Pierre Deltenre

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.)

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.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single‐nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta‐analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model = 1.77; 95% confidence interval [CI]: 1.42‐2.19; P = 2.78 × 10−7). This association was more pronounced in ALD (OR = 2.20; 95% CI: 1.80‐2.67; P = 4.71 × 10−15) than in CHC patients (OR = 1.55; 95% CI: 1.03‐2.34; P = 3.52 × 10−2). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development. (Hepatology 2014;59:2170–2177)

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.

Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease

BACKGROUND & AIMS A recent genome-wide association study identified genetic polymorphism (rs738409 C>G) in the PNPLA3/adiponutrin gene associated with liver steatosis. This variant has also been linked to increased risk of alcoholic liver disease (ALD) and cirrhosis in Mestizo Mexicans with excessive alcohol intake. Our aim was to study the influence of this polymorphism on European Caucasian patients with histologically suggestive ALD. METHODS Three-hundred-and-twenty-eight healthy controls and 330 ALD patients, among whom 265 had cirrhosis, were genotyped for the rs738409 polymorphism. We studied the impact of rs738409 on clinical and biological parameters, together with histological staging of steatosis and fibrosis. PNPLA3 messenger RNA (mRNA) levels were measured by quantitative real-time PCR according to the patients phenotype. RESULTS The G-allele was significantly more frequent in ALD patients than in controls (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.12-2.11 p = 0.008) and was, among ALD patients, significantly associated with steatosis (p = 0.048), fibrosis (p = 0.001), and greater risk of cirrhosis (p = 0.001). In multivariate analysis, rs738409 remained the strongest independent factor associated with risk of cirrhosis (OR = 2.08; 95% CI = 1.15-3.77; p = 0.02). Furthermore, the PNPLA3 mRNA liver expression level was significantly lower in patients with more advanced fibrosis (p = 0.03) and negatively correlated with the hepatic venous pressure gradient (r = -0.41, p = 0.006). CONCLUSIONS In European Caucasians, the rs738409 variant is associated with increased risk of ALD, liver damage, and cirrhosis. Further prospective studies are required to confirm these results and to evaluate the potential of PNPLA3 as both a predictor and a therapeutic target in ALD.

Predicted effects of treatment for HCV infection vary among European countries.

BACKGROUND & AIMS The dynamics of hepatitis C virus (HCV) infection, as well as screening practices and access to therapy, vary among European countries. It is important to determine the magnitude of the effects of such differences on incidence and mortality of infection. We compared the dynamics of infection and screening and treatment practices among Belgium, France, Germany, Italy, Spain, and the United Kingdom. We also assessed the effects of treatment with pegylated interferon and additional effects of triple therapy with protease inhibitors. METHODS We created a country-specific Markov model of HCV progression based on published epidemiologic data (on HCV prevalence, screening, genotype, alcohol consumption among patients, and treatments) and reports of competitive and hepatocellular carcinoma mortality for the 6 countries. The model was used to predict the incidence of HCV-related cirrhosis and its mortality until 2021 for each country. RESULTS From 2002 to 2011, antiviral therapy reduced the cumulative incidence of cirrhosis by 7.1% and deaths by 3.4% overall. Reductions in incidence and mortality values ranged from 4.0% and 1.9%, respectively, in Italy to 16.3% and 9.0%, respectively, in France. From 2012 to 2021, antiviral treatment of patients with HCV genotype 1 infection that includes protease inhibitor-based triple therapy will reduce the cumulative incidence of cirrhosis by 17.7% and mortality by 9.7% overall. The smallest reduction is predicted for Italy (incidence reduced by 10.1% and mortality by 5.4%) and the highest is for France (reductions of 34.3% and 20.7%, respectively). CONCLUSIONS Although HCV infection is treated with the same therapies in different countries, the effects of the therapies on morbidity and mortality vary significantly. In addition to common guidelines that are based on virologic response-guided therapy, there is a need for public health policies based on population-guided therapy.

Effect of binge drinking on the liver: an alarming public health issue?

Alcohol consumers show strong variations in demographic characteristics, alcohol intake, frequency, duration and profile of consumption. Individuals consuming up to two drinks per day (men) or one drink per day (women) are defined as moderate drinkers and do not have an increased risk compared to abstainers. Conversely, a high-risk pattern, defined as daily consumption above those limits, or binge drinking episodes, cause health, personal and social problems. This definition separates chronic drinkers from binge drinkers, as their drinking patterns are different. Binge drinking implies “drinking too much too fast”. Periods of binge drinking (several consecutive days, weeks or months) are typically followed by periods of abstinence or, in some cases, significantly lower levels of consumption.1 The threshold of alcohol intake per episode which is used to define binge drinking varies from one study to another. In order to propose a consensual definition, the National Institute on Alcohol Abuse and Alcoholism (Bethesda, Maryland, USA) defines binge drinking episodes as consumption of five or more drinks (male) or four or more drinks (female) in the space of about 2 h.2 This definition is not clear-cut. It does not consider the amount of alcohol intake in one binge episode, nor the possibility that some individuals may go on several binges during the same day. Moreover, the behaviour of some binge drinkers may overlap that of chronic drinkers, with several binges over several consecutive days. The latter issue has been partially addressed by previous studies showing that repetition of binge episodes during adolescence constitutes a risk factor for being a chronic drinker during adulthood. A considerable increase in binge drinking is currently being seen in Western countries. This tendency appears to be more striking in beer- and spirit-drinking cultures in the UK and northern Europe.3 Young people seem particularly prone to …

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10−9) and TM6SF2 (P = 7.89 × 10−10) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10−48) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Transjugular intrahepatic portosystemic shunt in refractory ascites: a meta-analysis

Abstract: Transjugular intrahepatic portosystemic shunt (TIPS) is a more effective treatment for refractory ascites than large volume paracentesis (LVP), but the magnitude of its effect in terms of control of ascites, encephalopathy and survival has not been established.

Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: A meta-analysis

BACKGROUND & AIMS In hepatitis C virus genotype 1 (HCV-1) patients with a rapid viral decline within the first month of therapy, a 24-week course of pegylated interferon (PEG-IFN) alpha and ribavirin treatment has been claimed to be as efficient as the standard 48-week duration. METHODS We performed a meta-analysis of 7 randomized controlled trials comparing less than 48 weeks to 48 weeks PEG-IFN alpha/ribavirin treatment in 807 HCV-1 patients with rapid viral decline. RESULTS SVR was significantly less frequent with short treatment duration than with 48 weeks of therapy, with a mean difference of -13.6% (95% CI: -22.8% to -4.4%, p=0.004). This difference was related to a higher relapse rate (mean difference: 9.9%, 95% CI: 4.1-15.7%, p<0.001). In a sensitivity analysis restricted to studies using only a weight-based ribavirin regimen, shorter therapy was also less efficient. In the subgroup of patients with undetectable HCV-RNA at week 4 and a low baseline HCV-RNA level (400,000 IU/ml), there was no significant difference in SVR rates between 24 and 48 weeks of treatment (mean difference: -3.10%, 95% CI: -8.6% to 2.4%, NS). CONCLUSIONS In HCV-1 patients with a rapid virological response, 24 weeks of combination therapy with PEG-IFN alpha and ribavirin should be considered only in subjects with low baseline viral load. However, the optimal cut-off defining low baseline viral load and the impact of the presence of other factors capable of altering treatment response, remain subject to debate.