PNPLA3 and end-stage liver disease – destigmatizing alcoholic cirrhosis?
Background and aims: End-stage liver disease represents a final path for hepatic disorders and can only be cured by liver transplantation. The rs738409 variant (I148 M) of the PNPLA3 gene is associated with a variety of liver malfunctions but has not been addressed in an end-stage liver disease setting.
Methods: The I148 M polymorphism was genotyped in a well characterized cohort of 421 Caucasian patients with end-stage liver disease, characterized as liver transplantation or current enrollment at Eurotransplant. We obtained a detailed history of alcohol consumption in patients with alcoholic liver disease (ALD)
Results: The G allele of the I148 M variant was significantly overrepresented in patients with ALD (p < 0.001), chronic viral hepatitis (p = 0.004) and cryptogenic liver cirrhosis (p = 0.002) compared to healthy controls. In addition, HCC development was tightly associated with the G allele for patients with ALD (Odds-ratio = 2.399; 95% CI: 1.292 – 4.455: p = 0.008) while there was no association for the remaining hepatic disorders. Analysis of alcohol consumption revealed that wildtype patients consumed significantly more alcohol than patients carrying either one or two mutate allele (CC = 731.0 ± 216.5; CG = 601.4 ± 172.2; GG = 523.3± 190.5 [g EtOH//week]; p = 0.001). Although alcohol intake of I148 M homozygous patients (GG) was boarderline to the cut-off value of 60 g alcohol/day, they still shared the same features of end-stage liver disease than wildtype patients.
Conclusions: In a cohort of end-stage liver disease patients we identified ALD to be predominantly affected by the I148 M polymorphism causing a significantly increased risk of HCC development. According to public perception ALD is a stigmatized hepatic disorder and one of the reasons for liver donation aversion. However, we were able to show that the I148 M polymorphism highly impairs hepatic malfunction in ALD patients despite reduced alcohol consumption compared to wildtype patients.