Vitamin D

by Pamela Smith, MD, MPH, MS

Vitamin D is not really a vitamin, since it can be made in the skin by exposure to sunlight.^1–3 For example, when a Caucasian adult wearing a bathing suit is exposed to the amount of sunlight that causes the skin to have a pink tint 24 hours later, this equals about 20,000 IU of vitamin D.⁴ Furthermore, when a patient uses topical sunscreens, they block vitamin D production by 97% to 100% by preventing the conversion of 7-dehydrocholesterol to vitamin D3. When the patient is exposed to the sun, 7-dehydrocholesterol is converted into vitamin D3 (cholecalciferol).^5,6

Patients may also obtain vitamin D2 or D3 from the diet. Only a few foods naturally contain vitamin D, such as fish (salmon, mackerel, and herring), mushrooms, butter, cream, and egg yolks. Some foods may be fortified with vitamin D, such as milk and orange juice.^7,8 About one-half of dietary vitamin D is absorbed by the enterocytes and then transported to the blood circulation via chylomicrons. Some of this vitamin D is taken up by fat and muscle before it reaches the hepatocytes.⁹

Vitamin D must be metabolized to become physiologically active. It is converted as either D2 or D3 to 25-OH vitamin D in the liver and then into the active form, 1,25(OH)2 (calcitriol) vitamin D, in the kidneys.¹⁰ Calcitriol is the most active form of vitamin D. It increases calcium and phosphorus absorption in the GI tract, induces osteroclast maturation for bone restructuring, increases calcium deposition in bone, and has a mild inhibitory effect on PTH. Calcitriol also modulates transcription of several genes.¹¹ Furthermore, vitamin D has neurotransmitter and neurologic function. Likewise it also affects the immune system by having anti-inflammatory affects.¹²

There are vitamin D receptors in the bone, intestines, brain, breast, prostate, and lymphocytes. Circulating 25(OH)D is taken up by numerous cells that contain 1-Ohase, which can make their own calcitriol. These include the breast, prostate, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, and brain.¹³ Some cells have nuclear, cytosolic, or membrane-bound vitamin D receptors: islet cells of the pancreas, monocytes, transformed B-cells, activated T-cells, neurons, prostate cells, ovarian cells, pituitary cells, and aortic endothelial cells.¹⁴

The therapeutic benefits of vitamin D are numerous:

• cardiovascular disease

• hypertension

• diabetes

• osteoarthritis

• multiple sclerosis

• depression

• epilepsy

• migraine headaches

• polycystic ovarian disease

• musculoskeletal pain

• autoimmune processes

• inflammatory conditions

• cancer prevention and treatment

• osteoporosis

• fibromyalgia (possible effect)

Let’s look at each of these individually. Deaths from heart disease are more common in the winter and in northern latitudes. In fact, the risk of having a myocardial infarction is twice as high if 25(OH)D levels are low (less than 34 ng/ml or 85 nmol/L).¹⁵ Vitamin D deficiency has also been shown to be a risk factor for congestive heart failure.¹⁶ Studies have shown that patients with congestive heart failure tend to have lower levels of vitamin D than controls.¹⁷

Readings on vitamin D levels in relationship to hypertension reveal that blood pressure is higher in the winter, northern latitudes, and with increased skin pigmentation. Patients treated with UV light three times a week for six weeks in one medical trial, who were hypertensive, had their blood pressure decrease.¹⁸ Low vitamin D levels have also been associated with insulin resistance and beta-cell dysfunction. When comparing the use of medications such as metformin, they help improve insulin sensitivity by 13%; whereas higher levels of vitamin D correlated with a 60% improvement in insulin sensitivity, according to one medical study.¹⁹

Reviewing the medical literature on osteoarthritis reveals the progression of osteoarthritis is made less by adequate vitamin D intake.²⁰

Multiple sclerosis (MS) is rare in sunny climates. A small study of 10 patients with MS for two years, treated with 5000 IU of D3, were found to have a reduction in the number of exacerbations of their disease and no adverse side effects were noted. Examining the use of vitamin D in another disease process, seasonal affective disorder, a study showed that a small amount, 400 to 800 IU, helped improve mood.²²

Seizures can be the initial manifestation of vitamin D deficiency. Low vitamin D levels decrease the threshold for and increase the incidence of seizures. Moreover, some anticonvulsants have been shown to cause vitamin D deficiency because they may interfere with the formation of calcitriol.²³ Supplementation with 4000 to 16,000 IU of D2 was shown to reduce seizure frequency in a placebo-controlled trial.²⁴

Vitamin D supplementation has also been shown to effectively help with migraine headaches. A study showed a reduction in frequency, duration, and severity of menstrual migraines in women with vitamin D deficiency when they increased their vitamin D intake.²⁵

Vitamin D deficiency is common in women with polycystic ovarian disease (PCOS). A study showed that supplementation with calcium and D2 normalized menstrual cycles and/or fertility in all nine of the women evaluated.²⁶ Vitamin D has even been shown to help with musculoskeletal pain. In a medical trial, vitamin D deficiency was found in 83% of almost 300 patients with low back pain. Supplementation with 5000 to 10,000 IU of vitamin D per day decreased the pain in almost 100% of the patients within three months. ²⁷

Furthermore, vitamin D has been shown to help with inflammatory conditions. When markers of inflammation such as IL-6 and CRP were measured, vitamin D supplementation was found to be effective in lowering these inflammatory markers. ²⁸

Inadequate exposure to sunlight has been shown by Grant to be associated with the following cancers²⁹:

• breast

• colon

• ovarian

• prostate

• bladder

• esophageal

• kidney

• lung

• pancreas

• rectal

• stomach

• uterine

• non-Hodgkin’s lymphoma

Grant proposed in his article that 23,000 American lives per year could be saved from a reduction in cancer mortality by supplementing with vitamin D or providing adequate exposure to UV light.³⁰ Garland et al. in their article discussed that if everyone had a 25(OH) vitamin D level greater than or equal to 55 ng/mL, at least 60,000 cases per year of colorectal cancer and 85,00 cases per year of breast cancer would be prevented in North America.³¹ Furthermore, studies have shown that when 25(OH) vitamin D levels are lower than 20 ng/mL, there is a 30% to 50% increase in developing and also dying of colorectal, prostate, breast, pancreatic, and esophageal cancer.^32–37 Likewise, another study showed that in men who had the greatest exposure to sunlight had a 3- to 5-year reprieve from developing prostate cancer compared with men who worked inside.³⁸ In another trial, the Physician Health Study, men with the highest levels of vitamin D had a decreased risk of developing colorectal, esophageal, pancreatic cancer, and leukemia.³⁹

Studies in patients who already have been diagnosed with cancer reveal that vitamin D supplementation may be helpful. For example, a study done on patients with metastatic prostate cancer who were given 2000 IU of D3 a day for up to 21 months showed a greater than 50% reduction in the rise in their PSA levels compared with before they received the vitamin D.⁴⁰ In another trial which was a prospective study, it revealed that women with early breast cancer with vitamin D levels below 50 nmol/l had an increased risk of distant recurrence and death compared with those with sufficient vitamin D levels.⁴¹ Vitamin D may be helpful in patients with cancer, since studies have shown that vitamin D regulates directly or indirectly 200 genes.⁴² These genes regulate proliferation, differentiation, apoptosis, and angiogenesis.⁴³ Calcitriol has been proposed to have several anticancer effects: growth arrest and differentiation, apoptosis, inhibition of invasion and metastasis, anti-inflammatory effects, regulation prostaglandin metabolism and signaling, and induction of mitogen-activated protein kinase phosphatase-5 (MKP).⁴⁴ Clinical trials using vitamin D to treat various cancers have shown some effectiveness.⁴⁵

Vitamin D has also been shown to be effective in preventing osteoporosis. A study concluded that vitamin D decreased the risk of vertebral and nonvertebral fractures.⁴⁶ Another report revealed that vitamin D supplementation reduced the relative risk of hip fracture by 26% and nonvertebral fracture by 23% compared with taking calcium alone or placebo.⁴⁷

One-half of patients studied with fibromyalgia were wound to be vitamin D deficient.⁴⁸ More studies need to be done to examine if vitamin D supplementation would help patients with fibromyalgia.

When measuring vitamin D, it is important to measure 25(OH)D. Studies in laboratory animals have shown that vitamin D binding protein (DBP) is important for total circulating 1,25(OH)2D3, but DBP does not influence the level of 1,25(OH)2 D3 that enters the cells and affects the making of vitamin D target proteins.⁴⁹ Therefore, measurement of 1,25(OH)2 D3 may not reflect the biologically active 1,25 (OH)2 D3 level.⁵⁰

Reviews have shown that supplementation is most effective with vitamin D3 rather than D2.^51,52

Some patients may have hypersensitivity syndrome and cannot take on an adequate amount of vitamin D. Some of these patients may have normal vitamin D levels when measured but become ill due to elevated calcium levels. Therefore, it is also important to measure calcium. Patients who may be predisposed to hypersensitivity syndrome are those with hyperparathyroidism, active cancers, and granulomatous diseases such as sarcoid, Crohn’s disease, and tuberculosis.⁵³ Also patients taking medications that may raise calcium levels such as thiazide diuretics.

Vitamin D is stored in the body. So patients can become toxic. The following are symptoms of vitamin D toxicity^54–57:

• hypercalcemia and hyperphosphatemia

• hypercalciuria and kidney stones

• anorexia

• nausea and vomiting

• thirst

• polyuria and polydipsia

• muscular weakness

• joint pains

• disorientation

• headache

• decrease in serum PTH

• decrease in GFR

• mobilization of bone resulting in an increased serum concentration of zinc

• ectopic calcification of soft tissues (kidney and lung)

• constipation

• hypertension

A medical study showed that vitamin D toxicity for most adults without hypersensitivity syndrome starts at 40,000 IU D3 a day.⁵⁸

In conclusion, vitamin D is a very important hormone that may help prevent and possibly treat some disease processes when the patient has optimal levels. It is paramount that vitamin D levels be measured, along with calcium and PTH hormone, before it is supplemented or prescribed.

Notes

1. Holick M. Vitamin D. In: Stipanuk M. Biochemical, Physiological, Molecular Aspects of Human Nutrition. St. Louis: Saunders/Elseiver; 2006:863–868.

2. Holick M. Phylogenetic and evolutionary aspects of vitamin D from phytoplankton to humans. In: Pang P et al., eds. Vertebrate Endocrinology: Functional and Biochemical Implications. Vol 3. Orlando, FL: Academic Press Inc.; 1969:7–43.

3. Holick M. Vitamin D deficiency. N Engl J Med. 2007;357:266–281.

4. Ibid.

5. Vasquez A et al. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther. 2004;19(5):35.

6. Matsuoka L et al. Sunscreens suppress cutaneous vitamin D3 synthesis. J Clin Endocrinol Metab. 1987;64:1165–1168.

7. Holick M. Vitamin D extraskeletal health. In: LeRoith D, ed. Endocrinology and Metabolism Clinics of North America. Philadelphia: Saunders Co.; 2010;39(2):381–400.

8. Bouillon R. Vitamin D: from photosynthesis. In: Degroot L et al., eds. Endocrinology. 5th ed. Philadelphia: Elsevier/Saunders; 2006:1435–1463.

9. Ibid.

10. Christakos S et al. Vitamin D metabolism. In: LeRoith D, ed. Endocrinology and Metabolism Clinics of North America. Philadelphia: Saunders Co.;2010;39(2):243–253.

11. Holick, M., et al. “Calcium and vitamin D: diagnostics and therapeutics,” Clin Lab Med 2000; 29(3):569–90.

12. Vasquez, op cit.

13. Ibid.

14. Ibid.

15. Scragg R et al. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 1990;19(3):559–563.

16. Kini S et al. A reversible form of cardiomyopathy. J Postgrad Med. 2003;49(1):85–87.

17. Zitterman A et al. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol. 2003;41:105–112.

18. Krause R et al. Ultraviolet B and blood pressure. Lancet. 1998;352(9129):709–710.

19. Chiu K et al. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820–825.

20. McAlindon T et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham study. Ann Int Med. 1996;125(5):353–359.

21. Goldberg P et al. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium, and vitamin D. Med Hypotheses. 1986;21(2):193–200.

22. Landsdowne A et al. Vitamin D3 enhances mood in healthy subjects during winter. Psychopharmacology. 1998;135(4):319–323.

23. Ali F et al. Loss of seizure control due to anticonvulsant-induced hypocalcemia. Amer Pharmacother. 2004;38(6):1002–1005.

24. Christiansen D et al. Anticonvulsant action of vitamin D in epileptic patients? A controlled pilot study. Br Med J. 1074;2(913):258–259.

25. Thys-Jacob S. Vitamin D and calcium in menstrual migraine. Headache. 1994;34(9):544–546.

26. Thys-Jacob S. Vitamin D and calcium dysregulation in the polycystic ovarian syndrome. Steroids. 1999;54(6):430–435.

27. Al Faraj S et al. Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine. 2003;28(2):177–179.

28. Van de Berge G et al. Bone turnover in prolonged critical illness: effect of vitamin D. J Clin Endocrinol Metab. 2003;88(10):4623–4632.

29. Grant W et al. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002;94(6):1867–1875.

30. Ibid.

31. Garland C et al. What is the dose-response relationship between vitamin D and cancer risk? Nutr Rev. 2007;65(8):S91–S95.

32. Gorham E et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta-analysis. Am J Prev Med. 2007;32(3):210–226.

33. Moan J et al. Addressing the health benefits and risks, involving vitamin D or skin cancer, of increased sun exposure. Proc Natl Acad Sci USA. 2008;105(2):668–673.

34. Garland C et al. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103(3–5):708–711.

35. Ahomen M et al. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control. 2000;11:847–852.

36. Giovannucci E et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst. 2006;98(7):451–459.

37. Krishnan A. The role of vitamin D and cancer prevention and treatment. In: LeRoith D. Endocrinology and Metabolism Clinics of North America. Philadelphia: Saunders Co.;2010;39(2):401–418.

38. Luscombe C et al. Exposure to ultraviolet radiation: association with susceptibility and age at presentation with prostate cancer. Lancet. 2001;358:641–642.

39. Giovannucci E. Cancer incidence and mortality and vitamin D in black and white male health professionals. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2467–2472.

40. Woo T et al. Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer. 2005;51(1):32–36.

41. Goodwin P et al. Prognostic effects of 25-hydroxyvitamin D levels in early breast cancer. J Clin Oncol. 2009;27(23):3757–3763.

42. Nagpal S et al. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005;26:662–687.

43. Holick 2007, ibid.

44. Smith P. Vitamin D: cancer prevention and treatment. Module I. Fellowship in Integrative Cancer Therapies; Phoenix, AZ; April 21, 2012.

45. Ibid.

46. Papadimitropoulos E et al. Meta-analyses of therapies for postmenopausal osteoporosis, VIII: meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Endocr Rev. 2002;23(4):560–569.

47. Bischoff-Ferrari H et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257–2264.

48. Huisman A et al. Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J Rheumatol. 2001;28(11):2535–2539.

49. Zella L et al. Vitamin D-binding protein influences total circulating levels of 1,25-dihydroxyvitamin D3 but does not directly modulate the bioactive levels of the hormone in vivo. Endocrinology. 2008;149:3656–3667.

50. Bikle D et al. Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab. 1985;61:969–975.

51. Trang H et al. Evidence that vitamin D3 increases serum 25-hydroxyvitmain D more efficiently than does vitamin D2. Am J Clin Nutr. 1998;68:854–858.

52. Armas L et al. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004;89:5387–5391.

53. Vasquez, op cit.

54. Buist R. Int Clin Nutr. 1984;4:159.

55. Quillin P. Beating Cancer with Nutrition. Carlsbad, CA: Nutrition Times Press Inc.; 2005.

56. Coombs G. Vitamin D. In: The Vitamins. 3rd ed. Burlington, MA: Elsevier Academic Press; 2008:145–179.

57. Bouillon, op cit.

58. Coombs, op cit.