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  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

• Q. Give the pathway for vitamin D synthesis?

  • 

• Q. Which are the precursors of Vitamin D?

  • 7-Dehydrocholesterol (Ra)
  • Ergosterol (Rb)

• Q. What happens to the vitamin D precursors in the presence of light?

  • In the presence of light, the vitamin D precursors undergo photoisomerization to Previtamin D
  • Previtamin D is an unstable compound and within 48 hours undergoes temperature-dependent molecular rearrangement to form Vitamin D

• Q. Why can't excess sunlight produce excess Vitamin D?

  • 1. Apart from the formation of Vitamin D, the Previtamin D also isomerizes to inert compounds called Lumisterol and Tachysterol. This prevents all the previtamin D from converting to vitamin D
  • 2. The melanin in the skin darkens with sunlight reducing the penetration of UV rays and hence putting a brake on the first step of vitamin D synthesis dependent on the light

• Q. What timing of sunlight helps vitamin D formation?

  • 10-11 am to 2-3 pm

• Q. What is the impact of sunlight exposure on Vitamin D levels?

  • Sunlight exposure improves vitamin D level to about 4 ng/ml In children in summer with 30 min sunlight exposure with 15-30% of body surface area
  • However, there is little increase in vitamin D in Winters

• Q. What skin melanin category do Indians belong to?

  • Category I- European skin
  • Category VII- African skin
  • Indians- Category- IV or V

• Q. What are the primary dietary sources of vitamin D?

  • Fortified Cereals
  • Fortified dairy products
  • Egg yolk
  • Fish oil

• Q. Why do vitamin D levels decline with aging?

  • It is mainly due to reducing skin synthesis of vitamin D

• Q. How is vitamin D transported?

  • Vitamin D binding protein

• Q. What is the half-life of 25 hydroxyvitamin D?

  • 15 days

• Q. What are the pathway for genomic and nongenomic actions of vitamin D?

  • 

• Q. What are the names of plant and animal sources of vitamin D? Which is more potent?

  • Plant- Ergocalciferol- vitamin D2
  • Animal- Cholecalciferol- vitamin D3
  • Both are equipotent

• Q. Where does vitamin D after it is absorbed?

  • Vitamin D is transported via a lymphatics
  • it is bound to Vitamin D binding protein (VDBP)and Albumin while in circulation
  • It goes to the liver, where it is converted to its storage form 25-Hydroxyvitamin D

• Q. Apart from 25-Hydroxyvitamin D, what else binds to the Vitamin D binding protein (VDBP)?

  • 1,25 Dihydroxyvitamin D also binds to the VDBP

• Q. What happens to animal models having deficiency of Vitamin D binding protein (VDBP)?

  • These mice have an increased tendency for toxicity due to 1,25 Dihydroxyvitamin D
  • It also leads to Vitamin D Deficiency

• Q. What does the polymorphism in the biding of Vitamin D binding protein (VDBP) produce?

  • It leads to vitamin D deficiency in a specific subset of patients

• Q. Which is the principal storage form of vitamin D, and what is its half-life?

  • Storage form is 25-Hydroxyvitamin D
  • Half-life is 15 days

• Q. Give the definitions of vitamin D deficiency and insufficiency?

  • Vitamin D levels
    • Deficiency <20 ng/ml
    • Insufficiency – 20-29 ng/ml
    • Sufficiency – 30-100 ng/ml
    • Toxicity – >150 ng/ml

• Q. Give the cutoffs for vitamin D in nmol/l

  • <30 nmol/l – inadequate
  • 30-50- insufficiency
  • 50-75- sufficiency
  • 75-125- no benefit of replacement
  • More than 125- toxicity

• Q. Where do these levels for normality come from?

  • They are based on when the PTH level rises
  • Hence they are correlated with PTH level

• Q. Which antitubercular drug reduces the 25 hydroxylations of vitamin D?

  • Isoniazid
  • This is because 25 hydroxylation of Vitamin D is a Cytochrome P450 like enzyme

• Q. How does vitamin D reduce blood pressure?

  • Vitamin D reduces renin and hence reduces the blood pressure

• Q. What is megalin and what is its importance in vitamin D metabolism?

  • Megalin is also called LRP2
  • it is a type of receptor
  • antibodies against megalin have been implicated in membranous nephropathy
  • Vitamin D binding protein (VDBP) is filtered by glomeruli and reabsorbed by megalin
  • Deficiency of megalin leads to loss of VDBP leading to severe Vitamin D Deficiency
  • It is also thought to cause reuptake of 25-Hydroxyvitamin D from that filtered by the kidney

• Q. Why is there Vitamin D Deficiency in nephrotic syndrome?

  • In nephrotic syndrome also there is loss of Vitamin D binding protein (VDBP)
  • This leads to deficiency of vitamin D

• Q. Do 1,25 Dihydroxyvitamin D level impact 25-Hydroxyvitamin D levels?

  • Yes
  • Increased conversion to 1,25 Dihydroxyvitamin D leads to lower 25-Hydroxyvitamin D levels

#Updates : Notes from Williams Textbook of Endocrinology

• Metabolism of Vitamin D

  • Q. Which are the precursors of Vitamin D?

    • 7-Dehydrocholesterol (Ra)
    • Ergosterol (Rb)

  • Q. What happens to the vitamin D precursors in the presence of light?

    • In the presence of light, the vitamin D precursors undergo photoisomerization to Previtamin D
    • Previtamin D is an unstable compound and within 48 hours undergoes temperature-dependent molecular rearrangement to form Vitamin D

  • Q. Why can't excess sunlight produce excess Vitamin D?

    • 1. Apart from the formation of Vitamin D, the Previtamin D also isomerizes to inert compounds called Lumisterol and Tachysterol. This prevents all the previtamin D from converting to vitamin D
    • 2. The melanin in the skin darkens with sunlight reducing the penetration of UV rays and hence putting a brake on the first step of vitamin D synthesis dependent on the light

  • Q. What is the half-life of active vitamin D, 1,25 Dihydroxyvitamin D ?

    • The half-life of this is 6-8 hours

  • Q. Where is the 1-alpha hydroxylase enzyme present?

    • It is present in proximal convoluted tubule
    • It is also a Cytochrome P450 enzyme

    • Ketoconazole can suppress this enzyme activity. Hence it can be used for the treatment of granulomatous disease-induced hypercalcemia #Clinicalpearl

  • Q. What is the critical difference between 25-hydroxylase and 1-alpha hydroxylase enzymes?

    • 1-alpha is a more tightly regulated enzyme unline 25-hydroxylase #Clinicalpearl

  • Q. Which substances stimulate and which suppresses the enzyme?

    • Stimulate
      • PTH
      • Increase serum phosphate
    • Success
      • Calcium
      • FGF23

  • Q. What is klotho ?

    • Alpa-klotho is a coreceptor for FGF23 and activates the same

    • Wikipedia
      • klotho is an enzyme that in humans is encoded by the KL gene.
      • There are three subfamilies of klotho: α-klotho, β-klotho, and γ-klotho.
      • α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21.[7]
      • When the subfamily is not specified, the word "klotho" generally means the α-klotho subfamily

  • Q. Apart from the PCT of the kidney, where else is the 1-alpha hydroxylase enzyme expressed?

    • 1. Keratinocytes
    • 2. Placenta
    • 3. Granulomatous tissue

      • This is the reason why granulomatous disease like sarcoidosis and tuberculosis produce hypercalcemia #Clinicalpearl

  • Q. What produces this enzyme in granulomatous tissue?

    • Macrophages produce this
    • This is in response too Interferon gamma
    • This is NOT regulated by routine regulators of 1-alpha hydroxylase like PTH etc
    • Treatment with the following can suppress its production
      • glucocorticoids
      • Ketoconazole
      • chloroquine

  • Q. What is the benefit for the macrophage to produce this enzyme?

  graph TD
     	A[Macrophages from 1,25 Dihydroxyvitamin D] 
     	A --> B[Activate Vitamin D receptor]
     	B --> C[Produce cathelicidin]
     	C --> D[This has antimicrobial property]
     	D --> E[Kills intracellular mycobacteria]

  • Q. What is the role of the 24 hydroxylase enzyme?
    • This converts 25 hydroxyvitamin D to 24,25 dihydroxyvitamin D
    • This is an active form of hormone
    • Deficiency of this enzyme can lead to hypercalcemia

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