Study Conduct

Scientific committees from the Association Française d'Etude du Foie, the Association Française de Chirurgie Hépato-Biliaire et de Transplantation, and the Agence de Biomédecine (the French government agency in charge of graft allocation) approved the study. All selected patients provided written informed consent for transplantation surgery.

Selection of the Study Patients

Seven transplant centers agreed to perform early liver transplantation in patients with severe alcoholic hepatitis not responding to medical therapy. Alcoholic hepatitis was considered to be severe if the Maddrey's discriminant function was greater than 32, calculated as follows: 4.6×(patient's prothrombin time in seconds−matched control's prothrombin time in seconds)+patient's serum bilirubin level in milligrams per deciliter. A Maddrey's discriminant function of greater than 32 is the threshold for initiating glucocorticoid treatment.6 Nonresponse to medical therapy was defined according to the Lille model as a score of 0.45 or more after 7 days of medical therapy or a continuous increase in the Model for End-Stage Liver Disease (MELD) score,11 reflecting an early worsening of liver function. Medical therapy consisted of standard medical care for severe liver insufficiency and use of glucocorticoids (40 mg per day of prednisolone for at least 7 days). Nonresponse to medical therapy is associated with 6-month survival of approximately 30%.7

We selected patients with severe alcoholic hepatitis who were considered to be candidates for early transplantation, according to the following criteria: nonresponse to medical therapy (as defined above), severe alcoholic hepatitis as the first liver-decompensating event, presence of close supportive family members, absence of severe coexisting or psychiatric disorders, and agreement by patients (with support from family members) to adhere to lifelong total alcohol abstinence. The selection process consisted of several meetings between four medical team circles, the patient's family, and the patient. The team circles were as follows: first, the inner circle, closest to the patient, comprising nurses, one resident, and one fellow; second, a specialist in addiction; third, senior hepatologists; and fourth, the outermost circle, consisting of an anesthetist and surgeons. The four team circles had to reach complete consensus on selection.

This selection process was performed at all seven participating centers, which provided data on all early transplantations performed until September 1, 2010. The Lille and Brussels centers started the program in November 2005; the others began later. Two study patients did not receive glucocorticoids because their physicians considered the benefits to be negligible. Additional details about the selection process are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Assessment of Alcohol Use after Transplantation

After transplantation, alcohol use was assessed at short intervals during informal interviews of patients and their families performed according to the design of previous studies.10,12,13 (See the Supplementary Appendix for additional details on assessment of alcohol use after transplantation.)

Data Collection

Development of biologic features of abnormal liver or kidney function was ascertained at least weekly from the first day of medical therapy until the patient was placed on the transplantation list. During the data collection period (i.e., the first day of medical therapy through 24 months after transplantation), we recorded data on all infections and subsequent treatment as well as any alcohol relapses, including those occurring more than 6 months after transplantation.

Burden of Early Liver Transplantation

The total number of transplantations and the number of transplantations for alcoholic liver disease were reported annually by all centers, starting with the first early transplantation and until September 1, 2010. Only the Lille and Brussels centers had prospective databases of patients with biopsy-proven severe alcoholic hepatitis. These databases systematically recorded data for all patients with severe alcoholic liver disease meeting the criteria for nonresponse to medical therapy and, for those not selected for early transplantation, the primary reason for exclusion.

Case–Control Study

Two patients whose disease was not responding to medical therapy — a case patient who underwent early transplantation and a control patient who did not — were matched with the use of two matching-selection processes. First, we nonrandomly selected the control patient who was the best fit for each case patient who underwent transplantation, according to age, sex, Maddrey's discriminant function, and Lille score (see the Supplementary Appendix).

Second, we randomly sampled control patients from a set of patients with severe alcoholic hepatitis who were listed in a combined prospective database of the Lille center. To avoid the risk of selecting the same control in the two matching procedures (nonrandom and random), we excluded all the matched controls who were already selected with the nonrandom matching procedure. The final combined database contained a total of 651 potential control patients. The random selection was performed by means of the global optimal algorithm14 (SAS software, version 9.2; SAS Institute) with the following preestablished ranges or values: age, ±10 years of the case patient's age; sex, same as the case patient; Maddrey's discriminant function, same category as the case patient's (<60, 60 to 90, or >90); and Lille score, ±0.15 of the case patient's score (see the Supplementary Appendix).

We also examined whether patients who underwent early liver transplantation owing to nonresponse to medical therapy had outcomes similar to patients whose disease had responded to medical therapy (i.e., those with a Lille score <0.45). To address this question, control patients with Lille scores less than 0.45 were matched to case patients on the basis of the global optimal algorithm, with terms for age, sex, and Maddrey's discriminant function (but not Lille score).

Statistical Analysis

Assuming 6-month survival rates of 70% among patients who underwent transplantation and 30% among the matched controls,15,16 we calculated that at least 18 patients and 18 controls would have to be included for the study to have a statistical power of at least 80% to show a significant difference in the survival rate between the two groups. Variables were compared between the two groups with the use of chi-square tests and t-tests. The follow-up time was defined as the period from the first day of medical therapy to the last follow-up visit. In the case–control study, we estimated patients' rate of survival (expressed as a percentage ±SE) by means of the Kaplan–Meier method and compared survival between the two groups by using the log-rank test. The first day of medical therapy was defined as the first day of glucocorticoid administration or, for the two patients not treated with glucocorticoids, the first day of admission. The rate of 6-month survival — the primary end point — was measured from the first day of medical therapy to the date of death from any cause. In addition, we performed an analysis over an extended follow-up period of 2 years. Data for patients without events of interest were censored at the date of the last follow-up visit. A Cox proportional-hazards analysis, after adjustment for the MELD score and center (Lille vs. other centers), was also performed. All P values are two-tailed.