Adrenal cortical function in homozygous familial hypercholesterolemia

The biosynthesis of adrenal corticosteroids requires a supply of cholesterol that can be derived from both local synthesis and uptake of plasma lipoproteins. Recent studies have provided evidence that receptor-mediated uptake of low density lipoproteins provides an important source of cholesterol for corticosteroid synthesis by human adrenocortical cells that are grown in tissue culture. In the present study we have examined parameters of adrenocortical function in three patients with homozygous familial hypercholesterolemia (two receptor negative, one receptor defective) to assess whether a decreased number of LDL receptors, measured in vitro, influences in vivo corticosteroid production under basal conditions and in response to prolonged stimulation with ACTH. Basal adrenocortical function (assessed by the serum concentrations of cortisol and ACTH plus urinary excretion of 17 OHCS, 17 KS, and urine-free cortisol) was normal in all three patients. Stimulation with intravenous ACTH resulted in rapid increases in the serum concentrations of cortisol in all patients. Plateau concentrations of cortisol during prolonged ACTH stimulation were lower in the two receptor-negative patients (36 to 41 μg/dl) but all subjects had at least a threefold increase over basal values. Excretion of urine-free cortisol was reduced in both receptor-negative patients (33% to 36% of controls); this was paralleled by decreased excretion of 17 KS in both patients and of 17 OHCS in one patient. Urine-free cortisol excretion was reduced in the receptor-defective patient (57% of controls), but excretion of 17 OHCS and 17 KS was not. The results suggest that patients with homozygous familial hypercholesterolemia have a mild impairment in delivery of cholesterol to the adrenal cortex during maximal stimulation of corticosteroid production but that the disease does not impair corticosteroid synthesis in the basal state.