Alcohol-Associated Hepatitis

Etiology

The National Institute on Alcohol Abuse and Alcoholism Alcoholic Hepatitis Consortia defines alcohol-associated hepatitis based on the following criteria:

• Onset of jaundice within 60 days of heavy alcohol consumption (>50 g/d) for a minimum of 6 months
• Serum bilirubin level >3 mg/dL
• Elevated aspartate aminotransferase (AST) level of 50 to 400 U/L 
• AST to alanine aminotransferase (ALT) ratio >1.5
• No other cause of acute hepatitis

The National Institute on Alcohol Abuse and Alcoholism classified alcohol-associated hepatitis into 3 categories: definite disease (based on histological diagnosis), probable disease (based on the above criteria), and possible disease (when another etiology might be present). When using the term alcohol-associated hepatitis, clinicians should understand the difference between alcohol-associated steatohepatitis and alcohol-associated hepatitis. Approximately 20% to 40% of individuals who consume alcohol in excess develop hepatic steatosis and eventually liver inflammation, known as alcohol-associated steatohepatitis. Alcohol-associated steatohepatitis is a diagnosis based on liver histology, whereas alcohol-associated hepatitis is mostly a clinical diagnosis. Typical features of alcohol-associated steatohepatitis on liver biopsy include steatosis, hepatocyte ballooning, neutrophil infiltration, Mallory-Denk hyaline inclusions, and zone 3 perivenular injury with pericellular fibrosis or a chicken-wire pattern of fibrosis. Alcohol-associated hepatitis is characterized by a 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 to ALT ratio greater than 1.5:1, with the absolute AST or ALT values typically never exceeding 400 U/L. Alcohol-associated hepatitis can occur in patients with any stage of alcohol-associated 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-associated chronic liver disease is neither dose-dependent nor is the correlation between the quantity of alcohol consumed and liver injury linear. Even shorter durations of excessive alcohol intake can lead to alcohol-associated hepatitis. A typical patient has a history of more than 50 to 60 g/d (40 g/d for women) of alcohol consumption for more than 6 months, after clinicians have ruled out other causes of acute hepatitis. Risk factors include a high body mass index, female sex, and a variant in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3). Clinical jaundice is a poor prognostic factor. Acute binge drinking is likely the trigger for alcohol-associated hepatitis in patients with a history of chronic, heavy alcohol use.[7][8][9][10]

Epidemiology

Approximately 85% of adults in the United States have consumed alcohol at some point in their lifetime, whereas 10.9% had alcohol use disorder in the past year, based on the 2023 National Survey on Drug Use and Health. According to the Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2022 National Survey on Drug Use and Health, excessive alcohol intake is one of the leading preventable causes of death in the United States. Alcohol use disorder in the past year was assessed among people aged 12 or older, by age group and demographic characteristics, numbers in thousands, 2022 and 2023.[SAMHSA. 2023 NSDUH Detailed Tables] Trends between 2011 and 2017 showed a significant increase in hospitalizations due to alcohol-associated hepatitis, from 0.7% to 0.9%, whereas mortality in this sample ranged from 5.3% to 5.5%.[6]

Pathophysiology

Alcohol undergoes oxidative metabolism in hepatocytes, leading to a reduction in the nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide (NAD:NADH) ratio. The reduced ratio promotes fat accumulation in the liver by increasing fatty acid uptake and lipogenesis, resulting from inhibition of triglyceride and fatty acid oxidation. Another known mechanism of alcohol-associated liver injury is the translocation of endotoxins in the form of lipopolysaccharides from the intestines into hepatocytes. In hepatic Kupffer cells, lipopolysaccharides bind to cluster of differentiation 14 and toll-like receptor 4, triggering the release of reactive oxygen species. Reactive oxygen species activate the release of cytokines such as tumor necrosis factor α, interleukin-8, monocyte chemotactic protein 1, and platelet-derived growth factor, all of which contribute to the accumulation of neutrophils and macrophages and the systemic clinical features of alcohol-associated liver injury. Recent studies indicate that patients with specific intestinal dysbiosis have been increasingly susceptible to alcoholic liver disease and alcohol-associated hepatitis. Further research in this area has identified that a change in the gut microbiome may be a contributing factor in alcohol-induced liver inflammation.[11]

Histopathology

A liver biopsy is generally not required to make the diagnosis of alcohol-associated hepatitis, except in uncertain cases. Classic histological features include steatosis, hepatocyte ballooning (swollen, damaged hepatocytes), predominantly neutrophilic infiltration, and Mallory-Denk bodies (eosinophilic cytoplasmic inclusions). Additional findings include pericellular fibrosis in a chicken-wire pattern and cholestasis. Damage is typically observed in the centrilobular region.

History and Physical

The clinical presentation of alcohol-associated hepatitis varies. A mild clinical presentation may be characterized by fever, right upper quadrant pain or discomfort, and elevations in aminotransferases that normalize with sobriety. Conversely, a severe presentation includes jaundice, ascites, hepatic encephalopathy, and coagulopathy. Characteristically, heavy alcohol use is typically observed within a few weeks before presentation, and the onset of symptoms is acute. The physical examination may reveal tachycardia, tachypnea, fever, hepatomegaly, and signs of portal hypertension. Spider angiomas, proximal muscle wasting, and gynecomastia are observed in severe cases of liver cirrhosis.

Evaluation

The diagnosis of alcohol-associated hepatitis is clinical, with supporting laboratory findings. All patients should have an abdominal imaging study to exclude biliary obstruction and liver diseases such as hepatocellular carcinoma and liver abscess. Liver tests may show elevated AST levels, whereas ALT levels are typically within the reference range, resulting in an AST-to-ALT ratio frequently greater than 1.5:1, with both values at 400 IU/L or less. Indirect biomarkers of hepatocyte damage associated with alcohol use, such as carbohydrate-deficient transferrin and γ-glutamyl transferase, have not shown clinical utility; conversely, direct markers such as blood alcohol level and ethyl glucuronide may be more predictive.[12] More recently, another direct biomarker, phosphatidylethanol, is increasingly used in cases of underreporting or discordance between the clinical presentation and the patient's history. Phosphatidylethanol testing can detect significant alcohol use up to 4 weeks after ingestion, and a cutoff of 20 ng/mL is used to indicate intentional use above minimal amounts.[13][14]

Ultrasonography is the first imaging test of choice to assess patients with alcohol-associated hepatitis. This imaging modality is useful for evaluating biliary obstruction and liver abscess. A liver biopsy is typically not required but may be necessary for excluding other disorders when the diagnosis is uncertain or when confounding factors are present. A liver biopsy should be performed with care because these patients may have coagulopathy and thrombocytopenia.

Establishing the severity of alcohol-associated hepatitis after diagnosis is crucial because severity directs the therapeutic approach. Several clinical models exist to assess the severity of alcohol-associated hepatitis and identify which patients are likely to benefit from a pharmacological approach. In 1977, the Maddrey discriminant factor included serum total bilirubin and prothrombin time to stratify patients at risk of 28-day mortality greater than 50%. These patients had a Maddrey discriminant factor greater than 32 and were deemed to benefit from corticosteroid therapy. Subsequent scoring systems include the Model for End-Stage Liver Disease (MELD) score; the Age, Bilirubin, International Normalized Ratio, and Creatinine score; the Glasgow Alcoholic Hepatitis Score, including age, bilirubin, international normalized ratio, blood urea nitrogen, and peripheral white blood cell count; and the Lille score. The Lille score uses data obtained at the beginning and end of 7 days of corticosteroid therapy to assess response and the subsequent need for further corticosteroid therapy or treatment discontinuation. A histological scoring system for the prognosis of patients with alcohol-associated hepatitis has also been proposed. Various combinations of scoring systems have been studied to improve the accuracy of outcome prediction, with the combination of the MELD and Lille scores potentially providing the greatest accuracy.[15][16][17][18]

Treatment / Management

Abstinence, along with adequate nutritional support, remains the cornerstone of the treatment of patients with alcohol-associated hepatitis. An addiction specialist is helpful in individualizing and enhancing the support required for abstinence. Approximately 10% to 20% of patients with alcohol-associated hepatitis are likely to progress to cirrhosis annually, and 10% of individuals with alcohol-associated hepatitis have regression of liver injury with abstinence.

Determining disease severity has implications for pharmacologic treatment candidacy and prognosis prediction. Patients with alcohol-associated hepatitis are subdivided into moderate or severe disease. The original MELD score is one of the tools used in this assessment, and calculators are readily available online. A MELD score greater than 20 indicates severe alcohol-associated hepatitis, whereas a score of 20 or less is considered moderate alcohol-associated hepatitis.[19] Patients with a MELD score of more than 20 have a predicted 90-day mortality rate of 20%.[20] The Maddrey discriminant function is another disease severity assessment tool. This tool uses prothrombin time and serum bilirubin, and calculators are also available online. Patients with a Maddrey discriminant function score greater than or equal to 32 are classified as having severe alcohol-associated hepatitis and a higher mortality risk and may therefore benefit from corticosteroid therapy.

Treatment for alcohol-associated hepatitis, particularly severe alcohol-associated hepatitis, focuses on 3 major areas: treating infections, nutrition, and controlling inflammation. Although infection is common in patients presenting with alcohol-associated hepatitis, particularly those receiving corticosteroids, strong guidance recommends against prophylactic antibiotics in all patients, suggesting that antibiotics should be used in confirmed cases of infection (see Table. Therapeutic Options for Alcohol-Associated Hepatitis).[21] Therefore, infection evaluation, including blood and urine cultures and a chest radiograph, should be incorporated into the overall assessment. Additional infection evaluation may be performed when clinically indicated by symptoms and the patient's overall condition. Regarding nutrition, a caloric intake of 35 kcal/kg/d with 1.2 to 1.5 g/kg/d of protein is recommended, as in critical illness. Oral or enteral feeding is preferred, but parenteral nutrition may be used when these routes are not possible.(A1)

Table. Therapeutic Options for Alcohol-Associated Hepatitis

Abbreviations: IL-1, interleukin-1; mDF, modified Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; TNF, tumor necrosis factor.

Patients with severe alcohol-associated hepatitis, with or without hepatic encephalopathy, are considered candidates for a short course of prednisolone (40 mg/d for 28 days). Prednisolone is preferred to prednisone because prednisolone does not require metabolism in the liver for therapeutic efficacy and has been more widely studied. For patients unable to take prednisolone orally, methylprednisolone 32 mg intravenously daily is an option. Glucocorticoids alter the expression of anti-inflammatory genes, thereby promoting their anti-inflammatory role. Contraindications to corticosteroid use include any active gastrointestinal tract bleeding, severe pancreatitis, uncontrolled diabetes, active infection, or renal failure. Patients with bacterial infection may be treated with corticosteroids after the infection has been appropriately controlled with antibiotics. The data on corticosteroids are mainly from the landmark UK-based Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, which showed a clear mortality benefit with corticosteroids after 28 days.[22] A subsequent meta-analysis showed similar findings. Conversely, pentoxifylline did not show similar results in this study.

Hepatorenal syndrome is one of the major causes of death in patients with alcohol-associated hepatitis. Patients with acute kidney injury or hepatorenal syndrome respond poorly to corticosteroid therapy. Pentoxifylline, a phosphodiesterase inhibitor, is another drug that was previously recommended and has shown benefit in cases of hepatorenal syndrome. However, pentoxifylline is no longer recommended for severe alcohol-associated hepatitis because of its unclear survival benefit. N-acetylcysteine has also been previously recommended for use with corticosteroids.[19]

The Lille score has been established to assess the response to therapy on day 4 or 7 of treatment.[23] Patients with a score greater than 0.45 are nonresponders with a much higher 6-month mortality risk (up to 75%), and corticosteroids should be discontinued in those cases. The Lille score may be used in association with the MELD score. Observational findings showed that patients with MELD scores between 21 and 29 respond better to corticosteroids compared with those with scores greater than 50.

Other developing modalities include granulocyte colony-stimulating factor, microbiome-based therapies, and anti-inflammatory medications. Studies have shown that granulocyte colony-stimulating factor and tumor necrosis factor inhibitors, such as infliximab, may have therapeutic potential; however, further research is needed before these therapies can be approved for alcohol-associated hepatitis.[24] Given the role of intestinal dysbiosis in liver inflammation, recent trials have shown promising results with microbiome modulation through fecal microbiota transplantation; however, further research is needed.[25](A1)

Patients with alcohol-associated hepatitis are prone to infections, especially while being treated with corticosteroids. Infection risk is particularly important because acute kidney injury and multiorgan dysfunction are associated with a poor prognosis. Patients with alcohol-associated hepatitis are also at risk of alcohol withdrawal. Lorazepam and oxazepam are the preferred benzodiazepines for prophylaxis and treatment of alcohol withdrawal.

Liver transplant may be considered for patients who do not respond to corticosteroid therapy and have a MELD score greater than 26. However, barriers to transplant include fear of recidivism, organ shortage, and social and ethical considerations. A 2015 survey of liver transplant programs revealed that only 27% of the programs offered a transplant to patients with alcohol-associated hepatitis.[26][27] Of 3290 liver transplants performed, 1.37% were performed in patients with a diagnosis of alcohol-associated hepatitis. The 6-month, 1-year, and 5-year survival rates were 93%, 93%, and 87%, respectively, and are comparable to those of patients with similar MELD scores. The recidivism rates are similar (17%) to those of patients who undergo transplant for alcohol-associated cirrhosis. Data increasingly indicate that carefully selected patients with severe alcohol-associated hepatitis and progressive liver failure can have good posttransplant outcomes compared to those who undergo transplant for other diagnoses. The palliative care team can play an important role in the care of patients who may not be candidates for liver transplant and have a poor prognosis, similar to palliative care involvement in other causes of liver failure.(B3)

Differential Diagnosis

The differential diagnoses of alcohol-associated hepatitis include metabolic dysfunction-associated steatohepatitis, acute or chronic viral hepatitis, drug-induced liver injury, fulminant Wilson disease, autoimmune liver disease, α1-antitrypsin deficiency, pyogenic hepatic abscess, ascending cholangitis, and cirrhosis-associated decompensation.

Prognosis

Patients with severe alcohol-associated hepatitis with a Maddrey discriminant function greater than 32 have a 30-day mortality rate of 30% to 50%. Patients with a MELD score greater than 20 carry a 20% 90-day mortality risk. Approximately 40% of patients with severe alcohol-associated hepatitis die within 6 months after the onset of the clinical syndrome. Hepatic encephalopathy and acute kidney injury at the time of presentation indicate a poorer outcome. Mild to moderate alcohol-associated hepatitis has a generally more benign course and is mostly reversible with cessation of alcohol consumption.

Complications

Common complications associated with alcohol-associated hepatitis include:

• Hepatic encephalopathy
• Acute kidney injury
• Variceal hemorrhage
• Coagulopathy
• Thrombocytopenia
• Ascites
• Spontaneous bacterial peritonitis