key: cord-0078607-5faxxeax authors: Zhong, Lixian; Wu, Chutian; Li, Yuting; Zeng, Qiuting; Lai, Leizhen; Chen, Sisi; Tang, Shaohui title: Nonalcoholic fatty liver disease and health outcomes: An umbrella review of systematic reviews and meta-analyses date: 2022-05-19 journal: Ther Adv Chronic Dis DOI: 10.1177/20406223221083508 sha: bf988e713b6290674803e0d2001ae3ae5ff20527 doc_id: 78607 cord_uid: 5faxxeax PURPOSE: A large number of systemic reviews and meta-analyses have explored the relationship between nonalcoholic fatty liver disease (NAFLD) and multiple health outcomes. The aim of this study is to conduct an umbrella review to assess the strength and evidence for the association between NAFLD and health outcomes. METHODS: We systematically identified the present meta-analyses of observational studies reporting an association between NAFLD and health outcomes. For each meta-analysis, we assessed the quality with AMSTAR2 and graded the epidemiologic evidence. RESULTS: Fifty-four articles comprising 111 unique meta-analyses were included in this study. Eighty-five unique outcomes showed significant associations (P ← 0.05), whereas 26 unique outcomes showed insignificant associations, and we cannot assess the epidemiologic evidence. For 85 significant health outcomes, four outcomes (carotid intima-media thickness (C-IMT), peak A velocity, left ventricle end-diastolic diameter, incident chronic kidney disease (CKD) in adult patients) was graded as high quality of evidence, 23 outcomes were graded as the moderate quality of evidence, and the remaining 58 outcomes were graded as weak quality of evidence. Fourty-seven (87.03%) studies showed critically low methodological quality. CONCLUSION: In this umbrella review, only four statistically significant health outcomes showed high epidemiologic evidence. NAFLD seems to relate to an increased risk of C-IMT, peak A velocity, left ventricle end-diastolic diameter, and incident CKD in adult patients. The global prevalence of nonalcoholic fatty liver disease (NAFLD) has only been increasing in the population and suspect to increase in the future leading to increase global burden. NAFLD affects up to 25% of adults, up to 3~10% of the Western pediatric population and increases up to 70% among obese children. 1 Many research studies have demonstrated how NAFLD can contribute to several disease processes including hepatic, extrahepatic diseases, and overall increase in mortality. 2, 3 It is becoming the most common and major cause of chronic liver disease worldwide, especially in high-income countries, resulting in considerable liver-related disease such as hepatocellular carcinoma (HCC), 4 cryptogenic liver cirrhosis, 5 and liver-specific mortality. 6 It is also a major cause of extrahepatic disease with earlier studies demonstrating that NAFLD also contributed to the risk of cardiovascular diseases 7, 8 and diabetes. 9 The risk factors for cardiovascular diseases and diabetes are also known for metabolic syndrome. According to Lonardo et al., 10 NAFLD is not only a manifestation but also a precursor of the metabolic syndrome. In recent research studies, there has been further investigation regarding NAFLD association with other diseases. A great number of studies and meta-analyses have journals.sagepub.com/home/taj 3 more than one critical weakness with or without critical defects is considered critically low methodologic quality. Discrepancies between AMSTAR 2 scores were resolved by discussion. We classified the evidence from meta-analyses of observational studies with the parameters that have been applied in various fields. [22] [23] [24] [25] [26] The parameters consist of the following criteria: (1) precision of the estimate (p value for the estimate ﹤ 0.001 27, 28 and the number of cases ⩾1000; (2) no heterogeneity (I 2 ﹤ 50% and p value for Cochran Q-test > 0.10); (3) no evidence of smallstudy effects (p value for Egger's test > 0.10). The strength of epidemiologic evidence was categorized into high (if all these criteria were satisfied), moderate (if p value for estimate ﹤ 0.001 with a maximum of 1 criterion was not satisfied), or weak (p value for estimate ﹤ 0.05 with all other cases). If the p value for estimate > 0.05, the evaluation of evidence quality was not applicable. According to the extracted raw data from each published study, we recalculated the missing data (ig. heterogeneity and publication bias) with a random-effects model whenever possible. When the p value was﹤0.05, the total impacts of pooled meta-analyses were considered significant. I 2 test and Q test were used to evaluate the heterogeneity between studies and publication bias was calculated by Egger's test. The p value ﹤ 0.1 for heterogeneity and publication bias were both considered significant. The results of systematic research and selection of eligible meta-analyses are summarized in Figure 1 . Overall, a total of 2200 research articles were investigated from PubMed (n = 1295), Web of Science (n = 862), and Cochrane database (n = 43). After excluding the 17 articles and 53 overlapping meta-analyses (Supplementary Table 1 ), 54 articles with 111 unique health outcomes were inclu ded (Table 1 ). The publication dates of these studies range from 2013 through 2021. Among the meta-analyses included in our umbrella review, the median number of primary studies was 7 (range: , the medium number of participants was 19,274 (range: 146-613,715 ) and the median number of cases was 1444 (range: 448 ). As we see in Figure 2 , health outcomes associated with NAFLD relate to the following categories of diseases: cardiovascular disorders (n = 36), cerebral and cerebrovascular disease (n = 5), skeletal system disorders (n = 9), mortality (n = 8), metabolic disorders (n = 3), digestive disorders (n = 20), nephrological disorders (n = 3), urological disorders (n = 2), serum marker disorders (n = 10), respiratory system disorders (n = 3), and other health outcomes (n = 12) ( Figure 2 ). Among 111 unique meta-analyses, 85 (76.58%) reported significant summary outcomes (p ﹤ 0.05) and the remaining 26 (23.42%) metaanalyses showed no significant association with NAFLD. According to the statistically significant outcomes, it can be concluded that NAFLD may increase the risk of a wide variety of diseases and have harmful effects on human health. According to Table 1 , we recalculated the two results of two articles 34,44 because they did not report the outcomes of heterogeneity. However, owing to the lack of raw data in one article, 46 we failed to recalculate the I 2 and the p value for the Cochran Q-test by random or fixed model, so the heterogeneity was not able to be evaluated. Among the 111 unique meta-analyses, only 26 (23.42%) health outcomes indicated no heterogeneity (I 2 ﹤ 50% and p value for Cochran Q-test ⩾ 0.1), whereas 85 (76.58%) health outcomes showed significant heterogeneity (I 2 ⩾ 50% and p value for Cochran Q-test ﹤ 0.1). Fifty-three outcomes were recalculated using the Egger's test through which the raw data in each included meta-analysis to evaluate for potential publication bias. Due to the small number of studies, there were still 21 outcomes in 15 articles that could not be recalculated using the Egger's test, 32, 40, 49, [57] [58] [59] 61, 65, 67, [70] [71] [72] 74 The 16 items including in AMSTAR 2 and the result of the methodological qualities assessment of the 54 included articles are presented in Table 2 . Only 7 (12.96%) articles were assessed to be low methodological quality, and the remaining 47 (87.04%) articles were assessed to be critically low ( Figure 3 ). It is worthy to note that there were no high/moderate methodological quality based on the AMSTAR 2 criteria. The major critical flaws were the absence of registered protocol (n = 40, 75.47%), the inadequacy of the literature search (n = 52, 96.30%) and without the list for excluding primary studies (n = 39, 72.22%). The results of epidemiologic evidence are shown in Table 3 . According to the criteria mentioned above, the assessment of epidemiologic evidence was not applicable for 26 (23.42%) health outcomes because their p value for pooled effects were more than 0.05 which was not statistically significant. The relevant criteria were considered to be not satisfied if a meta-analysis lacked the result of heterogeneity and publication bias. Among the remaining 85 statistically significant health outcomes, only 4 (3.60%) outcomes were rated as high epidemiologic evidence, 23 (20.72%) outcomes showed moderate Figure 4 ). Our umbrella review provides a comprehensive overview of the association between NAFLD and other health outcomes based on the existing evidence from identified 54 observational studies with 111 unique outcomes. We also critically evaluated the strength of evidence for all these associations with the criteria broadly applied to assess the epidemiologic evidence in the various field [22] [23] [24] [25] [26] and the quality of methodology of each publication, including in the current review. We found that NALFD increased the risk of 85 health outcomes that contained cardiovascular disorders, cerebral and cerebrovascular disorders, digestive disorders, nephrological disorders, urological disorders, metabolic disorders, mortality, skeletal system disorders, serum marker disorders, respiratory system disorders, and other health outcomes. However, 26 health outcomes had no relationship with NALFD and could not be assessed the epidemiologic evidence in this study. Only four outcomes (carotid intimal medial thickness (C-IMT), peak A velocity, left ventricle end-diastolic diameter (LVEDD), and incident CKD in adult patients) showed high epidemiologic evidence. The 81 remaining associations were either rated as moderate epidemiologic evidence or weak epidemiologic evidence. Heterogeneity and small-study effects were the two main reasons for the evidence rating downgrade in our study. NAFLD increased C-IMT which is considered as a marker of subclinical atherosclerosis with high epidemiologic evidence in the review. The potential mechanism seems to relate to high oxidative stress caused by steatosis-stimulated fatty-acid oxidation in the liver, increased insulin resistance, and macrophage activation. 7, 83, 84 Through early detection and intervention, subclinical atherosclerosis can be controlled and even reversed. 85 Therefore, for NAFLD, it is important to identify the C-IMT earlier. The cardiac function and Wijarnpreecha et al. 51, 52, 53 Mantovani et al. 16, 59, 60 High: 0-1 non-critical weakness. The systematic review provides an accurate and comprehensive summary of the results of the available studies that address the question of interest. >1 non-critical weakness. The systematic review has more than one weakness, but no critical flaws. It may provide an accurate summary of the results of the available studies that were included in the review. Low: 1 critical flaw with or without non-critical weaknesses. The review has a critical flaw and may not provide an accurate and comprehensive summary of the available studies that address the question of interest. Critically low: >1 critical flaw with or without non-critical weaknesses. The review has more than one critical flaw and should not be relied on to provide an accurate and comprehensive summary of the available studies. No 2, 4, 7, 9, 11, 13 , and 15 are the critical items. Table 2 . (Continued) journals.sagepub.com/home/taj 17 structure were also damaged by NAFLD. We demonstrated the association between NAFLD and peak A velocity and LVEDD was both graded as high. In NAFLD patients, the role of proinflammatory cytokines, insulin resistance, and dyslipidemia acts together on the cardiac metabolism and function, [86] [87] [88] which directly causes the impairment on the heart. In 2020, a large database analysis in Germany, comprised of 48,057 patients with NAFLD and 48,057 patients without NAFLD, supported that NAFLD constitutes an independent risk factor for CKD. 89 Similarly, in our umbrella review, the incidence of CKD was also increased by NAFLD with high epidemiologic evidence. There exists a common pro-inflammatory and profibrotic mechanism of disease progression in both NAFLD and CKD; furthermore, kidney-liver crosstalk also appears in NAFLD. 89 In addition to insulin resistance, pro-inflammatory factors, oxidative stress, the rein-angiotensin-aldosterone system also plays a role in the pathogenesis. [90] [91] [92] We noted that no study included in this umbrella review showed high/moderate methodologic evidence and only seven studies showed low methodological quality according to AMSTAR 2 criteria. The most critical flaws were the absence of registered protocol, the literature search's inadequacy, and the list for excluding individual studies. Eighty-five outcomes showed remarkable heterogeneity between studies. We concluded that this may be caused by several factors such as NAFLD severity, sex, the diagnosis of NAFLD, the study design, and body mass index, resulting in unreliable results. Among 111 health outcomes, 19 outcomes presented publication bias detected by Egger's test. The main reason for publication bias is that positive results are easier to publish than negative results, leading to incomplete literature included in the meta-analysis. Another common reason is that the study sample size is too small. Our umbrella review had several strengths. To our knowledge, it is the first umbrella review of observational meta-analysis and provides a comprehensive overview of the associations of NAFLD and health outcomes. A strong search strategy and data extraction were performed by two authors independently which made the result more reliable. Furthermore, we used validated AMSTR 2 tool to evaluate the methodological quality in our umbrella review. However, several limitations should be considered in the interpretation of our umbrella review. We did not evaluate the quality of the primary studies because it was beyond the scope of the current umbrella review. We conducted the review based on the published meta-analyses with the largest number of studies at present, and we might have missed some individual studies, which could have an influence on the results. In this umbrella review, 21 health outcomes publication bias could not be assessed due to the limited number of primary studies (less than two) and missing data which indicates unreliable results. Thus, more research is needed to investigate these associations that were based on small number of included studies. Another limitation to consider is that we could not conduct the subgroup analysis in this study (eg. sex differences, pre-menopausal, and postmenopausal women) owing to lack of raw data. As comprehension evolves, sex differences, and menopausal status are increasingly apparent in the prevalence, risk factors, progression, and outcomes in NAFLD. Numerous studies have indicated compare to women, men have higher risk and prevalence of NAFLD. 93, 94 But the prevalence of NAFLD is equal in men and postmenopausal women. 95 A meta-analysis pointed out that after age 50, women have a higher risk of developing advanced fibrosis than men. 96 However, several studies have shown that women have a higher incidence of NAFLD in early menarche and a higher risk of NASH and advanced fibrosis. 97, 98 Almost all of the included meta-analyses did not distinguish between sex, pre-menopausal, and post-menopausal women in the included participants, which made it difficult to re-analyze the results according to the sex difference and menopausal status. However, we recognize the importance of sex difference and menopausal status and will focus on this aspect in future studies. In summary, 54 studies explored 111 unique health outcomes; only four outcomes showed high epidemiologic evidence with statistical significance. 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The authors received no financial support for the research, authorship, and/or publication of this article. The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Consent statement and ethical approval are not required as the current study does not involve human participants and animal subjects. Shaohui Tang https://orcid.org/0000-0002-1859 -0876 The data used to support the findings of this study are included within the article. The primary data used to support the findings of this study are available from the corresponding author upon request. Supplemental material for this article is available online.