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Pathology > Exam I: Pathology III > Flashcards

Exam I: Pathology III Flashcards

1
Q

Ischemic and Hypoxic Injury

A

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

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2
Q

Ischemia

A

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

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3
Q

Post Ischemia/Hypoxia

A

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

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4
Q

Ischemic Cell Injury: Reversible Example

A

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!

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5
Q

Ischemic Injury: Irreversible

A

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

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6
Q

Irreversible Ischemic Injury Example

A

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

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7
Q

Ischemic Injury Treatment

A

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

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8
Q

Ischemia-Reperfusion Injury

A

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

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9
Q

Mechanisms of Reperfusion Injury

A

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

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10
Q

Ischemic Injury: Activation of Complement System & Inflammation

A

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

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11
Q

Chemical (Toxic) Injury: Prescription Drugs & Direct Injury

A

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

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12
Q

Chemical (Toxic) Injury: Conversion to Toxic Metabolites

A

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

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13
Q

Apoptosis: General Information

A

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

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14
Q

Causes of Apoptosis: Hormone Dependent

A

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

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15
Q

Causes of Apoptosis: Homeostasis

A

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

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16
Q

Causes of Apoptosis: Autoimmune Prevention and Usefulness

A

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

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17
Q

Apoptosis: Pathologic Conditions

A

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

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18
Q

Apoptosis: Viral Infections

A

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

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19
Q

Morphology of Apoptosis

A

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

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20
Q

Apoptosis and Caspases

A

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

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21
Q

Mechanism of Apoptosis

A

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)

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22
Q

Intrinsic Initiator Pathway of Apoptosis

A

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

23
Q

Extrinsic Initiator Pathway of Apoptosis

A

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

24
Q

Execution Phase of Apoptosis

A

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

25
Q

Apoptosis: Removal of Dead Cells

A

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

26
Q

Apoptosis: Clinicopathologic Correlations

A

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

27
Q

Autophagy

A

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

28
Q

Normal and Abnormal Cellular Accumulations

A

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

29
Q

Normal Endogenous Accumulation: Increased Rate

A

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

30
Q

Abnormal Endogenous Accumulation: Protein Defects

A

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

31
Q

Normal Endogenous Accumulation: Inherited/Genetic

A

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

32
Q

Abnormal Exogenous Accumulation: Lack of Machinery

A

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)

33
Q

Lipids

A

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

34
Q

Steatosis (Fatty Change)

A

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

35
Q

Lipid Mechanism for Accumulation

A

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

36
Q

Morphology of Fatty Change

A

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

37
Q

Gross Examination of the Liver and Heart for Steatosis

A

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)

38
Q

Cholesterol and Cholesterol Esters

A 
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
39
Q

Cholesterol/Cholesterol Esters: Pathologies

A

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

40
Q

Accumulation of Proteins

A

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

41
Q

Defects in Transport/Secretion of Proteins

A

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
42
Q

Hyaline Change Accumulation

A

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)

43
Q

Glycogen Accumulation

A

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

44
Q

Normal and Exogenous Pigment Accumulations

A

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

45
Q

Endogenous Pigment Accumulations

A

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

46
Q

Melanin Accumulation

A

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

47
Q

Hemosiderin Accumulation

A

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

48
Q

Iron Accumulation/Abundance

A

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

49
Q

Bilirubin Accumulation

A

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

50
Q

Dystrophic Calcification

A

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+

51
Q

Metastatic Calcification

A

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+

52
Q

Morphology of Pathologic Calcification

A

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

53
Q

Cellular Aging

A

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

Pathology (14 decks)

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