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Question 1

A/1 Causes, morphology and mechanisms of cell necrosis.

Answer 1

Necrosis is a form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell.

Causes:

1. Oxigen deprivation: Hypoxia, ischemia
2. Infectious agents
3. Physical agents: radiation, temperature
4. Immunologic ractiton
5. Aging: telomeres

Morphology:

1. Eosinophilia
2. Glassy appearance
3. Vaculated appearance
4. Myelin figures
5. Membrane fragmentation
6. Nuclear changes: Karyolysis, karyrorrhexis, pyknosis

Mechanisms:

1. ATP depletion
2. Mitochondrial damage
3. Ca⁺⁺ influx
4. ROS: DNA, lipids, proteins
5. Membrane damage
6. DNA damage

Types:

1. Coagulative
2. Liquifactive
3. Gangrenous: Sicca, Humida
4. Caseous: Coagulative + liquifactive
5. Fat: pancrease, enzymes leak out -> Fat released (chalky white appearance)
6. Fibrinoid: Endothil damage -> fibrin leaks out -> Ag-Ab complexes combine with it.

Question 2

A/2 The causes and mechanisms of apoptosis. Apoptosis in pathologic conditions.

Answer 2

Pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.

Causes:

• Physiologic:
  
  1. Embryogenesis
  2. Hormone dependent
  3. Death of inflammatory cells
  4. Death of proliferating cells
• Pathologic:
  
  1. DNA damage
  2. Mis-folded proteins
  3. Viral infection: viral (cell cycler arrest)
  4. Atrophy

Mechanisms:

• Intrinsic:
  
  • Cell injury -> BH3 receptors -> Bcl2 effectors (Bak-Bak, Bax-Bax channels) -> Cytochrome C leaks out -> Pro-caspase -> Caspase -> activation of effector caspase 3,6,7.
  • Regulated by Bcl-2
• Extrinsic:
  
  • Fas/TNF -> FaDD-> Pro-caspase -> Caspase -> activation of effector caspase 3,6,7.

Morphology:

1. Apoptotic bodies (Contain organels) -> undergo phagocytosis
2. Eosinophilic cytoplasm
3. Nuclei changes: Karyorrhexis
   4.

Question 3

A/3 Coagulative necrosis, organ manifestations

Answer 3

architecture is preserved. firm. denaturation of the proteins and enzymes -> coagulated. inflammatory cells migrate and digest.

Infarct: ischemic necrosis caused by occlusion of the arterial supply or the venous drainage.

• white (anemic) infarct:
  
  • Solid organs
• red (hemorrhagic) infarct: occurs in:-
  
  1. Venous occlusion
  2. Loose tissues
  3. Dual circulation
  4. Reperfusion

Organ manifestation:

Anemic:

• Kidney + spleen:
  
  • obstraction of an end artery
  • thromboemboli (usually from the heart - aneurysme/fibrilation)
  • Wedge shaped, pale, necrotic area.
  • Inflammatory response -> fibrotic scar
  • In kidney: Might lead to hypertension (renin-angiotensin-aldosteron).
• Gangrena sicca:
  
  • Atherosclerosis in extrimities
  • Mummification (might fall off)
  • Claudicartion intermittans
• AMI:
  
  • .

Hemorrhagic:

• AMI:
  
  • .
• Pulmonary:
  
  • ​Usually from DVT
  • Morphology depends on size:
    
    • Large -> hypoxia -> R sided HF -> death
    • Small -> damage to endothelial + pulmonary hemorrhage
  • Bronchial circulation can prevent.
  • Affects lower lobes
  • Wedge shaped, Red-blue -> 48 Hr -> red-brown (hemosiderin)
  • Final stage: fibrous replacment -> whitish scar.
• Intestinal:
  
  • ​Superior mesenteric-> duodenum + jejunum
  • Inferior mesenteric -> no infarct
  • Portal (hypercoagulability) -> entire intestine
  • Transmural -> 24 hr -> Bacteria -> gangrene -> perforation
  • Mural (mucosa + sub-mucosa) - > Multi focal lesions -> Edematorious thickening of the mucosa + Inflammation due to bacterial superinfection
  • Mucosal -> bacterial superinfection
  • Abdominal pain + bloody diarrhea

Question 4

A/4 Liquefactive necrosis, organ manifestations

Answer 4

enzymes are active and digest the tissue. seen in bacterial and fungal infection. heterolysis. autolysis. the tissue transforms into a liquid viscous mass. if initiated by an acute inflammation -> pus.

Anemic

Gangrene humida:

• infection superimposed the necrotic tissue.
• No immune.
• Microbe’s enzymes digest the tissue

Cerebral infarct:

• Thrombosis / Embolism (carotid atheroscelrosis / heart)
• Morphology:
  
  • Encephalomalacia alba: anemic progress to:
  • Encephalomalacia flava: liquifactive necrosis
  • Cysta post encephalomalacia: astrocytes around the cyst

Pulmonary abscesses:

• suppurative necrosis -> formation of cavities with pus surrounded by inflammatory cells.
• Morphology:
  
  • Aspiration -> Right: Upper lobe/upper part of lower lobe
  • Pneumonia / Bronchial obstraction -> Multiple, basal and diffusely scattered.
  • Septic / hematogenous spread -> multiple and everywhere
• Bloody and purulent sputum
• Consequences:
  
  • Rapture to the A.W
  • Bronchopleural fistula -> pneumotorax + empyema

Hemorrhagic:

• Encephalomalacia Rubra due to:
  
  • Reperfusion
  • thromb us in a vein
  • border line necrosis

Question 5

A/5 Acute myocardial infarction

Answer 5

Pathgenesis:

• Fixed coronaries + dynamic changes
  
  • Fixed coronaries - 70-75% due to atherosclerosis
  • Dynamic changes - disruption of the plaque (intra plaqueal hemorrhage, erosion, rapture) -> Platelet AAA -> ADP, TXA2, serotonin -> Vasospasem -> occlusion => ischemia
• ischemia -> ATP decrease -> pH decrease -> loss of contractility + reversible changes. (after 30_min -> irreversible)
• “Wavefront theory”: subendocardial affeceted first (Higher pressure & contrasction compresses capillaries) => transmural in 3-6 hours (theraputic window)

Morphology:

• According to the
• 0-0.5:
  
  • EM - swollen myofibers and swollen mitochondria
• 0.5-4:
  
  • EM - swollen myofibers and swollen mitochondria
  • Diaphorase reaction (DH)
• 4-12:
  
  • Coagulative necrosis starts -> Eosinophilia
  • Pale myocardium
• 12-24:
  
  • Nuclear changes
  • Dissociation of the organelles
• 2-3 day:
  
  • Reddish border line -> migration of PMNI
  • Macrophage system -> starts to dissolve the tissue
• 3-7 days:
  
  • Yellow myocardium (lipid deliberation)
  • Myomalacia (weakening of the texture of the myocardium)
• 7-30 days:
  
  • Regeneration, capillary proliferation.
  • fibroblasts ingrow from the capillaries and collagen deposits
  • Scar formation (firm whitish tissue)

Reperfusion methoods: ballon (w/wo stent), thrombolysis (tPA, streptokinase), bypass

• Reperfusion injuries: ROS, Ca⁺⁺ influx, Hemorrhage.

Clinical features:

• Substernal crushing pain + radiation - not relived by nitroglycerin. dyspnea, diaphoretic.
• ECG - ST elevation, Q-wave
• Serum levels of: CK-MB, Troponin T, Troponin I.

Consequnces: (CAMP CART)

• Cardiogenic shock
• Arrythmias
• Myocardial apture
• Pericarditis
• CIHD
• Aneurysm
• Reinfarction
• Thrombos formation

Question 6

A/6 The morphology and mechanisms of reversible cell injury, examples

Answer 6

Morphology and Mechanisms:

• Cellular swelling:
  
  • ATP decrease -> pump function decrease -> swelling
  • Vacuoles of pinched-off segments of ER.
• Fatty changes:
  
  • Accumulation of TAG
  • Fat vacuoles appear around the nucleus, pushon it aside
  • Reasons:
    
    • Starvation: increase fat mobilization
    • Hypoxia: Decrease oxidation
    • Alcohol: Decrease NAD⁺ (decreased oxidation)
    • Obesity
  • Microscopic changes:
    
    • Plasma membrane alterations
    • Mitochondrial swelling (phospholipid-rich amorphous densities)
    • Dilation of ER + ditachment of ribosomes
    • Clumping of chromatin

Examples:

• Hepatic steatosis:
  
  • Diffused
  • Reduced NAD; imparied lipoproteins.
  • Alcohol is the main reasone; DM (insulin resistance -> Fat intake)
  • Morphology: Vacules, displace the nucleus; enlarged liver (4-6kg), soft, yellowish, tense capsule.
  • Revarsible until fibrosis developes, start, around the central vein -> cirrhosis (oblitiration of the nodules creats scar tissue)
  • Nutmeg liver
    
    • Spotty, not diffused
  • Tiger heart
    
    • Hypoxia
    • Due to anemia, CO, COPD
  • Fatty heart
    
    • Fat arround the cells (in the Right side)

Question 7

A/7 Pathomorphology and complications of atherosclerosis

Answer 7

Chronic inflammatory response due to non denuding endothelial injury.

Risk factors

• Environmental than genetic
• Multiplication effect - exponential increse
• Major constitutional (non modifiable)
  
  • Age (40-60)
  • Sex (female premenopausal)
  • Genetics
• Major Modifiable
  
  • Hyperlipidemia
  • Smoking 1pack/day * 200
  • Hypertension
  • Diabetes
• Additional
  
  • ​Obesity
  • Lack of exercise
  • Stressful life

Pathogenesis

Non denuding EC injury -> ROS -> LDL oxidation -> Oxidzed LDL-scavenger receptor -> Macrophage become foam cells -> recruit more monocytes + ROS + release PDGF -> SMC (plaque stabilization) -> Fatty streak

Morphology

• Fatty streak - Lipid filled foam cells
• Primary plaque -
  
  • Lipid core - Cholesterol chrystals, foam cells, EMC, Cell debris, Calcium
  • Fibrous cap - SMC, EC, Collagen, neovascularization.
  • 2 shoulders - vulnerable areas of the plaque
• Secondary (complicated) plaque - THE CAR
  
  • Thrombus
  • Hemorrhage
  • Embolism
  • Calcification
  • Anurysem
  • Rupture

Prevention

• Primary prevention - exercise, hypertension control, diet, stop smoking
• Secondary prevention - Statins, aspirin, Beta blockers, Bypass.

Question 8

A/8 Amyloidosis

Answer 8

Extracellular deposits of fibrillar proteins responsible for the tissue damage (aggregation of misfolded proteins)

Proteins can be accumulated in the following way:

• Excess protein is presented to the cell (proteinuria)
• Increased protein synthesis (plasma cells)
• Cell injury. Alcohol (Mallory bodies)
• Abnormal folding of proteins (problems with chaperons)

Pathogenesis

• Misfolded proteins -> fibrilis -> 4-6 fibrils in β pleated configuration form an amyloid (resembles starch)

Important amyloid types:

• AL - precursor is immunoglobulin light chains, monoclonal B cell proliferation.
• AA - precursor is SAA normally synthesized in the liver
• Aβ - Cerebral lesions of Alzheimer disease (APP is the precursor)
• Transthyretin - binds thyroxine and retinol, deposits in the heart (Senile systemic amyloidosis)

Clasification of amyloidosis: RELIFA

• Reactive: AA type, systemic
• Endocrine: APUD-OMAs
• Localized: plasma cytoma
• Immunologic: Multiple myloma, AL type, systemic
• Falmilial: Familiar mediterinian fever, AA type, systemic
• Aging: TTR, Senile, systemic

Morphology

• Can be seen macroscopically when painted with iodine and sulfuroc acid
• Microsocpic staining - congo red
• Kidney - deposits in the peritubular area
• Spleen - Tubular or nodular
• Liver - Disses space, sinuses
• Heart - subendocardial elevations
• GI - is good for biopsy (Rectum, oral)

Clinical correlation

• Difficult to recognize (non-specific symptoms)
• Kidney failure
• Conduction disturbances
• 1 - 3 yr after diagnosis
• Amyloid can not be removed
• primary is the most common

Question 9

A/9 Exogenous and endogenous pigments

Answer 9

Exogenous: Tattoo, Carbon, Silicium

• Carbon:
  
  • Urbanic life
  • antraxosis
• Silicium -> pneumoconiosis
  
  • Phagocytosed by macrophages -> kill the macrophages -> leakage of lysosomal enzymes -> necrosis -> fibrosis -> increased lung resistance -> cor pulmonale -> Right sided heart failure
  • Types:
    
    • asymptomatic anthracosis
    • sCWP - little to no pulmonary disfunction (coal macules and nodules; upper lobe and upper of lower lobe)
    • cCWP - excessive fibrosis, lung function is compromised (Coalescence of the coal nodules)

Endogenous: Lipofuscin, hemosiderin, melanin

• Lipofuscin
  
  • Wear an tear, Brownish color perinuclear
  • Brown atrophy of the heart:
    
    • Heart is small, sharp edge, pointing downward; apical shortening, coronary are curly; brown color is seen. (this is a side affect)
• Hemosiderin
  
  • Hemoglobin derived granular pigment, yellow-brown, accumulates when there is a systemic/local excess of iron.
  • apoferrtin
  • stored in macrophages in the bone marrow, spleen and liver.
  • Prussian blue -> blue color
  • Local:
    
    • פנס בעין
    • Heart failure cells
  • Systemic:
    
    • general hemolysis
      
      • autoimmune hemolytic anemia
      • Toxic
    • All the organs become brown
  • free iron has a toxic effect (produce free radicals)
  • Hemochromatosis
    
    • Autosomal recessive (HFE gene on chromoosome 6)
    • lipid peroxidation, collagen formation, DNA damage
    • Morphology:
      
      • Liver -> cirhosis
      • Pancrease fibrosis -> DM
      • Heart -> cardiac dysfunction
      • joints -> atypical arthritis
      • Skin -> pigmentation
• Melanin:
  
  • Brown-black
  • thyrosinase enzyme
  • Alterations:
    
    • Frackels
    • Melasma: pregnant woman in the sun
    • Vetiligo
      
      • hereditary: thyrosinase enzyme
      • Autoimmune: Autoantibodies against melanocytes
    • Melanocyte nevus:
      
      • Benign congenital / acquired neoplasm
      • Junctional -> compound -> Dermal.
      • transformation leads to melanoma.

Question 10

A/10 Pathologic calcifications

Answer 10

Abnormal deposition of calcium salts + iron / magnesium

• Dystorphic calcification
  
  • associated with necrosis + aging
  • Pathogenesis:
    
    • Extracellular:
      
      • Membrane bound vesicles with Ca⁺⁺ inside -> membrane bound phosphatase -> phosphatase ions generation -> phosphate ions bind Ca⁺⁺ -> Crystal formation -> more and more (propagation)
    • Intracellular:
      
      • initiated in the mitochondria of dead/dying cells
    • Morphology:
      
      • grossly - white granules or clumps
      • Somtimes tuberculous lymph -> radio-opaque stone.
  • Diseases:
    
    • Calcifing aortic stenosis
    • arteficial valves
    • Atherosclerosis
    • Neoplasm
    • Infectious disease (tuberculosis)
• Metastatic calcificartion
  
  • Increased Ca⁺⁺ serum levels due to:
    
    • Neoplastic disease (multiple myloma _{osteoclast activation})
    • Increased PTH
    • VItamin D related
    • Renal faliure (increased phosphate retention)
  • Morphology:
    
    • Everywhere but principally affects the lung, vasculature, kidney, gastric mucosa.

Question 11

A/11 Stone formation

Answer 11

Gallstone (cholelithiasis)

• Risk factors:
  
  • Age, Gander (Women), Ethnic, heredity, decreased motility

Cholesterol stones

• Crystalline choloesterol monohydrate crystal
• Conditions for stone formation:

1. supersaturation
2. nucleation
3. hypomobility
4. Mucus hypersecretion

• Risk factors (more specific):
  
  • Demogrophy
  • Females (estrogen)
  • Obesity (weight reduction)
  • Hyperlipidemia
• Morphology:
  
  • Exclusively in the gallbladder (50-100% cholesterol):
    
    • Pure: yellow
    • Mixed with Ca⁺⁺-carbonate, phosphate, bilirubin: gray-white-blck
  • Firm. 80% radiolucent (Ca⁺⁺-carbonate are radio opaque)

Pigment stones:

• uCB
• Risk factors (more specific):
  
  • Asian
  • Chronic hemolytic syndrome
  • Biliary infection
  • GI disorders (chron, CF …)
• Morphology:
  
  • Black: sterile gallbladder, small in large quantities, crumble easily, 50-75% radiopaque.
  • Brown: Infected ducts, singly/small quantitie, soft, radiolucent

Clinical features:

• 70-80% asymptomatic throughout life
• Symptoms: pain, GB inflammation, empyema obstructive cholestasis, pancreatities.

Renal stone:

• Urolithiasis
• Types:
  
  • 80% - Calcium oxalate
    
    • 50% - Idiopathic hyperclciuria
    • 10% - Hypercalcemia -> hypercalcuria
    • 20% - Hyperuricosuria
    • High pH
  • 10% struvite (Mg, NH₃, PO₄^-3)
    
    • UTIs
  • 6-7% uric acid
    
    • Hyperuricemia (gout / leukemias)
    • Low pH
  • 1-2% cystine
• Increased urine concentration of the stone’s constituent
• Morphology:
  
  • Unilateral in 80%
  • Staghorn calculi: branching
• Clinical features:
  
  • Large stone -> asymptomatic
  • Small stone may pass the urether -> intense pain, hematouria
  • If blocks urine flow -> ulceration and bleeding
  • Patient is exposed to bacterial infection
  • Diagnosed radiologically