Vitamin D deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Vitamin D deficiency was a common disease that affects both children and adults living in industrialized cities. Rickets was scientifically described by British physicians in the 17th century. In the 20th century, German scientists discovered vitamin D and its influence on bone health. The importance of sunlight and diet to prevent rickets were emphasized in the 20th century. The fortification of milk with vitamin D beginning in the 1930s has made rickets a rare disease in the United States. ^[1]

• in 1645, Vitamin D deficiency was first described scientifically by Daniel Whistler, a British physician. His thesis was submitted in the University of Leiden, entitled “Inaugural medical disputation on the disease of English children which is popularly termed the rickets”.^[2]

• In 1650, Francis Glisson, a Cambridge physician, published a book in Latin, named “De Rachitide”. He described his careful observation of rachitic children in great detail.^[3]

• In 1822, Sniadecki identified the association of rickets with a lack of sunlight exposure. He noted that children living in the inner city of Warshaw had a high incidence of rickets than children of the adjacent rural area.^[4]

• In 1918, Mellanby discovered the antirachitic effect of cod liver oil.^[5]

• In 1922, Elmer McCollum et al. distinguished vitamin D from vitamin A. He suggested that vitamin D promotes calcium deposition.^[6]

• By the 1930s, Adolf Otto Reinhold Windaus at the University of Göttingen in Germany identified the chemical structure of the vitamin D and its precursor, 7-dehydrocholesterol.^[7] He received Nobel Prize in chemistry in 1928 for his work “on the sterols and their relationship to other natural products”.^[8]

• In 1822, Sniadecki was the first one to recognize the importance of sun exposure for the prevention and treatment of rickets.^[4]

• In 1890, Theobald Palm suggested using sunbaths to prevent rickets.^[9]

• In 1918, Mellanby prevented rickets in puppies with cod liver oil.^[5]

• In 1919, Huldschinski observed that exposing children to radiation from a lamp had a healing effect on rickets.^[10]

• In 1921, Hess and Unger exposed seven rachitic children to sunlight in New York City for several months and reported effective improvement of their disease.^[11]

• In the 1930s, the US government recommended to parents to expose their children to sunlight every day to prevent rickets.^[12]

• In the 1930s, for eradication of rickets in the United States and Europe, the fortification of milk with vitamin D was started.^[12] However, an outbreak of hypercalcemia in the 1950s, in Great Britain, resulted in discontinuation of this program in Europe until now.^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

According to the Global Consensus Recommendations on Prevention and Management of Nutritional Rickets and the Institute of Medicine (IOM), vitamin D deficiency is classified into two groups of deficient and Insufficient based on serum 25(OH)D level. It could be further classified as mild, moderate, and severe deficiency. Another classification scheme is based on etiology of vitamin D deficiency which classify it as acquired or inherited.

• According to the Global Consensus Recommendations on Prevention and Management of Nutritional Rickets and the Institute of Medicine (IOM), vitamin D deficiency is classified into two groups of deficient and Insufficient based on serum 25(OH) vit D3 level.^[1]

• Australian Family Physician classified vitamin D deficiency into three groups based on serum level of 25(OH) vit D.^[3]

• Vitamin D deficiency may be classified into two main groups of acquired or inherited based on the etiology.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Husnain Shaukat, M.D [2]

• The main sources of vitamin D are sunlight exposure, diet, and dietary supplements.^[1]
• The vitamin D synthesized in the skin is ergocalciferol or vitamin D3. The vitamin D which comes from plant sources is called D2 or cholecalciferol.
• Both cholecalciferol and ergocalciferol are inactive forms of vitamin D and sequentially activated in the liver and kidney to the active form of vitamin D, which exerts the biologic effects.
• Vitamin D refers to both cholecalciferol and ergocalciferol or vitamin D2 and vitamin D3.

Synthesis in the skin

• The synthesis of ergocalciferol (vitamin D3) occurs in the deeper layers of epidermis namely stratum spinosum and stratum basalis by the help of a chemical reaction involving UVB radiations (wavelength, 290 – 315 nm ) from sunlight.^[2]
• The UVB (wavelength, 290 – 315 nm ) radiations convert 7- dehydrocholesterol to pre-vitamin D3, which isomerizes to D3.
• The formation of vitamin D3 in the skin depends on sunlight exposure, the intensity of UVB and level of melanin pigment in the skin.
• The UVB intensity varies with season and latitude.
• The clothing and sun-screen also limit the exposure.
• Vitamin D synthesized in the skin and ingested from food is transported in the blood to the liver, while it is bound to vitamin D binding protein.

25 – Hydroxylation in the liver

• In the liver, vitamin D undergoes hydroxylation into 25 – hydroxyvitamin D3 with the help of one or more cytochrome P450 vitamin D hydroxylases.^[1]
• The common P 450 hydroxylases involved are CYP2R1, CYP2D11, and CYP2D25.
• The homozygous mutation of CYP2R1 gene was found in a patient with low circulating levels of 25 – hydroxyvitamin D3 with symptoms of vitamin D3 deficiency which suggests that CYP2R1 is the main enzyme involved in vitamin D hydroxylation in the liver.
• 25 – hydroxyvitamin D3 or calcifediol is the major circulating form of vitamin D and its serum level is used to assess the individual’s vitamin D status.
• After hydroxylation, 25 – hydroxyvitamin D3 is released into plasma where it is bound to the vitamin D binding protein and carried to the kidneys for activation.

1 Alpha hydroxylation in kidneys

• In the proximal renal tubule of the kidney, 25 – hydroxylated vitamin D undergoes further hydroxylation into 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) or calcitriol.^[3]
• The hydroxylation in the kidney is carried by 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene.
• This hydroxylation is under the influence of parathyroid hormone (PTH).
• 1,25-dihydroxy vitamin D3 (1,25(OH)2D3) or calcitriol is the active form of vitamin D and responsible for most of the biologic actions of vitamin D.

Parathyroid hormone (PTH), Vitamin D and mineral homeostasis The effect of parathyroid hormone on mineral metabolism is as follows:^[4][5]

• Effect of parathyroid hormone on calcium metabolism:
  • Direct effect:
    • Increased resorption of bones.
    • Decreases excretion from kidney.
  • Indirect effect:
    • Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
    • Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
    • Both these direct and indirect mechanism results in an increased serum calcium concentration.
• Effect of parathyroid hormone on inorganic phosphate metabolism:
  • Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
• Effect of parathyroid hormone on magnesium concentration:
  • Decreases excretion of magnesium resulting in increased serum magnesium concentretion.

Effect of minerals and vitamin D on parathyroid hormone:

• Decrease in serum calcium concentration stimulates parathyroid hormone.
• Calcium provides negative feedback on parathyroid hormone.
• Magnesium provides negative feedback on parathyroid hormone.
• Vitamin D decreases the concentration of parathyroid hormone.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Common causes of vitamin D deficiency are inadequate vitamin D skin production, less dietary vitamin D intake and impaired absorption. Other causes of vitamin D deficiency include vitamin D loss, abnormal metabolism, resistance to vitamin D and medication.^[1]

Vitamin D deficiency may be caused by:^{[1][2][3][4][5][6][7][8]}

• Inadequate vitamin D skin production
• Inadequate vitamin D dietary intake
• Vitamin D loss
• Malabsorption
• Impaired metabolism
• Resistance to Vitamin D
• Medication

• Antiepileptic medication
• Glucocorticoid
• Inadequate sun exposure including dark skin and clothing
• Inadequate vitamin D dietary intake
• Malabsorption

• Autosomal dominant hypophosphatemic rickets
• Celiac disease
• Chronic kidney disease: impaired renal 1α-hydroxylation
• Crohn disease
• Cystic fibrosis
• Highly active antiretroviral therapy (HAART)
• Hyperthyroidism
• Impaired enterohepatic circulation
• Nephrotic syndrome
• Post gastric bypass surgery
• Primary hyperparathyroidism
• Rifampin
• Sarcoidosis
• Severe liver failure: impaired hepatic 25-hydroxylation
• Short bowel syndrome
• St John’s wort
• Tuberculosis
• Type I hereditary vitamin D–dependent rickets
• Type II hereditary vitamin D–dependent rickets
• Vitamin D-resistant rickets
• Whipple disease
• X-linked familial hypophosphatemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Vitamin D deficiency must be differentiated from other diseases that cause generalized muscle and bone pain, such as fibromyalgia, chronic fatigue syndrome, polymyalgia rheumatica, and osteoarthritis.

Vitamin D deficiency must be differentiated from other conditions that may cause generalized muscle and bone pain. The following table summarizes different diagnoses and how to differentiate them.^[1][2][3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Vitamin D deficiency is common worldwide, and the incidence is increasing in the recent years. In the US, vitamin D deficiency is more prevalent among non-white ethnic groups. The prevalence is different based on different laboratory methods and the cut-off for the vitamin D deficiency.

• According to Institute of Medicine (IOM), based on the National Health and Nutrition Examination Survey (NHANES) 2003–2006, there is an overall 18.8% prevalence of serum 25OHD concentrations below 40 nmol/L in the US.^[1]

• However, data from the National Health and Nutrition Examination Surveys (NHANES) in 2001-2006 shows that one-quarter were at risk of vitamin D inadequacy (serum 25OHD 30–49 nmol/L), and 8% were at risk of vitamin D deficiency (serum 25OHD less than 30 nmol/L).^[2]

• Statistics from the Canadian Health Measures Survey (CHMS), Cycle 1, 2007–2009 shows that 13% of Canadians have vitamin D level below 40 nmol/L.^[1]

• Naugler et al. reported that based on the results from Calgary Laboratory Services and Census Canada data in 2010-2011 on individuals older than 25 years old residing in Calgary, Alberta, 26% of individuals had serum 25OHD levels of less than 50 nmol/L.^[3]

• In both sexes, the prevalence was lowest in children aged 1–8 years. Risk of deficiency increased significantly with age until age 30 in males and age 18 in females, after which it did not change significantly with age.^[2]

• There is a slightly higher prevalence of vitamin D deficiency in female than male. According to the National Health and Nutrition Examination Surveys (NHANES) in 2001-2006, the season-adjusted prevalence at risk of deficiency by age ranged from 1% to 8% in males and 1% to 12% in females.^[2]

• Non-hispanic white people are at lower risk of vitamin D deficiency than African-Americans, Hispanics and Asians.
• Analysis from Gozdzik A et al. study on 107 young adults in Toronto during winter of 2007, shows an association between serum 25OHD level and skin pigmentation. 34.4% of individuals with European ancestry had serum 25OHD levels of less than 50 nmol/L, whereas East and South Asians had 85.2% and 93.5% respectively.^[4]

• Chowdhury R. et al. in meta-analysis of observational studies, reported that the prevalence of vitamin D insufficiency (<75 nmol/L) was 69.5% for the United States and 86.4% for Europe. Severe Vitamin D deficiency (<25 nmol/L) were seen in 15% and 4% of general population in the United States and the Europe.^[5]
• In the Uppsala Longitudinal Study of Adult Men, a cohort study on 1194 swedish men during the winter season, there is only 5% prevalence of serum 25OHD levels below 40nmol/L.^[6]
• According to the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study on 1006 adolescents of 12.5-17.5 years old age, selected from 9 European countries, 39% of them had insufficient (50-75 nmol/L), 27% had deficient (27.5-49 nmol/L) and 15% had severely deficient (<27·5 nmol/L) levels of serum 25OHD.^[7]

• Puri S. et al. reported a result from a study on 3127 apparently healthy Delhi schoolgirls. It showed that 90.8% of them had insufficient serum 25OHD levels (<50 nmol/L) in both groups of low and high socioeconomic strata.^[8]
• Vitamin D deficiency is very common among Saudi women. About 80% of women in Adarawi MS et al. study demonstrated vitamin D deficiency (<50 nmol/L).^[9]
• There are relatively higher levels of serum 25OHD in Thailand compared to European, Middle eastern and other Asian countries. Chailurkit et al. reported 2.8 to 14.3% vitamin D deficiency (<50 nmol/L) overal in different regions of Thailand.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Important risk factors for vitamin D deficiency that can not be changed are non-western ethnicity, older age and colder seasons. Sedentary lifestyle and less sun exposure play a significant role in increasing vitamin D deficiency.

The risk factors of vitamin D deficiency can be categorized into three main groups; non-modifiable risk factors, modifiable risk factors, and also factors that are related to mothers’ conditions.^{[1][2][3][4][5][6][7][8]}

• Age
• Ethnicity: non-western ethnicity like African, Asian, Turkish, and Moroccan children are at greater risks than children of western ethnic background.
• Dark skin color
• Season: late fall, winter, and spring
• Geography: higher latitude, lower altitude, cloudy weather

• Life style including sedentary behavior, high child television watching, and less outdoor activities
• Less sun exposure including use of sunscreen or clothing
• Obesity
• Being underweight
• Less milk drinking
• Not taking vitamin D supplements
• Exclusive breastfeeding

• Lower maternal age
• Lower household income
• Multiparity
• Higher maternal BMI

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

According to the U.S. Preventive Service Task Force (USPSTF), screening for vitamin D deficiency is not recommended in asymptomatic, non-pregnant adults.

There is insufficient evidence to recommend routine screening for vitamin D deficiency. However, there is not enough research for the screening of vitamin D deficiency in at risk subpopulations such as African Americans or non-Caucasians.^[1]

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