Vitamin D deficiency
Vitamin D deficiency | |
---|---|
Other names | Hypovitaminosis D |
The normal process of Vitamin D absorption | |
Specialty | Endocrinology |
Symptoms | Usually asymptomatic |
Complications | Rickets, osteomalacia, other associated disorders |
Causes | Lack of vitamin D, inadequate sunlight exposure |
Risk factors | Age, people with dark skin, obesity, malabsorption, bariatric surgery, breastfed infants[1] |
Diagnostic method | Measuring the concentration of calcifediol in the blood |
Prevention | Sufficient sunlight exposure, dietary intake |
Treatment | Supplements |
Medication | Cholecalciferol, ergocalciferol, calcifediol |
Frequency | Severe deficiency (<30 nmol/L): Europe 13%, US 5.9%, Canada 7.4%. Deficiency (<50 nmol/L): Europe 40%, US 24%, Canada 37%[2] |
Vitamin D deficiency or hypovitaminosis D is a
Vitamin D can be synthesized in the skin under the exposure of UVB from sunlight. Oily fish, such as salmon, herring, and mackerel, are also sources of vitamin D, as are mushrooms. Milk is often fortified with vitamin D; sometimes bread, juices, and other dairy products are fortified with vitamin D.[1] Many multivitamins contain vitamin D in different amounts.[1]
Classifications
Vitamin D deficiency is typically diagnosed by measuring the concentration of the
- Severe deficiency: <12 ng/mL = <30 nmol/L[2]
- Deficiency: <20 ng/mL = <50 nmol/L
- Insufficient: 20–29 ng/mL = 50–75 nmol/L
- Normal: 30–50 ng/mL = 75–125 nmol/L
Vitamin D levels falling within this normal range prevent clinical manifestations of vitamin D insufficiency as well as
Signs and symptoms
In most cases, vitamin D deficiency is almost asymptomatic.[8] It may only be detected on blood tests but is the cause of some bone diseases and is associated with other conditions:[1]
Complications
- long bones.[9] The earliest sign of vitamin D deficiency is craniotabes, abnormal softening or thinning of the skull.[10]
- Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. Women with vitamin D deficiency who have been through multiple pregnancies are at elevated risk of osteomalacia.[11]
- bone mineral densityand increased bone fragility
- Increased risk of fracture[12][13]
- fasciculations) due to reduced blood calcium (hypocalcemia);[3][14] impaired muscle glycogen metabolism (abnormal glycogen accumulation), atrophy of type II (fast-twitch/glycolytic) muscle fibres, and diminished calcium uptake by the sarcoplasmic reticulum (needed for muscle contraction).[15]
- Periodontitis, local inflammatory bone loss that can result in tooth loss.[16]
- Pre-eclampsia: There has been an association of vitamin D deficiency and women who develop pre-eclampsia in pregnancy. The exact relationship of these conditions is not well understood.[17] Maternal vitamin D deficiency may affect the baby, causing overt bone disease from before birth and impairment of bone quality after birth.[9][18]
Risk factors
Those most likely to be affected by vitamin D deficiency are people with little exposure to sunlight.[26] Certain climates, dress habits, the avoidance of sun exposure and the use of too much sunscreen protection can all limit the production of vitamin D.[26]
Age
Elderly people have a higher risk of having a vitamin D deficiency due to a combination of several risk factors, including decreased sunlight exposure, decreased intake of vitamin D in the diet, and decreased skin thickness, which leads to further decreased absorption of vitamin D from sunlight.[27]
Fat percentage
Since vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are fat-soluble, humans and other animals with a skeleton need to store some fat. Without fat, the animal will have a hard time absorbing vitamin D2 and vitamin D3, and the lower the fat percentage, the greater the risk of vitamin deficiency, which is true in some athletes who strive to get as lean as possible.[28]
Malnutrition
Although rickets and osteomalacia are now rare in Britain, osteomalacia outbreaks in some immigrant communities included women with seemingly adequate daylight outdoor exposure wearing typical Western clothing.
Obesity
There is an increased risk of vitamin D deficiency in people who are considered overweight or obese based on their body mass index (BMI) measurement.[38] The relationship between these conditions is not well understood. There are different factors that could contribute to this relationship, particularly diet and sunlight exposure.[38] Alternatively, vitamin D is fat-soluble, so excess amounts can be stored in fat tissue and used during winter, when sun exposure is limited.[39]
Sun exposure
The use of
Regions far from the equator have a high seasonal variation of the amount and intensity of sunlight. In the UK, the prevalence of low vitamin D status in children and adolescents is found to be higher in winter than in summer.[43] Lifestyle factors such as indoor versus outdoor work and time spent in outdoor recreation play an important role.
Additionally, vitamin D deficiency has been associated with urbanisation in terms of both air pollution, which blocks UV light, and an increase in the number of people working indoors. The elderly are generally exposed to less UV light due to hospitalisation, immobility, institutionalisation, and being housebound, leading to decreased levels of vitamin D.[44]
Darker skin color
Because of melanin which enables natural sun protection, dark-skinned people are susceptible to vitamin D deficiency.[6][45] Three to five times greater sun exposure is necessary for naturally darker skinned people to produce the same amount of vitamin D as those with light skin.[45]
Malabsorption
Rates of vitamin D deficiency are higher among people with untreated
Critical illness
Vitamin D deficiency is associated with increased mortality in critical illness.[49] People who take vitamin D supplements before being admitted for intensive care are less likely to die than those who do not take vitamin D supplements.[49] Additionally, vitamin D levels decline during stays in intensive care.[50] Vitamin D3 (cholecalciferol) or calcitriol given orally may reduce the mortality rate without significant adverse effects.[50]
Breastfeeding
Infants who exclusively breastfeed need a vitamin D supplement, especially if they have dark skin or have minimal sun exposure.[51] The American Academy of Pediatrics recommends that all breastfed infants receive 400 international units (IU) per day of oral vitamin D.[51]
Pathophysiology
Decreased exposure of the skin to sunlight is a common cause of vitamin D deficiency.[1] People with a darker skin pigment with increased amounts of melanin may have decreased production of vitamin D.[3] Melanin absorbs ultraviolet B radiation from the sun and reduces vitamin D production.[3] Sunscreen can also reduce vitamin D production.[3] Medications may speed up the metabolism of vitamin D, causing a deficiency.[3]
The liver is required to transform vitamin D into
The kidneys are responsible for converting 25-hydroxyvitamin D to 1,25-hydroxyvitamin D. This is the active form of vitamin D in the body. Kidney disease reduces 1,25-hydroxyvitamin D formation, leading to a deficiency of the effects of vitamin D.[1]
Intestinal conditions that result in
Diagnosis
The serum concentration of calcifediol, also called 25-hydroxyvitamin D (abbreviated 25(OH)D), is typically used to determine vitamin D status. Most vitamin D is converted to 25(OH)D in the serum, giving an accurate picture of vitamin D status.[53] The level of serum 1,25(OH)D is not usually used to determine vitamin D status because it often is regulated by other hormones in the body such as parathyroid hormone.[53] The levels of 1,25(OH)D can remain normal even when a person may be vitamin D deficient.[53] Serum level of 25(OH)D is the laboratory test ordered to indicate whether or not a person has vitamin D deficiency or insufficiency.[53] It is also considered reasonable to treat at-risk persons with vitamin D supplementation without checking the level of 25(OH)D in the serum, as vitamin D toxicity has only been rarely reported to occur.[53]
Levels of 25(OH)D that are consistently above 200
Screening
The official recommendation from the United States Preventive Services Task Force is that for persons that do not fall within an at-risk population and are asymptomatic, there is not enough evidence to prove that there is any benefit in screening for vitamin D deficiency.[56]
Treatment
This article needs to be updated.(January 2021) |
UVB exposure
Vitamin-D overdose is impossible from UV exposure: the skin reaches an equilibrium where the vitamin degrades as fast as it is created.[57][58]
Sun tanning
Light therapy
Exposure to photons (light) at specific wavelengths of narrowband UVB enables the body to produce vitamin D to treat vitamin D deficiency.[59]
Supplement
In the United States and Canada as of 2016, the amount of vitamin D recommended is 400 IU per day for children, 600 IU per day for adults, and 800 IU per day for people over age 70.[60][61] The Canadian Paediatric Society recommends that pregnant or breastfeeding women consider taking 2000 IU/day, that all babies who are exclusively breastfed receive a supplement of 400 IU/day, and that babies living north of 55°N get 800 IU/day from October to April.[62]
Treating vitamin D deficiency depends on the severity of the deficit.[63] Treatment involves an initial high-dosage treatment phase until the required serum levels are reached, followed by the maintenance of the acquired levels. The lower the 25(OH)D serum concentration is before treatment, the higher is the dosage that is needed in order to quickly reach an acceptable serum level.[63]
The initial high-dosage treatment can be given on a daily or weekly basis or can be given in form of one or several single doses (also known as stoss therapy, from the German word Stoß, meaning "push").[64]
Therapy prescriptions vary, and there is no consensus yet on how best to arrive at an optimum serum level. While there is evidence that vitamin D3 raises 25(OH)D blood levels more effectively than vitamin D2,[65] other evidence indicates that D2 and D3 are equal for maintaining 25(OH)D status.[63]
Initial phase
Daily or weekly or monthly dose
For treating rickets, the American Academy of Pediatrics (AAP) has recommended that pediatric patients receive an initial two to three months of treatment with "high-dose" vitamin D therapy. In this regime, the daily dose of cholecalciferol is 1,000 IU for newborns, 1,000 to 5,000 IU for 1- to 12-month-old infants, and 5,000 IU for patients over 1 year of age.[64]
For adults, other dosages have been called for. A review of 2008/2009 recommended dosages of 1,000 IU cholecalciferol per 10 ng/mL required serum increase, to be given daily over two to three months.[66] In another proposed cholecalciferol loading dose guideline for vitamin D-deficient adults, a weekly dosage is given, up to a total amount that is proportional to the required serum increase (up to the level of 75 nmL/L) and within certain body weight limits, to body weight.[67]
According to new data and practices relevant to vitamin D levels in the general population in France, to establish optimal vitamin D status and frequency of intermittent supplement dosing,[68] patients with or at high risk for osteoporosis and vitamin D deficiency should start supplementation with a loading phase consisting of 50,000 IU weekly of vitamin D for 8 weeks in patients with levels <20 ng/mL and 50,000 IU weekly for 4 weeks in patients with levels between 20 and 30 ng/mL. Subsequently, long-term supplementation should be prescribed as 50,000 IU monthly. Should pharmaceutical forms suitable for daily supplementation become available, patients displaying good treatment adherence could take a daily dose determined based on the 25(OH)D level.
Until now, there are no consistent data suggesting the ideal regimen of supplementation with vitamin D, and the question of the ideal time between doses is still of debate. Ish-Shalom et al.[69] performed a study in elderly women to compare the efficacy and safety of a daily dose of 1,500 IU to a weekly dose of 10,500 IU and to a dose of 45,000 IU given every 28 days for two months. They concluded that supplementation with vitamin D can be equally achieved with daily, weekly, or monthly dosing frequencies. Another study comparing daily, weekly, and monthly supplementation of vitamin D in deficient patients was published by Takacs et al.[70] They reported equal efficacy of 1,000 IU taken daily, 7,000 IU taken weekly, and 30,000 IU taken monthly. Nevertheless, these consistent findings differ from the report by Chel et al.,[71] in which a daily dose was more effective than a monthly dose. In that study, the compliance calculation could be questionable since only random samples of the returned medications were counted. In a study by De Niet et al.,[72] 60 subjects with vitamin D deficiency were randomized to receive 2,000 IU vitamin D3 daily or 50,000 IU monthly. They reported a similar efficacy of the two dosing frequencies, with the monthly dose providing more rapid normalization of vitamin D levels.
Single-dose therapy
Alternatively, a single-dose therapy is used for instance if there are concerns regarding the patient's
Vitamin D doses and meals
The presence of a meal and the fat content of that meal may also be important. Because vitamin D is fat-soluble, it is hypothesized that absorption would be improved if patients are instructed to take their supplement with a meal. Raimundo et al.[73][74] performed different studies confirming that a high-fat meal increased the absorption of vitamin D3 as measured by serum 25(OH) D. A clinical report indicated that serum 25(OH) D levels increased by an average of 57% over a 2-month to 3-month period in 17 clinic patients after they were instructed to take their usual dose of vitamin D with the largest meal of the day.[75]
Another study conducted in 152 healthy men and women concluded that diets rich in monounsaturated fatty acids may improve and those rich in polyunsaturated fatty acids may reduce the effectiveness of vitamin D3 supplements.[76] In another study performed by Cavalier E. et al.,[77] 88 subjects received orally a single dose of 50,000 IU of vitamin D3 solubilized in an oily solution as two ampoules each containing 25,000 IU (D‐CURE®, Laboratories SMB SA, Brussels, Belgium) with or without a standardized high‐fat breakfast. No significant difference between fasting vs. fed conditions was observed.
Maintenance phase
Once the desired serum level has been achieved, be it by a high daily or weekly or monthly dose or by a single-dose therapy, the AAP recommendation calls for a maintenance supplementation of 400 IU for all age groups, with this dosage being doubled for premature infants, dark-skinned infants and children, children who reside in areas of limited sun exposure (>37.5° latitude), obese patients, and those on certain medications.[64]
Special cases
To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their
Co-supplementation with vitamin K
The combination of vitamin D and
Bioavailability
Not all D3 deficiencies can be effectively supplemented or treated with vitamin D3 on its own. Older people or those who have fatty liver or metabolic syndrome have a reduced ability to absorb vitamin D3.[82] In addition, in overweight or obese persons, excessive adipose tissue can sequester D3 from the circulation and reduce its access to other tissues.[82] With age or in obesity, metabolic activation of D3 may be reduced by liver steatosis or by microbiome imbalance.[82][83] Since Vitamin D is fat-soluble, it's advised to be taken with a meal high in fat since it significantly increase its uptake in healthy individuals.[84]
For vitamin D3 to perform its hormonal roles, it is converted into its biologically active metabolite, calcifediol, also known as 25-hydroxyvitamin D3, an activation occurring by a hydroxylation reaction in the liver via the cytochrome P450 system, and in the gut microbiome.[85]
Epidemiology
The estimated percentage of the population with a vitamin D deficiency varies based on the threshold used to define a deficiency.
Percentage of US population | Definition of insufficiency | Study | Reference |
---|---|---|---|
69.5% | 25(OH)D less than 30 ng/mL | Chowdury et al. 2014 | [86] |
77% | 25(OH)D less than 30 ng/mL | Ginde et al. 2009 | [87] |
36% | 25(OH)D less than 20 ng/mL | Ginde et al. 2009 | [87] |
6% | 25(OH)D less than 10 ng/mL | Ginde et al. 2009 | [87] |
Recommendations for 25(OH)D serum levels vary across authorities, and probably vary based on factors like age; calculations for the epidemiology of vitamin D deficiency depend on the recommended level used.[88]
A 2011
Applying the IOM standard to NHANES data on serum levels, for the period from 1988 to 1994 22% of the US population was deficient, and 36% were deficient for the period between 2001 and 2004; applying the Endocrine Society standard, 55% of the US population was deficient between 1988 and 1994, and 77% were deficient for the period between 2001 and 2004.[89]
In 2011 the Centers for Disease Control and Prevention applied the IOM standard to NHANES data on serum levels collected between 2001 and 2006, and determined that 32% of Americans were deficient during that period (8% at risk of deficiency, and 24% at risk of inadequacy).[89][91]
History
The role of diet in the development of
Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases.[34]
Research
Some evidence suggests vitamin D deficiency may be associated with a worse outcome for some cancers, but evidence is insufficient to recommend that vitamin D be prescribed for people with cancer.[93] Taking vitamin D supplements has no significant effect on cancer risk.[94] Vitamin D3, however, appears to decrease the risk of death from cancer but concerns with the quality of the data exist.[95]
Vitamin D deficiency is thought to play a role in the pathogenesis of
Evidence suggests that vitamin D deficiency may be associated with impaired immune function.
Review studies have also seen associations between vitamin D deficiency and pre-eclampsia.[100]
See also
- Hypervitaminosis D
- Vitamin D deficiency in Australia
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