‫بسم ال الرحمن الرحيم‬

Pathology Lecture 3
Now in the last lecture, I discussed the different types of cell injury, I
started to talk about the mechanisms, and I mentioned the
following: generally the function loss may occur before
morphological changes, a person may die due to infraction but still
you can see nothing. Sometimes later, you can find some damage
after looking at the light microscope then apparent morphological
.changes will appear
.First it is reversible, and then it may come irreversible

Now the progress of the condition and the results depend on the
following:, the type of injury, the duration, and the severity … the
longer the duration, or the more sever injury occurs, means that I
have worse prognosis, and by prognosis I mean the outcome of
.whatever happens
Now it also depends on the type of cell or the type of tissue, for
example if you take the type of muscle, skeletal can accommodate
ischemia or hypoxia for 2 to 3 hours, while cardiac can only
accommodate few minutes maybe 20 minutes. If you compare a
muscle with a neuron, neurons can last only few seconds of hypoxia
and ischemia, they die very quickly due to the specialization of each
tissue to a certain function. Now lets see the adequacy of blood
supply. A tissue which is already poorly oxygenated can
accommodate hypoxia more that a tissue which is highly
vascularized and which is used to get a high amount of blood with
.high amount of oxygen in it
Also hormones and nutrients have some effects, for example in
liver, healthy hepatocytes can stand damage and injury more than
.diseased ones, or malnutritioned ones
Some tissues can regenerate like the lever but neurons never
.generate so the regenerative tissue can withstand damage more
Always the genetic makeup plays a role, a healthy immune system
can adapt to an injury more that an immune system with a
.congenital defect

Now what are the steps and targets in cell injury? There are various
components which are very important and once they are damaged,
.the cell is dead

:Mitochondria-1
We know that mitochondria is the main site of ATP production , if -
we had hypoxia , this will lead to some pores in the membrane of
the mitochondria , the pores are called permeability transition
pores. This will cause errors (imbalance) in the membrane potential
between the inside and the outside of the mitochondria and this will
.make the mitochondria incapable of making ATP
Cytochrome C released in the cell will induce apoptosis which -
.induces the cell to death
:Cell membranes-2
Damage to the membranes for example the mitochondrial
membrane; damage to it will lead to an incapability of ATP
.production

:Other important sites of damage of membranes

Plasma membrane→ failure of Na pump leads to cellular-
.amounts of water
Lysosomal membrane → enzyme release, activation and-
.digestion of cell components
In lysosomal membrane damage, we have a lot of enzymes in the
lysosomes. These enzymes are released and activated. This release
will cause either a reversible or irreversible damage to the cell.
Once the digestive enzymes are fully released, then the injury is
.difficult to be reversed

Influx of calcium: now because of membrane damages we have -3

calcium ions influx which will increase the cytosolic calcium
concentration and this will lead to the activation of some enzymes.
These enzymes and their effects are illustrated in the figure. (Influx
of the calcium can be caused by the incapability of maintaining ATP
(.levels appropriate

4-Protein synthesis:
High fluid levels cause ribosomes to separate from the swollen
endoplasmic reticulum; this will decrease proteins synthesis which
will increase glycolysis which finally causes metabolic acidosis.
5- Genetic apparatus
DNA defects & mutations which are important in some cases of
cancer.

You have to keep in mind that injury at one point can induce other
harmful secondary results at another point; this is called the
cascading effect of an injury.

Now ok..the cell is injured ,when I see subcellular structures how do

we see them ? And what do we mean by subcellular?? Subcellular
means inside the cell and we can see them using the electron
.microscope, so all these changes are electron microscopic changes
You may have hypertrophy of liver cells by drugs basically because
the liver is involved in metabolism of a lot of drugs especially by the
p-450 enzyme system. As an example barbiturates and sometimes
.alcohol can cause hypertrophy of the hepatocytes

Mitochondrial alteration: Mitochondria also may increase in size or

.become very small, they may be increase in number

Cytoskeletal abnormalities: Cytoskeleton is the main framework of

the cells. Cells sometimes can have a cytoskeletal defect that
sometimes affects the mobility of the cell this for example immobile
cilia syndrome, the cilia on cells cant move ,this may lead to
infection through our respiratory system , because the cilia cant
. move and clear the air
Lysosomal catabolism:. Sometimes the cell digests itself by
autophagy, because of the defect of some component of the cell, it
will come and digest itself by the digestive enzymes. Now after
digestion , whatever residue from digestion exists in the cell as
indigestible material is called residual body and in some cases this
residual body will change to what is called lipofuscin pigment . This
component might be related to age, in certain diseases for example
in some case of heart failure they accumulate in the muscle cells of
the heart. These are indigestible residual bodies which are brown in
colour. We shall see on that there are several types of brown
pigments in the body, and there are various techniques to
differentiate these brown pigments whether they were lipofuscin or
.iron for example
:The morphological changes of the reversible injury
:You have
• Swelling of the cell and its organelles, this swelling causes blebs
of the plasma membrane.

• Detachment of the ribosome from the ER.

• Clumping of the nuclear chromatin.

Later on there will be increase in these swelling and dysfunction of
the mitochondria and this can lead to calcium deposit and this will
be a dead cell. In the dead cell there is total destruction of
membrane phospholipids and we also have irreversible damage of
.the nucleus
?Now what do we see in the nucleus by the light microscope
We have what is called pyknosis ,which means that the nucleus
shrinks and the cell dies , if you look at your sections in histology all
of them are stained by H&E (hemotoxyzyne , eiosn ) staining , so
nucleus is stained blue and the cytoplasm will have the pink stain
.Pyknosis gives a high basophilic appearance due to this shrinkage .
Then it will be dissolved by karyolysis, also it can undergo
karyorrhexis which is the break down into small pieces
(fragmentation) of the chromatin, and this is what happens in dead
.cells

(Depend on the pictures ( slide 54

-. You should know that blebs are reversible
And you can see in the picture some of myelin figure which is a sign-
. of the dead cell
Cytoplasm is empty and there is nothing on it-
. We have large densities in the mitochondria-
. The nucleus has broken down-

Now after death what happens , in some cases it is digested by

lysosomes , sometimes you have the release of enzymes into the
circulation which can be very helpful in diagnosis of the clinical
defect, here you have several constituents and that are digested ,
the enzymes and proteins leak into the extracellular space and as
an example of this in Myocardial Infarction, you have creatine
kinase and troponins ; these enzymes are released in the dead
cardiac muscles into the secretion and you see that somebody with
the myocardial infraction, we don't know exactly whether he has an
infraction or no , he is taken into the hospital , blood is drawn out
and we see that there is a rise in these enzymes in the blood and
this indicates that he has an infarction. This does not occur
immediately, it takes a bit of time to see changes in the
concentration of these enzymes, so sometimes if you bring the
patient to the hospital immediately, you will not see any changes in
the enzymes creatinine kinase and troponin, the changes are only
visible after a while. In liver injury there is increase in an alkaline
phosphatase , this when it's raised , it indicates that we have
possibly an obstruction in the bile ducts. We have also
.transaminases enzymes which also rise in the liver injury

The dead cells are converted to phospholipids masses and these

are called the Myelin Figures which are engulfed by phagocytosis or
.either broken down and calcified
Now if injured cells don't die, they may adapt to protect themselves,
it may change back to normal. Why should they adapt? They can
adapt to a new environment, sometimes they can do to escape from
.injury and to protect themselves from the injurious agents

:You have growth adaptations

Hyperplasia and Hypoplasia : hyperplasia means increase in the -

number of cells whereas hypoplasia means a decrease in the
.number of cells

Hypertrophy and atrophy : hypertrophy has nothing to do with the -

number of cells; it's the cell itself which is enlarging so you have a
big cell in hypertrophy or a small cell in atrophy. Now in some cases
hyperplasia and hypertrophy occur together which may result later
in an enlarged organ , when hypoplasia and atrophy occur together
.it results in a small size of organ

Metaplasia and dysplasia : Metaplasia is an adaptive change which -

allows the cell to change its features so that it can protect itself.
Dysplasia which is an abnormal type type of growth may precede
.malignancy

Now there are certain degenerations and sometimes they can

include accumulations, degenerations and accumulations aren't
synonymous, some are called turgid degenerations, some are
:accumulations. You have

hydropic change which is a collection of water in the cell leading to -

.edema
Fatty change -
Hyaline change -
Pigment storage -
.

.And we'll talk in details later on

The most common type of adaptation is regarding the cell size and
.number

… Now we'll talk in details

Atrophy : due to loss of cell substance and it's mainly due to -

protein degradation, often it's hormone dependent ; for example if
you have diabetes , then you have insulin insufficiency, as a result
.the pancreas will change in size
Or another example is TSH: Thyroid Stimulating Hormone from the
pituitary acting on the thyroid , when you have deficiency of thyroid
hormone the cells of the gland get smaller. When the gland is
completely atrophic, there's diminished function sometimes you'll
see a decrease in size, and atrophic cells in general have decrease
.in function

:Now atrophy could be

A) Physiological: for example when women is pregnant, the uterus

becomes large,, if you take a woman of 70 years old , atrophy
occurs in the uterus; it becomes small. Another example, the
breast... The breast in an old woman is smaller than in a woman
.who is feeding a baby

:B) Pathological
Decreased workload: if a patient is infected by certain disease, -
.he's lying in bed all the time; then you have disuse atrophy limbs

Loss of innervation: Here you have complete paralysis of the -

.limbs, in this case the muscles will get smaller in size

Decreased blood supply: As for example brain atrophy, in old age -

the brain becomes atrophic, of course you may have ischemia to the
brain because of atherosclerosis and by age the brain becomes
smaller , another pathological relevance is Alzheimer where the
.whole brain becomes smaller or different areas of the brain

Malnutrition: One case of it is called marasmus, which is very -

.severe in Africa especially in children but still rare nowadays

Lack of hormonal stimulation: for example in old age the testes -

.becomes very small

Ageing: it's called senile atrophy -

 … Here you have Disuse atrophy of muscle cells Big muscle

Small Muscle

Here is an atrophy of the frontal lobe, and of course it's pathological

…

Atrophy

Undescended testes: sometimes the testes don't descend into the -

scrotum , this is a congenital disease, the testes remain in the
abdomen or in the inguinal canal. And as you see in the figure below
there is a difference in size between the normal and the small
.atrophic undescened testes
.. Hypertrophy: the cells become bigger as you see below -

It's an increase in the cell size by a gain of cellular substance. Now if

you have a sufficient number of cells increasing in number and size;
you'll have organ hypertrophy, and it can be caused either by
increased in functional demand or by specific endocrine
.stimulations
With increasing demand, hypertrophy can reach a limit beyond
.which degenerative changes and organ failure can occur

:Now more examples

Skeletal muscles in physical workers and athletes, they grow -
their muscles. This is a physiological example
Smooth muscles in pregnant uterus where you have hyperplasia -
and hypertrophy. This is a physiological example
Cardiac muscles: Mostly pathological hypertrophy during -
.hypertension for example
If you remove one kidney or lung, there's always compensation in
.the other kidney or lung to adapt the removal of the organ

.… Here you have a picture of a big left ventricle in hypertension

Here you have a pregnant uterus, the normal uterus in the
centre compared to the last one which shows a pregnant uterus,
.you can see that the muscle cells are so increased in size

Hyperplasia: an increased in number of cells, if cells have mitotic -

ability they can synthesize DNA, both hyperplasia and hypertrophy
can occur. Sometimes hyperplasia may be a predisposing condition
.to neoplasia

• Types of Hyperplasia:
 1. Physiological Hyperplasia: (hormonal or
compensatory) :

.Hormonal uterine enlargement during pregnancy -

.Hormonal female breast in puberty & lactation -
.Compensatory hyperplasia in the liver -

2. Pathological Hyperplasia:

Hyperplasia of the endometrium of the uterus, and in -

this case it's due to excessive hormonal production , for
example in certain tumors of the ovaries they may secrete
a lot of estrogen ; stimulating the endometium and in this
.case , this may lead to cancer of the endometrium

Wound healing: it's a type of hyperplasia of various -

.components in the tissue which results in healing

Infection by papillomavirus which causes an increase in -

the size and number of the epidermis cells. This virus can
.cause skin warts and epidermal lesions

The picture below shows an endometrial hyperplasia in the

… uterus

:Capability of cells to divide

High capacity: these cells have the ability to (1
regenerate , such as : -epidermis of the skin is always
.changing
.hepatocytes : regenerate frequently -
bone marrow: is always regenerating, if it -
. doesn't you'll die
.fibroblasts -
intestinal epithelium -

:Low capacity (2
.Bone: little capacity to regenerate, cartilage has minimum -
.smooth muscles -

.Nil capacity: Neurons, cardiac muscle, skeletal muscle (3

When cardiac muscles and neurons are dead there's no *

replacement, whereas when liver cells are died , new liver cells
.regenerate

Done By: Safwan Abualrub

Thanks to Tariq Kewan

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