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To the Editor:

In a recent article in HEPATOLOGY, Valenti et al.1 reported an association of the patatin-like phospholipase domain containing 3 (PNPLA3) isoleucine-to-methionine substitution at position 148 (I148M; rs738409) with hepatitis C virus (HCV)-related chronic liver disease. In particular, they showed this genetic variant was associated with fatty liver and fibrosis progression in two independent cohorts of Caucasians with chronic HCV. In one study cohort, they also reported an independent association with hepatocellular carcinoma (HCC) in homozygous 148M carriers.1 Our goal was to examine the latter association in a cohort of individuals with HCV-related cirrhosis, comparing those with and without HCC.

We genotyped a total of 221 (male/female = 141/80) Caucasians at the Department of Gastroenterology, “Sapienza” University of Rome, Italy, for the PNPLA3 148M allele. Inclusion criteria were presence of clinical cirrhosis, HCV RNA positivity, surveillance for HCC for at least 2 years, and alcohol consumption of <20 and <30 g/day for women and men, respectively. Mean age was 58 ± 11 years, 31% had diabetes, and 41% had radiological and/or histological diagnosis of HCC.

We performed a multivariate analysis that included HCC as dependent variable and age, sex, diabetes, and the 148M genotype (148M homozygotes versus the other genotypes) as covariates. We found homozygosity for the 148M allele to be independently associated with HCC (odds ratio = 2.23, 95% confidence interval = 1.60-3.50, P = 0.008; Table 1).

Table 1. Suggested Evaluation of Patients With NAFLD
Disease RiskNAFLD Assessment
  • *

    According to recent guidelines, hemoglobin A1c can be used for screening for type 2 diabetes.

DiabetesMeasure the body mass index, waist circumference, fasting plasma glucose and insulin level, and hemoglobin A1c level.*
Perform the 75-g oral glucose tolerance test in NAFLD patients without known diabetes according to standard guidelines (i.e., the American Diabetes Association) to classify their glucose tolerance.
Calculate the fasting index of insulin resistance (homeostasis model assessment of insulin resistance), which is associated with the severity of liver disease and has prognostic value in NAFLD.
CVDAssess smoking status, measure blood pressure, plasma total cholesterol, low density lipoprotein(LDL)-cholesterol, high density lipoprotein(HDL) cholesterol and triglycerides.
Calculate the CVD risk score (i.e., Framingham risk score).
Perform B-mode carotid ultrasonography in patients without diabetes or established CVD who have intermediate CVD risk (Framingham risk score = 6%-20%) to measure carotid intima-media thickening according to recent guidelines6 (optional).
Liver-related (end-stage liver disease)Apply noninvasive tests (i.e., the serum cytokeratin 18 fragment assay, NAFLD fibrosis score, and FibroScan) to screen for the presence of NASH with or without advanced fibrosis.
If noninvasive tests yield a high probability of NASH (with or without advanced fibrosis), refer to a gastroenterologist for liver biopsy, the assessment of complications of cirrhosis (hepatic failure, portal hypertension, esophageal varices, and hepatocellular carcinoma), experimental treatments, and tight monitoring.
Liver biopsy remains necessary for staging and monitoring the course of liver disease in patients with NASH and if the diagnosis of NAFLD is in doubt.

Liver disease is a spectrum of conditions deriving from the presence of chronic liver damage over many years. It ranges from simple hepatocellular damage, to liver inflammation, fibrosis, cirrhosis, and ultimately HCC. The PNPLA3 I148M variant has been previously associated with nonalcoholic2 as well as alcoholic liver disease.3 Valenti et al. showed for the first time an association of the 148M allele with HCV-related liver steatosis and fibrosis. They also found a possible link with HCC. Our results support the latter association.

These data are consistent with the hypothesis of liver disease being a continuum of conditions where chronic stress acts on a genetically susceptible background, in a “two-hit” pathogenetic model. The PNPLA3 protein function remains mostly obscure, and at this time it is difficult to generate a hypothesis that may explain the association that was found.

Longitudinal studies on HCV fibrosis progression and HCC onset are needed to confirm the PNPLA3 association, and functional studies are required to understand the mechanisms underlying it.

References

  1. Top of page
  • 1
    Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, et al. Patatin-like phospholipase domain containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. HEPATOLOGY 2011; 53: 791-799.
  • 2
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40: 1461-1465.
  • 3
    Tian C, Stokowski RP, Kershenobich D, Ballinger DG, Hinds DA. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet 2011; 42: 21-23.

Stefano Ginanni Corradini M.D., Ph.D.*, Maria Antonella Burza M.D.* †, Antonio Molinaro M.D.*, Stefano Romeo M.D., Ph.D.† ‡, * Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy, † Institute of Metabolic Science, University of Cambridge, Cambridge, UK, ‡ Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.