Cellular Response to Injury

Question 1

Hypertrophy

Answer 1

1. Hypertrophy is an increase in the size of an organ or tissue due to an increase in the size
   of cells.
2. Other characteristics include an increase in protein synthesis and an increase in the size
   or number of intracellular organelles.
3. A cellular adaptation to increased workload results in hypertrophy, as exemplified by
   the increase in skeletal muscle mass associated with exercise and the enlargement of
   the left ventricle in hypertensive heart disease.

Question 2

Hyperplasia

Answer 2

1. Hyperplasia is an increase in the size of an organ or tissue caused by an increase in the
   number of cells.
2. It is exemplified by glandular proliferation in the breast during pregnancy.
3. In some cases, hyperplasia occurs together with hypertrophy. During pregnancy, uterine
   enlargement is caused by both hypertrophy and hyperplasia of the smooth muscle cells
   in the uterus.

Question 3

Aplasia

Answer 3

1. Aplasia is a failure of cell production.
2. During fetal development, aplasia results in agenesis, or absence of an organ due to
   failure of production.
3. Later in life, it can be caused by permanent loss of precursor cells in proliferative tissues,
   such as the bone marrow.

Question 4

Hypoplasia

Answer 4

1. Hypoplasia is a decrease in cell production that is less extreme than in aplasia.
2. It is seen in the partial lack of growth and maturation of gonadal structures in Turner
   syndrome and Klinefelter syndrome.

Question 5

Atrophy

Answer 5

1. Atrophy is a decrease in the size of an organ or tissue and results from a decrease in the
   mass of preexisting cells (Figure 1-1).
2. Most often, causal factors are disuse, nutritional or oxygen deprivation, diminished
   endocrine stimulation, aging, and denervation (lack of nerve stimulation in peripheral
   muscles caused by injury to motor nerves).
3. Characteristic features often include the presence of autophagic granules, which are
   intracytoplasmic vacuoles containing debris from degraded organelles.
4. In some instances, atrophy is thought to be mediated in part by the ubiquitin-proteosome pathway of protein degradation. In this pathway, ubiquitin-linked proteins are
   degraded within the proteosome, a large cytoplasmic protein complex.

Question 6

Metaplasia

Answer 6

the replacement of one differentiated tissue by another

Question 7

Squamous metaplasia

Answer 7

a. Squamous metaplasia is exemplified by the replacement of columnar epithelium at
the squamocolumnar junction of the cervix by squamous epithelium.
b. It can also occur in the respiratory epithelium of the bronchus, in the endometrium,
and in the pancreatic ducts.
c. Associated conditions include chronic irritation (e.g., squamous metaplasia of the
bronchi with long-term use of tobacco) and vitamin A deficiency.
d. This process is often reversible.

Question 8

Osseous metaplasia

Answer 8

a. Osseous metaplasia is the formation of new bone at sites of tissue injury.
b. Cartilaginous metaplasia may also occur

Question 9

Myeloid metaplasia (extramedullary hematopoiesis)

Answer 9

is proliferation of hematopoietic

tissue at sites other than the bone marrow, such as the liver or spleen.

Question 10

Causes of Hypoxic Cell Injury

Answer 10

Hypoxic cell injury results from cellular anoxia or hypoxia, which in turn results
from various mechanisms, including:
1. Ischemia (obstruction of arterial blood flow), which is the most common cause
2. Anemia, which is a reduction in the number of oxygen-carrying red blood cells
3. Carbon monoxide poisoning, which results in diminution in the oxygen-carrying capacity
of red blood cells by chemical alteration of hemoglobin
4. Decreased perfusion of tissues by oxygen-carrying blood, which occurs in cardiac failure,
hypotension, and shock
5. Poor oxygenation of blood secondary to pulmonary disease

Question 11

Early Stage of Hypoxic Cell Injury

Answer 11

Hypoxic cell injury first affects the mitochondria, with resultant decreased
oxidative phosphorylation and adenosine triphosphate (ATP) synthesis. Consequences of
decreased ATP availability include:
1. Failure of the cell membrane pump(ouabain-sensitive Na-K-ATPase) results in increased
intracellular Na and water and decreased intracellular K. This process causes cellular
swelling and swelling of organelles.
a. Cellular swelling, or hydropic change,is characterized by the presence of large vacuoles
in the cytoplasm.
b. Swelling of the endoplasmic reticulumis one of the first ultrastructural changes evident
in reversible injury.
c. Swelling of the mitochondriaprogresses from reversible, low-amplitude swelling to irreversible, high-amplitude swelling, which is characterized by marked dilation of the
inner mitochondrial space.
2. Disaggregation of ribosomes leads to failure of protein synthesis. Ribosomal disaggregation is also promoted by membrane damage.
3. Stimulation of phosphofructokinase activity results in increased glycolysis, accumulation
of lactate, and decreased intracellular pH. Acidification causes reversible clumping of
nuclear chromatin.

Question 12

Late Stage Hypoxic Cell Injury

Answer 12

1. Hypoxic cell injury eventually results in membrane damage to plasma and to lysosomal
   and other organelle membranes, with loss of membrane phospholipids.
2. Reversible morphologic signs of damage include the formation of:
   a. Myelin figures, whorl-like structures probably originating from damaged membranes
   b. Cell blebs, a cell surface deformity most likely caused by disorderly function of the
   cellular cytoskeleton

Question 13

Cell Death in Hypoxic Cell Injury

Answer 13

Finally, cell death is caused by severe or prolonged injury.
1. The point of no return is marked by irreversible damage to cell membranes, leading to
massive calcium influx, extensive calcification of the mitochondria, and cell death.
2. Intracellular enzymes and various other proteins are released from necrotic cells into the circulation as a consequence of the loss of integrity of cell membranes. This phenomenon is
the basis of a number of useful laboratory determinations as indicators of necrosis.
a. Myocardial enzymes in serum. These are discussed in more depth in Chapter 10.
(1) Enzymes that have been useful in the diagnosis of myocardial infarction (“heart
attack,” see Chapters 3 and 10) include the following:
(a) Aspartate aminotransferase (AST, previously known as SGOT)
(b) Lactate dehydrogenase (LDH)
(c) Creatine kinase (CK, also known as CPK)
(2) These markers of myocardial necrosis vary in specificity for heart damage, as well
as in the time period after the necrotic event in which elevations in the serum
appear and persist. The delineation of isoenzyme forms of LDH and CK has been
a useful adjunct in adding specificity to these measures.
(3) The foregoing enzymes are beginning to be replaced by other myocardial proteins
in serum as indicators of myocardial necrosis. Important examples include the
troponins (troponin I [TnI] and troponin T [TnT]) and myoglobin.
b. Liver enzymes in serum. These enzymes are discussed in more detail in Chapter 16.
Enzymes of special interest include the transaminases (AST and alanine aminotransferase [ALT]), alkaline phosphatase, and γ-glutamyltransferase (GGT).
3. The vulnerability of cells to hypoxic injury varies with the tissue or cell type. Hypoxic
injury becomes irreversible after:
a. 3–5 minutes for neurons. Purkinje cells of the cerebellum and neurons of the hippocampus are more susceptible to hypoxic injury than are other neurons.
b. 1–2 hours for myocardial cells and hepatocytes
c. Many hours for skeletal muscle cells

Question 14

Free radicals

Answer 14

1. These molecules have a single unpaired electron in the outer orbital.
2. Examples include the activated products of oxygen reduction, such as the superoxide
   (O2·) and the hydroxyl (OH·) radicals.

Question 15

Mechanisms that generate free radicals

Answer 15

1. Normal metabolism
2. Oxygen toxicity, such as in the alveolar damage that can cause adult respiratory distress
   syndrome or as in retrolental fibroplasia (retinopathy of prematurity), an ocular disorder
   of premature infants that leads to blindness
3. Ionizing radiation
4. Ultraviolet light
5. Drugs and chemicals,many of which promote both proliferation of the smooth endoplasmic reticulum (SER) and induction of the P-450 system of mixed function oxidases of the
   SER. Proliferation and hypertrophy of the SER of the hepatocyte are classic ultrastructural markers of barbiturate intoxication.
6. Reperfusion after ischemic injury

Question 16

Mechanisms that degrade free radicals

Answer 16

1. Intracellular enzymes, such as glutathione peroxidase, catalase, or superoxide dismutase
2. Exogenous and endogenous antioxidants, such as vitamin A, vitamin C, vitamin E, cysteine,
   glutathione, selenium, ceruloplasmin, or transferrin
3. Spontaneous decay

Question 17

Chemical Cell Injury

Answer 17

Chemical cell injury is illustrated by the model of liver cell membrane damage induced by carbon
tetrachloride (CCl4).
A. In this model, CCl4
is processed by the P-450 system of mixed function oxidases within the
SER, producing the highly reactive free radical CCl3·.
B. CCl3·diffuses throughout the cell, initiating lipid peroxidation of intracellular membranes.
Widespread injury results, including:
1. Disaggregation of ribosomes,resulting in decreased protein synthesis. Failure of the cell to
synthesize the apoprotein moiety of lipoproteins causes an accumulation of intracellular lipids (fatty change).
2. Plasma membrane damage, caused by products of lipid peroxidation in the smooth endoplasmic reticulum, resulting in cellular swelling and massive influx of calcium, with
resultant mitochondrial damage, denaturation of cell proteins, and cell death

Question 18

Necrosis

Answer 18

the sum of the degradative and inflammatory reactions occurring after tissue
death caused by injury (e.g., hypoxia, exposure to toxic chemicals); it occurs within living
organisms. In pathologic specimens, fixed cells with well-preserved morphology are
dead but not necrotic

Question 19

Autolysis

Answer 19

refers to degradative reactions in cells caused by intracellular enzymes indigenous to the cell. Postmortem autolysisoccurs after the death of the entire organism and is
not necrosis.

Question 20

4. Heterolysis

Answer 20

refers to cellular degradation by enzymes derived from sources extrinsic to
the cell (e.g., bacteria, leukocytes).

Question 21

Coagulative necrosis

Answer 21

a. Coagulative necrosis results most often from a sudden cutoff of blood supply to an
organ (ischemia), particularly the heart and kidney.
b. General preservation of tissue architecture is characteristic in the early stages.
c. Increased cytoplasmic eosinophilia occurs because of protein denaturation and loss of
cytoplasmic RNA.
d. Nuclear changes,the morphologic hallmark of irreversible cell injury and necrosis, are
characteristic. These include:
(1) Pyknosis, chromatin clumping and shrinking with increased basophilia
(2) Karyorrhexis, fragmentation of chromatin
(3) Karyolysis, fading of chromatin material
(4) Disappearance of stainable nuclei

Question 22

Liquefactive necrosis

Answer 22

a. Ischemic injury to the central nervous system (CNS) characteristically results in liquefactive necrosis. After the death of CNS cells, liquefaction is caused by autolysis.
b. Digestion, softening, and liquefaction of tissue are characteristic.
c. Suppurative infections characterized by the formation of pus (liquefied tissue debris
and neutrophils) by heterolytic mechanisms involve liquefactive necrosis.

Question 23

Caseous necrosis

Answer 23

a. This type of necrosis occurs as part of granulomatous inflammation and is a manifestation of partial immunity caused by the interaction of T lymphocytes (CD4, CD8,
and CD4-CD8-), macrophages, and probably cytokines, such as interferon-, derived
from these cells.
b. Tuberculosis is the leading cause of caseous necrosis.
c. Caseous necrosis combines features of both coagulative necrosis and liquefactive
necrosis.
d. On gross examination, caseous necrosis has a cheese-like (caseous) consistency.
e. On histologic examination, caseous necrosis has an amorphous eosinophilic
appearance.

Question 24

Gangrenous necrosis

Answer 24

a. This type of necrosis most often affects the lower extremities or bowel and is secondary
to vascular occlusion.
b. When complicated by infective heterolysis and consequent liquefactive necrosis, gangrenous necrosis is called wet gangrene.
c. When characterized primarily by

Question 25

Fibrinoid necrosis

Answer 25

a. This deposition of fibrin-like proteinaceous material in the arterial walls appears smudgy
and acidophilic.
b. Fibrinoid necrosis is often associated with immune-mediated vascular damage.

Question 26

Fat necrosis occurs in two forms.

Answer 26

a. Traumatic fat necrosis,which occurs after a severe injury to tissue with high fat content,
such as the breast
b. Enzymatic fat necrosis, which is a complication of acute hemorrhagic pancreatitis,
a severe inflammatory disorder of the pancreas
(1) Proteolytic and lipolytic pancreatic enzymes diffuse into inflamed tissue and literally digest the parenchyma.
(2) Fatty acids liberated by the digestion of fat form calcium salts (saponification, or
soap formation).
(3) Vessels are eroded, with resultant hemorrhage.

Question 27

Apoptosis

Answer 27

1. Apoptosis is a second morphologic pattern of tissue death. (The other is necrosis; see V.)
   It is often referred to as programmed cell death.
2. This is an important mechanism for the removal of cells. An example is apoptotic removal
   of cells with irreparable DNA damage (from free radicals, viruses, cytotoxic immune
   mechanisms), protecting against neoplastic transformation.
3. In addition, apoptosis is an important mechanism for physiologic cell removal during embryogenesis and in programmed cell cycling (e.g., endometrial cells during
   menstruation).
4. This involutional process is similar to the physiologic loss of leaves from a tree; apoptosisis a Greek term for “falling away from.”

Question 28

Morphological Features of Apoptosis

Answer 28

1. A tendency to involve single isolated cells or small clusters of cells within a tissue
2. Progression through a series of changes marked by a lack of inflammatory response
   a. Blebbing of plasma membrane, cytoplasmic shrinkage, chromatin condensation
   b. Budding of cell and separation of apoptotic bodies (membrane-bound segments)
   c. Phagocytosis of apoptotic bodies
3. Involution and shrinkage of affected cells and cell fragments, resulting in small round
   eosinophilic masses often containing chromatin remnants, exemplified by Councilman
   bodies in viral hepatitis

Question 29

Biochemical Processes of Apoptosis

Answer 29

1. Diverse injurious stimuli (e.g., free radicals, radiation, toxic substances, withdrawal of
   growth factors or hormones) trigger a variety of stimuli, including cell surface receptors
   such as FAS, mitochondrial response to stress, and cytotoxic T cells.
2. The extrinsic pathway of initiation is mediated by cell surface receptors exemplified by
   FAS, a member of the tumor necrosis factor receptor family of proteins. This pathway is
   initiated by signaling by molecules such as the FAS ligand, which in turn signals a series
   of events that involve activation of caspases. Caspases are aspartate-specific cysteine
   proteases that have been referred to as “major executioners” or “molecular guillotines.”
   The death signals are conveyed in a proteolytic cascade, through activation of a chain of
   caspases and other targets. The initial activating caspases are caspase-8 and caspase-9,
   and the terminal caspases (executioners) include caspase-3 and caspase-6 (among other
   proteases).
3. The intrinsic, or mitochondrial, pathway, which is initiated by the loss of stimulation by
   growth factors and other adverse stimuli, results in the inactivation and loss of bcl-2 and
   other antiapoptotic proteins from the inner mitochondrial membrane. This loss results
   in increased mitochondrial permeability, the release of cytochrome c, and the stimulation of proapoptotic proteins such as bax and bak. Cytochrome c interacts with Apaf-1
   causing self-cleavage and activation of caspase-9. Downstream caspases are activated by
   upstream proteases and act themselves to cleave cellular targets.
4. Cytotoxic T-cell activation is characterized by direct activation of caspases by granzyme B,
   a cytotoxic T-cell protease that perhaps directly activates the caspase cascade. The entry
   of granzyme B into target cells is mediated by perforin, a cytotoxic T-cell protein.
5. Degradation of DNA by endonucleases into nucleosomal chromatin fragments that are
   multiples of 180–200 base pairs results in the typical “laddering” appearance of DNA on
   electrophoresis. This phenomenon is characteristic of, but not entirely specific for,
   apoptosis.
6. Activation of transglutaminases crosslinks apoptotic cytoplasmic proteins.
7. The caspases consist of a group of aspartic acid-specific cysteine proteases that are activated during apoptosis.
8. Newer methods such as the TUNEL assay (Terminal Transferase dUTP Nick End Labeling)
   are ways to quantitate cleaving of nucleosomes and, thus, apoptosis. Similarly, caspase
   assays are coming into use as apoptotic markers. Surely more will follow.

Question 30

Regulation of apoptosis

Answer 30

mediated by a number of genes and their products. Important
genes include bcl-2 (gene product inhibits apoptosis), bax (gene product facilitates apoptosis), and p53 (gene product decreases transcription of bcl-2 and increases transcription of
bax, thus facilitating apoptosis).

Question 31

Fatty change (fatty metamorphosis, steatosis)

Answer 31

1. General considerations
   a. Fatty change is characterized by the accumulation of intracellular parenchymal triglycerides and is observed most frequently in the liver, heart, and kidney. For example, in
   the liver, fatty change may be secondary to alcoholism, diabetes mellitus, malnutrition, obesity, or poisonings.
2. Imbalance among the uptake, utilization, and secretion of fat is the cause of fatty change,
   and this can result from any of the following mechanisms:
   a. Increased transport of triglycerides or fatty acids to affected cells
   b. Decreased mobilization of fat from cells, most often mediated by decreased production
   of apoproteins required for fat transport. Fatty change is thus linked to the disaggregation of ribosomes and consequent decreased protein synthesis caused by failure of
   ATP production in CCl4
   -injured cells.
   c. Decreased use of fat by cells
   d. Overproduction of fat in cells

Question 32

Hyaline change

Answer 32

1. This term denotes a characteristic (homogeneous, glassy, eosinophilic) appearance in
   hematoxylin and eosin sections.
2. It is caused most often by nonspecific accumulations of proteinaceous material.

Question 33

Accumulations of exogenous pigments

Answer 33

1. Pulmonary accumulations of carbon (anthracotic pigment), silica, and iron dust
2. Plumbism (lead poisoning)
3. Argyria (silver poisoning), which may cause a permanent gray discoloration of the skin
   and conjunctivae (Figure 1-3)

Question 34

Melanin

Answer 34

a. This pigment is formed from tyrosine by the action of tyrosinase, synthesized in
melanosomes of melanocytes within the epidermis, and transferred by melanocytes to
adjacent clusters of keratinocytes and also to macrophages (melanophores) in the
subjacent dermis.
b. Increased melanin pigmentation is associated with suntanning and with a wide variety
of disease conditions.
c. Decreased melanin pigmentation is observed in albinism and vitiligo.

Question 35

Bilirubin

Answer 35

a. This pigment is a catabolic product of the heme moiety of hemoglobin and, to a minor
extent, myoglobin.
b. In various pathologic conditions, bilirubin accumulates and stains the blood, sclerae,
mucosae, and internal organs, producing a yellowish discoloration called jaundice.
(1) Hemolytic jaundice, which is associated with the destruction of red cells, is discussed in more depth in Chapter 11.
(2) Hepatocellular jaundice, which is associated with parenchymal liver damage, and
obstructive jaundice,which is associated with intra- or extrahepatic obstruction of
the biliary tract, are discussed more fully in Chapter 16.

Question 36

Hemosiderin

Answer 36

a. This iron-containing pigment consists of aggregates of ferritin. It appears in tissues as
golden brown amorphous aggregates and can be positively identified by its staining
reaction (blue color) with Prussian blue dye. It exists normally in small amounts as
physiologic iron stores within tissue macrophages of the bone marrow, liver, and
spleen.
b. It accumulates pathologically in tissues in excess amounts (sometimes massive)
(Table 1-3).
(1) Hemosiderosis is defined by accumulation of hemosiderin, primarily within tissue
macrophages, without associated tissue or organ damage.
(2) Hemochromatosis is more extensive accumulation of hemosiderin, often within
parenchymal cells, with accompanying tissue damage, scarring, and organ dysfunction. This condition occurs in both hereditary (primary) and secondary forms.
(a) Hereditary hemochromatosis is most often caused by a mutation in the Hfe
gene on chromosome 6.
(i) Hemosiderin deposition and organ damage in the liver, pancreas,
myocardium, and multiple endocrine glands is characteristic, as well as
melanin deposition in the skin.
(ii) This results in the triad of micronodular cirrhosis, diabetes mellitus, and
skin pigmentation. This set of findings is referred to as “bronze diabetes.”
Laboratory abnormalities of note include marked elevation of the serum
transferrin saturation because of the combination of increased serum iron
and decreased total iron-binding capacity (TIBC).
(b) Secondary hemochromatosis is most often caused by multiple blood transfusions administered to subjects with hereditary hemolytic anemias such as
-thalassemia major (Figure 1-4).

Question 37

Lipofuscin

Answer 37

a. This yellowish, fat-soluble pigment is an end product of membrane lipid peroxidation.
b. It is sometimes referred to as “wear-and-tear” pigment.
c. It commonly accumulates in elderly patients, in whom the pigment is found most
often within hepatocytes and at the poles of nuclei of myocardial cells. The combination of lipofuscin accumulation and atrophy of organs is referred to as brown
atrophy.

Question 38

Metastatic calcification

Answer 38

a. The cause of metastatic calcification is hypercalcemia.
b. Hypercalcemia most often results from any of the following causes:
(a) Hyperparathyroidism
(b) Osteolytic tumors with resultant mobilization of calcium and phosphorus
(c) Hypervitaminosis D
(d) Excess calcium intake, such as in the milk-alkali syndrome (nephrocalcinosis and
renal stones caused by milk and antacid self-therapy)

Question 39

Dystrophic calcification

Answer 39

a. Dystrophic calcification is defined as calcification in previously damaged tissue, such as
areas of old trauma, tuberculosis lesions, scarred heart valves, and atherosclerotic
lesions.
b. The cause is not hypercalcemia; typically, the serum calcium concentration is normal
(Figure 1-5).

Question 40

Abnormal protein aggregation

Answer 40

which is characteristic of amyloidosis; a number of neurodegenerative diseases, such as Alzheimer disease, Huntington disease, and Parkinson
disease; and perhaps prion diseases, such as “mad cow” disease

Question 41

Abnormal protein transport and secretion

Answer 41

which is characteristic of cystic fibrosis and antitrypsin deficiency