Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2015 – vol. 119, no. 2

INTERNAL MEDICINE - PEDIATRICS

UPDATES

VITAMIN D DEFICIENCY AND THE CLINICAL CONSEQUENCES Corina Galesanu 1, Veronica Mocanu 2 University of Medicine and Pharmacy“GrigoreT. Popa”- Iasi Faculty of Medicine 1. Department of Medical Specialties (I) 2. Department of Morpho-Functional Sciences *Corresponding author. E-mail: [email protected]

VITAMIN D DEFICIENCY AND THE CLINICAL CONSEQUENCES (Abstract): Vitamin D is important for good health, growth and strong bones. Vitamin D is mostly made in the skin by exposure to sunlight. Most foods contain very little vitamin D naturally, though some are fortified with added vitamin D. Hypovitaminosis D is associated with cardiovasc ular disease, the metabolic syndrome, type 2 diabetes mellitus, cancer as well as with increased mortality. Further, Vitamin D deficiency is related to depression and impaired cogn itive function. Increasing age and elevated body fat mass contribute to an increased risk of Vitamin D deficiency. A mild lack of vitamin D may not cause symptoms but can cause tiredness and general aches and pains. A more severe lack can cause serious problems such as rickets (in children) and osteomalacia in adults). During menopause, the decline of estrogens results in increased bone turnover, a decrease in bone mineral density and elevated fracture risk. Treatment is with vitamin D supplements. Some people are more at risk of vi tamin D deficiency, and so are recommended to take vitamin D supplements routinely. These include all pregnant and breastfeeding women, all infants (babies) and young children aged 6 months to 5 years, people aged 65 and over, and people who are not exposed to much sun. There are precise recommendations regarding a sufficient Vitamin D intake in order to prevent bone loss in peri- and postmenopausal women. It is also recommend routine supplements for certain people with darker skin, and for people with certain gut, liver or kidney diseases. Keywords: VITAMIN D DEFICIENCY, RICKETS, OSTEMALACIA, VITAMIN D SUPPLEMENTATION.

Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. In the past few years, there has been a proliferation of publications on the effects of vitamin D and/or calcium on skeletal and nonskeletal health. In 2011 at Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists Professor Paul D. Miller(1) presented a manuscript which represents a

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systematic review of data from the search engines of PubMed, Medscape, and Scopus. The search words used were “vitamin D”, “calcium”, “cardiovascular events”, “cardiovascular mortality”, “all-cause mortality”, “vascular calcification”, “chronic kidney disease”, “renal stones”, and “hyper-calciuria”. This presentation have followed of many other that they have tried to give an answer to what extent the level of vitamin D is responsible for bone patholo-

Vitamin D deficiency and the clinical consequences

gy as well as and other chronic disease. Another question has been which is optimum level of vitamin D to prevent these diseases. Most of the evidence is derived from case-control and cohort population studies. Minimal data are derived from prospective, double-blind, placebocontrolled studies. The evidence is, therefore, limited by the nature of the study designs. VITAMIN D. METABOLISM AND BIOLOGICAL FUNCTIONS Humans obtain vitamin D through dietary intake and exposure to sunlight. In this regard, even with the most intense and prolonged sunlight exposure, the maximum level of vitamin D that can be achieved is approximately 60 ng/mL. Cutaneous vitamin D3 production is influenced by skin pigmentation, sunscreen use, time of day, season, latitude, altitude, and air pollution(2) .Very few foods naturally contain vitamin D. The two major biologically inert precursors of vitamin D are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) . Vitamin D3 is formed when 7dehydrocholesterol in the skin is exposed to solar ultraviolet B, and then converted to previtamin D3. Excess UVB rays transform previtamin D3 into biologically inactive metabolites, tachysterol and lumisterol. Vitamin D2 is plant derived, produced exogenously by irradiation of ergosterol, and enters the circulation through diet. Both vitamin D precursors resulting from exposure to the sunshine and the diet are converted to 25-hydroxyvitamin D [25(OH)D] (calcidiol) when they enter the liver. 25(OH)D is the major circulating form of vitamin D. In order to be biologically active, additional hydroxylation in the

kidneys is needed to form active 1,25dihydroxyvitamin D [1,25(OH)2D] (calcitriol)=Hormone D(3). The 1,25(OH)2D performs many of its biologic functions by regulating gene transcription through a nuclear high-affinity vitamin D receptor (VDR)(4).This active metabolite of vitamin D binds to the nuclear VDR, which binds retinoic acid X receptor to form a heterodimeric complex that binds to specific nucleotide sequences in the DNA known as vitamin D response elements. There are estimated to be 200 to 2000 genes that have vitamin D response elements or that are influenced indirectly, possibly by epigenetics, to control a multitude of genes across the genome(4).It is universally accepted that the circulating level of 25-hydroxyvitamin D should be used as an indicator of vitamin D status due to its ease of measurement, long half-life in circulation (approximately 2 or 3 weeks), and the correlation of its level with clinical disease states . Vitamin D plays an important role in maintaining an adequate level of serum calcium and phosphorus. Without vitamin D, only 10 to 15% of dietary calcium and about 60% of phosphorus is absorbed (5). Therefore vitamin D has a great effect in forming and maintaining strong bones. It has also recently been found that vitamin D receptors exist in a variety of cells thus it has a biological effect on more than mineral metabolism (6). The 1,25(OH)2D interacts with its VDR in the small intestine to increase the efficiency of intestinal calcium absorption from approximately 10% to 15% up to 30% to 40% and intestinal phosphorus absorption from approximately 60% to 80%(7). It also interacts with VDR in osteoblasts to stimulate a receptor activator of nuclear factor kB ligand, which, in turn, interacts with receptor activator of nuclear

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Corina Galesanu, Veronica Mocanu

factor kB on immature preosteoclasts, stimulating them to become mature boneresorbing osteoclasts (8). The mature osteoclast removes calcium and phosphorus from the bone to maintain blood calcium and phosphorus levels. In the kidneys, 1,25(OH)2D stimulates calcium reabsorption from the glomerular filtrate(7). The VDR is present in most tissues and cells in the body. Many of these organs and cells, including the brain, vascular smooth muscle, prostate, breast, and macrophages, not only have a VDR but also have the capacity to produce 1,25(OH)2D(7). This production probably depends on the availability of circulating 25(OH)D, indicating the biological importance of sufficient blood levels of this vitamin D metabolite(8).

tion have also indicated that patients with serum 25(OH)D levels less than 20 ng/mL have increased bone turnover, bone loss, and, possibly, mineralization defects compared with patients with serum 25(OH)D levels of 20 ng/mL or greater. Similar relationships have been reported for fragilty, nonvertebral and hip fracture, and all-cause mortality, with poorer outcomes at less than 20 ng/mL. Thus, ESCEO recommended that 20 ng/mL be the minimal serum 25(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Also, in fragile elderly individuals who are at elevated risk for falls and fractures, ESCEO recommended a minimal serum 25(OH)D level of 30 ng/mL for the greatest effect on fracture(10).

VITAMIN D DEFICIENCY Vitamin D deficiency has been recognized as a pandemic phenomenon with a variety of health consequences (2). Low vitamin D status has been associated with an increased risk of type 1 diabetes mellitus, cardiovascular disease, certain cancers, cognitive decline, depression, pregnancy complications, autoimmunity and allergy (3). The US Endocrine Society recommended that vitamin D deficiency be defined as a 25(OH)D level of 20 ng/mL or less, vitamin D insufficiency as 21 to 29 ng/mL, and vitamin D sufficiency as 30 ng/mL or greater for children and adults. It suggested that maintenance of a 25(OH)D level of 40 to 60 ng/mL is ideal, and that up to 100 ng/mL is safe (9). Recent recommendations of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)(10) for the optimal management of elderly and postmenopausal women regarding vitamin D supplementa-

CAUSES OF VITAMIN D DEFICIENCY There are many causes of vitamin D deficiency. Generally, they can be divided into two groups: UVB-related deficiency and medical/physical condition-related deficiency. UVB-related deficiency. The elderly, due to the decreased presence of skin 7dehydrocholesterol which is the precursor for UVB mediated synthesis of vitamin D, are particularly at risk of vitamin D deficiency. Moreover, reduced mobility or institutionalization that discourages sun exposure, reduced renal production of 1,25dihydroxyvitamin D as well as decreased intake of fortified foods pose great difficulties in vitamin D formation in body. People with dark skin have great amounts of melanin in their epidermis. Melanin competes with 7-dehydrocholesterol for absorption of UVB photons. Therefore, people of color are less efficient in producing vitamin D than are whites. It has been established that

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the ozone layer can absorb UVB. Zenith angle decides the thickness of ozone layer which sunlight needs to penetrate and it is dependent on factors such as time of day, season of the year, and latitude. Thus those factors have great effects on vitamin D production (11). Sunscreens can efficiently absorb UVB radiation. This dramatically prevents the interaction of UVB with 7dehydrocholesterol, the process of previtamin D3 generation. Medical / physical condition - related deficiency. As a fat-soluble vitamin, vitamin D requires the presence of dietary fat in the gut for absorption. Certain pathological conditions, such as Crohn's disease, cystic fibrosis , celiac disease, surgical removal of part of the stomach or intestines are associated with fat malabsorption and thus may lead to vitamin D deficiency. It is well recognized that long-term use of some antiepileptic drugs, including phenobarbital, phenytoin, and carbamazepine and the antimicrobial agent rifampicin (RIF) can result in osteomalacia. Chronic kidney disease such as patients with stage 4 or 5 chronic kidney disease, as well as those requiring dialysis, leads to an inability to make sufficient 1,25-dihydroxyvitamin D which has a direct effect in inhibiting parathyroid hormones expression. Obese people are prone to be vitamin D deficient since they have lower 25 hydroxyvitamin D levels . A number of studies proved that the vitamin D3 precursor 7-dehydrocholesterol levels in the skin of obese people were not significantly different from non-obese people. One explanation was that the subcutaneous fat, which is known to store vitamin D, sequestered more of the cutaneous synthesized vitamin D, which results in less release of vitamin D from the skin into the circulation in the obese subject than non-

obese subject (12). VITAMIN D INADEQUACY- EPIDEMIOLOGY Prevalence of vitamin D deficiency in adolescents and adults. It has been estimated that 20% to 80% of US, Canadian, and European men and women are vitamin D deficient. The prevalence of serum 25(OH)D levels less than 20 ng/mL was almost one-third of the US population (32%). In the Healthy Lifestyle in Europe by Nutrition in Adolescence study, 25(OH)D levels less than 30 ng/mL were reported to be approximately 80% in adolescents from the 9 European countries. In a study on the vitamin D status of Australian adults, vitamin D deficiency (25[OH]D