Liver function tests are commonly used by clinicians for the diagnosis, monitoring, and prognosis of liver disease in patients. Serum aminotransferases are an easily measurable, low-cost screening tool for detecting asymptomatic liver disease. Aminotransferase levels may also be a good indicator of overall health, particularly for ascertainment of health status in the context of widespread obesity, metabolic syndrome, and cardiovascular disease, because many patients affected by these conditions are also at risk of having nonalcoholic fatty liver disease (1).
To determine the likelihood that liver disease is present, aminotransferase levels test results should be compared with values obtained from healthy individuals, whose distribution of aminotransferase levels is termed as the reference interval. The aminotransferases’ reference ranges are important for assessing their clinical utility as liver disease screening tests. Recent studies performed in adult populations have suggested that the upper reference limits (URLs) for alanine aminotransferase (ALT) should be revised to increase the detection of nonalcoholic fatty liver disease in light of changing lifestyle factors, particularly obesity, that influence aminotransferase concentrations (2,3). It should be noted that the reference range for ALT varies according to the chosen reference class (4); therefore, interlaboratory variation exists in the used ALT reference range (5). Because of strict selection procedures, voluntary blood or liver donors used as the reference class in previous adult studies represent the healthiest subset of the general population. Thus, the URL for ALT levels from such a cohort cannot be extrapolated to the general population. Furthermore, age and sex influence the URLs for ALT and aspartate aminotransferase (AST). ALT and AST levels increase from childhood to approximately age 40 years, with greater increases in men than in women (6). Therefore, URLs for aminotransferases should also be established for children and adolescents with separate URLs for boys and girls. Unfortunately, to date, standard URLs for aminotransferase levels in the pediatric population have not been established, and existing adult-based URLs are not appropriate for the adequate diagnosis of liver disease in this age group.
Given the current childhood obesity epidemic and the resulting increased risk of developing nonalcoholic fatty liver disease in older children and adults, the descriptive epidemiology of elevated aminotransferase levels provides important evidence of the burden of liver disease, highlights prevention needs and influences essential guidelines for how stringently these laboratory abnormalities should be evaluated in clinical practice. The prevalence and correlates of elevated aminotransferase levels have been reported in the U.S. adolescent population (7); however, the prevalence of elevated aminotransferase levels in Korean adolescents is still unknown.
The present study was designed to determine the URLs for aminotransferases and to describe the prevalence of and factors associated with elevated aminotransferase levels in Korean adolescents ages 10 to 19 years using data from the 2007 to 2009 Korea National Health and Nutrition Examination Survey (KNHANES) data.
KNHANES is a series of cross-sectional, national health and nutrition surveys designed to provide representative prevalence estimates for a variety of health measures and conditions. KNHANES is conducted by the Korean Centers for Disease Control. The survey design is a complex, stratified, multistage probability sampling of the civilian, noninstitutionalized Korean population. The procedures used to select the sample and conduct the interviews and examinations have been specified elsewhere (8). The present survey included an interview to obtain information concerning an individual's health history, health behaviors, and risk factors. A subsequent health examination was performed at a mobile examination center. Height, weight, and waist circumference were all measured in the mobile examination center using standardized techniques and calibrated equipment. A certified phlebotomist drew fasting morning blood samples from the examinee's arm for various blood tests.
Our analyses include data from 2007 to 2009 (KNHANES 2007–2009). In the 2007 to 2009 KNHANES, 31,705 individuals were sampled, and 23,632 individuals participated in the survey, which represents a response rate of 74.5%. From this population of participants, we extracted a total of 3364 adolescents ages 10 to 19 years. Of that number, 2746 adolescents submitted a valid fasting (≥8 hours) blood sample for the laboratory tests; these participants were included in the analytic sample. Sample weights were used to account for differential probabilities of selection and nonresponse (9) and were included in the estimation process for all of the analyses. The weighted data were subsequently adjusted to represent the resident Korean population for ages 10 to 19 years, as estimated by the Korea Census in 2005. Informed consent was obtained from all of the participants, and the protocol of the KNHANES and the study was approved by the institutional review board of the Korea Centers for Disease Control.
Selection of a Population at Low Risk For Liver Disease From the 2007 to 2009 KNHANES
Among the 2746 adolescent participants in the 2007 to 2009 KNHANES, we selected 1717 (62.5%) as being at clinically low risk for liver disease using the following exclusion criteria: serum hepatitis B surface antigen positive (n = 20), Alcohol Use Disorders Identification Test score (10) 8 or more (n = 58), having a body mass index (BMI) 85th percentile or more according to the 2007 Korea Centers for Disease Control growth charts (n = 577), any blood lipid abnormality such as low-density lipoprotein cholesterol (LDL-C) at least 130 mg/dL, triglycerides at least 150 mg/dL, or high-density lipoprotein cholesterol (HDL-C) <35 mg/dL (n = 277), fasting serum glucose at least 100 mg/dL (n = 73), and missing data (n = 24).
In the 2007 KNHANES, the central laboratory to be used was the Seoul Medical Science Institute in Seoul, Korea, which used an ADIVIA1650 analyzer (Siemens, Tarrytown, NY). In the 2008 KNHANES, the central laboratory changed to the Neodin Medical Institute in Seoul, Korea, which used a Hitachi Automatic Analyzer (Hitachi, Tokyo, Japan). Both of the laboratories were certificated by the Korean Society for Laboratory Medicine. Both analyzers employed the α-ketoglutarate reaction for the measurement of aminotransferase levels. Unfortunately, the distributions of the ALT and AST levels in sample populations were not compared between the central laboratories. Serum samples from all of the participants across the surveys were tested for HBs antigens (Electrochemiluminescence Immunoassay, Roche Diagnostics, Rotkreuz, Switzerland). Antibodies to the hepatitis C virus were not included in the KNHANES protocol.
Weighted means, frequencies, and cross-tabulations were computed. Sample weights were included in the estimation process for all of the analyses to reflect the differential probabilities of selection, nonresponse, and noncoverage. The 5th, 25th, 50th (median), 75th, 95th, and 97.5th percentiles for the ALT and AST levels were calculated by sex in the group at low risk for liver disease in the 2007 to 2009 KNHANES. We set the URLs for ALT and AST at the 97.5th percentile of the levels in the population at low risk for liver disease according to the recommendations of the American Gastroenterological Association (11). The prevalence of elevated aminotransferase levels was calculated for the entire population and among subgroups defined by predictors of elevated aminotransferases levels. A multiple logistic regression was used to estimate the odds ratios (ORs) of having elevated aminotransferase levels while controlling for all of the predictors that showed a significant association with elevated aminotransferase levels in the univariate analysis.
Table 1 shows the unweighted and weighted distribution of the characteristics of the 2007 to 2009 KNHANES adolescents ages 10 to 19 years. Relative to the entire sample, the group at low risk for having liver disease was more likely to be younger, girl, and by design, to have a lower BMI, waist circumference, lipid levels, fasting glucose, and aminotransferase levels. The ALT and AST distributions for boys and girls in the group at low risk for liver disease are shown in Table 2. For ALT, the 97.5th percentile was 33 IU/L for boys and 25 IU/L for girls. For AST, the corresponding concentrations were 33 IU/L for boys and 28 IU/L for girls.
We next calculated the prevalence of elevated ALT and AST by applying the URLs determined in the previous step to the entire 2007 to 2009 KNHANES adolescent population (Table 3). An elevated ALT level was present in 6.5% (95% confidence interval [CI] 5.6%–7.5%) of the study population. The prevalence of elevated ALT among the elevated ALT risk factor subgroups defined above is presented in Table 3. The prevalence of elevated ALT was higher in boys (8.2%) than in girls (4.5%, P < 0.05) and there were slight differences across the age groups. With an increasing degree of obesity and lipid abnormalities, there was a sharp increase in the prevalence of elevated ALT. This prevalence exceeded 30% in individuals with a BMI at least 95th percentile. The prevalence estimate of elevated AST was approximately 3.9% (95% CI 3.2%–4.7%). The trends for the prevalence of elevated AST by anthropometric and metabolic indices were similar to the trends observed for elevated ALT.
Elevated ALT levels were significantly associated with male sex, being in an older age group, and having a greater BMI and lipid levels (Table 4). Analysis of elevated AST levels revealed similar associations as the risk factors for having elevated ALT; however, there was a strong association between having elevated AST and belonging to a younger age group.
The KNHANES is the only population-based survey that provides nationally representative measurements of aminotransferase levels in the general Korean adolescent population. We estimated the 97.5th percentiles of ALT and AST levels as the URLs in the population at low risk for liver disease in the 2007 to 2009 KNHANES. We found that the URLs for serum ALT were 33 IU/L for boys and 25 IU/L for girls and that the corresponding limits for AST levels were 33 IU/L for boys and 28 IU/L for girls. Using these thresholds, we also estimated the weighted prevalence of elevated ALT and AST in the population as 6.5% and 4%, respectively. The prevalence of elevated ALT described in the present study is comparable to that of U.S. adolescents when a cutoff of ALT at least 30 IU/L for both sexes (7.4%) is used.
A substantial discrepancy exists between the thresholds calculated in the present study and URLs reported in previous studies. Several investigators have proposed revisions to the URL for serum ALT in adult populations. The upper limits for ALT chosen in studies of adults are consistently lower than those in the present study, despite the current data being derived from adolescents. The main reason for this discrepancy is the choice of the reference class used to derive the upper limits for the ALT levels. Most studies that address the definition of the URL utilize samples from blood donors (2), liver donors (3), or voluntary health promotion examinees from a single center (12), thereby representing only the healthiest subset of the general population. This explanation is further supported by a study that found that the variability in defined URLs for ALT was mainly attributable to differences in reference populations, rather than to interanalyzer variation (5). In addition, the URLs for ALT in several studies were derived using a 95th percentile cutoff, rather than a cutoff the 97.5th percentile, which may partially explain the lower values for the URLs of ALT in the studies of Prati et al (2) and Kang et al (12).
We found evidence of profound associations among the prevalence of abnormal ALT levels and sex (with boys having a higher prevalence than girls), older age, higher BMI, and abnormal lipid levels. These associations with the prevalence of elevated ALT are consistent with data from previous reports that found that the prevalence of elevated ALT is significantly associated with obesity, abnormal lipid levels, and insulin resistance (7,13). We also found weak evidence that the HBs antigen positivity was associated with the prevalence of elevated ALT and AST levels. This finding suggests that the measurement of aminotransferase levels is not suitable to screen for the detection of hepatitis B infection in a hepatitis B–endemic area. An unexpected reduction in the risk of elevated AST levels with increasing age was observed in the present study. This phenomenon could not be adequately explained by existing evidence. The half-life of total AST is 17 ± 5 hours, whereas that of mitochondrial AST averages 87 hours, which is the longest half-life of all of the aminotransferases (14). Accordingly, it would be interesting to investigate the patterns of AST subtype activities at different ages in adolescent populations.
The major strengths of the present study are that the data are representative of the Korean population and that the data were collected using standardized measurements; however, there are also a number of limitations. First, because of the cross-sectional nature of the data, only associations, not causality, can be examined. Second, a limitation of using the KNHANES is the reliance on a single aminotransferases measurement. Aminotransferase activity varies daily, and the degree of variation can increase under certain conditions, such as food ingestion, time of day, exercise, acute illness, or other forms of stress (15). Furthermore, the central laboratories and autoanalyzers used for aminotransferase measurement changed during the study period. Finally, we could not identify all of the potential causes of aminotransferase elevation, which is important because high levels of aminotransferases are considered to be a marker of nonalcoholic fatty liver disease in the absence of other specific causes. Individuals who have hepatitis B virus infection, have alcohol use disorder defined by the Alcohol Use Disorders Identification Test, are overweight or obese, or have abnormal lipid levels were excluded from the subgroup determined to be at low risk for liver disease; however, other causes of elevated aminotransferase levels, such as autoimmune hepatitis, hepatitis C, and iron overload were not excluded. The inclusion of a small number of such participants with undetected liver diseases and disease-related elevated aminotransferase levels may have falsely raised the URLs.
In conclusion, we determined the URLs for ALT and AST among the general Korean adolescent population, and using the thresholds identified, we estimated the weighted prevalence of elevated ALT and AST levels. We also found that elevated ALT levels are associated with male sex, older age, obesity, and having abnormal lipid levels, whereas elevated AST levels are associated with obesity, lower age, and abnormal lipid levels. These characteristics could be used by clinicians to identify people who may benefit from liver disease screening, thereby offering an opportunity to detect disease or to prevent disease progression by intervening at an early stage. Because of the current epidemic of childhood obesity and the subsequent increasing risk of nonalcoholic fatty liver disease, monitoring the secular trends in the prevalence of elevated aminotransferase levels, particularly in people at high risk for liver disease, may be needed. Aminotransferase URLs are being established for the first time, and our results may be useful in determining a baseline rate for monitoring the trends of liver disease in future KNHANES surveys.
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Keywords:Copyright 2012 by ESPGHAN and NASPGHAN
alanine aminotransferase; aspartate aminotransferase; prevalence; survey; upper reference limit