Pathology (Gen Principles) Flashcards
Hypertrophy
increase in size
involves gene activation and *protein synthesis, and production of organelles (for cellular fxn - mitochondria)
Hyperplasia
increase in cell number
production of new cells from stem cells - classic response to hormone stimulation
Ex: breast growth at puberty, liver regeneration (donation) and bone marrow (anemia)
physiologic changes of the uterus during pregnancy
smooth muscle undergoes hypertrophy and hyperplasia
Important note about permanent tissues
canNOT make new cells - so cannot undergo hyperplasia - hypertrophy ONLY
3 permanent tissues:
cardiac myocytes
skeletal muscle
nerves
3 permanent tissues
“terminally differentiated”
cardiac myocytes
skeletal muscle
nerves
pathologic hyperplasia
hyperplasia that progresses to dysplasia and cancer
ex: endometrial hyperplasia - due to estrogen
exception: benign prostatic hyperplasia (BPH) - due to androgens - not related to cancer and no increase in cancer risk
Atrophy
decrease in stress on the organ (less stress) - decrease in size and number
Mechanism:
apoptosis (decrease # of cells)
ubiquitin-proteasome degradation (decrease in cell size)
mechanism of atrophy
- decrease in # - apoptosis
- decrease in size
a. ubiquitin-proteasome degradation pathway - destroying the cytoskeleton
b. autophagy of cellular components and then destroyed by lysosomes
Metaplasia
change cell type in response to stress
most common involves surface epithelium
metaplastic cells are better to handle the new stress
Mechanism of metaplasia
REVERSIBLE reprogramming of stem cells - can progress to cancer
ex: Barrett esophagus and respiratory epithelium w/ cigarette smoke (to stratified squamous cell epithelium)
exception: apocrine metaplasia (fibrocystic change of the breast - does not increase the risk of breast cancer)
the exception to metaplasia as an increased risk to cancer
apocrine metaplasia (fibrocystic change of the breast - does not increase the risk of breast cancer)
Which vitamin deficiency can lead to metaplasia?
Vitamin A deficiency
- night blindness
- also necessary for immune cell maturation (PML - trapped in blast state (derivative of Vitamin A is a tx)
- can result in metaplasia (necessary for maintenance of specialized epithelial - conjunctival and upper respiratory tract - pulmonary infections)
ex: keratomalacia
keratomalacia - clouding and drying (xerophthalmia) of the eye caused by a Vitamin A deficiency
Mesenchyme tissues
Connective tissues
- blood vessels, bone, fat, cartilage
presence of bone within skeletal muscle
myositis ossificans (ex of an mesenchyme metaplasia) - muscle going to bone
bone is normal - look careful and see that there is a distinct separation between the bone and muscle (is not growing off the bone - so not a bone issue like osteosarcoma)
Dysplasia
REVERSIBLE disordered cellular growth
proliferation of precancerous cells (ex: CIN) - arises from long standing hyperplasia (endometrial hyperplasia) or metaplasia (Barrett esophagus)
if stress persists - leads to cancer IRREVERSIBLE
Aplasia
failure of growth/cellular production during embryogenesis
ex: unilateral renal agenesis (fails to develop one kidney)
Hypoplasia
decrease in cell production during embryogenesis - results in small organ
Ex: streak ovary in Turner syndrome
Characteristic changes that indicate dysplasia
pleomorphism, abnormal nuclei (hyperchromatic or large), and mitotic figures (clumped chromatin)
Hypoxia
low oxygen delivery to tissues - O2 final electron acceptor - needed for ATP/energy - impairs oxidative phosphorylation -cellular injury (Na+/K+ failure)
CO poisoning
carbon monoxide is an odorless gas that binds Hb more tightly than 02; PaO2 will be normal but SaO2 will be decreased - (O2 is in the blood, just not bound to Hb)
Ex: smoke from fires, exhaust from cars (suicide) and gas heaters
Clinical manifestation: cherry red appearance of the skin, early sign of *headache and then confusion until it gets to coma and death
Methemoglobinemia
iron in heme is oxidized to Fe3+ (normally in Fe2+ state) - so now Hb can no longer bind O2
PaO2 is normal, SaO2 decreased - (O2 is in the blood, just not bound to Hb)
Seen in oxidant stresses (sulfa and nitrate drugs) and in newborns
Clinical manifestation: chocolate-colored blood w/ cyanosis Tx: IV methylene blue (reduce Fe3+ to Fe2+)
Low ATP in cells
ATP needed for Na+/K+ pump (pushes Na+ out to maintain gradient) w/ failure Na+ will build up inside the cell - H20 follows - swelling (first signs of cellular injury)
Also:
Ca2+ pump - high cyclic Ca2+ (enzyme activator) and aerobic glycolysis
Initial phase in reversible injury
hallmark = cellular swelling
leads to loss of microvilli, membrane blabbing and swelling of the RER (ribosomes pop pff the ER - decreased protein synthesis)
Hallmark of irreversible cell injury
membrane damage (there are 3 membranes):
1. plasma membrane - cytosolic enzymes will leak out into the blood (serum testing - liver and cardiac damage)
2. mitochondrial membrane - Cystochrome C can leak out and cause apoptosis
3. Lysosomes - digestive enzymes are released to cause intracellular damage
Where is ETC is located in the mitochondrial?
inner mitochondrial membrane
Hallmark of cell death
loss of the nucleus
pyknosis (shrinking of nucleus), karyorrhexis breaking up the nucleus) and karyolysis (breaking down of those nuclei pieces)
Necrosis
death of a large group of cells and is followed by inflammation; NEVER PHYSIOLOGIC, always pathologic (some problem is present)
Coagulative necrosis
necrotic tissue that remains firm - cell shape and organ structure are preserved however the nucleus disappears
Note: caused by ischemic infarction of any organ BUT the brain!
Liquefactive necrosis
necrotic tissue becomes liquified due enzymatic lysis of cells and proteins; occurs in 3 main circumstances:
- brain infarction (mediated by microglia cells)
- abscess - neutrophil enzymes
- pancreatitis - pancreatitis enzymes
Gangrenous necrosis
resembles mummified tissue (dry gangrene); characteristic ischemia over the lower limb and GI tract
if infection occurs (superimposed) on dead tissue, then liquefactive necrosis aka “wet gangrene”
Caseous necrosis
soft, friable necrotic with “cottage cheese-like appearance; characteristic of TB and fungal infection
Fat necrosis
necrotic adipose tissue with a chalky-white appearance due to deposition of Ca2 (saponification)
- trauma to breast (car accident) - giant cells and calcifications on mammography and also pancreatitis in peripancreatic fat
Fibrinoid necrosis
necrotic damage to blood vessel wall; leaking proteins into vessel walls results in bright pink staining
Malignant HTN and vasculitis
In what circumstance would a 30 yr woman present with fibrinoid necrosis?
preeclampsia (HTN in 3rd trimester in pregnancy) - fibrinoid necrosis is seen in blood vessel irreversible injury typically due to long-standing HTN
CD8+ T cell-mediated killing of virally infected cells is an example of what type of cell death?
apoptosis; T cells release Granzyme B (enters pores) and perforin (perforates/creates pores) - activates executioner caspases
Intrinsic (mitochondrial) pathway
cellular injury, DNA damage or decreased hormonal stimulations which inactivates BCL2 (anti-apoptotic/don’t wanna die) - functions to keep mitochondrial membrane impermeable to cytochrome C so it is not released
release of cytochrome C initiates cell destruction
Extrinsic (death receptor) pathway
*FASL binds FAS death receptor (CD95) on target cell - occurs in negative selection in the thymus
TNF binds TNF receptor on target cells
Free radicals
chemical species with unpaired electron in their outer orbit - this unpaired electron has the ability to cause injury in the cell
pathological generation of free radicals
ionizing radiation (hydroxyls)
inflammation
metals (copper and iron)
drugs and chemicals (acetaminophen - converted by p450 enzymes and generate free radicals in the process) carbon tetrachloride (CCl4) is another big one
free radical damage
perioxidation of lipids
oxidation of DNA and proteins (damages DNA)
Elimination of free radicals
Antioxidants (ex: vitamin A,C, E)
Enzymes (SOD, Glutathione peroxidase and Catalase)
Metal carrier proteins (ferritin)
Enzymes that eliminate free radicals
O2 to O2- to H2O2 to OH- to H2O
- Superoxide dismutase (SOD) handles O2-/superoxide
- Catalase handles H2O2/peroxide
- Glutathione peroxidase handles OH-/hydroxyl (most dangerous free radical)
CCl4 free radical injury
typically exposure from dry cleaning industry
converted to CCl3 in the P450 enzymes of the liver - free radical damages the hepatocytes - cellular swelling - protein synthesis is reduced (decrease Apolipoprotein synthesis) - fatty change of the liver
Amyloid
misfolded protein that deposits in the *extracellular space and damages tissues
not one protein - broad characteristic of proteins that can be folded in a characteristic way - beta-pleated sheet configuration and picks up Congo red staining and apple-green birefringence under polarized light
apple-green birefringence under polarized light
characteristic of amyloid deposition
Primary amyloidosis
systemic deposition (throughout the body) of *AL amyloid derived from Ig light chain
associated with plasma cell dyscrasias (abnormality of plasma cells - overproduction of the light chains)
Secondary amyloidosis
systemic deposition (throughout the body) of *AA amyloid derived from SAA
SAA is an acute phase reactant (Increased in chronic inflammatory states, malignancy and familial Mediterranean fever)
Familial Mediterranean fever
dysfunctional neutrophils AR that occurs in a person of Mediterranean origin
presents with episodes of fever and *acute serosal inflammation
High SAA during attacks and these deposit as AA amyloid
Which organ is the most commonly involved in amyloid deposition?
the kidney
results in nephrotic syndrome (large loss of protein in the urine)
Senile cardiac amyloidosis
localized non-mutated *serum transthyretin deposits in the heart; usually asymptomatic; presents in elderly (80yrs)
Familial amyloid cardiomyopathy
localized mutated *serum transthyretin deposits in the heart; usually symptomatic and results in restrictive cardiomyopathy (5% of Blacks)
Acute inflammation
edema and neutrophils - key immune cell
TLRs
toll-like receptors present on innate immune cells and recognize PAMPs
Ex: CD14 on macrophages can recognizes LPS on gram (-) bacteria and activates immune genes NF-kB - leads to multiple immune mediators
Arachidonic Acid
released from cell membrane by phospholipase A2 acted on by COX or 5-lipooxygenase
COX produces prostaglandins - mediate vasodilation (at the arteriole) and increased vascular permeability (at the post-cap venule) (PGE2) - also mediates fever and pain
5-lipooxygenase products leukotrienes (LTE) - attract and activate neutrophils (LTB4)
Role of leukotriene B4 (LTB4)
produced by the 5-lopoxygenase pathway from Arachidonic Acid; functions to attract and activate neutrophils for acute inflammation
Role of prostaglandin E2 (PGE2)
produced by the COX pathway from Arachidonic Acid; functions to mediate vasodilation (at the arteriole) and increased vascular permeability (at the post-cap venule) and also mediates fever and pain
Role of leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4)
basically cause contraction of smooth muscle
vasoconstriction (arteriole), bronchospasm (bronchus) and increased vascular permeability
Mast cell activation
- tissue trauma
- complement proteins C3a and C5a
- cross-linking of cell-surface Ice by antigen
Immediate response of activation of mast cells
dumping/releasing of histamine - vasodilation (arteriole)
Delayed response on the activation of mast cells
production of arachidonic acid metabolites, particularly leukotrienes - attract and activate neutrophils (LTB4) - vasoconstriction (arteriole), bronchospasm (bronchus) and increased vascular permeability (LTC4, LTD4, LTE4)
Classical complement pathway
“GM makes classic cars”
C1 binds IgG or IgM that is bound to antigen
Alternate complement pathway
microbial products directly activate complement
Mannose-binding lectin pathway
MBL binds mannose on microorganism and activates complement
Key products of complement
C3a and C5a - trigger mast cell degranulation
C5a - chemotactic for neutrophils
C3b - opsonin for phagocytosis
MAC - lyses microbes by creating holes in the cell membrane
Hageman factor
inactive proinflammatory protein produced in liver and activated upon exposure to sub endothelial or tissue collagen
*plays an important role in DIC
Hageman factor
inactive proinflammatory protein produced in liver and activated upon exposure to sub endothelial or tissue collagen
*plays an important role in DIC
Mediators of pain
PGE2 and bradykinin -they sensitive nerve endings
Mediators of fever
- macrophage release of IL-1 and TNF
- increased COX in perivascular cells of hypothalamus
- increased PGE2 raised temp set point
Healing
begins when inflammation occurs; occurs via regeneration and repair
Labile tissues
tissues that are constantly regenerating: small and large bowel (stem cells in mucosal crypts), skin (stem cells in the basal layer) and bone marrow (hematopoietic stem cells - CD34+)
Stable tissues
tissues that are quiescent but can re-enter the cell cycle; regeneration of the liver by hyperplasia - each hepatocytes produces additional cells and then enters quiescence; also the proximal renal tubule
Permanent tissues
terminally differentiated tissues - myocardium, skeletal muscle and neurons; major healing is repair w/ fibrous (not regeneration)
Initial phase of repair
granulation tissue
fibroblasts deposit type III collagen, capillaries provide nutrients and myofibroblasts contract the wound
Granuloma
subtype of chronic inflammation w hallmark = epitheloid histiocytes
MOA: IL-12 from macrophages hits CD4+ converts into Th1 cell secretes IFN-gamma that gives macrophages an epitheloid histiocytes appearance
Granulation tissue vs a scar in healing
granulation tissue is from type III collagen by fibroblast; in a scar type III collagen is replaced w/ type I collagen (stability)
collagenase removes the type III collagen and requires a *zinc cofactor
Molecules that are important for healing and repair
TGF-alpha: epithelial and fibroblast growth factor
TGF-beta: important fibroblast growth factor and inhibits inflammation
PDGF: endothelium, smooth muscle, fibroblast growth factor
FGF: angiogenesis and skeletal development
VEGF: angiogenesis
The two cytokines that are secreted by macrophages that function to shut down inflammation and start the healing process
IL-10 (anti-inflammatory) and TGF-beta
pt has a large wound that has healed via secondary intention and 6 weeks later you notice that the wound is significantly reduced in size? What the mechanism that the wound reduces in size?
via myofibroblast - they have the ability to contract the wound and make it smaller
Delayed wound healing
prolonged healing of a wound; #1 cause is infection, then Vitamin C deficiency (scurvy) - necessary for strengthening of collagen, also lack of copper or zinc
Others: foreign body, ischemia, diabetes and malnutrition
Dehiscence
rupture of a wound; most commonly seen after abdominal surgery (the wound tears open)
Hypertrophic scar
excess production of scar tissue; predominantly made up of type I collagen
Keloid
excess production of scar tissue that is out of proportion to the wound; excess type III collagen; predisposition to Blacks; classically affects the earlobes
