Vitamin D status and arterial hypertension: a systematic review

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This is an excellent article from Nature Reviews Cardiology, 18 August 2009, and offers doctors CME 0.75 AMA PRA Category 1 Credits. Click blue link below for complete article.

Stefan Pilz¹, Andreas Tomaschitz¹, Eberhard Ritz² & Thomas R. Pieber¹

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A short excerpt is included here:

Vitamin D deficiency is common and is primarily caused by a lack of ultraviolet-B (UVB) radiation from reduced sun exposure, and the consequent limiting of vitamin D production in the skin. The vitamin D endocrine system regulates about 3% of the human genome. Observational data support the concept that vitamin D is involved in the pathogenesis of cardiovascular diseases and arterial hypertension. The antihypertensive properties of vitamin D include renoprotective effects, suppression of the renin–angiotensin–aldosterone system, direct effects on vascular cells, and effects on calcium metabolism, including prevention of secondary hyperparathyroidism. The results of clinical studies largely, but not consistently, favor the hypothesis that vitamin D sufficiency promotes lowering of arterial blood pressure. Randomized, placebo-controlled trials are greatly needed to clarify and definitively prove the effect of vitamin D on blood pressure. In general, the antihypertensive effects of vitamin D seem to be particularly prominent in vitamin-D-deficient patients with elevated blood pressure. Thus, in view of the relatively safe and inexpensive way in which vitamin D can be supplemented, we believe that vitamin D supplementation should be prescribed to patients with hypertension and 25-hydroxyvitamin D levels below target values.

Key points

• Vitamin D deficiency is common and can be attributed to reduced sun exposure, which limits ultraviolet-B (UVB)-induced vitamin D production in the skin
• Most cells express the vitamin D receptor (VDR) as well as 1-hydroxylase, which underlies several regulatory mechanisms and converts 25-hydroxyvitamin D (25[OH]D; used to classify vitamin D status) to 1,25-dihydroxyvitamin D (1,25[OH]2D)
• 1,25(OH)2D has high affinity for the VDR, but circulates in lower concentrations than 25(OH)D and is more an indicator of calcium homeostasis and kidney function than vitamin D status
• About 3% of the human genome is directly or indirectly regulated by the vitamin D endocrine system
• The antihypertensive effects of vitamin D include renoprotective effects, suppression of the renin–angiotensin–aldosterone system, effects on calcium homeostasis including the prevention of secondary hyperparathyroidism, and vasculoprotection
• Accumulating evidence—from insights into molecular mechanisms to the outcome of randomized trials—favors the hypothesis that vitamin D deficiency contributes to arterial hypertension, but further data are needed

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Introduction

Vitamin D insufficiency affects almost 50% of the population worldwide.¹ This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin. Levels of UVB radiation diminish with increasing distance from the earth’s equator, during the winter months, and as a result of air pollution. Black people absorb more UVB in the melanin of their skin than do white people and, therefore, require more sun exposure to produce same amounts of vitamin D.² Importantly, conditions associated with reduced UVB-induced vitamin D production, such as high latitude, industrialization, and dark skin, have all been associated with increased blood pressure values.² The logical hypothesis that high UVB-induced vitamin D production is associated with low blood pressure was confirmed by a small trial of 18 patients with untreated essential hypertension.³ The researchers found that systolic and diastolic blood pressure values were reduced by 6 mmHg after 6 weeks of UVB irradiation three times per week. UVB irradiation was also associated with a 162% rise in plasma 25-hydroxyvitamin D (25[OH]D) concentrations, but in hypertensive patients who received UVA irradiation, no significant change in 25(OH)D levels or blood pressure occurred.³

The high prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population.⁴ A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality.⁵ Furthermore, vitamin D insufficiency is associated with an increased risk of cardiovascular events, but whether this association reflects a causal relationship remains unclear.^{6, 7, 8} The effect of vitamin D on blood pressure could be one of the potential mechanisms underlying the link between vitamin D and cardiovascular disease. In this Review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and arterial hypertension, and examine the clinical data for this association.

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Vitamin D metabolism

In humans, the primary source of vitamin D is UVB-induced conversion of 7-dehydrocholesterol to vitamin D in the skin.¹ Just 10–20% of our vitamin D comes from dietary sources, such as fish, eggs, or vitamin-D-fortified milk (Figure 1).¹ Vitamin D is hydroxylated in the liver to 25(OH)D—the main circulating vitamin D metabolite, which is largely bound to vitamin D binding protein in serum, and is used to classify vitamin D status: vitamin D sufficient (25[OH]D 30 ng/ml [or 75 nmol/l]), vitamin D insufficient (25[OH]D 20–30 ng/ml [or 50–75 nmol/l]), and vitamin D deficient (25[OH]D <20 ng/ml [or <50 nmol/l]).¹ These cut-points are currently the most commonly used classification of vitamin D status, but some debate about exact threshold values still exists. Some researchers consider 25(OH)D levels of 10–20 ng/ml (25–50 nmol/l) as vitamin D insufficient and levels below 10 ng/ml (25 nmol/l) as vitamin D deficient, whereas others use a cut-off level of 40 ng/ml (100 nmol/l) to define sufficient vitamin D status.^{9, 10} 25(OH)D is transformed by renal or extrarenal 1-hydroxylase into 1,25-dihydroxyvitamin D (1,25[OH]2D), which circulates at much lower serum concentrations than 25(OH)D, but has a much higher affinity to the vitamin D receptor (VDR).¹¹ Serum levels of 1,25(OH)2D are mainly determined by renal 1,25(OH)2D production, which is closely related to calcium homeostasis, and is upregulated by parathyroid hormone, the concentration of which increases when calcium levels are low.^{1, 12} In addition, other factors such as fibroblast growth factor 23 and Klotho, which suppress 1-hydroxylase expression, have also been shown to regulate the renal conversion of 25(OH)D to 1,25(OH)2D.¹³ Studies have, however, shown that many other cell types, including those of the vascular wall, express 1-hydroxylase with subsequent intracellular conversion of 25(OH)D to 1,25(OH)2D, which exerts its effects at the level of the individual cell or tissue before being catabolized to biologically inactive calcitroic acid.^{1, 12, 14} These intracellular tissue levels of 1,25(OH)2D are determined by the concentration of circulating 25(OH)D, which is, therefore considered the best indicator of whole-body vitamin D status. Importantly, extrarenal 1-hydroxylase expression also underlies various regulatory mechanisms. In this context, extrarenal 1,25(OH)2D production in macrophages is stimulated by Toll-like receptor as part of the innate immune response against intracellular bacteria.¹⁵ Another example of extrarenal regulation of 1-hydroxylase is the increased production of 1,25(OH)2D by keratinocytes in wounds, which could be induced by transforming growth factor 1.¹⁶ 25(OH)D serum levels, therefore, provide a good estimate of vitamin D status, but regulation of 1-hydroxylase activity should also be considered.

1,25(OH)2D binds to the VDR and, after forming a heterodimer with the retinoid X receptor (RXR), binds to specific DNA sequences—the so called ‘vitamin D responsive elements’. These sequences are located in the promoter regions of various vitamin-D-dependent genes that are either upregulated or downregulated by the RXR–VDR complex.^{1, 12, 14} Approximately 3% of the human genome is directly or indirectly regulated by the vitamin D endocrine system, which supports the idea that vitamin D insufficiency has widespread adverse consequences for human health.¹⁴ In addition to cardiovascular pathology, vitamin D insufficiency can cause musculoskeletal, malignant, metabolic, or immunological diseases.^{1, 12, 14}

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Vitamin D Anti-hypertensive effects

(click link for slide)

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Vitamin D toxicity

When discussing the beneficial effects of vitamin D on blood pressure, one must consider that pharmacological doses of vitamin D have been shown to cause arterial hypertension, vascular stiffness, and atherosclerosis in rodents; whether this finding has any relevance for humans is unclear.¹²⁹ In humans, vitamin D toxicity and associated hypercalcemia—which can cause reversible hypertension—is observed when 25(OH)D levels are higher than 150 ng/ml (374.4 nmol/l).¹ In clinical trials, vitamin D toxicity was not observed with doses of up to 10,000 IU vitamin D per day, which is approximately the level of vitamin D production that can be achieved by endogenous UVB-induced vitamin D synthesis in the skin.^{130, 131} Consequently, at 10,000 IU vitamin D per day, and in the absence of increased vitamin D sensitivity (for example, sarcoidosis or tuberculosis), vitamin D supplementation is safe. Presumably there is a wide margin between the level of 25(OH)D needed for vitamin D sufficiency (30 ng/ml [or 75 nmol/l]) and the level of toxicity (>150 ng/ml [or >374.4 nmol/l]).

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Vitamin D supplementation

An intake of 1,000 IU (25 g) of vitamin D per day can be generally assumed to result in an increase in 25(OH)D levels of approximately 10 ng/ml (25 nmol/l).^{132, 133} Evidence indicates that daily, weekly, and monthly vitamin D dosing frequencies can equally increase serum 25(OH)D levels, which have a half-life of about 1 month. In this context, an oral vitamin D intake of 1,500 IU daily, 10,500 IU once weekly, or 45,000 IU once every 28 days has been demonstrated to result in similar increases of 15–16 ng/ml (37.4–40.0 nmol/l) in 25(OH)D levels.¹³⁴ The dose to correct vitamin D deficiency should be sufficiently high to achieve 25(OH)D levels of at least 30 ng/ml (75 nmol/l). For example, a patient with 25(OH)D levels of 10 ng/ml (25 nmol/l) should receive at least 2,000 IU daily, which corresponds to weekly doses of at least 14,000 IU or monthly doses of at least 56,000 IU. Several authors recommend loading doses in the initial phase of treatment (that is, 50,000 IU weekly for 8 weeks or 50,000 IU daily for 1 week) before starting maintenance therapy (that is, at least 1,000 IU vitamin D for a person with initial 25[OH]D levels of 20 ng/ml [50 nmol/l]).^{1, 10} Individual response to vitamin D doses does, however, vary widely and certain patients, such as those who are obese or suffer from malabsorption, might require much higher vitamin D doses than individuals without comorbidities.^{1, 133} Measurements of 25(OH)D levels are, therefore, useful to monitor 25(OH)D levels and to allow for adequate correction of the vitamin D dose. 25(OH)D levels should be reassessed 3–6 months after initiation of vitamin D supplementation. In patients with increased vitamin D sensitivity, such as those with sarcoidosis or tuberculosis, calcium should be measured in the initial phase of treatment. One problem with vitamin D treatment is that, although maintaining 25(OH)D levels above 30 ng/ml (75 nmol/l) is generally recommended, no consensus exists about optimal 25(OH)D levels. At present, many researchers recommend maintaining 25(OH)D levels between 30 and 60 ng/ml (75.0–149.8 nmol/l).^{1, 10} We do not know whether higher levels than this are beneficial or detrimental. Data from NHANES-III indicate a ‘J-shaped’ association between 25(OH)D levels and mortality, with the highest mortality in persons with the lowest 25(OH)D levels, but with slightly increasing mortality in those with supraphysiological 25(OH)D levels. However, other data indicate that particularly high levels of vitamin D are optimal for cancer prevention.^{4, 10}

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Conclusions

Accumulating evidence, ranging from insights into molecular mechanisms to the outcome of randomized controlled trials, favors the hypothesis that vitamin D deficiency contributes to arterial hypertension. The antihypertensive effects of vitamin D are mediated by renoprotective effects, suppression of the RAAS, by beneficial effects on calcium homeostasis, including the prevention of secondary hyperparathyroidism, and by vasculoprotection. However, definitive evidence from appropriately powered, controlled, intervention trials is lacking. Some inconsistent results from studies of the relationship between vitamin D status and arterial hypertension have been reported, possibly because the effects of 25(OH)D on blood pressure are not apparent in normotensive individuals with 25(OH)D levels within the normal range. In general, evidence for the antihypertensive effects of vitamin D is strongest in patients with elevated blood pressure and vitamin D deficiency; these patients would, in our opinion, benefit from vitamin D supplementation. In addition to cardiovascular sequelae, vitamin D deficiency has been associated with autoimmune, malignant, neurological, metabolic, and infectious diseases, as well as with bone fractures.^{1, 12, 14, 117, 130, 131} In view of the multiple health benefits of vitamin D and the high prevalence of vitamin D deficiency, as well as the easy, safe, and inexpensive ways in which vitamin D can be supplemented, we believe that the implementation of public health strategies for maintaining a sufficient vitamin D status of the general population is warranted.^{1, 12, 117, 130, 131}

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Vitamin D – A Steroid Hormone, Anti-inflammatory

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The Sunshine Vitamin Controversy

What should normal values  be for calcium homeostasis?

My attention was drawn to Vitamin D several years ago when a review appeared in the journal Neurology, published by the Academy of Neurology, that linked low levels of Vitamin D to Multiple Sclerosis.  The article was unusual for its length and the breadth of research cited over several decades.  More recently, a Johns Hopkins article published “the most conclusive evidence to date” that Low Vitamin D Levels Pose Large Threat to Health.

New publications on Vitamin D seem to appear every week with the focus on levels of 25-hydroxyvitamin D, also written as 25(OH)D. Its half life in serum is ~ 10 days to 3 weeks.

The biologically active form 1,25-dihydroxyvitamin D, written as 1,25(OH)D²,  is made in the kidneys and has a much shorter serum half-life of ~ 4-6 hours, thus making it less useful as a serum marker for measuring.

Sources & Metabolism: Vitamin D is a fat soluble vitamin that’s absorbed in the small intestine from  foods such as egg yolks, fatty fish, fish liver oils, fortified milk, margarine, and cereals.  Bile salts are required for absorption.  Sunlight stimulates the skin to synthesize vitamin D, but exposure of hands and face as little as 15 minutes may not be sufficient and it is not as effective for everyone.  It won’t work in winter months, it won’t work for the aged, for those who have pigmented skin, and it won’t work for those who cover their skin.

Vitamin D Metabolism

The Controversy –  How Do We Determine Normal Values?

Surprisingly, in a well designed multicenter study of healthy young Hawaiians in their 20’s who were exposed to at least 29 hours of sun per week, 51% were found to have vitamin D deficiency using the usual cut off of 30 ng/ml for normal.  This study from 2007 found the mean concentration of 31.6 ng/ml, and the highest of 62 ng/ml.  It raises the question whether

“it seems prudent to use this value [60 ng/ml] as an upper limit when prescribing vitamin D supplementation,”

rather than the generally published normal range of 30 to 80 ng/ml or even 100 ng/ml quoted in some labs.  This study is important in discussing the controversial question of what normal values should be for calcium homeostasis and reviews several possible explanations for inadequate production of D3 including genetic differences.

They note the highest reported values in “Nebraska outdoor workers… were between 81 and 84 ng/ml” but the assay system differed compared to theirs and results in a higher value.   Reviewing this study that was published in the Journal of Clinical Endocrinology & Metabolism has allowed me just now to readjust my own patient practice.

Laboratory Testing:  results can differ from one laboratory to another.  My hospital sends specimens to ARUP for testing, whereas Quest has acknowledged errors in laboratory testing and problems with standardization as reported by the New York Times here.

Function:  It is important for absorption of calcium and phosphorous from the small intestine, for bone health, osteoporosis, risk of falls, certain cancers(colon, breast, prostate), and possibly 6 to 7 years of longevity.  Deficiency of vitamin D is associated with suboptimal health and possibly increased pain; it is linked to infections, gum disease, hypertension, diabetes, coronary disease, neurological diseases such as Multiple Sclerosis, Parkinson’s Disease, dementia and Alzheimer’s Disease though it may not be causal. Its receptor is found all over the body including the brain.

I recommend this review by one of the best web resources at Memorial Sloan Kettering Cancer Center Herbs & Botanicals.

They quote a reference showing it reduces postmenopausal weight gain and “In adults with impaired fasting blood glucose, giving calcium and vitamin D reduced increases in plasma glucose and insulin resistance….”

It is the only vitamin that is a steroid hormone, and my interest increased on learning that it functions as an anti-inflammatory.  But as I tested blood levels for 25(OH) vitamin D and parathyroid hormone (PTH), I discovered more than 90% of my patients had vitamin D deficiency and a few had hyperparathyroidism.  There are four parathyroid glands next to the thyroid, and for some reason doctors have rarely tested their hormone levels.

***Persons with hyperparathyroidism should NOT take calcium or vitamin D.

It may lead to kidney stones and bone pain:  stones, bones and groans.***

Evidence for Optimizing Vitamin D Concentrations

On the other hand, if vitamin D is low, there is some evidence that replacement with vitamin D3 so that blood levels are in the high normal range, may help pain.  That is, it may raise the pain threshold and possibly have other benefits for health and longevity. It is desirable to avoid toxic levels of D as it causes hypercalcemia with depression, drowsiness, weakness, headache, polydipsia,  bone loss, and metastatic calcifications of many organs, soft tissues and blood vessels.  The generally quoted range of normal for 25(OH) vitamin D is 30 to 80, that varies with the lab.

Doesn’t that photo of the Great Western Divide make you want to get outside into the sun?

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes was reviewed by Heike Bischoff-Ferrari et al, in 2006,  though it has been superseded by much additional work since then.

To quote from their article:

This review summarizes the evidence for optimal serum  25(OH)D concentrations. The endpoint selection for this review was based the strongest evidence to date—ie, that from RCTs [randomized controlled trials], consistent evidence from prospective and cross-sectional epidemiologic studies, and strong mechanistic evidence or dose response relations.  BMD [bone mineral density], fracture prevention, lower-extremity function, falls, oral health, and colorectal cancer met these criteria. Weaker evidence exists of a beneficial effect of vitamin D on other diseases, including multiple sclerosis (15), tuberculosis (16), insulin resistance (17, 18), cancers other than colorectal (19 –22), osteoarthritis (23, 24), and hypertension (25–27), but these diseases are not considered here.

They did not review pain studies.  I would add that “weaker” evidence merely means that it must be confirmed by more studies, not that it excludes those conditions.  There is an epidemic of vitamin D deficiency in the country, and the incidence is very high in pain clinics as reported in several studies.

A new multi-center epidemiology study  “Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004”  by Ginde, et al, in 2006,  “demonstrate a marked decrease in serum 25(OH)D levels from the 1988-1994 to the 2001-2004 NHANES data collections.”  And like others before them, they point out:

“Current recommendations for vitamin D supplementation are inadequate to address the growing epidemic of vitamin D insufficiency.”

Summary:

Make sure your doctor checks both your 25(OH)Vitamin D and parathyroid hormone level (PTH) – not thyroid – to determine if you have hyperparathyroidism or if you have normal or low vitamin D.  That will determine if you need replacement or if you should stop using calcium and D as it will cause kidney stones and calcium deposits on your bones leading to pain.

If vitamin D levels are low it may result in increased physical pain and may cause or aggravate many medical conditions.

If PTH levels are high indicating hyperparathyroidism it will cause new painful conditions.

Intake does vary with the patient, the season, the age, but the recommended daily allowance may perhaps be double what it is now.  It is unclear when the federal government will adjust that dosage.   As always, your physician’s recommendation will be based upon blood levels of 25(OH)D and PTH.

Do not make changes in your dosage without careful evaluation.

Could this possibly be one of the most important areas of research this century?

The material on this site is for informational purposes only, and

is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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Welcome to my Weblog on Pain Management! Thanks for stopping by.

Seven years since I started this blog April 2009. It is very exciting to have this resource as a way to structure the many research publications and ideas I come across in Pain Management, Neurology, Integrative Medicine, Neuroimmunology and, yes, politics of medicine. I only wish I had had this tool decades ago so that I didn’t have to recreate the ones I’ve already reviewed and forgotten in the last 41 years, long before MRI scans and decades before computers in daily medicine. Now we all risk carpal tunnel from repetitive injury.

Chronic pain is often much more difficult to treat than cancer pain. It is tragic that < 1% of NIH budget goes for pain research, though 10 to 20% of the population in the US suffers from chronic pain, an estimated 60 million Americans, and the conditions are more prevalent among the elderly. Persons of all ages that I see tend to be more debilitated, often with anywhere from 3 to 14 different identifiable pain syndromes.

Many, including physicians, mistake pain as a symptom, failing to understand the reorganization that has occurred in the central nervous system due to neuro-plasticity; and they overlook the associated co-morbidity causing insomnia, weight gain due to medication or inactivity, depression, anxiety, spiritual and financial burdens. The lives of families and friends are diminished along with the person who has pain.

In the future, as time permits, I’ll be adding publications and articles to the site and occasionally posting with a frequency yet to be determined, hopefully twice a month.

Goals:

• This website is dedicated to providing educational resources to patients and healthcare professionals regarding the current understanding of pain medicine, an interdisciplinary field
• To discuss evidence-based information to improve the lives of patients who choose to use these therapies under the direction of informed physicians
• To distinguish between harmful treatments, beneficial treatments, and treatments that can be safely integrated with conventional treatment
• To encourage communication between patients, families and providers
• To educate both patients and health care providers who need a more comprehensive knowledge base with current and accurate information
• To promote ongoing professional growth through networking in a setting where treatments can be examined together to enhance lives

Please bear in mind, no information in this blog is intended to diagnose or treat any condition.

The opinions expressed here are my own, and are subject to change as new research becomes available.

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Join me on this journey……