Pathology - Cell Injury, Death And Adaptation

Front 1

How do cells ADAPT to environmental stress?

Back 1

hypertrophy, hyperplasia, aplasia, hypoplasia, atrophy, metaplasia, dysplasia

Front 2

What is hypertrophy?

Back 2

Increase in organ/tissue size due to increase in SIZE OF CELLS, w/increased expression of genes and protein synth

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What causes hypertrophy?

Back 3

Adaption to...
increased workload (hypertension), increased endocrine stim (puberty, preg)

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What is hyperplasia

Back 4

Increase in size of organ/tissue due to increase in NUMBER OF CELLS, w/inc express of growth-promoting genes (proto-oncogenes), inc DNA synth, cell div; may occur with hypertrophy

Front 5

Physiologic causes of hyperplasia?

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-compensatory (after partial hepatectomy)
-hormonal stim (breast devel)
-antigenic stim (lymphoid hyperplasia)

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Pathologic causes of hyperplasia?

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-endometrial hyperplasia
-prostatic hyperplasia of aging

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What is aplasia?

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Failure of cell production

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Examples of aplasia?

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-fetal development, can result in AGENESIS (absence of organ)
-late in life, permanent loss of precursor cells in proliferative tissues (e.g. marrow)

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What is hypoplasia?

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Decrease in cell production, less extreme than aplasia

Front 10

When is hypoplasia seen?

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partial lack of growth and maturation of gonadal structures in TURNER SYNDROME and KLINEFELTER SYNDROME

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What is atrophy?

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Decrease in size and functional ability of organ/tissue due to dec. in mass of pre-existing cells

Front 12

Markers of atrophy?

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Lipofuscin granules, autophagosomes on EM, intracytoplasmic vacuoles w/debris

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What causes atrophy?

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Disuse, ischemia, malnut, lack of endocrine stim, aging, denervation

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3 types of metaplasia?

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Squamous, osseous, and myeloid metaplasia

Front 15

What is metaplasia?

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Replacement of one differentiated tissue by another (usu. reversible)

Front 16

What is squamous metaplasia?

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When epithelial cells are replaced by squamous epith, often reversible

Front 17

Where does squamous metaplasia occur?

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-Replacement of columnar epith at squmocolumnar jn of cervix by squamous epith
-In resp epith of bronchus, endometrium, and panc ducts

Front 18

What causes squamous metaplasia?

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Chronic irritation (e.g. smoking), vit A deficiency

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What is osseus metaplasia?

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formation of new bone at sites of tissue injury (cartilaginous metaplasia may also occur)

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What is myeloid metaplasia?
aka. extramedullary hematopoiesis

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Prolif. of hematopoietic tissue in non-bone marrow sites (e.g. liver or spleen)

Front 21

What is dysplasia?

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Abnormal prolif of cells, characterized by changes in cell size, shape, loss of cellular organiz; premalignant
ex: cervical dysplasia

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What causes dysplasia?

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similar stimuli to those that produce cancer (HPV, esophageal reflux)

Front 23

Causes of hypoxic cell injury?

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Ischemia (most common), anemia, CO poisoning, decreased tissue perfusion (hypotens), dec oxygenation of blood (pulm disease)

Front 24

What happens during EARLY hypoxic cell injury? 3

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1.AFFECTS MITOCHONDRIA -> dec oxidative phosphorylation and ATP synth, and failure of memb pump

2. disaggregation of ribosomes and dec prot synth

3. Stim of phosphofructokinase

Front 25

What happens when Na-K ATPase fails?

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1. cellular SWELLING, aka hydropic change (large vacuoles in cytoplasm)
2. swelling of ER
3. swelling of mitochon

(Ca, H2O, Na influx, K efflux)

Front 26

What happens when phosphofructokinase activity increase?

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inc glycolysis, lactate accum, dec intracell pH (which causes reversible clumping of nuclear chromatin)

Front 27

What is a pathophysiological correlate of decreased protein synthesis?

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Lipid deposition (fatty change) --> apoproteins required for lipid mobilization

Front 28

What are the signs of reversible membrane damage?

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Myelin figures (whorl-like structures), cell blebs (cell surf deformity due to disrupted cytoskel)

Front 29

What happens during LATE hypoxic cell injury?

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MEMBRANE DAMAGE -> Ca influx into mitochondria, leakage of lysosomal enzymes

Front 30

When does the cell reach the POINT OF NO RETURN?

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massive Ca influx, irrevers damage to memb and oxidat phosphor, calcification of mitochon, intracellular activation of lysosomal hydrolases

Front 31

What are the cellular markers of the point of no return? (indicates necrosis)

Back 31

Myocardial enzymes in serum: AST (aspartate aminotransferase), LDH (lactate dehydrogenase), CK (creatine kinase), troponins, myoglobin
Liver enzymes in serum: ALT (alanine aminotransferase), AST, alkaline phosphatase, GGT (gamma-glutamyltransferase)

Front 32

How long does it take for hypoxic injury to become irreversible?

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3-5mins for neurons
1-2hrs of myocardium and hepatocytes
many hours for skel muscle

Front 33

How are free radicals generated?

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-Normal metabolism
-oxygen toxicity (alveolar damage/ARDS, retrolental fibroplasia)
-ionizing radiation
-UV light
-drugs and chemicals (promote prolif of SER and P-450 system)
-reperfusion after ischemic injury

Front 34

What are our protective factors against free radicals?

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1. Intracellular enzymes (glutathione peroxidase, catalase, superoxide dismutase)
2. Exogenous and enogenous antioxidants (vit A, C, E, cysteine, etc)
3. Spontaneous decay

Front 35

What is a good example of chemical injury to the liver?

Back 35

CCl4 -> *CCl3 by P-450 system in the SER

*CCl3 causes free radical injury:
1. disaggreg of ribosomes, dec protein synth, results in FATTY CHANGE
2. Memb damage, cell swelling, Ca influx, mitoch damage, protein denat, cell death

Front 36

What is necrosis?

Back 36

Sum of degradative and inflammatory reactions occuring AFTER TISSUE DEATH IS CAUSED BY INJURY; must be in a living organism though

Front 37

What is autolysis?

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degradative rxn in cells, caused by intracell enzymes indigenous to the cell

**postmortem autolysis occurs after organismal death but IS NOT NECROTIC**

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What is heterolysis?

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cellular degradation by enzymes derived from sources extrinsic to the cell

Front 39

What is coagulative necrosis?

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most common, results from sudden cutoff of blood supply, causes protein denaturation, usu occurs in heart, kidney

Front 40

Characteristic pathologic changes seen in coagulative necrosis?

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preservation of tissue architecture in early stages, increased eosinophilia, nuclear changes

Front 41

What is the morphologic hallmark of irreversible cell injury and necrosis?

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NUCLEAR CHANGES: pyknosis, karyorrhexis, karyolysis, disappearance of stainable nuclei

Front 42

What is pyknosis?

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chromatin clumping and shrinking with inc basophilia

Front 43

What is karyorrhexis?

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fragmentation of chromatin

Front 44

What is karyolysis?

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fading of chromatin material

Front 45

What is liquefactive necrosis?

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enzymatic liquefaction of necrotic tissues that results from interruption of blood supply (via autolytic mechs), usu in CNS, caused by ischemia (abscesses, brain infarcts, etc); also occurs in areas of bacterial infection (suppurative infections) via heterolytic mechs

Front 46

Where does liquefactive necrosis usually occur?

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usu in CNS (via autolytic mechs); also occurs in areas of bacterial infection (suppurative infections) via heterolytic mechs

Front 47

Characteristic pathologic changes seen in liquefactive necrosis?

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necrotic tissue soft and liquefied

Front 48

What is caseous necrosis?

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combination of coagulative and liquefactive necrosis; occurs as part of granulomatous inflammation, and is a manifestation of partial immunity caused by immune cells

Front 49

Characteristic pathologic changes seen in caseous necrosis?

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architecture not preserved, but tissue not liquefied, gross: cheese-like consistency
histologic: amorphous eosinophilic appearance

Front 50

In what disease is caseous necrosis most commonly seen?

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TB

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What are the common sites of gangrenous necrosis?

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usu. seen w/interruption of blood supply to: lower limbs, GI tract, gallbladder, testes

Front 52

What is wet gangrene?

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when complicated by infective heterolysis and consequent liquefactive necr

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What is dry gangrene?

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when characterized by coagulative necr w/o liquefaction

Front 54

What is fibrinoid necrosis?

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assoc w/immune-mediated vascular damage, characterized by deposition of fibrin-like proteinaceous material in arterial walls

Front 55

Characteristic pathologic changes of fibrinoid necrosis?

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smudgy pink appearance in vascular walls, eosinophilc homogeneous appearance

Front 56

What is fat necrosis?

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caused by the action of lipases on fatty tissue (e.g. w/pancreatic damage)

Front 57

What is traumatic fat necrosis?

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occurs after severe injury to tissue w/high fat content (eg breast)

Front 58

What is enzymatic fat necrosis?

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complication of acute hemorrhagic pancreatitis -> panc enzymes diffuse into tissue and digest parenchyma, liberated fatty acids form calcium salts (saponification), vessels are eroded, hemorrhage

Front 59

Characteristic pathologic changes of fat necrosis?

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necrotic fat cells, acute inflam, hemorrhage, calcium soap formation, clustering of lipid-laden macrophages (in panc)

Front 60

What is apoptosis?

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programmed cell death; active process under genetic control, mediated by cascade of capases (digest nuclear cytoskeleton proteins and activate endonucleases); impt mech for removal of cells; involves single cells or small clusters

Front 61

Morphologic changes associated with apoptosis?

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cytoplasmic and cell shrinking, increased eosinophilic staining, nuclear chromatin condenses and fragments, blebbing, cell fragments are phagocytosed, NO INFLAMMATORY REACTION

Front 62

Stimuli for apoptosis?

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-cell injury and DNA damage
-lack of horm/cytoki/growth factors
-receptor-ligand signals (Fas binding to Fas ligand, TNF binding to TNFR1)

Front 63

Biochemical changes in apoptosis?

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cytochrome-c and bcl-2 activate capases (digest nuclear cytoskeleton proteins and activate endonucleases); REGULAR DNA fragmentation at nucleosomal boundaries ("laddered" gel pattern)

Front 64

What genes regulate apoptosis?

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bcl-2 inhibits
bax stimulates
p53 stimulates by decreasing transcription of bcl-2 and increasing transcrip of bax

Front 65

Physiologic examples of apoptosis?

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embryogenesis, hormone-dependent apop (menstruation), selective death of lymphocytes in thymus

Front 66

Pathologic examples of apoptosis?

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viral hep (Councilman body), graft vs host disease, CF (duct obstruction and panc atrophy)

Front 67

Possible causes of fatty change (steatosis)?

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1. inc transport of triglyc or fatty acids to cells
2. dec mobilization of fat from cells (usu. due to dec apoproteins required for transport -> **thus fatty change is linked to disagg of ribo and dec prot synth**)
3. dec use of fat by cells
4. overproduction of fat in cells

usu in heart, liver, kidney

Front 68

What is hyaline change?

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protein accumulations in cells; appear homogeneous, glassy, eosinophilic

Front 69

Commonly accumulated exogenous pigments?

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carbon/silica/dust (pulmonary), plumbism (lead), argyria (silver)

Front 70

Commonly accumulated endogenous pigments?

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Melanin, bilirubin, hemosiderin, lipofuscin

Front 71

What are changes in melanin pigmentation indicative of?

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Increased pig: tanning, wide variety of disease conditions
Decreased pig: albinism, vitiligo

Front 72

Breakdown of what forms bilirubin?

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bilirubin is catabolic product of heme moiety of hemoglobin (and to small extent myoglobin)

Front 73

Types of jaundice?

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Hemolytic (destruc of RBCs)
Hepatocellular (assoc w/parenchymal liver damage)
Obstructive (assoc w/intra or extrahepatic obstruction of biliary tract)

Front 74

What is hemosiderin?

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iron-containing pigment, consists of golden-brown amorphous ferritin aggregates in tissues, stains blue w/Prussian blue dye

Front 75

What is local hemosiderosis?

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local deposition of hemosiderin (derived from breakdown of hemoglobin), usu results from hemorrhage

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What is systemic hemosiderosis?

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generalized hemosiderin deposition W/O tissue/organ damage; may result from hemorr, mult transfusions, hemolysis, excessive dietary iron, often w/EtOH consumption

Front 77

What is hemochromatosis?

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extensive accum of hemosiderin w/tissue damage, scarring, organ dysfn

Front 78

Characteristics of hereditary hemochromatosis?

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mutation in Hfe gene; causes TRIAD of micronodular cirrhosis, diabetes mellitus, skin pigmentation (= "bronze diabetes"); causes inc serum iron and dec total iron binding capac (TIBC)

Front 79

Common cause of secondary hemochromatosis?

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usu caused by mult blood transfusions administered to pts w/hereditary hemolytic anemias (eg beta thalassemia major)

Front 80

What is lipofuscin?

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yellowish, fat-soluble pigment, end product of memb lipid peroxidation, aka "wear and tear pigment"

Front 81

Where is lipofuscin most often seen?

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elderly pts, w/in hepatocyes and at poles of nuclei of myocardial cells

Front 82

What is "brown atrophy"?

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Combination of lipofuscin accum and atrophy of organs

Front 83

What is "bronze diabetes"?

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occus in hereditary hemochromatosis; caused by TRIAD of micronodular cirrhosis, diabetes mellitus, skin pigmentation

Front 84

Causes of metastatic calcification?

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hypercalcemia (usu resulting from hyperparathyroidism), osteolytic tumors, hypervitaminosis D, excess Ca intake

Front 85

Causes of dystrophic calcification?

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occurs in previously damaged tissues (eg old trauma, TB lesions, scarred valves, atherosclerotic lesions); NOT caused by hypercalcemia (normal serum Ca conc.)

Front 86

What is causal mechanism of abnormal protein folding?

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failure of structural stabilization or degradation by chaperones (e.g. ubiquitin, a heat shock protein)

Front 87

What are 2 major consequences of abnormal protein folding?

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abnormal protein aggregation, abnormal prot transport/secretion

Front 88

What diseases are characterized by abnormal protein aggregation?

Back 88

amyloidosis, Alzheimers, Huntingtons, Parkinsons, and perhaps prion diseases (eg mad cow)

Front 89

What diseases are characterized by abnormal protein transport and secretion?

Back 89

CF, alpha-1-antitrypsin deficiency