COMMENTARY

Treating Alcoholic Liver Diseases Requires a Full-Spectrum Approach

Rowen K. Zetterman, MD

Disclosures

July 16, 2018

Alcoholism: A Global Disorder

Consumption of alcohol-containing (ethanol) beverages is a worldwide cause of preventable alcoholic liver disease[1] and can add to the progression of other liver diseases, such as hepatitis C virus infection.[2] Alcohol is a significant worldwide cause of death, although more frequently in men than in women.[3]

A Danish study of patients with alcoholic hepatitis found a 5-year mortality of 47%, which rose to 69% for those with alcoholic hepatitis and cirrhosis.[4] Because of risk associations, patients suspected of having alcoholic liver disease should also be tested for hepatitis C and hepatitis B virus infection.[5,6]

Screening for excessive alcohol intake is an important preventive measure and should be standard of care during clinical evaluation of older children and adults. AUDIT (Alcohol Use Disorders Inventory Test) is a 10-question screen for increased alcohol consumption and alcohol dependence.[7] Patients with a positive screen should be referred for treatment intervention.

For those with evidence of liver injury, abstinence from further ethanol intake may be the most important treatment they receive to improve their long-term outcome, when coupled with treatment of their liver disease.[8]Baclofen has been used in selected patients to reduce recidivism.[3,8]

Elusive Pathophysiology

Multiple manifestations of liver disease can develop owing to alcohol. Fatty liver, alcoholic hepatitis, cirrhosis, acute-on-chronic liver failure, and hepatocellular carcinoma are all risks of significant alcohol intake.[9] Fatty liver is the most common histologic manifestation of chronic alcohol consumption. Hepatocellular carcinoma typically develops in patients with end-stage alcoholic cirrhosis but has been described in noncirrhotic alcoholic patients.

The pathophysiologic mechanism leading to end-stage alcoholic hepatitis and cirrhosis remains elusive. Only 10%-20% of chronic alcoholics are at risk for cirrhosis, despite similar alcohol consumption in all. Nutritional deficiencies, genetic predisposition, immune events, differences in ethanol metabolism, and effects of circulating endotoxins have been considered.[9] Alcohol increases intestinal permeability, and recent studies suggest that changes in the intestinal and circulating microbiome may have a role in the development of advanced alcoholic liver disease.[10,11]

The development of alcoholic liver disease seems to depend on the quantity and duration of ethanol intake, ethnicity, and genetic predisposition.[12] Despite greater overall death rates from alcohol for men, women who consume similar daily amounts of ethanol as men are at even greater individual risk of developing severe end-stage liver disease.[13,14] Hispanic males and Native Americans also have an increased risk for advanced alcoholic liver disease.[15,16]

Development of alcoholic liver disease may also be related to associated obesity and malnutrition.[17,18] Metabolic syndrome in alcoholic patients may increase the severity of developing alcoholic liver disease.[19] Type 2 diabetes mellitus increases mortality and hospitalization rates in those with alcoholic liver disease.[19,20] Patients with excessive alcohol consumption and coexisting obesity have a greater risk of developing alcoholic hepatitis and cirrhosis.[18,21,22] Analysis of patient information obtained in Scottish cohort studies found an additive effect of obesity to alcohol intake in development of liver disease.[22] Obesity may also increase the risk for hepatocellular carcinoma.[23]

Common Diseases

Fatty Liver Disease

Fatty liver is a common hepatic manifestation of excessive alcohol consumption, occurring in the majority of chronic alcoholics[24]; it is typically reversible with ethanol abstinence. Ethanol consumption can accelerate fibrosis and liver injury with other types of liver disease. In patients with nonalcoholic fatty liver disease, excessive alcohol consumption also increases progression and may be related to the subsequent development of hepatocellular carcinoma.[25]

Alcoholic Hepatitis

The mechanism that results in the progression of alcoholic liver injury to alcoholic hepatitis remains unclear. In some patients, a recent increase in total daily intake of alcohol precedes the clinical development of alcoholic hepatitis.[26]

It can be difficult to separate alcoholic hepatitis from advanced nonalcoholic fatty liver disease when both obesity and excessive alcohol consumption are present.[26] Patients with alcoholic hepatitis may have associated fever, right upper-quadrant pain and hepatic tenderness, systemic inflammatory response syndrome, and signs of portal hypertension with ascites, encephalopathy, and splenomegaly. Alcoholic hepatitis is variable in clinical severity. Patients with severe alcoholic hepatitis may have a 30-day mortality of more than 30%.[27] When alcoholic hepatitis develops on a background of alcoholic cirrhosis, acute-on-chronic liver failure may also result in high mortality.[28] Coexisting bacterial infection can occur in patients with severe alcoholic liver disease[29] and increase the risk for multiorgan failure.[30]

Liver biopsy is no longer routine in establishing the diagnosis in alcoholic liver disease.[3] It is beneficial, however, when the diagnosis of alcoholic liver disease is in question.[8] A recent histologic study found that the severity of hepatocyte ballooning degeneration and the density of Mallory-Denk bodies can predict the clinical response to corticosteroid treatment.[31]

To assess the clinical severity of alcoholic hepatitis, Maddrey discriminant function[32] and Model for End-Stage Liver Disease (MELD) scores[33] are commonly used. Alcoholic hepatitis is considered severe with a Maddrey discriminant function score > 32 or MELD score > 20,[8] although the MELD score may be a better indicator of outcome.[34] A combination of a pretreatment MELD score coupled with the Lille score[35] at the end of the first week of corticosteroid treatment is best for predicting disease severity and clinical outcome.[36,37] Patients with alcoholic hepatitis can recover with return of normal liver histology, although most present with or develop cirrhosis.

The clinical severity of alcoholic hepatitis may be increasing[38] and is associated with a greater prevalence of coexisting sepsis and signs of end-stage liver disease, including encephalopathy, gastrointestinal bleeding, and hepatorenal syndrome. Systemic inflammatory response syndrome[39] in patients with alcoholic hepatitis is predictive of a greater risk for multiorgan failure.[40]

Alcoholic Cirrhosis

Up to 20% of those with excessive alcohol consumption are at risk for development of hepatic cirrhosis.[41] Patients with alcoholic cirrhosis may develop portal hypertension and hepatocellular carcinoma and should be screened for esophageal varices and also receive a hepatic ultrasound every 6 months to screen for carcinoma. Cirrhotics who resume alcohol consumption and develop recurrent alcoholic hepatitis may present with acute-on-chronic liver injury and multiorgan failure.

The American College of Gastroenterology,[8] the American Gastroenterological Association,[40] and the European Association for the Study of the Liver[3] have all released recent guidelines for the evaluation and treatment of alcoholic liver disease.

Interventions and Treatments

For patients with alcoholic liver disease, early and continued abstinence from alcohol may be the most important treatment that can be offered.[8,40,42] Any medical treatment of such diseases should be performed by multidisciplinary teams that include alcohol addiction specialists,[8] and also entail psychosocial and behavioral therapies.[43,44]

Resumption of alcohol consumption after recovery from alcoholic hepatitis is associated with an increased risk for subsequent mortality.[37] Patients presenting with advanced alcoholic liver disease should be tested for infection, because the presence of this alongside alcoholic hepatitis may increase the risk for death and/or poor response to treatment.[30]

Because protein-calorie malnutrition is common in patients with alcoholic hepatitis,[45] they should be considered for nutritional supplementation.[8] To be sufficient, this nutritional treatment should provide 1-1.5 g protein/kg body weight and 30-40 kcal/kg body weight daily.[40]

In terms of pharmacotherapy, early trials suggested that pentoxifylline could improve survival in patients with advanced alcoholic hepatitis.[46] This appeared to be a consequence of reducing the development of hepatorenal syndrome, because those with elevated creatinine levels treated with pentoxifylline did not have improved survival. A subsequent randomized trial of pentoxifylline in severe alcoholic hepatitis did not show a positive effect.[47] Although pentoxifylline may reduce the risk for hepatorenal syndrome,[48] existing evidence does not support its use as the sole treatment for severe alcoholic hepatitis.[8]

There have been multiple randomized clinical trials of corticosteroids as therapy for alcoholic hepatitis.[48] Meta-analyses of these trials suggest this treatment leads to improved short-term mortality,[49,50,51] including reduced risk for hepatorenal syndrome when both corticosteroids and pentoxifylline are used.[49,51] The STOPAH trial[52] evaluated clinical response at 28 days of treatment with corticosteroids, pentoxifylline, or both compared with placebo in 1053 patients.[47] No therapy resulted in a statistically significant reduction of mortality, although corticosteroids had a greater reduction in mortality at 28 days compared with other groups. At 90 days after initiation of treatment, there was no observed differences in long-term outcome for any treatment.

On the basis of these many studies, current recommendations are that patients with severe alcoholic hepatitis (Maddrey discriminant function score > 32 or MELD score > 20) should receive corticosteroid treatment[8] with 32 mg of methylprednisolone daily for 28 days.[40] The Lille score[35] uses assessment of patient age, renal insufficiency, albumin, prothrombin time, bilirubin, and evolution of bilirubin on day 4[53] of day 7[35] to provide an early assessment of outcome of 28-day treatment response with corticosteroid therapy.

Corticosteroids may increase the risk for infection during treatment of alcoholic hepatitis. Increased levels of circulating bacterial DNA is predictive of infection up to 7 days before clinical recognition of sepsis.[54]

Transplantation

Liver transplantation is considered the last hope for treating patients with end-stage alcoholic liver disease. The number of liver transplants performed annually in the United States for alcoholic liver disease is increasing.[55] When complications of portal hypertension develop in patients with cirrhosis, transplantation should be considered and pretransplant evaluation planned.[8]

Six months of sobriety has been a prerequisite for consideration of liver transplantation for alcoholics. This recommendation is used to determine whether alcoholic hepatitis will have sufficient clinical improvement to avoid transplantation, to provide a treatment opportunity to reduce posttransplant alcohol relapse, and perhaps in response to public opinion about the shortage of donor livers and concerns about outcomes of transplanting those with alcoholic hepatitis.

Recent studies find that patients with alcoholic hepatitis are suitable candidates for liver transplantation.[56,57] Short- and long-term survival of patients transplanted for alcoholic hepatitis is similar to that in patients transplanted for end-stage alcoholic cirrhosis. Alcoholism relapse rates are also similar in both groups. This has led to liver transplantation being considered for highly selected patients with severe alcoholic hepatitis.[8] In managing those with severe alcoholic hepatitis, patients can be treated with corticosteroids and if there is lack of response by 7 days (as assessed by the Lille score), they can be considered for immediate liver transplantation.[56,58]

Patients transplanted for alcoholic hepatitis are not at higher risk for alcoholism relapse. A meta-analysis of 11 studies of liver transplantation for alcoholic hepatitis indicated that relapse does not significantly differ between this group and those transplanted for alcoholic cirrhosis.[59] This study also found that 6-month posttransplant survival is also similar. All patients transplanted for alcoholic liver disease should have regular assessment for recidivism, because increased mortality can occur with recurrent alcoholic hepatitis and cirrhosis.[60] There also is a significant risk for cardiovascular disease and carcinoma after liver transplantation in alcoholics.[61] Patients should be counseled to stop smoking to reduce smoking-related carcinomas and heart disease.[62]

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