06. Acute Alcoholic Hepatitis

Definition

  • Acute alcoholic hepatitis (AH) – acute-onset inflammatory liver disease with significant short-term mortality, which occurs in the context of chronic alcohol use.
  • Presents with worsening jaundice and elevated total bilirubin, moderate transaminase elevation, and tender hepatomegaly, often with SIRS criteria without evidence of localizing infection.

Etiology

  • Occurs in patients with a history of chronic, heavy alcohol use. However, alcohol use is often stopped prior to hospitalization as patients start to feel ill.
    • Practice guidelines suggest that 10-35% of people with significant alcohol use may develop alcoholic hepatitis and 8-20% will develop cirrhosis. These two entities are not mutually exclusive. The incidence of acute alcoholic hepatitis is unclear.
  • Acute alcoholic hepatitis is precipitated by alcohol-induced inflammatory pathways. Excess alcohol consumption results in increased intestinal permeability with increased bacterial translocation from the gut into the portal circulation. Alcohol also results in increased production of TNF-alpha and other proinflammatory cytokines. Neutrophil-mediated hepatocyte injury occurs. Glutathione is depleted by alcohol metabolism, increasing oxidative stress.

Differential Diagnosis

  • Acute decompensated cirrhosis, biliary obstruction, cholangitis, acute viral hepatitis, drug-induced liver injury (including APAP and herbal supplements), autoimmune hepatitis, ischemic hepatitis, Budd-Chiari syndrome.
  • Aggressive evaluation for infection should be pursued (causes significant mortality/morbidity but difficult to differentiate from the alcoholic hepatitis itself).

Evaluation

  • Clinical history: history of prolonged alcohol use or binge within prior 4-8 weeks, worsening jaundice, malaise, anorexia, fevers, abdominal pain, N/V, increased abdominal girth, or evidence of GI bleeding.
    • Screen for amount and frequency of alcohol intake, date of last alcohol consumption (often stopped well before hospitalization due to malaise), other substance/supplement use, and localizing infectious symptoms.
  • Clinical signs: rapid onset or acute worsening of jaundice, fever (38-40°C in 50%), tender hepatomegaly, neutrophilic leukocytosis, hepatic bruit, stigmata of liver disease (e.g., asterixis, palmar erythema, spider angioma, splenomegaly, ascites, edema, encephalopathy).
    • Assess for any localizing signs of infection and evidence of alcohol withdrawal.
  • Laboratory: total bilirubin >3mg/dL, elevated alk phos (usually <3x ULN), AST >1.5x ULN (but <400, if higher consider concurrent pathology), AST/ALT ratio ~2, and leukocytosis.
    • Ensure MELD labs are sent (LFTs, BMP, INR, and albumin) in addition to CBC and infectious workup (CXR, blood, and urine cultures). Consider diagnostic paracentesis to rule out SBP if ascites is present.
    • If first episode or uncertain diagnosis, evaluate for acute hepatitis A, B, C and autoimmune hepatitis (ANA, ASMA, IgG).
    • In patients with cirrhosis, leukocytosis may not be present due to splenomegaly and sequestration.
    • Very severe alcoholic hepatitis may present with severe hyperbilirubinemia, decreased synthetic function (significantly elevated INR), encephalopathy and potential multi-organ failure with DIC, hepatorenal syndrome, or acute pancreatitis.
  • Radiology: use US with Doppler to exclude other causes of liver injury including portal thrombosis, biliary obstruction, or hepatocellular carcinoma.
  • Biopsy: if multiple or unclear etiologies of liver disease (e.g. AST or ALT >400) or if alcohol use history undetermined, transjugular liver biopsy may be considered.
  • In one series, clinical diagnosis of alcoholic hepatitis based upon H&P, labs, and imaging was approximately 91% sensitive and 96% specific with 88% PPV.

Prognosis

  • Maddrey Discriminant Function (MDF) and MELD score should be calculated on all presenting patients.
  • Poor prognostic indicators (severe AH):
    • MDF ≥32 (predicts 1-month mortality of 20-50% with 86% sensitivity, 48% specificity).
    • MELD ≥20 (predicts a 20% 3-month mortality).
  • However, ability to maintain abstinence from alcohol has significant impact on mortality and utility of scoring systems.

Management

  • If severe AH (MDF≥32 or MELD≥20), initiate prednisolone 40mg daily assuming no contraindications (i.e. active HBV, sepsis, GI bleed, renal failure, pancreatitis).
    • Response to therapy can be determined at day 4 or 7 using the Lille score.
    • If patient does not respond to therapy (Lille >0.45) steroids should be discontinued. If a liver transplant center for AH or clinical trials are available, consider referrals vs. discussion of goals of care.
    • If Lille <0.45, continue daily treatment for 4 weeks followed by 2-4 week taper.
    • NNT = 7 to prevent one death.
  • Initiate GI prophylaxis with PPI > H2 blocker.
  • Nutritional support is very important (acute AH induces profound catabolic state). Enteral feeds, feeding tube if necessary (safe in non-bleeding esophageal varices).
    • Daily MVI, thiamine, folate, zinc.
    • Calorie-count – 35 Kcal/kg and 1.5g/kg of protein.
    • Include night-time nutrition/snack.
  • Avoid nephrotoxic medications and intravascular hypovolemia. Low threshold to initiate albumin IVF. Keep glucose <200 and Hgb >7.
  • Screen for comorbidities:
    • Screening for alcohol withdrawal, electrolyte abnormalities, hepatic encephalopathy, and gastrointestinal bleeding should be undertaken. Immediate treatment as discussed elsewhere.
    • Screening and immediate treatment of infection with low threshold to initiate broad-spectrum antibiotic therapy while workup is pending. Bacterial infections are associated with poor prognosis.
  • Counsel on the importance of strict abstinence from alcohol (self-help/12-step, psychiatric/behavioral therapy, pharmacotherapy with naltrexone, baclofen, gabapentin, acamprosate).
  • In patients with contraindication to glucocorticoid therapy, other therapies with potential (non-proven) efficacy include N-acetylcysteine, pentoxifylline, and GCSF.
    • Pentoxifylline inhibits TNF-α synthesis, cytokines and chemokines, but use is controversial. Treatment with 400mg PO TID may decrease incidence of HRS, HE and mortality, but subsequent trials and meta-analyses failed to demonstrate a survival benefit (see STOPAH trial).
    • One randomized trial has suggested that the combination of prednisolone with N-acetylcysteine may improve 1-month survival, however, a longer-term survival benefit has not yet been demonstrated.
    • Consultation with Gastroenterology is recommended in any patient for whom you are planning to give steroids, pentoxifylline, or N-acetylcysteine.

Key Points

  • Presentation of acute alcoholic hepatitis – acute onset of jaundice and hyperbilirubinemia, fever, leukocytosis, and tender hepatomegaly in a patient with chronic alcohol use.
  • Rule out and monitor for serious bacterial infection but recognize that acute AH can readily explain fever and leukocytosis with care not to delay diagnosis/therapy.
  • Do not overlook adequate enteral nutrition.
  • For patients with severe AH (MDF >32 or MELD >20), consider prednisolone 40mg daily if no contraindication. Determine response at Day 4 or 7 with Lille score. If patient responds, continue for 4 weeks followed by 2-4 week steroid taper.
  • Sustained abstinence from alcohol is the mainstay of therapy.

 

Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology. 2005;41(2):353‐358. doi:10.1002/hep.20503

Gholam PM. Prognosis and prognostic scoring models for alcoholic liver disease and acute alcoholic hepatitis. Clin Liver Dis 2016;20:491-497.

Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45(6):1348‐1354. doi:10.1002/hep.21607

Mathurin P, O'Grady J, Carithers RL, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255‐260. doi:10.1136/gut.2010.224097

Singal, Ashwani K MD, MS, FACG1; Bataller, Ramon MD, PhD, FACG2; Ahn, Joseph MD, MS, FACG (GRADE Methodologist)3; Kamath, Patrick S MD4; Shah, Vijay H MD, FACG4 ACG Clinical Guideline: Alcoholic Liver Disease, American Journal of Gastroenterology: February 2018 - Volume 113 - Issue 2 - p 175-194 doi: 10.1038/ajg.2017.469

Thursz MR, Richardson P, Allison M, et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619‐1628. doi:10.1056/NEJMoa1412278