Patatin-like phospholipase domain-containing protein 3 genotype and hepatocellular carcinoma in chronic hepatitis C

Authors

  • Luca Valenti M.D.,

    1. Department of Internal Medicine A.M. Migliavacca Center for Liver Disease First Division of Gastroenterology Università degli Studi, Fondazione IRCCS “Ca' Granda” Ospedale Maggiore Policlinico Milan, Italy
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  • Massimo Colombo M.D.,

    1. Department of Internal Medicine A.M. Migliavacca Center for Liver Disease First Division of Gastroenterology Università degli Studi, Fondazione IRCCS “Ca' Granda” Ospedale Maggiore Policlinico Milan, Italy
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  • Silvia Fargion M.D.

    1. Department of Internal Medicine A.M. Migliavacca Center for Liver Disease First Division of Gastroenterology Università degli Studi, Fondazione IRCCS “Ca' Granda” Ospedale Maggiore Policlinico Milan, Italy
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  • Potential conflict of interest: Nothing to report.

To the Editor:

We thank Ginanni Corradini and coworkers for their interest in our work.1

We have recently reported that the Ile148Met PNPLA3 (patatin-like phospholipase domain-containing protein 3) genotype, a strong genetic determinant of hepatic fat accumulation and progressive alcoholic as well as nonalcoholic steatohepatitis,2, 3 influences steatosis development, liver fibrosis, possibly antiviral treatment response, and the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC).1 Furthermore, almost contemporarily, Cai et al. found that, in line with our results, PNPLA3 genotype was associated with steatosis in patients with CHC who are not affected by viral genotype 3,4 whereas Müller et al. very recently confirmed the association of PNPLA3 genotype with steatosis and cirrhosis in German patients with CHC.5 These data suggest that PNPLA3 genotype (1) is a strong determinant of metabolic steatosis in CHC, (2) plays a causal role in determining the progression of liver disease, and (3) that the evaluation of PNPLA3 genotype might help identify patients who are at higher risk of complications, and in particular HCC, and might possibly be useful for the stratification of patients in studies aimed at HCC prevention. However, this latter conclusion awaits confirmation in larger prospective studies, because it was based on a retrospective analysis of 325 patients (107 with cirrhosis) who were followed at a single center.1

In response to our article, Ginanni Corradini et al. now report an association between homozygosity for the 148M PNPLA3 variant and HCC in a retrospective analysis conducted in an Italian population of 221 patients with CHC-related cirrhosis without excessive alcohol intake, which was independent of age, sex, and diabetes, thus providing an independent validation of our findings in another population, albeit of similar ethnicity.6 Strikingly, the magnitude of the association (odds ratio = 2.23, confidence interval = 1.6-3.5 and odds ratio = 2.16, confidence interval = 1.3-3.6 in this and our report, respectively) adjusted for the same confounders was also very consistent between the two studies.

As previously discussed,1 we agree that larger prospective studies in ethnically different populations and different liver diseases are required to confirm the association between PNPLA3 genotype and HCC, and functional studies on the still-mysterious PNPLA3 function are urgently needed. Nevertheless, these exciting findings may open new perspectives for the prevention and treatment of the complications of liver diseases, including but not limited to CHC.

Luca Valenti M.D.*, Massimo Colombo M.D.*, Silvia Fargion M.D.*, * Department of Internal Medicine, A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Università degli Studi, Fondazione IRCCS “Ca' Granda”, Ospedale Maggiore Policlinico, Milan, Italy.

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