Alexandre Louvet

Early Liver Transplantation for Severe Alcoholic Hepatitis

BACKGROUND A 6-month abstinence from alcohol is usually required before patients with severe alcoholic hepatitis are considered for liver transplantation. Patients whose hepatitis is not responding to medical therapy have a 6-month survival rate of approximately 30%. Since most alcoholic hepatitis deaths occur within 2 months, early liver transplantation is attractive but controversial. METHODS We selected patients from seven centers for early liver transplantation. The patients had no prior episodes of alcoholic hepatitis and had scores of 0.45 or higher according to the Lille model (which calculates scores ranging from 0 to 1, with a score ≥ 0.45 indicating nonresponse to medical therapy and an increased risk of death in the absence of transplantation) or rapid worsening of liver function despite medical therapy. Selected patients also had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence. Survival was compared between patients who underwent early liver transplantation and matched patients who did not. RESULTS In all, 26 patients with severe alcoholic hepatitis at high risk of death (median Lille score, 0.88) were selected and placed on the list for a liver transplant within a median of 13 days after nonresponse to medical therapy. Fewer than 2% of patients admitted for an episode of severe alcoholic hepatitis were selected. The centers used 2.9% of available grafts for this indication. The cumulative 6-month survival rate (±SE) was higher among patients who received early transplantation than among those who did not (77 ± 8% vs. 23 ± 8%, P<0.001). This benefit of early transplantation was maintained through 2 years of follow-up (hazard ratio, 6.08; P = 0.004). Three patients resumed drinking alcohol: one at 720 days, one at 740 days, and one at 1140 days after transplantation. CONCLUSIONS Early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. (Funded by Société Nationale Française de Gastroentérologie.).

The Lille model: A new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids†

Early identification of patients with severe (discriminant function ≥ 32) alcoholic hepatitis (AH) not responding to corticosteroids is crucial. We generated a specific prognostic model (Lille model) to identify candidates early on for alternative therapies. Three hundred twenty patients with AH prospectively treated by corticosteroids were included in the development cohort and 118 in its validation. Baseline data and a change in bilirubin at day 7 were tested. The model was generated by logistic regression. The model combining six reproducible variables (age, renal insufficiency, albumin, prothrombin time, bilirubin, and evolution of bilirubin at day 7) was highly predictive of death at 6 months (P < 0.000001). The area under the receiver operating characteristic (AUROC) curve of the Lille model was 0.89 ± 0.02, higher than the Child‐Pugh (0.62 ± 0.04, P < 0.00001) or Maddrey scores (0.66 ± 0.04, P < 0.00001). In the validation cohort, its AUROC was 0.85 ± 0.04, still higher than the other models, including MELD (0.72 ± 0.05, P = 0.01) and Glasgow scores (0.67 ± 0.05, P = 0.0008). Patients above the ideal cutoff of 0.45 showed a marked decrease in 6‐month survival as compared with others: 25% ± 3.8% versus 85% ± 2.5%, P < 0.0001. This cutoff was able to identify approximately 75% of the observed deaths. Conclusion: In the largest cohort to date of patients with severe AH, we demonstrate that the term “nonresponder” can now be extended to patients with a Lille score above 0.45, which corresponds to 40% of cases. Early identification of subjects with substantial risk of death according to the Lille model will improve management of patients suffering from severe AH and will aid in the design of future studies for alternative therapies. (HEPATOLOGY 2007.)

Prospective Study of the Long-Term Effects of Bariatric Surgery on Liver Injury in Patients Without Advanced Disease

BACKGROUND & AIMS Severe obesity is implicated in development of nonalcoholic fatty liver disease (NAFLD). Bariatric surgery induces weight loss and increases survival time of obese patients, but little is known about its effects on liver damage. We performed a 5-year prospective study to evaluate fibrosis and nonalcoholic steatosis (NASH) in severely obese patients after bariatric surgery. METHODS Bariatric surgery was performed on 381 patients. Clinical and biological data, along with liver biopsies, were collected before and at 1 and 5 years after surgery. RESULTS Five years after surgery, levels of fibrosis increased significantly, but 95.7% of patients maintained a fibrosis score <or= F1. The percentage of patients with steatosis decreased from 37.4% before surgery to 16%, the NAFLD score from 1.97 to 1, ballooning from 0.2 to 0.1. Inflammation remained unchanged. The percentage of patients with probable or definite NASH decreased significantly over 5 years, from 27.4% to 14.2%. The kinetics of insulin resistance (IR) paralleled that of steatosis and ballooning; the greatest improvements occurred within the first year and were sustained 5 years later. Steatosis and ballooning occurred more frequently in patients with a refractory IR profile. In multivariate analysis, the refractory IR profile independently predicted the persistence of steatosis and ballooning 5 years later. CONCLUSIONS Five years after bariatric surgery for severe obesity, almost all patients had low levels of NAFLD, whereas fibrosis slightly increased. Steatosis and ballooning were closely linked to IR; long-term effects could be predicted by early improvement in IR.

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data

Introduction A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) ≥32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. Aims To compare 28-day survival between corticosteroid- and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. Methods Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n=3), enteral nutrition (n=1) or an antioxidant cocktail (n=1). Results 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroid-treated patients than in non-corticosteroid-treated patients (79.97±2.8% vs 65.7±3.4%, p=0.0005). In multivariate analysis, corticosteroids (p=0.005), DF (p=0.006), leucocytes (p=0.004), Lille score (p<0.00001) and encephalopathy (p=0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score ≤0.16; ≤35th percentile), partial responders (Lille score 0.16–0.56; 35th–70th percentile) and null responders (Lille ≥0.56; ≥70th percentile). 28-day survival was strongly associated with these groupings (91.1±2.7% vs 79.4±3.8% vs 53.3±5.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p=0.006) and in partial responders (HR 0.38, p=0.04) but not in null responders. Conclusion Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients

BACKGROUND & AIMS The effects of bariatric surgery in patients with nonalcoholic fatty liver disease (NASH) are not well established. We performed a prospective study to determine the biological and clinical effects of bariatric surgery in patients with NASH. METHODS From May 1994 through May 2013, one hundred and nine morbidly obese patients with biopsy-proven NASH underwent bariatric surgery at the University Hospital of Lille, France (the Lille Bariatric Cohort). Clinical, biological, and histologic data were collected before and 1 year after surgery. RESULTS One year after surgery, NASH had disappeared from 85% of the patients (95% confidence interval [CI]: 75.8%-92.2%). Compared with before surgery, patients had significant reductions in mean ± SD body mass index (BMI, from 49.3 ± 8.2 to 37.4 ± 7) and level of alanine aminotransferase (from 52.1 ± 25.7 IU/L to 25.1 ± 20 IU/L); mean levels of γ-glutamyltransferases were reduced from 51 IU/L before surgery (interquartile range [IQR], 34-87 IU/L) to 23 IU/L afterward (IQR, 14-33 IU/L) and mean insulin resistance index values were reduced from 3.6 ± 0.5 to 2.9 ± 0.5 (P < .01 for each comparison). NASH disappeared from a higher proportion of patients with mild NASH before surgery (94%) than severe NASH (70%) (P < .05) according to Brunt score. In histologic analysis, steatosis was detected in 60% of the tissue before surgery (IQR, 40%-80%) but only 10% 1 year after surgery (IQR, 2.5%-21.3%); the mean nonalcoholic fatty liver disease score was reduced from 5 (IQR, 4-5) to 1 (IQR, 1-2) (each P < .001). Hepatocellular ballooning was reduced in 84.2% of samples (n = 69; 95% CI: 74.4-91.3) and lobular inflammation in 67.1% (n = 55; 95% CI: 55.8-77.1). According to Metavir scores, fibrosis was reduced in 33.8% of patients (95% CI: 23.6%-45.2%). Patients whose NASH persisted 1 year after surgery (n = 12) had lost significantly less weight (change in BMI, 9.1 ± 1.5) than those without NASH (change in BMI, 12.3 ± 0.6) (P = .005). Patients who underwent laparoscopic gastric banding lost less weight (change in BMI, 6.4 ± 0.7) than those who underwent gastric bypass (change in BMI, 14.0 ± 0.5) (P < .0001), and a higher proportion had persistent NASH (30.4% vs 7.6% of those with gastric bypass; P = .015). CONCLUSIONS Bariatric surgery induced the disappearance of NASH from nearly 85% of patients and reduced the pathologic features of the disease after 1 year of follow-up. It could be a therapeutic option for appropriate morbidly obese patients with NASH who do not respond to lifestyle modifications. More studies are needed to determine the long-term effects of bariatric surgery in morbidly obese patients with NASH.

Infection in Patients With Severe Alcoholic Hepatitis Treated With Steroids: Early Response to Therapy Is the Key Factor

BACKGROUND & AIMS In severe (Maddrey score >or=32) alcoholic hepatitis (AH), infection is classically viewed as a contraindication for corticosteroids, although specific data are lacking. This studys aims were (1) to evaluate the incidence of infection in patients with severe AH before and after corticosteroid treatment; (2) to determine whether infection contraindicates corticosteroids; and (3) to focus on predictive factors of development of infection. METHODS At admission, systematic screening of infection consisted of chest x-ray and blood, ascites, and urinary cultures. All patients were treated with prednisolone. Response to steroids was defined using the Lille model. RESULTS Two hundred forty-six patients with severe AH were prospectively included. Infections at admission were as follows: 63 infections (25.6%) were diagnosed: 28 (44.4%) spontaneous bacterial peritonitis or bacteremia, 8 (12.7%) pulmonary infections, 20 (31.7%) urinary tract infections, and 7 (11.2%) other infections. Patients infected before using corticosteroids had 2-month survival similar to that of others: 70.9% +/- 6.1% vs 71.6% +/- 3.4%, respectively, P = .99. Development of infection after steroids: 57 patients (23.7%) developed infection: 16 (28.1%) spontaneous bacterial peritonitis or bacteremia, 23 (40.3%) pulmonary, 10 (17.5%) urinary tract, and 8 (14.1%) other infections. Infection occurred more frequently in nonresponders than in responders: 42.5% vs 11.1%, respectively, P < .000001. In multivariate analysis, only the Lille model (P = .0002) independently predicted infection upon steroids use. The Lille model (P = .000001) and Model for End-Stage Liver Disease score (P = .006) were independently associated with survival, whereas infection was not (P = .52). CONCLUSIONS Severe AH is associated with high risk of infection. Infection screening is warranted but should not contraindicate steroids. In terms of mechanisms, nonresponse to steroids is the key factor in development of infection and prediction of survival.

Alcoholic liver disease: mechanisms of injury and targeted treatment

Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

BACKGROUND & AIMS There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

Prednisolone With vs Without Pentoxifylline and Survival of Patients With Severe Alcoholic Hepatitis: A Randomized Clinical Trial

IMPORTANCE Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis, a life-threatening disease. The benefit of their combination is unknown. OBJECTIVE To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis, as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32. Duration of follow-up was 6 months. The last included patient completed the study in October 2010. None of the patients were lost to follow-up for the main outcome. INTERVENTION Patients were randomly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day (n=133) for 28 days, or 40 mg of prednisolone and matching placebo (n=137) for 28 days. MAIN OUTCOMES AND MEASURES Six-month survival, with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model, which defines treatment nonresponders after 7 days of initiation of treatment. RESULTS In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups (69.9% [95% CI, 62.1%-77.7%] vs 69.2% [95% CI; 61.4%-76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36-0.46] vs 0.40 [95% CI, 0.35-0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%-71.3%] vs 61.9% [95% CI, 53.7%-70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups (8.4% [95% CI, 4.8%-14.8%] vs 15.3% [95% CI, 10.3%-22.7%], P = .07). CONCLUSION AND RELEVANCE In patients with alcoholic hepatitis, 4-week treatment with pentoxifylline and prednisolone, compared with prednisolone alone, did not result in improved 6-month survival. The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome, which was less frequent in the group receiving pentoxifylline. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01214226.

Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids

BACKGROUND/AIMS In severe alcoholic hepatitis (AH), 40% of patients will obtain no benefit from corticosteroids. Improvement in management of non-responders is warranted and only pentoxifylline can be considered an alternative. A two-step strategy was evaluated consisting of early withdrawal of corticosteroids and a switch to pentoxifylline for 28 additional days in non-responders identified using early change in bilirubin level. METHODS One hundred and twenty-one patients with AH were treated prospectively with corticosteroids, and the two-step strategy was proposed to 29 non-responders treated according to a two-step strategy who were compared to 58 matched non-responders treated with corticosteroids only. RESULTS Clinical and biological features of the two groups were similar. There was no survival improvement at 2 months in patients treated with the two-step strategy compared to controls: 35.5+/-6.3% vs 31+/-8.6%. After 21 days, biological evolution was similar for prothrombin time (-0.25s vs +0.2s), bilirubin (0.8 mg/dl vs 2.03 mg/dl) and creatinine (+0.16 mg/dl vs -0.7 mg/dl). In multivariate analysis, only age, evolution of bilirubin during the first week, creatinine and DF were associated with 2-month survival. CONCLUSIONS Non-responders to corticosteroids do not obtain any benefit from an early switch to pentoxifylline. Thus, the issue of management of non-responders remains unresolved.