Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis

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Abstract

Background/Aims

Nonalcoholic fatty liver disease (NAFLD) is associated with a multitude of adverse outcomes. We aimed to estimate the pooled incidence of NAFLD-related adverse events.

Methods

We performed a systematic review and meta-analysis of cohort studies of adults with NAFLD to evaluate the pooled incidence of adverse events.

Results

19,406 articles were screened, 409 full-text articles reviewed, and 79 eligible studies (1,377,466 persons) were included. Mean age was 51.47 years and body mass index 28.90 kg/m ². Baseline comorbidities included metabolic syndrome (41.73%), cardiovascular disease (CVD) (16.83%), cirrhosis (21.97%), and nonalcoholic steatohepatitis (NASH) (58.85%). Incidence rate per 1,000 person-years for mortality included: all-cause (14.6), CVD-related (4.53), non-liver cancer-related (4.53), and liver-related (3.10). Incidence for liver-related events included overall (24.3), fibrosis progression (49.0), cirrhosis (10.9), liver transplant (12.0), and hepatocellular carcinoma (HCC) (3.39). Incidence for non-liver events included metabolic syndrome (25.4), hypertension (25.8), dyslipidemia (26.4), diabetes (19.0), CVD (24.77), renal impairment (30.3), depression/anxiety (29.1), and non-liver cancer (10.5). Biopsy-proven NASH had higher incidence of HCC ( P=0.043) compared to non-NASH. Higher rates of CVD and mortality were observed in North America and Europe, hypertension and non-liver cancer in North America, and HCC in Western Pacific/Southeast Asia ( P<0.05). No significant differences were observed by sex. Time-period analyses showed decreasing rates of cardiovascular and non-liver cancer mortality and increasing rates of decompensated cirrhosis ( P<0.05).

Conclusions

People with NAFLD have high incidence of liver and non-liver adverse clinical events, varying by NASH, geographic region, and time-period, but not sex.

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Most cited references 36

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The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

Matthew J L Page, Joanne E McKenzie, Patrick Bossuyt … (2025)

The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, published in 2009, was designed to help systematic reviewers transparently report why the review was done, what the authors did, and what they found. Over the past decade, advances in systematic review methodology and terminology have necessitated an update to the guideline. The PRISMA 2020 statement replaces the 2009 statement and includes new reporting guidance that reflects advances in methods to identify, select, appraise, and synthesise studies. The structure and presentation of the items have been modified to facilitate implementation. In this article, we present the PRISMA 2020 27-item checklist, an expanded checklist that details reporting recommendations for each item, the PRISMA 2020 abstract checklist, and the revised flow diagrams for original and updated reviews.

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NAFLD: a multisystem disease.

Christopher Byrne, Giovanni Targher (2015)

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver-related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. For example, NAFLD increases risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD). Although the primary liver pathology in NAFLD affects hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and hepatocellular carcinoma, the majority of deaths among NAFLD patients are attributable to CVD. This narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease. The review discusses the factors involved in the progression of liver disease in NAFLD and the factors linking NAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD. The review will not discuss NAFLD treatments as these are discussed elsewhere in this issue of the Journal. For this review, PubMed was searched for articles using the keywords "non-alcoholic fatty liver disease" or "fatty liver" combined with "diabetes", "cardiovascular (or cardiac) disease", "cardiovascular mortality" or "chronic kidney disease" between 1990 and 2014. Articles published in languages other than English were excluded.

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Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.

Mattias Ekstedt, Hannes Hagström, Patrik Nasr … (2015)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease-specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease-specific mortality. In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (±5.6, range 6-33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04-1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11-2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02-7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, P = 0.07), whereas patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27-4.76, P < 0.001). NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality. © 2014 by the 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): April 2024

Publication date (Electronic): 26 January 2024

Volume: 30

Issue: 2

Pages: 235-246

Affiliations

[1 ]Larner College of Medicine at the University of Vermont, Burlington, VT, USA

[2 ]Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA

[3 ]Burrell College of Osteopathic Medicine, Las Cruces, NM, USA

[4 ]Carver College of Medicine at the University of Iowa, Iowa City, IA, USA

[5 ]Harvard Medical School, Boston, MA, USA

[6 ]Stanford University, Stanford, CA, USA

[7 ]Lane Library, Stanford University School of Medicine, Stanford, CA, USA

[8 ]Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

[9 ]Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

[10 ]The Karsh Division of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA, USA

[11 ]Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

[12 ]National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China

[13 ]Division of Gastroenterology and Hepatology, Palo Alto Veterans Affairs Medical Center, Palo Alto, CA, USA

[14 ]Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA

Author notes

Corresponding author : Mindie H. Nguyen Division of Gastroenterology and Hepatology, Stanford University Medical Center, 780 Welch Road, Palo Alto, CA 94304, USA Tel: +1-650-498-6081, E-mail: mindiehn@ 123456stanford.edu

[*]

Co-first authors contributed equally.

Editor: Won Kim, Seoul Metropolitan Boramae Hospital, Korea

Author information

Mindie H. Nguyen http://orcid.org/0000-0002-6275-4989

Article

Publisher ID: cmh-2023-0485

DOI: 10.3350/cmh.2023.0485

PMC ID: 11016479

PubMed ID: 38281814

SO-VID: 5e611626-a897-45f4-a1d1-49cbe5d86750

License:

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.

History

Date received : 20 November 2023

Date revision received : 8 January 2024

Date accepted : 25 January 2024

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Global incidence of adverse clinical events in non-alcoholic fatty liver disease: A systematic review and meta-analysis

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Karger: Gastroenterology

Most cited references 36

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

NAFLD: a multisystem disease.

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.

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