Alcoholic hepatitis

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Alcoholic hepatitis is a clinical syndrome with a broad range of manifestations, from vague malaise to fulminant liver failure. Alcoholic hepatitis should be suspected in patients with prolonged heavy alcohol use and recent-onset jaundice, fever, leukocytosis, and tender hepatomegaly. Characteristic findings from liver chemistries in alcoholic hepatitis include transaminitis and hyperbilirubinemia. A diagnosis of acute alcoholic hepatitis requires consideration of confounding factors, including differential diagnoses of alcoholic hepatitis, uncertain alcohol use, and atypical laboratory results. Laboratory-based prognostic scores (e.g., Maddrey discriminant function and MELD scores) can be used to assess severity and short-term prognosis and guide management. Complete abstinence from alcohol is advised for all patients and is considered the most effective intervention. Supportive management includes nutritional support, monitoring for alcohol withdrawal syndrome, and treatment for alcohol use disorder. Patients with severe alcoholic hepatitis may benefit from pharmacotherapy with glucocorticoids or, in selected cases, early liver transplantation. Patients with no response to glucocorticoids who are not candidates for early liver transplantation should be referred for palliative care.

• Incidence: ∼ 0.8% of all hospitalizations in the US per year ^[2][3]
• Survival ^[4]
  • 4-year survival: ∼ 58%
  • 1-year survival in patients with concomitant cirrhosis: ∼ 35%
  • 6-month survival for severe alcoholic hepatitis that does not respond to medical therapy: ∼ 30%

Epidemiological data refers to the US, unless otherwise specified.

• Risk factors include: ^[2][3][4][5]
  • History of chronic heavy alcohol use
  • Cigarette smoking
  • Genetic predisposition
  • Female sex ^[5]
  • Nutritional factors: obesity, malnutrition
  • Viral hepatitis: e.g., hepatitis C

• Acute hepatitis: tender hepatomegaly, acute jaundice, malaise, nausea, anorexia, fatigue, fever, weight loss, tachypnea
• Acute alcohol withdrawal: tremor, agitation, tachycardia, alcohol withdrawal seizures, alcohol withdrawal delirium
• Long-term alcohol use: rhinophyma, Dupuytren contracture, sarcopenia, temporal muscle wasting
• Cirrhosis : clinical features of liver cirrhosis (e.g., jaundice, ascites, palmar erythema, spider angiomata)

Acute alcoholic hepatitis may be reversible in mild cases. ^[2][3]

Symptoms of alcoholic hepatitis are nonspecific. The presence of acute-onset jaundice can help differentiate acute alcoholic hepatitis from decompensated cirrhosis. ^[6]

These recommendations are consistent with the 2019 American Association for the Study of Liver Diseases (AASLD) and 2018 American College of Gastroenterology (ACG) clinical guidelines. ^[2][3]

Approach ^[2][3]

Suspect alcoholic hepatitis in patients with suggestive clinical features and a history of chronic heavy alcohol use.

• Use the consensus definitions for alcoholic hepatitis to establish a definite, probable, or possible diagnosis.
• Obtain laboratory and imaging studies to support the diagnosis and rule out other causes of hepatitis and jaundice.
• Perform a thorough infectious disease workup guided by clinical suspicion.
• Assess severity using the Maddrey discriminant function or MELD score.
• Identify patients with alcohol use disorder (e.g., using the AUDIT-C score).

The presence of systemic inflammatory response syndrome (SIRS) criteria at admission is a predictor of multiorgan failure (especially AKI) and early death. ^[2][3]

Infections are common in patients with alcoholic hepatitis and are associated with a poorer prognosis. An infectious disease workup is recommended in all patients with alcoholic hepatitis. ^[2]

Consensus definitions for alcoholic hepatitis ^[3][4]

The AASLD recommends classifying patients according to the consensus definitions.

• Clinical diagnosis of alcoholic hepatitis
  • Onset of jaundice within the past 8 weeks
  • ≥ 6 months of ongoing alcohol consumption above the threshold and < 60 continuous days of abstinence from alcohol before jaundice onset
    • > 40 g alcohol per day for female patients
    • > 60 g alcohol per day for male patients
  • Characteristic findings from liver chemistries in alcoholic hepatitis
• Confounding factors
  • Atypical laboratory results
  • Uncertain alcohol use
  • Presence of other potential causes of liver disease; see “Differential diagnoses of alcoholic hepatitis.”
• Classification
  • Definite alcoholic hepatitis: clinical diagnosis PLUS histological confirmation
  • Probable alcoholic hepatitis: clinical diagnosis
  • Possible alcoholic hepatitis: uncertain clinical diagnosis because of the presence of confounding factors

Initial studies ^[2][7]

Laboratory studies

• Liver chemistries in alcoholic hepatitis
  • AST: > 50 IU/L
  • Both AST and ALT: < 400 IU/L
  • AST:ALT ratio: > 1.5
  • Total bilirubin: > 3 mg/dL
• Additional liver studies
  • GGT: > 100 IU/L
  • ALP: ↑
  • INR: > 1.5
  • Albumin: < 3 g/L
• CBC
  • WBC: > 12,000/mm³
  • Platelets: ↓ or ↑
  • Macrocytic anemia; (↓ hemoglobin with ↑ MCV)
• BMP: to assess for AKI and calculate severity scores

AST > ALT in alcoholic hepatitis: Remember “make a toAST with alcohol!”

Imaging studies

Obtain imaging studies in all patients to rule out differential diagnoses (e.g., biliary obstruction, cholangitis ).

• RUQ ultrasound with Doppler: (preferred): may show findings of fatty liver disease; (e.g., steatosis, hepatomegaly, and periportal edema) and/or cirrhosis ^[2][5]
• CT or MRI abdomen: may show findings of fatty liver disease (e.g., decreased liver attenuation, heterogeneous steatosis) and/or cirrhosis ^[5][8]

Additional diagnostic workup ^[2][7]

Obtain additional studies to exclude differential diagnoses and identify comorbidities; workup should be guided by clinical suspicion and may include the following:

• Infection
  • Workup for sepsis
  • Viral hepatitis panel
• Autoimmune hepatitis: e.g., ANAs, anti-smooth muscle antibodies, IgG levels
• Metabolic liver disease: e.g., serum ceruloplasmin, alpha-1 antitrypsin levels
• Drug-induced liver injury: e.g., medication review, urine toxicology, serum acetaminophen levels
• Nonalcoholic fatty liver disease (NAFLD): e.g., alcoholic liver disease/nonalcoholic fatty liver disease index (ANI) to help differentiate alcoholic liver disease from NAFLD ^[9]

Sepsis should always be ruled out in patients with alcoholic hepatitis and SIRS.

Liver biopsy ^[2][3]

• Indications: (not routinely recommended)
  • Unclear diagnosis because of the presence of confounding factors
  • Uncertain alcohol consumption
  • Recruitment to a clinical trial
• Technique: Transjugular liver biopsy is preferred. ^[2]
• Findings: signs of alcoholic steatohepatitis and/or cirrhosis (see “Pathology” in “Alcoholic liver disease” for details).

Histopathological findings of alcoholic steatohepatitis may be indistinguishable from findings of nonalcoholic steatohepatitis; the ANI can help differentiate between the two.

Prognostic scoring systems are used to guide management and determine disease severity. Severe alcoholic hepatitis is defined as Maddrey discriminant function ≥ 32 or MELD score > 20.

• Another alcoholic liver disease (e.g., decompensated cirrhosis)
• NAFLD
• Infection (e.g., acute cholangitis)
• Biliary obstruction (e.g., stones, tumors, strictures)
• Drug-induced liver injury (e.g., due to the use of acetaminophen, cocaine, prescription pharmaceuticals)
• Acute viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C)
• Autoimmune hepatitis
• Metabolic liver disease
• Ischemic hepatitis (e.g., due to hypotension, shock, massive blood loss, or cocaine or other vasoconstrictor use)

AST > 400 IU/L should raise concern for drug-induced liver injury or ischemic hepatitis. ^[4]

The differential diagnoses listed here are not exhaustive.

These recommendations are consistent with the 2019 AASLD and 2018 ACG clinical guidelines. ^[2][3]

Approach ^[2][3]

• Advise immediate alcohol cessation and monitor for alcohol withdrawal syndrome.
• Ensure adequate calorie and micronutrient intake.
• In patients with severe disease, consider glucocorticoid therapy and referral for early liver transplantation.
• Prevent and manage comorbidities and complications, including:
  • Infection and sepsis
  • Complications of cirrhosis (e.g., ascites, hepatic encephalopathy, esophageal variceal hemorrhage)
  • Prevention of AKI and hepatorenal syndrome
  • Mental health disorders and psychosocial factors (e.g., major depressive disorder, generalized anxiety disorder)

Disposition ^[2]

Consider ICU admission in any of the following situations:

• Extrahepatic organ failure
• Stage III or IV hepatic encephalopathy
• Respiratory failure or the need for ventilatory support
• Hemodynamic instability or septic shock

Supportive care

Alcohol cessation ^[2][3][6]

• Advise patients to abstain completely from alcohol; no amount of alcohol consumption is considered safe. ^[6]
• Assess for alcohol withdrawal syndrome. ^[2]
  • Calculate the patient's CIWA-Ar score.
  • Provide management for alcohol withdrawal (e.g., benzodiazepines).
• Refer to an addiction medicine specialist for treatment of alcohol use disorder.

Alcohol cessation is the only management strategy with proven long-term benefits in alcoholic hepatitis. ^[3][5]

Alcohol cessation may lead to alcohol withdrawal syndrome. ^[2]

Nutritional support ^{[2][3][6][14]}

Patients with alcoholic hepatitis may be very malnourished. Consider specialist consultation for specialized nutritional support.

• Enteral route is preferred.
• Ensure a caloric intake of 35–40 kcal/kg/day.
• Daily protein requirement: 1.2–1.5 g/kg
• Replete zinc and other trace elements.
• Replete thiamine and other B-complex vitamins.
• IV albumin is preferred over IV crystalloids for volume replacement.

Pharmacological therapy ^{[2][3][15][16]}

Evidence regarding the benefit of pharmacological treatment for alcoholic hepatitis is mixed.

Glucocorticoids ^[2]

The AASLD and ACG recommend glucocorticoid use in selected cases.

• Indication: Severe alcoholic hepatitis (i.e., MDF score ≥ 32 or MELD score > 20) and no contraindications ^[2][3]
• Preferred agents
  • Prednisolone (off label) ^[2]
  • Methylprednisolone (off label) ^[2]
• Monitoring: Calculate the Lille score to assess response after 4–7 days of treatment with glucocorticoids. ^[13]
  • Lille score ≥ 0.45: Patient is not responding; stop glucocorticoids and consider further treatment options (e.g., supportive care, palliative care, early liver transplantation).
  • Lille score < 0.45: Patient is responding; continue glucocorticoids to complete 28 days of treatment, followed by 2–4 weeks of taper.

Patients who do not respond within the first week of glucocorticoid treatment are unlikely to derive benefit from continued treatment. ^[2]

Other medications ^[16]

Other medications may be considered for patients with severe alcoholic hepatitis.

• N-Acetylcysteine ^[17]
  • May reduce complications and mortality when given in combination with glucocorticoids
  • Evidence that N-acetylcysteine improves outcomes is limited, but the risks of treatment are low.
• Pentoxifylline
  • No longer recommended by the AASLD
  • May be preferable to no intervention in specific situations (e.g., in patients with contraindications to glucocorticoid therapy, patients with AKI) ^[16]

Early liver transplantation ^[3][18]

• Definition: liver transplantation without 6 months of abstinence from alcohol
• Consider in patients with the following:
  • No response to supportive or pharmacological management
  • Favorable psychosocial profiles

Liver transplantation may be considered in selected patients with acute alcoholic hepatitis, even if they have not abstained from alcohol for the required 6 months.

• Check indications for ICU level of care.
• Obtain initial studies (e.g., CBC, liver chemistries, BMP, INR, RUQ ultrasound).
• Obtain an infectious disease workup (e.g., blood cultures).
• Consider referral for liver biopsy if confounding factors (e.g., differential diagnoses of alcoholic hepatitis, uncertain alcohol use) are present.
• Assess disease severity using the Maddrey discriminant function and MELD score.
• Start glucocorticoid therapy in patients with severe disease and no contraindications.
• Monitor response to glucocorticoids using the Lille score.
• Monitor and manage patients for alcohol withdrawal syndrome (e.g., using the CIWA-Ar score).
• Encourage abstinence from alcohol and provide treatment for alcohol use disorder.
• Consider referral for liver transplant in patients with severe disease who are unresponsive to supportive management and pharmacological treatment.