Alcoholic Hepatitis: From Pathogenesis to Treatment

By Sougioultzis, S; Dalakas, E; Hayes, P C; Plevris, J N

Key words: Alcoholic hepatitis – Diagnosis – Management – Pathophysiology – TNF-α inhibition

ABSTRACT

Alcoholic hepatitis is a serious complication of alcohol abuse due to its high mortality rates particularly at short term. It may complicate pre-existing alcoholic fatty liver or cirrhosis and is mainly diagnosed on clinical and laboratory grounds although liver biopsy is occasionally needed to exclude other pathology and confirm the diagnosis. Accumulating evidence suggests that cytokines and immunity are actively involved in its pathogenesis. Management includes abstinence and supportive care. Treatment with corticosteroids has been studied in several clinical trials with conflicting results. However, recent evidence supporting the beneficial effect of TNF-α inhibition provides an encouraging alternative. Here we summarise the current state in diagnosis and management of alcoholic hepatitis and briefly review the latest advances in pathophysiology that may lead to new therapeutic strategies for this difficult clinical condition. Data sources: Medline 1966-2005, EMBASE/Excerpta Medica 1980-2005, The Cochrane Library (2005 Issue 2) and contact with authors of published reports.

Introduction

Alcohol abuse causes a spectrum of histopathological changes in the liver that range from the usually benign fatty liver, observed in more than 90% of chronic alcoholics1,2 to the more serious lesions of alcoholic hepatitis (AH) and cirrhosis that fortunately develop in only 20%-40% of the individuals abusing alcohol for an extended period of time3,4. Although the amount and pattern of alcohol consumption is a well recognised predisposing factor for the development of serious liver pathology, environmental factors and host’s genetic make-up probably play significant roles that have not been entirely explored5-18.The consumption of alcohol has also been demonstrated to significantly increase the risk and progression of liver injury in subjects with concomitant diseases such as obesity19,20, hepatitis C21-23, and haemochromatosis24. From the pathology point of view, AH is characterised by neutrophil infiltration of the perivenular areas, along with other morphological changes suggestive of alcohol related liver injury, including hepatocyte ballooning and necrosis, presence of Mallory bodies and pericellular fibrosis. These lesions may co-exist with fatty infiltration or cirrhosis25.

For the clinician, AH refers to acute decompensation of the liver function in an individual with history of alcohol abuse. The clinical and laboratory features as well as the clinical assessment of severity and prognosis of AH will be described in detail below. A computer based search was performed for published worldwide studies on AH (Medline Search from 1966 to 2005, the search term was alcoholic hepatitis; EMBASE/Excerpta Medica 19802005; The Cochrane Library, Cochrane Hepatobiliary Group, 2005 Issue 2). Authors of published reports were contacted and provided information on unpublished studies and updated information of ongoing trials.

Pathophysiology

Current evidence suggests that alcoholic liver damage is the end result of the complex interplay between ethanol metabolism, inflammation and immunity. All hepatic cellular components, namely hepatocytes, Kupffer, stellate and endothelial cells, are involved, at some stage, in the pathogenesis of alcohol-induced liver injury. A brief overview of the current understanding of alcohol mediated liver injury follows.

Ethanol-induced oxidative stress

Ethanol is oxidised in hepatocytes first to acetaldehyde and subsequently to acetate, via two well-studied metabolic pathways. The first is the combination of cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase leading to its sequential oxidation; the second is the ethanol-inducible microsomal ethanol oxidizing system (MEOS) with its major component, cytochrome P450 2El (CYP2E1)26. Ethanol oxidation eventually generates reactive free radicals leading to oxidative stress, a condition that is further reinforced by the depletion of the antioxidants glutathione and vitamin E observed in chronic alcoholics26,27. Oxidative stress primes the transcription of several cytokines and growth factors, potentially from all hepatic cell types, leading to the attraction of immune cells to the hepatic parenchyma. In addition, it also results in the peroxidation of membrane and lipoprotein lipids, thus facilitating cellular necrosis and/or apoptosis28-30. Furthermore, acetaldehyde and other reactive molecules generated through ethanol oxidation have the propensity to bind covalently to proteins to form adducts which are potential neoantigens that trigger host’s adaptive immune response. Indeed, anti-acetaldehyde antibodies have been found in alcoholics31,32 and correlated with the severity of liver injury33, suggesting that they are probably involved in alcohol induced hepatic damage. Oxidative stress may also facilitate the production of auto-antibodies against phospholipids, alcohol dehydrogenase, cytochrome P4502E1 and antinuclear antibodies, which are detectable in 25%-50% of patients with AH and cirrhosis34-37. However, the role of autoimmunity in the pathogenesis of liver damage in alcoholics still remains speculative38.

Apart from the direct and indirect insults of ethanol to the liver, recent evidence suggests that alcohol ingestion also increases the translocation of endotoxin, and possibly other noxious substances, from the gut lumen to the portal circulation39,40. Endotoxin in turn, stimulates Kupffer cells to produce cytokines and free radicals, therefore perpetuating the oxidative stress, increasing further the hepatic cytokine load. Taken together, all the above constitute the current working hypothesis towards a rational and mechanistic approach to alcohol mediated liver injury. It should be pointed out that the exact sequence of events that leads to severe liver damage in alcoholics is still incompletely understood.

Tumour necrosis factor-α (TNF-α)

A lot of attention has been focused recently on the role of TNF- α and apoptosis. TNF-α is a macrophage-derived factor and is considered a key mediator in a wide variety of biological processes such as fever, septic shock, tissue injury, tumour necrosis and apoptosis. TNF-α transcripts trimerise to form the 51 kD active TNF-α ligand which can bind to either a 5SkD receptor (TNFRl], present on most cell types, or to a 75 kD receptor (TNFR2), expressed mainly by immune and endothelial cells41. The wide distribution of TNF receptors provides a possible explanation for its diverse biological effects. After binding to its receptors, TNF-α triggers a complex intracellular signalling cascade involving the activation of the transcription factor NF-α and mitogen-activated protein kinases (MAPKs), resulting in the production of pro-inflammatory cytokines, such as interleukin 6 (IL- 6) and interleukin 8 (IL-8) and upregulation of adhesion molecules41. TNF-α can also induce apoptosis in a wide variety of cell types42. However, normal hepatocytes seem to be resistant to the pro-apoptotic action of TNF-α, an effect that is thought to be mediated by the anti-apoptotic properties of NF-??43. In addition, animal studies have shown that TNF-α initiates liver regeneration after partial hepatectomy by activating TNFR144.

Despite the above observations that suggest a rather beneficial effect in the normal liver, TNF-α has been reported elevated in admission sera of patients with AH and its levels have been correlated with disease severity and mortality45,46. Concurring animal studies have shown that TNFRl knockout mice are resistant to alcohol induced liver damage47 and that the administration of TNF- α antibodies prevents liver injury in alcohol-fed rats48. It is therefore believed that TNF-α biologic activities are altered in alcoholic liver disease, favouring inflammation and apoptosis rather than hepatocyte proliferation. The underlying molecular mechanisms are still unclear but ongoing research suggests that alterations in the NF-κB related signalling49 probably influenced by the cytokine milieu and other pro-apoptotic pathways are involved29’43. Nonetheless, the effect of TNF-α blockade has been studied in a small number of patients with AH thus far, with encouraging results50,51. These clinical trials will be discussed in more detail in the treatment section of this review.

Hepatocyte apoptosis

Recent studies implicate hepatocyte apoptosis in the pathophysiology of AH. Specifically, several research groups have found that hepatocyte apoptosis is increased in patients with alcoholic liver disease28,30,52,53 and is correlated with both clinical28,30 and histological indices of severity30. Although correlation does not establish aetiological connection between the studied parameters, it surely highlights the necessity for further exploration on the role of apoptosis in alcoholic liver disease, bearing in mind that apoptosis may also be a protective mechanism aiming at the elimination of seriously damaged cells54. Admittedly, more research is needed in this field before therapeutic interference with apoptosis is attempted55.

Diagnosis

Alcohol abuse/dependency

AH is an acute disease, yet all patients give an extended history of alcohol a\buse that is sometimes difficult to obtain from them or even their relatives. Repeated questioning, perhaps from different care providers may be necessary. Questionnaires have also been developed to aid the clinician in gathering the necessary information but most of them are lengthy and are used mainly for research purposes56. Surrogate markers, such as carbohydrate- deficient transferrin, mitochondrial aspartate aminotransferase and serum sialic acid57″59, have also been evaluated as a more objective tool to document alcohol abuse, but they are not used in routine practice, since they do not add to the overall accuracy obtained by the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, γ-glutamyl transpeptidase (GGT) and mean corpuscular volume (MCV).

Clinical features

Presentation on admission may vary and depends to some extent on the severity of the underlying liver pathology3. Patients may present with non-specific complaints such as anorexia, fatigue, confusion and epigastric pain or with more severe symptoms indicative of hepatic failure, such as jaundice, ascites, hepatic encephalopathy or gastrointestinal haemorrhage.

Tender hepatomegaly, sometimes with an audible bruit, is a common finding in clinical examination and is due to fatty infiltration and hepatocyte swelling. Jaundice and moderate fever (~38C) are also characteristic clinical findings. Fever should prompt for rigorous evaluation to exclude other sources, such as bacterial peritonitis if ascites is present, pneumonia or urinary tract infection. Patients may also have stigmata of chronic liver disease, such as spider naevi, palmar erythema, parotid enlargement, Dupuytren’s contractures, gynaecomastia and testicular atrophy. Signs of poor nutrition, peripheral neuropathy, dementia or cardiomyopathy may also exist due to extrahepatic alcohol toxicity60.

Laboratory findings

Common laboratory abnormalities in patients with AH include elevation of serum transaminases, GGT and alkaline phosphatase concentrations as well as hyperbihrubinaemia and prolonged prothrombin time. Aminotransferases are generally moderately elevated, rarely exceeding 10 times the upper reference limit. Their serum levels do not reflect the underlying histology and therefore they do not have prognostic utility. Characteristically, the AST is disproportionately elevated as compared to the ALT and the ratio AST/ ALT is usually > 2, a value that is seldom observed in other hepatic diseases. The reason for this is unclear but it probably reflects a relative underproduction of ALT in AH due to the depletion of pyridoxal 5′-phosphate, a cofactor for the enzymatic activity of ALT61. Levels of serum aminotransferases exceeding 500IU/L should question the diagnosis or encourage the investigation for co- existing liver pathology such as viral, ischaemic or drug induced hepatitis. On the other hand, moderate elevations of aminotransferases with an AST/ALT ratio [asymptotically =] 1 are suggestive of chronic viral hepatitis62 or nonalcoholic steatohepatitis63 rather than AH.

Other criteria65 and serological markers, such interleukin-866, laminin and collagen type IV67 have also been shown to correlate with disease severity but they are not used in clinical practice.

Haematological abnormalities are common in AH, can aid in diagnosis and may have prognostic significance. The MCV is elevated because of alcohol bone marrow toxicity and is therefore a marker for alcohol abuse albeit with a sensitivity of 50% while GGT elevation seems to be slightly better for this purpose with a sensitivity of 72%68. Macrocytosis may also reflect poor nutritional status with concomitant cobalamin or folate deficiency. Peripheral leukocytosis, in the absence of infection, is considered a hallmark of AH. Moreover, increased polymorphonuclear infiltrate in liver biopsy has been correlated with decreased survival, especially in cirrhotics69. It has been reported that increased peripheral neutrophil counts are associated with improved 1 -year survival following corticosteroid therapy70. However, the above observations are not necessarily contradictory, allowing for the fact that neutrophilia may indicate severe disease which in turn has a higher likelihood of response to corticosteroids. Thrombocytopenia is also observed as a result of primary bone marrow hypoplasia and/or splenic sequestration.

Supplementary laboratory tests may also be used to exclude other liver diseases that could co-exist with AH, such as viral hepatitis, acetaminophen toxicity, haemochromatosis or Wilson’s disease. In this regard it must be pointed out that the srologie tests for haemochromatosis may be unreliable in alcoholic hepatitis. Plasma ferritin concentrations have been found increased in alcoholics despite the absence of iron overload, and serum transferrin saturation may exceed 60% due to the suppression of liver transferrin synthesis by alcohol71,72. Therefore, genetic testing or liver biopsy maybe required if the clinical suspicion of haemochromatosis is high.

Imaging studies and histology

Imaging studies, mainly ultrasonography or computed tomography are primarily used to exclude other pathology such as cholecystitis, biliary obstruction, portal vein thrombosis and tumours. Sometimes they may also provide clues to the diagnosis by disclosing signs of fatty liver infiltration or cirrhosis. In most cases, alcoholic hepatitis can be reliably diagnosed from a non-invasive work-up, namely history, physical examination, laboratory test, and imaging studies. It has been reported that the sensitivity and specificity of the clinical diagnosis of AH is 91% and 96%, respectively73. However, liver biopsy may be necessary if the diagnosis is in doubt or in cases where concomitant liver pathology cannot be definitely excluded by other methods.

Treatment

As already stated, AH in its severe form is a life threatening condition.

Patients may show a sudden and marked clinical deterioration during hospitalization, manifested by the development of ascites, encephalopathy, gastrointestinal bleeding or hepatorenal syndrome while the mortality in the acute phase has been estimated to be as high as 58%74. Therefore, intensive clinical management must start from the admission, especially in patients who present with jaundice or have a DF > 32. Ascites, encephalopathy and gastrointestinal bleeding are poor prognostic signs and require immediate attention and appropriate management. The mainstay of therapy is still based on abstinence and supportive care.

General guidelines include adequate volume replacement therapy preferably after monitoring through a central line, avoidance of diuretics as they may precipitate hepatorenal syndrome and the administration of vitamins including thiamine, folate pyridoxine and possibly vitamin K75. Early institution of nutritional support by mouth or through a nasogastric tube (at least 25 kcal/kg/day) to assist liver function76 is recommended as well as the early institution of broad spectrum antibiotics after blood, urine and ascitic cultures have been taken75. Management of alcohol withdrawal with diazepam or chlordiazepoxide, titrated to vital signs and the level of arousal, is also of importance. The gravity of severe AH has led to extensive research towards specific therapies to halt hepatic deterioration and improve short term mortality.

Corticosteroids

Corticosteroids have been quite extensively studied in this setting. Their potent immunosuppressive and antiinflammatory properties provide the rationale for their use. At least 12 randomised, controlled clinical trials have assessed the effectiveness of Corticosteroids in AH. Five reported improved survival following corticosteroid therapy64,77-80) and seven found no benefit81-87. Subsequent meta-analyses also produced conflicting results. Three of them88-90 suggested a beneficial role of Corticosteroids in alcoholic hepatitis while one questioned their efficacy91. Nonetheless, after reviewing the published clinical trials and three meta-analyses, the American College of Gastroenterology recommended glucocorticoid treatment in patients with severe AH (DF > 32)92. The proposed treatment is prednisolone, 40 mg daily for 4 weeks followed by a taper. It has been estimated that seven patients need to be treated with Corticosteroids to prevent one death. In addition, a recent study by Mathurin et al., showed that a fall in serum bilirubin levels at day 7 in severe AH (DF > 32) patients treated with Corticosteroids was an important predictive factor for improved survival at 6 months. However, whether Corticosteroids should be discontinued in patients without a drop in serum bilirubin by day 7 needs validation from additional studies93.

In contrast, the efficacy of Corticosteroids has not been adequately evaluated in patients with severe AH and concomitant pancreatitis, gastrointestinal bleeding, renal failure or active infection and therefore treatment is not recommended in these patient subgroups94. It is obvious from the above, that corticosteroid treatment is far from optimal in severe AH and it is not a widely accepted practice. Several clinicians are reluctant to use corticosteroids or reserve this treatment for carefully selected patients.

Pentoxifylline

A recent study by Akriviades et al. produced promising results50. These investigators conducted a prospective, randomised, double blind study of adequate size (101 patients) to test the efficacy of pentoxifylline (PTX) in severe AH (DF > 32). PTX is a non-selective phosphodiesterase inhibitor that has been shown to decrease TNF-cx gene transcription95 as well as the production of other cytokines and chemokines96. They found that the patients who received 400 mg PTX three times daily for 4 weeks had a 40% reduction in mortality as compared to the placebo group (vitamin B12). The reduction in 4- week mortality was mainly attributed to the concomitantdecrease in the incidence of hepatorenal syndrome by 65%-70%. Baseline serum TNF- α was elevated in both treatment and placebo groups and was decreased by PTX, especially in the subgroup of patients with the more severe form of disease. In addition, TNF-α levels markedly increased over the study period in non-survivors compared with survivors, irrespective of treatment, further suggesting a connection of TNF-α to the pathophysiology of alcoholic hepatitis. PTX was found safe with minor side effects from the gastrointestinal tract. The study by Akriviades et al. suggested a beneficial role of TNF-α blockade, however, PTX appears to be a pleiotropic molecule96 and the observed benefit may well be the result of additional, still undetermined mechanisms. These initial results are encouraging and a randomised clinical trial is currently ongoing to help determine whether PTX has a role to play in the standard treatment of patients with severe AH94,97.

Anti-TNF therapy

Based on this promising evidence suggesting a beneficial effect of TNF-α blockade, two research groups tested the efficacy of infliximab, a chimeric mouse-human anti-TNF monoclonal antibody that is currently used for the treatment of rheumatoid arthritis and Crohn’s disease98, in patients with severe AH. The first published trial aimed to evaluate the tolerance and effectiveness of infliximab combined with steroids99. Twenty patients with biopsy proven severe AH (DF > 32) received prednisone 40mg/day for 28 days and either a single infusion of infliximab (5 mg/kg IV) or placebo at study entry. Standard nutritional support and vitamin supplementation as well as prophylactic antibiotic therapy in patients with low-protein ascites were also given. Histology, plasma interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured at baseline and at day 10. Infliximab was well tolerated but it did not affect histology at day 10. In contrast, a significant reduction of cytokine levels at day 10 and of DF at day 28 was noted in the infliximab treatment arm compared with the prednisone alone group. The investigators concluded that this small randomised controlled study prompts for a larger-scale survival trial99.

The second published trial is an open label study that included 12 patients with biopsy proven AH and a DF > 32(51). All patients received a single infusion of infliximab, 5 mg/kg of body weight, in the first 5 days following admission along with the standard supportive care. Corticosteroid therapy was not allowed in this study. Serial measurements of serum TNF-α and other cytokines (interleukin (IL)-Iβ, IL-6, IL-8, interferon – gamma] were performed during the 28-days study period. Two of the patients died during hospitalization from sepsis while 10 remained alive for a median of 15 (12-20) months. During the study period, serum bilirubin levels, Maddrey score, neutrophil counts and C-reactive protein fell significantly and there was a decrease in the serum levels of pro-inflammatory cytokines, albeit not significant. This was a small, uncontrolled pilot study, but, based on the observed clinical and laboratory improvement of these seriously sick patients, the authors again concluded that larger randomised control trials of anti-TNF antibody are warranted in patients with severe alcoholic hepatitis51.

A multicentre randomised trial of infliximab in severe AH (DF > 32) was in place and stopped in October 2002 by the French drug agency (AFSSAPS) after an interim analysis of the data gathered from the first 36 patients100. The aim of this study was to test whether there is any additional benefit of high dose infliximab (10 mg/kg at baseline, 2 weeks and 4 weeks) in patients receiving prednisolone (40mg/day) for 4 weeks. The control group included patients taking only prednisolone at the same dose and the main end point was the 2- month mortality rate. The interim analysis disclosed a two-fold increase of deaths in the infliximab group vs. the placebo group, mainly attributed to infection. It is difficult to draw safe conclusions from the above and despite the limited experience, it seems likely that low dose infliximab is safer than high dose101. Future, carefully planned dose-response studies are needed to clarify the role of infliximab in severe alcoholic hepatitis. The experience gained from the use of this regimen in rheumatoid arthritis and Crohn’s disease may be helpful both in dose adjustment as well as in predicting possible adverse events.

An alternative anti-TNF treatment using etanercept, a P75- soluble TNF receptor: FC fusion protein that binds and neutralises soluble TNF102,103 was recently studied in patients with moderate or severe AH104. In this open label pilot study, 13 patients with moderate or severe AH were targeted for a 2-week treatment period. The 30 day survival rate of patients receiving etanercept was 92% although 23% of patients had to discontinue due to adverse events including infection, hepatorenal decompensation and GI bleeding. The study was not powered to demonstrate the efficacy of etanercept in AH although it supports the rationale for further larger controlled trials to assess its safety and efficacy97,100,101,104. Currently in progress is a Phase II randomised, double-blind, placebo-controlled trial using etanercept in patients with moderate or severe AH105. This multicentre study based at the Mayo Clinic under Dr. Vijay Shah will hopefully address the safety and efficacy issues of etanercept in treating AH.

Nutritional therapy

Patients with AH invariable have some degree of malnutrition and the severity of this protein-calorie malnutrition has been shown to closely correlate with mortality .. rate106,107. The underlying mechanisms responsible are yet unknown although it has been speculated that protein calorie malnutrition enhances liver damage and worsens mortality in AH patients by influencing the integrity of the immune system and impairing protein synthesis which is essential for hepatic regeneration108. Earlier clinical trials assessing the benefit of parenteral/enteral supplementation in patients with AH produced mixed results, suggesting that nutritional support improves the nutritional status and liver function of patients but not the early mortality rate108-112. Two recent randomised controlled clinical trials on enterai tube feeding and AH have been encouraging. The first trial by Cabr et al. compared the efficacy of total enteral nutrition to oral prednisolone in 71 patients with severe AH113. This trial demonstrated that during the treatment period of 28 days the mortality rates of the two groups were similar but in the immediate weeks after treatment the mortality rate was higher in the steroid treated group. The overall 1-year mortality rates between the steroid and the enterai feeding treated groups were 61% and 38% respectively and although this did not achieve statistical significance this trial raised the question of a potential synergistic effect of both treatments. To address this possibility, the same group conducted a pilot study with combined steroids and total enterai nutrition in patients with severe AH114. The authors concluded that a short course of steroids together with enteral nutrition is a good therapeutic option that needs further investigation by larger controlled trials.

Supportive treatments with potential benefit

The use of extracorporal liver support devices was developed to support patients with acute liver failure and was rarely used in patients with AH115-117. Recent clinical studies on a new non- biological extracorporal liver device known as the molecular adsorbents recirculating system (MARS) suggest a promising role in the treatment of severe AH118,119. The MARS device uses a hollow fibre dialyser in which the patient’s blood is dialysed against an albumin rich dialysate and allows for the transfer of albumin bound toxins into the dialysate. This dialysate is then perfused through a charcoal and anion exchange column to remove the toxins and regenerate the albumin rich dialysate. Heeman et al. conducted the first reported open label randomised controlled trial using MARS treatment on patients presenting with liver cirrhosis and a superimposed acute injury119. In this study many of the patients had AH as the precipitating event on the background of alcohol induced liver cirrhosis. Those patients receiving MARS treatment demonstrated an improved 30 day survival as well as an improvement in renal dysfunction, encephalopathy and hyperbilirubinaemia. Despite its small sample size and patient group heterogeneity the trial was encouraging and the authors concluded that further trials would be necessary to support their findings. Non-randomised MARS120,121 trials including a recent report by Jalan et al.118 which treated severe AH patients only, produced similar results to that of Heeman et al. In conclusion, MARS treatment appears to be a promising therapeutic option for patients with severe AH and randomised controlled trials are required to determine its efficacy in this group of patients.

Liver transplantation

The role of liver transplantation in acute AH remains controversial and there is limited data on its use as treatment. Most transplant programmes would exclude AH patients for consideration of a liver transplant because they have not met the requirement period of abstinence from drinking prior to transplantation122-124. The few studies that have looked at the outcome of transplanted patients with AH have tended to be small, retrospective studies where histological evidence of AH was identified in patients transplanted for chronic liver disease including alcoholic cirrhosis125-127. A more recent study by Tome et al. investigated the influence of superimposed AH on the outcome of liver transplantation in patients with alcoholic cirrhosis and compared them with patients with alcoholic cirrhosis alone123\. As with previous studies, AH was diagnosed histologically on the explanted livers and any patients with clinical signs of AH were not considered for transplantation. The authors demonstrated that survival post transplantation in alcoholic cirrhosis with superimposed AH was similar to alcoholic cirrhosis alone and to other causes of end stage liver disease.

Negative studies

Androgens have anabolic action by stimulating nucleic acid and protein synthesis thereby improving nutritional status and promoting cell repair and hepatic regeneration. Based on this notion, oxandrolone was studied for its effects in alcoholic hepatitis patients. Two randomised controlled trials by Mendenhall et al.84,128 failed to produce consistent results and a recently published systematic review could not demonstrate any significant beneficial effects of anabolic-androgenic steroids on any clinically important outcomes of patients with alcoholic liver disease129.

Insulin and glucagon have been shown to promote hepatic regeneration in an animal model130. Several studies have tested the efficacy of this approach in alcoholic hepatitis patients with conflicting results131,134. Moreover, complications including hypoglycaemic deaths have occurred.

Other groups have tried propylthiouracil (PTU) based on the theory that acute hepatitis patients are in a hypermetabolic state which in turn increases oxygen consumption and causes relative ischaemia in the perivenular areas. These changes are similar to those induced by thyroid hormone which together with concurring animal data135 justified the use of PTU. However, published clinical trials136,137 and a recent meta-analysis138 failed to demonstrate a uniform beneficial effect.

Colchicine has also been studied in alcoholic hepatitis as it has been shown that it inhibits leukocyte migration, inhibits collagen synthesis and enhances the activity of hepatic collagenases. However, two randomised controlled studies did not show any improvement in mortality139,140.

As briefly outlined above, none of these regimens have evidence based efficacy in alcoholic hepatitis and therefore none is currently recommended92,141,142.

Conclusion

Alcoholic hepatitis still remains a difficult to treat clinical condition. Abstinence, close monitoring and supportive care are the standard of care. Corticosteroids, despite the controversies about their efficacy, are still advocated by many clinicians. Ongoing basic research will help us to better understand the pathophysiology and will hopefully provide clues for targeted interventions. A lot of effort must also be devoted in clinical research in order to further clarify the role of promising new therapies such as pentoxifylline, anti-TNF treatment strategies and MARS.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2659_3, Accepted for publication: 24 June 2005

Published Online: 20 July 2005

doi:10.1185/030079905X56493

S. Sougioultzis, E. Dalakas, P. C. Hayes and J. N. Plevris

Department of Hepatology, The Royal Infirmary of Edinburgh and University of Edinburgh, UK

Address for correspondence: Dr J. N. Plevris, Department of Hepatology, The Royal Infirmary of Edinburgh, Chancellor’s Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK. Tl.: +44 131 242 1631; Fax: +44 131 242 1638; email: J.Plevris@ed.ac.uk

Copyright Librapharm Sep 2005