Regulation Of Calcium And Phosphate Flashcards
What are the normal limits of plasma calcium in the human body
2.20-2.60 mmol/L
- 40% is protein bound
- 50% is ionized clacium
10% is in the form of complexes with anions
Functions of extracellular and intracellular
Extracellular: (around 2.20-2.60 mmol/L)
- bone mineral
- blood coagulation
- membrane excitability
Intracellular: (usually within 10^-7M)
- neuronal activation
- hormone secretion
- muscle contraction
Calcium distribution in the body (NOT plasma)
67% = inorganic hydroxyapatite
28% = collagen
5% = noncollagenous proteins
99% is in the body’s skeleton at anytime!!
What are the three major organ systems that are responsible for calcium homeostasis
Bones
- PTH increases resorption
Kidneys
- PTH increases reabsorption
GI
- active vitamin D increases absorption
PTH direct responses in kidney ,GI and bone
Bones
- PTH stimulates osteoclasts to erode matrix and release stored calcium
- works synergistically with 1,25
Kidneys
- increases release of calcitriol which stimulates calcium reabsoption in kidneys and decreases phosphate reabsorption
- does both by stimulating Gs and Gi protein coupled receptors on PCT cells
Intestines
- acts indirectly on intestines by increasing 1,25 and calcitriol levels which work to enhanced and calcium absorption is increased
**all three increase calcium levels in blood
What receptors are on Chief cells in thyroid to release PTH?
Decreased in plasma calcium concentration is sensed by calcium sensing G-protein-coupled receptor (CaSR) on chief cells
The chief cells release PTH in response to activation of these receptors
What is the PTH receptor?
Gs protein coupled receptor
- upregulates cAMP, AC and eventually PKA
PTH gene expression
Upregulation of CaSR receptors on chief cells blocks expression of PTH gene (CaSR is a Gq-GI coupled receptor)
CaSR receptor activation upregulates PTH mRNA production which goes through multiple steps to become mature PTH in vesicles
- CaSR activation also overtime induces a negative regulation on CaSR downstream signaling
active vitamin D also plays a small role in this as well but instead upregulates CaSR gene expression which makes more CaSR receptors on chief cell surface
Active PTH = 84aa and half life = 5 minute
Inactive PTH = 34aa and half life = 30 seconds
PTH-related protein (PTHrP)
It is a peptide paracrine hormone produced by severe allergic adults tissues (skin, hair, breast, etc)
- bind to similar receptors to PTH but does have its own receptors part that it recognizes
- although it is similar in structure to PTH, PTH and PTHrP have their own unique genes**
Function
- regulates proliferation and differentiation
- relaxes smooth muscles in response to stretch of blood vessels/uterus/bladder
- during lactation also promotes maternal bone resorption and transport of calcium into milk
- regulates calcium transport across the placenta and helps regulate chondrocyte proliferation in growth plate of long bones
is not regulated by circulating calcium and does not play a role in Ca/Pi homeostasis
is associated with hypercalcemia of malignancy (especially lung and thyroid) where certain tumors secrete high levels of PTHrP and produces symptoms similar to hypercalcemia
Osteoblasts vs osteoclasts
Both arise from mesenchymal stem cells with produces osteoblasts
- osteoblasts then turn into osteocytes within mature bone and on signal multiple osteocytes can form into osteoclasts
- osteocytes can also turn back into osteoblasts via PTH binding
Osteoblasts turn into osteoclasts via M-CSF and RANKL binding
- OPG blocks this interactions of RANKL and RANK
PTH function on kidneys
PTH binds to Gs protein coupled receptors
And upregulates cAMP/AC/PKA which in the end inhibits NA+/Pi cotransport
- results in decreased phosphate reabsorption and phosphaturia (increased phosphate excretion)
Mechanism of calcium absorption in intestinal epithelial cells
1) calcium diffuses from lumen into cell down its electrochemical gradient
2) calcium becomes bound inside the cell to calbindin (D-28K)
3) calbindin bound to calcium is pumped across the basolateral membrane into the blood via Ca2/ATPase pumps
1,25-Dihydroxycholecalciferol induces synthesis of calbindin D-28K and ATP inside intestinal cells
Main effects of calcitonin
Antagonizes PTH secretion and actions based on increased plasma calcium levels
- triggered when calcium goes above 11mg/dL
Bones = inhibits osteoclast activity and promotes calcium deposition in bones
Kidney = inhibits calcitriol release and calcium reabsorption
Intestines = calcium absorption is decreased by limiting calmodulin (D-28K) production
calcitonin however does NOT play a major function in regulating serum calcium but rather antagonizes PTH
How does rickets/osteomalacia occur?
Deficiency in active vitamin D (1,25-OH) causes a decrease in intestinal absorption of calcium.
This results in an excess of PTH in an attempt to raise calcium levels to normal.
- however PTH also inhibits Pi reabsorption in the kidney which incidentally results in hypophosphatemia (THIS IS WHAT CASUES RICKETTS/OSTEOMALACIA)
Decrease phosphate results in less hydroxyapatite band weakened bones
Symptoms:
- bowed legs and knob-like rib heads as well as short stature in ricketts
- bone pain and muscle weakness in osteomalacia
Primary and secondary causes of hyperparathyroidism
Primary = within the hyperthyroid glands themselves
- carcinoma, adenoma or hyperplasia
Secondary = renal failure, vitamin D deficiency
Tertiary = parathyroid syndrome from ectopic cancer (almost always small cell lung cancer
What si the only form of active clacium?
Free ionized calcium (50% total in body)
What’s the easiest way to differentiate primary form secondary hypercalcemia?
Look at PTH levels
In primary = high and ignores negative feedback from elevated calcium levels
In secondary = low and is influenced by negative feedback
What is the purpose of alkaline phosphatase in hyperparathyroidism?
This enzyme is found in liver and bone and are increased in times of excess osteoblast activity and high bone turnover
- it is found primarily in primary hyperparathyroidism
Phosphate concentration in the body
Forms
- 84% = ionized and active
- 10% = protein bound
- 6% = complexed
Extracellular = 1.0 mmol/L
- functions to generate bone mineralization
Intracellular = 1.0-2.0 mmol/L
- more intracellular
- role = high energy bonds and regulation of proteins by phosphorylation
Where is most phosphate stored?
Bone and soft tissues
- unlike calcium which is 99% bone, bone contains roughly 85% phosphate and ST is 15%. These means significant soft tissue damage can lead to hyperphosphatemia and then subsequently an acute hypocalcemic event
Calcitonin effects on vitamin D and phosphate and calcium
Calcitonin released in excess calcium levels decreases phosphate reabsorption and calcium reabsoption in the kidneys increasing excretion of both
Calcitonin also limits activation of 1,25-OH and bone resorption which also increase urinary excretion of calcium
Differences in most common types of hyperparathyroidism
Primary hyperparathyroidism
- increases in PTH, (1,25-OH)
- increases in serum calcium
- decreases in serum phosphate
- calcinuria and phosphaturia are present
Surgical hypoparathryodism
- **low PTH and low (1,25-OH)
- **high phosphate in blood and low calcium in blood
- **low urine phosphate
Pseudohyperparathyroidism (defective Gs receptors for PTH)
- **decreased (1,25) w/ increased PTH
- decrease bone resorption
- low serum calcium with high phosphate
Malignant hypercalcemia (increased PTHrP)
- PTH is low, (1,25-OH) is high
- phosphaturia and cacinuria
- high serum calcium and low serum phosphate
Chronic renal failure
- high PTH and low (1,25-OH)
- decreased urine phosphate
- low serum calcium and high serum phosphate
Albright hereditary osteodystrophy (AHO)
Autosomal dominant condition that presents at birth. Caused by failure of the kidney to respond to PTH levels
- essentially T2DM for PTH on the kidneys
Produces pseudohypoparathryoridism
Clinical features
- short stock body and round facies
- short 4th/5th metacarpals and subcutaneous calcification
- developmental delay
FGF-23 and phosphate homeostasis
Is one of the primary regulators of phosphate
- is produced by osteocytes based on increased serum phosphorus and target the kidney
Activates
- increase phosphate in urine
Inhibts
- PTH secretion (negative feedback)
- (1,25-OH) production in kidneys
uses “Klotho-receptors” found on PCT cells to bind FGF-23 and reduce 1,25 product as well as inhbits phosphate reabsorption
Hyperphosphatemia
Caused when phosphate is >4.5 mg/dL in blood
Casues:
- renal insufficiency/ KCD
- hypopararhyodism and pseudohypoparathyrodism
- over use of heparin
- crush injuries, rhabdo and hyperthermia
- hemolytic anemia and tumor lysis syndrome
- chronic respiratory or metabolic acidosis
Treatment = reduce phosphate intake and use calcium carbonate (phosphate binding antacids)
Hypophosphatemia
Caused when serum phosphate drops below 2.5 mg/.dL
Causes:
- alcohol excessive use
- burns
- starvation
- overuse of diuretic
- hyperparathyroidism
- excess FGF23 via multiple genetic diseases
- Wilson disease or lead toxicity
- chronic HUS or amyloidosis or hemochromatosis
Clinical features
- muscle weakness
- respiratory failure
- heart failure
- seizures
- coma
Treatment = phosphate supplementation
Common biological markers that inhbit and promote bone growth/loss
Promote bone growth
- BMP/WNT activation
- normal intermittent PTH
- increased mechanical load and normal androgen levels
Inhibit bone growth
- B-adrenergic activation via leptin
- immobilization and aging (decreases osteoblast activity and lowers estrogen and testosterone levels)
- excess cortisol
Promotes bone degradation
- estrogen deficiency
- excess cortisol
- low PTH and calcium
- immobilization
Inhibits bone degradation
- estrogen
- bisphosphonate
- calcitonin
- calcium and vitamin D
- SERMs
How does testosterone and estrogen both promote bone growth?
Testosterone promotes bone deposition by up regulating osteoblasts
Estrogen = inhibits osteoclasts
both do different functions but essentially meet the same end goal
