Z Gastroenterol 2013; 51 - K156
DOI: 10.1055/s-0033-1352796

The frequent PNPLA3 risk variant p.I148 M is associated with decreased pruritus in cholestasis: novel role of a prosteatotic polymorphism

M Krawczyk 1, E Wunsch 2, F Grünhage 1, V Zimmer 1, M Milkiewicz 3, P Milkiewicz 2, 4, F Lammert 1
  • 1Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Homburg, Germany
  • 2Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland
  • 3Medical Biology Laboratory, Pomeranian Medical University, Szczecin, Poland
  • 4Liver Unit, Department of Liver Transplantation and General Surgery, Warsaw, Poland

Background and aims: The common PNPLA3 (adiponutrin) variant p.I148 M is associated with severe forms of liver diseases1. Of note, the minor allele [M] at this locus promotes the conversion of lysophosphatidic acid (LPA) into phosphatidic acid (PA)2, resulting in increased cellular diacylglycerol synthesis. Since LPA functions as a mediator of cholestatic pruritus3, we now investigate the effects of the PNPLA3 variant on itching in patients with primary biliary cirrhosis (PBC) and intrahepatic cholestasis of pregnancy (ICP).

Methods: We recruited 186 PBC patients (age range 22 – 83 years, 165 females, 68 with liver cirrhosis) and 201 females with ICP (age range 17 – 46 years). PBC symptoms were quantified with the PBC-27 and PBC-40 questionnaires. The PNPLA3 polymorphism was genotyped using a PCR-based assay with 5′-nuclease and fluorescence detection. Genotype and allele frequencies were compared with PBC- and ICP-free control cohorts (N = 250 and N = 198, respectively).

Results: The PBC patients who tested positive for the ‘gain-of-function’ PNPLA3 allele [M] reported significantly less itching in the PBC-27 (3.4 ± 0.5 vs. 5.1 ± 0.5, P = 0.02) and PBC-40 tests (3.6 ± 0.5 vs. 5.03 ± 0.50, P = 0.05) as compared to homozygous wild-type allele carriers. Of note, the wild-type allele substantially increased the odds (OR = 7.05, P = 0.04) to require plasmapheresis for refractory pruritus. In the ICP patients, the [M] allele was less frequent (19.7%) as compared to controls (27.0%, P < 0.05). Hence, carriers of the [MM] and [IM] genotypes were at reduced risk (OR = 0.58, 95% CI = 0.38 – 0.86, P = 0.007) of symptomatic ICP as compared to the carriers of the common genotype [II].

Conclusions: The PNPLA3 p.I148 M risk allele, previously associated with more severe hepatic phenotypes1, might be associated with decreased pruritus in patients with cholestasis. Conversely, the major allele [I] increases the risk of treatment refractory pruritus. This novel finding could be related to increased acyltransferase activity2 in liver and/or skin, which eventually results in decreased levels of LPA, the critical mediator of pruritus in chronic cholestasis.


[1] Sookoian et al. Hepatology 2011

[2] Kumari et al. Cell Metabolism 2012

[3] Kremer et al. Gastroenterology 2010