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. 2022 May 19;13:20406223221083508. doi: 10.1177/20406223221083508

Nonalcoholic fatty liver disease and health outcomes: An umbrella review of systematic reviews and meta-analyses

Lixian Zhong 1,*, Chutian Wu 2,*, Yuting Li 3,*, Qiuting Zeng 4, Leizhen Lai 5, Sisi Chen 6, Shaohui Tang 7,✉
PMCID: PMC9127863  PMID: 35620184

Abstract

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.

Keywords: health outcomes, meta-analysis, nonalcoholic fatty liver disease, umbrella reviews

Introduction

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 diseases7,8 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 demonstrated that NAFLD may increase the risk of various diseases, including gastrointestinal diseases,11–13 chronic kidney diseases (CKD),14,15 atrial fibrillation, 16 and all-cause and cause-specific mortality, 17 indicating that NAFLD poses a threat to human health.

Although multiple investigations explored the correlation between NAFLD and other health outcomes, the reported associations may be flawed. The magnitudes of the observed effects are affected by inherent biases such as selective bias, publication bias, and residual confounding.18,19 Despite many systematic reviews and meta-analyses that have examined NAFLD and other health outcomes, to our knowledge, there have been no systematic efforts to accurately summarize and critically appraise the evidence. Umbrella review is increasingly more important for overviewing the evidence of systematic and meta-analyses on a specific topic. An umbrella review focused on a specific disease that can provide important guidance and reliable evidence for prevention, diagnosis, and treatment. We performed an umbrella review of observational meta-analyses to comprehensively assess methodological quality, investigate potential bias, and evaluate the epidemiologic evidence of the associations between NAFLD and health information. We believe that this work can provide useful information about NAFLD and human health.

Materials and methods

We followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) protocols to research literature systematically. 20 Before beginning the umbrella review, we registered the protocol with PROSPERO (registration number: CRD42021279078).

Literature search

PubMed, Web of Science, and Cochrane Database of Systematic Reviews were searched from the initiation to September 2021. The search terms applied were (‘Meta-Analysis’ OR ‘metaanaly’ OR ‘meta-analy’ OR ‘Systematic review’ OR ‘systematic review’ AND ‘Nonalcoholic Fatty Liver Disease’ OR ‘NAFLD’ OR ‘Nonalcoholic Fatty Liver Disease’ OR ‘Fatty Liver, Nonalcoholic’ OR ‘Fatty Livers, Nonalcoholic’ OR ‘Liver, Nonalcoholic Fatty’ OR ‘Livers, Nonalcoholic Fatty’ OR ‘Nonalcoholic Fatty Live’ OR ‘Nonalcoholic Fatty Livers’ OR ‘Nonalcoholic Steatohepatitis’ OR ‘Nonalcoholic Steatohepatitides’ OR ‘Steatohepatitides, Nonalcoholic’ OR ‘Steatohepatitis, Nonalcoholic’). We also manually screened the reference to identify the eligible articles. LZ and WC independently conducted the literature search. Any discrepancies were discussed and resolved with ST.

Selection criteria

Two authors (LZ and CW) scrutinized independently the full texts of potentially eligible articles. Only the meta-analyses of the epidemiological studies examining the relationship between NAFLD and other health outcomes in humans were considered. Trials and meta-analyses of interventional trials were not available for our study. The protocols, abstracts of the conference, and letters to editors were also excluded. When several meta-analyses simultaneously reported the same health outcome, we included the one with the largest number of studies.

Data extraction

The data of included studies were extracted by two authors separately. For each eligible meta-analysis, we extracted the following information: the first author, publication year, the design of studies, the number of participants and cases, the effects sizes (SMD, WMD, MD, ORs, RRs, or HRs), the p values of pooled effects, Cochrane Q measurement, Egger ‘s test measurement and I 2 . When we met discrepancies, we resolved them through discussion.

Assessment of methodological quality

Two authors used AMSTAR 2, 21 which consists of 16 items, to assess the methodologic quality of each included meta-analysis independently. AMSTAR 2 is a strict and reliable measurement tool to evaluate the quality of systematic reviews and meta-analyses. According to the AMSTAR 2 scores, four grades (high, moderate, low, and critically low) were categorized to describe the result of methodologic quality. No or only one non-critical defect is considered high methodologic quality and more than one non-critical defect is considered moderate methodologic quality. Only one critical weakness with or without non-critical defects is considered low method quality and 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.

Evaluation of the evidence quality

We classified the evidence from meta-analyses of observational studies with the parameters that have been applied in various fields.22–26 The parameters consist of the following criteria: (1) precision of the estimate (p value for the estimate ← 0.00127,28 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 small-study 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.

Data analysis

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.

Results

Characteristics of the meta-analyses

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 included29–82 (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: 2–30), the medium number of participants was 19,274 (range: 146–613,715) and the median number of cases was 1444 (range: 44–36,448). 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%) meta-analyses 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.

Figure 1.

Figure 1.

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The PRISMA consort flow diagram of literature search and study selection.

Table 1.

Characteristics of the unique meta-analyses investigating the associations between NAFLD and multiple health outcomes.

Health outcomes Author Studies (n) NAFLD diagnosis Participants (n) Cases (n) Type of metric Effect size Heterogeneity Small-study effect
95% CI p value I 2 p value
Cardiovascular disorders
C-IMT in adult patients Madan et al. 33 20 observational studies Biopsy and US 19,274 8652 SMD 0.94 (0.78, 1.16) <0.001 0.0 0.754 0.14
Carotid plaque in adult patients Madan et al. 33 13 observational studies Biopsy and US 14,445 5399 OR 1.77 (1.21, 2.581) 0.003 0.0 0.561 0.76
C-IMT in pediatric patients Madan et al. 33 5 observational studies Biopsy and US 1121 312 SMD 1.08 (0.46, 1.71) 0.001 0.0 0.612 0.46
CAC Zhou et al. 54 5 cross-sectional studies and 2 cohorts Biopsy, US, and CT 29,531 12,606 OR 1.40 (1.22, 1.60) <0.00001 59.0 0.02 0.097*
Arterial stiffness Zhou et al. 54 4 cross-sectional studies Biopsy, US, and CT 50,369 10,867 OR 1.56 (1.24, 1.96) 0.0002 65.0 0.03 0.203*
Endothelial dysfunction Zhou et al. 54 3 cross-sectional studies Biopsy, US, and CT 426 280 OR 3.73 (0.99, 14.09) 0.05 67.0 0.05 0.019*
Subclinical atherosclerosis Ampuero et al. 31 4 cross-sectional studies and 6 cohort studies US 2932 NA OR 2.42 (1.98, 2.96) <0.001* 12.5 0.33 0.14
CAC score > 0 Jaruvongvanich et al. 37 12 cross-sectional studies US and CT NA NA OR 1.41 (1.26, 1.57) <0.001* 66.0 0.07 <0.01
CAC score > 100 Jaruvongvanich et al. 37 8 cross-sectional studies US and CT NA NA OR 1.24 (1.02, 1.52) >0.05* 42.0 0.10 0.62
Fatal CVD Targher et al. 41 7 cohort studies Biopsy, US, CT, and liver enzyme NA 1326 OR 1.31 (0.87, 1.97) 0.202 90.3 0.000 0.475
Fatal and non-fatal CVD Targher et al. 41 5 cohort studies Biopsy, US, CT, and liver enzyme NA 1272 OR 1.63 (1.06, 2.49) 0.025 83.0 0.000 0.274
Non-fatal CVD Targher et al. 41 5 cohort studies Biopsy, US, CT, and liver enzyme NA 385 OR 2.52 (1.52, 4.18) <0.001* 60.9 0.037 0.642
CAD Wu et al. 42 9 cross-sectional studies and 9 cohort studies Biopsy, US, and liver enzyme 20,198 NA HR 1.82 (1.23, 1.67) 0.002 57.2 0.096 0.248
CVD Veracruz et al. 81 12 cross-sectional studies, 16 cohort studies, and 2 case–control studies Biopsy, US, CT, and FLI 192,107 36,448 RR 1.78 (1.52, 2.08) <0.00001 95.0 <0.00001 0.185*
LVEF Borges-Canha et al. 55 14 cross-sectional studies Biopsy, US, and CT 25,338 17,583 MD –0.30 (–0.90, 0.30) 0.33 70.0 <0.00001 0.516*
Peak E velocity Borges-Canha et al. 55 8 cross-sectional studies Biopsy, US, and CT 17,605 15,160 MD –3.63 (–7.56, 8.98) 0.07 89.0 <0.00001 0.082*
E/e’ ratio Borges-Canha et al. 55 8 cross-sectional studies Biopsy, US, and CT 22,270 16,523 MD 1.05 (0.61, 1.50) <0.00001 93.0 <0.00001 0.228*
Peak A velocity Borges-Canha et al. 55 7 cross-sectional studies Biopsy, US, and CT 17,542 15,122 MD 3.55 (2.70, 4.39) <0.00001 4.0 0.4 0.976*
E/A ratio Borges-Canha et al. 55 12 cross-sectional studies Biopsy, US, and CT 25,149 17,461 MD –0.15 (–0.22, –0.88) <0.00001 94.0 <0.0001 0.845*
Isovolumic relaxation time Borges-Canha et al. 55 5 cross-sectional studies Biopsy, US, and CT 311 175 MD 10.00 (4.03, 15.97) 0.001 84.0 <0.0001 0.573*
Deceleration time Borges-Canha et al. 55 9 cross-sectional studies Biopsy, US, and CT 23,396 16,583 MD 13.04 (5.37, 20.71) 0.0009 89.0 <0.00001 0.001*
Left ventricle mass Borges-Canha et al. 55 6 cross-sectional studies Biopsy, US, and CT 18,785 15,093 MD 47.22 (33.25, 61.18) <0.00001 92.0 <0.00001 0.055*
Left ventricle end-diastolic diameter Borges-Canha et al. 55 8 cross-sectional studies Biopsy, US, and CT 19,482 16,192 MD 1.32 (0.93, 1.70) <0.00001 38.0 0.13 0.410*
Left ventricle end-systolic diameter Borges-Canha et al. 55 7 cross-sectional studies Biopsy, US, and CT 19,419 16,154 MD –0.31 (–1.28, 0.66) 0.53 93.0 <0.00001 0.402*
Left atrium diameter Borges-Canha et al. 55 8 cross-sectional studies Biopsy, US, and CT 20,704 16,334 MD 2.19 (1.04, 3.35) 0.0002 95.0 <0.00001 0.154*
Posterior wall thickness Borges-Canha et al. 55 7 cross-sectional studies Biopsy, US, and CT 19,428 16,160 MD 1.14 (0.75, 1.53) <0.00001 96.0 <0.00001 0.510*
Interventricular septum thickness Borges-Canha et al. 55 8 cross-sectional studies Biopsy, US, and CT 19,482 16,192 MD 1.06 (0.67, 1.45) <0.00001 94.0 <0.00001 0.738*
LV mass indexed to BSA Bonci et al. 32 4 cross-sectional studies Biopsy and US 254 160 SMD 0.84 (0.25, 1.41) <0.0001 78.8 <0.004 NA
LV mass indexed to height Bonci et al. 32 3 cross-sectional studies Biopsy and US 736 244 SMD 0.152 (–0.01, 0.32) 0.069 0.0 0.87 NA
EFT thickness Oikonomidou et al. 78 3 observational studies Biopsy 347 211 MD 1.17 (0.45, 1.89) <0.001 89.0 0.001 0.17*
GLS Oikonomidou et al. 78 3 observational studies Biopsy 146 67 MD –3.17 (–5.09, –1.24) <0.001 89.0 0.0001 0.875*
Diastolic cardiac dysfunction Wijarnpreecha et al. 51 - 53 12 cross-sectional studies US, CT, and ICD code 280,645 NA OR 2.02 (1.47, 2.79) <0.0001 89.0 <0.00001 0.0002
Cardiac conduction defect Wijarnpreecha et al. 71 3 cross-sectional studies US, CT, and ICD code 3651 NA OR 5.17 (1.34, 20.01) 0.02 96.0 <0.0001 NA
Atrial fibrillation Cai et al. 63 , 64 6 cohort studies US, CT, and FLI 613,715 7271 RR 1.19 (1.07, 1.31) 0.001* 54.0 0.05 0.227*
Epicardial adipose tissue Liu et al. 57 , 58 13 case–control studies NR 4540 2260 SMD 0.73 (0.51, 0.94) <0.001 88.6 0.000 NA
Hypertension and prehypertension Yao et al. 48 5 observational studies NR 36,534 NA OR 1.30 (1.14, 1.47) 0.000 65.6 0.002 0.001
Cerebral and cerebrovascular disease
Cerebrovascular accident Hu et al. 49 2 case–control studies and 7 cohort studies NR 6183 390 OR 2.32 (1.84, 2.93) <0.001 0.0 0.895 0.578
Ischemic stroke Hu et al. 49 2 case–control studies and 3 cohort studies NR 4009 313 OR 2.51 (1.92, 3.28) <0.001 0.0 0.828 0.001*
Cerebral hemorrhage Hu et al. 49 2 cohort studies NR 1980 51 OR 1.85 (1.05, 3.27) 0.034 0.0 0.544 NA
Stroke and cerebrovascular diseases Veracruz et al. 81 16 cohorts Biopsy, US, CT, and FLI 34,336 29,314 RR 2.08 (1.72, 2.51) <0.00001 91.0 <0.00001 0.02*
Stroke Mahfood Haddad et al. 44 3 cohort studies NR 2241 NA RR 2.09 (1.46, 2.98)* <0.001* 14.8* 0.309* 0.860*
Digestive disorder
Gallstone disease Qin and Ding 40 3 cross-sectional studies and 2 cohort studies Biopsy and US 42,623 15,377 OR 1.75 (1.51, 2.04) <0.01 57.0 0.05 NA
Cholangiocarcinoma Wongjarupong et al. 47 7 cross-sectional studies NR 138,213 1444 OR 1.95 (1.36, 2.79) 0.000 76.0 <0.01 0.82
HCC with/without cirrhosis Stine et al. 50 12 observational studies Biopsy and US 145,512 20,900 OR 1.43 (0.77, 2.65) 0.25 99.0 <0.00001 0.625*
HCC without cirrhosis Stine et al. 50 2 cross-sectional studies and 5 cohort studies Biopsy and US 23,059 3567 OR 2.61 (1.27, 5.35) 0.009 95.0 <0.00001 0.671*
ICC Liu et al. 69 6 case–control studies Biopsy, US, CT, and ICD code 466,101 NA OR 2.46 (1.77, 3.44) 0.000* 72.6 0.003 0.640*
ECC Liu et al. 69 5 case–control studies Biopsy, US, CT, and ICD code 458,582 NA OR 2.24 (1.58, 3.17) 0.000* 68.4 0.023 0.447*
Colorectal adenoma Chen et al. 56 8 cross-sectional studies and 4 cohort studies Biopsy and US 22,482 NA OR 1.49 (–1.20, 1.84) 0.000* 83.5 <0.001 0.945
Colorectal cancer Liu et al. 69 5 cross-sectional studies and 5 cohort studies Biopsy, US, CT, and ICD code NA NA OR 1.72 (1.40, 2.11) 0.000* 83.4 0.000 0.001*
Recurrent colorectal adenoma/cancer Chen et al. 56 4 cohort studies Biopsy and US 2201 NA OR 1.73 (1.12, 2.68) 0.014* 47.2 0.128 0.734
Right colon tumors Lin et al. 75 4 cross-sectional studies and 5 cohort studies Biopsy, US, and CT 7895 1012 OR 1.65 (1.44, 1.89) <0.00001 58.0 0.02 0.567*
Left colon tumors Lin et al. 75 4 cross-sectional studies and 5 cohort studies Biopsy, US, and CT 8675 1276 OR 1.41 (1.24, 1.61) <0.00001 59.0 0.02 0.601*
Esophagus cancer Mantovani et al. 76 , 77 5 cohort studies US and ICD code 140,014 125 HR 1.93 (1.19, 3.12) 0.008* 45.1 0.121 0.264*
Stomach cancer Mantovani et al. 76 , 77 6 cohort studies US and ICD code 155,944 597 HR 1.81 (1.19, 2.75) 0.005* 80.8 0.000 0.0345*
Pancreas cancer Mantovani et al. 76 , 77 3 cohort studies US and ICD code 55,655 115 HR 1.84 (1.23, 2.74) 0.003* 0.0 0.402 0.963*
IP by means of 5-6 h L/M or L/R De Munck et al. 66 7 observational studies Biopsy and US 205 119 SMD 0.79 (0.49, 1.08) <0.00001 0.0 0.43 0.532*
IP by means of serum zonulin De Munck et al. 66 5 observational studies Biopsy and US 353 191 SMD 1.04 (0.40, 1.68) 0.0001 86.0 <0.001 0.683*
Gastroesophageal reflux disease Xue et al. 62 6 cross-sectional studies, 2 cohort studies, and 1 case–control study US 79478 NA OR 1.28 (1.12, 1.44) 0.000* 82.0 0.000 <0.001
Overall survival of AP Váncsa et al. 70 2 cohort studies NR 1396 44 OR 2,81 (0.38, –20.03) 0.301* 68.7 0.074 NA
Moderately severe/severe AP Váncsa et al. 70 3 cohort studies NR NA NA OR 3.39 (1.51, 7.56) 0.003* 79.2 0.008 0.032*
Colorectal polyps Chen et al. 56 12 cross-sectional studies, 6 cohort studies, and 2 case–control study Biopsy and US 142,387 17,967 OR 1.45 (1.22, 1.72) 0.000* 72.4 0.057 NA
Skeletal system disorders
Total BMD Mantovani et al. 13 1 case–control study and 1 cross-sectional study Biopsy, US, and transient elastography 1994 690 WMD –0.04 (–0.16, 0.08) >0.05 98.9 0.000 NA
BMD at the lumbar spine Mantovani et al. 13 2 case–control studies and 7 cross-sectional studies Biopsy, US, and transient elastography 13,462 4368 WMD –0.01 (–0.03, 0.01) >0.05 92.2 0.000 NA
BMD at the femur Mantovani et al. 13 1 case–control studies, 6 cross-sectional studies Biopsy, US, and transient elastography 17,071 5151 WMD –0.01 (–0.02, 0.01) >0.05 94.3 0.000 NA
BMD at the pelvis Mantovani et al. 13 1 case–control studies and 4 cross-sectional studies Biopsy, US, and transient elastography 1446 5930 WMD 0.02 (–0.01, 0.05) >0.05 87.9 0.000 NA
Osteoporotic fractures Mantovani et al. 13 2 cross-sectional studies Biopsy, US, and transient elastography 10,456 NA OR 1.43 (1.00, 1.44) 0.051 55.1 0.083 0.008*
BMD at all anatomical sites Upala et al. 46 4 cross-sectional studies NR 1021 490 MD 0.021 (–0.004, 0.045) 0.098 NA NA 0.62
Skeletal muscle mass Cai et al. 63 6 cross-sectional studies and 1 cohort studies Biopsy, US, FLI, HIS, LAI, CNS, LFS, and NAS 29,533 7934 WMD –1.77 (–2.39, –1.15) 0.000 97.8 0.000 0.835
BMD in obese adolescent Sun et al. 61 6 case–control studies Biopsy, US, and MRI 453 217 WMD –0.03 (–0.05, –0.02) 0.000 60.2 0.039 NA
Z-scores Sun et al. 61 6 case–control studies Biopsy, US, and MRI 453 217 WMD –0.26 (–0.37, –0.14) 0.000 26.9 0.233 NA
Mortality
ACM Liu et al. 57 , 58 12 cohort studies NR 498,259 24,188 HR 1.34 (1.17, 1.54) 0.000* 80.0 0.000 >0.05
CVD mortality Liu et al. 57 , 58 7 cohort studies NR 471,849 5541 HR 1.13 (0.92, 1.38) 0.237* 57.5 0.028 0.405*
Cancer mortality Liu et al. 57 , 58 5 cohort studies NR 465,112 6924 HR 1.05 (0.89, 1.25) 0.562* 35.3 0.186 0.300*
Hepatocellular carcinoma mortality Liu et al. 57 , 58 2 cohort studies NR 470,775 255 HR 2.53 (1.23, 5.18) 0.000* 81.2 <0.01 NA
ACM in CVD patients Wu et al. 42 5 cohort studies Biopsy, US, and liver enzyme 21,186 3186 HR 1.14 (0.99, 1.32) 0.076 65.4 0.08 0.109
CVD mortality Wu et al. 42 5 cohort studies Biopsy, US, and liver enzyme 21,803 1903 HR 1.10 (0.86, 1.41) 0.440 64.9 0.002 0.378
COVID-19 mortality Singh et al. 79 2 cohort studies NR 7042 NA OR 1.01 (0.65, 1.58) 0.96 0.0 0.76 NA
ACM in female Khalid et al. 67 1 cross-sectional studies and 9 cohort studies Biopsy, US, and liver enzyme 10,877 NA OR 1.65 (1.12, 2.43) 0.012 98.7 <0.0001 NA
Metabolic disorders
T2D Mantovani et al. 76 , 77 26 cohort studies US and CT 418,564 22,67 HR 2.19 (1.93, 2.48) 0.000* 91.2 0.000 0.054*
Metabolic syndrome Ballestri et al. 34 12 cohort studies NR 81,411 14,514 RR 2.25 (1.62, 3.13)* <0.001* 99.3* 0.000* 0.219*
Diabetic retinopathy in T2D Song et al. 80 9 cross-sectional studies US 7170 2671 OR 0.94 (0.51, 1.71) 0.83* 96.0 <0.00001 0.902*
Urological disorders
Urolithiasis Wijarnpreecha et al. 51 - 53 7 cross-sectional studies and 1 cohort study US and CT 238,400 NA OR 1.81 (1.29, 2.56) 0.0007 28.8 0.25 0.74*
Urinary system cancers Mantovani et al. 76 , 77 4 cohort studies US and ICD code 120,851 414 HR 1.33 (1.04, 1.70) 0.025* 10.4 0.35 0.537*
Nephrological disorders
Prevalent CKD Musso et al. 30 16 cross-sectional studies Biopsy, US, and liver enzyme 27,012 2694 OR 2.12 (1.69, 2.66) <0.001* 77.0 <0.00001 0.473
Incident CKD Musso et al. 30 12 longitudinal studies Biopsy, US, and liver enzyme 28,680 2141 HR 1.79 (1.65, 1.95) <0.001* 0.0 0.83 0.644
Albuminuria Wijarnpreecha et al. 51 - 53 17 cross-sectional studies and 2 cohort studies US, FLI, and transient elastography 24,804 NA OR 1.67 (1.32, 2.11) 0.000* 76.0 0.000* 0.08
Serum marker disorders
Homocysteine level Dai et al. 35 6 cross-sectional studies and 2 case–control study Biopsy 935 538 SMD 0.66 (0.41, 0.92) 0.000 64.3 0.007 0.698
Folate level Dai et al. 35 5 cross-sectional studies and 2 case–control study Biopsy 802 331 SMD –0.26 (–0.69, 0.17) <0.05 85.7 0.000 0.344
Vitamin B12 Dai et al. 35 5 cross-sectional studies and 2 case–control study Biopsy 802 331 SMD 0.28 (–0.35, 0.92) <0.05 93.4 0.000 0.215
MPV Madan et al. 38 8 observational studies Biopsy and US 1428 842 SMD 0.612 (0.286, 0.938) 0.000 0.0 0.723 0.11
Circulating leptin Polyzos et al. 39 24 cross-sectional studies Biopsy 2006 775 SMD 0.64 (0.42, 0.86) <0.0001 77.6 <0.0001 0.98
Serum ferritin Du et al. 43 3 case–control studies Biopsy and US 225 101 SMD 1.01 (0.89, 1.13) <0.0001 88.4 0.000 0.602
C-reactive protein Liu et al. 57 , 58 19 case–control studies Biopsy and US 5313 2414 SMD 1,25 (0.81, 1.68) <0.00001 98.0 <0.00001 0.0023*
Serum resisting level Han et al. 72 8 cross-sectional studies and 8 case–control studies Biopsy and US 1961 1239 SMD 0.52 (0.00, 1.04) 0.047 95.9 0.000 NA
Visfatin Levels Ismaiel et al. 74 3 cross-sectional studies and 5 case–control studies, 1 cohort Biopsy, US, and CT 946 523 MD 3.361 (–0.175, 6.897) <0.05 97.1 <0.001 NA
Vitamin D deficiency Eliades et al. 29 9 observational studies NR 13,722 8520 OR 1.26 (1.17, 1.35) <0.001* 65.2 0.003 0.32
Respiratory system disorder
Predicted FEV1 Mantovani et al. 16 , 59 , 60 5 cross-sectional studies US and LFS 37,567 12,713 WMD –2,43 (–3.28, –1.58) <0.0001 69.7 0.010 0.13
Predicted FVC Mantovani et al. 16 , 59 , 60 4 cross-sectional studies US and LFS 25,829 9143 WMD –2.96 (–4.75, –1.17) <0.0001 91.7 0.000 0.21*
Lung cancer Mantovani et al. 76 , 77 5 cohort studies US and ICD code 140,014 837 HR 1.30 (1.14, 1.48) 0.000* 0.0 0.94 0.165*
Other health outcomes
Severe COVID-19 Hegyi et al. 73 3 cohort studies NR 7284 997 OR 5.22 (1.94, 14.03) 0.001* 85.1 0.001 0.921*
ICU admission of COVID-19 Hegyi et al. 73 3 cohort studies NR 7433 578 OR 2.29 (0.79, 6.63) 0.166* 85.1 0.001 0.122*
Depression Xiao et al. 82 4 cohort studies NR 38,047 3305 OR 1.29 (1.02, 1.64) 0.03* 73.0 0.01 0.420*
Endothelial dysfunction Fan et al. 36 2 cross-sectional studies and 9 case–control studies Biopsy and US 906 545 WMD –4.82 (–5.63, –4.00) 0.000 57.5 0.009 0.188
Carotid–femoral PWV Jaruvongvanich et al. 37 6 cross-sectional studies and 1 case–control study Biopsy, US, and CT 3957 783 MD 0.75 (0.37, 1.12) 0.000 89.0 <0.01 0.013
Brachial–ankle PWV Jaruvongvanich et al. 37 8 cross-sectional studies Biopsy, US, and CT NA NA MD 0.82 (0.57, 1.07) 0.000 92.0 <0.01 0.97
Augmentation index Jaruvongvanich et al. 37 5 cross-sectional studies and 1 case–control study Biopsy, US, and CT 12509 3334 MD 2.54 (0.07, 5.01) 0.044 73.0 0.01 0.11
Breast cancer Mantovani et al. 76 , 77 4 cohort studies US and ICD code 85,827 1347 HR 1.39 (1.13, 171) 0.002* 0.0 0.41 0.531*
Thyroid cancer Mantovani et al. 76 , 77 2 cohort studies US and ICD code 64,732 776 HR 2.63 (1.27, 5.45) 0.009* 0.0 0.72 NA
Female genital organ cancers Mantovani et al. 76 , 77 4 cohort studies US and ICD code 85,827 558 HR 1.62 (1.13, 2.32) 0.008* 40.8 0.15 0.296*
Prostate cancer Mantovani et al. 76 , 77 5 cohort studies US and ICD code 140,014 1002 HR 1.16 (0.82, 1.64) 0.39* 62.5 0.032 0.142*
Hematological cancers Mantovani et al. 76 , 77 2 cohort studies US and ICD code NA NA HR 1.47 (0.69, 3.12) 0.47* 62.3 0.029 NA
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C-IMT, carotid intima-media thickness; US, ultrasound; CT, computed tomography; FLI, fatty liver index; HIS, hepatic steatosis index; ICD, International Classification of Diseases; LAI, liver attenuation index; CNS, comprehensive NAFLD score; LFS, liver fat score; NFS, NAFLD fibrosis score; MRI, magnetic resonance imaging; CAC, coronary artery calcification; CVD, cardiovascular disease; CAD, coronary artery disease; LEVF, left ventricular ejection fraction; E/e’ ratio, early mitral velocity/early diastolic tissue velocity; E/A ratio, early mitral velocity/late mitral velocity ratio; BSA, body surface area; EFT, epicardial fat tissue; GLS, global longitudinal strain; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma, IP, intestinal permeability; AP, acute pancreatitis, BMD, bone mineral density; ACM, all-cause mortality; T2D, type-2 diabetes; CKD, chronic kidneys disease; MPV, mean platelet volume; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; ICU, intensive care unit; PWV, posterior wall velocity; NR, not reported.

*

The result was reanalyzed.

Figure 2.

Figure 2.

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Map of achievements associated with NAFLD.

Heterogeneity

According to Table 1, we recalculated the two results of two articles34,44 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).

Publication bias

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,32,40,49,57–59,61,65,67,70–72,74,76,79 thus we were not able to assess their publication bias. In the end, 71 health outcomes had no publication bias (p value for Egger’s test ⩾ 0.1) while 19 health outcomes presented publication bias (p value for Egger’s test ← 0.1).

Methodological Quality Assessment

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%).

Table 2.

Assessments of AMSTAR2 scores.

References AMSTAR 2 checklist Overall assessment quality
NO.1 NO.2 NO.3 NO.4 NO.5 NO.6 NO.7 NO.8 NO.9 NO.10 NO.11 NO.12 NO.13 NO.14 NO.15 NO.16
Madan et al. 33 Y N Y PY Y Y PY PY Y N Y Y Y Y Y Y Critically low
Zhou et al. 54 Y N Y PY Y Y PY PY N N Y Y Y Y Y Y Critically low
Ampuero et al. 31 Y N Y PY Y Y PY PY Y N Y N N Y Y N Critically low
Jaruvongvanich et al. 37 Y Y Y PY Y Y PY PY N N Y Y N Y Y Y Critically low
Targher et al. 41 Y Y Y PY Y Y PY Y Y N Y N Y Y Y N Critically low
Wu et al. 42 Y N Y PY Y Y PY Y Y N Y Y N Y N Y Critically low
Veracruz et al. 81 Y N Y PY Y Y PY PY Y N Y N Y Y Y Y Critically low
Borges-Canha et al. 55 Y N Y PY Y Y Y PY Y N Y Y Y Y Y Y Critically low
Bonci et al. 32 Y N Y PY Y Y PY PY N N Y N N Y Y Y Critically low
Oikonomidou et al. 78 Y Y Y Y Y Y PY PY Y N Y N N Y Y Y Critically low
Wijarnpreecha et al. 51 , 52 , 53 Y N Y PY Y Y Y PY Y N Y Y Y Y Y Y Critically low
Wijarnpreecha et al. 71 Y N Y PY Y Y PY PY Y N Y N Y Y N Y Critically low
Cai et al. 63 , 64 Y N Y PY Y Y PY Y Y N Y Y N Y Y Y Critically low
Liu et al. 57 , 58 Y N Y PY Y Y PY PY Y N Y N N Y N Y Critically low
Yao et al. 48 Y N Y PY Y Y PY PY N N Y N N N Y Y Critically low
Mantovani et al. 76 , 77 Y Y Y PY Y Y Y Y Y N Y Y Y Y Y Y Low
Ballestri et al. 34 Y N Y PY Y Y Y Y N N Y N N Y Y Y Critically low
Song et al. 80 Y N Y PY Y Y PY PY Y N Y Y Y Y Y Y Critically low
Qin and Ding 40 Y N Y PY Y Y PY PY Y N Y N N Y N Y Critically low
Wongjarupong et al. 47 Y Y Y Y Y Y PY PY Y N Y N Y Y Y Y Low
Stine et al. 50 Y N Y PY Y Y PY PY Y N Y N Y Y Y Y Critically low
Liu et al., 2021 Y N Y PY Y Y PY PY Y N Y N N N N Y Critically low
Chen et al. 56 Y N Y PY Y Y PY PY Y N Y Y Y Y Y Y Critically low
Munck et al. 66 Y N Y PY Y Y PY PY Y N Y N Y Y Y Y Critically low
Lin et al. 75 Y Y Y PY Y Y PY PY Y N Y Y Y Y Y Y Critically low
Xue et al. 62 Y N Y PY Y Y Y PY Y N Y Y Y Y Y Y Critically low
Váncsa et al. 70 Y Y Y PY Y Y Y PY Y N Y Y Y Y Y Y Critically low
Chen et al. 65 Y N Y PY Y N PY Y Y N Y Y Y N Y Y Critically low
Musso et al. 30 Y Y Y PY Y Y Y Y Y N Y Y Y Y Y Y Low
Wijarnpreecha et al. 51 , 52 , 53 Y N Y PY Y Y PY Y Y N Y Y Y Y Y Y Critically low
Wijarnpreecha et al. 51 , 52 , 53 Y N Y PY Y Y PY PY Y N Y N N Y Y Y Critically low
Mantovani et al. 13 Y Y Y PY Y N Y PY Y N Y Y Y Y Y Y Low
Upala et al. 46 Y Y Y PY Y Y N PY Y N Y Y N Y Y Y Critically low
Cai et al., 2019 Y N Y PY Y Y PY PY Y N Y Y Y Y Y Y Critically low
Sun et al. 61 Y N Y PY N Y PY PY Y N Y N N Y N Y Critically low
Fan et al. 36 Y N Y PY Y Y Y PY Y N Y N N Y Y Y Critically low
Jaruvongvanich et al. 37 Y Y Y PY Y Y Y PY Y N Y Y Y Y Y Y Low
Hu et al. 49 Y N Y PY N Y PY PY Y N Y Y Y Y Y Y Critically low
Mahfood Haddad et al. 44 Y N Y PY Y Y PY Y Y N Y Y Y Y Y Y Critically low
Liu et al. 57 , 58 Y N Y PY Y Y Y Y Y N Y Y Y Y Y Y Critically low
Singh et al. 79 Y N Y PY Y Y PY Y Y N Y Y N N Y Y Critically low
Khalid et al. 67 Y N Y PY Y Y PY Y Y N Y N Y Y Y Y Critically low
Dai et al. 35 Y N Y PY Y Y PY PY Y N Y Y N Y Y Y Critically low
Madan et al. 38 Y N N PY N Y PY PY Y N Y Y N N Y Y Critically low
Polyzos et al. 39 Y N Y PY Y Y Y PY Y N Y Y Y Y Y Y Critically low
Du et al. 43 Y N Y PY Y Y PY PY Y N Y Y Y N Y Y Critically low
Liu et al. 68 , 69 Y N Y PY Y Y PY PY Y N Y Y Y Y Y N Critically low
Han et al. 72 Y N Y PY Y Y PY PY Y N Y Y N Y Y Y Critically low
Mantovani et al. 76 , 77 Y Y Y PY Y Y Y Y Y N Y Y Y Y Y Y Low
Ismaiel et al. 74 Y N Y PY Y Y Y Y Y N Y N Y Y Y Y Critically low
Eliades et al. 29 Y N Y PY Y Y PY PY Y N Y N N Y Y Y Critically low
Mantovani et al. 16 , 59 , 60 Y Y Y PY Y Y Y PY Y N Y Y Y Y Y Y Low
Hegyi et al. 73 Y Y Y PY Y Y PY Y Y N Y N Y Y Y Y Critically low
Xiao et al. 82 Y N Y PY Y Y PY Y N N Y Y N Y Y Y Critically low
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AMSTAR 2 checklist (items in italic are considered critical):

1, PICO description; 2, protocol registered before the commencement of the review; 3, study design included in the review; 4, adequacy of the literature search; 5, two authors study selection; 6, two authors study extraction; 7, list for excluding individual studies; 8, included studies descripted in detail; 9, risk of bias for the single studies that included in the review; 10, source of funding of primary studies; 11, appropriateness of meta-analytical methods; 12, impact of risk of bias of single studies on the results of the meta-analysis; 13, consideration of risk of bias when interpreting the results of the review; 14 explanation and discussion of the heterogeneity observed; 15, assessment of presence and likely impact of publication bias; 16, funding sources and conflict of interest declared.

Abbreviations: Y, yes; PY, partial yes; N, no.

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.

Moderate: >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.

Figure 3.

Figure 3.

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Map of results of AMSTAR 2.

Strength of epidemiologic evidence

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 epidemiologic evidence, and 58 (52.25%) outcomes were graded as weak epidemiologic evidence (Figure 4).

Table 3.

The strength of epidemiologic evidence of 111 unique health outcomes.

Health outcomes Author, year Precision of the estimate Consistency of results No evidence of small-study effects (P > 0.1) Grade
> 1000 disease cases p < 0.001 I 2  < 50% and Cochran Q-test p > .10
Cardiovascular disorders
C-IMT in adult patients Madan et al. 33 Yes Yes Yes Yes High
Carotid plaque in adult patients Madan et al. 33 Yes No Yes Yes Weak
C-IMT in pediatric patients Madan et al. 33 No No Yes Yes Weak
CAC Zhou et al. 54 Yes Yes No No Weak
Arterial stiffness Zhou et al. 54 Yes Yes No Yes Moderate
Endothelial dysfunction Zhou et al. 54 No No No No Weak
Subclinical atherosclerosis Ampuero et al. 31 No Yes Yes Yes Moderate
CAC score > 0 Jaruvongvanich et al. 37 No Yes No No Weak
CAC score > 100 Jaruvongvanich et al. 37 No No (p > 0.05) Yes Yes NA
Fatal CVD Targher et al. 41 Yes No (p > 0.05) No Yes NA
Fatal and non-fatal CVD Targher et al. 41 Yes No No Yes Weak
Non-fatal CVD Targher et al. 41 No Yes No Yes Weak
CAD Wu et al. 42 No No No Yes Weak
CVD Veracruz et al. 81 Yes Yes No Yes Moderate
LVEF Borges-Canha et al. 55 Yes No (p > 0.05) No Yes NA
Peak E velocity Borges-Canha et al. 55 Yes No (p > 0.05) No No NA
E/e’ ratio Borges-Canha et al. 55 Yes Yes No Yes Moderate
Peak A velocity Borges-Canha et al. 55 Yes Yes Yes Yes High
E/A ratio Borges-Canha et al. 55 Yes Yes No Yes Moderate
Isovolumic relaxation time Borges-Canha et al. 55 No No No Yes Weak
Deceleration time Borges-Canha et al. 55 Yes Yes No No Weak
Left ventricle mass Borges-Canha et al. 55 Yes Yes No No Weak
Left ventricle end-diastolic diameter Borges-Canha et al. 55 Yes Yes Yes Yes High
Left ventricle end-systolic diameter Borges-Canha et al. 55 Yes No (p > 0.05) No Yes NA
Left atrium diameter Borges-Canha et al. 55 Yes Yes No Yes Moderate
Posterior wall thickness Borges-Canha et al. 55 Yes Yes No Yes Moderate
Interventricular septum thickness Borges-Canha et al. 55 Yes Yes No Yes Moderate
LV mass indexed to BSA Bonci et al. 32 No Yes No No Weak
LV mass indexed to height Bonci et al. 32 No No (p > 0.05) Yes No NA
EFT thickness Oikonomidou et al. 78 No Yes No Yes Weak
GLS Oikonomidou et al. 78 No Yes No Yes Weak
Diastolic cardiac dysfunction Wijarnpreecha et al. 51 , 52 , 53 No Yes No No Weak
Cardiac conduction defect Wijarnpreecha et al. 71 No No No No Weak
Atrial fibrillation Cai et al. 63 , 64 Yes No No Yes Weak
Epicardial adipose tissue Liu et al. 57 , 58 Yes Yes No No Weak
Hypertension and prehypertension Yao et al. 48 No Yes No No Weak
Cerebral and cerebrovascular disease
Cerebrovascular accident Hu et al. 49 No Yes Yes Yes Moderate
Ischemic stroke Hu et al. 49 No Yes Yes No Weak
Cerebral hemorrhage Hu et al. 49 No No Yes No Weak
Stroke and cerebrovascular diseases Veracruz et al. 81 Yes Yes No No Weak
Stroke Mahfood Haddad et al. 44 No Yes Yes Yes Moderate
Digestive disorder
Gallstone disease Qin and Ding 40 Yes No No No Weak
Cholangiocarcinoma Wongjarupong et al. 47 Yes Yes No Yes Moderate
HCC with/without cirrhosis Stine et al. 50 Yes No (p > 0.05) No Yes NA
HCC without cirrhosis Stine et al. 50 Yes No No Yes Weak
ICC Liu et al., 2021 No Yes No Yes Weak
ECC Liu et al., 2021 No Yes No Yes Weak
Colorectal adenoma Chen et al. 56 No No Yes Yes Weak
Colorectal cancer Liu et al., 2021 No Yes No No Weak
Recurrent colorectal adenoma/cancer Chen et al. 56 No No Yes Yes Weak
Right colon tumors Lin et al. 75 Yes Yes No Yes Moderate
Left colon tumors Lin et al. 75 Yes Yes No Yes Moderate
Esophagus cancer Mantovani et al. 76 , 77 No No Yes Yes Weak
Stomach cancer Mantovani et al. 76 , 77 No No No No Weak
Pancreas cancer Mantovani et al. 76 , 77 No No Yes Yes Weak
IP by means of 5-6 h L/M or L/R Munck et al. 66 No Yes Yes Yes Moderate
IP by means of serum zonulin Mu Munck et al., 2020 No Yes No Yes Weak
Gastroesophageal reflux disease Xue et al. 62 No Yes No No Weak
Overall survival of AP Váncsa et al. 70 No No (p > 0.05) No No NA
Moderately severe/severe AP Váncsa et al. 70 No No No No Weak
Colorectal polyps Chen et al. 65 Yes Yes No No Weak
Skeletal system disorders
Total BMD Mantovani et al. 13 No No (p > 0.05) No No NA
BMD at the lumbar spine Mantovani et al. 13 Yes No (p > 0.05) No No NA
BMD at the femur Mantovani et al. 13 Yes No (p > 0.05) No No NA
BMD at the pelvis Mantovani et al. 13 Yes No (p > 0.05) No No NA
BMD at all anatomical sites Upala et al. 46 No No (p > 0.05) No No NA
Osteoporotic fractures Mantovani et al. 13 No No (p > 0.05) No No NA
Skeletal muscle mass Cai et al., 2019 Yes Yes No Yes Moderate
BMD in obese adolescent Sun et al. 61 No Yes No No Weak
Z-scores Sun et al. 61 No Yes Yes No Weak
Mortality
ACM Liu et al. 57 , 58 Yes Yes No No Weak
CVD mortality Liu et al. 57 , 58 Yes No (p > 0.05) No Yes NA
cancer mortality Liu et al. 57 , 58 Yes No (p > 0.05) Yes Yes NA
Hepatocellular carcinoma mortality Liu et al. 57 , 58 No Yes No No Weak
ACM in CVD patients Wu et al. 42 Yes No (p > 0.05) No Yes NA
CVD mortality Wu et al. 42 Yes No (p > 0.05) No Yes NA
COVID-19 mortality Singh et al. 79 No No (p > 0.05) Yes No NA
ACM in female Khalid et al. 67 No No No No Weak
Metabolic system disorders
T2D Mantovani et al. 76 , 77 Yes Yes No No Weak
Metabolic syndrome Ballestri et al. 34 Yes Yes No Yes Moderate
Diabetic retinopathy in T2D Song et al. 80 Yes No (p > 0.05) No Yes NA
Urological disorder
Urolithiasis Wijarnpreecha et al. 51 , 52 , 53 No Yes Yes Yes Moderate
Urinary system cancers Mantovani et al. 76 , 77 No No Yes Yes Weak
Nephrological
Prevalent CKD Musso et al. 30 Yes Yes No Yes Moderate
Incident CKD Musso et al. 30 Yes Yes Yes Yes High
Albuminuria Wijarnpreecha et al. 51 , 52 , 53 No Yes No No Weak
Serum marker disorders
Homocysteine level Dai et al. 35 No Yes No Yes Weak
Folate level Dai et al. 35 No No (p > 0.05) No Yes NA
Vitamin B12 Dai et al. 35 No No (p > 0.05) No Yes NA
MPV Madan et al. 38 No Yes Yes Yes Moderate
Circulating leptin Polyzos et al. 39 No Yes No Yes Weak
Serum ferritin Du et al. 43 No Yes No Yes Weak
C-reactive protein, CRP Liu et al. 68 , 69 Yes Yes No No Weak
Serum resistin level Han et al. 72 Yes No No No Weak
Visfatin Levels Ismaiel et al. 74 No No (p > 0.05) No No NA
vitamin D deficiency Eliades et al. 29 Yes Yes No Yes Moderate
Respiratory system disorder
Predicted FEV1 Mantovani et al. 16 , 59 , 60 Yes Yes No Yes Moderate
Predicted FVC Mantovani et al. 16 , 59 , 60 Yes Yes No Yes Moderate
Lung cancer Mantovani et al. 76 , 77 No Yes Yes Yes Moderate
Other health outcomes
Severe COVID-19 Hegyi et al. 73 No No No Yes Weak
ICU admission of COVID-19 Hegyi et al. 73 No No (p > 0.05) No Yes NA
Depression Xiao et al. 82 Yes No No Yes Weak
Endothelial dysfunction Fan et al. 36 No Yes No Yes Weak
Carotid–femoral PWV Jaruvongvanich et al. 37 No Yes No No Weak
Brachial–ankle PWV Jaruvongvanich et al. 37 No Yes No Yes Weak
Augmentation index Jaruvongvanich et al. 37 Yes No No Yes Weak
Breast cancer Mantovani et al. 76 , 77 Yes No Yes Yes Weak
Thyroid cancer Mantovani et al. 76 , 77 No No Yes No Weak
Female genital organ cancers Mantovani et al. 76 , 77 No No Yes Yes Weak
Prostate cancer Mantovani et al. 76 , 77 Yes No (p > 0.05) No Yes NA
Hematological cancers Mantovani et al. 76 , 77 NO No (p > 0.05) No No NA
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C-IMT, carotid intima-media thickness; CAC, coronary artery calcification; CVD, cardiovascular disease; CAD, coronary artery disease; LEVF, left ventricular ejection fraction; E/e’ ratio, early mitral velocity/early diastolic tissue velocity; E/A ratio, early mitral velocity/late mitral velocity ratio; BSA, body surface area; EFT, epicardial fat tissue; GLS, global longitudinal strain; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; ECC, extrahepatic cholangiocarcinoma, IP, intestinal permeability; AP, acute pancreatitis, BMD, bone mineral density; ACM, all-cause mortality; T2D, type-2 diabetes; CKD, chronic kidneys disease; MPV, mean platelet volume; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; ICU, intensive care unit; PWV, posterior wall velocity.

Note. The strength of epidemiologic evidence was rated as follows:

High, if all criteria were satisfied: precision of the estimate (p < .001 and >1000 disease cases), consistency of results (I 2  < 50% and Cochran Q-test p > .10), and no evidence of small-study effects (p > .10).

Moderate, if a maximum of 1 criterion was not satisfied and a p < .001 was found.

Weak, in other cases (p < .05).

NA, p values are greater than 0.05, so the epidemiologic quality of these meta cannot be rated.

Figure 4.

Figure 4.

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Map of results of evidence assessment.

Discussion

Main findings and interpretation

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 field22–26 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 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 pro-inflammatory cytokines, insulin resistance, and dyslipidemia acts together on the cardiac metabolism and function,86–88 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.90–92

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.

Strength and limitations

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 post-menopausal 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 post-menopausal 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.

Conclusion

In summary, 54 studies explored 111 unique health outcomes; only four outcomes showed high epidemiologic evidence with statistical significance. NAFLD may be related to the increased risk of C-MIT, peak A velocity, LVEDD, and incident CKD in adult patients. However, more robust studies and investigations are needed to achieve high epidemiologic evidence for the associations between NAFLD and health outcomes.

Supplemental Material

sj-docx-1-taj-10.1177_20406223221083508 – Supplemental material for Nonalcoholic fatty liver disease and health outcomes: An umbrella review of systematic reviews and meta-analyses
Click here for additional data file. (103.7KB, docx)

Supplemental material, sj-docx-1-taj-10.1177_20406223221083508 for Nonalcoholic fatty liver disease and health outcomes: An umbrella review of systematic reviews and meta-analyses by Lixian Zhong, Chutian Wu, Yuting Li, Qiuting Zeng, Leizhen Lai, Sisi Chen and Shaohui Tang in Therapeutic Advances in Chronic Disease

Acknowledgments

The authors would like to acknowledge all authors of the original studies that were included in this meta-analysis.

Footnotes

Author contributions: Lixian Zhong: Conceptualization; Data curation; Formal analysis; Methodology; Writing – original draft; Writing – review & editing.

Chutian Wu: Conceptualization; Data curation; Formal analysis; Methodology.

Yuting Li: Conceptualization; Data curation; Formal analysis; Methodology.

Qiuting Zeng: Data curation; Formal analysis.

Leizhen Lai: Data curation; Formal analysis.

Sisi Chen: Data curation; Formal analysis.

Shaohui Tang: Conceptualization; Writing – original draft; Writing – review & editing.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement: 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: Consent statement and ethical approval are not required as the current study does not involve human participants and animal subjects.

Availability of data and material: 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: Supplemental material for this article is available online.

Contributor Information

Lixian Zhong, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China.

Chutian Wu, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China.

Yuting Li, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China.

Qiuting Zeng, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China.

Leizhen Lai, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China.

Sisi Chen, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, P.R. China.

Shaohui Tang, Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510630, P.R. China.

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