|Year : 2021 | Volume
| Issue : 4 | Page : 434-441
Clusters and components of metabolic syndrome (MeS) as a predictor for fatty liver: A cross-sectional study
Varanasi Yugandar Bhargav1, Mayank Jain2, Tom Alen3, Chandan Kumar Kedarisetty1, Preetam Arthur3, Mu Karthikeyan1, Thamarai S Selvan1, Jayanthi Venkataraman1
1 Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
2 Department of Gastroenterology, Arihant Hospital and Research Centre, Indore, Madhya Pradesh, India
3 Department of General Medicine, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
|Date of Submission||09-Feb-2021|
|Date of Decision||14-Jun-2021|
|Date of Acceptance||16-Jun-2021|
|Date of Web Publication||12-Jan-2022|
Dr. Varanasi Yugandar Bhargav
Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600116, Tamil Nadu.
Source of Support: None, Conflict of Interest: None
Aim: Metabolic syndrome (MeS) refers to metabolic risk factors with different phenotype combinations. The study aim was to determine the clusters of MeS components by age and gender as predictors for the presence of fatty liver (FL). Materials and Methods: The cohort consisted of 990 subjects, undergoing executive health check between January 2019 and February 2020. Baseline data, anthropometric parameters, and ultrasound findings were noted. Patients with normal ultrasound were categorized as group 1 and those with FL as group 2. MeS is defined and clustered and risk of predicting FL was analyzed in age and gender. Results: Of the 990 subjects, 689 (69.6%) had FL (group 2); 554 patients (56%) were >45 years. Females had significant grade 1 (P < 0.05) and grade 2 (P < 0.01) FL, ≥45 years, and MeS of three or more components in FL, both above (P < 0.01) and below (P < 0.03) 45 years of age. Waist circumference (WC), diabetes mellitus (DM) with hypertension, triglyceride, and high-density lipoprotein (cluster 3) were statistically significant in males, both <45 and >45 years of age (P < 0.001); in females, the same cluster was statistically significant only for >45 years (P <0.001). Conclusion: Females ≥45 years had significant FL. MeS of three or more components was seen in both above and below 45 years in females with FL when compared with males. The highest risk clusters were the ones that included WC and WC + DM, indicating that the clusters associated with WC alone or in combination with DM had the highest risk for FL when compared with the other MeS combinations.
Keywords: Chronic hepatitis, fatty liver, fibrosis, insulin resistance, non-alcoholic fatty liver disease
|How to cite this article:|
Bhargav VY, Jain M, Alen T, Kedarisetty CK, Arthur P, Karthikeyan M, Selvan TS, Venkataraman J. Clusters and components of metabolic syndrome (MeS) as a predictor for fatty liver: A cross-sectional study. J Diabetol 2021;12:434-41
|How to cite this URL:|
Bhargav VY, Jain M, Alen T, Kedarisetty CK, Arthur P, Karthikeyan M, Selvan TS, Venkataraman J. Clusters and components of metabolic syndrome (MeS) as a predictor for fatty liver: A cross-sectional study. J Diabetol [serial online] 2021 [cited 2022 Jan 27];12:434-41. Available from: https://www.journalofdiabetology.org/text.asp?2021/12/4/434/335603
| Introduction|| |
Non-alcoholic fatty liver disease (NAFLD) manifests as a spectrum wherein at one end we have an innocuous fatty liver (FL) with normal liver biochemistry and at the other end steatohepatitis evolving to severe fibrosis, cirrhosis, and hepatocellular carcinoma. Worldwide, the prevalence of NAFLD, especially in the form of FL, is increasing exponentially with the rising incidence of various components of metabolic syndrome (MeS)., Occurrence of MeS can occur with various combinations. NAFLD has been redefined as a metabolic dysfunction-associated fatty liver disease, wherein there is hepatic steatosis along with combination of other criteria such as overweight/obesity, presence of diabetes mellitus (DM), hypertension (HT), dyslipidemia, and a prothrombotic or proinflammatory state. Almost 50–88% of diabetics have an FL. FL is largely related to enhancing triglyceride (TG) lipolysis and free fatty acid (FFA) release secondary to insulin resistance. The FFA is taken up by the liver leading to fatty infiltration.
The risk factors predisposing a person with NAFLD to atherosclerotic cardiac disease, cerebrovascular accident, DM, or chronic kidney disease are due to the clustering of various components of MeS such as truncal adiposity (visceral), dyslipidemia, HT, and elevated blood glucose levels. What components of MeS are associated with FL needs to be addressed. More recent studies have shown that FL may itself be responsible for inducing a proinflammatory and a prothrombotic state, both of which on their own can trigger the various complications of NAFLD.,,, The components of MeS exist in several permutations and combinations (at least 16) in either gender and in various age groups. Each of these permutations and combinations would have different pathophysiological connotations in terms of morbidity, and treatment therefore needs to be tailored to address each of the individual MeS component.
Several studies including our own study have addressed the issue of age and gender differences in NAFLD.,, However, none of the studies has looked into the cluster phenomenon of MeS by age and gender in relation to NAFLD. Wang et al. reported NAFLD to be more prevalent among men, elderly, and in post-menopausal women; other studies have reported the high risk in women for NAFLD, cardiovascular disease, and cerebrovascular accident as they approach the menopausal phase mainly due to increase in the incidence of MeS., The presence or absence of MeS in the pre- and post-menopausal phase in the presence of FL in these patients is not known. Several of these can be attributed to differences in cluster combinations of MeS, lifestyle changes, sex hormone physiology, and post-menopausal state.,
We report our observations on prevalence of MeS and cluster combinations of MeS components by age and gender in patients with FL in south Indian population, screened during master health check in our cross-sectional study.
| Materials and Methods|| |
Subjects who were residents of Tamil Nadu, registered for an executive health check between January 2019 and February 2020 at our institute, were included in the study. All subjects had an ultrasonogram (USG) of the abdomen as a part of master health check. Based on the USG diagnosis, patients were categorized as those with a normal USG (group 1) and those with FL (group 2).
Adults, above 18 years of age and belonging to either gender, residents of Tamil Nadu for at least a year, with or without known co-morbidities such as DM, HT, and dyslipidemia (controlled or uncontrolled while on medication) were included in the study.
Baseline patient information included age and gender. Anthropometric measurements such as height (in cm), weight (in kg), waist and hip circumference (in cm) were recorded during the first visit. The waist circumference (WC) was assessed at the highest point on the iliac crest at the end of a normal expiration and hip circumference at the widest part of hips with an inch tape. Blood pressure was noted in right arm after 20 min of rest in sitting position along with resting pulse rate.
Blood samples were collected during the first visit for complete hemogram, liver biochemistry, lipid profile (automated analyzer), blood sugar: fasting and post-prandial blood sugar (glucose oxidase method), HbA1C (high-performance liquid chromatography (HPLC)), HBsAg and anti-HCV antibody tests (chemiluminescence immunosorbent assay). USG was performed by experienced radiologists using conventional B-mode USG using the standard parameters which differentiated normal liver and FL and graded FL as grades 1, 2, and 3., None of the patients had transient elastography (Fibroscan) or a liver biopsy.
Definition of components of MeS
We followed the Modified National Cholesterol Education Program: Adult Treatment Panel III (2004) and Asia–Pacific/Indian Modifications for defining MeS. An individual was considered to have an MeS if he/she had three or more of the five metabolic components:
- a. Truncal obesity: WC ≥90 cm in males and ≥80 cm in females;
- b. DM: ≥ Fasting glucose (mg/dL) ≥ 100 mg/dL, type 2DM or known DM on treatment;
- c. HT: ≥130/85 mmHg, or on treatment;
- d. High-density lipoprotein (HDL): ≤40 mg/dL in males and ≤50 mg/dL in females;
- e. Serum TG: ≥150 mg/dL or on treatment.
Pregnant women, patients consuming alcohol more than 40 g/week in men and more than 20 g/week in women, and other known etiologies for chronic liver disease (viral hepatitis, autoimmune hepatitis, Wilson disease, and hemochromatosis) were excluded. Non-alcoholic steatohepatitis secondary to total parenteral nutrition, post-jejunoileal bypass, or medications such as estrogens, amiodarone, tamoxifen, and anti-tuberculous therapy were excluded.
The primary outcome of the study was to determine prevalence of MeS and its clusters (three or more components) in patients with FL and risk stratification of these cluster components for FL.
This single-center study conformed to the Declaration of Helsinki and was approved by the Institutional Ethics Committee. The study follows the guidelines for reporting observational studies (Strengthening the Reporting of Observational Studies in Epidemiology statement). An informed written consent was taken from each patient at the time of enrollment.
[Figure 1] shows the cross-sectional study protocol that was followed for patients being evaluated for FL during master health check. For analysis, patients were categorized as group 1 if USG was normal and group 2 if USG showed FL (any grade). The two groups were compared for individual and combinations of components of MeS. In order to study the MeS clusters, the two highest prevalent individual components of MeS were determined. Clusters of MeS (three and more components) were then categorized to ascertain significance by age, gender, and grades of FL.
Normally distributed continuous variables were expressed as mean (SD) and the continuous variables with skewed distribution as median (interquartile range). The χ2 (or Fisher’s exact) test compared differences between the groups for categorical variables. To find the significant difference between the bivariate samples in independent groups, unpaired sample t-test was used. A P-value of less than 0.05 was taken as significant. All statistical tests were performed using Statistical Package for the Social Sciences (SPSS) for Windows, version 23 (IBM Corp., Armonk, NY, USA).
| Results|| |
Of the 990 subjects [Table 1], there were 301 (30.4%) patients in group 1 and the remaining 689 (69.6%) in group 2. In both groups, males were more than females. Females in group 2 were significantly older compared with those in group 1 (50.7 ± 11.7 vs. 46.5 ± 12.8 years; P < 0.001). Patients in group 2 were more obese compared with those in group 1 (≥ 25 kg/m2; P <0.001) and this was statistically significant. The mean age of cohorts in our study in males and females was 45 years [Table 1].
|Table 1: Baseline features of males and females with normal US (group 1) and FL (group 2)|
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[Table 2] shows the distribution of the cohort by age, gender, and grades of FL. Overall, majority of the patients (both genders) were above the age of 45 years; female patients above 45 years had significant FL (grades 1 and 2) compared with males.
|Table 2: Distribution of cohort (990) by age, gender, and presence of FL|
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Among the 5 MeS components, overall, 738 (74.5%) patients had raised WC, 632 (63.8%) were diabetic, 536 (54.1%) had low HDL, 437 (44.1%) were hypertensives, and 316 (31.9%) had raised TGL; WC and DM were the top 2 components in the hierarchy of MeS. Combinations of MeS of three or more were significant in group 2 (FL) (P < 0.001).
For MeS prevalence and cluster analysis, we took the mean cut-off of 45 years for males and females. This cut-off also coincided with the average age of 46.2 years for menopause in Indian women.[Table 3] shows the comparative MeS by age and gender in groups 1 and 2. MeS of three or more components was significantly high among females with FL, both above and below 45 years (P-values <0.01 and <0.05, respectively).
Cluster analysis of MeS
Taking into account the hierarchy of MeS components, DM and WC were used as either independent or combination components for cluster analysis with the other three, i.e., HT, TGL, and HDL [Table 4]. There were a total of 16 permutations and combinations. These were categorized into four clusters based on the denominator: Cluster 1: WC; Cluster 2: DM; Cluster 3: WC + DM; Cluster 4: absence of WC and DM. Any cluster containing less than 5% of the total was considered insignificant and was excluded for comparison between the two groups. Cluster 4 (HT+TGL+HDL) had less than 1% combination in both groups and was not included for comparative cluster analysis. Cluster 3 (WC +DM) are predominant in gender distribution of both groups [Figure 2].
|Table 4: Clusters of three MeS components (HT, TGL, and LDL) in combination with WC and/or DM|
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|Figure 2: Clusters of MeS (%) in male and female patients in groups 1 and 2|
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Cluster 3 in males was predominant both below and above the age of 45 years, and this was statistically significant (P-value <0.001), whereas the same cluster 3 was statistically significant only above the age of 45 years in females (P < 0.001) [Figure 3]A and B.
|Figure 3: A: Cluster differences in MeS in males with FL (n = 448). B: Cluster differences in MeS in females with FL (n = 448). **P-value <0.05 tested by using the one-way analysis of variance test between group clusters, $P-value <0.05 tested by using the χ2 test between age groups (<45 and ≥45 years)|
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When each cluster of the MeS was compared for the association with FL with respect to controls (group 1), using logistic regression, the overall risk of MeS for FL in the cohort was four times [odds ratio (OR) 3.8, confidence interval (CI) 2.7–4.9], whereas for individual clusters 1, 2, and 3, it was 5.2 times (OR 5.2, CI 2.8–9.5), 2.7 times (OR 2.7, CI 1.4–5.1), and 3.6 times (OR 3.6, CI 2.6–4.9), respectively [Table 5]. A hierarchy was noted among the clusters for FL, it being higher for Cluster 1 followed by Cluster 3 and Cluster 2. The highest risk clusters were the ones that included WC and WC + DM, indicating that the clusters associated with WC with or without combination of DM had the highest risk for FL compared with the other MeS combinations [Table 5].
| Discussion|| |
The study compared components and clusters of MeS in two groups of patients: those with and those without FL by age and gender in a cohort who had a USG during a master health check. Significant number of patients attending the screening program were above 45 years. Females more than 45 years had significant prevalence of FL when compared with males of the same age in the cohort. MeS components three or more were high in a female with FL both above and below 45 years, correlating with the average menopausal age in an Indian woman, i.e., 46.2 years at which the risk of FL arises probably due to the changes in sex hormone physiology. Of the five components of MeS, irrespective of the age, gender, and US findings (both groups), the highest prevalence of individual components of MeS was WC (738; 74.5%), followed by DM (632; 63.8%), HDL (532; 53.7%), HT (437; 44.1%), and TGL (316; 31.9%) in that order [Table 1]. Among the 4 clusters that included 16 combinations of MeS components, Cluster 3 (WC+ DM+ any or all 3) was significant in male patients both above and below 45 years (P-value 0.001 vs. <0.001), whereas it was significant only above 45 years in females (P-value <0.001).
Most studies in literature have addressed single component of MeS as risk for NAFLD. Kotronen et al. reported that nearly 90.0% of NAFLD had associated with at least one component of MeS. In a prospective observational study of 4401 apparently healthy individuals, Hamaguchi et al. could predict that subjects with MeS had 4–11 times higher risk for a future NAFLD. We believe the MeS components WC with or without the presence of DM can predict FL in men and in women above the age of 45 years. This needs validation in future prospective study. An increase in MeS has been reported with increase in age and often in women. In our study, MeS was common in female patients with FL and was significantly high above 45 years.
There are a few studies that have addressed differential combinations of MeS as a risk factor for NAFLD. Two studies reported that NAFLD was associated with type 2 DM (28–55%) and dyslipidemia (27–92%)., A third study described hypertriglyceridemia and low HDL-cholesterol level in 62% and 54% of NAFLD patients, respectively. We had earlier reported that male gender and high body mass index (BMI) were associated with FL in men, whereas in female gender above 40 years, DM and raised TG were independently associated with FL.
None of the studies have addressed clusters/combinations of MeS as risk predictors for FL. The significant link between WC and DM, reported in south Asian population, is projected in this study as two important components of MeS that correlate with FL. Our study has further shown a significant age and gender difference in MeS among males and females below and above the age of 45 years as risk factors for FL. Female patients in the perimenopausal period have significant risk for FL, especially in association with MeS ≥3 components, WC and DM combinations being the most common.
Limitations of the study
The numbers of patients with grade 2 and grade 3 FL were few, especially in female patients.
Intra-observer variation of radiological diagnosis of FL is mainly between normal and grade 1 FL.
No validation of USG abdomen diagnosis of FL was done with gold standard (magnetic resonance imaging or liver biopsy).
| Conclusion|| |
Females ≥45 years had significant FL in the study. MeS of three or more components was seen in females both above and below 45 years with FL when compared with males. The highest risk clusters were the ones that included WC and WC + DM, indicating that the clusters associated with WC alone or in combination with DM had the highest risk for FL compared with the other MeS combinations.
CKK, TA, and JV made the study concept and design; acquisition of data done by VYB, TA, MK, TSS; statistical analysis done by MJ and JV; drafting of manuscript done by VYB, PA, MJ; critical revision of manuscript done for important intellectual content done by CKK and JV; administrative and technical support by JV.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]