Abstract
Background: Ornithine transcarbamylase deficiency (OTCD) is most popular among urea cycle disorders (UCDs), defined by the loss of function in any of the enzymes associated with ureagenesis. Corticosteroid administration to UCD patients, including OTCD patients, is well known to induce life-threatening hyperammonemia. The mechanism has been considered nitrogen overload due to the catabolic effect of corticosteroids; however, the pathophysiological process is unclear. We evaluated the effects of corticosteroids on urea cycle enzyme expressions and urea cycle-associated metabolites in OTC-deficient mice.Methods: The clinical courses of two adult-onset OTCD patients were presented. To elucidate the mechanism of hyperammonemia induced by corticosteroid administration in OTCD patients, we developed a mouse model by administering corticosteroids to OTCspf-ash mice deficient in the OTC gene. Dexamethasone (DEX; 20 mg/kg) was administered to the OTCspf-ash and wild-type (WT) mice at 0 and 24 h, and the serum ammonia concentrations, the levels of the hepatic metabolites, and the gene expressions of urea-cycle-related genes were analyzed.Results: Two adult-onset OTCD patients received multimodal treatment, including dialysis, and recovered completely from severe hyperammonemia. The ammonia levels in Otcspf-ash mice that were administered DEX tended to increase at 24 h and increased significantly at 48 h. The metabolomic analysis showed that the levels of citrulline, arginine, and ornithine did not differ significantly between Otcspf-ash mice that were administered DEX and normal saline; however, the level of aspartate was increased drastically in Otcspf-ash mice owing to DEX administration (P < 0.01). Among the enzymes associated with the urea cycle, mRNA expressions of carbamoyl-phosphate synthase 1, ornithine transcarbamylase, arginosuccinate synthase 1, and arginosuccinate lyase were significantly downregulated by DEX administration in both the Otcspf-ash and WT mice (P < 0.01).Conclusions: We elucidated that corticosteroid administration induced hyperammonemia in Otcspf-ash mice by suppressing urea-cycle-related gene expressions as early as 24 h. Since the urea cycle intermediate amino acids, such as arginine, might not be effective because of the suppressed expression of urea-cycle-related genes by corticosteroid administration, we should consider an early intervention by renal replacement therapy in cases of UCD patients induced by corticosteroids to avoid brain injuries or fatal outcomes.
Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium
