The Effect of Overweight and Obesity on Liver Biochemical Markers in Children and Adolescents

Magnus J. Johansen; Julie Gade; Stefan Stender; Christine Frithioff-Bøjsøe; Morten A. V. Lund; Elizaveta Chabanova; Henrik S. Thomsen; Oluf Pedersen; Cilius E. Fonvig; Torben Hansen; Jens-Christian Holm

Disclosures

J Clin Endocrinol Metab. 2020;105(2) 

In This Article

Discussion

This study provides age- and sex-specific reference values for plasma concentrations of ALT, AST, LDH, GGT, bilirubin, and ALP from a large population-based cohort of children and adolescents aged from 6 to 18 years. In comparison, children and adolescents with overweight or obesity exhibited higher concentrations of ALT in all age groups, even among the youngest children younger than 10 years of age. The increase was most pronounced in boys older than 13 years of age.

Previous studies have reported pediatric reference values for some of the liver biochemical markers analyzed in this study. Bussler et al.[36] provided age- and sex-specific percentile curves for ALT, AST, and GGT in a cohort of 3131 healthy and normal weight German girls and boys aged 11 months to 16 years. Overall, the percentile curves for ALT, AST, and GGT in the German study were similar to those observed in the population-based cohort in the present study. For example, the median ALT concentration was approximately 20 U/L in boys and girls older than 6 years of age in both studies. The upper limit of normal ALT, defined as the 97th percentile, ranged from 24 U/L to 32 U/L in girls, and from 30 U/L to 38 U/L in boys in the study by Bussler et al..[36] These data are overall comparable with the 97.5th percentiles reported in the present study. Li et al.[37] found that concentrations of ALT and AST declined with age among 1394 healthy children from China aged 2 to 14 years, in agreement with the patterns observed in the present study and others.[21,36] The concentrations of ALP decline during childhood, increase during puberty, and decrease again after puberty, reflecting changes in bone growth during childhood and puberty.[21,36,38] The patterns observed for ALP concentrations in the present study are similar to those reported in previous studies.[38,39]

Percentile curves for biochemical markers of liver damage have not previously been reported from a large cohort of children with overweight or obesity. However, several studies have reported that children with obesity have increased biochemical markers of liver damage.[36–39] In agreement with these previous studies, we found that children and adolescents with overweight or obesity had elevated concentrations of ALT, the most liver-specific of the biochemical markers assessed in the present study. The other biochemical markers of liver damage were less influenced by adiposity in our study.

The increased plasma concentrations of ALT in girls and boys with overweight or obesity might reflect the presence of NAFLD or nonalcoholic steatohepatitis in many of these children. We found increased BMI-SDS to be associated with higher ALT in children with overweight and obesity, and among boys (but not girls) from the population-based cohort, observations that are consistent with the well-established causal link between obesity and NAFLD. The age-related increase in ALT in the cohort with overweight and obesity was more pronounced in boys than in girls. It is possible that hormonal (eg, testosterone) or behavioral (eg, alcohol intake) changes in boys explains the age-associated increase in ALT concentrations, and that these effects are amplified by overweight and obesity in the oldest age group of the boys.[40] Another explanation could be that boys with overweight or obesity tend to accumulate more visceral fat compared with girls with overweight or obesity, who are more prone to store excess fat subcutaneously.[41] Visceral fat is a stronger risk factor for the development of NAFLD than is subcutaneous fat.[42]

Hepatic steatosis defined by a liver fat content of >5% was confirmed by 1H-MRS in 9.9% of the girls and in 21% of the boys with available measurements. These prevalences are lower than those reported in a recent study of 408 children with obesity and liver fat content assessed by 1H-MRS (22.6 % for girls and 29.4 % for boys).[34] The lower prevalence in our study is likely the result of having included children with normal weight in the sub-cohort. We found that cutoff values of 24.5 U/L and 34.5 U/L in girls and boys, respectively, were optimal for classifying hepatic steatosis. These cutoff values were lower than those reported by Yu et al.[34] (30 U/L in girls and 42 U/L in boys), but nevertheless yielded comparable AUC (0.79 and 0.72 in boys and girls, respectively, in our study versus 0.81 and 0.75 in Yu et al.[34]). The differences in optimal cutoffs are likely owing to differences in cohort characteristics.

There are several limitations to our study that should be considered. We did not screen for viral infections that might affect liver enzyme levels, such as hepatitis C. However, the prevalence of hepatitis C is less than 0.4% in the Danish general population.[23] Alcohol consumption was self-reported, which is likely to suffer from some degree of misreporting. Another limitation is that we did not quantify liver fat content on all the participants. It is therefore possible that some children in the population-based cohort had asymptomatic fatty liver disease affecting their liver enzyme concentration. The modest number of participants in some of the 1-year age strata is another potential limitation. The percentile values for groups with less than 40 individuals (eg, boys and girls with overweight or obesity aged 16–18) should therefore be interpreted with caution.

Blood samples were drawn within 30 days of the 1H-MRS, but not necessarily on the same day as the 1H-MRS was performed. Thus, concentrations of liver biochemical markers might have changed for some of the participants in the 30 day timeframe from blood sampling to the 1H-MRS assessment. Finally, even though the biochemical markers examined here are commonly used to evaluate liver damage, some of them are not entirely liver specific. For example, elevated AST may reflect muscle, heart, or pancreas injury, and LDH is also a marker of hemolysis and tissue breakdown in general.

Our study also has certain strengths that should be noted. The population-based cohort was based on a large, homogeneous cohort of children, and the sample size of our cohort is comparable with, or larger than, previous studies aimed at establishing pediatric reference values. We were also able to exclude individuals with diseases or intake of medication known to influence plasma liver enzymes. Furthermore, we accounted for alcohol intake by excluding individuals who consumed more than 60 g of alcohol per week. Other strengths are that blood samples were collected in a standardized manner and analyzed in the same laboratory, minimizing inter-individual variation caused by nonbiological factors.

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