Pathology – Lecture 6

Tuesday 5-10-2010
Done By: Lujain Shomali

In The Name of Allah

Before starting the lecture.. The CR had an announcement
about the internal labs:

1) You need to study for the Micro lab only the manual and
the handouts of these labs .. there's no need to have the
slides coz they're only headlines

2) About Patho lab ,you are going to have your copy of

Web Path CD for the first week lab about " Cell Injury ",
and it's about 29 slides .. and every week you will be told
about the new slides of the next lab.

3) for the Genetics lab there's a manual + available slides

every Monday in "Al Jam3yya "..

*P.S : Micro & Patho labs examinations don't have a

special "Mid-Term" exam ,instead they're included with
their material theoretical exams( first, second, final ),
while Genetics lab exam is considered as "Mid-Term" one
& is going to be held at 8/11/2010 -iA- .

Now let's begin ..

In the last lecture we started talking about cell death and

we know that it's an irreversible process that includes
Necrosis and Apoptosis and Autolysis.

Autolysis (‫)تفسخ‬, is the death of tissue and starts after cell

death .It's a path process dealing with enzymes which
break down the cell body and it involves the process of
auto digestion and lysis in the presence of living cells.

We started to talk about necrosis which is an irreversible

change & it's dissolution of local groups of cells.

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Remember: Apoptosis happens to a Single cell while
necrosis is to a group of cells.

These processes of cell death increases the eosinophilia

which means the dead cells are more pink than other
living ones.

Pyknosis is a change which involves the nucleus, and the

nucleus becomes smaller and darker (more basophilic). (In
fact, the eosinophilia deals with the cytoplasmic part of
the cell).

Karyorrhexis means break down of the nucleus to small

fragments.

Karyolysis means the dissolution of the nucleus (it

disappears).

* Remember the difference between autolysis and

heterolysis .

Why should this occur ?

The process of Necrosis consists of two things. There's

enzymatic digestion of the cell, and denaturing of proteins.

There are various types of necrosis including the

Coagulative, Liquefactive, Caseous, Fat, Gummatous, and
Fibrinoid necrosis.

We won't take a look at Gummatous or Fibrinoid necrosis.

(Basically the Gummatous is a syphilitic infection
producing what's called a Granuloma and we'll hear more
about that later on. As for Fibrinoid necrosis, most of it is
seen in the blood vessel wall & many of it is related to
severe hyper tension. Most of the vessels become
necrotic, eosinophilic, and infiltrated by inflammatory
cells)

Now what happens after necrosis? (sequels of

necrosis) :

2
- The dead cells are autolysed by their enzymes.

- Phagocytosis (macrophages attack the necrotic tissue)

- Organization & fibrous repair: there's usually a fibrous

scar left in the area of necrotic tissue.

-Dystrophic calcification (sometimes after cells death

they're followed by Dystrophic calcification not metastatic.
Remember that won't happen always)

(1) Coagulative necrosis :

The commonest type of necrosis & most of it is due to
ischemia, so that sometimes it is called ischemic
infarction .

×it is seen in the kidney, adrenals, and it's typical for the
heart myocardial infarction(‫)الجلطة واحتشاء العضلة القلبية‬. Gross
appearance: very firm.

× in ischemic and hypoxic injury a large amount of

calcium ions enter the cells so they cause cell death, that's
why it's suspected that high levels of intracellular calcium
plays a role in coagulative necrosis (calcification).

×it also results in denaturing all proteins in the cell and

also includes enzymes since many of them are proteins.

×Histological: there will be preservation of the tissue’s

basic architecture & cellular outlines since the cells are not
completely digested (and it’s important to remember this
since it is different from other types of necrosis). When
using (H&E) staining the tissue appears faint (pale) and
more eosinophlic, but you can recognize the hazy (blurred)
appearance of the dead cells, and because they're dead
they will be devoid of nuclei.

3
 This picture shows a kidney with a wedge-shaped
(triangular) necrotic area. It's quite solid. Notice that
necrosis follows the pattern of blood supply. It's large
toward the periphery where the blood is less, and it's
smaller where there is better supply toward the center. So
in highly vascularized tissue, necrosis is smaller and less
spread and vice versa.

(2) Liquefactive necrosis:

Liquefactive necrosis is different, Autolysis predominates
and results in liquefaction. So what really happens is
instead of being solid it's like a cystic area has an abscess,
like what results in bacterial infections. It is especially
seen in hypoxia of the brain when the large amounts of
lipids there are denaturing to form a very soft area.

×Brain cells have a large amount of hydrolytic digestive

enzymes (hydrolases). These enzymes cause the neural
tissue to become soft and liquefied.

× Liquefactive necrosis is what causes pus (collection of

acute inflammatory cells and necrotic tissue) to form.
Neutrophils have many enzymes (e.g. Hydrolytic
enzymes ) which are secreted in regard to abscess, and
destroy the tissue; that's why
infections are generated.

There's a large number of

Pyogenic microorganisms
(antigens, bacterial,
occasionally fungal infections)
that produces pus too (e.g. the
staph, the strept, and so on ).

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×In the figure :

1- part of the brain and you can see that the reddish area
which is soft (not solid like the coagulative necrosis)cavity
filled with liquids. Later on this will be replaced by gliosis
and never by fibrosis (we'll hear about it in the future)

2-a lung abscess; it could be a bacterial or fungal

infection. Whatever it is, it leads to the same thing. (Look
at the middle of the superior lobe)

3-a histological appearance of a liver abscess. All these

dark colored cells are neutrophils which release a lot of
enzymes which digest the tissue and produce these
cavities.

(3) Caseous necrosis:

Caseous necrosis is a special type of necrosis mostly seen
in tuberculosis (TB: bacterial infection) but it can be seen
in some fungal infections that may behave like TB.

× Caseous comes from cheese; the white cheese which

breaks down into small white soft pieces just like ceaseous
necrosis.

× Histologically: it has white cheesy material in the center

and is surrounded by Epitheloid cells (they are cells which
look like epithelium but they're really macrophages).
Macrophages play a role in TB, they engulf the
microbacteria. The microbacteria after that remain inside
the macrophages, and sometimes the macrophages come
together to form a multi-nucleated cell that is called
"Langhans giant cell" (we will hear about it more when
we take the chronic inflammation which is a very specific
chronic inflammatory process)

5
× caseous necrosis is a modified coagulative necrosis, and
this small modification is caused by the lipopolysaccharide
capsule of TB bacilli.

- left: you can see the caseous necrosis as the yellow

material ( this should be white but the snapshot make it
yellow ).

-right: (histological view) at the top right border there's

Acellular necrotic tissue rimmed by inflammatory cells ( it
may show also multi nucleated giant cells ). Here we have
caseous necrosis of TB, but this condition can be seen in
other diseases.

(4) Fat necrosis :

Fat necrosis is not related to an inflammatory process nor
ischemia. Fat necrosis is one of two:

• Traumatic Fat necrosis occurs usually in fatty tissue it

can be seen in the fat female breast, in the gluteal
region and other areas which have trauma.

6
 × it's presented as a hard lump (mass) in the breast
or wherever, the destroyed fat related to trauma is
released and engulfed again by macrophages
producing a foreign body giant cell reaction not the
Langerhans, it's a different type of giant cell which is
called the foreign body giant cell. It engulfs the fat
and it could engulf anything, for example it may be
related to a surgical process engulfing part of sutures
or if you pricked your hand by a small piece of wood
that won't get out, your giant cells will take it (or by
macrophages which changed to giant cells ). And this
process may result in dystrophic calcification later on.

• Enzymatic fat necrosis, the commonest cause is

acute pancreatitis. As you know, the pancreas has
many powerful enzymes so when the pancreas
becomes acutly inflammated (which is a very
dangerous process and a medical emergency that
has to be treated quickly!), the enzymes there are
released into the abdominal cavity and peritoneum
and other organs and start the digestion of the
peritoneal fat. You'll have the same appearance of
foreign body giant cell inflammation in the fat. And in
this case the areas which are involved in the active
digestion become soft, saponificated and also
calcified.

× saponification areas are those which look like soap

bubbles

×note : in either of the two types the picture is very

similar( the histology)! So pictures won't help in identify
the type.

Remember : calcification grossly looks yellowish white,

while microscopically using H&E staining it looks blue !

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 - left side : normal fat │ right side : saponified fat │and
in between there's the reaction with acute
inflammatory cells and fibrosis that follows
calcification.

Gangrene:
Gangrene is necrosis with putrefaction (‫ )تعفن‬but the rest of
the organ is normal. There are two types of gangrene:

a. Wet gangrene: a type of coagulative necrosis usually

due to ischemia, and after that liquefactive necrosis due to
a superimposed infection (a strong bacterial infection)

Q: A girl asks: "What do we mean by Superimposed ? "

A: We mean by it " that things lay on other things and

come later on" for example if a soldier has a very bad
wound in his leg in a war, after a few days it becomes
bluish and this leg gradually dies because of a strong

8
bacterial infection which destroys it and releases toxins all
over the body and he will die unless his leg was
amputated. And sometimes it could happen in operating
theatres (surgery room) and then the operating theatre is
closed due to the danger of infections.

b. Dry gangrene: is total ischemia to the tissue without

superimposed infections. It's especially seen in severe
atherosclerosis because the blood supply does not come
to the limbs properly, and you can see it in uncontrolled
diabetes patients. Sometimes they get blue toes and the
toes just fall off! You can see many of diabetes patients on
a wheel chairs. Why? Because they have amputation of
their legs or feet or something like that!

× In this case the dead tissue just dry off. Again it’s a form
of coagulative necrosis, and it's usually associated with
peripheral vascular disease. Peripheral vascular disease is
related to atherosclerosis and diabetes. It's a very known
complication of diabetes. That's why diabetics always have
to protect their feet.

Gas gangrene : this is also wound contamination, even

worse than wet gangrene ! Because it's an infection by a
certain type of bacteria –Clostridia- which
produces a lot of toxins. This actually is what is seen in
wars and operating theatres.

Q: A guy asks : " Is it possible that dry gangrene spreads

?"

A: Well, gangrene if it is untreated it will spread whether it

was dry, wet, or gas gangrene. So if there's gangrene in
the toes and it wasn't amputated, it will gradually extend
to the whole foot then the whole leg and extends more
and more. In dry gangrene there's no infection but the
dead tissue spreads spontaneously! So that when surgeon
want to get rid of gangrene, he looks at where there's a

9
change of the color and takes a safety margin, not exactly
where the color has changed.

Dr. Samir al Basheer said there's no need to go over the book for the
gangrene subject.

Apoptosis :

apoptosis is different from necrosis in that it's a

programmed process. it's called "Programmed Cell Death
by Suicide".. the cell kills itself ! after the cell dies it
remains intact ( not like the other cases )( by the way, this
is a common question in the exam .. so take care of it !
:D )

×it's characterized by the death of a single cell or small

clusters of cells resulting in cell shrinkage not lysis or
swelling because the cell will remain as is, as you'll see
later on. Apoptosis is unlike necrosis where there's death
of large amounts of tissue with inflammatory reaction and
it's always pathological, while apoptosis is often
physiological and occasionally pathological.

× Apoptosis is an active process ( needs energy; not

passive ) which depends on signals which will cause
protein break down within the cell causing the cell death.
Apoptosis involves cell shrinkage, the chromatin will
condense and this cell produces some blebs which will be
taken up as apoptotic bodies by phagocytosis.

× Now there are two main pathways where apoptosis will

be triggered. One is called the Intrinsic pathway which is
related to mitochondria, and the Extrinsic which depends
on certain receptors on the cell surface which trigger cell
death.

1. Intrinsic pathway : there's a set of genes which

control this process in the mitochondria, they belong to
the Bcl-2 family. Bcl-2 genes send signals if there's any

10
harm to the cell (e.g. UV, trauma, infection or
whatever).These signals monitors the mitochondrial
permeability, and once this is altered, Cytochrome c which
is inside the mitochondria is released. This is called Pro-
apoptotic (it initiates apoptosis).

2. Extrinsic pathway: signals come from outside the

cell, and then end up finally triggering apoptosis. A set of
enzymes are activated, these are called Caspases and
they're many subtypes (two sets): Pro-apoptotic, and Anti-
apoptotic ( anti-apoptotic include Bcl-2 itself and Bcl-xL .)

× Things to know :

-Cytochrome c activates caspase-9 that triggers

apoptosis .(this is important)

-FAS (Fas Ligand) and TNF1 (Tumor Necrosis Factor type

I ) are examples on extrinsic apoptotic receptors .

11
-at the left side : (1) is injury of the cell like radiation,
toxins, free radicals that enter the cell and cause DNA
damage. (2) the Bcl-2 family are also activated. when that
is activated, the p53 gene, which is related to one of the
protein triggering apoptosis, is also activated. then the
pro-apoptotic molecules go to the initiator caspases (which
initiate the whole process). the extrinsic dead receptors
also trigger the initiator caspases. then both of these
signals along with the initiator caspases activates the
Executioner caspases. (3) that will cause the activation of
the breakdown of cytoskeleton, and endonucleasis , so
that they breakdown the cell.

× if you read about it in the book it's a bit complicated but

this is governed by sets of genes all of them belongs to
the Bcl-2 family and some of them are Pro-apoptotic and
others are not. There's always in every system in the body
a Trigger and a Counter-Trigger, like for example
hemolysis , and a lysis of the thrombus.

Physiologic apoptosis

1) during development and embryogenesis. when you

read embryology you see that tissues change continuosaly
from conception(fertilization) till adulthood. Through this
period things which transform will close off, regress, and
maybe disappear !

(2) Homeostatic mechanism to maintain cell population.

There are many cells in the body which continuously divid,
so if all the cells have lived you would have over
production of cells ! this is compensated by programmed
death of cells . for example if you looked at mucosa of the
intestine there are many many mitotic figures, it's always
changing. the same thing for the epidermis.

(3) immune reaction - defense mechanism : elimination of

self reacting lymphocytes. there're many antigens in the
body and sometimes there is an abnormal immune

12
responses in that the T lymphocytes which becomes auto-
reactive, and they destroy the body's cells. So this is
prevented by apoptosis. another example, some
lymphocytes become lymphotoxic cells which means they
contain a lot of harmful toxins, so they must die by
apoptosis whatever the pathway is.

(4) In aging

(5) Shedding of menstrual endometrium : involution of

formal dependent tissue such as the menstrual cycle of
the female every month, the endometrium is completely
lost and then replaced and this is a hormonal dependent
process.

(6) Regression of the breast after weaning (‫)فطام‬: after

weaning the breasts reduce in size by a combination of
hypotrophy and hypoplasia involving a lot of apoptotic
processes.

Pathologic apoptosis

(1) Prostatic ‘atrophy’ after castration : the prostate

gradually shrinks after removal of the testes for any
reason, let's say a tumor.

(2) Death of inflammatory cells after inflammation : if

there's an acute inflammatory process with a lot of
neutrophils, the neutrophils themselves die after the
infusion.

(3) When cells are damaged by disease or injurious

agents:

a. DNA damage e.g. radiation, chemotherapy, Cytotoxic

drugs: In cancer the aim of these therapies is to induce
apoptosis and to kill as many cells as possible to induce
apoptosis. Sometimes apoptosis is accompanied by rapidly
proliferating cells. In fact the chemotherapy triggers death
to the newly dividing cells. The more rapidly dividing the
tissue is, the more sensitive the cells are to radiation or

13
chemotherapy. For example, if the lower part of a male
body is exposed to radiation, the sperms generated in the
testes are affected the most and killed rapidly so the male
become finally sterile. the same thing is applied on the
bone marrow.

b. Viral infections e.g. viral hepatitis (A, B or C), papilloma

viruses (HPV), targets different individual cells in the
body.

c. Neoplasia & malignancy: tumors that regress or

involute, in fact, the more rapidly dividing they are the
more you see apoptosis in them, and it can be induced.

d. Deletion of auto reactive T cells in thymus

e. rejection of transplants : if somebody has a new kidney

and it may die because of rejection and apoptotic activity.

× erythrophoresis is a process where there is breakdown

of certain components e.g. the cytoplasm, the plasma,
urine, or whatever. it's done in the lab and an electric
current passes through this and breakdown the sub types.

14
 - this is the erythrophoresis for the DNA.(A) The
shortest one is the normal cell. (B) is DNA with a
step-ladder shape. (C) is a diffused DNA.

×now you see that apoptosis is a step-ladder because it's

a programmed process, and the smudged one is due to
necrosis.

now here I want to summarize the differences between

apoptosis and necrosis :

This table is taken directly from the book. Dr. Samir said it's important to
look over it plus the other table listed below..

Aging and
Cellular Death :

15
× Theories

- Aging is caused by accumulations of injurious events

- Aging is the result of a genetically controlled

developmental program. (this program is not cell death,
it's Aging)

× Mechanisms

1. Genetic, environmental, and behavioral

2. Changes in regulatory mechanisms

3. Degenerative alterations

× the genetic factors are various you can see many people
of the same family live for a 100 years, while in other
families they only live around 60 years ! that's really
genetically oriented, and it may be involved in failure of
repair mechanisms. There's some genes are called "Clock
genes" which time our lives. "Telomerase" which are
present at the end of chromosomes, and when the cells
divide over and over, chromosomes become SHORTER
with each cycle! the shorter they are, the less is the life of
the cell. So, there's a continuous shortening of the
chromosomes till the cell dies.( we're going to talk about
telomerase later in the "neoplasia" chapter ).

× Environmental mechanism is really related to the

generation of a lot of Free Radicals (FR) which ultimately
ends in accumulation of lipofuscin pigment. This will be
seen in aging tissues.

× the last thing, there will be an accumulation of abnormal

proteins, these are a complicated protein with certain
glucose, and both of these produces a complicated
glycosylation age products. These are called "AGES". The
more AGES you form, the shorter is your life. And that's

16
present very much in uncontrolled diabetic patients and
ends up in cell death.

Finally I apologize if there's a lot of

.mistakes
Best Wishes to all of You
(: .. And good luck in your exams
This hand out is done by : Lujain Ali Al-Shomali

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 ‫ة وََتجّهما‬
‫سماءُ كئيبـــــ ٌ‬ ‫قا َ‬
‫ل ال ّ‬
‫سما‬
‫م في ال ّ‬ ‫قُْلـــــت ابتسم َيكفي الّتجهّ ُ‬
‫جّرعتني عَل َْق ً‬
‫ما‬ ‫ل الّليـــالي َ‬
‫قــا َ‬
‫ت العَل َْقما‬ ‫عــ َ‬ ‫جَر ْ‬
‫ن َ‬ ‫م وَل َئ ِ ْ‬ ‫س ْ‬ ‫ت ابت َ ِ‬ ‫قلـــــ ُ‬
‫هما ً‬ ‫م ِبالّتـــــبّرم ِ دِْر َ‬ ‫ك ت َغْن َ ُ‬‫أ َُترا َ‬

‫مغَْنما‬ ‫سُر ِبالَبشا َ‬ ‫َ‬

‫شة ِ َ‬ ‫خ َ‬ ‫ت تَ ْ‬ ‫م أْنـــــــــ َ‬ ‫أ ْ‬
‫ن‬ ‫شَفتي َ َ‬ ‫خط ٌَر على َ‬
‫كأ ْ‬ ‫حل َ‬ ‫صا ِ‬‫يا َ‬
‫طما‬‫ح ّ‬ ‫ن ي َت َ َ‬ ‫جــــــــــــــهِ أ ْ‬ ‫ت َت َث َّلما‪ ،‬والوَ ْ‬
‫جى‬ ‫ح ُ‬
‫ك والد ّ َ‬ ‫ض َ‬
‫ب تَ ْ‬ ‫شه َ‬‫ن ال ّ‬‫ك فإ ِ ّ‬‫ح ْ‬‫فاض َ‬
‫ب ال َن ْ ُ‬
‫جما‬ ‫حــــــــ ّ‬
‫كـــــــــــذا ن ُ ِ‬‫م‪ ،‬وَ َ‬‫مَتلط ِ ٌ‬
‫ُ‬
‫س ُتسعِد ُ كائنـــا‬
‫ة لي َ‬ ‫قال البشا َ‬
‫ش ُ‬
‫مْر َ‬
‫غما‬ ‫دنيــــا ويذ ْهَ ُ‬
‫ب ُ‬ ‫َيأتـــي إلى ال ّ‬
‫دى‬ ‫ك والّر َ‬ ‫م ب َي ْن َ َ‬
‫م ما دا َ‬
‫س ْ‬
‫ت ابت َ ِ‬
‫قل ُ‬
‫سما‬ ‫شب ٌْر فإّنــــــــــــك ب َْعــــــــد ُ ل َ ْ‬
‫ن ت ََتب ّ‬ ‫ِ‬
‫‪ -‬إيليا أبو ماضي ‪-‬‬

‫‪"If you don't like something, change it. If you can't‬‬

‫‪change it , then change your attitude..‬‬

‫!! ‪DON'T COMPLAIN‬‬

‫‪18‬‬