Pathology Flashcards
reversible cell injury
low ATP –> low Ca2+ and Na+/K+ pumps –> cellular swelling and mitochondrial swelling
Ribosomal/ polysomal detachment –> decrease protein synthesis
Blebbing
Nuclear change
Rapid loss of function
Myelin figures
Irreversible cell injury
breakdown of plasma membrane –> cytosolic enzymes leak outside of cell, influx of Ca2+ –> activate degradative enzymes
mitochondrial damage –> loss of ETC –> low ATP
cytoplasmic vacuolization (apoptosis)
Rupture of lysosomes –> autolysis
Nuclear degradation- pyknosis –> karyorrhexis –> karyolysis
Amorphous densities
Apoptosis
ATP dependent programmed cell death
Activate Caspases –> cellular breakdown
Deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis and karyorrhexis
cell membrane intact without inflammation
DNA laddering
Intrinsic mitochondrial pathway
Tissue remodeling in embryogenesis. When regulating factor is withdrawn from a proliferating cell population or after exposure to injurious stimuli
Regulated by Bcl-2 family (BAX and BAK= pro and Bcl-2 and Bcl-xL= anti)
BAX and BAK –> form pores in mitochondrial membrane –> release cytochrome C –> activate caspases
Bcl-2 and Bcl-xL keep mitochondrial membrane impermeable –> prevent cytochrome C release
Extrinsic pathway
Ligand receptor interactions (FasL bind Fas or TNFa bind to its receptor) or via immune cell
Fas-FasL necessary in thymic medullary negative selection
Fas mutations increase numbers of circulating self reacting lymphocytes
Necrosis
Exogenous injury -> plasma membrane damage –> enzymatic degradation and protein denaturation, intracellular components leak –> local inflammatory reaction
Coagulative necrosis
Ischemic/ infarcts in most tissue
–> denature enzymes –> proteolysis blocked
Preserved cellular architecture but nuclei disappear
Increase cytoplasmic binding of eosin stain
Liquefactive necrosis
Bacterial abscesses, brain infarcts
Neutrophils release lysosomal enzymes –> digest
Early: cellular debris and macrophages
Late: cystic spaces and cavitation (brain)
Neutrophils and cell debris seen with bacterial infection
Caseous Necrosis
TB, Histoplasma, capsulatum, Nocardia
Macrophages wall off the infecting microorganism –> granular debris
Fragmented cells and debris surrounded by lymphocytes and macrophages
Fat Necrosis
Enzymatic- acute pancreatitis
Nonenzymatic- traumatic
Damaged pancreatic cells release lipase which break down TG –> bind calcium –> saponification
Outlines of dead fat cells without peripheral nuclei
Saponification appears blue
Fibrinoid Necrosis
Immune vascular reactions
Nonimmune vascular reactions
Immune complex deposition or plasma protein leakage from damaged vessel
Vessel walls are thick and pink
Gangrenous Necrosis
Distal extremity and GI tract, after chronic ischemia
Dry- ischemia –> coagulative
Wet- superinfection –> liquefactive superimposed on coagulative
Ischemia
inadequate blood supple to meet demand
decreased arterial perfusion, decrease venous drainage, shock
Watershed area
receive blood supple from most distal branches of 2 arteres with limited collateral vascularity
Susceptible to ischemia
Red infarct
venous occlusion and tissues with multiple blood supplies and with reperfusion injury
Pale infarct
occurs in solid organs with a single blood supply
Free radical injury
damage via membrane lipid peroxidation, protein modification, DNA breakage.
initiated via radiation exposure, metabolism of drugs, WBC oxidation burst
Eliminated by scavenging enzymes, spontaneous decay, antioxidants and metal carrier proteins
Dystrophic calcification
In abnormal tissues Tends to be localized TB, liquefactive necrosis of chronic abscesses, fat necrosis, infarcts, thrombi, schistasomiasis, congenital CMV, toxo, rubella, psammoma bodies, CREST, atherosclerotic plaques Secondary to injury or necorisis Normal serum Ca2+
Metastatic calcification
in normal tissues
Widespread
Interstitial tissues of kidney, lung and gastric mucosa
Secondary to hypercalcemia or high Calcium phosphate product levels
Abnormal Ca2+ in serum
Lipofuscin
yellow brown wear and tear pigment associated with normal aging
composed of polymers of lipids and phospholipids complexed with protein. May be derived through lipid peroxidation of polyunsaturated lipids and subcellular membranes
Autopsy of elderly person will reveal deposits in heart, colon, liver, kidney, eye
Amyloidosis
Abnormal aggregation of proteins into B pleated linear sheets –> insoluble fibrils –> cell damage and apoptosis.
Congo Red
Tubular BM enlarged on light microscopy
Primary Amyloidosis
AL protein seen in plasma cell disorder (multiple myeloma)
Secondary Amyloidosis
AA protein
seen in chronic inflammatory conditions
Dialysis related amyloidosis
B2 microglobulin
ESRD or long term dialysis
Alzheimer disease amyloidosis
B amyloid protein cleaved from amyloid precursor protein
T2DM amyloidosis
islet amyloid polypeptide
deposition of amylin in pancreatic islets
Medullary thyroid cancer amyloidosis
Calcitonin
Isolated atrial amyloidosis
ANP common in normal aging
increased risk of A fib
systemic senile amyloidosis
normal
in cardiac ventricles
cardiac dysfunction more insidious than AL
Familial amyloid cardiomyopathy
mutated ATTR
ventricular endomyocardium deposition –> restrictive cardiomyopathy, arrhythmias
Familial amyloid polyneuropathies
mutated ATTR
Inflammation
Response to eliminated initial cause of cell injury, remove necrotic cells, initiate tissue repair
Harmful if reaction is excessive or prolonged
Cardinal signs of inflammation
Rubor via vasodilation and increased blood flow (histamine, PG, bradykinin, NO)
Tumor via endothelial contration –> leak protein rich fluid –> increase interstitial oncotic pressure (leukotrienes, histamine, 5HT)
Dolor via sensitization of sensory nerve endings (bradykinin, PGE2, histamine)
Funtio laesa
Fever
Pyogens induce macrophages to release IL1 and TNF –> increase COX in perivascular cells of hypothalamus –> increase PGE2 –> increase temp set point
Leukocytosis
elevated WBC
increase plasma acute phase proteins
factors whose serum concentrations change in response to inflammation
produced by liver (IL6)
Acute phase reactants that are upregulated
Ferritin- bind and sequester iron
Fibrinogen- coagulation factor = ESR
Serum amyloid A- prolonged elevation –> amyloidosis
Hepcidin- decrease iron absorption and iron release –> anemia of chronic disease
CRP- opsonin (fix complement) nonspecific sign of ongoing inflammation
Acute phase reactants that are down regulated
Albumin- to conserve AA
Transferrin- internalized by macrophages to sequester iron
ESR
RBC normally - charge
inflammation –> decrease - charge –> aggregation –> increase ESR
High ESR
anemia infection inflammation cancer renal disease pregnancy
Low ESR
SCD polycythemia HF microcytosis hypofibrinogenemia
Acute inflammation
transient and early response to injury or infection
Neutrophils
Rapid onset and short duration
via infection, trauma, necrosis, foreign bodies
Mediated by TLR, arachidonic acid, neutrophils, eosinophils, Ab, mast cells, basophils, complement
Vascular vasodilation and extravasation of leukocytes
Leukocyte extravasation
- Margination and rolling- E selectin and P selectin
- Tight binding- ICAM1 bind LFA1 and VCAM1 bind VLA4
- Diapedesis- PECAM1 bind PECAM
- Migration- C5a, IL8, LTB, kallikrein, PAF
Chronic inflammation
prolonged inflammation with mononuclear infiltration –> tissue destruction and repair
via persistent infection –> type IV hypersensitivity, autoimmune diseases, prolonged exposure to toxins and foreign material
Th1 cells –> IFNy –> macrophage classical activation
Th2 –> IL4/13 –> macrophage alternative activation
Lead to scarring amyloidosis and neoplastic transformation
Tissue mediators for would healing
FGF --> angiogenesis TGFB --> angiogenesis and fibrosis VEGF --> angiogenesis PDGF --> vascular remodeling and smooth muscle cell migration and fibroblast growth for collagen synthesis metalloproteinases --> tissue remodeling EGF --> cell growth via TK
Inflammatory wound healing phase
3 days after
Platelets, neutrophils, macrophages
clot formation, increase vessel permeability and neutrophil migration into tissue. macrophage clean up debris
Proliferative wound healing phase
day 3- weeks
fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages
Deposition of granulation tissue and Type 3 collagen, angiogenesis, epithelial cells proliferation, dissolution of clot, wound contraction
Delayed if Vitamin C or copper deficient
Remodeling wound healing phase
1 week - 6 months Fibroblasts Type 3 collagen replaced by Type 1 collagen --> increase tensile strength collagenases break down Type 3 collagen Delayed if Zn deficient
Granulomatous inflammation
induced by T cell response to infection, immune mediated diseases and foreign bodies
wall off a resistant stimulus without completely eradicating or degrading it –> persistent inflammation –> fibrous organ damage
Histology of Granulomatous inflammation
epithelioid cells surrounded by lymphocytes and multinucleated giant cells
Caseating- central necrosis (TB, fungal)
Non caseating- no central necrosis (autoimmune diseases)
Mechanism Granulomatous inflammation
- APCs present Ag to CD4 –> secrete IL12 –> CD4 differentiate in th1 cells
- Th1 cells secrete IFNy –> macrophage activation
- macrophages increase cytokine secretion –> form epithelioid macrophages and giant cells
Scar formation
occurs when repair cannot be accomplished by cell regeneration alone
Nonregenerated cells are replaced by connective tissue
Associated with excess TGFB
Hypertrophic scar
Increase Type 3 collagen Parallel collagen Confined to borders of original wound infrequent recurrence No prediposition
Keloid Scar
INCREASED Type 3 and 1 collagen Disorganized collagen extends beyond border of original wound with claw like projections Frequent recurrence Increased incidence in dark skin
Neoplasia and Neoplastic progression
- Normal cells
- Dysplasia- loss of uniformity in cell size and shape
- CIS- irreversible severe dysplasia that involves the entire thickness of epithelium but does not penetrate the BM
- Invasive carcinoma- invade BM using collagenases and hydrolases. inactivate E cadherin
- Metastasis- spread to distance organs via lymphatics or blood
Tumor Grade
degree of cellular differentiation and mitotic activity on histo
Tumor Stage
degree of localization based on site and size of primary lesion, spread to regional LN, metastasis
More prognostic
TNM- tumor size, node, metastasis
Hallmarks of cancer
Growth signal, self sufficiency (PDGF, HER2, RAS, MYC, CDK)
Anti growth signal insensitivity (Rb, NF2)
Evasion of apoptosis (TP53, BCL-2)
Limitless replication
Sustained angiogenesis (VEGF)
Tissue invasion (E- cadherin)
Metastasis
Warburg effect- shift glucose metabolism away from oxidative phosphorylation
Immune evasion (low MHC)
Immune checkpoint interactions
PD-1 and PDL- 1/2 –> T cell dysfunction (inhibit via PD 1 antag)
CTLA4 outcompetes CD28 for B7 on APCs –> loss of T cell costimulatory signal (inhibited by anti CTLA4)
Common metastases
Sarcomas - via blood
Carcinomas- via lymphatics except follicular thyroid, choriocarcinoma, RCC, hepatocellular
Metastasis to brain
Lung > breast > melanoma, colon, kidney
