Introduction. The prevalence of metabolic disease is increased in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), however, there is limited knowledge regarding the mechanisms through which it occurs.
Aim and objectives: (1) Explore the health status of CAH juvenile patients, insisting on early signs of metabolic disease; (2) Assess the metabolic phenotype and transcriptomic analysis of a 21-hydroxylase deficient zebrafish model; (3) Compare the clinical and zebrafish data to identify evolutionarily conserved and distinct aspects of the molecular mechanisms underlying the pathophysiology of CAH.
Methodology. Clinical and biological data from a UK-wide multicentre study involving 107 children with 21OHD were analysed. The phenotype and transcriptome of cyp21a2-/- zebrafish mutants were compared to wild-type siblings.
Results. There was increased weight gain in CAH patients compared to controls, a small number of patients also having abnormal lipid profiles. Leptin, adiponectin and lipid metabolites correlated with the glucocorticoid dose, body mass index, Homeostatic Model Assessment for Insulin Resistance and plasma androgens. Adult cyp21a2-/- zebrafish mutants were larger, with more body fat compared to controls. Differential gene expression and overrepresentation analysis of gene ontology (GO) terms showed significant dysregulation of several metabolic processes in larvae and adult livers, with marked downregulation of genes involved in mitochondrial oxidative phosphorylation and energy homeostasis.
Conclusions. In CAH, metabolic comorbidities develop as a combined effect of GC replacement and GC deficiency. Although frank metabolic disease is rare in children with CAH, subtle changes are already present in the blood metabolites and may serve as early markers of metabolic risk. Insights from cyp21a2-/- zebrafish complete the clinical findings, indicating that cortisol deficiency has complex metabolic effects, likely centred around the suppression of ATP synthesis and energy homeostasis. Better treatment and monitoring strategies are needed in CAH, targeting the development of metabolic disease at an early stage.
