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December 2013

Entrenamientos semana 25/11 al 1/12

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Semana que empez贸 con los primeros d铆as cargada de piernas, pero que recuper茅 muy bien. Acabo con buenas sensaciones corriendo y muy buenas nadando. Seguimos sumando y definiendo objetivos 馃檪

LUNES: 2km de nataci贸n + 2h de btt. Las piernas como palos, recupernadome del media marat贸n de monta帽a

MARTES: 2,5 km de nataci贸n + 60min de running + 60min gym

MIERCOLES: 60 min de running con algunas series cortas

JUEVES: 3.2 km de nataci贸n 聽+ 2h de bici

VIERNES: 70 min de running

S脕BADO: 90 min de running por monta帽a + 4km de nataci贸n

DOMINGO: largo dia de viaje + 40min de running

 

Diagn贸stico y tratamiento de la deficiencia de vitamina D

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Os cuelgo una revisi贸n cl铆nica publicada 聽BMJ sobre vitamina D.

Aviso: tost贸n para los que no nos dedicamos a esto

Diagnosis and management of vitamin D deficiency

BMJ聽2010;聽340聽doi: http://dx.doi.org/10.1136/bmj.b5664聽(Published 11 January 2010)

Cite this as:聽BMJ聽2010;340:b566

Summary Points

  • Vitamin D insufficiency is common in the UK population

  • Vitamin D deficiency typically presents with bony deformity (rickets) or hypocalcaemia in infancy and childhood, and with musculoskeletal pain and weakness in adults

  • Many other health problems鈥攊ncluding cardiovascular disease, type 2 diabetes, several cancers, and autoimmune conditions鈥攈ave recently been associated with vitamin D insufficiency

  • Risk factors include skin pigmentation, use of sunscreen or concealing clothing, being elderly or institutionalised, obesity, malabsorption, renal and liver disease, and anticonvulsant use

  • Vitamin D status is most reliably determined by assay of serum 25-hydroxyvitamin D (25-OHD)

  • Rickets and osteomalacia should be treated with high strength calciferol (ergocalciferol or colecalciferol) for 8-12 weeks, followed by regular vitamin D supplements

Rickets in children and osteomalacia in adults are the classic manifestations of profound vitamin D deficiency. In recent years, however, non-musculoskeletal conditions鈥攊ncluding cancer, metabolic syndrome, infectious and autoimmune disorders鈥攈ave also been found to be associated with low vitamin D levels.1聽The spectrum of these common disorders is of particular concern because observational studies have demonstrated that vitamin D insufficiency is widespread in many northern regions of the world, including industrialised countries.23聽The increasing prevalence of disorders linked to vitamin D deficiency is reflected in the several hundred children with rickets treated each year in the UK.4聽However, these children represent a small proportion of the individuals with a suboptimal vitamin D status in the UK population.135

A recent nationwide survey in the United Kingdom showed that more than 50% of the adult population have insufficient levels of vitamin D and that 16% have severe deficiency during winter and spring.5聽The survey also demonstrated a gradient of prevalence across the UK, with highest rates in Scotland, northern England, and Northern Ireland.5聽People with pigmented skin are at high risk, as are the elderly; obese individuals; those with malabsorption, short bowel, or renal or liver disease; and individuals taking anticonvulsants, rifampicin, or highly active antiretroviral drugs.

In this article we discuss the diagnosis and management of vitamin D insufficiency and deficiency in children and adults according to evidence from descriptive and observational studies, randomised trials, and meta-analyses.

What are the sources of vitamin D?

Vitamin D refers to the precursors of the active secosteroid hormone 1,25-dihydroxyvitamin D3聽(1,25-OH2D3), also known as calcitriol. The major natural source of vitamin D is from skin photosynthesis following ultraviolet B solar irradiation (box 1).

Box 1 Sources of vitamin D

  • Ultraviolet B sunlight exposure

  • >90% of mankind鈥檚 vitamin D supply is derived from ultraviolet B light

  • Oily fish including trout, salmon, mackerel, herring, sardines, anchovies, pilchards, and fresh tuna

  • Amount will depend on preparation, with smoked herring containing approximately 4 渭g (160 IU) per 100 g and raw herring 40 渭g (1600 IU) per 100 g

  • Cod liver oil and other fish oils

  • Egg yolk

  • 0.5 渭g (20 IU) per yolk)

  • Mushrooms

  • Small quantities

  • Supplemented breakfast cereals, mainly supermarket 鈥渙wn brands鈥 in the UK

  • Typically between 2 渭g and 8 渭g (80-320 IU) per 100 g

  • Margarine and infant formula milk

  • Statutory supplementation in the UK

In a fair skinned person, 20 minutes to 30 minutes of sunlight exposure on the face and forearms at midday is estimated to generate the equivalent of around 2000 IU of vitamin D. Two or three such sunlight exposures a week are sufficient to achieve healthy vitamin D levels in summer in the UK. For individuals with pigmented skin and, to a lesser extent, the elderly, exposure time or frequency need to be increased twofold to 10-fold to get the same level of vitamin D synthesis as fair skinned young individuals.6w1聽Unfortunately, for six months of the year (October to April), all of Scandinavia, much of western Europe (including 90% of the UK), and 50% of the North American landmass lies above the latitude that permits exposure to the ultraviolet B wavelengths necessary for vitamin D synthesis,w2聽leaving millions of people reliant on exogenous sources of vitamin D.

Given this periodic lack of photosynthesis at high latitudes, vitamin D is also a micronutrient. Only a relatively small number of foods contain substantial amounts of vitamin D, the most significant dietary sources being oily fish and cod liver oil.7聽The farmed fish that is commonly consumed in the UK may have less vitamin D content than wild fish.w3聽Egg yolk, liver, and wild mushrooms contain small quantities of vitamin D. The amount in most vegetable sources is negligible.

The recommended daily intake of vitamin D in the UK is 400 IU (10 渭g) per day for an adult, 280 IU (7 渭g) for children aged between 6 months and 3 years, and 340 IU (8.5 渭g) per day for infants under 6 months.7聽However, these recommendations only provide sufficient vitamin D to prevent osteomalacia and rickets,8聽and such an intake alone, in the absence of skin synthesis, will not provide optimal status. Accordingly, several learned bodies have recently increased their recommendations for vitamin D intake.9w4

Food supplementation policies differ considerably between countries. Milk is widely fortified, but in the UK only infant formula milk and margarine have statutory vitamin D supplementation (1-2.5 渭g (40-100 IU) per 100 kCal and 8 渭g (320 IU) per 100 g, respectively). Thus, the typical UK diet, and that of many other countries, is profoundly lacking in vitamin D. A low dietary vitamin D intake, combined with the lack of skin synthesis for half of the year, is reflected in the disturbingly high prevalence of vitamin D insufficiency across the UK.35

How can vitamin D deficiency and insufficiency be determined?

Vitamin D status is most reliably determined by assay of serum 25-hydroxyvitamin D (25-OHD). Individuals with symptomatic osteomalacia or rickets have serum 25-OHD concentrations of less than 25 nmol/l (10 渭g/l), reflecting profound vitamin D deficiency (table 1). A much larger proportion of the UK population (about 50% in spring) have vitamin D insufficiency, with serum 25-OHD concentrations between 25 nmol/l and 50 nmol/l (10-20 渭g/l).35

View this table:

Table 1

鈥係erum 25-hydroxyvitamin D concentrations, health, and disease

Several observational studies have shown that vitamin D insufficiency, although not enough to cause symptomatic bone and muscle disease, is associated with an increased risk of mortality10111213聽and of several common diseases including cardiovascular disease,1213聽type 2 diabetes,14聽bowel cancer, breast cancer,1516聽multiple sclerosis,17聽and type 1 diabetes18聽(table 2). An expert consensus is developing that optimal vitamin D status, reflected by optimal calcium handling and best health, is when serum concentrations of 25-OHD are 75 nmol/l (30 渭g/l) or more.819聽Serum 25-OHD has a circulating half life of two to three weeks, but levels are regularly replenished from fat stores.
View this table:

Table 2

鈥侲vidence for association of circulating 25-hydroxyvitamin D level or vitamin D supplementation with major health outcomes

Circulating active vitamin D (1,25-dihydroxyvitamin D3聽or calcitriol) has a short half life and is closely linked to parathyroid hormone production. Serum levels of calcitriol do not reflect vitamin D status and should not be measured unless abnormalities of vitamin D metabolism are suspected.

Who is at risk of vitamin D insufficiency and deficiency?

At northern latitudes, the major risk factor for D insufficiency and deficiency at all ages is pigmented skin (box 2). This is also a key risk factor in sunnier climates such as Australia, where a large case series has demonstrated an increasing incidence of vitamin D deficiency in young people.20聽This report and many European case series of children with vitamin D deficiency over the last 20 years have consisted primarily of immigrant children or first generation offspring of immigrant parents with dark skin. In a recent report from Denmark, however, half of very young patients with nutritional rickets were ethnic Europeans.21

Box 2 Risk factors for vitamin D insufficiency and deficiency

  • Pigmented skin (non-white ethnicity)

  • Lack of sunlight exposure or atmospheric pollution

  • Skin concealing garments or strict sunscreen use

  • Exclusively breast fed

  • Multiple, short interval pregnancies

  • Elderly, obese, or institutionalised

  • Vegetarian (or other non-fish eating) diet

  • Malabsorption, short bowel, or cholestatic liver disease

  • Use of anticonvulsants, rifampicin, cholestyramine, highly active antiretroviral treatment (HAART), or glucocorticoids

Sunscreen with a sun protection factor 15 or more blocks more than 99% of dermal vitamin D synthesis. Strict adherence to use of sunscreens when outdoors, or the use of a veil, headscarf, or other concealing clothing, places individuals with fair skin at similar risk of vitamin D deficiency to those with pigmented skin. Elderly and institutionalised individuals are at risk because of the relatively large amount of time such people spend indoors, as well as a reduced dermal capacity to generate vitamin D.

Numerous case series and some experimental studies highlight the fact that vitamin D deficiency may be present at birth, with neonatal and infant vitamin D status dependent upon maternal vitamin D status.w5w6聽Multiparity, short spacing between pregnancies, and non-white maternal skin are major risk factors for vitamin D deficiency.w722聽Infants exclusively breast fed, particularly beyond six months of age, are at increased risk because the vitamin D content of breast milk will not meet their requirements.22聽Delayed introduction of solid food, picky eating habits, and poor diet also raise the risk.

The Department of Health recommends daily supplementary vitamin drops containing 400 IU of calciferol for all infants and preschool children,23聽and this view is endorsed by the European Society for Paediatric Endocrinology.24Supplementation is particularly important for infants in the north of the UK, those with darker skin pigmentation, and fussy eaters.23

Weaning foods frequently contain low quantities of calcium, and nutritional rickets (as a consequence of calcium and not vitamin D deficiency) has been reported in children with adequate levels of 25-OHD.w8聽Such findings reinforce the importance of focusing on the calcium content of a child鈥檚 diet in addition to vitamin D status.w9

How do patients with vitamin D deficiency present?

Children

Severe vitamin D deficiency may cause hypocalcaemic seizures or tetany, particularly in the neonatal period and again during the phase of rapid growth in adolescence. From the age of 6 months, children with vitamin D deficiency commonly present with bony deformity (rickets). Bowing of the legs (genu varum) is typical, but knock knees (genu valgum) can also occur. Anterior bowing of the femur and internal rotation at the ankle are frequently found, along with swelling at the wrist, prominent costochondral joints, and a soft, deformable skull (craniotabes).25聽Children with vitamin D deficiency may be irritable and reluctant to weight bear, and manifest impaired growth.2122聽Height is usually affected more profoundly than weight.21

An increased susceptibility to infections and respiratory symptoms in children with vitamin D deficiency may be a manifestation of 鈥渞achitic lung,鈥 where respiratory function is compromised by a pliable rib cage and muscle weakness.w10聽Severe vitamin D deficiency can result in cardiomyopathy and potentially fatal heart failure.w11

Adults

Pain and proximal muscle weakness dominate the clinical picture of vitamin D deficiency in adults. Rib, hip, pelvis, thigh, and foot pain are typical. More diffuse muscular aches and muscle weakness, including in the limbs and back, are also common and may be labelled as 鈥渇ibromyalgia鈥 or as a somatisation of depression.26聽Low bone density on dual energy X ray absorptiometry scanning, or osteopenia on plain radiography, may also reflect osteomalacia, and these findings warrant assessment of vitamin D status.

What investigations are necessary?

Children

Vitamin D deficiency should be suspected in children with known risk factors who are unwell with pain, irritability, and poor growth or skeletal deformity, and in all children with a seizure disorder. Blood can be taken in primary care for measurement of levels of calcium, phosphate, alkaline phosphatase, and serum 25-OHD, which is the most robust marker for vitamin D status (table 1). Haemoglobin levels should also be measured because iron deficiency anaemia frequently coexists with rickets.w12Parathyroid hormone concentrations are typically elevated in neonates and young infants with vitamin D deficiency, but may be within the reference range.

If there is diagnostic uncertainty鈥攂ecause of atypical clinical manifestations, a lack of risk factors, atypical biochemistry, focal pain, or asymmetrical deformity鈥攖hen radiographs should be arranged to confirm rickets. In addition, a small number of children have hereditary or renal rickets. These rarer diagnoses need to be considered in the absence of known risk factors, in the presence of atypical biochemistry (for example, persistent hypophosphataemia, normal alkaline phosphatase, or elevated creatinine), and in children who fail to reduce alkaline phosphatase levels or respond clinically following vitamin D treatment. Referral for specialist assessment is appropriate in these circumstances.

The clinician must be vigilant for a secondary cause of vitamin D deficiency in both children and adults, such as covert coeliac disease or cystic fibrosis causing malabsorption.

Adults

More than 80% of adults with osteomalacia have a high concentration of serum alkaline phosphatase. Hypocalcaemia and hypophosphataemia are less consistently present, depending on the severity and chronicity of the disease and the patient鈥檚 dietary calcium intake. Elevation of plasma parathyroid hormone鈥攕econdary hyperparathyroidism鈥攊s typical of osteomalacia but is not found in about 20% of adults with vitamin D insufficiency. It is good practice to image areas of focal pain in adults, particularly if they persist or worsen during treatment (suggesting bony metastases).27

How should rickets and osteomalacia be treated?

Children

Oral calciferol in the bioequivalent forms of either ergocalciferol (yeast derived vitamin D2) or colecalciferol (fish or lanolin derived vitamin D3) is the treatment of choice for children with rickets.92527聽The principal aim of therapy is to replenish vitamin D stores; patients are then continued on a lower maintenance dose. Large bolus doses are also equally effective. Tablet, capsule, or oily suspensions of calciferol are available (box 3).

Box 3 Preparations of calciferol available in the UK

Solutions and drops
  • Dalivit (LPC Pharmaceuticals Ltd, Luton, Bedfordshire)*

  • Colecalciferol 400 IU per 0.6 ml

  • Abidec (Chefaro UK, Huntingdon, Cambridgeshire)*

  • Colecalciferol 400 IU per 0.6 ml

  • Healthy Start vitamin drops*

  • Colecalciferol 300 IU per 5 drops

  • Ergocalciferol oily solution

  • 3000 IU/ml

Tablets and capsules鈥
  • Calcium and vitamin D (400 mg calcium and 400 IU ergocalciferol)

  • Colecalciferol 20鈥000 IU (Dekristol; MIBE, Brehna, Germany)

  • Ergocalciferol 10鈥000 IU or 50鈥000 IU (UCB Pharma, Slough, Berkshire)

Parenteral
  • Ergocalciferol 300鈥000 IU per ml

  • *Multivitamin preparations; not suitable for prolonged high dose therapy owing to the risk of vitamin A toxicity.

  • 鈥燨ther ergocalciferol and colecalciferol preparations are available off prescription.

Children aged less than 1 year should be treated with 3000 IU of calciferol daily, increasing to 6000 IU daily after 1 year of age (box 4).2224聽Calcium supplementation (50 mg/kg a day) is advisable during the first weeks of therapy in the growing child.2220聽A maintenance dose of 400 IU calciferol daily is appropriate for a child of any age.22聽A relatively rapid biochemical response is typically seen in children, with normalisation of alkaline phosphatase levels within three months. It is likely that the mother, siblings, and other family members of a child with rickets are also vitamin D deficient.9聽At a minimum, a maintenance dose of calciferol is recommended for other family members.

Box 4 Treatment of vitamin D deficiency and insufficiency

Deficiency (25-OHD <25 nmol/l)
ADULT
  • 10鈥000 IU calciferol daily or 60鈥000 IU calciferol weekly for 8-12 weeks*

  • or

  • Calciferol 300鈥000 or 600鈥000 IU orally or by intramuscular injection once or twice

CHILD
  • Under 6 months: 3000 IU calciferol daily for 8-12 weeks

  • Over 6 months: 6000 IU calciferol daily for 8-12 weeks

  • or

  • Over 1 year: 300鈥000 IU calciferol, as a one off high dose therapy (Stoss regimen)鈥

Insufficiency (25-OHD 25-50 nmol/l) or maintenance therapy following deficiency
ADULT
  • 1000-2000 IU calciferol daily

  • or

  • 10鈥000 IU calciferol weekly

CHILD
  • Under 6 months: 200-400 IU calciferol daily鈥

  • Over 6 months: 400-800 IU calciferol daily

  • *To convert IU to 渭g of calciferol, divide by 40.

  • 鈥燨ne off high dose treatments are effective, but should be followed by a maintenance therapy dose of calciferol.

  • 鈥200 IU may be inadequate for breastfed babies with low vitamin D stores at birth.

Adults

Calciferol has a high therapeutic index. It has been estimated that a regular daily dose of 1000 IU raises serum 25-OHD by 25 nmol/l28; however, vitamin D toxicity occurs at 25-OHD values above 500 nmol/l.29聽In adults, calciferol treatment, in a daily dose of 10鈥000 IU or a weekly dose of 60鈥000 IU, will lead to restoration of body stores of vitamin D over eight to 12 weeks. Thereafter, a maintenance dose of 1000-2000 IU calciferol daily or 10鈥000 IU weekly is adequate. Short acting, potent vitamin D analogues such as 1-伪 calcidol or calcitriol are ineffective in correcting vitamin D deficiency and may lead to hypercalcaemia. Clinicians should avoid giving combined calcium and vitamin D preparations in the long term because the calcium component is usually unnecessary, makes for unpalatability, and reduces concordance.

In adults with severe malabsorption, or those in whom concordance with oral therapy is suspect, an intramuscular dose of 300鈥000 IU calciferol monthly for three months followed by the same dose once or twice a year is an alternative treatment approach. Pathological lesions in the bone are characterised by undermineralisation and may take many months to heal. Levels of serum alkaline phosphatase and parathyroid hormone will start to decline during the first three months of treatment in adults, but may take a year to fall into the reference range. Given that few adults have truly reversible risk factors for vitamin D deficiency, the assumption should be that supplementation will be needed life long, or life long during winter months (dependent upon latitude and dress habits).

How should moderate vitamin D insufficiency be managed?

From a public health perspective, primary prevention of vitamin D deficiency in a country such as the UK is socially as well as medically justifiable.30聽The key groups for healthcare professionals to target are infants, children, adolescents, and pregnant women, particularly those with dark skin. Many individuals of non-white ancestry living in the Midlands and north of the UK are at particularly high risk of vitamin D insufficiency (including doctors). Most elderly and institutionalised people in other areas of the UK are also at high risk. Fair skinned people who eat oily fish twice weekly or who get regular suberythematous sunlight exposure through outdoor work or leisure activity may have adequate vitamin D status; most other fair skinned people will be vitamin D insufficient, particularly in the winter and spring.

Given the clear and mounting evidence of the substantial disease burden associated with moderate vitamin D insufficiency (table 2), information about appropriate sunlight exposure, the use of vitamin D supplements, and eating oily fish should be made available to the whole population. In particular, health visitors and midwives can implement current Department of Health recommendations by distributing children鈥檚 vitamin drops, which should be universally available through Healthy Start, Sure Start, and similar government schemes. Furthermore, we believe that a more robust approach to statutory food supplementation with vitamin D (for example, in milk) is needed in the UK, as this measure has already been introduced successfully in many other countries at similar latitude.

Conclusions

Vitamin D deficiency and insufficiency are common in the UK. Health professionals have been slow to respond to this problem even though the issue has been highlighted in the literature for a number of years. Rickets and osteomalacia are entirely preventable diseases that are becoming increasingly common in the UK population, and vitamin D insufficiency now seems unequivocally linked to several other common and morbid conditions. Local initiatives have been implemented to address this issue, but the high number of patients presenting with symptomatic vitamin D insufficiency highlights the fact that we have some way to go. A change in UK public health policy is long overdue.

Sources and selection criteria

We searched the PubMed database for articles including the term vitamin D. We identified further references from the original articles and recent review articles. We only studied articles in the English language, and gave priority to systemic reviews, meta-analyses, and clinical guidelines published within the last 10 years.

Tips for the non-specialist

  • Suspicions regarding a suboptimal vitamin D status in someone at risk are likely to be correct

  • Treatment is not the same as supplementation: the recommended daily amount of 400 IU vitamin D will be insufficient to treat an adult with osteomalacia and will lead to very slow response in most children with rickets

  • If a child has vitamin D insufficiency or deficiency, assume the mother and other siblings are similarly affected and will need therapy as well

  • Compliance with long term vitamin D supplementation is often poor: one off, high dose oral or intramuscular therapy is an effective option if concordance is suspect

Unanswered questions

  • How much does vitamin D insufficiency contribute to north/south health inequality in the UK?

  • Would eradication of vitamin D insufficiency in the UK reduce cancer incidence and improve cancer outcomes?

  • Does poor vitamin D status cause obesity, or is it a consequence of obesity?

  • Are individuals genetically susceptible to vitamin D insufficiency or toxicity?

Ongoing research

More than 150 clinical trials of vitamin D are listed on ClinicalTrials.gov. Some key trials include:

  • The VITamin D and omegA-3 TriaL (VITAL)

  • A study of colecalciferol 2000 IU daily, fish oil, or placebo in 20鈥000 older individuals (>60 yrs), with cardiovascular disease and cancer incidence as outcomes.

  • Vitamin D and Calcium Homeostasis for Prevention of Type 2 Diabetes (CaDDM) (NCT00436475)

  • Treatment of vitamin D insufficiency: does vitamin D increase calcium absorption, bone mass and muscle mass and function in women past menopause who have mildly low vitamin D levels? (NCT00933244)

  • Evaluation of vitamin D requirements during pregnancy (NCT00292591)

  • Development of vitamin D as a therapy for breast cancer鈥攑hase II (NCT00656019)

  • Vitamin D supplement in preventing colon cancer in African Americans with colon polyps (NCT00870961)

  • Health benefits of vitamin D and calcium in women with PCOS (polycystic ovarian syndrome) (NCT00743574)

  • Vitamin D3聽supplementation and the T cell compartment in multiple sclerosis (MS) (NCT00940719)

Additional educational resources

Resources for healthcare professionals

Notes

Cite this as:BMJ聽2010;340:b5664

Footnotes

  • We are very grateful to G Rylance, W Ross, and R Quinton for helpful comments on the manuscript, and to P Chen for sharing supplementary data included in their meta-analysis.17

  • Contributors: SP and TC both wrote the original manuscript and subsequent revisions.

  • Funding: No funding was received.

  • Competing interests: All authors have completed the Unified Competing Interest form at聽www.icmje.org/coi_disclosure.pdf聽(available on request from the corresponding author) and declare (1) No financial support for the submitted work from anyone other than their employer; (2) No financial relationships with commercial entities that might have an interest in the submitted work; (3) No spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work; (4) No non-financial interests that may be relevant to the submitted work.

  • Provenance and peer review: Commissioned; externally peer reviewed.

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