Vitamin D

 
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Physiology

Vitamin D is obtained primarily from dietary sources in animals. Vitamin D is mostly thought of with respect to calcium and phosphate status, however many cells contain vitamin D receptors and vitamin D is needed for general metabolic and immune processes. There are several forms of vitamin D, including calcidiol (produced in the liver) and calcitriol (produced in the kidney with the aid of the enzyme α1-hydroxylase (lacking in horses). Calcitriol is a far more active form of vitamin D than calcidiol. Vitamin D binds to a vitamin D receptor, which then influences cellular processes via altering gene transcription. For more information on the forms of vitamin D, refer to the mineral overview page. Vitamin D production is influenced by PTH, ionized calcium and phosphate concentrations and vitamin D itself, which inhibits its own production.

Increased production
  • ↑ PTH (stimulates α1 hydroxylase)
  • ↓ ionized calcium
  • ↓ phosphate
Decreased production
  • Calcidiol (inhibits α1 hydroxylase)
  • ↑ ionized calcium
  • ↑ phosphate
 

The main sites of action for calcium and phosphate metabolism of vitamin D are:

Site of action Effect
Intestine (main site)
  • ↑ calcium and phosphate absorptionby increasing calbindins (calcium binding proteins) in intestinal epithelial cells: Will ↑ ionized calcium and phosphate concentrations
Kidney
  • Promotes calcium absorption in distal convoluted tubule via increasing calbindins: Will ↑ ionized calcium concentration.
Bone
  • Facilitates the action of PTH on osteoblasts (promotes osteolysis through osteoclastogenic factors released by osteoblasts): Will increase ↑ ionized calcium and phosphate concentrations
  • Stimulates RANKL production from osteoblasts or stromal cells. Binds to RANK on osteoclasts, promoting osteolysis.
  • Inhibits PTH secretion when ionized calcium concentrations are normal.
 

Methods

Assays for vitamin D3 and its metabolites are available (e.g. Michigan State University Diagnostic Center) and encompass radioimmunoassays, chemiluminescence immunoassays, and liquid chromatography with tandem mass spectrophotometry (gold standard). The most commonly measured form is calciodiol, which does limit interpretation of the influence of vitamin D metabolites on calcium and phosphate concentrations.

Sample considerations

For calcidiol, serum is recommended, whereas plasma (heparn or EDTA) can be used for measurement of calcidiol.

Non-disease effects

  • Age: Concentrations of calcitriol were higher in kittens at 3 and 6 months of age compared to cats of 9, 12 and 15 months of age (mean values decreased over time after 6 months of age. In contrast, calcidiol concentrations were lowest in 3 month old kittens (Pineda et al 2013).
  • Season: Because vitamin D concentrations are influenced by ultraviolet light, values may be affected by season. A study in camelids showed seasonal variation in vitamin D levels in neonates, yearlings and adults, with highest values for vitamin D in the summer and fall months (July to November). Since vitamin D affects (increases) calcium and phosphate concentrations, this could have an effect on results for these minerals, however, there was little effect apparent in adult or yearling animals. Phosphate was influenced more by age than vitamin D concentrations in neonates (Smith and Van Saun, 2001).

Disease

A 2017 review summarized current knowledge of vitamin D status in various disease in dogs and cats (Parker et al 2017). The most common reason for measuring vitamin D is for the diagnostic work up of high or low ionized calcium concentrations. Because there is a wide range of vitamin D metabolite concentrations in healthy animals, which is likely a consequence of diet (Sharp et al 2015), results should be ideally interpreted with respect to calcium concentrations. However, with links between low vitamin D status and mortality, there is increasing interest in vitamin D concentrations in various diseases, including inflammation, cancer and organ disease (Parker et al 2017). Most studies measure calcidiol and do not take into account renal conversion of vitamin D to its most active form. Therefore, low calcidiol concentrations should be interpreted with caution (particularly due to the wide range of normal values and overlap with experimental controls) and may not mean low vitamin D status, but could reflect increased conversion to the most active form, calcitriol). As for all clinical pathologic tests, altered values could be due to changes in input (diet, absorption, UV light), metabolism in the body (liver production of calcidiol, renal production of calcitriol, production or loss of vitamin D binding proteins), and output (loss of vitamin D or binding proteins in urine, increased inactivation to 24,25 dihydroxycholecalciferol).

Excess vitamin D

Excess vitamin D is expected to result in high ionized calcium and phosphate concentrations. This can result in dystrophic mineralization in organs (e.g. intestine, kidney) with attending consequences (gastric ulceration, chronic renal disease). Excess vitamin D is caused mostly by intoxication with vitamin D-containing compounds, including rodenticides and anti-psoriasis creams (Hilbe et al 2000, Murphy 2002). Excretion of vitamin D by macrophages (which contain the α1-hydroxylase enzyme) has been postulated to be the mechanism behind hypercalcemia in dogs with granulomatous disease (Mellanby et al 2006) and some dogs with lymphoma (Rosol et al 1992Gerber et al 2004).

Deficient vitamin D

Low concentrations of vitamin D occur in various diseases and is mediated through several mechanisms as outlined below:
  • Dietary deficiency: A deficiency of vitamin D in the diet can result in rickets (Chesney and Hedberg 2010, Dittmer and Thompson 2011), skeletal abnormalities due to abnormal physeal development. Dietary deficiency of phosphate can also result in rickets.
  • Genetic defects in the vitamin D receptor: This is called hereditary vitamin D-resistant rickets and can result in similar skeletal abnormalities as that seen with vitamin D or phosphate deficiency. The latter was suspected to be the cause of skeletal abnormalities and high calcitriol concentrations in a 5 month old Pomeranian (Levine et al 2009).
  • Inflammation: Vitamin D (calcidiol) appears to be decreased in human patients with inflammation, acting as a negative acute phase reactant (Parker et al 2017).
  • Renal disease: Low calcitriol concentrations can be seen in some dogs and cats with renal disease, including acute kidney injury, protein-losing  nephropathy and chronic renal disease. The most common cited mechanism for low calictriol in chronic renal disease is decreased activity of α1 hydroxylase in failing renal proximal tubular cells, however other mechanisms could contribute including decreased intake from inappetence or anorexia and inflammation. Loss of urinary binding proteins with proteinuria could lead to increased urinary losses of vitamin D and low serum concentrations (Parker et al 2017).
  • Gastrointestinal disease: Decreased concentrations of vitamin D can occur due to inadequate absorption from the gut, e.g. inflammatory bowel disease. This could be due to lack of vitamin D binding proteins, fat malabsorption (vitamin D is a fat soluble enzyme), or intestinal inflammation (Parker et al 2017).
  • Cancer: Low concentrations of calcidiol are seen in dogs and cats with various types of cancer, but whether this is a cause or consequence of the disease is unknown. There was a higher risk of cancer in dogs with lower vitamin D concentration (alternatively, the risk of low vitamin D could be associated with cancer) (Selting et al 2016). Of interest, supplementation of vitamin D can enhance chemotherapeutic effects in dogs with cancer (Malone et al 2010, Parker et al 2017), although this may be tumor type specific, since the link between vitamin D and cancer is not seen with all forms of cancer (Willcox et al 2016).
 
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