Vitamin D deficiency pathophysiology

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

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].

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The progression to [disease name] usually involves the [molecular pathway].

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The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Synthesis and Metabolism

• The main sources of vitamin D are sunlight exposure, diet, and dietary supplements.
• 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.
• 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.
• 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.
• 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.

Genetics

• [Disease name] is transmitted in [mode of genetic transmission] pattern.
• Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
• The development of [disease name] is the result of multiple genetic mutations.

Gross Pathology

• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].