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Departments of Pediatrics (T.S.B., S.E.T., C.W.Y., R.W., W.V.T., M.S., A.A.S., S.C.) and Diagnostic Radiology (T.R.G., X.P., R.T.C.), and the General Clinical Research Center (J.D.), Yale University School of Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Dr. Sonia Caprio, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208064, New Haven, Connecticut 06520. E-mail: sonia.caprio{at}yale.edu.
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Abstract |
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Methods: In a multiethnic cohort of 392 obese adolescents, alanine aminotransferase (ALT) levels were related with parameters of insulin sensitivity, glucose, and lipid metabolism as well as adipocytokines and biomarkers of inflammation. A subset of 72 adolescents had determination of abdominal fat partitioning and intrahepatic fat accumulation using magnetic resonance imaging.
Findings: Elevated ALT (>35 U/liter) was found in 14% of adolescents, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance as well as rising free fatty acids and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (18–35 U/liter). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and increased triglycerides, visceral fat, and deep to superficial sc fat ratio. The prevalence of the metabolic syndrome was significantly greater in those with fatty liver.
Interpretation: Deterioration in glucose and lipid metabolism is associated even with modest ALT elevations. Hepatic fat accumulation in childhood obesity is strongly associated with the triad of insulin resistance, increased visceral fat, and hypoadiponectinemia. Hence, hepatic steatosis may be a core feature of the metabolic syndrome.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Importantly, several studies in adults have found that high levels of hepatic enzymes, particularly alanine aminotransferase (ALT), predict later development of type 2 diabetes mellitus (T2DM) (5). Recently Nadeau et al. (6) reported a high prevalence of elevated ALT among children with T2DM, unrelated to age, body mass index (BMI), and glycemic index. Thus, elevations in ALT may be not only a marker of liver injury and a surrogate for fatty liver disease but also an early indicator of looming diabetes. The relationship among alterations in glucose and lipid metabolism, elevations in biomarkers of liver injury, and the presence of hepatic steatosis has not been characterized in obese youth. Given that the liver plays a critical role in maintaining glucose and lipid homeostasis, we hypothesized that deterioration in glucose and insulin metabolism might emerge as a function of increasing ALT elevations and hepatic fat accumulation. As a biomarker of liver injury, we measured ALT levels in a large multiethnic cohort of obese youth and examined how ALT elevations were related to alterations in insulin sensitivity, glucose tolerance, and inflammatory markers. Additionally, fast-gradient echo magnetic resonance imaging (fast-MRI) pulse sequences enabled the measurement of intrahepatic fat accumulation in a single breath hold, and abdominal magnetic resonance was used to quantify visceral and sc fat. These imaging techniques, combined with the characterization of the metabolic phenotypes, provided us with a clear delineation of the metabolic defects of obese youth with rising ALT levels and fatty liver.
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Subjects and Methods |
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We studied a multiethnic cohort of 392 overweight/obese adolescents recruited from our Pediatric Obesity Clinic. Some of these participants are part of a larger study on the prevalence of glucose intolerance and the metabolic syndrome in childhood obesity and thus were previously reported (7). Subjects were eligible if they were healthy, 10–21 yr of age, and had a BMI greater than the 85th percentile (97% had a BMI > 95th percentile). As part of the history of dietary intake, questions related to alcohol consumption were obtained in all subjects. Study participants were excluded if they consumed alcohol or were on medications that might affect liver function tests. This led to an a priori exclusion of 89 subjects because they were taking medications that potentially affect ALT. In our cohort, all subjects denied the use of alcohol. As described in Table 1
, there were 138 white (35%), 130 African-American (33%), and 124 Hispanic (32%) adolescents. The Yale University School of Medicine Human Investigation Committee approved the study, and written informed consent/assent was obtained.
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Subjects were invited to the Yale General Clinical Research Center at 0800 h after an overnight fast, as previously reported (7). Their weight, height, and blood pressure were measured, and their BMI was calculated. Baseline fasting measures of plasma glucose, insulin, c-peptide, proinsulin, adiponectin, leptin, C-reactive protein (CRP), IL-6, free fatty acids (FFAs), lipid profile, and liver enzymes were obtained. Subsequently a standard 3-h oral glucose tolerance test (OGTT) was performed, and blood samples were obtained every 30 min for the measurements of plasma glucose, insulin, and c-peptide. Prediabetes (impaired glucose tolerance) was defined by a 2-h blood glucose of 140–199 mg/dl, in accordance with the American Diabetes Association guidelines.
Markers of insulin sensitivity and ß-cell function
To assess insulin sensitivity, the whole-body insulin sensitivity index was calculated using the Matsuda Index (8, 9). To evaluate ß-cell function, we calculated the ratio between fasting proinsulin and insulin because disproportionate hyperproinsulinemia is a marker of ß-cell dysfunction (10). Insulin clearance was calculated using the molar ratio of the areas under the curve (AUCs) for c-peptide and insulin.
Biochemical markers of liver injury
ALT was chosen as our primary marker of liver injury and as a surrogate for suspected fatty liver. ALT, aspartate aminotransferase (AST), and 
-glutamyltransferase (GGT) were measured by the Yale-New Haven Hospital Clinical Chemistry Laboratory using standard automated kinetic enzymatic assays. The reference range for ALT from the Yale Laboratory is 0–35 U/liter; therefore, ALT greater than 35 U/liter was considered abnormal. Because our clinical laboratory’s cutoff for ALT values is somewhat lower than the more commonly used cutoff point of greater than 40 U/liter (1, 11, 12), we cross-analyzed our data using the 40 U/liter cutoff. This analysis did not qualitatively change any of the results presented in this study; therefore, we elected to report our analysis with the reference range established for our clinical laboratory. To assess the relationship and clinical relevance of ALT levels within the normal range, we divided the range in half and created two categories [low-normal ALT (0–17 U/liter) and high-normal ALT (18–35 U/liter)] by which we presented our metabolic studies. Repeatability for classification into ALT categories was examined in a group of subjects (n = 103) with ALT measured twice (median elapsed time between ALT measurements 5.1 months, range 0.6–15.4 months). There was good agreement between repeated categorization (weighted kappa 0.76). The overall proportion of agreement was 82%, whereas the proportion of specific agreement for those with a high ALT was 90%.
Biochemical analyses
Plasma glucose levels were measured using the YSI 2700 STAT analyzer (Yellow Springs Instruments, Yellow Springs, OH). Plasma insulin, proinsulin, leptin, and adiponectin levels were measured using RIA assays from Linco Research (St. Charles, MO). C-peptide was measured using an assay from Diagnostic Products Corp. (Los Angeles, CA). CRP was measured using the ultrasensitive assay (Kamiya Biomedical, Thousand Oaks, CA). IL-6 was measured using a highly sensitive solid-phase ELISA (R&D Systems, Minneapolis, MN).
Imaging studies
Measurement of hepatic fat accumulation was performed using MRI along with the Dixon method as modified by Fishbein et al. (13). The method is based on phase-shift imaging in which hepatic fat fraction (HFF) is calculated from the signal difference between the vectors resulting from in-phase and out-of-phase signals. One hepatic slice pair was obtained during a breath hold of 15 sec. Using the MRIcro software program (14), five regions of interest were drawn on each image, and the mean pixel signal intensity level was recorded. The HFF was calculated in duplicate from the mean pixel signal intensity data using the formula: [(Sin – Sout)/(2 * Sin)] * 100.
Because of the skewed HFF distribution, the presence or absence of steatosis was determined by a threshold value for HFF. We measured HFF in 15 lean, nondiabetic subjects (age 21.6 ± 8.2 yr; BMI 21.6 ± 2.1 kg/m2), resulting in a mean HFF of –1.5 ± 2.6%. Due to unavoidable image heterogeneity, normal nonfatty livers returned similar signals with in- and out-of-phase sequences, resulting in negative HFF values for some subjects. These values were equated with undetectable fat accumulation. We chose an HFF cutoff of 5.5% (>2.5 SD above the mean of our controls) as the threshold to denote steatosis. In support of our cutoff value are the results from a recent study that applied a direct measure of hepatic triglyceride content using magnetic resonance spectroscopy to a cohort of 345 lean, nondiabetic adults. In that study, the 95th percentile of hepatic triglyceride content was 5.56% (15).
Abdominal MRI studies were performed on a Siemens Sonata 1.5-Tesla system. The pulse sequence was a T1-weighted fast low angle shot gradient echo. Slices were acquired using a 400-cm field of view (echo time 4.76, repetition time 100, 4 excitations, 90-degree flip angle, matrix 256 x 128, bandwidth 140). The midaxial section was positioned to pass through the L4/L5 disk space. Images were imported into the Yale Bioimage Suite software package (16). Visceral, sc, deep sc, and superficial sc fat areas were determined. The fascia superficialis was used as the division between the deep and superficial sc fat as described by Ross et al. (17). Thresholding was applied to separate fat from soft tissue.
Total body composition was measured by dual-energy x-ray absorptiometry with a Hologic scanner (Boston, MA).
Repeatability of abdominal MRI and hepatic fat fraction
To assess the repeatability of the MRI technique, measurements were obtained (<10 min apart) on 12 subjects (four lean, eight overweight/obese). The within-subject coefficients of variation for visceral fat, sc fat, deep sc fat, and superficial sc fat were 8.4, 2.9, 3.3, and 5.7%, respectively, indicating good repeatability. For the HFF, the within-subject SD was 1.9%. In addition, fast-MRI images were compared with biopsy results in two obese adolescents diagnosed with severe macrovesicular steatosis and bridging fibrosis (stage 3). The calculated HFFs in the two subjects were 38.5 and 39.1%, values that were consistent with the histopathological analyses. Studies by Fishbein et al. (18) showed an excellent correlation in hepatic fat quantification between liver biopsy interpretation (steatosis score) and MRI measurements in subjects with predominantly macrovesicular steatosis, the lesion associated with NAFLD (r = 0.85, P < 0.001).
Statistical methods
Statistical analyses were performed with SAS (version 9.1; SAS Institute Inc., Cary, NC). Analyses of covariance and logistic regression with adjustment for age, gender, race/ethnicity, and BMI z-score were used to compare means and proportions, respectively, across categories (ALT and HFF). For comparisons across ALT categories, significance tests for linear trend and for differences between low- and high-normal ranges were performed. Interpretation for linear trend was based on statistical models using ALT as a continuous variable. For the ease of presenting clinically relevant means instead of slopes, we chose to divide the normal range in half, creating two categories that were not based on the outcome variable’s response.
Where appropriate, log transformations were used to normalize variables with positively skewed distributions. Unless otherwise stated, data are expressed as frequencies or means/geometric means with 95% confidence intervals (CIs) as appropriate.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As shown in Table 1, abnormally high ALT (mean 68 U/liter) was seen in 14% of the subjects. This group also had elevated AST and GGT levels (data not shown). Subjects were of similar age between ALT categories, but there was a clear gender difference, with 72% males in the abnormal ALT category. BMI z-score increased, and the racial/ethnic distribution shifted across ALT categories. Whereas African Americans comprised approximately 33% of the entire cohort, they comprised only 15% of those within the abnormal ALT category.
Metabolic parameters according to ALT category (Fig. 1 and Table 2)
Fasting plasma glucose was similar across ALT categories (Fig. 1). In contrast, postchallenge plasma glucose excursions rose to significantly higher levels as ALT increased. Of note, the AUC for glucose was already higher (P = 0.01) in subjects in the high-normal ALT range, compared with those in the low-normal ALT range. Mean 2-h postchallenge plasma glucose levels also rose significantly through ALT categories (Table 2). This deterioration in glucose tolerance was associated with markedly greater insulin and c-peptide levels and AUCs. Independence from potential confounders, including BMI z-score, ethnicity, gender, and age, strengthens the link between worsening glucose metabolism and rising ALT categories.
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). Insulin clearance was similar across ALT categories (data not shown). Adiponectin, CRP, IL-6, and leptin levels remained unchanged as ALT levels increased.
Metabolic parameters in relation to hepatic fat accumulation
To assess whether serum ALT levels are associated with the actual liver fat content as assessed by MRI technology, a random subset of subjects (n = 72) underwent HFF measurement using a modified Dixon method (13). Subset analyses revealed similar race/ethnic distribution and BMI/BMI z-score for the subset (n = 72), compared with the entire cohort (n = 398). However, the subset was older than the larger cohort. HFF ranged from undetectable to 41%. Subjects were grouped according to HFF category (HFF > 5.5 or < 5.5%). As shown in Table 3, 32% of subjects had an HFF greater than 5.5%. Similar to the male and white/Hispanic predominance seen with rising ALT (Table 1), male gender was significantly associated with hepatic steatosis. A different ethnic distribution, albeit not statistically significant, was also noted in subjects with fatty liver.
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). Nonetheless, only 48% of subjects with fatty liver had abnormal ALT levels. Obese adolescents with a high HFF had a significantly greater AUC for glucose (P < 0.03); however, significance was lost after adjusting for confounders (P = 0.08). Additionally, those with a high HFF were significantly more insulin resistant, compared with those with a low HFF, and had higher triglycerides and lower adiponectin (Fig. 2). Furthermore, subjects with a high HFF had a significantly greater prevalence of the metabolic syndrome (Table 3). As previously reported, we modified the criteria from the National Cholesterol Education Adult Treatment Program in making the diagnosis of the metabolic syndrome in children (7).
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Despite comparable percent total body fat in obese adolescents with high and low HFF (Table 3), visceral fat was significantly higher in subjects with a high HFF (Fig. 2). Subcutaneous fat was similar in the unadjusted analysis (P = 0.8); however, after adjustment, subjects with steatosis had significantly less sc fat [529 cm2 (95% CI 481–578 cm2) vs. 600 cm2 (95% CI 564–637 cm2), P = 0.03]. When the sc depot was further broken down into deep and superficial sc fat, it became apparent that the overall lower amounts of sc fat in subjects with fatty liver were primarily a function of decreased superficial sc fat. The deep sc fat was similar in both groups. Therefore, the overall composition of the sc fat depot was significantly different in the two groups as demonstrated by the deep to superficial sc fat ratio (Fig. 2).
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Discussion |
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), even after controlling for potential confounders. These metabolic alterations were further exaggerated when ALT was elevated outside the normal range. Intrahepatic fat accumulation was found in 32% of obese adolescents and was associated with increased visceral fat and decreased superficial sc fat, marked insulin resistance, and hypoadiponectinemia (Fig. 2). Furthermore, obese adolescents with fatty liver had a higher prevalence of the metabolic syndrome. Associations between surrogate markers of insulin resistance and elevations in ALT have been found by other studies, in cohorts of obese Japanese (19) and Chinese (20) children and in biopsy-proven steatosis in a group of mostly Hispanic and Caucasian boys (21). In addition to demonstrating that insulin resistance is strongly and independently correlated with rising ALT levels, our study is the first to observe that subtle alterations in glucose tolerance and lipid metabolism are associated with rising ALT in obese youth. In adults, prospective studies have found that ALT levels predict the development of T2DM in Pima Indians (5). In middle-aged Caucasian males, even ALT elevations in the normal range predicted the development of T2DM (22). Conceivably, increased ALT levels, secondary to fatty liver deposits, may mark the pathophysiological mechanisms that predate the development of T2DM. The fact that in our study shifts in glucose metabolism were associated with even a modest rise in ALT suggests that abnormalities in liver function tests in obese youth may not only predict liver disease but also herald the development of T2DM.
The association of elevated FFAs with high ALT in our study may denote an undesirable effect on liver function (portal theory), including impaired insulin-mediated suppression of glucose production and insulin-mediated glucose uptake (23). However, it remains unclear whether intrahepatic fat accumulation is a consequence (24) or cause (25) of the observed metabolic derangements in insulin sensitivity and lipid metabolism (elevated triglycerides and FFAs).
In contrast to recent findings in adults (26), we did not find that proinflammatory markers (CRP, IL-6) were associated with elevations in ALT in obese youth. A potential explanation for this finding is that most of the obese youth in this study may have been in an early, less inflammatory disease state and that these proinflammatory biomarkers may play a more important role as the disease progresses.
Using imaging techniques, we more firmly established the connection between hepatic fat accumulation and alterations in metabolism in obese youth. Steatosis (HFF > 5.5%) was associated with subtle changes in glucose tolerance, severe insulin resistance, rising triglycerides, and the metabolic syndrome. Thus, in obese youth, hepatic steatosis could be a core feature of the metabolic syndrome, a proposition already in discussion for adults (2, 27).
Hypoadiponectinemia was strongly associated with hepatic steatosis, as reported in adults (28, 29). States of low adiponectin may be causally linked to NAFLD, as demonstrated by an amelioration of fatty liver infiltration in ob/ob mice after adiponectin administration (30). Furthermore, a recent clinical trial demonstrated that the marked increase in adiponectin after pioglitazone treatment was closely related to a decrease in hepatic fat content (31). Whereas the imaging studies support a physiological link between adiponectin and liver fat accumulation, we could not confirm a direct association between adiponectin and ALT. This lies in contrast to the findings of a recent pediatric study that demonstrated a correlation between ALT and adiponectin among obese subjects with and without abnormalities in ALT and lean controls (32). However, the analysis was not controlled for BMI, which was significantly different in the three groups. The imaging component of our study allowed us to demonstrate a direct association of adiponectin with hepatic fat accumulation, independent of BMI. In fact, we observed that many children with fatty liver as assessed by HFF had ALT levels within the normal range. Therefore, we hypothesize that a negative correlation between adiponectin and ALT did not emerge due to ALT being an imperfect biochemical surrogate marker for steatosis. In addition, we presume that other factors (environmental and/or genetic) may contribute to ALT elevations beyond the presence of steatosis.
Taken together, the adult studies and our observations strongly suggest that the triad of hypoadiponectinemia, insulin resistance, and fatty liver may set the stage for the development of T2DM in obese youth and may warrant early intervention.
The role of visceral obesity and NAFLD has been studied primarily in adults (33, 34) and in a recent small pediatric study (35). In our study, visceral fat was found to be tightly linked with fatty liver. The mechanism by which visceral fat contributes to fatty liver is still controversial. The portal/visceral hypothesis is based on the higher rates of lipolysis in visceral fat, leading to increased delivery of FFAs to the liver via the portal vein (36), although this theory has been questioned (37). New paradigms of ectopic fat storage disease have emerged, which focus away from the portal/FFA model to allow for a more comprehensive view of the endocrine, autocrine, and paracrine effects of fat storage disease (38).
We also found that variations in the composition of the sc fat depot are linked to NAFLD. In our analysis, subjects with hepatic steatosis had a higher deep to superficial sc fat ratio (Fig. 2). This is interesting in light of the recent findings that deep sc and visceral fat followed a highly congruent pattern of association with AUC for glucose and insulin during the OGTT, whereas superficial sc fat manifested metabolic protection through a powerful relation to leptin and a weak association with insulin resistance (39). Another study found that, in males but not females with T2DM, deep sc fat was associated with peripheral and hepatic insulin resistance (40). This may explain why earlier studies that were exclusively comprised of males found total sc fat to be more strongly related to insulin resistance and glucose metabolism than was visceral fat (41). To our knowledge, this is the first study to demonstrate a relationship between sc fat composition and steatosis. Whereas cause and effect cannot be established in a cross-sectional study, we hypothesize that, whereas visceral fat may be an important contributor to steatosis, changes in potentially protective fat depots (superficial sc tissue) and contributory fat depots (deep sc tissue) may create an adipocyte-driven hormonal milieu conducive to hepatic steatosis.
Although the association between ALT and HFF was significant (r = 0.52, P < 0.0001), only half of the subjects with a high HFF had ALT levels considered abnormal by today’s commonly accepted normal values. Therefore, relying on the current ALT cutoff value as a screening tool may overlook children with significant steatosis. Indeed, in our study, some obese adolescents had prominent steatosis (HFF > 30%) despite normal ALT. Interestingly, a large study of adult blood donors suggested that previous reference ranges for liver enzymes may have included individuals with NAFLD, thereby falsely elevating the normal range (12). The authors concluded that a healthy reference range for ALT may lie less than 19 U/liter for women and 30 U/liter for men. In our cohort, nearly 80% of subjects with an HFF greater than 5.5% had ALT levels greater than 18 U/liter. These findings cast doubt on the normal ranges that we currently use for ALT in pediatrics.
Abnormal ALT levels and fatty liver assessed by fast-MRI were more common in boys. On the other hand, African-American adolescents were significantly less likely to have abnormal ALT levels. These gender and ethnic differences have also been reported by Schwimmer et al. (42). Although the nature of our data does not allow us to deduce that the relationship between ethnicity and visceral fat is linked to fatty liver disease, we speculate that the lower prevalence of ALT abnormalities and steatosis in African-American youth may be due to the inherently low visceral fat in African-American subjects.
In summary, we found that deterioration in glucose and lipid metabolism was associated even with modest ALT elevations. One third of obese youth presented with fatty liver as measured by fast-MRI, of which only half had ALT levels outside the normal range. Although our data are cross-sectional, we were able to show that the nature of a child’s fat depots may be connected to an imbalance in the adipocyte-driven hormonal and substrate milieu, possibly leading to hypoadiponectinemia and rising FFA and triglyceride levels. This may exacerbate insulin resistance and ß-cell dysfunction, thereby setting the stage for T2DM.
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Acknowledgments |
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Footnotes |
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First Published Online August 15, 2006
Abbreviations: ALT, Alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; fast-MRI, fast-gradient echo MRI pulse sequences; FFA, free fatty acid; GGT, -glutamyltransferase; HFF, hepatic fat fraction; MRI, magnetic resonance imaging; NAFLD, nonalcoholic fatty liver disease; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes mellitus.
Received May 10, 2006.
Accepted August 9, 2006.
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or adiponectin? Hepatology 40:46–54[CrossRef][Medline]This article has been cited by other articles:
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