Vitamin Biomarkers: 1,25(OH)2D Vitamin D

Optimal Takeaways

Calcitriol, also known as 1,25(OH)2D, is the active form of vitamin D. This bioactive hormone is produced by enzymatic conversion of 25(OH)D, the circulating reservoir or “storage” form of vitamin D. While measurement of 25(OH)D is the most common method of assessing vitamin D status, evaluation of 1,25(OH)2D may be indicated in certain circumstances including kidney disease, cardiometabolic disorders, and in those with symptoms of vitamin D deficiency despite normal 25(OH)D, pregnancy.

Low calcitriol may be associated with bone disease, liver or kidney disease, hypertension, cardiovascular disease, metabolic syndrome, pregnancy complications, and oxidative stress. Elevated calcitriol may be related to excess calcium in the blood or urine, granulomatous disorders, and signs of toxicity, including mental status changes, gastrointestinal disturbances, and dehydration.

Standard Range: 18 - 72 pg/mL (43.20 – 172.80 pmol/L)

The ODX Range: 35 - 55 pg/mL (84 - 132 pmol/L)  

Low levels of 1,25(OH)2D/calcitriol may be seen with vitamin D deficiency and lack of 25(OH)D substrate (Lips 2007), 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 calcitriol has also been associated with metabolic syndrome, hypertriglyceridemia, low HDL-C (Bea 2015, Karhapaa 2010), neuromuscular dysfunction, chronic kidney disease risk, hypertension, heart failure, cardiovascular disease risk (Tomaschitz 2010), and pregnancy complications (Albahlol 2020). Low calcitriol was independently and progressively associated with worsening and more severe community-acquired pneumonia (Pletz 2014).

Vitamin D insufficiency, in general, can be associated with inflammation, increased bone turnover and fracture risk, decreased bone density, myopathy, immune dysregulation (Sassi 2018), endothelial dysfunction, hypertension, adverse cardiac outcomes, infertility, pregnancy complications, obesity, insulin resistance, diabetes, skin hyperpigmentation, pollution, smoking, genetic factors (Apostolakis 2018), dental caries, periodontitis, preeclampsia, infectious 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 levels of 1,25(OH)2D/calcitriol can be seen with hypercalcemia, hypercalciuria (Tebben 2016, Kavathia 2010), nephrocalcinosis, lymphoma, granulomatous disorders (Amrein 2020), Williams-Beuren syndrome, increased 1-alpha-hydroxylase, inhibition of 24-hydroxylase, and symptoms of toxicity including apathy, confusion, abdominal pain, vomiting, polydipsia, polyuria, and dehydration (Marcinowska 2018).

An overabundance of 1,25(OH)2D may be seen with sarcoidosis (Kavathia 2010), tuberculosis, IBD, rheumatoid arthritis, hereditary vitamin D-resistant rickets (Dirks 2018), inborn errors of vitamin D receptor metabolism, increased extra-renal hydroxylation in lymphoproliferative disease, unregulated hydroxylation of 25(OH)D by activated macrophages (Lips 2007), and autoimmune conditions (Blaney 2009).

Overview

The bioactive form of vitamin D is 1,25(OH)2D, a hormone called calcitriol, that must be produced in the body from 25(OH)D through a two-step process. The liver is responsible for the first hydroxylation that produces 25(OH)D from food or cutaneous sources, a magnesium-dependent enzymatic process. The second hydroxylation that produces active calcitriol also depends on magnesium and occurs primarily in the kidney (Gropper 2021). However, other cells and tissues can hydroxylate 25(OH)D to the active form, including bone, intestine, pancreas, prostate, platelets, and immune cells. In the immune system, calcitriol suppresses cytokine release, inflammation, and autoimmunity and supports innate immunity against pathogens (Sassi 2018).

Calcitriol levels are tightly regulated by parathyroid hormone, calcium, and phosphate. It has a half-life of approximately 4 hours compared to the 25(OH)D form, which reflects reserve stores and has a half-life of approximately 2-3 weeks. Calcitriol is not considered the best indicator of vitamin D status and may not reflect a vitamin D deficiency. It can even be elevated with deficiency due to secondary hyperparathyroidism. However, measuring 1,25(OH)2D (calcitriol) may be appropriate in certain circumstances, such as disordered metabolism of 25(OH)D or phosphate, including kidney disease, phosphate-losing disorders, oncogenic osteomalacia, rickets, and granuloma-forming disorders such as sarcoidosis and lymphoma (Holick 2017)

Emerging research suggests that measuring calcitriol may have additional benefits, including immune support, due to its direct antimicrobial and inflammation-modulating activities. A cross-sectional study of 300 subjects with community-acquired pneumonia found that 82% had vitamin D deficiency, defined as a 25(OH)D below 20 ng/mL (50 nmol/L). In the study, 25(OH)D and 1,25(OH)2D were lower in those requiring hospitalization and with longer lengths of stay. However, only a lower 1,25(OH)2D was associated with increasing pneumonia severity. Lower mean calcitriol was observed in those with respiratory, hepatic, renal, and cardiac comorbidities, though only renal comorbidities reached statistical significance with a mean 1,25(OH)2D of 34.1 pg/mL (81.84 pmol/L) (Peltz 2014).

Research also reveals an association between calcitriol and increased incidence of metabolic syndrome, including significantly increased triglycerides and low HDL-cholesterol, in a cross-sectional analysis of subjects who completed clinical trials for colorectal cancer. The lowest incidence of metabolic syndrome occurred in individuals with a mean calcitriol of 46.6 pg/mL (111.84 pmol/L) compared to a level below 33.2 pg/mL (79.68 pmol/L) (Bea 2015).

Calcitriol is believed to inhibit the synthesis of renin in the kidney, which may account for the antihypertensive and organ-protective benefits attributed to vitamin D. In a cohort of 3,296 patients referred for coronary angiography, lower levels of both 25(OH)D and 1,25(OH)2D were associated with higher PTH levels and upregulated renin-angiotensin system (RAS). Activation of RAS is recognized as a possible cause of cardiovascular and kidney disease. In the study, a deficient level of 25(OH)D below 20 ng/mL (50 nmol/L) correlated with a calcitriol level of 30.5 pg/mL (73.2 pmol/L); 25(OH)D of 20-30 ng/mL (50-75 nmol/L) correlated with calcitriol of 37.7 pg/mL (90.48 pmol/L); and 25(OH)D above 30 ng/mL correlated with calcitriol of 41.7 pg/mL (100.08 pmol/L) (Tomaschitz 2010).

Vitamin D regulates the genes that facilitate embryo implantation, control inflammation, and protect against infection; insufficiency is associated with several pregnancy complications. In one study of 322 pregnant Arabian women, the mean level of 1,25(OH)2D was below 35 pg/mL (84 pmol/L) in subjects with preeclampsia, gestational diabetes, ectopic pregnancy, and premature membrane rupture compared to a mean of 111 pg/mL (266.40 pmol/L) in pregnant controls. Concentrations of 1,25(OH)2D are expected to increase over the pregnancy, and decreased levels were significantly associated with infection, inflammation, diabetes, and compromised kidney function. Measuring both 25(OH)D and 1,25(OH)2D would be prudent before and during pregnancy (Albahlol 2020).

A calcitriol level above 45.83 pg/mL (110 pmol/L) was strongly associated with autoimmune disorders, including multiple sclerosis, psoriasis, and lupus, in a study of 100 Canadians despite low levels of 25(OH) in some cases. Researchers suggest that bacterial metabolites associated with autoimmunity may interfere with the feedback mechanism that degrades excess 1,25(OH)2D, as well as possible vitamin D receptor dysregulation. Levels of 1,25(OH)2D above 45.83 pg/mL may warrant further investigation in those at risk for autoimmune disorders (Blaney 2009).

References

Albahlol, Ibrahim A et al. “Vitamin D Status and Pregnancy Complications: Serum 1,25-di-hydroxyl-Vitamin D and its Ratio to 25-hydroxy-Vitamin D are Superior Biomarkers than 25-hydroxy-Vitamin D.” International journal of medical sciences vol. 17,18 3039-3048. 18 Oct. 2020, doi:10.7150/ijms.47807

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

Bea, Jennifer W et al. “Concentrations of the vitamin D metabolite 1,25(OH)2D and odds of metabolic syndrome and its components.” Metabolism: clinical and experimental vol. 64,3 (2015): 447-59. doi:10.1016/j.metabol.2014.11.010

Blaney, Greg P et al. “Vitamin D metabolites as clinical markers in autoimmune and chronic disease.” Annals of the New York Academy of Sciences vol. 1173 (2009): 384-90. doi:10.1111/j.1749-6632.2009.04875.x

Dirks, Niek F et al. “The When, What & How of Measuring Vitamin D Metabolism in Clinical Medicine.” Nutrients vol. 10,4 482. 13 Apr. 2018, doi:10.3390/nu10040482

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

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

Karhapaa, P et al. “Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias.” Journal of internal medicine vol. 268,6 (2010): 604-10. doi:10.1111/j.1365-2796.2010.02279.x

Kavathia, Dashant et al. “Elevated 1, 25-dihydroxyvitamin D levels are associated with protracted treatment in sarcoidosis.” Respiratory medicine vol. 104,4 (2010): 564-70. doi:10.1016/j.rmed.2009.12.004

Lips, Paul. “Relative value of 25(OH)D and 1,25(OH)2D measurements.” Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research vol. 22,11 (2007): 1668-71. doi:10.1359/jbmr.070716

Marcinowska-Suchowierska, Ewa et al. “Vitamin D Toxicity-A Clinical Perspective.” Frontiers in endocrinology vol. 9 550. 20 Sep. 2018, doi:10.3389/fendo.2018.00550

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

Pletz, Mathias W et al. “Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity.” Respiratory research vol. 15,1 53. 27 Apr. 2014, doi:10.1186/1465-9921-15-53

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

Tebben, Peter J et al. “Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment.” Endocrine reviews vol. 37,5 (2016): 521-547. doi:10.1210/er.2016-1070

Tomaschitz, Andreas et al. “Independent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the renin-angiotensin system: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.” Clinica chimica acta; international journal of clinical chemistry vol. 411,17-18 (2010): 1354-60. doi:10.1016/j.cca.2010.05.037