Abstract
We examined whether alanine aminotransferase/aspartate aminotransferase (ALT/AST), a marker of hepatosteatosis, may be associated with a wider constellation of variables related to metabolic syndrome in Japanese women. Body fat and distribution, and metabolic syndrome-related variables were measured in 311 young and 148 middle-aged women. We had Pearson’s correlation analysis and then stepwise multivariate linear regression analyses. In both middle-aged and young women, ALT/AST was associated with homeostasis model assessment insulin resistance (HOMA-IR), trunk/leg fat ratio and pulse rate. In middle-aged women but not in young women, ALT/AST was associated with waist circumference, fasting glucose, triglyceride, HDL cholesterol (inversely), systolic, diastolic and mean blood pressure (BP). Further, in middle-aged women only, the ratio was associated with BMI, percentage body fat, apolipoprotein B and plasminogen activator inhibitor-1. Among these variables, pulse rate in young women and systolic BP in middle-aged women were associated with ALT/AST independently of trunk/leg fat ratio, a sophisticated measures of abdominal fat accumulation, HOMA-IR, fasting glucose, triglyceride and HDL cholesterol. In conclusion, ALT/AST was associated with pulse rate in young women and with systolic BP in middle-aged women independently of abdominal fat accumulation and insulin resistance. It is noted that their waist circumference averaged < 80 cm and ALT < 30 U/L, suggesting minimum accumulation of abdominal and hepatic fat, respectively, key drivers of insulin resistance and metabolic syndrome.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13340-023-00689-z.
Keywords: ALT/AST, Hepatosteatosis, Pulse rate, Blood pressure, Triglyceride, Metabolic syndrome
Introduction
Metabolic syndrome, characterized by a core set of disorders, including central/abdominal obesity, impaired fasting glucose, high blood pressure (BP), high triglyceride (TG) and low HDL cholesterol, is associated with insulin resistance and has been shown to be an important predictor of type 2 diabetes and cardiovascular disease [1]. Studies have provided evidence that a wider constellation of disorders may be part of the metabolic syndrome cluster, including subclinical inflammation [2], oxidative stress [3], sympathetic overactivity [4], nonalcoholic fatty liver disease (NAFLD), [5] and hypercoagulability [6].
Insulin resistance is also the pathophysiological hallmark of NAFLD [7]. Although NAFLD is frequently associated with overweight/obesity, it is also observed in nonobese but insulin resistant subjects [8]. Accumulation of intrahepatic lipid is associated not only with hepatic and muscle insulin resistance but also with the features of metabolic syndrome [8]. NAFLD is common in Asian countries despite low BMI [9]. We have recently shown that ALT/AST was associated with insulin resistance and β-cell function even in nonobese Japanese women, suggesting a pathophysiologic basis in its prediction of diabetes risk [10].
Studies have reported that a ratio of alanine aminotransferase to aspartate aminotransferase (ALT/AST), a surrogate measure of NAFLD [11–15], and its reciprocal (i.e., AST/ALT) are associated with metabolic syndrome [16, 17]. However, studies on lean Asian women are limited. Liver fat content has been shown to be higher in Japanese than non-Hispanic whites, despite a lower mean BMI in Japanese men [18]. Moreover, Japanese men had a higher increase in liver fat with a small increase in BMI than non-Hispanic whites [18]. Therefore, the present study investigated whether ALT/AST might be associated with markers of subclinical inflammation, oxidative stress and hypercoagulability in addition to the core set of disorders in female Japanese students and their middle-aged mothers.
Methods
We examined 311 female university students and 148 their middle-aged biological mothers as previously reported [10, 19, 20]. Women who reported to have clinically diagnosed acute or chronic inflammatory diseases, endocrine, cardiovascular, hepatic and renal diseases, and those on a diet to lose weight and hormonal contraception were excluded from the study. The study was approved by the Ethics Committees of the Mukogawa Women’s University (No. 07-28 on 19/02/2008). This research followed the tenets of the Declaration of Helsinki. All participants gave written informed consent after the experimental procedure had been explained.
Participants received measurements of anthropometric indices, body composition and BP and blood sampling after 12-h overnight fasting as previously described [10, 19, 20]. Systolic and diastolic BP and pulse rates were measured using an automated sphygmomanometer (BP-203RV II, Colin, Tokyo, Japan) after participants had rested at least 5 min. The measurements were repeated after 2–3 min, and the average of the measurements was used for analyses. Mean BP was calculated as diastolic BP plus pulse pressure/3. Pulse pressure is the difference between systolic and diastolic BP. In fasted blood samples, the following were measured [19, 20]: plasma glucose, serum insulin, TG, cholesterol, high-density lipoprotein (HDL) cholesterol, apolipoprotein AI (ApoAI), B-100 (ApoB), high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α) and plasminogen activator inhibitor-1 (PAI-1). Serum ALT and AST were measured using an autoanalyzer (AU5232, Olympus, Tokyo, Japan). Homeostasis model assessment insulin resistance (HOMA-IR) was calculated as a product of fasting insulin (μU/mL) and fasting glucose (mg/dL)/405 [21].
Metabolic syndrome was defined according to the criteria of the Japanese Society of Internal Medicine [22]. In 105 young women, in whom waist circumference data were missing, obesity defined using Asian criteria [23] as BMI ≥ 25.0 kg/ m2 was used instead of waist circumference because it is reported that BMI was not inferior to waist circumference as a practical marker of the metabolic risk clustering in Japanese people [24].
Urinary 8-epi-prostaglandin F-2α (8-epi-PGF2α), a marker of oxidative stress [25], was measured in the first-voided morning urine sample and expressed as pg/mg/creatinine. We used an enzyme-linked immunosorbent assay (8-Isoprostane EIA kit, Cayman, Ann Arbor, MI). Intra- and inter- assay CV were 7.5% and 9.2%, respectively.
Whole-body dual-energy X-ray absorptiometry (DXA) (Hologic QDR-2000, software version 7.20D, Waltham, MA) was used to measure lean tissue mass, fat mass and bone mineral mass for arms, legs (lower-body), trunk and the total body [17]. BMI and percentage body fat were used as markers of general adiposity and waist circumference and the ratio of trunk to leg fat [26] as markers of abdominal fat accumulation.
Data were mean ± SD. Due to deviation from normal distribution, ALT and hsCRP were logarithmically transformed for analyses. Bivariate correlations of ALT/AST with anthropometric and cardiometabolic parameters were evaluated by Pearson’s correlation analysis. Stepwise multivariate linear regression analyses were performed to further identify the most significant variables contributing to the variation of ALT/AST. Variables which showed significant associations with ALT/AST were included as independent variables. All regression models included fasting glucose, TG, HDL cholesterol and systolic BP as independent variables. The following variables were included as additional independent variables: model A: waist circumference, model B: trunk/leg fat ratio, model C: trunk/leg fat ratio and HOMA-IR, model D: trunk/leg fat ratio and pulse rate. Differences between two groups were made with two-sample t test. Comparisons among three groups were analyzed using analysis of variance and then Bonferroni's multiple comparison procedure. Data on waist circumference and urinary 8-epi-PGF2α were missing in 105 young women. A two-tailed p < 0.05 was considered statistically significant. All calculations were performed with SPSS system 23 (SPSS Inc, Chicago, IL).
Results
On average, middle-aged mothers and their daughters were nonobese rather slim and mean serum ALT and AST were within the normal reference range (Table 1). Among 311 young women, 303 (97.4%) had no abnormalities in all five core components of metabolic syndrome. Middle-aged mothers had higher BMI, percentage body fat, waist circumference and trunk/leg fat ratio and hence higher serum ALT, AST and ALT/AST compared with their daughters (Table 1). However, there was no difference in HOMA-IR between two groups of women, and only three middle-aged women (2.0%) had metabolic syndrome. They had higher fasting glucose, TG, ApoB, serum and LDL cholesterol and BP whereas pulse rate did not differ. Middle-aged women also had higher HDL cholesterol and ApoA1 and lower hsCRP despite higher waist circumference. Other markers of inflammation and oxidative stress were higher in middle-aged women.
Table 1.
Anthropometric and cardiometabolic features of young and middle-aged Japanese women
| Young | Middle-aged | ||||||
|---|---|---|---|---|---|---|---|
| n = 311 | n = 148 | p values | |||||
| Age (years) | 20.5 | ± | 1.2 | 49.8 | ± | 3.6 | < 0.001 |
| Body mass index (kg/m2) | 20.4 | ± | 2.2 | 22.0 | ± | 2.8 | < 0.001 |
| Waist circumference (cm) | 71.2 | ± | 5.7a | 78.7 | ± | 8.1 | < 0.001 |
| Trunk fat (kg) | 7.0 | ± | 2.5 | 8.8 | ± | 3.4 | < 0.001 |
| Leg fat (kg) | 5.6 | ± | 1.5 | 5.4 | ± | 1.7 | 0.185 |
| Trunk/leg fat ratio | 1.25 | ± | .25 | 1.64 | ± | .39 | < 0.001 |
| Percentage body fat (%) | 27.8 | ± | 5.5 | 30.1 | ± | 7.3 | 0.001 |
| AST (U/L) | 17 | ± | 5 | 21 | ± | 13 | 0.001 |
| ALT (U/L) | 13 | ± | 7 | 20 | ± | 18 | < 0.001 |
| ALT/AST | .74 | ± | .24 | .91 | ± | .26 | < 0.001 |
| Fasting glucose (mg/dL) | 83 | ± | 7 | 89 | ± | 14 | < 0.001 |
| HOMA-IR | 1.28 | ± | .78 | 1.21 | ± | .71 | 0.354 |
| Triglyceride (mg/dL) | 58 | ± | 34 | 81 | ± | 36 | < 0.001 |
| Cholesterol (mg/dL) | 182 | ± | 28 | 224 | ± | 35 | < 0.001 |
| HDL cholesterol (mg/dL) | 75 | ± | 13 | 77 | ± | 16 | 0.059 |
| LDL cholesterol (mg/dL) | 96 | ± | 24 | 130 | ± | 30 | < 0.001 |
| Apolipoprotein A1 (mg/dL) | 164 | ± | 20 | 178 | ± | 22 | < 0.001 |
| Apolipoprotein B (mg/dL) | 70 | ± | 15 | 93 | ± | 19 | < 0.001 |
| Systolic BP (mmHg) | 106 | ± | 10 | 121 | ± | 16 | < 0.001 |
| Diastolic BP (mmHg) | 61 | ± | 8 | 74 | ± | 11 | < 0.001 |
| Mean BP (mmHg) | 78 | ± | 8 | 90 | ± | 13 | < 0.001 |
| Pulse rate (bpm) | 65 | ± | 10 | 67 | ± | 12 | 0.218 |
| PAI-1 (ng/mL) | 21 | ± | 13 | 24 | ± | 15 | 0.045 |
| hsCRP (μg/dL) | 29 | ± | 69 | 17 | ± | 54 | 0.067 |
| log hsCRP | 1.05 | ± | .50 | .58 | ± | .70 | < 0.001 |
| TNF-α (pg/mL) | .68 | ± | .48 | .77 | ± | .38 | 0.051 |
| Urine 8-epi-PGF2α (pg/mg) | 328 | ± | 107a | 367 | ± | 186 | 0.022 |
Mean ± SD a: n = 206, b: n = 129, ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; bpm, beats per minute, HDL: high-density lipoprotein, hsCRP: high-sensitivity C-reactive protein, HOMA-IR: homeostasis model assessment insulin resistance. LDL: low-density lipoprotein, PAI-1: plasminogen activator inhibitor-1, TNF-α: tumor necrosis factor-α, 8-epi-PGF2α: 8-epi-prostaglandin F-2α
Young women showed significant associations of ALT/AST with only three variables: trunk/leg fat ratio, HOMA-IR and pulse rate although an association with diastolic BP was marginally significant (Table 2). In middle-aged women, ALT/AST was further associated with waist circumference, fasting glucose, TG, HDL cholesterol, systolic, diastolic and mean BP. In addition, the ratio was associated with BMI, percentage body fat, ApoB and PAI-1. In both middle-aged and young women, there was no association with hsCRP, TNF-α and urinary 8-epi-PGF 2α.
Table 2.
Pearson’s correlation analyses of alanine aminotransferase/aspartate aminotransferase in young and middle-aged Japanese women
| Young | Middle-aged | |||
|---|---|---|---|---|
| r | p values | r | p values | |
| Body mass index | 0.103 | 0.071 | 0.325 | < 0.001 |
| Waist circumference | 0.081 | 0.248 | 0.366 | < 0.001 |
| Trunk/leg fat ratio | 0.134 | 0.019 | 0.340 | < 0.001 |
| Percentage body fat | 0.027 | 0.634 | 0.345 | < 0.001 |
| Fasting glucose | 0.046 | 0.423 | 0.259 | 0.001 |
| HOMA-IR | 0.163 | 0.004 | 0.456 | < 0.001 |
| Triglyceride | 0.054 | 0.344 | 0.332 | < 0.001 |
| Cholesterol | 0.026 | 0.649 | 0.057 | 0.492 |
| HDL cholesterol | 0.009 | 0.880 | − 0.161 | 0.051 |
| LDL cholesterol | 0.010 | 0.861 | 0.072 | 0.386 |
| Apolipoprotein A1 | 0.057 | 0.320 | − 0.081 | 0.329 |
| Apolipoprotein B | 0.024 | 0.667 | 0.165 | 0.045 |
| Systolic BP | 0.071 | 0.216 | 0.425 | < 0.001 |
| Diastolic BP | 0.108 | 0.058 | 0.391 | < 0.001 |
| Mean BP | 0.100 | 0.080 | 0.429 | < 0.001 |
| Pulse rate | 0.126 | 0.027 | 0.207 | 0.012 |
| PAI-1 | 0.023 | 0.691 | 0.250 | 0.002 |
| hsCRP | 0.038 | 0.506 | 0.049 | 0.553 |
| log hsCRP | 0.035 | 0.544 | 0.142 | 0.085 |
| TNF-α | − 0.031 | 0.588 | 0.040 | 0.626 |
| Urine 8-epi-PGF2α | 0.080 | 0.251 | 0.080 | 0.335 |
Data are correlation coefficients (r). Significant correlations are indicated by bold figures. Abbreviations are the same as in Table 1
We have done stepwise multivariable linear regression analysis for ALT/AST as a dependent variable (Table 3). All models included fasting glucose, TG, HDL cholesterol and systolic BP as independent variables. The following variables were included as additional independent variables: waist circumference (model A), trunk/leg fat ratio (model B), trunk/leg fat ratio and HOMA-IR (model C) and trunk/leg fat ratio, HOMA-IR and pulse rate (model D). Independent determinants of ALT/ST emerged in middle-aged women, A: waist circumference, systolic BP and TG, B: trunk/leg fat ratio, systolic BP and TG, C and D: trunk/leg fat ratio, systolic BP and HOMA-IR, in young women, A: none emerged (data not shown), B: trunk/leg fat ratio, C: trunk/leg fat ratio and HOMA-IR, D: trunk/leg fat ratio and pulse rate.
Table 3.
Stepwise multivariable linear regression analyses for alanine aminotransferase/aspartate aminotransferase as a dependent variable in young and middle-aged Japanese women
| Model A: middle-aged | Standardized β | p values | Adjusted R2 | Cumulative R2 |
|---|---|---|---|---|
| Waist circumference | 0.194 | 0.016 | 0.026 | |
| Triglyceride | 0.199 | 0.01 | 0.047 | |
| Systolic BP | 0.296 | < 0.001 | 0.175 | 0.248 |
| Model B: middle-aged | ||||
| Trunk/leg fat | 0.205 | 0.008 | 0.053 | |
| Triglyceride | 0.19 | 0.014 | 0.027 | |
| Systolic BP | 0.334 | < 0.001 | 0.182 | 0.263 |
| Model B: young | ||||
| Trunk/leg fat ratio | 0.162 | < 0.001 | 0.024 | 0.024 |
| Model C: middle-aged | ||||
| HOMA-IR | 0.295 | < 0.001 | 0.196 | |
| Trunk/leg fat ratio | 0.164 | 0.032 | 0.018 | |
| Systolic BP | 0.299 | < 0.001 | 0.089 | 0.303 |
| Model C: young | ||||
| HOMA-IR | 0.103 | 0.024 | 0.008 | |
| Trunk/leg fat ratio | 0.144 | 0.002 | 0.024 | 0.033 |
| Model D: young | ||||
| Trunk/leg fat ratio | 0.162 | 0.001 | 0.019 | |
| Pulse rate | 0.147 | 0.001 | 0.025 | 0.044 |
All models included fasting glucose, triglyceride, HDL cholesterol and systolic blood pressure (BP) as independent variables. Additional independent variables included: model A: waist circumference, model B: trunk/leg fat ratio, model C: trunk/leg fat ratio and homeostasis model assessment insulin resistance (HOMA-IR), model D: trunk/leg fat ratio and pulse rate
When two groups of women were divided according to respective tertile of ALT/AST. In young women, pulse rate was higher in the high compared to median tertile whereas trunk/leg fat ratio did not differ among three groups (Fig. 1). Waist circumference and trunk/leg fat ratio were higher in the high compared to the other two groups of middle-aged women. Serum TG increased in middle-aged women in a stepwise fashion from the low through median to high tertile (Fig. 2). Systolic, diastolic and mean BP were higher in the high compared to the other two groups of middle-aged women.
Fig. 1.
Pulse rate, trunk/leg fat ratio and waist in young (circles) and middle-aged Japanese women (squares) grouped according to respective tertile of alanine aminotransferase/aspartate aminotransferase. Mean ± SD. Means not sharing the same alphabet are significantly different with each other at p < 0.05 or less by Bonferroni’s multiple comparison procedure. Blue, yellow and red symbols represent the low, median and high tertile, respectively
Fig. 2.
Serum triglyceride, systolic, diastolic and mean blood pressure (BP) in middle-aged Japanese women grouped according to tertile of alanine aminotransferase/aspartate aminotransferase. Mean ± SD. Means not sharing the same alphabet are significantly different with each other at p < 0.05 or less by Bonferroni’s multiple comparison procedure. Blue, yellow and red symbols represent the low, median and high tertile, respectively
Discussion
The current study has shown that ALT/AST, a marker of hepatosteatosis [10–13], was associated with pulse rate, trunk/leg fat ratio, a sophisticated measures of abdominal fat accumulation [26], and HOMA-IR in both young and middle-aged women. In addition, middle-aged women showed associations with all core components of metabolic syndrome as previously reported [14–17] whereas young women showed no association, except for marginally significant association with diastolic BP. Further, in middle-aged women only, the ratio was associated with ApoB and PAI-1, a marker of impaired fibrinolysis, and hence hypercoagulability [6] although there was no association with markers of subclinical inflammation and oxidative stress. Among these variables, pulse rate and systolic BP were associated with ALT/AST in young and middle-aged women, respectively, independently of abdominal fat accumulation and insulin resistance. It is noteworthy that their waist circumference averaged <80 cm and ALT <30 U/L, suggesting minimum accumulation of abdominal and hepatic fat, respectively, key drivers of insulin resistance and metabolic syndrome.
Kim et al. [27] studied 1017 postmenopausal women, who attended a health examination program, and found that resting heart rate, a simple but reliable marker of sympathetic cardiovascular function [28], was positively associated with NAFLD. This observation may be in line with our finding of an association of ALT/AST with pulse rates in young women as pulse rates seem to be equal to heart rates in women whose age averaged 20.5 years and BMI 20.4 kg/m2 although heart rates were not measured in the present study. Previous clinical studies have suggested that autonomic imbalance might increase the risk of NAFLD [29, 30]. Increased resting heart rate has been shown to be associated with the higher risk of metabolic syndrome in studies mainly carried out in middle-aged or older subjects [31, 32].
Many studies reported associations of ALT or NAFLD with BP elevations and incident prehypertension and hypertension [33–37]. As reviewed previously [37], “NAFLD is a multisystem disease and may induce multiple systemic adverse effects, including inflammation, insulin resistance and oxidative stress, to drive hypertension”. In the present study, ALT/AST was associated with systolic BP independently of abdominal fat accumulation and insulin resistance and was not associated with markers of inflammation and oxidative stress in middle-aged women. Masuo et al [38] have shown that sympathetic nerve hyperactivity precedes hyperinsulinemia and BP elevation in a young, nonobese Japanese population. They subsequently suggested that weight gain-induced sympathetic overactivity evaluated by fasting plasma norepinephrine and pulse rates was tightly linked to weight gain–induced BP elevation [39]. When taken together, we speculated that sympathetic nerve hyperactivity may be associated with independent associations of ALS/AST with pulse rate in young women and with systolic BP in middle-aged women although we did not measure autonomic nervous system function. Among the variables included in the metabolic syndrome definition, BP appears to be most closely related to the sympathetic overdrive [4].
We reported that the BMI of 18-year-old daughters was associated with their mothers' BMI (r=0.30, p<0.0001) measured when they were 18 years old [40]. As 148 among 311 young women were daughters of 148 middle-aged women in the present study, the observation that sympathetic nerve hyperactivity precedes BP elevation in a nonobese Japanese population [38] may be analogous to our finding of associations of ALS/AST with pulse rate, a global index of the influence of the autonomic nervous system on the heart, in young women and with systolic BP in middle-aged women.
Ruhl and Everhart [41] investigated the relation of ALT and body composition measured by DXA in 11,821 adults and found that trunk fat was associated with increased ALT in men and women whereas extremity fat was independently inversely associated among women. These observations may be in line with our findings of association between ALT/AST and trunk/leg fat ratio, a combined indicator of increased trunk fat and decreased leg fat, in young and middle-aged women.
Subcutaneous adipose tissue, mainly located in gluteofemoral or leg region, is the largest and best storage site as fat and the main source of intrahepatic TG in patients with NAFLD derives from adipose-tissue-derived FFA [42]. Asian populations including Japanese may have a reduced ability to expand subcutaneous fat [43]. Associations between a marker of fatty liver (ALT/AST) and insulin resistance found in young lean Japanese women in the present study may be related to the hypothesis that fatty liver may be a sensitive marker for the failure of the adipose tissue to expand in Japanese [18] although we did not measure intrahepatic TG in the present study. We suggested that reduced subcutaneous fat mass, a proxy of impaired adipose tissue expandability, may be associated with lower birthweight [44] and positive family history of type 2 diabetes [45] in young Japanese women.
The strength of this study includes a sophisticated measures of body composition measured by DXA and homogeneous study population (female university students and their biological mothers) with scarce confounding factors [20, 21]. The cross-sectional design, relatively small sample size, and a single measurement of biochemical variables are limitations of this study. The participants were not checked for causes of liver damages including hepatitis B or C viruses. We used many surrogates in the present study, which may be less accurate. Finally, as we studied Japanese women only, results may not be generalized to other sex, races or ethnicities.
In conclusions, ALT/AST was associated with pulse rate in young women and with systolic BP in middle-aged women independently of abdominal fat accumulation and insulin resistance. It is noted that their waist circumference averaged < 80 cm and ALT < 30 U/L, suggesting minimum accumulation of abdominal fat and hepatic fat, respectively, key drivers of insulin resistance and metabolic syndrome.
Disclosure
None of the authors have any potential conflicts of interest to declare associated with this research.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank all participants for their dedicated and conscientious collaboration.
Author contributions
SMI, ATK, MH and MT, collected data and prepared tables. KK, MK and BW analyzed data and prepared Fig. 1 and 2. TK wrote the manuscript, and KF reviewed and edited it. All authors approved the final version of the manuscript to be published. TK supervised the study, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding
No funding was received for this article.
Data availability
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Declarations
Conflict of interest
None of the authors have any potential conflicts of interest.
Human rights statement
The study was approved by the Ethics Committees of the Mukogawa Women’s University (No. 07–28 on 19/02/2008).
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.