Factors underlying the association of body mass index with serum ALT in Chinese hypertensive adults without known hepatic diseases

Factors underlying the association of body mass index with serum ALT in Chinese hypertensive adults without known hepatic diseases 1 first-author 2 1 3 4 5 6 7 8 1 1 1 1 1 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:huoyong@263.net.cn †E-mail:huoyong@263.net.cn huoyong@263.net.cn Department of Cardiology, Peking University First Hospital, Beijing 100034, China Department of Cardiology, Peking University First Hospital, Beijing 100034, China Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China Department of Clinical Pharmacology, Peking University First Hospital, Beijing 100034, China Department of Clinical Pharmacology, Peking University First Hospital, Beijing 100034, China Department of Pharmacy, the First Affiliated Hospital of Academy of Military Medical Sciences of China, Beijing 100071, China Department of Pharmacy, the First Affiliated Hospital of Academy of Military Medical Sciences of China, Beijing 100071, China Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai 200032, China Department of Cardiology, the First Clinical Medical College of Harbin Medical University, Harbin 150001, China Department of Cardiology, the First Clinical Medical College of Harbin Medical University, Harbin 150001, China Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China Department of Cardiology, the First Affiliated Hospital of China Medical University, Shenyang 110001, China Department of Cardiology, the First Affiliated Hospital of School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China Department of Cardiology, the First Affiliated Hospital of School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China Guangdong Institute of Nephrology, Southern Medical University, Guangzhou 510515, China Guangdong Institute of Nephrology, Southern Medical University, Guangzhou 510515, China Objective: 2 High body mass index (BMI) is considered as the most important risk factor for elevated serum alanine aminotransferase (ALT) concentration. This study examined an array of factors, including waist circumference (WC) and folate deficiency, which may mediate the association of BMI with serum ALT concentration in Chinese hypertensive adults without known hepatic diseases. Methods: 2 A multicenter, cross-sectional study was carried out. A total of 378 patients with mild or moderate hypertension and without known hepatic diseases were recruited from five hospitals in Harbin, Shanghai, Beijing, Xi’an, and Nanjing. Results: 2 Of the 360 hypertensive patients with complete data in our final analysis, 13.6% had high ALT concentrations ( > 40 IU/L). Factors including BMI, WC, triglyceride level, and folate concentration were associated with ALT concentration in univariate analysis. Consistently higher prevalence rates of elevated ALT were observed in subjects with lower folate concentrations (≥12 vs. < 12 nmol/L, 9.9% vs. 17.8%, P =0.03), with higher BMI (≥28 vs. < 28 kg/m 2 , 21.5% vs. 11.4%, P =0.02) or higher WC (≥90 vs. < 90 cm, 18.5% vs. 10.0%, P =0.02). However, in multivariate analysis, the association between BMI and ALT concentration disappeared ( P =0.802 in males and 0.369 in females), while WC in females ( P < 0.001) and folate concentration ( P =0.036 in males and 0.044 in females) remained as significant predictors for ALT concentration. Conclusions: 2 This multicenter study demonstrated that WC and low folate concentration were important factors underlying the association between BMI and ALT concentrations in Chinese hypertensive adults without known hepatic diseases. Alanine aminotransferase (ALT) Body mass index (BMI) Waist circumference (WC) Folate Introduction 1 Serum alanine aminotransferase (ALT) activity has been considered as a reliable and sensitive marker of a variety of hepatic disorders. Emerging data also suggest that ALT may well predict a range of health outcomes. Kim et al. ( 2004 2004 ) analyzed the association between ALT concentration and mortality in a large, prospective cohort in Korea. They found a continuous and positive association between ALT concentration and all-cause mortality, or mortality from liver diseases, cancers, and cardiovascular diseases in men with adjustment for almost all the traditional risk factors. Furthermore, ALT (both in normal and elevated ranges) was independently associated with the long-term development of multiple metabolic disorders and cardiovascular diseases (Schindhelm et al., 2007 2007 ; Goessling et al., 2008 2008 ; Yun et al., 2009 2009 ). The cause of abnormal ALT concentration is incompletely understood. High body mass index (BMI) is considered as the most important risk factor for elevated ALT concentration (Salvaggio et al., 1991 1991 ; Sull et al., 2009 2009 ; Kim and Jo, 2010 2010 ). However, waist circumference (WC) is correlated with central fat, which provides a greater supply of potentially hepatotoxic fatty acids to the liver, and may be a stronger predictor for elevated ALT concentrations than BMI (Ruhl and Everhart, 2003 2003 ). Furthermore, folate deficiency may possibly accelerate or promote hepatic injury by increasing hepatic homocysteine (Hcy) and S -adenosylhomocysteine concentrations, decreasing hepatic S -adenosylmethionine and glutathione concentrations, increasing lipid peroxidation, or promoting insulin resistance (Björck et al., 2006 2006 ; Purohit et al., 2007 2007 ). We hypothesized that folate deficiency and WC may at least partly mediate the association between BMI and serum ALT concentration in populations without folic acid fortification. To our knowledge, no similar studies have been published, particularly in Chinese hypertensive populations. A better understanding of factors that modulate the ALT concentration in subjects without known hepatic diseases will help us to perform more aggressive monitoring, lifestyle interventions, or medications in target populations. Materials and methods 1 This was a multicenter, cross-sectional study conducted in China. The details regarding “Participants”, “Data collection procedures”, and “Laboratory methods” have been previously described (Qin et al., 2012a 2012a ; 2012b 2012b ; 2012c 2012c ). Briefly, a total of 378 hypertensive patients aged 18–75 years old, with seated systolic blood pressure (SBP) between 140 and 180 mmHg and/or seated diastolic blood pressure (DBP) between 90 and 110 mmHg, were recruited from one hospital in each of five cities (Harbin, Shanghai, Beijing, Xi’an, and Nanjing) located in different regions, from September to December, 2005. Participants were excluded if they were pregnant or had serious self-reported diseases, including cardiovascular diseases such as myocardial infarction, hepatic diseases such as hepatitis and hepatocirrhosis, chronic kidney diseases, tumor, type 1 diabetes, or uncontrolled type 2 diabetes (fasting plasma glucose > 11.1 mmol/L). This study was approved by the Ethics Committee of Peking University First Hospital in Beijing, China. Participants signed informed consents before their enrollment. Demographic and baseline clinical information was obtained according to standard operating procedures. Because of the positively skewed distributions of the ALT, Hcy and folate concentrations, the natural logarithms of these variables were used in all statistical analyses as continuous variables. Means or medians were calculated for population characteristics by gender. The differences in population characteristics between males and females were compared via Student’s t -tests. With adjustment for age, sex, and study centers, we separately examined the relationships between ln-transformed ALT concentration [ln (ALT)] and SBP, DBP, WC, total cholesterol (TC) level, high-density lipoprotein cholesterol (HDL-C) level, triglyceride (TG) level, and the ln-transformed folate concentration [ln (folate)]. Partial R-squares were provided for each explanatory factor. A multivariable regression model was also used to evaluate the association between the ln (ALT) and major explanatory factors. SAS software version 6.12 (SAS Institute, USA) was used for the analysis. Results 1 A total of 378 hypertensive patients were enrolled, of whom only 360 with complete data for BMI, WC, and folate concentration were included in our final analysis. Compared with female subjects, who accounted for 57.5% of the whole population, male subjects had significantly higher mean WC, DBP, Hcy [(19.4±15.7) vs. (12.5±7.0) μmol/L, P < 0.001), aspartate transaminase (AST), and ALT [(28.8±14.9) vs. (23.3±12.9) IU/L, P < 0.001] levels, but lower TC, HDL-C, and folate [(12.7±5.9) vs. (14.8±6.3) nmol/L, P =0.001] levels (Table 1 1 ). BMI: body mass index; WC: waist circumference; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; FPG: fasting plasma glucose; Hcy: homocysteine; ALT: alanine aminotransferase; AST: aspartate transaminase. Data are presented as mean±standard deviation (SD), some with median in parenthesis Characteristic Male ( n= 153) Female ( n= 207) P Age (year) 58.6±9.8 57.5±9.2 0.263 BMI (kg/m 2 ) 25.5±3.0 25.8±3.5 0.403 WC (cm) 90.2±9.8 85.8±8.3 0.000 SBP (mmHg) 152.5±11.0 152.8±11.1 0.844 DBP (mmHg) 93.6±7.5 91.8±8.3 0.029 TC (mmol/L) 4.8±1.3 5.0±1.0 0.029 TG (mmol/L) 1.6±1.0 1.7±0.9 0.439 HDL-C (mmol/L) 1.2±0.3 1.3±0.3 0.000 FPG (mmol/L) 5.5±1.2 5.5±1.1 0.921 Folate (nmol/L) 12.7±5.9 (11.4) 14.8±6.3 (13.7) 0.001 Hcy (μmol/L) 19.4±15.7 (14.9) 12.5±7.0 (10.8) <0.001 ALT (IU/L) 28.8±14.9 (26.0) 23.3±12.9 (20.0) <0.001 AST (IU/L) 27.3±10.9 (25.4) 24.8±8.3 (24.0) 0.022 In this population, 49 (13.6%) of the total subjects, including 26 (17.0%) males and 23 (11.1%) females, had an elevated ALT concentration ( > 40 IU/L). In univariate analysis, BMI ( r =0.187, P < 0.001), WC ( r =0.265, P < 0.001), TG ( r =0.176, P < 0.001) and folate concentrations ( r =−0.107, P =0.04) were significantly associated with ALT concentration. Consistently, a lower prevalence rate of elevated ALT was observed in subjects with higher folate concentrations (≥12 vs. < 12 nmol/L, 9.9% vs. 17.8%, odds ratio (OR)=0.51; 95% confidence interval (CI): 0.27–0.94, P =0.03), and higher prevalence rates of elevated ALT were observed in subjects with higher BMI (≥28 vs. < 28 kg/m 2 , 21.5% vs. 11.4%, OR=2.1; 95% CI: 1.1–4.1, P =0.02) or higher WC (≥90 vs. < 90 cm, 18.5% vs. 10.0%, OR=2.0; 95% CI: 1.1–3.8, P =0.02). With adjustment for age and study centers, BMI, WC, TG, and the ln (folate) (Table 2 2 ; each P < 0.01, except BMI, P =0.011) in males and BMI, WC, fasting plasma glucose (FPG), and the ln (folate) (Table 2 2 ; each P < 0.01, except BMI, P =0.018 and ln (folate), P =0.030) in females were significantly associated with the ln (ALT). The model is ln(ALT)=age+study center+single factor BMI: body mass index; WC: waist circumference; SBP: systolic blood pressure; DBP: diastolic blood pressure; TC: total cholesterol; TG: triglyceride; HDL-C: high-density lipoprotein cholesterol; FPG: fasting plasma glucose; Hcy: homocysteine 2 Characteristic 4 Male 4 Female β SE P P-R β SE P P-R  BMI 0.035 0.014 0.011 0.043 0.024 0.010 0.018 0.028  WC 0.014 0.004 0.002 0.063 0.015 0.004 <0.001 0.065  SBP 0.002 0.004 0.695 0.001 0.003 0.003 0.359 0.004  DBP −0.001 0.006 0.915 <0.001 0.007 0.005 0.141 0.011  TC 0.011 0.033 0.740 <0.001 0.057 0.041 0.166 0.010  TG 0.146 0.043 <0.001 0.074 0.066 0.038 0.086 0.015  HDL −0.124 0.148 0.404 0.005 −0.140 0.117 0.231 0.007  FPG 0.020 0.041 0.623 0.002 0.098 0.036 0.007 0.036  ln (Hcy) −0.092 0.081 0.259 0.009 −0.159 0.090 0.078 0.015  ln (folate) −0.280 0.103 0.007 0.048 −0.211 0.096 0.030 0.017 In the multivariate analysis (Table 3 3 ), the association between BMI and ALT concentration was eliminated, but ln (folate) was still negatively associated with ALT concentration regardless of gender (males, P =0.036; females, P =0.044). WC significantly predicted ALT concentration only in females ( P =0.002). In addition, TG significantly predicted ALT concentration only in males ( P =0.031), and FPG was positively related to ALT concentration only in females ( P =0.008). The model is ln(ALT)=age+study center+all the significant factors in Table 2 2 BMI: body mass index; WC: waist circumference; TG: triglycerides; FPG: fasting plasma glucose 2 Characteristic 3 Male 3 Female β SE P β SE P  Age −0.005 0.005 0.229 −0.003 0.004 0.468  BMI −0.006 0.022 0.802 −0.012 0.014 0.369  WC 0.009 0.007 0.199 0.017 0.006 0.002  TG 0.099 0.046 0.031  FPG 0.091 0.034 0.008  ln(folate) −0.209 0.100 0.036 −0.180 0.089 0.044 Discussion 1 The characteristics of relatively high ALT concentrations (Shen et al., 2003 2003 ) and low folate concentrations (Forman et al., 2005 2005 ) in hypertensive populations make them particularly suitable for evaluating the possible association between folate and ALT concentrations in patients with hypertension. This is the first study to report on the role of traditional risk factors and folate status in the elevation of ALT concentration in Chinese hypertensive adults without known hepatic diseases. In agreement with previous studies (Salvaggio et al., 1991 1991 ; Sull et al., 2009 2009 ; Kim and Jo, 2010 2010 ), there was a positive linear association between BMI and ALT concentration. However, following multivariate regression analysis, this association disappeared ( P > 0.05), while WC and folate concentration remained as significant predictors for ALT concentration. Previous studies reported that the ALT concentration was highly associated with the metabolic syndrome (Park et al., 2005 2005 ; Oh et al., 2006 2006 ). Abdominal obesity has been proposed to play an important role in the mechanism of metabolic syndrome. WC has proven to be a better surrogate for abdominal obesity than BMI or waist-to-hip ratio in Chinese populations (Feng et al., 2006 2006 ). Abdominal obesity leads to high levels of free fatty acids and cytokines, which may lead to fat accumulation and infiltration and decreased hepatocyte integrity (Kern et al., 2001 2001 ; Tamura and Shimomura, 2005 2005 ). Consistent with our results, truncal obesity was reported (Angulo, 2002 2002 ) to be an important risk factor for nonalcoholic fatty liver diseases, even in patients with a normal BMI. Accordingly, ALT concentration was also significantly correlated with other components of the metabolic syndrome (TG or FPG) in our study. The possible gender difference should be further evaluated in future studies. While folate deficiency is recognized as being causally related to cardiovascular diseases (Wald et al., 2002 2002 ), its role in hepatic injury is uncertain. Increasing evidence suggests that changes in methionine/folate metabolism may contribute to the development of hepatic injury (Qin et al., 2012a 2012a ). Welzel et al. ( 2007 2007 ) observed that low folate concentration was significantly associated with higher ALT concentration in hepatitis B surface antigen-positive patients. Our results further proved that low folate levels, which are independent of traditional risk factors, may predict a higher ALT concentration in hypertensive Chinese adults without known hepatic diseases. We did not find a significant association between the plasma Hcy level and ALT concentration. We speculate that the hepatic Hcy level (Antoniades et al., 2009 2009 ) or the folate concentration itself (Verhaar et al., 2002 2002 ), but not plasma Hcy level, was more closely related to the change in ALT concentration. Kim et al. ( 2005 2005 ) reported that ALT concentration was independently associated with the incidence of stroke. A population increase in serum folate concentration after folic acid fortification produced a significant decrease in stroke mortality (Yang et al., 2006 2006 ). These results showed that low folate concentration may be one of the explanations for increased ALT concentration and for the increased risk of cardiovascular diseases, especially stroke. Most importantly, our previous study showed that a daily dose of 0.8-mg folic acid treatment may be beneficial in lowering serum ALT concentration, particularly in men and/or in subjects with ALT concentrations of > 40 IU/L (Qin et al., 2012a 2012a ). Our study had the following strengths. This was a multicenter survey in China and all of the centers achieved similar results, which suggests that our findings may be applicable to populations in different regions of China. However, caution is needed in generalizing our findings from this hypertensive Chinese population to other populations. Furthermore, we did not collect detailed information on alcohol consumption in this study. However, an association between alcohol consumption and ALT concentration was eliminated after adjustment for BMI or WC (Lee et al., 2001 2001 ), suggesting that this information may not have affected our results. 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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000(5). Informed consent was obtained from all patients for being included in the study. 10.1631/jzus.B1200330 Project supported by the Ministry of Science and Technology of China (No. 2012zx09101-105) and the National Basic Research Program (973) of China (No. 2012CB517703) 2012-11-26 2013-07-19 2013-06-03 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2013 2013 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 08 14