Alcoholic Liver Disease

Definition, Etiology, PathogenesisTop

Alcohol-related disorders account for 3.8% of annual global deaths and 48% of all deaths from liver disease in the United States.

Ethanol is absorbed in the stomach (20%) and the small intestine (80%). It is metabolized mainly in the liver via 2 enzymatic steps. Ethanol is first oxidized to acetaldehyde, a highly unstable and toxic intermediate metabolite, by the enzyme called alcohol dehydrogenase. Acetaldehyde is then further metabolized to a nontoxic metabolite called acetic acid by aldehyde dehydrogenase. Acetaldehyde is responsible for many of the systemic toxic effects of ethanol including alcoholic liver disease. In addition, coingestion of alcohol with other drugs (eg, acetaminophen [INN paracetamol], isoniazid) may further enhance its hepatotoxicity.

Liver injury develops in the following stages:

1) Alcoholic fatty liver: Alcohol-induced accumulation of macrovesicular steatosis within hepatocytes.

2) Alcoholic hepatitis: Macrovesicular steatosis and necroinflammatory changes in the liver.

3) Alcoholic liver cirrhosis.

The individual stages of alcoholic liver disease are not clearly distinct and may overlap. Less than 20% of individuals with chronic heavy alcohol use develop end-stage liver disease. Genetic (eg, variations in the PNPLA3 gene), behavioral, and environmental risk factors are all important in the development of the disease. Women are more susceptible to alcohol-induced liver injury compared with men and tend to have more rapid progression. Obesity and viral hepatitis B and C are also associated with increased risk of accelerated liver injury and cirrhosis in patients with chronic heavy alcohol use.

The “safe” amount of weekly alcohol consumption is not entirely known and may be presented as different thresholds by different resources. The following levels of consumption are thought to carry a low or minimal risk of liver disease: <16 to 21 units per week (<4 units per day on most days) for a healthy male (1 unit = 8 g of alcohol = a half of 341 mL of 5% beer, cider, or cooler = a half of 142 mL of 12% wine = 0.75 oz or 22 mL of distilled alcohol), and <11 to 14 units per week (<3 units per day on most days) for a healthy female. Please note that 1 unit of alcohol is defined differently depending on the country: in the United States, 1 unit is an equivalent of ~14 g of alcohol, which represents a standard small beer, small glass of wine, or 1.5 oz of liquor. The above-listed units (8 g of alcohol) contain about half of that amount. It may be worth pointing out that according to a recent largest epidemiologic study, no amount of alcohol appears safe if other causes of death (eg, accidents) are taken into account.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. GBD 2016 Alcohol Collaborators. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2018 Sep 22;392(10152):1015-1035. doi: 10.1016/S0140-6736(18)31310-2. Epub 2018 Aug 23. Review. Erratum in: Lancet. 2018 Sep 29;392(10153):1116. Erratum in: Lancet. 2019 Jun 22;393(10190):e44. PubMed PMID: 30146330; PubMed Central PMCID: PMC6148333.

Clinical Features and Natural HistoryTop

1. Alcoholic fatty liver disease (alcohol-related steatosis) is present in ~90% of patients with chronic heavy alcohol use. It is often asymptomatic, although sometimes it may cause mild right upper quadrant or epigastric tenderness, pain, nausea, and anorexia. On physical examination the liver may be enlarged and tender to palpation. The condition often resolves with abstinence, but it may progress to hepatitis and cirrhosis in ~8% to 20% of patients.

2. Alcoholic hepatitis (alcohol-related steatohepatitis) may cause fatigue, nausea, vomiting, loss of appetite, right upper quadrant or epigastric pain, hepatomegaly, and tenderness. Up to 80% of patients who present with severe alcohol hepatitis may already have features of cirrhosis. Features of a severe presentation include jaundice, ascites, encephalopathy, low-grade fever, and neutrophilic leukocytosis.

3. Alcoholic cirrhosis is not markedly different from cirrhosis of other etiologies. Superimposed alcohol hepatitis leads to liver decompensation and is clinically categorized as acute-on-chronic liver failure.

DiagnosisTop

1. Laboratory features: There are no definitive laboratory tests to diagnose alcohol-related liver disease. Alcohol-related fatty liver is diagnosed on the basis of chronic alcohol misuse, elevated serum gamma-glutamyl transferase (GGT) levels, and signs of fatty infiltration on ultrasonography. A patient presenting with alcoholic hepatitis may have an elevated serum GGT level, bilirubin >51 micromol/L, elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT) typically <500 IU/L (often <300 IU/L), and an AST/ALT ratio of >1.5 to 2. Additional laboratory abnormalities may include elevated serum alkaline phosphatase (ALP) levels, elevated ferritin, elevated prothrombin time (PT)/international normalized ratio (INR), a variety of electrolyte disturbances (eg, hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia), respiratory alkalosis, acute kidney injury, macrocytic anemia, thrombocytopenia, and leukocytosis with neutrophilic predominance.

2. Imaging and histopathologic features:

1) Ultrasonography is readily completed to evaluate for signs of cirrhosis and portal hypertension (eg, nodular-appearing liver, ascites, splenomegaly) and to exclude other etiologies of liver diseases or associated conditions (eg, Budd-Chiari syndrome, portal vein thrombosis). Ultrasonography may reveal nonspecific liver hyperechogenicity secondary to fatty infiltration.

2) Vibration-controlled transient elastography (VCTE) is an effective noninvasive test for staging the degree of liver fibrosis. Patients should abstain from alcohol for 1 to 3 weeks prior to completion of this test for improved accuracy, as active alcohol consumption and, in particular, alcohol hepatitis increase liver stiffness measurements and may overestimate the degree of liver fibrosis. VCTE overestimates liver stiffness in acute alcoholic hepatitis secondary to active liver inflammation. In general, VCTE results may progressively improve for up to several months after the elimination of the liver insult; initially by dampening of the necroinflammatory process (falsely elevates score) and subsequently by some regression in liver fibrosis.

3. Liver biopsy is not routinely recommended if the clinical, laboratory, and imaging data are suggestive of alcohol-related liver disease. Histologic examination of liver biopsy specimens may reveal macrovesicular steatosis, balloon hepatocyte degeneration, Mallory bodies, and in later stages necroinflammatory lesions and cirrhosis.

Diagnostic Criteria

Clinical diagnosis of alcoholic hepatitis is often defined as onset of jaundice within the prior 8 weeks, ongoing alcohol consumption (>40 g in women and >60 g in men) for >6 months, <2 months of abstinence prior to presentation/jaundice, AST 50 to 400 IU/L, and AST/ALT ratio >1.5. An infection may present a very similar picture to alcoholic hepatitis among patients with cirrhosis. A number of clinical predictive tools have been developed to determine the severity of alcohol-related hepatitis. These include the Model for End-Stage Liver Disease and Seum Sodium Concentration (MELDNa) score, Maddrey discriminant function (MDF) score, and Glasgow alcoholic hepatitis score (GAHS).

Severe alcoholic hepatitis is defined as MDF ≥32, MELDNa ≥21, or GAHS ≥9. These scores may be calculated manually or online (eg, at mdcalc.com).

Differential Diagnosis

Differential diagnosis should include (1) other causes of fatty liver (see Nonalcoholic Fatty Liver Disease); (2) hepatitis (eg, viral hepatitis/infection, drug-induced liver injury, autoimmune hepatitis).

TreatmentTop

1. Abstinence: Complete abstinence from alcohol may allow for regression of alcohol-related liver changes in patients without cirrhosis and reduces mortality in patients with progression to end-stage liver disease. Psychosocial support and participation in an alcohol abstinence program are highly recommended and may reduce the likelihood of relapse.

2. Nutrition: Management of calorie and protein malnutrition (calorie intake, 35-40 kcal/kg/d; protein intake, 1.2-1.5 g/kg/d) and other dietary deficiencies associated with alcohol misuse is necessary; these most commonly include deficiencies of vitamin A, D, thiamine, folic acid, pyridoxine, and zinc.

3. Pharmacologic therapies can be considered in patients with severe alcoholic hepatitis. Of note, there is considerable discussion regarding each of those therapies and the current North American clinical practice guidelines suggest the use of glucocorticoidsEvidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Thursz MR, Richardson P, Allison M, et al; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278. PubMed PMID: 25901427. Lee YS, Kim HJ, Kim JH, et al. Treatment of Severe Alcoholic Hepatitis With Corticosteroid, Pentoxifylline, or Dual Therapy: A Systematic Review and Meta-Analysis. J Clin Gastroenterol. 2017 Apr;51(4):364-377. doi: 10.1097/MCG.0000000000000674. Review. PubMed PMID: 27636406. Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev. 2019 Apr 9;4:CD001511. doi: 10.1002/14651858.CD001511.pub4. PubMed PMID: 30964545; PubMed Central PMCID: PMC6455893. (preferably prednisolone) with lesser evidence for the addition of N-acetylcysteine (NAC), and suggest against the use of pentoxifylline.Evidence 3Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Lee YS, Kim HJ, Kim JH, et al. Treatment of Severe Alcoholic Hepatitis With Corticosteroid, Pentoxifylline, or Dual Therapy: A Systematic Review and Meta-Analysis. J Clin Gastroenterol. 2017 Apr;51(4):364-377. doi: 10.1097/MCG.0000000000000674. Review. PubMed PMID: 27636406. All those therapies are used at least by some (see Appendix).

4. Manage complications of cirrhosis and liver failure.

5. Liver transplant is a definitive therapy for patients eligible in a given jurisdiction with alcoholic cirrhosis or alcoholic hepatitis and account for 15% and 20% of all liver transplants in the United States and Europe, respectively.

Prognosis and Follow-UpTop

Severe alcoholic hepatitis is associated with a 1-month mortality rate of 20% to 50%. Nonsevere alcoholic hepatitis is associated with a 1-month mortality of <10%. Long-term outcomes are largely dependent on the presence of cirrhosis and maintenance of abstinence.

The frequency of follow-up visits depends on the stage of liver disease and severity of alcohol misuse. Clinicians should assess biochemical markers of liver function and screen for symptoms of portal hypertension or other complications of cirrhosis. Among patients with cirrhosis, liver ultrasonography should be performed every 6 months as part of screening for hepatocellular carcinoma (see Cirrhosis).

AppendixTop

Glucocorticoids: The largest randomized control trial (STOPAH study1; N = 1103) showed a trend towards mortality benefit at 28 days when compared with placebo (13.8% vs 18%; P = 0.056). A follow-up meta-analysis of randomized clinical trials including the STOPAH study showed that glucocorticoids reduce short-term mortality by 46%.2,3 Conversely, a recent Cochrane review by Pavlov et al4 concluded that the quality of evidence for or against the use of glucocorticoids is low or very low and more data are needed to make a more decisive recommendation.

Glucocorticoid use in severe alcoholic hepatitis is currently recommended by the American Association for the Study of Liver Diseases (AASLD) and the American College of Gastroenterology (ACG) among patients without absolute contraindications (active hepatitis B or tuberculosis). Relative contraindications include sepsis, infection, uncontrolled diabetes, and active gastrointestinal bleeding. Oral prednisolone is preferred over prednisone, as prednisone requires conversion to prednisolone by the liver. The usual dose is 40 mg/d for 4 weeks followed by tapering over 2 to 4 weeks. The Lille score (incorporating age, PT/INR, bilirubin, creatinine, and albumin; available at mdcalc.com) may be calculated on day 4 or 7 to determine the probability of favorable prognosis in the setting of glucocorticoid treatment. Glucocorticoids should be discontinued in patients with a Lille score ≥0.45.

NAC: In a 2011 randomized clinical trial Nguyen-Khac et al5 showed that NAC was associated with a short-term survival benefit at 28 days when used in combination with prednisolone (8% vs 24%; P = 0.006). A systematic review and network meta-analysis, comprising of 22 RCTs, that was subsequently published in 2015, included the aforementioned trial along with 3 other RCTs studying NAC. It found that NAC, but not pentoxifylline, may have additional short-term mortality benefit when added to prednisolone.3 The AASLD and EASL both give a weak recommendation to consider adding intravenous NAC to prednisolone in patients with severe alcoholic hepatitis with more studies needed to confirm efficacy and optimal dosing/duration of therapy.

Pentoxifylline did not show a survival benefit when compared with placebo in the STOPAH trial.6 A recent meta-analysis of 22 studies suggested that pentoxifylline may be associated with a 30% reduction in 28-day mortality based on low-quality evidence.2,3 The AASLD guideline on alcoholic liver disease originally published in 2010 recommended its use (400 mg tid for 4 weeks) in patients with contraindications to glucocorticoids, however in the 2018 guidelines the AASLD no longer recommends use of pentoxifylline in alcoholic hepatitis.

1 Thursz MR, Richardson P, Allison M, et al; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278. PubMed PMID: 25901427.

2 Lee YS, Kim HJ, Kim JH, et al. Treatment of Severe Alcoholic Hepatitis With Corticosteroid, Pentoxifylline, or Dual Therapy: A Systematic Review and Meta-Analysis. J Clin Gastroenterol. 2017 Apr;51(4):364-377. doi: 10.1097/MCG.0000000000000674. Review. PubMed PMID: 27636406.

3 Singh S, Murad MH, Chandar AK, et al. Comparative Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review and Network Meta-analysis. Gastroenterology. 2015 Oct;149(4):958-70.e12. doi: 10.1053/j.gastro.2015.06.006. Epub 2015 Jun 16. Review. PubMed PMID: 26091937.

4 Pavlov CS, Varganova DL, Casazza G, Tsochatzis E, Nikolova D, Gluud C. Glucocorticosteroids for people with alcoholic hepatitis. Cochrane Database Syst Rev. 2019 Apr 9;4:CD001511. doi: 10.1002/14651858.CD001511.pub4. PubMed PMID: 30964545; PubMed Central PMCID: PMC6455893.

5 Nguyen-Khac E, Thevenot T, Piquet MA, et al; AAH-NAC Study Group. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011 Nov 10;365(19):1781-9. doi: 10.1056/NEJMoa1101214. PubMed PMID: 22070475.

6 Thursz MR, Richardson P, Allison M, et al; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278. PubMed PMID: 25901427.