Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH; such as Child-Turcotte-Pugh score, the Maddrey discriminant function, the Lille Model, the model for end stage liver disease scores, and the Glasgow alcoholic hepatitis score. At present, Corticosteroids or pentoxifylline are the current pharmacologic treatment options; though the outcomes from the therapies are poor. Liver transplantation as the treatment of alcoholic hepatitis remains controversial, and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option. Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.

Alcoholic liver disease (ALD) represents a spectrum of conditions ranging from reversible fatty liver to alcoholic hepatitis (AH), and cirrhosis. AH is an acute hepatic inflammation associated with significant morbidity and mortality that occurs in a subset of patients who consume excessive amounts of alcohol[1]. According to our recent study, there were 56809 hospital admissions with the primary diagnosis of AH, which accounted for 0.71% of all admission in the United States in 2007[1]. The average total charges during hospitalization for AH were $37769; which was higher than that from acute myocardial infarction, acute cerebrovascular disease, and acute pancreatitis[1]. Hospitalized AH patients result in significant healthcare cost and utilization[1]. In severe cases, patients have a very poor prognosis, with short term mortality around 30%-50%[2]. A typical patient with AH provides a history of an average daily consumption of over 80 g of ethanol for over 5 years[3].

The pathogenesis of alcoholic hepatitis is multifactorial. Current evidence suggests that the damage is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity[4]. Such metabolic pathways generate reactive oxygen species that are potent inducers of lipid peroxidation, which in turn causes hepatocyte death by necrosis or apoptosis. High levels of endotoxemia also have been documented among patients who have AH, probably because of increased intestinal permeability[4]. Endotoxin (lipopolysaccharide) binds to lipopolysaccharide-binding protein, and the complex then attaches to the CD14 molecule on Kupffer’s cells that triggers pathways to cause Kupffer’s cell activation[5]. A variety of cytokines are released because of the heightened Th1 response, in particular interferon-gamma and tumor necrosis factor-alpha (TNF-α)[6]. Chemotactic factors such as interleukin-8 cause migration of polymorphonuclear leukocytes to hepatic lobules[7]. These changes induce the systemic inflammatory response syndrome characterized by malaise, fever, and peripheral neutrophil leukocytosis. TNF-α mediates its effects by binding to two cell surface molecules, TNF-R1 and TNF-R2[8]. TNF-R1 is the main inducer of hepatocytotoxicity through necrosis or apoptosis. Ethanol metabolism generates acetaldehyde, and malondialdehyde is one of the end products of lipid peroxidation[9]. Both compounds bind to cellular proteins to form stable adducts. The variable immune response to these neoantigens may contribute to the individual susceptibility to AH. It is likely that both nonimmunologic (oxidative stress, cytokine injury) and immunologic factors play important roles in the pathogenesis of AH[10]. A variety of treatment options in AH share a common treatment goal of blocking the myriad of innate immunologic responses[4,11,12].

AH patients generally present with fever, jaundice, hepatomegaly, ascites and/or hepatic encephalopathy. The cardinal sign of AH is the rapid onset of jaundice. Physical examination usually reveals a malnourished patient with fever, low blood pressure and tachycardia. Jaundice and ascites are universal and a significant number of patients have hepatic encephalopathy[13]. If palpable, the liver is usually enlarged and tender. A minority have an audible bruit in the right upper quadrant, believed to be due to increased blood flow in the hepatic artery[14]. Laboratory studies characteristically reveal serum levels of aspartate aminotransferase (AST) that are more than twice the upper limit of the normal range, although rarely above 300 IU per milliliter, whereas serum levels of alanine aminotransferase (ALT) are lower. The ratio of the aspartate aminotransferase level to the alanine aminotransferase level is usually greater than 2, although this finding is neither specific nor sensitive[15]. Elevation in the gamma glutamyltransferase level is more sensitive (70%) but less specific (65%-80%) than elevation of AST or ALT for excessive alcohol consumption[16]. Other biochemical and hematologic parameters often seen during AH include hypokalemia, hypomagnesemia, hyperuricemia, hypertriglyceridemia, and hyperferritinemia[17]. A low zinc level, hypoalbuminemia, and low blood urea nitrogen may indicate malnutrition[18]. An elevated mean corpuscular erythrocyte volume is found frequently in those ingesting more than 50 g alcohol per day[19]. Leukocytosis and thrombocytopenia are commonly seen. The white blood cell count is often elevated, although it may be even higher with leukemoid reactions. Thrombocytopenia may be transitory or persistent in those who have concomitant cirrhosis. Liver biopsy normally shows ballooning degeneration, focal hepatocyte necrosis, and neutrophilic infiltration[4,20].

Several clinical scoring systems, the Child-Turcotte-Pugh score (CTP)[21], the Maddrey discriminant function[22], the Lille Model[23], the model for end stage liver disease (MELD) scores[24], and the Glasgow alcoholic hepatitis score[25], have been derived to predict the clinical outcomes of patients with AH. The assessment of the disease severity becomes an important and practical issue for clinicians involved in the management of patients with AH. Many scoring systems have been developed for use in clinical practice.

CTP is traditionally used for cirrhotic patients with mortality rates of about 10% to 15%, 25% to 30%, and 70% to 80% at 1 year for stages A, B, and C, respectively. Although it is not a traditional scoring system for AH patients, the CTP score was useful in predicting mortality at 3 to 6 mo[26-28]. Presently, the CTP score is not widely used for assessing severity of AH.

The discriminant function index (DFI) was initially described by Maddrey et al[22] in a placebo-controlled study to assess the benefit of corticosteroid therapy in 55 patients with AH. Using the formula: 4.6 × prothrombin time (PT) in seconds + serum bilirubin (mg/dL), patients with a DFI above 93 and treated with placebo had a 28 d survival of 25%, whereas those with a score of 93 or lower had 100% survival. This score was then modified (modified discriminant function or mDF) using prolongation of PT in seconds (over control) instead of absolute value of PT[29]. Patients without treatment and mDF score of 32 or higher and/or the presence of encephalopathy had a 28 d survival of about 65%. One study confirmed this observation with untreated patients having 28 d survival of 68% among patients with mDF ≥ 32[30]. The current practice guideline recommends that AH patients with mDF score of ≥ 32 should be considered for corticosteroid therapy[31]. The advantages of the mDF are its simplicity of calculation and validation in many clinical trials. However, non-standardization of the PT testing with laboratory to laboratory variation depending on the type of thromboplastin used by the laboratory is a limitation[32].

About 40% of patients with severe AH failed to respond to treatment with steroids. In a prospective study on 320 biopsy-proven severe AH, non-responders to steroids could be identified based on early change in bilirubin level and other five variables. This led to the development of Lille score[23]. Survival at 6 mo was lower for patients with a Lille score of 0.45 or higher compared with patients with Lille score of less than 0.45 (25% vs 85%, P < 0001). The corticosteroid was discontinued for patients with a Lille score of 0.45 or greater at 1 week. The Lille score maintains accuracy in predicting the survival when used across a range. In a retrospective study on 641 biopsy-proven AH, a linear correlation with survival was seen among groups with Lille score of less than 0.16, 0.16 to 0.56, or greater than 0.56 with survival rates of 87%, 70%, and 21%, respectively at 6 mo[33]. The drawback of this scoring system is that it does not guide initiation of steroid treatment because it cannot be calculated at the time of admission.

The MELD score was initially developed to predict survival in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunting. It has since been revised and validated to predict survival for patients with cirrhosis and is the basis for organ donor allocation in liver transplantation[24,26,34]. Laboratory values used to calculate the MELD score are the international normalized ratio, creatinine, and bilirubin. Two recent studies showed that MELD score is useful for predicting 3 mo mortality of patients with severe AH not treated with corticosteroids[27,35]. Its accuracy was comparable to that of DF in predicting 3 mo mortality of patients with severe AH[35]. Using the optimal cutoff point (21 for MELD and 37 for DF), MELD had a sensitivity of 75% and a specificity of 75% and DF a sensitivity of 88% and a specificity of 65%. Another study confirmed that DF and MELD had similar accuracy in predicting survival of patients with AH[27].

The Glasgow Alcoholic Hepatitis Score (GAHS) was developed in an effort to overcome the low specificity of the Maddrey DF and lack of an optimal predictive cutoff point for the MELD score. It was derived from a retrospective analysis of patients with ALD, with logistic regression used to identify variables associated with mortality[25]. GAHS is a scoring system based on age, serum bilirubin, blood urea nitrogen, PT, and the peripheral white cell count. GAHS ≥ 9 is a predictor of mortality and is more accurate than DF in predicting both 28- and 84 d mortality but is equivalent to MELD in predicting 28 d mortality[25].

An ideal prognostic scoring system should be simple, accurate, validated and should be able to guide treatment initiation and response. However, we still do not have a single scoring system that passes all these criteria. At present, the mDF score continues to be used for initiating treatment and the Lille score for guiding treatment response. Table 1 showed the scoring system to assess the severity of AH.

General treatment of alcoholic hepatitis includes treatment of ascites by salt restriction and the use of diuretics, and treatment of hepatic encephalopathy by lactulose and gut-cleansing antibiotics. Infection should be treated with appropriate antibiotics, chosen according to the sensitivity of the organism isolated[36]. A daily protein intake of 1.5 g/kg of body weight is recommended. Administration of B-complex vitamins is required to prevent Wernicke encephalopathy[37]. Benzodiazepine should be used for acute alcoholic withdrawal syndrome with caution due to potential encephalopathy precipitated. Careful and frequent monitoring with a validated withdrawal-symptom scale such as the Clinical Institute Withdrawal Assessment for Alcohol should be considered[38]. Pharmacological therapies for AH are discussed below.

In summary, alcoholic hepatitis is still a major problem in the United States due to significant morbidity and mortality. Currently, corticosteroids or pentoxifylline are the main pharmacological treatment options; though the outcomes from the therapies are poor. Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological/hepatoprotective agents to treat AH. There are several ongoing studies supported by the National Institute on Alcohol Abuse and Alcoholism through multi-institutional consortia to test several novel compounds for AH[64]. Once completed, it is expected that the results from these trials will lead to the advancement in the therapy for patients with AH.