Main endocrine modulators of vitamin D hydroxylases in human pathophysiology

Vitamin D is considered to be devoid of direct biological activity. It must be first hydroxylated in the liver by a 25-hydroxylase (25OHase), then in the kidney by a 1 alpha-hydroxylase (1 alpha OHase) which is responsible for the synthesis of the active metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D). The activity of 1 alpha OHase is known to be under the control of a series of endocrine modulators, particularly parathyroid hormone (PTH) and estrogens. We report here our studies in humans concerning the behaviour of vitamin D hydroxylases in some pathological conditions. In chronic liver disease no severe impairment of vitamin D-25-hydroxylation has been observed, except in the latest stages: this is probably due to the great functional reserve of the liver, so that normal levels of serum 25OHD can be maintained on condition that the vitamin D supply is adequate. 1 alpha OHase is impaired in chronic renal failure due to the decrease in the number of functioning nephrons. It has been demonstrated that kidney transplantation restores normal 1,25(OH)2D levels. A decrease in 1,25(OH)2D production due to reduced PTH stimulation has been observed in hypoparathyroidism: in these patients a subcutaneous substitution therapy with synthetic human parathyroid hormone resulted in restoration of normal 1,25(OH)2D levels. A reduced activity of 1 alpha OHase due to reduced estrogen stimulation plays a key role in postmenopausal osteoporosis. In these patients estrogens increase 1,25(OH)2D levels, as it has been demonstrated directly and indirectly. In the aforementioned pathological conditions an impairment of calcium absorption has been observed; it was directly related to the reduced production of 1,25(OH)2D. Treatment with 1,25(OH)2D3 was effective in restoring normal calcium absorption. In postmenopausal osteoporosis the reduced levels of 1,25(OH)2D were accompanied by serum levels of 25-hydroxyvitamin D (25OHD) higher than in age-matched control women. In these cases long-term treatment with physiological doses of 1,25(OH)2D3 resulted in a progressive decrease in 25OHD serum levels which approached to the normal range. These findings are likely to be related one to another: the low 1,25(OH)2D levels are responsible for reduced product-inhibition of 25OHase, so that the synthesis of 25OHD increases. A similar mechanism occurs in renal failure and in hypoparathyroidism.