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Liver Pathology Overview (incl Hep G)





LIVER NOTES
--largest visceral gland, regenerates!! from as little as 25% to full size
--hepatocytes are unipotent stem cells: can make more of themselves
--liver disease is usually insidious onset, long time between onset and dx
--liver may injure and heal without detection
--inflam disorders dominate clinical concerns bcs many are long term
--liver involved in any blood borne infx
--besides viral infx the liver may encounter TB, malaria, Staph, salmonella, candida, amobiasis

LIVER FUNCTIONS
-metab of carbs, prots, fat
-produce bile
-detox of endo and exo-genous substances
-produce coag factors
-store glucose, B12, iron, copper
-reticuloendothelial system contains immune cells--sieve for antigens brought by portal

DOMINANT PRIMARY DZS OF LIVER
--viral hep (Hepatitis A, B, C, D, E, EBV, CMV, and yellow fever)
--non-viral hep (salmonella, candida, entamoeba histolytica, TB, malaria, TSS dt staph endocarditis)
--alcoholic dz
--non-alcoholic fatty liver
--hepatocellular carcinoma
--fulminant liver failure (toxins: benzene, amanita mushroom, acetomenophen & alcohol)

INCIDENCE
--in US 75/100,000 newly dx'd CHRONIC liver dz per year
--of those, 57% have hep C, 24% alcohol induced dz, 9% non-alc fatty liver, 4% hep B

FIVE GENERAL RESPONSES in liver dz
1) degeneration & intracellular accumulation (dt toxic or immunologic insult, hepatocytes swell or "baloon" and organelles may clump)(accumulations incl: iron/hemosiderin, copper, TG's)
2) necrosis and apoptosis (Councilman bodies are shrunken dying hepatocytes w/ fragmented nuclei, cells stain eosinophilic)(piecemeal necrosis in chronic active hep)
3) inflammaton (hepatitis is the word for liver inflam, lymphocytes do the damage in viral infx, inflam is a rxn to toxic or ischemic hepatocyte necrosis) (lymphocyts collect in portal tracts and migrate into areas of periportal parenchyma) (apoptotic hepatocytes don't incite inflam, but scavenger macrophages-Kupfer cells and monos-engulf cell frags generating localized clumps of inflam cells activating cytokine cascade)
4) regeneration (hepatocytes live a long time and proliferate when their neighbors die)(marked by mitoses, thickening of hepatocyte cords and possible disorganizatino fo parenchymal structure)
5) fibrosis (with chronic inflam fibrosis forms, scarring, irreversible)(causes problems with blood flow and perfusion, nodules of hepatocytes are isolated from each other-->cirrhosis)


HEPATITIS
--chronic hepatitis is defined as more than 6 month with histological documentation of liver inflam and necrosis
--Hep B, C, and B&D cause chronic infx
--#1 cause of hepatitis worldwide: B
--#1 cause of hepatitis in the US: alcohol
--NON-VIRAL causes of hepatitis: chronic alcoholism, Wilson's dz, alpha 1-antitrypsin deficiency, drugs and other hepatotoxins, various autoimmune dzs
--posts on hepatitis A, B, C, D, E follow this one
--mild hep = limited to portal tracts, lymphocytes, macrophages, occasional plasma cells, neuts and eos, with liver architecture preserved but individual hepatocytes necrotic, diffuse granular cytoplasm, ground glass hepatocytes

HEPATITIS G
--Hep G Virus is found in 1-2% of blood donors and has no know pathogenic activity
--HGV has been found in the sera of Hep C patients and terms and "innocent bystander" virus
--transmission of G uncertain
--causes 0.3% of the acute hepatitis in US
--infection persists for many years
--ALT is persistently abnormal
--serologic assays under development
--can be detected by RT-PCR

CIRRHOSIS
--hallmark of irreversible liver damage is deposition of fibrous tissue
--fibrosis begins at portal tracts, then periportal, followed by linking of fibrous septa btw lobules-->cirrhosis with regenerative nodules of hepatocytes growing out of a mesh of scar
--ETIO: autoimmune, hepatotoxins (carbon tetrachloride, mushrooms), drugs (acetamenophen) plus alcohol, idiopathic
--morphology of end stage cirrhosis not helpful in determining cause
--40% of deaths from cirrhosis are attributed to alcohol-induced liver dz

FULMINANT HEPATITIS
--when hepatic insufficiency progresses from onset of Sx to hepatic encephalopathy within 2-3 weeks
--12% dt viral usu hep B
--HAV infx may reactivate latent HBV with poor prognosis
--50% dt drug ahd chem toxicity (direct toxicity or secondary inflam) mc acetaminophen but also isoniazid, halothan, methyldopa
--misc other causes such as mycotoxic amanita phalloides mushroom account for the rest
--18% etio unknown
--TX: liver transplant, IV NAC
--MORPH: entire liver or only areas involved, liver may shrink to 500gm, capsule wrinkly from shrinkage, necrotic areas are muddy red, mushy with blotchy green bile stains, microscopically destruction of hepatocytes leaves collapsed reticulum and portal tracts
--mb little inflam rxn
--if pt survives a few days, mb massive inflam to begin phagocytotic cleanup
--if pt survives a week, regeneration will begin, with longer survival liver may completely regrow
--if centrilobular zonal necrosis by direct hepatotoxins or ischemia, parenchymal framework preserved
--if more massive destruction, framework is lost and regeneration is disorderly with nodular masses that do not resemble the original lobular form

NON-ALCOHOLIC NON-VIRAL LIVER DISEASES

NAFLD = NONALCOHOLIC FATTY LIVER DISEASE
--resembles fatty liver from boozin'
--men and women equally affected
--assocated with: obesity, dyslipidemia, hyperinsulinemia, insulin resistance, type 2 diabetes
--Dx: exclusion (esp of alc)
--elevated serum aminotransferases (ALT, AST, GGT) in 24% of general US pop
--AST:ALT ratio usu <1 in NAFLD
--31% of men and 16% of women have it, 31 million Americans
--MORPH: steatosis, large & small vesicles of fat mainly TG's accumulate in hepatocytes
--mild: no inflam or hepatocyte death or scarring, ASx, is it a disease state?
--now thought to account for up to 70% of chronic hepatitis of unknown cause
--contributes to progression of other dz such as hep C
--incidence of hepatocellular carcinoma associated is unknown at this time

NASH = NONALCOHOLIC STEATOHEPATITIS
--intermediate form of liver damage
--DX: BX. shows steatosis, multifocal parenchymal inflam, Mallory hyaline bodies, hepatocyte death (ballooning degeneration and apoptosis) and sinusoidal fibrosis.
--affects 2-5% of Americans
--elevations in liver enzymes with n other apparent reason for live dz (no alc, liver toxi meds or viruses)
--COMPLICATION: cirrhosis after years of subclinical progression of inflam and fibrosis

HEMOCHROMATOSIS
--accumulation of iron, deposited in parenchymal organs such as liver and pancreas, also heart (CHF), joints (arthritis), skin ("bronze diabetes")
--primary h dt genetic defect causing excessive iron absorbtion
--secondary usudt excessive administration of iron usu blood transfusions
--"bronze diabetes" is iron deposition in skin in conjuction with diabetes dt h

WILSON'S DZ
--autosomal recessive
--accumulation of copper in liver, brain, eyes
--liver bears the brunt
--fatty change mild to moderate, vacuolated nuclei and occasional focal hepatocyte necrosis
--acute hepatitis may mimick viral except for fatty changes and excess copper demonstrated by special stains (in serum, see increased Cu and decreased cerruloplasm (carrier))
--chronic hepatitis of Wilson's exhibitsmoderate to severe inflam and necrosis with macrovesicular steatosis, vacuolated hepatocellular nuclei, and Mallory bodies, plus the copper deposition seen with sepcial stains
--progresson of chronic-->cirrhosis
--EYE: Kayser-Fleischer's ring is brownish green, pathognomic for Wilson's dz




ALPHA 1-ANTITRYPSIN DEFICIENCY
--autosomal recessive
--low serum levels of this protease inhibitor
--A-AT inhibits lung elastase and other proteases released from neuts @ inflam
--deficiency can-->liver damage
--microscopic liver changes: round or oval cytoplasmic globular inclusions in hepatocytes with are prominent when prepared with special stains (PAS positive)


PRIMARY BILIARY CIRRHOSIS
--PBC
--autoimmune dz w/ T cell mediated destrx of bile ducts of liver
--chronic, progresive and often fatal
--W:M 6:1
--age 20-80, peak incident between 40-50
--histol: granulomatous destruction of medium sized intrahepatic bile ducts
--AB's to mitochondria!
--sheets of inflam cells
--S/Sx: hepatomegaly, foul smelling oily stools, xanthomas



--S/SX: xanthelasmas dt increased chol

--S/Sx: pruritis dt bile salts in skin, abdominal pain dt liver swelling
--S/Sx: later: jaundice
--LABS: elevated bili, alk phos, GGT and cholesterol
--DX: positive anti-mitochondrial antibody test, positive in up to 95% of cases

PRIMARY SCLEROSING CHOLANGITIS
--PSC
--bile ducts become inflamed, then fibrosed and scarred
--segmental stricture and dilation of bile ducts: beaded appearance with barium in biliary tree
--high incidence of coexisting inflam bowel dz, esp ULCERATIVE COLITIS
--70% of PSC pts have UC, 4% of UC pts have PSC
--stenoses, dilations, beating of intrahepatic ducts
--mb ASx, consider workup with persistently elevated alk phos
--Sx: pruritis, jaundice, progressive weakness
--Complic: cholangiocarcinoma (from bile duct epithelium)
--etio: unknown, despite assoc w/ UC
--theoretical mechanisms: toxin release from gut, immune mediated damage or ischemia

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