Should patients with alcoholic hepatitis be considered for liver transplantation?

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Abbreviations

DSM‐IV

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

eLT

early liver transplantation

HRAR

High‐Risk Alcohol Relapse

LT

liver transplantation

The theory of fields adapted from Blaise Pascal's théorie des ordres by the philosopher Andre Comté‐Sponville consists of analyzing unresolved questions in specific fields of reflection1 (Fig. 1). As proposed in a recent article,2 this review discusses the ethical, moral, and scientific aspects of the controversial issue of liver transplantation (LT) in alcoholic hepatitis (AH) that does not respond to medical treatment.

Figure 1.

The four fields of Andre Comté‐Sponville's fields theory. Adapted from Blaise Pascal's théorie des ordres.

A moral analysis applies the notions of good and evil based on the Judeo‐Christian tradition, which associates alcoholism with vice and cowardice. Alcoholic diseases are therefore considered to be self‐inflicted. The 6‐month abstinence rule can be seen as a kind of penance that becomes morally mandatory. This view affects both public opinion and the attitude of health care providers who participate in candidate selection. As Payen and Pageaux have pointed out, even at the beginning of the 21st century, the moral ambiguity surrounding alcohol addiction as an indication for liver transplantation continues to be a source of debate.2

Ethically, the principles of medical practice that are beneficence, nonmaleficence, equity, justice, and autonomy apply to the entire patient population and not just one single patient.3, 4, 5 This raises the ethical question of organ allocation in an era of organ shortage. Indeed, the validation of any new indication for LT is at the expense of other existing indications, in particular those classified as “non–self‐inflicted” liver disease.6 In addition, the increased number of patients on the waiting list forces clinicians to adapt the allocation system according to rational rules that involve allocating grafts to patients with the greatest urgency and expected good graft survival. Early liver transplantation (eLT) for patients with AH who do not respond to medical treatment, raises other ethical issues: (1) a risk for decreased graft survival because of recurrence of heavy drinking and/or nonadherence to immunosuppressive regimen, although the latter has not been reported in alcoholic patients; (2) an increase in additional hospitalization costs related to disease severity for a new indication still being evaluated in the scientific community; and (3) risk for a reduction in organ donation because of a breach in the implicit contract between transplant centers and society.3

Conversely, the ethics of medical practice according to the Hippocratic Oath states that the best treatment must be provided to patients according to existing scientific knowledge, and that all forms of discrimination and arbitrariness be abandoned in the treatment of patients. This principals were reassessed in 2008 at the International Summit on Transplant Tourism and Organ Trafficking, the final statement of which is often referred to as the ‘Istambul Declaration’.7 Reconciliation of this ethical dilemma can only be advanced by scientific evidence.

Many studies indicate that the 6‐month mortality rate in patients with AH who do not respond to medical treatment is more than 70%, with a mean survival time of 51 days.8 Early identification of patients with a low likelihood of survival can help in the management of severe AH. Because there is no other effective medical treatment in this setting, eLT has been proposed as salvage therapy for patients with no other therapeutic options. However, eLT in patients with AH who do not respond to medical treatment does not follow current recommendations requiring a period of abstinence before considering alcoholic patients as candidates for LT.9 The 6‐month abstinence rule has been adopted by most transplant centers even though there is little evidence to confirm the validity of this criterion alone for predicting alcohol relapse. For example, in patients who are abstinent for at least 6 months, 25% of the cases on the waiting list consume alcohol and 5% to 15% of patients who receive transplants relapse to heavy drinking after LT, resulting in a high risk for recurrent cirrhosis on the liver graft.3, 10 Furthermore, the use of this rule alone results in a significant number of candidates with a low risk for alcohol relapse having to wait 6 months before being placed on the transplantation waiting list. Therefore, in the last American Association for the Study of Liver Diseases guidelines for referral to LT, evaluation by an addiction specialist has been recommended before 6 months.11 Because of the limitations of the 6‐month rule, several centers have prospectively attempted to improve prediction of alcohol relapse and identified independent predictors of relapse such as alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV), a family history of alcoholism, a history of other substance use, prior alcohol rehabilitation, the presence of psychiatric comorbidities, and High‐Risk Alcohol Relapse (HRAR) scale score greater than 3 (Table 1).12, 13, 14, 15

Table 1.

Major Risk Factors, Other Than Duration of Abstinence, of Post–Liver Transplantation Alcohol Relapse (Any Pattern of Use) Identified in Recent Prospective Studies

HRAR scale score > 3

Alcohol dependence according to DSM‐IV

Prior alcohol rehabilitation

Family history of alcoholism

History of other substance use

History of depressive disorders or psychiatric comorbidities

Besides the moral and ethical considerations, LT in patients with AH is complex for several reasons. First, the diagnosis of AH in 30% to 50% of liver explants is not necessarily a sign of hidden alcohol consumption because the inflammatory process may continue for more than 1 year after alcohol consumption is stopped.16, 17, 18 Recipients who have a diagnosis of AH on the liver explant have a similar risk for alcohol relapse. Data have clearly shown that patient and graft survival are not influenced by the presence of AH regardless of its severity, according to the Maddrey score.16, 17, 19 Therefore, the presence of AH on the explant does not seem to influence the efficacy of LT.

Because of the limitations of the 6‐month rule and available data on AH, a French consensus conference has recommended performing a trial evaluating eLT in patients with AH who do not respond to medical therapy.18 In the first pilot study performed by French and Belgian centers, 26 patients with severe AH as first episode of decompensation who did not respond to medical therapy underwent eLT.8 The lack of response to medical therapy was assessed by the Lille model in more than 90% of cases, and all patients were evaluated according to a strict selection protocol. Family support, an absence of severe coexisting or psychiatric disorders, and patient agreement to lifelong total alcohol abstinence were mandatory. The selection process required consensus of four decision‐making circles: circle 1: nurse, resident and fellow; circle 2: addiction specialist; circle 3: senior hepatologist; circle 4: surgeons and anesthetists (Fig. 2). Survival of these patients at 6 months was better than in matched control patients [77% ± 8% versus 23% ± 8% (P < 0.001), respectively] with a survival benefit of up to 2 years [71% ± 9% versus 23% ± 8% (P < 0.001), respectively]. Relapsed alcohol consumption occurred in 12% of patients after LT.8

Figure 2.

Selection process for liver transplantation of patient with alcoholic hepatitis not responding to medical therapy according to the four decision‐making circles.

The benefit to survival and a low rate of alcohol relapse were recently confirmed in three studies evaluating eLT. In the largest study, eLT was offered to 28 patients who were aware of their condition and who fulfilled the following criteria: signature of a contract of abstinence, the presence of a supportive family, a stable work history, and demonstration of awareness of their past substance abuse. Six months survival was higher in eLT patients than in patients who were not selected for LT (87% versus 25%), and alcohol relapse occurred in 7% of cases.20 In the pilot study, patient and graft survival seem to be worse than the usual rates for LT in patients with alcoholic cirrhosis without associated AH, although this reduced survival was not observed in the subsequent eLT studies.20 Thus, further data are needed to assess whether graft and patient survival in eLT differs from that in other indications.

The selection process should be standardized according to objective criteria to reassure the public and care providers, even though this restrictive selection process is not required for other diseases such as fulminant hepatic failure caused by voluntary acetaminophen poisoning or patients with obesity‐induced liver injury. Further studies are needed to determine the burden of this indication. In the pilot study, 3% of grafts were used for this indication, but these results must be analyzed based on a very strict selection protocol.8 Better use of available scores or the development of new prognostic tools could prevent unnecessary transplantation because approximately 30% of nonresponders live without transplantation. An approach that combines the results of static and dynamic scores could improve predicted outcomes in patients with AH.21 Progress in the management of the most severely ill patients is also warranted because 30% to 50% of selected patients die before receiving a liver graft, mostly from sepsis.20

Finally, some clinicians fear that modified LT guidelines will decrease organ donations because alcoholic candidates are viewed by the public as less deserving than patients with other diagnoses.3, 22 However, it should be pointed out that other self‐inflicted diseases that require costly medical care (e.g., tobacco use, resulting in lung cancer, chronic obstructive pulmonary disease, and myocardial infarction) are not as controversial as LT for alcoholic patients. A recent survey of 503 Americans showed that 82% of them were neutral about the eLT program for AH and were more concerned by the age of the candidates and family support.23 However, this survey has potential biases in relation to the characteristics of the population that make it impossible to draw any firm conclusions on the opinion of the general public. Thus, further expert scientific data are still needed to determine whether organ donations will be affected if expert guidelines for indications of LT are modified. Until now, limiting care because of a patient's perceived responsibility or a lack of sympathy by the general public has been considered unethical.3 Public information campaigns should be improved based on scientific data and medical ethics to prevent any impact on organ donations.

In conclusion, arguments based on scientific results and medical ethics suggest that eLT could be an effective therapeutic option in patients with AH who do not respond to medical therapy. The impact on organ donation and public perception must be clarified. Further studies are needed to standardize the selection process, to evaluate remaining uncertainties, and to provide experts with additional data to draft future guidelines for this indication.