Alcoholic Liver Disease

• Three distinctive, overlapping forms of alcoholic liver injury: –Hepatocellular steatosis or fatty

change–Alcoholic hepatitis(steatohepatitis) –Steatofibrosis

• Cirrhosis develops in only a small fraction of chronic alcoholics

Morphology• Changes begin in acinus zone 3 and

extend outward toward portal tracts with increasing severity of injury

Hepatic Steatosis (Fatty Liver)

• Intake of alcohol lipid droplets accumulate in hepatocytes

• Increases with amount and chronicity of alcohol intake

• Begins as small droplets (microvesicular) coalesce into large droplets(macrovesicular)

• Macroscopically liver is large (4 to 6 kg), soft, yellow and greasy.

• Fatty change is completely reversible if there is abstention from further intake of alcohol

Alcoholic Hepatitis (Steatohepatitis)

• Characterized by:1. Hepatocyte swelling and

necrosis: Single or scattered foci of cells

undergo swelling (ballooning) and necrosis

Swelling results from accumulation of fat and water, & proteins that are normally exported.

2. Mallory-Denk bodies: Present as clumped, amorphous,

eosinophilic material in ballooned hepatocytes

Made up of tangled skeins of intermediate filaments keratins 8 and 18 in complex with other proteins such as ubiquitin

Characteristic but not specific feature of alcoholic liver disease, also present in non-alcoholic fatty liver disease and in periportal distributions in Wilson disease and in chronic biliary tract diseases.

3. Neutrophilic reaction: Neutrophils permeate hepatic

lobule and accumulate around degenerating hepatocytes, having Mallory-Denk bodies

may be admixed with mononuclear cells

Alcoholic steatofibrosis• Activation of sinusoidal stellate cells

and portal fibroblasts, giving rise to fibrosis

• Begins with sclerosis of central veins • Perisinusoidal scar then accumulates

in space of Disse of centrilobular region, spreading outward, encircling individual or small clusters of hepatocytes in chicken wire fence pattern

• Webs of scar eventually link to portal tracts and then begin to condense into central-portal fibrous septa.

• With developing nodularity, cirrhosis becomes established

• Micronodular or Laennec cirrhosis end-stage alcoholic liver disease

Pathogenesis• Daily intake of >/=80 gm of ethanol

generates risk for severe hepatic injury and ingestion of >/=160 gm for 10 to 20 years is associated more consistently with severe injury

• Only 10% to 15% of alcoholics develop cirrhosis

• Other factors also influence development and severity of alcoholic liver disease. These include:–Gender: Women more susceptible

to hepatic injury than men –Related to alcohol pharmacokinetics

and metabolism, and estrogen-dependent response to gut-derived endotoxin (LPS) in liver

• Ethnic and genetic differences: In US, cirrhosis rates are higher for African American drinkers than for white Americans drinker.

• Genetic polymorphisms in detoxifying enzymes and some cytokine promoters may play significant roles

• Comorbid conditions: Iron overload and infections withHCV and HBV synergize with alcohol

• Hepatocellular steatosis results from:1. Increased lipid biosynthesis

resulting from increased generation of reduced nicotinamide adenine dinucleotide (NADH) by enzymes of alcohol metabolism, alcohol dehydrogenase and acetaldehyde dehydrogenase

2. Impaired assembly and secretion of lipoproteins

3. Increased peripheral catabolism of fat, releasing free fatty acids into circulation.

Cause of alcoholic hepatitis

• Acetaldehyde induces lipid peroxidation and acetaldehydeprotein adduct formation, disrupting cytoskeletal and membrane function.

• Cytochrome P-450 metabolism produces reactive oxygen species that react with cellular proteins, damage membranes, and alter hepatocellular function

• Alcohol impairs hepatic metabolism of methionine decreases glutathione levels sensitizing liver to oxidative injury.

• Induction of cytochrome P-450 enzymes enhances conversion of other drugs (acetaminophen) to toxic metabolites.

• Alcohol causes release of bacterial endotoxin from gut into portal circulation, inducing inflammatory responses in liver

• Alcohol stimulates release of endothelins from sinusoidal endothelial cells, causing vasoconstriction and contraction of activated myofibroblastic stellate cells, leading to decrease in hepatic sinusoidal perfusion

Clinical Features• Hepatic steatosis hepatomegaly,

with mild elevation of serum bilirubin and alkaline phosphatase levels

• Alcoholic hepatitis range from minimal to those that mimic acute liver failure

• Nonspecific symptoms malaise, anorexia, weight loss, upper abdominal discomfort, and tender hepatomegaly

Laboratory findings

• Hyperbilirubinemia• Elevated serum aminotransferases

and alkaline phosphatase• Neutrophilic leukocytosis• Serum AST:ALT levels - 2:1

Complications• Hepatic coma• Massive gastrointestinal hemorrhage• Intercurrent infection • Hepatorenal syndrome • Hepatocellular carcinoma