Prevalence and determinants of non-alcoholic fatty liver disease in lifelines: A large Dutch population cohort

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Abstract

Background & aims

Non-alcoholic fatty liver disease is an increasing health issue that develops rather unnoticed with obesity, type 2 diabetes mellitus and metabolic syndrome. We investigated prevalence, determinants and associated metabolic abnormalities of non-alcoholic fatty liver disease in the largest population-based cohort to date.

Methods

Biochemical characteristics, type 2 diabetes mellitus and metabolic syndrome were determined in the Lifelines Cohort Study (N = 167,729), a population-based cohort in the North of the Netherlands. Non-alcoholic fatty liver disease was defined as Fatty Liver Index (FLI)≥60. Exclusion criteria were age <18 years, immigrants, missing data to assess FLI and metabolic syndrome, excessive alcohol use, previous-diagnosed hepatitis or cirrhosis and non-fasting blood sampling.

Results

Out of 37,496 included participants (median age 44 years, 62.1% female), 8,259 (22.0%) had a FLI≥60. Individuals with a FLI≥60 were more often male, older, obese, had higher levels of hemoglobinA1c, fasting glucose, liver enzymes, total cholesterol, low-density lipoprotein cholesterol, triglycerides, c-reactive protein and leucocytes and lower high-density lipoprotein cholesterol (all P<0.0001). Participants with a FLI≥60 showed higher prevalence of type 2 diabetes mellitus (9.3% vs. 1.4%), metabolic syndrome (54.2% vs. 6.2%), impaired renal function (20.1% vs. 8.7%) and cardiovascular disease (4.6% vs. 1.6%) (all P<0.0001). Multivariable logistic analysis showed that smoking, hemoglobin, leucocytes, c-reactive protein, platelets, alanine aminotransferase, alkaline phosphatase, albumin, impaired renal function (OR 1.27, 95%CI 1.15–1.41), metabolic syndrome (OR 11.89, 95%CI 11.03–12.82) and its individual components hyperglycemia (OR 2.53, 95%CI 2.34–2.72), hypertension (OR 1.89, 95%CI 1.77–2.01) and reduced high-density lipoprotein cholesterol (OR 3.44, 95%CI 3.22–3.68) were independently associated with suspected non-alcoholic fatty liver disease (all P<0.0001).

Conclusion

Twenty-two percent (22.0%) of the population in the North of the Netherlands is suspected to suffer from non-alcoholic fatty liver disease, coinciding with a significant increased risk of type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease and impaired renal function.

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Most cited references 23

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Long-term follow-up of patients with nonalcoholic fatty liver.

Nila Rafiq, Chunhong Bai, Yun Fang … (2009)

Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH) convincingly. NASH is the only subtype of NAFLD that has been shown to progress relatively, although these findings were reported from studies with short follow-up periods. We assessed the long-term outcomes of a NAFLD cohort. Patients with NAFLD established by biopsy were identified in databases and categorized as NASH or non-NASH. Mortality data and causes of death were obtained from National Death Index Plus. The nonparametric Kaplan-Meier method with log-rank test and multivariate analyses with a Cox proportional hazard model were used to compare different NAFLD subtypes and to identify independent predictors of overall and liver-related mortality. Of 173 NAFLD patients (age at biopsy, 50.2 +/- 14.5 y; 39.9% male; 80.8% Caucasian; 28.9% with type II diabetes), 72 (41.6%) had NASH and 101 (58.4%) had non-NASH NAFLD. Over the follow-up period, the most common causes of death were coronary artery disease, malignancy, and liver-related death. Although overall mortality did not differ between the NAFLD subtypes, liver-related mortality was higher in patients with NASH (P < .05). Independent predictors of liver-related mortality included histologic NASH, type II diabetes, older age at biopsy, lower albumin levels, and increased levels of alkaline phosphatase (P < .05). This long-term follow-up evaluation of NAFLD patients confirms that NASH patients have increased liver-related mortality compared with non-NASH patients. In addition, patients with NAFLD and type II diabetes are especially at risk for liver-related mortality.

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Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population.

Angela Favuzzi, Amalia Gastaldelli, Allan Flyvbjerg … (2009)

Patients with fatty liver (FL) disease have a high risk of developing diabetes and cardiovascular diseases. The aim was to evaluate the association between FL, insulin resistance (IR), coronary heart disease (CHD) risk, and early atherosclerosis in a large European population (RISC Study). In 1,307 nondiabetic subjects (age 30-60 years) recruited at 19 centers, we evaluated liver enzymes, lipids, insulin sensitivity (by euglycemic-hyperinsulinemic clamp), glucose tolerance (by 75 g oral glucose tolerance test), carotid atherosclerosis as intima media thickness (IMT), CHD risk by the Framingham Heart study prediction score, and physical activity (by accelerometer). The presence of FL was estimated using the fatty liver index (FLI; >60, likelihood >78% presence FL; FLI 91% absence of FL). Subjects were divided into three groups: G1: FLI 60 (n = 234), G2: intermediate group (n = 465). Compared to G1, G3 included more men (70% versus 24%) and people with impaired glucose tolerance (23% versus 5%). IMT increased with FLI (G3 = 0.64 +/- 0.08 versus G1 = 0.58 +/- 0.08 mm, P < 0.0001). FLI was associated with increased CHD risk (r = 0.48), low-density lipoprotein cholesterol (r = 0.33), alanine aminotransferase (r = 0.48), aspartate aminotransferase (r = 0.25), systolic blood pressure (r = 0.39) and IMT (r = 0.30), and reduced insulin sensitivity (r = -0.43), high-density lipoprotein cholesterol (r = -0.50), adiponectin (r = -0.42), and physical activity (r = -0.16, all P < 0.0001). The correlations hold also in multivariate analysis after adjusting for age, gender, and recruiting center. In middle-age nondiabetic subjects, increased IMT, CHD risk, and reduced insulin sensitivity are associated with high values of FLI.

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Minireview: adiposity, inflammation, and atherogenesis.

Mark Law, W Hsueh, Calum Lyon (2003)

Adipose tissue is a dynamic endocrine organ that secretes a number of factors that are increasingly recognized to contribute to systemic and vascular inflammation. Several of these factors, collectively referred to as adipokines, have now been shown regulate, directly or indirectly, a number of the processes that contribute to the development of atherosclerosis, including hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Several adipokines are preferentially expressed in visceral adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Not surprisingly, approaches that reduce adipose tissue depots, including surgical fat removal, exercise, and reduced caloric intake, improve proinflammatory adipokine levels and reduce the severity of their resultant pathologies. Systemic adipokine levels can also be favorably altered by treatment with several of the existing drug classes used to treat insulin resistance, hypertension, and hypercholesterolemia. Greater understanding of adipokine regulation, however, should result in the design of improved treatment strategies to control disease states associated with increase adiposity, an important outcome in view of the growing worldwide epidemic of obesity.

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Author and article information

Contributors

Salvatore Petta: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 2 February 2017

Publication date Collection: 2017

Volume: 12

Issue: 2

Electronic Location Identifier: e0171502

Affiliations

[1 ]Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

[2 ]Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

[3 ]Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Università degli Studi di Palermo, ITALY

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceptualization: EB MA TS RD KNF BA HB.
Data curation: EB MA BA.
Formal analysis: EB MA.
Investigation: EB.
Methodology: EB MA BA HB.
Supervision: HB.
Validation: MA BA.
Visualization: EB.
Writing – original draft: EB.
Writing – review & editing: EB MA TS RD KNF BA HB.

* E-mail: e.h.van.den.berg@ 123456umcg.nl

Article

Publisher ID: PONE-D-16-42638

DOI: 10.1371/journal.pone.0171502

PMC ID: 5289609

PubMed ID: 28152105

SO-VID: 829d0c49-c934-4805-98d0-8e3a751c8c45

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 October 2016

Date accepted : 20 January 2017

Page count

Figures: 1, Tables: 4, Pages: 15

Funding

The Lifelines Cohort Study was supported by the Netherlands Organization for Scientific Research [grant 175.010.2007.006]; the Economic Structure Enhancing Fund of the Dutch government; the Ministry of Economic Affairs, Education, Culture and Science and Health, Welfare and Sports; the Northern Netherlands Collaboration of Provinces; the Province of Groningen; University Medical Center Groningen; the University of Groningen; the Dutch Kidney Foundation; the Dutch Diabetes Research Foundation and the National Consortium for Healthy Ageing and the BioSHaRE-EU consortium (KP7, project reference 261433). The funders had no role in study design, data collection and analyses, decision to publish, or preparation of the manuscript.

Custom metadata

Data Availability The manuscript is based on data from the Lifelines cohort study. Lifelines adheres to standards for open data availability. The data catalogue of Lifelines is publicly accessible www.lifelines.net. All international researchers can apply for data at the Lifelines research office. The Lifelines system allows access for reproducibility of the study results.

Prevalence and determinants of non-alcoholic fatty liver disease in lifelines: A large Dutch population cohort

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Abstract

Background & aims

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Conclusion

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PLOS Climate

Most cited references 23

Long-term follow-up of patients with nonalcoholic fatty liver.

Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population.

Minireview: adiposity, inflammation, and atherogenesis.

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