Flashcards in Parathyroid hormone metabolism Deck (41):
What types of cells make up the parathyroid glands?
oxyphil cells and chief cells
- chief cells make PTH, oxyphil role unknown
What nerve is closely located to thyroid and parathyroid glands?
- recurrent laryngeal nerve
Embryologically what are the parathyroids derived from?
- 3rd and 4th branchial pouches that migrate
Are extra parathyroid glands common?
- yes, especially along the path of embryologic migration
- most common place is in lower pole of thyroid, next in there-thymic tract
Who is the main player in controlling Ca2+ and phosphate homeostasis in the body?
- it is a 84 -aa protein
- packaged is cytoplasmic granules that contain proteases
- very short half life (minutes) once it is released
- PTH feeds back to stimulate conversion of 25-hydroxycholecalciferol in kidney to 1,25-dihydroxycholecaleciferol (calcitriol)
Once PTH is released where is it degraded at?
- by liver and kidney to mostly c-terminal fragments (happens in 2-4 minutes)
percentages of PTH in hypo, hyper and normocalcemic states?
- normocalcemic state: PTH 20% of total circulating intact PTH hormone
- hypocalcemia: PTH increases to 33%
- Hypercalcemia: decreases to 4%
Effect of decreased plasma Ca2+?
- lead to increased PTH which leads to resorption from bone and release of Ca2+ and phosphate, kidney: increase phosphate excretion and increased calcium reabsorption, increased calcitriol formation
- net effect: increase in plasma calcium concentration with no change or decrease in plasma phosphate
What controls the secretion of PTH?
- Ca2+ controls secretion of PTH
Where can you find calcium-sensing receptors in the body?
- parathyroid cells: Ca2+ is ligant
- kidney: regulates Ca2+ handling by renal tubules
hence hypercalcemia directly promotes excretion of Ca2+
Calcium feedback control?
- adequate/elevated Ca2+ blocks PTH from activating 25-hydroxycholecalcetriol
- adequate intake blocks leaching Ca2+ from the bones
- adequate levels maintain balanced renal absorption of Ca2+ and phosphate
What is PTHrP?
- PTH-related protein
- secreted by nonmetastatic solid tumors and some pts with non-hodgkin lymphoma
- increases bone resorption and distal tubule Ca2+ reabsorption
- less likely to stimulate 1,25-dihydroxyvitamin D production
- Doesn't increase Ca absorption from the intestines
What is calcitonin?
- peptide hormone secreted by thyroid gland- parafollicular cells
- stimulated by high Ca2+ levels
What is function of calcitonin?
- it decreases plasma Ca2+, decreases absorptive activities osteoclasts, and decreases formation of new osteoclasts
- weak effect in humans compared to PTH
Physiology of Ca2+?
involved partial absorption from intestines
- filtration in kidneys with 100-200 mg excreted
- 1% in ECF flows in and out of cells
- and of this 1% -> 50% bound to albumin and 50% is in ionized state
Where is most of Ca found in the body?
- 99% remain in bone as hydroxyapatite -> reservoir for Ca and phosphate
Where is most of phosphate in body stored?
- 85% stored in bone
- 14-15% in cells
- 1% in ECF: as phospholipids, esterphosphates, and inorganic phosphates
- several forms are for buffers in acid-base changes
What does active vitamin D increase?
- increase Ca2+ uptake in intestines -> blood Ca2+ level increases -> homeostasis -> blood Ca levels -> when blood Ca levels fall -> PTH secreted from parathyroid glands and this stimulates Ca release from bone and stimulates Ca uptake in kidneys -> this uptake in kidenys activates Vitamin D
What is Ca's function in the body?
- normal bone density
- clotting cascade
- muscle function: smooth, cardiac, skeletal
- transmission of nerve signals
- intracellular signaling of many cellular hormones
Relationship b/t Ca and Phosphate?
- tend to be opposite, when one rises the other falls
- both are necessary for normal bone density
- Ca is usually reabsorped in kidneys and phosphate is excreted when plasma levels of Ca are low
Sources of Vit D?
- photoisomeriztion: of provitamin D in skin to Vit D3 (cholecalciferol)
- binds to VIt D binding proteins and is further metabolized
- intestinal absorption from diet from fortified milk, fatty fish and cod-liver oil, lesser extent: eggs
- liver stores Vit D, excess is stored in adopose tissue (fat soluble vitamin)
Where is cholecalciferol (VIt D3) formed?
- formed in the skin
- converted to 25-hydroxy Vit D in the liver, but prevented from over accumulating (vit stored in liver for months)
Where is 1,25 dihydroxycholecalciferol formed?
- formed in proximal tubules of the kidney
- most active form of Vit D
- this step is stimulated by PTH
Vitamin D metabolism?
- closely coupled with Ca 2+ homeostasis, serum Ca2+ and phosphate levels and PTH
- with hypocalcemia increased PTH increases activity of alpha-1-hydroxylase in kidney resulting in increased levels of calcitriol which decreases the renal excretion of Ca and increases excretion of phosphate and increases resorption of Ca from bones and increases intestinal absorption of Ca
- Vit D increases Ca absorption from GI tract
- impt in bone deposition and absorption
- must be converted in liver and kidneys to active metabolite - 1, 25-dihydroxycholecalciferol (Calcitriol)
What does calcitriol increase?
increases absorption of Ca2+ in kidneys
Concentration of calcitrol depends on what?
- availability of calcidiol
- activity of renal enzyme alpha-1-hydroxylase: regulated by - PTH, low serum level of phosphate, plasma calcitriol concentration: activity of 24-hydroxylase gene is increased by calcitriol which inactivites it, and PTH reduces gene activity
Functions of calcitriol?
- binds to vit D receptor: in intestine and parathyroid glands
- most impt action: promotes enterocyte differentiation which promotes intestinal absorption of Ca2+
other effects: stimulates phosphate absorption, directly suppresses PTH at level of parathyroid glands, and allows PTH induced osteoclast activation
Calcitriol activity on parathyroids?
- parathyroids contain vitamin D receptors and calcitriol binds to the receptors and inhibits PTH synthesis and inhibits parathyroid cell proliferation
Result of metabolic activation of Vitamin D to calcitriol?
- increase in serum Ca and phosphate concentrations
Function of osteoblasts and osteoclasts?
- osteoblasts: continually deposit bone even in adults, on outer surfaces of bone and in bone cavities
- osteoclasts: continually absorb bone, found in bone matrix
- in adults: deposition and absorption are equal
What happens in bone remodeling?
- bone adjusts its strength to stress applied to it, new matrix is tougher and less brittle than old matrix
- bone that is stressed has greater deposition of bone matrix: osteoblastic activity is stimulated, the bone is stronger and more dense
Remodeling cycle of the bone?
Resorption (2 weeks): osteoclasts remove mineral and matrix on trabecular and cortical bone. High local concentrations of Ca may regulate this process
Reversal (4-5 weeks): mononuclear cells appear on bone surface, they lay down a glycoprotein rich matrix so new osteoblasts can adhere
Formation (up to 4 months): waves of osteoblasts lay down bone until resorbed bone is completely replaced
- when phase is completed the surface is covered with flattened lining of cells and there is a prolonged resting period
Effects of PTH on kidney
- increased Ca resorption in renal tubules - kindeys convert Vit D to its active form
Effects of PTH on bone?
- increased osteoclast activity - releases Ca2+ and PO4
Effects of PTH on GI tract?
- GI tract will increase absorption of Ca2+ and PO4
What are the 3 hormones that regulate calcium concentration?
- PTH, calcitonin, and Vit D
Action of PTH and Vitamin D? Action of calcitonin?
PTH and Vit D- raise blood Ca level
Calcitonin - lower Ca blood level
When is PTH secreted?
- in response to low blood calcium level, regulated not by pituitary gland but by serum calcium concentration
How does PTH increase blood calcium?
- by stimulating osteoclasts to break down bone, increasing reabsorption of Ca by kidneys
- increasing conversion of inactive Vit D to active Vit D (which increases Ca reabsorption from the GI tract)
- also decreases reabsorption of phosphate by kidneys leading to loss in urine, impt because PTH action on bone increases release of both Ca and phosphate, by decreasing reabsorption of phosphate by kidneys, PTH prevents hyperphosphatemia
Action of Vit D?
- Vit D increases gut absorption of Ca and phosphate, increases bone resorption and also increases phosphate reabsorption in the kidneys so Vit D increases both Ca and phosphate levels in the blood.