Parathyroid Gland & Calcium Metabolism

Parathyroid Gland & Calcium Parathyroid Gland & Calcium MetabolismMetabolism

CaCa++ ++ ↑ → weakness ↓ → tetany ↑ → weakness ↓ → tetany3 factors PTH, Vitamin D, Calcitonin3 factors PTH, Vitamin D, Calcitonin3 tissues Bone, Intestine, Kidneys3 tissues Bone, Intestine, KidneysParathyroid Hormone (PTH)Parathyroid Hormone (PTH)84 a.a peptide translated as a pre-84 a.a peptide translated as a pre-

prohormoneprohormone Regulation of synthesis & release:Regulation of synthesis & release:↓ ↓ [Ca[Ca++++] → ↑ PTH; ↑ [Ca] → ↑ PTH; ↑ [Ca++++] → ↓ PTH] → ↓ PTHLittle if any regulation by POLittle if any regulation by PO44 ––

Maximum secretion of PTH Maximum secretion of PTH occurs at plasma Caoccurs at plasma Ca++++ below 3.5 below 3.5 mg/dl mg/dl

At CaAt Ca++++ above 5.5 mg/dl, PTH above 5.5 mg/dl, PTH secretion is maximally inhibitedsecretion is maximally inhibited

On bone (1º target tissue):On bone (1º target tissue):PTH ↑ resorption of CaPTH ↑ resorption of Ca++++& PO& PO44

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(cAMP) mediated effect(cAMP) mediated effect On intestine:On intestine:↑ ↑ absorption of Caabsorption of Ca++++& PO& PO44

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An indirect effect through ↑ vitamin D An indirect effect through ↑ vitamin D synthesissynthesis

On kidneys:On kidneys:↑ ↑ reabsorption of Careabsorption of Ca++++, ↑↑↑ excretion of PO, ↑↑↑ excretion of PO44

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(cAMP mediated effect) (cAMP mediated effect)

Synthesis of vitamin DSynthesis of vitamin D Skin, UV lightSkin, UV light

7- 7- dehydrocholesterol Cholecalciferol dehydrocholesterol Cholecalciferol (D(D33))

LiverLiver 25(OH) cholecalciferol 25(OH) cholecalciferol KidneyKidney 1,25(OH) 1,25(OH)22

cholecalciferolcholecalciferol (Calcifediol; Calcidiol) (Calcitriol)(Calcifediol; Calcidiol) (Calcitriol) PTHPTH DietDiet

Vitamin D Vitamin D ((Normal daily Normal daily requirementrequirement 400 IU/day)400 IU/day)

On intestine (1º target tissue):On intestine (1º target tissue):↑ ↑ absorption of Caabsorption of Ca++++& PO& PO44

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On bone:On bone:↑ ↑ bone resorptionbone resorption On kidney:On kidney:↑ ↑ reabsorption of Careabsorption of Ca++++& PO& PO44

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CalcitoninCalcitonin (32 a.a peptide) (32 a.a peptide)Synthesized and released from parafollicular Synthesized and released from parafollicular

cells of the thyroidcells of the thyroid Regulation of synthesis & release:Regulation of synthesis & release:↑ ↑ [Ca[Ca++++] → ↑ calcitonin; ↓ [Ca] → ↑ calcitonin; ↓ [Ca++++] → ↓ calcitonin] → ↓ calcitonin Effects:Effects:On bone: ↓ bone resorption (↓CaOn bone: ↓ bone resorption (↓Ca++++&PO&PO44

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movement)movement)On kidneys: ↑ CaOn kidneys: ↑ Ca++++& PO& PO44

-- -- excretionexcretion? On intestine: ↓ Ca? On intestine: ↓ Ca++++& PO& PO44

-- -- absorptionabsorption

May be more important in May be more important in regulating bone remodeling than in regulating bone remodeling than in CaCa++++ homeostasis: homeostasis:

Evidence:Evidence: Chronic excess of calcitonin Chronic excess of calcitonin does not produce hypocalcemia and does not produce hypocalcemia and removal of parafollicular cells does removal of parafollicular cells does not cause hypercalcemia. not cause hypercalcemia.

PTH and Vitamin DPTH and Vitamin D33 regulation regulation dominate dominate

PTHPTH Vit. DVit. D CalcitoninCalcitonin

[ Ca[ Ca++++] ↑ ↑ ] ↑ ↑ ↓ ↓

[PO[PO44----] ↓ ↑ ] ↓ ↑

↓ ↓

Disorders affecting the parathyroids:Disorders affecting the parathyroids:Hyposecretion (hypoparathyroidism):Hyposecretion (hypoparathyroidism): Causes:Causes:- Thyroidectomy (most common cause)Thyroidectomy (most common cause)- IdiopathicIdiopathic- ↓ ↓ sensitivity of target tissues to PTH sensitivity of target tissues to PTH

(pseudohypoparathyroidism)(pseudohypoparathyroidism)

Symptoms of hypoparathyroidism:Symptoms of hypoparathyroidism:Are those of hypocalcemia:Are those of hypocalcemia:Parasthesia, Parasthesia, tingling lips, fingers, and tingling lips, fingers, and

toes, toes, carpopedal spasm, carpopedal spasm, muscle cramps, muscle cramps,

tetanic contractions, convulsions tetanic contractions, convulsions (seizures) (seizures)

BronchospasmBronchospasmDepression, anxiety, Depression, anxiety, abdominal pain abdominal pain Cataract... Cataract...

Lab. Tests (hypoparathyroidism):Lab. Tests (hypoparathyroidism):- ↓ ↓ blood [Cablood [Ca++++]]- ↑ ↑ blood [POblood [PO44

----]]- ↓ ↓ urinary [cAMP] urinary [cAMP] - ↓ ↓ urinary [PTH]urinary [PTH]- ↓ ↓ urinary [Caurinary [Ca++++]]- ↓ ↓ urinary [POurinary [PO44

----]]

RRxx of hypoparathyroidism: of hypoparathyroidism:- Vitamin D Vitamin D Calcifediol, Calcitriol, Ergocalciferol, Calcifediol, Calcitriol, Ergocalciferol, αα--

Calcidol, Dihydrotachysterol…Calcidol, Dihydrotachysterol…Drug of choice for chronic casesDrug of choice for chronic cases- CaCa++++ supplement supplementCaCa++ ++ rich dietrich dietCaCa++ ++ salts (chloride, gluconate, carbonate...)salts (chloride, gluconate, carbonate...)Drug of choice in acute casesDrug of choice in acute cases- Teriparatide (synthetic rPTH)-recently Teriparatide (synthetic rPTH)-recently

approved in the management of osteoporosisapproved in the management of osteoporosis

Hypersecretion (hyperparathyroidism):Hypersecretion (hyperparathyroidism): Causes:Causes:- 1º hyperparathyroidism (adenomas)1º hyperparathyroidism (adenomas)- 2º hyperparathyroidism2º hyperparathyroidism2º to any cause of hypocalcemia2º to any cause of hypocalcemia e.g. malabsorption syndrome, renal e.g. malabsorption syndrome, renal

disease…disease…- 3º hyperparathyroidism3º hyperparathyroidismResults from hyperplasia of the parathyroid Results from hyperplasia of the parathyroid

glands and a loss of response to serum glands and a loss of response to serum calcium levels; this disorder is most often calcium levels; this disorder is most often seen in patients with chronic renal failureseen in patients with chronic renal failure

Symptoms of hyperparathyroidism:Symptoms of hyperparathyroidism:Are those of hypercalcemia:Are those of hypercalcemia:Generalized weakness and fatigueGeneralized weakness and fatiguedepression, bone pain, muscle pain depression, bone pain, muscle pain

(myalgias), decreased appetite, (myalgias), decreased appetite, feelings of nausea and vomiting, feelings of nausea and vomiting, constipation, polyuria, polydipsia, constipation, polyuria, polydipsia, cognitive impairment, kidney stones cognitive impairment, kidney stones and osteoporosis…and osteoporosis…

Lab. Tests (hyperparathyroidism):Lab. Tests (hyperparathyroidism):- ↑ ↑ blood [Cablood [Ca++++]]- ↓ ↓ blood [POblood [PO44

----]]- ↑ ↑ urinary [cAMP] urinary [cAMP] - ↑ ↑ urinary [PTH]urinary [PTH]- ↑ ↑ urinary [Caurinary [Ca++++]]- ↑ ↑ urinary [POurinary [PO44

----]]Bone x-ray → bone decalcificationBone x-ray → bone decalcification

RRxx of hyperparathyroidism: of hyperparathyroidism:- Low CaLow Ca++++ diet diet- NaNa++ phosphate phosphate- Steroids e.g. Prednisolone... ↓ CaSteroids e.g. Prednisolone... ↓ Ca++++

absorptionabsorption- CalcitoninCalcitonin- Surgery (best Rx)Surgery (best Rx)- Cinacalcet (Cinacalcet (calcimimetic) (oral tab) calcimimetic) (oral tab) is used is used

to treat patients with chronic kidney disease to treat patients with chronic kidney disease who are on dialysis & also used to treat who are on dialysis & also used to treat patients with 1º & 2º hyperparatyroidism & patients with 1º & 2º hyperparatyroidism & cancer of parathyroid gland cancer of parathyroid gland

Other drugs effective in the Other drugs effective in the management of hypercalcemia:management of hypercalcemia:

- DiureticsDiureticse.g. Furosemide (↑ Cae.g. Furosemide (↑ Ca++++ excretion) excretion)- PlicamycinPlicamycin- BiophosphonatesBiophosphonatesEtidronate, Pamidronate…Etidronate, Pamidronate…↑ ↑ bone formation and ↓ bone bone formation and ↓ bone

resorption resorption

Paget’s diseasePaget’s diseaseRare bone disorder characterized by Rare bone disorder characterized by

deminaralization of bone, disorganized deminaralization of bone, disorganized bone formation, ↑ bone resorption, bone formation, ↑ bone resorption, fractures, spinal cord injuries, deafness…fractures, spinal cord injuries, deafness…

RRxx::- Salmon calcitonin (drug of choice), S.C, I.M- Salmon calcitonin (drug of choice), S.C, I.M- Biophosphanates, orally- Biophosphanates, orallyEtidronate, alendronate, residronate, Etidronate, alendronate, residronate,

pamidronate…pamidronate…