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. 2024 Jul 2;5(3):126–138. doi: 10.14744/hf.2023.2023.0042

From NAFLD to MASLD: Meta-analysis and systematic review of NAFLD patients in Turkiye in terms of metabolic profile and MASLD potential

Sevginur Akdas 1, Nuray Yazihan 1,2,✉
PMCID: PMC11237240  PMID: 39006144

Abstract

Non-alcoholic Fatty Liver Disease (NAFLD) is both a cause and a consequence of metabolic disturbances. Consequently, the disease term has recently changed to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Turkiye is one of the leading countries with high incidences of diseases such as diabetes, obesity, metabolic syndrome, and fatty liver. This study aims to identify the metabolic parameters and MASLD potential of NAFLD in Turkiye. All NAFLD studies conducted in Turkiye were systematically searched using the keywords “fatty liver disease” AND “ Turkiye “ on PubMed, Scopus, and Web of Science databases. A total of 2653 articles were scanned, and 120 studies were eligible for meta-analysis. The metabolic parameters were meta-analyzed from a broad perspective. According to the meta-analysis results, there were significant increases in waist circumferences (mean difference: 10.90, p<0.00001), HOMA-IR (mean difference: 2.13, p<0.00001), aspartate aminotransferase (AST) (mean difference: 17.82, p<0.00001), systolic blood pressure (SBP) (mean difference: 5.86, p<0.00001), and C-reactive protein (CRP) levels (mean difference: 0.95, p<0.00001). These parameters are representative biochemical findings of disturbed glucose metabolism, lipid profile, blood pressure, and acute phase response mechanisms. Furthermore, the analysis of all related parameters commonly found among the articles confirmed these metabolic dysfunctions. NAFLD is a metabolic disease that encompasses multiple pathways related to glucose and lipid metabolism, vascular function, inflammation, and acute phase responses. Additionally, our results suggest that Turkish NAFLD patients identified in previous studies mostly have MASLD. This is the first meta-analysis study indicating changes in metabolism-related parameters with a cumulative meta-analysis of all Turkish NAFLD studies.

Keywords: Diabetes, fatty liver disease, hypertension, inflammation, lipid profile, metabolism

Introduction

Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of ≥5% hepatic steatosis without a competing liver disease such as viral hepatitis, autoimmune hepatitis, hemochromatosis, Wilson’s disease, or alcoholic liver disease, and without the use of steatosis-inducing medications. Non-alcoholic steatohepatitis (NASH)[1] occurs with histopathological findings that cause hepatic damage, fibrosis, cirrhosis, and mortality in a smaller subset of patients with NAFLD.[2] Furthermore, with the participation and agreement of 236 panelists from 56 countries, new medical terms were introduced to the scientific field. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the new designation for NAFLD and is defined by the detection of liver steatosis (via liver histology, non-invasive biomarkers, or imaging) together with at least one of three criteria: overweight or obesity, type 2 diabetes mellitus, or clinical evidence of metabolic dysfunction such as high waist circumference or abnormal lipid or glycemic profiles. Similarly, the term for nonalcoholic steatohepatitis was changed to “metabolic-associated steatohepatitis” (MASH) to refer to steatohepatitis patients with metabolic dysfunctions.[3,4] Also, diagnostic criteria were updated. In the presence of steatotic liver disease (SLD), the identification of any cardiometabolic risk factor alone would lead to a diagnosis of MASLD, provided no other causes of hepatic steatosis are evident. If additional contributors to steatosis are discovered, it suggests a combination etiology. Specifically, in cases involving alcohol, it is referred to as MASLD with increased alcohol intake (MetALD). In situations where explicit cardiometabolic criteria are absent, other potential causes must be ruled out. If none are found, this is categorized as cryptogenic SLD. However, depending on clinical judgment, it could also be considered as a possible MASLD, warranting periodic reassessment on a case-by-case basis.[4]

NAFLD is a significant burden of health problems that cause chronic liver diseases worldwide. A very recent meta-analysis examined the up-to-date incidence of NAFLD with data from 1,201,807 individuals across 63 studies. According to this global analysis, the incidence of NAFLD was found to be 4,613 per 100,000 person-years, particularly high in men, with a dramatic increase of more than threefold between 2000 and 2015.[5] According to regional results in 2019, NAFLD occurs in 31.29% of the Middle East, 30.45% of South America, 27.37% of Asia, 24.13% of North America, 23.71% of Europe, and 13.48% of Africa.[6] Nearly 30% of the world’s population is currently challenged with this health problem.[7]

In America, the number of NAFLD patients, which was 83 million in 2015, is expected to increase to 100.9 million by 2030, a 21% increase, while the prevalence of NASH cases will increase by 63% from 16.52 million to 27.00 million cases.[8] The prevalence of NAFLD is estimated to be 20%–30% in the European Union, and about 3% is NASH. The advanced fibrosis incidence in NASH patients was 67.95 in 1,000 person-years. Liver-specific mortality in the pooled NAFLD versus non-NAFLD incidence rate ratio was found to be 1.94. The adjusted liver-specific mortality hazard ratio for NAFLD patients was 2.60. Although the prevalence of advanced fibrosis among NAFLD patients in the USA and Europe was 10–15%, fibrosis development was found to be lower in the Asia region compared to Western countries.[9] In Turkiye, multi-center prevalence studies are limited in showing the current NAFLD status. However, recent published data pointed to an alarming prevalence of 48.3%, which seems reasonable when compared with the obesity prevalence in Turkiye.[10]

NAFLD is a part of the metabolic syndrome hepatic outcomes and is commonly seen in obese and diabetic patients. Whether NAFLD is a cause or consequence of insulin resistance has been debated for a long time. On the other hand, “lean-NAFLD” can be seen in non-obese subjects, especially in low-income countries or rural areas.[11] This meta-analysis aimed to evaluate all NAFLD cases and their control data in the literature to show the metabolic profile of the disease in Turkiye cumulatively for the first time. The MASLD potential of these patients was discussed according to meta-analysis results.

Materials and Methods

Study Design

To determine the metabolic profile of Turkish NAFLD patients, all NAFLD studies conducted in Turkiye were systematically searched using the keywords “fatty liver disease” and “Turkiye” on PubMed, Scopus, and Web of Science databases. All characteristics and biochemical data were screened and collected for related meta-analysis. Inclusion criteria were established as providing suitable data (using international units) of biochemical parameters for NAFLD-diagnosed patients and a healthy control group.

The parameters of NAFLD diagnosis were generally based on ultrasound screening. Many studies confirmed ultrasound screening results with histopathological examinations after liver biopsy and used elevated liver enzyme levels as inclusion criteria. Exclusion criteria were generally similar across studies, excluding individuals with viral hepatitis, hemochromatosis, Wilson’s disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, biliary obstruction, α1-antitrypsin deficiency, ischemic cardiac or cerebrovascular disease, impaired renal function, malignancies, previous abdominal surgery, medication use, and daily alcohol intake exceeding 20 g/day. Several studies also excluded chronic conditions such as coronary artery disease, acute chronic renal failure, hypertension, and diabetes. Some studies set the alcohol intake exclusion limit at 30 or 40 g/day. Detailed information about the inclusion and exclusion criteria of each study was given in Appendix 1.

There were no additional restrictions for individual characteristics. The systematic search continued until July 2023. PRISMA statement guidelines were followed for this meta-analysis. Since this article is a meta-analysis, ethics committee approval is not required.

Statistical Analysis

Cumulative data analysis was conducted to show the metabolic comorbidities of Turkish NAFLD patients. All analysis procedures were performed according to the Cochrane Handbook (cochrane.org/handbook). Mean and standard deviation values of each marker that was cumulatively assessed were entered into the RevMan 5.3 program. Weighted analysis was automatically performed by RevMan 5.3 according to the power of articles. Study power is calculated by RevMan, based on values for effect size magnitude, sample size, the number of studies, and the amount of between-study variability. The I2 was used to measure heterogeneity, which can be seen at the bottom of each figure. I2% values of 0–25, 25–50, 50–75, and 75–100 represent no, low, moderate, and high heterogeneity, respectively. The fixed and random effect models were used according to the heterogeneity tau2 value to combine the results. If the tau2 value is found as 0, the fixed effect model can be used. However, in all our results, the tau2 value was found to be different from 0, which led us to use the random effect model for a better assessment. RevMan 5.3 (Cochrane Collaboration, Copenhagen, 2014) software was used for the meta-analysis, and GraphPad Prism 6 software was used for correlation analysis and visualizing the results.

Results

In total, 2653 articles were scanned. As a result of the screening, 2533 studies were found ineligible for this meta-analysis. The remaining 120 studies were eligible for meta-analysis, and all data on patient and control groups from these studies[10,12–130] were evaluated (Fig. 1).

Figure 1.

Figure 1

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Flow diagram of study selection.

Obesity-Glucose Metabolism Related Parameters

Data from 14138 NAFLD and 15335 healthy individuals showed that the BMI level is significantly higher in the NAFLD group (Mean difference: 3.48, 95% CI: [3.02, 3.94], p<0.00001). Waist circumference in the NAFLD group (n=4650) was increased compared to the control group (n=7346) (Mean difference: 10.90 cm, 95% CI: [9.83, 11.96], p<0.00001) (Fig. 2). Data from 6769 NAFLD and 7646 healthy individuals showed that fasting blood glucose levels were higher in the NAFLD group (Mean difference: 12.32 mg/dl, 95% CI: [9.96, 14.69], p<0.00001). HbA1c% values were higher in the NAFLD group (n=1254) than in the control group (n=1327) (Mean difference: 0.52, 95% CI: [0.28, 0.76], p<0.0001). Insulin levels were also higher in the NAFLD group (n=3194) compared to the control group (n=1881) (Mean difference: 6.73, 95% CI: [5.94, 7.53], p<0.00001). The HOMA-IR values showed a significant increase in the NAFLD group (n=7341) compared to the control group (n=8381) (Mean difference: 2.13, 95% CI: [1.95, 2.32], p<0.00001) (Fig. 3).

Figure 2.

Figure 2

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The random effect model of cumulative meta-analysis for waist circumference data obtained from NAFLD and control individuals.

Figure 3.

Figure 3

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The random effect model of cumulative meta-analysis for HOMA-IR data obtained from NAFLD and control individuals.

Liver Function Parameters

AST values of the NAFLD group (n=9357) were higher than those of the control group (n=11080) (mean difference: 17.82 IU/L, 95% CI: [15.47, 20.17], p<0.00001) (Fig. 4). Similarly, ALT levels in the NAFLD group (n=12535) were increased compared to the healthy group (n=14434) (mean difference: 35.11 IU/L, 95% CI: [31.27, 38.95], p<0.00001). Increased ALP levels were observed in NAFLD patients (n=2615) compared to healthy controls (n=4452) (mean difference: 12.10 IU/L, 95% CI: [8.38, 15.83], p<0.00001). GGT levels in the NAFLD group (n=5756) were higher than in the control group (n=7634) (mean difference: 21.73, 95% CI: [19.35, 24.10], p<0.00001). No significant difference was found in total bilirubin levels between the NAFLD group (n=830) and control group (n=735) (mean difference: 0.07, 95% CI: [-0.01, 0.16], p=0.10). Similarly, albumin levels showed no significant difference between groups (NAFLD group n=1994, control group n=1752) (mean difference: -0.02, 95% CI: [-0.09, 0.05], p=0.55).

Figure 4.

Figure 4

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The random effect model of cumulative meta-analysis for AST data obtained from NAFLD and control individuals.

Hyperlipidemia Related Parameters

Increased levels of triglycerides were found in NAFLD patients (n=9052) compared to healthy individuals (n=10489) (Mean difference: 49.34 mg/dl, 95% CI: [44.24, 54.44], p<0.00001). HDL levels of the NAFLD group (n=9097) were lower than those of the control group (n=10522) (Mean difference: -2.59 mg/dl, 95% CI: [-3.86, -1.32], p<0.0001). LDL levels of the NAFLD group (n=8695) were higher than those of the control group (n=10249) (Mean difference: 13.52, 95% CI: [10.94, 16.10], p<0.00001). Total cholesterol levels of NAFLD patients (n=8823) were also increased compared to controls (n=9699) (Mean difference: 22.59, 95% CI: [18.94, 26.24], p<0.00001).

Blood Pressure Parameters

Systolic blood pressure (SBP) was higher in NAFLD patients (n=3778) compared to controls (n=2987) (mean difference: 5.86 mmHg, 95% CI: [5.39, 8.14], p<0.00001) (Fig. 5). Diastolic blood pressure was also increased in NAFLD patients (n=3778) compared to controls (n=2987) (mean difference: 3.83 mmHg, 95% CI: [2.55, 5.11], p<0.00001).

Figure 5.

Figure 5

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The random effect model of cumulative meta-analysis for Systolic Blood Pressure (SBP) data obtained from NAFLD and control individuals.

Acute Phase Reactants

CRP values of the NAFLD group (n=3765) were higher than those of the control group (n=5859) (Mean difference: 0.95 mg/L, 95% CI: [0.72, 1.19], p<0.00001) (Fig. 6. ESR was prolonged in the NAFLD group (n=786) compared to the healthy group (n=482) (mean difference: 2.35 mm/hr, 95% CI: [0.47, 4.23], p<0.01). Ferritin levels in NAFLD patients (n=1921) were increased compared to the control group (n= 3812) (Mean difference: 45.63 ng/mL, 95% CI: [32.72, 58.54], p<0.00001). Hemoglobin levels were also higher in the NAFLD group (n=398) than in the control group (n=780) (Mean difference: 0.28, %95 CI: [0.12, 0.43], p=0.0004). Serum creatinine levels of NAFLD patients (n=2650) were higher than those of healthy controls (n=2479) (mean difference: 0.07 mg/dL, 95% CI: [0.05, 0.09], p<0.00001).

Figure 6.

Figure 6

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The random effect model of cumulative meta-analysis for CRP data obtained from NAFLD and control individuals.

Correlation Results

Correlation analysis indicated that obesity and glucose metabolism parameters such as fasting blood glucose, waist circumference, insulin, and HOMA-IR levels were associated with liver function, as evidenced by increases in ALT, AST, and GGT enzyme levels. Fasting blood glucose correlated with AST (p<0.0001, r=0.401), ALT (p<0.0001, r=0.276), and GGT (p=0.018, r=0.245). Waist circumference levels were found to be correlated with AST (p<0.0001, r=0.371), ALT (p<0.0001, r=0.368), and ALP (p=0.04, r=0.50). Similarly, insulin/HOMA-IR levels correlated with AST (p=0.001/p<0.0001, r=0.342/0.760), ALT (p<0.0001/p<0.0001, r=0.369/0.710), and GGT levels (p=0.017/p<0.0001, r=0.289/0.495).

Discussion

Our meta-analysis showed that Turkish NAFLD patients have glucose metabolism disorders, hyperlipidemia, and impaired liver functions compared to the control group. Blood pressure values were elevated in NAFLD patients. Furthermore, CRP, ESR, Ferritin, Hemoglobin, and Creatinine levels, which were determined as acute phase reactants, were elevated in NAFLD patients in Turkiye. These results suggest that NAFLD patients in Turkiye carry a high risk of metabolic dysfunction and that Turkish NAFLD patients detected in previous studies might mostly have MASLD.

The pathogenesis of NAFLD, specifically whether NAFLD precedes insulin resistance or vice versa, has been debated for a long time. Diacylglycerol is recognized as a key factor of lipid-induced insulin resistance in the liver. Elevated diacylglycerol activates protein kinase C, which phosphorylates and inhibits the insulin receptor, thereby impairing glucose metabolism in NAFLD primarily through this mechanism.[131]

The global prevalence of NAFLD is 30%,[7] and a 2016 meta-analysis reported a pooled analysis for NASH prevalence at 59.10% among biopsied NAFLD patients. According to comorbidity analysis, the prevalence of obesity was 51.34%/81.83%, diabetes was 22.51%/43.63%, hyperlipidemia was 69.16%/72.13%, hypertriglyceridemia was 40.74%/83.33%, hypertension was 39.34%/67.97%, and metabolic syndrome was 42.54%/70.65% among NAFLD/NASH patients worldwide. These results indicate that the prevalence of comorbidities rises with the development of NASH compared to NAFLD without steatohepatitis.[8] However, a 2023 meta-analysis showed that the incidence of NAFLD was higher among those with obesity, diabetes, hyperlipidemia, and metabolic syndrome, though the differences were not significant. Only tobacco use status showed significant incidence differences among patient characteristics.[5]

A single-center study investigating Turkiye’s NAFLD profile revealed that 90.4% of NAFLD patients had biopsy-proven NASH, and simple steatosis was rare (9.6%). The clinical outcomes indicated that significant fibrosis was present in 6.4%, advanced fibrosis in 32.6%, and cirrhosis in 61% of patients. Overweight (32.6%), obesity (61%), diabetes (33.5%), and metabolic syndrome (63%) were frequently seen comorbidities in these patients. This may be because this hospital is a tertiary referral center, and Fibroscan is commonly used to indicate biopsy.[9] These results provide evidence that NAFLD/NASH is an epidemic in Turkiye. A study conducted in five different centers in the East-Southeastern Anatolia Regions of Turkiye showed that 85% were overweight, 37% were obese, 18% had type 2 diabetes mellitus, and 80.6% had hyperlipidemia. According to multivariate regression analysis, age, diabetes, and aspartate aminotransferase were related to the severity of the disease.[24]

Is It “Non-Alcoholic Fatty Liver Disease” or “Metabolic Dysfunction Associated Steatotic Liver Disease”?

Our results show that NAFLD is not solely a liver-based disease; it is both a cause and consequence of metabolic disturbances. Insulin resistance and glucose metabolism-related parameters support this hypothesis. After many critical meetings, authorities agreed that MASLD is a more appropriate overarching term. This new designation integrates the current understanding of patient heterogeneity encompassed by the acronym NAFLD and offers terminology suggestions that more accurately reflect the pathogenesis. It is believed that this new term will accelerate the transition to novel treatments and will facilitate sub-phenotyping efforts of the disease with future studies.[4,132,133]

A recent meta-analysis involving cohorts from the USA, Japan, and Turkiye revealed negative implications of type 2 diabetes in relation to NAFLD. The study found that participants with type 2 diabetes had a significantly elevated risk of hepatic decompensation at 1, 3, and 5 years compared to those without type 2 diabetes. After considering various confounding factors, it was determined that type 2 diabetes and glycated hemoglobin were independent predictors of hepatic decompensation. Furthermore, even after adjusting for baseline liver stiffness assessed by magnetic resonance elastography, the association between type 2 diabetes and hepatic decompensation remained consistent. Notably, type 2 diabetes emerged as an independent predictor of hepatocellular carcinoma development.[134]

Another recent meta-analysis aimed to explore the relationship between the triglyceride and glucose (TyG) index, calculated as fasting triglyceride divided by fasting glucose, and the risk of NAFLD. The results revealed a positive and linear association between the TyG index and the risk of NAFLD. Each additional unit of the TyG index was associated with a higher risk of NAFLD, with a summary odds ratio (OR) of 2.84.[135]

The findings of our meta-analysis, combined with results from other studies, emphasize the importance of assessing metabolic parameters in understanding the development and prognosis of NAFLD. This highlights the need for countries with a high incidence of NAFLD, such as Turkiye, to focus on developing metabolic approaches for the treatment and monitoring of these conditions. By emphasizing metabolic factors, healthcare professionals can better manage and address the challenges posed by NAFLD.

Our meta-analysis has for the first time indicated the overall metabolic profile and MASLD potential of NAFLD patients in Turkiye. While acknowledging the limitations of our work due to the quality of the studies and data in the literature, we recognize several specific constraints. Some limitations stem from the characteristics of the fatty liver patients, the design of the studies, and the procedures of the centers where they were performed, affecting the determination of the disease or patients’ states and introducing heterogeneity. High statistical heterogeneity of the data was observed. Additionally, we did not include comorbidity or disease severity status (in terms of liver fibrosis) in our analysis due to the limited amount of studies and the heterogeneity among these studies. Our primary goal was to analyze the metabolic profile of the patients cumulatively, and we acknowledge that further studies and meta-analyses are needed to assess the effects of disease stages on the metabolic profile. It would also be beneficial to evaluate these in future studies due to changes in terminology and disease diagnosis.

We are aware of the risk of bias among studies, particularly those using the same cohort in studies conducted by the same group within a close time period. Although inclusion and exclusion criteria were mainly similar among studies, some excluded specific chronic diseases that could affect the biochemical profiles of selected patients. We accepted this heterogeneity as a limitation of our meta-analysis. However, we believe that our meta-analysis provides a comprehensive overview with a significant amount of data, specifically from Turkiye. These bias risks and limitations might have a minor impact given the extensive dataset.

Given the recency of the MASLD terminology, there are not many studies targeting exact MASLD patients according to specific diagnostic criteria for MASLD. Therefore, our study couldn’t distinctly show the MSFLD and NAFLD difference or the MASLD profile of Turkiye. We acknowledge these limitations in the ongoing debate,[136] yet our results support the notion that many patients included in our meta-analysis might have MASLD, according to our cumulative results.

Conclusion

In conclusion, NAFLD is a metabolic disease that involves multiple pathways related to glucose and lipid metabolism, vascular function, inflammation, and acute phase responses. This was demonstrated through the cumulative meta-analysis of all Turkish NAFLD studies to date. These cumulative results are important for defining the metabolic profile of NAFLD patients in Turkiye and could serve as a valuable reference for many countries in Europe, Asia, and the Middle East. Additionally, the new term MASLD could be more appropriate, reflecting the related metabolic outcomes assessed cumulatively in our meta-analysis.

Footnotes

How to cite this article: Akdas S, Yazihan N. From NAFLD to MASLD: Meta-analysis and systematic review of NAFLD patients in Turkiye in terms of metabolic profile and MASLD potential. Hepatology Forum 2024; 5(3):126–138.

Author Contributions

Concept – SA, NY; Design – SA, NY; Supervision – NY; Data Collection and/or Processing – SA, NY; Analysis and/or Interpretation – SA, NY; Literature Search – SA, NY; Writing – SA; Critical Reviews – NY.

Conflict of Interest

The authors have no conflict of interest to declare.

Use of AI for Writing Assistance

Not declared.

Financial Disclosure

The authors declared that this study has received no financial support.

Peer-review

Externally peer-reviewed.

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