SEVERE DEFICIENCY OF 1,25-DIHYDROXYVITAMIN D-3 IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - ASSOCIATION WITH IMMUNOLOGICAL HYPERACTIVITY ANDONLY MINOR CHANGES IN CALCIUM HOMEOSTASIS

The serum level of 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D], the biol ogically most potent metabolite of vitamin D, is tightly regulated wit hin narrow limits in human healthy adults. 1,25-(OH)(2)D deficiency is rare and is associated with disturbances in calcium and bone metaboli sm. We have previously reported a marked decrease in serum levels of 1 ,25-(OH)(2)D in human immunodeficiency virus (HIV)infected patients. T he present study was designed to further examine the causes and conseq uences of severe 1,25-(OH)(2)D deficiency in these patients. The desig n was a prospective cohort study. Fifty-four HIV-infected patients cli nically classified according to the revised criteria from Centers for Disease Control and Prevention and healthy controls were studied. Para meters related to vitamin D and calcium metabolism as well as immunolo gical and nutritional status were determined. Twenty-nine of the patie nts (54%) had serum levels of 1,25-(OH)(2)D below the lower reference limit, and 18 of these had undetectable levels. In contrast, HIV-infec ted patients had normal serum levels of 25-hydroxyvitamin D and vitami n D-binding protein. HIV-infected patients as a group had modestly dep ressed serum calcium and PTH levels. There were, however, no correlati ons between these parameters and serum levels of 1,25-(OH)(2)D. There were no differences in serum calcium or PTH levels or nutritional stat us when patients with severe 1,25-(OH)(2)D deficiency were compared to other patients, but patients with undetectable 1,25-(OH)(2)D had sign ificantly elevated serum phosphate levels. Furthermore, patients with undetectable 1,25-(OH)(2)D levels were characterized by advanced clini cal HIV infection, low CD4(+) lymphocyte counts, and high serum levels of tumor necrosis factor-alpha (TNF alpha).We conclude that inadequat e 1 alpha-hydroxylation of 25-hydroxyvitamin D seems to be the most li kely cause of 1,25-(OH)(2)D deficiency in HIV-infected patients, possi bly induced by an inhibitory effect of TNF alpha. The low 1,25-(OH)(2) D and high TNF alpha levels observed may impair the immune response in HIV-infected patients both independently and in combination and may r epresent an important feature of the pathogenesis of HIV-related immun odeficiency. Markedly depressed 1,25-(OH)(2)D serum levels are also pr esent in certain other disorders characterized by immunological hypera ctivity. Thus, the findings in the present study may not only represen t a previously unrecognized immune-mediated mechanism for induction of 1,25-(OH)(2)D deficiency in human disease, but may also reflect the i mportance of adequate serum levels of 1,25-(OH)(2)D for satisfactory p erformance of the immune system in man.