Vitamin D deficiency


Vitamin D deficiency, or hypovitaminosis D is defined as a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate sunlight exposure. Vitamin D deficiency can also be caused by inadequate nutritional intake of vitamin D, disorders limiting vitamin D absorption, and conditions impairing vitamin D conversion into active metabolites—including certain liver, kidney, and hereditary disorders. Deficiency impairs bone mineralization, leading to bone softening diseases such as rickets in children. It can also worsen osteomalacia and osteoporosis in adults, leading to an increased risk of bone fractures. Muscle weakness is also a common symptom of vitamin D deficiency, further increasing the risk of fall and bone fractures in adults. Vitamin D deficiency is associated with the development of schizophrenia.
UVB from sunlight is a large source of vitamin D. Oily fish such as salmon, herring, and mackerel are also sources of vitamin D, as are mushrooms. Milk is often fortified with vitamin D and sometimes bread, juices, and other dairy products are fortified with vitamin D as well. Many multivitamins now contain vitamin D in different amounts.

Classifications

Vitamin D deficiency is typically diagnosed by measuring the concentration of the 25-hydroxyvitamin D in the blood, which is the most accurate measure of stores of vitamin D in the body. One nanogram per millilitre is equivalent to 2.5 nanomoles per litre
Vitamin D levels falling within this normal range prevent clinical manifestations of vitamin D insufficiency as well as vitamin D toxicity from taking in too much vitamin D.

Signs and symptoms

Vitamin D deficiency can be asymptomatic, but may also cause several problems including:
Vitamin D deficiencies are often caused by decreased exposure of the skin to sunlight. People with a darker pigment of skin or increased amounts of melanin in their skin may have decreased production of vitamin D. Melanin absorbs ultraviolet B radiation from the sun and reduces vitamin D production. Sunscreen can also reduce vitamin D production. Medications may speed up the metabolism of vitamin D, causing a deficiency. Some types of liver diseases and kidney diseases can decrease vitamin D production leading to a deficiency. The liver is required to transform vitamin D into 25-hydroxyvitamin D. This is an inactive metabolite of vitamin D but is a necessary precursor to create the active form of vitamin D.
In liver disease, the 25-hydroxyvitamin D may not be formed, leading to a vitamin D deficiency. 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 often prevents 1,25-hydroxyvitamin D from being formed, leading to a vitamin D deficiency. Intestinal conditions that result in malabsorption of nutrients may also contribute to vitamin D deficiency by decreasing the amount of vitamin D absorbed via diet. In addition, a vitamin D deficiency may lead to decreased absorption of calcium by the intestines, resulting in increased production of osteoclasts that may break down a person's bone matrix. In states of hypocalcemia, calcium will leave the bones and may give rise to secondary hyperparathyroidism, which is a response by the body to increase serum calcium levels. The body does this by increasing uptake of calcium by the kidneys and continuing to take calcium away from the bones. If prolonged, this may lead to osteoporosis in adults and rickets in children.

In schizophrenia

Vitamin D deficiency is a common problem associated with the development of schizophrenia. People with schizophrenia generally have lower levels of vitamin D. The environmental risk factors of seasonality of birth, latitude, and migration, linked to schizophrenia are all suggested to implicate a vitamin D deficiency. Other health conditions such as maternal obesity as a risk factor for schizophrenia are also seen to be associated with vitamin D deficiency.
Vitamin D plays an active role in the development of many organ systems including the brain, and is essential for the normal development of the nervous system.
Maternal vitamin D deficiency causes the neurodevelopmental defects during the prenatal development of the brain, that are evident in schizophrenia. Vitamin D deficiency in the developing brain influences neurotransmission that can alter brain rhythms and the metabolism of dopamine. Vitamin D receptors and their enzymes CYP27B1 and CYP24A1 are found in various regions of the brain showing that vitamin D is established as a neuroactive, neurosteroid hormone essential for the development of the brain and of its normal function.
Inflammation as a causative factor in schizophrenia is normally suppressed by vitamin D.

Risk factors

Those most likely to be affected by vitamin D deficiency are people with little exposure to sunlight. 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.

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.

Fat percentage

Since vitamin D3 and vitamin D2 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.

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. Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish, and eggs, and low intakes of high-extraction cereals. In sunny countries where rickets occurs among older toddlers and children, vitamin D deficiency has been attributed to low dietary calcium intakes. This is characteristic of cereal-based diets with limited access to dairy products. Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are about 20% stronger than at sea level on the same latitude, almost two-thirds of 500 children had mild rickets in the late 1920s. An increase in the proportion of animal protein in the 20th-century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. One study of children in a hospital in Uganda however showed no significant difference in vitamin D levels of malnourished children compared to non-malnourished children. Because both groups were at risk due to darker skin pigmentation, both groups had vitamin D deficiency. Nutritional status did not appear to play a role in this study.

Obesity

There is an increased risk of vitamin D deficiency in people who are considered overweight or obese based on their body mass index measurement. The relationship between these conditions is not well understood. There are different factors that could contribute to this relationship, particularly diet and sunlight exposure. Alternatively, vitamin D is fat-soluble therefore excess amounts can be stored in fat tissue and used during winter, when sun exposure is limited.

Sun exposure

The use of sunscreen with a sun protection factor of 8 can theoretically inhibit more than 95% of vitamin D production in the skin. In practice, however, sunscreen is applied so as to have a negligible effect on vitamin D status. The vitamin D status of those in Australia and New Zealand is unlikely to have been affected by campaigns advocating sunscreen. Instead, wearing clothing is more effective at reducing the amount of skin exposed to UVB and reducing natural vitamin D synthesis. Clothing which covers a large portion of the skin, when worn on a consistent and regular basis, such as the burqa, is correlated with lower vitamin D levels and an increased prevalence of vitamin D deficiency.
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. 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.

Darker skin color

The reduced pigmentation of light-skinned individuals may result in higher vitamin D levels and that, because melanin acts like a sun-block, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes.

Malabsorption

Rates of vitamin D deficiency are higher among people with untreated celiac disease, inflammatory bowel disease, exocrine pancreatic insufficiency from cystic fibrosis, and short bowel syndrome, which can all produce problems of malabsorption. Vitamin D deficiency is also more common after surgical procedures that reduce absorption from the intestine, including weight loss procedures.

Critical illness

Vitamin D deficiency is associated with increased mortality in critical illness. 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. Additionally, vitamin D levels decline during stays in intensive care.
Vitamin D3 or calcitriol given orally may reduce the mortality rate without significant adverse effects.

Diagnosis

The serum concentration of calcifediol, also called 25-hydroxyvitamin D, is typically used to determine vitamin D status. Most vitamin D is converted to 25D in the serum, giving an accurate picture of vitamin D status. The level of serum 1,25D is not usually used to determine vitamin D status because it often is regulated by other hormones in the body such as parathyroid hormone. The levels of 1,25D can remain normal even when a person may be vitamin D deficient. Serum level of 25D is the laboratory test ordered to indicate whether or not a person has vitamin D deficiency or insufficiency. It is also considered reasonable to treat at-risk persons with vitamin D supplementation without checking the level of 25D in the serum, as vitamin D toxicity has only been rarely reported to occur.
Levels of 25D that are consistently above 200 nanograms per milliliter are thought to be potentially toxic, although data from humans are sparse. Vitamin D toxicity usually results from taking supplements in excess. Hypercalcemia is often the cause of symptoms, and levels of 25D above 150 ng/mL are usually found, although in some cases 25D levels may appear to be normal. Periodic measurement of serum calcium in individuals receiving large doses of vitamin D is recommended.

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.

Treatment

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. 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.
Treating vitamin D deficiency depends on the severity of the deficit. 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 25D serum concentration is before treatment, the higher is the dosage that is needed in order to quickly reach an acceptable serum level.
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.
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 25D blood levels more effectively than vitamin D2, other evidence indicates that D2 and D3 are equal for maintaining 25D status.

Initial phase

Daily or weekly or monthly dose

For treating rickets, the American Academy of Pediatrics has recommended that pediatric patients receive an initial two- to three-month treatment of "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-months old infants, and 5,000 IU for patients over 1 year of age.
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. 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 and, within certain body weight limits, to body weight.
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, 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 25D 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. performed a study in elderly women to compare the efficacy and safety of a daily dose of 1500 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 patient was published by Takacs et al. They reported an equal efficacy of 1000 IU taken daily, 7000 IU taken weekly, and 30,000 IU taken monthly.
Nevertheless, these consistent findings differ from the report by Chel et al. in which a daily dose was more effective than a monthly dose. In that study, the compliance calculation could be questionable, as only random samples of the returned medications were counted.
In a study by De Niet et al. 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 a 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 compliance. The single-dose therapy can be given as an injection, but is normally given in form of an oral medication.

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. performed different studies confirming that a high-fat meal increased the absorption of vitamin D3 as measured by serum 25 D. A clinical report indicated that serum 25 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. 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.
In another study performed by Cavalier E. et al. 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 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, obese patients, and those on certain medications.

Special cases

To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered to patients who have had their parathyroid glands removed or with hypoparathyroidism. Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D.

Epidemiology

The estimated percentage of the population with a vitamin D deficiency varies based on the threshold used to define a deficiency.
Percentage of
U.S. population		Definition of
insufficiency		StudyReference
69.5%25D less than 30 ng/mLChowdury et al. 2014
77%25D less than 30 ng/mLGinde et al. 2009
36%25D less than 20 ng/mLGinde et al. 2009
6%25D less than 10 ng/mLGinde et al. 2009

Recommendations for 25D 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.
A 2011 Institute of Medicine report set the sufficiency level at 20 ng/ml, while in the same year The Endocrine Society defined sufficient serum levels at 30 ng/ml and others have set the level as high as 60 ng/ml. As of 2011 most reference labs used the 30 ng/ml standard.
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.
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.

History

The role of diet in the development of rickets was determined by Edward Mellanby between 1918 and 1920. In 1921, Elmer McCollum identified an antirachitic substance found in certain fats that could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D. The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid 7-dehydrocholesterol, the precursor of vitamin D.
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 of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases.

Research

A great deal of research has been conducted to understand whether low levels of vitamin D may cause or be a result of other conditions.
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. Taking vitamin D supplements has no significant effect on cancer risk. Vitamin D3, however, appears to decrease the risk of death from cancer but concerns with the quality of the data exist.
Vitamin D deficiency is thought to play a role in the pathogenesis of non-alcoholic fatty liver disease.
Some studies have indicated that vitamin D deficiency may play a role in immunity. Those with vitamin D deficiency may have trouble fighting off certain types of infections. It has also been thought to correlate with cardiovascular disease, type 1 diabetes, type 2 diabetes, and some cancers.
Review studies have also seen associations between vitamin D deficiency and preeclampsia.