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Severe Deficiency of 1,25-Dihydroxyvitamin D₃ in Human Immunodeficiency Virus Infection: Association with Immunological Hyperactivity and Only Minor Changes in Calcium Homeostasis

Section of Clinical Immunology and Infectious Diseases, Medical Department A, and Research Institute for Internal Medicine, University of Oslo (C.J.H., P.A., F.M., S.S.F.), and the Department of Clinical Chemistry (L.M.), The National Hospital-Rikshospitalet; and the Hormone Laboratory, Aker University Hospital (E.H.), Oslo, Norway

Address all correspondence and requests for reprints to: Pl Aukrust, M.D., Ph.D., Research Institute for Internal Medicine, The National Hospital-Rikshospitalet, N-0027 Oslo, Norway. E-mail: pal.aukrust{at}klinmed.uio.no

The serum level of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D], the biologically most potent metabolite of vitamin D, is tightly regulated within narrow limits in human healthy adults. 1,25-(OH)₂D 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)₂D in human immunodeficiency virus (HIV)-infected patients. The present study was designed to further examine the causes and consequences of severe 1,25-(OH)₂D 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)₂D 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)₂D. There were no differences in serum calcium or PTH levels or nutritional status when patients with severe 1,25-(OH)₂D deficiency were compared to other patients, but patients with undetectable 1,25-(OH)₂D had significantly elevated serum phosphate levels. Furthermore, patients with undetectable 1,25-(OH)₂D levels were characterized by advanced clinical HIV infection, low CD4⁺ lymphocyte counts, and high serum levels of tumor necrosis factor- (TNF).

We conclude that inadequate 1-hydroxylation of 25-hydroxyvitamin D seems to be the most likely cause of 1,25-(OH)₂D deficiency in HIV-infected patients, possibly induced by an inhibitory effect of TNF. The low 1,25-(OH)₂D and high TNF 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)₂D 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)₂D deficiency in human disease, but may also reflect the importance of adequate serum levels of 1,25-(OH)₂D for satisfactory performance of the immune system in man.

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