Pathoma: Growth adaptations, cell injury and death Flashcards
Hypertrophy
increase in size of the organ
involves gene activation, protein synthesis, and production of organelles
Hyperplasia
increase in number of cells in the organ
involves the production of new cells from stem cells
Permanent Tissues
Cardiac muscle
skeletal muscle
nerve
cannot make new cells
undergo hypertrophy only
Pathologic hyperplasia progresses to
dysplasia and eventually cancer
exception - benign prostatic hyperplasia, does not increase the risk for prostate cancer
Atrophy
decrease in stress leads to decrease in organ size by a decrease in size and number cells
what process decreases the number of cells in atrophy
apoptosis
what processes decreases the cell size in atrophy
ubiquitin-proteasome degradation of cytoskeleton - intermediate filaments of cytoskeleton are tagged with ubiquitin and destroyed by proteasomes
autophagy of cellular components - generation of autophagic vacuoles - fuse with lysosomes whose hydrolytic enzymes breakdown cellular components
metaplasia
change in stress on an organ leads to a change in cell type - most commonly one epithelium to another better able to handle the new stress
occurs via reprogramming stem cells
may be reversible by treating stressor
persistent stress - can progress to dysplasia and eventually cancer
Barrett’s Esophagus
Barrett’s Esophagus
esophagus normally lined by nonkeratinizing squamous epithelium - can handle friction of food bolus
acid reflux from the stomach causes metaplasia to nonciliated, mucin-producing columnar cells- better able to handle stress of acid
Vitamin deficiency that can lead to metaplasia
vitamin A
necessary for differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye
vit A deficiency can cause goblet cell/columnar epithelium of conjunctiva to undergo metaplasia into keratinizing squamous epithelium
dry eyes (xerophtalmia) can lead to destruction of the cornea and blindness
What condition occurs in response to healing in trauma that causes mesenschymal tissues to undergo metaplasia
myositis ossificans
connective tissue within muscle changes to bone during healing after trauma
Dysplasia
disordered cellular growth
most often refers to proliferation of precancerous cells
often arises from longstanding pathologic hyperplasia or metaplasia
Aplasia
failure of cell production during embryogenesis
ex. unilateral renal agenesis
hypoplasia
decrease in cell production during embryogenesis, resulting in a relatively small organ
ex. streak ovary in Turner syndrome
Common causes of cell injury
inflammation nutritional deficiency or excess hypoxia trauma genetic mutations
hypoxia
low oxygen delivery to tissue
oxygen is the final electron acceptor in the electron transport chain of oxidative phos
decreased oxygen impairs ox phos, resulting in decreased ATP production
lack of ATP leads to cell injury
causes of hypoxia
ischemia
hypoxemia
decreased oxygen carrying capacity of blood
ischemia
decreased blood flow through an organ
decreased arterial perfusion - atherosclerosis
decreased venous drainage - Budd-Chiari syndrome
Shock - generalized hypotension -> poor tissue perfusion
hypoxemia
low partial pressure of oxygen in the blood - PaO2 decreased PaO2
hypoventilation - increased PaCO2 -> decreased PaO2
diffusion defect - PaO2 not able to push as much O2 into the blood due to a thicker diffusion barrier (interstitial pulmonary fibrosis)
V/Q mismatch - blood bypasses oxygenated lung or oxygenated air cannot reach blood
decreased O2 carrying capacity
hemoglobin loss or dysfunction
anemia - normal PaO2
carbon monoxide poisoning - PaO2 normal - cherry red appearance of skin, early sign is HA
Methemoglobinemia - iron in heme is oxidized to Fe3+ which cannot bind oxygen - PaO2 normal - seen in oxidant stress - cyanosis with chocolate colored blood - Tx is intravenous methylene blue which helps reduce Fe3+ back to Fe2+
hallmark of reversible cellular injury
cellular swelling - cytosol swelling results in loss of microvilli and membrane blebbing
swelling of the rough ER results in dissociation of ribosomes and decreased protein synth
Hallmark of irreversible cellular injury
membrane damage - results in cytosolic enzymes leaking into the serum (cardiac troponin), additional calcium entering cell
End result is cell death
Mitochondrial Membrane Damage
results in loss of the electron transport chain (inner mito membrane), cytochrome c leaking into cytosol (activates apoptosis)
lysosomal membrane damage
results in hydrolytic enzymes leaking into cytosol, which are activated by the high intracellular calcium
Mechanisms of cell death
necrosis and apoptosis
morphologic hallmark of cell death
loss of nucleus
occurs via nuclear condensation (pyknosis)
fragmentation(karyorrhexis)
and dissolution (karyolysis)
Necrosis
death of large groups of cells followed by acute inflammation
never physiologic
Coagulative Necrosis
necrotic tissue that remains firm
organ structure is preserved but nucleus disappears
characteristic of ischemic infarction of any organ except the brain
often wedge-shaped and pale
red infarction arises if blood re-enters loosely organized tissue
Liquefactive Necrosis
necrotic tissue that becomes liquefied
enzymatic lysis of cells and protein results in liquefaction
characteristic of - brain infarction - proteolytic enzymes from microglial cells liquefy the brain
abscess - proteoplytic enzyes from neutrophils liquefy tissue
pancreatitis - proteolytic enzymes from pancreas liquefy parenchyma
Gangrenous Necrosis
coagulative necrosis that resembles mummified tissue - dry gangrene
characteristic of ischemia of lower limb and GI tract
if superimposed infection of dead tissues occurs then liquefactive necrosis ensues - wet gangrene
Caseous Necrosis
soft and friable necrotic tissue with cottage cheese-like appearance
combination of coag and liquefactive necrosis
characteristic of granulomatous inflammation due to tuberculous or fungal infection
Fat Necrosis
necrotic adipose tissue with chalky-white appearance due to deposition of calcium
characteristic of trauma to fat and pancreatitis-mediated damage of peripancreatic fat
FA released by trauma or lipase join with calcium via a saponification
Saponification
dystrophic calcification in which calcium deposits on dead tissues
necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate
Metasstatic calcification
high serum calcium or phosphate levels lead to calcium deposition in normal tissues
Fibrinoid Necrosis
necrotic damage to blood vessel wall
leaking proteins into vessel wall results in bright pink staining of the wall microscopically
characteristic of malignant hypertension and vasculitis
Apoptosis
programmed cell death
ATP (energy) dependent
endometrial shedding during menstrual cycle
removal of cells during embryogenesis
CD8+ T cell-mediated killing of virally infected cells
Morphology of Apoptosis
dying cell shrinks - cytoplasm becomes more eosinophilic
nucleus condenses and fragments
apoptotic bodies fall from the cell and are removed by macrophages - not followed by inflammation
Apoptosis is mediated by
caspases - which activate proteases and endonucleases
proteases break down cytoskeleton
endonucleases break down DNA
Caspases are activated by
intrinsic and extrinsic pathway
intrinsic mitochondrial pathway
cell injury - DNA damage - or decreased hormonal stimulation leads to inactivation of Bcl2
lack of Bcl2 allow cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases
extrinsic receptor - ligand pathway
FAS ligand binds FAS death receptor (CD95) on target cell - activates caspases
TNF binds TNF receptor on target cell - activates caspases
Cytotoxic CD8+ T cell -mediated apoptotic pathway
perforins secreted by CD8+T cell create pores in membrane of target cell
granzyme from CD8+ T cell enters pores and activates caspases
CD8+ T-cell killing of virally infected cells is an example
pathologic generation of free radicals occurs with
ionizing radiation - water hydrolyzed to hydroxyl free radical
inflammation - NADPH oxidase generates superoxide ions during oxygen dependent killing by neutrophils
metals - copper and iron
drugs and chemicals - p450 system of liver metabolizes drugs, generating free radicals
free radicals cause cellular injury via
peroxidation of lipids and oxidation of DNA and proteins
DNA damage is implicated in aging and oncogenesis
Elimination of Free radicals
antioxidants - glutathione and vit A, C, E
Enxymes - superoxide dismutase - mito
- glutathione peroxidase - mito
- catalase - peroxisomes
Metal Carrier Protiens - transferrin and ceruloplasmin
Carbon Tetrachloride - CCl4
organic solvent used in dry cleaning
converted to CCl3 free radical by p450 system of hepatocytes
causes cell injury with swelling of RER -> ribosomes detach, impairing protein synthesis
decreased apolipoproteins lead to fatty change in the liver
reperfusion injury
return of blood to ischemic tissue results in production of O2 derived free radicals which further damage tissue
leads to rise in cardiac enzymes (troponin) after reperfusion of infarcted myocardial tissue
amyloid
misfolded protein that deposits in the extracellular space thereby damaging tissues
multiple proteins can be deposited as amyloid
- Beta pleated sheets
- congo red staining and apple - green birefringence
Primary systemic amyloidosis
systemic deposition of AL amyloid - derived from immunoglobulin light chain
associated with plasma cell dyscrasias (mult. myeloma)
Secondary systemic amyloidosis
systemic deposition of AA amyloid - derived form serum amyloid-associated protein (SAA) - acute phase reactant that is increased in chronic inflammatory states - malignancy and familial Mediterranean fever
Familial Mediterranean Fever
AR
episodes of fever and acute serosal inflammation
high SAA during attacks deposits as AA amyloid in tissues
Localized Amyloidosis
senile cardiac amyloidosis
- non-mutated serum transthyretin deposits in the heart
- usually asymptomatic
Familial amyloid cardiomyopathy
mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy
Amylin (derived from insulin) deposits where
islets of pancreas in DM
Alzheimer Amyloid are derived from
Beta amyloid precursor protein -> AlphBeta amyloid -> deposits in brainformin amyloid plaques
gene for APP is on chromosome 21
Dialysis associated amyloidosis
Beta2 - macroglobulin deposits in joints
medullary carcinoma of the thyroid
calcitonin (produced by tumor cells) deposits within the tumor (tumor cells in an amyloid background)
