I148M PNPLA3 variant and progressive liver disease: A new paradigm in hepatology

Authors

  • Luca Valenti M.D.,

    1. Department of Internal Medicine Università degli Studi di Milano Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico Milan, Italy
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  • Anna Alisi Ph.D.,

    1. Unit of Hepato-metabolic Diseases and Liver Research Unit “Bambino Gesù” Children's Hospital and Research Institute Rome, Italy
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  • Valerio Nobili M.D.

    1. Unit of Hepato-metabolic Diseases and Liver Research Unit “Bambino Gesù” Children's Hospital and Research Institute Rome, Italy
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  • Potential conflict of interest: Nothing to report.

To the Editor:

We read with great interest the article recently published in this journal.1 In that study, Sookoian and Pirola presented the results of a meta-analysis including 2,651 patients undergoing liver biopsy, in which the strength of I148M patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant on nonalcoholic fatty liver disease (NAFLD) severity across different populations was evaluated, together with its potential influence on intermediate associated phenotypes. The power of this study has shown that the I148M polymorphism impacts not only hepatic triglyceride content, but also the susceptibility toward a more aggressive disease (i.e., liver fibrosis). The I148M variant also influences alanine aminotransferase activity, without affecting body mass, insulin resistance, or serum lipid levels. The large dataset investigated allowed measurement of the strength of PNPLA3 genotypes on NAFLD and disease severity, which was consistent with an additive genetic model, with the only exception of a likely dominant effect of the G allele onto fibrosis. Notably, the GG genotype was associated with a 73% increase in hepatic fat content and a 3.2-fold higher risk of steatohepatitis and fibrosis, and explained 9%-33% of NAFLD variability, depending on the ethnic group.1

The same approach could be particularly useful in children affected by NAFLD, mostly because of the potential benefits of disease prediction before its clinical manifestation.2

These findings support data demonstrating a similar effect of the I148M polymorphism on the risk of alcoholic liver disease, which shares many features with NASH, and alcoholic cirrhosis in heavy drinkers in multiple ethnic groups,3 and with steatosis and fibrosis progression in chronic hepatitis C.4 Preliminary observations from cross-sectional studies also argue for an extension toward hepatocellular carcinoma development of the risk conferred by the 148M allele.4

In conclusion, it is likely that the I148M PNPLA3 variant is a common inducer of liver damage progression associated with histological features of steatohepatitis in the presence of metabolic, toxic, or viral risk factors (Fig. 1).

Figure 1.

A simplified working model showing the influence of the I148M PNPLA3 variant on the progression of chronic liver diseases.

Two major challenges lay now ahead: a better understanding of PNPLA3 biology to unravel novel therapeutic targets, and evaluation of the impact of PNPLA3 and other novel genetic risk factors on clinical practice in order to improve the diagnostic protocols and personalize therapeutic strategies.

Luca Valenti M.D.*, Anna Alisi Ph.D.†, Valerio Nobili M.D.†, * Department of Internal Medicine, Università degli Studi di Milano, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy, † Unit of Hepato-metabolic Diseases and Liver Research Unit, “Bambino Gesù” Children's Hospital and Research Institute, Rome, Italy.

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