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Annals of Clinical & Laboratory Science 33:257-264 (2003)
© 2003 Association of Clinical Scientists

Association Between Elevated Serum Hepatic Enzyme Activity and Total Body Fat in Obese Humans

Jong Weon Choi
Department of Laboratory Medicine, College of Medicine, Inha University, Inchon, South Korea

Address correspondence to Jong Weon Choi, MD, PhD; Department of Laboratory Medicine, Inha University Hospital, 7-206, 3-ga, Shinheung-dong, Jung-gu, Inchon, 400-711, South Korea; tel 82 32 890 2503; fax 82 32 890 2529; e-mail jwchoi{at}inha.ac.kr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgement
 References
 
To investigate the associations between obesity and serum hepatic enzyme activities, we measured total body fat (TBF), body mass index (BMI), and hepatic biochemical parameters in 732 apparently healthy adults. TBF was assessed using a body fat analyzer. Serum activities of alanine and aspartate aminotransferase (ALT and AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and lactate dehydrogenase (LD) were determined by standard spectrophotometric methods. Mean activities (± SD) of serum ALT and AST in men with high fatness were 51.2 ± 12.6 U/L and 32.9 ± 9.2 U/L, which were significantly higher than those in men with low fatness (23.5 ± 7.4 U/L and 22.5 ± 7.8 U/L, p <0.01). Of 147 men with high fatness, 56 (38.1%) had serum ALT levels above the upper limit of normal, whereas only 9.5% (31/328) of men with low or desirable fatness showed elevated serum ALT activities (p <0.01). Serum ALT, AST, and GGT activities correlated significantly with TBF in both overweight men and women. Among subjects having high TBF, those with fatty liver showed significantly higher incidence of elevated hepatic enzymes, compared to those without fatty liver. In short, elevated serum hepatic enzyme activities are associated with TBF and a high prevalence of fatty liver is observed in subjects with elevated TBF.

(received 9 February 2003; accepted 15 April 2003)

Keywords: Obesity, total body fat, serum hepatic enzymes, fatty liver


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgement
 References
 
Diseases characterized by distinctly abnormal values of one or more enzymes in serum can be readily distinguished from clinically similar states in which the serum values for the respective enzymes remain normal. The enzymologic approach to liver disease provides assistance in making a diagnosis, monitoring the course, and documenting subclinical evidence of disease [1]. The five serum enzymes that are most commonly used in evaluating liver function are alanine aminotransferase (ALT), aspartate amino-transferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LD), and {gamma}-glutamyl transferase (GGT) [2].

Obesity is a condition of abnormally increased body fat, resulting from increased energy intake relative to energy expenditure. It is well known that obesity has increased risk of hypertension, heart disease, and diabetes mellitus [3,4]. Recently, some investigators have reported that abnormal serum levels of hepatic enzymes are frequently found in subjects with obesity or hyperlipidemia [5–7]. However, most of these studies have been based primarily on measurement of body mass index (BMI) without assessing total body fat (TBF), hepatitis B or C viral markers, or gender differences. In a previous study, we demonstrated that TBF more accurately reflects serum lipid concentrations than BMI in obese humans, and that the association between TBF and serum lipid concentrations was stronger in men than in women [8]. In the present study, we assess the relationships between serum hepatic enzyme activities and TBF, especially as compared to BMI, in both men and women.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgement
 References
 
We measured BMI, TBF, and serum activities of ALT, AST, ALP, LD, and GGT in 732 healthy subjects (475 men; 257 women; age 27 to 69 yr, median 45 yr) who were seen for routine health screening. A questionnaire was given to the subjects to determine behavioral habits, such as smoking and alcohol consumption. The subjects were all South Koreans from middle-class families; there were no significant differences in racial distribution or socioeconomic status among the groups. We excluded 42 subjects from this study: in 35 subjects the serum tested positive for hepatitis B virus surface antigen (HBsAg) or antibody to hepatitis C virus (anti-HCV). In 7 subjects there was a history of recent surgical operation and treatment with drugs. Subjects with positive tests for antibody to HBsAg (anti-HBs) or antibody to hepatitis B virus core antigen (anti-HBc) were not excluded. This study was approved by the Ethical Committee of Inha University Hospital, and informed consent was obtained from all subjects.

Venous blood was drawn into evacuated, serum separator tubes after subjects had fasted overnight. Serum ALT, AST, and GGT activities were assayed with an automatic chemical analyzer (Hitachi 747, Hitachi, Tokyo, Japan), and ALP and LD activities were measured with a dry-chemistry analyzer (Vitros 950, Ortho-Clinical Diagnostics, New York, NY) within 4 hr after collection. The serum ALT, AST, and GGT activities were analyzed by spectrophotometric methods using SICDIA L ALT, AST, and {gamma}-GTP reagents (Eiken Chemical Industries, Tokyo, Japan), and ALP and LD activities were analyzed by multiple-point rate tests using Vitros ALKP and LDH slides (Ortho-Clinical Diagnostics) [9–11].

HBsAg, anti-HBs, anti-HBc, and anti-HCV were assayed with an AxSYM analyzer (Abbott Laboratories, Abbott Park, IL) by microparticle enzyme immunoassay (MEIA) using AxSYM HBsAg (V2; mouse monoclonal coated micro-particles), AxSYM AUSAB (recombinant subtype ad and ay), AxSYM CORE, and AxSYM HCV reagents (Abbott Laboratories), respectively [12,13].

The upper limits of normal values of serum hepatic enzymes were defined as ALT (43 U/L), AST (38 U/L), ALP (140 U/L), LD (597 U/L), and GGT (75 U/L for men; 45 U/L for women), which were established as cutoff values in our laboratory based on 95% confidence limits for 155 healthy adults. Hepatitis B or C virus infection was defined as positive MEIA results. The HBsAg assay calculated a result based on the ratio of the sample rate to the stored index calibrator mean rate (S/N) for each sample, and samples with S/N values 2.00 were considered reactive. The HCV assay was based on the ratio of the sample rate to the cutoff rate (S/ CO) for each sample, and specimens with S/CO values 1.00 were considered reactive.

Body adiposity was assessed using a leg-to-leg bioelectric impedance device, the Tanita body fat analyzer (TBF-611, Tanita, Tokyo, Japan), which enables simultaneous measurements of body weight, impedance, fat-free mass, total body water, and fat percentage, while the subject stands on the stainless steel electrode [14]. The reproducibilities of TBF and fat-free mass measurements were determined in 25 subjects, each of whom was measured twice at a 1-wk interval. The coefficient of variance (CV) of TBF measurements was <3.9%. The CV for the fat-free mass was <4.7%.

The presence of fatty liver was determined by sonographic examination. BMI was determined as body weight in kilograms divided by the square of the height in meters (kg/m2). The reference interval of BMI was defined as 18.5 to 22.9 kg/m2 and overweight as a BMI 23.0 kg/m2, which was based on WHO criteria for Asian populations [15].

The reference range of desirable fatness was defined as a TBF of 12.0 to 21.9% in men and a TBF of 20.0 to 30.9% in women, which were taken as provisional cutoff values based on the 95% confidence limits for the 276 men and 122 women who showed normal BMI.

Subjects were assigned to 3 groups according to BMI: underweight (BMI 18.5 kg/m2, n = 78), healthy weight (18.5 BMI 23.0 kg/m2, n = 398), and overweight (BMI 23.0 kg/m2, n = 256). The subjects were also assigned to another 3 groups based on TBF: low fatness (TBF 12.0% in men, n = 34; TBF 20.0% in women, n = 25), desirable fatness (12.0 TBF 22.0% in men, n = 294; 20.0 TBF 31.0% in women, n = 133), and high fatness ( TBF 22.0% in men, n = 147; TBF >31.0% in women, n = 99). To investigate sequential changes in serum ALT, AST, and GGT activities with increasing TBF, we categorized the subjects into 7 groups; <5th percentile for TBF (TBF 11.7% in men; TBF 17.9% in women), 5–25th per centile (11.7%< TBF 13.1% in men; 17.9%<TBF 23.4% in women), 25–50th percentile (13.1%<TBF 16.6% in men; 23.4%< TBF 28.3% in women), 50–75th percentile (16.6%< TBF 20.1% in men; 28.3%< TBF 33.4% in women), 75–90th per centile (20.1%< TBF 23.6% in men; 33.4%< TBF 36.3% in women), 90–95th percentile (23.6% TBF 28.2% in men; 36.3% TBF 38.6% in women), and >95th percentile (TBF >28.2% in men; TBF >38.6% in women).

Data analysis was performed with the SAS 6.12 software package (SAS Institute Inc, Cary, NC). Non-parametric tests were used since distributions of most of the analyzed variables were non-Gaussian by the Kolmogorov-Smirnov test. The Mann-Whitney U test was used to calculate the statistical significance of differences. Correlation coefficients were calculated by Spearman’s method. All p values 0.01 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgement
 References
 
The mean values of serum hepatic enzyme activities in relation to TBF and BMI are summarized in Table 1Go. There were no significant differences in serum hepatic enzyme activities between the subjects with low fatness and desirable fatness, nor between underweights and healthy weights in both men and women. However, serum activities of ALT, AST, and GGT in men with high fatness averaged 51.2 ± 12.6 U/L, 32.9 ± 9.2 U/L, and 67.5 ± 20.6 U/L, which were significantly higher than in men with low fatness (23.5 ± 7.4 U/L, 22.5 ± 7.8 U/L, and 27.3 ± 13.9 U/L, p < 0.01, respectively). Serum activities of ALT and GGT were also significantly higher in women with high fatness than in women with low fatness (p <0.01). There was no significant difference in serum ALP and LD activities between men with low fatness and high fatness. However, women with high fatness showed higher serum ALP and LD activities than women with low fatness (p <0.01).


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  		Table 1. Serum hepatic enzyme activities in relation to total body fat and body mass index (data are means ± SD)
 
As shown in Table 2Go, 38.1%, 17.0%, and 18.4% of men with high fatness (TBF 22.0%, n = 147) displayed serum levels of ALT, AST, and GGT above the upper limits of normal; these levels were significantly higher than those for men with low or desirable fatness (TBF <22.0%, n = 328, 9.5%, 4.9%, and 7.3%, p <0.01, respectively). The incidences of subjects with elevated serum activities of hepatic enzymes were also significantly higher in the women with high fatness than in women with low or desirable fatness. In particular, women with high fatness showed a high incidence of elevated ALP and LD activities, compared to women with low or desirable fatness, although in men there were no significant differences in the incidence of elevated ALP and LD activities between these groups.


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  		Table 2. Prevalence of elevated serum hepatic enzyme activities, fatty liver, and other characteristics in subjects with high fatness.
 
No significant differences were observed in the prevalence of subjects with anti-HBs and anti-HBc or alcohol consumers between the high fatness group and the low or desirable fatness group. However, fatty liver was more frequently observed in the subjects with high fatness than in the subjects with low or desirable fatness (p <0.01). Hepatic enzyme activities and incidence of the subjects showing serum enzyme levels above the upper limit of normal values were significantly higher in the subjects with fatty liver than in subjects with no evidence of fatty liver (Tables 3Go and 4Go, p <0.01, respectively).


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  		Table 3. Serum hepatic enzyme activities in subjects with fatty liver (U/L; mean ± SD).
 

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  		Table 4. Elevated serum hepatic enzyme activities in relation to the presence of fatty liver in subjects with high fatness.
 
The serum activities of ALT, AST, and GGT were correlated significantly with TBF in overweight men and women; however, serum ALP and LD activities correlated with TBF and BMI only in overweight women (Table 5Go). The relationship between hepatic enzyme activities and TBF is illustrated by Fig. 1Go, which is a plot of the sequential change of the mean ALT, AST, and GGT activities during 7 stages from the 5th percentile to the 95th percentile for TBF. The serum ALT, AST, and GGT activities increased with TBF in men and women.


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  		Table 5. Correlation coefficients of serum hepatic enzyme activities versus TBF and BMI in 256 overweight subjects.
 


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  		Fig. 1. Relationship of total body fat (TBF) to the mean activities of serum alanine aminotransferase (ALT, circles), aspartate aminotransferase (AST, triangles), and {gamma}-glutamyl transferase (GGT, rectangles) in 475 men (closed symbols) and 257 women (open symbols). As total body fat increases, the mean activities of serum ALT, AST, and GGT are increased.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgement
 References
 
In this study of serum hepatic enzyme activities in relation to TBF, we found that elevated ALT, AST, and GGT activities are associated with increased TBF in overweight men and women, and ALP and LD are correlated with TBF in overweight women.

Our findings are in general agreement with a previous study [16], which demonstrated that BMI is strongly associated with increased serum activities of liver enzymes, such as ALT, AST, and GGT. Some investigators reported that serum ALT, AST, and GGT enzymes showed marked increases in mean levels with increasing BMI [17]. In contrast, Mala et al [18] reported that there was no effect of decrease of BMI on serum ALT and AST activities. These inconsistencies may reflect the differences of subject populations among the studies.

We investigated behavioral factors, eg, alcohol consumption and smoking, and the prevalence of hepatitis B and C viral markers, as well as fatty liver in the subjects. There were no significant differences in the incidences of alcohol consumption or smoking, or in the positive rate of anti-HBs and anti-HBc tests between the subjects with high fatness and those with low or desirable fatness. However, the prevalence of subjects with fatty liver was significantly higher in the individuals with high fatness than in subjects with low or desirable fatness. Among the subjects having high TBF, those with fatty liver showed significantly higher incidence of elevation of serum hepatic enzymes, compared to those without fatty liver. These results suggest that elevated serum hepatic enzyme activities may be associated with high prevalence of fatty liver, which is observed in the subjects with elevated TBF.

This confirms the reports of other investigators, who found that serum aminotransferase activities were related to the severity of fatty liver in obese subjects [19,20]. Interestingly, the present study shows, for the first time, that ALP and LD activities are associated with increase of TBF and BMI in overweight women but not in men. ALP and LD activities are influenced by gender, especially in relation to obesity.

We evaluated the association between serum hepatic enzyme activities and TBF, especially as compared to BMI. The subjects with high fatness exhibited significantly higher AST (in men) and GGT activities (in women), compared to the corresponding subjects with low fatness. However, when we compared serum AST and GGT activities on the basis of BMI, no significant differences were observed between the overweight and underweight subjects. These results suggest that increased TBF shows a closer association with serum hepatic enzyme activities, at least AST activities in men and GGT activities in women, than does increased BMI.

Because in this study we relied upon a questionnaire self-reported by the subjects, we could not measure objectively the behavioral habits of the subjects; smoking and alcohol consumption were not quantified. A protracted history of atypical dietary habits or the possibility that subjects might harbor viruses that affect the liver, other than Hepatitis B or C, might influence the results. We stress the limitations of the current study in regard to factors that might have affected the results.

In conclusion, this study shows that increased TBF is associated with elevated serum ALT, AST, and GGT activities in men and is associated with elevated ALT and GGT, as well as ALP and LD activities in women. Elevated serum hepatic enzyme activities are associated with the high prevalence of fatty liver, which was frequently observed in subjects with high fatness. Further research is needed to verify this finding.


   Acknowledgement
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgement
References
 
This work was supported by Inha University Research Grant (INHA-30180).


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgement
 References
 

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