Evaluation of elevated serum liver enzymes and metabolic syndrome in the PERSIAN Guilan cohort study population (2025)

Objective

The purpose of this study is to evaluate the association between elevated serum liver enzymes and Metabolic Syndrome (MetS) in Prospective Epidemiological Research Studies of the Iranian Adults (PERSIAN) Guilan Cohort Study (PGCS) population.

Methods

This cross-sectional study involved 10,519 individuals between the ages of 35 and 70 enrolled in the PGCS. The gathered data encompassed demographic information, anthropometric measurements, blood pressure, and biochemical indicators. MetS was defined by the National Cholesterol Education Program–Adult Treatment Panel III criteria (NCEP-ATP III). The associations between elevated liver enzymes and MetS were examined using logistic regression analysis. Odds ratio (OR) and 95% confidence interval (CI) were calculated.

Results

The prevalence of MetS was 41.8%, and the prevalence of elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) were 19.4, 4.6, 11.6, and 5.1%, respectively. In the unadjusted model, elevated ALT, AST, and GGT were associated with increased odds of MetS (OR=1.55, 95% CI: 1.41–1.71; OR=1.29, 95% CI: 1.07–1.55, and OR=1.90, 95% CI: 1.69–2.14, respectively). These associations remained significant for ALT and GGT after adjustment for some demographic and clinical characteristics (aOR=1.31, 95% CI: 1.17–1.46 and aOR=1.30, 95% CI: 1.14–1.49, respectively). In addition, the odds of MetS increased with the number of elevated liver enzymes, up to almost 1.32-fold among subjects with three/four elevated liver enzymes.

Conclusion

The higher incidence of elevated liver enzymes was associated with an increased likelihood of MetS. Including liver markers in diagnosing and predicting MetS holds promise and is considered a possible approach.

Keywords: Metabolic syndrome, Liver enzymes, Risk factors, Alanine transaminase- aspartate transaminase

2.1. Study populations

This cross-sectional study was conducted on 10,519 individuals between the ages of 35 and 70 who were enrolled in the PGCS population, which is part of PERSIAN in 2022. A comprehensive PGCS profile has been published, providing detailed information [17]. The study was confirmed by the ethical committee of the Guilan University of Medical Sciences, Rasht, Iran (IR.GUMS.REC. 1401.325), and all individuals gave their consent to participate in the study.

2.2. Data collection

Data collection at the cohort center involved the registration of participants, demographic information, anthropometric measurements, blood pressure, and biochemical indicators. The demographic characteristics involved age, gender, location of residence, marital status, smoking, occupation, and education obtained with face-to-face interviews. The PERSIAN cohort protocol assessed Blood pressure using a cuff pressure gauge (MTM Munich, Germany). Weight (kg), height (cm), and waist circumference (WC) (cm), as anthropometric markers, were measured based on the cohort study protocol. History of hepatotoxic drug consumption and fatty liver disease was assessed based on the questions “Has a physician diagnosed NAFLD? (yes/no)" and “Have you used hepatotoxic drugs before? (yes/no)."

2.3. Biochemical measurements

Blood samples were collected from the antecubital vein following a fasting period of 12h. Liver enzymes, such as AST, ALT, ALP, and GGT, as well as the lipid profile, which included triglyceride (TG), total cholesterol (TC), HDL-C, low-density lipoprotein cholesterol (LDL-C), and fasting blood sugar (FBS), were assessed using a Biotecnica auto-analyzer (BT 1500, Italy) in medical laboratory of the cohort center. Elevated liver enzymes were defined as follows: ALT ≥32 U/L in males/≥ 22 U/L in females, AST ≥37 U/L in males/≥ 31 U/L in females, GGT ≥49 U/L in men/≥ 32 U/L in females, and ALP ≥307 U/L in both male and female [18].

2.4. Definition of metabolic syndrome

The MetS prevalence was defined according to the National Cholesterol Education Program Adult- Treatment Panel III (NCEP-ATP III) criteria [19]. Individuals were categorized as having MetS if they had central obesity (WC≥95cm for males and WC≥80cm for females) in addition to two other four components. The components comprising the MetS involved TG≥150mg/dl or previous diagnosis of hypertriglyceridemia; HDL ≤40mg/dl in males and ≤50mg/dl in females or Specific medications for these fat disorders; systolic blood pressure (SBP) ≥130mmHg or diastolic blood pressure (DBP) ≥85mmHg or previously diagnosed hypertension; and FBS ≥100mg/dl or previous diagnosis of DM.

2.5. Statistical analysis

This study expressed continuous variables as mean±standard deviation (SD) and categorical variables as number (percentage). Differences in continuous and categorical variables between participants with and without MetS were tested by independent T-test and Chi-Square test (or Cochran–Armitage test for trend), respectively. We determined the association of MetS with elevated liver enzymes using logistic regression analysis. Odds ratio (OR) and 95% confidence interval (CI) were calculated. ORs were adjusted for demographic and clinical characteristics. Model 1 was unadjusted; Model 2 was adjusted for age and sex; Model 3 was adjusted for variables in Model 2 and marital status, years of education, occupation, place of residency, wealth score index (WSI), body mass index (BMI), physical activity, smoking, hookah smoking, opium consumption, and alcohol consumption; Model 4 was adjusted for variable in Model 3 and fatty liver, hepatitis B, hepatitis C, use of lipid-lowering drugs and hepatotoxic drugs. All data analyses were done SPSS for Windows, version 16.0 (SPSS Inc., Chicago, IL, USA), and the significance level was set at 0.05.

3.1. Demographic and clinical characteristics of the participants

Table 1 outlines the demographic and clinical characteristics of the participants. The mean age of the participants was 51.52±8.90 years, and 53.6% were female. Of the participants, 90.6% were married, 6.1% had a university education, 54.5% were employed, 56.2% were rural residents, 32.7% had obese-BMI, 24.6% were smokers, 13.3% consumed alcohol, 6.6% had fatty liver disease, and 16.6% used hepatotoxic drugs. Patients with MetS were older, more female sex, more widowed, more unemployed, reported less smoking and hookah smoking and less consumption of opium and alcohol, had low WSI, high BMI, and low psychical activity, and were more likely to have fatty liver and reported more use of lipid-lowering drugs and hepatotoxic drugs.

3.2. Prevalence of elevated live enzymes and MetS

The prevalence of elevated ALT, AST, GGT, and ALP was 19.4, 4.6, 11.6, and 5.1%, respectively. The prevalence of elevated ALT, AST, and GGT was higher in females than in males (P<0.001, P=0.040, P<0.001, respectively). The prevalence of elevated ALT decreased with age (P for trend<0.001), whereas the prevalence of elevated ALP increased with age (P for trend<0.001). The prevalence of MetS was 41.8% in this study and was more prevalent in females than in males (56.3% vs 25.0%, P<0.001). The prevalence of MetS increased with age; the lowest was 34.1% in those aged 35–44 years (P for trend<0.001) (Table 2).

3.3. Prevalence of MetS based on elevated ALT using logistic regression

The prevalence of MetS was higher among participants with elevated ALT than those with normal ALT levels (50.5% vs 39.7%, P<0.001). Similar results were also obtained for AST and GGT (P=0.007 and P<0.001, respectively) (Table 3 and Fig. 1). In the unadjusted model (Model 1), elevated ALT was associated with 55% increased odds of MetS (OR=1.55, 95% CI: 1.41–1.71). This association remained significant after adjustment for age and sex (OR=1.61, 95% CI: 1.45–1.78) (Model 2). In model 3, after adjustment for other socio-demographic characteristics, the OR also remained statistically significant (OR=1.36, 95% CI: 1.22–1.51). In Model 4, after further adjustment for fatty liver, hepatitis B, hepatitis C, use of lipid-lowering drugs, and use of hepatotoxic drugs, participants with elevated ALT were 1.31-fold more likely to have MetS in comparison to participants with normal ALT (OR=1.31, 95% CI: 1.17–1.46).

3.4. Prevalence of MetS based on elevated AST using logistic regression

In the unadjusted model, participants with elevated AST were more likely to have MetS than people with normal AST (OR=1.29, 95% CI: 1.07–1.55). Similar results were obtained after adjusting for sex and age (OR=1.26, 95% CI: 1.03–1.53). In Model 3 and Model 4, there was no longer a significant association between elevated AST and MetS (OR=1.07, 95% CI: 0.87–1.31 and OR=1.03, 95% CI: 0.84–1.27, respectively). In the unadjusted model, elevated GGT was associated with 90% increased odds of MetS (OR=1.90, 95% CI: 1.69–2.14). Similar results were obtained after adjusting for age and sex (OR=1.52, 95% CI: 1.34–1.73). The OR also remained statistically significant in Model 3 and Model 4 (OR=1.33, 95% CI: 1.17–1.52 and OR=1.30, 95% CI: 1.14–1.49, respectively).

3.5. Prevalence of MetS based on elevated ALP using logistic regression

The presence of elevated ALP was not associated with MetS in both unadjusted model (OR=1.13, 95% CI: 0.95–1.35) (Model 1) and all adjusted models- Model 2 (OR=1.01, 95% CI: 0.84–1.22), Model 3 (OR=0.99, 95% CI: 0.82–1.21), and Model 4 (OR=0.97, 95% CI: 0.79–1.19).

3.6. Prevalence of MetS based on elevated liver enzymes

The prevalence of MetS among participants with 0, 1, 2, and 3 or 4 elevated liver enzymes was 38.6, 48.4, 51.2 and 57.0%, respectively. In other words, the prevalence of MetS increased with increasing the number of elevated liver enzymes (P for trend<0.001) (Table 3 and Fig. 2). In unadjusted analysis, compared with participants without any elevated liver enzymes, the OR of MetS was 1.50 (95% CI: 1.35–1.65) for participants with one elevated liver enzyme, 1.67 (95% CI: 1.44–1.94) for participants with two elevated liver enzymes, 2.11 (95% CI: 1.65–2.69) for participants with three or four elevated liver enzymes, with a significant trend in OR with an increasing number of elevated liver enzymes (Table 3 and Fig. 2). Similar results were obtained after adjusting for age and sex. The same pattern, but with lower ORs, was observed after adjusting for variables in Model 3 and Model 4.

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Data Availability Statement

The datasets used and/or analyzed during the present study are available from the corresponding author upon reasonable request.