Vitamin D deficiency pathophysiology: Difference between revisions
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{{CMG}}; {{AE}} {{HS}} | {{CMG}}; {{AE}} {{HS}} | ||
==Overview== | ==Overview== | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Synthesis and Metabolism=== | ===Synthesis and Metabolism=== | ||
*The main sources of vitamin D are sunlight exposure, diet, and dietary supplements. | *The main sources of vitamin D are sunlight exposure, diet, and dietary supplements.<ref name="pmid18329892">{{cite journal| author=Holick MF| title=Vitamin D status: measurement, interpretation, and clinical application. | journal=Ann Epidemiol | year= 2009 | volume= 19 | issue= 2 | pages= 73-8 | pmid=18329892 | doi=10.1016/j.annepidem.2007.12.001 | pmc=2665033 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18329892 }} </ref> | ||
*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. | *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. | *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. | *Vitamin D refers to both cholecalciferol and ergocalciferol or vitamin D2 and vitamin D3. | ||
'''Synthesis in the skin''' | '''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. | *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.<ref name="pmid16886050">{{cite journal| author=Holick MF| title=Resurrection of vitamin D deficiency and rickets. | journal=J Clin Invest | year= 2006 | volume= 116 | issue= 8 | pages= 2062-72 | pmid=16886050 | doi=10.1172/JCI29449 | pmc=1523417 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16886050 }} </ref> | ||
*The UVB (wavelength, 290 - 315 nm ) radiations convert 7- dehydrocholesterol to pre-vitamin D3, which isomerizes to D3. | *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 formation of vitamin D3 in the skin depends on sunlight exposure, the intensity of UVB and level of melanin pigment in the skin. | ||
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*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. | *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''' | '''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. | * In the liver, vitamin D undergoes hydroxylation into 25 - hydroxyvitamin D3 with the help of one or more cytochrome P450 vitamin D hydroxylases.<ref name="pmid18329892">{{cite journal| author=Holick MF| title=Vitamin D status: measurement, interpretation, and clinical application. | journal=Ann Epidemiol | year= 2009 | volume= 19 | issue= 2 | pages= 73-8 | pmid=18329892 | doi=10.1016/j.annepidem.2007.12.001 | pmc=2665033 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18329892 }} </ref> | ||
* The common P 450 hydroxylases involved are CYP2R1, CYP2D11, and CYP2D25. | * 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. | * 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. | ||
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* 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. | * 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''' | '''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. | * 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.<ref name="pmid15585789">{{cite journal |vauthors=DeLuca HF |title=Overview of general physiologic features and functions of vitamin D |journal=Am. J. Clin. Nutr. |volume=80 |issue=6 Suppl |pages=1689S–96S |year=2004 |pmid=15585789 |doi= |url=}}</ref> | ||
* The hydroxylation in the kidney is carried by 25-hydroxyvitamin D3 1-alpha-hydroxylase, which is the product of the CYP27B1 human gene. | * 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). | * 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. | * 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''' | '''Parathyroid hormone (PTH), Vitamin D and mineral homeostasis''' | ||
The effect of [[parathyroid hormone]] on [[mineral]] [[metabolism]] is as follows:<ref name="pmid14184232">{{cite journal |vauthors=HARRISON MT |title=INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS |journal=Postgrad Med J |volume=40 |issue= |pages=497–505 |year=1964 |pmid=14184232 |pmc=2482768 |doi= |url=}}</ref><ref>{{cite book | last = Nussey | first = Stephen | title = Endocrinology : an integrated approach | publisher = Bios NCBI | location = Oxford, UK Bethesda, Md | year = 2001 | isbn = 1-85996-252-1 }}</ref> | |||
*Effect of [[parathyroid hormone]] on [[calcium]] [[metabolism]]: | *Effect of [[parathyroid hormone]] on [[calcium]] [[metabolism]]: | ||
**Direct effect: | **Direct effect: | ||
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{{familytree | | | | | | | |`|-|-|-|-|-|-|-|-|-|-|-|-|-|-| F01 |-|-|'| | |F01=Increased serum concentration of [[calcium]]}} | {{familytree | | | | | | | |`|-|-|-|-|-|-|-|-|-|-|-|-|-|-| F01 |-|-|'| | |F01=Increased serum concentration of [[calcium]]}} | ||
{{familytree/end}} | {{familytree/end}} | ||
<br><br> | <br><br> | ||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
Latest revision as of 19:18, 9 October 2017
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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]
Overview
Pathophysiology
Synthesis and Metabolism
- 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.
- Direct effect:
- 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:
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.
The Sequence of Events in Parathyroid, Vitamin D, and Mineral Homeostasis
| Parathyroid hormone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kidney | Bone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Decreased excretion of magnesium | Increasead conversion of inactive 25-hydroyx vitamin D to the active 1,25-dihydroy xvitamin D | Increase excretion of inorganic phosphate | Decrease excretion of calcium | Increased resorption of bone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased serum concentration of magnesium | Increased absorption of calcium from gut | Decreased serum concentration of inorganic phosphate | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prevents precipitation of calcium phosphate in bones | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased serum concentration of calcium | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
References
- ↑ 1.0 1.1 Holick MF (2009). "Vitamin D status: measurement, interpretation, and clinical application". Ann Epidemiol. 19 (2): 73–8. doi:10.1016/j.annepidem.2007.12.001. PMC 2665033. PMID 18329892.
- ↑ Holick MF (2006). "Resurrection of vitamin D deficiency and rickets". J Clin Invest. 116 (8): 2062–72. doi:10.1172/JCI29449. PMC 1523417. PMID 16886050.
- ↑ DeLuca HF (2004). "Overview of general physiologic features and functions of vitamin D". Am. J. Clin. Nutr. 80 (6 Suppl): 1689S–96S. PMID 15585789.
- ↑ HARRISON MT (1964). "INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS". Postgrad Med J. 40: 497–505. PMC 2482768. PMID 14184232.
- ↑ Nussey, Stephen (2001). Endocrinology : an integrated approach. Oxford, UK Bethesda, Md: Bios NCBI. ISBN 1-85996-252-1.