Recent reports demonstrated that the PNPLA3 (patatin-like phospholipase domain containing-3) isoleucine-to-methionine variant at residue 148 (I148M) influences steatosis and liver damage progression in chronic hepatitis C (CHC).1-4
The article by do O and coworkers now report that in 176 German patients with CHC who underwent liver transplantation, there was no significant effect of PNPLA3 genotype on fibrosis after 5 years of follow-up.5 Unfortunately, steatosis assessment was not available. Other major drawbacks limit the validity of these findings. First, previous studies have shown that the effect of PNPLA3 on fibrosis in CHC follow a recessive model,1-4 so that this study5 had only 30% power to detect a two-fold increased risk. Furthermore, the effect might be less relevant in patients carrying genotype-3 hepatitis C virus, but viral features were not reported. Most importantly, the authors could only evaluate recipient genotype, so that they had no information on PNPLA3 status in the transplanted liver. However, it is most commonly held that the 148M PNPLA3 variant predisposes to liver damage by acting directly at the level of hepatocytes.6 Therefore, the purported evidence does not exclude a clinically relevant role of PNPLA3 genotype in determining the outcome of orthotopic liver transplantation for CHC, opposite to what has been suggested. Additional, adequately powered studies with systematic evaluation of steatosis, viral features, and both donor and recipient PNPLA3 genotype are required to clarify this issue. Indeed, such a study would be of utmost importance for the following reasons: (1) it would clarify the cell type (hepatocytes versus adipocytes, or both) whose metabolic function is deranged due to PNPLA3 variants, which has not been possible in mouse studies due to different expression pattern and mechanism of regulation of this gene, with implications for the design of new therapies, and (2) it would possibly provide useful information for organ allocation. A cooperative effort is warranted to achieve these goals.