Vitamin D

Vitamin D

  • Vitamin D deficiency is a well-established risk factor for bone disease.1 Emerging data suggest a pleiotropic role of this agent in a broad range of organ functions and health outcomes. Low vitamin D levels are highly associated with endothelial dysfunction, atherosclerosis, heart attack, heart failure, stroke as well as silent and symptomatic CAD (coronary artery disease), CVD (cardiovascular disease) and death.1-11
  • In a large study of more than 41,000 people, vitamin D deficiency was associated with highly significant increases in the prevalence of diabetes, hypertension, hyperlipidemia, metabolic syndrome, and peripheral vascular disease whereas higher blood levels were associated with lower risk for CVD events, as well as lower total and cardiovascular mortality.1, 4-7
  • In large prospective cohort studies, low levels of 25(OH)D (<37.5 nmol/l) compared with normal levels (>75 nmol/l) were associated with 6-fold  risk of developing hypertension in men and 3-fold risk in women, over 4–8 years.12 However, findings from randomized trials of vitamin D supplementation to lower blood pressure are inconsistent.7  If vitamin D supplementation lowers blood pressure, its widespread use could have major public health benefits.13
  • Vitamin D concentrations are inversely associated with insulin resistance (IR) and metabolic syndrome (MS) and its components particularly, low HDL and waist girth in several populations.2, 3, 13-16 Improving vitamin D status in insulin resistant women resulted in improved IR and sensitivity, but no change in insulin secretion. Optimal vitamin D concentrations for reducing IR were shown to be 80-119 nmol/l, providing further evidence for an increase in the recommended adequate levels.17
  • Lower 25(OH)D concentrations  are associated with several components of the metabolic syndrome including increased values for waist circumference, triglycerides, HDL-C, and glucose. 13 18Most notably, each 10 ng/dL increment in 25(OH)D concentration was associated with a 5 mg/dL increase in HDL-C and  50% to 70% reduction in the risk of  metabolic syndrome after adjustment for age and sex. 19 13
  • The pathogenesis of diabetes involves both beta-cell dysfunction and insulin resistance. Vitamin D deficiency correlates with beta-cell dysfunction and insulin resistance as well as diabetes.6, 20 Clinical studies designed specifically to assess the effect of vitamin D supplementation  (2000 to 7000 IU) on glucose metabolism and metabolic risk factors  are currently underway.13
  • The proposed explanation for the relationship between low vitamin D and obesity is reduced bioavailability of vitamin D in obese people after either UVB exposure or oral administration of vitamin D because of its sequestration in adipose tissue.21, 22
  • Some studies have implicated  25-OH vitamin D in widespread muscular pain, especially in those taking statins.23
  • The close association of lower vitamin D status with various metabolic disturbances and adverse health outcomes indicate that substantial potential exists for improving public health through efforts to increase vitamin D intake if these relationships are causal. 


  • Ultraviolet B (UVB) light-dependent conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) in the skin is the main source of vitamin D which is converted to its active form 1,25-dihydroxycholecalciferol [1,25(OH)2D] in the kidney. This active form regulates transcription of over 200 genes with antiproliferative, prodifferentiative, and immunomodulatory effects.24 
  • Vitamin D act as a powerful endogenous inhibitor of RAAS (renin-angiotensin-aldosterone system) activity, which plays a major role in blood pressure regulation, and serum vitamin D concentrations inversely correlate with blood pressure. Vitamin D also inhibits NF-kB activity, which is a key transcription factor regulating the expression of multiple proinflammatory and proatherogenic cytokines.6
  • In addition, vitamin D deficiency affects cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation and has direct effects on vascular smooth muscle cell calcification and proliferation.

Causes of vitamin D deficiency are given in Table 119 A.

Table 119 A. Causes of Vitamin D deficiency6

Nutritional/absorptive decreased nutritional vitamin D intake
small bowel resection
gastric surgery (resection or gastric bypass)
total parenteral nutrition (TPN)
hepatic disease – reduced vitamin D absorption
breast-fed infants; vitamin D requirements cannot be met by human milk alone. 
Reduced Vitamin D synthesis elderly – less efficient synthesis of vitamin D in the skin
dark skin (people with darker skin require threefold to six-fold more exposure)
hepatic disease – decreased 25(OH)D synthesis
renal disease – decreased 1,25(OH)2D synthesis
Avoidance of unprotected sun exposure or spending most day indoor (institutionalized)
wearing clothes that reduce UVB exposure (i.e. because of religious beliefs)
Reduced bioavailability obesity
Increased requirement pregnancy
Medications anticonvulsant drugs

 Managing low levels of vitamin D 

  • The prevalence of vitamin D deficiency varies from 65% to 77% 4, 25, 26 and is more common among women, as high as 80%.4, 25, 27
  • Although vitamin D deficiency is frequently unrecognized clinically, laboratory measurement is easy to perform and treatment of vitamin D deficiency is relatively well tolerated and inexpensive. Given the ease of vitamin D measurement and replacement, prospective studies of vitamin D supplementation to prevent and treat CVD are urgently needed.1, 4
  • Vitamin D adequacy is evaluated by measuring serum 25(OH) Vitamin D concentration, as this is the primary circulating form of vitamin D. The prevalence of vitamin D insufficiency, defined by a 25-hydroxyvitamin D level <30 ng/mL (<75 nmol/L) in the United States was 77% in 2004.26  However 40-50ng/ml is considered ideal and many people with statin induced myalgia may require higher levels. Levels > 150ng/mL is toxic and should be avoided.11Although the use of vitamin D supplementation may have increased since 2004, it is likely that the majority of US citizens continue to have inadequate vitamin D status.
  • Dietary sources of vitamin D are limited except for cod liver oil (1360 IU per serving of one teaspoon), salmon (960 IU per serving of 100 g) and mackerel (457 IU per serving of 100 g). 28  Given that few foods are rich dietary sources of vitamin D, supplementation of the diet through consumption of vitamin D-fortified foods or dietary supplements may be necessary to maintain sufficient vitamin D status.28
  • Higher intakes of vitamin D, including supplementation when the diet is inadequate, can be recommended due to the low known risk and high potential public health benefits.
  • While the Institute of Medicine recommends 200 IU/day of dietary vitamin D intake, results from some studies have suggested that 800-1000 IU/day of dietary vitamin D may be needed to maintain sufficient vitamin D status, particularly in locations where sun exposure is limited and for high risk groups such as the elderly and dark-skinned individuals.19, 29 Substantially larger doses are needed to treat vitamin D deficiency.6
  • Serum 25(OH)D concentrations undergo strong seasonal variation at high latitudes and are influenced by vitamin D intake, skin pigmentation, and sun exposure.30 
  • Current vitamin D daily recommended intake (DRI) of 200IU from birth through age 50 years, 400 IU from age 51 to 70, and 600IU from above 70 years is likely insufficient to achieve optimal vitamin D level of 75nmol/l. 31 Vitamin D intoxication, which can be serious, causing hypercalcemia and/or hypercalciuria 32, is rare and may be caused by inadvertent or intentional ingestion of excessively high doses becoming apparent when 25(OH)D levels exceed 250–375nmol/l.33, 34 For example, 5000 IU vitamin D daily supplement for 12 months in sun-deprived nursing home residents did not change serum calcium or caused hypercalcemia. 35 
  • The upper limit of vitamin D intake may be as high as 10,000IU daily.36 Therefore, established safety profile of vitamin D supplementation provides a wide safety margin and supports an adult supplement dose of 800–1000 IU daily.24, 37
  • People with overt vitamin D deficiency require 10,000–50,000IU vitamin D monthly until stores are repleted. 6 On average, 100 IU of vitamin D increases 25(OH)D serum concentration by 2–3nmol/l.37 
  • The median levels also vary by ethnicity. 4, 25 38 Levels below 20 ng/mL is considered deficiency, 20-29.99 ng/mL as having insufficiency and >30 ng/mL as normal although 40 to 50 ng/ml is considered ideal.11, 25
  • A vitamin D-replete state may reduce costs and confer survival advantages in critical illness. It is recommended that 25(OH)D levels be routinely checked and deficiencies treated in ICU patients.39


1. Anagnostis P, Athyros VG, Adamidou F, Florentin M, Karagiannis A. Vitamin D and cardiovascular disease: a novel agent for reducing cardiovascular risk? Curr Vasc Pharmacol. Sep 2010;8(5):720-730.

2. Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. Jun 9 2008;168(11):1174-1180.

3. Dobnig  H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med. Jun 23 2008;168(12):1340-1349.

4. Anderson J L, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. Oct 1 2010;106(7):963-968.

5. Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. Jun 11 2007;167(11):1159-1165.

6. Baz-Hecht M, Goldfine AB. The impact of vitamin D deficiency on diabetes and cardiovascular risk. Curr Opin Endocrinol Diabetes Obes. Apr 2010;17(2):113-119.

7. Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. Jan 29 2008;117(4):503-511.

8. Dendukuri N, Chiu K, Brophy JM. Validity of electron beam computed tomography for coronary artery disease: asystematic review and meta-analysis. BMC Med. 2007;5:35.

9. Watson KE, Abrolat ML, Malone LL, et al. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation. 1997;96(6):1755-1760.

10. Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension. Jan 2011;57(1):63-69.

11. Dong JY, Zhang YH, Qin LQ. Erectile dysfunction and risk of cardiovascular disease: meta-analysis of prospective cohort studies. J Am Coll Cardiol. Sep 20 2011;58(13):1378-1385.

12. Forman JP, Giovannucci E, Holmes MD, et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension. May 2007;49(5):1063-1069.

13. Vaidya A, Forman JP. Vitamin D and hypertension: current evidence and future directions. Hypertension. Nov 2010;56(5):774-779.

14. Ford  ES, Ajani UA, McGuire LC, Liu S. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care. May 2005;28(5):1228-1230.

15. Reis JP. vM, D., Miller ER, 3rd. Relation of 25-hydroxyvitamin D and parathyroid hormone levels with metabolic syndrome among US adults. Eur J Endocrinol. Jul 2008;159(1):41-48.

16.  Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Diabetes. Oct 2008;57(10):2619-2625.

17. von Hurst P R, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient – a randomised, placebo-controlled trial. Br J Nutr. Feb 2010;103(4):549-555.

18. Hypponen  E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes. Feb 2008;57(2):298-305.

19. Maki KC, Rubin MR, Wong LG. Serum 25-hydroxyvitamin D is aindependently associated with high-density lipopprotein cholestrol and and the metabolic syndrome in men and women. J Clinical lipidology. 2009;3:289-296.

20. Mattila C, Knekt P, Mannisto S, et al. Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care. Oct 2007;30(10):2569-2570.

21. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. Sep 2000;72(3):690-693.

22. Konradsen S, Ag H, Lindberg F, Hexeberg S, Jorde R. Serum 1,25-dihydroxy vitamin D is inversely associated with body mass index. Eur J Nutr. Mar 2008;47(2):87-91.

23.  Macfarlane GJ, Palmer B, Roy D, Afzal C, Silman AJ, O’Neill T. An excess of widespread pain among South Asians: are low levels of vitamin D implicated? Ann Rheum Dis. Aug 2005;64(8):1217-1219.

24. Holick M F. Vitamin D deficiency. N Engl J Med. Jul 19 2007;357(3):266-281.

25. Hekimsoy Z, Dinc G, Kafesciler S, et al. Vitamin D status among adults in the Aegean region of Turkey. BMC Public Health. Dec 23 2010;10(1):782.

26. Holick M. F, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. Apr 2008;87(4):1080S-1086S.

27. Mavroeidi A, O’Neill F, Lee PA, et al. Seasonal 25-hydroxyvitamin D changes in British postmenopausal women at 57 degrees N and 51 degrees N: a longitudinal study. J Steroid Biochem Mol Biol. Jul 2010;121(1-2):459-461.

28. Heaney R P. Functional indices of vitamin D status and ramifications of vitamin D deficiency. Am J Clin Nutr. Dec 2004;80(6 Suppl):1706S-1709S.

29. Maki KC, Rubin MR, Wong LG, McManus JF, Jensen CD, Lawless A. Effects of vitamin D supplementation on 25-hydroxyvitamin D, high-density lipoprotein cholesterol, and other cardiovascular disease risk markers in subjects with elevated waist circumference. Int J Food Sci Nutr. Jun 2011;62(4):318-327.

30. Gozdzik A, Barta JL, Weir A, et al. Serum 25-hydroxyvitamin d concentrations fluctuate seasonally in young adults of diverse ancestry living in toronto. J Nutr. Dec 2010;140(12):2213-2220.

31. Holick M F, Siris ES, Binkley N, et al. Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab. Jun 2005;90(6):3215-3224.

32. Jacobus CH, Holick MF, Shao Q, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med. Apr 30 1992;326(18):1173-1177.

33. Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med. Jul 5 2001;345(1):66-67.

34. Klontz KC, Acheson DW. Dietary supplement-induced vitamin D intoxication. N Engl J Med. Jul 19 2007;357(3):308-309.

35. Mocanu V, Stitt PA, Costan AR, et al. Long-term effects of giving nursing home residents bread fortified with 125 microg (5000 IU) vitamin D(3) per daily serving. Am J Clin Nutr. Apr 2009;89(4):1132-1137.

36. Hathcock J. N, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr. Jan 2007;85(1):6-18.

37. Vieth R, Bischoff-Ferrari H, Boucher BJ, et al. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. Mar 2007;85(3):649-650.

38. Sulaiman R A, Sharratt CL, Lee PW, et al. Ethnic differences in umbilical cord blood vitamin D and parathyroid hormone–South Asians compared to Whites born in the UK. J Matern Fetal Neonatal Med. Nov 2010;23(11):1315-1317.

39. McKinney JD, Bailey BA, Garrett LH, Peiris P, Manning T, Peiris AN. Relationship between vitamin D status and ICU outcomes in veterans. J Am Med Dir Assoc. Mar 2011;12(3):208-211.

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