Alcohol related Liver Disease ALD = alcoholic liver disease Changes in liver that occur due to excessive consumption of alcoholic referred to as Alcoholic liver disease. It varies from fatty change to alcoholic hepatitis and cirrhosis. It is the most common form of liver disease in the US. It may be asymptomatic or symptomatic. AMOUNT OF ALCOHOL INTAKE: More = higher Data from Robbins 80 grams/day for 10-20 years = “generates significant risk” 160 grams/day for 10-20 years = “Associated more consistently with severe injury Six pack of beer = ~100 grams Four 6 oz. glasses of wine = ~90 grams Four shots of liquor = ~85 grams Fall 10 A Jalan

Alcohol related Liver Disease= Alcoholic liver disease. Describe Etiology, pathogenesis and morphological features of Alcoholic liver disease. Describe clinical features and complications of Alcoholic Liver Disease Fall 10 A Jalan

Alcohol related Liver Disease= Alcoholic liver disease. Pathological changes in liver that occur due to excessive consumption of alcohol (Ethanol) referred to as Alcoholic liver disease. Most common cause of liver injury> 2million –USA, 27000 deaths per year. ____________________________________ALD include clinical-pathological spectrum: Fatty liver (Hepatic steatosis or fatty change) Alcoholic hepatitis Fibrosis Alcoholic cirrhosis Hepatocellular carcinoma MC manifestation of ALD is fatty change. Fall 10

Alcoholic liver disease Figure 18-23 Alcoholic liver disease. The interrelationships among hepatic steatosis, hepatitis, and cirrhosis are shown, along with a depiction of key morphologic features at the morphologic level Alcoholic liver disease The interrelationships among hepatic steatosis, hepatitis, and cirrhosis Fall 10 A Jalan

Factors influence the development and severity of alcoholic liver disease: 1. Gender – women more susceptible. 2. Ethnic differences. 3. Genetic and environmental factors. 4. Co-morbi conditions-Iron overload, HBV, HCV. 5. Consumption amount of alcohol [drinking pattern] 6. Others – Obesity, dietary factor& smoking, etc Short-term ingestion- 80 gm of alcohol over one to several days generally produces mild, reversible hepatic steatosis. 160gm per day over 10-20 yrs severe liver injury. Ascites. Fall 10 A Jalan

Hepatic Steatosis-Fatty change Is the most common* type of ALD. a\w moderate intake of alcohol. Susbstrates of alcohol metabolism are used to synthesize liver triglycerides. Characterized initially by: Accumulation of small lipid droplets in hepatocytes- microvesicular steatosis Characterized later by: Accumulation of larger droplets of lipids causing macrovesicular type of steatosis. Liver becomes enlarged, soft and greasy and yellow. Alcohol is the MCC of fatty change in the liver: Metabolism of alcohol causes production of three substrates that contribute to the synthesis of triglycerides in the liver. [alcohol-metabolizing enzymes] These substances are: NADH + H+ (causes buildup of dihydroxyacetone phosphate  glycerol 3 phosphate (carbohydrate backbone of TG) acetate (form actyl Coa) acetyl CoA (used to make up FA) Alcohol also interferes with the synthesis of apolipoproteins (therefore VLDL) cannot be excreted and hence gets accumulated. Increased NADH inhibits beta oxidation of fatty acids in mitochondria. A Jalan

Alcoholic liver disease- Pathogenesis Alcohol is toxic by itself. Metabolism (Oxidation) of alcohol causes production of three substrates that contribute to the synthesis of triglycerides in the liver: (1) Increases the ratio of reduced nicotinamide adenine dinucleotide/oxidized nicotinamide adenine di-nucleotide (NADH + H+) in hepatocytes. (2) Acetate (form actyl CoA). (3) Acetyl CoA (used to make up FA) Enzymes involved: Two major enzymes of alcohol metabolism, alcohol dehydrogenase and acetaldehyde dehydrogenase. Outcome: Impaired assembly and secretion of lipoproteins. Increased NADH inhibits beta oxidation of fatty acids in mitochondria. Excess Reactive oxygen species (ROS) 

Normal liver Liver showing fatty change And hepatomegaly Acute Fatty Change: Increase in Liver Size Liver showing fatty change And hepatomegaly Fall 10 A Jalan

Fatty change: liver Oil Red O stain for fat Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver. Most common cause for fatty change is alcoholism. Lipids , water and glycogen, all appear as clear spaces within cells. Stain for lipid : Oil red O and Sudan IV Stain for glycogen : PAS Water does not stain with any stain. Fall 10 A Jalan 9

Hepatic Steatosis-Fatty change Clinical finding and lab findings: Tender hepatomegaly without fever or neutrophilic leukocytosis. Condition is reversible - if alcohol consumption stops. No evident fibrosis seen Increased transaminases* (AST>ALT) Fall 10 A Jalan

Alcoholic Hepatitis (Alcoholic Steatohepatitis) Acute inflammation with fibrosis is found in 15% of alcoholic liver diseases.. The disease is still reversible, but many patients who continue drinking develop cirrhosis. Is associated with bouts of heavy drinking in excess of 100g/day for more than a year.

Alcoholic hepatitis Pathogenesis Pathogenesis: uncertain Acetaldehyde (the major intermediate metabolite of alcohol) is a metabolic product of alcohol. It adduct\complexes with a protein to form a complex. The complex Damages hepatoctyes and hepatocyte cytoskeleton Stimulates collagen synthesis by Ito cells* around the central vein resulting in Perivenular fibrosis* Damaged hepatocytes release chemo-attractants for neutrophils  Cause further damage  hepatitis Acetaldehyde (the major intermediate metabolite of alcohol) induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function. Cytochrome P-450 metabolism produces reactive oxygen species (ROS) that react with cellular proteins, damage membranes, and alter hepatocellular function Fall 10 A Jalan

Alcoholic Hepatitis (Alcoholic Steatohepatitis)- Morphology Gross findings: Liver is enlarged (hepatomegaly) and tender. Microscopic findings: Hepatocyte swelling Focal liver cell necrosis. Mallory bodies* -characteristic Damaged cytokeratin intermediate filaments in hepatocytes Fatty change Neutrophilic infiltration Perivenular fibrosis* : fibrosis developing around terminal hepatic venule  by prominent activation of sinusoidal stellate cells and portal tract fibroblasts. Is characterized by liver cell necrosis In the centrilobular region. Mallory body: these inclusions are characteristic but not entirely specific for alcoholic hepatitis

Alcoholic Hepatitis: The hallmark is the presence of neutrophils surrounding necrotic hepatocytes + Mallory bodies. Fall 10

Alcoholic hepatitis Neutrophils Mallory body Figure 18-25. A, The cluster of inflammatory cells marks the site of a necrotic hepatocyte. A Mallory body is present in a second hepatocyte (arrow). Figure 18-25 Alcoholic hepatitis. B, Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous tissue Alcoholic hepatitis Neutrophils Mallory body Fall 10 A Jalan

Perivenular fibrosis

Alcoholic hepatitis- clinical features Patients present with: Fever, jaundice Painful hepatomegaly Absolute Neutrophilic leukocytosis. Other findings: Macrocytic anemia ( due to folate deficiency). Abnormal coagulation tests ( prolonged PT) Lab findings: Increased Transaminases : AST>ALT. Markedly increased GGT- enzyme induction by alcohol. Elevated total bilirubin. Ascites. Fall 10 A Jalan

Alcoholic hepatitis complications Clinical complications: In end-stage alcoholic causes of death are Hepatic encephalopathy- hepatic coma. Inter-current infection. Alcoholic cirrhosis. Massive GIT bleeding. Hepato-renal syndrome Hepatocellular carcinoma Other findings: Macrocytic anemia ( due to folate deficiency) Absolute neutrophilic leukocytosis Abnormal coagulation tests ( prolonged PT) Fall 10 A Jalan

Alcoholic cirrhosis Final and largely irreversible form of ALD. May develop in 1 and 2 yrs- as complication of Viral hepatitis. Irregularly brown shrunken liver with nodularity. Initially the developing fibrous septa are delicate and extend through sinusoids from central to portal regions as well as from portal tract to portal tract. Regenerative activity of entrapped parenchymal hepatocytes generates uniform micronodules. Manifests as chronic liver disease: Jaundice and Hypoalbuminemia etc. Fall 10

The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring. The greenish tint of some nodules is due to bile stasis Figure 18-26 Alcoholic cirrhosis. A, The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring. The greenish tint of some nodules is due to bile stasis. A hepatocellular carcinoma is present as a budding mass at the lower edge of the right lobe (lower left of figure). Fall 10 A Jalan Alcoholic cirrhosis

The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top (Masson trichrome). Figure 18-26 Alcoholic cirrhosis. B, The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top (Masson trichrome). Alcoholic cirrhosis Fall 10 A Jalan