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Gastroentérologie Clinique et Biologique
Vol 28, N° 10  - octobre 2004
pp. 845-851
Doi : GCB-10-2004-28-10-0399-8320-101019-ART2
Predictive factors of alcohol relapse after orthotopic liver transplantation for alcoholic liver disease
 

Mathieu Miguet [1], Elisabeth Monnet [1], Claire Vanlemmens [1], Pascal Gache [2], Michel Messner [3], Stephane Hruskovsky [4], Jean Marc Perarnau [5], Georges-Philippe Pageaux [6], Christophe Duvoux [7], Anne Minello [8], Patrick Hillon [8], Solange Bresson-Hadni [1], Georges Mantion [1], Jean-Philippe Miguet [1]
[1] Hôpital Jean Minjoz, Besançon
[2] Hôpital cantonal de Genève, Suisse
[3] Hôpital Pontchaillou, Rennes
[4] Hôpital de médecine post graduée, Bratislava, Slovaquie
[5] Hôpital Bon Secours, Metz
[6] Hôpital Saint Eloi, Montpellier
[7] Hôpital Henri Mondor, Créteil
[8] Hôpital du Bocage, Dijon.

Tirés à part : M. MIGUET [1]

[1] Service de Médecine B2, Hôpital Paul Morel, 41, avenue Aristide Briand, 70000 Vesoul.

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Facteurs prédictifs d’une reprise de consommation d’alcool après transplantation hépatique pour cirrhose alcoolique
Objectifs

Cette étude prospective examine les associations entre des variables sociologiques et alcoologiques recueillies avant transplantation hépatique pour cirrhose alcoolique et le risque de reprise de consommation d'alcool après transplantation.

Méthodes

Cinquante cinq malades, issus d'une étude prospective randomisée multicentrique de 120 malades comparant la transplantation hépatique aux thérapeutiques habituelles en terme de survie à 2 ans dans une population de malades atteints de cirrhose alcoolique Child-Pugh B, ont été transplantés entre 1994 et 2002. Tous les malades avaient le même questionnaire à l'inclusion, et un recueil homogène des informations tous les 3 mois, jusqu'à 60 mois.

Résultats

Cinquante et un malades sur 55 ont pu être analysés. Le suivi moyen était de 35,7 mois (1-86 mois). Le taux estimé de reprise d'une consommation d'alcool (quelle qu'elle soit) à 12 mois était de 11 % et à 24 mois de 30 %. Le taux estimé de reprise d'une consommation > 140 grammes/semaine était de 11 % à 12 mois et de 22 % à 24 mois. La seule variable entraînant une augmentation significative du taux de reprise était la durée du sevrage avant la transplantation de moins de 6 mois, avec 79 % de reprise à 24 mois versus 23 % pour les malades sevrés depuis au moins 6 mois (P = 0,0003). Une durée de sevrage de moins de 6 mois augmentait le risque d'une reprise de consommation de plus de 140 grammes/semaine (RR ajusté = 5,5; IC95 % = 1,3-24,5; P = 0,02).

Conclusion

La durée d'abstinence avant transplantation hépatique pour cirrhose alcoolique, évaluée dans cette étude prospective, est un facteur de risque de reprise de la consommation d'alcool après transplantation. L'intérêt de ce critère de sélection des candidats à la transplantation hépatique pour cirrhose alcoolique est pour la première fois démontré par une étude prospective.

Abstract
Objectives

The objective of this prospective study was to determine whether sociological and/or alcohol-related behavioral factors could be predictive of relapse after orthotopic liver transplantation for alcoholic liver disease.

Methods

Fifty-five liver-transplanted patients out of a series of 120 alcoholic cirrhotic patients were enrolled in a randomized prospective study. This study was initially designed to compare the 2 year survival in intent-to-transplant patients versus in-intent-to-use conventional treatment patients. For all patients, an identical questionnaire was completed at inclusion, and every 3 months for 5 years to collect data on alcohol-related behavior factors.

Results

Fifty-one patients fulfilled the criteria for the study. The mean follow-up was 35.7 months (range: 1-86). Rate of alcohol relapse was 11% at one year and 30% at 2 years. Alcohol intake above 140 g a week was declared by 11% and 22% of patients at one and 2 years, respectively. The only variable leading to a significantly lower rate of relapse was abstinence for 6 months or more before liver transplantation (23% vs 79%, P = 0.0003). This variable was also significant for patients whose alcohol intake was greater than 140 g per week (P = 0.003) (adjusted relative risk = 5.5; 95%CI = 1.3-24.5; P = 0.02). Multivariate analysis (Cox model) showed that abstinence for 6 months or more before liver transplantation was the unique predictive variable.

Conclusion

In this prospective study of 51 patients transplanted for alcoholic liver disease, abstinence before liver transplantation was the only predictive factor of alcohol relapse after liver transplantation.


Alcoholic cirrhosis is the leading cause of chronic liver disease-related death in France. Liver transplantation has improved prognosis in patients with terminal liver disease but has also raised considerable debate, some authors considering these patients to have a “self-inflicted” disease. The risk of alcohol relapse after transplantation further complicates the question. The debate has become a public issue because of the imbalance between organ procurement and demand. Transplantation teams must intensify their efforts to avoid alcohol relapse after liver transplantation.

We conducted a prospective study in 51 liver transplant recipients treated for alcoholic liver disease between 1994 and 2001 in order to search for factors predictive of alcohol relapse after liver transplantation and to measure its frequency and impact.

Patients and methods
Study design and inclusion criteria

This was a prospective cohort study of patients undergoing orthotoptic liver transplantation (LT) for alcoholic cirrhosis. The diagnosis of alcoholic cirrhosis was based on histological evidence or the usual clinical signs, and biological and morphological findings.

The patients included in this cohort had participated in a multicentric randomized trial which started in 1994 (TRANSCIAL, Transplantation pour Cirrhose Alcoolique). TRANSCIAL was designed to compare LT versus conventional treatment in patients aged less than 66 years with Child-Pugh B alcoholic cirrhosis and a Béclère risk score ≪ 4.04 (appendix) whose condition led to one or more of the complications listed in table I. Non-inclusion criteria are listed in table II.

Detailed data concerning the patient's alcoholic disease as well as management practices and its consequences were collected at inclusion using a questionnaire. Each patient was also re-evaluated by an investigator every three months for up to 60 months post-transplantation. The question of alcohol intake was examined and alcoholemia and/or alcoholuria were measured at each visit.

Alcohol abstinence was encouraged but was not mandatory for patient inclusion.

Study variables and definition of alcohol relapse

The following sociological data were collected for each patient: sex, age at inclusion, marital status (single, married or concubinage, divorced, widow(er)), inclusion arm (LT vs other treatment).

Variables concerning the history of the patient's drinking behavior included: age at onset of regular drinking, duration of alcohol consumption, alcohol-dependence or not based on the DSM-IV criteria (Diagnostic and Statistical Manual of Mental disorders, revised fourth version), attempted abstinence before inclusion (yes or no), prior management (consultation with specialist, abstinence cure, member of an association of former drinkers) or not, history of chronic alcoholism in first-degree relatives, type of alcoholic beverage (fermented beverages or spirits  fermented beverages), alcohol intake in grams per week, change in drinking habits since diagnosis of cirrhosis (abstinence or not), abstinence at time of inclusion (abstinence for less than 3 months versus more than 3 months), duration of abstinence before LT (≪ 6 months versus ≥ 6 months).

Drinking any alcoholic beverage after LT was considered as alcohol relapse and was determined from the patient's statements, from serum and urine tests, or from comments by the investigator or the patient's family or friends. Two post-transplantation events were studied:i) alcohol relapse versus absence of alcohol relapse and ii) alcohol relapse with intake > 140 g/week versus absence of alcohol relapse or relapse with intake ≤ 140 g/week. Once-off drinking/occasional drinking was considered as relapse with intake ≪ 140 g/week. The date of the post-transplantation event was recorded.

Statistical analysis

The risk of alcohol relapse over time was determined with the Kaplan-Meier method. The time to relapse was taken as the time between LT and the date of relapse. Univariate analysis (comparison of relapse curves with the log-rank test) was applied to search for a correlation between risk of relapse and study variables: sociodemographic variables (age, sex, marital status), type of alcoholic beverage, history of the alcoholic disease. Multivariate analysis (age- and sex-adjusted Cox model) was performed to test variables showing a significant correlation in univariate analysis. Correlations were considered significant for P ≤  0.05.

Results
Study cohort

Fifty-five patients included in the TRANSCIAL trial underwent LT between January 1995 and 2002. Four patients were excluded from the present analysis because of intra-operative death (N = 2) or lack of data on alcohol intake since transplantation (N = 2).

At the time of LT, mean age of the 51 patients retained for study was 48.7 years (range: 35-64, median 48). Since some data were missing for certain variables, results are expressed as a function of the number of patients with reliable data.

The cohort included 39 men and 12 women. The TRANSCIAL randomization was “transplantation” for 37 and “other treatment” for 14. Due to aggravation of their disease, all 14 of the “other treatment” patients eventually had LT. Nineteen patients lived alone (single, divorced, widowers) and 32 lived in a couple. Thirty patients (59%) were alcohol-dependent according to the DSM IV score ( ≥ 3) and 21 (41%) were not. Alcohol intake (usual intake for at least one year before inclusion) was, on average, 930 g/week (range: 350-2800, median 700). Age at onset of regular alcohol consumption was, on average, 24.5 years (range: 15-42, median 25). Thirty-three patients (69%) drank mainly fermented beverages (beer and/or wine) and 15 (31%) drank spirits, sometimes with fermented beverages. The duration of the chronic alcoholism was less than 25 years for 27 patients (56%) and ≥ 25 years for 21 (44%). Thirty-three patients (65%) had attempted to stop drinking at least once before inclusion and 18 (35%) had never attempted. Eighteen patients (37%) had participated in management schemes (consultation with a specialist, meetings with former drinkers, hospital weaning program) and 31 (63%) had not. After diagnosis of cirrhosis, 31 patients (63%) were abstinent and 18 (37%) continued regular consumption (but generally with lower intake). Twenty-one patients (42%) had at least one first-degree relative with chronic alocholism and 29 (58%) did not. At inclusion in the TRANSCIAL trial, 8 patients (16%) were non-abstinent or had been abstinent for less than three months versus 26 (51%) who were abstinent for 3 months to one year and 17 (33%) who had been so for more than one year. The duration of abstinence before LT was less than 6 months for 6 patients (12%) and ≥ 6 months for the other 45 (88%). Mean follow-up after transplantation was 35.7 months (range: 1-86, median 35).

The time from inclusion to transplantation for patients in the LT arm was, on average, 6.5 months (range: 0-36 months, median 4 months).

Recurrent alcohol consumption

Alcohol relapse was observed after LT in 13 patients. Consumption was a once-off/occasional event or ≪ 140 g/week for 4 and > 140 g for the 9 others. The rate of relapse (all levels of consumption) was 11% at 12 months and 30% at 24 months (figure 1).

The rate of relapse at 12 and 24 months is expressed as a function of the study variables in table III. The only variable correlated with a significantly lower rate of relapse was duration of abstinence before transplantation (≪ 6 months versus ≥ 6 months). The estimated rate of relapse at 24 months was 79% in patients who were abstinent for less than 6 months and 23% in patients who were abstinent for 6 months or more. Figure 2 illustrates the rate of relapse over time in these two subgroups.

Four of the 6 patients who were abstinent for less than 6 months resumed alcohol consumption within 19 months of LT. Three of them drank more than 140 g/week and had started drinking again during the first year after LT.

Considering patients whose post-transplantation alcohol intake was > 140 g/week in comparison with the subgroup of patients who were abstinent or had “moderate relapse”, duration of abstinence before inclusion was also a significant predictive factor in univariate analysis but was no longer significant in multivariate analysis (age-adjusted Cox model). For these patients, the rate of relapse at 24 months was 58%, compared with 18% for patients who were abstinent for 6 months or more before LT (adjusted RR: 5.5, 95%CI: 1.3-24.5, P = 0.02). These results are detailed in tables IV and V.

Thus, the only variable correlated with a risk of recurrent alcohol consumption after LT was abstinence for less than 6 months before transplantation. In these patients, the risk of relapse was higher irrespective of the level of consumption.

Discussion

At the first consensus conference held by the National Institute of Health (NIH) in 1983, LT was not retained as a therapeutic option for patients with end-stage alcoholic liver disease [1]. At that time, transplantation results were mediocre and using a donor organ for an alcoholic cirrhotic patient was considered questionable. The 3 year survival rate at that time was 20% [2]. Later studies demonstrated that survival was as good in patients with alcoholic cirrhosis as in other recipients [3, 4, 5 et 6], to the order of 63% at 5 years. It was even demonstrated that 5 year survival was better in comparison with non-transplanted patients with Child-Pugh C cirrhosis (58% vs 31%) [7]. At the second consensus conference on LT indications held in 1993, it was concluded that LT is an effective treatment in terms of survival, but that validation was necessary due to the problem of relapse after LT [8]. Thus, in the current context of donor organ shortage, the crucial problem is the prevention of alcohol relapse. Several studies have attempted to identify factors predictive of alcohol relapse [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 et 20] but prospective trials are scarce. Results available to date, summarized in table VI, were mainly obtained from retrospective studies (10 out of 12) including a small number of patients.

In our prospective study, we found that that the rate of alcohol relapse was 11% at one year and 30% at two years. These rates are within the range reported in the literature (13-50%) [9, 10, 11, 12, 13, 14, 16, 17, 18, 19 et 20]. Limiting the analysis to those patients whose relapse corresponded to a level of alcohol intake which could be harmful for the graft (> 140 g/week), the 1 year relapse rate remains unchanged at 11% but the 2 year rate falls to 22%. This suggests that the earlier recurrences concern patients who will have high level alcohol consumption, as has been demonstrated by others [13 et 25]. In this prospective study, we questioned the patients every three months about their alcohol drinking. The relapse rates can thus be considered reliable, although a posteriori questioning or anonymous questionnaires generally reveal higher rates [13]. Other authors have used liver tests to search for signs of alcohol relapse [9 et 18] but the non-specific nature of abnormal results limits the usefulness of this approach. We remarked for instance that MCV (> 1003 and γGT (> 2 times the upper normal value) were never noted simultaneously in any of our patients.

None of the study variables describing the patient's history of alcohol consumption (duration and quantity, dependence, prior care, family history, age when the patient began drinking) were predictive of relapse. Likewise, the general demographic variables (age, sex, marital status) did not show any difference between relapse and non-relapse patients. The sample size must nevertheless be taken into consideration. Finally, only one variable, abstinence for less than 6 months before transplantation (defined as the time between the last consumption of an alcoholic beverage and transplantation) was the only variable significantly predictive of relapse in comparison with patients abstinent for 6 months or more. This finding is in line with the results reported by certain authors [10, 14, 16 et 18] but in disagreement with those of others [12, 13, 17 et 20]. Our study is however the first prospective study demonstrating that the duration of abstinence before LT affects the risk of alcohol relapse after LT.

Notwithstanding its predictive value, an important question is the usefulness of abstinence for 6 months before LT. It is generally accepted that 6 months abstinence can, in certain patients, improve liver function and contribute to better general status at transplantation, even to the point of reconsidering the indication for transplantation [21]. But such improvement is not observed in patients with very severe disease whose “probationary” period can be very dangerous [22]. Tang et al. [13] state that waiting 6 months is not advisable for this type of patient, concentrating on prevention of alcohol relapse after LT being more beneficial. The impact of alcohol relapse on survival, rejection, or compliance was not within the scope of the present study and will be examined in later work. In the literature, massive and rapid recurrent ethanol intake is associated with death and histological alterations [11, 13, 15, 23, 24 et 25], but overall survival in the cases reported has not been different between relapsing and non-relapsing patients [23, 25 et 26]. Moreover, relapse does not appear to decrease compliance nor increase the number of acute or chronic rejections, nor the number of infectious episodes [14]. However, a French team recently reported a few cases of acute rejection directly attributable to poor observance in patients who drank more than 140 g/week [25]. Thus for the patient, alcohol relapse after LT appears to have a moderately deleterious (short-term) effect. But for the public in general, the impact is much more harmful, particularly in terms of organ donation. We must inform the public that alcoholism is a disease and not a misdemeanor.

Recidivism is a common condition, well known by specialists working with alcoholic patients. It is classically considered as a useful step towards prolonged abstinence which enables self-awareness of alcohol-dependence [27]. For 35% of the patients in our cohort, the first abstinence experience occurred during the pre-transplantation period. Thus, although we did not observe any association between absence of abstinence experience before LT and alcohol relapse after LT, one could assume that a certain percentage of the transplanted patients had not yet gone through the alcohol dependence self-awareness process, a point emphasizing the need for better screening and management of chronic alcoholism.

In conclusion, alcohol relapse after liver transplantation for alcoholic cirrhosis is relatively frequent. Earlier studies searching for potentially predictive factors and our work presented here point to one common factor: less than 6 months abstinence before liver transplantation. The effect of abstinence for 6 months or more appears to be significant since liver function can improve, even to the point where the indication for transplantation can be reconsidered. The length of this period is also useful to measure the level of the patient's motivation for abstinence. But, for some patients with particularly severe disease, it may be too long and realistically unattainable, and thus ethically unacceptable as a mandatory phase before transplantation. Moreover, several studies appear to point to an absence of a mid-term effect or increased risk of infection or rejection in patients who relapse after transplantation. Determining which patients can benefit from a 6 month period of abstinence before transplantation is thus one of the difficult tasks of the transplantation team. Implementation of preventive measures designed to avoid relapse after transplantation is another.

Références

[1]
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[2]
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Définitions

LT liver transplantation
NIH National Institute of Health

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Acknowledgements

Chantal Milan, Population Epidemiology Center, EPI 106, Dijon; Estelle Naudet-Colin, Jean Minjoz Hospital, Besançon; Jean Bernard, Poitiers University Hospital; Sébastien Dharancy, Claude Huriez Hospital, Lille; Sophie Hillaire, Beaujon Hospital, Clichy; Jean-Pierre Vinel, Purpan Hospital, Toulouse; Gérard Thieffin, Robert Debré Hospital, Reims; P. Mathurin, Lille; and the participating gastrointestinal surgeons and units.

APPENDIX

Beclere model risk score

R = 0.5374 Log(toal bilirubin in µmol/L) — 0.0520 (serum albumin in g/L) + (age in years) + 0.4690 (encephalopathy)*.

* encephalopathy = 0 if absent

1 if present (irrespective of clinical presentation)

Référence: Poynard et al. Lancet 1994; 344: 502-7.





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