Liver transplantation for alcoholic liver disease

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Alcoholic liver disease (ALD) is one of the most common causes of cirrhosis and indications for liver transplantation (LT) in Europe and North America.1, 2 Despite patient and graft survival outcomes similar to those after LT for other etiologies of liver disease, ALD has been considered a controversial indication for LT. The reluctance to perform transplantation for patients with ALD stems in part from the view that alcoholics bear responsibility for their illness,3 and there is also the perception that a person with alcoholism is likely to relapse into alcohol use after LT and thereby damage the allograft.4

Patients with ALD should be referred to an LT center when complications of liver disease develop or when the Model for End‐Stage Liver Disease (MELD) score exceeds 12. Poynard et al.5 showed that there was a survival benefit when patients with ALD and decompensated liver disease underwent transplantation, whereas there was no survival benefit when alcoholic patients with better compensated liver function underwent transplantation. In contrast, a retrospective analysis of the United Network for Organ Sharing database suggested that ALD patients derived a survival benefit at relatively low MELD scores.6

LT as a treatment for life‐threatening alcoholic hepatitis is particularly controversial. Factors that determine the reversibility of ALD (with or without superimposed alcoholic hepatitis) in response to alcohol abstinence are largely unknown. A recent multicenter pilot study7 has shown that early LT can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy.

Evaluation and Selection of Candidates

Because LT is a treatment for life‐threatening liver disease, the evaluation and selection of patients for LT should consider the risk of dying (in other words, the prognosis) without LT. In the past, the Child‐Turcotte‐Pugh classification was used to evaluate the severity of liver cirrhosis, whereas in recent years, the prognostic model of choice has been the MELD score, which is based on the serum creatinine level, serum total bilirubin level, and international normalized ratio.8 There are two prognostic models specific for ALD: the first, by a French group (Beclere model), uses only variables that are readily available to the clinician (serum bilirubin, albumin, age in years, and encephalopathy),9 and the second, by a Birmingham, UK group, is based on a similar methodology and incorporates serum bilirubin, blood urea, serum albumin, ascites, and bacterial peritonitis.10 Although these models share common elements, the choice of which to use is up to the clinician, who should use the model in tandem with a careful clinical assessment of each individual patient with ALD.

Chronic hepatitis C virus (HCV) infection often coexists with ALD, and the combination may act synergistically to cause liver disease. Consequently, the combination of alcoholism and HCV infection is common among patients under evaluation for LT. HCV‐positive patients who have an alcohol intake greater than 50 g/day develop cirrhosis at a faster rate than HCV‐positive patients with a lower alcohol intake.11 Therefore, it is incumbent on the transplant center to consider alcoholism in all HCV patients referred for LT (and vice versa).

Primary hepatocellular carcinoma may complicate alcoholic cirrhosis. The candidate's management is based on the assessment of the accepted criteria for LT in the presence of hepatocellular carcinoma.12

In addition to evaluating the severity of the liver disease and its complications, the pretransplant investigation should focus on comorbidities such as pancreatitis, neuropathy, cardiovascular disease, myopathy, renal insufficiency, nutritional status, and infections. All alcoholic candidates evaluated for LT should have a test for tuberculosis reactivity. Careful screening for cancer is also important. Alcoholic patients being evaluated for LT need a careful dental evaluation, and tooth extraction may be required.

A multidisciplinary approach that assesses not only medical suitability but also psychological suitability for LT is essential for all patients with ALD. The utility of a pretransplant requirement of 6 months' abstinence (the so‐called 6‐month rule) is controversial, although it is widely used by many centers worldwide. Six months' abstinence, when used in isolation from a more nuanced psychosocial evaluation, is an inadequate predictor of posttransplant abstinence.13, 14 Table 1 summarizes the assessment of the candidate with alcohol‐related liver cirrhosis for LT.

Table 1.

Assessment of the Candidate With Alcohol‐Related Liver Cirrhosis for LT

	Assessment
Severity of liver disease	Child‐Turcotte‐Pugh score
	MELD score
	Beclere model
	Birmingham model
Complications of liver disease
Portal hypertension	Abdominal Doppler ultrasound
	Esophagogastroduodenoscopy
	Wedge pressure measurement
Hepatocellular carcinoma	Liver ultrasound
	Liver CT scan or MRI
	Alpha‐fetoprotein
HCV infection	HCV RNA
	Genotype
	Interleukin‐28 genotype
Medical comorbidities
Cardiovascular disease	Electrocardiogram
	Chest X‐ray
	Echocardiography
	Holter test
	Myocardioscintigraphy
	Dobutamine echocardiography
	Cardiac catheterization
Renal impairment	Renal function tests
	Renal ultrasound
Acute and chronic pancreatitis	Abdominal ultrasound
	CT scan
	Pancreatic amylase
Neurological alterations	Electroencephalography
	Brain imaging (CT scan and MRI)
	SPECT, PET, and BAER only in select patients
Nutritional status	Body mass index
Gastrointestinal and respiratory tract malignancies	Esophagogastroduodenoscopy
	Colonoscopy
	Laryngoscopy
	Chest X‐ray
	Lung CT scan
	Bronchoscopy
Tuberculosis	Skin test for reactivity to purified protein derivative
	Chest X‐ray
	Bronchoscopy
Psychosocial evaluation
Alcohol use assessment	Alcohol abuse or dependence
	Amount and duration of alcohol consumption
	Alcohol abstinence
	Previous alcohol rehabilitation
Psychological/psychiatric disorders	Psychological/psychiatric evaluation
Smoking or other substance abuse	Psychological evaluation
	Toxicological evaluation
Social and family support
Awareness of liver disease	Interview with patient and his or her family
Adherence to medical regimens	Questionnaires
	Educational training

Abbreviations: BAER, brainstem auditory evoked response; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single‐photon emission computed tomography.

Abbreviations.

AASLD

American Association for the Study of Liver Diseases

ALD

alcoholic liver disease

BAER

brainstem auditory evoked response

CT

computed tomography

HCV

hepatitis C virus

LT

liver transplantation

MELD

Model for End‐Stage Liver Disease

MRI

magnetic resonance imaging

PET

positron emission tomography

SPECT

single‐photon emission computed tomography

Management on the Transplant Waiting List

While on the waiting list, patients with decompensated liver disease should undergo regular follow‐up. Each patient's MELD score should be updated, and surveillance for hepatocellular carcinoma and monitoring for clinical signs of portal hypertension should be undertaken. The monitoring of abstinence from alcohol is required during the wait‐list phase, but the best method is still controversial. Recently, rates of alcohol use ranging from 25% to 35% have been recorded for ALD candidates for LT with either confidential interviews or measurements of methanol, a specific serum biomarker for alcohol use.15, 16 A trusting therapeutic relationship between the patient and clinicians will promote candor and expedite the initiation of treatment of alcoholism when it is appropriate.17, 18

Medical Management of ALD LT Recipients

Table 2 summarizes the recommendations of the 2013 guidelines of the American Association for the Study of Liver Diseases (AASLD) for the posttransplant management of patients undergoing transplantation for ALD.19 Patients who have undergone LT for ALD have survival rates similar to those for LT recipients without a diagnosis of ALD, although mortality is increased in patients with comorbid ALD and HCV.6, 20 Indeed, in comparison with patients with other etiologies (e.g., HCV), few patients undergoing transplantation on account of ALD die because of advanced liver disease due to alcohol relapse. In contrast, death from cardiovascular causes and de novo malignancies, particularly of the aerodigestive tract, are significantly overrepresented among patients undergoing transplantation for ALD.14, 20, 21 There is no association between new‐onset cancers and alcohol relapse, whereas a causal linkage with resumed cigarette smoking is very likely. Patients undergoing LT for ALD who were smokers before transplantation tend to quickly reestablish smoking at addictive levels.22

Table 2.

Recommendations of the AASLD Guidelines Committee for Patients With ALD Who Survive LT

1. All patients with a prior diagnosis of ALD should be encouraged to remain abstinent from alcohol (grade 1, level B).

2. Patients should be encouraged to enter therapy or counseling if they relapse into alcohol use (grade 1, level C).

3. All patients with a prior diagnosis of ALD who are users of tobacco should be encouraged to undertake smoking cessation (grade 1, level B).

4. Careful attention should be paid to the risk of cardiovascular disease and/or new‐onset cancers of the aerodigestive tract, especially in cigarette smokers (grade 1, level A).

This table is based on Lucey et al.19

Drinking Relapses After LT

There is a wide variation in the reported rates of alcoholic relapse after transplantation, which range from approximately 10% to 90%.14 These data mostly refer to studies that defined relapse as any use instead of distinguishing between occasional lapses or slips and harmful or addictive drinking.14 An analysis of a longitudinal, prospective cohort of ALD transplant recipients yielded five patterns of alcohol use after transplantation4 (see Fig. 1). Eighty percent of the patients either did not drink (pattern 1) or consumed only small amounts occasionally (pattern 2). Conversely, in the remaining 20%, there were three patterns of harmful drinking, which were based on the time to relapse and whether the patients demonstrated sustained heavy use or subsequently modified their drinking.

Figure 1.

Patterns of drinking behavior in a prospective cohort of ALD patients followed at a single center. Reprinted with permission from American Journal of Transplantation.4 Copyright 2010, John Wiley & Sons, Inc.

ALD patients who relapse into harmful drinking are at risk for alcoholic liver injury, including alcoholic hepatitis, delirium tremens, alcoholic pancreatitis, pneumonia, and reduced patient survival.14

Treatment of Addiction After LT

Many ALD LT recipients exhibit a low motivation for undergoing treatment for alcoholism while expressing a strong sense of having recovered from alcoholism and denying craving.23 It is likely that these responses indicate an absence of internal prompts to consume alcohol, and they probably correspond to groups 1 and 2 in the Pittsburgh cohort (see Fig. 1) with no or only occasional minor drinking. An additional impediment to treatment is that some of the candidate medications, such as naltrexone, are potentially hepatotoxic.24 The challenge for the posttransplant management team is to identify those patients at higher risk of relapse in order to provide them with the support needed to prevent a relapse into harmful drinking. While not supported by a randomized trial, a structured management plan comprising an assessment by a psychiatrist skilled in the care of alcoholics, the initiation of treatment in patients who have not been treated in the past, encouragement to participate in motivational enhancement, and the use of an abstinence contract has shown encouraging results.²⁵