Protean Manifestations of Vitamin D Deficiency, Part 2

Deficiency and Its Association With Autoimmune Disease, Cancer, Infection, Asthma, Dermopathies, Insulin Resistance, and Type 2 Diabetes

David S.H. Bell, MD

South Med J. 2011;104(5):335-339. 

Abstract and Introduction

Abstract

Vitamin D deficiency is epidemic and its manifestations are protean. Vitamin D deficiency is associated with autoimmune diseases (particularly multiple sclerosis and type 1 diabetes) and has been associated with infection, allergy, asthma, and dermopathies (particularly psoriasis). Asthma may be worsened by vitamin D deficiency and correction of the deficiency has been shown to improve the manifestations of asthma. Vitamin D deficiency has been associated with multiple cancers, including those of the breast, colon, ovary, and prostate. Due mainly to increased insulin resistance but also to an impairment in insulin release, vitamin D deficiency is associated with the development of type 2 diabetes. In addition, the complications of diabetes may be worsened by vitamin D deficiency.

Introduction

Currently largely due to decreased exposure to sunlight and the epidemic of obesity over the past twnety years there has been an epidemic of vitamin D deficiency. While vitamin D deficiency is classically associated with rickets and osteomalacia its effects are protean. In this article, I review some of these associations-autoimmune diseases, cancer, dermopathies, infection, asthma, insulin resistance and type 2 diabetes.

Vitamin D Deficiency and Autoimmune Disease

When 1-25-OH vitamin D attaches to and activates its nuclear receptor there is a decrease in the formation of macrophages from monocytes and a reduced presentation of antigen containing macrophages to T lymphocytes. Synthesis of immunoglobulins by B lymphocytes and maturation of antigen presenting dendritic cells are also suppressed and delayed sensitivity reactions are inhibited by 1-25 OH vitamin D. Vitamin D receptor activation also has an anti-proliferative effect on activated lymphocytes and suppresses the generation and activity of natural killer lymphocytes.[1,2] The development of vitamin D deficiency results in reactivation of these inflammatory processes and an increased risk for auto-immune diseases. The suppression by 1-25-OH vitamin D of T cell activation and function is achieved through suppression of the T helper 1 (Th-1)-mediated inflammatory immune response which is a key component of vitamin D's capacity to block the development of Th-1 driven autoimmune diseases.[3]

Autoimmune diseases that have been associated with vitamin D deficiency include multiple sclerosis (MS), rheumatoid arthritis, Crohn disease, psoriasis and type 1 diabetes. In addition, polymorphisms of the genes for the vitamin D receptor have been associated with Hashimoto diease, Graves disease, and Addison diseases, but these autoimmune diseases have not to date been reported to be associated with vitamin D deficiency.[4,5]

With type 1 diabetes the development of autoimmunity to pancreatic beta cells may even occur in utero when maternal vitamin D deficiency exists.[6] In addition, vitamin D deficiency, which occurs especially in breast-fed infants, has been shown to increase the incidence of type 1 diabetes.[7,8] In a Finnish study of 10,266 children who received 2000 IU of vitamin D daily for the first year of life, after 30 years the relative risk of developing type 1 diabetes was reduced by 78%.[7]

The availability of sunlight and the association of latitude with autoimmune diseases is best illustrated by the epidemiological patterns associated with MS. In a retrospective Australian study it was found that of all the cases of MS that were diagnosed between 1920 and 1950, there was a 30% higher risk of being diagnosed as having MS if the birth occurred in November and December than if the birth occurred in May and June.[9] This corresponded to lower maternal sunlight exposure five to nine months before birth, and the results of this study initiated an Australian recommendation that supplemental vitamin D be given during pregnancy to avoid maternal vitamin D deficiency and MS in the offspring.[10] Of more than 35,000 pairs of mothers and daughters in the Nurses Mothers Study, 199 nurses developed MS. Comparing mothers who had the highest and lowest vitamin D intake during pregnancy, there was a significant 45% reduction in the development of MS in the daughters of mothers who during pregnancy had a high vitamin D intake. This study also showed that mothers who had a daily intake of four or more glasses of milk, when compared with those with an intake of less than three daily glasses, had a 45% lower risk of having a daughter develop MS.[11] The association of vitamin D deficiency with both obesity and autoimmune disease was shown in a prospective study in which women judged to be obese at age 18 had a 225% increased risk of developing MS.[12] Of veterans who develop MS, the onset is at an earlier age in residents of more northern latitudes and veterans with a history of a lower vitamin D intake.[13]

Vitamin D Deficiency and Infection

In the mid-19th century the power of sunshine to prevent and slow the progression of tuberculosis was recognized. Stimulation of the nuclear 1-25-OH vitamin D receptor results in the expression of anti-microbial peptides which reduce the growth of mycobacterium tuberculosis within the macrophages.[14] Patients with active tuberculosis have been shown to have lower vitamin D levels in spite of the ability of the tuberculosis granuloma to increase the conversion of 25 to 1-25-OH vitamin D because of increased CYP27B1 expression and Toll-like receptor signaling.[15] In active tuberculosis and sarcoidosis, the increased the conversion of 25 to 1-25 OH vitamin D may occasionally cause hypercalcemia.

The incidence of upper respiratory tract infection, regardless of the time of year, is progressively increased with vitamin D deficiency, with the increase being inversely proportional to 25-OH vitamin D levels.[16] The most likely reason for the inverse relationship of vitamin D with infection is that vitamin D improves the efficacy of the barriers to infection that are present in the gut, lung, placenta, and skin. The improved efficacy of these barriers occurs because vitamin D increases the production of cathelicidin, a bactericidal protein. Decreased 1-25-OH vitamin D levels in monocytes and macrophages diminish the expression of genes that activate the Toll-like receptor pathway and the production of cathelicidin and other bactericidal proteins.[17] Indeed it has recently been reported that patients (mostly elderly) who were hospitalized with clostridium difficile enteritis and had a 25-OH vitamin D level of <21 ng/dL, had a 36% 30-day clearance rate of clostridium difficile compared with 53% in those whose 25-OH-vitamin D level was above this level. In addition, the mortality rate was significantly higher (56% versus 33%) in those with lower 25-OH vitamin D levels.[18]

Vitamin D, Psoriasis and Asthma

Vitamin D deficiency, through its effect on the immune system, can result in the development of both atopic dermatitis and psoriasis. The onset and the worsening of the features of dermatological psoriasis is associated with the winter months, northern latitudes, and vitamin D deficiency.[19] A recent randomized controlled study of Irish patients with psoriasis who were given UVB light therapy three times per week during the winter months showed an improvement in the dermal manifestations of psoriasis, which was associated with an increase in vitamin D levels.[20] The study also showed that during winter months 75% of psoriatic subjects were vitamin D deficient.[20]

A major allergic manifestation of vitamin D deficiency is asthma. Children taking inhaled glucocorticoids for asthma have been shown to have not only lower vitamin D levels but also higher IGE levels and inferior lung function.[21] Vitamin D deficiency has an effect on increasing the Thi1-Thi2 ratio balance, which causes smooth muscle contraction, airway inflammation, prostaglandin disregulation, and airway remodeling. In vitro anti-inflammatory markers such as MKP-1 and IL-10 are decreased with the addition of vitamin D. In vivo, the response to dexamethasone in vitamin D-deficient asthmatics was improved tenfold when vitamin D levels were normalized, and in the repletion resulted in decreased utilization of inhaled and oral glucocorticoids as well as inhaled beta agonists. Indeed, for each 1-ng/mL increase in the serum 25-OH-vitamin D level, FEV1 increased by 21 mL/minute, and when 25-OH vitamin D levels were corrected to above 30 ng/mL airway reactivity decreased by 50%.[22] Furthermore, the dose of metacholine that was required to decrease the FEV1 by 20% was decreased by 53.7% and MAP-kinase expression on mononuclear cells increased.[23] The prevalence of asthma has been shown to increase with an increasing body mass index which may be due to vitamin D deficiency.

Vitamin D and Cancer

The greater the distance from the Equator, the greater is the incidence and prevalence of cancer. Furthermore, cancer survival has been shown to be improved in both hemispheres if the cancer was diagnosed during the summer months.[24] The likely explanation for an increased risk of developing a cancer and a worsened prognosis from the cancer in higher latitudes is vitamin D deficiency.[23,24]

The likely mechanism for vitamin D's ability to protect against cancer is that 1-25-OH vitamin D is anti-proliferative and promotes the ordered differentiation of cells. 1-25 OH vitamin D also inhibits telomerase expression, apoptosis, and angiogenesis, which facilitates the spread of tumors.[25–27] In addition, gene expression associated with DNA repair and maintenance of genome integrity is induced by 1-25-OH vitamin D.[25]

Colon, breast, ovary, and prostate cancers have been associated with vitamin D deficiency. Increasing vitamin D intake reduces the risk of both breast and colon cancers by 50%, prostate cancer by 49% and ovarian cancer by 36%.[28] The level of 25-OH vitamin D, even within the "normal range," has been shown to be inversely proportional to the risk for cancer.[29] For example, there is a linear relationship between 25-OH vitamin D levels and breast cancer up to a 25-OH vitamin D level of 62 ng/mL. Mortality from cancer may also be associated with vitamin D deficiency because the 10-year mortality for breast cancer has been shown to be higher (26% versus 14%) in those with 25-OH-vitamin D levels <30 ng/mL when compared with those with levels >30 ng/mL.[29,30]

In the National Health and Nutrition Examination Survey (NHANES) men older than age 40 who had an elevated serum parathyroid hormone (PTH) level (assumed to be due to vitamin D deficiency), had an increase in both the free and total prostate specific antigen (PSA) levels, even after adjustment for age, race and 25-OH vitamin D levels.[31] Indeed, if PTH was above the upper limit of normal, the incidence of an elevated PSA was increased by 43%. In African American males who have a higher incidence and prevalence of prostate cancer, PTH was also higher, indicating that vitamin D deficiency may be an explanation for the higher incidence of prostate cancer in African American men.[31]

Vitamin D and Type 2 Diabetes Mellitus (T2DM)

In the Framingham Offspring Study, those in the highest tertile of 25-OH vitamin D levels had a 40% lower incidence of T2DM than those in the lowest tertile. Furthermore, those in the highest 25-OH vitamin D tertile had significantly lower fasting glucose levels and less insulin resistance as evidenced by lower fasting insulin levels and a 12.7% significantly lower HOMA IR (a measure of insulin resistance) than the lowest tertile.[32]

The proposed mechanisms for the improved insulin resistance achieved by correction of low vitamin D levels are:

  1. that 1-25-OH vitamin D directly stimulates the insulin receptor

  2. that by regulating extracellular calcium, calcium flux and cystolic calcium, the uptake of glucose by myocytes and adipocytes is improved

  3. that by activating the nuclear PPAR delta receptor which regulates free fatty acid metabolism in both the adipocyte and myocyte vitamin D improves insulin resistanceand

  4. through suppressing the activity of the renin-angiotensin-aldosterone system: vitamin D also lowers resistance to the action of insulin.[33]

A feature of insulin resistance and the metabolic syndrome is the presence of tissue fat (particularly in the myocardium, liver and voluntary muscle). By CT scan estimation of the quantity of muscle fat it has been shown that there is a strong negative correlation between the fat content of voluntary muscle and vitamin D levels and in those who had vitamin D deficiency, the volume of muscle fat is increased by 23.6%.[34] In a study of obese African American adolescents not only was vitamin D deficiency highly prevalent but in those with a 25-OH vitamin D levels below 15 ng/ml insulin sensitivity was decreased as evidenced by elevated insulin levels on an oral glucose challenge.[35] Inflammation which is a key component of the metabolic syndrome, is also increased with vitamin D deficiency due to both an increased generation and effectiveness of inflammatory cytokines.[36] In a study of critically ill patients, C-reactive protein levels which are proportional to increases in interleukin-6 levels, were with vitamin D supplementation reduced by more than 25%.[37]

The majority of insulin-resistant subjects do not develop T2DM because they are able to produce enough insulin to overcome resistance to the action of insulin. Therefore, for T2DM to develop in insulin-resistant subjects less than optimal beta cell function must be present. Beta cell function is usually reduced by 50% at the time of the diagnosis of T2DM, 25% five years after the diagnosis, and 10% or less after ten years, which is when most patients with T2DM need insulin.[38] The major factor in the loss of beta cell function in T2DM is accelerated apoptosis, which has been shown to be increased with vitamin D deficiency and decreased when vitamin D deficiency is corrected.[39] The mechanism by which vitamin D deficiency causes beta cell dysfunction is by decreasing glucose-stimulated insulin release rather than by decreasing basal insulin secretion.[39] This is probably because decreased nuclear 1-25-OH vitamin D levels causes an imbalance between extracellular and cystolic calcium which decreases calcium flux which in turn inhibits insulin release. In most but not all studies, correction of vitamin D deficiency improves both insulin release and post-prandial glucose levels.[39]

In prospective studies of vitamin D supplementation the incidence of T2DM has been shown to be reduced. For example, in the Nurse's Health Study those nurses who had a daily intake of at least 800 IU of vitamin D had a 33% lower incidence of T2DM than nurses who had a 200-IU daily intake.[40] A Finnish study showed similar results, but the relationship with vitamin D intake was attenuated after adjusting for BMI, which is not surprising because the vitamin D deficiency was most likely due to obesity.[41] In another Finnish study men in the highest 25-OH vitamin D quartile had a significantly reduced incidence of T2DM and this association persisted even after multivariate adjustments, including an adjustment for obesity.[42] A prospective study of the English community of Ely showed that after ten years the initial levels of serum 25-OH vitamin D were inversely associated with the development of insulin resistance and T2DM.[43] In NHANES, 25-OH vitamin D levels were inversely associated with HbA1c levels in subjects who did not report having diabetes, which supports a mechanistic link between lower vitamin D levels and the risk of developing T2DM.[44]

A prospective interventional study of vitamin D intake and its association with T2DM was performed as part of the Women's Health Initiative. Supplementation with 400 IU of vitamin D daily had no effect on the development of insulin resistance or T2DM and supplementing with 700 daily units had no effect on those who had normal glucose tolerance at baseline.[45] However, if at baseline impaired fasting glucose was present, supplementation with 700 IU of vitamin D daily during the next three years resulted in a decreased development of both insulin resistance and T2DM.[45] This reduction was similar to the reductions in conversion from impaired glucose tolerance to T2DM that occurred in the Diabetes Prevention Trial with lifestyle modification or metformin.[46]

Pregnant women with pre-existing diabetes are more likely to have vitamin D deficiency.[47] In addition, with gestational diabetes lower 25-OH vitamin D levels have been documented.[48,49] In non-diabetic pregnancies the administration of vitamin D in daily doses of 4000 IU compared with daily doses of 2000 or 400 IU has been shown to decrease the incidence of both preterm labor and birth and also to significantly lower the rate of infections that occur during pregnancy.[50] In the pregnant patient with pre-existing T2DM or gestational diabetes the administration of a single large intravenous dose of 1-25-OH vitamin D has been shown to decrease both insulin resistance and the fasting glucose level.[51]

The chronic microvascular complications of diabetes may also be associated with vitamin D deficiency. In NHANES, the prevalence of diabetic nephropathy was significantly increased by 79% in those with vitamin D insufficiency and by 85% in those with vitamin D deficiency.[52] This association persisted after adjustments for race, gender, hypertension, cholesterol level, cigarette smoking and the use of blockers of the renin-angiotensin system.[52] Although an inverse relationship between 1-25-OH vitamin D and the severity of diabetic retinopathy has been reported in patients with diabetic nephropathy[53] an independent relationship between 25-OH vitamin D levels and diabetic retinopathy has to date not been reported. In addition, while the pain of diabetic neuropathy may be helped with vitamin D replacement, vitamin D deficiency has not been directly associated with diabetic neuropathy.

Conclusion

An association of vitamin D deficiency with autoimmune disease (particularly multiple sclerosis and type 1 diabetes) is well established, and vitamin D supplementation has the potential to avoid the development of type 1 diabetes. Vitamin D deficiency has also been associated with infection and allergy and correction of vitamin D deficiency may improve the manifestations of asthma. Because 1-25-OH-vitamin D is anti-proliferative and promotes differention as well as inhibiting apoptosis and angiogenesis, vitamin D deficiency is associated with an increased risk of developing multiple cancers including colon, breast and prostate cancers and is associated with a worsened prognosis from these cancers. Through an effect on insulin resistance and insulin release vitamin D deficiency is associated with type 2 diabetes and may also be associated with diabetic complications.

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