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Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis

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Summary

Background

Although non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, it is increasingly being identified in non-obese individuals. We aimed to characterise the prevalence, incidence, and long-term outcomes of non-obese or lean NAFLD at a global level.

Methods

For this systematic review and meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library from inception to May 1, 2019, for relevant original research articles without any language restrictions. The literature search and data extraction were done independently by two investigators. Primary outcomes were the prevalence of non-obese or lean people within the NAFLD group and the prevalence of non-obese or lean NAFLD in the general, non-obese, and lean populations; the incidence of NAFLD among non-obese and lean populations; and long-term outcomes of non-obese people with NAFLD. We also aimed to characterise the demographic, clinical, and histological characteristics of individuals with non-obese NAFLD.

Findings

We identified 93 studies (n=10 576 383) from 24 countries or areas: 84 studies (n=10 530 308) were used for the prevalence analysis, five (n=9121) were used for the incidence analysis, and eight (n=36 954) were used for the outcomes analysis. Within the NAFLD population, 19·2% (95% CI 15·9–23·0) of people were lean and 40·8% (36·6–45·1) were non-obese. The prevalence of non-obese NAFLD in the general population varied from 25% or lower in some countries (eg, Malaysia and Pakistan) to higher than 50% in others (eg, Austria, Mexico, and Sweden). In the general population (comprising individuals with and without NAFLD), 12·1% (95% CI 9·3–15·6) of people had non-obese NAFLD and 5·1% (3·7–7·0) had lean NAFLD. The incidence of NAFLD in the non-obese population (without NAFLD at baseline) was 24·6 (95% CI 13·4–39·2) per 1000 person-years. Among people with non-obese or lean NALFD, 39·0% (95% CI 24·1–56·3) had non-alcoholic steatohepatitis, 29·2% (21·9–37·9) had significant fibrosis (stage ≥2), and 3·2% (1·5–5·7) had cirrhosis. Among the non-obese or lean NAFLD population, the incidence of all-cause mortality was 12·1 (95% CI 0·5–38·8) per 1000 person-years, that for liver-related mortality was 4·1 (1·9–7·1) per 1000 person-years, cardiovascular-related mortality was 4·0 (0·1–14·9) per 1000 person-years, new-onset diabetes was 12·6 (8·0–18·3) per 1000 person-years, new-onset cardiovascular disease was 18·7 (9·2–31·2) per 1000 person-years, and new-onset hypertension was 56·1 (38·5–77·0) per 1000 person-years. Most analyses were characterised by high heterogeneity.

Interpretation

Overall, around 40% of the global NAFLD population was classified as non-obese and almost a fifth was lean. Both non-obese and lean groups had substantial long-term liver and non-liver comorbidities. These findings suggest that obesity should not be the sole criterion for NAFLD screening. Moreover, clinical trials of treatments for NAFLD should include participants across all body-mass index ranges.

Funding

None.

Introduction

Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the global population and is associated with metabolic derangements such as diabetes, obesity, hyperlipidaemia, and hypertension.1 NAFLD can progress from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, hepatocellular carcinoma, and death.1 NAFLD has surpassed viral hepatitis as the leading cause of morbidity due to chronic liver disease in western countries, given the recent therapeutic advances for both chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV). The prevalence of NAFLD has also increased in the other parts of the world, such as Asia.2 Additionally, NAFLD is increasingly being recognised in non-obese individuals, who might even have worse outcomes than obese individuals with NAFLD, with more rapid development of cirrhosis.3, 4, 5, 6

Therefore, we aimed to characterise the prevalence of, and factors associated with, non-obese or lean NAFLD at a global level, the incidence of NAFLD in non-obese individuals, and the long-term clinical sequelae of NAFLD in this population. Such data could help health-care systems develop appropriate guidance and interventions to treat this liver disease.

Research in context

Evidence before this study

Non-alcoholic fatty liver disease (NAFLD) affects about 25% of the global population. Although commonly associated with obesity, NAFLD is increasingly being identified in non-obese individuals. However, data on the global prevalence of non-obese NAFLD and its associated outcomes are scarce. Before undertaking this study, we searched four databases (PubMed, Embase, Scopus, and the Cochrane Library) using the search terms “NAFLD” AND “Non-obese” without any language restrictions, for articles published from database inception to May 1, 2019. No meta-analysis of such a study has been published.

Added value of this study

In this systematic review and meta-analysis, we estimated that the overall prevalence of non-obese NAFLD was 40·8% among the NAFLD population and 12·1% in the general population. The prevalence of lean NAFLD was 19·2% among the NAFLD population and 5·1% in the general population. The incidence of NAFLD among non-obese people was 24·6 per 1000 person-years. Among people with non-obese or lean NALFD, about 39·0% had non-alcoholic steatohepatitis (NASH) and 29·2% had significant fibrosis; incidence of all-cause mortality was 12·1 per 1000 person-years, of liver-related mortality was 4·1 per 1000 person-years, of cardiovascular-related mortality was 4·0 per 1000 person-years, incidence of new-onset hypertension was 56·1 per 1000 person-years, new-onset diabetes was 12·6 per 1000 person-years, and new-onset cardiovascular disease was 18·7 per 1000 person-years.

Implications of all the available evidence

Around 40% of people with NAFLD are not obese but they have high mortality and are just as metabolically unhealthy as obese people with NAFLD; almost 40% of non-obese people with NAFLD have NASH and almost 30% have significant fibrosis. Therefore, screening for NAFLD should consider other metabolic risks besides bodyweight, and clinical trials of treatments for NAFLD should include participants across all body-mass index ranges.

Section snippets

Search strategy and selection criteria

This systematic review and meta-analysis was done in accordance with PRISMA guidelines (appendix pp 2–3).7 We searched for published studies in PubMed (including MEDLINE), Embase, Scopus, and the Cochrane Library from inception to May 1, 2019, using search terms that were chosen in collaboration with an experienced medical librarian (CDS) so that as many relevant articles for each hypothesis could be retrieved.8

Our search term for PubMed (from inception to May 1, 2019) was as follows:

Results

We retrieved 2806 articles using our search method. After removing duplicates, 1528 records were retained (figure 1). We excluded 1212 ineligible titles and abstracts using the aforementioned exclusion criteria. Consequently, we retained and evaluated the full text of 316 published articles. After adding 42 studies from the bibliographies of relevant articles and excluding 265 ineligible citations, 93 reports were included in the study analysis. These 93 reports covered 24 countries and areas:

Discussion

We found that the global prevalence of non-obese NAFLD among the NAFLD population was just over 40% and the prevalence of non-obese NAFLD in non-obese population was almost 20%, suggesting that non-obese NAFLD contributes to a large share of the burden of this chronic liver disease. Additionally, contrary to the common belief that non-obese NAFLD is more prevalent among Asian countries, we found that Europe had the highest (about 50%) and eastern Asia had the lowest prevalence of non-obese

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