AJCN Tufts Nutrition Symposium, Boston & Online Sept 2009
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American Journal of Clinical Nutrition, Vol. 88, No. 1, 16-21, July 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Relation between alanine aminotransferase concentrations and visceral fat accumulation among nondiabetic overweight Korean women1,2

Hye Ryoung Song1, Kyung Eun Yun1 and Hye Soon Park1

1 From the Department of Family Medicine, Paik Hospital, College of Medicine, Inje University, Seoul, Korea (HRS), and the Department of Family Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (KEY and HSP)

2 Reprints not available. Address correspondence to HS Park, Department of Family Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul, Korea (South). E-mail: hyesoon{at}amc.seoul.kr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background:Alanine aminotransferase (ALT) is used as a surrogate marker for nonalcoholic fatty liver disease (NAFLD), which is frequently observed among obese subjects. Reported data were scanty about the relation between ALT concentrations and visceral fat accumulation measured by computed tomographic (CT) scanning in a large sample.

Objective:We investigated the association between ALT concentrations and visceral fat accumulation measured by CT scanning, among nondiabetic overweight Korean women.

Design:A cross-sectional study was performed in 903 nondiabetic overweight [body mass index (BMI; in kg/m2) ≥ 25] Korean women aged 20–80 y. The area of abdominal visceral adipose tissue (VAT) was measured by CT scan. Anthropometric and cardiometabolic variables were measured.

Results:Elevated ALT (>40 IU/L) concentrations were found in 14.9% of the subjects. ALT concentrations were significantly correlated with all anthropometric and cardiometabolic variables after adjustment for age and alcohol consumption (P < 0.05). The adjusted odds ratios for elevated ALT concentrations according to the quartiles of VAT were 1.51 (95% CI: 0.83, 2.76), 3.16 (95% CI: 1.55, 6.49), and 15.15 (95% CI: 4.57, 50.00) in the second (76.9–102.6 cm2), the third (102.7–135.0 cm2), and the fourth (135.1–382.7 cm2) quartiles, respectively, compared with the first quartile (23.0–76.8 cm2) (P for trend < 0.001). In the multiple linear regression model, the VAT was significantly positively associated with ALT concentrations (standardized β = 0.206, P < 0.001), whereas the regression coefficients of other anthropometric and cardiometabolic variables were not significant.

Conclusions:ALT concentrations have a strong association with visceral fat accumulation, and VAT is the main predictor of elevated ALT concentrations in the context of NAFLD among nondiabetic overweight Korean women.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Elevated alanine aminotransferase (ALT) concentrations are frequently observed among obese subjects. After excluding alcoholic, viral, and autoimmune liver diseases, nonalcoholic fatty liver disease (NAFLD) is considered as the main cause of elevated ALT in obese subjects (1). NAFLD is classified into 2 categories: simple fatty liver, which has a favorable clinical outcome, and nonalcoholic steatohepatitis, which is intractable and progressive (2). Nonalcoholic steatohepatitis can result in chronic liver disorders with a risk of progression to cirrhosis or hepatocellular carcinoma (2, 3).

NAFLD is considered to be the hepatic manifestation of the metabolic syndrome (4). With the rising prevalence of obesity and the metabolic syndrome, NAFLD has also been increasing in the Asia-Pacific region as well as in Western countries (5–7). One recent study showed that the prevalence of NAFLD among Korean adults is somewhat higher (18.7%) (8) than those found in previous works performed in Eastern countries (9–13%) (9, 10).

Several methods are used to diagnose NAFLD (11). Although liver biopsy is the standard for diagnosis of hepatic steatosis, ultrasonography and biochemical tests are easily used in clinical settings. Because ALT is closely related to liver fat accumulation (12), ALT is used as a surrogate marker for NAFLD in epidemiologic studies (13–15).

Previous studies reported that ALT concentrations are highly associated with the metabolic syndrome (16, 17). In addition, recent studies have indicated that abdominal fat (18), particularly visceral fat, closely correlated with NAFLD (19–21). However, there were scanty data reported about the relation between ALT concentrations and visceral fat accumulation measured by computed tomography (CT) scanning in a large sample. Therefore, we investigated the association between ALT concentration and visceral fat accumulation measured by CT scanning, to determine which component has a greater effect on ALT concentrations among nondiabetic overweight Korean women.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study subjects
A cross-sectional, hospital-based study was performed in 903 overweight [body mass index (BMI; in kg/m2) ≥ 25] women, aged 20–80 y, who had visited the hospital for management of obesity between March 2001 and December 2005 at the Obesity Clinic of Asan Medical Center in Seoul, Korea. Subjects were excluded if they had a history of diabetes or showed fasting plasma glucose concentrations > 126 mg/dL. Subjects whose consumption of alcohol was >70 g/wk were also excluded. Subjects were excluded if they were pregnant or lactating or had a prior history of hypothyroidism, Cushing disease, malignancy, severe debilitating diseases, or other liver diseases, including chronic viral hepatitis, autoimmune hepatitis, primary biliary cirrhosis, and drug-induced liver disease. Subjects with a history of intentional reduction in weight in the preceding 6 mo of the current study or treatment with any antiobesity agent were excluded. Among the included subjects, 119 (13.2%) and 51 (5.6%) subjects were on medication for hypertension and hyperlipidemia, respectively. The study was approved by the Institutional Review Board of Asan Medical Center.

Anthropometric measurements and abdominal fat accumulation
Body weight and height were measured while the subjects were wearing light clothing without shoes. BMI was calculated. Waist circumference (WC) measurements were taken from the midlevel between the lower extent of the rib cage and the iliac crest. The percentage of body fat was determined with the use of bioelectrical impedance analysis (Inbody 3.0; Biospace, Seoul, Korea).

Cross-sectional abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by CT scanning on a Siemens Somaton Scanner (Erlangen, Germany). Each subject was placed in the supine position, and a cross-sectional scan 10 mm thick and centered at the L4–L5 vertebral disc space was obtained with the use of a radiograph of the skeleton as a reference to establish the position of the scans to the nearest millimeter. The area of total adipose tissue was measured by delineation with a graph pen, followed by computation of the adipose tissue area with an attenuation range of –190 to –30 Hounsfield units. The area of abdominal VAT was measured by drawing a line within the muscle wall surrounding the abdominal cavity. The area of SAT was calculated by subtracting the VAT area from the total adipose tissue area.

Cardiometabolic risk factors and biochemical analysis
Blood pressure was measured in a sitting position after a 10-min rest period. Two readings each of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded at 5-min intervals, and the averages of these readings were used for data analysis. Fasting blood samples were taken in the morning after an 8-h overnight fasting period. Fasting plasma glucose (FPG), triacylglycerol, HDL-cholesterol, and ALT concentrations were measured with an autoanalyzer (Hitachi 747 autoanalyzer; Hitachi, Tokyo, Japan). Hepatitis B surface antigen and antibody were measured by radioimmunoassay (MICROLAB AT plus; Hamilton Co, Reno, NV), hepatitis C antibody was tested by chemiluminescent microparticle immunoassay (Architect i2000; Abbott Lab, Abbott Park, IL). A human insulin-specific radioimmunoassay kit (Linco Research Inc, St Charles, MO) was used to measure the insulin concentrations. The homeostasis model assessment-insulin resistance (HOMA-IR) method was used to measure the index of insulin resistance with the use of the following formula: HOMA-IR = fasting insulin (in µU/mL) x FPG (in mg/dL)/405 (22). Elevated ALT was defined as an enzyme activity > 40 IU/L (16, 23).

Statistical analysis
All descriptive statistical results are presented as mean ± SEM. Pearson's correlation coefficients were calculated to determine the associations between ALT and anthropometric variables and cardiometabolic risk factors. The study subjects were divided into quartiles on the basis of VAT value: the first (23.0–76.8 cm2), the second (76.9–102.6 cm2), the third (102.7–135.0 cm2), and the fourth (135.1–382.7 cm2) quartiles. The linear-by-linear association test was used to analyze dose-dependent relation (P for trend) in the frequency of elevated ALT concentrations (>40 IU/L) according to the quartiles of VAT. The odds ratios (ORs) and 95% CIs were assessed with the use of multiple logistic regression analysis to determine the risks of elevated ALT concentrations according to the quartiles of VAT after adjustment for age, amount of alcohol consumption, and cardiometabolic risk factors. Stepwise multiple linear regression analyses were performed with the use of ALT as a dependent variable and age, amount of alcohol consumption, obesity indexes, and cardiometabolic risk factors as independent variables. All analyses were performed with the use of SPSS version 14.0 (SPSS Inc, Chicago, IL). A 2-tailed P value < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of the study subjects
The characteristics of the study subjects are presented in Table 1Go. The frequency of elevated ALT concentrations was 14.9% in the subjects in this study. The mean BMI and percentage of body fat were 30.12 ± 0.12 and 36.74 ± 0.17%, respectively. The mean WC and visceral fat area were 95.08 ± 0.33 cm and 110.65 ± 1.63 cm2, respectively.


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  		TABLE 1. Baseline characteristics of the study subjects1

 
Correlation between ALT concentrations and anthropometric and cardiometabolic variables
The correlation between ALT concentrations and anthropometric and cardiometabolic variables are shown in Table 2Go. Although ALT concentrations were not significantly correlated with age, ALT concentrations were significantly correlated with all anthropometric (BMI, percentage of body fat, WC, SAT, and VAT) and cardiometabolic (FPG, triacylglycerol, HDL cholesterol, SBP, DBP, fasting insulin, and HOMA-IR) variables after adjustment for age and alcohol consumption (P < 0.05).


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  		TABLE 2. Correlation coefficients between alanine aminotransferase (ALT) concentrations and anthropometric and cardiometabolic variables in the study subjects1

 
Relation between ALT concentrations and visceral fat accumulation
The frequency of elevated ALT concentrations according to each quartile of VAT was 3.6%, 10.2%, 17.9%, and 28.4% in the first (23.0–76.8 cm2), the second (76.9–102.6 cm2), the third (102.7–135.0 cm2), and the fourth (135.1–382.7 cm2) quartiles, respectively (Figure 1Go). The dose-dependent relation between frequency of elevated ALT concentrations and visceral fat accumulation was observed (P for trend < 0.001). The adjusted ORs for elevated ALT concentrations according to the quartiles of VAT are shown in Table 3Go. With the use of the ORs in the first quartile (23.0–76.8 cm2) as a reference, the ORs for elevated ALT concentrations were 1.51 (95% CI: 0.83, 2.76), 3.16 (95% CI: 1.55, 6.49), and 15.15 (95% CI: 4.57, 50.00) in the second (76.9–102.6 cm2), the third (102.7–135.0 cm2), and the fourth (135.1–382.7 cm2) quartiles, respectively (P for trend < 0.001).


Figure 1
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  		FIGURE 1.. Frequency of elevated alanine aminotransferase (ALT) concentrations (>40 IL/L) according to the quartiles of visceral adipose tissure (VAT) among the study subjects. The number of subjects represented by each of the bars according to the quartiles of VAT were 8 (3.6%), 22 (10.2%), 40 (17.9%), and 59 (28.4%) in the first (23.0–76.8 cm2), second (76.9–102.6 cm2), third (102.7–135.0 cm2), and fourth (135.1–382.7 cm2) quartiles, respectively. A dose-dependent relation between frequency of elevated ALT concentrations and VAT was observed. P value for trend was analyzed by using the linear-by-linear association test (P for trend <0.001). The error bars represent 95% CIs.

 

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  		TABLE 3. Odds ratios (ORs) and 95% CIs for elevated alanine aminotransferase (ALT) concentrations according to quartile (Q) of visceral adipose tissue (VAT) in the study subjects1

 
Prediction of anthropometric and cardiometabolic variables for ALT concentrations
The regression coefficient of all variables for ALT concentrations in the multiple linear regression model is shown in Table 4Go. The VAT was significantly positively associated with ALT concentrations (standardized β = 0.206, P < 0.001), whereas the regression coefficients of other anthropometric and cardiometabolic variables were not significant.


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  		TABLE 4. Multiple linear regression coefficients for alanine aminotransferase (ALT) concentration as a dependent variable and anthropometric and cardiometabolic variables as independent variables1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Obesity, insulin resistance, and metabolic syndrome have been reported as factors associated with NAFLD (4, 24, 25). In most cases, NAFLD causes elevation of ALT concentrations, which is most closely related to liver fat accumulation, and consequently ALT has been used as a marker of NAFLD. Our study indicates that ALT concentrations have a strong association with visceral fat accumulation. Furthermore, visceral fat has a greater effect on ALT concentrations than other anthropometric or cardiometabolic variables among nondiabetic overweight women.

An elevated ALT is considered a consequence of hepatocyte damage as a result of NAFLD. ALT was previously known to be the predictor of the development of type 2 diabetes (13) and was related to insulin sensitivity (26). Insulin resistance, increased proinflammatory cytokine production, oxidative stress, and mitochondrial dysfunction leading to hepatocyte damage or destruction are all posed as important pathophysiologic mechanisms of NAFLD (27, 28). An elevated ALT in obesity has the physiologic significance in terms of the potential of the fatty liver that is common in the metabolic syndrome. In our study, visceral fat accumulation plays a key role for the elevation of ALT concentrations in nondiabetic overweight Korean women.

Our findings are in accordance with a recent study showing that the severity of fatty liver diagnosed by ultrasonography was positively correlated with visceral fat accumulation and insulin resistance (19–20). Visceral obesity leads to an elevated release of free fatty acids from the VAT and subsequent accumulation in hepatocytes, further enhancing hepatic steatosis (29, 30). Furthermore, cytokines released from the VAT, including interleukin-6 and tumor necrosis factor-{alpha}, both associated with decreased hepatic insulin sensitivity (31), may further enhance fatty infiltration and decrease hepatocyte integrity.

ALT might be up-regulated as a compensatory response to the impaired hepatic insulin signaling or, alternatively, may leak more easily out of the hepatocytes as a consequence of fatty infiltrations and subsequent damage (32). The cutoff for elevated ALT concentrations in our study was defined as an ALT ≥ 40 IU/L. In some studies, ALT ≥ 19 IU/L or ALT ≥ 30 IU/L for women were used as cutoffs for elevated ALT concentrations (1, 18). However, ALT ≥ 40 IU/L was used not only in the previous studies (16, 17) but also usually in a clinical setting. The cutoff value in this study was 40 IU/L, which is higher than the previous study (1, 18); therefore, the possibility of overestimation for the prevalence of elevated ALT concentrations might be low.

Previous studies have found that abdominal fat distribution measured by WC or waist-hip ratio is related to ALT concentrations (33). However, at a given WC or BMI, assessment of visceral fat accumulation is important for evaluation of cardiometabolic complications. Particularly, Asians have more VAT than do whites (34), and Asians generally tend to have a higher risk of metabolic abnormalities at a lower BMI than do whites, which may be due to the propensity of Asians to have central obesity and an increased incidence of diabetes (35). Our study indicated that visceral fat is the strongest predictor for NAFLD among the anthropometric variables.

Because VAT has a role in the development of metabolic syndrome, several studies have reported threshold values of VAT accumulation associated with cardiometabolic risk. For the Japanese, a VAT cutoff of 100 cm2 was established to predict the risk of obesity-related disorders in both men and women (36). Recently, the ethnic-specific VAT cutoff of 70 cm2 in Korean women was suggested for detecting metabolic complications (37). In the current study subjects, the cutoffs of the second and the third quartiles of VAT were {approx}70 cm2 and 100 cm2, respectively.

Several studies have shown that ALT is related to features of the metabolic syndrome (13, 38, 39). Accordingly, ALT concentrations were significantly correlated with all components of the metabolic syndrome (FPG, triacylglycerol, HDL cholesterol, SBP, and DBP) in our study. In addition, insulin resistance plays an important role in the pathogenesis of NAFLD (40, 41). Our findings show significant associations between ALT concentrations as a marker for NAFLD and fasting insulin and HOMA-IR as markers for insulin resistance.

There were some limitations to the current study. First, liver biopsy, which is the standard to establish a histologic diagnosis of NAFLD, was not performed (42). When ALT concentrations are not elevated, this does not guarantee the absence of NAFLD, because normal ALT concentrations have been observed in patients with NAFLD diagnosed by liver biopsy (43). Second, because ALT is a marker of liver injury, it would be better to measure liver fat as a component of VAT. In fact, CT scanning is capable of distinguishing different tissue types on the basis of their attenuation characteristics, which are a function of tissue density and chemical composition. A lower mean liver attenuation value relative to that of the spleen indicates fatty infiltration of the liver (44). Unfortunately, we have missed to identify liver fat in the current study. Third, our results might not be generalizable because study subjects were limited to nondiabetic overweight Korean women. Last, because our study was designed as a cross-sectional study, a causal relation could not be defined.

In summary, the current study indicates that ALT concentrations have a strong association with visceral fat accumulation, and VAT is the main predictor of elevated ALT concentrations in the context of NAFLD among nondiabetic overweight Korean women. Reduction of VAT is as important for improvement of NAFLD as other cardiometabolic components of the metabolic syndrome.


   ACKNOWLEDGMENTS
 
The author's responsibilities were as follows—HSP: was involved in the conception and design of the study; HRS, KEY, and HSP: contributed to data analysis and interpretation of data; HRS: drafted the manuscript; all authors participated in critically revising the manuscript and approved the final version of the manuscript to be published. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication January 23, 2008. Accepted for publication March 29, 2008.





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