Sy14-4primary Hepatocellular Damage and Suppressed Fat Mobilization in Heavy Drinkers With Pnpla3 G Genotype

Abstract

PNPLA3 GG genotype has been identified as important progression factor in patients with ALD and NAFLD. Since PNPLA3 function remains poorly understood, we here studied genotype distribution and various noninvasive, serum and molecular markers of liver damage and steatosis in 521 heavy drinkers (mean alcohol consumption 191.2 g per day) prior and after alcohol withdrawal. Liver histology was obtained in 80 patients and allowed additional immunostaining for lipid droplet (LD)-associated proteins (N = 47) and expression of mRNA transcripts (N = 24). PNPLA3 GG carriers (8.2%) drunk significantly less high percentage beverages (23% vs 55%, p < 0.001) and showed no increased weight, BMI or diabetes. Liver stiffness (LS) was significantly elevated in G carriers (median 18 vs. 11 kPa) and correlated with histological signs of fibrosis (r = 0.8) and liver damage (ballooning, r = 0.7), but not with steatosis. In CG carrier, LS decreased significantly from 17.6 to 12.7 but less in GG carriers. Moreover, hepatic fat content as quantified by CAP did not significantly differ between the groups and decreased equally by 30 dB/m. On the molecular level, key molecules, important for lipolysis and flow of free fatty acids to the liver, were drastically reduced in G allele carriers. These included the liver-synthesized serum ApoA1, the LD-associated protein perilipin5 and the recently identified hepatoprotective transcriptional cofactor transducin beta-like-related 1 (TBLR1). Conclusion: In heavy drinkers, PNPLA3 GG primarily correlates with hepatocyte damage resulting in a reversible, inflammationassociated increase of LS and the suppression of key molecules that are important for lipolysis and hepatocellular fat mobilization.

CAP: a Novel Era to Better Quantitate Fatty Liver?

“…Indeed, only a minority (15%) of patients with non-alcoholic fatty liver (NAFLD) will progress to advanced end stage liver disease despite the abundance of liver fat in the remaining patients. Moreover, the recently discovered new genes involved in NAFLD and alcoholic liver disease (ALD) progression such as PNPLA3 [6] seem to primarily cause hepatocyte damage rather than steatosis [7]. In line with this, alcoholic steatohepatitis (ASH) rather than steatosis seems to be the major risk for cirrhosis development in patients who consume alcohol [8].…”

“…This is a major challenge for following-up hepatic steatosis over time. It should also be mentioned that fat can change rapidly not only in response to drugs, but also alcohol or dietary changes [7]. Conventional screening tools for steatosis have been ultrasound, and to some extent CT and MRI, especially proton MRI spectroscopy [10].…”

“…However, many questions remain open that should be addressed in future studies: How does CAP changes in response to fast kinetics such as alcohol detoxification, binge drinking, after nutrition and the intake of certain drugs? The first recent data seem to indicate that CAP rapidly decreases within 5 days by 30 dB/m after alcohol detoxification [7]. How does CAP compare to ultrastructural features such as microvesicular or macrovesicular steatosis?…”