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Histological hepatocyte damage precedes steatosis in ALD patients with genetic variant l148 M in PNPLA3
Aim: The non-synonymous single nucleotide polymorphism rs738409C->G in PNPLA3 that substitutes methionine for isoleucine at residue 148 (I148 M) has been identified as major genetic confounding factor of liver steatosis and fibrosis progression both in patients with alcoholic and non-alcoholic liver disease (ALD and NAFLD). Since the PNPLA3 function remains largely unknown, we here studied in detail sub-histological scores and mRNA transcripts in a large cohort of well characterized ALD patients.
Patients and methods: 217 patients with ALD were enrolled for PNPLA3 genotype analysis (RT-PCR) with routine laboratory tests, ultrasound, morphometric data and liver stiffness (Fibroscan). In 141 patients, a second LS measurement was performed after alcohol detoxication. Liver biopsies with Kleiner and Chevallier scores were available in 75 cases, additional mRNA transcripts of genes relevant of steatosis, oxidative stress and iron metabolism in 24 patients.
Results: PNPLA3 genotypes CC, CG and GG were distributed as follows: 44.2%, 46.5% and 9.2%. PNPLA3 GG allelic variant correlated significantly with histological signs of hepatocyte damage such as microgranulomas and ballooning (r> 0.3, P < 0.005) but less with histological steatosis (r = 0.24, P < 0.05). A weaker association was found in the GC genotype. In contrast, CC genotype was negatively associated with ballooning and markers of fibrosis (hyaluronic acid, morphometry, P < 0.05). Notably, PNPLA3 genotype did not affect the resolution of LS or inflammation after alcohol detoxification. Among the mRNA transcripts, PNPLA3-GG was most significantly correlated with transcriptional cofactor transducin beta-like-related 1 (TBLR1, r = –0.553, P < 0.005), a recently identified protective factor against hepatic steatosis in the metabolic syndrome.
Conclusion: PNPLA3-GG genotype seems to cause hepatocyte damage preceeding steatosis in patients with ALD. The strong negative association between TBLR1 and PNPLA3-GG highlights a novel molecular link of PNPLA3-mediated (patho)physiology.