Vitamin D Synthesis and Action

Vitamin D

• Vitamin D increases both plasma calcium (Ca²⁺) and phosphate levels.
• Vitamin D synthesis depends on calcium status, prolactin, parathyroid hormone, and estrogens.
• Vitamin D is also known as 1,25-dihydroxycholecalciferol.

Vitamin D Synthesis

• Vitamin D synthesis starts with 7-dehydrocholesterol in the skin, converted to cholecalciferol (vitamin D3) via UV light.
• Dietary intake and supplements also contribute to vitamin D levels.
• Cholecalciferol is then converted to calcidiol (25-hydroxyvitamin D) in the liver.
• Calcidiol is converted to calcitriol (1,25-dihydroxyvitamin D) in the kidney, the active form of vitamin D.
• An inactive metabolite, 24,25-dihydroxyvitamin D, is also produced in the kidney.
• The active form of Vitamin D, calcitriol, increases intestinal Ca2+ and phosphate absorption.

Vitamin D Action

• The intestines are the major site of action for vitamin D.
• Vitamin D increases Ca²⁺ and phosphate absorption (indirectly).
• A calcium channel in the intestinal lumen, TRPV6 is involved.
• Vitamin D induces the synthesis of calbindin D-28K, a protein that binds Ca²⁺.
• Calbindin shuttles calcium across cells.
• Kidney has a minor role; it reabsorbs Ca²⁺ and phosphate.
• Bones also have a minor role by acting with PTH (parathyroid hormone) to affect osteoclast activity and bone resorption (old bone). It stimulates bone (new) mineralization in response to high Ca²⁺ levels.

Calcitonin

• Calcitonin is a product of parafollicular C cells in the thyroid.
• It's a 32 amino acid peptide.
• Calcitonin short-term action is quickly secreted in response to elevated blood calcium (Ca²⁺).
• Calcitonin decreases blood calcium levels.
• It acts primarily to inhibit osteoclast bone resorption to maintain blood calcium.
• Calcitonin has little long-term effect.
• Deficiency in calcitonin does not have significant pathophysiological consequences.

Other Hormones Affecting Bone Turnover

• Estrogen and androgens decrease bone reabsorption.
• Cortisol increases bone reabsorption.
• Thyroxine is necessary for fetal bone development and is anabolic during growth. (stimulates bone mass).
• In adults, thyroxine has catabolic effects that increase bone turnover.
• Local factors (IGF 1, TGF, PG's, BMP) affect osteoblast proliferation and activity and bone formation
• Certain growth factors relate to increased bone turnover in relation to inflammation.

Hypocalcemia

• Hypocalcemia is defined as total serum calcium less than 8.8 mg/dL or ionized calcium less than 4.7 mg/dL when plasma protein concentration is normal.
• Symptoms of hypocalcemia include hyperreflexia, spontaneous twitching, muscle cramps, reduced threshold potential, tingling and numbess (effect on sensory nerves) and muscle twitching (effect on motor neurons).
  • Trousseau's sign (spasms in the hands) and Chvostek's sign (facial spasms) may also occur.

Hypocalcaemia - causes

• Vitamin D deficiency: Lack of Vit D intake, lack of ability to absorb or metabolize vit D.
• Kidney or liver disorder: Inability to convert inactive Vitamin D forms.
• Children: Rickets - skeletal deformities and growth failure
• Adults: soft weight bearing bones. Osteomalacia.
• Renal Resistance: Kidney's inability to produce 1,25-hydroxycholecalciferol or congenital absence of a specific enzyme responsible.

Hypoparathyroidism

• Hypoparathyroidism occurs after thyroid/parathyroid surgery or radioactive iodine ablation of the thyroid.
• Autoimmune and congenital factors can also cause this.
• Symptoms include low PTH, hypocalcemia, and hyperphosphatemia.
• Treatment involves hormone replacement, with calcium and vitamin D supplements.

Pseudohypoparathyroidism

• An inherited autosomal dominant disorder.
• Defect in the PTH receptor.

Hypercalcemia:

• Hypercalcemia can result from primary or tertiary hyperparathyroidism, familial hypocalciuric hypercalcemia, or ectopic secretion of parathyroid hormone (PTH).

• Vitamin D excess (vitamin D ingestion, calcitriol excess) causes hypercalcemia, as does PTHrP secreting tumors or malignant cell infiltration causing bone destruction (and calcium release).

Hyperparathyroidism

• Primary hyperparathyroidism: Characterized by increased parathyroid hormone (PTH) production, resulting in hypercalcemia, bone resorption, increased calcium reabsorption in tubules, and high calcium in the urine. Kidney stones also result.
• Secondary hyperparathyroidism: Caused by hypocalcemia (due to vitamin D deficiency or chronic renal failure) – high PTH levels compensate for low blood calcium concentrations.

Malignancy Associated Hypercalcemia

• Common cause of elevated serum calcium, especially in hospitalized patients with various cancers.
• Mechanisms include increased bone resorption via PTHrP (parathyroid hormone-related protein) causing calcium release into circulation, PTH, 1,25-dihydroxyvitamin D and intestinal calcium absorption mechanisms also occur.

Osteoporosis

• Osteoporosis is characterized by decreased total bone mass due to long-term low dietary intake of calcium and vitamin D, deficiencies in vitamin C (for collagen synthesis), immobilization or mechanical stress or menopause (lack of estrogen), or certain drugs like anticonvulsants and glucocorticoids.
• Microscopy shows differences between normal bone and osteoporotic bone.

Osteopenia

• Osteopenia is a condition characterized by a lower bone mass than the normal range. It is a precursor to osteoporosis.

Osteomalacia

• Osteomalacia is a softening of the bones due to decreased normal matrix of bones and deficient mineralization.

This quiz covers the synthesis and action of Vitamin D, exploring its impact on calcium and phosphate levels in the body. It discusses the conversion processes in the skin, liver, and kidney, as well as the role of Vitamin D in intestinal absorption. Test your understanding of Vitamin D and its metabolic pathways.