01 - Cell injury, death and adaptations

Question 1

Hypertrophy

Answer 1

1. Defined as the increase in the size of cells. Increased cell size is due to larger numbers of organelles and other cellular components. The size of the entire organ may also be increased.
2. Causes of Hypertrophy
   a. Increased functional demand (increased workload)
   b. Specific hormonal stimulation
3. Hypertrophy may be physiologic or pathologic.
   a. Examples of physiologic hypertrophy – uterine enlargement during pregnancy, muscle enlargement in athletes
   b. Examples of pathologic hypertrophy – cardiac hypertrophy secondary to hypertension (HTN) or valve dysfunction

Question 2

Hyperplasia

Answer 2

1. Defined as an increase in the number of cells in an organ or tissue.
2. Hyperplasia may be physiologic or pathologic.

a. Causes of Physiologic Hyperplasia
1) Hormonal hyperplasia – breast proliferation during puberty and pregnancy
2) Compensatory hyperplasia – compensates for tissue lost due to removal or disease
b. Causes of Pathologic Hyperplasia
1) Usually caused by excessive hormonal or growth factor stimulation
2) Creates fertile soil for neoplastic proliferation of cells
3) Example – endometrial hyperplasia secondary to excess estrogenic stimulation

3. Hyperplasia and hypertrophy are closely related and may occur concurrently in tissue capable of cell division.

Question 3

Atrophy

Answer 3

1. Defined as shrinkage in the size of a cell due to loss of cell substance.
2. Causes of Atrophy
   a. Decreased workload, including immobilization
   b. Loss of innervation
   c. Diminished blood supply
   d. Inadequate nutrition
   e. Loss of endocrine stimulation
   f. Aging
3. Proteolytic Systems Involved in Atrophy
   a. Ubiquitin-proteasome pathway – degrades proteins from nucleus and cytosol
   b. Autophagy – lysosomal enzymes degrade sequestered senescent organelles

Question 4

Metaplasia

Answer 4

1. Defined as a reversible change in which one adult cell type is replaced by another adult cell type.
2. Metaplasia involves epithelial cells most commonly, but may involve mesenchymal cells.
3. Example – squamous metaplasia may occur in the respiratory tract of smokers

Question 5

Mechanisms of irreversible injury (necrosis)

Answer 5

1. Cell is unable to reverse mitochondrial dysfunction.

2. Cell develops profound disturbances in membrane function.

Question 6

Reversible cell injury

Answer 6

1. Cellular swelling
   a. Occurs whenever cells are incapable of maintaining ionic and fluid homeostasis.
   b. It is caused by increased intracellular water accumulation, often related to increased membrane permeability or loss of function of the sodium pump resulting in increased intracellular sodium.
   c. Other terms for cellular swelling include hydropic change and vacuolar degeneration.
2. Fatty change
   a. Manifested by appearance of small or large fat vacuoles in the cytoplasm.
   b. Occurs in hypoxic injuries and some forms of toxic injuries. It may also be a manifestation of metabolic derangements.
   c. It is a less universal reaction than cellular swelling and is seen principally in cells involved in fat metabolism.

Question 7

Necrosis

Answer 7

1. Necrosis refers to a sequence of morphologic changes that accompany cell death in cells that have sustained a lethal injury.
2. The morphologic appearance of necrosis is the result of two processes.
   a. Enzymatic digestion of the cell
   1) Autolysis – hydrolytic enzymes derived from dead cells themselves
   2) Heterolysis – enzymes derived from lysosomes of leukocytes (outside cell!)
   b. Denaturation of proteins
   c. Cytoplasmic changes in necrosis – eosinophilia
3. THE MICROSCOPIC HALLMARKS OF NECROSIS ARE SEEN IN THE NUCLEUS

a. Karyolysis – fading of the nucleus
Enzymatic digestion of nucleus
b. Pyknosis – shrinkage and darkening of the nucleus
Denaturation of nuclear proteins
c. Karyorrhexis – fragmentation of the pyknotic or partially pyknotic nucleus

Question 8

Coagulative necrosis

Answer 8

1) Characterized primarily by denaturation of proteins.
2) Occurs because both lysosomal and structural proteins are denatured, thus blocking autolysis.
3) Therefore, basic cell outline is preserved for several days.
4) Coagulative necrosis is characteristic of hypoxic death in all tissues except the brain.
5) Coagulative necrosis is classically seen in myocardial infarction.

Question 9

Liquefactive necrosis

Answer 9

1) Progressive catalytic degradation of cell structures occurs as a result of autolysis or heterolysis.
2) Process often leaves a defect containing leukocytes.
3) Characteristic mainly of focal bacterial infections.
4) Characteristic also of hypoxic death of the central nervous system.
Enzymatic digestion!

Question 10

Gangrenous necrosis

Answer 10

1) Gangrene is a term used in clinical practice when necrosis of a limb occurs as a result of compromised blood supply. Gangrene is often complicated by secondary bacterial infection. Gangrene is characteristically seen in diabetics.
2) In dry gangrene, coagulative necrosis predominates.
3) In wet gangrene, liquefactive necrosis predominates.

Question 11

Caseous necrosis

Answer 11

1) This distinctive form of coagulative necrosis is encountered in tuberculosis. The process of necrosis completely obliterates tissue architecture and cell outlines.
2) The term “caseous” is derived from its gross appearance, which is dry, white and cheesy.

Question 12

Fat necrosis

Answer 12

1) This is a descriptive term applied to focal areas of fat destruction resulting from abnormal release of activated pancreatic enzymes into pancreatic tissue or the peritoneal cavity.
2) Fatty acids combine with calcium to produce grossly identifiable chalky white areas.

Question 13

Fibrinoid necrosis

Answer 13

1) This special form of necrosis usually occurs associated with immune-mediated reactions involving blood vessels.
2) Antigen-antibody complexes combine with fibrin to form a pink amorphous layer in the blood vessel wall.

Question 14

Pathways of apoptosis

Answer 14

a. Mitochondrial Pathway = Intrinsic Pathway – Release cytochrome. More common
b. Death Receptor Pathway = Extrinsic Pathway – Death receptor pathway, needs binding of cell w/another cell.

Examples:

1. Growth factor deprivation – important in hormone-sensitive cells, lymphocytes and neurons
2. DNA damage – important in prevention of neoplastic transformation
3. Accumulation of misfolded proteins – important in some degenerative CNS diseases and diabetes
4. Apoptosis of self-reactive lymphocytes – important to prevent development of autoimmunity
5. Cytotoxic T lymphocyte-mediated apoptosis – important in target cell killing by CTLs

Question 15

Intracellular accumulations: Fatty Change

Answer 15

1. Appearance of fat vacuoles represents an absolute increase in intracellular lipids.
2. Fatty change is an indicator of reversible cell injury.

Question 16

Intracellular accumulations: Cholesterol + Cholesterol Esters

Answer 16

1. Phagocytic cells become overloaded with complex lipids.

2. Lipid-laden phagocytic cells are called foam cells.

Question 17

Intracellular accumulations: Proteins

Answer 17

1. May accumulate due to –
2. Examples – Russell bodies in plasma cells, alcoholic hyaline in hepatocytes, neurofibrillary tangle in brain cells in Alzheimer disease

Question 18

Intracellular accumulations: Glycogen

Answer 18

1. May accumulate due to –
2. “Glycogen Storage diseases” – a class of inborn errors of metabolism in which abnormal products collect within cells throughout the body

Question 19

Intracellular accumulations: Exogenous pigments

Answer 19

a. Anthracosis
1) Carbon dust particles accumulate in macrophages of the lungs.
2) Anthracosis is seen in the lungs of all city dwellers.
3) It does not usually seem to cause problems.
4) Very heavy carbon deposits may greatly reduce respiratory function in “coal worker’s pneumoconiosis.”

b. Silicosis – Silicon is damaging to lungs, does not breakdown easily. Causes dense pleural thickening. Persistent immune response. Causes physical dmg

c. Tattoo
1) Introduction of pigments into the dermis causes tattoos. Tattoos are usually harmless.

2) Amalgam tattoo – Oxidized silver, embedded amalgam. Usually posterior, gingival. Alloy broken down and embedded in CT

Question 20

Intracellular accumulations: Endogenous pigments

Answer 20

a. Hemosiderin
1) This golden yellow to brown granular or crystalline pigment is derived from hemoglobin breakdown. It is a form of stored iron.
2) Hemosiderosis results from systemic overload of iron.
3) Hereditary hemochromatosis is an autosomal recessive Mendelian genetic disease that produces extreme systemic iron overload.

b. Bilirubin
1) This is a brown-green pigment derived from hemoglobin.
2) It is normally seen in bile.
3) Jaundice is the clinical result of excess bilirubin and is seen as yellow discoloration of the skin and sclerae.

c. Lipofuscin
1) This brownish-yellow granular intracytoplasmic pigment is an indigestible residue of autophagy.
2) Autophagy
a) Damaged organelles and/or portions of cytosol are sequestered from the cytoplasm in an autophagic vacuole, a membrane-bound sack.
b) Autophagic vacuoles then fuse with preexisting lysosomes to become autophagolysosomes.
c) Cellular debris not totally digested by autolysosomes persists as membrane-bound residual bodies, or may be extruded.
d) Undigested residual pigment persisting following intracellular lipid peroxidation is termed lipofuscin pigment (or “wear and tear” pigment).
e) Autophagy is commonly involved in the removal of damaged cell organelles during cell injury and the cellular remodeling of differentiation. It is particularly pronounced in cells undergoing atrophy.

d. Melanin – This is a dark brown granular pigment is normally found within melanocytes in the skin and some other organs.

Question 21

Dystrophic calcification

Answer 21

1. If necrotic debris is not rapidly removed by scavenger cells, calcium and other mineral salts are deposited.
2. Serum calcium levels and calcium metabolism are normal.
   NO CALCIUM LEVEL ABNORMALITY!!! Cells must die first!

Question 22

Metastatic calcification

Answer 22

1. Defined as deposition of calcium salts in vital (living) tissue.
2. It is due to increased levels of serum calcium (hypercalcemia).
3. Serum calcium may be elevated in several systemic conditions.
4. Calcinosis refers to “large” areas of metastatic calcification.
   Due to high calcium serum levels! Never + muscles!