Disorders of Cell Growth, Intracellular Accumulations, Radiation Injury and Iatrogenic Diseases

Question 1

Define the following terms.
(a) Apoptosis
(b) Pyroptosis
(c) Oncosis
(d) Autophagy

Answer 1

(a) Apoptosis: This is a form of programmed cell death that occurs in a controlled and regulated manner.

(b) Pyroptosis: This is a form of apoptosis that is accompanied by the release of the fever-inducing cytokine IL-1 (pyro refers to fever) and is typically triggered by microbial infections.

(c) Oncosis: Also known as ischemic cell death, oncosis is a form of accidental cell death characterized by cell swelling due to ATP depletion. It occurs when cells are subjected to injury or stress, such as ischemia, leading to ionic imbalance, membrane rupture, and subsequent cell death.

(d) Autophagy: This is a cellular process that involves the degradation and recycling of damaged organelles and proteins. During autophagy, cellular components are enclosed in autophagosomes, which then fuse with lysosomes for degradation.

Question 2

List three categories of disordered cell growth and give examples of each.

Answer 2

Excessive growth: hypertrophy, hyperplasia
Diminished growth: atrophy, hypoplasia
Abnormalities of cellular differentiation: metaplasia, dysplasia

Question 3

Distinguish between:
(a) hypertrophy and hyperplasia
(b) atrophy and hyoplasia
(c) metaplasia and dysplasia

Answer 3

(a) Hypertrophy refers to an increase in the size of cells, leading to an increase in the size of the affected organ or tissue whereas hyperplasia refers to an increase in the number of cells in an organ or tissue, often resulting in an increase in the overall size of the organ or tissue.

(b) Atrophy refers to the reduction in size or wasting away of an organ or tissue due to a decrease in cell size or number, whereas hypoplasia is the underdevelopment or incomplete development of an organ or tissue, resulting in fewer cells than normal.

(c) Metaplasia refers to the reversible transformation of one differentiated cell type into another differentiated cell type, whereas dysplasia refers to the abnormal development or growth of cells within tissues or organs, often indicating a precancerous state.

Question 4

What processes does hypertrophy involve?

Answer 4

Gene activation, protein synthesis, and production of organelles.

Question 5

How does hyperplasia occur?

Answer 5

Through the production of new cells from stem cells.

Question 6

Can hypertrophy and hyperplasia occur together? Give an example.

Answer 6

Yes, they generally occur together. Example: Uterus during pregnancy.

Question 7

Which tissues undergo hypertrophy only and why?

Answer 7

Permanent tissues like cardiac muscle, skeletal muscle, and nerve tissue, because their ability to proliferate and produce new cells is extremely restricted.

Question 8

What happens to cardiac myocytes in response to systemic hypertension?

Answer 8

They undergo hypertrophy, not hyperplasia.

Question 9

What can pathologic hyperplasia progress to?

Answer 9

Dysplasia and eventually cancer.

Question 10

What is a notable exception to pathologic hyperplasia progressing to cancer?

Answer 10

Benign Prostatic Hyperplasia (BPH), which does not increase the risk for prostate cancer.

Question 11

What leads to a decrease in organ size (atrophy)?

Answer 11

A decrease in stress, such as decreased hormonal stimulation, disuse, or decreased nutrients/blood supply.

Question 12

How does atrophy occur?

Answer 12

Via a decrease in the size and number of cells.

Question 13

How does the decrease in cell number occur in atrophy?

Answer 13

Through apoptosis, a form of programmed cell death.

Question 14

How does the decrease in cell size occur in atrophy?

Answer 14

Through ubiquitin-proteasome degradation of the cytoskeleton and autophagy of cellular components.

Question 15

What happens in ubiquitin-proteasome degradation?

Answer 15

Intermediate filaments of the cytoskeleton are tagged with ubiquitin and destroyed by proteasomes.

Question 16

What role do autophagic vacuoles play in autophagy?

Answer 16

They engulf damaged organelles and proteins, then fuse with lysosomes whose hydrolytic enzymes break down the cellular components.

Question 17

What are the main pathways involved in reducing cell size during atrophy?

Answer 17

The ubiquitin-proteasome pathway and autophagy.

Question 18

(a) What type of cell growth adaptation is seen in Barret’s esophagus?
(b) Define Barret’s esophagus and state its cause.

Answer 18

(a) metaplasia
(b) Barret’s esophagus is a condition where the normal squamous epithelium lining of the esophagus is replaced by non-ciliated mucin-producing columnar cells. This change is typically a response to chronic acid reflux or gastroesophageal reflux disease (GERD), where stomach acid frequently backs up into the esophagus causing damage.
[Diagram 1] [Image 1] [Image 2]

Question 19

How does metaplasia occur?

Answer 19

(1) Via reprogramming of stem cells, which then produce new cell types.
(2) It may also occur through colonization by differentiated cell populations from adjacent sites.

Question 20

Is metaplasia reversible?

Answer 20

Yes. If the underlying cause or stressor that induced the metaplasia is removed, the affected tissue can often revert to its original cell type.

Question 21

Deficiency of which Vitamin may result in epithelial metaplasia?

Answer 21

Vitamin A

Question 22

Identify and define the disorder: [Image].

Answer 22

myositis ossificans: This is a type of metaplastic change that primarily occurs in muscle following trauma, whereby connective tissues undergo ossification.

Question 23

From what conditions can dysplasia often arise?

Answer 23

Dysplasia can often arise from longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus).

Question 24

What happens if the stress causing dysplasia persists?

Answer 24

If the stress persists, dysplasia can progress to carcinoma, which is irreversible.

Question 25

Identify the disorder: [Image].

Answer 25

left ventricular hypertrophy

Question 26

Intracellular accumulations

What are four main mechanisms that lead to abnormal intracellular accumulations?

Answer 26

✔ Inadequate removal of a normal substance secondary to defects in packaging and transport, as in fatty change (steatosis) in the liver. [lipid-related]
✔ Accumulation of an endogenous substance as a result of genetic or acquired defects in its folding, packaging, transport, or secretion, as with certain mutated forms of α1-antitrypsin. [protein related]
✔ Failure to degrade a metabolite due to inherited enzyme deficiencies, typically lysosomal enzymes. The resulting disorders are called lysosomal storage diseases.
✔ Deposition and accumulation of an abnormal exogenous substance when the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulation of carbon or silica particles is an example of this type of alteration.

Question 27

Intracellular accumulations

(a) What is steatosis?
(b) What are two types of steatosis?

Answer 27

(a) Steatosis, also known as fatty liver disease, is the abnormal accumulation of fat within cells, most commonly affecting the liver.

(b) Types:
🍺 Alcohol-related liver disease (ALD)
🍺 Non-alcoholic fatty liver disease aka. metabolic dysfunction-associated steatotic liver disease (MASLD)

Question 28

Intracellular accumulations

Briefly discuss the following pathologic processes associated with abnormal intracellular acculumation of cholesterol and cholesterol esters.
(a) Atherosclerosis
(b) Xanthomas

Answer 28

(a) Atherosclerosis:
🩺 Smooth muscle cells and macrophages in the aorta and large arteries accumulate lipid vacuoles containing cholesterol and cholesterol esters.
🩺 These cells, known as foam cells, form yellow cholesterol-laden atheromas.
🩺Rupture of these cells releases cholesterol into the extracellular space, forming crystals that can cause local inflammation.

(b) Xanthomas:
🩺 Characterized by intracellular cholesterol accumulation within macrophages.
🩺 Found in the subepithelial connective tissue of the skin and tendons, forming tumorous masses.
[Diagram] [Image 1] [Image 2] [Image 3]

Question 29

Intracellular accumulations

Briefly discuss the following pathologic processes associated with abnormal intracellular acculumation of cholesterol and cholesterol esters.
(a) Cholesterolosis
(b) Niemann-Pick disease, type C

Answer 29

(a) Cholesterolosis:
🩺 Focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder.
🩺 The mechanism of accumulation is unknown.
[Image 1] [Image 2] [Image 3]

(b) Niemann-Pick disease, type C
🩺 A lysosomal storage disease caused by mutations affecting cholesterol trafficking.
🩺 Results in cholesterol accumulation in multiple organs.
[Diagram]

Question 30

Intracellular accumulations

(a) What are glycogen storage diseases?
(b) How is glycogen identified in tissue samples?

Answer 30

(a) Glycogen storage diseases, or glycogenoses, are genetic disorders with enzymatic defects in glycogen synthesis or breakdown, leading to massive glycogen accumulation, causing cell injury and cell death.

(b) Glycogen appears as clear vacuoles in the cytoplasm and is best identified with staining techniques like Best carmine or PAS reaction, and validated by diastase digestion.

Question 31

Intracellular accumulations

Briefly discuss key causes of protein accumulation.

Answer 31

(1) Reabsorption droplets
In conditions like proteinuria, where there is excessive protein loss in the urine, the kidney’s proximal tubules reabsorb more protein, leading to visible protein droplets in the cytoplasm.

(2) Excessive production
When cells produce normal secreted proteins in excessive amounts, these proteins can accumulate within the endoplasmic reticulum (ER). For example, plasma cells synthesizing large amounts of immunoglobulins can develop large inclusions called Russell bodies.

(3) Defective transport and secretion
Mutations can slow down protein folding, causing partially folded proteins to accumulate in the ER.

(4) Cytoskeletal protein accumulation
Various cytoskeletal proteins, such as keratin filaments and neurofilaments, can accumulate due to cell injury. For instance, keratin filaments accumulate in liver cells in alcoholic liver disease, forming alcoholic hyaline.

(5) Abnormal protein aggregation
Abnormal or misfolded proteins can aggregate and deposit in tissues, interfering with normal cellular functions. This is seen in diseases like amyloidosis, where protein aggregates can be intracellular, extracellular, or both.

Question 32

Intracellular accumulations

What is the most common exogenous pigment and how does it affect the lungs?

Answer 32

🩺 The most common exogenous pigment is carbon (coal dust). When inhaled, it enters the alveoli in the lungs where it is engulfed by macrophages. Some of these macrophages, filled with carbon particles, remain in the lung tissue. Over time, the accumulation of these carbon-laden macrophages leads to the blackening of the lung tissue, a condition known as anthracosis.
🩺 Other macrophages transport the carbon particles to the lymph nodes via the lymphatic system.
[Image 1] [Image 2] [Image 3] [Image 4]

Question 33

Intracellular accumulations

How does carbon dust affect coal miners specifically?

Answer 33

In coal miners, aggregates of carbon dust can induce a fibroblastic reaction or emphysema, leading to a serious lung disease known as coal worker’s pneumoconiosis.

Question 34

Intracellular accumulations

What happens to pigments introduced into the skin through tattooing?

Answer 34

Tattoo pigments are phagocytosed by dermal macrophages, where they remain for the life of the individual. These pigments do not usually evoke any inflammatory response.

Question 35

Intracellular accumulations

What is lipofuscin and what is its significance?

Answer 35

Lipofuscin is an insoluble pigment, also known as lipochrome or wear-and-tear pigment. It is composed of polymers of lipids and phospholipids in complex with protein. Its significance lies in being an indicator of free radical injury and lipid peroxidation.
[Image 1] [Image 2] [Image 3]

Question 36

Intracellular accumulations

How does lipofuscin appear in tissue sections and where is it commonly found?

Answer 36

Lipofuscin appears as a yellow-brown, finely granular cytoplasmic pigment, often perinuclear. It is commonly seen in aging patients or those with severe malnutrition and cancer cachexia.

Question 37

Intracellular accumulations

What is melanin and how is it formed?

Answer 37

Melanin is an endogenous brown-black pigment. It is produced when the enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes.

Question 38

Intracellular accumulations

What is hemosiderin and how is it stored in the body?

Answer 38

Hemosiderin is a hemoglobin-derived, golden yellow-to-brown pigment. It is a major storage form of iron.

Question 39

Intracellular accumulations

Where is hemosiderin commonly found and what causes its excess accumulation?

Answer 39

Hemosiderin is commonly found in the mononuclear phagocytes of the bone marrow, spleen, and liver. Excess accumulation can occur due to local hemorrhages (e.g., bruises) or systemic conditions like hemochromatosis, hemolytic anemias, and repeated blood transfusions.

Further notes:
How do hemolytic anaemias cause the accumulation of hemosiderin?
🩺 Hemolytic anemias involve the premature destruction of RBCs, leading to the release of hemoglobin into the bloodstream.
🩺 Hemoglobin from the destroyed RBCs is broken down, releasing iron. This iron is then taken up by macrophages.
🩺 The iron is stored within macrophages as ferritin. When there is an excess of iron, ferritin molecules aggregate to form hemosiderin granules.
🩺 These hemosiderin granules accumulate in various tissues, including the spleen, liver, bone marrow, and kidneys, leading to hemosiderosis.

Question 40

What is an iatrogenic disease?

Answer 40

An iatrogenic disease is a condition that is caused by medical treatment or procedures rather than by an underlying disease.

Question 41

What are two theories that attempt to explain the basis of the effects of ionizing radiation?

Answer 41

(a) Target theory: injury results due ionization of
specific cellular components. Targets include nucleic acids, enzymes and proteins that bear the SH group.
(b) Poison theory: injury results from ionization and production of free radicals. This results in membrane injury.

Question 42

What are some chromosomal changes that may occur due to radiation injury?

Answer 42

(a) Deletions
(b) Translocations
(c) Fragmentation
(d) Adhesion breaks between chromosomes
(e) Polyploidy and aneuploidy