The serum level of 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D], the biologically most potent metabolite of vitamin D, is tightly regulated within narrow limits in human healthy adults. 1,25-(OH)(2)D deficiency is rare and is associated with disturbances in calcium and bone metabolism. We have previously reported a marked decrease in serum levels of 1,25-(OH)(2)D in human immunodeficiency virus (HIV)infected patients. The present study was designed to further examine the causes and consequences of severe 1,25-(OH)(2)D deficiency in these patients. The design was a prospective cohort study. Fifty-four HIV-infected patients clinically classified according to the revised criteria from Centers for Disease Control and Prevention and healthy controls were studied. Parameters related to vitamin D and calcium metabolism as well as immunological and nutritional status were determined. Twenty-nine of the patients (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-infected patients had normal serum levels of 25-hydroxyvitamin D and vitamin D-binding protein. HIV-infected patients as a group had modestly depressed serum calcium and PTH levels. There were, however, no correlations between these parameters and serum levels of 1,25-(OH)(2)D. There were no differences in serum calcium or PTH levels or nutritional status 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 significantly elevated serum phosphate levels. Furthermore, patients with undetectable 1,25-(OH)(2)D levels were characterized by advanced clinical HIV infection, low CD4(+) lymphocyte counts, and high serum levels of tumor necrosis factor-alpha (TNF alpha). We conclude that inadequate 1 alpha-hydroxylation of 25-hydroxyvitamin D seems to be the most likely cause of 1,25-(OH)(2)D deficiency in HIV-infected patients, possibly 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 represent an important feature of the pathogenesis of HIV-related immunodeficiency. Markedly depressed 1,25-(OH)(2)D serum levels are also present in certain other disorders characterized by immunological hyperactivity. Thus, the findings in the present study may not only represent a previously unrecognized immune-mediated mechanism for induction of 1,25-(OH)(2)D deficiency in human disease, but may also reflect the importance of adequate serum levels of 1,25-(OH)(2)D for satisfactory performance of the immune system in man.
