Insomnia and risk of nonalcoholic fatty liver disease: A systematic review and meta-analysisK Wijarnpreecha1, C Thongprayoon1, P Panjawatanan2, P Ungprasert3
1 Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA
2 Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
3 Department of Internal Medicine, Division of Rheumatology, Rochester, Minnesota, USA; Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
Keywords: Insomnia, meta.analysis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, sleep quality
Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic hepatitis and cirrhosis in Western countries as the prevalence of obesity has been steadily increasing over the past few decades. Pathology of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) which can ultimately progress to cirrhosis. Metabolic syndrome and insulin resistance are the prime risk factors for NAFLD., Other risk factors include hypertension, dyslipidemia, polycystic ovary syndrome, and hypothyroidism.,
Insomnia and excessive daytime sleepiness (EDS), defined as the inability to maintain wakefulness and alertness during the major waking episodes of the day with sleep occurring unintentionally almost daily for at least 3 months, are ones of the most common sleep-related disorders in adults., Many studies have shown an association between both conditions and adverse health outcomes including the increased risk of psychiatric disorders, drug abuses, diabetes, cardiovascular disease as well as increased incidence of motor vehicle accident.,,,,
Interestingly, insomnia and EDS could also increase the risk of NAFLD as observed in several epidemiologic studies.,,,,,, Nonetheless, the results of those studies were inconsistent. To further investigate this possible association, we conducted this systematic review and meta-analysis of observational studies reporting the risk of NAFLD among those who had insomnia or EDS.
Two investigators (K.W. and P.U.) independently searched published studies indexed in MEDLINE and EMBASE database from inception to December 2015 using the search strategy that included the terms for “sleep” and “NAFLD” as described in [Online Supplementary Data 1 available online [Additional file 1]]. No language limitation was applied. A manual search for additional studies using references of selected retrieved articles was also performed.
The inclusion criteria were as follows: (1) case–control, cross-sectional, or cohort studies evaluating the association between insomnia or EDS and NAFLD, (2) odds ratios (ORs), risk ratios, hazard ratios or standardized incidence ratio with 95% confidence intervals (CI) were provided, and (3) participants without insomnia or EDS were used as comparators in cohort study while participants without NAFLD were used as comparators in case–control and cross-sectional study.
Study eligibility was independently determined by the two investigators noted above. Differences in the determination of study eligibility were resolved by mutual consensus. The quality of each study was also independently evaluated by each investigator using Newcastle–Ottawa quality assessment scale. This scale evaluated each study in three domains including the selection of the participants, the comparability between the groups and the ascertainment of the exposure for case–control study and the outcome of interest for cohort study. The modified Newcastle–Ottawa scale as described by Herzog et al. was used for cross-sectional study.
A standardized data collection form was used to extract the following data from each study: Title of the study, name of the first author, year of study, year of publication, country of origin, number of participants, demographic data of the participants, methods used to identify and verify the insomnia, EDS and NAFLD, adjusted effect estimates with 95% CI and covariates that were adjusted in the multivariate analysis.
To ensure the accuracy, this data extraction process was independently performed by all investigators. Data discrepancy was resolved by referring to the original articles.
Data analysis was performed using Review Manager 5.3 Software from the Cochrane Collaboration (London, United Kingdom). Adjusted point estimates and standard errors from the individual study were combined using the generic inverse variance method of DerSimonian and Laird, which assigned the weight of each study based on its variance. In light of the high likelihood of between-study variance because of different study designs and populations, we used a random-effect model rather than a fixed-effect model. Cochran's Q test and I2 statistic were used to determine the between-study heterogeneity. A value of I2 of 0%–25% represents insignificant heterogeneity, >25% but <50% represents low heterogeneity, >50% but <75% represents moderate heterogeneity, and >75% represents high heterogeneity.
Our search strategy yielded 2117 potentially relevant articles (781 articles from MEDLINE and 1,336 articles from EMBASE). After the exclusion of 723 duplicated articles, 1394 of them underwent title and abstract review. A total of 1341 articles were excluded at this stage since they were case report, letter to editor, review article or interventional study, leaving 53 articles for a full-length article review. Forty of them were excluded since they did not report the outcome of interest while six articles were excluded since they were descriptive studies without comparators. Therefore, seven studies (three cross-sectional studies and four case–control studies) met our eligibility criteria and were included in the meta-analysis.,,,,,, [Figure 1] outlines the literature review and study selection process. The characteristics and quality assessment of the included studies of insomnia and EDS are described respectively in [Table 1] and [Table 2]. PRISMA (Preferred reporting Items for Systematic Reviews and Meta-Analysis) is provided as [Online Supplementary Data 2 available online [Additional file 2] ]. It should be noted that the inter-rater agreement for the quality assessment was high with the kappa statistics of 0.75.
We found a significantly increased risk of NAFLD among participants with insomnia with the pooled OR of 1.13 (95% CI, 1.00–1.27), as shown in [Figure 2]. The statistical heterogeneity was moderate with an I2 of 62%. We also found an increased risk of NAFLD among participants with EDS with the pooled OR of 2.21 even though the 95% CI was wider and did not reach statistical significance (95% CI, 0.84–5.82), as shown in [Figure 3]. The statistical heterogeneity was moderate with an I2 of 62%.
Evaluation for publication bias
We did not perform an evaluation for publication bias as the number of studies included in the meta-analyses was too small.
The association between insomnia/EDS and risk of NAFLD has been observed in epidemiologic studies even though the results were inconsistent. This meta-analysis was conducted with the aims to summarize all available data. We found a small but significantly increased risk of NAFLD among participants who had insomnia compared to those with good sleeping. We also found an increased risk of NAFLD among participants with EDS even though the result did not reach statistical significance due to a smaller number of included studies. The mechanism behind this association remains unknown, but there are some potential explanations.
First, it has been shown that several inflammatory cytokines essential for the pathogenesis of NAFLD, such as interleukin-6 and tumor necrotic factor alpha, are inducible by lack of sleep.,, These cytokines can increase adipocyte lipolysis, resulting in hepatic overflow of free fatty acid, and impaired insulin signaling. Second, insomnia may increase appetite as a result of hormonal changes such as increased ghrelin level and decreased leptin level, leading to more calories intake and obesity, the major risk factor for NAFLD., Third, insomnia and EDS are associated with fatigue. Therefore, those with insomnia or EDS might be less physically active and are at higher risk of obesity and metabolic syndrome.
Although the quality of included studies was high as reflected by the high Newcastle–Ottawa scores, we acknowledged that there were some limitations.
First, data on insomnia and EDS may be less reliable as most included studies used self-administered questionnaires. Second, the statistical heterogeneity was moderate in this meta-analysis. We suspect that the differences in study designs, populations, and methods used to verify NAFLD were responsible for this inter-study variability. Third, about half of the included studies were cross-sectional studies that would not allow us to establish a temporal relationship between NAFLD and sleep disturbance. It is possible that NAFLD might have negative effects on physiology of sleep and the insomnia/EDS are a consequence of NAFLD, not risk factors for NAFLD. In fact, this study is a meta-analysis of observational studies that, at best, could only demonstrate an association but cannot prove causality as unknown confounders could play a certain role behind the association.
In summary, an increased risk of NAFLD was observed among participants who had insomnia or EDS. Whether this association is causal remains unclear. Further investigations are required to establish the role of sleep for the prevention of NAFLD.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]