PNPLA3 148M Carriers with Inflammatory Bowel Diseases Have Higher Susceptibility to Hepatic Steatosis and Higher Liver Enzymes

Inflammatory bowel diseases (IBD) are immune-mediated disorders characterized by remittent and relapsing progressive inflammation of the gastrointestinal tract. There are 2 major clinical forms of IBD: Crohn's disease (CD) and ulcerative colitis (UC).1 IBD are often associated with extraintestinal manifestations involving various organs. Extraintestinal manifestations of the skin, eyes, and peripheral joints usually follow the disease activity, whereas extraintestinal manifestations involving the hepatobiliary and pulmonary systems typically do not parallel the disease activity.2–4 Increased circulating levels of aminotransferases represent one of the most frequently described IBD-related liver diseases; this is usually ascribed to nonalcoholic fatty liver disease.4 Indeed, the prevalence of hepatic steatosis ranges from 13% to 100% in individuals with IBD5 and with no differences between CD and UC.5,6 Several possible mechanisms underlying IBD-related hepatic damage have been already described, including malnutrition, protein loss, and medications.5 Despite a large number of studies on liver abnormalities, the pathogenesis of hepatic steatosis and liver damage in individuals with IBD is not completely understood, and it is not known whether IBD per se represent an independent risk factor for this condition. The patatin-like phospholipase domain-containing 3 (PNPLA3) protein is a triglyceride and retinyl esterase lipase7–9 highly expressed in human hepatocytes and hepatic stellate cells. The PNPLA3 rs738409 genetic variant is a guanine to cytosine substitution at position 617 of the gene, and it encodes an isoleucine to methionine substitution at position 148 (I148M) of the PNPLA3 protein. This substitution results in a loss of function of the protein enzymatic activity.10–13 The PNPLA3 I148M substitution is a major common genetic determinant of hepatic fat content13 and progression to chronic liver disease under a large variety of harmful stimuli for the liver including severe obesity,14 visceral adiposity,15 diet,16,17 viruses,11,18 iron overload,19 and excess alcohol consumption.20 However, it is not yet known whether PNPLA3 148M carriers with IBD are more susceptible to chronic liver disease. The aim of this study was to investigate whether carriers of PNPLA3 148M allele with IBD have higher risk of liver steatosis and increase in transaminases levels. Here, we show for the first time that carriers of the PNPLA3 148M allele with IBD have a greater risk of hepatic steatosis and increased circulating alanine transaminase (ALT) in a cohort of 158 patients from Southern Italy. We further confirm the higher ALT levels in an independent cohort of 207 individuals with IBD from Northern Italy.