Calcitropic Hormones

Lungs REF: Guyton physiology 11^th edition page 983

• Cholecalciferol (Vitamin D3) Is Formed in the Skin.
• Cholecalciferol Is Converted to 25–Hydroxycholecalciferol in the Liver.
• Formation of 1, 25-Dihydroxycholecalciferol takes place in the Kidneys

Keratinocytes REF: Harrison 18^th ed chapter 352

“Vitamin D is produced in keratinocytes of skin and maximum production is in stratum basal”

1, 25-dihydroxyvitamin D [1, 25(OH)₂ D] is the major steroid hormone involved in mineral ion homeostasis regulation.

In response to ultraviolet radiation of the skin, a photochemical cleavage results in the formation of vitamin D

from 7-dehydrocholesterol. Cutaneous production of vitamin D is decreased by melanin and high solar protection factor sunblocks,

which effectively impair skin penetration by ultraviolet light.

Vitamin D from plant sources is in the form of vitamin D2, whereas that from animal sources is vitamin D3.

Vitamin D is subsequently 25-hydroxylated in the liver.

25-hydroxyvitamin D [25(OH)D], is the major circulating and storage form of vitamin D

The second hydroxylation, required for the formation of the mature hormone, occurs in the kidney to form

1,25-dihydroxyvitamin D [1,25(OH)2D]

1, 25-dihydroxycholecalciferol REF: Ganong 22ed chapter 21, Harrison 17^TH edition chapter 21

Vitamin-D: Synthesis and Metabolism

1, 25-dihydroxyvitamin D [1, 25(OH) 2D] is the major steroid hormone involved in mineral ion homeostasis regulation

Vitamin D is subsequently 25-hydroxylated in the liver by cytochrome P450—like enzymes in the mitochondria and microsomes. The activity of this hydroxylase is not tightly regulated, and the resultant metabolite, 25-hydroxyvitamin D [25(OH) D], is the major circulating and storage form of vitamin D

The second hydroxylation, required for the formation of the mature hormone, occurs in the kidney. The 25-hydroxyvitamin D-1-hydroxylase is a tightly regulated cytochrome P450—like mixed function oxidase expressed in the proximal convoluted tubule cells of the kidney

Thyroid gland

Lower Ca level

Vitamin D from the skin or diet is metabolized primarily in the liver to 25-hydroxyvitamine D3. 25D is the ‘storage’ form of vitamin D and is used to determine the vitamin D status of individuals. The last and rate limiting step in the synthesis of ‘active’ 1,25D is catalyzed by the mitochondrial enzyme 1 hydroxylase and is conventionally known to take place in kidneys.

Calcitonin is a hypocalcemic peptide hormone that in several mammalian species acts as an antagonist to PTH. The hypocalcemic activity of calcitonin is accounted for primarily by inhibition of osteoclast-mediated bone resorption and secondarily by stimulation of renal calcium clearance.

Calcitonin is primarily secreted by the parafollicular C cells of the Thyroid gland. It is a hormone secreted in response to elevated blood calcium. It stimulates calcium deposition in bone and calcium excretion by the kidneys, thus reducing blood calcium.

Here there are signs of early renal failure. This reduces the levels of 1 alpha-hydroxylase in the proximal tubule cells, thereby reducing the conversion of 25-hydroxyvitamin D, the inactive form of vitamin D, to 1,25-dihydroxyvitamin D, the most active form.

The 25-hydroxycholecalciferol is converted in the cells of the proximal tubules of the kidneys to the more active metabolite 1,25-dihydroxycholecalciferol, which is also called calcitriol or 1,25-(OH)2D3. 1,25-Dihydroxycholecalciferol is also made in the placenta, in keratinocytes in the skin, and in macrophages.

Ref: Barrett K.E., Barman S.M., Boitano S., Brooks H.L. (2012). Chapter 21. Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone. In K.E. Barrett, S.M. Barman, S. Boitano, H.L. Brooks (Eds), Ganong’s Review of Medical Physiology, 24e.

In response to ultraviolet radiation of the skin, a photochemical cleavage results in the formation of vitamin D from 7-dehydrocholesterol. Vitamin D enters the circulation, whether absorbed from the intestine or synthesized cutaneously, bound to vitamin D–binding protein, an alpha-globulin synthesized in the liver. Vitamin D is subsequently 25-hydroxylated in the liver by cytochrome P450–like enzymes in the mitochondria and microsomes. The second hydroxylation, required for the formation of the mature hormone, occurs in the kidney. The 25-hydroxyvitamin D-1 alpha-hydroxylase is a tightly regulated cytochrome P450–like mixed-function oxidase expressed in the proximal convoluted tubule cells of the kidney.

C i.e. Parathormone (PTH) promotes absorption of Ca²⁺ from intestine promotes absorption of calcium from intestineQ via activation of vitamin D (1,25, dihydroxy cholecalciferol)

• A large amount of calcium is filtered in the kidney but 98-99% of filtered Ca²⁺ is reabsorped: (d/t action of PTH) – 60% from proximal tubuleQ

– 25% from loop of henle

– Small extent in distal tubule

• Calcitonin is stimulated when there is hypercalcemiaQ.

B i.e. Decreased bone resorption

Calcitonin causes hypocalcemia by inhibiting bone resorptionQ by direct action on osteoclastsQ.

Ans. D i.e. None of the option

Two hormones serve as primary regulators of the calcium in blood: parathyroid hormone and calcitonin.

Parathyroid hormone stimulates bones to release calcium into blood, digestive tract to absorb more calcium and kidneys to excrete less calcium and activate more vitamin D.

Calcitonin slows the release of calcium from bones (inhibits resorption)

Other hormones which affects calcium metabolism are:

• 1, 25-dihydroxycholecalciferol
• Glucocorticocoids
• Growth hormone
• Thyroid hormones
• Estrogens
• Insulin

Causes of hypercalcemia include:

• Overactivity of parathyroid glands: primary hyperparathyroidism
• Cancer: lung and breast cancer, multiple myeloma, paraneoplastic syndrome
• Metastasis to bones also increases risk of hypercalcemia.
• Other diseases: tuberculosis and sarcoidosis
• Medications: lithium, Thiazide diuretics

Ans. D i.e. Skin – liver – kidney

Ans. B i.e. Vitamin D

The vitamins that are considered antioxidants include vitamin A, vitamin C, vitamin E and beta carotene, but many minerals like selenium, lycopine and zeaxanthin are also antioxidants.

Ans. C: 1, 25 hydroxy Vitamin D (Calcitriol)

Calcitriol (1, 25-DHCC) is the biologically active form of vitamin D

Calcitriol/ 1, 25-dihydroxycholecalciferol/ 1,25-dihydroxyvitamin D3

• It is the hormonally active form of vitamin D with three hydroxyl groups (abbreviated 1,25-(OH)2D3 or simply 1, 25 (OH)2D).
• It increases the level of calcium (Ca2+) in the blood by (1) increasing the uptake of calcium from the gut into the blood, (2) decreasing the transfer of calcium from blood to the urine by the kidney, and (3) increasing the release of calcium into the blood from bone
• Calcitriol increases blood calcium levels ([Ca2+]) by promoting absorption of dietary calcium from the gastrointestinal tract and increasing renal tubular reabsorption of calcium thus reducing the loss of calcium in the urine.
• Calcitriol also stimulates release of calcium from bone by its action on the osteoblasts, causing them to release RANKL, which in turn activates osteoclasts.
• Calcitriol acts in concert with parathyroid hormone (PTH) in all three of these roles.
• For instance, PTH also stimulates osteoclasts.
• However, the main effect of PTH is to increase the rate at which the kidneys excrete inorganic phosphate (Pi), the counterion of Ca2+.
• The resulting decrease in serum phosphate causes Ca5 (PO4)30H to dissolve out of bone thus increasing serum calcium.
• PTH also stimulates the production of calcitriol.
• Many of the effects of calcitriol are mediated by its interaction with the calcitriol receptor, also called the vitamin D receptor or VDR.The maintenance of electroneutrality requires that the transport of Ca2+ ions catalyzed by the intestinal epithelial cells be accompanied by counterions, primarily inorganic phosphate.
• Thus calcitriol also stimulates the intestinal absorption of phosphate.Calcitriol also inhibits the release of calcitonin, a hormone which reduces blood calcium primarily by inhibiting calcium release from bone.
• Calcitriol is produced in the cells of the proximal tubule of the nephron in the kidneys by the action of 25-hydroxy­vitamin D3 1-alpha-hydroxylase, a mitochondrial oxygenase and an enzyme which catalyzes the hydroxylation of 25-hydroxycholecalciferol (calcifediol).
• The activity of the enzyme is stimulated by PTH.
• The reaction is an important control point in Ca2+ homeostasis.
• The production of calcitriol is also increased by prolactin, a hormone which stimulates lactogenesis, a process which requires large amounts of calcium.

Ans. is ‘c’ i.e., Calcitriol

Vitamin D

• Vitamin D is the major vitamin involved in the absorption of calcium.
• Beside dietary intake, cutaneous synthesis is the other and more important source of vitamin D (cholecalciferol) in the body. The keratinocytes of stratum corneum of the epidermis of skin contain 7-dehydrocholesterol which is converted to Vitamin D₃ (cholecalciferol) by the action of sunlight (UV light).
• This vitamin D₃ (Cholecalciferol) is converted to calcidiol (calcifediol or 25 hydroxy cholecalciferol or 25-hydroxy vitamin D₃) by 25 hydroxylase in the liver.
• Calcidiol is the major circulating form of vitamin D3.
• Calcidiol is then converted to Calcitriol (1-25 dihydroxy-cholecalciferol or 1-25 dihydroxy vitamin D3) by 1-a hydroxylation in kidney.
• The final hydroxylation in kidney is rate limiting step.
• Calcitriol is the active form of vitamin D.
• Dietary vitamin D is absorbed in ileum and requires bile salts.
• When Ca² level is high, little calcitriol is produced, and the kidney produce the relatively inactive metabolite 24, 25 dihydroxycholecalciferol instead.

Ans. is ‘c’ i.e., Vitamin D

Active form of vitamin D i.e. 1-25 dihydroxy-cholecalciferol is a vitamin produced in kidney.

It acts on intranuclear receptors to regulate gene expressions (transcription factors).

Ans. is ‘b i.e., Major regulating factor is parathormone

Calcium excretion by kidney

Calcium is both filtered and reabsorbed in kidneys but not secreted.

Thus renal excretion of kidney is –

Renal calcium excretion = Filtered calcium – Calcium reabsorbed

Normally, 99% of filtered calcium is reabsorbed in kidney.

1) PCT : Maximum calcium is reabsorbed in PCT. About 65% of filtered calcium is absorbed here.

2) Loop of Henle : About 25-30% of calcium is reabsorbed in loop of Henle (only from thick ascending limb).

3) DCT and collecting tubules : About 4-9% of calcium is reabsorbed in DCT and collecting tubules.

Primary controller of renal tubular reabsroption is parathormone. It increases calcium reabsorption in Loop of Henle (thick ascending limb) and distal tubules.

Vitamin D (calcitriol) and calcitonin also stimulate calcium absorption in thick ascending limb of loop of Henle and distal tubule, although these hormones are not as important quantitatively as PTH in reducing renal excretion.

Ans. is `b’ i.e., Decreased serum Ca⁺⁺

Ans. is ‘b’ i.e., 1-hydroxylation in liver

Ans. is ‘b’ i.e., DCT

Paratharmone

• Paratharmone is 84 aminoacid polypeptide hormone secreted from parathyroid glands.
• Its secretion is regulated by plasma Ca++ concentration — fall in Ca++ concentration increases the secretion of paratharmone.

Actions

• PTH increases resorption of calcium from bone  → most prominant action.
• PTH increases calcium reabsorption from distal tubules of kidney.
• PTH decreases phophate reabsorption from proximal tubules of kidney.
• PTH has no direct effect on calcium absorption from intestine but increases it indirectly by enhancing the formation of calcitriol by activating la-hydroxylose.
• PTH decreases calcium level in milk, saliva, and ocular lens — may be responsible for development of cataract in hypothyroidism.

Ans. is ‘b’ i.e., 25 hydroxyvitamin D

Though, 1, 25 dihydroxyvitamin D (calcitriol) is the active form of vitamin D, its serum measurement does not provide any information about vitamin D status because it is often normal or elevated due to secondary hyperparathyroidism associated with vitamin D deficiency…

Measurement of 25 hydroxyvitamin D (calcifedial) in serum provides more accurate information of vitamin D status. The usual values are :-

• < 20 ng/ml → Deficiency
• 20-29 ng/ml → Insufficiency
• 30-100 ng/ml → Normal
• > 100 ng/ml → Toxicity