Regulation of calcium Parathyroid, Vitamin D & Calcitonin

Calcium
Required for muscle contraction, blood clotting, transmission of nerve impulses, cardiac repolarization. Concentration of Ca++ mediated by
Parathyroid gland Parafollicular C cells Vitamin D Kidney Bone Intestine

Calcium in the Plasma and Interstitial Fluid Body

Total Ca concentration in blood is normally kept at 9.4mg/dL, which is equivalent to 2.4 mmol/L 41% bound to plasma proteins (1 mmol/L) 9% complexed to anions (phosphate, citrate, sulfate) (0.2 mmol/L) 50% is free, ionized only this fraction is biologically active (1.2 mmol/L) or (2.4 mEq/L)

Inorganic phosphate in the extracellular fluid

Important functions of phosphate
Development of bone Structural part of high energy transfer and storage compounds Phosphate buffer system

Inorganic phosphate in the plasma mainly in two forms: HPO4- and H2PO4 The total quantity of phosphorus in the blood is 4 mg/dL

Calcium homeostasis
Calcium homeostasis involves THREE systems (bone, kidney and GI tract) and THREE hormones (parathyroid hormone, calcitonin and vitamin D) Sources of calcium are dietary (absorbed in the gut) and bone Bone remodeling is constant bone is formed and resorbed at the same rate

Calcium homeostasis

Bone
Osteoclast : a large multinucleated cell which absorbs and removes bone tissue Osteoblast: a type of cell involved in bone remodeling that helps to build bone Bone resorption: a type of bone loss (resorption) due to osteoclastic activity

Vitamin D
Sources
Food Vitamin D2 UV light mediated cholesterol metabolism D3 D2 and D3 are converted to 25(OH)-D by the liver 25(OH)-D is converted to 1,25(OH)2-D by the Kidney
Increases bone resorption Increases GI absorption of dietary Ca++ and phosphate Increases renal reabsorption of calcium and phosphate

Metabolism

Function

Synthesis and activation of vitamin D

Activation of vitamin D3 to form 1,25dihydroxycholecalciferol

Action of vitamin D on intestine

The major actions of 1,25dihydroxycholecalciferol are on the intestine. 1,25-dihydroxycholecalciferol increases both Ca and phosphate absorption.

Action of vitamin D on renal

The actions of 1,25-dihydroxycholecalciferol on the kidney are parallel to its actions on the intestine it stimulates both Ca and phosphate reabsorption. In the kidney, the actions of 1,25dihydroxycholecalciferol differs from PTH. PTH stimulates Ca reabsorption and inhibits phosphate reabsorption, whereas 1,25 dihydroxycholecalciferol stimulates the reabsorption of both ions.

Bone
1,25-dihydroxycholecalciferol acts synergistically with PTH to stimulate osteoclast activity and bone resorption.

Role of vitamin D
Stimulates GI absorption of both calcium and phosphate Stimulates renal reabsorption of both calcium and phosphate Stimulates bone resorption
Net effect of Vitamin D serum calcium serum phosphate

Anatomy of the Parathyroid Glands & Microscopic Appearance of Chief Cells

Tiny, yellow brown parathyroid glands Usually four glands behind the thyroid gland The glandular cells contain oxyphil cells and chief cells The chief cells secrete parathyroid hormone

PTH secretion is regulated by the plasma Ca concentration

When the total Ca2+ concentration is in the normal range (i.e., 10 mg/ dL) or higher, PTH is secreted at a low (basal) level. However, when the plasma Ca2+ concentration decreases to less than 10 mg/ dL, PTH secretion is stimulated, reaching maximal rates when the Ca2+ concentration is 7.5 mg/ dL.

The ionized Ca2+ concentration regulates secretion by the parathyroid glands.

Plasma Calcium Concentration & PTH Secretion

100

PTH secretion (% maximal rate)

50

10

12

14

Total plasma [Ca2+] (mg/ dL)

Action of PTH on small intestine

PTH indirectly stimulates intestinal Ca2+ absorption via activation of vitamin D. PTH stimulates renal 1-alpha-hydroxylase, the enzyme that converts 25-hydroxycholecalciferol to the active form, 1,25-hydroxycholecalciferol. 1,25-hydroxycholecalciferol promotes Ca2+ uptake by the gut

Action of PTH on kidney

(1) PTH inhibits phosphate reabsorption by inhibiting Na+ phosphate co-transport in the proximal convoluted tubule. As a result of this action, PTH causes phosphaturia, an increased excretion of phosphate in urine.
(2) PTH stimulates Ca2+ reabsorption. This second renal action of PTH is on the distal convoluted tubule and complements the increase in plasma Ca2+ concentration that resulted from the combination of bone resorption and phosphaturia.

Action of PTH on bone

In bone, PTH causes an increase in bone resorption. When PTH levels are chronically elevated, as in hyperparathyroidism, the rate of bone resorption is persistently elevated, which increases the serum Ca2+ concentration. The overall effect of PTH on bone is to promote bone resorption, delivering both Ca2+ and phosphate to ECF.

PTH, Calcium & Phosphate

Role of PTH
Stimulates renal reabsorption of calcium Inhibits renal reabsorption of phosphate Stimulates bone resorption Inhibits bone formation and mineralization

Net effect of PTH

serum calcium serum phosphate

Calcitonin
It is synthesized and secreted by the parafollicular or C cells of the thyroid gland. The major stimulus for calcitonin secretion is increased plasma Ca concentration The major action of calcitonin is to inhibit osteoclastic bone resorption which decreases the plasma Ca concentration . Decreases the reabsorption of phosphate and calcium from the kidney. Net effect will be to reduce both plasma calcium and phosphate concentration . A physiologic role for calcitonin in is uncertain because neither thyroidectomy (with decreased calcitonin) nor thyroid tumors (with increased calcitonin levels) causes a derangement of Cametabolism, as would be expected if calcitonin had important regulatory functions.

Parathyroid Hormone
Excess activity of the parathyroid gland causes rapid absorption of calcium from the bones, with resultant hypercalcemia Hypofunction of the parathyroid gland causes hypocalcemia

Parathyroid Glands: Disorders

Hypoparathyroidism - trauma to or removal of parathyroid gland results in hypocalcemia (low blood Ca2+) effects include: Neurons become too excitable muscle tetany spasms/cramps respiratory paralysis death.

Parathyroid Glands: Disorders

Hyperparathyroidism - rare; caused by parathyroid gland tumor results in hypercalcemia (excess Ca2+ levels in blood) effects include: depression of nervous system (because of effect on sodium permeability; increased Ca2+ decreases permeability), abnormal reflexes, skeletal muscle weakness nausea, vomiting, kidney stones (due to increased Ca2+ in urine) calcium deposits in soft tissues bones become soft

Primary Hyperparathyroidism

Plasma [PTH]

Plasma [1,25-(OH)2-D3]

Bone Resorption

Urine Phosphate Ca2+

Plasma [Ca2+]

Plasma [Phosphate]

* Primary disturbance

Secondary Hyperparathyroidism
Disorder Vitamin D deficiency Plasma Plasma [PTH] [1,25-(OH)2-D3] (2) * Bone Urine Phosphate

Plasma Plasma [Ca2+] [Phosphate]

Resorption Osteomalacia

Chronic renal failure

(2)

Resorption
Osteomalacia

Phosphate ( GFR)*

* Primary events or disturbances

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