Flexner – pathology is ultra important
Bichat – importance of dissection/autopsy
Virchow – father modern pathology
- importance of studying cells
4 disease aspects
- etiology = cause
- pathogenesis = mechanism
- morphologic change
- clinical significance = signs/symp
Adaptations
1. atrophy – decrease SIZE/function of cell
a. caused by: dec workload, loss innervation, low blood, bad nutrition, loss
trophic stimulation, aging
2. hypertrophy – increase SIZE/function cell
a. caused by: inc demand in tissues unable of cell division (musc, etc) due to
physiological (inc exercise, uterus during pregnancy) or patho (left
ventricular hypertension) reasons
b. inc size due to inc cell proteins and organelles
3. hyperplasia – inc NUMBER of cells due to physio (hormonal, compensatory) or
patho (excessive hormone/growth factor) – also inc size/func of organ/tis
a. thyroid hyperplasia = graves disease
b. panhypopituitaryism (Sheehan syndrome) = inc pres on pit gland causes
death of gland
c. protooncogenes – code for cell death/division
d. bone marrow response to hemorrhage, repair broken bones (fracture
callus), benign prostatic hyperplasia
4. metaplasia – adult cell changes to different cell type (reversible)
a. caused by chronic irritation/inflammation/stress to cell
i. Barrett’s esophagus) – ciliated columnar change to squam
epithelium
1. precursor to cancer (as are most chronic inj cells)
ii. bladder – trans epith change to squam due to chronic infection/irrit
5. modifying metabolism – fatty acid mobilization, osteoclast stim (via parathyroid
hormone), hepatic enzymes for drug metab
Cell Stress Response – reduce coding for normal/structural prots (housekeeping)…inc
prod for organizing/protective prots (cell stress genes aka heat shock proteins)
- HSPs label shit from cell to be removed (old junk and extra mitochon, ER, etc)
- ubiquitin binds shit to form “inclusion bodies” aka “Mallory’s hyaline” (pink
from liver alcoholism) aka “Lewy body” in neural cells
- ubiquitin acts as cofactor for proteolysis (removal prots)
CELL INJURY – occurs to membrane, mito, cytoskeleton, DNA
- injury to 1 results in 2ndary injury to others
- ischemia/hypoxia, free radicals, viruses, chemicals
Mechanisms of Cell Injury
1. ischemia/hypoxia/apoxia
a. isc = red bl sup LEADS TO hyp = O2 deficiency
b. hyp causes red ATP prod > depletes cellular ATP > failure Na/K and Ca
pumps > K leaves, Na, H20, Ca enter > cell swelling, loss of microvilli,
blebs, ER swelling, myelin figures
c. increase Calcium cases activation of:
i. protein kinases – phosphorylate prots
ii. ATPase – dec ATP
iii. Phospholipases – membrane damage
iv. Endonuclease – nuc chromatin damage
v. Proteases – cytoskel/mem damage
d. Depleting ATP > stim phosphofructokinase > + glycolysis > + lactic acid/ph >
i. Clumping of chromatin, release of lysosomal enzymes >
1. detach ribosomes from RER
2. dec prot synth
3. degrade cytoplasmic/nuc components > damage mem
4. cell death
2. FREE RADICALS – formed by absorption of radiant energy, redox rxns during
respiration (mito), metab of drugs & exogenous chem., intracell odidase rxns
(xanthine), oxygen therapy, neutrophils
a. Most important are reactive oxygen species
i. Superoxide anion
ii. Hydroxyl radical
iii. Hydrogen peroxide
b. Innate defenses to above
i. Superoxidase dismutase, glutathione peroxidase, catalases,
antioxidants (vit E)
c. Damagine Effects
i. Peroxidation of lipids > mem damage
ii. Thiol containing prot damage > ion pump damage
iii. DNA damage > impaired prot synth
iv. Mito damage > Ca influx
d. Re-Perfusion Necrosis – blood supply re-established causing huge
amounts of reactive oxy spp to be generated by mito and xanthine oxidase
i. Xanthine oxidase – oxidizes xanthine to generate reactive oxy spp
ii. Iron – Fe3+ is normally reduced by superoxide anions to Fe2+
1. FENTON RXN: h2o2 rxn w/ Fe2+ to prod hydroxyl radical
iii. Innate mechanisms unable to protect and cell damage/death occurs
e. Cause injury by lipid peroxidation of mem, damaging DNA, damaging
prot structure by cross linking sulhydryl groups
f. Pen is small
3. VIRUSES
a. Directly cytopathic – pore in mem > chem. Equil > cell death
i. Polio (ssRNA)
ii. Genome translated into prot, embeds in mem, forms pore
b. Indirectly cytopathic – DNA transcribed into mRNA, then prot by host’s
RNA polymerase
i. Hep B (dsDNA)
ii. Viral prot plugs pore, Tcell recognizes as foreign > T cell disrupts
hosts mem integ > cell death
4. CHEMICAL
a. Directly cytopathic – chem act directly w/ organelle to cause death
i. Heavy metals (Hg, Pb)
1. mercury – binds to sulfhydryl > inhib ATPase dependent
transport > inc mem permeability > death
b. indirectly cytopathic – only toxic when body metabolizes them
i. hepatotoxins
1. CCL4 and acetaminophen
a. Metab by P450 oxidase located in liver ER
b. Cause mem damage via perox of mem phoslips
c. Metab produces free radicals
Reversible Injury
1. Swelling – 1st change recognized in almost all injuries
a. Mem damage = loss of ability to maintain fluid homeo
b. Aka hydropic change aka cloudy swelling aka vacuolar degen (from
development of small intracellular vacuoles)
2. Fatty Change – caused by metabolic derangement of injured cells normally
handling lipids – usually seen in liver – 4 mechanisms
a. Inc FFA mobilization – diabetes mellitus
b. Inc conversion of FA into TAG – alcohol
c. Red oxidation of TAGs into ACA – hypoxia, alcohol
d. Deficiency of lipid acceptor prot (apoproteins) preventing export of
formed TAGs – genetic disease, prot malnutrition
Lethal Injury : Necrosis = enzymatic dig of cell + denaturation of prots
1. 2 types of enz digestion
a. autolysis = intrinsic enz
i. changes in cyto and nuc
b. heterolysis = enz from other cells
2. early necrotic cell
a. inc cyto eosinophilia due to loss of cytoRNA
b. pyknosis = nuc becomes small w/ inc basophils
i. indicates that DNA transcription has ceased
c. karyorrhexis = fragmentation of nuc
d. karylolysis = complete dissolution of nuc
3. TYPES OF NECROSIS
a. Coagulative – dead tissue appearing FIRM and PALE – most common
i. Preservation of structural outline of coagulated cells
1. due to injury that denatures structural prots AND enzymatic
prots, preventing protolysis
ii. characteristic of hypoxic cell death (except in brain)
b. Liquefactive aka Colliquative – dead tis appears semiliquid
i. Dissolution of tis by hydrolytic enz
ii. Necrosis in brain due to arterial occlusion (i.e. cerebral
infarct/necrosis due to bacterial inf)
iii. Also occurs in infections
c. Gangrenous
i. Combo of coagulative w/ superimposed infection with liquefactive
ii. Called “wet gangrene”
d. Casseous – dead tis is soft and white (like cream cheese)
i. Dead cells form amorphous proteinaceous mass, but no original
architecture is present (as it was in coagulative)
ii. As seen in tuberculosis
e. Gummatous – dead tis is firm and rubbery
i. Dead cells form amorphous proteinaceous mass w/ no original
architecture (same as casseous)
ii. Only used to describe syphilis
f. Hemorrhagic – dead tis w/ extravasated red cells
i. Occurs when cell death is due to venous blockage
g. Fat – chalky white areas
i. Occurs when pancreatic enz released into peritoneal cavity during
acute pancreatitis
ii. Enz liquefy fat cell mem and hydrolyze TAGs
1. released FA combing w/ Ca to prod chalky, white areas
iii. also seen after trauma to fat i.e. breast injury
h. Fibrinoid – fibrin deposits in necrotic vessel wall due to vasculitis and
hypertension
Apoptosis – intentional, normal cell death by synthesis/activation of cytosolic proteases
1. Examples
a. Destruction of cells during embryogenesis
i. implantation
b. Hormonal-dependent physiological involution
i. Endometrium during menstruation, breast after weaning, prostate
after castration
c. Cell depletion in proliferating populations
i. Intestinal crypt epithelium
ii. Cell death in tumors
d. Depletion of immune T cell populations
2. Involution – physiological organ atrophy via apoptosis
3. Stages
a. Priming - Enz for apop synthesized
i. Once primed cell only survives if “saved” by trophic factor (bcl-2)
b. Cell surface specializations lost
c. Nuc chromatin condenses (organelles remain normal)
d. Endonucleases cleave chromosomes into indiv nucleosome frags
e. Apoptic bodies – cell split into fragments (each containing good
organelles and mito)
f. Neighboring cells phagocytize frags
Subcellular Responses to Injury
1. Cytoskeletal Abnormalities (cytoskel = microtubules, thin actin, thick mysosin)
a. Reflected by defects in motion/organelle movements and sometimes
accumulation of fibrillar material
b. Microtubule Defects
i. Chediak-Higashi syndrome = defect in microtubule polymerization
giving leukocytes difficulty phago bacteria
ii. Male sterility – can be caused by microtubule org defect
preventing sperm motility
iii. Bronchiectasis – microtub defect immobilizing cilia
c. Intermediate filament defects
i. Mallory body – accumulation of intermed fil in alcoholic liver
2. Lysosomal Abnormalities – lyso contain hydrolytic enz synth in RER and
packaged in golgi (called primary lysosomes)
a. 2ndary lyso = primary lyso that is fused with phagosome
b. break down phago material in 2 ways
i. heterophagy – most common in neutrophils and macrophages
1. handles shit taken up by endo/pino cytosis
2. phagocytosis of bacteria/apoptitic cells
ii. autophagy – involves intracellular organelles/cytosol
1. stuff packaged into “autophagic vacuole”
a. formed from ribosome-free RER regions which fuse
with pre-existing prim lyso
2. used to remove damaged organelles…especially in nutrient
deficient atrophy situations
c. lyso also used to store things that cant be metab
d. lyso deficiency is bad genetic disease
3. Mito Alterations – change in #/size of mito
a. Megamitochondria = huge mito seen in alc liver
b. Cells w/ many or larger mito have a “eosinophilic” (aka pink) appearance
4. SER Induction – SER hypertrophy
a. Barbiturate abuse
b. Increased SER volume leads to more efficient metab of drugs (tolerance)
Intracellular Accumulations
1. Accum Processes
a. Metab rate unable of removing normal endo substance – fat change in
liver due to TAG accum
b. Endo substance cant be metab or its deposited in amorphous/filamentous
form – storage disease
c. Abnormal exo substance accum – carbon particles
2. Lipids – abnormal accum of TAG in parenchymal cells
3.
4.
5.
6.
a. Steatosis = fatty change caused by prot malnut, diabetes, obesity, anoxia
and alcohol abuse
b. Foam cells – macrophages filled w/ lipids
c. Atherosclerosis – fat under inner layer of artery (usually cholesterol)
d. Xanthomas – intracellular accum of chol in macrophages
i. Formed by Clusters of foamy cells in subepithelial con tis
e. Cholesterolosis – accum of chol filled macros in gallbladder
Proteins – less common than accum of lipids
a. Russel bodies – eosiniphilic inclusions formed by enlarged ER of plasma
cells synthesizing immunoglobulins
b. Alpha-1-antitrypsin – deficiency causes accum of trypsin in liver ER
Glycogen - seen in people w/ glucose/glycogen metabolism problems (diabetes)
Pigments – endo or exo colored things that accumulate
a. Carbon – most common exo
i. Inhaled and picked up by alveolar macros then taken to
tracheobronchial lymph nodes
ii. Anthracosis = blackening of lungs
b. Lipofuscin – wear and tear/aging pigment
i. Derived from lipid peroxidation of polyunsat lipids of membranes
ii. Not injurious itself, but indicative of free radical injury
iii. Prominent in aging livers and hearts, malnourishment, and cancer
cachexia
iv. Accompanied by organ shrinkage (brown atrophy)
c. Iron : Hemosiderin – hemoglobin deprived, gold/brown pigment where
iron is stored
i. Accumulates due to excess iron
ii. Normally iron is carried by TRANSFERRINS and stored in
association with APOFERRITIN to form FERRATIN MICELLES
1. excess causes ferritin to form hemosiderin
iii. Hemosiderosis – common bruise
1. hemoglobin transformed to hemosiderin
2. green color caused by biliverdin
3. yellow caused by bilirubin
iv. Hemochromatosis – liver/pancreas damage
1. leads to liver fibrosis, heart failure, diabetes
d. Bilirubin – normal bile pigment; accum called jaundice
Calcium – abnormal deposition of Ca salts
a. Dystrophic – occurs in dying tis
i. Sign of previous injury OR cause of dysfunction
1. calcific valvular disease
2. atherosclerosis
b. Metastatic calcification – occurs in normal tissue when there is
hypercalcemia > 11mg/dL
i. When in lung can cause respiratory deficits
ii. Nephrocalcinosis – Ca deposits in kidneys
1. leads to renal damage