4.0Populations at High Risk for Deficiency

1.0

ABSTRACT

Vitamin D deficiency has recently been linked to many chronic diseases such as MS (multiple sclerosis), cancer, rheumatoid arthritis, and diabetes. It has been a topic of debate among healthcare providers on whether or not it is beneficial to test and treat patients who have vitamin D deficiency. This paper looks at the potential mechanism of vitamin D in these disease processes and evaluates the various studies in the literature focusing on vitamin D levels and chronic diseases. This paper concludes by recommending that physicians in Allegheny County, PA, test all their adult patients for vitamin D deficiency, especially during the winter months. Vitamin D deficiency and the link to chronic disease have vast significance in the field of public health both in Allegheny County, PA, and nationwide.

TABLE OF CONTENTS

1.0The Role of vitamin D

2.0Vitamin d and current literature

3.0vitamin d guidelines

4.0populations at high risk for deficiency

5.0conclusion

BIBLIOGRAPHY...... 10

List of tables

Table 1: Institute of Medicine and Endocrinology Society Vitamin D Recommendations

List of figures

Figure 1. Vitamin D Production...... 3

Figure 2. Diseases Associated with Vitamin D Deficiency...... 5

1

1.0 The Role of vitamin D

It is estimated that over seventy percent of Americans are vitamin D deficient, many of which live in the northern part of the United States (“Harvard Health Journals, 2007). Recently, there have been many studies showing an inverse relationship between vitamin D levels and a variety of diseases such as osteoporosis, colon cancer, multiple sclerosis (MS), rheumatoid arthritis, systemic lupus erythematosus, and type 1 and 2 diabetes (Wranicz& Szostak-Wegierek, 2014). Vitamin D is now thought to act like an important prohormone which helps regulate the immune system (Coen, 2008). It is very important for most people in and around the Pittsburgh, PA, area to get their vitamin D levels tested annually and absolutely crucial during the winter months.

The body makes vitamin D through one of two main processes. The primary way that vitamin D is produced in the body is mediated by the UVB rays of the sun. The sun acts as a catalyst converting 7-dehydrocholesterol (which is naturally present in the skin) into vitamin D3, or cholecalciferol, that is then converted to calcidiol, 25(OH)2D, via the liver. Calcidiol is then converted into the active form of vitamin D or calcitriol, 1,25(OH)2D. This process is demonstrated more clearly in Figure (Holick et.al. 2004). Foods and dietary supplements work slightly different by using a plant based sterol, ergosterol, rather than the rays of the sun. Vitamin D2, or ergocalciferol, is converted to calcidiol via the liver, then calcitriol via the kidney (Holick et.al. 2004). For the purposes of this paper, Vitamin D2 and D3 are used interchangeably. Clinically, ergocalciferol is only 30-50% as potent as cholcalciferol and thus requires higher doses (Holick & Chen, 2008).

Current blood testing of vitamin D measures calcidiol, the inactive form of vitamin D which may not accurately represent the uptake by the bodies VDR (vitamin D3 receptors). At a biochemical level, calcitriol binds to the VDR and interacts with retinoid X receptor (RXR). This binding either induces or represses the expression of the affected gene (Haussler et.al. 2012). VDRs occur in almost every tissue and cell of the body (Vimaleswaran et.al. 2013). Some examples of places where VDR’s exist include adipose tissue, pancreatic beta cells, lymphocytes B and T, thyroid gland, cardiac tissue, cancer cells, adrenal glands, kidney, brain, and lungs. The wide distribution of VDRs suggests additional actions of vitamin D3, apart from maintaining calcium and phosphate homeostasis (Wranicz & Szostak-Wegierek, 2014).

Schematic representation of cutaneous production of vita-min D and its metabolism and regulation of calcium homeostasis and cellular growth. During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin absorbs solar ultraviolet B (UVB) radiation and is converted to previtamin D3 (preD3). Once formed, preD3 undergoes thermally induced transformation to vitamin D3. Further exposure to sunlight converts preD3 and vitamin D3 to biologically inert photoproducts. Vitamin D coming from the diet or from the skin enters the circulation and is metabolized in the liver by vitamin D-25-hydroxylase (25-OHase) to 25-hydroxyvitamin D3 [25(OH)D3]. 25(OH)D3 reenters the circulation and is converted in the kidney by 25-hydroxyvitamin D3-1α-hydroxylase (1-OHase) to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. A variety of factors, including serum phosphorus (Pi) and parathyroid hormone (PTH), regulate the renal production of 1,25(OH)2D. 1,25(OH)2D regulates calcium metabolism through its interaction with its major target tissues, the bone, and the intestine. 1,25(OH)2D3 also induces its own destruction by enhancing the expression of 25-hydroxyvitamin D-24-hydroxylase (24-OHase). 25(OH)D is metabolized in other tissues for the purpose of regulation of cellular growth. VDR, vitamin D receptor.

Figure 1. Vitamin D Production

2.0 Vitamin d and current literature

It is well known that vitamin D increases intestinal absorption of calcium and prevents rickets in children and osteoporosis in adults (“Harvard Health Journals,” 2007). However, current literature suggests that vitamin D plays an even more important role as an immune modulator by regulating cell growth and reducing inflammation (Ritterhouseet.al. 2014). VDRs are known to regulate over 220 genes and they are involved many functions, including pro-apoptosis, immune regulation, anti-inflammation and others (Chiang & Chen, 2013). Studies by Ritterhouse et.al.found that vitamin D modulates B cell responses to anti- and pro-inflammatory stimuli and induces cytotoxic T cells, Tregs, and monocyte-derived macrophages (Ritterhouse et.al.2014).

Various clinical studies have associated low vitamin D levels with cancer and other chronic diseases. In two prospective, cohort studies, over 187,000 patient’s vitamin D levels were evaluated and followed up to 20 years. In women whose serum vitamin D levels were in the highest quartile, a 40% decrease of MS was observed. (Munger et.al. 2004) The Women’s Health Initiative established that participants with baseline calcidiol levels of less than 12 ng/mL had a 253% higher risk of developing colorectal cancer compared with women who started out at levels over 24 ng/mL. (Wactawski-Wendeet.al. 2006) Other diseases associated with vitamin D deficiency are shown in Figure 2 (Holick & Chen, 2008).

A schematic representation of the major causes of vitamin D deficiency and potential health consequences. AODM, adult onset diabetes mellitus; CHD, coronary heart disease; FEV1, forced expiratory volume in 1 s; HAART, highly active antiretroviral therapy; HBP, high blood pressure; MS, multiple sclerosis; RA, rheumatoid arthritis; TB, tuberculosis; URI, urinary tract infection.

Figure 2. Diseases Associated with Vitamin D. Deficiency

A study in Sweden conducted at the medical university of Karolinska Institutet showed that concentrations of tacrolimus and sirolimus varied in individuals depending on their vitamin D levels. The patient’s drug levels became toxic during the winter due to vitamin D deficiency (Lindh et.al. 2011). This study exhibits the effects of vitamin D on CYP enzymes in the liver that are important in breaking down pharmaceutics. It has been demonstrated that calcitriol can also enhance the transcription of CYP3A4 via a VDR-mediated pathway (Wang et.al. 2013). These studies continue to be published and will change the way vitamin D is viewed by health care providers.

3.0 vitamin d guidelines

In the US, we look to two organizations for vitamin D recommendations: The Institute of Medicine and The Endocrine Society. In 2010, the Institute of Medicine recommended that blood levels of calcidiol over 20ng/ml are all that is needed for good bone health for practically all individuals (IOM, 2010). In 2011, the Endocrine Society recommended that blood levels of calcidiol over 30ng/ml are sufficient for bone health (Holick et.al. 2011). These levels were primarily based on data for bone health and did not take other disease states into consideration. The Endocrine Society made a statement that long term clinical trials are needed to determine the influence of vitamin D levels on other disease states (Holick et.al. 2011).

Table 1: Institute of Medicine and Endocrinology Society Vitamin D Recommendations

*Serum concentrations of 25(OH)D(calcidiol)

4.0 populations at high risk for deficiency

Both the Institute of Medicine and the Endocrine Society recommend 600 international units (IU) of vitamin D per day for children 1 and older and adults aged 19 to 50 years old. Adults 50 to 70 years old are recommended to get between 600 and 800 IU of vitamin D daily (Holick et.al. 2011). The Endocrine Society acknowledged these recommendations may not get the patients’ calcidiol levels to the recommended 30 ng/ml. Harvard School of Public Health made a statement about the updated guidelines, “For bone health and chronic disease prevention, many people are likely to need more vitamin D then even these new government guidelines recommend.” (“Harvard Health Journals,” 2007)

The Endocrine Society recommends screening for individuals at high risk of vitamin D deficiency. Risk factors for vitamin D deficiency include: darker skin color, males, over 65 years old, religious groups which wear excess clothing, exclusively breast fed babies, inhabitation in areas of low natural UVB, increased BMI, genetic variations in vitamin D receptors (VDR), and fat malabsorption disorders, such as gastric bypass (Holick et.al. 2011). Having one or more of these factors will put a person at risk of vitamin D deficiency and annual blood testing is recommended.

Obesity has become an epidemic in the United States and is a major concern for public health. Obesity puts people at risk of vitamin D deficiency, even when proper supplementation occurs. Studies conducted using radio-labeled vitamin D3 show that the highest levels of vitamin D accumulate in adipose tissue. This sequestration of vitamin D in adipose tissue decreases the vitamins bioavailability (Vimaleswaran et.al. 2013).

Pittsburgh, PA, lies at 40 degrees latitude, which makes it part of the northern hemisphere. It is extremely difficult for a person in Allegheny County to maintain adequate vitamin D levels during the winter months for many reasons. Shortened daylight hours, high levels of air pollution and concealing winter clothing create a barrier for UVB to reach the skin. Most people in Allegheny County, PA, are not able to produce adequate vitamin D from sunlight during these months. This puts nearly everyone in Allegheny County at risk of vitamin D deficiency during the winter months and they should be screened and potentially supplemented to prevent the seasonal drop due to lack of sun exposure.

5.0 conclusion

The purpose of this review is to encourage testing in high risk individuals, including all persons in Allegheny County, PA, during the winter months. Vitamin D deficiency is a very essential topic which is only beginning to be understood in terms of public health and chronic diseases. Testing your patients and recommending vitamin D supplementation when necessary is a cheap, cost effective, and safe way to improve your patient’s health and possibly prevent or delay some life-altering diseases.

BIBLIOGRAPHY

Chiang, K.C. & Chen, T. (2013) The Anti-Cancer Actions of Vitamin D. Anti-Cancer Agents in Medicinal Chemistry;13(1): 126-139.

Coen G. Vitamin D: an old prohormone with an emergent role in chronic kidney disease. (2008). Journal of Nephrology, 21 (3):313-323.

Harvard Health Journals. (February 2007). Vitamin D and your health. Harvard Men’s Health Watch. Boston, Massachusetts.

Haussler, M.R., Whitfield, G.K., Kaneko, I., Haussler, C.A., Hsieh, D., Hsieh, J, & Jurutka, P.W. (2012) Molecular Mechanisms of Vitamin D. Springer Science+Business Media, LLC. DOI 10.1007/s00223-012-9619-0

Holick, M.F., Binkley, N.C., Bischoff-Ferrari, H.A., Gordon, C.M., Hanley, D.A., Heaney, R.P,...& Weaver, C.M. (2011) Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 96 (7). DOI:

Holick, M.F. (2004) Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. American Journal of Clinical Nutrition; 79(3): 362-371.

Holick, M.F. & Chen, T.C. (2008) Vitamin D deficiency: a worldwide problem with health consequences. American Journal of Clinical Nutrition; 87 (4): 1080S-1086S.

Holick, M.F. (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. American Journal of Clinical Nutrition; 80 (6) 1678S-1688S.

IOM (Institute of Medicine) (2010) Dietary Reference Intakes for Vitamin D and Calcium. Washington, DC: The National Academies Press.

Lindh, J.D., Andersson, M.L., Eliasson, E., & Bjorkhem-Bergman, L. (2011) Seasonal Variation in Blood Drug Concentrations and a Potential Relationship to Vitamin D. Drug Metabolism and Disposition, 39 (5): 933-937. doi: 10.1124/dmd.111.038125.

Munger K.L, Zhang, S.M., O’Reilly, E., Hernan, M.A., Olek, M.J., Willett, W.C., & Ascherio, A. (2004). Vitamin D intake and incidence of multiple sclerosis. Neurology, 62:60–5.

Riachy, R., Vandewalle, B., Moerman, E., Belaich, S., Lukowiak, B., Gmyr, V….& Pattou, F. (2006). 1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor. Apoptosis, 11: 151–159.

Ritterhouse LL, Lu R, Shah HB, Robertson JM, Fife DA, et al. (2014) Vitamin D Deficiency in a Multiethnic Healthy Control Cohort and Altered Immune Response in Vitamin D Deficient European-American Healthy Controls. PLoS ONE 9(4): e94500. doi:10.1371/journal.pone.0094500

Schleithoff, S.S., Zittermann, A., Tenderich, G., Berthold, H.K., Stehle, P.,& Koerfer, R. (2006). Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.American Journal of Clinical Nutrition,83: 754–759.

Vimaleswaran, K.S., Berry, D.J., Hyppönen, Lu, C., Tikkanen, E., Pilz, S., Jiraki, L.T.,...Hyppönen, E. (2013) Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts. PLoS ONE

DOI: 10.1371/journal.pmed.1001383

Wactawski-Wende, J.,Kotchen. J.M., Anderson, G.L., Assaf, A.R.,Brunner, R.L., Ph.D., O'Sullivan, M.J.,....& Manson, J.E. (February 2006)The Women's Health Initiative Investigators.New England Journal of Medicine, 354:684-696 DOI: 10.1056/NEJMoa055222

Wang, Z., Schuetz, E.G., Xu, Y., Thummel, K.E. (2013) Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. Journal of Steriod and Biochemical Molecular Biology, 136: 54-58. DOI: 10.1016/j.jsbmb.2012.09.01

Wranicz, J. & Szostak-Wegierek, D. (2014) Health Outcomes of Vitamin D. Part 1, Characteristics and classic role. Rocz Panstw Zakl Hig ;65(3):179-84.

1