Oral β-Hydroxybutyrate Supplementation in Two Patients with Hyperinsulinemic Hypoglycemia: Monitoring of β-Hydroxybutyrate Levels in Blood and Cerebrospinal Fluid, and in the Brain by In Vivo Magnetic Resonance Spectroscopy

In persistent hyperinsulinemic hypoglycemia of infancy, ketone body concentrations are abnormally low at times of hypoglycemia, depriving the brain of its most important alternative fuel. The neuroprotective effect of endogenous ketone bodies is evidenced by animal and human studies, but knowledge about exogenous supply is limited. Assuming that exogenous ketone body compounds as a dietetic food might replace this alternative energy source for the brain, we have monitored the fate of orally supplemented dl sodium β-hydroxybutyrate (β-OHB) in two 6-mo-old infants with persistent hyperinsulinemic hypoglycemia for 5 and 7 mo, while on frequent tube-feedings and treatment with octreotide. Near total (95%) pancreatectomy had been ineffective in one patient and was refused in the other. In blood, concentrations of β-OHB increased to levels comparable to a 16- to 24-h fast while on dl sodium β-OHB 880 to 1000 mg/kg per day. In cerebrospinal fluid, concentrations of β-OHB increased to levels comparable to a 24- to 40-h fast, after single dosages of 4 and 8 g, respectively. High ratios of β-OHB to acetoacetate indicated exogenous origin of β-OHB. An increase of intracerebral concentrations of β-OHB could be demonstrated by repetitive single-voxel proton magnetic resonance spectroscopy by a clear doublet at 1.25 ppm. Oral dl sodium β-OHB was tolerated without side effects. This first report on oral supplementation of dl sodium β-OHB in two patients with persistent hyperinsulinemic hypoglycemia demonstrates effective uptake across the blood–brain barrier and could provide the basis for further evaluation of the neuroprotective effect of β-OHB in conditions with hypoketotic hypoglycemia.