Gender differences in healthy ranges for serum alanine aminotransferase levels in adolescence

Background & Aims

There is a worldwide epidemic of obesity among adolescents who subsequently are at increased risk for the development of non alcoholic fatty liver disease (NAFLD). The serum alanine aminotransferase (ALT) is the most frequently used test for screening these individuals, but no age and gender-specific upper limits of normal (ULN) based on healthy population data in children are available. The objective of the present study was to define ULN for ALT in healthy children in order to use this as a tool for case finding.

Methods

A total of 975 school children (aged 7–18 years) were included in the study cohort. Highly significant correlations (all p<0.001) were noted between ALT values and measures of BMI, systolic and diastolic blood pressure, insulin levels, HOMA-IR, total cholesterol and triglyceride concentrations. In order to define the population with no risk factors, we excluded subjects having abnormal values for factors that correlated with ALT. This population comprised 186 boys and 185 girls.

Results

In boys, median serum ALT levels were 16 IU/L and 9, 11, 18, and 30 IU/L for the 5th, 25th, 75th, and 95th percentiles. In girls, median serum ALT was 13, and 7, 9, 16, and 21 IU/L for the 5th, 25th, 75th, and 95th percentiles, respectively. The ULNs for ALT were 30 IU/L and 21 IU/L for boys and girls respectively. We found a linear relationship between age and ALT in females (p<0.001) but not in males. By multiple logistic regression, independent predictors of an elevated ALT included the BMI, waist hip ratio and levels of serum total cholesterol. In females, age was an additional inverse predictor.

Conclusions

In children and adolescents, these normal limits for ALT should be applied. Those with persistent elevations should be investigated further.     

Gender difference in serum bisphenol A levels may be caused by liver UDP-glucuronosyltransferase activity in rats

Gender difference in human bisphenol A (BPA) concentrations was revealed by determining serum BPA. We studied the serum concentrations and the metabolism of BPA in rats by an HPLC system. Rat serum BPA concentrations were significantly higher in males (24.9+/-7.38 ng/ml, P=0.026, n=10) than in females (8.27+/-3.11 ng/ml, n=10), as in humans. The resultant enzyme reaction products of BPA glucuronidation in the rat liver microsomes fraction were analyzed by an HPLC system. The ratio of BPA glucuronidation in the microsome reaction was significantly higher (P=0.015) in female than in male rats. The mRNA expression of UDP-glucuronosyltransferase 2B1 (UGT2B1), an isoform of UGT related to BPA glucuronidation, in the rat liver was analyzed by a real-time quantitative RT-PCR. The relative expression level of UGT2B1 mRNA was significantly higher (P<0.001) in female than in male rat livers. The gender difference in serum BPA concentrations may be explained by the difference in clearance based on the UGT activities.     

Identity of alanine:glyoxylate aminotransferase with alanine:2-oxoglutarate aminotransferase in rat liver cytosol

Rat liver soluble fraction contained 3 forms of alanine: glyoxylate aminotransferase. One with a pI of 5.2 and an Mr of approx. 110,000 was found to be identical with cytosolic alanine:2-oxoglutarate aminotransferase. The pI 6.0 enzyme with an Mr of approx. 220,000 was suggested to be from broken mitochondrial alanine:glyoxylate aminotransferase 2 and the pI 8.0 enzyme with an Mr of approx. 80,000 enzyme from broken peroxisomal and mitochondrial alanine:glyoxylate aminotransferase 1. These results suggest that the cytosolic alanine: glyoxylate aminotransferase activity is due to cytosolic alanine: 2-oxoglutarate aminotransferase.     

Upper limits of normal for serum alanine aminotransferase levels in chinese han population

Background and Objectives

Serum alanine aminotransferase (ALT) activity is the most common tool for the assessment of liver diseases. However, it is not clear whether the current normal ALT range really discriminate patients with or without liver diseases. The present study was to establish a new normal range of ALT and examine its ability to identify patients with hepatitis B or nonalcoholic fatty liver disease (NAFLD) in Chinese Han population.

Methods

53037 adults were included in this study from January 1st 2008 to August 31st 2010. The 95th percentile of ALT in population with relative low risk factors for liver diseases was set as the new upper limits of normal ALT in gender-specific manner.

Results

The 95^th percentile levels at low risk factors for liver diseases were achieved at 35 U/L for men and 23 U/L for women. The concordance statistics for detection were 0.873 (95%CI: 0.865–0.881) for HBV and 0.932 (95%CI: 0.927–0.937) for NAFLD in men while 0.857 (95%CI: 0.850–0.864) for HBV and 0.909 (95%CI: 0.903–0.915) for NAFLD in women. The median sensitivity of the current used ALT upper limit (40 U/L) was 6.6% for HBV and 29.7% for NAFLD and median specificity was 98.7% for men and 99.4% for women. Using our new-derived thresholds, the sensitivities ranged from 35.3% to 61.1% and the specificities were 94.8% for men and 94.6% for women.

Conclusions

Our results suggest that upper limits of ALT 35 U/L for men and 23 U/L for women in Chinese Han population. Re-consideration of normal limits of ALT should be recommended.

Trial Registration

ChiCTR.org ChiCTR-OCS-11001173     

Response of hepatic alanine:glyoxylate aminotransferase 1 to hormone differs among mammalia

The subcellular distribution and substrate specificity of hepatic alanine:glyoxylate aminotransferase 1 have been reported to differ among mammalia. In the present study, the response of this enzyme to hormone (glucagon) was found to differ among mammalia.     

Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1

We have previously shown that in some patients with primary hyperoxaluria type 1 (PH1), disease is associated with mistargeting of the normally peroxisomal enzyme alanine/glyoxylate aminotransferase (AGT) to mitochondria (Danpure, C.J., P.J. Cooper, P.J. Wise, and P.R. Jennings. J. Cell Biol. 108:1345-1352). We have synthesized, amplified, cloned, and sequenced AGT cDNA from a PH1 patient with mitochondrial AGT (mAGT). This identified three point mutations that cause amino acid substitutions in the predicted AGT protein sequence. Using PCR and allele-specific oligonucleotide hybridization, a range of PH1 patients and controls were screened for these mutations. This revealed that all eight PH1 patients with mAGT carried at least one allele with the same three mutations. Two were homozygous for this allele and six were heterozygous. In at least three of the heterozygotes, it appeared that only the mutant allele was expressed. All three mutations were absent from PH1 patients lacking mAGT. One mutation encoding a Gly----Arg substitution at residue 170 was not found in any of the control individuals. However, the other two mutations, encoding Pro----Leu and Ile----Met substitutions at residues 11 and 340, respectively, cosegregated in the normal population at an allelic frequency of 5-10%. In an individual homozygous for this allele (substitutions at residues 11 and 340) only a small proportion of AGT appeared to be rerouted to mitochondria. It is suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import.     

Intramitochondrial localization of alanine aminotransferase in rat-liver mitochondria: comparison with glutaminase and aspartate aminotransferase

Summary The removal of the outer mitochondrial membrane and hence of constituents of the intermembrane space in rat-liver mitochondria using digitonin showed that phosphate-dependent glutaminase, alanine and aspartate aminotransferase were localized in the mitoplasts. Further fractionation of mitoplasts following their sonication resulted in 90% of glutaminase, 98% of alanine aminotransferase and 48% of aspartate aminotransferase being recovered in the soluble fraction while the remainder of each enzyme was recovered in the sonicated vesicles fraction. These results indicated that glutaminase and alanine aminotransferase were soluble matrix enzymes, the little of each enzyme recovered in the sonicated vesicles fraction being probably due to entrapment in the vesicles. Aspartate aminotransferase had dual localization, in the inner membrane and matrix with the high specific activity in sonicated vesicles confirming its association with the membrane. Activation experiments suggested that the membrane-bound enzyme was localized on the inner side of the inner mitochondrial membrane.     

The levels of GA3 and GA20 may be associated with dormancy release in Onopordum nervosum seeds

Endogenous levels of two gibberellins, GA₃ andGA₂₀, were quantified in unimbibed Onopordumnervosum seeds collected from two different populations, whichshoweddifferences in their germination capacity. After purifying the seed extracts,gibberellin levels were evaluated by gas chromatography mass spectrometry byusing selected ion monitoring (GC-MS-SIM) adding deuterated gibberellins asinternal standards. The intraspecific differences in germination capacity wereassociated with differences in the endogenous levels of both gibberellins. Thecontents of GA₃ and GA₂₀ in seeds with high germinationrate were twice and five times higher, respectively, than those from seeds witha low germination rate, indicating a possible role of gibberellins in dormancyrelease in this plant species.     

Serum gamma-glutamyltransferase within its normal range predicts a chronic elevation of alanine aminotransferase: a four year follow-up study

BACKGROUND: Previous epidemiological and experimental studies support the concept that serum gamma-glutamyltransferase (GGT) activity within its normal range is related to oxidative stress. Since oxidative stress plays a crucial role in the pathogenesis of various liver diseases, serum GGT may predict development of liver damage. METHODS: A total of 6,523 healthy male workers with normal alanine aminotransferase (ALT, <35 U/l) in a steel manufacturing company were followed for four years. Liver damage was defined as a chronic elevation of serum ALT (both 2001 and 2002). RESULTS: After adjusting for age, body mass index, alcohol consumption, cigarette smoking, exercise, and baseline value of ALT, in comparison with the group whose GGT level was <10 U/l, the adjusted relative risks for elevated ALT level among those with GGT levels 10-19, 20-29, 30-39, and over 40 U/l was 1.0, 2.5, 4.7, 7.4, and 12.0, respectively (P for trend <0.01). More importantly, this association was similarly observed even among non-drinkers; the corresponding relative risks were 1.0, 1.8, 3.8, 5.6, and 6.2 (P for trend <0.01). However baseline ALT did not predict abnormal GGT level four years later. CONCLUSION: Serum GGT levels within normal range predict incidence of chronic elevation of ALT. Oxidative stress might explain this relationship.     

Serum gamma-glutamyltransferase within its normal range predicts a chronic elevation of alanine aminotransferase: A four year follow-up study

Background: Previous epidemiological and experimental studies support the concept that serum gamma-glutamyltransferase (GGT) activity within its normal range is related to oxidative stress. Since oxidative stress plays a crucial role in the pathogenesis of various liver diseases, serum GGT may predict development of liver damage.

Methods: A total of 6,523 healthy male workers with normal alanine aminotransferase (ALT, <35?U/l) in a steel manufacturing company were followed for four years. Liver damage was defined as a chronic elevation of serum ALT (both 2001 and 2002).

Results: After adjusting for age, body mass index, alcohol consumption, cigarette smoking, exercise, and baseline value of ALT, in comparison with the group whose GGT level was <10?U/l, the adjusted relative risks for elevated ALT level among those with GGT levels 10–19, 20–29, 30–39, and over 40?U/l was 1.0, 2.5, 4.7, 7.4, and 12.0, respectively (P for trend <0.01). More importantly, this association was similarly observed even among non-drinkers; the corresponding relative risks were 1.0, 1.8, 3.8, 5.6, and 6.2 (P for trend <0.01). However baseline ALT did not predict abnormal GGT level four years later.

Conclusion: Serum GGT levels within normal range predict incidence of chronic elevation of ALT. Oxidative stress might explain this relationship.     

Later chronotype is associated with higher hemoglobin A1c in prediabetes patients

The circadian system is known to play a role in glucose metabolism. Chronotype reflects the interindividual variability in the phase of entrainment. Those with later chronotype typically prefer later times in the day for different activities such as sleep or meals. Later chronotype has been shown to be associated with metabolic syndrome, increased diabetes risk and poorer glycemic control in type 2 diabetes patients. In addition, “social jetlag”, a form of circadian misalignment due to a mismatch between social rhythms and the circadian clock, has been shown to be associated with insulin resistance. Other sleep disturbances (insufficient sleep, poor sleep quality and sleep apnea) have also been shown to affect glucose metabolism. In this study, we explored whether there was a relationship between chronotype, social jetlag and hemoglobin A1c (HbA1c) levels in prediabetes patients, independent of other sleep disturbances. A cross-sectional study was conducted at the Department of Family Medicine, Ramathibodi Hospital, Bangkok, from October 2014 to March 2016 in 1014 non-shift working adults with prediabetes. Mid-sleep time on free day adjusted for sleep debt (MSFsc) was used as an indicator of chronotype. Social jetlag was calculated based on the absolute difference between mid-sleep time on weekdays and weekends. The most recent HbA1c values and lipid levels were retrieved from clinical laboratory databases. Univariate analyses revealed that later MSFsc (p = 0.028) but not social jetlag (p = 0.48) was significantly associated with higher HbA1c levels. Multivariate linear regression analysis was applied to determine whether an independent association between MSFsc and HbA1c level existed. After adjusting for age, sex, alcohol use, body mass index (BMI), social jetlag, sleep duration, sleep quality and sleep apnea risk, later MSFsc was significantly associated with higher HbA1c level (B = 0.019, 95% CI: 0.00001, 0.038, p = 0.049). The effect size of one hour later MSFsc on HbA1c (standardized coefficient = 0.065) was approximately 74% of that of the effect of one unit (kg/m²) increase in BMI (standardized coefficient = 0.087). In summary, later chronotype is associated with higher HbA1c levels in patients with prediabetes, independent of social jetlag and other sleep disturbances. Further research regarding the potential role of chronotype in diabetes prevention should be explored.