Alcohol-associated hepatitis (ALD) is a severe, progressive, inflammatory, and cholestatic liver disease occurring in patients with long-term heavy alcohol use (60 to 80 g/day in men and 20 to 40 g/day in women). Main characteristics include rapid onset of jaundice, hepatomegaly, generalized malaise, and subtle systemic inflammatory response features. The clinical diagnosis of ALD and alcohol-associated hepatitis can be accurate; however, the diagnostic accuracy is increased by the use of liver biopsy. A consensus report from the National Institute on Alcoholism and Alcohol Abuse defined the clinical diagnosis of acute alcohol-associated hepatitis. This working definition of alcohol-associated hepatitis includes the onset of jaundice within 60 days of ongoing alcohol consumption of more than three drinks (∼40g) per day for women and four drinks (∼50 to 60g) per day for men for a minimum of 6 mo, a serum bilirubin level greater than 3 mg/dl, an elevated serum AST level (>50 IU/L), a serum AST:ALT ratio greater than 1.5, and no other obvious cause for hepatitis. This consensus statement proposed classifying patients with alcohol-associated hepatitis as definite when a liver biopsy was used to establish the diagnosis, probable when the clinical and laboratory features were present without potential confounding problems, and possible when confounding problems were present.¹

• ALD
• Alcoholic Hepatitis
• AH

• •Approximately 2 million people in the U.S. (about 1% of the population) are affected by alcoholic liver disease.
• •Alcohol-associated hepatitis accounts for 0.08% to 0.09% of admissions in the U.S. Almost 7% during their initial hospitalization and 40% of those with severe disease die within 6 mo of clinical presentation.²
• •Typical presentation age: 40 to 50 yr. Majority occurs before age 60.
• •Patients with alcoholic hepatitis typically drink more than 100 g of alcohol daily for two or more decades.
• •Excessive alcohol intake is the third leading preventable cause of death in the U.S.

Common presenting symptoms include:

• •Rapid onset of jaundice within 60 days of heavy alcohol consumption (>50 g/day) for at least 6 mo
• •Jaundice with duration <3 mo
• •Right upper quadrant abdominal/epigastric pain
• •Nausea/vomiting
• •Malaise
• •Low-grade fever
• •Anorexia
• •Abdominal distention/pain (due to ascites)
• •Weight loss or malnourishment
• •Proximal muscle wasting and weakness
• •Complications of liver impairment (GI bleed; confusion, lethargy, ascites)

Findings on physical examination include:

• •Jaundice and ascites
• •Hepatomegaly, with tender liver on palpation
• •Fever (first exclude other causes of fever, such as spontaneous bacterial peritonitis, urinary tract infection [UTI], pneumonia)
• •Asterixis (a flapping tremor)
• •Splenomegaly
• •Tachycardia/tachypnea
• •Hypotension
• •Peripheral edema
• •Abdominal distention with shifting dullness (ascites)
• •Hepatic bruit (may occur in >50% of patients)
• •With coexistent cirrhosis, look for:
  1. 1.Gynecomastia
  2. 2.Proximal muscles wasting
  3. 3.Spider angiomata
  4. 4.Altered hair distribution

• •Hepatitis B
• •Hepatitis C
• •Nonalcoholic steatohepatitis (NASH)
• •Chronic pancreatitis
• •Drug-induced liver injury
• •Hemochromatosis
• •Cholangitis

• •Diagnosis of ALD is clinically supported by laboratory findings.
• •The standard screening test for alcohol abuse is the Alcohol Use Disorders Identification Test (AUDIT).
• •A thorough and detailed history is needed.
• •Relevant questions may include:
  1. 1.When patient started drinking
  2. 2.Number of times patient drinks per day
  3. 3.How many years of regular/daily drinking
  4. 4.Types of alcohol
  5. 5.Home or bar drinking
  6. 6.Rehabilitation for drinking
  7. 7.Social problems (e.g., arrest for public intoxication or driving under the influence, marital discord due to alcoholism)
  8. 8.A typical patient may have a long history of excessive alcohol intake (>100 g of alcohol per day for at least 20 yr)
• •Abdominal imaging with ultrasound (the imaging of choice) to rule out gallstones, biliary, and other liver diseases such as liver abscess or hepatocellular carcinoma.

The best biomarkers of harmful ethanol use are γ-glutamyltransferase (GGT), aspartate aminotransferase (AST), ethyl glucuronide (ETG), and phosphatidyl ethanol.

• •Only one third of hospitalized patients with fatty liver have laboratory abnormalities, which usually consist of mild increases in serum AST and ALT levels
• •Elevated transaminase (aspartate aminotransferase [AST] >45 U/L but <500 U/L; however, some patients may not have elevations in ALT, AST in early phases)
• •AST: Alanine aminotransferase [ALT] ratio ≥2:1
• •S-bilirubin >5 mg/dl
• •Increased prothrombin time [PT]/international normalized ratio [INR]
• •Elevated GGT
• •Carbohydrate-deficient transferrin (CDT) is a reliable marker for chronic alcoholism
• •Elevated C-reactive protein [CRP is a good marker of alcoholic hepatitis]
• •Electrolyte disorder (hypokalemia, hypomagnesemia, low zinc, hypophosphatemia)
• •Hypoalbuminemia
• •Hyperferritinemia
• •CBC (may reveal leukocytosis with bandemia or anemia or thrombocytopenia); mean corpuscular volume (MCV) may be elevated
• •Screening tests to rule out other conditions include checking:
  1. 1.Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HB_cAb) (IgM), hepatitis A antibody (IgM)
  2. 2.Antihepatitis C antibody, hepatitis C ribonucleic acid (RNA)
  3. 3.Ferritin-transferrin saturation
  4. 4.Alpha-fetoprotein
  5. 5.Alkaline phosphatase
• •Laboratory criteria of severe alcoholic hepatitis are defined as:
  1. 1.Maddrey Discriminant Function (MDF) score >32, which is calculated as follows: MDF = 4.6 × prothrombin time-control-prothrombin time + total bilirubin (mg/dl)
  2. OR
  3. 2.Model for End-Stage Liver Disease (MELD) >21
  4. AND/OR
  5. 3.Hepatic encephalopathy. There are other models for determining severity such as the Alcohol Hepatitis Histologic Score (AHHS) or for prognostication such as the MELD + Lille combination models.

Ultrasonography is the preferred imaging study. The earliest histologic change in alcohol-related liver disease is macrovesicular steatosis.

• •Liver biopsy is rarely needed
• •Useful to:
  1. 1.Confirm the diagnosis
  2. 2.Evaluate the effect of coexisting disease
  3. 3.Rule out cirrhosis
  4. 4.Exclude other diagnoses (especially other causes of liver diseases, biliary obstruction, Budd-Chiari syndrome)
• •Typical histologic findings include:
  1. 1.Micro- or macrovesicular steatosis
  2. 2.Hepatocyte injury (ballooning degeneration and focal hepatocyte necrosis)
  3. 3.Mallory-Denk bodies (characteristic of alcoholic hepatitis)
  4. 4.Perivenular fibrosis
  5. 5.Portal and lobular inflammation with neutrophils or lymphocyte infiltration

• •Abstinence, together with adequate nutritional support, is the cornerstone of management.
• •Abstinence from alcohol (this improves both short- and long-term survival).
• •Nonpharmacologic methods to promote abstinence include cognitive-behavioral therapy (CBT), Alcoholics Anonymous (AA) attendance, and motivational interviewing.
• •Pharmacologic aids include using naltrexone, acamprosate, or baclofen.
• •Monitor abstinence with breath test or urine drug screen (for use in past 3 days) or hair sample analysis for ethyl glucuronide (test alcohol intake within the last few months).
• •Smoking cessation (to decrease oxidative stress).
• •Treatment of substance abuse.

• •Good nutrition is an essential part of treatment because many patients with ALD have severe protein-calorie malnutrition as well as deficiencies of trace minerals and several vitamins.
• •Nutritional support includes:
  1. 1.Liberal vitamin supplementation (especially thiamine, folic acid, vitamin K)
  2. 2.Mineral supplementation (but not iron)
  3. 3.Calorie counting is essential. A high calorie intake (1.2 to 1.4 times the normal resting intake) may be required
  4. 4.Protein intake of 1.2 to 1.5 g/kg of ideal body weight per day will provide adequate support. Exception: In patients with severe encephalopathy, protein restriction may be required
  5. 5.Fluid management

Severe ALD may require treatment. Severity can be assessed by calculating the MELD score or MDF score or the Glasgow score.

• •An MDF score ≥32 indicates significant or severe ALD (30-day mortality of 50%).
• •MELD score can easily be calculated (visit https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/). This score predicts short-term survival in patients with cirrhosis. A score >20 predicts increased short-term mortality.
• •Glasgow score: Contains four variables (BUN, PT, WBC count, and bilirubin). A score ≥9 indicates increased mortality.

Indications for hospitalization include:

• •MDF ≥32
• •MELD >20
• •Glasgow score >8
• •Hepatic encephalopathy

Patients with severe ALD may be treated with glucocorticosteroids (prednisolone 40 mg/day for 28 days with a 2-wk taper). Glucocorticosteroids reduce hepatic injury, suppress inflammation, and promote liver regeneration. However, not all studies have demonstrated consistent therapeutic benefits for steroids, even in high-risk patients.⁴ Prednisolone should be discontinued if bilirubin does not decrease by day 17. An alternative agent for patients with contraindications to corticosteroids is pentoxifylline. Pentoxifylline is not effective in patients who do not respond to prednisone, and data supporting its use is weak.

• •Liver transplantation could be considered for patients with MELD >26 and unresponsive to steroids.
• •Usually reserved for patients with end-stage liver disease. Patients whose hepatitis is not responding to medical therapy have a 6-mo survival rate of approximately 30%. Since most hepatitis deaths occur within 2 mo, early liver transplantation is attractive and associated with higher than 80% survival at 3 yr.
• •Patients with ALD must be sober for at least 6 mo before they can be eligible for consideration for liver transplantation. However, transplantation candidates should not be based solely on 6 mo abstinence, and other factors, such as social support and need for rehabilitation, should be considered.

Severe acute ALD may require intensive care unit (ICU) care and referral to different subspecialists:

• •GI/hepatology (for patients with evidence of GI hemorrhage)
• •Nutritional services
• •Nephrology (for acute renal failure, hepatorenal syndrome)
• •Neurology (for change in mental status, seizures)
• •Infectious disease (for fever/leukocytosis)

• •Three prospective studies demonstrated that patients with mDF values of 32 or greater have a poor prognosis, with 1-mo mortality rates of 35% to 50% (Table 2). As a result, the MDF has been incorporated into the selection criteria for most therapeutic trials of patients with alcohol-associated hepatitis. The prognosis of patients with MDF values greater than or equal to 32 can be further stratified by the presence of encephalopathy and development of acute kidney injury. Three other prognostic models, the MELD score, the Glasgow alcohol-associated hepatitis score, and the ABIC score, have been shown to predict survival in patients with severe alcohol-associated hepatitis (Tables 3-5). Although none is perfect, each of these models appears to be effective in selecting patients for medical therapy. The short-term survival of patients with MDF values less than 32 have ranged from 83% to 100% in various studies. To determine the prognosis of all patients with alcohol-associated hepatitis more accurately, a scoring system (ABIC) has been proposed that separates patients into three groups with predicted 3-mo survival rates of 25%, 70%, and 100% based on the patient’s age, bilirubin, INR, and creatinine, respectively¹ (see Table 4).

• •Referral to substance abuse treatment programs may be helpful.
  1. 1.Stress to patients that there are limited long-term drug treatments for ALD.
  2. 2.Maintaining good general nutrition is important.
  3. 3.Advise patient about the risk of taking certain medications, especially acetaminophen.
• •Periodic follow-up to monitor patient’s response to check basic metabolic panel (BMP) and liver function tests (LFTs).
• •Encourage alcohol abstinence. Abstinence improves long-term survival.
• •If patient develops liver cirrhosis, check serum alpha-fetoprotein every 6 mo and liver ultrasound annually to rule out hepatocellular carcinoma.
• •Vaccinate patient against hepatitis A and B viruses, pneumococci, influenza A virus, and routine adult vaccinations, if appropriate.

• Alcoholic Hepatitis (Patient Information)