Diagnosis of Dysregulated Vitamin D Metabolism Chronic inflammation is associated with a range of unhealthy aging phenotypes and a decreased likelihood of successful aging. [1] For example, Phillips et al. [2] found that individuals who were metabolically healthy had lower serum levels of inflammatory markers compared with their non-metabolically healthy counterparts. Assessing vitamin D metabolites and diagnosing dysregulated vitamin D metabolism has the potential to guide clinical practice. Vitamin D status is currently determined by measuring the level of 25(OH)D which, presumably, reflects the levels of other vitamin D metabolites (e.g., vitamin D3, vitamin D2 and 1,25(OH)2D, etc.). This measurement may not, however, provide enough information to assess vitamin D endocrine function. Although 25(OH)D is the major circulating metabolite of vitamin D and the form most often assessed clinically, it is the active 1,25-dihydroxylated form of the hormone that is responsible for its biological effects. The clinical utility of measuring 1,25(OH)D is not fully understood, but it is clear that associations are being made between this active metabolite of vitamin D and disease states.[3, 4] Measurement of both the active metabolite and its precursor is essential to diagnose dysregulated vitamin D metabolism; assays of 1,25(OH)2D and 25(OH)D provide valuable tools to assess inflammation in chronically ill patients. [5] Vitamin D status encompasses more than vitamin D intake; 1,25(OH)2D formation isn't directly regulated by parental vitamin D and it may be affected by the same factors that cause a decrease in serum 25(OH)D.
Currently, 1,25(OH)2D is not being used as a measure associated with vitamin D nutritional status or as an intermediate marker related to health outcomes, or even routinely assessed in vitamin D research. In the context of solving the puzzle of vitamin D deficiency, the reasons cited for this lapse fail to consider the possibility of abnormal levels in the presence of chronic inflammation: - 1,25(OH)2D has a short half-life (hours) and fluctuates rapidly.
However, a high result may be discovered even at trough level. - 1,25(OH)2D levels are regulated by PTH, calcium, phosphate.
This isn't true in chronic illness when extra-renal production is prevalent. - 1,25(OH)2D doesn't decrease until 25(OH)D is very low.
Low 25(OH)D may be a sign that 1,25(OH)2D is abnormally high. - 1,25(OH)2D is only over-produced in hypercalcemic disease states such as sarcoidosis.
Studies show this isn't true. [6] - 1,25(OH)2D may be elevated as a result of up-regulation of the CYP27B1 enzyme. This begs the question "Why is this enzyme elevated?"
Measuring both 25(OH)D and 1,25(OH)2D (also PTH, calcium, and phosphate when indicated) as clinical markers in chronic disease is more likely to provide a true picture of vitamin D status, than measuring 25(OH)D alone. [7] Consider assessing 1,25(OH)2D in patients with low 25(OH)D, abnormal lab results (especially inflammatory markers), a diagnosis of autoimmune disease or other chronic inflammatory illness, or signs of chronic systemic inflammation. For example, elevated 1,25(OH)2D is observed in Crohn's disease. [8] Each vitamin D metabolite test has specific parameters that must be followed to ensure accurate results. D-metabolites Tests
Serum 25(OH)D
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- CPT code: 82306
- Performed at most labs
- No special handling needed
- Lowest mortality reported at 20 ng/ml
- Immunosuppression reported when higher than 30 ng/ml
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Serum 1,25(OH)2D
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- CPT code: 82652
- ICD-9 codes:
- 275.40 Disorder of calcium metabolism, unspecified
- 733.00 Osteoporosis, unspecified
- 733.90 Osteopenia
- 780.9 Fatigue
- A specialized lab is required
- Special handling of the sample is necessary- freeze for transport to avoid degradation due to agitation
- A low result may be inaccurate due to sample mishandling
- A high result is always accurate
- Maximum normal = 45 pg/ml
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In written correspondence (2013), vitamin D researcher Martin Hewison (Professor in Residence at the David Geffen School of Medicine UCLA), stated, "I agree that 1,25(OH)2D is a forgotten component of the vitamin D and human health story - I think measurement of serum 1,25(OH)2D will be more common as LC:MS techniques improve." References - Akbaraly TN, Hamer M, Ferrie JE, et al. Chronic inflammation as a determinant of future aging phenotypes. CMAJ. Sep 2013.
- Phillips CM, Perry IJ. Does Inflammation Determine Metabolic Health Status in Obese and Nonobese Adults? J Clin Endocrinol Metab. Oct 2013(98(10)):E1610-E1619.
- Strathmann FG, Laha TJ, Hoofnagle AN. Quantification of 1α,25 Dihydroxy Vitamin D by Immunoextraction and Liquid Chromatography-Tandem Mass Spectrometry. Clin Chem. Jul 2011;57(9):1279-1285.
- Antonoglou G, Knuuttila M, Niemel� O, et al. Serum 1,25(OH)D Level Increases After Elimination of Periodontal Inflammation in T1DM Subjects. J Clin Endocrinol Metab. Oct 2013(98(10):):3999-4005.
- Hollis B. Detection of vitamin D and its major metabolites. In: Feldman D, Pike JW, Glorieux F, eds. Vitamin D. San Diego: Elsevier Academic Press; 2005.
- Blaney GP, Albert PJ, Proal AD. Vitamin D metabolites as clinical markers in autoimmune and chronic disease. Ann N Y Acad Sci. Sep 209;1173:384-90.
- Perez T. Bacteria induced vitamin D receptor dysfunction in autoimmune disease; theoretical and practical implication for interpretation of serum vitamin D metabolite levels. Paper presented at: 6th International Congress on Autoimmunity, 2006; Porto, Portugal.
- Abreu MT, Kantorovich V, Vasiliauskas EA, et al. Measurement of vitamin D levels in inflammatory bowel disease patients reveals a subset of Crohn's disease patients with elevated 1,25-dihydroxyvitamin D and low bone mineral density. Gut. Aug 2004;53(8):1129-36.
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