Week 3

The parathyroids consist of 4 glands located adjacent to the thyroid gland Each gland weighs approximately 40 mg The two superior glands are usually found near the posterior aspect of the capsule The inferior glands are most often located near the inferior thyroid margin

PTH gene is in chromosome 11 PTH is synthesized as a 110 amino acid polypeptide called pre-pro-PTH It is cleaved to pro-PTH (90 amino acids) and then PTH (84 amino acids) PTH is the major storage, secreted and biologically active form of the hormone. Ca regulates synthesis, release and degradation of PTH

Parathyroid hormone is the most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid. is secreted from cells of the parathyroid glands and finds its major target cells in bone and kidney. primary hormone that is stored, secreted and functions in the body.

Type 1 parathyroid hormone receptor: Binds both parathyroid hormone and amino- terminal peptides of PTHrP. Type 2 parathyroid hormone receptor: Binds parathyroid hormone but shows very low affinity for PTHrP.

The PTH1R also mediates the paracrine actions of PTHrP, which play a particularly vital role in the process of endochondral bone formation. These important functions, the likely involvement of the PTH1R in certain genetic diseases affecting skeletal development and calcium homeostasis,

The PTH2R suggest involvement in regulation of fear, anxiety, reproductive behaviours.

Directly involved in the bones, kidneys, and the small intestine Effects of PTH in the Bones -Stimulates the release of calcium in an indirect process through osteoclasts which ultimately lead to resorption of the bones Effects of PTH on the Kidneys -Targets the distal convoluted tubule and collecting duct, directly increasing calcium reabsorption. -Parathyroid hormone decreases phosphate reabsorption at the proximal convoluted tubule Activates vitamin D • Plays a role in calcium reabsorption in the distal convoluted tubule via calbindin-D, a cytosolic vitamin D dependent calcium binding protein. In the small intestine, vitamin D allows the absorption of calcium

The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium re-absorption in response to alterations in extracellular calcium concentrations.

Activation of phospholipase C : Leads to generation of the second messenger’s diacylglycerol and inositol trisphosphate. Inhibition of adenylate cyclase:- which suppresses intracellular concentration of cyclic AMP.

PTH and calcitriol are the major hormones modulating calcium and phosphate homeostasis

When blood calcium is high the Thyroid gland releases Calcitonin to drop the calcium blood levels When blood calcium is low the Parathyroid gland releases PTH to increase the calcium blood levels

Bone metabolism is a dynamic process that balances bone formation and bone resorption Central to this process is the RANK/RANKL/OPG pathway Bone formation Performed by stimulating osteoblasts and inhibiting osteoclasts Bone resorption -Performed by active osteoclast Stimulated by RANKL in normal process Stimulated by PTH in pathologic process (metastatic disease) Interleukin 1 (IL-1)stimulates osteoclast differentiation and thus bone resorption

A clinical syndrome causing signs and symptoms that result from ↑ PTH, PTH induced bone resorption and hypercalcemia • Primary • Secondary • Tertiary

Generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It probably is the most common cause of hypercalcemia

Overall incidence is 42 in 100,000 Incidence increases with age Prevalence is 1:1000 Female to male ratio is 2-3:1

Overproduction of PTH by parathyroid chief cells Effect of PTH on bone → increased bone resorption → ↑ release of calcium phosphate → ↑ calcium levels Induces RANKL expression in osteoblasts → binding of RANKL to RANK on osteoclasts → activation of osteoclasts Induces IL-1 expression in osteoblasts → activation of osteoclasts Effect of PTH on the kidneys → ↑ phosphate excretion (phosphaturia)

Occurs most commonly in advanced chronic kidney disease when decreased formation of active vitamin D in the kidneys and other factors lead to hypocalcemia and chronic stimulation of PTH secretion.

↓calcium and/or ↑ phosphate blood levels leads to → reactive hyperplasia of the parathyroid glands → ↑ PTH secretion Chronic kidney disease → impaired renal phosphate excretion → ↑ phosphate blood levels→ ↑ PTH secretion In addition, CKD → ↓ biosynthesis of active vitamin D → ↓ intestinal calcium resorption + ↓ renal calcium reabsorption → hypocalcemia → ↑ PTH secretion

Chronic renal disease → refractory and autonomous secretion of PTH → hypercalcemia Renal disease → secondary or tertiary hyperparathyroidism → renal osteodystrophy → bone lesions Familial hypocalciuric hypercalcemia benign condition that causes chronically elevated serum calcium and reduced calcium excretion.

Deficient parathyroid hormone secretion Inability to Make Active Parathyroid Hormone. Resistance to Parathyroid Hormone (pseudo-hypoparathyroidism).

Lack of PTH leads to decreased blood levels of calcium (hypocalcemia) and increased levels of blood phosphorus (hyperphosphatemia). There are no symptoms of too little parathyroid hormone other than the symptoms due to having a blood calcium that is too low.

Deficient PTH secretion without a defined cause (e.g. surgical injury) is termed Idiopathic hypoparathyroidism. This disease is rare and can be congenital or acquired later in life. Congenital: Patients in this category are born without parathyroid tissues. Acquired: Arises because the immune system has developed antibodies against parathyroid tissues

Characterised by hypocalcemia (too low blood calcium levels) and hyperphosphatemia (too high blood phosphorus levels) But they are distinguished by the fact that they DO produce NORMAL parathyroid hormone. The problem is that their bones and kidneys do not respond to the parathyroid hormone