The management of alcoholic liver disease

Transcription

1 Journal of Hepatology 38 (2003) S2 S13 The management of alcoholic liver disease Stephen F. Stewart, Christopher P. Day* Centre for Liver Research, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK 1. Introduction Alcoholic liver disease (ALD) is the commonest cause of cirrhosis in the Western world, currently one of the ten most common causes of death [1]. Deaths from cirrhosis rose with per capita alcohol consumption from the 1950s to the 1970s in many Western countries, but have since declined out of proportion to the minor decrease in intake [2]. While this may be partly explained by changes in the age and ethnic background of these populations, it also seems likely to reflect advances in the management of patients with both alcohol and non-alcohol-related advanced liver disease. Clearly, any improvement in the management of the general complications of liver disease will have a beneficial effect on the management of patients with advanced ALD. However, this review principally focuses on treatment strategies that have been specifically directed at mechanisms involved in the pathogenesis of alcohol-related liver injury and considers their current and future role in the management of patients with the various stages of ALD. 2. The spectrum of ALD The spectrum of ALD ranges from fatty liver (steatosis), present in most, if not all heavy drinkers, through steatohepatitis, fibrosis and ultimately cirrhosis (Fig. 1). Patients with alcohol-related steatosis rarely present with liverrelated symptoms or signs and are usually identified following the discovery of abnormal liver blood tests performed during the routine investigation of either known or covert excessive drinkers. Although fatty liver is reversible with abstention [3], it is a risk factor for progression to fibrosis and cirrhosis in patients who continue drinking, particularly when the steatosis is severe and present in a mixed micro/ macrovesicular distribution [4]. Between 20 and 40% of persistent heavy drinkers will develop more serious liver disease. In some, the presentation will be with the syndrome * Corresponding author. Tel.: ; fax: address: c.p.day@ncl.ac.uk (C.P. Day). of acute alcoholic hepatitis (AH), characterised by fever, hepatomegaly and leukocytosis in association with the clinical and laboratory features of liver failure. Others will present for the first time with complications of portal hypertension, encephalopathy, or symptoms related to the development of hepatocellular carcinoma. Importantly, patients with histologically advanced ALD can be asymptomatic and have either mildly abnormal, or even normal, liver blood tests [5]. As a result, in patients without clinical evidence of decompensated liver disease, the staging of ALD requires liver biopsy. Whatever the stage of disease, abstinence from alcohol is the cornerstone of management and accordingly, will be reviewed first. This will be followed by a review of the specific treatment options available for patients presenting with acute AH, and finally, the treatment of patients with alcohol-related cirrhosis including the indications for, and the results of, orthotopic liver transplantation. 3. Achieving abstinence Since cessation or a marked reduction in alcohol intake has been shown to improve the histology and/or survival of patients with all stages of ALD [6 8], measures aimed at establishing and maintaining abstinence are a critical component of the management of patients with ALD (see Table 1). In our view, this is best achieved by close liaison between liver physicians and addiction psychiatrists with support from specialist alcohol nurses and trained counsellors [9]. Available treatments for alcohol-dependent patients can be divided into psychological and pharmacological. The so-called brief interventions are the simplest form of psychological therapy and can be implemented by nonpsychiatric staff. These interventions involve educating and informing patients regarding the nature of their problem and providing them with advice on how to go about changing their behaviour. In spite of the apparent simplicity of this form of management, brief interventions have been shown to significantly increase the chances of heavy drinkers moderating their drinking at 6 and 12 months in an outpatient setting [10,11], and have also been shown to be cost-effective [12]. With only minimal training, medical and /03/$30.00 q 2003 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. doi: /s (02)

2 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 S3 Fig. 1. Stages of ALD: figures in parenthesis refer to frequency of different lesions in biopsy surveys of unselected heavy drinkers. nursing staff can also deliver a variety of manual-guided psychosocial treatments including cognitive-behavioural therapy, and motivational enhancement therapy, both of which have been shown to reduce drinking in dependent patients in a randomised controlled trial [13]. As an alternative, or preferably as an addition, to psychological therapies, some patients may derive benefit from pharmacological therapy. Both acamprosate and naltrexone have been shown to reduce drinking days and increase abstinence rates in several randomised controlled trials and a recent meta-analysis [14 16]. Acamprosate is derived from taurine and its beneficial effect is thought to be via inhibition of glutamate neurotransmission. This leads to a reduction in the neuronal excitation normally observed Fig. 2. Putative mechanisms of hepatocyte injury in AH with potential targets for therapy: (A) anti-endotoxin therapy; antibiotics, probiotics, enteral nutrition; (B) anti-cytokine therapy; corticosteroids, pentoxifylline (PTX), Infliximab; (C) anti-apoptotic therapy; caspase inhibitors; (D) antioxidants; (E) immune-based therapy; corticosteroids.

3 S4 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 Table 1 Therapy for patients with ALD shown to improve abstinence rates Treatment during alcohol withdrawal due to the removal of alcoholinduced stimulation of the g-aminobutyric acid (GABA)- mediated inhibitory pathway. Importantly for patients with ALD, acamprosate, unlike naltrexone, is well tolerated in all but patients with Childs Pugh C cirrhosis and its benefit appears to persist for at least 1 year following treatment withdrawal [17]. Disulfiram, an inhibitor of acetaldehyde dehydrogenase, has been used for many years in the management of alcohol-dependent patients. It induces an acetaldehyde-mediated adverse reaction to alcohol intake characterised by nausea and flushing. Trials of effectiveness, however, give conflicting result [18,19]. The drug also requires compliance and the potential for hepatotoxicity has limited its use in patients with established ALD [20]. Importantly, there have been no formal trials of either psychological or pharmacological therapies in drinkers with ALD. Previous evidence, however, showing that the severity of alcohol dependence in ALD patients is less than that observed in an unselected group of alcohol-dependent patients [21], suggests that these treatments may be even more beneficial in the ALD population. Consistent with the low level of dependency, our own experience is that up to 50% of ALD patients will either abstain completely or achieve a significant reduction in intake after being given simple advice by physicians during their initial presentation, with a significant survival benefit compared to continued heavy drinkers [22]. 4. Alcoholic hepatitis Reference Non-pharmacological: Brief interventions [10, 11] Cognitive behavioral therapy [13] Motivational enhancement therapy [13] Pharmacological: Naltrexone [14] Acamprosate [15] AH covers a spectrum of disease from a subclinical histological condition to patients presenting with acute liver failure. Independent predictors of survival in these latter patients are serum bilirubin concentration, the prolongation of prothrombin time (PTT) and the presence of hepatic encephalopathy. The two laboratory indices have been combined to derive a discriminant function (DF; bilirubin [mg/dl] [PTT prolongation]), and a value of 32 or greater has been shown to predict a high short-term mortality in several prospective studies [23 26]. Accordingly, almost all treatment trials in patients with AH have been restricted to patients with DF greater than 32 and/or encephalopathy and have examined short-term (usually 1 month) mortality only. Patients with less severe disease appear to have a good short-term prognosis even when jaundiced [27]. Accordingly, in these patients and in severe patients surviving their initial presentation, treatment is focussed on achieving abstinence, which has been convincingly shown to improve long-term outcome [6,8]. Reports that some patients with AH can progress to cirrhosis even with abstention [8], and that patients with coexisting AH and cirrhosis have a worse long-term survival than patients with cirrhosis only [28] do, however, suggest the need for longer-term treatment trials in patients with AH. Progress in developing specific treatments for acute AH has been hampered by a poor understanding of disease pathogenesis. Animal models suggest that AH occurs as a result of oxidative stress and endotoxin-mediated cytokine release (see Fig. 2) which act through leukocyte recruitment and activation to cause hepatocyte dysfunction, apoptosis and necrosis [29 34]. However, evidence for these mechanisms in humans is either absent or, at best, indirect. Perhaps reflecting this paucity of information, many treatment modalities have been tried in patients with AH, however, none have been consistently shown to have a beneficial effect and, accordingly, none have achieved consensus status among practising hepatologists. First, we will review results with the most promising treatments evaluated thus far, corticosteroids, PTX and enteral nutrition. Next, we will review the important negative studies and finally, discuss some novel approaches that have recently been, or are currently being evaluated (see Table 2) Corticosteroids Of all the treatments available for patients with severe AH, corticosteroids are the most intensively studied and probably the most effective. Steroids are aimed at suppres- Table 2 Pharmacological therapy for alcoholic hepatitis a Treatment Benefit References Corticosteroids 111 [24 26, 37 41] Pentoxifylline 11 [46] Enteral nutrition 11 [51,52] b Infliximab 1 [79,80] MARS 1 [83] Antioxidants - [66 68] Insulin/glucagon - [72 74] Anabolic steroids -- [75] Propylthiouracil -- [77,78] a 111, evidence of survival benefit from more than one RCT and at least one positive meta-analysis; 11, evidence of survival benefit from at least one RCT with no negative trials; 1, preliminary evidence of biochemical improvement with no survival studies performed; --, evidence of a consistent lack of beneficial effect on survival from more than one RCT and/or a meta-analysis; - evidence of a lack of effect on survival from more or the same number of RCTs than show any beneficial effect. b This trial showed similar survival to treatment with corticosteroids rather than an improved survival compared to placebo.

4 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 S5 sing or switching-off the florid inflammatory response observed in liver biopsies from patients with severe AH. The mechanism of this effect is, at least in part, through the inhibition of NFkB transcriptional activity [35], with the transcription of many inflammatory cytokines, chemokines and adhesion molecules dependent on this ubiquitous signalling cascade [36]. Two potential side effects of steroids used in medium/high dose include poor wound healing and increased susceptibility to infection, with the latter, a particular problem in this group of patients. Concern over these adverse effects, coupled with a continued uncertainty over efficacy has contributed to the reluctance of many clinicians to prescribe steroids for patients with AH. Patients with AH form a heterogeneous population, both in severity, and probably in disease pathogenesis. Without careful exclusion, preferably by liver biopsy, it is difficult to differentiate a patient with severe acute AH, from one with alcohol or non-alcohol-induced cirrhosis who has decompensated while drinking. Many initial steroid trials were poorly designed and included patients with a variety of disease severities and almost certainly patients without AH. Most of these trials showed no treatment benefit. However, two randomised controlled trials focussing only on patients that had the worst prognosis, defined by a DF more than 32 and/or encephalopathy [24,26], showed a survival benefit in the steroid-treated patients. Several meta-analyses have attempted to resolve the controversy, and although most have shown a survival benefit [37 39], this has not been a universal finding [40]. Rather than performing a further conventional meta-analysis, the authors of the last three large randomised controlled trials have recently pooled their individual patient data, only including patients with encephalopathy and/or a discriminant function.32 [41]. This study showed that steroids improved survival vs. placebo (85 vs. 65%), with placebo treatment, increasing age and creatinine independent predictors of mortality on multivariate analysis. A weakness of this study is that two of the three original trials included gastrointestinal bleeding as a contraindication, while one did not and only one trial required a liver biopsy for diagnosis. Nonetheless, the large numbers (102 on placebo, 113 on steroids) make this the most robust meta-analysis to date. Despite 13 randomised controlled trials, and six metaanalyses, the debate over the use of steroids continues. It appears that they are probably beneficial in patients with severe disease, however, mortality on treatment remains high, particularly when renal impairment is present, and treatment is relatively contraindicated in the large number of patients with concomitant infection and gastrointestinal bleeding. It is because of these limitations that alternative therapeutic strategies have been, and continue to be, sought Pentoxifylline Animal models of acute alcohol-mediated liver injury suggest that tumour necrosis factor a (TNFa) plays a central role in disease pathogenesis [32,42]. Furthermore, monocytes from patients with AH produce TNFa constitutively and at higher levels than controls in response to endotoxin [43] and serum levels are high on admission to hospital and correlate with mortality [44]. PTX is a non-selective phosphodiesterase inhibitor that is approved for use in claudication at a dose of 400 mg three times a day due to its effect on red blood cell deformability. In the late 1980s, PTX was observed to have an anti-cytokine effect, later attributed to a reduction in TNFa gene transcription [45] and, accordingly, to reduced levels of important downstream TNFa effectors including other pro-inflammatory cytokines, chemokines and adhesion molecules. The first randomised controlled trial of PTX in 101 patients with AH was reported in 2000 [46]. The effective claudication dose was given for 28 days to patients with a DF greater than 32 and lead to a 40% reduction in mortality compared to placebo. The secondary end-point of hepatorenal syndrome (HRS) was reduced in the treated population by 65%. Importantly, almost all of the improvement in survival was due to a fall in mortality from HRS suggesting that PTX may have a specific beneficial effect in AH patients developing this ominous complication [47]. Clearly, further trials are needed to determine whether PTX should become standard treatment for patients with AH. In particular, comparisons should be made with steroids and placebo (in patients in whom steroids are contraindicated), and trials of PTX in combination with steroids should be performed Nutritional supplementation Trials investigating the role of nutritional supplementation have been prompted by the degree of protein calorie malnutrition seen in patients presenting with acute AH and the correlation between the severity of malnutrition and mortality [48]. Initial trials with parenteral amino acid therapy yielded conflicting results [49,50], however, more consistent and promising results have been reported from two randomised controlled trials of enteral tube feeding. The first compared enteral tube feeding of an energydense formula supplying 2115 kcal/day with an isocaloric standard oral diet [51]. The enteral feed contained whole protein plus branched-chain amino acids, medium- and long-chain triglycerides and maltodextrin. Thirty-five severely malnourished cirrhotics were randomised and inhospital mortality was 12% in the tube fed group compared to 47% in the oral group. This prompted a further study 10 years later comparing enteral feeding to steroids in 71 patients with acute severe AH. In this trial, whilst there was no difference in mortality between the groups during the 28-day treatment period, deaths occurred earlier in the steroid-treated patients and the mortality rate was lower in the enterally fed group in the year following treatment. The overall mortality rate at 1 year was 61 and 38%, in steroidand enteral-treated groups, respectively. Whilst this difference did not reach conventional significance ðp ¼ 0:26Þ, it

5 S6 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 must be appreciated that this treatment was being compared with what is currently considered to be the best available treatment. Furthermore, the trial is ongoing [52], with a further 69 patients expected to be recruited. In summary, nutritional supplementation may have a role in improving medium to long-term survival in patients with severe AH. While patients benefit most, the mechanisms by which they derive benefit and the potential beneficial effect of enteral nutrition in combination with steroids and/or PTX is, as yet, unclear. There is no doubt, however, that this form of treatment deserves further investigation Antioxidants Table 3 Factors contributing to oxidative stress in alcoholic liver disease Sources of reactive oxygen species CYP2E1 Aldehyde oxidase Xanthine oxidase Mitochondria Deficient antioxidants GSH Selenium Vitamins A,C,E Co-enzyme Q Interest in the potential value of antioxidant therapy in the treatment of AH has arisen as a result of the growing body of evidence implicating oxidative stress as a key mechanism in alcohol-mediated hepatotoxicity. Several potential sources of reactive oxygen species (ROS) have been suggested as potential sources of oxidative stress in patients with ALD and animal models of alcohol-induced liver injury (see Table 3). These include the ethanol-inducible cytochrome P450 (CYP) 2E1 [53], aldehyde and xanthine oxidases and increase in the NADH/NAD ratio resulting in increased electron flow along the respiratory electron transport chain [54]. The principal ROS arising from these sources are the superoxide anion, hydrogen peroxide and hydroxyl and hydroxyethyl radicals, the latter arising during ethanol metabolism by CYP2E1 [53,55]. ROS are capable of initiating lipid peroxidation that can directly damage plasma and intracellular membranes [56] and lead to the release of reactive aldehydes with potent pro-inflammatory and pro-fibrotic properties [57]. These products of lipid peroxidation can be detected in the peripheral blood of heavy drinkers [58] and in the livers of patients with ALD [59], where the magnitude of lipid peroxidation correlates with the degree of liver injury [60]. Sustained ethanol abuse also results in a diminution of host antioxidant defences. Both the hydroxyethyl radical and acetaldehyde, the first product of ethanol metabolism, can bind glutathione (GSH), a tripeptide that acts as a direct free radical scavenger. Consumption of GSH during oxidative stress and inhibition of one of its key synthetic enzymes S-adenosyl methionine (SAMe) synthetase contribute further to the decreased levels of hepatic GSH observed in ALD [61]. Heavy drinkers are also deficient in the antioxidant trace element selenium [62], the antioxidant vitamins A, C and E [63,64] and Coenzyme Q [65]. Trace elements are critical for the activity of two key antioxidant enzymes, the superoxide dismutases (SOD1 and SOD2), which are manganese and zinc/magnesium dependent, respectively, and GSH peroxidase which is selenium dependent. Coenzyme Q, which is present in plasma and mitochondrial matrix membranes, has emerged as one, if not the most important, natural free radical scavengers. It is partly derived from the diet, but is also synthesized in the liver. These considerations have recently lead to three trials investigating the effect of antioxidant supplementation in patients with severe AH. In the first study, 56 patients were randomised to receive vitamin E, selenium and zinc supplementation or placebo [66]. Whilst treated patients had an in-hospital mortality of 6.5 compared with 40% in the placebo group, the entry criteria and patient details were not clear. The second trial compared steroids with an antioxidant cocktail (vitamins A, C, E, selenium, allopurinol, desferrioxamine and N-acetylcysteine) and was stopped after an interim assessment found steroid treatment to be associated with a significantly higher survival [67]. This trial did not examine whether antioxidants conferred any benefit in patients in whom steroids were contraindicated, or in combination with steroids. The most recent study investigated the role of antioxidants in patients with severe AH stratified by gender and steroid treatment. The active group received a loading dose of N-acetylcysteine of 150 mg/kg followed by 100 mg/kg/day for 1 week, and vitamins A E, biotin, selenium, zinc, manganese, copper, magnesium, folic acid and Coenzyme Q daily for 6 months. The decision to treat with steroids was made by the supervising clinician according to conventional criteria [68]. While white blood cell count and bilirubin at trial entry were both associated with increased mortality, antioxidant therapy showed no benefit either alone or in combination with steroids. In summary, on the basis of the data available thus far, high dose antioxidant therapy confers no survival benefit in patients with severe AH Other negative studies Hepatic mitogens The observation that survival in patients with severe AH correlates with the intensity of hepatocyte staining for proliferating cell nuclear antigen [69], implies that the liver s capacity for regeneration is an important determinant of outcome and suggests that therapy directed at enhancing proliferation might be beneficial. An infusion of insulin and glucagon has been shown to improve liver regeneration in a rat partial hepatectomy model [70], and to improve survival in a mouse model of fulminant hepatitis [71]. These observations were the stimulus to several trials investigating the role of insulin and glucagon therapy in the treatment of patients with severe AH. While the first trial showed a significant reduction in mortality in the treated group [72],

6 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 S7 two subsequent larger studies showed no benefit with one reporting a high incidence of hypoglycaemia [73,74]. At present, therefore, this form of therapy cannot be recommended. Anabolic steroids have also been shown to promote hepatocyte regeneration, however, three large randomised controlled trials with either testosterone or oxandrolone in males with AH have reported no treatment benefit [75] Propylthiouracil Centrilobular hypoxia is a feature of animal models of ALD and has been postulated to play a role in the liver injury, which is characteristically most severe in the centrilobular acinar zone 3 [76]. The hypoxia has been attributed to the hypermetabolic state induced by ethanol which is similar to the hypermetabolic state associated with hyperthyroidism, and can be attenuated in the rodent model of ALD by the anti-thyroid drug, PTU [76]. Two trials have evaluated the role of this drug in improving short-term mortality in patients with AH. Although the first trial reported a more rapid improvement in clinical and laboratory indices, neither trial showed any survival benefit [77,78] Experimental therapies In addition to the treatments described above, several novel therapies for acute AH are currently undergoing investigation. The most promising of these is the anti- TNFa antibody, Infliximab. This chimeric human/mouse monoclonal antibody binds to TNFa and blocks its biological effects. Its potential use in AH has been suggested by its reported benefit in several other inflammatory conditions, the putative role of TNFa in the pathogenesis of ALD and a report that anti-tnfa antibodies ameliorate the liver injury in a mouse model of ALD [42]. To date, there have been no randomised controlled trials of Infliximab in patients with AH, however, two initial reports have demonstrated an improvement in biochemistry and a satisfactory safety profile when used alone [79] or in combination with steroids [80]. The safety aspect is important since experience with Infliximab in other diseases has raised concerns over the risk of infection [81]. This could potentially limit the number of patients with AH suitable for treatment and was the rationale for excluding patients with severe disease (DF. 55) from one of the initial trials [80]. The beneficial role of TNFa in promoting liver regeneration is another potential problem for anti-tnfa treatments in patients with AH for the reasons discussed above [82]. Large randomised controlled studies are required to determine which patients benefit most from treatment, the important adverse effects and the optimal duration of therapy. A further experimental therapy that may benefit patients with AH is the molecular adsorbents recycling system (MARS). The primary aim of this treatment is to support impaired liver function while the liver recovers or the patient undergoes liver transplantation. It may, therefore, have a role in patients with AH either alone or in combination with other pharmacological therapies. The principal of the MARS procedure is to dialyse blood against an albumin solution aimed at removing albumin-bound toxins including bilirubin and bile salts. To date, only small series of patients with AH have been treated with this procedure [83], however, clinical improvement has been reported in these cases and further randomised trials are awaited with interest Treatment of HRS in AH As alluded to above, in patients with severe AH, the development of renal failure is associated with a survival of less than 10% even with intensive management and renal support [84]. Perhaps the most significant advance in the management of patients with advanced liver disease over the past decade has been the introduction of albumin infusions combined with splanchnic vasoconstrictor agents for patients with HRS. This combination appears to significantly improve the survival of patients with cirrhosis who have this life-threatening complication [85 87]. Although no randomised trials have specifically examined this form of therapy in patients with AH, the previously reported high mortality in AH patients with HRS suggests that it will have a significant and beneficial impact on patient survival. 5. Alcoholic cirrhosis While the high mortality of severe AH, coupled with the young age of many of the patients, makes it an important area for therapeutic trials, the vast majority of patients with ALD in clinical practice have advanced fibrosis or cirrhosis. These patients may be asymptomatic or present with symptoms related to portal hypertension, advanced liver failure or the development of hepatocellular carcinoma. As discussed above, the most important therapy is achieving and maintaining abstinence, since this has been shown to improve survival in both well compensated and decompensated patients [7,88]. Unfortunately, as with AH, no adjunctive pharmacotherapies have been consistently shown to improve survival in more than one randomised controlled trial, although some have shown promise and will be reviewed below (see Table 4). Potential reasons for the lack of progress thus far include: (a) a lack of a clear understanding of disease pathogenesis; (b) problems with compliance in long-term treatment trials; and (c) the confounding effect of drinking behaviour during the duration of the trial. As a result, at present the management of patients with advanced fibrotic ALD is directed primarily at preventing and treating the complications of portal hypertension, liver failure and hepatocellular carcinoma and deciding if and when to consider patients for orthotopic liver transplantation.

7 S8 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 Table 4 Pharmacological therapy for alcoholic cirrhosis a Treatment Benefit References Propylthiouracil 11 [89] S-adenosylmethionine 11 [101] Silymarin - [99,100] Colchicine -- [92,95] Phosphatidylcholine? a 11, evidence of survival benefit from at least one RCT with no negative trials; --, evidence of a consistent lack of beneficial effect on survival from more than one RCT and/or a meta-analysis; -, evidence of a lack of effect on survival from more or the same number of RCTs than show any beneficial effect;?, RCT ongoing, results awaited Pharmacological therapy Propylthopuracil In contrast to its lack of effect in patients with acute AH, PTU may improve the long-term survival of patients with alcoholic cirrhosis. There has, however, been only one trial reported thus far [89]. In this study, the investigators went to great lengths to assess drinking behaviour and compliance by checking daily urine samples for alcohol and a drug biomarker. Treatment for 2 years improved mortality in the patient group as a whole, particularly in patients who continued to drink moderately during the trial. No improvement was seen in abstinent patients, who had an excellent prognosis on drug or placebo or in continued heavy drinkers who had a universally bad prognosis. Although the patient numbers were high (310), a large percentage of patients were either non-compliant or dropped out of the study. For this reason and the lack of any confirmatory studies, PTU has not been widely adopted by the liver community. In view of the promising results, however, it does seem surprising that no centres have attempted to repeat the study, which remains an excellent model of how to perform a randomised controlled trial in this potentially difficult group of patients Colchicine This anti-inflammatory drug has been evaluated in the treatment of patients with alcohol and non-alcohol-related cirrhosis because of its anti-fibrotic effect in vitro [90,91]. To date, clinical results have been conflicting. The most convincing evidence supporting the use of colchicine comes from a study including 100 patients followed up for up to 14 years. Survival was 75 and 34% in treated and placebo groups, respectively. Some patients appeared to have a resolution of their cirrhosis to either minimal fibrosis or normal histology [92]. Three further trials, however, with median follow-ups of 1, [93] 6 [94] and 40 [95] months have all shown no benefit. A recent meta-analysis has also reviewed 14 randomised controlled trials and found no benefit of colchicine treatment on mortality or liver histology [96] Antioxidants In addition to trials in patients with AH the accumulating evidence that oxidant stress is involved in the pathogenesis of ALD has prompted trials of antioxidants in patients with chronic disease. Two trials have evaluated the drug silymarin, which is the active component of the herb milk-thistle and has potent antioxidant properties in vitro [97] and in vivo [98,99]. The first trial in 170 patients with cirrhosis (92 had ALD) followed up for between 2 and 6 years reported a beneficial effect on survival [100]. In contrast, a later, larger study of 200 patients with cirrhotic ALD, followed up for 5 years showed no benefit [101]. SAMe, which acts as both an antioxidant by replenishing GSH and a methyl donor maintaining cell membrane fluidity, has also been evaluated in patients with alcoholic cirrhosis. Using death or liver transplantation as a combined end-point, Mato and colleagues reported a significant beneficial effect of SAMe treatment in patients with Child s A and B cirrhosis [102]. Clearly further trials with this agent are awaited with interest Phosphatidylcholine It is an essential component of all cell membranes and is vulnerable to attack by lipid peroxidation. Through mechanisms that are, as yet, unclear, dietary supplementation with phosphatidylcholine has been shown to attenuate ethanolinduced fibrosis in baboons [103]. Potential mechanisms of action include stimulation of collagenase [104] and acting as a sink for free radicals [105]. A long-term trial in patients with alcoholic cirrhosis is near to completion in the United States. No interim analysis has been presented. 6. Liver transplantation for advanced ALD Since the initial report of its success in 1988 [106], ALD has become an increasingly common indication for orthotopic liver transplantation in both Europe [107] and North America [108]. However, transplantation for ALD remains controversial, principally due to concerns over the risk of post-transplant recidivism and its effect on outcome and public opinion at a time of increasing donor shortage. This issue, coupled with a perception that these patients are more likely to have contraindications to transplantation due either to extra-hepatic complications of excessive alcohol abuse or to an associated lack of self-care has contributed to a continued reluctance of many centres to offer transplantation to patients with ALD. An accumulating number of reports of transplantation in patients with ALD have now provided a firm evidence base from which these issues can now be addressed (see Table 5) Outcome of liver transplantation for ALD Several studies have convincingly demonstrated that the survival of patients transplanted for cirrhotic ALD is comparable to patients with cirrhosis of alternative aetiologies, with 5- and 10-year survivals lying somewhere

8 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S13 S9 Table 5 Factors supporting orthotopic liver transplantation in selected patients with ALD Factor Reference Improved survival and quality of [110,112] life versus non-transplanted controls Survival similar to other etiologies [108] No increased risk of post-operative [109] complications or resource utilisation compared to other etiologies Extra-hepatic comorbidities of [119] alcohol excess are rarely contraindications to surgery and most improve with pre-operative abstinence Risk of significant recidivism is [110, , 118, 121] low, it cannot be predicted and has little, if any, impact on medium term outcome Public opinion is likely to support transplantation for abstinent patients with a low risk of recidivism between those of patients transplanted for cholestatic and viral hepatitis-related liver disease [109]. Furthermore, there is no evidence that patients with ALD have a higher frequency of post-operative complications or resource utilisation compared to patients transplanted for other indications despite being transplanted at a more advanced stage of disease [110]. The improvement in quality of life following transplantation also compares favourably with other indications in the short-term [111], although not after 3 years follow-up [110]. The reason for this decline is unclear, but does not seem to be related to a return to problem drinking. As for other indications, the decision to offer transplantation to a patient with ALD is based on their expected survival with and without transplantation. Without transplantation, survival depends on the severity of their liver disease and their subsequent drinking behaviour. Patients with Childs C cirrhosis have a 1 year survival of 50 85% compared to 75 95% in patients with Childs B [112]. This suggests that in the absence of other predictors of high mortality, such as, a history of spontaneous bacterial peritonitis, recurrent variceal haemorrhage or the development of hepatocellular carcinoma, transplantation should be restricted to patients with Childs C cirrhosis. In support of this policy, Poynard and colleagues recently demonstrated that ALD patients whose disease severity approximated to a Childs Pugh score of 11 or higher had a significantly improved 2 year survival compared to matched controls [113], while in the UK, the 1 and 2 year survival of 87 and 82% compares well with the 41 and 30% survival predicted from the Beclere prognostic model (personal communication) [113]. The potential effect of abstinence on prognosis of these patients has lead most units to adopt a policy of offering transplantation to patients whose Childs Pugh score remains high after a period of abstinence Post-transplant recidivism Perhaps the greatest concern when considering transplantation for patients with ALD is the risk of recidivism and its effect on outcome and public opinion. With respect to the frequency of recidivism, this depends critically on its definition. Studies that have considered any alcohol use posttransplantation as a relapse have reported recidivism rates as high as 49% [ ] whilst those that have restricted the definition to heavy or problem drinking have reported lower rates of 10 15% [111, ]. With respect to the influence of recidivism on outcome, thus far, there are few data on which to base firm conclusions. From the information available, the incidence of graft dysfunction related to recidivism ranges from 0 17% and mortality ranges from 0 5% [114,117,119,121]. In the most recent and longest-term study, although the recidivism rates were 30% with many showing evidence of recurrent disease on their protocol biopsies, neither recidivism nor histology affected 84 month survival rates [122]. In spite of this, apparently reassuring report, it does, however, seem likely that as studies increase their length of follow-up, the frequency of advanced histology and significant morbidity and mortality in recidivists will rise. It is, therefore, imperative that patients are monitored carefully for relapse following transplantation with relapsers offered appropriate counselling. It is important that this is done for all ALD patients since, at present, and contrary to some early reports, no factors have been identified that reliably predict the risk of post-transplant recidivism prior to transplantation. Efforts to minimise the risk of post-transplant recidivism are important not only for the individual patient, but also to avoid the likely adverse effect this has on the organ donating public Public opinion With organ shortage as a significant problem and while the decision to be an organ donor remains voluntary in most European countries, it is imperative that the public are convinced that donated livers are being given to the most deserving patients. A recent UK study clearly demonstrated that, when compared to other patient groups, the general public, primary care physicians and gastroenterologists, all place patients with ALD well down their list of patients most deserving a liver transplant [123]. The perception that patients with ALD have played a significant role in their disease and the widely held belief that, once a drinker always a drinker seem likely to be the most important factors contributing to this negative view of ALD patients. It is, therefore, vital that the public are made aware that patients are only offered transplantation if they fail to recover after a period of abstinence and that the incidence of significant post-transplant recidivism is low.

9 S10 S.F. Stewart, C.P. Day / Journal of Hepatology 38 (2003) S2 S Comorbidity Excessive alcohol consumption can, and often does, affect many organ systems apart from the liver and this can potentially give rise to contraindications to surgery. An increased risk of pancreatitis, cardiomyopathy, osteoporosis, cerebrovascular disease, dementia and malnutrition might all be expected to limit the numbers of patients fit for surgery. In practice, however, although most transplant units routinely screen ALD patients for cardiac and cerebral complications of excessive alcohol intake, this results in the exclusion of very few patients [120]. Similarly, despite the increased risk of psychiatric comorbidity in heavy drinkers, this rarely, if ever leads to the exclusion of patients at the stage of transplant assessment [120]. This seems likely to be attributable either to patients with significant physical or psychiatric comorbidities not being referred for formal transplant assessment and/or to the tendency of many alcohol-related morbidities to improve during the period of abstinence required by most units prior to assessment Pre-operative abstinence In light of the above considerations, it is perhaps not surprising that most centres require patients to have been abstinent for a period of time prior to assessment. This is primarily to give the liver a chance to recover spontaneously, however, it also allows time for other alcoholrelated morbidities to recover thereby, improving the patient s fitness for surgery and, importantly, satisfies public opinion. During this period, the patient can also be put in contact with alcohol treatment services for support both prior to and following transplantation. Whilst there is broad consensus on the need for a period of pre-transplant abstinence, there is far less agreement on the requirement for a minimum duration. Many units have previously insisted on a 6-month period of abstinence, possibly attributable to early reports that this was a positive predictor of post-transplant abstinence [111]. However, more recently, this view has been challenged with several studies showing that, in the long-term, 6 months abstinence has little if any predictive power for subsequent drinking habits [119]. Furthermore, the price of insisting on a fixed abstinence period may be death in some patients. A recent study demonstrating that the chance of recovery in patients with decompensated ALD can be predicted as early as 3 months [124], has led some observers to suggest that, if required at all, the minimum period of abstinence could safely be reduced to 3 months rather than 6 months [125]. Currently, it appears that, in practice, most centres do not adhere strictly to a fixed period of abstinence, instead preferring to assess each case on an individual basis and listing the patient when it is considered that recovery is unlikely [109] Transplantation for AH Clearly, many of these issues are pertinent when it comes to considering the possibility of transplanting patients with severe acute AH. A reasonable period of abstinence is not possible to assess the liver s potential for spontaneous recovery, significant comorbidities are almost universal and formal psychiatric assessment and pre-transplant counselling is often precluded by the severity of the illness. Accordingly, although these patients undoubtedly have a poor prognosis without transplantation, most clinical centres do not consider these patients for liver transplantation. Nonetheless, there have been isolated reports of survival following transplantation of these patients [84,126] and a recent report that the presence of histological AH in the explanted liver of patients transplanted for apparently chronic stable ALD, is not associated with a worse prognosis or an increased risk of recidivism [127]. Clearly, some patients with AH can benefit from transplantation, however, more data is required before any firm recommendations can be given on which patients (if any) are likely to derive the most benefit. 7. Conclusions The management of patients with ALD is challenging and rewarding. At its core are strategies aimed at achieving and maintaining abstinence, which require close collaboration between physicians, psychiatrists and psychologists. The high mortality of severe AH, highlights the need for better therapy and our increased understanding of the precise mechanisms of ethanol-induced liver injury, has at last recently been translated into the development of several promising therapeutic modalities. In contrast, little progress has, as yet, been made towards the development of specific pharmacotherapy for advanced fibrosis and cirrhosis. Management of these patients is, therefore, restricted to detecting and treating the usual complications of advanced liver disease and liver transplantation when indicated. Transplantation improves survival in well-selected patients. Relapse to heavy drinking is uncommon and as yet, has not been shown to adversely affect outcome. Declaration The authors who have taken part in this study have not a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. 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