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02-08-16.KEEF.Parathyroid and Ca Homeostasis (M edit)
Terms in this set (81)
Likely Not on Test but in lecture
What hormone that acts within the kidney and plays a part in water balance acts on Gs receptors?
Name the 3 organ systems with involvement in calcium and phosphate regulation
2. GI tract
What amount of calcium is absorbed from daily intake? What is the Fractional excretion (FE) of calcium in the kidney?
About 300 mg of the 1000 mg intake is absorbed by the intestines.
The FE is about 1.5%.
What amount of phosphate is absorbed from daily intake?
What is the Fractional excretion (FE) of phosphate in the kidney?
About 600 mg of 900 mg intake is absorbed by the intestines.
The FE is about 10%.
Where in the intestines is calcium absorbed? Where are these active vs passive processes?
Calcium is absorbed throughout the small intestine. It is active in the duodenum and jejunum and passive in the ileum.
Describe calcium absorption from the lumen into the cell and from the cell into interstitial space.
Calcium enters the cell through passive absorption along its electrochemical gradient through TRP channels but is then requires energy to move into the interstitial space via a Ca ATPase or Na/Ca transporter.
Calcium may also move into the interstitial space passively via paracellular junctions.
How is calcium concentration maintained low within intestinal cells while absorbing calcium?
Calcium after entering cells is bound to calcium binding proteins such as calbindin as well as actively pumped out into the interstitial fluid.
Where in the intestines is phosphate absorbed? Where are these active vs passive processes?
Phosphate is absorbed throughout the small intestine an is active in all areas including the duodenum, jejunum, and ileum.
How is phosphate absorbed into intestinal cells? How is phosphate moved into the interstitial space?
It requires energy for absorption and so is absorbed using the energy from Na gradient and moved into the cell with Na.
Phosphate movement into the interstitial space is along its electrochemical gradient and so is passive without energy input.
How does the body reabsorbs calcium in the proximal tubule?
The majority is reabsorbed passively via paracellular routes but there is some absorption transcellular.
How is transcellular absorption of calcium similar in the kidney and the intestine?
Both involve a passive absorption into the cell through channels down it's electrochemical gradient. This then requires active transport out of the cell into the interstitial space using a Ca/ATPase or Ca/Na antiporter.
*PS calbindin is also inside kidney cells
How does the body reabsorb calcium in the distal tubule?
Calcium resorption is transcellular in the distal tubule. Resorption is also upregulated via PTH.
How does Parathyroid Hormone stimulate increased calcium resorption in the distal tubule?
PTH increases absorption via stimulating Gs receptor that then increases cAMP and PKA and leads to increased transcription of Ca channels (TRP channel) for the calcium to flow more freely down its electrochemical gradient.
What is the effect of the active form of Vitamin D on calcium re absorption in the kidney?
It increases re absorption
Describe where and how in the tubule phosphate is reabsorbed?
All resorption of phosphate is active within the kidney. 80% is reabsorbed in the proximal tubule, 10% is reabsorbed in the distal tubule, and 10% of the phosphate is excreted in urine.
Contrary to calcium resorption, what is the effect of PTH on phosphate resorption?
PTH decreases the resorption of phosphate in the kidney.
Describe phosphate resorption into the cell. Describe phosphate movement from the cell to the interstitial space.
Phosphate in the kidney similar to the intestine is first actively reabsorbed into the cell using the Na gradient and then is removed from the cell to the interstitial space via anion exchange or facilitated diffusion.
What is the purpose of osteoblasts?
Osteoblasts form osteoids with collagen.
Osteoblasts also produce alkaline phosphatase which can free phosphates from pyrophosphate. These free phosphates along with calcium can be used to mineralize osteoids.
How is calcified bone matrix formed?
Via the mineralization of osteoids. Formed via combination of collagen in osteoids with hydroxyapatite crystals.
What is an osteocyte?
An osteocyte is a "retired" or less active form of osteoblasts.
What is an osteoclast?
An osteoclast is a cell which secretes acid that helps to break down bone and can lead to freeing calcium and phosphate into plasma.
What makes up an osteoclast?
An osteoclast is formed via the fusion of monocyte/macrophage precursors.
What effect does PTH have on osteoblasts?
PTH leads to osteoblasts synthesizing macrophage colony stimulating factor (M-CSF) which leads to the formation of osteoclast precursors.
What happens with the binding of RANK ligand to the RANK receptor?
The maturation of osteoclasts from their precursor
What is osteoprotegerin?
The "decoy receptor" that is secreted by osteoblasts and binds to the RANK ligand on osteoblasts. This prevents binding of the ligand to RANK receptors on osteoclasts precursors and prevents maturation to osteoclasts.
What is osteoporosis?
decreased osteoid +minerals. (Occurs with an imbalance of bone formation/resorption.)
What is osteopetrosis?
Increased osteoid and minerals (due to a dysfunction of osteoclasts. Leads to increased hardness and density of bones.)
What is osteomalacia?
Decreased mineralization. (Softening of the bones due to a lack of mineralization commonly caused by Vit D insuffiency. In children it is called Rickets.)
What is osteogenesis imperfecta?
Decreased osteoid. (A group of inherited bone disorders in which the quality/quantity of collagen is compromised)
What is the most common drug for treatment of osteoporosis that works by inhibiting osteoclasts?
Bisphosphates work by inhibiting osteoclasts.
Calcitonin as well as estrogen both inhibit osteoclast activity as well which is why after menopause with decreasing estrogen women are more likely to get osteoporosis.
How does Denosumab work to help osteoporosis?
Mimics the effect of decoy receptor osteoprotegerin and inhibits maturation of osteoclasts from their precursors. Blocks RANK ligands.
How does Teriparatide work to help osteoporosis?
Similar to PTH and stimulates osteoblast activity increasing bone growth. It is given subQ and is generally reserved for patients with severe osteoporosis.
What are two rapid (non hormonal) means of regulating blood calcium levels?
Release of calcium that is bound to proteins.
Exchange with bone (1% of bone available to give up minerals)
What is calcitriol?
The active form of vitamin D. Derived from steroids.
Which cell of the parathyroid produces PTH?
How does increasing calcium levels regulate the release of PTH?
Increased plasma Ca decreases PTH secretion.
Increased Ca levels bind to a Gq receptor that downstream leads to the release of calcium from within the endoplasmic reticulum. This calcium activates phospholipase 2 and leads to the formation of arachidonic acid (AA). AA then inhibits the synthesis and release of PTH from chief cells.
What effect does PTH have on plasma calcium and phosphate levels?
PTH increases plasma concentration of both calcium and decreases plasma phosphate via affecting resorption. PTH release is stimulated by decreased levels of plasma calcium and increased levels of phosphate.
What effect does calcitriol have on PTH release?
Calcitriol decreases PTH release from chief cells via inhibiting PTH synthesis. This is negative feedback since PTH increases formation of calcitriol.
Where is calcitonin formed? What causes its formation?
Formed within C cells of the thyroid gland. (.1% of thyroid cells). Works the opposite of PTH so that with increased Ca levels, there is increased calcitonin formation. Calcitonin works to increase bone formation as well as increase calcium excretion in the kidney.
What are the effects of PTH and calcitonin on bone resorption?
PTH leads to increased osteoclast activity in order to increase plasma calcium levels. Calcitonin leads to decreased osteoclast activity due to high plasma calcium levels.
What important enzyme is necessary in the formation of calcitriol and where does the reaction take place?
1-alpha-hydroxylase is the last step in forming calcitriol and takes place in the proximal tubule of the kidney. It increases the enzymes activity by 1000x.
Calcitriol modulates the calcium and phosphate regulation in bones, kidneys, and intestines. Briefly describe each.
Bone: Increase mobilization of Ca and phosphate via bone breakdown
Kidney: Decreases Ca and Pi excretion
Intestine: Increases Ca and Pi absorption
General rule is increasing serum levels of Ca and Pi
Here is a brief summary on bone formation/resorption
Key points: PTH tends to balance more towards resorption but does both formation/resorption
Calcitonin blocks osteoclast activity so blocks resorption
Important to understand this diagram. "favorite diagram"
Don't forget PTH is essential for life. Without it you get hypocalcemic tetany.
Hypocalcemic tetany results from reduced Ca2+ binding to the cell surface resulting in reduced surface charge. This effectively "depolarizes" the membrane and activates sodium channel in nerve and muscle. A classic clinical sign of hypocalcemic tetany is known as the Chvostek sign, which is twitching or contraction of the facial muscles in response to tapping the facial nerve at a point anterior to the ear and above the zygomatic bone.
What effect does hypoparathyroidism have on Serum calcium, phosphate, PTH, and alkaline phosphotase?
Decreases calcium. Increases phosphate. Decreases PTH due to injury/surgery most commonly. No change in alk phos.
What is pseudohypoparathyroidism? What effect does it have on calcium, phosphate, PTH, and alk phos levels?
Pseudohypoparathyroidism is a lack of response to PTH due to a defect in the response pathway. This leads to elevated PTH with decreased calcium and increased phosphate. No change in alk phos.
What is osteomalacia/rickets? What effect does it have on calcium, phosphate, PTH, and alk phos levels?
Softening of the bone due to a lack of calcium in bone material which is often caused by Vitamin D deficiency. The lack of vitamin D leads to a lack of dietary calcium absorption so to increase the low plasma Ca there is an increase of PTH and a decrease in plasma phosphate. Alk phos is increased as it promotes bone resorption to calcium ions.
What is chronic kidney disease? What effect does it have on calcium, phosphate, PTH, and alk phos levels?
Loss of kidney function and loss of alpha hydroxylase activity preventing formation of active vitamin D (calcitriol).
Similar to osteomalacia/rickets the lack of vitamin D prevents absorption of calcium from the diet. The low calcium promotes PTH which increases plasma Ca via bone breakdown but due to loss of kidney function there is a lack of phosphate secretion leading to phosphate build up.
Calcium low. Phosphate high. PTH high. Alk phos high.
What is hypocalcemia typically associated with?
Elevated phosphate levels but NOT ALWAYS.
Ex. No phosphate elevation in rickets.
What is Vitamin D intoxication? What effect does it have on calcium, phosphate, PTH, and urine calcium levels?
Vitamin D intoxication is highly elevated levels of Vitamin D from patients taking extreme amounts of supplements. The elevated Vit D leads to increased absorption of Calcium in the intestines as well as promoting phosphate resorption in the kidneys. The high plasma calcium inhibits PTH secretion so that is low. But the high plasma calcium leads to very high levels of calcium in the urine.
What is primary hyperparathyroidism? What effect does it have on calcium, phosphate, PTH, and urine calcium levels?
Primary hyperparathyroidism is generally caused by a tumor called an adenoma which promotes secretion of PTH.
The increased PTH leads to increased serum calcium levels along with decreased phosphate due to increasing its excretion. This also leads to increased calcium in the urine.
Here is a table for differentials of hypo-and hypercalcemia
What is FHH?
What happens to PTH release?
What happens to calcium secretion?
What happens to plasma Calcium levels?
Familial Hypocalciuric hypercalcemia
Caused by a mutation in gene coding for the calcium sensing receptor CasR
Perceived low calcium causes increased PTH released
PTH then decreases calcium excretion
Calcium plasma levels will increase
Where is the calcium sensing receptor (CasR) found?
What is its purpose?
CasR is found within the membrane of chief cells of parathyroid as well as within kidney tubule cells in thick ascending limb
The purpose of CasR is to protect tissues from elevated extracellular levels of Ca. In the chief cells it inhibits the release of PTH and in the kidneys it prevents the reabsorption of calcium, both of which accomplish lowering plasma Ca levels.
Bone cells enclosed in bone matrix are called?
a protein secreted by osteoblasts that constitutes more than half of bone by volume
the cell that expresses the signaling molecule RANKL on its surface
Osteoclasts are descended from what?
bone marrow stem cells
A protein secreted by osteoblasts that bind to RANKL serving s a "decoy receptor"
the cell that causes bone resorption
What happens if hypocalcemia tetany? (think of her pneumonic)
CATS go numb
Numbness/prickling in hands, feet, mouth, lips
T/F - need Calcitonin but not PTH for life. Without it, you would die?
FALSE. Need PTH for life but not calcitonin
Why are Ca and P regulated in opposite manners?
To avoid "ectopic foci" when both Ca and P are high and can precipitate into soft tissues
When PTH is low you get ____
What enzyme activates Vitamin D?
25-hydroxyvitamin D3 1-alpha hydroxylase
precursor to osteoblasts? osteoclasts?
Where on the thyroid gland would you find the parathyroids?
What 2 things are made in the thyroid? what is made by the parathyroid?
thyroid: TSH and Calcitonin (thyrocalcitonin)
pseudohypoparathyroidism is analogous to?
nephrogenic diabetes insipidus
treatment of hypoparathyroidism? (2) what would you add for chronic renal failure?
1. restore and maintain Ca levels
2. vitamin D supplements
(add restrict phosphate for chronic renal failure)
T/F PTH inhibits Calcium reabsorption in the distal nephron?
T/F - PTH is necessary for life but calcitonin is not?
True. PTH need. Calcitonin don't.
What levels would you expect to be elevated if someone has renal disease?
Is calcium transport in the kidneys and intestine
enhanced by PTH or calcitriol?
Calcitriol (not PTH)
T/F more calcium than phosphorous is excreted in the feces?
Ca: 850 out of 1000
P: 300 out of 900
Would you expect increased or decreased plasma calcium in osteomalacia?
decreased calcium levels
What is the primary role of calcitriol?
enhance calcium reabsorption by the intestines
Order from greatest to least fractional excretion by the kidneys?
PAH, urea, Ca, creatinine, P, glucose
Where in the nephron does PTH increased Ca reabsorption and where does it inhibit P reabsorption?
Ca increase: distal
P decrease: proximal
What would you expect P levels to be in osteomalacia?
P levels should be down
What is osteopenia?
reabsorbing more bone than making
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