EASL Clinical Practice Guidelines

Liver transplantation

Trends in liver transplantation of alcoholic liver disease

Alcoholic liver disease is one of the most common causes of cirrhosis and indications for OLT in Europe and the USA [[220], [221], [222]]. The reluctance to transplant livers in alcoholics stems partly from the view that alcoholics are responsible for their illness and that a relapse can damage the allograft. An opinion poll in Great Britain showed that family physicians believed that, given the scarcity of donor organs, alcoholic patients should take lower priority than other candidates, even when the latter had less chance of a successful outcome from transplantation [223]. The conviction that alcoholism is self-inflicted must be reconciled with the strong evidence supporting genetic and environmental influences on alcohol dependence diagnosed by the DSM-IV diagnostic system [224].

However, graft and patient survival rates among alcoholics after LT are similar to those seen after transplantation for other aetiologies of liver disease [[225], [226], [227]]. A significant increase (8.3%) in the proportion of patients transplanted for alcoholic liver disease was observed between the periods 1988–1995 and 1996–2005 [228].

Indications and contraindications

Alcoholic cirrhosis

Most programs require a 6-month period of abstinence prior to evaluation of alcoholic patients. The 6-month period of abstinence is presumed: (a) to permit some patients to recover from their liver disease and obviate the need for LT; and (b) to identify subsets of patients likely to maintain abstinence after LT. Nevertheless, data concerning the utility of the 6-month rule as a predictor of long-term sobriety are controversial. The survival benefit related to LT appears restricted to patients with advanced decompensation (i.e. 11–15 points on the Child–Pugh score) [229]. Conversely, a randomized controlled study demonstrated that immediate listing for liver transplantation did not show a survival benefit compared with standard care for Child-Pugh stage B (i.e. Child–Pugh ⩽9) alcoholic cirrhosis. In addition, immediate listing for transplantation increased the risk for extrahepatic cancer [230].

Alcoholic hepatitis

A substantial number of patients with severe alcoholic hepatitis, fail to recover despite abstinence and medical therapy [231]. Nevertheless, if there is no substantial improvement by 3 months of medical management, including abstaining from alcohol, the chances of spontaneous recovery by patients with ASH and cirrhosis are poor [232]. The classical opinion of European and North American experts considering ASH as a contraindication for transplantation has been recently challenged by a case controlled study showing an unequivocal improvement of survival in patients who received early transplantation [192]. The investigators concluded that despite the fact that early LT for severe AH patients who fail medical therapy improves survival is contravenes the 6-month abstinence rule [192]. These results support future evaluation of LT in carefully-selected patients with severe AH who do not respond to medical therapy. However, early LT is relevant only in a very small minority of patients [192].

Assessing the severity of liver disease and timing for liver transplantation

In Child–Pugh stage B alcoholic cirrhosis, immediate listing for LT did not show a survival benefit compared with standard care [230].

In most centers, the MELD score is mainly used to prioritize patients awaiting LT [233]. MELD can also be used to estimate the survival benefit following LT [233]. ALD does not influence liver transplant survival benefit [234].

Previous studies have failed to demonstrate that other clinical manifestations of liver decompensation, such as variceal hemorrhage, hepatic encephalopathy, new onset ascites or spontaneous bacterial peritonitis, were independent predictors of survival over and above the MELD score [235]. Nonetheless, the onset of any of these features in an abstinent alcoholic should prompt the managing physician to consider referral to a transplant center.

Evaluation of the alcoholic patient for LT

The 6-month rule

A psycho-social assessment to establish the likelihood of long-term abstinence after liver transplantation should be performed in patients with alcoholic liver disease. It is common practice to evaluate alcohol abuse and dependence according to the well-established diagnostic criteria such as the DSM-IV diagnostic system [224]. Since alcohol abuse and dependence may be associated with personality disorders, depression, anxiety, poly-substance abuse, and other psychiatric disorders, a psychiatric evaluation may be necessary [236]. The role of the length of pre-transplantation abstinence, the so called “6-month rule”, as predictor of post-transplantation abstinence is still questionable [[237], [238],[239], [240], [241]]. There is however a subset of patients with end-stage liver disease and alcohol dependence who might be identified before LT as likely to remain abstinent after LT. A multidisciplinary approach that evaluates not only medical but also psychological suitability for liver transplantation is then mandatory.

Medical assessment of the alcoholic candidate

The pre-transplant investigation should assess pancreatic function, renal function, nutritional status as well as detecting central and peripheral neuropathy, myopathy and cardiomyopathy [[242], [243], [244], [245]]. The high prevalence of double exposition to alcohol and tobacco justify additional screening for atherosclerosis and ischemic heart disease. It is also crucial to rule out any neoplastic disease or pre-neoplastic conditions, since such patients appear to have a higher incidence of certain malignancies after LT, especially of the upper airways and upper gastrointestinal tract [242].

Post-LT follow-up and management

Relapse

In studies of alcohol use after LT, “relapse” is defined as any alcohol intake. This is in contrast to studies from the literature on addiction medicine in which success is defined in terms of relative reduction of drinking and relapses as a resumption of heavy alcohol intake. Studies which have evaluated relapse into alcohol consumption after LT for alcoholic cirrhosis have reported a wide range of frequencies (10–50%) in up to 5 years follow-up [[227], [241]]. There are many flaws in these data. First, as mentioned, is the reliance on “any use” to define relapse. Another caveat with these estimates relates to the difficulty of getting accurate data on drinking behavior. Most studies document alcohol consumption after transplantation by retrospective analysis of routine screening tests, questionnaires or interviews with patients and/or family during follow-up. There is a substantial risk that these methods may underestimate the patient's real drinking habits, partly due to retrospection, but also due to the pressures on patients to deny drinking. It is thought that between 33% and 50% of alcoholic transplant recipients start drinking again after transplantation and that about 10% resume heavy drinking mostly within the first year after transplantation [246].

Few studies have attempted to treat alcoholism within the context of LT and alcoholic LT recipients usually refuse standard treatments for alcoholism [247]. A case controlled study observed that alcoholic patients awaiting LT have less craving for alcohol and less motivation for treatment than alcoholics in the non-transplant setting, despite similar lifetime drinking histories [248].

Extrahepatic complications

The incidence of cardiovascular events is higher in patients transplanted for alcoholic liver disease compared to patients transplanted for other causes of liver disease (8% versus 5.3%) [228]. It is also likely that the incidence of chronic kidney disease, diabetes mellitus, hypertension, and other components of the metabolic syndrome may be higher after transplantation for alcoholic liver disease than other indications. Increased vigilance and proactive management are required to further improve long-term outcomes [249].

The risk of de novo malignancies rises from 6% before LT to 55% 15 years post LT. These malignancies also account for a significant risk of late death [[242], [250], [251]]. The incidence of de novo tumors as cause of death was at least twofold higher in patients transplanted for alcoholic liver disease compared to other indications [228]. After LT there were no differences between patients, with or without alcohol relapse, in terms of drug compliance, incidence of rejection or adherence to check-ups [252]. Patients transplanted for alcoholic liver disease return to society and lead active and productive lives, despite the fact they seem less likely to be involved in structured social activities than patients transplanted for non-alcoholic liver disease [253].

Survival

From a recent analysis based on ELTR data, it has been demonstrated that patient survival at 1, 3, 5, and 10 years from first transplantation was 84%, 78%, 73%, and 58%, respectively in alcoholic liver disease patients. This survival rate was significantly higher than in HCV and HBV-related liver disease recipients and cryptogenic cirrhosis patients [228]. The incidence of deaths due to all social causes, including suicide, was twice as high in patients transplanted for alcoholic liver disease compared with other indications [228].

Recommendations

Suggestions for future studies

  1. Studies evaluating the effects of new immunosuppressive regimens on the risk of cardiovascular disease and de novoneoplasms are warranted.
  2. In patients with severe ASH not responding to medical therapy, early LT need to be further evaluated in carefully-selected patients.