title: Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis.
abstract: 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-alpha (TNFalpha). We conclude that inadequate 1alpha-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 TNFalpha. The low 1,25-(OH)2D and high TNFalpha 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.
authors.affiliation: Medical Department A, and Research Institute for Internal Medicine, University of Oslo, Norway.
authors.forename: C J
authors.initials: CJ
authors.lastname: Haug
authors.forename: P
authors.initials: P
authors.lastname: Aukrust
authors.forename: E
authors.initials: E
authors.lastname: Haug
authors.forename: L
authors.initials: L
authors.lastname: Mørkrid
authors.forename: F
authors.initials: F
authors.lastname: Müller
authors.forename: S S
authors.initials: SS
authors.lastname: Frøland
mesh_terms: D000293:Adolescent; D000328:Adult; D002116:Calcitonin / Q000097:blood; D002117:Calcitriol / Q000172:deficiency*; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D003967:Diarrhea / Q000503:physiopathology; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000503:physiopathology*; D006706:Homeostasis; D006801:Humans; D018655:Lymphocyte Count; D008286:Malabsorption Syndromes / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood; D014807:Vitamin D / Q000378:metabolism; D015431:Weight Loss
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D014807:Vitamin D; D002116:Calcitonin; D002117:Calcitriol; D002118:Calcium