Exam I: Pathology III

Question 1

Ischemic and Hypoxic Injury

Answer 1

Ischemia and Hypoxia are the most common types of cell injury
Study ways to preserve cells after hypoxia
Have hypoxia and ischemia at the same time, but ischemia causes a lot more tissue injury than hypoxia itself
Hypoxia: reduction of O2 available; more transient

Question 2

Ischemia

Answer 2

Ischemia: supply of O2 and nutrients is decreased due to decreased blood flow (mechanical obstruction)
Secondary to pathologic problem like atherosclerosis
Compromises the delivery of substrates for glycolysis

Ischemic tissues: aerobic metabolism compromised, anaerobic energy generation stopped, glycolytic substrates are exhausted, glycolysis is inhibited, accumulation of metabolites
Ischemia tends to cause more rapid and severe cell and tissue injury than does hypoxia in the absence of ischemia

Question 3

Post Ischemia/Hypoxia

Answer 3

Oxygen tension within the cell decreases causing loss of oxidative phosphorylation and decreased generation of ATP
Decreased ATP leads to failure of the Na+ pump causing Na, Ca2+, and water in (cell swelling), and K+ out
Progressive loss of glycogen
Decreased protein synthesis

Question 4

Ischemic Cell Injury: Reversible Example

Answer 4

Example: Heart muscle ceases to contract within 60 seconds of coronary occlusion
Loss of contractility does not mean cell death
Continued hypoxia causes worsening ATP depletion and further deterioration
Cytoskeleton disperses leading to loss of ultrastructural features (microvilli and formation of blebs) and formation of myelin figures (degenerating cellular membranes)
Seen within the cytoplasm (in autophagic vacuoles) or extracellularly
Mitochondria swell, ER dilated, whole cell is swollen, but if O2 is restored all these things can be reversed!

Question 5

Ischemic Injury: Irreversible

Answer 5

If ischemia persists, irreversible injury and necrosis ensue!!!!
Irreversible injury= severe swelling of mitochondria, extensive damage to plasma membranes which give rise to myelin figures, swelling of lysosomes, and large, flocculent, amorphous densities develop in the mitochondrial matrix
Necrosis is occurring ONLY if there is acute inflammation and neutrophils are present from ongoing injury

Question 6

Irreversible Ischemic Injury Example

Answer 6

Myocardium
Irreversible injury
Seen as early as 30 to 40 minutes after ischemia
Massive influx of calcium into the cell (ischemic zone)
Death—mainly necrosis, but apoptosis also contributes
Apoptotic pathway is activated by release of pro-apoptotic molecules from leaky mitochondria
Widespread leakage of cellular enzymes into extracellular space
Dead cells replaced by large masses (myelin figures)
Phagocytosed by leukocytes
Degraded further into fatty acids

Question 7

Ischemic Injury Treatment

Answer 7

Despite many investigations there are no reliable therapeutic approaches for reducing the injurious consequences of ischemia in clinical situations
Most useful strategy in ischemic (and traumatic) brain and spinal cord injury
Transient induction of hypothermia (core body temperature to 92°F)
Reduces the metabolic demands of the stressed cells
Decreases cell swelling, suppresses the formation of free radicals, inhibits the host inflammatory response
Also prevents herniation of brain into the brain stem = death

Question 8

Ischemia-Reperfusion Injury

Answer 8

Restoration of blood flow to ischemic tissues promotes recovery of cells (reversibly injured)
Certain circumstances: blood flow is restored to cells that have been ischemic but have not died and paradoxical injury is exacerbated
Reperfused tissues may sustain loss of cells in addition to the cells that are irreversibly damaged at the end of ischemia
Contributes to tissue damage
Myocardial and cerebral infarction
Following therapies to restore blood
Reperfusion injuries are better than death.. obviously

Question 9

Mechanisms of Reperfusion Injury

Answer 9

New damaging processes during reperfusion
Death of cells that might have recovered otherwise
Proposed mechanisms:
1 Damage may be initiated during reoxygenation causing increased generation of reactive oxygen and nitrogen species
2. Cellular antioxidant defense mechanisms are compromised by ischemia causing the accumulation of free radicals
Mediators of cell injury (calcium) may also enter reperfused cells causing further damage to various organelles (especially mitochondria) and increasing the production of free radicals

Question 10

Ischemic Injury: Activation of Complement System & Inflammation

Answer 10

Ischemic injury: associated with inflammation as a result of the production of cytokines, which cause additional tissue injury
Activation of the complement system may contribute to ischemia-reperfusion injury
Involved in host defense
Important mechanism of immune injury

Question 11

Chemical (Toxic) Injury: Prescription Drugs & Direct Injury

Answer 11

Frequent problem in clinical medicine
Major limitation to drug therapy: many drugs are metabolized in the liver= toxic liver injury
Most frequent reason for terminating therapeutic use or development of a drug

Direct injury: combining with critical molecular components; example: Mercuric chloride poisoning
Mercury binds to the sulfhydryl groups of cell membrane proteins causing increased membrane permeability and inhibition of ion transport
Damage to cells that use, absorb, excrete, or concentrate the chemicals aka gastrointestinal tract and kidney

Question 12

Chemical (Toxic) Injury: Conversion to Toxic Metabolites

Answer 12

Most toxic chemicals are not biologically active in their native form and must be converted to reactive toxic metabolites to act on target molecules
Accomplished by cytochrome P-450 mixed-function oxidases in the smooth ER of the liver and other organs
Cause membrane damage and cell injury
Formation offree radicalsand subsequent lipid peroxidation

Example: CCl4, (dry cleaning industry): converted by cytochrome P-450 to ˙CCl3 (free radical)
Causes lipid peroxidation and damages cellular structures
Example: Acetaminophen: converted to a toxic product during detoxification in the liver
Cell injury

Question 13

Apoptosis: General Information

Answer 13

Pathway of cell death induced by a tightly regulated suicide program
Activate enzymes, degradation of the cells’ nuclear DNA along with nuclear and cytoplasmic proteins
Cells break up into fragments (apoptotic bodies) that contain portions of the cytoplasm and nucleus
Plasma membrane of the apoptotic cell and bodies remains intact, but the structure is altered for phagocytes
Dead cell and its fragments—rapidly devoured
Contents of the cell are not leaked out
Cell death by this pathway does not elicit an inflammatory reaction in the host
Normal phenomenon
Serves to eliminate cells that are no longer needed
Maintains a steady number of various cell populations in tissues

Question 14

Causes of Apoptosis: Hormone Dependent

Answer 14

Involution of hormone-dependent tissues upon hormone withdrawal
Endometrial cell breakdown during the menstrual cycle
Ovarian follicular atresia in menopause
Regression of the lactating breast after weaning
Prostatic atrophy after castration

Question 15

Causes of Apoptosis: Homeostasis

Answer 15

Cell loss in proliferating cell populations to maintain a constant number (homeostasis)
Immature lymphocytes in the bone marrow
Thymus that fails to express useful antigen receptors
B lymphocytes in germinal centers
Epithelial cells in intestinal crypts

Question 16

Causes of Apoptosis: Autoimmune Prevention and Usefulness

Answer 16

Elimination of potentially harmful self-reactive lymphocytes before or after they have completed their maturation to prevent reactions against one’s own tissues
Death of host cells that have served their useful purpose
Neutrophils in an acute inflammatory response
Lymphocytes at the end of an immune response

Question 17

Apoptosis: Pathologic Conditions

Answer 17

Apoptosis eliminates cells that are injured beyond repair without eliciting a host reaction, thus limiting further tissue damage
Death by apoptosis is responsible for loss of cells in a variety of pathologic states like DNA damage, radiation, cytotoxic anticancer drugs, and hypoxia which can produce free radicals
Accumulation of misfolded proteins due to mutations in the genes encoding these proteins or damage caused by free radicals
Accumulation of these proteins in the ER = ER stress

Question 18

Apoptosis: Viral Infections

Answer 18

Cell death in certain infections
Viral infections: apoptosis is induced by the virus
Adenovirus and HIV infections
Host immune response (viral hepatitis)
Pathologic atrophy in parenchymal organs after duct obstruction like in pancreas, parotid gland, and kidney

Question 19

Morphology of Apoptosis

Answer 19

Cell shrinkage, dense cytoplasm, tightly packed organelles
In other forms of cell injury, an early feature is cell swelling, not shrinkage like in necrosis, reversible and irreversible cell injury
Chromatin condensation is the most characteristic feature of apoptosis
Chromatin aggregates peripherally into dense masses in various shapes and sizes
Nucleus may break up into two or more fragments
Cytoplasmic blebs and apoptotic bodies
Fragmentation into membrane-bound apoptotic bodies
Phagocytosis of apoptotic cells or cell bodies via macrophages

Question 20

Apoptosis and Caspases

Answer 20

Specific feature of apoptosis: activation of several members of a family of cysteine proteases = caspases, which cleave after aspartic acid residues
Divided functionally into two groups
1. Initiators: caspase-8 and caspase-9
2. Executioners: caspase-3 and caspase-6
Exist as inactive pro-enzymes, or zymogens
Undergo an enzymatic cleavage to become active
Presence of cleaved, active caspases is a marker for cells undergoing apoptosis

Question 21

Mechanism of Apoptosis

Answer 21

Divided
Initiation phase: caspases become catalytically active
Execution phase: caspases trigger the degradation of critical cellular components

Two pathways:
Intrinsic (mitochondrial)
Extrinsic (death-receptor initiated)

Question 22

Intrinsic Initiator Pathway of Apoptosis

Answer 22

Intrinsic (Mitochondrial) Pathway of Apoptosis
Major mechanism of apoptosis in mammalian cells
Result of increased mitochondrial permeability
Result of release of pro-apoptotic molecules (death inducers) into the cytoplasm
Leads to activation of the initiator caspase-9

Question 23

Extrinsic Initiator Pathway of Apoptosis

Answer 23

Extrinsic (Death Receptor-Initiated) Pathway of Apoptosis
Initiated by engagement of plasma membrane death receptors on a variety of cells
Death receptors are members of the TNF receptor family
Death domain= cytoplasmic domain involved in protein-protein interactions that delivers apoptotic signals
Leads to activation of the caspase-8 and -10

Question 24

Execution Phase of Apoptosis

Answer 24

Two initiating pathways converge to a cascade of caspase activation to mediate the final phase of apoptosis
Enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases, caspase-3 and -6, which act on many cellular components

Question 25

Apoptosis: Removal of Dead Cells

Answer 25

Apoptotic bodies break cells up into "bite-sized" edible for phagocytes Healthy cells are not eaten, only apoptotic ones because they are labeled with phosphatidylserine on inner leaflet of plasma membrane Phospholipid "flips" out and is expressed on outer layer of membrane, and recognized by several macrophage receptors

Question 26

Apoptosis: Clinicopathologic Correlations

Answer 26

Growth Factor Deprivation: hormone-sensitive cells deprived of the relevant hormone, lymphocytes that are not stimulated by antigens and cytokines, and neurons deprived of nerve growth factor die by apoptosis DNA Damage: exposure of cells to radiation or chemotherapeutic agents

Question 27

Autophagy

Answer 27

Process in which a cell eats its own contents as a survival mechanism due to nutrient deprivation and recycles the digested organelles and portions of cytosol for energy First sequestered from the cytoplasm in an autophagic vacuole then fuses with lysosomes to form an autophagolysosome so cellular components are digested by lysosomal enzymes

Question 28

Normal and Abnormal Cellular Accumulations

Answer 28

Normal: Water, lipids, proteins, and carbohydrates - accumulates in excess Abnormal substances: 1. Exogenous: mineral or products of infectious agents 2. Endogenous: product of abnormal synthesis or metabolism May be harmless to the cells, but occasionally they are severely toxic Location: mainly the cytoplasm (frequently within phagolysosomes) and sometimes the nucleus

Question 29

Normal Endogenous Accumulation: Increased Rate

Answer 29

Normal endogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it Fatty change in the liver and reabsorption protein droplets in the tubules of the kidneys

Question 30

Abnormal Endogenous Accumulation: Protein Defects

Answer 30

Abnormal endogenous substance, accumulates because of defects in protein folding and transport and an inability to degrade the abnormal protein efficiently. Accumulation of mutated α1-antitrypsin in liver cells Mutated proteins in degenerative disorders of the CNS

Question 31

Normal Endogenous Accumulation: Inherited/Genetic

Answer 31

Normal endogenous substance accumulates because of defects, usually inherited, in enzymes that are required for the metabolism of the substance Storage diseases: genetic defects in enzymes involved in the metabolism of lipids and carbohydrates

Question 32

Abnormal Exogenous Accumulation: Lack of Machinery

Answer 32

Abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites Accumulations of carbon particles and nonmetabolizable chemicals (silica)

Question 33

Lipids

Answer 33

All major classes of lipids can accumulate in cells Triglycerides Cholesterol/cholesterol esters Phospholipids: components of the myelin figures found in necrotic cells

Question 34

Steatosis (Fatty Change)

Answer 34

Abnormal accumulations of triglycerides within parenchymal cells Seen in the liver- major organ involved in fat metabolism Occurs in heart, muscle, and kidney Causes: toxins, protein malnutrition, diabetes mellitus, obesity, sometimes pregnancy Most common causes of significant fatty change in the liver (developed countries) and alcohol abuse Nonalcoholic fatty liver disease is associated with diabetes and obesity

Question 35

Lipid Mechanism for Accumulation

Answer 35

Triglyceride accumulation in the liver from free fatty acids from adipose tissue or ingested food, which are normally transported into hepatocytes and esterified to triglycerides, converted into cholesterol or phospholipids, or oxidized to ketone bodies Excess accumulation of triglycerides within the liver Excessive entry or defective metabolism and export of lipids Such defects are induced by alcohol Hepatotoxin that alters mitochondrial and microsomal functions leads to increased synthesis and reduced breakdown of lipids

Question 36

Morphology of Fatty Change

Answer 36

Most often seen in the liver and heart Appears as clear vacuoles within parenchymal cells from intracellular accumulations of water or polysaccharides (e.g., glycogen) may also produce clear vacuoles Identification of lipids requires the avoidance of fat solvents commonly used in tissue preparation Prepare frozen tissue sections of either fresh or aqueous formalin-fixed tissues Sections may then be stained with Sudan IV or Oil Red-O Orange-red color to the contained lipids to tell if lipid accumulation or a different substance

Question 37

Gross Examination of the Liver and Heart for Steatosis

Answer 37

Gross examination--Liver Mild fatty change may not affect the gross appearance Progressive accumulation causes the organ to enlarge and become increasingly yellow Extreme instances--liver may weigh 2-4 times normal Bright yellow, soft, greasy Gross examination—Heart Grossly apparent bands of yellowed myocardium Alternating bands of darker, red-brown, uninvolved myocardium (tigered effect)

Question 38

Cholesterol and Cholesterol Esters

Answer 38

``` Most cells use cholesterol for the synthesis of cell membranes- without intracellular accumulation of cholesterol or cholesterol esters Intracellular vacuoles--several pathologic processes Atherosclerosis cause atherosclerotic plaques in smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries (filled with lipid vacuoles) Foamy appearance (foam cells) with yellow cholesterol-laden atheromas ```

Question 39

Cholesterol/Cholesterol Esters: Pathologies

Answer 39

Xanthomas: intracellular accumulation of cholesterol within macrophages (acquired and hereditary hyperlipidemic states) Clusters of foamy cells are found in the subepithelial connective tissue of the skin and in tendons Cholesterolosis: focal accumulations of cholesterol-laden macrophages in the lamina propria of the gallbladder Niemann-Pick disease, type C: lysosomal storage disease caused by mutations affecting an enzyme involved in cholesterol trafficking causing cholesterol accumulation in multiple organs

Question 40

Accumulation of Proteins

Answer 40

Rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm Reabsorption droplets in proximal renal tubules- renal diseases associated with protein loss in the urine May be normal secreted proteins that are produced in excessive amounts Plasma cells engaged in active synthesis of immunoglobulins

Question 41

Defects in Transport/Secretion of Proteins

Answer 41

Defective intracellular transport and secretion of critical proteins 1. α1-antitrypsin deficiency leading to emphysema 2. Accumulation of cytoskeletal proteins such as microtubules, thin actin filaments, thick myosin filaments, and intermediate filaments a. Alcoholic hyaline: eosinophilic cytoplasmic inclusion in liver cells composed predominantly of keratin intermediate filaments b. Neurofibrillary tangle--Alzheimer disease: neurofilaments and other proteins

Question 42

Hyaline Change Accumulation

Answer 42

Alteration within cells or in the extracellular space Homogeneous, glassy, pink appearance Descriptive histologic term rather than a specific marker for cell injury Produced by a variety of alterations Not a specific pattern of accumulation Glassy pink appearance; bubble gum pink (older/left side) and bright pink (newer/right side)

Question 43

Glycogen Accumulation

Answer 43

Readily available energy source stored in the cytoplasm of healthy cells Excessive intracellular deposits of glycogen seen in patients with an abnormality in either glucose or glycogen metabolism Appear as clear vacuoles within the cytoplasm Dissolves in aqueous fixatives: tissues are best fixed in absolute alcohol and stained with Best carmine or the PAS reaction Rose-to-violet color to the glycogen

Question 44

Normal and Exogenous Pigment Accumulations

Answer 44

Colored substances: some of which are normal constituents of cells (melanin) Others are abnormal and accumulate in cells only under special circumstances Exogenous pigments (coming from outside the body) 1. Carbon (coal dust): ubiquitous air pollutant of urban life where accumulations blacken the tissues of the lungs (anthracosis) and the involved lymph nodes 2. Tattooing: localized, pigmentation of the skin Pigments inoculated are phagocytosed by dermal macrophages

Question 45

Endogenous Pigment Accumulations

Answer 45

Endogenous pigments (synthesized within the body) Lipofuscin: insoluble pigment, also known as lipochrome or wear-and-tear pigment Not injurious to the cell or its functions Telltale sign of free radical injury and lipid peroxidation Yellow-brown, finely granular cytoplasmic, often perinuclear (close to nucleus), pigment in tissue sections Seen in cells undergoing slow, regressive changes Prominent in the liver and heart in aging patients and patients with severe malnutrition and/or cancer cachexia

Question 46

Melanin Accumulation

Answer 46

Endogenous Non-hemoglobin-derived brown-black pigment, so no iron stain Formation: enzyme tyrosinase catalyzes the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes The only endogenous brown-black pigment

Question 47

Hemosiderin Accumulation

Answer 47

Hemoglobin-derived, so iron stain; also can mean that patient had/has a hemorrhage Golden yellow-to-brown, granular or crystalline pigment Serves as one of the major storage forms of iron Represents aggregates of ferritin micelles Seen normally in mononuclear phagocytes of the bone marrow, spleen, and liver, which are actively engaged in red cell breakdown

Question 48

Iron Accumulation/Abundance

Answer 48

Coarse, golden, granular pigment within the cell's cytoplasm Visualized in tissues using Prussian blue histochemical reaction Underlying cause: localized breakdown of red cells Systemic hemosiderosis where mononuclear phagocytes in the liver, bone marrow, spleen, and lymph nodes with scattered macrophages throughout other organs

Question 49

Bilirubin Accumulation

Answer 49

Normal major pigment found in bile Derived from hemoglobin Contains no iron Yellow golden brown color in bile ducts

Question 50

Dystrophic Calcification

Answer 50

Pathologic calcification Local deposition in dying tissues Normal serum levels of calcium Absence of derangements in calcium metabolism Encountered in areas of necrosis: coagulative, caseous, or liquefactive type In cells that are dying; patients will have normal levels of Ca2+ (no trouble with metabolism) but tissue destruction is occurring and being replaced with Ca2+

Question 51

Metastatic Calcification

Answer 51

Pathologic calcification Deposition of calcium salts in otherwise normal tissues Hypercalcemia secondary to some disturbance in calcium metabolism Can have renal failure, or something wrong that causes the patient to be unable to metabolize the Ca2+

Question 52

Morphology of Pathologic Calcification

Answer 52

Calcium salts are basophilic, amorphous granular, clumped appearance Intracellular or extracellular, or in both locations Over time, heterotopic bone may be formed in the focus of calcification Lamellations (psammoma bodies) are present in benign and malignant conditions No cells within in whatsoever; more clumped appearance Over time you may see purple/dark matter with bone next to it in the heart valve for example = heterotropic bone Have elevated serum Ca2+ or other pathologic conditions

Question 53

Cellular Aging

Answer 53

Progressive decline in cellular function and viability caused by genetic abnormalities and accumulation of cellular and molecular damage from effects of exposure to exogenous influences Aging is a regulated process influenced by a limited number of genes and associated with definable mechanistic alterations Radiation from the sun, environmental factors that injure cells, cancer drugs, cholesterol, diabetes = cell damage Known changes that contribute to cellular aging such as decreased cellular replication and accumulation of metabolic and genetic damage Cellular life span is determined by a balance between damage resulting from metabolic events within the cell and counteracting molecular responses that repair the damage like DNA repair and protein homeostasis Cancer cells will develop with the more cell divisions you have