Pathology - Cell Injury, Death and Adaptation

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How do cells ADAPT to environmental stress?: hypertrophy, hyperplasia, aplasia, hypoplasia, atrophy, metaplasia, dysplasia
What is hypertrophy?: Increase in organ/tissue size due to increase in SIZE OF CELLS, w/increased expression of genes and protein synth
What causes hypertrophy?: Adaption to...
increased workload (hypertension), increased endocrine stim (puberty, preg)
What is hyperplasia: 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
Physiologic causes of hyperplasia?: -compensatory (after partial hepatectomy)
-hormonal stim (breast devel)
-antigenic stim (lymphoid hyperplasia)
Pathologic causes of hyperplasia?: -endometrial hyperplasia
-prostatic hyperplasia of aging
What is aplasia?: Failure of cell production
Examples of aplasia?: -fetal development, can result in AGENESIS (absence of organ)
-late in life, permanent loss of precursor cells in proliferative tissues (e.g. marrow)
What is hypoplasia?: Decrease in cell production, less extreme than aplasia
When is hypoplasia seen?: partial lack of growth and maturation of gonadal structures in TURNER SYNDROME and KLINEFELTER SYNDROME
What is atrophy?: Decrease in size and functional ability of organ/tissue due to dec. in mass of pre-existing cells
Markers of atrophy?: Lipofuscin granules, autophagosomes on EM, intracytoplasmic vacuoles w/debris
What causes atrophy?: Disuse, ischemia, malnut, lack of endocrine stim, aging, denervation
3 types of metaplasia?: Squamous, osseous, and myeloid metaplasia
What is metaplasia?: Replacement of one differentiated tissue by another (usu. reversible)
What is squamous metaplasia?: When epithelial cells are replaced by squamous epith, often reversible
Where does squamous metaplasia occur?: -Replacement of columnar epith at squmocolumnar jn of cervix by squamous epith
-In resp epith of bronchus, endometrium, and panc ducts
What causes squamous metaplasia?: Chronic irritation (e.g. smoking), vit A deficiency
What is osseus metaplasia?: formation of new bone at sites of tissue injury (cartilaginous metaplasia may also occur)
What is myeloid metaplasia? aka. extramedullary hematopoiesis: Prolif. of hematopoietic tissue in non-bone marrow sites (e.g. liver or spleen)
What is dysplasia?: Abnormal prolif of cells, characterized by changes in cell size, shape, loss of cellular organiz; premalignant
ex: cervical dysplasia
What causes dysplasia?: similar stimuli to those that produce cancer (HPV, esophageal reflux)
Causes of hypoxic cell injury?: Ischemia (most common), anemia, CO poisoning, decreased tissue perfusion (hypotens), dec oxygenation of blood (pulm disease)
What happens during EARLY hypoxic cell injury? 3: 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
What happens when Na-K ATPase fails?: 1. cellular SWELLING, aka hydropic change (large vacuoles in cytoplasm)
2. swelling of ER
3. swelling of mitochon

(Ca, H2O, Na influx, K efflux)
What happens when phosphofructokinase activity increase?: inc glycolysis, lactate accum, dec intracell pH (which causes reversible clumping of nuclear chromatin)
What is a pathophysiological correlate of decreased protein synthesis?: Lipid deposition (fatty change) --> apoproteins required for lipid mobilization
What are the signs of reversible membrane damage?: Myelin figures (whorl-like structures), cell blebs (cell surf deformity due to disrupted cytoskel)
What happens during LATE hypoxic cell injury?: MEMBRANE DAMAGE -> Ca influx into mitochondria, leakage of lysosomal enzymes
When does the cell reach the POINT OF NO RETURN?: massive Ca influx, irrevers damage to memb and oxidat phosphor, calcification of mitochon, intracellular activation of lysosomal hydrolases
What are the cellular markers of the point of no return? (indicates necrosis): 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)
How long does it take for hypoxic injury to become irreversible?: 3-5mins for neurons
1-2hrs of myocardium and hepatocytes
many hours for skel muscle
How are free radicals generated?: -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
What are our protective factors against free radicals?: 1. Intracellular enzymes (glutathione peroxidase, catalase, superoxide dismutase)
2. Exogenous and enogenous antioxidants (vit A, C, E, cysteine, etc)
3. Spontaneous decay
What is a good example of chemical injury to the liver?: 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
What is necrosis?: Sum of degradative and inflammatory reactions occuring AFTER TISSUE DEATH IS CAUSED BY INJURY; must be in a living organism though
What is autolysis?: degradative rxn in cells, caused by intracell enzymes indigenous to the cell

**postmortem autolysis occurs after organismal death but IS NOT NECROTIC**
What is heterolysis?: cellular degradation by enzymes derived from sources extrinsic to the cell
What is coagulative necrosis?: most common, results from sudden cutoff of blood supply, causes protein denaturation, usu occurs in heart, kidney
Characteristic pathologic changes seen in coagulative necrosis?: preservation of tissue architecture in early stages, increased eosinophilia, nuclear changes
What is the morphologic hallmark of irreversible cell injury and necrosis?: NUCLEAR CHANGES: pyknosis, karyorrhexis, karyolysis, disappearance of stainable nuclei
What is pyknosis?: chromatin clumping and shrinking with inc basophilia
What is karyorrhexis?: fragmentation of chromatin
What is karyolysis?: fading of chromatin material
What is liquefactive necrosis?: 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
Where does liquefactive necrosis usually occur?: usu in CNS (via autolytic mechs); also occurs in areas of bacterial infection (suppurative infections) via heterolytic mechs
Characteristic pathologic changes seen in liquefactive necrosis?: necrotic tissue soft and liquefied
What is caseous necrosis?: combination of coagulative and liquefactive necrosis; occurs as part of granulomatous inflammation, and is a manifestation of partial immunity caused by immune cells
Characteristic pathologic changes seen in caseous necrosis?: architecture not preserved, but tissue not liquefied, gross: cheese-like consistency
histologic: amorphous eosinophilic appearance
In what disease is caseous necrosis most commonly seen?: TB
What are the common sites of gangrenous necrosis?: usu. seen w/interruption of blood supply to: lower limbs, GI tract, gallbladder, testes
What is wet gangrene?: when complicated by infective heterolysis and consequent liquefactive necr
What is dry gangrene?: when characterized by coagulative necr w/o liquefaction
What is fibrinoid necrosis?: assoc w/immune-mediated vascular damage, characterized by deposition of fibrin-like proteinaceous material in arterial walls
Characteristic pathologic changes of fibrinoid necrosis?: smudgy pink appearance in vascular walls, eosinophilc homogeneous appearance
What is fat necrosis?: caused by the action of lipases on fatty tissue (e.g. w/pancreatic damage)
What is traumatic fat necrosis?: occurs after severe injury to tissue w/high fat content (eg breast)
What is enzymatic fat necrosis?: complication of acute hemorrhagic pancreatitis -> panc enzymes diffuse into tissue and digest parenchyma, liberated fatty acids form calcium salts (saponification), vessels are eroded, hemorrhage
Characteristic pathologic changes of fat necrosis?: necrotic fat cells, acute inflam, hemorrhage, calcium soap formation, clustering of lipid-laden macrophages (in panc)
What is apoptosis?: 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
Morphologic changes associated with apoptosis?: cytoplasmic and cell shrinking, increased eosinophilic staining, nuclear chromatin condenses and fragments, blebbing, cell fragments are phagocytosed, NO INFLAMMATORY REACTION
Stimuli for apoptosis?: -cell injury and DNA damage
-lack of horm/cytoki/growth factors
-receptor-ligand signals (Fas binding to Fas ligand, TNF binding to TNFR1)
Biochemical changes in apoptosis?: cytochrome-c and bcl-2 activate capases (digest nuclear cytoskeleton proteins and activate endonucleases); REGULAR DNA fragmentation at nucleosomal boundaries ("laddered" gel pattern)
What genes regulate apoptosis?: bcl-2 inhibits
bax stimulates
p53 stimulates by decreasing transcription of bcl-2 and increasing transcrip of bax
Physiologic examples of apoptosis?: embryogenesis, hormone-dependent apop (menstruation), selective death of lymphocytes in thymus
Pathologic examples of apoptosis?: viral hep (Councilman body), graft vs host disease, CF (duct obstruction and panc atrophy)
Possible causes of fatty change (steatosis)?: 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
What is hyaline change?: protein accumulations in cells; appear homogeneous, glassy, eosinophilic
Commonly accumulated exogenous pigments?: carbon/silica/dust (pulmonary), plumbism (lead), argyria (silver)
Commonly accumulated endogenous pigments?: Melanin, bilirubin, hemosiderin, lipofuscin
What are changes in melanin pigmentation indicative of?: Increased pig: tanning, wide variety of disease conditions
Decreased pig: albinism, vitiligo
Breakdown of what forms bilirubin?: bilirubin is catabolic product of heme moiety of hemoglobin (and to small extent myoglobin)
Types of jaundice?: Hemolytic (destruc of RBCs)
Hepatocellular (assoc w/parenchymal liver damage)
Obstructive (assoc w/intra or extrahepatic obstruction of biliary tract)
What is hemosiderin?: iron-containing pigment, consists of golden-brown amorphous ferritin aggregates in tissues, stains blue w/Prussian blue dye
What is local hemosiderosis?: local deposition of hemosiderin (derived from breakdown of hemoglobin), usu results from hemorrhage
What is systemic hemosiderosis?: generalized hemosiderin deposition W/O tissue/organ damage; may result from hemorr, mult transfusions, hemolysis, excessive dietary iron, often w/EtOH consumption
What is hemochromatosis?: extensive accum of hemosiderin w/tissue damage, scarring, organ dysfn
Characteristics of hereditary hemochromatosis?: 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)
Common cause of secondary hemochromatosis?: usu caused by mult blood transfusions administered to pts w/hereditary hemolytic anemias (eg beta thalassemia major)
What is lipofuscin?: yellowish, fat-soluble pigment, end product of memb lipid peroxidation, aka "wear and tear pigment"
Where is lipofuscin most often seen?: elderly pts, w/in hepatocyes and at poles of nuclei of myocardial cells
What is "brown atrophy"?: Combination of lipofuscin accum and atrophy of organs
What is "bronze diabetes"?: occus in hereditary hemochromatosis; caused by TRIAD of micronodular cirrhosis, diabetes mellitus, skin pigmentation
Causes of metastatic calcification?: hypercalcemia (usu resulting from hyperparathyroidism), osteolytic tumors, hypervitaminosis D, excess Ca intake
Causes of dystrophic calcification?: occurs in previously damaged tissues (eg old trauma, TB lesions, scarred valves, atherosclerotic lesions); NOT caused by hypercalcemia (normal serum Ca conc.)
What is causal mechanism of abnormal protein folding?: failure of structural stabilization or degradation by chaperones (e.g. ubiquitin, a heat shock protein)
What are 2 major consequences of abnormal protein folding?: abnormal protein aggregation, abnormal prot transport/secretion
What diseases are characterized by abnormal protein aggregation?: amyloidosis, Alzheimers, Huntingtons, Parkinsons, and perhaps prion diseases (eg mad cow)
What diseases are characterized by abnormal protein transport and secretion?: CF, alpha-1-antitrypsin deficiency

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