Pathology- Growth, Celluar injury, Cell death Flashcards
Hyperplasia
Increase in cell number; involves production of new cells from stem cells
Hypertrophy
Increase in cell size; involves gene activation, protein synthesis, and organelle production.
What is the clinical significance of hyperplasia?
Hyperplasia can progress to dysplasia and eventually cancer
EXCEPTION: BPH–> not associated with increased risk of cancer
What is the mechanism of atrophy?
- Decrease in cell number- apoptosis
- Decrease in cell size- ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular contents
- ubiquitin-proteosome: ubiquitin tagged on intermediate filaments & proteosome destroys
- autophagy: vacuoles of cellular contents fuse with lysosomes
Metaplasia
: A change in stress is met with a change in cell type that is better able to handle new stress
- occurs via a reprogramming of stem cells to new cell type
- REVERSIBLE
- If persistent can progress to dysplasia and eventually cancer
Barrett’s esophagus is a classic example of what? Explain.
Metaplasia; esophageal stratified squamous epithelium changes to stomach simple columnar with goblet cels
What is the significance of apocrine metaplasia?
Apocrine metaplasia is seen in fibrocystic changes of the breast but DOES NOT have an increased risk of cancer!
What is the significance of vitamin A?
Vitamin A has several functions:
- Important in immune cell maturation –> PML
- Vitamin A deficiency (VAD) can be secondary to iron deficiency; iron is necessary ti uptake vitamin A
- Vitamin A is necessary for maintenance of specialized epithelia = so if VAD can develop metaplasia of those epithelium
- Conjunctiva: thin squamous epithelium maintained by vit. A; if VAD = metaplasia to stratified keratinized squamous epithelium called Keratomalacia
How is myositis ossificans and example of metaplasia?
: myositis ossificans usually occurs after skeletal muscle injury/trauma
-in the healing process connective tissue within the muscle undergoes metaplasia to bone
Aplasia
: failure of growth during embryogenesis resulting in no organ/structure
Hypoplasia
decreases in cell production during embryogenesis resulting in smaller organs
Dysplasia
: disordered cell growth; loss of cellular orientation, shape, and size
- often refers to proliferation of precancerous cells
- often arises in the setting of long-standing hyperplasia or metaplasia
- REVERSIBLE
- can progress to carcinoma
Hypoxia
Low delivery of oxygen to tissue
-causes of hypoxia include: ischemia, hypoxemia, and decreased oxygen carrying capacity of the blood.
Ischemia
:decreased flow of blood through an organ
-Arises in (1) decreased arterial perfusion, (2) decreased venous drainage, (3) shock= hypotension
Hypoxemia
: a low partial pressure of oxygen in the blood
-Arises with (1) high altitude, (2) hypoventilation, (3) diffusion defect, (4) V/Q mismatch
What is the process of reversible cellular injury?
: Hypoxia = impairs oxidative phosphorylation= decreased ATP
- low ATP –> Na/K pump and Ca2+ pump failure
- retained Na+ and water follows= cellular swelling –> loss of microvilli, membrane blebbing, ribosomal RER detachment (decreased protein synthesis)
- increased cytosolic Ca2+–> can activate harmful enzymes
- switch to anaerobic respiration = lactic acid = decreased pH –> denature proteins and DNA
- REVERSED WITH OXYGEN
What is the process of irreversible cellular injury?
: hallmark is membrane damage
- Plasma membrane damage: cytosolic enzymes leak into ECF, additional Ca2+ leaks into cell
- Mitochondrial membrane: loss of electron transport chain, cytochrome c leaks into cytosol –>apoptosis
- lysosome membrane: hydrolytic enzymes leak into cytosol and in turn activated by Ca2+
- end result is cell death
Necrosis
:aka cellular murder! Never physiologic, always caused by exogenous injury/underlying pathologic process, followed by acute inflammation
What morphologic changes constitute cell death?
:Loss of the cell nucleus!
- Pyknosis: nuclear condensation
- Karyorrhexis: nuclear fragmentation
- Karyolysis: dissolution (disappear) as DNAases and RNAases degrade chromatin
Coagulative necrosis
: cell shape and organ structure are preserved
-proteins denature and coagulate preserving cellular architecture but nucleus disappears, very eosinophilic
- Characteristic of heart, kidney and liver infarction but can occur in any organ EXCEPT BRAIN
-
Pale Infarct
occur in solid tissues with a single blood supply (heart, kidney, spleen)
-infarcted is often wedge-shaped
Red Infarction
occur in loose tissues with multiple blood supplies (liver, lungs, intestine)
-result of reperfusion
Liquefactive necrosis
: necrotic tissue that becomes liquefied; enzymatic lysis of cells and proteins
- Brain: enzymes from microglial cells
- abscess: enzymes from neutrophils
- pancreatitis: pancreatic enzymes liquefy parenchyma
Gangrenous necrosis
: Coagulative necrosis that resembles mummified tissue; common in limbs (DM patients) and GI tract
- dry gangrene: ischemic coagulative
- wet gangrene: superimposed infection of dead tissue, liquefactive necrosis ensues
Caseous necrosis
:soft friable necrotic tissue, cottage-cheese like appearance. combination of coagulative necrosis and liquefactive necrosis
-characteristic of granulomatous inflammation (TB) or fungal infection
Fat necrosis
:necrotic adipose tissue with chalky white appearance d/t deposition of calcium
-Characteristic of pancreatitis (saponification) and breast (trauma)
Recall: Saponification –> pancreatic enzymes released including lipase = degrade surrounding fat cells –> triglycerides + Ca2+ = saponification (dystrophic calcification)
Fibrinoid necrosis
:necrotic damage to blood vessel wall
- leaking of proteins including fibrin into blood vessel wall = bright pink staining of the wall
- characteristic of malignant hypertension and vasculitis
Apoptosis
Programmed cell death; ATP dependent
- Characterized by pyknosis, membrane blebbing, karyorrhexis, and formation of apoptotic bodies that are then phagocytosed.
- dying cell shrinkage leads to more eosinophilic cytoplasm
DNA laddering
sensitive indicator of apoptosis; during karyorrhexis endonucleases cleave at internucleosomal regions = 180 bp fragments
What is the mechanism of cell death in radiation therapy?
Causes apoptosis in tumor and surrounding tissue via hydroxyl free radial formation and dsDNA breakage
-note: rapidly dividing cells are susceptible to radiation therapy (skin, GI tract)
Caspases
:mediate apoptosis; present in the cytoplasm
- activate proteases–> breakdown cytoskeleton
- activate endonucleases–> break down DNA
Intrinsic mitochondrial pathway
:activated in cellular injury; DNA damage, or decreased hormonal stimulation
- BAX & BAK = pro-apoptoic proteins; inactivate Bcl-2
- Bcl-2= anti-apoptotic protein
- Bcl-2 normally binds to Apaf-1 which prevents the release of cytochrome c from mitochondrial matrix
- when Bcl-2 inactivated in apoptosis Apaf stimulates the release of cytochrome c
What is the consequence of over-expression of Bcl-2?
Over-expression of Bcl-2 leads to over inhibition of Apaf-1 = decreases caspase activation = tumorogenesis
-Ex. follicular lymphoma
Extrinsic apoptotic pathways
- FAS-FAS ligand: FAS ligand binds to FAS receptor (CD95) on target cell
- binding causes multiple FAS molecules to come together forming a death domain + FADD
- FADD activates caspases
- necessary in thymic negative selection; CTLs can express Fas ligand - Immune CTL release of perforin and granzyme B = activation of caspases
- TNF (tumor necrosis factor) binds TNF receptor and activates caspases
What is the significance of defective FAS-FAS ligand interactions?
basis for autoimmune disorders
pg 220 FA
How do free radicals cause damage?
- peroxidation of lipids in cellular membrane
2. oxidation of protein and DNA = protein modification & DNA damage
Name the antioxidants.
Vitamin A,C, E & glutathione
What enzymes eliminate free radicals?
Superoxide dismutase (in mito): superoxide --> H2O2 Catalase (in peroxisomes): H2O2 --> O2 + H2O Glutathione peroxidase (in mito): 2GSH + free radical --> Gs-SG and H2O
How are transitional metals kept from creating free radicals?
carrier proteins - eg. transferrin and ceruloplasmin
Pathologic generation of free radicals
- Ionizing radiation: water hydrolyzed to OH (most damaging free radical)
- Inflammation: NADPH oxidase generates superoxide = respiratory burst
- Transition metals: Fe2+ and Cu2+ (hemocromatosis & Wilson’s disease); fenton rxn
- Drugs/chemicals - acetaminophen overdose
Carbon Tetrachloride (CCl4)
:solvent in dry cleaning industry
CCl4 converted to CCl3 free radical in p450 system in liver = reversible cell damage –> RER swelling and ribosomal dissociation = decrease in apolipoproteins
- decrease in apolipoproteins = fatty liver change
How is damage mediated in reperfusion injury?
: return of blood also brings oxygen –> free radical generation which further damages tissue
- seen esp after thrombolytic therapy
- in cardiac injury this is why there is continued increase in cardiac enzymes
Basic characteristics of amyloidosis
: amyloid is a misfolded protein that deposits in extracellular space = damage tissues
- caused by multiple proteins but all; (1) B-pleated sheet configuration, (2) stain congo red, and (3) show apple green birefringence under polarized light
- diagnosis requires biopsy that shows microscopic features
- damaged organs must be transplanted, amyloid cannot be removed
Primary amyloidosis
:deposition of AL in tissues; AL is derived from Ig light chains
- associated with plasma cell disorder or multiple myeloma
Secondary amyloidosis
:deposition of AA (amyloid A )derived from SAA in multiple tissues
-SAA is an acute phase reactant so secondary amyloidosis seen in states of chronic inflammation: IBD, spondyloarthropathy, RA, SLE
What organs tend to be affected in systemic amyloidosis? What are the manifestations?
Primary and secondary amyloidosis = systemic amyloidosis
- Kidney (most commonly effected): nephrotic syndrome
- heart: restrictive cardiomyopathy or arrhythmia
- GI: tongue enlargement, malabsorption, hepatosplenomegaly
- Brain: neuropathy
Familial Mediterranean Fever
:d/t dysfunction of neutrophils = inflammation w/o infection
- autosomal recessive
- presents as episodes of fever and acute serosal inflammation (can mimic appendicitis, arthritis, or myocardial infarction)
Senile cardiac amyloidosis
: non-mutated/WT serum transthyretin deposits in heart
-usually asymptomatic; slow progression of cardiac dysfunction
Familial amyloid cardiomyopathy
:mutated serum transthyretin in heart –> restrictive cardiomyopathy and eventual heart failure
Where do you expect to find amyloid deposition in DM II patients>
: amylin deposition in pancreatic islets
-increased insulin production secondary to insulin resistance–> amylin derived from insulin
What kind of amyloid is seen in Alzheimer’s disease?
: ABeta amyloid derived from Beta-amyloid precursor protein; forms amyloid plaques
What is the significance of Beta-amyloid precursor protein being on chromosome 21?
Most individuals with Down syndrome (trisomy 21) develop alzheimers by age 21.
Where do you expect to see amyloid deposition in ESRD patients or patients on dialysis?
: B2-microglobulin deposits in joints
-B2-microglobulin (MHC I) not filtered well from the blood
“Tumor cells in an amyloid background” after fine needle aspiration of the thyroid?
Medullary carcinoma; c-cells of tumor produce calcitonin; calcitonin deposits as amyloid
