title: Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with thePNPLA3variant I148M.
abstract: OBJECTIVE
  To investigate the influence ofPNPLA3genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.
  
  
  METHODS
  Caucasian heavy drinkers (n= 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients.
  
  
  RESULTS
  ThePNPLA3 rs738409genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r= 0.404,P< 0.005), ballooning (r= 0.319,P< 0.005) and less with steatosis (r= 0.264,P< 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r= 0.828,P< 0.005), ballooning (r= 0.516,P< 0.005), steatohepatitis (r= 0.319,P< 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47%vs6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable toPNPLA3G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers.
  
  
  CONCLUSIONS
  In heavy drinkers,PNPLA3GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression inPNPLA3GG carriers.
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rausch
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Peccerella
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Eray
authors.initials: E
authors.lastname: Yagmur
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Helmut-Karl
authors.initials: HK
authors.lastname: Seitz
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.affiliation: Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mueller
keywords: Adiponutrin; Alcohol withdrawal; Alcoholic liver disease; Inflammation; Liver stiffness; PNPLA3; Transient elastography