Alcoholic Liver Disease
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Alcoholic Liver Disease Alcoholic liver disease: A spectrum of clinical syndromes and pathologic changes in the liver caused by alcohol (ethanol).
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Pathogenesis -A linear correlation generally exists between the dose and duration of alcohol abuse and the development of liver disease -For alcoholic hepatitis, patients consume 80 g of alcohol daily for almost a decade, whereas the average threshold to develop cirrhosis is 160 g daily over 8 to 10 yr. Duration is important. -Alcohol is a hepatotoxin whose metabolism creates profound liver cell derangements. Apparent variations in susceptibility (only 10 to 15% of alcoholics develop cirrhosis) and the greater susceptibility of females (even when adjusting for smaller body size) to alcohol-induced liver disease suggest that other factors are also significant. One may be that females have decreased alcohol dehydrogenase in their gastric mucosa, lessening metabolism. -Immunologic status does not appear to help determine susceptibility to alcohol, but immunologic mechanisms (particularly cytokine mediators) may be important in the inflammatory response and in liver injury
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Metabolism of Alcohol -Alcohol is readily absorbed from the GI tract, and > 90% is metabolized by the liver through oxidative mechanisms involving mainly alcohol dehydrogenase and certain microsomal enzymes (microsomal ethanol oxidizing system). Alcohol cannot be stored and must be metabolized. -Alcohol dehydrogenase produces acetaldehyde, the major catabolite, which is further oxidized to acetate. Acetaldehyde may be toxic to the liver and other organs. The conversion of alcohol to acetaldehyde and of the latter to either acetate or acetyl coenzyme A involves the generation of reduced nicotinamide adenine dinucleotide (NADH), which shuttles into mitochondria, increasing the NADH/nicotinamide adenine dinucleotide ratio and thus the redox state of the liver. Thus, alcohol metabolism promotes a reduced intracellular state that interferes with carbohydrate, lipid, and other aspects of intermediary metabolism.
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-The oxidation of alcohol is coupled with the reduction of pyruvate to lactate, which promotes hyperuricemia(?????, ???? lactate? uric acid? ??? ??), hypoglycemia, and acidosis(???). Alcohol oxidation also is coupled with the reduction of oxaloacetic acid to malate. This may explain the reduced activity of the citric acid cycle, reduced gluconeogenesis(??? ??? ??), and increased fatty acid synthesis associated with alcohol metabolism. -Glycerophosphate increases after alcohol consumption; the glycerol produced promotes increased triglyceride synthesis and leads to hyperlipidemia. -Although O2 consumption is normal after alcohol ingestion, there is a metabolic shift from O2 consumption during the breakdown of fatty acids to the oxidation of alcohol to acetate. -This shift may explain the reduced lipid oxidation and increased ketone formation recorded after alcohol ingestion. Alcohol metabolism may also induce a local hypermetabolic state in the liver, promoting hypoxic damage in zone 3 (the area around the terminal hepatic venules). The net effect is a reduced redox state, inhibited protein synthesis, and increased lipid peroxidation.
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-Alcohol induces the microsomal ethanol oxidizing system, which is responsible in part for alcohol metabolism. Alcohol also induces microsomal P-450, which is involved in drug metabolism. Thus, the alcohol abuser acquires an increased tolerance to alcohol and drugs (eg, sedatives, tranquilizers, antibiotics), and neurologic adaptation develops. The result is a complex interaction between drugs, other chemicals, and alcohol.
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Pathology -The spectrum of hepatic pathology associated with prolonged alcohol consumption ranges from the simple accumulation of neutral fat in hepatocytes to cirrhosis and hepatocellular carcinoma. The widely accepted fatty liver-alcoholic hepatitis-cirrhosis spectrum is a concept of convenience. -Fatty liver or steatosis (see also Ch. 39) appears to be the initial change and is the most common response to alcohol ingestion. Fat accumulates in zones 3 (centrizonal) and 2 (midzonal). Fatty cysts probably represent late stages of the fatty change. -Alcoholic hepatitis includes the macrovesicular fatty change plus a diffuse inflammatory response to injury and necrosis (often focal); established cirrhosis may also be present.
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-Mallory (alcoholic hyaline) bodies are fibrillar proteins of intracytoplasmic inclusions within swollen hepatocytes; these cells contain little or no fat. With hematoxylin and eosin stain, Mallory bodies appear as irregular aggregates of purplish red material. Although characteristic of alcoholic hepatitis, Mallory bodies are also found in some cases of Wilson's disease, Indian childhood cirrhosis, cirrhosis following small-bowel bypass surgery, primary biliary cirrhosis (or other causes of prolonged cholestasis), diabetes mellitus, morbid obesity(????), and hepatocellular carcinoma. -Alcoholic cirrhosis represents end-stage disease, developing in 10 to 20% of those who are chronically heavy drinkers.
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Symptoms, Signs, and Diagnosis -Patients with a fatty liver are usually asymptomatic. In 33%, the liver is enlarged, smooth, and occasionally tender. Routine biochemical studies are often within normal limits; gamma-glutamyl transpeptidase (GGT) is often elevated. Vascular spiders(??????) and features of hyperestrogenism and hypoandrogenism from the alcoholism per se may be evident. -Patients with alcoholic hepatitis may present with fatigue, fever, jaundice, right upper quadrant pain, a hepatic bruit(??), tender hepatomegaly, and leukocytosis(??????), but so may patients with sepsis(???), cholecystitis(???), or mechanical extrahepatic biliary obstruction.
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-Cirrhosis may also be relatively asymptomatic, have features of alcoholic hepatitis, or be dominated by complications: portal hypertension with splenomegaly(???), ascites, hepatorenal syndrome(??? ???), hepatic encephalopathy, or even hepatocellular carcinoma.
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Laboratory Findings -various abnormalities of RBC morphology -elevated MCV(??????) -Thrombocytopenia(??? ???) -The activity of serum ALT is depressed (caused by a depletion of pyridoxal 5´-phosphate) relative to that of serum AST (AST:ALT ratio > 2). -The value of GGT(gamma-glutamyl transpeptidase ) lies not in its specificity but in its being markedly elevated in patients with excessive alcohol intake or alcoholic liver disease. MCV, GGT, and alkaline phosphatase are the best combination of routine tests to identify chronic alcohol abuse.
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Prognosis and Treatment With abstinence, nonfibrotic liver damage may be reversed, and the survival of patients with alcoholic hepatitis, fibrosis, and cirrhosis improves. In theory, treatment of alcoholic liver disease is simple and straightforward; in practice, it is difficult: the patient must stop drinking alcohol. Acute alcohol withdrawal requires supportive care, fluid and electrolyte balance, and sedatives (eg, benzodiazepines) carefully titrated to the severity of the withdrawal symptoms. Excessive sedation in patients with marked liver disease can precipitate hepatic encephalopathy
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The widely accepted fatty liver-alcoholic hepatitis-cirrhosis spectrum is a-Alcoholic cirrhosis rep
The widely accepted fatty liver-alcoholic hepatitis-cirrhosis spectrum is a-Alcoholic cirrhosis represents end-stage disease, developing in 10 to 20% ...