AP parathyroid Flashcards
Structure and Location of Parathyroid Glands
posterior side of the thyroid
Synthesis of PTH
¢PTH is translated as a pre-prohormone.
¢Cleavage of leader and pro-sequences yield a biologically active peptide of 84 aa.
¢Cleavage of C-terminal end yields a biologically inactive peptide.
Regulation of PTH
¢The dominant regulator of PTH is serum Ca2+.
¢Secretion of PTH is INVERSELY related to calcium
¢PTH triggers Ca2+ reabsorption in renal tubule & Ca2+ release from bone
¢Act in concert with vitamin D to restore Ca2+
¢Chief cells in parathyroid have extracellular calcium-sensing receptor
¢Receptor activated by Ca2+ in ECF, which inhibits PTH secretion & proliferation of parathyroid cells
¢Rapid ↑ PTH secretion in response to ↓ serum Ca2+
Effects of PTH
- The overall action of PTH is to increase plasma Ca2+ levels and decrease plasma phosphate levels.
- PTH acts directly on the bones to stimulate Ca2+ resorption (activating osteoclasts) and kidney to stimulate Ca2+ reabsorption in the distal tubule of the kidney
- PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D3 mediated Ca2+ absorption.
………. also serves as a stimulus for PTH secretion?
¢Hyperphosphatemia
Primary Hyperparathyroidism
- Loss of calcium homeostasis due to excessive PTH secretion (adenomatous or hyperplastic parathyroid tissue)
- Hypercalcemia due to
- PTH-induced bone resorption
- intestinal calcium absorption and
- renal tubular reabsorption
-Pathophysiology related to both PTH excess and concomitant excessive production of 1,25-(OH)2-D
Hyperparathyroidism - Symptoms
Symptoms from ↑ serum Ca2+
- Mild hypercalcemia – goes unnoticed
- Severe hypercalcemia:
- Kidney – frequent urination to filter and get rid of calcium, kidney stones
- Muscle weakness
- ↓ central & peripheral nerve signals
- Bone pain
- GI upset, nausea
Hypoparathyroidism
•HYPOCALCEMIA
–Inadequate response of the Vitamin D-PTH axis to hypocalcemicstimuli
•Concomitant decrease in 1,25-(OH)2-D
•Can lead to tetany of muscles if untreated
•PTH-deficient hypoparathyroidism
–Reduced or absent synthesis of PTH (removal of excessive parathyroid tissue during thyroid or parathyroid surgery)
•PTH-ineffective hypoparathyroidism
–Synthesis of biologically inactive PTH
•PTH-resistant hypoparathyroidism
–Due to defect in PTH receptor-adenylate cyclase complex
PTH Related Peptide (PTHrP)
¢Marked structural homology with PTH
¢PTHrP and PTH bind to the same receptor and PTHrPreproduces full spectrum of PTH activities
¢PTHrP is produced in many tissues unlike PTH
¢Tissue growth and differentiation factor (bone and cartilage)
Osteoporosis & PTH
-Chronic elevated levels of parathyroid hormone (PTH) will increase bone resorption
would seem to be an unlikely candidate for the treatment of osteoporosis
-However, intermittent administration of recombinant human PTH has been shown to stimulate bone formation more than resorption, at least over the first 12 months of treatment
Teriparatide – recombinant hPTH
- Anabolic therapy for osteoporosis
Describe the key steps in the synthesis of vitamin D and its role in regulation of serum calcium and phosphate levels
- No longer a vitamin but is considered a hormone
- Vitamin D (cholecalciferol) generated from 7-dehydrocholesterol on exposure to UV light
- Also obtained from dietary sources
- Prohormone without significant biological activity
- Transported to liver in bound form (vitamin D-binding protein)
- Metabolized in liver to 25-hydroxyvitamin D (25(OH)2D), also known as calcidiol
- 25(OH)2D is transported to kidney
Describe the key steps in the synthesis of vitamin D and its role in regulation of serum calcium levels
¢25(OH)2D is converted enzymatically to 1,25-dihydroxyvitamin D (1,25(OH)2D3), also known as calcitriol, in renal cortex
- 1alpha hydroxylase is the enzyme
- PTH, hypocalcemia & hypophosphatemia ↑ conversion
- Calcitriol binds to the intestinal vitamin D receptor and increases the expression of calcium-binding proteins
- As a result, calcium and phosphorous intestinal absorption is increased
Vitamin D Actions
¢Lipid soluble hormone - binds to nuclear receptor called vitamin D receptor (VDR), which is analogous to steroid hormones
- Regulates gene transcription in target cells
- Primary effect: to stimulate absorption of Ca2+ from the intestine
- induces the production of calcium binding proteins which sequester and allow Ca2+ to be absorbed against a high Ca2+gradient
Calcitonin
- Produced by parafollicular cells (C cells) of thyroid gland
- Secreted in response to elevated levels of serum Ca2+
- Responds only to relatively large changes in serum Ca2+
- While PTH and vitamin D act to ↑ plasma Ca2+–calcitonin causes a ↓ in plasma Ca2+
- Calcitonin is a physiological antagonist to PTH with regard to Ca2+ homeostasis
Calcitonin Actions
- The target cell for calcitonin is the osteoclast.
- Calcitonin acts via increased cAMP concentrations to inhibit osteoclast motility and cell shape and inactivates them.
- The major effect of calcitonin administration is a rapid fall in Ca2+ caused by inhibition of bone resorption.
Calcitonin…..cont’d
- Role of calcitonin in normal Ca2+ control is not understood
- may be more important in control of bone remodeling.
- Used clinically in treatment of hypercalcelmia and in certain bone diseases in which sustained reduction of osteoclastic resorption is therapeutically advantageous
