Vitamin Biomarkers: Vitamin D

Optimal Takeaways

Vitamin D is not just a vitamin, it is a hormone precursor that ultimately gets converted to the hormone calcitriol in the body. The precursor can be found in limited amounts in food in the form of vitamin D2 from plants and vitamin D3 from animals. We can also produce the precursor from a cholesterol-based compound in the skin upon exposure to sunlight.

However, the precursor must first be converted to 25(OH)D in the liver and then converted to the active form 1,25(OH)2D called calcitriol in other tissues, especially the kidney. Insufficiency of vitamin D and its actions is associated with bone disease, malnutrition, liver or kidney disease, inflammation, and certain medications. Elevated vitamin D is associated with excess supplementation, calcium dysregulation, bone demineralization, pain, gastrointestinal complications, dehydration, and confusion.

Standard Range: 30.00 – 100.00 ng/mL (74.88 – 249.60 nmol/L)

The ODX Range: 50.00 – 90.00 ng/mL (124.80 – 224.64 nmol/L)

Low vitamin D levels can be seen with osteomalacia, osteoporosis, rickets, malnutrition, malabsorption, renal or liver disease, acute inflammatory disease, inadequate sun exposure, and use of certain medications, including corticosteroids, orlistat, cholestyramine, barbiturates, and phenytoin (Pagana 2021).

Low vitamin D levels can also be associated with inflammation, increased bone turnover and fracture risk, decreased bone density, myopathy, immune dysregulation including rheumatoid arthritis and asthma (Sassi 2018), endothelial dysfunction, hypertension, adverse cardiac outcomes, infertility, pregnancy complications, insulin resistance, diabetes, skin hyperpigmentation, pollution, smoking, genetic factors (Apostolakis 2018), obesity (though adipose stores may be increased), non-alcoholic fatty liver disease (Szymczak-Pajor 2022), metabolic syndrome, hypertriglyceridemia (Bea 2015), dental caries, periodontitis, preeclampsia, infections disease, cancer, neurological disorders (Holick 2017), decreased calcium absorption, increased parathyroid hormone (Gossiel 2014), reduced antioxidant capacity, decreased glutathione, and oxidative stress (Jain 2020).

High vitamin D levels can be seen with excess supplementation, Williams syndrome (Pagana 2021), hypercalcemia, hypercalciuria, nephrocalcinosis (Amrein 2020), bone demineralization, and pain (Chang 2019). Vitamin D toxicity is associated with apathy, confusion, abdominal pain, vomiting, polydipsia, polyuria, and dehydration (Marcinowska 2018).

Overview

Vitamin D is a complex compound consumed in food or made in the skin in one form but requires activation by the liver and kidney or other tissues to exert its actions as a hormone in another form. In its primary role, the active form of vitamin D regulates calcium and phosphorus absorption and levels in the blood, promotes calcium reabsorption in the kidney, supports bone mineralization, and inhibits parathyroid hormone release. The vitamin D metabolite most measured is 25(OH)D, reported as the total of 25(OH)D2 and 25(OH)D3. The 25(OH)D metabolite is produced in the liver by hydroxylation of the vitamin D that comes from food or production in the skin. The bioactive form 1,25(OH)2D (calcitriol) can be measured as well, especially if signs of deficiency are present despite normal 25(OH)D levels. Vitamin D deficiency can occur with inadequate exposure to UVB light from the sun, insufficient intake or absorption from food, or dysfunction of the liver or kidney (Pagana 2021). Production of 25(OH)D in the liver and conversion to active 1,25(OH)2D are both dependent on magnesium. Therefore, magnesium insufficiency can jeopardize vitamin D status (Gropper 2021). Vitamin D also regulates magnesium absorption from the gastrointestinal tract (Ahmed 2020), further complicating vitamin D status in the face of magnesium insufficiency.

Circulating 25(OH)D is considered the general reservoir or inactive “storage” form of vitamin D and the biomarker most often measured to assess vitamin D status. Debate over “normal” ranges persists. However, most scientists and clinicians agree that a level of 30 ng/mL (75 nmol/L) or below is insufficient. For example, optimal bone metabolism may not be achieved until 25(OH)D reaches at least 30-50 ng/mL (75-125 nmol/L) (Apostolakis 2018), while a level of at least 30-40 ng/mL (75-100 nmol/L) should be sufficient to maintain muscle health (Gropper 2021). Endocrine Society Guidelines suggest that a vitamin D intake of at least 1500-2000 IU per day may be needed to maintain serum 25(OH)D above 30 ng/mL (Holick 2011). Researchers note that the level of serum 25(OH)D observed in sunny countries is 54-90 ng/mL (134.78-224.64 nmol/L) and that a level above 100 ng/mL (250 nmol/L) is considered excess. A level above 150 ng/mL (325 nmol/L) is considered intoxication (Grant 2005).

Vitamin D insufficiency and low circulating 25(OH)D levels have been associated with obesity despite increased concentrations of vitamin D stored in adipose tissue. However, significant weight loss of greater than 15% in obese postmenopausal women was associated with a significant increase in circulating 25(OH)D of 7.7 ng/mL (19.22 nmol/L) (Vranić 2019). Vitamin D status should be monitored, and intervention adjusted during periods of weight loss.

Vitamin D should be assessed in at-risk populations, especially those with limited sun exposure and inadequate dietary intake. Only a small number of unfortified foods contain vitamin D, such as egg yolks, oily fish, organ meats that contain vitamin D3, and some plant-based foods, such as mushrooms which contain vitamin D2. Other foods may be artificially fortified with vitamin D and should be considered when assessing vitamin D status. If needed, supplementation can increase blood levels of 25(OH)D by 0.7-1.0 ng/mL (1.75-2.5 nmol/L) for each 100 IU of vitamin D3 provided until a level of 40 ng/mL (99.84 nmol/L) is reached, at which point the increase becomes more subtle. Those at most significant risk of vitamin D insufficiency include darkly pigmented skin, inadequate sun exposure, obesity, restricted diet, intestinal malabsorption, pancreatic insufficiency, cholestasis, hyperparathyroidism, diabetes, liver or kidney disease, and use of certain medications including glucocorticoids, antiretrovirals, antifungals, and anticonvulsants. Although sun exposure will not lead to vitamin D toxicity due to conversion to inactive forms, supplementation can lead to toxicity, especially if blood levels reach 100-150 ng/mL (250-375 nmol/L). Symptoms of vitamin D toxicity include loss of appetite, vomiting, pain, muscle weakness, polydipsia, polyuria, nephrocalcinosis, and bone demineralization (Chang 2019).

Vitamin D has receptors throughout the body, and its effects extend beyond bone health, with evidence suggesting an association between vitamin D insufficiency and cardiovascular disease, type 2 diabetes, and cancer. Meta-analysis finds the lowest risk for type 2 diabetes at a 25(OH)D of 65 ng/mL (162.24 nmol/L) and the lowest risk for colorectal cancer at a 25(OH)D of 55 ng/mL (137.28 nmol/L). However, risk follows a U-shaped curve and can increase at very high levels (Ekmekcioglu 2017).

An inverse relationship was previously observed between 25(OH)D levels and colon, breast, and ovarian cancer. Researchers estimate that half of colon cancer cases in North America could be prevented by maintaining a 25(OH)D of at least 34 ng/mL (84.86 nmol/L), and half of breast cancer cases may be prevented with a 25(OH)D of at least 52 ng/mL (129.79 nmol/L). Researchers subsequently recommend a maintenance level for 25(OH)D level of 50-90 ng/mL (125-225 nmol/L) (Garland 2007).

Research suggests that levels of 25(OH)D should also be part of a breast cancer risk assessment. Analysis of data from randomized and prospective trials with a total of 5,038 subjects found that a serum 25(OH)D of 60 ng/mL (150 nmol/L) or above was associated with the lowest risk of breast cancer. In contrast, a level below 20 ng/mL (50 nmol/L) carried the most significant risk (McDonnell 2018).

In general, if supplementation is indicated, each 1000 IU (25 ug) dose of vitamin D3 should increase blood levels by 10 ng/mL (25 nmol/L). Supplementation with vitamin D3 is preferred by some practitioners as vitamin D2 may not increase blood levels as dramatically or bind vitamin D receptors as effectively as D3 (Moyad 2009). However, one placebo-controlled double-blind study of 34 healthy subjects demonstrated that both D2 and D3 were efficacious. The study found that 82% of subjects had insufficient vitamin D levels with 25(OH)D below 30 ng/mL (75 nmol/L). Supplementation with either 1,000 IU vitamin D2 or 1,000 IU vitamin D3 for 11 weeks effectively increased serum 25(OH)D and also maintained 1,25(OH)2D (Biancuzzo 2013).

References

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Amrein, Karin et al. “Vitamin D deficiency 2.0: an update on the current status worldwide.” European journal of clinical nutrition vol. 74,11 (2020): 1498-1513. doi:10.1038/s41430-020-0558-y

Apostolakis, Michail et al. “Vitamin D and cardiovascular disease.” Maturitas vol. 115 (2018): 1-22. doi:10.1016/j.maturitas.2018.05.010

Biancuzzo, Rachael M et al. “Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation.” The Journal of clinical endocrinology and metabolism vol. 98,3 (2013): 973-9. doi:10.1210/jc.2012-2114

Chang, Szu-Wen, and Hung-Chang Lee. “Vitamin D and health - The missing vitamin in humans.” Pediatrics and neonatology vol. 60,3 (2019): 237-244. doi:10.1016/j.pedneo.2019.04.007

Ekmekcioglu , Cem et al. “25-Hydroxyvitamin D Status and Risk for Colorectal Cancer and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Epidemiological Studies.” International journal of environmental research and public health vol. 14,2 127. 28 Jan. 2017, doi:10.3390/ijerph14020127

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Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P. Advanced Nutrition and Human Metabolism. 8^th edition. Wadsworth Publishing Co Inc. 2021.

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Holick, Michael F. “The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention.” Reviews in endocrine & metabolic disorders vol. 18,2 (2017): 153-165. doi:10.1007/s11154-017-9424-1

Jain, Sushil K et al. “The potential link between inherited G6PD deficiency, oxidative stress, and vitamin D deficiency and the racial inequities in mortality associated with COVID-19.” Free radical biology & medicine vol. 161 (2020): 84-91. doi:10.1016/j.freeradbiomed.2020.10.002

McDonnell, Sharon L et al. “Breast cancer risk markedly lower with serum 25-hydroxyvitamin D concentrations ≥60 vs <20 ng/ml (150 vs 50 nmol/L): Pooled analysis of two randomized trials and a prospective cohort.” PloS one vol. 13,6 e0199265. 15 Jun. 2018, doi:10.1371/journal.pone.0199265

Moyad, Mark A. “Vitamin D: a rapid review.” Dermatology nursing vol. 21,1 (2009): 25-30, 55.

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Sassi, Francesca et al. “Vitamin D: Nutrient, Hormone, and Immunomodulator.” Nutrients vol. 10,11 1656. 3 Nov. 2018, doi:10.3390/nu10111656    

Szymczak-Pajor, Izabela et al. “The Action of Vitamin D in Adipose Tissue: Is There the Link between Vitamin D Deficiency and Adipose Tissue-Related Metabolic Disorders?.” International journal of molecular sciences vol. 23,2 956. 16 Jan. 2022, doi:10.3390/ijms23020956

Vranić, Luka et al. “Vitamin D Deficiency: Consequence or Cause of Obesity?.” Medicina (Kaunas, Lithuania) vol. 55,9 541. 28 Aug. 2019, doi:10.3390/medicina55090541