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{{Vitamin D deficiency}}
{{Vitamin D deficiency}}


{{CMG}}; {{AE}}  
{{CMG}}; {{AE}} {{HS}}
==Overview==
==Overview==
The exact pathogenesis of [disease name] is not fully understood.
OR
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to [disease name] usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.


==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.  
Line 45: Line 19:
*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.
Line 51: Line 25:
* 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'''
==Genetics==
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>
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
*Effect of [[parathyroid hormone]] on [[calcium]] [[metabolism]]:
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
**Direct effect:
*The development of [disease name] is the result of multiple genetic mutations.
***Increased [[resorption]] of [[Bone (disambiguation)|bones]].
==Associated Conditions==
***Decreases [[excretion]] from [[kidney]].
 
**Indirect effect:
==Gross Pathology==
***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]].
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
***Decreased serum [[inorganic phosphate]] concentration prevents [[Precipitation (chemistry)|precipitation]] of [[calcium phosphate]] in [[Bone (disambiguation)|bones]].
 
***Both these direct and indirect mechanism results in an increased serum [[calcium]] concentration.
==Microscopic Pathology==
*Effect of [[parathyroid hormone]] on [[inorganic phosphate]] [[metabolism]]:
*On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
**Increases [[excretion]] of [[Phosphate|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 [[Mineral|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]].
<br><br><br>
<div style="text-align: center;">'''The Sequence of Events in Parathyroid, Vitamin D, and Mineral Homeostasis''' </div>
<br>
{{familytree/start |}}
{{familytree | | | | | | | | | | | | A01 |A01='''Parathyroid hormone'''}}
{{familytree | | | | | | | |,|-|-|-|-|^|-|-|-|-|-|-|-|-|-|-|-|-|-|-|.|}}
{{familytree | | | | | | | B01 | | | | | | | | | | | | | | | | | | B02 | | |B01=[[Kidney]]|B02=[[Bone]]}}
{{familytree | |,|-|-|-|-|-|+|-|-|-|-|v|-|-|-|-|-|-|.| | | | | | | |!| }}
{{familytree | C01 | | | | C02 | | | C03 | | | | | C04 | | | | | | C05 |C01=Decreased [[excretion]] of [[magnesium]]|C02=Increasead conversion of inactive [[25-hydroyx vitamin D]] to the active [[1,25-dihydroy xvitamin D]]|C03=Increase [[excretion]] of inorganic [[phosphate]]|C04=Decrease [[excretion]] of [[calcium]]|C05=Increased [[resorption]] of [[bone]]}}
{{familytree | |!| | | | | |!| | | | |!| | | | | | |!| | | | | | | |!| |}}
{{familytree | D01 | | | | D02 | | | D03 | | | | | |`|-|-|-|-|.| | |!|D01=Increased serum concentration of [[magnesium]]|D02=Increased absorption of [[calcium]] from [[gut]]|D03=Decreased [[serum]] concentration of inorganic [[phosphate]]}}
{{familytree | | | | | | | |!| | | | |!| | | | | | | | | | | |!| | |!|}}
{{familytree | | | | | | | |!| | | | |`|-|-| E01 |-|-|-|-|.| |!| | |!| E01=Prevents precipitation of [[calcium phosphate]] in [[bones]]}}
{{familytree | | | | | | | |!| | | | | | | | | | | | | | |!| |!| | |!| | | | | |}}
{{familytree | | | | | | | |`|-|-|-|-|-|-|-|-|-|-|-|-|-|-| F01 |-|-|'| | |F01=Increased serum concentration of [[calcium]]}}
{{familytree/end}}
<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 minerals and vitamin D on 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. ↑ 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.
  2. ↑ 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.
  3. ↑ DeLuca HF (2004). "Overview of general physiologic features and functions of vitamin D". Am. J. Clin. Nutr. 80 (6 Suppl): 1689S–96S. PMID 15585789.
  4. ↑ HARRISON MT (1964). "INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS". Postgrad Med J. 40: 497–505. PMC 2482768. PMID 14184232.
  5. ↑ Nussey, Stephen (2001). Endocrinology : an integrated approach. Oxford, UK Bethesda, Md: Bios NCBI. ISBN 1-85996-252-1.

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