Growth Adaptations, Cellular Injury, and Cell Death (Pathoma) Flashcards
Hypertrophy
Increase in size of cells (i.e. cardiac muscle cells in HTN)
Involves: Gene actiation, protein synthesis, and production of organelles.
Often occures w/ hyperplasia (i.e. pregnant uterus)
Permanent tissues can only undergo hypertrophy (i.e. cardiac myocytes, skeletal muscle, and nerves)
Hyperplasia
Increase in number of cells
Involves production of new cells from stem cells (i.e. Benign Prostatic Hyperplasia)
Often occures w/ hypertrophy (i.e. pregnant uterus)
Cannot occur in permanent tissues.
Pathologic hyperplasia can progress to dysplasia and cancer (i.e. endometrial hyperplasia; exception is BPH)
Atrophy
Decrease in stress –> decrease in size.
Occurs via size or number of cells (both called atrophy and occur together)
Decrease in number occurs via apoptosis
Decrease in size occurs via Ubiquitin proteosome degredation of cytoskeleton or autophagy of cellular components
Decrease in cell number occurs via?
Apoptosis
Decrease in cell size occurs via
Ubiquitin proteosome degredation of cytoskeleton or autophagy of cellular components
Metaplasia
Change in stress on organ leads to change cell type.
Most commonly involves surface eptithelium.
Metaplastic cells are better able to handle the new stress
Example: Barrert esophagus changing from squamous to columnar non ciliated mucinous epithelium in response to GERD to better handle stomach acid)
Occurs via reprogramming of stem cells which then produce the new cell type (this is reversible –> i.e. treating GERD –> reverses Barrett’s esophagous)
Under persistent stress metaplasia can progress to dysplasia and eventually cancer (i.e. Barrett’s; key exception is apocrine metaplasia of the breast)
Vitamin A deficiency can result in metaplasia (keratomalacia or M3 leukemia).
Mesenchymal tissues can undergo metaplasia (i.e. myositis ossificans)
Deficiency of what can result in metaplasia?
Vitamin A.
I.e. keratomalacia or Acute Promyelocytic Leukemia (M3))
Thus Rx for M3 is All-Trans-Retinoic-Acid (ATRA) is a Vit. A derivative.
Keratomalacia
Vit. A deficiency causes goblet cell/columnar epithelium of conjunctiva to undergo metaplasia into keratinizing squamous epithelium. Becomes thick and causes blindness
Think Nick Kristof –> Helen Keller International –> Vitamin A capsules and GMO sweet potatoes
Dry eyes (xeroopthalmia) can also lead to destruction of the cornea (keratomalacia) and blindness
Myositis ossificans
Inflammation of skeletal muscle (i.e. after trauma) can cause skeletal muscle to undergo metaplasia into bone.
Don’t be tricked into picking osteosarcoma (myositis ossificans is not connected to bone)
Dysplasia
Disordered cellular growth
Proliferation of precancerous cells
Arises from longstanding pathologic hyperplasia or metaplasia
Key is REVERSIBLE
If stress persists, dysplasia progresses to carcinoma (irreversible –> key distinction)
Aplasia
Failure of cell production during embryogenesis
I.e. Renal agenesis
Hypoplasia
Decrease in cell production during embryogenesis
Results in relatively small organ
I.e. streak ovary in Turner Syndrome
Cellular injury
Stress exceeds cell’s ability to adapt
Likelihood depends on type of stress, its severity, and type of cell affected
Neurons are highly susceptible to ischemic injury vs. skeletal muscle is resistant
Slowly developing ischemia results in atrophy (Renal Artery Stenosis) vs. Acute ischemia (renal artery embolus) results in injury
Common causes of injury: inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.
Hypoxia
Low oxygen delivery to tissue
Oxygen needed to run ETC and make ATP.
Due to: ischemia (poor blood flow due to atherosclerosis, venous thrombosis, or shock), hypoxemia (i.e. COPD), or decreased O2 carrying capacity (i.e. severe anemia).
Budd-Chiari Syndrome
Thrombus forms in Hepatic Vein causing ischemia of liver. and infarction in liver parenchyma and death.
MCC is Polycythemia Vera
Another classic example is Lupus anticoagulant.
Ischemia causes?
Atherosclerosis (i.e. angina)
Venous Thrombosis (i.e. Budd-Chiari Syndrome)
Shock (hypoperfusion in hypovolemia etc.)
Hypoxemia
Low partial pressure of O2 in blood (PaO2 PAO2–> PaO2 –> SaO2
Thus any change of FiO2 such as altitude; or PA02 decrease due to increased PACO2 in hypoventilation or COPD, would cause hypoxemia and thus eventually SaO2
Causes: Altitude, hypoventilation, diffusion defect, and V/Q mismatch
Decreased O2 carrying capacity
Arises w/ Hb loss (anemia –> normal PaO2 and SaO2!) or dysfunciton (CO poisoning or methemoglobinemia)
CO poisoning
Binds Hb more avidly than O2
PaO2 nromal, SaO2 decreased (not on pulse-oximeter however)
Exposures include smoke from fires and exhaust from cars or gas heaters.
Classic finding is cherry red appearance of skin.
Early sign is headache (key sign in taking hx), significant exposure can lead to coma and death.
Methemoglobinemia
Iron in heme is oxidized to Fe3+ which cannot bind O2 (Fe2+ binds O2!)
PaO2 normal, Sa02 is decreased
Seen w/ oxidant stress (i.e. sulfa and nitrate drugs or in newborns
Classic finding is cyanosis w/ chocolate-covered blood.
Rx: I.V. Methylene Blue (reduces Fe3+ back to Fe2+)
Low ATP disrupts what key cellular functions?
Na/K pump –> cellular swelling
Ca++ pump –> activates unwanted enzymes –> apoptosis
Aerobic glycolysis –> poor ATP production and lactic acid buildup –> DNA and protein denaturation at low pH’s
Reversible Injury
Cellular Swelling! due to loss of Na/K pump.
Leads to loss of microvilli (key in small bowel), membrane blebbing (loss of integrity of cytoskeleton due to swelling) , and swelling of RER (loss of loosely associated ribosomes)
Irreversible injury
Long standing
Hallmark is Membrane Damage
1.) Plasma membrane –> enzymes from inside cell –> i.e. cardiac troponin test in M.I. or AST/ALT in liver damage
- ) Mitochondrial Membrane –> disrupts ETC on inner mitochondrial membrane and releases cytochrome C –> activation of apoptosis
- ) Lysosome membrane –> release of lytic enzymes and join w/ intracellular Ca++ and causes damage of cellular organelles
End result is cell death
Morphologic hallmark of cell death?
Loss of nucleus!!!
Occurs via pyknosis (shrinking into ink dot), karyorrhexis (breaking of nucleus into big pieces) and karyolysis (broken into small building blocks)
Two mechanisms of cell death
Necrosis (Cellular homicide) and Apoptosis (Cellular suicide)
Necrosis
Death of a large group of cells followed by ACUTE INFLAMMATION (i.e. neutrophilia following MI)
Due to underlying pathologic process; never physiologic
Severeal Types:
- ) Coagulative Necrosis - tissue remains firm. Characteristic of ischemic infarction in any organ except brain.
- ) Liquefactive Necrosis - tissue becomes liquified by enzymatic degredation (brain infarction, abscess, pancreatitis)
- ) Gangrenous Necrosis - (resembles mumified tissue –> lower limb and GI; wet or dry)
- )Caseous Necrosis - Soft and friable (cottage-cheese) from combo of liquifactive and coagulative. Granulomas (TB vs. Fungal)
- ) Fat Necrosis - Chalky white appearance due to calcium deposition. Due to damage to tissue and subsequent saponificaiton.
- ) Fibrinoid necrosis - damage to blood vessel wall. Bright pink. Malignant HTN or vasculitis.
Area of infarcted tisse is often what shape?
Wedge shaped and pale
Due to anatomy of branching vessels being most common thrombus point.. Wedge points to area of occlusion.
Red infarction arises if?
Blood reenters the tissue and a loosely organized tissue.
Classic example is testicular torsion causing venous collapse and subsequent ischemia. Artery remains patent causing red infarction.
Coagulative necrosis
Necrotic tissue remains firm –> cell shape and organ structure are preserved but nucleus dissapears.
Characteristic of ischemic infarction anywhere except brain.
Area is often pale and wedge shaped.
Red infarction if reperfused and loose tissue.
Liquefactive Necrosis
Necrotic tissue becomes liquified due to enzymatic lysis of cells and protein
Characteristic of:
- )Brain Infarction - proteolytic enzymes from microglial cells
- ) Abscess - proteolytic enzymes of neutrophils
- ) Pancreatitis - proteolytic enzymes of the pancreas
Gangrenous Necrosis
Coagulative necrosis that resembles mummified tissue (dry gangrene)
Characteristic of ischemia of lower limb (diabetics –> popliteal atherosclerosis –>ischemia –> gangrenous necrosis ) and small bowel.
Wet gangrene if there is a superimposed infection of dead tissue causing concurrent liquefactive necrosis.
Caseous Necrosis
Soft and friable tissue w/ cottage cheese appearance
Combination of coagulative and liquefactive necrosis
Characteristic of granulomatous inflammation due to TB or fungal infections
Fat Necrosis
Necrotic adipose tissue w/ chalky-white appearance due to calcium.
Characteristic of trauma to fat (i.e. big boobed runner –> important for masses and mammogram ddx), or pancreatitis-mediated damage of peripancreatic fat.
Occurs via saponification –> fatty acids released by trauma or lipase join w/ calcium. (example of dystrophic calcification)
Two mechanisms of calcium deposition in tissue
Dystrophic calcification - Damaged tissue serves as nidus w/ subsequent calcium depositon. Normal serum calcium and phosphate.
Metastatic calcification –> High serum Ca or PO4 causes deposit of calcium throughout body (doesn’t have to be metastatic cancer, i.e. hyperparathyroidism!)
Fibrinoid Necrosis
Damage to blood vessels
Has bright pink staining.
Indicative of malignant HTN or vasculitis.
Know that fibrinoid necrosis of placenta is common in preecclampsia (along w/protienuria). Common test question.
Caused by leaking of proteins (i.e. fibrin) into vessel wall
Apoptosis
Energy-dependent, genetically programmed cell death.
Ivolves single cells or small groups.
Examples: Endometrial shedding, removal of cells during embryogenesis, CD8+ T cell-mediated killing in virally infected cells.
Morphology: (translation is falling of leaves)
- Dying of cell shrinks (becomes eosinophillics)
- Apoptotic bodies fall from cell are removed by macrophages; NO INFLAMMATION
Mediated by caspases –> activate proteases (break down cytoskeleton) and endonucleases (break down DNA)
2 Pathways:
Intrinsic mitochondrial pathway. Cellular injury, DNA damage, decreased hormonal stimulation inactivates Bcl2. Cytochrome C leads from inner mitochondrial matrix into cytoplasm.
Extrinsic receptor-ligand pathway. FAS ligand binding FAS death receptor (CD95). (This is key for negative selection of T cells in Thymus )or TNF binds TNF receptor on target cell.
Cytotoxic CD8+ T-cell mediated pathway. CD8’s release perforin to form holes and granzymes to activate caspases. (i.e. CD8 killing virally infected cell.)
Generation of free radicals
Physiologic:
Oxidative phosphorylation
Pathologic
Ionizing Radiation
Inflammation (Neutrophils w/ oidative burst using NADPH oxidase making superoxide)
Metals (copper and Iron –> fenton reaction if left unbound. Wilson’s disease or hemochromatosis –> mechanism of pathology)
Drugs and Chemicals (Acetaminophen and CCl4)
Free radical damage
Peroxidation of lipids
Oxidation of DNA (oncogenesis!) and proteins
Elimination of free radicals
Antioxidants (Vitamin A,C, and E)
Enzymes (Superoxide Dismutase, Glutathione peroxidase, and Catalase)
Metal carrier proteins (i.e. transferrin to carry iron in blood)
Enzymes that neutralize free radicals
Superoxide dismutase (O2- –> H202)
Glutathione peroxidase (in mitochondria) 2GSH + free radical –> GS-SG and H202
Catalase (in peroxisome) H202 –> 02 and H20
CC:l4 Free radical injury
CCL4 is converted to the free radical CCL3 in the p450 system of the liver.
This damage causes cellular swelling and ribosomes to be kicked off the RER thus decreasing protein sythesis causing lack of apoliproteins –> fats to accumulate in the liver –> fatty liver.
Think dry cleaner.
Reperfusion injury
I..e Post MI
Irreversible injury to cells –> cellular contents released (troponins rise) –> reperfusion –> inflammatory cells along with reperfused O2 –> reperfusion injury –> cardiac troponins continue to rise
Amyloid
Misfolded protein that can be deposited in extracellular space thereby damaging tissues.
Multiple proteins can deposit as amyloid
Beta-sheet configuration
Congo red staining and apple-green birefringence under polarized light.
Often around blood vessels
Deposition can be systemic or localized.
Primary Amyloidosis
Systemic deposition of AL amyloid which is derived from immunoglobin light chain.
Associated w/ plasma cell dyscrasias (i.e. MM)
Classic clinical findings:
Kidney is most common affected organ (usually nephrotic syndrome).
Restrictive cardiomyopathy, or arrhythmias
Tongue enlargement, malabsorbtion, and h/smegaly
Dx: biopsy –> esp. abdominal fat pad and rectum
Damaged organs must be tranplanted –> can’t be removed.
Secondary Amyloidosis
Systemic deposition of AA amyloid derived from SAA
SAA is an acute phase reactant that is increased in chronic inflammatory states (i.e. SLE, RA, etc.), malignancy, and Familial Mediterranean Fever.
Classic clinical findings:
Kidney is most common affected organ (usually nephrotic syndrome).
Restrictive cardiomyopathy, or arrhythmias
Tongue enlargement, malabsorbtion, and h/smegaly
Dx: biopsy –> esp. abdominal fat pad and rectum
Damaged organs must be tranplanted –> can’t be removed.
Familial Mediterranean Fever
Dysfunction of neutrophils (AR); occurs of Mediterranean origin
Presents w/ episodes of fever and acute serosal inflammaiton (i.e.pericarditis, arthritis)
High SAA during attacks depostis AA
Senile cardiac amyloidosis
Non-mutated serum transthyretin deposits in heart
Usually asymptomatic
Present in 25% of individuals >80y.o.
Familial Amyloid Cardiomyopathy
Mutated serum transthyretin deposits in heart
Leads to restrictive cardiomyopathy
5% of AA carry mutated gene
Non-insulin dependent DM II
Amylin deposits in the islets of the pancreas
Derived from insulin
Alzheimer’s disease
Abeta deposits in brain, forming amyloid plaques
Derived from Beta-amyloid precursor protein (on chromosome 21 –> early onset alzheimer’s in Down’s
Dialysis-associated amyloidosis
Beta2-microglobulin deposits in joints in dialysis patients.
Medullary carcionoma of thyroid
Calcitonin deposits within tumor
Tumor of C-cells
i.e. fine needle biopsy of thyroid mass will show tumor cells w/ amyloid background.
