Medical Management of Severe Alcoholic Hepatitis

Acute alcoholic hepatitis is a clinical syndrome characterized by sudden onset of jaundice, malaise, anorexia and occasionally abdominal pain associated with fever, tachycardia, leukocytosis and other evidence of a systemic inflammatory response in an individual who has been drinking heavily within the preceding eight weeks. By definition, serum bilirubin is elevated with modest elevation in aminotransferases less than 400 iu/ml. The AST/ALT ratio is usually greater than 1.5. The term alcoholic hepatitis is also applied to histological changes of steatosis, ballooning degeneration of hepatocytes, accumulation of Mallory-Denk bodies and infiltration with neutrophils that characterize steatohepatitis.1 Although not required for the diagnosis of acute alcoholic hepatitis or decisions regarding treatment, liver biopsy can be helpful in patients in whom there are other confounding conditions.

Estimating the severity of alcoholic hepatitis in critically ill patients with high bilirubin and prolonged INR’s guides the need for anti-inflammatory treatments in addition to supportive care for these patients. Laboratory parameters provide more accurate assessment of prognosis than any clinical features. Both the Maddrey discriminant function (MDF) (greater than 32) and the Mayo model for end-stage liver disease (MELD) score (greater than 20) define severe alcoholic hepatitis and high mortality within the first 30 days with supportive treatment alone.2

Acute alcoholic hepatitis represents decompensation of underlying alcoholic liver disease in patients with recent heavy drinking. Cirrhosis is present at the time of diagnosis in almost 85 percent of patients with severe alcoholic hepatitis. Normal serum creatinine underestimates the degree of renal impairment in these patients, because muscle mass is often low due to underlying sarcopenia. Acute kidney injury develops frequently in those with severe alcoholic hepatitis and is a harbinger of progression to multi-organ failure syndrome. Pneumonia, urinary tract infections, and spontaneous bacterial peritonitis and bacteremia are also common in these patients and may develop in the second or third week. Some experts classify acute alcoholic hepatitis as a form of acute on chronic liver failure.3 Other than recent heavy drinking, the events that trigger the decompensation remain a subject of investigation.

Abstinence is critical in long-term prognosis for patients with any form of alcoholic liver disease. Unfortunately, no FDA approved medications have been proven safe to use in patients with advanced alcoholic liver disease, so treatment of the underlying alcohol use disorder should be supportive. Cognitive/behavioral approaches are helpful, but typically patients with alcoholic hepatitis are too ill to begin this treatment immediately. We actively encourage abstinence at the time of diagnosis and continue efforts to engage patients in treatment at every follow-up visit.

Enteral nutritional support in the form of a high calorie (30-40 kcal/kg body weight), high protein (1-1.5 g/kg body weight) diet is recommended and safe in patients with alcoholic hepatitis, even when accompanied by hepatic encephalopathy.4 Parenteral nutrition provided some benefit in improving biochemical parameters in clinical trials, but did not impact short-term mortality. The gut mucosal barrier in animal models of alcoholic liver disease and in patients with alcoholic hepatitis is impaired and likely contributes to infections in these patients. One of the possible benefits of enteral compared to parenteral nutrition is the favorable impact on the gut mucosa. Micronutrients, particularly zinc, may also restore gut mucosal integrity. Since most patients with alcoholic hepatitis are zinc deficient, we routinely supplement with 220 mg of zinc sulfate daily.5


Abstinence is critical in longterm prognosis for patients with any form of alcoholic liver disease.


Careful monitoring for infection, including routine blood cultures at the time of presentation is necessary because of the high risk of infection in these patients. Prompt recognition and treatment of infection is necessary, but we do not use prophylactic antibiotic treatment for more than 48 hours pending results of cultures, since broad spectrum antibiotics increase the risk of C. difficile and fungal infections. The high risk of acute kidney injury requires careful attention to fluid balance and avoidance of nephrotoxic agents, including contrast dye. Diuretic therapy in the acute stage of alcoholic hepatitis may be associated with volume depletion and decreased renal perfusion that can precipitate acute kidney injury. In the absence of pulmonary vascular congestion, we avoid diuretics for treatment of ascites and edema. We use both albumin infusion and midodrine for any patient who develops acute kidney injury. Norepinephrine infusion may be used in those with severe impairment.

In those patients not enrolled in clinical trials, we begin anti-inflammatory treatment with 32 mg of methylprednisolone daily in those with an MDF greater than 32 or MELD greater than 20. Most studies and meta-analysis suggest a benefit of glucocorticoids on survival within the first 30 days,6 but not beyond this time. However, glucocorticoid therapy increases the risk of infection beginning after the second week of treatment in those who are “non-responders” based on Lille score — a medical tool used to determine mortality risk in patients suffering from alcoholic hepatitis and not reacting to steroid therapy. The Lille score should be assessed at day seven to determine whether continued treatment is likely to be beneficial. Combining glucocorticoids with intravenous N-acetylcysteine reduced the risk of infection and improved short-term survival in one study.7 Shorter durations of treatment combined with enteral nutrition may also provide benefits in short-term survival and theoretically avoid the risk of infection seen with longer treatments. The published trials with pentoxifylline have been disappointing so we no longer use this medication outside of clinical trials in which it is combined with other drugs.

A number of new treatments are currently under investigation. These include anakinra, an interleukin 1 receptor blocker, granulocyte colony stimulating factor, amoxicillin, rifaximin, obeticholic acid, bovine colostrum and an interleukin 22 analogue.8 Improved understanding of the pathogenesis of alcoholic liver injury combined with improved recognition and prevention of complications such as infection and acute kidney injury that lead to development of multi-organ failure will hopefully improve the outcome of severe acute alcoholic hepatitis.

Dr. Mitchell received sponsorship for his travel from Gilead for a lecture he gave in China. Dr. Mitchell’s wife owns stock in J&J and Pfizer.

References
1. Crabb, D.W., Bataller, R., Chalasani, N.P. et al, Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia. Gastroenterology. 2016;150(4):785-90.
2. Mitchell, M.C., Friedman, L.S., McClain, C.J. Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017;15(1):5-12.
3. Jalan, R., Gines, P., Olson, J.C. et al, Intensive Enteral Nutrition Is Ineffective for Patients With Severe Alcoholic Hepatitis Treated With Corticosteroids. Gastroenterology. 2016;150(4):903-10 e8.
4. Moreno, C., Deltenre, P., Senterre, C. et al, High-Resolution Rectoanal Manometry for Identifying Defecatory Disorders and Rectal Structural Abnormalities in Women. Clin Gastroenterol Hepatol. 2017;15(3):412–420.5.
5. Zhong, W., McClain, C.J., Cave, M., Kang, Y.J., Zhou, Z. The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction. Am J Physiol Gastrointest Liver Physiol. 2010;298(5):G625-33.
6. Thursz, M.R., Richardson, P., Allison, M. et al, Trial S. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619-28.
7. Nguyen-Khac, E., Thevenot, T., Piquet, M.A. et al, Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365(19):1781-9.
8. Aday, A.W., Mitchell, M.C., Casey, L.C. Alcoholic hepatitis: current trends in management. Curr Opin Gastroenterol. 2017;33(3):142-8.

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