Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 18, 2016; 8(35): 1547-1556
Published online Dec 18, 2016. doi: 10.4254/wjh.v8.i35.1547
Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M
Vanessa Rausch, Teresa Peccerella, Carolin Lackner, Eray Yagmur, Helmut-Karl Seitz, Thomas Longerich, Sebastian Mueller
Vanessa Rausch, Teresa Peccerella, Helmut-Karl Seitz, Sebastian Mueller, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, 69120 Heidelberg, Germany
Carolin Lackner, Institute for Pathology, Medical University Graz, 8036 Graz, Austria
Eray Yagmur, Laboratory Diagnostics Center, RWTH-University Hospital Aachen, Aachen and Medical Care Center, Dr. Stein and colleagues, 41169 Mönchengladbach, Germany
Thomas Longerich, Institute of Pathology, RWTH-University Hospital Aachen, 52074 Aachen, Germany
Author contributions: Rausch V and Mueller S contributed to the conception and design of the study, analyzed and interpreted the data and wrote the manuscript; Rausch V, Peccerella T, Lackner C, Yagmur E and Longerich T contributed to the acquisition and analysis of data; Lackner C, Seitz HK and Longerich T critically revised the manuscript and approved the final version.
Supported by The German Research Foundation (DFG, RA-2677/1-1); and the Dietmar Hopp-Foundation, No. 2301196.
Institutional review board statement: The study was approved by the Ethical Committee of the University of Heidelberg.
Conflict-of-interest statement: The authors declare that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Data sharing statement: Patients gave informed consent before inclusion in the study; the presented data are anonymized and the risk of identification is very low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Sebastian Mueller, MD, PhD, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Zeppelinstraße 11-33, 69120 Heidelberg, Germany.
Telephone: +49-6221-483210 Fax: +49-6221-483494
Received: March 22, 2016
Peer-review started: March 23, 2016
First decision: July 4, 2016
Revised: August 22, 2016
Accepted: September 13, 2016
Article in press: September 18, 2016
Published online: December 18, 2016

To investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.


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.


The PNPLA3 rs738409 genotype 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% vs 6%) 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 to PNPLA3 G 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.


In heavy drinkers, PNPLA3 GG 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 in PNPLA3 GG carriers.

Keywords: Liver stiffness, Alcoholic liver disease, Adiponutrin, PNPLA3, Transient elastography, Alcohol withdrawal, Inflammation

Core tip: The role of the PNPLA3 rs738409 variant (CG and GG) on histology and liver stiffness in response to alcohol detoxification was studied in a large monocentric cohort of heavy drinkers with various stages of ALD. About 20% of our patients with alcoholic liver cirrhosis were attributable to PNPLA3 G variants with an OR to develop cirrhosis of 1.295. Our data further show that PNPLA3 GG carriers primarily develop ballooning and not steatosis causing a delayed resolution of liver stiffness after alcohol withdrawal. We suggest that the delayed ballooning-associated stiffness elevation may contribute to fibrosis progression (see also the sinusoidal pressure hypothesis).