Recent research trends and updates on nonalcoholic fatty liver disease

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Abstract

Nonalcoholic fatty liver disease (NAFLD), together with metabolic syndrome and obesity, has shown a rapid increase in prevalence worldwide and is emerging as a major cause of chronic liver disease and liver transplantation. Among the various phenotypes of NAFLD, nonalcoholic steatohepatitis (NASH) is highly likely to progress to development of end-stage liver disease and cardiometabolic disease, resulting in liver-related and non-liver–related mortality. Nonetheless, there is no standardized pharmacotherapy against NASH and many drugs are under development in ongoing clinical trials. To develop a successful anti-NASH drug, it is necessary to select an appropriate target population and treatment outcomes depending on whether the mode of action is anti-metabolic, anti-inflammatory or anti-fibrotic. Recently, innovative surrogate markers have been investigated to replace hard outcomes such as liver histology and mortality and reduce the clinical trial duration. Currently, several drugs with fast track designation are being tested in phase III clinical trials, and many other drugs have moved into phase II clinical trials. Both lean NAFLD and typical obese NAFLD have been extensively studied and genetic variants such as PNPLA3 and TM6SF2 have been identified as significant risk factors for lean NAFLD. In the near future, noninvasive biomarkers and effective targeted therapies for NASH and associated fibrosis are required to develop precision medicine and tailored therapy according to various phenotypes of NAFLD.

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Most cited references 48

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Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Stefano Romeo, Julia Kozlitina, Chao Xing … (2008)

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ethnic groups. To identify genetic variants contributing to differences in hepatic fat content, we performed a genome-wide association scan of nonsynonymous sequence variations (n=9,229) in a multiethnic population. An allele in PNPLA3 (rs738409; I148M) was strongly associated with increased hepatic fat levels (P=5.9×10−10) and with hepatic inflammation (P=3.7×10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was > 2-fold higher in PNPLA3-148M homozygotes than in noncarriers. Resequencing revealed another allele associated with lower hepatic fat content in African-Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ethnic and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

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Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.

J. Ludwig, T Viggiano, D McGill … (1980)

Nonalcoholic steatohepatitis is a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis. Described here are findings in 20 patients with nonalcoholic steatohepatitis of unknown cause. The biopsy specimens were characterized by the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates, and, in most instances, Mallory bodies; Evidence of fibrosis was found in most specimens, and cirrhosis was diagnosed in biopsy tissue from three patients. The disease was more common in women. Most patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis. Presence of hepatomegaly and mild abnormalities of liver function were common clinical findings. Currently, we know of no effective therapy.

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Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.

Silvia Sookoian, Carlos Pirola (2011)

Our objective was to estimate the strength of the effect of the I148M (rs738409 C/G) patatin-like phospholipase domain containing 3 (PNPLA3) variant on nonalcoholic fatty liver (NAFLD) and disease severity across different populations. We performed a systematic review by a meta-analysis; literature searches identified 16 studies. Our results showed that rs738409 exerted a strong influence not only on liver fat accumulation (GG homozygous showed 73% higher lipid fat content when compared with CC ones, data from 2,937 subjects; P < 1 × 10(-9) ), but also on the susceptibility of a more aggressive disease (GG homozygous had 3.24-fold greater risk of higher necroinflammatory scores and 3.2-fold greater risk of developing fibrosis when compared with CC homozygous; P < 1 × 10(-9) ; data from 1,739 and 2,251 individuals, respectively). Nonalcoholic steatohepatitis (NASH) was more frequently observed in GG than CC homozygous (odds ratio [OR] 3.488, 95% confidence interval [CI] 1.859-6.545, random model; P < 2 × 10(-4) ; data from 2,124 patients). Evaluation of the risk associated with heterozygosity for the variant suggests that the additive genetic model best explains the effect of rs738409 on the susceptibility to develop NAFLD. Nevertheless, carrying two G alleles does not seem to increase the risk of severe histological features. Meta-regression showed a negative correlation between male sex and the effect of rs738409 on liver fat content (slope: -2.45 ± 1.04; P < 0.02). The rs738409 GG genotype versus the CC genotype was associated with a 28% increase in serum alanine aminotransferase levels. By summarizing the amount of evidence, this study provided unequivocal evidence of rs738409 as a strong modifier of the natural history of NAFLD in different populations around the world. Copyright © 2011 American Association for the Study of Liver Diseases.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Mol Hepatol

Journal ID (iso-abbrev): Clin Mol Hepatol

Journal ID (publisher-id): CMH

Title: Clinical and Molecular Hepatology

Publisher: The Korean Association for the Study of the Liver

ISSN (Print): 2287-2728

ISSN (Electronic): 2287-285X

Publication date (Print): March 2019

Publication date (Electronic): 8 August 2018

Volume: 25

Issue: 1

Pages: 1-11

Affiliations

[1 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea

[2 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea

[3 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea

[4 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hanyang University Seoul Hospital, Seoul, Korea

[5 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea

[6 ]Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea

[7 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

[8 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Korea

[9 ]Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea

Author notes

Corresponding author : Yong Kyun Cho Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro, Jongno-gu, Seoul 03181, Korea Tel: +82-2-2001-2080, Fax: +82-2-2001-2049 E-mail: choyk2004.cho@ 123456samsung.com

Sang Hoon Park Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, 1 Singil-ro, Yeongdeungpo-gu, Seoul 07441, Korea Tel: +82-2-829-5121, Fax: +82-2-846-4669 E-mail: sanghoon@ 123456hallym.or.kr

Joo Hyun Sohn Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hanyang University Guri Hospital, 153 Gyeongchun-ro, Guri 11923, Korea Tel: +82-31-560-2225, Fax: +82-31-555-2998 E-mail: sonjh@ 123456hanyang.ac.kr

[*]

JJ Yoo and W Kim contributed equally as co-first authors;

[†]

YK Cho, SH Park, and JH Sohn contributed equally as co-corresponding authors.

Author information

Yong Kyun Cho http://orcid.org/0000-0002-9231-006X

Sang Hoon Park http://orcid.org/0000-0002-9495-4432

Joo Hyun Sohn http://orcid.org/0000-0002-8977-4509

Article

Publisher ID: cmh-2018-0037

DOI: 10.3350/cmh.2018.0037

PMC ID: 6435971

PubMed ID: 30086613

SO-VID: 406fab7c-fa43-4a8e-9aec-d2eba2c526c7

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Recent research trends and updates on nonalcoholic fatty liver disease

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Most cited references 48

Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.

Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.

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