Background
Hypertension is a major contributing factor for cardiovascular disease (CVD) and one of the leading causes of death in the world [
1,
2]. The world prevalence of hypertension was 26% in 2000 which is projected to be increased by 29.2% in 2025 [
3]. The incidence of hypertension is increasing in developing countries along with developed countries [
4]. In the Asian region, hypertension has become a significant concern affecting over 35% of the adults and the countries especially in South-East Asia are particularly facing the increasing burden of hypertension [
5,
6]. The incidence of hypertension in Bangladesh has increased rapidly in the past years [
7,
8]. Hypertension and its complications are responsible for a significant portion of the death of the Bangladeshi population and a burden for the national economy. Early diagnosis and management of increased blood pressure before hypertension development may be cost-benefit in terms of reducing premature morbidity and mortality in general people [
9].
The interrelationship between liver dysfunction and the development of hypertension is being increasingly recognized. The liver is a vital organ in metabolism that plays numerous roles included synthesis, degradation, storage, and biotransformation of bio-molecules in the human body [
10]. The liver enzymes alanine and aspartate aminotransferase (ALT and AST), γ-glutamyltransferase (GGT), and alkaline phosphatase (ALP) have been widely used as a good marker of liver health [
11]. The elevated levels of ALT, AST, and GGT reflect an excess fat deposition in the liver, a condition termed as nonalcoholic fatty liver disease (NAFLD). These enzymes are suggested to have substantial clinical and epidemiological significance as convenient surrogate markers of NAFLD and related liver dysfunction [
12,
13]. Some epidemiological studies have demonstrated an association of ALT and GGT with metabolic syndrome, CVD and type 2 diabetes [
14‐
17]. In previous studies, CVD has been demonstrated as a leading cause of death in NAFLD, with higher rates coinciding with increased liver-related mortality throughout follow-up investigations [
18‐
20].
An association between higher serum GGT levels and hypertension has been reported in some longitudinal and cross-sectional studies [
15,
21‐
24]. However, most of the previous studies assessed the relationship that included only one or two hepatic enzymes and their findings were inconsistent. The epidemiological data concerning the extent of elevated liver enzymes in the Bangladeshi hypertensive individuals are not available yet. To address these issues, we conducted a cross-sectional study to examine the association of all four liver enzymes with hypertension in Bangladeshi adults.
Methods
Study participants and area
This cross-sectional study was conducted between October 2017 and September 2018 at the Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh. More than 350 participants aged above 18 years were invited randomly to take part in the study, among them 302 subjects agreed to participate. The participants included general adults from Sylhet city regions, academic and non-academic staffs and university adult students. The inclusion criteria were: both gender, aged above 18 years, free from severe chronic illness and willing to participate. Exclusion criteria: participants with a history of hepatotoxic drugs intake, alcohol intake (alcohol consumption is generally prohibited in Bangladesh from religion restriction), and severe chronic or acute evidence of liver diseases reported by participants were excluded from the study. Written informed consent obtained from all participants before inclusion in the study. This study was approved by the internal Ethics Committee at the Department of Biochemistry and Molecular Biology of Shahjalal University of Science and Technology. All steps in the method section were conducted out following the relevant guidelines and regulations.
Anthropometric and blood pressure data
Trained personnel measured the anthropometric and blood pressure (BP) data and recorded in the questionnaire form according to the standard procedure described elsewhere [
25‐
27]. An individual’s body weight and height were measured to calculate the BMI (kg/m
2). Using a digital BP machine (Omron M10, Omron Corporation, Tokyo, Japan), individuals BP was measured on the left arm in a sitting position after the participant rested for 10 min. The first BP measurement was discarded to avoid possible effects of anxiety, and the mean value of the second and third measurements was count for systolic blood pressure (SBP) and diastolic blood pressure (DBP). The participants were requested to avoid coffee, tea and smoking for 30 min before BP measurements. Physical activity was categorized as low, medium and adequate based on participation in any activities such as jogging, bicycling, swimming or daily sports. The questionnaire also asked about the smoking status of the participants (yes or no). Individual food habits and brief lifestyle information were also recorded in the questionnaire form.
Sample collection and biochemical analysis
The participants were at least 10–12 h of overnight fast before providing the blood samples. From each participant, about 5 ml of the venous blood was drawn in a plain dry vacutainer tube using disposable syringes. Serum was separated and stored at − 80 °C in the laboratory until biomarkers analysis. Serum concentrations of glucose, total cholesterol (TC), triglycerides (TG), albumin and total protein were measured by colorimetric methods. Activities of serum liver enzymes ALT, AST, GGT and ALP were measured by kinetic methods. All measurements were done using commercially available diagnostic kits (Human Diagnostic, Germany, except GGT from Vitro Scient, Egypt) with a biochemistry analyzer (Humalyzer 3000, USA).
Diagnostic criteria
The liver enzymes at elevated levels were defined as one or more measurement of: AST > 35 U/L in men/ > 31 U/L in women, ALT > 45 U/L in men/ > 34 U/L in women,, GGT > 55 U/L in men/ > 38 U/L in women [
28] and ALP > 128 U/L in men/ > 98 U/L in women [
29]. Hypertension (stage 2) was defined as resting SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg or by treatment for hypertension [
30,
31].
Statistical data analysis
Baseline data are expressed as mean ± standard deviation, whereas, the categorical data are mentioned as percentages. Pearson’s correlation coefficient test (two-tailed) was performed to examine the correlation between hepatic markers and baseline variables. The differences between anthropometric and baseline characteristics in the gender and case-control groups were done by independent sample t-test. Associations between liver enzymes and hypertension were evaluated by multinomial logistic regression analysis. A p-value of < 0.05 was set statistically significant. Statistical data analyses were done using IBM SPSS software (version 23).
Discussion
The present study demonstrates that serum ALT and GGT are positively associated with the prevalence of hypertension. This study provides the first information on the association between liver enzymes and hypertension among Bangladeshi adults.
In the present study, the prevalence of elevated hepatic enzymes (ALT, AST, and GGT) was significantly higher among hypertensive individuals. The serum level of ALT was about one and a half and GGT was two times higher in hypertensive subjects than in the normotensive individuals. When age was taken into account, elevated GGT levels were more likely to be found in persons at high risk of hypertension. A high prevalence of elevated levels of ALT and GGT demonstrated a higher risk for hypertensive females and males than their normotensive counterparts. A similar result was found in a previous study that reported a high prevalence of elevated ALT in the hypertensive group compared to the normotensive group [
9].
In our study, both SBP and DBP were significantly associated with ALT, AST and GGT. However, in regression analysis, only ALT and GGT were significantly associated with hypertension even after adjustment of potential confounders. Our results for GGT are in agreement with the findings of previous prospective studies [
15,
21‐
24,
32] that showed baseline serum GGT was an independent risk factor for hypertension development. We also observed an increasing trend for the mean levels of ALT, AST and GGT in the prehypertension and hypertensive group compared to the normotensive group. Higher levels of GGT were previously reported in prehypertensive Korean, Japanese, Chinese, and US adults [
33‐
36].
In the present study, serum ALT showed an independent association with hypertension in Bangladeshi adults. A similar finding was observed in a previous study that reported ALT as a potential indicator of hypertension in Chinese senior adults [
9]. There is no simple explanation for why a serum ALT showed an independent association with hypertension in the Bangladeshi population. One possibility may be that hypertensive individuals develop NAFLD after a long period of elevated blood pressure [
37]. The postulated mechanism could be that increased blood pressure activates pro-inflammatory responses such as TNF-α and interleukin adiponectin and leptin that contribute to hepatotoxicity [
38]. This needs further investigation. Serum AST and ALP did not show a significant association with hypertension in the present investigation. Up to now, a very limited number of studies evaluated the association of AST and ALP with hypertension and their findings are inconsistent [
39,
40]. Moreover, a wide variation has been observed on the prevalence of elevated liver enzymes in the previous studies. Different reference values, age range, ethnicity, and demography might be considerable factors for the observed variations of these studies.
The biological mechanism underlying the relationships between hepatic enzymes and hypertension remains unclear. Study evidence suggests a link of NAFLD with CVD [
21]. Some cross-sectional studies showed a higher incidence of NAFLD in hypertensive individuals, as compared with those with normal BP [
37,
41]. A recent follow-up study showed that fatty liver development is related to hypertension in Korean adults [
42]. On the other hand, a potential mechanism for the link between GGT and hypertension might be related to oxidative stress and the role of cellular GGT in the catabolism of extracellular antioxidant glutathione [
21,
35]. Also, it has been reported that cellular GGT may be related to reactive oxygen species production in the presence of transition metals [
43]. In parallel, oxidative stress is documented to be associated with hypertension [
44] and antioxidant enzyme genes polymorphisms, including few of the glutathione-S-transferase genes, have been reported to be correlated with the risk of hypertension in the general adults [
45,
46]. Further investigations are required to confirm the postulated mechanisms between elevated liver enzymes and incident hypertension in the general population.
The strength of the present study included an adjustment for well-known hypertensive risk factors including age, BMI, lipids, smoking and physical activities to examine the relationships. However, some limitations of the present study should be considered. First, we measured the hepatic enzymes at baseline level which may not represent the long-term profile. The second limitation of the present study is a small sample size. Third, the cross-sectional nature of the study may preclude any casual relationship between hepatic enzymes and hypertension. Moreover, hepatitis B and C infection were not measured among the participants that may have effects on elevated hepatic enzymes.
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