Skip to main content
  • Research article
  • Open access
  • Published:

Global epidemiology of type 2 diabetes in patients with NAFLD or MAFLD: a systematic review and meta-analysis

Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) shares common pathophysiological mechanisms with type 2 diabetes, making them significant risk factors for type 2 diabetes. The present study aimed to assess the epidemiological feature of type 2 diabetes in patients with NAFLD or MAFLD at global levels.

Methods

Published studies were searched for terms that included type 2 diabetes, and NAFLD or MAFLD using PubMed, EMBASE, MEDLINE, and Web of Science databases from their inception to December 2022. The pooled global and regional prevalence and incidence density of type 2 diabetes in patients with NAFLD or MAFLD were evaluated using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression.

Results

A total of 395 studies (6,878,568 participants with NAFLD; 1,172,637 participants with MAFLD) from 40 countries or areas were included in the meta-analysis. The pooled prevalence of type 2 diabetes among NAFLD or MAFLD patients was 28.3% (95% confidence interval 25.2–31.6%) and 26.2% (23.9–28.6%) globally. The incidence density of type 2 diabetes in NAFLD or MAFLD patients was 24.6 per 1000-person year (20.7 to 29.2) and 26.9 per 1000-person year (7.3 to 44.4), respectively.

Conclusions

The present study describes the global prevalence and incidence of type 2 diabetes in patients with NAFLD or MAFLD. The study findings serve as a valuable resource to assess the global clinical and economic impact of type 2 diabetes in patients with NAFLD or MAFLD.

Peer Review reports

Background

Type 2 diabetes is a worldwide public health burden, which accounts for about 90–95% of diabetes mellitus [1]. Over the past 40 years, the number of adults with diabetes mellitus has quadrupled from 108 million in 1980 to 463 million in 2019 globally [2, 3]. This figure is predicted to be 579 million in 2030 and 700 million in 2045 [2, 4]. Moreover, it is estimated that the amount of direct health care expenditures attributed to type 2 diabetes in 2007 was $232 billion, whereas in 2019, it soared to $760 billion [5]. Thus, it is essential to curb the rise of type 2 diabetes in order to minimize economic expenses and protect individuals and communities from its enduring negative consequences.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, encompassing a spectrum that includes hepatic steatosis, non-alcoholic steatohepatitis (NASH), advanced liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Currently, one in four people in the world suffers from NAFLD [6]. Eventually, 20 million people will die from NAFLD-related liver disease [7]. In clinical settings, NAFLD has been reported to share similar pathophysiological mechanism (such as insulin resistance, defective hepatic lipidic profile, and abnormal triglyceride metabolism) with type 2 diabetes [8,9,10] and is strongly associated with it [9, 11, 12]. A recent meta-analysis has revealed that NAFLD increases the risk of type 2 diabetes incident by approximately twofold [13]. Therefore, reducing the prevalence of NAFLD could help mitigate the impact of type 2 diabetes to some extent. However, to the best of our knowledge, there are no reports on global prevalence and incidence density of type 2 diabetes among NAFLD patients that can be used to delineate its epidemiological features [13,14,15,16,17].

Furthermore, given that NAFLD is closely related to several metabolic diseases, the term metabolic-associated fatty liver disease (MAFLD) was proposed in 2020 to better describe these coexisting conditions and reflect the etiology of fatty liver diseases [18, 19]. MAFLD is defined based on evidence of hepatic steatosis and is simultaneously accompanied by at least one of the following conditions: obesity, diabetes, or metabolic dysregulation [18]. Of note, these conditions are closely related to type 2 diabetes. However, no research to date has reported on the epidemiological features of type 2 diabetes among MAFLD patients.

Therefore, the present study utilized a comprehensive meta-analysis to report the worldwide incidence and prevalence of type 2 diabetes among individuals with NAFLD or MAFLD.

Methods

Search terms, included and excluded criteria

The present systematic review and meta-analysis were in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines [20]. The study protocol was registered in PROSPERO with an ID number of CRD42022335692 (https://www.crd.york.ac.uk/prospero/).

Two researchers independently conducted a literature search in the PubMed, EMBASE, MEDLINE, and Web of Science databases in the period from their inception to December 2022 using a combination of the following search terms related to type 2 diabetes in NAFLD or MAFLD: "fatty liver" (OR "NAFLD" OR "nonalcoholic fatty liver disease" OR "nonalcoholic steatohepatitis "OR "hepatic steatosis" OR "MAFLD" OR " metabolic associated fatty liver disease") AND "diabetes" NOT "animals"[mesh]. The search included all observational studies conducted in adults (≥ 18 years old) published in peer-reviewed journals until December 2022. In addition to the initial database search, references obtained from the retrieved publications were also searched to identify any additional articles that may have been missed.

The following publications were excluded: reviews or abstracts; studies that were unable to ascertain the NAFLD diagnosis; studies on patients with viral hepatitis B and C (HBV/HCV), or other liver-related disease or excess alcohol consumption; studies with patients under 18 years old or pregnant individuals; studies that did not report screening for excess alcohol use; studies reporting on type 1 diabetes; studies that included only groups with certain metabolic condition, such as morbidly obese patients; and studies not published in the English language. If multiple studies were conducted using the same population, the most recent data were utilized for the present analysis.

Data extraction and analysis

Usable data from eligible studies were independently extracted by two authors (H. L. and J. J.). Any discrepancies in their decisions were resolved through consultation with a third author (L. C.). The following data were extracted from each study: title, author (s), study year, publication year, study location (country and region), study design, NAFLD diagnosis, sample size, average age, percentage of males, and number of participants with NAFLD or MAFLD.

To estimate the pooled prevalence, the prevalence rates were combined in random-effects meta-analyses (normal-normal model) that took into account inter-study heterogeneity. Moreover, meta-analysis was performed using logit transformed proportions to obtain better statistical properties [21]. To address the potential for misestimation due to liver index and hospital records of NAFLD definition, a sensitivity analysis was performed after excluding those studies, based on previous reports [5, 6]. The percentage of males, average age of the sample population, geographic region, diagnostic method, follow-up duration, and publication year were examined both in univariate and multivariate meta-regression models. A funnel plot, Begg-Mazumdar’s rank correlation test, and Egger’s regression test were used to estimate whether there were any publication or related biases. The detailed data analysis was observed in Additional file 1. Supplementary Methods [5, 6, 21,22,23].

In addition, Joinpoint Regression Analysis was used to calculate the average annual percent change (AAPC) and the corresponding 95% CIs in the temporal trend of each part with natural log-transformed rates. All analyses were performed using the Stata version 17.0 software (Stata Corp, College Station, TX, USA), R version 4.0.5, and Joinpoint version 4.7.0.0. Bilateral P < 0.05 was considered as statistically significant.

Furthermore, GRADEpro version 3.6.1 was used to assess evidence quality and grading of recommendation strength in the included studies in the quantitative synthesis—meta-analysis, in accordance to the grading of recommendation, assessment, and evaluation (GRADE) instrument [24]. This assessment was based on the considerations of study design, consistency, directness, heterogeneity, precision, publication bias, and other aspects reported by studies included in this systematic review. The quality of the evidence was rated as high, moderate, low, or very low [25].

Patient and public involvement statement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Results

The electronic search yielded 26,131 articles (Additional file 2: Fig. S1). A total of 20,017 records were retained after removing the duplicates. Furthermore, 18,116 records with ineligible titles and abstracts were excluded based on the aforementioned exclusion criteria, in addition to 1506 records with no available information, not describing observational studies, including teenage subjects, not written in English, without baseline data, and with the same study participants. As a result, 395 reports were included in the final study analysis. Of those, 364 studies focused on the epidemiological research on type 2 diabetes in NAFLD patients, while 42 studies reported on the MAFLD research.

Prevalence of type 2 diabetes among patients with NAFLD or MAFLD

The pooled global prevalence of type 2 diabetes among patients with NAFLD or MAFLD was 28.1% (95% confidence interval [CI] 25.1–31.3%). Specifically, a total of 340 studies including a total 5,563,639 patients with NAFLD were included in the study (Additional file 3: Table S1 [26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362]). Briefly, the median age of these participants was 50.6 (range 33.1–78.0) years, with 51.2% of NAFLD patients being male (range 9.0–94.3%) (Additional file 3: Table S2). The estimated global prevalence of type 2 diabetes among patients with NAFLD was 28.3% (95% confidence interval [CI] 25.2–31.6%; Fig. 1). The prevalence of type 2 diabetes among patients with NAFLD was dramatically increased from 28.4% (95% CI 24.4–32.7%) in 2002 to 34.1% (95% CI 30.8–37.5%) in 2022 (Additional file 2: Fig. S2), similar to the results of the AAPC, especially for Australia, South America, and Southeast Asia (all P < 0.05) (Additional file 3: Table S3). Across the region, pooled prevalence estimates ranged from 24.1% in East Asia (n = 102; 95% CI 21.3–27.2%; I2 = 100.0%) to 47.1% in Africa (n = 4; 95% CI 20.6–59.7%; I2 = 95.1%). The pooled prevalence of type 2 diabetes in NAFLD patients across countries is listed in Fig. 2. Across diagnosis of NAFLD, the pooled prevalence of type 2 diabetes among patients with NAFLD was the lowest in index (n = 20; 17.4%; 95% CI 11.8–25.1%; I2 = 100.0%) and the highest in hospital records (n = 19; 45.2%; 95% CI 31.2–60.0%; I2 = 100.0%). Furthermore, sensitivity analyses results that excluded studies that using liver index and hospital records as NAFLD definitions, were consistent with the overall study findings (28.2% vs. 28.3%; Additional file 3: Table S4).

Fig. 1
figure 1

The prevalence of type 2 diabetes among patients with NAFLD—stratified by age, region, publication year, sample size, and diagnosis of NAFLD. Mixed diagnostic methods refer to the definition of NAFLD in a study using more than one diagnostic method

Fig. 2
figure 2

The prevalence of type 2 diabetes among patients with NAFLD across 40 countries

For secondary analysis (Additional file 3: Table S5), the pooled prevalence values for type 2 diabetes among patients with NAFLD were 15.7% (n = 19; 95% CI 11.7–20.7%; I2 = 99.8%) and 22.2% (n = 25; 95% CI 17.2–28.0%; I2 = 99.8%) for males and females, respectively. The pooled prevalence of type 2 diabetes among patients with lean-NAFLD was 15.2% (n = 19; 95% CI 10.8–21.0%; I2 = 99.5%), while the prevalence among non-lean NAFLD patients was 25.9% (n = 23; 95% CI 20.3–32.5%; I2 = 99.8%). Moreover, the present study further investigated the prevalence of type 2 diabetes among NAFLD patients with or without Corona Virus Disease 2019 (Covid-19). As shown, the prevalence of type 2 diabetes for those with Covid-19 was 18.7% (n = 2; 95% CI 5.8–46.1%; I2 = 99.2%) and 28.4% (n = 338; 95% CI 25.2–31.7%; I2 = 100.0%) for those without Covid-19.

The univariate meta-regression analysis indicated that study design (P = 0.02), mean age (P < 0.0001), proportion of males (P = 0.03), publication year (P = 0.01), and NAFLD diagnosis (P < 0.0001) were significantly associated with the prevalence of type 2 diabetes (Additional file 3: Table S6). In the multivariate analysis, mean age (P < 0.0001), publication year (P = 0.03), and NAFLD diagnosis (P < 0.0001) remained significantly associated with the prevalence of type 2 diabetes.

In addition, a total of 40 studies, including 1,169,899 patients with MAFLD were evaluated in the analyses (Additional file 3: Table S7 [171, 248, 251, 271, 307,308,309, 313, 335, 349, 363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391]). The median age of the participants was 50.9 (range 35.1–68.4) years, with 53.3% of MAFLD patients being male (range 23.9–85.4%; Additional file 3: Table S8). The pooled global prevalence of type 2 diabetes among patients with MAFLD was 26.2% (95% CI 23.9–28.6%; Additional file 2: Fig. S3). Across the geographic location, the highest pooled prevalence of type 2 diabetes in MAFLD patients was reported in West Asia (n = 1; 81.5%; 95% CI 79.3–83.5%) and the lowest prevalence in East Asia (n = 21; 21.1%; 95% CI 18.6–23.8%; I2 = 99.3%). The pooled prevalence of type 2 diabetes in MAFLD patients across countries is shown in Additional file 2: Fig. S4. Moreover, the results from AAPC analysis indicated that there was an increased trend of prevalence in type 2 diabetes populations with MAFLD (Additional file 3: Table S9). For meta-regression analysis, only geographic region (P < 0.05) was significantly associated with the prevalence rates both in univariate and multivariate meta-regression analyses (Additional file 3: Table S10).

Incidence density of type 2 diabetes among patients with NAFLD or MAFLD

The pooled global incidence density of type 2 diabetes among patients with NAFLD or MAFLD was 24.0 per 1000-person year (95% CI 20.3–28.4). To be specific, a total of 36 studies evaluated in the incidence analysis, included 1,327,087 patients with NAFLD (Additional file 3: Table S11 [43, 82, 174, 203, 221, 233, 262, 274, 285, 349, 392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417]). Briefly, the median age of these participants was 48.3 (range 30.7–69.4) years, and a median follow-up time of 5.05 years. In addition, 61.2% (range 36.0–90.5) of patients with NAFLD were male (Additional file 3: Table S12). The estimated global incidence density of type 2 diabetes among patients with NAFLD was 24.6 per 1000-person year (95% CI 20.7 to 29.2; Fig. 3). There was a substantial decrease in the incidence of type 2 diabetes among patients with NAFLD from 28.3 per 1000-person year in 2003 to 16.1 per 1000-person year in 2022 (Additional file 2: Fig. S5), while no significant trend of AAPC analysis was observed (Additional file 3: Table S13). Across the region, pooled incidence density estimates ranged from 17.0 per 1000-person year (n = 1; 95% CI 16.1 to 18.0) in Australia to 81.6 per 1000-person year (n = 3; 95% CI 57.5 to 114.6; I2 = 99.5%) in North America. The pooled incidence density of type 2 diabetes in NAFLD patients across countries is listed in Fig. 4. Subgroup differences were significant in NAFLD diagnosis, where the pooled incidence density was the highest in liver biopsy (n = 9; 41.9 per 1000-person year; 95% CI 24.5 to 70.6; I2 = 99.9%) and the lowest in liver index (n = 5; 20.8 per 1000-person year; 95% CI 13.0 to 33.2; I2 = 100.0%), except for mixed diagnostic methods (the definition of NAFLD in a study using more than one diagnostic method). In the secondary analysis, the pooled type 2 diabetes incidence density among patients with NAFLD for males was slightly lower than that of females (9.7 vs. 10.5). Additionally, sensitivity analyses results, which excluded studies that used index and hospital records for NAFLD diagnosis, also demonstrated results similar to those observed in the whole population (Additional file 3: Table S14). Only the region (P = 0.04) demonstrated a significant association with the incidence density of type 2 diabetes in the univariate and multivariate analysis (Additional file 3: Table S15).

Fig. 3
figure 3

The incidence density of type 2 diabetes among patients with NAFLD—stratified by age, region, publication year, sample size, and diagnosis of NAFLD. Mixed diagnostic methods refer to the definition of NAFLD in a study using more than one diagnostic method

Fig. 4
figure 4

The incidence density of type 2 diabetes among patients with NAFLD across 8 countries

Moreover, only three studies from East Asia with a total of 5222 patients with MAFLD were included in the incidence analysis (Additional file 3: Table S16 [349, 418, 419]). The median age of these participants was 45.2 (range 40.0–54.9) years, with a median follow-up time of 10 years (Additional file 3: Table S17). Studies on the incidence density of type 2 diabetes among patients with MAFLD were all from China and had a pooled incidence density of 26.9 per 1000-person year (95% CI 7.3 to 44.4; Additional file 3: Table S18).

Level of evidence

Overall, the quality of the evidence for the results of the GRADE system assessment was rated as very low (Additional file 2: Fig. S6). Heterogeneity was the main factor leading to the limited quality of the evidence.

Discussion

The present study determined that the global prevalence of type 2 diabetes among NAFLD patients is 28.3%, with the lowest prevalence rate observed in East Asia. The global incidence density of type 2 diabetes among NAFLD is 24.6 per 1000-person year. The epidemiological features of type 2 diabetes among patients with MAFLD were consistent, showing a pooled prevalence of 26.2% and an incidence density of 26.9 per 1000-person year.

According to the World Health Organization (WHO), the prevalence of diabetes rose to approximately 10% (537 million) in 2019 and is expected to reach 783 million by 2045 [420]. Thus, the prevalence of type 2 diabetes is more than double that of the general population. Consistently, a previous meta-analysis has reported a global prevalence of type 2 diabetes associated with NAFLD of 22.5% for the period of 1989–2015 [6], which was lower than the values in the present study (28.3%). Although several studies have demonstrated that NAFLD is associated with a nearly two-fold increased risk of type 2 diabetes incident, compared to that in non-NAFLD individuals [15, 16], the global incidence density of type 2 diabetes in NAFLD patients remains unclear. A meta-analysis of 33 studies from 2000 to June 2020 has shown a crude incidence of 18.1% among NAFLD patients with type 2 diabetes [17]. This figure was somewhat higher than the value reported in the present findings (14.9%), which might be attributed to the untransformed rate calculation.

Based on the present meta-analysis, the epidemiological features of type 2 diabetes in NAFLD patients are highly heterogenous across geographic regions. Higher prevalence of type 2 diabetes in NAFLD patients was observed in Africa (especially North Africa), South America, and Australia, while lower rates were found in Europe and Asia. As well, results from AAPC indicated that the increased trends of type 2 diabetes among NAFLD were significant in Australia, South America, and Southeast Asia. Consistently with our findings, South America has been reported to have the highest prevalence of NAFLD in 2019, while Europe and Asia showed lower rates [421]. The highest prevalence of age-standardized diabetes worldwide was observed in the Middle East and North Africa (12.2%), and the lowest prevalence of diabetes was found in Europe (6.3%) [422]. Furthermore, higher incidence density of type 2 diabetes among NAFLD populations was noted in North America, while lower incidence was observed in Australia. Regarding to the AAPC, an increased trend of incidence density has been found in East Asia, whereas a downward trend was observed in Europe. With the rapid social and economic development of middle socio-demographic index countries and developing countries in East Asia such as China, great changes have taken place in diet structure and lifestyles. For instance, smoking has been reported to increase the prevalence of NAFLD and advanced liver fibrosis [423]. Soft drinks, the leading source of added sugar worldwide, have been linked to obesity, insulin resistance, and NAFLD [424]. However, basic infrastructure is insufficient to support a healthy lifestyle, and current health services are unable to identify the onset of diabetes in people with NAFLD early and intervene in a timely manner. In addition, population aging accelerates the occurrence of these chronic diseases. According to the WHO, there were 1 billion people worldwide over the age of 60 years in 2019, and this number will rise to 1.4 billion by 2030 and 2.1 billion by 2050 [425]. Both NAFLD and type 2 diabetes are closely associated with aging. The worldwide prevalence of NAFLD has increased from 25.5% in or before 2005 to 37.8% in 2016 or later [426]. Additionally, 135.6 million people aged 65–99 years were living with diabetes in 2019. It is estimated that the number of people over the age of 65 years with diabetes will reach 195.2 million by 2030 and 276.2 million by 2045 [427]. Thus, the increasing disease burden of type 2 diabetes among NAFLD patients is closely related to aging. Intensive measures should be planned and implemented in less developed countries to prevent further increases in the burden of disease and to strengthen health services.

The prevalence and incidence of type 2 diabetes among NAFLD patients also vary depending on the diagnostic methods for NAFLD. Although liver biopsy remains the gold standard for diagnosis of fatty liver, it has limitations due to sampling variability, invasiveness, and high cost [428]. Numerous non-invasive biomarkers, including liver index (serum markers) and imaging modalities, are preferred for practical applications. Consistent with published literature [6], the present study found that liver index can underestimate the prevalence rate of type 2 diabetes, while hospital records may overestimate it. Studies have shown that analyses using liver enzymes (blood tests only) to estimate the prevalence of NAFLD consistently yield lower results than those using imaging studies. In North America, for example, the prevalence of NAFLD diagnosed via ultrasound is 24%, but only 13% if a blood test is used [6]. Additionally, aminotransferase levels may be only mildly elevated in NAFLD individuals, so that up to 78% of patients with NAFLD may actually have normal liver enzyme levels [429]. These findings can explain why publication bias was no longer present when studies using blood tests as the sole means of diagnosing NAFLD were removed in the sensitivity analysis. However, after excluding studies using liver index or hospital records for NAFLD diagnosis, the sensitivity analyses results were still consistent with those of the main analyses, which may be attributed to the lack of studies on liver index and hospital records for NAFLD diagnosis. Clearly, these data also support the importance of selecting the most accurate method to diagnose NAFLD, such as imaging or histology [430].

Results from secondary analysis indicated a significantly higher prevalence of type 2 diabetes in non-lean NAFLD patients, compared to lean NAFLD patients. These findings were consistent with observations in the general population. As reported by a previous systematic review and meta-analysis, a similar phenomenon has been observed in the general population. A study has reported that the overall prevalence of lean NAFLD was 19.2% among the NAFLD population and 5.1% in the general population [431]. Except for the fact that obesity is a relevant risk factor for type 2 diabetes, the observed difference in the prevalence of type 2 diabetes between lean and non-lean NAFLD patients may be related to the differences in genetic variations, as well as in gut microbiota among different ethnic populations. Compared to non-lean NAFLD individuals, lean NAFLD individuals showed better metabolic and histological characteristics. In addition, a previous microbiome study has also indicated a significant difference in fecal and blood microbiota profiles between lean and non-lean NAFLD patients [432]. Additionally, the rate of type 2 diabetes in NAFLD populations has also suggested a sex difference, with the condition being more common in females than males. However, it is worth noting that the sex differences in the prevalence of type 2 diabetes and NAFLD are often thought to depend on the patients’ reproductive stage of life [433, 434]. Specifically, there are more cases of type 2 diabetes or NAFLD in males before the age of puberty, whereas postmenopausal females have a higher prevalence of type 2 diabetes or NAFLD. Studies on the sex subgroup populations are needed to better understand these differences. In addition, published evidence has reported that there were several direct links (e.g., insulin resistance, immune injury) between Covid-19 and the metabolic and endocrine systems. Not only are patients with metabolic dysfunction, such as NAFLD and diabetes, at an increased risk of developing severe Covid-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders [10, 435]. Moreover, only two studies included adults Covid-19 patients from China and Mexico have reported that a much higher prevalence of NAFLD was observed in Covid patients than that reported in the general population (25%). Of which, these patients also had significantly higher proportions of diabetes than the non-NAFLD cases [302, 353]. On the contrary, research from the UK Biobank has revealed no causal relationship between NAFLD and Covid-19 using Mendelian Randomization Analysis [436]. Since the study samples we included were not comprehensive and representative enough, we found the pooled prevalence of type 2 diabetes in NAFLD individuals was lower among Covid-19 patients than in non-Covid-19 patients. Further studies were still warranted to explore the impact of Covid-19 on metabolic disorders.

According to the present results, the prevalence of type 2 diabetes in MAFLD patients was lower than that in NAFLD patients, with the highest prevalence in Europe and the lowest prevalence in Asia. In fact, observational data meta-analysis has reported that Europe has the highest pooled prevalence of MAFLD, followed by Asia and North America [437]. It is worth noting that there are slight differences in prevalence between NAFLD and MAFLD in published epidemiological studies, where the prevalence for MAFLD is often higher than that for NAFLD [437]. Evidence from the 2017–2018 National Health and Nutrition Examination Survey, which is a cohort study conducted in a representative sample of the general US population, has shown that the prevalence values for NAFLD and MAFLD based on imaging diagnose were 37.1 and 39.1%, respectively [438]. Since there is limited evidence regarding the prevalence of type 2 diabetes in MAFLD, further studies are still needed. Moreover, research related to the incidence density of type 2 diabetes among MAFLD patients has only been published in China. Thus, the incidence results are not directly comparable to the global values. Given the fact that the MAFLD criteria are more practical and have higher ability for identifying at-high-risk patients than that of the NAFLD criteria [251], more studies from diverse geographic locations are necessary to obtain a more comprehensive understanding of the incidence of type 2 diabetes in MAFLD patients worldwide.

A key strength of the present analysis is that it first presents a comprehensive overview of the global epidemiological features of type 2 diabetes among NAFLD and MAFLD patients. This work provides essential data to develop policies to address this rising health concern. However, several limitations warrant consideration. First, significant heterogeneity was present in the included studies, which contribute to a low evaluation of evidence quality by GRADE system. However, the quality of initial evidence of observational studies is low. Unexplored factors, such as comorbid conditions of NAFLD or MAFLD, may have contributed to the heterogeneity. Second, some variations arising from different diagnostic methodologies should be acknowledged. The use of liver enzymes to estimate the prevalence of NAFLD may underestimate the true prevalence of NAFLD, compared to liver biopsy and imaging modalities [6]. Another limitation is the scarcity of data on the incidence of type 2 diabetes among MAFLD patients from numerous countries, preventing a complete global overview. Moreover, given that we mainly focused on studies about NAFLD, those with alcohol drinking were excluded. This could underestimate the epidemiological rate of MAFLD. In addition, studies we included in the present study might not represent the geographical areas to which they belong, further national and representative studies are still warranted.

Conclusions

The present meta-analysis results are important for primary care physicians, specialists, and health policy makers, given the increasing burden of type 2 diabetes among patients with NAFLD and/or MAFLD over the last few years. With more than one-fifth of NAFLD or MAFLD adults affected by type 2 diabetes globally, it is crucial to focus on the development and complications of NAFLD and implement strategies to mitigate its impact.

Availability of data and materials

The study-specific summary data included in the meta-analysis can be obtained from the corresponding authors at yxia@cmu.edu.cn.

Abbreviations

AAPC:

Average annual percent change

CI:

Confidence interval

Covid-19:

Corona Virus Disease 2019

HCC:

Hepatocellular carcinoma

MAFLD:

Metabolic-associated fatty liver disease

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

WHO:

World Health Organization

References

  1. Ahmad E, Lim S, Lamptey R, Webb DR, Davies MJ. Type 2 diabetes. Lancet (London, England). 2022;400(10365):1803–20.

    Article  PubMed  Google Scholar 

  2. IDF diabetes Atlas. 9th edn. Brussels, Belgium: International Diabetes Federation: International Diabetes Federation; 2019 Available from: https://www.diabetesatlas.org.

  3. Tinajero MG, Malik VS. An Update on the Epidemiology of Type 2 Diabetes: A Global Perspective. Endocrinol Metab Clin North Am. 2021;50(3):337–55.

    Article  PubMed  Google Scholar 

  4. Ogurtsova K, Guariguata L, Barengo NC, Ruiz PL-D, Sacre JW, Karuranga S, et al. IDF diabetes Atlas Global estimates of undiagnosed diabetes in adults for 2021. Diabetes Res Clin Pract. 2022;183:109118.

    Article  PubMed  Google Scholar 

  5. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801.

    Article  PubMed  Google Scholar 

  6. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, MD). 2016;64(1):73–84.

    Article  PubMed  Google Scholar 

  7. Rinella M, Charlton M. The globalization of nonalcoholic fatty liver disease: Prevalence and impact on world health. Hepatology (Baltimore, MD). 2016;64(1):19–22.

    Article  PubMed  Google Scholar 

  8. Tanase DM, Gosav EM, Costea CF, Ciocoiu M, Lacatusu CM, Maranduca MA, et al. The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). J Diabetes Res. 2020;2020:3920196.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments. Nat Rev Gastroenterol Hepatol. 2021;18(9):599–612.

    Article  PubMed  Google Scholar 

  10. Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 2022;10(4):284–96.

    Article  PubMed  Google Scholar 

  11. Younossi ZM. Non-alcoholic fatty liver disease - A global public health perspective. J Hepatol. 2019;70(3):531–44.

    Article  PubMed  Google Scholar 

  12. Loomba R, Abraham M, Unalp A, Wilson L, Lavine J, Doo E, et al. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis. Hepatology (Baltimore, MD). 2012;56(3):943–51.

    Article  PubMed  Google Scholar 

  13. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43(8):617–49.

    Article  PubMed  Google Scholar 

  14. Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic Fatty Liver Disease and Risk of Incident Type 2 Diabetes: A Meta-analysis. Diabetes Care. 2018;41(2):372–82.

    Article  CAS  PubMed  Google Scholar 

  15. Morrison AE, Zaccardi F, Khunti K, Davies MJ. Causality between non-alcoholic fatty liver disease and risk of cardiovascular disease and type 2 diabetes: A meta-analysis with bias analysis. Liver Int. 2019;39(3):557–67.

    Article  CAS  PubMed  Google Scholar 

  16. Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, Nascimbeni F, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31(5):936–44.

    Article  CAS  PubMed  Google Scholar 

  17. Mantovani A, Petracca G, Beatrice G, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut. 2021;70(5):962–9.

    Article  CAS  PubMed  Google Scholar 

  18. Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73(1):202–9.

    Article  PubMed  Google Scholar 

  19. Nan Y, An J, Bao J, Chen H, Chen Y, Ding H, et al. The Chinese Society of Hepatology position statement on the redefinition of fatty liver disease. J Hepatol. 2021;75(2):454–61.

    Article  CAS  PubMed  Google Scholar 

  20. Moher D, Liberati A, Tetzlaff J, Altman DG, Group, P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals Int Med. 2009;151(4):264–9.

    Article  Google Scholar 

  21. Sutton AJ, Song F, Gilbody SM, Abrams KR. Modelling publication bias in meta-analysis: a review. Stat Methods Med Res. 2000;9(5):421–45.

    Article  CAS  PubMed  Google Scholar 

  22. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.

    Article  PubMed  Google Scholar 

  23. Hu J, Dong Y, Chen X, Liu Y, Ma D, Liu X, et al. Prevalence of suicide attempts among Chinese adolescents: A meta-analysis of cross-sectional studies. Compr Psychiatry. 2015;61:78–89.

    Article  PubMed  Google Scholar 

  24. Higgins J, Green SR. Cochrane Handbook for Systematic Review of Interventions. 2011. Version 5.1.0. http://handbook-5-1.cochrane.org.

  25. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6.

    Article  PubMed  Google Scholar 

  26. Shimada M, Hashimoto E, Kaneda H, Noguchi S, Hayashi N. Nonalcoholic steatohepatitis: risk factors for liver fibrosis. Hepatol Res. 2002;24(4):429–38.

    Article  PubMed  Google Scholar 

  27. Shi YW, Wang QY, Zhao XY, Sun YM, Kong YY, Ou XJ, et al. Non-obese patients with nonalcoholic fatty liver disease may use a lower liver stiffness cut-off to assess fibrosis stages. J Dig Dis. 2020;21(5):279–86.

    Article  PubMed  Google Scholar 

  28. Kichian K, McLean R, Gramlich LM, Bailey RJ, Bain VG. Nonalcoholic fatty liver disease in patients investigated for elevated liver enzymes. Can J Gastroenterol. 2003;17(1):38–42.

    Article  PubMed  Google Scholar 

  29. Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clinical Gastroenterol Hepatol. 2004;2(3):262–5.

    Article  Google Scholar 

  30. Han E, Kim MK, Im SS, Jang BK, Kim HS. Non-alcoholic fatty liver disease and sarcopenia is associated with the risk of albuminuria independent of insulin resistance, and obesity. J Diabetes Complications. 2022;36(8):108253.

    Article  CAS  PubMed  Google Scholar 

  31. Bahcecioglu IH, Koruk M, Yilmaz O, Bolukbas C, Bolukbas F, Tuncer I, et al. Demographic and clinicopathological characteristics of nonalcoholic fatty liver disease in the East-Southeastern Anatolia regions in Turkey. Med Princ Pract. 2006;15(1):62–8.

    Article  PubMed  Google Scholar 

  32. Nonomura A, Enomoto Y, Takeda M, Tamura T, Kasai T, Yoshikawa T, et al. Clinical and pathological features of non-alcoholic steatohepatitis. Hepatol Res. 2005;33(2):116–21.

    Article  PubMed  Google Scholar 

  33. Ong JP, Elariny H, Collantes R, Younoszai A, Chandhoke V, Reines HD, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg. 2005;15(3):310–5.

    Article  PubMed  Google Scholar 

  34. Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY. Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease. Dig Dis Sci. 2005;50(12):2338–43.

    Article  PubMed  Google Scholar 

  35. VoPham T, Kim NJ, Berry K, Mendoza JA, Kaufman JD, Ioannou GN. PM(2.5) air pollution exposure and nonalcoholic fatty liver disease in the Nationwide Inpatient Sample. Environ Res. 2022;213:113611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Thomas CE, Yu YC, Luu HN, Wang R, Paragomi P, Behari J, et al. Neutrophil-lymphocyte ratio in relation to risk of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease. Cancer Med. 2023;12(3):3589–600.

    Article  CAS  PubMed  Google Scholar 

  37. Lima ML, Mourão SC, Diniz MT, Leite VH. Hepatic histopathology of patients with morbid obesity submitted to gastric bypass. Obes Surg. 2005;15(5):661–9.

    Article  PubMed  Google Scholar 

  38. Weston SR, Leyden W, Murphy R, Bass NM, Bell BP, Manos MM, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology (Baltimore, MD). 2005;41(2):372–9.

    Article  PubMed  Google Scholar 

  39. Arun J, Clements RH, Lazenby AJ, Leeth RR, Abrams GA. The prevalence of nonalcoholic steatohepatitis is greater in morbidly obese men compared to women. Obes Surg. 2006;16(10):1351–8.

    Article  PubMed  Google Scholar 

  40. Wong VW, Hui AY, Tsang SW, Chan JL, Tse AM, Chan KF, et al. Metabolic and adipokine profile of Chinese patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2006;4(9):1154–61.

    Article  CAS  PubMed  Google Scholar 

  41. Wong VW, Hui AY, Tsang SW, Chan JL, Wong GL, Chan AW, et al. Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2006;24(8):1215–22.

    Article  CAS  PubMed  Google Scholar 

  42. Riley TR 3rd, Kahn A. Risk factors and ultrasound can predict chronic hepatitis caused by nonalcoholic fatty liver disease. Dig Dis Sci. 2006;51(1):41–4.

    Article  PubMed  Google Scholar 

  43. Fan JG, Li F, Cai XB, Peng YD, Ao QH, Gao Y. Effects of nonalcoholic fatty liver disease on the development of metabolic disorders. J Gastroenterol Hepatol. 2007;22(7):1086–91.

    Article  CAS  PubMed  Google Scholar 

  44. Khurram M, Ashraf MM. A clinical and biochemical profile of biopsy-proven non-alcoholic Fatty liver disease subjects. J Coll Physicians Surg Pak JCPSP. 2007;17(9):531–4.

    PubMed  Google Scholar 

  45. Zhang L, Pu K, Chai Z, Dixon JB. Family history of coronary heart disease is associated with a higher incidence of nonalcoholic fatty liver disease Central obesity the likely link. Obes Res Clin Pract. 2007;1(2):I–ii.

    Article  PubMed  Google Scholar 

  46. Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57(10):1441–7.

    Article  CAS  PubMed  Google Scholar 

  47. De Lusong MA, Labio E, Daez L, Gloria V. Non-alcoholic fatty liver disease in the Philippines: comparable with other nations? World J Gastroenterol. 2008;14(6):913–7.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hossain N, Afendy A, Stepanova M, Nader F, Srishord M, Rafiq N, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(11):1224–9 (1229.e1221-1222).

    Article  CAS  PubMed  Google Scholar 

  49. Bjørnå ER, Engelsen MT, El-Serag HB, Ness-Jensen E. Prevalence and risk factors of nonalcoholic fatty liver disease in a general population, the HUNT study. Scand J Gastroenterol. 2023;58(5):505–11.

    Article  PubMed  Google Scholar 

  50. Kashyap SR, Diab DL, Baker AR, Yerian L, Bajaj H, Gray-McGuire C, et al. Triglyceride levels and not adipokine concentrations are closely related to severity of nonalcoholic fatty liver disease in an obesity surgery cohort. Obesity (Silver Spring, Md). 2009;17(9):1696–701.

    Article  CAS  PubMed  Google Scholar 

  51. Sung KC, Ryan MC, Wilson AM. The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects. Atherosclerosis. 2009;203(2):581–6.

    Article  CAS  PubMed  Google Scholar 

  52. Frith J, Day CP, Henderson E, Burt AD, Newton JL. Non-alcoholic fatty liver disease in older people. Gerontology. 2009;55(6):607–13.

    Article  CAS  PubMed  Google Scholar 

  53. Poster exhibition. Hepatology international. 2009;3(1):86–220. PMID: 19669375.

  54. Abu-Freha N, Cohen B, Weissmann S, Hizkiya R, Abu-Hammad R, Taha G, et al. Comorbidities and Outcomes among Females with Non-Alcoholic Fatty Liver Disease Compared to Males. Biomedicines. 2022;10(11):2908.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234–8.

    Article  PubMed  Google Scholar 

  56. Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology (Baltimore, MD). 2010;52(3):913–24.

    Article  CAS  PubMed  Google Scholar 

  57. Doycheva I, Zhang T, Amjad W, Thuluvath PJ. Diabetes and Hepatocellular Carcinoma: Incidence Trends and Impact of Liver Disease Etiology. J Clin Exp Hepatol. 2020;10(4):296–303.

    Article  PubMed  Google Scholar 

  58. Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42(7):503–8.

    Article  CAS  PubMed  Google Scholar 

  59. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;59(9):1265–9.

    Article  PubMed  Google Scholar 

  60. Gokulakrishnan K, Anjana RM, Indulekha K, Anuradha S, Mohan V. Association of hypoadiponectinemia with non-alcoholic fatty liver disease in urban south Indians–(CURES - 81). Indian J Med Res. 2010;132:271–7.

    CAS  PubMed  Google Scholar 

  61. Liu CC, Hung CL, Shih SC, Ko HJ, Lu YT, Wu YJ, et al. Age-related Differences in the Clinical Presentation, Associated Metabolic Abnormality, and Estimated Cardiovascular Risks from Nonalcoholic Fatty Liver Disease: A Cross-sectional Study from Health Evaluation Center in Taiwan. Int J Gerontol. 2010;4(4):184–91.

    Article  CAS  Google Scholar 

  62. Manchanayake J, Chitturi S, Nolan C, Farrell GC. Postprandial hyperinsulinemia is universal in non-diabetic patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2011;26(3):510–6.

    Article  CAS  PubMed  Google Scholar 

  63. Bianchi G, Bertaccini G, et al. 337 NON ALCOHOLIC FATTY LIVER DISEASE AND AGING. PREVALENCE AND ASSOCIATED FACTORS. J Hepatol. 2010;52:S141. https://search.ebscohost.com/login.aspx?direct=true&db=edsbl&AN=RN268932148&lang=zh-cn&site=eds-live.

  64. Shams ME, Al-Gayyar MM, Barakat EA. Type 2 Diabetes Mellitus-Induced Hyperglycemia in patients with NAFLD and normal LFTs: Relationship to Lipid Profile, Oxidative Stress and Pro-Inflammatory Cytokines. Sci Pharm. 2011;79(3):623–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Touzin NT, Bush KN, Williams CD, Harrison SA. Prevalence of colonic adenomas in patients with nonalcoholic fatty liver disease. Ther Adv Gastroenterol. 2011;4(3):169–76.

    Article  Google Scholar 

  66. Uslusoy HS, Nak SG, Gülten M. Noninvasive predictors for liver fibrosis in patients with nonalcoholic steatohepatitis. World J Hepatol. 2011;3(8):219–27.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Nakamura A, Yoneda M, Fujita K, Tajima K, Kikuchi K, Nakajima A, et al. Impact of glucose tolerance on the severity of non-alcoholic steatohepatitis. J Diabetes Investig. 2011;2(6):483–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Valenti L, Nobili V, Al-Serri A, Rametta R, Leathart JB, Zappa MA, et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol. 2011;55(6):1409–14.

    Article  CAS  PubMed  Google Scholar 

  69. Loosen SH, Roderburg C, Demir M, Qvartskhava N, Keitel V, Kostev K, et al. Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of osteoporosis and bone fractures. Z Gastroenterol. 2022;60(8):1221–7.

    Article  CAS  PubMed  Google Scholar 

  70. Machida T, Obara T, Miyazaki M, Inoue J, Mano N. Trends in drug prescriptions for type 2 diabetes, hypertension, and dyslipidemia among adults with non-alcoholic fatty liver disease. Ann Hepatol. 2022;27(4):100699.

    Article  CAS  PubMed  Google Scholar 

  71. Kim D, Choi SY, Park EH, Lee W, Kang JH, Kim W, et al. Nonalcoholic fatty liver disease is associated with coronary artery calcification. Hepatology (Baltimore, MD). 2012;56(2):605–13.

    Article  CAS  PubMed  Google Scholar 

  72. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140(1):124–31.

    Article  PubMed  Google Scholar 

  73. Cotrim HP, Parise ER, Oliveira CP, Leite N, Martinelli A, Galizzi J, et al. Nonalcoholic fatty liver disease in Brazil Clinical and histological profile. Annals Hepatol. 2011;10(1):33–7.

    Article  Google Scholar 

  74. Oladunjoye O, Oladunjoye AO, Dhital R, Poudel D, Oladiran OD, Oke IO, et al. A Retrospective Study of Hospitalizations in the USA: Proportion of Hospitalizations With Non-Alcoholic Fatty Liver Disease in Non-Obese Population. Cureus. 2021;13(9):e17869.

    PubMed  PubMed Central  Google Scholar 

  75. Tabibian JH, Lazo M, Durazo FA, Yeh HC, Tong MJ, Clark JM. Nonalcoholic fatty liver disease across ethno-racial groups: do Asian-American adults represent a new at-risk population? J Gastroenterol Hepatol. 2011;26(3):501–9.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Zein CO, Unalp A, Colvin R, Liu YC, McCullough AJ. Smoking and severity of hepatic fibrosis in nonalcoholic fatty liver disease. J Hepatol. 2011;54(4):753–9.

    Article  CAS  PubMed  Google Scholar 

  77. Barchetta I, Angelico F, Del Ben M, Baroni MG, Pozzilli P, Morini S, et al. Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes. BMC Med. 2011;9:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chandok N, Minuk G, Wengiel M, Uhanova J. Serum ferritin levels do not predict the stage of underlying non-alcoholic fatty liver disease. J Gastrointestin Liver Dis. 2012;21(1):53–8.

    PubMed  Google Scholar 

  79. Sun L, Lü SZ. Association between non-alcoholic fatty liver disease and coronary artery disease severity. Chin Med J. 2011;124(6):867–72.

    CAS  PubMed  Google Scholar 

  80. He S, Bao W, Shao M, Wang W, Wang C, Sun J, et al. Risk factors for non-alcoholic fatty liver disease in a Chinese population. Acta Gastro-Enterol Belg. 2011;74(4):503–8.

    Google Scholar 

  81. Francque S, De Maeght S, Adler M, Deltenre P, de Galocsy C, Orlent H, et al. High prevalence of advanced fibrosis in association with the metabolic syndrome in a Belgian prospective cohort of NAFLD patients with elevated ALT Results of the Belgian NAFLD registry. Acta Gastro-enterol Belg. 2011;74(1):9–16.

    CAS  Google Scholar 

  82. Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic Fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol. 2012;107(2):253–61.

    Article  CAS  PubMed  ADS  Google Scholar 

  83. Vuppalanchi R, Gould RJ, Wilson LA, Unalp-Arida A, Cummings OW, Chalasani N, et al. Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. Hep Intl. 2012;6(1):379–85.

    Article  Google Scholar 

  84. Bambha K, Belt P, Abraham M, Wilson LA, Pabst M, Ferrell L, et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology (Baltimore, MD). 2012;55(3):769–80.

    Article  CAS  PubMed  Google Scholar 

  85. Zhang X, Wong VW, Yip TC, Tse YK, Liang LY, Hui VW, et al. Colonoscopy and risk of colorectal cancer in patients with nonalcoholic fatty liver disease: a retrospective territory-wide cohort study. Hepatol Commun. 2021;5(7):1212–23.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Swellam M, Hamdy N. Association of nonalcoholic fatty liver disease with a single nucleotide polymorphism on the gene encoding leptin receptor. IUBMB Life. 2012;64(2):180–6.

    Article  CAS  PubMed  Google Scholar 

  87. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, et al. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine. 2012;91(6):319–27.

    Article  PubMed  Google Scholar 

  88. Valantinas J, Apanaviciene DA, Maroziene L, Sveikata A. The prevalence of metabolic risk factors among outpatients with diagnosed nonalcoholic fatty liver disease in Lithuania. Med Sci Monit. 2012;18(5):Ph57-62.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Gupta AC, Misra R, Sakhuja P, Singh Y, Basir SF, Sarin SK. Association of adiponectin gene functional polymorphisms (-11377C/G and +45T/G) with nonalcoholic fatty liver disease. Gene. 2012;496(1):63–7.

    Article  CAS  PubMed  Google Scholar 

  90. Fracanzani AL, Valenti L, Russello M, Miele L, Bertelli C, Bellia A, et al. Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease. PLoS ONE. 2012;7(7):e41183.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  91. Hatziagelaki E, Karageorgopoulos DE, Chounta A, Tsiavou A, Falagas ME, Dimitriadis G. Predictors of impaired glucose regulation in patients with non-alcoholic fatty liver disease. Exp Diabetes Res. 2012;2012:351974.

    Article  PubMed  Google Scholar 

  92. Shi L, Liu ZW, Li Y, Gong C, Zhang H, Song LJ, et al. The prevalence of nonalcoholic fatty liver disease and its association with lifestyle/dietary habits among university faculty and staff in Chengdu. Biomed Environ Sci BES. 2012;25(4):383–91.

    PubMed  Google Scholar 

  93. Al-hamoudi W, El-Sabbah M, Ali S, Altuwaijri M, Bedewi M, Adam M, et al. Epidemiological, clinical, and biochemical characteristics of Saudi patients with nonalcoholic fatty liver disease: a hospital-based study. Ann Saudi Med. 2012;32(3):288–92.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Goh SC, Ho EL, Goh KL. Prevalence and risk factors of non-alcoholic fatty liver disease in a multiracial suburban Asian population in Malaysia. Hep Intl. 2013;7(2):548–54.

    Article  Google Scholar 

  95. Kumar R, Rastogi A, Sharma MK, Bhatia V, Garg H, Bihari C, et al. Clinicopathological characteristics and metabolic profiles of non-alcoholic fatty liver disease in Indian patients with normal body mass index: Do they differ from obese or overweight non-alcoholic fatty liver disease? Indian J Endocrinol Metab. 2013;17(4):665–71.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Patel NS, Peterson MR, Lin GY, Feldstein A, Schnabl B, Bettencourt R, et al. Insulin Resistance Increases MRI-Estimated Pancreatic Fat in Nonalcoholic Fatty Liver Disease and Normal Controls. Gastroenterol Res Pract. 2013;2013:498296.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Abrams GA, Kunde SS, Lazenby AJ, Clements RH. Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease. Hepatol (Baltimore, MD). 2004;40(2):475–83.

    Article  Google Scholar 

  98. Ha Y, Hwang SG, Rim KS. The Association between Vitamin D Insufficiency and Nonalcoholic Fatty Liver Disease: A Population-Based Study. Nutrients. 2017;9(8):806.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Reddy SK, Hyder O, Marsh JW, Sotiropoulos GC, Paul A, Alexandrescu S, et al. Prevalence of nonalcoholic steatohepatitis among patients with resectable intrahepatic cholangiocarcinoma. J Gastrointest Surg. 2013;17(4):748–55.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Hashiba M, Ono M, Hyogo H, Ikeda Y, Masuda K, Yoshioka R, et al. Glycemic variability is an independent predictive factor for development of hepatic fibrosis in nonalcoholic fatty liver disease. PLoS ONE. 2013;8(11):e76161.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  101. Bakhshipour A, Kaykhaei MA, Moulaei N, Mashhadi MA. Prevalence of coeliac disease in patients with non-alcoholic fatty liver disease. Arab J Gastroenterol. 2013;14(3):113–5.

    Article  PubMed  Google Scholar 

  102. Ghamar Chehreh ME, Vahedi M, Pourhoseingholi MA, Ashtari S, Khedmat H, Amin M, et al. Estimation of diagnosis and treatment costs of non-alcoholic Fatty liver disease: a two-year observation. Hepat Mon. 2013;13(5):e7382.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Stepanova M, Rafiq N, Makhlouf H, Agrawal R, Kaur I, Younoszai Z, et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig Dis Sci. 2013;58(10):3017–23.

    Article  CAS  PubMed  Google Scholar 

  104. Cheah WL, Lee PY, Chang CT, Mohamed HJ, Wong SL. Prevalence of ultrasound diagnosed nonalcoholic fatty liver disease among rural indigenous community of Sarawak and its association with biochemical and anthropometric measures. Southeast Asian J Trop Med Public Health. 2013;44(2):309–17.

    PubMed  Google Scholar 

  105. Zelber-Sagi S, Lotan R, Shibolet O, Webb M, Buch A, Nitzan-Kaluski D, et al. Non-alcoholic fatty liver disease independently predicts prediabetes during a 7-year prospective follow-up. Liver Int. 2013;33(9):1406–12.

    Article  CAS  PubMed  Google Scholar 

  106. Chang Y, Jung HS, Yun KE, Cho J, Cho YK, Ryu S. Cohort study of non-alcoholic fatty liver disease, NAFLD fibrosis score, and the risk of incident diabetes in a Korean population. Am J Gastroenterol. 2013;108(12):1861–8.

    Article  CAS  PubMed  ADS  Google Scholar 

  107. Nakahara T, Hyogo H, Yoneda M, Sumida Y, Eguchi Y, Fujii H, et al. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol. 2014;49(11):1477–84.

    Article  CAS  PubMed  ADS  Google Scholar 

  108. Hyogo H, Yamagishi S, Maeda S, Fukami K, Ueda S, Okuda S, et al. Serum asymmetric dimethylarginine levels are independently associated with procollagen III N-terminal peptide in nonalcoholic fatty liver disease patients. Clin Exp Med. 2014;14(1):45–51.

    Article  CAS  PubMed  Google Scholar 

  109. Angulo P, George J, Day CP, Vanni E, Russell L, De la Cruz AC, et al. Serum ferritin levels lack diagnostic accuracy for liver fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014;12(7):1163-1169.e1161.

    Article  CAS  PubMed  Google Scholar 

  110. Loomba R, Wong R, Fraysse J, Shreay S, Li S, Harrison S, et al. Nonalcoholic fatty liver disease progression rates to cirrhosis and progression of cirrhosis to decompensation and mortality: a real world analysis of Medicare data. Aliment Pharmacol Ther. 2020;51(11):1149–59.

    Article  CAS  PubMed  Google Scholar 

  111. Li Y, Liu L, Wang B, Wang J, Chen D. Hematocrit is associated with fibrosis in patients with nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol. 2014;26(3):332–8.

    Article  PubMed  Google Scholar 

  112. Pulixi EA, Tobaldini E, Battezzati PM, D’Ingianna P, Borroni V, Fracanzani AL, et al. Risk of obstructive sleep apnea with daytime sleepiness is associated with liver damage in non-morbidly obese patients with nonalcoholic fatty liver disease. PLoS ONE. 2014;9(4):e96349.

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  113. Del Ben M, Polimeni L, Baratta F, Bartimoccia S, Carnevale R, Loffredo L, et al. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative stress in patients with Nonalcoholic Fatty Liver. Int J Hepatol. 2014;2014:784985.

    PubMed  PubMed Central  Google Scholar 

  114. Ybarra J, Fernández S, Sánchez-Hernández J, Romeo JH, Ballesta-Lopez C, Guell J, et al. Serum alanine aminotransferase predicts interventricular septum thickness and left ventricular mass in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2014;26(6):654–60.

    Article  CAS  PubMed  Google Scholar 

  115. Catanzaro R, Calabrese F, Occhipinti S, Anzalone MG, Italia A, Milazzo M, et al. Nonalcoholic fatty liver disease increases risk for gastroesophageal reflux symptoms. Dig Dis Sci. 2014;59(8):1939–45.

    Article  CAS  PubMed  Google Scholar 

  116. Pemmasani G, Yandrapalli S, Aronow W. Sex differences in cardiovascular diseases and associated risk factors in non-alcoholic steatohepatitis. Am J Cardiovasc Dis. 2020;10(4):362–6.

    PubMed  PubMed Central  Google Scholar 

  117. Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61(1):75–81.

    Article  CAS  PubMed  Google Scholar 

  118. Rakha EA, Adamson L, Bell E, Neal K, Ryder SD, Kaye PV, et al. Portal inflammation is associated with advanced histological changes in alcoholic and non-alcoholic fatty liver disease. J Clin Pathol. 2010;63(9):790–5.

    Article  PubMed  Google Scholar 

  119. Gianotti G, Cenni A, Bianchi G, Masetti M, Zappoli P, Muscari A, et al. Diastolic dysfunction and cardiovascular risk in old subjects: possible association with NAFLD? Arch Gerontol Geriatr. 2014;58(2):188–95.

    Article  PubMed  Google Scholar 

  120. Feng RN, Du SS, Wang C, Li YC, Liu LY, Guo FC, et al. Lean-non-alcoholic fatty liver disease increases risk for metabolic disorders in a normal weight Chinese population. World J Gastroenterol. 2014;20(47):17932–40.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Andrade GC, Fujise LH, Santana JEF, Oliveira F, Silva Rde C. Non-alcoholic fatty liver disease (NAFLD) in different populations A clinical and epidemiological study sample of São José do Rio Preto. Rev Assoc Med Bras (1992). 2016;62(3):218–26.

    Article  PubMed  Google Scholar 

  122. Cavalcante LN, Stefano JT, Machado MV, Mazo DF, Rabelo F, Sandes KA, et al. Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal. World J Hepatol. 2015;7(10):1433–8.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Shil BC, Saha M, Ahmed F, Dhar SC. Nonalcoholic Fatty Liver Disease: Study of Demographic and Predictive Factors. Euroasian J Hepato-gastroenterol. 2015;5(1):4–6.

    Article  Google Scholar 

  124. Hung CS, Tseng PH, Tu CH, Chen CC, Liao WC, Lee YC, et al. Nonalcoholic Fatty liver disease is associated With QT prolongation in the general population. J Am Heart Assoc. 2015;4(7):e001820.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Yamazaki H, Tsuboya T, Tsuji K, Dohke M, Maguchi H. Independent Association Between Improvement of Nonalcoholic Fatty Liver Disease and Reduced Incidence of Type 2 Diabetes. Diabetes Care. 2015;38(9):1673–9.

    Article  CAS  PubMed  Google Scholar 

  126. Chang CC, Wu CL, Su WW, Shih KL, Tarng DC, Chou CT, et al. Interferon gamma-induced protein 10 is associated with insulin resistance and incident diabetes in patients with nonalcoholic fatty liver disease. Sci Rep. 2015;5:10096.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  127. Long MT, Wang N, Larson MG, Mitchell GF, Palmisano J, Vasan RS, et al. Nonalcoholic fatty liver disease and vascular function: cross-sectional analysis in the Framingham heart study. Arterioscler Thromb Vasc Biol. 2015;35(5):1284–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kwak MS, Kim D, Chung GE, Kim W, Kim YJ, Yoon JH. Cholecystectomy is independently associated with nonalcoholic fatty liver disease in an Asian population. World J Gastroenterol. 2015;21(20):6287–95.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Praveenraj P, Gomes RM, Kumar S, Karthikeyan P, Shankar A, Parthasarathi R, et al. Prevalence and Predictors of Non-Alcoholic Fatty Liver Disease in Morbidly Obese South Indian Patients Undergoing Bariatric Surgery. Obes Surg. 2015;25(11):2078–87.

    Article  PubMed  Google Scholar 

  130. Käräjämäki AJ, Pätsi OP, Savolainen M, Kesäniemi YA, Huikuri H, Ukkola O. Non-alcoholic fatty liver disease as a predictor of atrial fibrillation in middle-aged population (OPERA Study). PLoS ONE. 2015;10(11):e0142937.

    Article  PubMed  PubMed Central  Google Scholar 

  131. Abdel-Razik A, Mousa N, Shabana W, Yassen AH, Abdelsalam M, Wahba MM, et al. De novo Portal Vein Thrombosis in Non-Cirrhotic Non-Alcoholic Fatty Liver Disease: A 9-Year Prospective Cohort Study. Front Med. 2021;8:650818.

    Article  Google Scholar 

  132. Idilman IS, Tuzun A, Savas B, Elhan AH, Celik A, Idilman R, et al. Quantification of liver, pancreas, kidney, and vertebral body MRI-PDFF in non-alcoholic fatty liver disease. Abdom Imaging. 2015;40(6):1512–9.

    Article  PubMed  Google Scholar 

  133. Du T, Yu X, Yuan G, Zhang J, Sun X. Combined influence of nonalcoholic fatty liver and body size phenotypes on diabetes risk. Cardiovasc Diabetol. 2015;14:144.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Tateishi R, Okanoue T, Fujiwara N, Okita K, Kiyosawa K, Omata M, et al. Clinical characteristics, treatment, and prognosis of non-B, non-C hepatocellular carcinoma: a large retrospective multicenter cohort study. J Gastroenterol. 2015;50(3):350–60.

    Article  CAS  PubMed  Google Scholar 

  135. Huang JF, Yeh ML, Yu ML, Huang CF, Dai CY, Hsieh MY, et al. Hyperuricemia inversely correlates with disease severity in Taiwanese nonalcoholic steatohepatitis patients. PLoS ONE. 2015;10(10):e0139796.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Kumar MS, Singh A, Jaryal AK, Ranjan P, Deepak KK, Sharma S, et al. Cardiovascular Autonomic Dysfunction in Patients of Nonalcoholic Fatty Liver Disease. Int J Hepatol. 2016;2016:5160754.

    Article  PubMed  PubMed Central  Google Scholar 

  137. Ballestri S, Nascimbeni F, Romagnoli D, Lonardo A. The independent predictors of non-alcoholic steatohepatitis and its individual histological features. Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment. Hepatol Res. 2016;46(11):1074–87.

    Article  CAS  PubMed  Google Scholar 

  138. Pelusi S, Petta S, Rosso C, Borroni V, Fracanzani AL, Dongiovanni P, et al. Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disease. PLoS ONE. 2016;11(9):e0163069.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Wu KT, Kuo PL, Su SB, Chen YY, Yeh ML, Huang CI, et al. Nonalcoholic fatty liver disease severity is associated with the ratios of total cholesterol and triglycerides to high-density lipoprotein cholesterol. J Clin Lipidol. 2016;10(2):420-425.e421.

    Article  PubMed  Google Scholar 

  140. Tapper EB, Lai M. Weight loss results in significant improvements in quality of life for patients with nonalcoholic fatty liver disease: A prospective cohort study. Hepatol (Baltimore, MD). 2016;63(4):1184–9.

    Article  Google Scholar 

  141. Uhanova J, Minuk G, Lopez Ficher F, Chandok N. Nonalcoholic Fatty Liver Disease in Canadian First Nations and Non-First Nations Patients. Can J Gastroenterol Hepatol. 2016;2016:6420408.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Goh GB, Issa D, Lopez R, Dasarathy S, Dasarathy J, Sargent R, et al. The development of a non-invasive model to predict the presence of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2016;31(5):995–1000.

    Article  CAS  PubMed  Google Scholar 

  143. Petrović G, Bjelaković G, Benedeto-Stojanov D, Nagorni A, Brzački V, Marković-Živković B. Obesity and metabolic syndrome as risk factors for the development of non-alcoholic fatty liver disease as diagnosed by ultrasound. Vojnosanit Pregl. 2016;73(10):910–20.

    Article  PubMed  Google Scholar 

  144. Hagström H, Nasr P, Ekstedt M, Kechagias S, Önnerhag K, Nilsson E, et al. Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease. Scand J Gastroenterol. 2017;52(2):159–65.

    Article  PubMed  Google Scholar 

  145. Conti F, Vukotic R, Foschi FG, Domenicali M, Giacomoni P, Savini S, et al. Transient elastography in healthy subjects and factors influencing liver stiffness in non-alcoholic fatty liver disease: An Italian community-based population study. Dig Liver Dis. 2016;48(11):1357–63.

    Article  PubMed  Google Scholar 

  146. Koo BK, Kim D, Joo SK, Kim JH, Chang MS, Kim BG, et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J Hepatol. 2017;66(1):123–31.

    Article  PubMed  Google Scholar 

  147. Fracanzani AL, Pisano G, Consonni D, Tiraboschi S, Baragetti A, Bertelli C, et al. Epicardial Adipose Tissue (EAT) thickness is associated with cardiovascular and liver damage in Nonalcoholic fatty liver disease. PLoS ONE. 2016;11(9):e0162473.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Treeprasertsuk S, Piyachaturawat P, Soontornmanokul T, Komolmit P, Wisedopas-Klaikaew N, Tangkijavanich P. Accuracy of noninvasive scoring systems to assess advanced liver fibrosis in Thai patients with nonalcoholic fatty liver disease. Asian Biomed. 2016;10:S49–55-S55.

    CAS  Google Scholar 

  149. Wong VW, Wong GL, Yeung JC, Fung CY, Chan JK, Chang ZH, et al. Long-term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: A prospective cohort study. Hepatol (Baltimore, MD). 2016;63(3):754–63.

    Article  Google Scholar 

  150. Dichtel LE, Corey KE, Misdraji J, Bredella MA, Schorr M, Osganian SA, et al. The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol. 2017;8(1): e217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Toshikuni N, Tsuchishima M, Fukumura A, Arisawa T, Tsutsumi M. Associations of fatty liver disease with Hypertension, Diabetes, and Dyslipidemia: comparison between alcoholic and nonalcoholic Steatohepatitis. Gastroenterol Res Pract. 2017;2017:9127847.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Chan WK, Treeprasertsuk S, Imajo K, Nakajima A, Seki Y, Kasama K, et al. Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative. Aliment Pharmacol Ther. 2018;47(6):816–25.

    Article  CAS  PubMed  Google Scholar 

  153. van den Berg EH, Gruppen EG, James RW, Bakker SJL, Dullaart RPF. Serum paraoxonase 1 activity is paradoxically maintained in nonalcoholic fatty liver disease despite low HDL cholesterol. J Lipid Res. 2019;60(1):168–75.

    Article  PubMed  Google Scholar 

  154. Wen X, Wang S, Taveira TH, Akhlaghi F. Required warfarin dose and time in therapeutic range in patients with diagnosed Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH). PLoS ONE. 2021;16(9):e0251665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Lee HW, Kim BK, Kim SU, Park JY, Kim DY, Ahn SH, et al. Prevalence and predictors of significant fibrosis among Subjects with Transient Elastography-Defined Nonalcoholic Fatty Liver Disease. Dig Dis Sci. 2017;62(8):2150–8.

    Article  PubMed  Google Scholar 

  156. Petta S, Eslam M, Valenti L, Bugianesi E, Barbara M, Cammà C, et al. Metabolic syndrome and severity of fibrosis in nonalcoholic fatty liver disease: An age-dependent risk profiling study. Liver Int. 2017;37(9):1389–96.

    Article  CAS  PubMed  Google Scholar 

  157. Singh A, Kumar MS, Jaryal AK, Ranjan P, Deepak KK, Sharma S, et al. Diabetic status and grade of nonalcoholic fatty liver disease are associated with lower baroreceptor sensitivity in patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2017;29(8):956–61.

    Article  CAS  PubMed  Google Scholar 

  158. Weinstein G, Zelber-Sagi S, Preis SR, Beiser AS, DeCarli C, Speliotes EK, et al. Association of Nonalcoholic Fatty Liver Disease With Lower Brain Volume in Healthy Middle-aged Adults in the Framingham Study. JAMA Neurol. 2018;75(1):97–104.

    Article  PubMed  Google Scholar 

  159. Morio R, Hyogo H, Hatooka M, Morio K, Kan H, Kobayashi T, et al. The risk of transient postprandial oxyhypoglycemia in nonalcoholic fatty liver disease. J Gastroenterol. 2017;52(2):253–62.

    Article  CAS  PubMed  Google Scholar 

  160. Patel YA, Gifford EJ, Glass LM, McNeil R, Turner MJ, Han B, et al. Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration. Aliment Pharmacol Ther. 2018;47(2):268–78.

    Article  CAS  PubMed  Google Scholar 

  161. Dallio M, Masarone M, Errico S, Gravina AG, Nicolucci C, Di Sarno R, et al. Role of bisphenol A as environmental factor in the promotion of non-alcoholic fatty liver disease: in vitro and clinical study. Aliment Pharmacol Ther. 2018;47(6):826–37.

    Article  CAS  PubMed  Google Scholar 

  162. Jun DW, Kim SG, Park SH, Jin SY, Lee JS, Lee JW, et al. External validation of the non-alcoholic fatty liver disease fibrosis score for assessing advanced fibrosis in Korean patients. J Gastroenterol Hepatol. 2017;32(5):1094–9.

    Article  CAS  PubMed  Google Scholar 

  163. Kim S, Chang Y, Sung E, Kim CH, Yun KE, Jung HS, et al. Non-alcoholic fatty liver disease and the development of nephrolithiasis: A cohort study. PLoS ONE. 2017;12(10): e0184506.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Tasneem AA, Luck NH, Majid Z. Factors predicting non-alcoholic steatohepatitis (NASH) and advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Trop Doct. 2018;48(2):107–12.

    Article  PubMed  Google Scholar 

  165. Bae JC, Kim SK, Han JM, Kwon S, Lee DY, Kim J, et al. Additive effect of non-alcoholic fatty liver disease on the development of diabetes in individuals with metabolic syndrome. Diabetes Res Clin Pract. 2017;129:136–43.

    Article  CAS  PubMed  Google Scholar 

  166. Abdeldyem SM, Goda T, Khodeir SA, Abou Saif S, Abd-Elsalam S. Nonalcoholic fatty liver disease in patients with acute ischemic stroke is associated with more severe stroke and worse outcome. J Clin Lipidol. 2017;11(4):915–9.

    Article  PubMed  Google Scholar 

  167. Kim SS, Cho HJ, Kim HJ, Kang DR, Berry JR, Kim JH, et al. Nonalcoholic fatty liver disease as a sentinel marker for the development of diabetes mellitus in non-obese subjects. Dig Liver Dis. 2018;50(4):370–7.

    Article  PubMed  Google Scholar 

  168. Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. Hepatol Commun. 2018;2(1):48–57.

    Article  PubMed  Google Scholar 

  169. Peng H, Wang M, Pan L, Cao Z, Yao Z, Chen Q, et al. Associations of serum multivitamin levels with the risk of non-alcoholic fatty liver disease A population-based cross-sectional study in U.S. adults. Front Nut. 2022;9:962705.

    Article  Google Scholar 

  170. Janovsky C, Cesena FH, Valente VAT, Conceição RDO, Santos RD, Bittencourt MS. Association between Thyroid-Stimulating Hormone Levels and Non-Alcoholic Fatty Liver Disease Is Not Independent from Metabolic Syndrome Criteria. Eur Thyroid J. 2018;7(6):302–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Yoneda M, Yamamoto T, Honda Y, Imajo K, Ogawa Y, Kessoku T, et al. Risk of cardiovascular disease in patients with fatty liver disease as defined from the metabolic dysfunction associated fatty liver disease or nonalcoholic fatty liver disease point of view: a retrospective nationwide claims database study in Japan. J Gastroenterol. 2021;56(11):1022–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Shahab O, Biswas R, Paik J, Bush H, Golabi P, Younossi ZM. Among Patients With NAFLD, Treatment of Dyslipidemia Does Not Reduce Cardiovascular Mortality. Hepatol Commun. 2018;2(10):1227–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Patel P, Hossain F, Horsfall LU, Banh X, Hayward KL, Williams S, et al. A pragmatic approach identifies a high Rate of Nonalcoholic fatty liver disease with advanced Fibrosis in diabetes clinics and at-risk populations in primary care. Hepatol Commun. 2018;2(8):893–905.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Akuta N, Kawamura Y, Arase Y, Saitoh S, Fujiyama S, Sezaki H, et al. Hepatocellular carcinoma is the most common liver-related complication in patients with histopathologically-confirmed NAFLD in Japan. BMC Gastroenterol. 2018;18(1):165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kwon YJ, Kim JH, Jung DH. Association between nonalcoholic fatty liver disease and intraocular pressure in Korean adults. J Glaucoma. 2018;27(12):1099–104.

    Article  PubMed  Google Scholar 

  176. Qin S, Wang S, Wang X, Wang J. Liver stiffness assessed by transient elastography as a potential indicator of chronic kidney disease in patients with nonalcoholic fatty liver disease. J Clin Lab Anal. 2019;33(2):e22657.

    Article  PubMed  Google Scholar 

  177. Chung GE, Youn J, Kim YS, Lee JE, Yang SY, Lim JH, et al. Dietary patterns are associated with the prevalence of nonalcoholic fatty liver disease in Korean adults. Nutrition. 2019;62:32–8.

    Article  PubMed  Google Scholar 

  178. De Silva S, Li W, Kemos P, Brindley JH, Mecci J, Samsuddin S, et al. Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of South Asian descent. Front Gastroenterol. 2018;9(2):115–21.

    Article  Google Scholar 

  179. Koo BK, Um SH, Seo DS, Joo SK, Bae JM, Park JH, et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int. 2018;38(4):695–705.

    Article  CAS  PubMed  Google Scholar 

  180. Mazzotti A, Caletti MT, Brodosi L, Di Domizio S, Forchielli ML, Petta S, et al. An internet-based approach for lifestyle changes in patients with NAFLD: Two-year effects on weight loss and surrogate markers. J Hepatol. 2018;69(5):1155–63.

    Article  PubMed  Google Scholar 

  181. Kimura T, Tanaka N, Fujimori N, Sugiura A, Yamazaki T, Joshita S, et al. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol. 2018;24(13):1440–50.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Labenz C, Huber Y, Kalliga E, Nagel M, Ruckes C, Straub BK, et al. Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany. Aliment Pharmacol Ther. 2018;48(10):1109–16.

    Article  CAS  PubMed  Google Scholar 

  183. Pardhe BD, Shakya S, Bhetwal A, Mathias J, Khanal PR, Pandit R, et al. Metabolic syndrome and biochemical changes among non-alcoholic fatty liver disease patients attending a tertiary care hospital of Nepal. BMC Gastroenterol. 2018;18(1):109.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Tuttolomondo A, Petta S, Casuccio A, Maida C, Corte VD, Daidone M, et al. Reactive hyperemia index (RHI) and cognitive performance indexes are associated with histologic markers of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD): a case control study. Cardiovasc Diabetol. 2018;17(1):28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Li H, Hu B, Wei L, Zhou L, Zhang L, Lin Y, et al. Non-alcoholic fatty liver disease is associated with stroke severity and progression of brainstem infarctions. Eur J Neurol. 2018;25(3):577-e534.

    Article  CAS  PubMed  Google Scholar 

  186. Ooi GJ, Burton PR, Bayliss J, Raajendiran A, Earnest A, Laurie C, et al. Effect of Body Mass Index, Metabolic Health and Adipose Tissue inflammation on the severity of non-alcoholic fatty liver disease in Bariatric surgical patients: a prospective study. Obes Surg. 2019;29(1):99–108.

    Article  PubMed  Google Scholar 

  187. de la Aller Fuente R, Mora Cuadrado N, Tafur C, de la López Gómez JJ, Gómez Cuesta S, García Sánchez MC, et al. Histopathological differences in patients with biopsyproven nonalcoholic fatty liver disease with and without type 2 diabetes. Endocrinol Diabetes nutr. 2018;65(6):354–60.

    Article  Google Scholar 

  188. Rabelo F, Stefano JT, Cavaleiro AM, Lima RVC, de Campos Mazo DF, Carrilho FJ, et al. Association between the CYBA and NOX4 genes of NADPH oxidase and its relationship with metabolic syndrome in non-alcoholic fatty liver disease in Brazilian population. Hepatobiliary Pancreat Dis Int. 2018;17(4):330–5.

    Article  CAS  PubMed  Google Scholar 

  189. Nigam P, Pandey RP, Pawar M, Indurkar M. CLINICAL PROFILE OF NAFLD PATIENTS AND ITS CORRELATION WITH METABOLIC SYNDROME. J Evol Med Dent Sci. 2018;7(4):433–6.

    Article  CAS  Google Scholar 

  190. Omrani HR, Golmohamadi S, Asadi N. Non-Alcoholic Fatty Liver Disease and Associated Risk Factors among Hemodialysis Patients. 2018. https://doi.org/10.5742/MEWFM.2018.93354. https://search.ebscohost.com/login.aspx?direct=true&db=edsaml&AN=edsaml.117456&lang=zh-cn&site=eds-live.

  191. Gordon SC, Fraysse J, Li S, Ozbay AB, Wong RJ. Disease Severity Is Associated With Higher Healthcare Utilization in Nonalcoholic Steatohepatitis Medicare Patients. Am J gastroenterol. 2020;115(4):562–74.

    Article  Google Scholar 

  192. Shah AS, Khan S, Rahim H, Chishti KA, Khan AG. Prevalence of non alcoholic fatty liver and Non alcoholic Steatohepatitis in Peshawar Cantonment, Khyber Pakhtunkhwa Pakistan. Pak J Pharm Sci. 2018;31(1):193–8.

    PubMed  Google Scholar 

  193. Chen HJ, Yang HY, Hsueh KC, Shen CC, Chen RY, Yu HC, et al. Increased risk of osteoporosis in patients with nonalcoholic fatty liver disease: A population-based retrospective cohort study. Medicine. 2018;97(42):e12835.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Alam S, Anam K, Islam S, Mustafa G, Mamun AA, Ahmad N. Clinical, anthropometric, biochemical and histological character of nonalcoholic fatty liver disease without Insulin Resistance. J Clin Exp Hepatol. 2019;9(2):176–81.

    Article  PubMed  Google Scholar 

  195. Hamaguchi M, Hashimoto Y, Obora A, Kojima T, Fukui M. Non-alcoholic fatty liver disease with obesity as an independent predictor for incident gastric and colorectal cancer: a population-based longitudinal study. BMJ Open Gastroenterol. 2019;6(1):e000295.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Khammas ASA, Hassan HA, Salih SQM, Kadir H, Ibrahim RM, Nasir NNM, et al. Prevalence and risk factors of sonographically detected non alcoholic fatty liver disease in a screening centre in Klang Valley, Malaysia: an observational cross-sectional study. Porto Biomed J. 2019;4(2):e31.

    Article  PubMed  Google Scholar 

  197. Moolla A, Motohashi K, Marjot T, Shard A, Ainsworth M, Gray A, et al. A multidisciplinary approach to the management of NAFLD is associated with improvement in markers of liver and cardio-metabolic health. Front Gastroenterol. 2019;10(4):337–46.

    Article  Google Scholar 

  198. Nabi O, Lacombe K, Boursier J, Mathurin P, Zins M, Serfaty L. Prevalence and Risk Factors of Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in General Population: the French Nationwide NASH-CO Study. Gastroenterol. 2020;159(2):791-793.e792.

    Article  CAS  Google Scholar 

  199. Shida T, Oshida N, Oh S, Okada K, Shoda J. Progressive reduction in skeletal muscle mass to visceral fat area ratio is associated with a worsening of the hepatic conditions of non-alcoholic fatty liver disease. Diabetes Metab Syndr Obes. 2019;12:495–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Tsou P, Wu CJ. Serum Vitamin E Levels of Adults with Nonalcoholic Fatty Liver Disease: An Inverse Relationship with All-Cause Mortality in Non-Diabetic but Not in Pre-Diabetic or Diabetic Subjects. J Clin Med. 2019;8(7):1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Azuma S, Asahina Y, Kakinuma S, Azuma K, Miyoshi M, Inoue E, et al. Diabetic Retinopathy as a Risk Factor Associated with the Development of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. Dig Dis. 2019;37(3):247–54.

    Article  PubMed  Google Scholar 

  202. Blackett JW, Verna EC, Lebwohl B. Increased Prevalence of Colorectal Adenomas in Patients with Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. Dig Dis. 2020;38(3):222–30.

    Article  PubMed  Google Scholar 

  203. Cho HJ, Hwang S, Park JI, Yang MJ, Hwang JC, Yoo BM, et al. Improvement of Nonalcoholic fatty liver disease reduces the risk of type 2 Diabetes Mellitus. Gut and liver. 2019;13(4):440–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Jaafar RF, Hajj Ali AM, Zaghal AM, Kanso M, Habib SG, Halaoui AF, et al. Fibroscan and low-density lipoprotein as determinants of severe liver fibrosis in diabetic patients with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2019;31(12):1540–4.

    Article  CAS  PubMed  Google Scholar 

  205. Kim D, Kim W, Joo SK, Kim JH, Harrison SA, Younossi ZM, et al. Predictors of nonalcoholic steatohepatitis and significant fibrosis in non-obese nonalcoholic fatty liver disease. Liver Int. 2019;39(2):332–41.

    Article  CAS  PubMed  Google Scholar 

  206. Maev IV, Samsonov AA, Palgova LK, Pavlov CS, Shirokova E, Starostin KM. Real-world comorbidities and treatment patterns among patients with non-alcoholic fatty liver disease receiving phosphatidylcholine as adjunctive therapy in Russia. BMJ Open Gastroenterol. 2019;6(1):e000307.

    Article  PubMed  PubMed Central  Google Scholar 

  207. Udelsman BV, Corey KE, Lindvall C, Gee DW, Meireles OR, Hutter MM, et al. Risk factors and prevalence of liver disease in review of 2557 routine liver biopsies performed during bariatric surgery. Surg Obes Relat Dis. 2019;15(6):843–9.

    Article  PubMed  Google Scholar 

  208. Ciardullo S, Monti T, Sala I, Grassi G, Mancia G, Perseghin G. Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in US Adults Across Blood Pressure Categories. Hypertension. 2020;76(2):562–8.

    Article  CAS  PubMed  Google Scholar 

  209. Yılmaz Y, Kanı HT, Demirtaş C, Kaya E, Sapmaz AF, Qutranji L, et al. Growing burden of nonalcoholic fatty liver disease in Turkey: A single-center experience. Turkish J Gastroenterol. 2019;30(10):892–8.

    Article  Google Scholar 

  210. Han J, Wang Y, Yuan Z, Liu L, Zhao M, Guan Q, et al. Nonalcoholic fatty liver disease represents a greater metabolic burden in patients with atherosclerosis: A cross-sectional study. Medicine. 2019;98(11):e14896.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Mahamid M, Khoury T, Mahamid B, Sbeit W, Mari A, Nseir W. The interplay between abdominal aortic aneurysm, metabolic syndrome and fatty liver disease: a retrospective case-control study. Diabetes Metabolic Syndr Obes. 2019;12:1743–9.

    Article  CAS  Google Scholar 

  212. Zhou X, Li Y, Zhang X, Guan YY, Puentes Y, Zhang F, et al. Independent markers of nonalcoholic fatty liver disease in a gentrifying population-based Chinese cohort. Diabetes Metab Res Rev. 2019;35(5):e3156.

    Article  PubMed  PubMed Central  Google Scholar 

  213. Wu J, Zeng C, Yang Z, Li X, Lei G, Xie D, et al. Association Between Dietary Selenium Intake and the Prevalence of Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. J Am Coll Nutr. 2020;39(2):103–11.

    Article  PubMed  Google Scholar 

  214. Gawrieh S, Wilson LA, Cummings OW, Clark JM, Loomba R, Hameed B, et al. Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels. Am J Gastroenterol. 2019;114(10):1626–35.

    Article  PubMed  PubMed Central  Google Scholar 

  215. Barb D, Bril F, Kalavalapalli S, Cusi K. Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes. J Clin Endocrinol Metab. 2019;104(8):3327–36.

    Article  PubMed  PubMed Central  Google Scholar 

  216. Zhang X, Zhou X, Han X, Fu Z, Wang L, Li Y, et al. The Morbidity and Comorbidity of Nonalcoholic Fatty Liver Disease and Different Glucose Intolerance Strata in a Community-Based Chinese Population. Metab Syndr Relat Disord. 2020;18(6):284–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Luo K, Bian J, Wang Q, Wang J, Chen F, Li H, et al. Association of obesity with chronic kidney disease in elderly patients with nonalcoholic fatty liver disease. Turkish J Gastroenterol. 2019;30(7):611–5.

    Article  Google Scholar 

  218. Simon TG, Trejo MEP, McClelland R, Bradley R, Blaha MJ, Zeb I, et al. Circulating Interleukin-6 is a biomarker for coronary atherosclerosis in nonalcoholic fatty liver disease: Results from the Multi-Ethnic Study of Atherosclerosis. Int J Cardiol. 2018;259:198–204.

    Article  PubMed  PubMed Central  Google Scholar 

  219. Li Y, He F, He Y, Pan X, Wu Y, Hu Z, et al. Dose-response association between physical activity and non-alcoholic fatty liver disease: a case-control study in a Chinese population. BMJ Open. 2019;9(3):e026854.

    Article  PubMed  PubMed Central  Google Scholar 

  220. Tu S, Zhao R, Fang H, Wang L, Shao A, Sheng J. Association between Non-Alcoholic Fatty Liver Disease and Intracerebral Hemorrhage. Cell Transplant. 2019;28(8):1033–8.

    Article  PubMed  PubMed Central  Google Scholar 

  221. Önnerhag K, Dreja K, Nilsson PM, Lindgren S. Increased mortality in non-alcoholic fatty liver disease with chronic kidney disease is explained by metabolic comorbidities. Clin Res Hepatol Gastroenterol. 2019;43(5):542–50.

    Article  PubMed  Google Scholar 

  222. Weinstein G, Davis-Plourde K, Himali JJ, Zelber-Sagi S, Beiser AS, Seshadri S. Non-alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle-aged adults: The Framingham Study. Liver Int. 2019;39(9):1713–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Ulasoglu C, Enc FY, Kaya E, Yilmaz Y. Characterization of Patients with Biopsy-Proven Non-Alcoholic Fatty Liver Disease and Normal Aminotransferase Levels. J Gastrointestin Liver Dis. 2019;28(4):427–31.

    Article  PubMed  Google Scholar 

  224. Zhao H, Hu B. Risk factors for Non-alcoholic Fatty Liver Disease in Chinese population: a five-year follow-up study. Iran Red Crescent Med J. 2019;21(7):e91064.

    Article  Google Scholar 

  225. Tada T, Toyoda H, Sone Y, Yasuda S, Miyake N, Kumada T, et al. Type 2 diabetes mellitus: A risk factor for progression of liver fibrosis in middle-aged patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2019;34(11):2011–8.

    Article  CAS  PubMed  Google Scholar 

  226. Niriella MA, Kasturiratne A, Pathmeswaran A, De Silva ST, Perera KR, Subasinghe S, et al. Lean non-alcoholic fatty liver disease (lean NAFLD): characteristics, metabolic outcomes and risk factors from a 7-year prospective, community cohort study from Sri Lanka. Hep Intl. 2019;13(3):314–22.

    Article  Google Scholar 

  227. Rong HJ, Meng CR, Chen ZY, Xue L. Biomarkers of non-alcoholic fatty liver disease in a Chinese population: a cross-sectional survey. Int J Clin Exp Med. 2019;12(2):1827–34.

    CAS  Google Scholar 

  228. Poynard T, Peta V, Deckmyn O, Pais R, Ngo Y, Charlotte F, et al. Performance of liver biomarkers, in patients at risk of nonalcoholic steato-hepatitis, according to presence of type-2 diabetes. Eur J Gastroenterol Hepatol. 2020;32(8):998–1007.

    Article  CAS  PubMed  Google Scholar 

  229. McGhee-Jez AE, Chervoneva I, Yi M, Ahuja A, Nahar R, Shah S, et al. Nonalcoholic fatty liver disease after Pancreaticoduodenectomy for a cancer diagnosis. J Pancreat Cancer. 2021;7(1):23–30.

    Article  PubMed  PubMed Central  Google Scholar 

  230. Tahir F, Majid Z, Majid B, Ahmed J, Zaman A, Tariq M, et al. Anthropometric Measurements and Lifestyle Characteristics of Individuals with Non-alcoholic Fatty Liver Disease. Cureus. 2020;12(2):e7016.

    PubMed  PubMed Central  Google Scholar 

  231. Bian H, Zhu X, Xia M, Yan H, Chang X, Li X, et al. Impact of type 2 diabetes on nonalcoholic steatohepatitis and advanced fibrosis in patients with nonalcoholic fatty liver disease. Endocr Pract. 2020;26(4):444–53-453.

    Article  PubMed  Google Scholar 

  232. Clough GF, Chipperfield AJ, Thanaj M, Scorletti E, Calder PC, Byrne CD. Dysregulated Neurovascular Control Underlies Declining Microvascular Functionality in People With Non-alcoholic Fatty Liver Disease (NAFLD) at Risk of Liver Fibrosis. Front Physiol. 2020;11:551.

    Article  PubMed  PubMed Central  Google Scholar 

  233. Kogiso T, Sagawa T, Kodama K, Taniai M, Hashimoto E, Tokushige K. Development and course of diabetes according to genetic factors and diabetes treatment among patients with nonalcoholic fatty liver disease. Nutrition. 2021;83:111080.

    Article  CAS  PubMed  Google Scholar 

  234. An JN, Joo SK, Koo BK, Kim JH, Oh S, Kim W. Portal inflammation predicts renal dysfunction in patients with nonalcoholic fatty liver disease. Hep Intl. 2020;14(5):798–807.

    Article  Google Scholar 

  235. Lisboa QC, Nardelli MJ, Pereira PA, Miranda DM, Ribeiro SN, Costa RSN, et al. PNPLA3 and TM6SF2 polymorphisms in Brazilian patients with nonalcoholic fatty liver disease. World J Hepatol. 2020;12(10):792–806.

    Article  PubMed  PubMed Central  Google Scholar 

  236. Qiao ZP, Zheng KI, Zhu PW, Gao F, Zheng MH. Lower levels of plasma NT-proBNP are associated with higher prevalence of NASH in patients with biopsy-proven NAFLD. Nutr Metab Cardiovasc Dis. 2020;30(10):1820–5. PMID: 32636124.

  237. Hirose S, Matsumoto K, Tatemichi M, Tsuruya K, Anzai K, Arase Y, et al. Nineteen-year prognosis in Japanese patients with biopsy-proven nonalcoholic fatty liver disease: Lean versus overweight patients. PLoS ONE. 2020;15(11):e0241770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Ishiba H, Sumida Y, Seko Y, Tanaka S, Yoneda M, Hyogo H, et al. Type IV Collagen 7S is the most accurate test for identifying advanced Fibrosis in NAFLD with type 2 diabetes. Hepatol Commun. 2021;5(4):559–72.

    Article  CAS  PubMed  Google Scholar 

  239. Xia W, Yang N, Li Y. Analysis of Risk Factors for Adverse Cardiovascular Events in Elderly Patients with Acute Myocardial Infarction and Non-Alcoholic Fatty Liver Disease (NAFLD). Med Sci Monit. 2020;26:e922913.

    Article  PubMed  PubMed Central  Google Scholar 

  240. Afolabi PR, Scorletti E, Calder PC, Byrne CD. Factors independently associated with cardiorespiratory fitness in patients with non-alcoholic fatty liver disease. Liver Int. 2020;40(12):2998–3007.

    Article  CAS  PubMed  Google Scholar 

  241. Ma C, Liu Y, He S, Zeng J, Li P, Ma C, et al. C-Peptide: A Mediator of the Association Between Serum Uric Acid to Creatinine Ratio and Non-Alcoholic Fatty Liver Disease in a Chinese Population With Normal Serum Uric Acid Levels. Front Endocrinol. 2020;11:600472.

    Article  Google Scholar 

  242. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49(4):608–12.

    Article  PubMed  Google Scholar 

  243. Ahmed HS, Pedersen N, Jayanna MB, Ten Eyck P, Sanchez A, Murali AR. Predictive Factors and Time to Development of Hepatic Decompensation in Patients with Non-alcoholic Fatty Liver Disease. J Gen Intern Med. 2020;35(5):1523–9.

    Article  PubMed  PubMed Central  Google Scholar 

  244. Giraldi L, Miele L, Aleksovska K, Manca F, Leoncini E, Biolato M, et al. Mediterranean diet and the prevention of non-alcoholic fatty liver disease: results from a case-control study. Eur Rev Med Pharmacol Sci. 2020;24(13):7391–8.

    CAS  PubMed  Google Scholar 

  245. Linge J, Ekstedt M, Dahlqvist LO. Adverse muscle composition is linked to poor functional performance and metabolic comorbidities in NAFLD. JHEP Rep. 2021;3(1):100197.

    Article  PubMed  Google Scholar 

  246. Li CH, Chou YT, Shen WC, Lu FH, Yang YC, Wu JS, et al. Increased risks of different grades of non-alcoholic fatty liver disease in prediabetic subjects with impaired fasting glucose and glucose tolerance, including the isolated glycosylated hemoglobin levels of 5.7–6.4% in a Chinese population. J Diabetes Investig. 2020;11(5):1336–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Su Y, Liu Z, Yang L, Li Y, Jiang S, Yao H, et al. PPARγ gene Pro12Ala variants reduce the risk of obese individuals to non-alcoholic fatty liver: A study in Uygur Chinese population residing in Northwestern China. Clin Res Hepatol Gastroenterol. 2020;44(6):894–904.

    Article  CAS  PubMed  Google Scholar 

  248. Sun DQ, Jin Y, Wang TY, Zheng KI, Rios RS, Zhang HY, et al. MAFLD and risk of CKD. Metabolism. 2021;115:154433.

    Article  CAS  PubMed  Google Scholar 

  249. Miller A, McNamara J, Hummel SL, Konerman MC, Tincopa MA. Prevalence and staging of non-alcoholic fatty liver disease among patients with heart failure with preserved ejection fraction. Sci Rep. 2020;10(1):12440.

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  250. Sinn DH, Kang D, Chang Y, Ryu S, Cho SJ, Paik SW, et al. Non-alcoholic fatty liver disease and the incidence of myocardial infarction: A cohort study. J Gastroenterol Hepatol. 2020;35(5):833–9.

    Article  PubMed  Google Scholar 

  251. Lin S, Huang J, Wang M, Kumar R, Liu Y, Liu S, et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver international : official journal of the International Association for the Study of the Liver. 2020;40(9):2082–9.

    Article  PubMed  Google Scholar 

  252. Rahman MM, Kibria MG, Begum H, Haque M, Sultana N, Akhter M, et al. Prevalence, risk factors and metabolic profile of the non-obese and obese non-alcoholic fatty liver disease in a rural community of South Asia. BMJ Open Gastroenterol. 2020;7(1):e000535.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Wang X, Han F, Ji Z, Shen L, Shen Y. Association between Non-alcoholic Fatty Liver Disease and the Severity of Coronary Artery Stenosis in Eastern Chinese Population. Hepat Mon. 2021;21(11):e122772.

  254. Iritani S, Akuta N, Kawamura Y, Kajiwara A, Kasuya K, Fujiyama S, et al. Non-invasive predictors of prognosis of Asian patients with histopathologically-confirmed lean nonalcoholic fatty liver disease. BMC Gastroenterol. 2020;20(1):368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Stefano JT, Guedes LV, de Souza AAA, Vanni DS, Alves VAF, Carrilho FJ, et al. Usefulness of collagen type IV in the detection of significant liver fibrosis in nonalcoholic fatty liver disease. Ann Hepatol. 2021;20:100253.

    Article  CAS  PubMed  Google Scholar 

  256. Kanwal F, Kramer JR, Li L, Dai J, Natarajan Y, Yu X, et al. Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease. Hepatology. 2020;71(3):808–19.

    Article  PubMed  Google Scholar 

  257. Björkström K, Widman L, Hagström H. Risk of hepatic and extrahepatic cancer in NAFLD: A population-based cohort study. Liver Int. 2022;42(4):820–8.

    Article  PubMed  PubMed Central  Google Scholar 

  258. Boga S, Koksal AR, Sen İ, Kurul Yeniay M, Yilmaz Ozguven MB, Serin E, et al. Liver and pancreas “Castor and Pollux” regarding the relationship between hepatic steatosis and pancreas exocrine insufficiency. Pancreatology. 2020;20(5):880–6.

    Article  CAS  PubMed  Google Scholar 

  259. Miele L, Grattagliano I, Lapi F, Dajko M, De Magistris A, Liguori A, et al. Non-alcoholic fatty liver disease and the risk of fibrosis in Italian primary care services: GPS-NAFLD Study: GPS-NAFLD Study. Liver Int. 2022;42(12):2632–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Ng CH, Chan KE, Chin YH, Zeng RW, Tsai PC, Lim WH, et al. The effect of diabetes and prediabetes on the prevalence, complications and mortality in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2022;28(3):565–74.

    Article  PubMed  PubMed Central  Google Scholar 

  261. Adrian T, Sørensen IMH, Knop FK, Bro S, Ballegaard ELF, Nordestgaard BG, et al. Prevalence of non-alcoholic fatty liver disease in patients with chronic kidney disease: a cross-sectional study. Nephrol Dial Transplant. 2022;37(10):1927–34.

    Article  CAS  PubMed  Google Scholar 

  262. Dai W, Zhang Z, Zhao S. The risk of type 2 diabetes and Coronary artery disease in non-obese Patients with non-alcoholic fatty liver disease: a cohort study. Front cardiovasc med. 2021;8:680664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Hu PF, Zeng X, Zou ZY, Tang W, Guo YB, Yuan ZL, et al. The presence of NAFLD in nonobese subjects increased the risk of metabolic abnormalities than obese subjects without NAFLD: a population-based cross-sectional study. Hepatobiliary Surg Nutr. 2021;10(6):811–24.

    Article  PubMed  PubMed Central  Google Scholar 

  264. Alswat K, Sanai FM, Al-Hamoudi W, Ismail M, Dahlan Y, AlGhamdi HS, et al. Clinical and Metabolic Chara