His fingernails had a distal thin brown-pink transverse band, a white nail bed, and no lunula.
MOHANNAD DUGUM, MD
Department of Internal Medicine, Medicine Institute, Cleveland Clinic
NIZAR ZEIN, MD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic; Associate Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
ARTHUR McCULLOUGH, MD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH
IBRAHIM HANOUNEH, MD
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western University, Cleveland, OH
ADDRESS: Ibrahim Hanouneh, MD, Department of Gastroenterology and Hepatology, A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: [email protected]
Alcoholic hepatitis, in its severe form, is a devastating acute condition that requires early recognition and specialized tertiary medical care. This paper summarizes its epidemiology, pathophysiology, assessment, and treatment.
ALCOHOLIC HEPATITIS, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.
Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.
New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.
ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER
Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.1
Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, TABLE 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.2
Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.
Alcoholic hepatitis varies in severity from mild to life-threatening.3 Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.4 Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.7
Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.8 The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.9 Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.
FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION
Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.
The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.10 Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.
In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (FIGURE 1).11
Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.12
THE DIAGNOSIS IS MAINLY CLINICAL
The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.13
Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.
Elevated liver enzymes and other clues
Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.
In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,14 with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.
Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.15
Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.
Screen for alcohol intake
Women are at higher risk of developing alcoholic hepatitis
During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.16 Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.17
Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.18,19 The CAGE questionnaire consists of four questions:
A yes answer to two or more questions is considered clinically significant.
Is liver biopsy always needed?
Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.20
However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.
Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.
In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.21
However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.
The major enzymes involved in alcohol metabolism are CYP2E1 and ADH
Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.22
ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS
Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (TABLE 2).
The MDF (Maddrey Discriminant Function)6 system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.6
The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.
The MELD (Model for End-stage Liver Disease) score. Sheth et al23 compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.
Another study found a MELD score of 21 to have the highest sensitivity and speciﬁcity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.24
The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.25
The GAHS (Glasgow Alcoholic Hepatitis Score)26 was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.26
The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days27:
Both the GAHS and ABIC score are limited by lack of external validation.
The Lille score.28 While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on ﬁve pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.28
His fingernails had a distal thin brown-pink transverse band, a white nail bed, and no lunula.
When managing a patient with chronic alcohol abuse who is beginning to withdraw, expect the unexpected.
A variety of questionnaires can be used. The important thing is to be proactive about screening for this very common yet underrecognized problem...
We have learned much about the neurochemical basis of alcohol dependence over the past 20 years, but we still have only a few drugs for treating...
Alcoholic hepatitis can mimic an infection, presenting with fever and elevated white blood cell count.
Evaluating for infections in these patients is important, as about a quarter of them are infected at the time of presentation.