Astrid Marot

Alcohol intake increases the risk of HCC in hepatitis C virus-related compensated cirrhosis: A prospective study.

BACKGROUND & AIMS Whether alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. The aim of this study was to determine the impact of alcohol intake and viral eradication on the risk of hepatocellular carcinoma (HCC), decompensation of cirrhosis and death. METHODS Data on alcohol intake and viral eradication were prospectively collected in 192 patients with compensated HCV-related cirrhosis. RESULTS 74 patients consumed alcohol (median alcohol intake: 15g/day); 68 reached viral eradication. During a median follow-up of 58months, 33 patients developed HCC, 53 experienced at least one decompensation event, and 39 died. The 5-year cumulative incidence rate of HCC was 10.6% (95% CI: 4.6-16.6) in abstainers vs. 23.8% (95% CI: 13.5-34.1) in consumers (p=0.087), and 2.0% (95% CI: 0-5.8) vs. 21.7% (95% CI: 14.2-29.2) in patients with and without viral eradication (p=0.002), respectively. The lowest risk of HCC was observed for patients without alcohol intake and with viral eradication (0%) followed by patients with alcohol intake and viral eradication (6.2% [95% CI: 0-18.4]), patients without alcohol intake and no viral eradication (15.9% [95% CI: 7.1-24.7]), and patients with alcohol intake and no viral eradication (29.2% [95% CI: 16.5-41.9]) (p=0.009). In multivariate analysis, lack of viral eradication and alcohol consumption were associated with the risk of HCC (hazard ratio for alcohol consumption: 3.43, 95% CI: 1.49-7.92, p=0.004). Alcohol intake did not influence the risk of decompensation or death. CONCLUSIONS Light-to-moderate alcohol intake increases the risk of HCC in patients with HCV-related cirrhosis. Patient care should include measures to ensure abstinence. LAY SUMMARY Whether alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. In this prospective study, light-to-moderate alcohol intake was associated with the risk of hepatocellular carcinoma in multivariate analysis. No patients who did not use alcohol and who reached viral eradication developed hepatocellular carcinoma during follow-up. The risk of hepatocellular carcinoma increased with alcohol intake or in patients without viral eradication and was highest when alcohol intake was present in the absence of viral eradication. Patients with HCV-related cirrhosis should be strongly advised against any alcohol intake. Patient care should include measures to ensure abstinence.

Liver stiffness and platelet count for identifying patients with compensated liver disease at low risk of variceal bleeding

The 2015 Baveno VI guidelines recommend against performing upper gastrointestinal endoscopy in patients with compensated cirrhosis who have a liver stiffness <20 kPa and a platelet count >150 000/mm³ because of a low prevalence of varices at risk of bleeding in this population. The aim was to synthesize the available evidence on the usefulness of the combined use of liver stiffness and platelet count to identify patients without oesophageal varices.

Systematic review with meta-analysis: self-expanding metal stents in patients with cirrhosis and severe or refractory oesophageal variceal bleeding.

The prognosis of patients with cirrhosis and acute variceal bleeding is very poor when the standard‐of‐care fails to control bleeding. New treatment modalities are needed in these patients.

Liver transplantation for alcoholic hepatitis: A systematic review with meta-analysis

Background The rate of alcohol relapse among patients who underwent liver transplantation for alcoholic hepatitis (AH) is not precisely known. Aim Synthesize the available evidence on liver transplantation for AH to assess alcohol relapse and 6-month survival. Methods Meta-analysis of trials evaluating liver transplantation for AH, either clinically severe or diagnosed on the explant. Results Eleven studies were included. The pooled estimate rate for alcohol relapse was 0.22 (95% CI = 0.12–0.36) in overall analysis with high heterogeneity between studies (I2 = 76%), 0.20 (95% CI = 0.07–0.43) in the subgroup analysis including patients with clinically severe AH (I2 = 84%), 0.14 (95% CI = 0.08–0.23) among patients with clinically severe AH in sensitivity analysis excluding the discrepant studies that did not use stringent selection criteria for liver transplantation (I2 = 0%), and 0.15 (95% CI = 0.07–0.27) for recurrent harmful alcohol consumption among patients with clinically severe AH (I2 = 3%). The risk of alcohol relapse was not different between AH transplanted patients and patients with alcoholic cirrhosis who underwent elective liver transplantation in sensitivity analysis excluding the discrepant studies (OR = 1.68, 95%CI = 0.79–3.58, p = 0.2, I2 = 16%). The pooled estimate rate for 6-month survival was 0.85 (95% CI = 0.77–0.91, I2 = 49%), and 0.80 among patients transplanted for clinically severe AH (95% CI = 0.69–0.88, I2 = 30%). AH transplanted patients had similar 6-month survival to patients with alcoholic cirrhosis who underwent elective liver transplantation (OR = 2.00, 95% CI = 0.95–4.23, p = 0.07, I2 = 0%). Conclusion Using stringent selection criteria, 14% of patients with clinically severe AH have alcohol relapse after liver transplantation. The percentage of alcohol relapse of AH transplanted patients is similar than that of patients who underwent elective liver transplantation.

Alcoholic liver disease confers a worse prognosis than HCV infection and non-alcoholic fatty liver disease among patients with cirrhosis: An observational study

Background Cirrhosis is a heterogeneous clinical condition that includes patients at wide-ranging stages of severity. The role of the underlying liver disease on patient prognosis remains unclear. Aim To assess the impact of the underlying liver disease on the occurrence of hepatocellular carcinoma (HCC) and death. Methods Data related to the occurrence of HCC and death were collected during a 21-year period among patients with cirrhosis related to alcoholic liver disease (ALD) (n = 529), chronic hepatitis C virus (HCV) infection (n = 145) or non-alcoholic fatty liver disease (NAFLD) (n = 78). Results At inclusion, ALD patients were younger than HCV and NAFLD patients (56 vs. 67 vs. 63 years; p<0.001) and had worse liver function (percent of patients with Child-Pugh stages B or C: 48% vs. 8% vs. 17%; p<0.001). During follow-up, 85 patients developed HCC and 379 died. The 10-year cumulative incidence rate of HCC was lower in ALD patients than in HCV and NAFLD patients (8.4% vs. 22.0% vs. 23.7%; p<0.001). The 10-year cumulative incidence rates of mortality were not statistically different between ALD, HCV and NAFLD patients (58.1% vs. 47.7% vs. 49.9%; p = 0.078). Alcohol abstinence and viral eradication were associated with reduced mortality among ALD and HCV patients, respectively. In multivariate analyses, ALD was associated with a reduced risk of HCC (0.39; 95% CI, 0.20–0.76; p = 0.005) but with a higher risk of mortality (1.53; 95% CI, 1.20–1.95; p<0.001). ALD patients died more frequently from decompensation of cirrhosis. Conclusion Despite a lower incidence of HCC, patients with ALD-related cirrhosis have a worse outcome than those with chronic HCV infection or NAFLD-related cirrhosis.

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis

OBJECTIVES: Variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O‐acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol‐related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC. METHODS: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol‐related cirrhosis and HCC and in 1165 controls with alcohol‐related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression. RESULTS: The development of HCC was independently associated with PNPLA3 rs738409 (ORadjusted 1.84 [95% CI 1.55‐2.18], p = 1.85 × 10‐12) and TM6SF2 rs58542926 (ORadjusted 1.66 [1.30‐2.13], p = 5.13 × 10‐05), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (ORadjusted 1.04 [0.88‐1.24], p = 0.61) was not significant. The population‐attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined. CONCLUSIONS: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol‐related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk‐stratification of patients with alcohol‐related cirrhosis, and genotype‐guided screening algorithms would optimize patient care.

Effect of abstinence on the prognosis of patients with alcoholic liver disease: A word of caution

To the Editor: We read the article by Lackner and collaborators [1] with great interest. The main goal of this study was to assess factors associated with long-term prognosis in patients with biopsy-proven alcoholic liver disease (ALD). Although this study is of major clinical relevance, we believe it deserves several comments. The authors concluded that alcohol abstinence determines the long-term prognosis of patients with ALD. However, this statement is not supported by the study results because abstinence was not associated with improved survival in multivariate analysis. As this study included a limited number of patients, the lack of significance may be related to false negative results. In addition, the authors choose to perform separate analyses in patients with early/compensated and decompensated ALD, which further increased the risk of type II error, especially in the group of patients with compensated ALD which comprised of only 60 patients. Furthermore, the authors also chose to include all variables that reached a p value <0.20 in univariate analyses, in the multivariate model. As a result, a significant number of variables were taken into account in these analyses. Considering that only 13% of the patients with compensated ALD had died from liverrelated complications at 5 years, only a couple variables should have been included in the Cox regression analysis. Unfortunately, a power calculation was not available. Finally, non-significant results of the univariate analyses as well as the results of all multivariate analyses were not provided. Hence, the reader does not have access to many relevant data allowing for an accurate interpretation of the study results. In studies like this one, a large number of patients, followed for a long period of time are required to ensure that enough events occur. Thus, the statistical analyses performed in both compensated and decompensated patients should have been of interest to assess the impact of abstinence on patient prognosis in the whole study population. Another matter of debate concerns the statistical approach used in this study. While we acknowledge that liver-related causes accounted for most of the deaths in patients with cirrhosis related to ALD, not taking into account other causes of deaths would have require the use of appropriate models of disease progression. It is unclear why authors used a Cox regression analysis rather than competing risk analysis, as recommended [2]. Hence, even if the study of Lackner and collaborators brought some useful data, many drawbacks limit the interpretation of their

Individualized prediction of hepatocellular carcinoma occurrence in a large cohort of patients with cirrhosis

To the Editor; We read with interest the article from Sharma and collaborators. The authors proposed a score based on four variables (age, sex, etiology of cirrhosis, and platelet count) to predict the risk of hepatocellular carcinoma (HCC) in a cohort of 2,079 patients with cirrhosis validated in an external cohort. Points were assigned to each independent predictor of HCC according to its hazard ratio (HR) to create the Toronto HCC Risk Index (THRI). This score stratifies patients into three equally spaced categories to obtain low (<120), medium (120–240) and high (>240) risk thresholds. As interest in the individualized prediction of the risk of HCC in patients with cirrhosis is increasing, we took the opportunity to evaluate the usefulness of such a model to predict HCC occurrence in another large cohort of patients with cirrhosis. We evaluated the risk of HCC among 752 patients with cirrhosis and divided them into three etiologies of liver disease: alcoholic liver disease (ALD) (n = 529), chronic hepatitis C virus (HCV) infection (n = 145), and non-alcoholic fatty liver disease (NAFLD) (n = 78). During follow-up, 85 patients (11%) developed HCC. Three variables were independently associated with a risk of HCC: age (HR 1.03; 95% CI 1.00–1.06; p = 0.03); male gender (HR 2.41; 95% CI 1.39–4.15; p = 0.002), and etiology of cirrhosis (HR 0.39 for ALD; 95% CI 0.20–0.76; p = 0.005). Platelet count used as a continuous variable did not reach statistical significance (HR 1.00; 95% CI

Characteristics of patients with hepatitis B virus and hepatitis C virus dual infection in a Western European country: Comparison with monoinfected patients

The epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is continuously evolving. Updated data on dual HBV and HCV infection are still needed. AIMS To assess the main characteristics of patients with HBV and HCV dual infection, to compare these with those of patients infected with either HBV or HCV and, among patients with dual infection, to assess fibrosis according to HCV replication. METHODS Data of 23 patients with dual infection were compared to data from 92 age and sex-matched HBV or HCV monoinfected patients. RESULTS Patients with dual infection were more often immigrants from Africa or Asia than HCV or HBV patients (52% vs. 20% and 22%, respectively, P=0.01). Intravenous drug use was the route of transmission in 22% of patients with dual infection, which was less frequent than in HCV patients (41%) but more frequent than in HBV patients (0%). Extensive fibrosis or cirrhosis was as frequent among dual-infected patients as among those with HCV or chronic hepatitis B infection (19% vs. 29% vs. 14%, respectively, P=0.4), even when fibrosis stage was reported considering the duration of infection. In dual-infected patients, the prevalence of extensive fibrosis or cirrhosis was similar in patients with and without detectable HCV RNA (18% vs. 20%). CONCLUSIONS Patients with HBV and HCV dual infection were more often immigrants from Africa or Asia and had similar fibrosis stages than HCV or HBV monoinfected patients. In patients with dual infection, extensive fibrosis or cirrhosis was not associated with HCV replication.

SEMS should be considered in patients with cirrhosis and uncontrolled variceal bleeding

We read the article by Escorsell et al. with great interest. This is the first randomized, controlled trial comparing self-expanding metal stent (SEMS) and balloon tamponade in acute refractory variceal bleeding in patients with cirrhosis. Although this study showed that SEMSs have greater efficacy in the control of bleeding and present less serious adverse events than does balloon tamponade, it failed to demonstrate a survival benefit. Even if randomized, controlled trials are considered the best way to assess the impact of an intervention, this is probably not the case when SEMSs are used to control acute refractory variceal bleeding for the following reasons. First, blinding the therapeutic intervention was not possible. Second, the investigators used patients treated with balloon tamponade as controls despite high rates of serious adverse events and rebleeding after balloon deflation. Thus, patients treated with balloon tamponade were not perfect controls. Third, patients enrolled in this study likely differed from the average patient seen in daily practice. This statement is supported by the 11 exclusion criteria mentioned in the study design and by the low number of patients included during a 3-year period, despite the many centers participating in the study. This is a clear limitation of this study that reduces the robustness of the conclusions. In the specific setting of acute refractory variceal bleeding, the results from observational studies may seem more relevant to clinical practice. In line with this comment, a recent meta-analysis (which already included Escorsell’s results) assessed the usefulness of SEMS in patients with cirrhosis and severe or refractory variceal bleeding. This metaanalysis showed that failure to control bleeding occurred in 18% of cases. Fewer than 40% of patients treated with SEMS died after 30 days and only 12% died from recurrent bleeding. Even if these results are not a proof that SEMS reduce mortality, this percentage compares favorably to the mortality rates reported in previous studies. Furthermore, a significant percentage of patients had access to transjugular intrahepatic portosystemic shunt (26%) or to liver transplantation (10%), which underlines that SEMS can also serve as a bridge to a more definitive treatment. Overall, we believe that SEMS should be considered in patients with cirrhosis and uncontrolled variceal bleeding. How early SEMS should be placed during the course of acute variceal bleeding to achieve better control of bleeding and prevention of rebleeding before the development of more-severe liver dysfunction remains to be assessed.