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Alcohol and the Liver





ALCOHOL/ACETOMENOPHEN INJURY
--never use tylenol for hangovers: NEVER!!!
--alcohol impairs hepatic metabolism of methionine-->decreased intrahepatic glutathione
--glutathione = GSH is major antioxidant, so without it the liver can sustain oxidative injury
--alcohol induces cytochromes P-450 and increases catabolism of alcohol in the endoplasmic reticulum, (the more you drink the more you can drink) and that same pathway also increases conversion of acetomenophen to toxic metabolites
--P-450 metabolism produces reactive oxygen species that react with cellular proteins, damage membranes and change function of liver cells
--women have lower levels of gastric alcohol dehydrogenase and are more susceptible than men

ALCOHOLIC LIVER DZ
--alcohol is the 5th leading cause of death in the US, many related to automobile accidents
--40% of cirrhosis deaths are attributed to alcohol
--three forms of alc liver dZ: hepatic steatosis, alcoholic hepatitis, and cirrhosis
--the first two conditions may develop independently, so these are not a continuum
--alcohol directly affects microtubular and mitochondrial function and membrane fluidity
--alcohol interferes with mitochondrial and microsomal function-->lipid accumulation
--alcohol metabolized-->acetaldehyde-->acetate
--acetaldehyde = a reactive oxygen species = ROS-->lipid peroxidation-->oxidative damage
--following even moderate intake of alcohol, microvesicles of lipid accumulate in hepatocytes
--with chronic intake lipids accumlate into large clear macrovesicular globules which compress the organelles and displace the nucleus to the periphery of the hepatocyte
--MORPHOLOGY of STEATOSIS: fatty liver is large (4-6kg), soft, yellow and greasy
--fatty change is reversible with abstention from alcohol, and adequate nutrition
--steatosis may become evident as hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase OR there may be no clinical or biochemical evidence at all
--severe hepatic dysfunction unusual at this stage
--HEPTATITIS appears relatively acutely often after a BINGE: bout of drinking, symptoms range from mild to fulminant hepatic failure
--S/Sx: malaise, anorexia, wt loss, upper abdominal discomfort, tender hepatomegaly, hyperbilirubinemia, elevated alk phos, and mb neutrophilic leukocytosis
--MORPHOLOGY of HEPATITIS dt alc incl: hepatocyte sweeling and necrosis, accumulation of fat, water and prots ie keratin, deposition of hemosiderin in hepatocytes and Kupffer cells, neuts in lobule and accumulate around degenerating hepatocytes esp those wth mallory bodies. Lymphocytes and macrophages enter portal tracts and parenchyma. Inflam activates fibroblasts.
--protein accumulations become visible as eosinophilic ctoplasmic inclusions: MALLORY BODIES
--MALLORY BODIES also seen in non-alc steatohepatitis (NASH), primary biliary cirrhosis, Wilson's dz and hepatocellular tumors
--10-15% of alcoholics deveop cirrhosis, women more susceptible
--woman 2-3 drinks/day for 5 years-->may result in cirrhosis
--repeated bouts of acute alcoholic hepatitis--> cirrosis in 1/3 of pts in a few years
--with abstinence at this stage hepatitis may abate or persist/progress
--PROGRESSION: early CIRRHOSIS liver is yellow-tan, fatty and enlarged over 2kg, then shrinks, turns brown and looses fat, to under 1kg, then cirrhosis develops in 1-2 year span
--initial fibrous bands are delicate, regenerative activity--> micronodules on liver surface
--as fibrin deposition increases, fibrous septae dissect and surround nodules, nodules are scattered, larger, irregular sizes, scar tissue takes over, pale and tough
--bile stasis may follow. Mallory bodies rarely evident this late.
--S/Sx: complications of portal hypertension including hemorrhoids, variceal hemorrhage, or malaise, weakness, weight loss, loss of appetite, LATER: jaundice, ascites, peripheral edema dt impaired albumin synthesis
--stigmata of cirrhosis: grossly distended abdomen, wasted extremities, caput medusa, splenomegaly: these indicate end stage cirrhotic disease
--end stage cirrhosis looks just like cirrhosis from other causes
--cirrhosis may develop without evidence of previous steatosis or hepatitis
--end-stage alcoholic, proximate CAUSES OF DEATH:
1) hepatic coma
2) massive GI hemorrhage
3) intercurrent infx
4) hepatorenal syndrome following a bout of alcoholic hepatitis (no hepatic compromise but acute creatinine rise)
5) hepatocellular carcinomain 3-6% of cases







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