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Need for surveillance of hepatocellular carcinoma in patients with alcoholic cirrhosis

Published:October 11, 2018DOI:https://doi.org/10.1016/j.jhep.2018.09.027

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      • Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis
        Journal of HepatologyVol. 69Issue 6
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          Primary liver cancer has a high incidence in Europe, especially in France, which has almost 9,000 cases per year.1 In more than 90% of cases, hepatocellular carcinoma (HCC) occurs in patients with cirrhosis. Alcohol is the leading cause of the underlying cirrhosis that is associated with HCC in France; it is responsible for more than 60% of the cases,2 which is much higher than the proportion of cases from hepatitis B and C and non-alcoholic steatohepatitis. Although precise data are lacking, as France has lost its longstanding European leadership in alcohol consumption, one can speculate that alcoholic cirrhosis is currently the main cause of HCC occurrence in Europe, and it will gain an even more important predominance as alcoholic consumption is on the rise in many countries, while active viral infection is on the decline.
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      Excessive and prolonged alcohol intake is a major cause of advanced liver disease and a major driver of liver-related hospitalisations worldwide.
      • Pimpin L.
      • Cortez-Pinto H.
      • Negro F.
      • Corbould E.
      • Lazarus J.V.
      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      In Europe, alcohol-related liver disease (ALD) is the main cause of disability-adjusted life years among adults with alcohol abuse. ALD comprises a broad spectrum ranging from asymptomatic stages to cirrhosis, as well as alcoholic hepatitis and hepatocellular carcinoma (HCC).
      • Seitz H.K.
      • Bataller R.
      • Cortez-Pinto H.
      • Gao B.
      • Gual A.
      • Lackner C.
      • et al.
      Alcoholic liver disease.
      Unfortunately, most patients are identified at late stages, when mortality is very high despite drinking cessation. Early detection of ALD at asymptomatic stages is therefore mandatory. Multiple studies have shown cumulative risk of HCC around 1–1.5% per year in patients with alcoholic cirrhosis, which is close to the threshold proposed for HCC surveillance.
      • Testino G.
      • Leone S.
      • Borro P.
      Alcohol and hepatocellular carcinoma: a review and a point of view.
      The incidence of HCC is lower than in other aetiologies such as viral hepatitis and non-alcoholic fatty liver disease. While there is some debate on the need to perform surveillance in patients with alcoholic cirrhosis, HCC screening is recommended by liver societies in all patients with alcohol-related cirrhosis including the European Association for the Study of Liver Diseases.
      European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L
      EASL Clinical Practice Guidelines: Management of alcohol-related liver disease.
      Identifying patients with alcoholic cirrhosis at higher risk of developing HCC would be clinically relevant. Several genetic and environmental factors have been proposed to influence the risk of developing HCC among patients with alcoholic cirrhosis. The amount of daily alcohol influences the risk of HCC, yet there is no established threshold. There are no data on the role of the duration or pattern of drinking (continuous vs. binge) on HCC development. Regarding other risk factors, women have higher incidence of cirrhosis and HCC with lower levels of alcohol ingestion. Genetic polymorphisms also affect the predisposition to HCC in ALD. The PNPLA3 gene polymorphism (C > G) increases the risk of HCC with an OR of 2.20 (1.80–2.67) for G allele.
      • Stickel F.
      • Buch S.
      • Nischalke H.D.
      • Weiss K.H.
      • Gotthardt D.
      • Fischer J.
      • et al.
      Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis.
      Importantly, cigarette smoking, which is common among alcoholic patients, significantly increases the risk of developing HCC.
      • Altamirano J.
      • Bataller R.
      Cigarette smoking and chronic liver diseases.
      Unfortunately, patients with ALD are less frequently screened and have less adherence. Therefore, HCC is diagnosed at advanced stages in this patient population who have lower survival rates.
      • Bucci L.
      • Garuti F.
      • Camelli V.
      • Lenzi B.
      • Farinati F.
      • Giannini E.G.
      • et al.
      Comparison between alcohol- and hepatitis C virus-related hepatocellular carcinoma: clinical presentation, treatment and outcome.
      In the present issue, Ganne-Carrié et al. report the results of a large multicentre study investigating the incidence of HCC in patients with alcoholic cirrhosis.
      • Ganne-Carrie N.
      • Chaffaut C.
      • Bourcier V.
      • Archambeaud I.
      • Perarnau J.M.
      • Oberti F.
      • et al.
      Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis.
      The study was conducted at 22 hepatology centres in France and Belgium. Patients with biopsy-proven compensated cirrhosis were prospectively enrolled. All patients had at least 10 years of excessive alcohol consumption, which was considered the underlying cause of the liver disease. Viral and other aetiologies, including metabolic syndrome were excluded. Pre-inclusion abdominal ultrasound (US) screening excluded the presence of HCC at enrolment. Surveillance for HCC was based on 6-monthly US and diagnosis of HCC was based on contrast enhanced CT-scan or MRI or biopsy, according to current clinical practical guidelines. A total of 652 patients were enrolled and prospectively followed for a median of 29 months (IQR 12.2–41.4). Overall, 153 patients were lost to follow-up. Forty-three patients developed HCC: 1 and 2-year cumulative risks were 1.8% and 5.2% and the incidence was 2.9 per 100 patient-years. The major conclusion of this study is that the observed HCC incidence is high enough to justify surveillance in patients with alcoholic cirrhosis. This study shades light on the current debate on whether HCC screening is cost-effective
      • Kansagara D.
      • Papak J.
      • Pasha A.S.
      • O’Neil M.
      • Freeman M.
      • Relevo R.
      • et al.
      Screening for hepatocellular carcinoma in chronic liver disease. A systematic review.
      in these patients. The debate is fuelled by the fact that population-based studies from Denmark and the UK have reported an annual risk of 1% or less.
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sorensen H.T.
      • Vilstrup H.
      Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a Danish nationwide cohort study.
      • West J.
      • Card T.R.
      • Aithal G.P.
      • Fleming K.M.
      Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study.
      In fact, based on an annual threshold risk of 1.5% for cost-effectiveness of HCC screening,
      • Testino G.
      • Leone S.
      • Borro P.
      Alcohol and hepatocellular carcinoma: a review and a point of view.
      the risk observed in the present study largely supports screening in alcoholic cirrhosis.
      Although the study was well designed and provides novel insights on the risk of HCC in alcoholic cirrhosis, it is not free from some risk of bias. The first issue is the relatively low number of patients (i.e., 5–6) included per year at each of the 22 participating centres, resulting in the enrolment of approximately a half of the total predicted sample size (652 of 1,200) according to the study protocol (https://clinicaltrials.gov/ct2/show/NCT01213927). This is surprising for hepatology centres located in areas where alcohol abuse is the most prevalent cause of cirrhosis. Moreover, only 54 of the 706 eligible patients were excluded, raising the possibility that patient enrolment may have not been consecutive for some inadvertent reason. Another potential source of bias is the loss to follow-up of 153/652 patients without any apparent explanation. Although the liver disease status and the baseline consumption were similar in dropout patients compared to the entire cohort, it is possible that patients with active alcohol consumption, which are particularly prone to HCC development, were more frequently lost to follow-up. To explore the possible effect of such a large proportion of dropouts on the study results, the authors performed sensitivity analyses figuring a worse scenario where all the patients lost had HCC at the last visit and a best scenario where none of these patients had developed HCC at the end of the study. These analyses showed a 1-year HCC risk of 7.3% and 1.4%, respectively. No corresponding sensitivity analysis was performed for the observed incidence rate. However, from the reported incidence of 2.9/100 patient-years, an incidence rate of 14/100 patient-years may be calculated in the worst scenario and 2.5 in the best, accounting for the 18 months since the last visit required to classify the patient as dropout. Therefore, the large number of dropouts leaves an appreciable amount of uncertainty regarding the true risk of HCC in the recruited population. However, the major study conclusion, that the risk is high enough to justify a surveillance programme, remains valid because the lowest risk estimation in the best scenario of 1.4% is very close to the 1.5% risk threshold for the cost-effectiveness of surveillance. Additionally, the reported explorative prognostic analysis is not free from the risk of distorted results mainly due to overfitting. The total number and list of candidate prognostic indicators is not reported and 12 significant variables at univariable analysis were included in the multivariable model. Since it is recommended to include approximately 1 variable per 10 outcome events to minimise the risk of overfitting, the analysis performed in this study may bear a considerable risk of overfitting having included approximately 3 variables per 10 outcome events (12 for 41 events). The inclusion of 2 variables (coffee consumption and alpha-fetoprotein) with approximately 15% of missing values (although substituted by multiple imputation) further adds to the risk of distorted results of the prognostic analysis.
      Despite these limitations, the study by Ganne-Carrié et al. convincingly demonstrates that the incidence of HCC in alcohol-related cirrhosis is enough to justify performing HCC screening with regular imaging techniques, mainly abdominal US. Given the important number of non-compliant patients, it is highly advisable that physicians motivate patients with alcohol-related liver cirrhosis to undergo HCC screening regularly.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

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