Q2
LONG ANSWER
10M
★ High-yield
Describe the synthesis, activation and functions of vitamin D. Discuss the features of rickets and osteomalacia.
Nature and Forms
Vitamin D = a fat-soluble prohormone, since it is synthesised in the body, transported in blood, and acts on distant tissues through a nuclear receptor.
| Form | Origin |
|---|---|
| Vitamin D3 (cholecalciferol) | Skin, from 7-dehydrocholesterol; also animal foods |
| Vitamin D2 (ergocalciferol) | Plants and yeast, from ergosterol |
| 25(OH)D3 (calcidiol) | Liver — the storage and circulating form; the one measured |
| 1,25(OH)2D3 (calcitriol) | Kidney — the active hormone |
Synthesis and Activation
7-Dehydrocholesterol in skin → UV-B light (290–315 nm) → Cholecalciferol (D3) → liver — 25-hydroxylase → 25(OH)D3 — half-life 2–3 weeks → kidney — 1α-hydroxylase (rate-limiting, in the PCT) → calcitriol — 1,25(OH)2D3
- Sunlight is the chief source — 15–30 minutes of exposure to face and arms several times a week suffices
- 25(OH)D is measured, not calcitriol, because it has the longest half-life and reflects total stores
- Transported bound to vitamin D binding protein
Regulation of 1α-hydroxylase
| Stimulated by | Inhibited by |
|---|---|
| Parathyroid hormone — the chief regulator | Calcitriol itself (feedback) |
| Low serum calcium | High calcium |
| Low serum phosphate | FGF-23 |
| Prolactin, oestrogen, growth hormone | High phosphate |
- The alternative enzyme 24-hydroxylase makes the inactive 24,25(OH)2D, diverting the pathway when calcium is plentiful
Actions
| Target | Action | Mechanism |
|---|---|---|
| Intestine (chief target) | ↑ Absorption of calcium and phosphate | Induces calbindin and the TRPV6 channel |
| Bone | Permits normal mineralisation; with PTH, mobilises calcium | Stimulates osteoblasts and, indirectly, osteoclasts via RANKL |
| Kidney | ↑ Reabsorption of calcium and phosphate | Direct |
| Parathyroid | ↓ PTH synthesis | Negative feedback |
| Other | Immune modulation, cell differentiation, insulin secretion, muscle function | VDR is present in most tissues |
CLINICAL PEARL
Contrast with PTH: both raise calcium, but vitamin D raises phosphate while PTH lowers it. Vitamin D acts chiefly on the gut; PTH on bone and kidney. This is the commonest discriminating question on calcium metabolism.
Deficiency — Rickets and Osteomalacia
| Feature | Rickets (child) | Osteomalacia (adult) |
|---|---|---|
| Defect | Failure of mineralisation at the growing epiphyseal plate | Failure of mineralisation of newly formed osteoid |
| Head | Craniotabes, delayed fontanelle closure, frontal bossing | — |
| Chest | Rachitic rosary, Harrison sulcus, pigeon chest | — |
| Limbs | Widened wrists, bowing of legs, knock knees | Bone pain and tenderness |
| Other | Delayed dentition, pot belly, hypotonia, delayed walking | Proximal myopathy — waddling gait, pseudofractures (Looser zones) |
| X-ray | Cupping, splaying and fraying of metaphyses | Pseudofractures, reduced density |
Biochemical findings
| Test | Result |
|---|---|
| Serum calcium | Low or normal (kept up by PTH) |
| Serum phosphate | Low |
| Alkaline phosphatase | Markedly raised — the most useful screening test |
| PTH | Raised (secondary hyperparathyroidism) |
| 25(OH)D | Low — the diagnostic test |
Causes of Deficiency and Resistance
- Inadequate sunlight — dark skin, veiling, urban living, air pollution, prolonged indoor life
- Dietary lack — exclusive breast feeding without supplements
- Malabsorption — coeliac disease, cystic fibrosis, cholestasis
- Chronic kidney disease — 1α-hydroxylase fails → renal osteodystrophy; needs calcitriol, not cholecalciferol
- Liver disease — impaired 25-hydroxylation
- Anticonvulsants (phenytoin, phenobarbitone) induce P450 and accelerate degradation
- Vitamin D dependent rickets — type I (1α-hydroxylase defect, responds to calcitriol); type II (receptor defect, resistant)
- Vitamin D resistant rickets — X-linked hypophosphataemia; a renal phosphate leak with high FGF-23
Applied Aspects
- Vitamin D deficiency is extremely common in India despite abundant sunshine — skin pigmentation, clothing, pollution and indoor working all contribute
- Hypervitaminosis D — hypercalcaemia, nephrocalcinosis, metastatic calcification, polyuria. The most toxic of all vitamins in overdose
- Sarcoidosis and tuberculosis — macrophages express 1α-hydroxylase independently of PTH → hypercalcaemia
- Prevention — 400 IU daily in infancy; supplementation in pregnancy, the elderly and the housebound
All questions in Vitamins
- Q1Describe the chemistry, sources, functions and deficiency manifestations of vitamin A. Add a note on hypervitaminosis A. ★
- Q2Describe the synthesis, activation and functions of vitamin D. Discuss the features of rickets and osteomalacia. ★
- Q3Describe the coenzyme forms, functions and deficiency manifestations of thiamine, riboflavin and niacin. ★
- Q4Describe the absorption, functions and deficiency of vitamin B12 and folic acid. Explain the methyl trap hypothesis and differentiate the two deficiencies. ★
- Q5Describe the functions of vitamin C. Discuss the manifestations of scurvy and its biochemical basis. ★
- SN1Describe the functions and deficiency of vitamin K. Explain the action of warfarin. ★
- SN2Describe the functions, deficiency and clinical significance of vitamin E.
- SN3Describe the coenzyme functions and deficiency of vitamin B6. Add a note on drug-induced deficiency. ★
- SN4Describe xerophthalmia with its stages, causes and prevention. ★
- SN5Write a short note on pellagra. ★
- SN6Define antivitamins. Give examples with their mechanisms and clinical significance.
- SN7Describe the functions and deficiency of biotin and pantothenic acid.