PHYS - Calcium and Phosphate Metabolism Flashcards
What are the symptoms of hypocalcemia?
Decreased plasma calcium levels causes:
- Hyperreflexia
- Spontaneous twitching
- Muscle cramp
- Tingling
- Numbness
What is Trousseau Sign?
When a hand becomes hyperflexed at the wrist as a result of the use of a blood pressure cuff.
Positive Trosseau Sign indicates hypocalcemia
What is Chvostek sign?
Twitching of facial muscles when tapping on the facial nerve
Positive Chvosek sign indicates hypocalcemia
What are the symptoms of hypercalcemia?
Increased plasma calcium levels cause:
- Diarrhea
- Reduced appetite
- polyuria (excessive urination)
- Polydipsia (excessive thirst)
- Muscle weakness
- Hyporeflexia
- lethargy (lack of energy/enthusiasm)
- Coma
How does hypocalcemia affect membrane excitability?
Hypocalcemia = Decreased extracellular [Ca2+]
Decreased extracellular Ca2+ causes a reduction in activation threshold, causing an increase in membrane excitability
Causes spontaneous Action Potentials, leading to tetany, tingling, numbness, spontaneous muscle twitching
How does hypercalcemia affect membrane excitability?
Hyperycalcemia = Increased extracellular [Ca2+]
Increased extracellular Ca2+ causes an increase in activation threshold potential, making it more difficult to achieve an Action Potential (reducing cell membrane excitability)
Causes nervous system to become depressed and reflex responses are slowed
How do changes in plasma protein concentration affect Ca2+ concentration?
Increased plasma protein concentration increases total Ca2+ concentration
But causes no change in ionized Ca2+
How does anion concentration affect Ca2+ concentration?
Increased anion concentration (such as phosphate) will cause a decrease ionized Ca2+
Ca2+ cations will become complexed with Phosphate anions
How does acid-base abnormalities affect Ca2+ concentration?
Acid-Base affects Ca2+ binding to Albumin
Albumin prefers binding to H+, which compete for binding sites with Ca2+
When pH is low, there is a large concentration of H+ competing for Albumin binding sites, meaning there are less available for Ca2+. Therefore, acidic conditions will promote an increase in free Ca2+ and a reduction in protein-bound Ca2+
When pH is high, there is a low concentration of H+ competing for Albumin binding sites, meaning there are more sites available for Ca2+. Therefore, basic conditions will promote a decrease in free ionized Ca2+ and an increase in protein-bound Ca2+
What are the three organ systems, and three hormones involved in calcium homeostasis?
Bone, Intestines, Kidneys
PTH, Calcitonin, Calcitriol (AKA vitamin D)
How does PTH affect Ca2+ and Phosphate homeostasis?
- Promotes renal reabsorption of Ca2+ from nephron lumen
- Promotes bone resorption of Ca2+
(increases blood Ca2+ levels)
- Inhibits renal reabsorption of Pi from nephron lumen
- Promotes Bone resorption of Pi
PTH activates Clacitriol (Vitamin D) - which promotes intestinal absorption of both Ca2+ and Pi
PTH increases urinary cAMP levels (due to Gs signaling, which increases intracellular cAMP levels)
How does Calcitriol (vitamin D) affect Ca2+ homeostasis?
Calcitriol promotes absorption of Ca2+ from the GI tract
Calcitriol promotes bone resorption of Ca2+
How does calcitonin affect Ca2+ homeostasis?
Calcitonin inhibits bone resorption of Ca2+
How is PTH gene expression and secretion regulated?
CaSR receptors detect extracellular Ca2+
When Ca2+ binds to CaSR receptors, it activates Gi and Gq signaling cascades, resulting in the inhibition of PTH gene expression and inhibition of PTH secretion
VItamin D (steroid hormone) diffuses through the parathyroid cell membrane and inhibits PTH gene expression, while also stimulating CaSR receptor gene expression
What affect does Magnesium have on PTH secretion?
In cases of severe hypomagnesemia (which can be caused by alcoholism) PTH synthesis and secretion is inhibited
What secondary messenger cascade does PTH utilize at its targets?
PTH binds to GPCRs that utilize a Gs signaling cascade
G-alpha S subunit acivates adenylyl cyclase
Adenylyl cyclase converts ATP into cAMP
cAMP activates PKA
PKA phosphorylates target proteins
How is Calcitriol production regulated?
PTH, decreased Ca2+ levels, and decreased Pi levels each promote activity of 1 - alpha - hydroxylase ezyme (AKA CYP1-alpha)
1-alpha-hydroxylase is the enzyme responsible for the final step in Vitamin D synthesis
How does PTH work on bone?
PTH binds with receptors on osteoblast cells (cells that build bone)
Short-term action of PTH causes buildup of bone
Activates osteoblasts secrete cytokines, which activate osteoclasts (bone mineralizing cells)
Long-term action of PTH causes bone mineralization indirectly
What cell does Vitamin D act on in the bone?
Osteoclasts
What is M-CSF?
Macrophage Colony Stimulating Factor
Induce stem cells to differentiate into osteoclast precursors, then into mononuclear osteoclasts, then into multinucleated mature osteoclasts
What is RANKL?
Receptor Activator for NF-kB Ligand
cell surface protein on osteoblasts that is the PRIMARY MEDIATOR OF OSTEOCLAST FORMATION
Binds with RANK, which is a cell surface receptor found on precursor osteoclast cells
What is OPG?
Osteoprotegerin
It is a decoy receptor for RANKL, produced by Osteoblast cells in order to inhibit RANKL/RANK interaction
How do PTH and Vitamin D help regulate RANKL and OPG?
PTH promotes RANKL, inhibits OPG
Vitamin D also promotes RANKL
How does PTH conduct its actions on the kidney, and where does it occur?
PTH acts on the Proximal Tubule by interacting with a Gs GPCR
- Causes inhibition of the Na+/Phosphate cotransporter on the apical membrane (facing the nephron lumen)
- cAMP generated from this interaction enters the Urine
THINK PPP - PTH blocks PHOSPHATE reabsorption in the PROXIMAL TUBULE
PTH acts on the Distal Convoluted Tubule to promote Ca2+ reabsorption from the nephron lumen into the blood stream
What are the actions of Vitamin D on the kidney?
Vitamin D promotes Ca2+ AND Phosphate reabsorption from the nephron lumen
(while PTH promotes Ca2+ reabsorption, but inhibits Phosphate reabsorption)
How does Vitamin D promote Ca2+ absorption in the Intestine?
Vitamin D is a steroid hormone. It diffuses across the epithelial cell membrane and promotes transcription of specific proteins
1) TRPV6 Ca2+ channel on the apical membrane, allows Ca2+ to enter the epithelial cell from the intestinal lumen
2) Na+/Ca2+ Antiporter - Protein found on the basolateral membrane that brings 3 Na+ ions into the cell for every 1 Ca2+ ion it sends out of the cell
3) H+/Ca2+ ATPase - Protein found on the basolateral membrane that brings 1 H+ into the cell fro every 1 Ca2+ ion it sends out of the cell. Uses ATP
How does Calcitonin act on bone?
Calcitonin is released from parafollicular C cells of the thyroid gland in response to high blood Ca2+ levels
The receptor for calcitonin in the bone is found on osteoclast cells
Calcitonin decreases the activity and number of osteoclast cells
What is the general role of Calcitonin?
To increase blood Ca2+ and Phosphate levels by promoting bone deposition and blocking kidney Ca2+ reabsorption
How does Estradiol-17beta affect Ca2+ metabolism?
Estradiol-17beta is one of the most potent regulators of osteoblast and osteoclast function
It promotes intestinal absorption of Ca2+ and renal reabsorption of Ca2+
Estrogen promotes survival of osteoblasts and apoptosis of osteoclasts
- Favors bone formation over resorption
Menopausal women are at greater risk of developing osteoporosis due to drop in estrogen secretion
How do adrenal glucocorticoids (such as cortisol) affect Ca2+ metabolism?
Cortisol promotes bone resorption of calcium, inhibit intestinal absorption of calcium
Individuals treated with high levels of glucocorticoids can develop osteoporosis
What is Primary Hyperparathyroidism and what does it ultimately cause?
Primary Hyperparathyroidism is when one of the parathyroid glands has a functional adenoma that is hypersecreting PTH
Causes Hypercalcemia and Hypophosphatemia
What are the three main symtpoms of Primary Hyperparathyroidism?
Stone, Bones, and Groans
Kidney Stones due to hypercalciuria
Increased bone resorption
Constipation (groans)
How is Primary Hyperparathyroidism treated?
Parathyroidectomy
What is Secondary Hyperparathyroidism?
Increased PTH secretion due to low Ca2+ blood levels
Typically caused by renal failure or vitamin d deficiency
What is Albright Hereditary Osteodystrophy?
AKA Pseudohypoparathyroidism Type 1a
Inherited autosomal dominant disorder that causes a defect in the PTH receptor, rendering it incapable of activation
Causes increased circulating levels of PTH, hyperphosphatemia, hypocalcemia
Administration of exogenous PTH produces no response
What are some symtpoms of Albright Hereditary Osteodystrophy?
AKA Pseudohypoparathyroidism Type 1a
Symptoms include:
- Short stature
- Short neck
- Obesity
- Subcutaneous calcification
- Shortened metatarsals and metacarpals (fingers and toes)
What is humoral Hypercalcemia of Malignancy?
When a tumor secretes a protein called PTH-related Peptide (PTHrP)
It is capable of binding and activating PTH receptors
Causes similar symptoms to Hyperparathyroidism, except PTH and Vitamin D levels are low
Increased blood calcium levels, decreased blood phosphate levels
Treated with Furosamide (inihbits calcium reabsorption in the kidney) and Etidronate (inhibits bone resorption)
What is FHH?
Familial Hypocalciuria Hypercalcemia
It is an autosomal dominant disorder that causes a mutation that deactivates the CaSR receptor in the parathyroid gland.
Causes parathyroid cells to have a decreased sensitivity to Calcium levels.
What is Rickets?
Impaired vitamin D metabolism in children
Results in insufficient Ca2+ and phosphate levels causing bone growth failure and skeletal abnormalities
Two types:
Type 1: Decreased 1-alpha-hydroxylase enzyme (prevents syntehsis of Vitamin D)
Type 2: Decreased Vitamin D receptor
What is Osteomalacia?
Impaired vitamin D metabolism in adults
New bones fail to mineralize
Causes weight bearing bones to soften and bend
How is osteoporosis treated?
Anabolic therapy: PTH supplementation (initially PTH promotes bone deposition)
Antiresorptive therapy (prevent mineralization of bone): Estrogen, Bisphosphonates, selectiv estrogen receptor modulators, calcitonin, RANKL inhibitors
