Alcoholic hepatitis

Overview
Alcohol associated liver disease ranges from asymptomatic fatty liver, to alcoholic hepatitis, to end-stage cirrhosis and liver failure. Many patients will remain asymptomatic during much of this progression. Alcoholic hepatitis is an inflammatory, necrotizing process in the liver that appears to contribute to the development of hepatic cirrhosis. Denial is an important component of alcoholism, so appropriate questioning and honest responses are necessary to ascertain the appropriate history. CAGE questioning (Cut down, Annoyed, Guilty, Eye opener) has been shown to be useful in predicting significant alcoholism.

Etiology
Ethanol, mostly in alcoholic beverages, is a significant cause of hepatitis. Usually alcoholic hepatitis comes after a period of increased alcohol consumption.

Alcoholic hepatitis is distinct from cirrhosis caused by long term alcohol consumption. Alcoholic hepatitis can occur in patients with chronic alcoholic liver disease and alcoholic cirrhosis. Alcoholic hepatitis by itself does not lead to cirrhosis, but cirrhosis is more common in patients with long term alcohol consumption. Patients who drink alcohol to excess are also more often than others found to have hepatitis C. The combination of hepatitis C and alcohol consumption accelerates the development of cirrhosis in Western countries.

Some alcoholics get an acute hepatitis or inflammatory reaction to the cells affected by fatty change. This is not directly related to the dose of alcohol. Some people seem more prone to this reaction than others. This is called alcoholic steatonecrosis and the inflammation probably predisposes to liver fibrosis.

Epidemiology and Demographics

 * Asians are at a reduced risk
 * Women at greater risk for equivalent EtOH doses; may relate to lower levels of gastric mucosa alcohol dehydrogenase

Risk Factors

 * Malnutrition
 * Obesity
 * Hepatotoxins
 * Coexistant liver disease
 * Particularly hepatitis B or C. Hepatitis C is more common in alcoholics, and may be more virulent in this population, associated with even greater risk of hepatoma.

Pathophysiology

 * The amount and duration of alcohol (EtOH) necessary to damage the liver is variable and relates to host factors.
 * Most patients with established liver disease continuously consume 60-80 g/day of ETOH (about 8 beers, one liter of wine, or half a pint of liquor) for 10 to 20 years. After 20 years of such behavior, most will have fatty changes, but only half will have cirrhosis.
 * Cirrhosis occurs in women at ~40gm EtOH/day for >10 years
 * Cirrhosis occurs in men at ~80gm EtOH/day for >10 years
 * Diffuse focal liver cell necrosis with polymorphonuclear, mononuclear, fatty infiltration. Neutrophilic infiltration in particular is unusual for other forms of hepatitis.
 * Mallory bodies
 * Perinuclear eosinophilic inclusions from intermediate filaments found in alcohol liver disease that can also be seen in fatty liver, primary biliary cirrhosis, hepatitis C, obesity.
 * Perivenular inflammation
 * “Ballooning” of hepatocytes results from the accumulation of fat and water.
 * Swollen hepatocytes and collagen deposition leads to increased sinusoidal pressures, and perhaps portal hypertension.
 * Perisinusoidal fat cells transform into fibroblasts.
 * Other non-essential changes that might be present include bridging necrosis, bile duct proliferation, and cholestasis.

Molecular Biology

 * Potential mechanisms of alcohol associated liver disease include:
 * ETOH generates excess NADH, which slows gluconeogenesis, increasing lactate production, and leading to fatty acid accumulation.
 * Acetaldehyde is a toxic metabolite that can impai hepatocyte function
 * Alcohol metabolism consumes oxygen and contributes to centrilobular hypoxia
 * Neutrophil infiltration – perhaps in association with reactive oxygen species
 * Other minor pathways of alcohol metabolism are upregulated in alcoholics, which may produce more dangerous oxygen intermediates. A microsomal pathway has been called the microsomal enzyme oxidation system (MEOS).  Polymorphisms of enzymes in this system (P4502E1 in particular) may contribute to the predisposition of some individuals to alcohol associated liver damage.  P4502E1 also appears to increase acetominophen metabolism to toxic metabolites, and may play a role in acetominophen associated liver disease in patients who drink alcohol.
 * Inflammation and collagen deposition in the perivenular (zone 3) region of the hepatic sinusoids and the space of Disse, impede flow, increasing pressure. Perivenular cell necrosis may be found.

Some signs and pathological changes in liver histology include: If chronic liver disease is also present:
 * Mallory's Hyaline - a condition where pre-keratin filaments accumulate in hepatocytes. This sign is not limited to alcoholic liver disease, but is often characteristic.
 * Ballooning degeneration - hepatocytes in the setting of alcoholic change often swell up with excess fat, water and protein; normally these proteins are exported into the bloodstream. Accompanied with ballooning, there is necrotic damage. The swelling is capable of blocking nearby biliary ducts, leading to diffuse cholestasis.
 * Inflammation - Neutrophilic invasion is triggered by the necrotic changes and presence of cellular debris within the lobules. Ordinarily the amount of debris is removed by Kupffer cells, although in the setting of inflammation they become overloaded, allowing other white cells to spill into the parenchyma. These cells are particularly attracted to hepatocytes with Mallory bodies.
 * fibrosis
 * Cirrhosis - a progressive and permanent type of fibrotic degeneration of liver tissue.

Differential Diagnosis

 * Presentation may be complicated by superimposed alcohol related illness:
 * Malnutrition
 * Pancreatitis
 * Vitamin deficiency
 * Cardiomyopathy
 * Other common causes of hepatitis should be considered:
 * Viral Hepatitis
 * Acetominophen or other toxins
 * Ischemia
 * Hemachromatosis

Diagnosis
The ratio of aspartate aminotransferase to alanine aminotransferase is usually > 2.

History and Symptoms
Alcoholic hepatitis is characterized by a variable constellation of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen ascites, and modest elevation of liver blood tests. Alcoholic hepatitis can vary from mild with only liver test elevation to severe liver inflammation with development of jaundice, prolonged prothrombin time, and liver failure. Severe cases are characterized by either obtundation (dulled consciousness) or the combination of elevated bilirubin levels and prolonged prothrombin time; the mortality rate in both categories is 50% within 30 days of onset.


 * Fever--if signficant, other sources should be ruled out
 * Abdominal pain--occurs in some, but should raise the suspicion for other processes, like pancreatitis or spontaneous bacterial peritonitis (SBP)
 * Nausea and vomiting
 * Anorexia
 * Weight loss
 * Hepatomegaly
 * Splenomegaly
 * Jaundice
 * Ascites
 * Transient portal venous obstruction, in addition to fixed fibrosis, likely contributes, and so ascites may improve as hepatitis recovers
 * Bleeding
 * Alcohol withdrawal
 * Stigmata of chronic liver disease
 * Spider angiomas
 * Palmer erythema
 * Gynecomastia
 * Ascites
 * Encephalopathy
 * Many acute presentations occur in patients with some degree of chronic injury

Laboratory Findings

 * AST:ALT (aspartate aminotransferase:alanine aminotransferase) classically 2:1
 * Reason for ratio not clear
 * There may be disproportional damage to mitochondria releasing AST
 * Alcoholics may have relative deficiencies of pyridoxal-6-phosphatase
 * > 300-500 worry about other hepatotoxins
 * Alkaline phosphatase, gamma-glutamyltranspeptidase (GGT) and bilirubin often rise proportionally, and may persist for weeks after transaminases normalize.
 * A leucocytosis is commonly seen. If other causes can be excluded, the degree of rise correlates with severity of hepatic injury.

Other Diagnostic Studies

 * Liver biopsy is indicated in patients with acute liver failure, and patients with persistent laboratory abnormalities for more than 6 months. Biopsy may be indicated sooner in patients without a clear diagnosis.
 * Disease staging difficult on clinical grounds. Liver biopsy is more informative

Risk Stratification and Prognosis

 * Poor prognostic factors include:
 * Leukocytosis not due to other causes
 * Hepatic fibrosis and cirrhosis
 * Ascites
 * Encephalopathy
 * Renal failure
 * Elevated bilirubin
 * Elevated prothrombin time (PT)
 * Discriminant function, as described above, is a predictor or severity.
 * DF > 32 – Mortality 35% without steroids, in patients without encephalopathy. Mortality 45% in patients with encephalopathy.
 * Abstinence appears to help slow or stop the progression of alcohol associated liver disease.
 * In patients with advanced disease, cirrhosis can develop in patients who stop, but is much more likely to develop in those patients who continue to drink.
 * Maddrey, et al #maddrey described the Discriminant Function (DF) formula to determine patients who might respond:
 * DF =  4.6  x  (PT – control PT)  +  Total Bilirubin 
 * DF > 32 has been been associated with a high death rate, up to 50% in some studies, with improved prognosis with steroid treatment.
 * A recent study showed a fall in one month mortality from 35 to 6%. Another showed a fall in six month mortality 55 to 16%.
 * Effect on long term mortality not clear

Treatment
Clinical practice guidelines by the American College of Gastroenterology recommend corticosteroids.


 * Mild disease is characteristically treated conservatively with supportive care:
 * Nutrition, thiamine, folate
 * Monitory/management of alcohol withdrawal
 * Consideration of possible infection, spontaneous bacterial peritonitis (SBP)
 * Alcoholic rehabilitation

Corticosteroids
Patients with a discriminant function score > 32 or hepatic encephalopathy should be considered for treatment with prednisolone 40 mg daily for four weeks followed by a taper.

Pentoxifylline
A randomized controlled trial found that 5 patients with a discriminant function score > 32 and at least one of palpable tender hepatomegaly, fever, leukocytosis, hepatic encephalopathy, or hepatic systolic         bruit  must be treated with pentoxifylline 400 mg orally 3 times daily for 4 weeks for one to prevent one patient from dying.

Acute Pharmacotherapies

 * In very severe disease, such as those with encephalopathy or other markers of advanced disease, treatment with steroids may improved outcome – Prednisolone 40 mg every day for 4 weeks and then tapered.
 * Possible contraindications to steroids must be considered, such as acute infection, gastrointestinal (GI) hemorrhage, etc.
 * Other considerations:
 * Acetaminophen use should be < 2gm / day
 * Fasting also increases risks of acetaminophen toxicity in alcoholics
 * Propylthiouracil (PTU) has been tried in these patients and may be moderately effective in patients who continue the treatment and discontinue alcohol.
 * Colchicine 0.6 mg by mouth, twice daily may help to slow progression of liver disease, though the data is not conclusive.

Additional Sources

 * 1) maddrey pmid=2834829 Maddrey, WC. Alcoholic hepatitis. Sem in Liv Disease 1988;9:91.
 * 2) carithers pmid=2648927 Carithers, RL, et al. Methylprednisolone therapy in patients with severe acute alcoholic hepatitis. Ann Int Med 1989;110:685.
 * 3) friedman Friedman, SL. Alcoholic liver disease. UpToDate, 1997.
 * 4) ramond pmid=1531090 Ramond, MR, et al. Randomized trial of prednisolone in patients with severe alcoholic hepatitis. NEJM 1992;326:507.
 * 5) imperiale pmid=2142869 Imperiale, TF. Do corticosteroids reduce mortality from alcoholic hepatitis. Ann of Int Med 1990;113:299.
 * 6) rosman pmid=8633498 Rosman, AS,et al. Alcoholism is associated with hepatitis C but not hepatitis B. Am J Gastroent 1996;91:498.
 * 7) mathurin pmid=8964410 Mathurin, P, et al. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroent 1996;110:1847.
 * 8) morgan pmid=8737007 Morgan, MY. The treatment of alcoholic hepatitis. Alcohol alcohol 1996;31:117.

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Hepatita Alcoolică