Liver Transplantation in Patients with Alcoholic Liver Disease
Review Article for ‘Liver Transplantation’
Author: Michael R. Lucey
Words: 4,459 (not including abstract, references, figures or tables)
Address for correspondence:
M.R. Lucey MD, Division of Gastroenterology and Hepatology, Department of
Medicine, 4142 UWMF Centennial Building, 1685 Highland Ave, Madison, WI
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While alcoholic liver disease (ALD) is one of the most common indications for liver
transplantation (LT), there are yet unresolved controversies about the goals of
treatment, referral, evaluation, and selection of patients with ALD for LT, and care
after LT. It is uncertain whether there is a large unmet need for LT among patients
with ALD, on account of the unmeasured effects in this population of recent drinking,
relapse and recovery with abstinence. ALD patients who are referred for LT
evaluation need careful assessment of the extrahepatic effects of alcohol-related end-
organ damage. Although it is clear that there is a relationship between the length of
sobriety and future abstinence, the present methods to predict future drinking are
inexact. The survival of ALD patients after LT is as good as non-ALD patients,
although patients with co-incident ALD and HCV have greater mortality and
morbidity. After LT, ALD patients are at increased risk of developing malignancies
and cardiovascular disease. These risks appear to be linked to smoking cigarettes.
Covert drinking occurs both before and after transplantation, and approximately 20%
of patients return to harmful drinking after LT. Harmful drinking after LT, rather
than slips, causes liver damage and reduces survival. Better therapies for controlling
addiction to alcohol and to nicotine are needed in ALD patients both before and after
Alcoholic liver disease (ALD) is the second most common diagnosis among patients
undergoing liver transplantation in the US and Europe (1, 2). ALD, either alone or in
combination with HCV infection, accounts for 20% of all the primary transplants that
have taken place in the US from 1988 to 2009, comprising more than 19,000
recipients. This is a remarkable number, especially when it is contrasted to the
prediction, made at the landmark NIH consensus conference in 1984 that not many
patients with alcoholic liver disease would be selected for liver transplantation (3).
Moreover, the outcome for patients transplanted for ALD is at least as good as that
for most other diagnoses, and better than that for HCV (4). However, the apparent
success of LT for ALD masks a more complex reality. There are, as yet, unresolved
controversies regarding LT in patients with ALD. In this review I will address
several of these contentious issues including what are the goals of treatment; how are
patients referred, evaluated, and selected for LT, and what impact the diagnosis of
ALD has on care after LT?
The Goals of Treatment
The goal of LT is to treat life-threatening liver failure or cancer that is intractable to
medical management. Medical management of ALD starts with abstinence from
alcohol. Alcoholic patients who maintain abstinence can recover from advanced liver
failure, and reestablish stable liver function, with resolution of portal hypertension (5,
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6). Unfortunately, alcoholism is a disease of relapses and remissions, and this pattern
persists even after life-threatening episodes such as a variceal hemorrhage (7). The
frequency of recovery from decompensated liver failure due to ALD is restricted by
the frequency relapse to drinking (8). A therapeutic formulation addressing LT for
ALD needs to encompass the psychological as well as the somatic health of the
potential candidate. Put another way, LT should be seen as a treatment of end-stage
liver failure, within a comprehensive care program that addresses management of
addictions to alcohol, cigarettes, or any other drugs of addiction.
Referral of ALD Patients for Liver Transplant Evaluation
The combined prevalence of alcohol abuse and dependence in the US is estimated at
84.5 per 1,000 of the population aged 18 and older, which translates to approximately
18 million adults at risk for alcoholic liver disease (9). The estimated age-adjusted
death rate related to liver cirrhosis in 2005 was 9.2, which translated to approximately
27,000 deaths (9). In 2004, liver disease, not including viral hepatitis, accounted for
2.4 million ambulatory care visits (10). Liver disease was the third most common
digestive diagnosis on hospital discharge records (10). Although these data do not
provide a precise estimate of the prevalence of patients with life-threatening ALD
suitable for LT, previous authors have asserted that ALD patients are under-referred
for LT in the US (11).
On the other hand, data documenting the process of referral and evaluation of patients
with problem drinking are inconclusive on this point. Julapalli et al described a
cohort of 199 patients with liver disease who received their medical care at a large
metropolitan Veteran Affairs medical center, albeit one without a liver transplant
program, between October 2001 and September 2003 (12). All of the cohort met
guidelines for referral for possible liver transplantation; yet despite 300 clinical
encounters, only 15 patients were eventually referred for evaluation. Even when those
patients with a history of recent alcohol use were removed from consideration, the
presence of ALD was a significant negative determinant regarding whether referral
for LT had been considered. In contrast, in a retrospective study of patients in a
community hospital in South Wales, UK from 1987 to 1990, while ALD was the most
common diagnosis among patients who were not referred to a liver transplant unit,
continuing drinking was the usual explanation, which the writer considered
appropriate (13). Similarly, when Veldt et al undertook a prospective assessment of
patients admitted to a French in-patient liver unit on account of alcohol-associated
liver failure, the combination of death in the initial hospital stay, recovery with
abstinence, and alcoholic relapse during immediate follow up, meant that very few
actual transplant candidates emerged (8). Thus whether there is an unmet need for
transplantation in patients with liver failure due to ALD remains unanswered.
There may also be a lack of recognition of the contribution of alcohol excess to liver
failure arising in the general community. Day et al identified patients with liver
failure in their referral population, in whom alcohol abuse or addiction was not
recognized or acknowledged by the referring physician (14). Whether this was a
tactical omission on the referring physicians part, or a genuine lack of recognition is
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not known, but their data underscore the need for vigilance about the diagnosis of
alcohol disorders in the liver transplant population.
The attitude of physicians to alcohol addiction is a likely influence on the referral of
ALD patients for LT. Neuberger has shown that, in the UK at least, the general
public, general practitioners and gastroenterologists alike, hold a pejorative view of
patients with alcohol abuse and dependence, in relation to liver transplantation (15).
It is also possible that many primary care providers and community
gastroenterologists are confused about when to refer their ALD patients for LT
evaluation, and about whether a specific interval of abstinence is needed before
referral. The role of an interval of sobriety in the process of selecting patients for LT
will be considered below. In my experience, liver transplant programs would prefer
for potential patients to be referred, rather than ‘triaged’ in the community. As a rule
of thumb, any ALD patient who is failing to improve after 3-months abstinence is
unlikely to improve with medical management, and should be considered for referral
to a transplant center (8).
Evaluation for LT
A comprehensive evaluation of an ALD patient must assess all tissues at risk from
alcoholic damage. Cardiac function, kidney function, the central and peripheral
nervous system, and the immune system are at risk from chronic alcohol abuse. Each
system should be studied carefully, in addition to the standard assessment of liver
function and hepatocellular carcinoma. Interpreting data testing the integrity of
extrahepatic organ systems is often complicated by competing explanations for
abnormal findings. For example, we have difficulty distinguishing hepatic
encephalopathy from Wernicke’s encephalopathy, painful peripheral neuropathy due
to alcohol from that due to other causes especially diabetes, while the full effects of
the alcohol-associated myopathic heart may be masked by the reduced systemic
vascular resistance (afterload) common in patients with advanced liver disease.
Alcohol Use by ALD Candidates for LT
The evaluation of the patient with ALD differs from that in other potential candidates
for LT as it must take into account the history of addiction, not only to alcohol, but
also often to nicotine, and other drugs of addiction, either recently or in the past. One
important question regards whether the potential ALD candidate is whether the
candidate is drinking now. By and large, only stable alcoholics who are thought to be
abstinent are referred to transplant programs (16). Two recent studies have shown
that a not inconsiderable proportion of these supposedly abstinent ALD patients
undergoing evaluation for LT or on the waiting list continue to drink (17, 18). This
underlies the difficulty in established accurate data on alcohol use, especially when it
is not in the patient’s interest to admit to drinking. Indeed, this inhibition on candor
militates against the best interests of the patient, by making it more difficult for the
patient to acknowledge a slip and seek help to reestablish sobriety (19).
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Prognosis for Sobriety, Sobriety as Prognosis
Outside the special circumstance of alcoholic hepatitis, which will be discussed
below, most ALD patients who are likely to be considered for LT have already
established an interval of abstinence. There remains controversy as to the minimal
interval necessary to be acceptable for LT. In 1997, a consensus conference of the
American Association for the Study of Liver Diseases and the American Society of
Transplantation concluded that … ‘there is a strong consensus for requiring that most
alcoholic patients should be abstinent from alcohol for at least 6 months before they
can be listed for liver transplantation’ (20). This is often referred to as ‘the six-
In 1997, it was declared that the first purpose of the six-month interval was as a
mechanism to allow recovery with medical management from alcohol-induced liver
failure. However, since then, the six-month rule has mostly been discussed as a
prognostic tool to predict subsequent alcoholic relapse, often referred to as
‘recidivism’. In the literature on alcoholism, six months appears too short to
determine meaningful abstinence, and Vaillant has suggested that sobriety is robust
after 5 years (21). Data from single center, usually retrospective, studies have yielded
conflicting data on whether six-months abstinence is predictive of drinking after
transplantation (reviewed in 11and 22. See also 23, 34, 25). These data mostly refer
to studies in which relapse was defined as ‘any use’. The circumstances of abstinence
are usually not defined, and abstinence because of admission to hospital is not
distinguished from abstinence at home. In recent years, the emphasis has shifted to
consideration of the pattern of drinking rather than the frequency of ‘any use’ (26).
Harmful or addictive drinking is defined as drinking more than 5 drinks a day for a
man, 4 drinks a day for a woman, or drinking for more than 4 successive days in
either sex. Whereas a metanalysis of studies using the ‘any use standard’ found that
the six month rule was independently predictive, albeit weakly, of future drinking,
along with poor social support and a family history of alcoholism (28), recent studies
are more supportive of the association between duration of abstinence and subsequent
harmful drinking (11, 24, 25). At the same time, the six-month rule been challenged
as both limiting access to LT of appropriate candidates, whilst admitting
inappropriate ones. Yates has shown, in modeling studies that a requirement for six
months abstinence would penalize some patients with short sobriety but who would
not relapse in the future (28).
In the 1990s, Beresford proposed a broad-based examination of psychological health
to assess risk of relapse after liver transplantation (16). Drawing on studies of
alcoholics in the non-transplant setting, he described several positive and negative
prognostic factors to aid in prediction of abstinence after transplantation. The
favorable factors are the acknowledgement by the patient of their addiction, the
presence of strong social support (such as a spouse, a job and a home), and four
prognostic elements, also indicative of social integration, identified by Vaillant:
substitute activities, source of improved self esteem or hope, a ‘rehabilitation
relationship’ and perception by the drinker of negative consequences of relapse to
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drinking. Negative prognostic factors are pre-existing psychotic disorder, unstable
character disorder, unremitted poly-drug abuse, repeated unsuccessful attempts at
rehabilitation and social isolation. In addition he was of the opinion that patients
meeting criteria for dependency were at higher risk than patients with a diagnosis of
alcohol abuse, an observation that was later confirmed prospectively by DiMartini et
al (29). Beresford advocated a comprehensive psychosocial assessment for two
reasons. First, nearly 80% of the patients referred had good prognosis scores, and
second he stated that ‘the range among the various factors is too wide to justify using
any one as a strict inclusion or exclusion criterion’ (16). Instead, on completion of
his/her assessment, the addiction specialist should be able to give an estimate of the
risk of alcoholic relapse, and to recommend treatment where appropriate (16). It was
then up to the transplant team to integrate this prognostic assessment into the
comprehensive clinical review in order to determine whether to place the patient on
the waiting list. Since then, evaluation by an addiction specialist has become a
common feature of LT programs for ALD patients, and subsequent reviews have
supported the importance of social integration as a predictor of post-transplant
More recently, De Gottardi et al reported a retrospective 5-year follow up study of
387 ALD patients who received LT at 2 European centers (24). All were required to
have at least 3 months abstinence prior to transplantation, although most had longer
intervals of sobriety. 11.7% reported harmful drinking after LT. Three pre-transplant
factors were predictive of harmful drinking: abstinence of less than 6 months;
diagnosis of anxiety or depression, and a positive screen using the HBAR (high-risk
alcoholism relapse) scale, a prognostic scale previously described in US patients in
the Veterans Affairs health system. HBAR counts years of drinking, number of drinks
per day, and number of previous inpatient rehabilitations for alcoholism. The
strengths of this study include it’s large cohort number, it’s length of follow up, and
the concentration on harmful drinking rather than slips. It also is mindful of the
importance of psychiatric co-morbidity in the assessment whereas it is not as
subjective as the Michigan Score. On the other hand, the De Gottardi study was
retrospective; it only included patients accepted for and proceeding to transplantation,
it entailed infrequent measures of use of alcohol after the first year and it was largely
restricted to ‘good risk’ candidates.
In view of the difficulty of getting accurate alcohol histories from patients who might
be disadvantaged by their candor, an alternative approach is to use histology of the
explanted liver as an indicator of recent drinking by ALD liver transplant recipients.
Two studies where this was done found that that while neither the presence of
histological alcoholic hepatitis in the explant nor a history of drinking within 6
months correlated with subsequent relapse, post transplant relapse was correlated
with less than 12 months abstinence (30,31).
Against the background of these conflicting data, the consensus regarding
pretransplant abstinence and the suitability of patients with alcoholic hepatitis for
transplantation has varied from country to country. France has moved away from the
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6-month rule to a comprehensive psychosocial assessment (32) whereas the United
Kingdom preclude transplantation in patients with alcoholic hepatitis (33) although
this position has been challenged recently (34). In the US, the evaluation process
usually results in presentation of a comprehensive clinical and psychosocial
assessment to the transplant selection committee. When the transplant program
selection committee decides to recommend transplantation, approval of the third party
payer is necessary before proceeding with placement on the LT waiting list. In the
case of patients with ALD, this discussion often turns on the issue of prognosis for
sobriety after LT. The six-month rule has been widely adopted by the US insurance
industry. Although there are no published data on the frequency of a denial of
coverage by a third party payor when the transplant program wants to proceed, nor
data on the frequency that the patient dies in the aftermath of that decision, occasional
anecdotes have been reported (35,36). Similarly, there are personal reflections by
insurance medical officers on the difficulty they face in such cases (37).
Table 1 outlines some of the lessons that can be drawn regarding the place of sobriety
in gauging prognosis and vice versa? It remains true that the severely ill patient who
has been drinking recently, but who has other favorable indicators of addiction
prognosis poses great difficulty to the transplant program.
Selection of ALD Patients for LT
The plasticity of ALD, particularly in response to abstinence, makes it difficult to
determine accurately the prognosis of alcoholic liver injury independent of LT. This
assessment is crucial, since all LT programs would prefer to avoid transplantation in
those patients who have a good potential for recovery of liver function with
abstinence and medical therapies. Studies from France, either using mathematical
models or a prospective study have suggested that only ALD patients with Child-
Pugh class C liver failure derived a benefit in post-transplant survival (38, 39, 40) In
contrast, a retrospective analysis of the UNOS database, estimating survival benefit,
that encompassed survival/mortality before and after transplantation, showed that
ALD patients with relatively low MELD scores in the 9 to 11 range derived a
survival benefit (4). The present system of organ allocation in the US ensures that
LT is confined to ALD patients with severe liver failure or hepatocellular cancer and
high urgency of dying without LT.
LT in Severe Alcoholic Hepatitis.
Patients with severe alcoholic hepatitis present particular challenges to transplant
teams, since they have invariably consumed alcohol in the previous month. Those
patients who have failed to respond to corticosteroids carry a very high 90 day
mortality. Heretofore, as in the AST/AASLD 1997 guidelines, alcoholic hepatitis
was an absolute contraindication to placement on the transplant waiting list, which is
also the position endorsed by the UK Liver Advisory Group (20, 33). However, data
are emerging from a European multicenter study in which a carefully selected group
of patients with a first episode of severe alcoholic hepatitis, who have failed medical
treatment, and who have favorable psychosocial assessment that LT demonstrated
excellent intermediate term survival after LT, with a low frequency of post transplant
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harmful drinking (41). Consequently, transplant groups on both sides of the Atlantic
have argued for placement on the liver transplant waiting list in the occasional
patients with life-threatening alcoholic hepatitis who meet the stringent criteria
described above (34, 42).
Management of Addictions, including Alcoholism, prior to LT
There are few published data about treating addictions in the period of evaluation or
on the waiting list. Some programs have recommended requiring the candidate to
sign a ‘contract’ to remain abstinent. Many centers encourage attendance at support
groups such as Alcoholics Anonymous, but data on the efficacy of contracts or AA in
this particular population are lacking. Georgiou et al reported a pilot study of
psychosocial intervention, in the form of 3 structured meetings, administered in the
preparatory phase for liver transplantation (43).While this demonstrated that such a
positive reinforcement approach was feasible, it did not assess the efficacy of such
intervention in regards to subsequent alcohol use. A recently published randomized
trial in patients under evaluation for, or awaiting LT at two US centers compared the
impact of one such positive reinforcement technique, motivational enhancement
therapy (MET), to advice to attend AA or local counseling, referred to as treatment as
usual (TAU) (19). The study revealed considerable hidden drinking, including
harmful drinking; in ALD patients awaiting LT, while the effects of MET were
modest at best (see Figure 1).
Although smoking cigarettes is widespread in this population, we lack data on
efficacious strategies to combat smoking during the evaluation stages before LT.
Mortality and Morbidity after LT in ALD patients
ALD patients selected for LT in the US have similar survival both before and after
the operation to LT recipients without a diagnosis of ALD, (2,4). Analysis of large
multicenter databases from the US and Europe have shown greater mortality in
patients with co-morbid ALD and HCV (2,4), although this was not found in one
single center series (44). It is possible that the advent of more efficacious therapies
for HCV either before or after transplantation will improve survival in co-morbid
While ALD patients have similar survival to non-ALD liver transplant recipients, the
cause of death after transplantation differs in ALD recipients compared to non-ALD
recipients. A retrospective analysis of the European Liver Transplant Registry
(ELTR) by Burra et al showed that cardiovascular causes and de novo malignancies
were significantly over-represented in the patients transplanted for ALD compared to
the non-ALD recipients (2). Similarly, Watt et al showed in a prospective cohort of
780 primary graft recipients that ALD was significantly associated with the risk of
death from cardiovascular causes after one year post-LT (45). Studies from the ELTR
and several single centers have suggested that patients transplanted for ALD have an
increased incidence of de novo cancers after transplantation, which are associated
with worse survival (46, 47,48, 49). These studies do not show an association
between new-onset cancers and alcohol relapse. In some, albeit not all of these
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studies, new tumors were concentrated in the aero-digestive tract. The stratification
of cardiovascular deaths and of new onset cancers of the aero-digestive tract in
patients receiving LT for ALD strongly hints to a causal linkage with cigarette
smoking. Smoking is prevalent in ALD patients undergoing evaluation for LT, and
DiMartini et al have shown that ALD liver transplant recipients who were smokers
before transplantation quickly reestablish smoking at addictive levels (50). If the link
between cigarette smoking and death from either cancer or cardiovascular disease is
correct, it points the way to improving post transplant health through promotion of
smoking cessation in alcoholic, as in all, liver transplant recipients.
Drinking relapses after LT
There is a wide variation in reported rates of alcoholic relapse after transplantation
ranging from about 10% to 90% (22). These data mostly refer to studies in which
relapse was defined as ‘any use’, rather than distinguish between occasional lapses or
‘slips’ and harmful or addictive drinking (26). Analysis of the longitudinal
prospective cohort of ALD transplant recipients maintained by DiMartini and
colleagues has yielded 5 patterns of alcohol use after transplantation, including 3
separate patterns of addictive drinking based on the time to relapse, and the
subsequent course (51) (see Figure 2). Eighty per cent of patients either did not drink
or only consumed small amounts occasionally. Conversely, in the remaining 20 %,
there were 3 patterns of harmful drinking. The patterns varied according to the time to
relapse, and whether the patients demonstrated sustained heavy use or subsequently
modified their drinking. These data are similar to the retrospective data from Tang et
al in which harmful drinking was found in 16% of a smaller cohort (52).
Data on consequences of alcoholic relapse have tended to be anecdotal and are often
based on retrospective accounts from single centers. These anecdotal reports suggest
that patients who relapse to harmful drinking are at risk of alcoholic liver injury
including alcoholic hepatitis, delirium tremens, alcoholic pancreatitis, and pneumonia
(53, 54, 55). Two single-center studies have suggested that relapse to harmful
drinking is associated with reduced survival (56, 57). Furthermore, the causes of
death in the patients who returned to heavy consumption of alcohol tended to be liver-
related, whereas abstinent ALD patients died of cardiovascular disease and malignant
tumors. These data strongly suggest that controlling heavy drinking is an appropriate
goal after LT in ALD patients.
Evidence of alcohol relapse occurring in conjunction with failure to take
immunosuppression is patchy, with some accounts suggesting such an association
between alcoholic relapse and so-called ‘non-compliance’, whereas other have
contended that non-compliance is no more common than in non-ALD patients (53,
54, 55, 58). In addition, it is likely that the social and familial negative consequences
of abusive drinking seen among alcohol dependent persons will be seen when alcohol
relapse occurs after transplantation, although good data on this point are not readily
available. There is a need for more systematic assessment of the consequences of
relapse to harmful drinking in liver transplant patients.
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Quality of Life (QOL) after LT
Assessment of QOL) after LT has shown that whereas quality measures improve in
LT patients in most domains compared to their status prior to transplantation, LT
recipients continue to have many deficits compared to age-matched control
populations (59, 60). These observations are drawn from studies with many
limitations, including cross-sectional study design, inconsistent, non-specific or non-
validated study instruments, and short-intervals of follow-up. Given the long-term
survival of many LT patients, the question remains whether these short-term
increments in QOL are sustained or even improve over the longer term.
Unfortunately, the converse may be true. In a 12-year longitudinal follow up study
of 381 LT recipients who survived at least 4 post operative years in 3 US centers,
Ruppert et al found that the early QOL gains gradually diminished over time in all
diagnostic groups, including patients with ALD, as manifested by worsening physical
symptoms, fatigue and a greater sense of being unwell (61). Neither the presence of
the pre-LT diagnosis of ALD, nor the use of alcohol or cigarettes after LT was
associated with worse long-term QOL. These data on the lack of impact of the
diagnosis of ALD on post LT QOL are in agreement with most, albeit not all,
previous studies (60). In contrast, Ruppert’s study indicated that patients carrying
the combination diagnoses of ALD and HCV infection had the worse long-term QOL.
This observation in the dual diagnosis group is complementary to the worse survival
outcome reported in this group (2,4).
Treatment of Addiction after LT
Just as there are few studies of therapy of alcoholism before LT, there is a paucity of
investigation into treatment of alcoholism after LT. There are several difficulties to
overcome when contemplating structured treatment studies in this population. First,
the alcoholic patients who receive liver transplants are probably not homogeneous in
regards to risk of relapse to addiction. Many have a strong sense of having recovered
from alcoholism, denying craving and consequently expressing low motivation for
undergoing treatment (62). This is in contrast to patients in alcoholism treatment
units, where endorsing the treatment model is considered a favorable prognostic
indicator. This resistance to treatment may reflect the fear that a declaration of a
desire for alcohol would be interpreted by the transplant team as a sign of poor
candidacy or lack of commitment to sobriety. It is likely that some of these responses
are genuine, and indicate an absence of internal prompts to consume alcohol. Lack of
interest in receiving treatment for alcoholism was one reason for failure to recruit to a
trial of naltrexone in alcoholic LT recipients (63). An additional impediment was that
LT recipients were unwilling to take a potentially hepatotoxic medication such as
naltrexone. In contrast, Bjarnsson et al introduced into their transplant program a
plan for structured management of alcoholism, comprising assessment by a
psychiatrist skilled in care of alcoholics, initiation of treatment in patients who had
not been treated in the past, encouragement to participate in motivational
enhancement and use of an abstinence contract (58). The protocol was started before
and continued after transplantation with interviews at 3 months, 1 year, 3 years and 5
years. In consecutive patients, they observed a reduction in the prevalence of alcohol
use when compared to a matched historical control group (48% versus 22%) although
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they don’t report their data in terms of harmful drinking. Future treatment initiatives
should be targeted to the sub-cohort of ALD patients with persistent cravings, with
the goal of preventing harmful drinking such as the acceleration in drinking shown in
some of the DiMartini’s cohort (51).
Similarly, we need studies designed to enable the LT recipients to stop smoking
cigarettes. Whether considering drinking alcohol or smoking by the ALD liver
transplant recipient, the treatment under study should have no hepatotoxicity, and the
end-point of the study should be control of the addictive behavior rather than patient
or graft survival.
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