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Highlights & Basics
- Vitamin D deficiency is the most common nutritional deficiency worldwide. Definitions regarding optimal serum concentrations vary according to the source used. However, there is broad clinical consensus that serum 25-hydroxyvitamin D concentrations <20 nanograms/mL are suboptimal for human health. Furthermore, many guidelines and experts recommend maintaining a serum 25-hydroxyvitamin D concentration >30 nanograms/mL, particularly in older adults.
- Main causes include sun avoidance, increased skin pigmentation, inadequate dietary and supplemental vitamin D intake, malabsorption syndromes, obesity, and use of certain drugs. Acquired and inherited disorders that either reduce or prevent the metabolism of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D also present with biochemical and skeletal abnormalities seen with vitamin D deficiency, but in a more severe form.
- Most patients are asymptomatic. Severe prolonged vitamin D deficiency causes decreased growth and rickets in children, and osteomalacia, osteopenia, and osteoporosis in adults.
- In addition to the skeletal effects, it is now increasingly recognized that vitamin D deficiency is associated with an increased risk of many chronic diseases, including cancer, autoimmune diseases, type 2 diabetes, heart disease and hypertension, neurocognitive dysfunction, infectious diseases (including respiratory tract infections, tuberculosis, and COVID-19), and schizophrenia. Vitamin D deficiency/insufficiency has been associated with increased risk for morbidity and mortality associated with COVID-19.
- Both vitamin D deficiency and vitamin D insufficiency are corrected by giving vitamin D2 or vitamin D3 in treatment doses followed by lifelong maintenance doses. Additional replacement with 1,25-dihydroxyvitamin D or one of its active analogs is necessary for those with disorders of vitamin D metabolism, including patients with chronic kidney disease.
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Production, metabolism, and biologic functions of vitamin D on calcium metabolism and bone health (D represents D2 and D3). Abbreviations: CaBP, calbindin; ECaC, epithelial calcium channel; FGF-23, fibroblast growth factor 23; preD3, previtamin D3; RANKL, receptor activator of nuclear factor-kappaB ligand; 1,25(OH)2D, 1,25-dihydroxyvitamin D; 1-OHase, 25-hydroxyvitamin-1-hydroxylase; 7-DHC, 7-dehydrocholesterol; 24-OHase, 1,25-dihydroxyvitamin D-24-hydroxylase; 25-OHase, vitamin D-25-hydroxylase; 25(OH)D, 25-hydroxyvitamin D
Chemical structure of vitamin D
Differential effects of various disorders of calcium, phosphate, bone, and vitamin D metabolism on serum levels of calcium, phosphate, and 1,25-dihydroxyvitamin D. Abbreviations: ADHR, autosomal-dominant hypophosphatemic rickets; FGF-23, fibroblast growth factor 23; HRBP, heterologous ribonuclear binding protein; VDR, vitamin D-resistant; XLHR, X-linked hypophosphatemic rickets, TIO, tumor-induced osteomalacia; 1-OHase, 25-hydroxyvitamin-1-hydroxylase
Bone biopsy of trabecular bone demonstrating (A) increased osteoclastic activity due to secondary hyperparathyroidism; (B) normal; and (C) wide osteoid seams (light-pink area), which are classic for osteomalacia
Extrarenal production of 1,25-dihydroxyvitamin D to modulate immune function, cell growth, and insulin production. Abbreviations: AB, activated B lymphocyte; AT, activated T lymphocyte; BS, blood sugar; CD, cathelicidin; LPS, lipopolysaccharide; TLR, toll-like receptor; VDR-RXR, vitamin D receptor-retinoid X receptor; 1,25(OH)2D, 1,25-dihydroxyvitamin D; 1-OHase, 25-hydroxyvitamin-1-hydroxylase; 24-OHase, 1,25-dihydroxyvitamin D-24-hydroxylase; 25(OH)D, 25-hydroxyvitamin D
Schematic representation of paracrine and intracrine function of vitamin D and its metabolites and actions of 1,25-dihydroxyvitamin D on the innate and adaptive immune systems. Abbreviation: 1,25(OH)2D: 1,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D, IFN-Ƴ: interferon- Ƴ; IL: interleukin; MHC: membrane histocompatibility complex, TH1: T helper 1; TH2: T helper 2; TH17: T helper 17; Treg: regulatory T cell, TNF-alpha: Tumor necrosis factor- alpha; TLR2: toll-like receptor 2; TLR4: toll-like receptor 4
Sources of vitamin D
Inward or outward bowing of the legs is a typical sign of classic rickets
X-rays of a wrist from a child with vitamin D-deficiency rickets before (left panel) and after (right panel) treatment with vitamin D
Radiograph of the femoral shaft in a patient with osteomalacia demonstrating a "pseudofracture" (also known as Looser's zone) on the medial aspect of the mid-femoral shaft
Citations
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Munns CF, Shaw N, Kiely M, et al. Global consensus recommendations on prevention and management of nutritional rickets. J Clin Endocrinol Metab. 2016 Feb;101(2):394-415.[Abstract][Full Text]
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