Vitamin D is very essential for calcium absorption from the GI tract.
But vitamin D itself is not an active substance.
Instead, vitamin D has to be converted into 1, 25-dihydroxycholecalciferol in the liver and kidney in the presence of Parathormone (PTH).
Vitamin D deficiency is very common now a days due to sedentary lifestyle, lack of sun exposure etc etc…
I have divided this article in 3 different portions.
In this portion, Physiology of Vitamin D metabolism & absorption in body, clinical features of vitamin D deficiency & general mode of treatment is discussed.
Instead, vitamin D has to be converted into 1, 25-dihydroxycholecalciferol in the liver and kidney in the presence of PTH.
The 1,25-dihydroxycholecalciferol is the active product. Activation of vitamin D. There are various forms of vitamin D. But, the most important one is vitamin D3.
It is also known as cholecalciferol.
Vitamin D3 is synthesized in the skin from 7-dehydrocholesterol, by the action of ultraviolet rays from the sunlight.
It is also obtained from dietary sources. The activation of vitamin D3 occurs in two steps-
Cholecalciferol (vitamin D3) is converted into 25- hydroxycholecalciferol in the liver. This process is limited. and is inhibited by 25-hydroxycholecalciferol itself by feedback mechanism.
This inhibition is essential for two reasons:
i. Regulation of the amount of active vitamin D .
ii. Storage of vitamin D for months together. If vitamin D3 is converted into 25-hydroxycholecalciferol, it remains in the body only for 2 to 5 days. But vitamin D3 is stored in liver for several months.
25-hydroxycholecalciferol is converted into 1,25- dihydroxycholecalciferol (calcitriol) in kidney. It is the active form of vitamin D3. This step needs the presence of PTH.
Role of Calcium Ion in Regulating 1, 25-Dihydroxycholecalciferol:-
When blood calcium level increases, it inhibits the formation of 1,25-dihydroxycholecalciferol.
The mechanism involved in the inhibition of the formation of 1,25-dihydroxycholecalciferol is as follows:
1. Increase in calcium ion concentration directly suppresses the conversion of 25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol. This effect is very mild
2. Increase in calcium ion concentration decreases the PTH secretion, which in turn suppresses the conversion of 25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol. This regulates the calcium ion concentration of plasma itself indirectly, i.e. when the PTH synthesis is inhibited, the conversion of 25-hydroxycholecalciferol into 1,25-hydroxycholecalciferol is also inhibited. Lack of 1,25-dihydroxycholecalciferol, decreases the absorption of calcium ions from the intestine, from the bones and from the renal tubules as well. This makes the calcium level in the plasma to fall back to normal.
Actions of 1, 25-Dihydroxycholecalciferol:-
1. It increases the absorption of calcium from the intestine, by increasing the formation of calcium binding proteins in the intestinal epithelial cells. These proteins act as carrier proteins for facilitated diffusion, by which the calcium ions are transported. The proteins remain in the cells for several weeks after 1,25-dihydroxycholecalciferol has been removed from the body, thus causing a prolonged effect on calcium absorption
2. It increases the synthesis of calcium-induced ATPase in the intestinal epithelium
3. It increases the synthesis of alkaline phophatase in the intestinal epithelium
4. It increases the absorption of phosphate from intestine along with calcium.
VITAMIN D DEFICIENCY:-
Vitamin D is a fat-soluble vitamin that plays an important role in calcium homeostasis and bone metabolism. Vitamin D deficiency can lead to osteomalacia and rickets in children and osteomalacia in adults. The fortification of milk with vitamin D in the 1930s was effective in eradicating rickets in the world. However, subclinical vitamin D deficiency is still widely prevalent in both developed and developing countries with a worldwide prevalence of up to 1 billion.1 This subclinical vitamin-D deficiency is associated with osteoporosis, increased risk of falls and fragility fractures. Many conflicting recent studies are now showing an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression.2
1. Decreased dietary intake and/or absorption.
Certain malabsorption syndromes such as celiac disease, short bowel syndrome, gastric bypass, inflammatory bowel disease, chronic pancreatic insufficiency, and cystic fibrosis may lead to vitamin D deficiency. Lower vitamin D intake orally is more prevalent in the elderly population.3
2. Decreased sun exposure.
About 50% to 90% of vitamin D is absorbed through the skin via sunlight while the rest comes from the diet. Twenty minutes of sunshine daily with over 40% of skin exposed is required to prevent vitamin D deficiency.4 Cutaneous synthesis of vitamin D declines with aging. Dark-skinned people have less cutaneous vitamin D synthesis. Decreased exposure to the sun as seen in individuals who are institutionalized, or have prolonged hospitalizations can also lead to vitamin D deficiency5. Effective sun exposure is decreased in individuals who use sunscreens consistently.
3. Decreased endogenous synthesis.
Individuals with chronic liver disease such as cirrhosis, hyperparathyroidism, renal failure and 1-alpha hydroxylase deficiency.
4. Increased hepatic catabolism.
Medications such as phenobarbitol, carbamazepine, dexamethasone, nifedipine, spironolactone, clotrimazole, and rifampicin induce hepatic p450 enzymes which activate degradation of vitamin D.6
5. End organ resistance.
End organ resistance to vitamin D can be seen in hereditary vitamin D resistant rickets.
Vitamin D deficiency is a global public health issue. About 1 billion people worldwide have vitamin D deficiency, while 50% of the population has vitamin D insufficiency.1 The prevalence of patients with vitamin D deficiency is highest in the elderly, obese patients, nursing home residents, and hospitalized patients.
Vitamin D deficiency may be related to populations who have higher skin melanin content and who use extensive skin coverage, particularly in Middle Eastern countries.
over 80% of adults in Pakistan, India, and Bangladesh are Vitamin D deficient. In the United States, 61% of the elderly population is vitamin D deficient whereas 90% in Turkey, 96% in India, 72% in Pakistan, and 67% in Iran were vitamin D deficient.6
The majority of patients with vitamin D deficiency are asymptomatic. However, even mild chronic vitamin D deficiency can lead to chronic hypocalcaemia and hyperparathyroidism which can contribute risk of osteoporosis, falls and fractures especially in the elderly population.
Patients with a prolonged and severe vitamin D deficiency can experience symptoms associated with secondary hyperparathyroidism including bone pain, arthralgias, myalgias, fatigue, muscle twitching (fasciculations), and weakness.
Fragility fractures may result from chronic vitamin D deficiency leading to osteoporosis.
In children, irritability, lethargy, developmental delay, bone changes, or fractures can be symptoms of vitamin D deficiency.
It is not recommended to screen asymptomatic individuals for vitamin-D deficiency.
High-risk individuals shall be evaluated.
Vitamin D sufficiency or deficiency is evaluated by the measurement of serum 25-hydroxyvitamin D.
Optimal serum levels of 25-hydroxyvitamin D is still a matter of controversy.
The International Society for Clinical Densitometry and International Osteoporosis Foundation recommend minimum serum levels of 25-hydroxyvitamin D of 30 ng/mL to minimize the risk of fall and fractures in older individuals.11
There is insufficient data about the maximum safe up her level of serum 25-hydroxyvitamin D, however, at high levels such as above 100 ng/mL, there is a potential risk of toxicity due to the secondary hypercalcemia.
In patients where vitamin-D deficiency has been diagnosed, it is important to evaluate for secondary hyperparathyroidism and levels of parathyroid hormone and serum calcium shall be checked.
The severity of vitamin D deficiency is divided into mild, moderate, and severe. 9
Mild deficiency: 25-hydroxyvitamin D less than 20 ng/mL
Moderate deficiency: 25-hydroxyvitamin D less than 10 ng/mL
Severe deficiency: 25-hydroxyvitamin D less than 5 ng/mL
• Celiac sprue
• Cystic fibrosis
• End-stage liver disease
• Inadequate sunlight exposure
• Lack of dietary intake
• Use of antiepileptic medications
Management of Vitamin D deficiency:-
The amount of vitamin D required to treat the deficiency depends largely on the degree of the deficiency and underlying risk factors.
• Initial supplementation for 8 weeks with Vitamin D3 either 6,000 IU daily or 50,000 IU weekly can be considered.8 Once the serum 25-hydroxyvitamin D level exceeds 30 ng/mL, a daily maintenance dose of 1,000 to 2,000 IU is recommended.
• Children who are vitamin D deficient require 2000 IU/day of vitamin D3 or 50,000 IU of vitamin D3 once weekly for 6 weeks. Once the serum 25(OH)D level exceeds 30 ng/mL, 1000 IU/day maintenance treatment is recommended. According to the American Academy of Paediatrics, infants who are breastfed and children who consume less than 1 L of vitamin D-fortified milk need 400 IU of vitamin D supplementation.
• Calcitriol can be considered where the deficiency persists despite treatment with vitamin D2 and/or D3. The serum calcium level shall be closely monitored in these individuals due to an increased risk of hypercalcemia secondary to calcitriol.
• Calcidiol can be considered in patients with fat malabsorption or severe liver disease
Toxicity and Side Effect Management:-
Vitamin D is a fat-soluble vitamin, hence, toxicity is possible, although rarely noted. Hypervitaminosis D results from excess oral intake and not due to excessive sunlight exposure. Toxicity has been reported at a serum 25-hydroxyvitamin D level of more than 88 ng/mL. Acute intoxication can lead to acute hypercalcemia that can cause confusion, anorexia, vomiting, polyuria, polydipsia, and muscle weakness. Chronic intoxication can lead to nephrocalcinosis and bone pain.
1. Nair R, Maseeh A. Vitamin D: The “sunshine” vitamin. J Pharmacol Pharmacother. 2012 Apr;3(2):118-26.
2. Holick MF. Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South. Med. J. 2005 Oct;98(10):1024-7.
3. Czernichow S, Fan T, Nocea G, Sen SS. Calcium and vitamin D intake by postmenopausal women with osteoporosis in France. Curr Med Res Opin. 2010 Jul;26(7):1667-74.
4. Naeem Z. Vitamin d deficiency- an ignored epidemic. Int J Health Sci (Qassim). 2010 Jan;4(1):V-VI.
5. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS. Hypovitaminosis D in medical inpatients. N. Engl. J. Med. 1998 Mar 19;338(12):777-83.
6. Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem? J. Steroid Biochem. Mol. Biol. 2014 Oct;144 Pt A:138-45.
7. Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P, Morales-Torres J, Yoshimura N. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010 Jul;21(7):1151-4.
8. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM., Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011 Jul;96(7):1911-30.
9. Gani LU, How CH. PILL Series. Vitamin D deficiency. Singapore Med J. 2015 Aug;56(8):433-6; quiz 437.
10. Essentials of Medical Physiology Sixth Edition K Sembulingam PhD and Prema Sembulingam PhD
In Part 2, I will further explain, how homoeopathic medicine helps in vitamin D replacement & improves absorption in deficients. (Homoeopathic theraputics)
– Dr. Nidhi Dave