see also:

• calcium
• calcitonin
• parathyroid hormone (PTH)
• bone physiology
• ultraviolet light exposure (UV)
• patient information sheets:
  • RCH - rickets (pdf)

• Inadequate vitamin D nutrition is associated with impaired intestinal calcium absorption and must be corrected for ingested calcium to be effective.
• As the vitamin D content of our diet is generally low, people with low levels of sunlight exposure (the chronically-ill, housebound, people in residential care, some ethnic groups) are at high risk for vitamin D deficiency. Dark-skinned people, especially veiled women, are an important risk group. Their vitamin D status in pregnancy is a particular concern. Daily needs are probably of the order of 800 IU in these high-risk groups. This can be given as oral vitamin D2 1000 IU daily.
  • to achieve a target serum level of 40ng/mL to reduce cardiac events, the Target-D study in 2023 showed that 87% required more than 2000IU/d and 15% required 10,000IU/d ¹⁾
• foods that contain vitamin D include:
  • egg yolks, oily fish (salmon, tuna, sardines), liver, beef, some fortified products including cereals & dairy products.
• fair-skinned children need 5-10 minutes exposure to both arms in the early morning or late afternoon sun each day without sunscreen.
  • avoid middle of the day (except in Winter when 7-30min midday exposure per day is required), as UV damage is greater then.
  • dark-skinned children need longer exposures of 15-60min a day.
• a recent study of more than 24,000 NSW blood samples showed 58 per cent had low Vitamin D levels (62 per cent for women) in spring - with the figure only dipping to 36 per cent (42 per cent for women) in summer.
• obesity reduces vit D levels by sequestering it in adipose tissue

• may cause or increase risk of:
  • rickets in children
  • multiple sclerosis and other auto-immune conditions
  • breast cancer and other non-skin cancers
  • type 1 diabetes
  • Crohn's disease
  • hypertension (1,25(OH)2D3 suppresses the production of renin)
  • AMI and heart disease
  • depression
  • schizophrenia
  • immune impairment and increased risk or severity of infections
    • COVID-19 coronavirus (2019-nCoV / SARS-CoV-2) ²⁾
  • need for LUSCS in birth
  • shorter sleep duration ³⁾
  • erectile dysfunction via increased superoxide and SLPI downregulation ⁴⁾
    • increases penile fibrosis, as indicated by greater collagen deposition
    • significantly decreased EFS-induced relaxation and reduces the EFS-induced increase in intra-cavernosal pressure (ICP)
    • significantly reduced acetylcholine-induced nitric oxide (NO)-dependent relaxation
    • relaxation induced by the phosphodiesterase 5 inhibitor (PDE5i) sildenafil reduced
    • however, the relaxation induced by riociguat, the soluble guanylyl cyclase stimulator, was unchanged

• “Vitamin D” refers to a group of closely related sterols:
  • Skin:
    • 7-dehydrocholesterol + UVB light ⇒ preVitamin D ⇒ vitamin D3 (cholecalciferol) which takes 8hrs for completion
      • Vit D3 then is either:
        • released into extracellular space where all of it can bind to vitamin D binding protein, or,
        • if further UVB irradiation, it will isomerize into lumisterol₃ and tachysterol₃
        • this effectively means a limit of 15% of the 7-dehydrocholesterol can be converted to vit D3 reducing risk of vitamin D toxicity ⁵⁾
  • orally ingested vitamin D3:
    • the SDR42E1 gene on chromosome 16 is crucial for taking up vitamin D from the gut and further metabolizing it
      • a specific mutation can be associated with vitamin D deficiency ⁶⁾
    • it is incorporated into chylomicrons which are transported into the lymphatic system and then into the venous system where approximately 60% of the vitamin D3 is bound to the vitamin D binding protein and 40% is rapidly cleared in the lipoprotein bound fraction
  • Liver: 25-hydroxylase converts cholecalciferol to:
    • ⇒ 25-hydroxycholecalciferol
  • Kidney: 1-alpha-hydroxylase converts 25-hydroxycholecalciferol to:
    • ⇒1,25 dihydroxycholecalciferol (calcitriol)

• UVB light with wavelengths of 290–315 nm penetrate into the skin and are absorbed by proteins, DNA and RNA as well as 7-dehydrocholesterol which is in the cell membrane of epidermal cells incorporated within the fatty acid hydrocarbon side chain and polar head group of the triglycerides
• the rigid planar structure of 7-dehydrocholesterol sandwiched in between the triglyceride fatty acid hydrocarbon tails could only be transformed into the planar czc conformer of previtamin D3 upon exposure to solar UVB radiation
• the UVB causes an activation of the double bonds in 7-dehydrocholesterol causing them to rearrange and open up the B ring to form the seco-steroid (split steroid) previtamin D3 and once formed, this unstable conformer rapidly converted to vitamin D3
• as vitamin D3 is thermodynamically more stable and also more flexible it is ejected out of the plasma membrane into the extracellular space and diffuses into the capillary bed in the dermis where it is bound to the vitamin D binding protein (DBP) for transport to the liver.
• further UV radiation converts vitamin D3 into isomers lumisterol₃ and tachysterol₃ thereby preventing toxicity

• even at midday at low latitudes in summer, only 1% of solar UVB reaches the earth's surface
• all of the UVB radiation up to approximately 290 nm is efficiently absorbed by the stratospheric ozone layer, plus the ozone layer absorbs approximately 99% of the UVB radiation with wavelengths 291–320 nm
• the degree of UVB radiation and also vit D3 production depends upon:
  • how much atmosphere it must pass - this is mainly related to the elevation of the sun in the sky
  • the presence or absence of an ozone layer
  • air pollution including nitrous oxide, sulfur dioxide and ozone
  • glass and plastic - absorbs all UVB
  • use of sunscreens or clothing on skin
  • degree of skin pigmentation
    • those with pale skin type 2 produce 30x more vit D3 than dark skinned (skin type 5) people with same dose UVB, although the darker skinned people are able to increase vit D3 by 15-fold if UVB dose is raised by 5x ⁷⁾
  • advancing age decreases vit D3 production as 7-dehydrocholesterol concentrations in human epidermis were inversely related to age and thus elderly have 1/3rd the production capacity
  • altitude - higher altitudes mean less atmosphere and thus more UV
    • Mt Everest base camp at 5300m gets 5x the UVB as Agra at 169m altitude
• very little if any vitamin D3 can be produced in the skin before 10 a.m. and after 3 p.m. even in the summer time
• at latitudes grater than 33deg, UVB is insufficient in winter to generate vitamin D3
  • in Boston at 42°N, essentially no vitamin D3 can be produced in the skin from November through February
  • those in Edmonton Canada at 52° North, Bergen Norway at 60° North, or Ushuaia Argentina at 55° South are unable to produce any significant vitamin D3 for about 6 months of the year
• after a UVB dose, serum levels of vit D3 peak by 24-48hrs then gradually fall over the next 3-5 days, whereas after an oral dose of vit D3, levels peak at about 18hrs and fall rapidly over next 1-2 days

• Not stringently regulated, but:
  • feedback inhibition by calcium and phosphate on 1alpha-hydroxylase;
  • increased by parathyroid hormone (PTH);
  • increased [1,25] ⇒ inhibition of 1alpha-hydroxylase;
    • ⇒ facilitation of 24-hydroxylase (kidney) which produced inactive 24,25 instead of 1,25;
    • ⇒ decreased prod. of m-RNA for parathyroid hormone;
  • prolactin ⇒ facilitation of 1alpha-hydroxylase;
  • oestrogens ⇒ increased 1,25 binding protein ⇒ increased bound [1,25], but no change in free [1,25];
  • hyperthyroidism ⇒ decreased [1,25], increased osteoporosis;
  • metabolic acidosis ⇒ decreased production 1,25;
• it seems endocrine disrupting chemicals (EDCs) exposures may reduce vit D levels ⁸⁾

• calcitriol binds the vitamin D receptor (VDR) in enterocytes and increases calcium transport across digestive epithelia through the gatekeeper transient receptor potential vanilloid 6 (TRPV6) transporter
• Calcitriol binds VDR in parathyroid cells, decreasing parathyroid hormone (PTH) synthesis and this may increase urine calcium excretion
• increased GIT Ca absorption via:
  • increased GIT Ca binding protein (via DNA effect);
  • increased enterocyte basolateral Ca pumping out of cell into ECF;
• decreased renal Ca excretion via increased Ca tubule reabsorption;
• mobilisation of Ca & P from bone via increased osteoclast activity & numbers;
• THUS: ⇒ increased serum levels of calcium and phosphate
• HOWEVER, the increased calcium absorption from GIT may increase hypercalciuria in some people, especially at higher levels or in those at risk, and resultant increase risk of urolithiasis / renal stones / renal calculi and renal colic⁹⁾
• in addition, VDR binds specifically to genomic DNA, recognizing the motif RGKTSA. ¹⁰⁾
  • In complex with retinoid X receptor (RXR), VDR preferentially binds to direct repeat sequences in the euchromatin.
  • Various “pioneer factors” facilitate VDR in opening chromatin, which is crucial for efficient binding.
  • VDR's genomic actions involve protein-protein interactions with the Mediator complex and RNA polymerase II, influencing transcription.
  • Vitamin D also exerts epigenomic effects, altering DNA methylation, histone modifications, and chromatin organization, dynamically shaping the cell's epigenetic landscape.
  • These genomic and epigenomic effects contribute to vitamin D's modulatory role in hematopoiesis and immunocompetence, affecting human immune cells, particularly in monocytes.

• due to either:
  • inadequate intake of Vit D provitamins eg. vegetarian diets, breastfed babies whose mothers have low vitamin D levels.
  • malabsorption of vit D eg. short bowel syndrome, liver disorders affecting fat absorption
  • inadequate exposure to sunlight eg. dark skinned people, those who do not get sun exposure without sunscreens.
  • failure of liver prod. of 25-hydroxylase;
  • failure of renal prod. of 1alpha-hydroxylase;
  • defect of target cell 1,25 receptors;
  • hyperparathyroidism
• ⇒ hypocalcaemia ⇒ failure of new bone to adequately mineralise;

• may occur due to:
  • excessive oral intake
  • increased calcitriol production by granuloma cells as in sarcoidosis
  • increased calcitriol production in the kidneys as in primary hyperparathyroidism
  • idiopathic increased calcitriol production which may be seen in¹¹⁾:
    • a subset of idiopathic hypercalciuric stone formers with absorptive hypercalciuria
    • the mechanisms may involve:
      • SLC34A1 mutations coding for the NPT2a phosphate transporter and fibroblast growth factor-23 suppression
      • high protein intakes and glomerular hyperfiltration
      • lower serum 24,25-hydroxyvitamin D/25-hydroxyvitamin D ratio perhaps due to a relative 25-hydroxyvitamin D 24-hydroxylase deficiency due to CYP24A1 polymorphisms
  • some cases of idiopathic infantile hypercalcaemia:
    • mutations of CYP24A1, the enzyme encoding 25-hydroxyvitamin D 24-hydroxylase
• some people tend to be more susceptible to the adverse effects of high levels of vitamin D such as hypercalcaemia:
  • eg. Williams-Beuren syndrome (WBS), sarcoidosis, some lymphoma patients
• the increased calcium absorption from GIT may increase hypercalciuria in some people, especially at higher levels or in those at risk, and resultant increase risk of renal_calculi and renal colic¹²⁾, although many studies suggest this risk is not broadly applicable as risk was not detected in the general population ¹³⁾

• foods (other than oily fish or liver) contain very little vitamin D thus it is difficult to obtain enough vitamin D from dietary sources even when consuming foods fortified with vitamin D
• oral supplements are an important source of vit D for many
• for every 100 IUs of vitamin D ingested the circulating concentration of 25(OH)D increases by approximately 0.6–1.0 ng/mL
• it is generally recommended that all adults receive 1500–2000 IUs of vitamin D daily or 50,000 IUs of vitamin D2 (equivalent to 3300 IUs of vitamin D daily) once every 2 weeks as maintenance dose
  • a daily vitamin D supplement dose of 2000 IU (50 µg) to raise and maintain serum 25(OH)D concentrations >50 nmol/L (20 ng/mL) and >75 nmol/L (30 ng/mL) in >99% and >90% of the general adult population, respectively ¹⁴⁾
  • elderly are more susceptible to toxicity and thus dose may need to be lowered to 800 IU daily
• vitamin D is fat soluble upon its ingestion or production in the skin vitamin D3 gets incorporated into the body fat and thus makes less frequent but higher doses an option to create stores
• HOWEVER, administration to patients in excess of their daily requirements can cause hypercalcaemia, hypercalciuria and hyperphosphataemia
  • Usually vitamin D intoxication is not observed until a 25(OH)D > 200 ng/mL and this usually requires a prolonged intake of extremely high doses of vitamin D for at least several months
• most but not all of the literature supports the concept that vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25(OH)D
• Patients who have a BMI > 30 often need 3–5 times as much vitamin D to both treat and prevent recurrence of vitamin D deficiency
• Patients on glucocorticoids, anti-seizure medications and AIDS medications may also need more vitamin D to both treat and prevent vitamin D deficiency
• Patients however with granulomatous disorders such as sarcoidosis and some lymphomas have a hypersensitivity to vitamin D because of the uncontrolled conversion of 25(OH)D to 1,25(OH)2D by activated macrophages within the granulomas and should have lower doses.

• apparently 1/3rd less potent than vitamin D3.
  • The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5387-5391
• but equally effective as vitamin D3
  • as little as 100 IU of vitamin D2 was found to be effective in the prevention of rickets
  • ScienceDaily (Jan. 7, 2008)

• usual dose is 1,000 IU once a day orally with meals but recommended is now 2000IU daily except in elderly
• Ostelin Vitamin D

• the active form of vitamin D
• can be used to Rx secondary hyperparathyrpidism but this risks hypercalcaemia and hyperphosphataemia

• a vitamin D analogue with less risk of hypercalcaemia in Rx of secondary hyperparathyroidism
  • Aust Prescr 2008

• Sensible sun exposure can be an excellent source of vitamin D for both children and adults
• Sensible means never to be exposed to an amount of sunlight that would cause a sunburn since this is the major cause for both melanoma and non-melanoma skin cancer
• Tanning beds which emit UVB radiation (estimated about 95% of tanning beds in the United States) can be a good source of vitamin D especially for patients with malabsorption syndromes as long as it is dosed correctly
• Exposing 20% of the body surface to an amount of sunlight equal to 0.5 MED is equivalent to ingesting approximately 1400–2000 IUs of vitamin D3.
• Always protect the face with a hat or sunscreen since it provides very little vitamin D3 and is most sun exposed and more prone to skin damage and skin cancer from sun exposure