Hepatitis, Alcoholic

Article Author:
Niraj Shah
Article Editor:
Savio John
Updated:
12/1/2017 1:26:32 PM
PubMed Link:
Hepatitis, Alcoholic

Introduction

Excessive alcohol consumption could result in alcoholic, fatty liver disease or steatosis, alcoholic hepatitis (AH), and eventually cirrhosis. Alcoholic hepatitis is a severe syndrome of alcoholic liver disease (ALD), characterized by rapid onset of jaundice, malaise, tender hepatomegaly, and with subtle features of systemic inflammatory response. The recent worsening profile and trends of patients with AH related hospitalizations in the United States suggest its importance in the current realm of clinical practice with its subsequent management.

Etiology

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), Alcoholic Hepatitis Consortia defines AH to include the following:

  • The onset of jaundice within 60 days of heavy alcohol consumption (more than 50 g/day) for a minimum of 6 months
  • with serum bilirubin more than 3 mg/dL
  • elevated aspartate aminotransferase (AST) to 50 U/L to 400 U/L 
  • AST: ALT (alanine aminotransferase) ratio more than 1.5, and
  • No other cause of acute hepatitis. 

While using the terminology alcoholic hepatitis, it is important to understand the difference between alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH). About 20% to 40% of those who drink alcohol in heavy amounts and have fatty liver eventually develop liver inflammation, which is known as ASH. ASH is a diagnosis based on liver histology, while AH is a clinical diagnosis. The typical features of ASH on liver biopsy are steatosis, hepatocyte ballooning, infiltration of neutrophils, Mallory-Denk hyaline inclusions and zone 3 perivenular injury with pericellular fibrosis or chicken-wire pattern of fibrosis. AH, on the other hand, is characterized by history of chronic heavy alcohol consumption until at least 3 to 4 weeks before the onset of jaundice, fever, tachycardia, tachypnea, hepatomegaly, leukocytosis with neutrophilia, and an AST: ALT elevation greater than 1.5:1 with the absolute value of AST/ALT typically never exceeding 500 U/L. AH can occur in patients with any stage of the alcoholic liver disease.

Although the amount of alcohol ingested is the most important risk factor for the development of chronic liver disease, the progression to alcohol-induced chronic liver disease is neither dose-dependent nor is the correlation with the quantity of alcohol consumed and liver injury linear. Even shorter durations of alcohol abuse could lead to AH. A typical patient would be between 40 to 60 years of age with a history of more than 100 g/day of alcohol consumption for a decade, in whom you have ruled out other causes of acute hepatitis. Risk factors include a high BMI (body mass index), female sex, and having a genetic variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3). Clinical jaundice is a poor prognostic factor. Acute binge drinking is likely the trigger for AH in patients with a history of chronic, heavy alcohol abuse.

Epidemiology

Approximately two-thirds of adults in the United States drink alcohol, while 7.2% suffer from alcohol use disorder (AUD). Excessive alcohol intake is the third leading preventable cause of death in the United States. A 10-year survey, from 2001 through 2011 from 211 hospitals revealed a 0.08% to 0.09% admissions related to alcoholic hepatitis.

Pathophysiology

Alcohol undergoes an oxidative metabolic pathway in the hepatocytes, leading to a reduced ratio of the nicotinamide adenine dinucleotide (NAD) to NADH. This promotes lipogenesis by inhibiting oxidation of triglyceride and fatty acids.

Another known mechanism of alcohol-induced liver injury is the translocation of endotoxins in the form of lipopolysaccharides (LPS), from the intestines into the hepatocytes. In the hepatic Kupffer cells, the LPS binds to CD 14 and toll-like receptor 4 to release a barrage of reactive oxygen species (ROS). The ROS activates the release of cytokines such as tumor necrosis factor alpha (TNF alpha), interleukin-8, monocyte chemotactic protein 1 (MCP-1) and platelet-derived growth factor (PDGF), all of which leads to accumulation of neutrophils, macrophages and systemic clinical features of alcohol injury.

Recent studies indicate patients with specific intestinal dysbiosis been increasingly susceptible to alcoholic liver disease and AH.

Histopathology

A liver biopsy is generally not required, except in uncertain cases to delineate the etiology of the hepatic injury. The classical histological features include steatosis, hepatocellular ballooning representing steatohepatitis, cholestasis, chicken-wire fibrosis, cirrhosis in severely ill patients, neutrophilic and lymphocytic infiltration, and Mallory-Denk bodies.

History and Physical

The clinical presentation ranges from mild to severe. A mild clinical presentation would be a patient presenting with fever, right upper quadrant pain or discomfort and elevations in aminotransferases that normalizes with sobriety. While a severe presentation would include jaundice, ascites, hepatic encephalopathy, and coagulopathy.

Evaluation

The differential diagnosis of AH includes nonalcoholic steatohepatitis, acute or chronic viral hepatitis, drug-induced liver injury, fulminant Wilson’s disease, autoimmune liver disease, alpha-1 antitrypsin deficiency, pyogenic hepatic abscess, ascending cholangitis or decompensation associated with hepatocellular carcinoma. The diagnosis of AH is a clinical one with supporting laboratory findings of AH. All patients should have had an abdominal imaging study to exclude biliary obstruction and liver diseases such as hepatocellular carcinoma and liver abscess.

Several trials and models exist to determine the severity of alcoholic hepatitis, to ascertain which patients would likely benefit from a pharmacological approach. In 1977, the Maddrey discriminant factor (MDF), included serum total bilirubin and prothrombin time to segregate patients with a 28-day mortality risk of greater than 50%. These patients had an MDF greater than 32 and were deemed to benefit from steroid therapy. Subsequent scoring systems included the model for end-stage liver disease (MELD) score, the ABIC score (including the age, bilirubin, international normalized ratio and the creatinine score), the Glasgow AH score (including the age, bilirubin, international normalized ratio, blood urea nitrogen and the peripheral white blood count) and the Lille score. The Lille score obtains data from the beginning and end of the first week of steroid therapy to assess response and subsequent need for further steroid therapy. A histological scoring system for the prognosis of patients with alcoholic hepatitis has also been proposed. Various combinations of scoring systems have been studied to predict outcomes accurately, and the combination of the MELD and the Lille score is one. 

Treatment / Management

Abstinence along with adequate nutritional support remains the cornerstone of management of patients with AH. An addiction specialist could help individualize and enhance the support required for abstinence. About 10% to 20% of patients with AH are likely to progress to cirrhosis annually, and 10% of the individuals with AH have regression of liver injury with abstinence.

Patients with AH are subdivided into mild-moderate AH or severe AH. Patients with an MDF greater than 32, MELD score greater than 20, ABIC score category C, or a Glasgow AH score of 9 predicts higher mortality with a diagnosis of severe AH. Patients with severe AH with or without hepatic encephalopathy are considered candidates for a short course of prednisolone (40 mg/day for 28 days). Prednisolone is preferred to prednisone as it does not require metabolism in the liver for its therapeutic efficacy. For patients unable to take it orally, methylprednisolone, 32 mg intravenously daily, is an option. However, failure to respond to steroids within a week evident by a Lille score of greater than 0.45 indicates lack of response to steroids which then should be discontinued. For patients with a Lille score of less than 0.45 (Lille responders), prednisolone should be continued for another three weeks. Glucocorticoids alter the expression of anti-inflammatory genes, thus promoting its anti-inflammatory role. Contraindications to steroid use include any active gastrointestinal (GI) bleeding, severe pancreatitis, uncontrolled diabetes, active infection or renal failure. Such patients may be managed with pentoxifylline (400 mg orally, three times a day for 28 days). Hepatorenal syndrome is one of the major causes of death in patients with AH. Patients with acute kidney injury or hepatorenal syndrome respond poorly to corticosteroid therapy. Patients with bacterial infection may be treated with corticosteroids after the infection has been appropriately controlled with antibiotics. Response to prednisolone is graded as complete if Lille score is less than 0.16, partial if Lille score is between 0.16 and 0.56), or null if Lille score is greater than 0.56. A Lille score of more than 0.45 after 1 week of corticosteroid therapy is associated with 75% mortality at 6 months.

Many recent trials, including the STOPAH trial and meta-analysis of the use of steroids and Pentoxifylline, reveal only short-term (28-day) mortality improvements with not much difference of 6-month, or 1-year mortality. In STOPAH trial, however, patients with less severe AH were included, and most patients were recruited with a clinical diagnosis of AH. Thus it is possible that patients with decompensated alcoholic cirrhosis may have received a diagnosis of AH, which significantly alters the result of the trial. Anti-TNF (tumor necrosis factor) agents like Infliximab and Etanercept have been used with no proven survival benefits. Anti-TNF agents may even increase the incidence of infections and death.

Patients with AH are prone to infections, especially when on steroids. This is in particularly important as it might lead to a poor prognosis, acute renal injury, and multi-organ dysfunction. Patients with AH are at risk of alcohol withdrawal. Lorazepam and oxazepam are the preferred benzodiazepines for prophylaxis and treatment of alcohol withdrawal. Daily caloric intake should be documented in patients with AH, and nutritional supplementation (preferably via mouth or NG tube) should be considered if oral intake is less than 1200 kcal in a day.

A liver transplantation could be considered for patients not responsive to steroids and with a MELD of greater than 26. However, varied barriers including fear of recidivism, organ shortage, and social and ethical considerations exist. A survey of liver transplant programs conducted in 2015 revealed only 27% of the programs offering a transplant to AH patients. Of the 3,290 liver transplants performed 1.37% were on AH patients. The six month, one year and 5-year survival was 93%, 93% and 87% respectively, the outcomes of which are comparable to patients with similar MELD scores. The recidivism rates are similar (17%) to patients transplanted for alcohol-related cirrhosis.

Prognosis

Patients with severe alcoholic hepatitis with an MDF greater than 32 have a 30-day mortality of 30% to 50%. Forty percent of the patients with severe alcoholic hepatitis die within 6 months after the onset of the clinical syndrome. Jaundice and hepatic encephalopathy at the time of presentation indicate a poorer outcome.

Pearls and Other Issues

The combination of systemic illness, malnutrition, concurrent renal injury, infections, lack of response to glucocorticoids or pentoxifylline result in poorer outcomes in severe AH. Further understanding of the pathophysiology of alcohol-induced liver injury, early recognition, including complications and potentially better pharmacological approach could in future improve clinical outcomes in patients with severe AH. A better understanding of alcohol-related liver injury, inflammation, liver fibrosis, and liver regeneration and associated gut-barrier permeability and dysfunction, along with newer pharmacological breakthroughs to treat AH would likely improve our present management strategies.