dependent Clotting Factors
 Factor IX
Prehepatic  Factor X
 Increased IB  Factor VII
 Hemolytic anemia  Factor II
 Burns Hepatitis B Surface Antigen
 Starvation  Also known as HBsAg
 Present in carrier state
Hepatic  Earliest marker for hepatitis to be detected
 Increased DB,IB,GGT  If patient (90%) recovers, it is replaced by Hepatitis B
 Liver injury surface antibody (HBs)
 Hepatic carcinoma  If there is persistence for more than six months,
 Hepatitis results to chronic carrier state and maybe associated
 Cirrhosis with hepatocellular carcinoma

Post-hepatic Hepatitis B Core Antigen

 Increased DB, ALP  HBcAg
 Carcinoma of the bile ducts  the only marker for hepatitis present in “window
 Gall stones phase”
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Chronic Alcohol Abuse <2

Hepatitis B Envelope Antigen (HBE) Strenous exercise
 Marker of infectivity Chronic Hepatitis
Cirrhosis <5
Hepatits B Surface Antibody Neoplasia
 HBs Cholestatic Jaundice <10
 If present indicates: convalescence, recent Acute Viral Hepatitis >10
immunization Acute Drug-induced
hepatitis
Alpha Fetoprotein (AFP)
 marker increased in liver carcinoma Causes of Elevated Serum Alkaline Phosphatase Levels
 maybe also increased in open neural tube defects Cause Magnitude of ALP
 maybe secondary to aflatoxin Increase (Multiples of ALP)
Acute Hepatitis
Alpha1 Antitrypsin (AAT) (viral,toxin,or alcohol-
 maybe increased with panacinar emphysema induced) 2
Cirrhosis
Ceruloplasmin Acute fatty liver
 oxidase enzyme and a donor for copper
 if decreased, is diagnostic of Wilson’s Disease Postnecrotic cirrhosis
 maybe associated with Kayser-Fleischer Rings in Infectious Mononucleosis 5
cornea Cholestatic hepatitis 10
(especially drug-induced)
Primary biliary cirrhosis 15-20
Causes of Elevated Serum Aminotransferase Levels Carcinoma (primary or
Causes Magnitude of ALT or AST metastatic)
increase (Multiples or
ULN) Physiologic jaundice: 0-7 DAYS
Obesity Pathologic jaundice: >10 DAYS

LUNG ABSCESS 1
- refers to a localized area of suppurative necrosis within
the pulmonary parenchyma, resulting in the formation
of one or more large cavities
- necrotizing pneumonia: used to describe a similar
process resulting in multiple small cavitation; often
coexists or evolves into lung abscess
- causative organism may be introduced into the lung by
any of the follow-ing mechanisms:
 Aspiration of infective material
From carious teeth or infected sinuses or tonsils,
particularly likely during oral surgery, anesthesia,
coma, or alcoholic intoxication and in debilitated
patients with depressed cough reflexes
 Aspiration of gastric contents
usually accompanied by infectious organisms from
the oropharynx
 As a complication of necrotizing bacterial
pneumonias
particularly those caused by:
S. aureus
Streptococcus pyogenes
K. pneumoniae
Pseudomonas spp.
type 3 pneumococci (rarely)
- Mycotic infections and bronchiectasis may also lead
to lung abscesses
 Bronchial obstruction
particularly with bronchogenic carcinoma
obstructing a bronchus or bronchiole. Impaired
drainage, distal atelectasis, and aspiration of blood
and tumor fragments all contribute to the
development of abscesses. An abscess may also
form within an excavated necrotic portion of a
tumor.
 Septic embolism
from septic thrombophlebitis or from infective
endocarditis of the right side of the heart
 hematogenous spread of bacteria in disseminated
pyogenic infection.
This occurs most characteristically in staphylococcal
bacteremia and often results in multiple lung
abscesses.
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Anaerobic bacteria are present in almost all lung abscesses,
sometimes in vast numbers, and they are the exclusive isolates
in one third to two thirds of cases.
- most frequently encountered anaerobes are
commensals normally found in the oral cavity,
principally species of Prevotella, Fusobacterium,
Bacteroides, Peptostreptococcus, and micro-aerophilic
streptococci
Morphology
Abscesses range: (diameter) few millimeters to large cavities 5
to 6 cm across
- Pulmonary abscesses resulting from aspiration of
infective material are much more common on the
right side (with its more vertical airways) than on the
left, and most are single.
- Right side: tend to occur in the posterior segment of
the upper lobe and in the apical segments of the lower
lobe
- Abscesses that develop in the course of pneumonia or
bronchiectasis commonly are multiple, basal, and
diffusely scattered.
- Septic emboli and abscesses arising from
hematogenous seeding are commonly multiple and
may affect any region of the lungs.
LUNG TUMORS 2
Solitary Pulmonary Nodule
 Term applied to peripheral lung nodule <5cm
 Etiology
1. Granuloma
2. Primary lung cancer
3. Bronchial Carcinoid
 Px <35yo risk: <1% ( more likely benign)
 Px >50 yo risk: 50-60% (more likely malignant)
Most common Lung tumor:
 Metastatic
 Appears as multiple lesions
 Source: Breast (bc of proximity)
 Mc presentation: Dyspnea
Clinical Findings of Lung Cancer
 Cough (75%)
 Weight loss ( drastic)
 Hemoptysis
- Focus of suppuration enlarges, ruptures into airways,
contained exudate may be partially drained, producing
an air-fluid level on radiographic examination.
- abscesses rupture into the pleural cavity and produce
bronchopleural fistulas, the consequence of which is
pneumothorax or empyema
- Embolization of septic material to the brain:
meningitis or brain abcess
- Histologic examination: suppurative focus is
surrounded by variable amounts of fibrous scarring
and mononuclear infiltration (lymphocytes, plasma
cells, mac-rophages), depending on the chronicity of
the lesion.
Clinical Features:
- Manifestation are like bronchiesctasis and include
prominent cough that usually yields copious amounts
of foul-smelling, purulent, or sanguineous sputum;
occasionally, hemoptysis occurs
- Clubbing of the fingers, weight loss, and anemia may
all occur
- When a lung abscess is suspected in an older person,
underlying carcinoma must be considered
(bronchogenic carcinoma)
- Chronic cases: secondary amyloidosis may develop
- Treatment: antibiotic therapy, surgical drainage
- Mortality rate: ~10%
Treatment based on tumor location
 Hilar/central area: chemotherapy
 Peripheral: surgery
Pancoast tumor
 Superior sulcus tumor
 Small cell carcinoma in the apex of the lung
 Produces Honer syndrome:
- Ipsilateral lid lag
- Miosis
- Anhydrosis
Lung Cancer
 Primary lung cancer: mc fatal cancer in both men and
women
- Adenocarcinona: non-smokers
- Squamous cell carcinoma: smokers
- >30% of cancer deaths in men
- >25% of cancer deaths in women
 Incidence: declining in men, increasing in women
 Peak incidence: 55-66 yo
 Etiology: mc cause is smoking
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- 85% primary  Mc cell type overall (35%)

- 15% secondary  Mc in women and non smokers but still patients are
 Most common oncogenes smokers
- KRAS  Peripheral: tx is surgery
- MYC family  K-RAS mutation is more likely in smokers
- HER-2/neu  Hilar lymph nodes most common site (metastasis)
- BCL-2 Squamous Cell Carcinoma
- EGFR (epidermal growth factor receptor)
 Classification  Strongly associated with smoking (30%)
1. Small cell carcinoma (15%)  Mc carcinoma to cavitate
2. Non Small cell carcinoma (85%)  Poor prognosis
3.  P53 gene, CDK inhibitor p16 and RAS mutations
Small Cell Carcinoma  HER-2/neu is overexpressed in approximately 30% of
cases
 98% associated with smoking  Associated with PTHrP production
 Also known as “Oat Cell Carcinoma”  Keratin pearls: stage 1 tumor (well differentiated)
 Highly metastatic
 Centrally located
 Originate in the neuroendocrine cells in the bronchus Large Cell Carcinoma
called Feyrter cells
 Peripheral (15%): tx is surgery
 May lead to ectopic production of hormones like ADH
 Very large: >4cm
and ACTH that may result in paraneoplastic syndromes
 Cells involved has not differentiated to squamous or
 RB, p53 mutations are common
adenocarcioma
 BCL-2 is highly expressed in >90%
 Clinico Pathologic staging:
- Limited: lung a nd lymph nodes close to the Bronchial Carcinoid
affected lung
 <5% of primary lung cancer
 < 40yo
 Locally invasive, not metastatic
 Not related to smoking
 Maybe central or peripheral
 Mc primary lung tumor in Children
 Nesting cell
 Morphology
- Most carcinoids originate in main bronchi and
grow in one of two patterns:
- Extensive 1. an obstructing polypoid, spherical,
intraluminal mass
2. a mucosal plaque penetrating the bronchial
Non Small Cell Carcinoma wall to fan out in the peribronchial tissue—
the so-called collar-button lesion.
1. Adenocarcinoma - Histologically, typical carcinoidsare composed of
2. Squamous Cell Carcinoma nests of uniform cells that have regular round
3. Large Cell Carcinoma nuclei with “salt-and-pepper” chromatin, absent
4. Bronchial Carcinoma or rare mitoses, and little pleomorphism.
 (+) MYC mutations - Atypical carcinoid tumors display a higher mitotic
 (+)EGFR mutations rate (but less than small or large cell carcinomas)
 Fare better than small cell carcinoma and focal necrosis. Have a higher incidence of
lymph node and distant metastasis. Demonstrates
TP53 mutations in 20% to 40% of cases
Adenocarcinoma

MAD COW DISEASE 1

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 A prion disease from ingestion of tissues from cattle with
bovine spongiform encephalopathy. Exposure to BSE
(consumption of contaminated food or blood transfusion)
was linked to the new variant form of Creutzfeldt-Jakob
disease characterized by presence of extensive cortical
plaques surrounded by a “halo” of spongiform change.
MEMBRANOPROLIFERATIVE GN 1
A. Types
 Type I
 Type II (dense deposits)
B. Clinical features
 May be nephritic, nephrotic, or mixed
 May be secondary to many systemic
disorders (SLE, endocarditis), chronic
infections (HBV, HCV, HIV) and malignancies
(chronic lymphocytic leukemia)
C. Lab
 ↓ serum C3
 C3 nephritic factor (MPGN type II)
D. Light Microscopy
 Lobulated appearance of glomeruli
 Mesangial proliferation and basement
membrane thickening
MULTIPLE ENDOCRINE NEOPLASIA 1
SYNDROMES
1. Multiple endocrine neoplasia (MEN) syndromes are
autosomal dominant conditions with incomplete
penetrance that are characterized by hyperplasia and
tumors of endocrine glands.
 Prions are abnormal forms of a cellular protein that cause
rapidly progressive neurodegenerative disorders that may
be sporadic, familial, or transmitted. This group of
diseases includes Creutzfeldt-Jakob disease, Gerstmann-
Straussler-Scheinker syndrome, fatal family insomnia, and
kuru in humans; scrapie in sheep and goats; mink-
transmissible encephalopathy; chronic wasting disease of
deer and elk; and bovine spongiform encephalopathy
 Splitting of the basement membrane (“tram-
tracking” – distinguishing characteristic) may
be seen with a silver or periodic acid Schiff
(PAS) stain
E. Immunofluorescence
 Type I: granular C3 pattern often with IgG,
C1q, and c4
 Type II: granular and linear C3 pattern
F. Electron Microscopy
 Type I: subendothelial and mesangial immune
complex deposits
 Type II: dense deposits within GBM
G. Prognosis
 Slowly progressive course, resulting in
chronic renal failure over the course of 10
years
 High incidence of recurrence in transplants
2. MEN I (Werner syndrome) features tumors of the pituitary
gland, parathyroids, and pancreas. It is associated with
peptic ulcers and the ZollingerEllison syndrome. The
affected gene is MEN I, a tumor suppressor gene that
encodes a nuclear protein called menin.
3. MEN II (Ila or Sipple syndrome) features medullary
carcinoma of the thyroid, pheochromocytoma, and
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parathyroid hyperplasia or adenoma. The genetic mutation
involves RET proto-oncogene, which is a receptor tyrosine
kinase for members of the glial cell line-derived
neurotrophic factor family of extracellular signaling
molecules.
MULTIPLE SCLEROSIS 1
Definition: Autoimmune demyelinating disorder
characterized
by disctinct episodes of neurologic deficits.
 White matter disease
Pathogenesis:
1. Autoimmune disease initiated by:
a. Genetic factors ( HLA-DR2)
b. Environmetal factors
* Microbial pathogens ( e.g., EBV, herpesvirus 6,
Chlamydophilapneumoniae)
2. CD4 TH1 cells and TH17 cells react against self myelin
antigens
a. CD4 TH1 cells secrete interferon-γ, which
activates
macrophages ( produce TNF-α)
b. TH1 cells release cytokines that recruit
neutrophils and monocytes
c. Antibodies produced by autoreactive B cells
damage myelin sheath/oligodendrocytes
(type II hypersensitivity reaction)
Clinical Findings:
MYASTHENIA GRAVIS 1
- A chronic autoimmune disease which is due to
autoantibodies directed against skeletal muscle
acetylcholine receptors
- Female: Male ratio 2:1 in young adults; Male
predominance in Older patients
Pathogenesis:
1. Anti-acetylcholine receptor antibodies
- 85% of patients
- Lead to aggregation and degradation of the receptors,
and damages Postsynaptic membrane thru
complement fixation
- Morphological alteration of Postsynaptic membrane
and depletion of Acetylcholine receptors
- Limits myofibers’ response to Acetylcholine
2. Antibodies against Muscle-specific receptor Tyrosine
Kinase
4. MEN III (IIb) features medullary carcinoma of the thyroid,
pheochromocytoma, and mucocutaneous neuromas.
There is a genetic mutation of RET ("rearranged during
transfection") proto-oncogene.
 Episodic course punctuated by acute relapses and
remissions (80-90% of cases)
 Frequent initial manifestation: Optic/Retrobulbar
neuritis
 Spasticity, Increased deep tendon reflexes, muscle
spasms, paresthesias
 Difficulties with the voluntary control of the
bladder function
CHARCOT’S TRIAD
 S- Scanning speech (sound drunk)
 I – Intention speech
 N- Nystagmus
Lab Findings:
 Increased CSF leukocyte count
 Increased CSF protein
 Increased CSF MBP ( active disease)
 High resolution electrophoresis shows
oligoclonal
bands.
- Pathogenic; can be passively transferred via serum
from affected individuals and therapeutic maneuvers
that decrease autoantibody levels
- Do not fix the complement; Interfere with trafficking
and clustering of acetylcholine receptor within
sarcolemmal membrane
- Net effect of which is decreased Acetylcholine
receptor function
Morphology:
- LM: ordinarily unremarkable
- junctional folds are greatly reduced or abolished at the
neuromuscular junction, and diminished AChR expression
Clinical course:
1. Anti-AchR antibodies
- Presents with fluctuating weakness that worsens with
exertion
- Diplopia and Ptosis- extraocular muscles
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- Severe generalized muscle weakness requiring
mechanical ventilation (some cases)
- Strongly associated with patients with Thymoma
(tumor of thymic epithelial cells) 10% and Thymic
Hyperplasia (appearance of B-cell follicles in the
thymus) in young adults 30%
2. Antibodies against Muscle-Specific Tyrosine Kinase
- More focal muscle involvement (Neck, Shoulder,
Facial, Respiratory, and Bulbar muscles)
NEOPLASIA 3
Neoplasm- an abnormal mass of tissue in which the growth
exceeds and is uncoordinated with that of normal tissues,
and persists in the same manner after cessation of stimuli
which evoke the change
Characteristics:
a. Autonomous
b. Excessive
c. Disorganized
2 basic components:
a. Neoplastic Cells- constitute tumor parenchyma
b. Reactive stroma- Connective Tissue, Blood
vessels, macrophages and lymphocytes
Stromal Connective tissue- provides structural framework
for growth of cells
a. Scant stroma- soft and fleshy tumors
b. Desmoplasia- abundant collagenous stroma
c. Scirrhous- Stony hard
General Classification:
1. Benign- relatively innocent; localized; doesn’t spread;
locally resectable; add -oma as suffix
o Epithelial- derived from 3 germ layers;
epithelial lining (e.g. squamous cells);
examples: Squamous papilloma, Adenoma
o Mesenchymal- derived from mesoderm (CT,
fat, bone, cartilage, lymphs and BVs)
examples: Lipoma, Chondroma
2. Malignant- Cancer; invasive; capable of metastasis;
red flag
o Mesenchymal- suffix -sarcoma; examples:
fibroblast= fibrosarcoma, fat cells=
liposarcoma, striated muscles=
rhabdomyosarcoma, smooth muscles=
leiomyosarcoma
o Epithelial- suffix -carcinoma; examples:
Adenocarcinoma, SQCA
3. Mixed tumors- divergent differentiation of a single
neoplastic clone along 2 lineages
Diagnosis:
Clinical History, Physical findings, ID of autoantibodies,
and Electrophysiologic studies
- Decrement in muscle response with repeated muscle
stimulation
Treatment:
Acetylcholinesterase inhibitors (1st line)- ↑ half-life of Ach
Plasmapheresis and Immunosupressive drugs
(glucocorticoids, cyclosporine and rituximab)- ↓Ab Titers
Thymectomy- for patients with Thymoma
a. Benign Mixed Tumor- contains epithelial
components within a myxoid stroma with
islands of cartilage and bone; 1 germ layer
b. Teratomas- from Totipotential cells; 3
germlayers; examples: Pleomorphic Adenoma
(m.c.)
“Trivial” Lesions
1. Hamartoma- mass composed of cells native to the
organ (e.g. mole, pulomonary chondroid hamartoma)
2. Choristoma- mass composed of normal cells in a
wrong location; heterotropic (e.g. Pancreatic
Choristoma (m.c.) in liver gallbladder an GIT, Ectopic
brain tissue in nasal cavity)
Exceptions: (malignant tumors w/ an -oma suffix)
a. Seminoma- seminal epithelium of testis
b. Dysgerminoma- germ cells of ovary
c. Glioma- glial cells of brain; e.g. Astrocytoma,
Oligodendroglioma, ependymoma
d. Lymphoma- Lymphoid cells
e. Insulinoma, Gastrinoma, Somatostatinoma,
Glucagonoma- Pancreatic Islets; can be benign or
malignant
Classification of Neoplasms:
I. Based on Clinical behavior
a. Benign
b. Malignant
c. Borderline Malignant- used on ovarian
tumors and low-grade malignant tumors
II. Based on Cell origin
a. Carcinomas
b. Sarcomas
TUMOR DIFFERENTIATION
Differentiation- extent which neoplastic parenchymal cells
resemble normal parenchymal cells morphologically and
functionally
Malignant neoplasms
- Well-Differentiated- retains functional capacities of
their normal counterparts (e.g. Well-diff. SQCA-
synthesize keratin)
- Poorly Diff./ Undiff. Tumors- alter functional capacity
(e.g. Paraneoplastic Syndromes)
Terms:
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Metaplasia- replacement of one type of cell with another type; 2. Insensitivity of growth-inhibitory signals
closely related to environmental change and tissue damage 3. Altered cell metabolism
and repair (e.g. Barrett’s esophagus) 4. Evasion of Apoptosis
5. Limitless replicative potential (Immortality)
Dysplasia- Disordered growth; Loss of uniformity and 6. Sustained Angiogenesis
architectural orientation 7. Metastatic and Invasive ability
o Mild to moderate- REVERSIBLE 8. Ability to evade Host immune response
o Severe- CA-In-situ/ Pre-invasive (confined ONCOGENESIS
within basement membrane) a. Oncogene- promote autonomous cell growth; by
Anaplasia- lack of differentiation mutated proto-oncogenes
a. Pleomorphism- variation in size and shape of cells and b. Proto-oncogene- unmutated cellular counterparts
nuclei c. Oncoproteins- products of the latter; devoid of
b. Abnormal nuclear morphology- Hyperchromatism, internal regulatory elements; not dependent on GF or
enlarged nuclei external signals= AUTONOMOUS GROWTH; Induce
c. Mitoses- bizarre, bipolar, tripolar, multipolar spindles mutation to proto-oncogenes→ active oncogenes=
d. Loss of Polarity- anarchic or disorganized fashion TUMOR DEVELOPMENT
e. Necrosis GROWTH FACTORS
Metastasis- no.1 criteria for malignancy Tumor Suppressor Genes
Invasiveness- no.2 criteria for malignancy Inhibitors of Mitogenic Signaling Pathways
PATHWAYS OF SPREAD 1. APC (Adenomatous polyposis cell protein)
1. Direct Seeding- open spaces without barriers; - Function: Inhibits WNT signaling
peritoneal cavity- m.c. - Familial Syndromes: Familial colonic polyps and
2. Lymphatic Spread- follows natural routes of lymphatic carcinomas
drainage (e.g. Breast CAs) - Sporadic Cancers: Gastric, Colon, and Pancreatic CA;
3. Hematogenous Spread- involves more of veins; typical Melanoma
of sarcomas; liver and lungs- mostly involved
EPIDEMIOLOGY 2. NF-1 (Neurofibromin-1)
I. Environmental Factors - Function: Inhibits RAS/MAPK signaling
a. Infectious agents - Familial Syndromes: Neurofibromatosis type-1
b. Smoking (neurofibromas and malignant peripheral nerve
c. Alcoholic Consumption sheath tumors)
d. Diet - Sporadic Cancers: Neuroblastoma, Juvenile Myeloid
e. Obesity Leukemia
f. Reproductive History
g. Carcinogens 3. NF-2 (Merlin)
II. Age - Function: Cytoskeletal stability, Hippo pathway
a. Peak incidence >55 y.o. signaling
b. Main COD among Women (40-79) and Men - Familial syndromes: Neurofibromatosis type 2
(60-79); Mostly Carcinomas (acoustic schwannoma and meningioma)
c. Children- Leukemias, CNS - Sporadic Cancers: Schwannoma, Meningioma
d. Biphasic Lymphoma
III. Acquired predisposing conditions 4. PTCH (Patched)
a. Chronic Inflammatory Disorders (e.g. - Function: Inhibits Hedgehog Signaling
H.pylori- Gastric CA) - Familial Syndromes: Gorlin Syndrome (Basal Cell CA,
b. Precursor Lesions (e.g. Barrett’s Esophagus- Medulloblastoma, several benign tumors)
Esopahgeal CA) - Sporadic CA: Basal Cell CA, Medulloblastoma
c. Immunodeficiency states (e.g. EBV-
lymphoma) 5. PTEN (Phosphatase and tensin homologue)
CARCINOGENESIS- from accumulation of complement - Function: Inhibits PI3K/AKT Signaling
mutations over time - Familial Syndromes: Cowden Syndrome (variety of
4 classes of Regulatory Genes: benign skin, GI, and CNS growths, breast, endometrial,
1. Growth-promoting Oncogenes and thyroid CA)
2. Growth-inhibiting Oncogenes - Sporadic CA: Diverse cancers, CAs and Lymphoid
3. Apoptotic Genes tumors
4. Genes for DNA repair
Cellular and Molecular Hallmarks 6. SMAD2, SMAD4
1. Self-sufficiency in growth survivals
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- Function: Component of TGFB signaling pathway, - FXN: Repair of Double stranded breaks in DNA
repressors of MYC and CDK4 expression, inducers of - FS: Familial breast and ovarian CA, Male breast CA,
CDK inhibitor expression Chronic lymphocytic leukemia (BRCA2)
- Familial Syndromes: Juvenile Polyposis - SC: Rare
- Sporadic CAs: Colonic and Pancreatic CA
Inhibitors of Cell Cycle Progression 2. MSH2, MLH1, MSH6
1. RB (Retinoblastoma protein) - FXN: DNA mismatch repair
- “Governor of Proliferation” - FS: Hereditary nonpolyposis colon CA
- Function: inhibitor of G/S transition during cell cycle - SC: Colonic and endometrial CA
progression Unknown Mechanisms
- Familial Syn: Familial Retinoblastoma Syndrome 1. WT1 (Wilms Tumor-1)
- Sporadic Cas: Retinoblastoma, Oteosarcoma, Breast - FXN: Transcription factor
CAs, Colon and Lung CA - FS: Familial Wilms tumor
- SC: Wilms tumor, Leukemias
2. CDKN2A
- p16/INK4a and p14/ARF 2. MEN1 (Menin)
- Function: p16: negative regulator of cyclin-dependent - FXN: Transcription Factor
kinases; p14: indirect activator of p53 - FS: Multiple Endocrine Neoplasia-1
- FS: Familial melanoma - SC: Pituitary, parathyroid, and pancreatic endocrine
- SC: Pancreatic, Breast, and Esophageal CA, melanoma, tumors
leukemias
GROWTH FACTOR RECEPTORS
Inhibitors of Pro-Growth Programs of Metabolism and 1. Tyrosine Kinase
Angiogenesis - Transmembrane protein with an external ligand-
1. VHL (Von Hippel Lindau protein) binding domain and a cytoplasmic tyrosine kinase
- Fxn: Inhibitor of hypoxia induced transcription factors domain
(e.g. HIF1a) - Point mutation, gene arrangement, and gene
- FS: Von-Hippel Lindau Syndrome (cerebellar amplification
hemangioblastoma, retinal angioma, renal cell CA) - Growth Factor Receptor Mutation:
- SC: Renal Cell CA o ERBB1- EGFR Point mutation- Lung CA
o ERBB2- Her2 gene amplification- Breast Ca
2. STK11 (Liver kinase B1 (LKB1)) o Gene arrangement- ALK gene- gene deletion
- Activate AMPK family of kinases; suppress cell growth chromosome 5 binds w/ EML4 gene→ EM4-
when nutrients are low ALK fusion→ Lung CA
- FS: Peutz-Jeghers syndrome (GI polyps, GI CAs, - Target Therapy:
Pancreatic CA) o Block ERBB2/Her2 for Breast CA
- SC: Diverse o Block ERB1 and EML-ALK fusion gene for Lung
CA
3. SDHB, SDHD PROTEINS INVOLVED IN SIGNAL TRANSDUCTION
- Succinate dehydrogenase complex subunits B and D 1. Ras
- TCA Cycle, Oxidative phosphorylation - Member of G-proteins that binds GTP and GDP
- FS: Familial Paraganglioma, familial - GTP-bound= Active; GDP-bound= quiescent
pheochromocytoma - GTP activity- accelerated by GAPs w/c decrease signal
- SC: Paraganglioma transduction
Inhibitors of Invasion and Metastasis - Point mutation- m.c.
1. CDH1 (E-Cadherin) - Mutated activated GTP-bound form→ pro-growth
- FXN: Cell adhesion, inhibition of cell motility signals continuously→ MAPK and PI3K/AKT pathway
- FS: Familial Gastric CA stimulation→ RAPID CELL GROWTH
- SC: Gastric CA, Lobular Breast CA - Diseases: 90%-Pancreatic CA and cholangioCA; 50%-
Enablers of genomic stability colon, endometrial and thyroid; 30%- Lung adenoCA,
1. TP53 (p53 protein) myeloid leukemia
- “Guardian of the Genome”
- FXN: Cell cycle arrest 2. BRAF
- FS: Li-Fraumeni Syndrome - 100% Hairy cell leukemia, >60%- melanoma, 80%-
- SC: Most human Cancers benign nevi, other CA e.g. colon
DNA Repair Factors - A serine/threonine protein kinase; sits at the top of
1. BRCA1, BRCA2 (Breast cancer 1 and 2) MAPK cascade
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3. PI3K ANGIOGENESIS
- Heterodimer composed regulatory and catalytic Factors:
subunits 1. Hypoxia- stabilze HIF1a→produce VEGF and bFGF→
- Part of serine/threonine protein kinase endothelial proliferation
- Key signaling code= AKT 2. Mutations of tumor suppressor genes and oncogenes
- Braking factor: PTEN 3. Transcription of VEGF- influenced by RAS-MAP kinase
- “Gain of Function” mutation pathway and GOF mutation of RAS; ↑VEGF and bFGF
NOTE: Therapy: stop angiogenesis= BEVACIZUMAB-AVASTIN-
- RAS- most frequent mutation in human CA neutralize VEGF
- BRAF- relatively successful for melanomas GENOMIC INSTABILITY
- PI3K- still ongoing a. HNPCC
- DNA mismatch repair- HALLMARK= Microsatellite
NONTYROSINE KINASE RECEPTORS instability
1. ABL - Germline mutations in MSH2 and MLH1 genes
- CML and ALL - Others: TGFB-receptor II genes, TCF component of B-
- Translocation of chrom 9-22 + fusion of BCR gene → catenin pathway and BAX
BCR-ABL fusion→ activate TK activity of ABL
b. Ataxia-Telengiectasia
2. JAK2 - Aka Louis-Bar syndrome
- MPD (PV, Essential thrombocytosis and primary - Defect in ATM gene
myelofibrosis)
- Point mutation c. Xeroderma Pigmentosum
- JAK/STAT activation - AR; Genetic defect in nucleotide excision repair (NER)
NUCLEAR REGULATORY PROTEINS enzyme
1. MYC oncogene - Mutated p53
- Master transcriptional regulator of cell growth
- FXNS: d. Bloom syndrome
a. Activates expression of genes involved in cell - Excessive homologous recombination
growth (e.g. Cyclin D)
b. Upregulate expression of Telomerase e. Fanconi Anemia
c. Reprogram Somatic Cells into Pluripotent - AR; genetic defect- proteins responsible for DNA
Stem Cells repair
- Diseases: - Increased incidence of CA (AML)
o Burkitt’s lymphoma- MYC amplification BRCA1- breast CAs in females; prostate CAs in males
o Breast, Colon, Lung – MYC amplification BRCA2- Breast CAs in both sexes; CA of ovary, pancreas, bile
o Neuroblastoma- NMYC amplification ducts, stomach, melanocytes and B lymphocytes
o Lung CA- LMYC amplification CHROMOSOMAL CHANGES
o Signaling pathways mutation- elevate MYC 1. Translocations
 RAS/MAPK- many CAs a. Burkitt lymphoma- dysregulation of c-myc gene
 Notch signaling- hematologic by 3 chrom. Translocation; t(8,14)(q24;q32)
 Wnt signaling- colon CA b. CML- Phiiladelphia Chromosome (chr 9 and 22)
 Hedgehog- medulloblastoma c. Follicular lymphoma- chr 14 and 18;
CELL CYCLE REGULATORS overexpression of bcl2 gene
1. Cyclin and CDKs d. Mantle cell lymphoma- rare; chr 11 and 14
a. CDK-cyclin complexes- phosphorylates crucial
target proteins→ cell cycle 2. Deletions
b. CDK inihbitors (CDKIs)- silence CDKs and exert a. RB gene- chr 13q14
negative control of cell cycle b. VHL gene- chr 3p25
Important checkpoints in Cell cycle:
 G1/S transition 3. Point Mutation
 G2/M transition a. RAS protein
WARBURG EFFECT
- A Growth Promoting Metabolic Alteration 4. Gene amplification
- Distinct form of cell metabolism characterized by high- a. N-Myc- Neuroblastoma 25-30%; poor prognosis
level of glucose uptake and increase fermentation via
glycolytic pathway
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b. ERBB2- located at long arm of chr17q12; 15-30% - Scale from I-III

of breast CAs; poor prognosis; Tx: trastuzumab Staging
and NeuVax - Determine extent of spread of tumor
5. Promoter Hypermethylation - Radiographic, surgical, histologic and Nodal
a. p16 involvement
b. BRCA1 LAB DIAGNOSIS
6. Chromothrypsis 1. Biopsy
- Several chromosomal rearrangements 2. Cytologic Smears
3. FNAB
Molecular basis of multistep carcinogenesis 4. Immunohistochemistry
1. Activation of RAS 5. FISH
2. Inactivation of RB 6. Flow Cytometry, PCR, DNA Microassays
3. Inactivation of p53 TUMOR MARKERS
4. Inactivation of PP2A Common:
5. Expression of Telomerase 1. PSA- prostate Ca
2. CEA- colon, pancreas, stomach and breast
CLINICAL ASPECTS 3. AFP- Hepatocellular CAs and Yolk sac tumors
Grading of Tumors 4. HCG- ChorioCA, Testicular tumor
- Microscopic examinations of tumor tissues obtained 5. CA 125- Ovarian
by biopsy 6. Gamma globulin- Multiple myeloma

NEPHRITIS 2
Acute Poststreptococcal GN - Complete recovery in >95% of cases
- Rapidly Progressive Glomerulonephritis (RPGN) (1%)
 Synonyms- acute proliferative GN; postinfectious GN - Chronic Glomerulonephritis (2%)
 Clinical features Adult
i. Decreasing in incidence in the United States. - Complete recovery (60%)
ii. Children affected more frequently than adult. - RPGN/Chronic Renal Disease (40%)
iii. Occurs 24 weeks after a streptococcal infection
of the throat or skin.
iv. Organism: Hemolytic group A streptococci Rapidly Progressive Glomerulonephritis (RPGN)
v. May be caused by other bacteria, viruses, and
parasites and systemic diseases (SLE and  Synonym: Crescentic Glomerulonephritis
polyarteritis nodosa [PAN])  Clinical feature: rapid progression to severe
vi. Nephritic syndrome renal in weeks or months
 Light microscopy
 Laboratory studies - Hypercellular glomeruli
- Elevated antistreptolysin O (ASO) titers - Crescent formation in Bowman space
- Low serum complement - Crescents originate from the parietal
epithelial cell
 Light microscopy  Immunofluorescence
- Hypercellular glomeruli with neutrophils and - Variable
monocytes - May show granular or linear deposits of
- Red cell casts in the renal tubules immunoglobulin and complement
 Immunofluorescence  Electron microscopy i. ii. iii.
- granular deposits of IgG, IgM and C3 - Variable
subepithelial area - May or may not have electron dense
- this deposits are known as “humps” deposits
 Electron microscopy - GBM disruption and discontinuity is
- subepithelial (humps) immune complex commonly seen
deposits  Prognosis
 Treatment - poor with rapid progression to acute renal
- conservative fluid management failure end stage renal disease
 Prognosis  Type I (25%)
Children - antiGBM +
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- May have a pulmonary component
(Goodpasture syndrome)
- High prevalence of HLA subtypes
 Type II (25%)
- Immune complex mediated
- Characteristic (lumpy bumpy) granular
patterns of staining
 Type III (> 50%)
- Pauci immune type
- Anti GBM (-)
- Anti Neutrophil Cytoplasmic Antibodies
(ANCA) +
- Associated with Wegener granulomatosis
or microscopic polyarthritis
Membranous Glomerulonephritis
 Most common cause of Nephrotic Syndrome in
adults.
 Etiology
- Most (85%) cases are idiopathic
- Drugs (penicillamine)
- Infections (hepatitis virus B and C, syphilis,
etc.)
- Systemic diseases (SLE, diabetes mellitus,
etc.)
- Associated with malignant carcinomas of
the lung and colon
- There may be a genetic predisposition
 Electron Microscope (EM)
- findings Diffuse thickening of the
glomerular capillary wall
- Subepithelial deposits along the basement
membrane
- silver Effacement of podocyte foot
processes
 Light Microscope
- Spikes projecting from the glomerular
basement membrane
NUTRITIONAL DISORDERS 3
Maramus
 Deficiency of almost all nutrition, notable
protein and calories
 Typically in children below 1
 Retard growth, loss of muscle, loss of
subcutaneous fat (wasting away)
Water soluble vitamin
 Immunofluorescence
- granular and linear pattern of IgG and C3
e
 Prognosis
- Variable course
- Spontaneous remission
- Persistent proteinuria
- Endstage renal disease
CHRONIC GLOMERULONEPHRITIS
 Definition
- the final/ end stage of many forms of
glomerular disease and is characterized by
progressive renal failure, uremia and
ultimately death
 Clinical features
- Anemia, anorexia and malaise
- Proteinuria, hypertension and azotemia
 Gross
- Small
- Shrunken Kidneys
 Micro
- hyalinization of glomeruli, interstitial
fibrosis, atrophy of tubules and lymphocytic
- infiltrates Urinalysis shows broad waxy
casts
 Treatment
- dialysis and renal transplantation
 Percentage of Progression to Chronic GN
- Post streptococcal GN (12%)
- RPGN (90%)
- Membranous GN (40%)
- Focal Glomerulosclerosis (50-80%)
- Membranoproliferative GN (50%)
- IgA Nephropathy (30-50%)
vs Kwashiorkor
 Protein deficiency but adequate calories
 Children above 1
 Same as marasmus but preservation of
subcutaneous fat ( Fatty liver)
 Severe edema and depigmented bands
vs. Fat soluble vitamin
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-gain from food and excreted in urine -

VitB1(thiamin)- carbohydrate and amino acid VitA-rhodopsin synth.; glycoprotein synth.

And metabolism -Night blindness, squamous metaplasia
-Beri-Beri, Wernicke-Karsakoff Mostly in the eyes, Xeropthalmia, and
Syndrome Keratomalacia
B2(riboflavin)-FAD and FMN oxidation reduction VitD(calciferol)-active form 1,25-(OH)D(calcitriol)
Process Promotes intestinal Ca absorption like
-Cheilosis, corneal vascularization PTH, enhances calcification of bones
,glossitis, dermatitis -Rickets in children; osteomalacia in
B3(niacin)-NAD and NADP for glycolysis, citric Adults
Acid cycle and oxidation VitE(tocopherol)-antioxidant
-Pellargra -possible neurologic dysfunction
B6(pyridoxine)-transamination, porphyrin synt VitK-synthesis of y-carboxyglutamyl (clotting
Convert tryptophan to niacin Factors II, VII, IX, X and protein C)
-neurologic dysfunction, -Hemorrhagic diatheses
Convulsion in infants and
Cheloisis
B12(cobalamin)-folate synth and form dUMP to
dTMP in DNA synth
-Megaloblastic anemia and
Neurologic dysfunction
Folic acid-DNA synth
-Megaloblastic anemia and neurologic
Dysfunction
VitC-hydroxylation of proline and lysine in
Collagen synth., hydroxylation of dopamine
To norepinephrine
-Scurvy, poor wound healing, hemorrhage
Source
B12-food of animal origin VitA-liver, egg yolk, and butter
Rest of B Vit- cereals, gree vegetables, fish, meat VitD-absorbed UV by the skin
And dairy foods VitE-??
Folic acid-same as Rest of B Vit VitK-produce by intestinal bacteria, some
Vit C-fruits Yellow vegetable and dairy products

PARATHYROIDISM 1
HYPERPARATHYROIDISM - well-circumscribed, soft, tan to reddish brown
- elevated PTH nodule, delicate capsule
- feedback inh by elev serum Ca
• Primary hyperparathyroidism: an autonomous - uniform, polygonal chief cells with small, centrally
overproduction of PTH, from an adenoma or hyperplasia placed nuclei
of parathyroid tissue Primary hyperplasia
- leads to asymptomatic hypercalcemia - involves all 4 glands, assymetrical
- Most common -- Adenoma: 85% to 95% (Cyclin D1 - chief cell hyperplasia (mc), glands
gene inversions leading to overexpression of cyclin diffuse/multinodular
D1, MEN1 mutations) - water clear cell hyperplasia, islands of oxyphils and
Primary hyperplasia (diffuse or nodular): 5% to 10% poorly developed,delicate fibrous strands may
Parathyroid carcinoma: ~1% envelop the nodules
- Adults, F>M Parathyroid CA
- enlarge one parathy-roid gland and consist
Morphology of gray-white, irregular masses
Parathyroid Adenoma - uniform and resemble normal parathyroid
- solitary, in close proximity to thyroid/ectopic site cells,and are arrayed in nodular or
- 0.5 to 5 g trabecular patterns
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- enclosed by a dense, fibrous capsule
- diagnosis: invasion of surr tissues and metastasis
Symptoms
- Skeletal: if untreated
osteoporosis
brown tumors
osteitis fibrosa cystica (von Recklinghausen disease
of bone)- severe
- Urinary tract: PTH-induced hypercalcemia
- GI: disturbances, including constipation, nausea,
peptic ulcers, pancreatitis, and gallstones
- CNS: alterations, including depression, lethargy,
and eventually seizures
- Neuromuscular abnormalities, including weakness
and fatigue
- Cardiac manifestations, including aortic or mitral
valve calcifications (or both)
• Secondary hyperparathyroidism: compensatory
hypersecretion of PTH in response to prolonged
hypocalcemia, from chronic renal failure (mc), low dietary
intake of Ca, steatorrhea, and vitamin D def
- Inc chief cells, water clear cells
- Dec fat cells
- metastatic Ca: lungs, heart, stomach, and blood
vessels
- renal osteodystrophy may regress
- calciphylaxis from vasc Ca
- Tx: vit D, phosphate binders
• Tertiary hyperparathyroidism: persistent hypersecretion of
PTH even after the cause of prolonged hypocalcemia is
corrected, for example after renal transplant
HYPOPARATHYROIDISM
• Surgically induced hypoparathyroidism
PARKINSON DISEASE 1
- neurodegenerative disease marked by a
prominent hypokinetic movement disorder that
is caused by loss of dopaminergic neurons
from the substantia nigra
- masked facies (diminished facial expression),
stooped posture, slowing of voluntary
movement, festinating gait, rigidity, and a
“pillrolling” tremor
- caused by dopaminergic antagonists or by
toxins, exposure to MPTP, pesticides
- unknown: triad - tremor, rigidity, and
bradykinesia (confirm by LDOPA replacement
therapy)
- genetic: α-synuclein, mitochondrial dysfunction,
LRRK2
- removal of all the parathyroid glands during
thyroidectomy, excision (mistaken as LN) during
radical neck dissection, or removal of large
parathyroid tissue in the treatment of primary
hyperparathyroidism
• Autoimmune hypoparathyroidism
- assoc with chronic mucocutaneous candidiasis and
primary adrenal insufficiency common in childhood
• Autosomal-dominant hypoparathyroidism
- CASR gof leads to suppressed PTH, resulting in
hypocalcemia and hypercalciuria
• Familial isolated hypoparathyroidism (FIH)
- A rec and A dom
• Congenital absence of parathyroid glands
- DiGeorge syndrome
Symptoms
- Hypercalcemia: tetany - neuromuscular irritability,
Chvostek sign and Trousseau sign
- Mental status changes
- Intracranial manifestations
- Ocular disease
- Cardiovascular manifestations
- Dental abnormalities
PSEUDOHYPOPARATHYROIDISM
- end-organ resistance to the actions of PTH
(hypocalcemia, hyperphosphatemia, and elevated
circulating PTH) TSH (mild), and FSH/LH
(hypergonadotropic hypogonadism in females
- Tx: LDOPA replacement therapy, deep brain
stimulation, early therapeutic trials of neural
transplanta tion and gene therapy
Morphology
- pallor of the substantia nigra and locus
ceruleus (loss of pigmentation)
- Lewy bodies- single or multiple cytoplasmic,
eosinophilic, round to elongated inclusions that
often have a dense core surrounded by a
pale halo
Dementia - 10-15% of PD px
- fluctuating course, hallucinations, and prominent
frontal signs
- wide spread Lewy bodies in neurons in the
cortex and brainstem
- Lewy neurites (aggregated protein)
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PELVIC INFLAMMATORY DISEASE 1
PELVIC INFLAMMATORY DISEASE
- ascending infection from vulva or vagina—> spreads upwards
to involve most structures in the female genital system
- pelvic pain, adnexal tenderness, fever and vaginal discharges
- gonococcus- most common cause of PID
- chlamydia- 2nd most common
- polymicrobial (staph, strep C. perfringens); usually
after spontaneous or induced abortions; normal to abnormal
deliveries (puerperal infections)
 Gonoccoal Infection
- 2-7 days after inoculation; involves usually
endocervical mucosa
- may spread upwards to involve the fallopian tubes
and tubo-ovarian region; endometrium usually spared
- MX: marked acute inflammation confined to the
superficial mucosa
PHERESIS 1
Plateletpheresis
- prepared from whole blood (stored at 20-24C prior
to processing or apheresis
- whole blood processing: light spin (to remove red
cells) followed by centrifugation (to spin down platelets and
white cells) express supernatant plasma into another bag for
freezing (FFP) remaining plasma, platelets and white cells=
platelets
- conditions: for severe thrombocytopenia and
platelet dysfunction prophylactic use of platelets when platelet
count is low is controversial- threshold depends on patient’s
risk of bleeding contraindicated in TTP and heparin induced
thrombocytopenia
- platelets from donors who are within 48 hours of
taking drugs (e.g. aspirin) that impair platelet function should
not be used as a single donor (apheresis product or single unit
for new born)
- platelet refractories—> the lack of expected
response is usually due to Ab to HLA class I Ag or
platelet specific Ag
- transfusion in average sized adult: 1 unit of platelets
raises platelet count 5000-10000/uL
1 apheresis unit raises 20000- 60000/uL
RED BLOOD CELL TESTS 1
Components of CBC
 White blood cell count (WBC or leukocyte count)
 WBC differential count
 Red blood cell count (RBC or erythrocyte count)
 Hematocrit (Hct)
- inflammatory exudates—>intracellular gm(-)
diplococci
- Def. Dx: culture or PCR
- Acute suppuraltive salpingitis—> tubal mucosa
becomes congested and infiltrated with neutrophils,
lymphocytes and plasma cells—> tubal lumen fills with
purulent exudate—> leaks out to the fimbriated end—>
spillage into ovary—>salpingo-oophoritis
- Tubo-ovarian abscess—> pus within ovary and tube
- Pysosalpinx—> pus within tubal lumen
- Hydrosalpinx—>dilated fluid filled tubal lumen
- Acute Cx: peritonitis, bacteremia—> endocarditis,
meningitis, suppurative arthritis
- Chronic sequelae: tubal adhesions and
obstruction—> infertility, ectopic pregnancy,
intestinal obstruction
- Tx: early—> can be treated with penicillin
later stage—>difficult
transfuse within 4 hours after pooling in an open system
- pH ≥6.2 at end of storage; stored in volume of
plasma necessary to maintain pH, usually 40-70 cc for
whole blood derived platelets
- store with continuous gentle agitation at 20-24C
(room temp)
- outdate= 5 days
- may have some residual RBCs; consider
administering RgIg to D- women of childbearing age who have
received D pos platelets
Granulocyte pheresis
- obtained by apheresis
- G-CSF increases yield
- for neutropenic patients with documented g(-) sepsis
who have not responded to antibiotics
- can transmit CMV, induce HLA immunization and
cause GVHD if not irradiated
- stored without agitation at 20-24C for up to 24hrs
but should be transfused ASAP
- should be ABO compatible with recipient;
crossmatch if 2>mL RBCs
 Hemoglobin (Hbg)
 Mean corpuscular volume (MCV)
 Mean corpuscular hemoglobin (MCH)
 Mean corpuscular hemoglobin concentration (MCHC)
 Red cell distribution width (RDW)
 Platelet count
 Mean Platelet Volume (MPV)
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The complete blood count (CBC) is one of the most commonly
ordered blood tests. The complete blood count is the
calculation of the cellular (formed elements) of blood. These
calculations are generally determined by special machines that
analyze the different components of blood in less than a
minute. A major portion of the complete blood count is the
measure of the concentration of white blood cells, red blood
cells, and platelets in the blood.
Procedure: The complete blood count (CBC) test is performed
by obtaining a few milliliters (one to two teaspoons) of blood
sample directly form the patient. It can be done in many
settings including the doctor's office, laboratories, and
hospitals. The skin is wiped clean with an alcohol pad, and a
needle is inserted through the area of cleansed skin into to
patient's vein (one that can be visualized from the skin.) The
blood is pulled from the needle by a syringe or by a connection
to a special vacuumed vial where it is collected. This sample is
taken to the laboratory for analysis.
The values generally included are the following:
 White blood cell count (WBC) is the number of white
blood cells in a volume of blood. Normal range varies
slightly between laboratories but is generally between
4,300 and 10,800 cells per cubic millimeter (cmm).
This can also be referred to as the leukocyte count and
can be expressed in international units as 4.3 to 10.8 x
109 cells per liter.
 White blood cell (WBC) differential count. White blood
count is comprised of several different types that are
differentiated, or distinguished, based on their size
and shape. The cells in a differential count are
granulocytes, lymphocytes, monocytes, eosinophils,
and basophils.
A machine generated percentage of the different types of
white blood cells is called the automated WBC differential.
These components can also be counted under the microscope
on a glass slide by a trained laboratory technician or a doctor
and referred to as the manual WBC differential.
 Red cell count (RBC) signifies the number of red blood
cells in a volume of blood. Normal range varies slightly
between laboratories but is generally from 4.2 to 5.9
million cells/cmm. This can also be referred to as the
erythrocyte count and can be expressed in
international units as 4.2 to 5.9 x 1012 cells per liter.
Red blood cells are the most common cell type in blood and
people have millions of them in their blood circulation. They
are smaller than white blood cells, but larger than platelets.
 Hemoglobin (Hb). This is the amount of hemoglobin in
a volume of blood. Hemoglobin is the protein
molecule within red blood cells that carries oxygen
and gives blood its red color. Normal range for
hemoglobin is different between the sexes and is
approximately 13 to 17.5 grams per deciliter for men
and 12 to 15.5 for women (international units 8.1 to
11.2 millimoles/liter for men, 7.4 to 9.9 for women).
 Hematocrit (Hct). This is the ratio of the volume ofred
cells to the volume of whole blood. Normal range for
hematocrit is different between the sexes and is
approximately 45% to 50% for men and 37% to 45%
for women. This is usually measured by spinning down
a sample of blood in a test tube, which causes the red
blood cells to pack at the bottom of the tube.
 Mean corpuscular volume (MCV) is the average
volume of a red blood cell. This is a calculated value
derived from the hematocrit and red cell count.
Normal range may fall between 80 to 100 femtoliters
(a fraction of one millionth of a liter).
 Mean Corpuscular Hemoglobin (MCH) is the average
amount of hemoglobin in the average red cell. This is a
calculated value derived from the measurement of
hemoglobin and the red cell count. Normal range is 27
to 32 picograms.
 Mean Corpuscular Hemoglobin Concentration
(MCHC) is the average concentration of hemoglobin in
a given volume of red cells. This is a calculated volume
derived from the hemoglobin measurement and the
hematocrit. Normal range is 32% to 36%.
 Red Cell Distribution Width (RDW) is a measurement
of the variability of red cell size and shape. Higher
numbers indicate greater variation in size. Normal
range is 11 to 15.
 Platelet count. The number of platelets in a specified
volume of blood.Platelets are not complete cells, but
actually fragments of cytoplasm (part of a cell without
its nucleus or the body of a cell) from a cell found in
the bone marrow called a megakaryocyte. Platelets
play a vital role in blood clotting. Normal range varies
slightly between laboratories but is in the range of
150,000 to 400,000/ cmm (150 to 400 x 109/liter).
 Mean Platelet Volume (MPV). The average size of
platelets in a volume of blood.
Functions of cells in CBC : The cells in the CBC (white blood
cells, red blood cells, and platelets) have unique functions.
Generally speaking, white blood cells are an essential part of
the immune system and help the body fight infections. Each
different component of the white blood cell (the WBC
differential) plays a specific role in the immune system.
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Red blood cells are essential in transporting oxygen to all the
cells in the body to serve their functions. The hemoglobin
molecule in the red blood cell is the vehicle for the
transportation of oxygen. Platelets are a part of the blood
clotting system in the body and help in preventing bleeding.
Uses of CBC : Your doctor may order this test for a variety of
reasons. It may be a part of a routine check-up or screening, or
as a follow-up test to monitor certain treatments. It can also be
done as a part of an evaluation based on a patient's symptoms.
For example, a high WBC count (leukocytosis) may signify an
infection somewhere in the body or, less commonly, it may
signify an underlying malignancy. A low WBC count
(leukopenia) may point toward a bone marrow problem or
related to some medications, such as chemotherapy. A doctor
may order the test to follow the WBC count in order to monitor
the response to a treatment for an infection. The components
in the differential of the WBC count also have specific functions
and if altered, they may provide clues for particular conditions.
A low red blood cell count or low hemoglobin may
suggest anemia, which can have many causes. Possible causes
of high red blood cell count or hemoglobin (erythrocytosis)
may include bone marrow disease or low blood oxygen levels
(hypoxia).
A low platelet count (thrombocytopenia) may be the cause of
prolonged bleeding or other medical conditions that affect the
production of platelets in the bone marrow. Conversely, a high
platelet count (thrombocytosis) may point toward a bone
marrow problem or severe inflammation.
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RED CELL DISORDERS 2

RED BLOOD CELL DISORDERS 2. Mean Corpuscular Hemoglobin (MCH)
Red Blood Cell Disorders - mean or average amount of Hb per cell
Quantitative Qualitative Hb x 10 = pg
Anemia 1. Abnormality in RBC
1. Blood loss morphology 3. Mean Corpuscular Hemoglobin Concentration (MCHC)
2. Decreased 2. Abnormality in - Mean or average hemoglobin concentration (in grams)
production function per 100 ml of packed red blood cells
3. Increased Intracorpuscular/inherent to Hb x 100 = g/dl (%)
destruction red cells Hct
Polycythemia
Mechanism of Anemia
1. Effective Erythropoiesis
Anemia - Results in the production of 90% or more mature
- differentiated RBCs in the circulation
ANEMIA Ex. Blood loss
Operational Definition:
Reduction, from baseline value of: 2. Ineffective erythropoiesis
 total Red Blood Cells (RBCs) - Refers to production of progenitor cells that are defective
 circulating Hemoglobin (Hb) that they are destroyed prior to or shortly after leaving BM
 amount of Hematocrit (Hct) Ex. Megaloblastic anemia, Thalassemia
-below the reference range for healthy individuals of the same
-sex, age and race under similar environmental conditions. 3. Insufficient erythropoiesis
- quantitative lack of erythroid precursors in the marrow
- absent or severe of the marrow and replacement by fat
Parameters Adult Adult Ex. Aplastic anemia
Male Female

Red Blood 4.6 – 6.0 x 4.0 – 5.4 x

Cells (RBC) 1012/L 1012/L
I.According to RBC morphology by Indices Range
Hematocrit 40 – 50 % 35 – 49 % RBC MCV MCH MCHC Anemia
(Hct) (0.40 – 0.50 (0.35 – 0.49 Morphology (fl) (pg) (%)
L/L) L/L) Normocytic/ 80- 27-32 32-36 -acute blood
normochromic 100 loss
Hemoglobin 14.0 – 18.0 12.0 – 15.0 -hemolytic
(Hb) g/dL g/dL anemia
140 – 180 120 – 150 g/L -aplastic (early
g/L stage)
-myelophthisic
anemia
ANEMIA -stem-cell
Functional Definition: related
-Decrease in the oxygen carrying capacity of the blood. anemias
-Clinical signs and symptoms result from the diminished Macrocytic/ high Low Normal -megaloblastic
delivery of oxygen to the tissues normochromic -anemia of lier
disease
Parameters: -chronic
 CBC – RBC count, Hemoglobin (Hb), Hematocrit (Hct) aplastic
 Red cell indices: -acute
hemolytic (with
1. Mean corpuscular volume (MCV) shift
- mean or average size of the individual red cells reticulocytosis)
Hct x 10 = fl Microcytic/ Low Normal Normal -anemia of
RBC normochromic chronic
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inflammation THROMBOTIC THROMBOCYTOPENIC PURPURA

Microcytic/ low low low -IDA - Disseminated thrombotic occlusions of the microcirculation
hypochromic -thalassemia HEMOLYTIC UREMIC SYNDROME
-lead poisoning - Verocytotoxin produced by bacteria; i.e. E.coli, S.
-porphyrias pneumoniae
-sideroblastic TRAUMATIC CARDIAC HEMOLYTIC ANEMIA
anemia
II. Pathophysiologic classification: 2. Infection
A. Blood loss HEMOLYTIC ANEMIA DUE TO MALARIA, BABESIA, BARTONELLA
B. Caused by decrease production of RBC AND EHRLICHIA INFECTION
C. Caused by increased destruction or loss:
3. Chemical and physical agents
Caused by decrease production of RBC TOXINS AND BURNS
1. Disturbance of hematopoietic stem cell proliferation and
differentiation: 4. Antibody - mediated
APLASTIC ANEMIA HEMOLYTIC ANEMIA SECONDARY TO WARM
2. Disturbance of DNA Synthesis: REACTING ANTIBODIES
MEGALOBLASTIC ANEMIA 5. . Blood loss
3. Disturbance of hemoglobin synthesis:
IRON DEFICIENCY ANEMIA Chronic Blood Loss
THALASSEMIA  Rate of loss >>>>> Regenerative capacity of erythroid
4. Disturbance of proliferation and differentiation precursors
ANEMIA OF CHRONIC RENAL DSE  Iron reserves are depleted
ANEMIA OF ENDOCRINE DISORDERS
5. Unknown or multiple mechanisms: Aplastic Anemia
ANEMIA OF CHRONIC DISEASE  Failure or suppression of multipotent myeloid stem
ANEMIA WITH BONE MARROW INFILTRATION cells – Pancytopenia
-Anemia
SIDEROBLASTIC ANEMIA -Neutropenia
-Thrombocytopenia
Caused by increased destruction or loss  Inadequate production or release of differentiated cell
lines
A. Intracorpuscular Abnormality/ Intrinsic Abnormality
1. Membrane defect Aplastic Anemia
HEREDITARY SPHEROCYTOSIS - defect in Etiology:
spectrin, ankyrin, protein 4.2 I. Acquired
HEREDITARY ELLIPTOCYTOSIS defect spectrin α i. Idiopathic ( in 65% of cases)
and β chain, protein 4.1 ii. Chemical agents
HEREDITARY PYROPOIKILOCYTOSIS - Spectrin - Dose related - Idiosyncratic
deficiency > alkalyting agent >Chloramphenicol
2. Enzyme deficiency > Antimetabolic >Phenylbutazone
GLUCOSE -6-PHOSPHATE DEHYDROGENASE > Benzene >Insecticides
PYRUVATE KINASE > Chloramphenicol
PORPHYRIA > Inorganic arsenicals
3. Globin abnormality Aplastic Anemia
HEMOGLOBINOPATHIES Etiology
Hemoglobin S - α2β2 6Glu -- val iii. Physical agents
Hemoglobin C - α2β2 6Glu – Lys ex. Whole-body irradiation
4. Paroxysmal nocturnal hemoglobinur iv. Viral infections
- acquired membrane abnormality causing an increase ex. Non-A non-B Hepatitis
susceptibility of blood cells to complement CMV
EBV
B. Extracorpuscular abnormality/ Extrinsic abnormality HVZ
1. Mechanical v. Others
MICROANGIOPATHIC HEMOLYTIC ANEMIA Aplastic Anemia
- Fibrin deposits inside the lumens of arterioles and vessel Etiology
walls
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II. Inherited Etiology: Drug therapy, Infections

Fanconi anemia In patients with thymoma
Diamond Blackfan syndrome  Female:Male = 2:1
 Insidious
Aplastic Anemia  Immunologic mechanisms
Morphology
 Bone marrow Pure Red Cell Aplasia
-Markedly hypocellular Diamond Blackfan Syndrome
-Populated by fat cells. Fibrous stroma and scattered -Congenital PRCA
lympocytes and plasma cells -1 year to 6 year old
“ dry tap” -Associated with Developmental anomalies:
 Growth retardation
 Peripheral smear:  Mental retardation
-Normocytic, normochromic red cells  Genital hypoplasia
-Slight macrocytosis Laboratory:
-Absent reticulocytosis  Severe normocytic and normochromic anemia;
Sometimes slightly macrocytic
Aplastic Anemia  Bone marrow – Red cell aplasia
Morphology – Normal granulocytic and
Secondary changes: megakaryocytic cell line
-Fatty changes in the liver and kidney  Hemoglobin F increased (5 to 25%)
-Systemic hemosiderosis  Increased red cell adenosine deaminase (ADA)
Aplastic Anemia Megaloblastic Anemias
Clinical Features Impaired DNA synthesis
 Insidious onset Types
 Symptoms related to paucity of: 1. Vitamin B12 deficiency
red cells – anemia * Pernicious Anemia
platelets – bleeding * Imerslund’s Syndrome
neutrophils – infection 2. Folic acid deficiency
 Splenomegaly is absent
 Treatment: Bone marrow transplantation or 1. Cobalamin (Vitamin B12) Deficiency
immunosuppresion Mechanisms:
I. Inadequate Intake
Fanconi Anemia - Extremely rare
 Congenital aplastic anemia - Seen in persons who completely
 Autosomal recessive inheritance abstain from animal food, milk and eggs.
 With or without congenital anomalies: 2. Defective Production of Intrinsic factor
-Hyperpigmentation - Most common cause
-malformations of extremities - PERNICIOUS ANEMIA
-Short stature Megaloblastic Anemias
-microcephaly Pernicious Anemia
-Hypogonadism - Failure of gastric mucosa to secrete
-malformations of other organs, Heart and kidneys intrinsic factor

Fanconi Anemia Pernicious Anemia

 Pancytopenia becomes obvious after 1. Pathological lesions of the fundus and body of the stomach
infancy and usually significant by eight year - gastric mucosal atrophy
 Increased levels of fetal hemoglobin (HB F) and i - selective loss of parietal and chief cells from the gastric
Antigen mucosa
- submucosal lymphocytic infiltrates.
Pure Red Cell Aplasia 2. Autoantibodies are directed against the a- und b-subunit of
 Rare the gastric H+/K+- ATPase, a hydrogen transporting enzyme,
 Absence of or near – absence of red cell precursors responsible for the acidification of the stomach lumen.
 Primary or secondary
Secondary: 3. Gastrectomy
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4. Achlorhydria even after histamine stimulation

Imerslund’s Syndrome 5. Inability to absorb an oral dose of cobalamine (Schilling test)
-Inherited autosomal recessive trait 6. Excretion of methylmalonic acid in the urine
-Mainfest during the first 2 years of life
-Deficiency in receptor site in the terminal ileum. For Folic acid deficiency
7. Decreased folate in the serum or red cells
Other Causes of Vitamin B12 Deficiency 8. Increased excretion if FIGlu after administered dose of
Crohn’s Disease histidine
- affects the terminal ileum
Diphyllobotrium latum infection Iron Deficiency Anemia
- lodges in the ileum  Most common form of anemia worlwide
Zollinger Ellison syndrome  Normal Iron Metabolism:
- hypersecretion of gastric juice, results to low pH with -Primarily absorbed in the duodenum
interference in the binding of VitB12 to the intrinsic factor -Total body iron = 2 gms in women
6 gms in men
-80 % functional iron is in Hemoglobin, myoglobin and iron
containing enzymes
2. Folic acid deficiency
i. Inadequate Intake of folate Etiology:
- Nutritional deficiency 1. Low dietary intake
- Liver disease associated with alcoholism 2. Malabsorption – sprue and celiac diseases
ii. Defective absorption of folate 3. Increased demands – pregnancy &
- Occurs in association of malabsorption malignancy
syndromes 4. Chronic blood loss – GI and FGT bleeding
iii. Increased Requirement for folate
- Occurs in pregnancy and infants Clinical features
- Also in malignancies 1. Peripheral blood
- Hypochromic, microcytic anemia
Ineffective erythropoiesis 2. Bone Marrow
Defective DNA Synthesis - Normoblastic hyperplasia
(N) RNA and protein synthesis - Loss of sideroblasts
and stainable iron in
Delay or block in mitotic division reticuloendothelial
cells
Asynchronism between the cytoplasmic maturation and 3. Other organs
nuclear maturation - due to depletion of iron-containing
enzymes:
Megaloblastic cells  Koilonychia
 Atrophy of tongue and gastric mucosa
Increased hemolytic destruction 4. Iron Content
IDA Normal Reference Value
Megaloblastic Anemias *Serum Iron (low) Adults: 50 - 60 ug/dL
Diagnostic Features: (9- 29 umol/L)
1. Pancytopenia *Serum Iron Adult: 250 – 400 ug/ dL Binding
 Severe megaloblastic Capacity (high) (45 - 72 umol/L)
anemia *Serum Ferritin (low) Adult: 12 - 300 ug/L
 Leukopenia with *% Sat. of TIBC < 15% Adult: 20 - 50 %
hypersegmented neutrophils *Serum transferrin
 Mild to moderate Receptors (low)
thrombocytopenia Hemolytic Anemia
Introduction
2. Neurologic changes Mean life span of a RBC - 120days; undergo metabolic and
3. Striking reticulocytic response and improvement in chemical changes  loss of deformability  macrophages
hematocrit levels after parenteral administration of vitamin recognize changes  phagocytosis
B12
RBC Destruction
For Vitamin B12 deficiency
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extravascular intravascular - substances in the but acquired condition

-takes place in the -destruction of severely plasma that lyses RBCs
reticuloendothelial damaged blood cells ex. 1. Membrane defect
system (liver, bone normally occurs Infectious agents – -Hereditary
marrow, lymph nodes intravascularly Malarial, sepsis Spherocytosis
and circulating -account for 80% of rbc Chemical agents – Toxins -Hereditary Elliptocytosis
monocytes) destruction & Drugs -Hereditary
-account for 90% or red Poikilocytosis
cell destruction Circulating antibodies 2. Enzyme deficiency
- conditions affecting the Glucsoe-6-Phosphate
Definition: anatomy of the vascular Dehydrogenase
Those anemia which result from premature and excessive system Pyruvate Kinase
destruction of red cells either within the blood vessels or ex. 3. Globin Abnormalities
outside it. Mechanical Hemoglobinopathies
- Microangiopathic 4. Acquired Membrane
Classification of Hemolytic Anemia - Traumatic uremic Abnormality
- Acute vs. Chronic syndrome PNH
- Inherited vs. Acquired - Prosthetic valves
- Intrinsic vs. Extrinsic
- Intravascular vs. Extravascular Physical agents - Burns
Blood loss
acute chronic
-rapid onset -Rbc lifespan is
-Isolated, episodic or chronically shortened
paroxysmic -categories extravascular intravascular
-hemolysis either 1. Bone marrow maybe  RBCs are  Destruction of
disappears or subsides able to compensate -> engulfed by the severely
between episodes anemia may not be macrophage damaged blood
evident. and lyzed by cell occurs in the blood
-examples 2. bone marrow cannot their digestive stream andcan
Paroxysmal cold generate rbc fast system lyze by fragmentation
hemoglobinuria enough->anemia in the spleen and
Paroxysmal nocturnal bone marrow
hemoglobinuria -examples 1. Inherited:
Hemolytic transfusion Thalassemia Membrane
reaction Hemoglobinopathies abnormalities
G6PD Enzyme deficiencies
Globin
abnormalities
inherited acquired 2. Acquired Membrane
-passed off to offspring -develop in individuals Abnormality – PN
by mutant gene of who were previously
parents hematologically normal  Such
but acquired condition classification is
-ex. that lyses rbc readily
Thalassemias distinguished by
Hemoglobinopathies -ex. results of
Infectious diseases laboratory
(malaria) testing
PNH
HEREDITARY SPHEROCYTOSIS
Extrinsic Intrinsic also known as Minkowski–Chauffard syndrome
(extracorpuscular) (Intracorpuscular) - Intrinsic defect in the red blood cell membrane
-Conditions that arise -Develop in individuals skeleton
from outside the who were previously - Inherited disorder:
RBCs hematologically normal
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 75% - an autosomal dominant inheritance  Episodic Intravascular and Extravascular Hemolysis

pattern  Triggers of hemolysis:
 Compound heterozygosity (inheritance of 2 1. Infections
different defect) - Viral hepatitis, Pneumonias, Typhoid fever
- Highest prevalence in Northern Europe – 1 in 5,000 2. Drugs
- Anti-malarial drugs, Sulfonamides, Nitrofurantoin
Morphology : 3. Food – Fava beans
Spherocytes
Small, dark-staining red cells, Clinical Features:
lacking central zone of pallor Acute Hemolysis
-Usually starts 2 to 3 days following exposure
Characteristics
1. Anemia
Hemolytic anemia 2. Hemoglubinuria
Reticulocytosis 3. Hemoglobinemia
Bone marrow erythroid hyperplasia -No features related to chronic hemolysis
Hemosiderosis (splenomegaly and cholelithiasis.
Jaundice -Recovery phase:
Pigment stones (Cholelithiasis) Reticulocytosis
Splenomegaly Morphology:
Bite cells
Clinical Features: Heinz bodies - due to high level of oxidants cross-linking of
Diagnosis: reactive sulfhydryl groups of hemoglobin  denatured
-Family history hemoglobin
-Hematologic findings
-Laboratory evidence – MCHC (increased) SICKLE CELL DISEASE
 An inherited disease of the red blood cells.
Characteristic Clinical Features:  Affect the proteins inside the red blood cells -
-20-30% patients – mild disease HEMOGLOBIN.
-Anemia  Deoxygenated red blood undergo transformation from
-Jaundice – requires exchange transfusion normal biconcave disk to sickle - shaped structure.
-Splenomegaly History:
1910 - first described by James Herrick in the blood of an
Aplastic crises Hemolytic crises anemic black medical student.
-triggered by acutre -produced by 1949 - Pauling et.al., first identify molecular basis of an
parvovirus inection intercurrent events inherited trait - Single amino acid substitution
-around 1-2 weeks (infectious 1987 - diagnosis by polymerase chain reaction (PCR) became
mononucleosis)-> available.
increased splenic SICKLE CELL DISEASE
destruction Pathogenesis:
 Homozygous for the Hb S gene
Treatment: -supportive, -splenectomy - 80 - 90% of total hemoglobin is Hb S
- Remaining is Hb F and Hb A2
- Sickle Cell Anemia (Hb SS)
GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY  Heterozygous for Hb S gene
 Glucose-6-Phosphate Dehydrogenase is involved in - 8 to 10% of African-Americans
the Hexose Monophosphate shunt/Pentose Phospate - 40 % or 1/3 of total hemoglobin is Hb S
Pathway  Reduction of oxidized form of - Sickle Cell Trait (Hb S)
glutathione/detoxifies accumulated peroxide.
 Recessive x-linked trait  Males > Females Epidemiology:
 Variants that cause most of the clinically significant  Common among blacks
Hemolytic anemia: -Africa - 40 % of the population are heterozygous
1. G6PD- - 10% of Americal Blacks -US - 10 % are carriers of the trait
2. G6PD Mediterranean – prevalent in the Middle East - 1 in 650 (pop. of 50,000) has Sickle cell anemia
 Protective against Plasmodium falciparum  Gene also encountered in parts of the Mediterranean
Pathogenesis: basin, Middle East and India
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 Gene also prevalent in areas endemic for falciparum -Adding Sodium hydrosulfite results to lysis of RBC and
malaria. reduction of Hb S.
Homozygous form -Polymers of Hb S obstruct light rays and produce opacity.
- HB SS (α2βς2) - due to point mutation -Useful for screening
- Valine is substituted for glutamic acid at the 6th position of β -
globin chain. Osmotic Fragility Test
-Increasing proportion of red blood cells lyse upon exposure to
Heterozygous form - Hb AS increasing hypo-osmotic saline solution.
-Red blood cells sickle when O2 saturation is < 40% -OFT usually decreased
Example: Unpressurized aircraft -Not specific
Deep sea diving
-Does not affect life span of patient. Treatment:
-Normal blood counts and morphology 1. symptomatic
-Does not require treatment - pain management- narcotics (morphine and
hydromorphone)
Pathology and clinical features: - reduce number of crises- Hydroxyurea, exchange
Major pathologic manifestations: transfusion
1. chronic hamolysis 2. bone marrow transplant
2. microvascular occlusion
3. tissue damage THALASSEMIA
- Derived from the Greek word for sea (thalassa), and
the medical term for a deficiency in the number of red
blood cells (anemia)
- Heterogenous group of heritable anemias that have in
Morphology: common quantitatively defective synthesis of either α
1. Peripheral blood picture or β chains of the normal hemoglobin A tetramer
- Anemia - usually normocytic normochromic (α2β2)
- Increased polychromasia - reticulocytosis
- Normoblast may be seen Epidemiology:
- Numerous Target cells - Originally observed in Italian and Greek coast.
- Howell - Jolly and Pappenheimer bodies - Also seen in the Mediterrenean basin, Middle East,
- Numerous Sickle cells Parts of Pakistan, India, Southeast Asia, Southern
Part of USSR, China and Northern Regions of African
2. Bone marrow continent.
- Normoblastic hyperplasia - Most frequent in malaria epidemic areas.
- Increased Iron storage major Lifelong transfusion
requirement
Diagnosis: Hemoglobin Electrophoresis intermedia Moderate anemia
Cellulose acetate electrophoresis at pH 8.6 Minimal or no
* For Sickle Cell Trait (Hb AS) transfusion needed
35 - 45 % Hb S Normal Hb F minor Slight anemia at worst
50 - 65 % Hb A Normal to slightly inc. Hb A2 silent Detectable only by
family studies
Polymerase Chain Reaction (PCR)
Specific syndromes are defined by affected globin chain:
Sickling Test – Metabisulfite α - Thalassemia - impaired synthesis of α globin chain.
-Adding Sodium Metabisulfite to blood enhances β - Thalassemia - impaired synthesis of β globin chain
deoxygenation and sickling of the red blood cell.
-Drawback:
1. Does not distinguish Hb AS from Hb SS and other Hb S
syndromes. Alpha Beta
2. Positive test may occur with other rare abnormal -deletion of alpha-globin -nonsense, splice and
hemoglobin (Hb C Harlem and Hb I). gene (s) frameshift mutations in
3. False negative test may occur if Hb S is less than 10% or -symptoms can begin in beta-globin gene
there is inadequate deoxygenation. fetal life -symptoms begin in
-complicated infancy/childhood
Solubility Test – Dithionate
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inheritance- 4 alpha -simple AR inheritance; - mild anemia with some

genes genotype-phenotype hypochromia and microcytosis
correlation - poikilocytosis
- basophilic stippling
β-THALASSEMIA - target cells
Molecular Pathogenesis: Homozygous
- Extremely heterozygous - hypochromic and microcytic
1.Most commonly by point mutation on chromosome 11 anemia
2.Less commonly deletion of part of the gene - marked anisocytosis and
poikilocytosis
Molecular Pathogenesis: - target cells, ovalocytes,
Categories siderocytes, nucleated RBCs
1.βo mutations associated with absent β-globin synthesis - extreme normoblastosis
2.β+ mutations reduced but detectable βo sythesis - cabot rings, howell-jolly
bodies
Examples
 Splicing mutation 2. Bone Marrow
-Most common cause of βo Thalassemia Heterozygous
-Lie within introns and exons - Normoblastic hyperplasia
 Promoter region mutation - Increased Iron storage
-Associated with β+ Thalassemia Homozygous
-Reduce transcription by 75% to 80% - Marked normoblastic
 Chain termination mutation hyperplasia
-Block translocation and prevent synthesis of any functional β - Increased Iron storage
globin - Increased sideroblast
- Normoblast with inclusions
Mechanism of Anemia: 3. Osmotic Fragility Tests
1. Deficiet Hb A synthesis Heterozygous - Decreased OFT
 “Underhemoglobinization” microcytic hypochromic red cells Homozygous - Increased OFT
with abnormal oxygen transport capacity 4. Blood Indices
Diminished survival of red cells and their precursors Heterozygous : Increased RBC
2. Ineffective erythropoiesis Decreased HCT and Hb
3. Extravascular Hemolysis Low MCH and MCV; N to Low MCHC
Homozygous : Severe derangement

5. Increased Indirect Bilirubin

syndromes Genetic disorder manifestation β – Thalassemia
1.Heterozygous One (1) normal β - Moderate Treatment :
β- Thalassemia/ globin chain and two reduction of Hb Symtomatic
β- Thalassemia (2) normal α - globin A (α2 β2) 1. Iron chelation
Minor/ chains usually Increased Hb 2. Transfusion therapy
Cooley’s Trait produces βζ chains to A2 (α2δ2) Alpha - Thalassemia
(β0/β or β+/β) bind the normal α - - Reflects the failure of one or more of the four (4) α -
globin chains gene loci on chromosome 16 to function.
Histopathogenesis:
2. Homozygous Pronounced/complete Normal or - 80 % of cases reflect gene deletion
β - Thalassemia reduction (β+) or moderately - less commonly by point mutation
/β- absence (β0) of β increased Hb Alpha – Thalassemia
Thalassemia chain production A2 (α2δ2) Epidemiology:
Major/ Cooley’s * Increased Hb - Limited to the tropical and subtropical regions of the
Anemia (β0 /β0 F (α2γ2) world.
or β+/ β+) - Carriers have been reported to resist infection by
Plasmodium falciparum.
Clinical Presentation: Alpha – Thalassemia
1. Peripheral Blood
Heterozygous Diagnosis - Alpha - Thalassemia
All forms of Thalassemia show:
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1. Hypochromic microcytic anemia - Hb M

2. Ineffective erytropoiesis 2. High oxygen affinity hemoglobinopathy
3. Hemolysis
B. Inappropriate erythropoietin production
Hydrops with Bart’s Hb 1. Neoplasms
- Marked anisocytosis and poikilocytosis - Renal cell carcinoma
- Marked microcytosis and erythroblastosis - Cerebellar hemangioma
- Absent ABO and Rh incompatibility - Hapatoma
- Alkaline Electrophoresis: - Uterine fibroids
Large quantities of Hb Bart’s (γ4) - Adrenal cortical neoplasms
Some Hb H (β4)
Hemoglobin H Disease 2. Renal pathology
- Blood: Decreased MCV and MCH - Renal cysts
Hypochromia, target cells and anisopoikilocytosis - Hydronephrosis
Reticulocytes usually 4 to 5 % - Transplantation
Hb H precipitates (BCB)
Heinz bodies Absolute Polycythemia - Primary
- Electrophoresis:
Hb H (β4) accounts for 4 to 30 % Polycythemia Vera/Erythremia/
Traces of Hb Bart’s (γ4) Primary Polycythemia
Panmyelosis – excessive proliferation of erythrocytes
Alpha - Thalassemia – Excessive proliferation of megakaryocytes
Treatment – Excessive proliferation of granulocytes
Symtomatic - Unknown etiology

Polycythemia Criteria for diagnosis:

-erythrocytosis 1. Increased Total RBC volume
-elevated hct above normal range Males > 36 ml/Kg
1. Total red cell mass is normal, but the hematocrit is Female > 32 ml/Kg
elevated because 2. Normal arterial oxygen >92%
the plasma volume is decreased 3. Either splenomegaly, of two of the following
ex. Dehydration a. thrombocytosis >400 x 109/L
Shock b. Leukocytosis > 12 x 109/L
Patients on diuretics C. NAP/LAP (leukocyte alkaline phosphatase)
2. Spurious polycythemia (Stresspolycythemia; D. Vitamin B12 >900ug/L or
Gaisbock’s Syndrome) Unsaturated binding capacity > 2200 ug/L
- Red cell mass high normal and the plasma volume is Other Laboratory:
low normal Blood:
- Usually seen in men, with high incidence of tobacco 1. PBS: - immature leukocytes and
smoking, tend to be obese and have hypertension increased basophil
2. Indices: Hemoglobin
MCH and MCHC – normal to
Absolute Polycythemia 3. ESR
- Increase in total red cell mass
Secondary polycythemia Polycythemia Vera/Erythremia/
- Due to erythropoietin production Primary Polycythemia
A. Appropriate erythropoietin production; hypoxia Other tests:
1. Arterial oxygen unsaturation: 1. (increased) Uric acid ------ renal stones
- High altitude 2. Normal arterial oxygen saturation
- Pulmonary diseases Bone marrow:
- Cyanotic heart disease Hypercellullar with erythroid, granulocytic,
- Smoker’s polycythemia and megakaryocytic hyperplasia
- Methhemoglobinemia
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RENAL TUMORS 2
SOURCE: ROBBINS
BENIGN NEOPLASMS
Renal Papillary Adenoma
o Arising from tubular epithelium
o Most frequently papillary
o Morphology
- Small tumors (<0.5 cm) in diameter
- Present invariably within the cortex and appear
grossly as pale yellow-gray, discrete, well-
circumscribed nodules
- Mx: complex, branching, papillomatous structures
with numerous complex fronds
- Cells may grow as tubules, glands, cords, and sheets
of cells (cuboidal to polygonal in shape and have
regular, small central nuclei, scanty cytoplasm and no
atypia
- Do not differ from low-grade papillary renal cell
carcinoma
- Size of tumor is used as prognostic feature
Angiomyolipoma
- Benign neoplasm consisting vessels, smooth muscle
and fat originating from perivascular epitheloid cells
- Present in 25% to 50% of pxs with tuberous sclerosis
(caused by loss-of-function in the TSC1 and TSC2 tumor
suppressor genes
- Tuberous scleros is characterized by lesions of cerebral
cortex producing epilepsy and mental retardation, variety of
skin abnormalities, and unusual benign tumors at other
sites such as the heart
- Clinica: due largely to their susceptibility to spontaneous
haemorrhage
Oncocytoma:
- Epithelial neoplasm composed of large eosinophilic
cells having small, roud, benign-appearing nuclei that
have large nucleoli
- Thought to arise from intercalated cells of collecting
ducts and accounts for approx. 5-15% of renal
neoplasms
Eosinophilic cells have numerous mitochondria
- Tumors are tan to mahogany brown, homogenous, and
usually encapsulated with central scar in one-third of
cases
- Achieve a large size (up to 12 cm)
MALIGNANT NEOPLASM
Renal Cell Carcinoma
- Tobacco- most significant risk factor
- Additional risk factor: obesity (women); HTN; unopposed
estrogen therapy and exposure to asbestos, petroleum
products and heavy metals.
- Risk factor also in px with end stage renal disease
- Morphology: arise in any portion of the kidney but
commonly affecting the poles
Classification of renal cell carcinoma:
Clear cell carcinoma:
- Most common type (70—80%) of renal cell cancers
- Tumors are made up of cells with clear or granular
cytoplasm and nonpapillary
- Can be familial but 95% are sporadic
- Loss of sequences on the short arm of chromosome 3;
deleted region harbors the VHL gene (3p35.3); second
non deleted allele of the VHL shows mutation or
hypermethylation induced inactivation in up to 80% of
clear cell cancers
- Morphology:
 arise from proximal tubular epithelium and
usually occur as solitary unilateral lesions
 bright yellow-gray white spherical masses of
variable size that distort the renal outline
 yellow color is prominent lipid accumulations
in tumor cells
 large areas of gray-white necrosis and foci of
hemorrhagic discoloration
 growth pattern varies from solid to trabecular
(cordlike) or tubular (resembling tubules)
 tumor cells have rounded or polygonal shape
and abundant or granular cytoplasm which
contain glycogen and lipids
 tumors have delicate branching casculature
and may show cystic as well as solid areas
 tendency to invade renal vein, in which it may
grow as column of cells that extend up to the
IVC, sometimes to the right side of the heart
Papillary Carcinoma
- Accounts for 10-15% of renal cancers
- Papillary growth pattern and occurs in both familial and
sporadic forms
- Assoc with 3p deletions
- Common cytogenetic abnormalities are trisomies 7 and
17 and loss of Y in male px in the sporadic form, and
trisomy 7 in the familial form
- Morphology:
 Arise from distal convoluted tubules
 Can be multifocal and bilateral
 Typically hemorrhagic and cystic esp when large
 Tumor is composed of cuboidal or low columnar
cells arranged in papillary formations
 Interstitial foam cells are common in papillary
cores
Chromophobe carcinoma:
- 5% of renal cell cancers and composed of cells with
prominent cell membranes and pale eosinophilic
cytoplasm usually with a halo around the nucleus
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- These tumors show multiple chromosome losses and
extreme hypodiploidy
- Grow from intercalated cells of collecting ducts and have
an excellent prognosis compared with that of clear cell
and papillary cancers
- Morphology: made up of pale eosinophilic cells, often
with perinuclear halo, arranged in solid sheets with conc
of largest cells around the blood vessels
Xp11 translocation carcinoma
- Occurs in young pxs
- Translocation of the TFE3 gene located at Xp 11.2 ->
results in overexpression of the TFE3 transcription factor
- Consists of clear cell cytoplasm with papillary architecture
Collecting duct (Bellini duct) carcinoma
- Represents approx. 1% or less of renal epithelial
neoplasms
- Arise from collecting duct cells in the medulla
- Characterized by malignant cells forming glands
enmeshed within a prominent fibrotic stroma, typically in
medullary location
- Medullary carconinoma – morphologically similar
neoplasm seen in px with sickle cell trait
- Morphology: rare variant showing irregular channels lined
by highly atypical epithelium with hobnail pattern.
Sarcomatoid changes arise infrequently in all types of
renal cell carcninoma and are decidedly ominous feature
Clinical features of RCC:
- Costovertebral pain, palpable mass and hematuria (most
reliable clue)
- Tendency to metastasize widely before giving rise to any
local symptoms or signs
- Most common metastasis are the lungs (50%), bones
(33%), regional lymph nodes, liver, adrenal, and brain
- 5 year SR of persons with renal cell carcinoma is about
70% and as a high 95% in the absence of dstant
metastases
- Tx: radical nephrectomy to preserve renal fx; drugs
inhibiting VEGF in various tyrosine kinase
Urothelial Carcinoma of the pelvis
- Approx. 5-10% of primary renal tumors originate from
urothelium of renal pelvis
- Range from benign papillomas to invasive urothelial
(transitional cell) carcinomas
- May block urinary outflow and lead to palpable
hydronephrosis and flank pain
- May occasionally be multiple involving pelvis, ureters,
and bladder
- Increased incidence of urothelial carcinomas of the
renal pelvis in individuals with Lynch syndrome and
analgesic nephropathy
- 5 year SR vary from 50-100% for low grade noninvasive
lesions to 10% with high grade infiltrating tumors
SOURCE: KAPLAN USMLE
1. Benign tumors of the kidney.
a. Cortical adenomas are small, encapsulated cortical nodules
measuring
less than 3 cm; they are a common finding at autopsy.
b. Angiomyolipomasare hamartomas composed of fat, smooth
muscle,
and blood vessels, common in patients with tuberous sclerosis.
2. Renal cell carcinoma (RCC), also called hypernephroma, is
most common
in ages 50 to 70, with males being affected more than females.
- Risk factors include cigarette smoking; chronic analgesic
use; asbestosexposure; chronic renal failure and acquired
cystic disease; and vonHippel-Lindau disease (VHL tumor
suppressor gene).
- b. Gross examination typically demonstrates a large,
solitary yellow massfound most commonly in the upper
pole. Areas of necrosis and haemorrhage are commonly
present. The tumor often invades the renal vein andmay
extend into the inferior vena cava and heart.
- c. Microscopically, several histologic variants can occur,
including clearcell carcinoma (most common type,
polygonal cells with clear cytoplasm),papillary carcinoma,
chromophobe carcinoma, and sarcomatoidrenal cell
carcinoma (poor prognosis).
- d. Clinical features. The "classic" triad ( 1 0%) includes
hematuria, palpablemass, and flank pain. A variety of
paraneoplastic syndromesfrom ectopic hormone
production can occur, including
polycythemia(erythropoietin production),
hypertension (renin production),Cushing syndrome
(corticosteroid synthesis), hypercalcemia
(PTHlikehormone), and feminization or
masculinization (gonadotropinrelease). Renal cell
carcinoma may also cause secondary amyloidosis,
aleukemoid reaction, or eosinophilia.
- e. There is a high incidence of metastasis on initial
presentation.
3. Wilmstumor (nephroblastoma) typically presents as a large
abdominal mass with peak age 2 to 5.
- Risk factors. WAGR syndrome is the cluster of
Wilmstumor, aniridia,genital anomalies, and mental
retardation. Beckwith-Wiedemann syndromehas
increased risk of childhood cancers (e.g.,
Wilmstumor, hepatoblastoma)and congenital
anomalies (e.g., macroglossia, macrosomia,midline
abdominal wall defects [e.g., omphalocele, umbilical
hernia] , earcreases or ear pits, neonatal
hypoglycemia, and hemihypertrophy).
- b. Tumor suppressor genes that are implicated in
Wilmstumor includeWT- 1 ( llp l 3) and WT-2 ( l lplS).
- c. Pathologically, Wilmstumor grossly causes a large,
solitary tan mass.Microscopic exanimation reveals a
tumor containing three
elements:metanephricblastema, epithelial elements
(immature glomeruli andtubules), and stroma.
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- d. Treatment is with surgery, chemotherapy, and
radiation; this combinationtherapy yields an
excellent prognosis, with long-term survival rateof
90%.
SKIN DISORDERS 2
Acne Vulgaris formation:
1. Hyperproduction of sebum within a sebaceous gland.
2. Formation of a plug blocking the pilosebaceous unit.
3. Inflammatory reaction to Propionibacterium acnes; an
anaerobic bacterium, and a component of skin flora.
4. Follicular wall rupture and spread of perifollicular
inflammation
Tx: topical retinoids and/or topical antibiotics
Oral doxycycline or tetracycline (moderate acne)
Isotretinoin (Accutane) – nodulocystic acne
Rosacea:
 Age group is older than 30 years
 Distinguishing features: Telangiectasis, rhinophyma,
lack of comedones
 Triggered with extreme temperature or winds,
strenuous exercise, severe sunburn, foods (alcohol,
caffeinated beverages, spicy foods)
 Tx: topical antibiotics (metronidazole); oral antibiotics
(tetracyclines)
Lichen Planus
 Inflammatory lesions of the skin of unknown etiology
but sometimes associated with hepatitis C infection.
 This condition is remembered and recognized by the 4
Ps mnemonic: purple, polygonal, pruritic papules
 Maybe assoc with Wickham’s striae (whitish line
visible with papules) and Koebner phenomenon (new
lesions that appear along lines of trauma; usually
appear patterns after scratching)
 tx: high potency topical steroids
Pityriasis Rosea
 secondary to virus, begin with a virus-like prodrome
and a heald patch (raised oval, pink patch, with central
clearing) which forms on the back and follow skin
cleavage lines in a “Christmas tree” pattern
 appears on trunk and confused with tineacorporis
Keloid
 firm, shiny nodule of scar tissue (type 1 collagen) as a
result of granulation tissue (type 3 collagen)
 overgrows the boundaries of initial injury, unlike
hypertrophic scars which are raised scars that respect
wound margins
 common in African American individuals
Contact dermatitis
4. Transitional cell carcinomas can involve the renal pelvis as well
as the urinary bladder.
 delayed type IV hypersensitivity rx in which antigen
absorption recruits previously sensitized T cells to
initiate local inflammation
 lesions are well-circumscribed, erythematous plaques
that may have vesicles or bullae over the area of
exposure
 common allergens: poison ivy, rubber, nickel
(jewelry& buttons)
 tx: avoidance of culprit allergen and topical steroids;
systemic steroids (severe cases)
Atopic dermatitis (Eczema)
 itch that rashes
 begin as itching that erupts into an erythematous,
scaling lesion
 atopic triad: eczema->asthma->allergic rhinitis
 tx: protecting the skin from excessive drying, avoiding
irritants, and applying topical steroids and
moisturizers (emollients)
Urticaria (Hives)
 Pruritic wheals caused by mast cell degranulation
spilling histamines and other inflammatory mediators
into surrounding tissue
 Acute urticaria (<6 weeks) 2ndary to an environmental
allergy
 Chronic urticarial – autoimmune condition
 Tx: 2nd generation H1-antagonists (antihistamines)
Psoriasis
 Caused by interaction between the environment and
genetics (HLA-B27) that causes a local inflammatory rx
and hastens the growth cycle of the epidermis, leading
to thickened skin from keratinocyte accumulation at
affected sites.
 Presents as red papules with silvery scales that
coalesce into well-defined plaques, often extensor
surfaces (elbows and knees)
 Peeling of scale will reveal pinpoint bleeding (Auspitz
sign); and affects nail beds (pitting) and joints
(psoriatic arthritis)
 Tx: methotrexate or tumor necrosis factor alpha
inhibitors
Langerhans Cell Histiocytosis (Histiocytosis X)
 Abnormal proliferation of histiocytes
 Presents as red papules on scalp or trunk that may
display crusting or scaling
 Characteristic: painful osteolytic bone lesions of the
skull
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 Skin biopsy reveal Langerhans cells which are very
large (x4 larger than a lymphocyte)
AUTOIMMUNE DISEASES:
Pemphigus Vulgaris
 Caused by IgG antibodies within the epidermis that
attack desmosomes and lead to a loss of adhesion
between keratinocytes (acantholysis)
 Formation of painful, flaccid, intraepidermal bullae
 Bullae may expand on gentle stroking normal-
appearing adjacent skin (Nikolsky sign) and may
rupture, leading to erosions
Bullous pemphigoid (BP)
 Less severe autoimmune which attack
hemidesmosomes, which connect epidermal basal
cells to the basement membrane
 Binding of complement leads to destruction of
basement membrane, separation of dermoepidermal
junction, and the formation of subepidermal blisters.
 Creates appearance of tense bullae and subsequent
erosions at the site of ruptured bullae
CONDITIONS OF PIGMENTATION
Vitiligo
 AI condition in which antibodies destroy melanocytes
within the epidermis.
 Subsequent absence of melanin leads to
depigmentation in flat, well circumscribed macules or
patches.
 Key feature: absent melanocyte
Albinism
 Autosomal recessive inability to convert tyrosine into
melanin (non-functional tyrosinase enzyme)
 Pale skin, white hair, and blue eyes
 Key feature: increased melanocytes
Solar lentigo
 “old age spots”
 Benign lesions are areas of increased pigmentation,
often seen in older patients who had years of UV-light
exposure.
 Key feature: increased melanocytes
Melasma:
 Estrogen and progesterone stimulate melanocytes
during pregnancy or oral contraceptive use to increase
production of melanin
 Hyperproduction of melanin = formation of
hyperpigmented macules and patches on sun-exposed
areas
 Also known as mask of pregnancy
 Key feature: increased melanin
Nevocellular Nevus (Common Mole)
 Benign nests of normal lymphocytes that need no
intervention
 Come in junctional, intradermal, compound varieties
 Key feature: increased melanocytes
Ephelis (common freckles)
 Contain normal numbers of melanocytes but
increased conc of melanin
 Key feature: increased melanin
SKIN INFECTIONS AND INFESTATIONS
Cellulitis
 Infx of deep dermal and subcutaneous tissue often
caused by Staph aureus or Strep pyogenes
 Direct penetration of bacteria into the skin
 Presents as streaky painful, warm, erythematous,
edematous lesion with or without fever
 Tx: antibiotics
Erysipelas
 Similar to cellulitis although infection is of the
superficial dermis and lymphatics
 Commonly occur in children and those with impaired
lymphatic drainage.
 S pyogenes- most common pathogen
 Well-circumscribed with raised borders
Impetigo
 S aureus or S pyogenesinfx of the face, begins as
vesicles and pustules that later rupture, producing the
characteristic honey colored crust
Staphylococcal Scalded Skin Syndrome (SSSS)
 Severe and generalized form of bullous impetigo
 S aureus skin infection produces exfoliative exotoxin, a
protease that acts on desmoglein at the stratum
granulosum to produce tense itraepidermal bullae
followed by flaky, nonscarring desquamation
 Predominant in neonates and accompanied by fever
Necrotizing fasciitis
 Flesh-eating rapidly progressive infection of
subcutaneous tissue including fat and fascia that
spreads alingfascial planes
 Cause: polymicrobial or monomicrobial
 S pyogenes – most likely the organism
 Spreads from a site of local trauma or surgery
 Characterized by extreme painm fever, induration
(hardening of skin_ and skip lesions (noncontinuous
islands of infected tissues
 Sepsis is common
 Tx: IV antibiotics and debridement
Gas gangrene:
 Condition caused by Clostridium perfringens
 Crepitus results from CH4 and CO2 production by the
pathogen
Dermatophytes:
 Superficial fungal infection of skin or nails in which
fungus survives by metabolizing keratin.
 Caused by Epidermophyton, Microsporum, and
Tridophytonspp
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 Infxs are named after their location on the body
(tineacapitis – head; tineapedis – foot; tineacorporis –
body; tineacruris – groin)
 Tineacorporis – presents as raised, erythematous, oval
ring worm.
 KOH – confirmatory demonstrating presence of
hyphae.
 Tx: antifungals
TineaVersicolor:
 caused by Malasseziaglobosa or Malassezia furfur –
hyperpigmented or hypopigmented macules and
patches assoc scaling
 lesion on trunk and arms
 KOH reveals spaghetti and meatballs appearance of
hyphae and yeast, respectively
Scabies:
 Superficial infection caused by Sarcoptesscabiei which
burrows into the skin to live and reproduce
 Mite is spread through person-to-person contact
 Most profound feature : severe pruritis caused by
delayed (type IV) hypersensitivity rx to the mites, their
eggs and feces.
 Rash usually consists of erythematous papules with
secondary excoriations
 Burrow is pathognomonic and appears as a thin raised
line along the skin
 Crusted scabies – severe infestation that is assoc with
immunosuppression
 Mineral oil prep – confirmatory by direct visualization
of the mites or eggs
 Tx: topical permethrin
Oral hairy leukoplakia
 White hairy patch found on the side of the tongue
caused by opportunistic infection of Epstein-Barr virus.
 Presence of leukoplakia should be concerning for HIV
 Lesion can be distinguished from thrush/oral
candidiasis; leukoplakia can’t be scraped off easily and
tends to occur on the sides of the tongue
Leukoplakia
 White patch on the tongue or oral mucosa 2ndary to
squamous hyperplasia.
 Can’t be scraped off easily
 Considered precancerous -> progress to SCC
 Highly assoc with tobacco use
 Tx: cessation of any carcinogenic habits and/or
surgical removal
Verrucae (warts)
 Viral infection with human papillomavirus (HPV)
causing acanthosis and hyperkeratosis
 Cells are enlarged, irregular nuclei (koilocytes) are
present
 Tx: cryotherapy
 Verruca vulgaris: common wart, often found on the
hand; raised rough papule
 Verruca plantaris: smooth, flat wart, found on foot;
pinpoint bleeding is often present
 Condylomaacuminatum: genital warts caused by HPV
subtypes 6 and 11
DERMATOLOGIC MANIFESTATIONS OF INTERNAL DISEASE
Erythema nodusum:
 Inflammatory condition of subcutaneous fat
(panniculitis) resulting in tender erythematous
nodules, often over the shins
 Assoc with strep infection, drugs, sarcoidosis, TB, and
fungal infections
Erythema Multiforme:
 Multiple target-shaped lesions with multiform primary
lesions (macules, papules, vesicles)
 Hypersensitivity reaction to drugs leading to IgM
deposition in the skin, but erythema multiforme may
also be secondary to infection or malignancy
Stevens-Johnson Syndrome:
 Erythema multiforme but eith more extensice and
systemic symptoms including mucous membrane
involvement, fevers, diffuse erosions, and crusting
 Lesion cover <10% of the BSA
Toxic Epidermal Necrolysis:
 A more severe form of Stevens-Johnson syndrome
with lesions covering >30% of the body surface area.
 These conditions overlap when 10% to 30% of the
body surface is involved.
Erythema Marginatum:
 Nonpruritic, erythematous, transient, ringed lesions of
the trunk.
 This rash is one of the major criteria for rheumatic
fever.
Erythema Chronicum Migrans:
 Expanding bull’s eye–shaped erythematous plaque at
site of Ixodes tick bite and pathognomonic of early,
localized Lyme disease
 Caused by localized infection with Borreliaburgdorferi
(not hypersensitivity). Multiple lesions indicate the
spirochete has spread hematogenously.
 Treatment is with doxycycline.
Dermatitis Herpetiformis:
 Pruritic vesicles and papules on an erythematous base
(herpetiform), especially over extensor surfaces
(elbows and knees).
 Caused by dermal IgA deposits in association with
celiac disease. This condition is responsive to a gluten-
free diet.
Acanthosis Nigricans:
 Velvety hyperpigmentation of skin overlying body
folds associated with elevated insulin levels, which
alter dermatologic growth factors
 Elevated insulin is most commonly a result of insulin
resistance in type 2 diabetes. Other endocrine
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disorders, such as polycystic ovary syndrome, may also
be causative.
Stasis Dermatitis:
 Brawny discoloration of dependent areas (feet and
ankles) due to hemosiderin deposits from
extravasation of erythrocytes as a result of venous
hypertension.
 Pedal edema is often present. The venous
hypertension may simply be due to venous valve
dysfunction, but heart failure may also be the
underlying cause.

SKIN TUMORS 2
1. BCC 5. Melanoma
- most common malignancy - malignant tumor of melanocytes
- do not metastasize, locally invasive - ABCDEs:
- develop in stratum basale often from UV induced asymmetry
damage borders are irregular
o Gx: appear as "pearly nodules w/ rolled color variance
edges, central ulceration and tengiectasias diameter is >6mm
may be present evolution (growing, changing color and
o Dx: biopsy showing basal cells with peripheral becomes pruritic)
pasilading - metastasize if they enter vertical phase
o Tx: excision - depth of invasive correlate mortality
2. Actinic keratosis - precursor lesion: dysplastic nevus that should be
- Precancerous biopsied
- occur in sun exposed area may progress to SCC - positive for S-100
o Gx: excess keratin build up forming
crusty, scaly, rough papules 6. Seborrheic keratosis
o Dx: PE, biopsy - benign proliferation of keratinocytes
o Tx: cryotherapy or topical 5-fluorouracil - does not need a biopsy
3. SCC o Gx: warty stuck on appearing lesion
- occasionally metastasize other:
- risk factor include sun exposure, immunosuppresion, - multiple SK indicating underlying malignancy like
arsenic exposure, chronic draining sinus tracts from gastric adenocarcinoma (signs of Leser-Trelat)
osteomyelitis
o Gx: appear as scaling plaques 7. Strawberry hemangioma
o Dx: biopsy keratin pearls - benign vascular tumor that appear in neonates
others: - involutes in childhood
- SCC that grows in area of previous scarring (Marjolin - no treatment unless it ulcerates or located near the
Ulcer) eye
- SCC in glans penis caused by HPV 16 and 18
(Erythroplasia of Queyrat) 8. Cherry hemangioma
- benign proliferation of capillaries
4. Keratoacanthoma - more common with age
- subtype of SCC - no treatment
- grows so large that it outstrips blood supply, necrosis - will not involute on their own
and resolves with some scar
o Gx: forms a dome with keratin scales and
debris atop it.

SUMPTOMS OF INAPPROPRIATE ADH SECRETION 1

- signs and symptoms of siadh: causes excess amounts
of free water reabsorbed in collecting duct:
o hyponatremia
o cerebral edema(neurologic dysfunction)
o hypertension
o urine sp. gravity is increase or concentrated
SYSTEMIC LUPUS ERYTHEMATOSUS 1
- autoimmune disease involving multiple organ
- presence of ANA
- more common in females
CLINICAL PRESENTATION:
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- malar rash - photosensitivity

- discoid rash

THYROID TUMOR 5
Key concepts:  Papillary (>85%)
 Follicular (5-15%)
 Most are solitary
 Anaplastic (<5%)
 Nodules that are solitary, in younger patients, in males
 Medullary (5%)
= more likely to be NEOPLASTIC
 Follicular adenomas: most common benign neoplasm -Pathogenesis: gain of function mutation of RAS, MAP kinase,
 Papillary carcinoma: most common malignancy PI-3 kinase
 Functional nodules that take up radioactive iodine
Papillary
(hot nodules) are more likely BENIGN
-gain of function mutation: RET/NTRK1 receptor tyrosine kinase
Adenomas
-discrete, solitary or serine/threonine kinase BRAF
-derived from follicular epithelium (aka follicular adenoma) -most common form of thyroid cancer
-not forerunners to carcinomas (but possible)
-Majority: nonfunctional; some causes thyrotoxicosis -occur any age, highest in 25-50
-if functional, independent of TSH stimulation
-Pathogenesis: -exposure to ionizing radiation

 gain of function of TSH receptor/GNAS -> follicular
cells secrete thyroid hormone independent of TSH
(thyroid autotomy) -> hyperthyroidism, hot nodule
 TSHR and GNAS mutation rare in follicular carcinomas,
thus rare malignant transformation
 Nonfunctional adenoma: mutations of RAS/PIK3CA
-Solitary/multifocal, some are encapsulated
-Excellent prognosis
-Microscopic hallmarks: papillae, Orphan Annie eye nuclei
(nuclei optically clear or empty; diagnosis can be made on
these alone); psammoma bodies

-Morphology: -First manifestation: mass on cervical lymph nodes; but cervical

nodal metastasis do not influence prognosis
 Hallmark: intact, well-formed capsule
-most single that move freely
-Clinical features:
-advanced disease -> hoarseness, dysphagia, cough, dyspnea
 Most: unilateral painless mass
 Larger masses -> difficulty swallowing -hematogenous metastases-> most commonly in LUNGS
 Cold nodules: take up less radioactive iodine -cold masses in scintiscan
compared to normal
 Evaluation: US, FNAB Follicular
 Definitive diagnosis: capsular integrity, thus
-mutation that activates RAS or the PI-3K/AKT arm of receptor
determined only after resection
tyrosine kinase
 Do not recur and metastasize, excellent prognosis
-frequent in areas with dietary iodine deficiency
Carcinomas
-F>M (3:1), often in older people, peak: 40-60
-F>M in early and middle adult; F=M in childhood and late adult
-Morphology: single nodules, well-circumscribed, (+)
-most derived from epithelium (except medullary) and well
occasionally with Hurtle cells
differentiated
-Clinical course: slowly expanding, painless
-Major risk: exposure to ionizing radiation in the first 2
decades of life + deficiency of dietary iodine -warm on scintiscan

-Major subtypes: -regional lymph nodes rarely involved; hematogenous

dissemination (common)
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-Prognosis: depend on extent of invasion and stage at
presentation
Anaplastic/Undifferentiated
-highly aggressive and lethal, mortality rate approaching 100%
-can arise: de novo or dedifferentiation of well differentiated
papillary and follicular carcinoma
-More on older people; mean age: 65
-Morphology: anaplastic cells (giant, spindle, mixed spindle and
giant)
-Clinical course: rapidly enlarging bulky neck mass, most
already spread to adjacent neck structures or has metastasized
THYROIDITIS 2
THYROIDITIS: inflammation of the thyroid gland (Robbins, p.
1086)
Clinically significant subtypes:
 Hashimoto
 Granulomatous (de Quervain)
 Subacute lymphocytic thyroiditis
HASHIMOTO
-Autoimmune disease -> destruction of the thyroid gland ->
gradual and progressive thyroid failure
-Most common cause of hypothyroidism in areas where iodine
levels are sufficient
-Goiter + intense lymphocytic infiltration of the thyroid
(strumalymphomatosa)
-Prevalence: 45-65 y/o; F>M (10:1 to 20:1); also occur in
children (major cause of nonendemic goiter in the
pediapopulation)
-Strong genetic component
-Increased susceptibility if (+) polymorphisms of cytotoxic T
lymphocyte-associated antigen 4 (CTLA4) and protein tyrosine
phosphate-22 (PNPN22); CTLA4 and PNPN22 also associated
with Type 1 DM
-↑ risk of other autoimmune disease
-painless enlargement of thyroid gland + hypothyroidism
-Pathogenesis:
to lungs, symptoms related to compression and invasion, no
effective therapy death in < 1 year
Medullary
-neuroendocrine neoplasm; derived from parafollicular cells or
C cells
-secrete CALCITONIN like normal C cells; could also elaborate
serotonin, ACTH, VIP
-associated with MEN 2 syndrome
-associated with RET mutation
-Morphology: solitary nodule (if sporadic), bilateral and
multicentricity (in familial cases); (+) amyloid deposits in
stroma derived from calcitonin polypeptide; multicentric C cell
hyperplasia (features of familial medullary cancers)
 (+) circulating antibodies against thyroglobulin and
thyroid peroxidase -> progressive depletion of thyroid
epithelial cells by apoptosis and replacement of
thyroid parenchyma by mononuclear cell infiltration
and fibrosis
 Hashitoxicosis (disruption of follicles release free T4
and T3; TSH elevated) -> hypothyroidism (↓T4, T3;
↑TSH)
-Immunologic mechanism resulting to cell death:
 CD8+ cytotoxic cell mediated cell death: destroy
thyroid follicular cells
 Cytokine-mediated cell death: activation of CD4+ T
cells -> production of inflammatory cytokines (eg
interferon y) -> activation of macrophage -> damage
to follicles
 Antibody- dependent cell-mediated cytotoxicity (less
likely mechanism): binding of antithyroglobulin and
antithyroid peroxidase antibodies
-Morphology:
 Thyroid diffusely enlarged and symmetric; localized
enlargement may be seen
 Capsule intact, fibrosis does not extend to capsule
 Mononuclear inflammatory infiltrate
 Atrophic follicles
 Hurtle cells- eosinophilic granular cytoplasm
Granulomatous / de Quervain
-most common cause of thyroid pain
-Prevalence: 40-50 y/o; F>M (4:1)
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-Pathogenesis:
 Trigger: viral infection (upper respiratory infection)
 Stimulated cytotoxic T lymphocytes -> damage thyroid
follicular cells
 Associated with coxsackievirus, mumps, measles,
adenovirus
 Peaks in summer
 Virus-initiated thus process is limited
-Morphology:
 Unilaterally or bilaterally enlarged
 Firm, intact capsule
 (+) aggregates of lymphocytes, activated
macrophages, plasma cells
 (+) multinucleate giant cells
-Clinical course:
TUBERCULOSIS 1
- chronic pulmonary& systemic disease most often caued
by Mycobacterium tuberculosis.
- detected by tuberculin (PPD or Mantoux) skin test:
o 5 mm for pxs w/ HIV hx, immunocompromised,
contact w/ a known TB case, or w/ xray suggestive
of TB
o 10 mm for pxs w/ hx of travel to a high prevalence
place, residences or employees w/ high risk settings,
o 15 mm for pxs with no identifiable risk factors
- primary infection is subclinical in most pxs and results in
asymptomatic latency that reactivates in 10-20% of the
pxs
- immunity to a tubercularinfxn is mediated by TH1 cells
w/c stimulate macrophages to kill the bacteria
- immune response is effective but causes hypersensitivity
and tissue destruction
- reactivation of infectionor reexposure to a previously
sensitized host = rapid mobilization of defense reaction
but also tissue necrosis
- hematogenous and lymphatic spread
Prognosis: if localized to the lungs = generally, favorable; but
it worsens significantly when the disease occurs in aged,
debilitated, or immunosuppressed persons, who are at high
risk for the development of miliary tuberculosis, and in
those with multidrug-resistant tuberculosis.
 Inflammation of thyroid transient even if not treated
 Normal thyroid function returns
 ↑T4, T3
Subacute Lymphocytic (Painless)
-mild hyperthyroidism, goitrous enlargement
-more common in middle aged; F>M
-Can occur during postpartum (postpartum thyroiditis)
-Most ptx: (+) antithyroid peroxidase
-can progress to overt hypothyroidism
Reidel
-Less common form of thyroiditis
-Rare; extensive fibrosis of thyroid gland and contiguous
structures
-Manifestation of autoimmune IgG4-related disease
SSX:
 Localized secondary tuberculosis may be
asymptomatic
 Systemic manifestations = malaise, anorexia, weight
loss, fever (low grade and remittent) and night sweats.
 When cavitation is present = sputum (+) for tubercle
bacilli, w/ some degree of hemoptysis and pleuritic pain
 Extrapulmonary manifestations = infertility (tuberculous
salpingitis),headache and neurologic deficits
(tuberculous meningitis), and back pain and paraplegia
(Pott disease)
Morphology:
 1-1.5 cm gray-white inflamm. w/ consolidation (Ghon
nodule) w/ central caseous necrosis
 Regional nodes also often caseate; parenchymal lesion +
nodal involvement = Ghon complex
 Lymphatic and hematogenous dissemination to other
parts of the body➡cell-mediated immunity controls the
infection ➡ Ghon complex undergoes progressive fibrosis
➡ radiologically detectable calcification (Ranke complex)
 Histologic examination = sites of active involvement =
caseating and noncaseating granulomas w/c consist of
epithelioid histiocytes and multinucleate giant cells.
-Diagnosis of pulmonary disease is based in part on the
history and on physical and radiographic findings of
consolidation or cavitation in the apices of the lungs.
Ultimately, however, tubercle bacilli must be identified.
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TUMOR MARKERS 2
- Biochemical assays for tumorassociated enzymes, - BCR-ABL: Chronic Myeloid Leukemia
hormones, and other tumor markers in the blood cannot - HER2/NEU: Breast CA
be utilized for definitive diagnosis of cancer; however, they - ER/PR: Breast CA
can be useful screening tests and in some instances have - EGFR: Lung CA
utility in quantitating the response to therapy or detecting - NMYC: Neuroblastomas
disease recurrence. Examples are: - ALK: Lung CA
 PSA for prostatic carcinoma but can be also seen in - BRAF: Melanoma, Colon adenocarcinoma, Papillary
BPH thyroid CA, Langerhans cells histiocytosis, Hairy cell
 CEA (carcinoembryonic antigen) for carcinomas of leukemia
colon,pancreas, stomach, and breast - PIK3CA: Colorectal CA
 Alpha fetoprotein for for hepatocellular carcinomas, - BRCA 1:marked risk for ovarian CA
yolk sac remnants in the gonads, teratocarcinomas, - BRCA 2: slight risk of ovarian CA, assoc. frequently
and embryonal cell carcinomas with male breast CA
***both BRCA genes increases the risk for prostatic and
However, An increasing number of molecular techniques pancreatic CA
are being used for the diagnosis of tumors and for
predicting their behavior. Examples are:

VOLVULUS 1
- Twisting of a loop of bowel about its mesenteric point - Because it is rare, volvulus can be overlooked
of attachment is termed volvulus; it results in both clinically.
luminal and Vascular compromise.
- Thus, volvulus presents with features of both
obstruction and infarction.
- It occurs most often in large redundant loops of
sigmoid colon, followed in frequency by the cecum,
small bowel, stomach, or, rarely, transverse colon.