14 - Hormones of Ca Metabolism Flashcards
Describe the process of “making bone”
Calcium is the reason we can build a skeleton and stand upright
- The reason is that calcium forms insoluble salts
- Calcium chloride + sodium phosphate = crystalization
What happens when calcium phosphate crystals form in the joints?
There are times when there are calcium phosphate crystals in the joints –> called pseudo gout (real gout is uric acid crystals)
- This is an indication that serum calcium is too high
What is the role of calcium?
- Required for enzyme activities, both directly and indirectly
- Directly (citric acid cycle, glycogen degradation)
- Indirectly (calmodulin***)
- Mediates hormone responses as second messenger
- Essential for blood coagulation
- Essential for muscle contraction
- Required for stability of bone (mineralization, hydroxylapatite)
Describe the goal of the regulatory processes involving calcium
All the regulatory processes will be about keeping the extracellular calcium concentration fluid constant ***
How much of serum calcium is free? How much is bound?
In serum, about 50% of Ca2+ is free and 50% bound to proteins or small molecules.
Describe the difference between free and bound calcium
- In serum, only 50% of calcium is free calcium, meanign it is active calcium for signaling
- If it is bound to albumin, it is not active
- If someone has normal serum calcium, but are showing signs of hypercalcemia, look at the albumin… If albumin is high there may be a lot of calcium bound to albumin in that case
Describe the regulation of calcium and phosphate together
Calcium and phosphate are regulated inversely
- Mobilization of bone calcium (to increase serum Ca2+) is accompanied by increase in phosphate excretion in the urine
- High phosphate intake (soda) leads to increased Ca2+ excretion –> not good
What are the hormones of calcium metabolism?
- Calcitriol
- Parathyroid hormone
- Calcitonin
Describe the function of calcitriol
Calcitriol (1,25(OH)2D3) stimulates Ca2+ uptake in the gut
Describe the function of parathyroid hormone (PTH)
- Parathyroid hormone (PTH) stimulates resorption of bone Ca2+ into the serum.
- PTH also stimulates synthesis of calcitriol in the kidney
- Parathyroid hormone stimulates the resorption of calcium from bone into the serum
Both of these (calcitriol and PTH) try to increase the concentration of calcium in the serum
Describe the function of calcitonin
Calcitonin (CT) stimulates Ca2+ excretion by the kidney
What typically causes increased levels of calcium
A disease process
What is calcistat?
- The regulatory circuits tasked with keeping the serum calcium level constant are designated as the calcistat
- Keeps the calcium concentration steady
- The “main players” are the gut, bone and kidney
What is the most important “player” in teh calcistat?
Kindey because it has two roles
- Kidney needs to synthesize 1,25-OH2D3 and resorb calcium from the urine
- Kidney disease will impair the ability to absorb calcium from gut (carcitriol) and leads to a lot of loss of Ca in urine
What do we do to increase serum calcium?
3 ways
- diet
- bone
- kidney
Describe the sequence of events that occur when there is low serum calcium
- First thing that happens in low calcium is an increase in PTH
- Stimulates synthesis of calcitriol, suppresses secretion of Calcium and increases resorption from bone
- Calcium sensors are located in the parathyroid and is stimulated by low calcium
- If calcium concentration is too high, much less is going on… PTH is low
What is the active form of vitamin D? Inactive form?
1,25(OH)2D3 = active
24,25(OH)2D3 = inactive
24, 25 version is not active, so it is not helping to retain a lot of calcium from the gut
Describe the state of high serum calcium
- If calcium is high, calcitonin should be low
Describe the synthesis of parathyroid hormone
- Parathyroid hormone (PTH) is a peptide hormone
- PTH is synthesized in the chief cells of the parathyroid glands
Describe the synthesis of calcitonin
- Calcitonin (CT) is a peptide hormone
- CT is synthesized in the thyroid glands
What do calcitonin and parathyroid hormone synthessi have in common?
Both peptides made from a similar pathway and they need to be cleaved to be active
Describe the action of PTH on cells
- PTH binds to PTH receptors in the plasma membrane of target cells
- Binding of PTH to receptors leads to activation of
- The cAMP/Protein Kinase A pathway
- The Phospholipase C/Protein Kinase C pathway
- Depending on what cell you’re looking at –> just know that the target cells respond in one way or another
What is the physiological action of PTH in the kidney?
- Increases resorption of Ca2+ in the distal tubule, the collecting ducts and the ascending limb of the loop of Henle
- Stimulates phosphate excretion
- Stimulates the synthesis of calcitriol
What is the physiological action of PTH on bone?
Stimulates the resorption of Ca2+ by osteoclasts
Describe the basics of osteoclasts and osteoblasts
- Overall bone mass does not change because there is an equilibrium dynamic between osteoblasts and osteoclasts
- More clasts, less blasts –> bone resorption
- More blasts, less clasts –> bone building
B = build bone
Macrophage then degrade the byproduts/debris
Describe how you can detect the levels of PTH
- There is a very fast immunoassay is available, allows for intra-op detection
How is this used in hyperparathyroid surgery?
- In case of hyperparathyroidism, thyroid glands are resected to lower PTH production
- Immunoassay allows for monitoring of PTH production
What is one complication that can arise in hyperparathyroid surgery?
- Parathyroids may be hard to find
- 13% of population has accessory or supernumerary PT glands
- 15-20% have ectopic PT glands
These ectopic glands could be hyperactive –> need to look for them
What is the action of calcitonin?
Calcitonin action aims at lowering the serum calcium concentration
How does calcitonin lower serum calcium concentration?
- Calcitonin acts through G-protein coupled receptors (receptors signal via cAMP levels)
- In bone, inhibits resorption of Ca2+
- In the kidney, stimulates Ca2+ excretion
What is the source of calcitriol?
Calcitriol (1,25(OH)2D3) is synthesized from cholesterol
Describe the synthesis of calcitriol
- It is a water-insoluble steroid derivative
- Calcitriol synthesis involves skin, liver and kidney (in this order)
- Naked skin to sunlight –> calcitriol production
- Also taken up by the diet
- Starts in the skin, goes to the liver and ends in the kidney for synthesis
Describe the end stage of calcitriol synthesis
KIDNEY is the organ that actually makes the active form of calcitriol –> If the kidney is not around, there is no way to convert 24,25 to 1,25 and calcitriol will not be able to act on calcium then
What is the action of calcitriol?
- Enters cells and binds to a nuclear receptor (nVDR)
- Can also bind to non-classical, membrane receptors
- Target organs: Intestine, bone, kidney
- Stimulates transcription of:
- Ca2+ binding proteins
- Ca2+ ATPase
- Facilitators of vesicle formation
Describe the side effects of hypercalcemia
Formation of kidney stones, degradation of the skeleton (bones and moans)
Antacids can get serum calcium too high - by using Tums
Describe the side effects of hypocalcemia
Neurological impairment, cardiovascular collapse, hypotension and dysrhythmias (in severe cases
What disease can develop from hypocalcemia?
- Ricketts (osteomalacia)
- Osteoporosis
- Renal osteodystrophy
Describe Ricketts (osteomalacia)
- Ricketts (Osteomalacia) results from low vitamin D levels or insufficient Ca2+ intake
- Osteoid matrix and cartilage are formed, but not mineralized
- Leads to soft, pliable bones –> bowing of the legs
Describe osteoporosis
Osteoporosis
- Multifactorial and largely unknown causes
- Loss of bone mineral – predisposes to breaks
Describe renal osteodystrophy
Renal osteodystrophy
- Kidney disease leads to Ca2+ loss in urine, insufficient Calcitriol production
A 24-month old boy, dark complexion presents with ankle deformities, tibial torsion and severe bowing.
Breast-fed until 15 months, little solid food, no vitamin supplements.
Physical examination shows growth and developmental retardation.
Serum Ca2+, 25OH D3 and 1,25 OH2D3 levels low normal. PTH elevated about 20-fold.
This kid is NOT sick – he normal calcium, so there is no endocrine problem
Everything is working to keep the calcium normal
The problem is his diet ***
Low dietary calcium intake is the most important contributing factor
It also has to do with insufficient exposure to sunlight, but very few people get enough sunlight, they are just able to make up for it in their diet
What other hormones influence calcium homeostasis?
- GH
- Glucocorticoids
- Estrogens
How does GH influence calcium homeostasis?
Stimulates bone remodeling
How do glucocorticoids influence calcium homestasis?
- Reduce GI absorption
- Decrease calcium resorption in the kidney
- Inhibit bone formation
- Stimulate PTH secretion
How do estrogens influence calcium homeostasis?
- Increase calcium reabsorption in the kidneys
- Inhibit PTH-mediated bone resorption in the bone
