الرحيم الرحمن الله بسمPathology Lecture 3Now 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.

1-Mitochondria : -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.

2-Cell membranes: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.

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

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

Big muscle

Small Muscle

-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..

Atrophy

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:1 (High capacity: these cells have the ability to 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

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

-smooth muscles.

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

*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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