Protean Manifestations of Vitamin D Deficiency, Part 3

Association With Cardiovascular Disease and Disorders of the Central and Peripheral Nervous Systems

David S.H. Bell, MD

South Med J. 2011;104(5):340-344. 

Abstract and Introduction

Abstract

Vitamin D deficiency is associated with the risk factors of inflammation, insulin resistance and endothelial dysfunction, and left ventricular hypertrophy. As a result there is an increase in cardiovascular events (CVEs) associated with vitamin D deficiency. Vitamin D deficiency itself or secondary hyperparathyroidism or both may be responsible for the increase in CVEs. Correction of vitamin D deficiency may decrease the incidence of CVEs. Vitamin D deficiency is also associated with Alzheimer disease, schizophrenia, depression, and chronic pain and muscle weakness. Vitamin D deficiency is early treated with oral vitamin D supplements which may improve the manifestations of the diseases associated with vitamin D deficiency.

Introduction

Vitamin D deficiency is common and its manifestations protean. This article reviews the association of vitamin D deficiency with diseases of the cardiovascular and nervous systems.

Vitamin D and Cardiovascular Disease

Vitamin D deficiency is associated with the cardiac risk factors of insulin resistance, hypertension, vascular calcification, inflammation and left ventricular hypertrophy. Vitamin D has also been associated with an increased incidence of congestive heart failure and an increased mortality resulting from the heart failure.[1]

Deficiency of vitamin D results in an increased expression of genes that are associated with activation of the renin-angiotensin system and genes that are associated with malfunction of calcium channels.[2] Therefore, activation of these genes is likely to lead to hypertension, left ventricular hypertrophy and congestive heart failure.

Hyperparathyroidism (whether primary or secondary to vitamin D deficiency) has also been associated with insulin resistance, inflammation, increased carotid intima-medial thickening and cardiac events.[3] Levels of vitamin D <18 ng/mL are associated with a 40% increase in cardiac events and in NHANES, an increase in cardiovascular mortality.[4] Compared with a 25-OH vitamin D level of >15 ng/mL those with a 25-OH vitamin D level <15 ng/mL had a 53% increase in cardiovascular disease and those with a level below 10 ng/ml had an 80% increase.[4] In older US adults 25-OH vitamin D levels are inversely associated with cardiovascular events and all-cause mortality.[5] Evidence that vitamin D deficiency is associated with the risk factors of inflammation and endothelial dysfunction was shown in those with lower 25-OH vitamin D levels who had increased asymmetrical dimethyl arginine levels, which is a measure of endothelial dysfunction, and higher C-reactive protein levels, which is a measure of inflammation.[6]

Whether it is increased parathyroid hormone (PTH) levels or simply vitamin D deficiency itself that is responsible for the association of vitamin D deficiency with inflammation and insulin resistance was addressed in 1017 morbidly obese subjects, 68% of whom were judged to have insulin resistance. Although there were no differences in 25-OH-vitamin D levels between the insulin-resistant and non-insulin-resistant subjects, PTH was higher and magnesium levels lower in those with insulin resistance. In fact, patients with PTH levels in the second through fourth quartiles had between a 47% and a 109% increased chance of having insulin resistance even after adjusting for other risk factors.[7] In this study, 1-25-OH vitamin D, magnesium, and PTH levels were not associated with insulin resistance and PTH levels were associated with the presence of elevated systolic and diastolic blood pressure levels.[7]

When hypertension is accompanied by a deficiency of vitamin D, correction of the vitamin D deficiency may result in improved blood pressure levels. An older controlled study showed that an increase in vitamin D levels, induced by thrice weekly UVB light therapy, resulted in an average drop in systolic blood pressure of 6 mm Hg.[8] In a Scottish blinded placebo-controlled study performed at the end of winter, vitamin D-deficient individuals were given a single dose of 100,000 U of vitamin D or a placebo. Compared with the placebo group systolic blood pressure dropped by 14 mm Hg and flow-mediated dilatation increased by 2.3% in the group given vitamin D.[9] In a later study single doses of 100,000 and 200,000 units of vitamin D3 resulted in not only the expected improvement in systolic blood pressure in both groups but also a significant decline in brain natriuretic peptide level with the 200,000 unit but not the 100,000 unit dose, indicating that with the higher dose there was an improvement in left ventricular function.[10]

Vitamin D replacement has also been shown to increase total high-density lipoprotein levels mainly due to an increase in the size of the high-density lipoprotein particle.[11] The increase in high-density lipoprotein particle size improves reverse cholesterol transportation which has also been shown to improve with vitamin D replacement.[12] Furthermore in an in vitro study which utilized macrophages from type 2 diabetic subjects, the uptake of oxidized low-density lipoprotein and the formation of foam cells was increased when vitamin D was absent. However, in the presence of vitamin D there was activation of the 1-25-OH vitamin D receptor which decreased the uptake of oxidized low-density lipoprotein by the macrophages and foam cell formation.[13]

Surrogate markers of atherosclerosis have also been shown to be increased with both vitamin D deficiency and secondary hyperparathyroidism. With hyperparathyroidism there are increases in carotid stiffness, thickness of carotid plaques, and intima-medial thickness.[14] In fact, for each 10 pg/mL elevation of PTH, carotid stiffness increased by 91%. In subjects with type 2 diabetes mellitus, vitamin D deficiency, with or without hyperparathyroidism, has been shown to be strongly and directly associated with carotid atherosclerosis.[14]

In type 2 diabetes mellitus patients, 75% of who are hypertensive, an already high rate of cardiovascular events is further increased with vitamin D deficiency. In the Framingham Heart Study the presence of vitamin D deficiency did not increase cardiac events in non-hypertensive subjects, but in hypertensive subjects with a 25-OH vitamin D level <15 ng/mL, after five years the probability of CV disease was increased by 62% when compared with hypertensive subjects who had vitamin D levels >15 ng/mL. That vitamin D deficiency is not just associated with cardiac events but may be the cause of these events, was shown in a prospective study where after one year subjects who had their vitamin D levels normalized had a 30% lower morality.[16] In this study the threshold for 25-OH vitamin D above which there was no further benefit in mortality, cardiovascular events or heart failure was 43 ng/mL.[16]

Vitamin D deficiency has also been associated with heart failure (HF). In 3299 subjects having coronary angiography and prospectively followed for seven years, low initial 25-OH vitamin D levels were associated with both HF and sudden cardiac death.[17] A recent NHANES study showed that compared with those with a normal 25-OH vitamin D level (>30 ng/dL), subjects with a level between 20 and 29 ng/dL had twice the frequency of death due to heart failure, whereas those with levels <20 ng/dL had a 3.4-fold increased risk. Indeed those who died of HF were 50% more likely to have a deficiency of vitamin D.[18] In another study, vitamin D deficiency was also associated with a lower exercise tolerance in patients who had systolic HF.[19] It is possible that these negative outcomes are associated with inflammation because HF is an inflammatory state associated with increased levels of inflammatory cytokines, and patients with the highest cytokine levels have the worst prognosis. In HF patients cytokine levels are further increased with vitamin D deficiency and can be reduced with vitamin D replacement.[20] HF is also associated with increased activity of the renin-angiotensin aldosterone system which may be further increased with vitamin D deficiency and ameliorated with vitamin D replacement.[21]

The association of vitamin D deficiency with HF may also be because of secondary hyperparathyroidism. Not only is excessive PTH associated with insulin resistance, inflammation, and vascular stiffness but it is also associated with myocardial hypertrophy and fibrosis.[22,23] Through activation of the 1-25-OH vitamin D nuclear receptor, vitamin D has been shown to suppress myocardial hypertrophy and abrogate the hypercontractability of the myocardium that is observed with diastolic HF.[24,25] Therefore the association of vitamin D deficiency with HF is likely due to both the effects of vitamin D deficiency and secondary hyperparathyroidism on the myocardium. Based on the available evidence it is likely that HF can be avoided, and with existing HF exercise tolerance can be improved and mortality decreased by correcting the deficiency of vitamin D.

Central Nervous System Manifestations of Vitamin D Deficiency

At least in vitro, vitamin D seems to be neuroprotective.[26] In Alzheimer disease, 1-25-OH vitamin D receptors are downregulated and in older adults cognitive function may be inversely related to vitamin D levels as assessed by a simple mini-mental status examination.[27,28] Higher 25-OH vitamin D levels have also been associated with better memory and information processing, with information processing but not memory persisting after adjustments for other risk factors.[29] In another study, cognitive impairment was most pronounced when the 25-OH vitamin D level was <14 ng/dL.[30]

Low vitamin D levels are associated with chronic fatigue. In a group of head injury patients 80% of those with vitamin D deficiency compared with 40% of those with normal 25-OH vitamin D levels complained of chronic fatigue, especially in the presence of a coexisting sleep disorder.[31] Vitamin D deficiency may also be associated with an increased risk of developing Parkinson disease because cross-sectional studies of patients with Parkinson disease have shown an association with vitamin D deficiency.[32] For example, a cross-sectional study from the southeastern United States showed that the prevalence of vitamin D deficiency was significantly increased in subjects with parkinsonism compared with controls (55% versus 36%) and even subjects with Alzheimer disease (41%).[33] A Finnish longitudinal cohort study after multiple adjustments found that the risk of developing Parkinson disease was 70% less in those in the top quartile versus those in the bottom quartile of 25-OH vitamin D levels.[32]

Although vitamin D deficiency has an association with depression, it is difficult to differentiate whether the vitamin D deficiency is the cause or a consequence. In a large cross-sectional population study, both the presence and the severity of depression were strongly associated with both low vitamin D and high PTH levels.[34] As would be expected, vitamin D deficiency often accompanies seasonal affective disorder, for which UVB therapy will improve both the vitamin D level and the depression. In the CHIANTI study of Italian men and women older than age 65 lower vitamin D levels were associated with an increase in depressive symptoms.[35]

Schizophrenia has a much higher prevalence at the Arctic Circle than it does at the Equator. Poor prenatal care may also be a factor at higher latitudes where the darker-skinned Inuit population need a higher intake of vitamin D. Exposure to low vitamin D intake in utero and in early life has clearly been shown to adversely affect brain development and may be associated with the development of schizophrenia.[36] A retrospective study from Finland showed that vitamin D supplementation during the first year of life was associated with a reduced risk of schizophrenia in men but not women.[37]

Pain, Muscle Weakness, Degenerative Joint Disease, and Vitamin D Deficiency

Both chronic pain and muscle weakness can result from vitamin D deficiency. 25-OH vitamin D levels <12 ng/dL have been associated with severe pain and muscle weakness, which have both rapidly resolved with vitamin D replacement.[38,39] It has been estimated that 90% of non-fibromyalgia-related muscle pain may be due to vitamin D deficiency and also that the pain associated with diabetic neuropathy can be alleviated when vitamin D deficiency is corrected.[40] In contrast, pain associated with fibromyalgia has never been shown to be associated with vitamin D deficiency nor to be improved with vitamin D supplementation.[41] US servicemen returning from Iraq and Afghanistan often have musculoskeletal pain due to demineralized bone hydration, expanding and stretching the periosteum. Vitamin D deficiency due to lack of sun exposure with battle dress is responsible for these findings, and correction of vitamin D deficiency results in a rapid resolution of the musculoskeletal pain.[39]

Improvement in neuropathic pain with the correction of vitamin D deficiency should not be surprising because vitamin D through its receptor modulates neuronal differentiation, growth, and function.[42] A deficiency of vitamin D impairs nociceptor function, worsens nerve damage, and lowers the pain threshold.[43] Neuromuscular coordination also improves with correction of vitamin D deficiency as evidenced by the decreased frequency of falls in elderly subjects.[44]

With degenerative joint disease, correction of vitamin D deficiency may result in relief of pain due to not only elevation of the pain threshold but also an effect on the underlying disease. A study of men with a 25-OH vitamin D levels between 15 and 30 ng/mL compared with those with a level >30 ng/dL showed a 2.19% increased prevalence of osteoarthritis of the hip. A possible reason for the association of vitamin D deficiency and degenerative joint disease is that the Wnt pathway, from which chemicals that are important in cartilage formation are generated, is regulated by 1-25-OH vitamin D. In addition, chondrocyte metabolism is adversely affected by a deficiency of vitamin D. Vitamin D also regulates the ratio of RANKL to osteoprotegrin so that a deficiency of vitamin D will result in a deterioration in the formation and repair of the articular bone.[45]

A common painful situation is statin-induced myalgia, myositis, or occasionally rhabdomyolysis. Statin-induced myopathies most commonly occur with statins that are fat-soluble and/or inhibit the hepatic enzyme CYP3A4. The clinical experience has been that myopathies associated with statin therapy can often be resolved by correcting vitamin D deficiency and a recent single case study reported resolution of statin myalgias with vitamin D replacement.[46] However, a larger retrospective observational study showed that vitamin D levels were significantly lower in patients with myalgias and that in myalgic subjects correction of vitamin D deficiency resulted in the resolution of statin-induced myalgias in 92%.[47] An Australian prospective study found that four of six patients with statin-induced myalgias and vitamin D deficiency following correction of this deficiency on rechallenge with the same statin were statin tolerant.[48] However, in a retrospective analysis, vitamin D levels did not show an association with myalgias in the Treating to New Targets study, in which subjects were treated with either simvastatin 80 mg or atorvostatin 10 mg.[49]

Treating Vitamin D Deficiency

Nutritionally, vitamin D can be derived from dairy foods and fatty fish such as salmon, mackerel, and tuna. However, 20 minutes of sunshine or five to seven minutes in a tanning bed generate five times more vitamin D3 than that obtained from eating 3 ½ ounces of salmon.[50] Exposure to sunlight also increases the risk of skin malignancies, so that various recommendations for the prudent use of sunscreen such as leaving the arms and legs free of sunscreen or delaying use of sunscreen for 20 minutes after exposure have been advocated. However, oral supplementation with either vitamin D2 or vitamin D3 is probably a safer but less physiological way to normalize vitamin D levels. Proponents of cholecalciferol (vitamin D3) claim that D3 is 3- to 10-fold more effective in raising 25-OH vitamin D levels, has a higher affinity for the vitamin D binding protein, results in more 25-OH vitamin D generation, and has a greater affinity for the vitamin D receptor. Proponents of D3 also claim that vitamin D3 but not vitamin D2 (ergocalciferol, a synthetic vitamin D product) has been shown to prevent bone fractures. However, most clinicians believe that there is little if any difference between supplementation with D3 and D2 and because D2 is more readily available, it is the most prescribed vitamin D replacement therapy.[51]

When vitamin D deficiency is diagnosed, doses of 50,000 to 100,000 U weekly dependent upon the 25-OH vitamin D level are recommended. After three months if the 25-OH vitamin D level is in the sufficiency range, the weekly dose that resulted in the correction of the 25-OH vitamin D level should be administered on a monthly basis or more frequently depending on monitoring of 25-OH vitamin D levels.[1,51] In severe cases of vitamin D deficiency such as those that occur after gastric bypass surgery, higher and more frequently administered doses may be necessary.

Conclusion

Vitamin D deficiency is common, easily detected, and easily treated. Vitamin D deficiency is also associated with insulin resistance, type 2 diabetes, cardiovascular disease, central and peripheral nervous system dysfunction and chronic pain syndromes. Whether early recognition and correction of vitamin D deficiency may prevent reverse or ameliorate these diseases has not been established or even assessed. As a result, the Institute of Medicine reported that a 25-OH vitamin D level is adequate for bone strength and that it was not clear whether higher levels are beneficial for other medical conditions because studies are based on associations and do not prove causality. It was also stated that a level >50 ng/mL had the potential for adverse health effects (hypercalciuria and nephrolithiasis) and that a level between 20 and 50 ng/mL is safe and effective for bone health. However, particularly with cardiovascular disease, outcomes of vitamin D replacement therapy have been encouraging. Research into the prevention and improvement of conditions associated with vitamin D deficiency is urgently needed. Should these outcome studies show a benefit from correcting vitamin D deficiency, it will then be proven that screening for vitamin D deficiency is both beneficial and cost-effective.

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