Regulation of Calcium and Phosphate Metabolism Flashcards
How does the amount of calcium change during aging?
- decreases in the amount of calcium absorbed from dietary intake and in dietary intake of calcium
- existing bone cells are reabsorbed by the body faster than new bone is made
- aging contributes to osteopenia or osteoporosis
Where is calcium predominantly located in the body?
bones and teeth 99%
What are the percentages of calcium in ECF, plasma, and ICF?
LO1
ECF- 0.1%
plasma - <0.5%
ICF - 1%
What is the biologically active form of calcium?
LO1
free, ionized calcium
What does ultrafilterable mean?
can cross membranes
What are the percentage of calcium in the blood?
LO1
protein bound 40%
ultrafilterable 60%
- complexed to ions 10%
- ionized calcium 50% *biologically active form
When is calcium higher than 10 normal for the patient’s age?
teenage years/puberty
What is the normal range for calcium?
9-10
What is hypocalcemia?
- definition
- symptoms
- indicators
- decreased plasma calcium concentration
- symptoms: hyperflexia, spontaneous twitching, muscle cramp, tingling, numbness
- indicators: Chvostek sign and Trousseau sign
What is Chvostek sign?
twitching of the facial muscles elicited by tapping on the facial nerve
What is Trousseau sign?
carpopedal spasm upon inflation of a blood pressure cuff
What is hypercalcemia?
- definition
- symptoms
- increased plasma calcium concentration
- symptoms: decreased QT interval, constipation, lack of appetite, polyuria, polydipsia, muscle weakness, hyporeflexia, lethargy, coma
How do changes in plasma calcium concentration influence membrane excitability?
LO2
decreased ECF calcium –> increased excitability of sensory and motor nerves and muscle by lowering threshold potential for Na channels –> less inward current required to depolarize to threshold and fire action potentials (hypocalcemic tetany)
- sensory neurons: tingling and numbness
- motor neurons: spontaneous muscle twitches
What can calcium levels in plasma be altered by?
- changes in plasma protein concentration –> total Ca2+ same direction as plasma proteins (no change in ionized calcium)
- changes in ion concentration –> change in fraction of calcium complexed with anions –> opposite directions
- acid-base abnormalities –> change the fraction of calcium bound to albumin b/c H+ competes for binding spots
What organ systems are involved in calcium homeostasis?
LO4
bone, kidney, and intestine
What hormones are involved in calcium homeostasis?
LO4
parathyroid hormone, calcitonin, vitamin D
What hormone does not contribute to homeostasis of calcium, but still has a role?
calcitonin
What happens in bone remodeling?
LO4
bone deposition
bone resorption
- stimulated by PTH and vit D
- inhibited by calcitonin
-no net gain or loss of Ca2+
What happens in the SI regarding calcium?
LO4
- absorption of Ca2+ stimulated by vit D
- secretion of Ca2+
-net 200 mg absorbed
What happens in the kidneys regarding calcium?
LO4
filtration
resorption
-stimulated by PTH
200 mg excreted
What must occur to maintain Ca2+ balance?
LO4
amount Ca2+ absorbed in GI must equal amount excreted in urine
What is the relationship between Ca2+ and phosphate?
-normal range
LO5
phosphate
- ECF concentration of Pi is inversely related to Ca2+
- Normal range is 2.5-4.5 mg/dL
What is the distribution of Pi in the body?
bone 85% plasma <1% -84% ionized -`10% protein bound -6% complexed to various cations, including K+ and Na+ ICF 15%
What cells secrete PTH?
LO5
chief cells of parathyroid glands
Describe PTH
- type of hormone
- structure
- synthesis
- storage
- peptide hormone
- single chain polypeptide with 84 aa
- preproPTH (115 aa)
- proPTH (90 aa)
- packaged into secretory granules
Where is the biologically active part of PTH?
N-terminus 1-34 aa
Is the PTH secretion low or high with high calcium?
low
Is PTH secretion low or high with low calcium?
high
Explain the CaSR
LO6
- receptor on parathyroid monitoring extracellular side
- calcium binds receptor –> inhibits PTH gene
What is the effect of vit D on PTH?
LO6
PTH is needed for the active form of vit D, so active form of vit D inhibits PTH gene.
What sensors are used by CaSR?
Gq and Gi
Describe regulation of PTH in chronic hypercalcemia
causes decreased synthesis and storage of PTH, increases breakdown of stored PTH, and release of inactive PTH fragment into the circulation
Describe regulation of PTH in chronic hypocalcemia
causes increased synthesis and storage of PTH and hyperplasia of parathyroid glands (secondary hyperparathyroidism)
What is the effect of magnesium on regulation of PTH?
**future practice
- parallel but less significant effects on PTH secretion
- severe hypomagnesemia is exception: result of chronic Mg2+ deplesion as in alcoholism –> inhibition of PTH synthesis, storage, and secretion
What is the receptor for PTH?
G alpha protein linked adenylyl cyclase –> cAMP
What are the actions of PTH on bone?
LO7
increased bone resorption
What are the actions of PTH on kidney?
LO7
decreased phosphate reabsorption (phosphaturia)
increased calcium reabsorption
increased urinary cAMP
What are the actions of the PTH on the intestine?
LO7
increased calcium absorption (indirect via vit D)
How does vitD affect calcium and phosphate homeostasis?
LO8
promotes mineralization of new bone through its coordinated actions in the regulation of both Ca2+ and Pi plasma concentrations
Describe vit D/cholecalciferol
- prohormone
- physiologically inactive
- must be successively hydroxylated to an active metabolite
Describe vitamin D synthesis
LO9
7-dehydrocholesterol --UV light (skin)--> or diet--> cholecalciferol --liver (25-hydroxylase)--> 25-OH-cholecalciferol (main circulating form but low activity) --kidney 24-hydroxylase --> inactive 24,25-(OH)2-cholecalciferol OR --1alpha hydroxylase --> 1,25 (OH)2 cholecalciferol (active)
What stimulates 1 alpha hydroxylase?
low calcium concentration
high PTH
low phosphate concentration
What is the other name for 1 alpha hydroxylase?
LO10
CYP1alpha
What is the negative feedback loop of PTH and 1,25-dihydroxycholecalciferol?
LO11
PTH stimulates Gs of epithelial cell of PT –> cAMP/PKA –> CYP1alpha gene –> 1 alpha hydroxylase
25(OH) vit D –1 alpha hydroxylase–> 1,25 (OH)2 vit D level sensed by parathyroid chief cells –> inhibit gene expression of PTH gene
What are the actions of PTH on bone formation and resorption?
LO12
- receptors on osteoblasts
- short term: bone formation via direct action on osteoblasts
- long term: increased bone resorption (indirect action on osteoclasts mediated by cytokines from osteoblasts)
How does vit D interact with PTH on bone?
LO12
acts synergistically with PTH to stimulate osteoclast activity and bone resorption
What are the actions of calcitonin in bone resorption?
LO13
decrease calcium and Pi concentrations by inhibiting bone resorption
- calcitonin receptors expressed on osteoclasts
- decreased activity and number of osteoclasts
- major stimulus is increased Ca2+
What is M-CSF?
macrophage colony-stimulating actors
-induce stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and mature multinucleated osteoclasts
What is RANKL?
receptor activator for NF-kappa B ligand
- cell surface protein produced by osteoblasts, bone lining cells, and apoptotic osteocytes
- primary mediator of osteoclast formation
What is RANK?
cell surface protein receptor on osteoclastss and osteoclast precursors
What is OPG?
osteoprotegerin: soluble protein produced by osteoblasts; decoy receptor for RANKL; inhibits RANKL/RANK interaction
What is OPG?
osteoprotegerin: soluble protein produced by osteoblasts; decoy receptor for RANKL; inhibits RANKL/RANK interaction
What does PTH do on bone agent/factors?
increases RANKL, decreases OPG
What does vitamin D do on bone agent/factors?
increases RANKL
What is the mechanism of PTH on the kidney?
- binds receptor
- Gs
- AC
- cAMP
- PKA
- phosphorylation
- inhibits Na+/phosphate transporter –> phosphaturia
What is the action of vit D on the kidney?
sitmulates BOTH Ca2+ and Pi reabsorption
What is the mechanism of vit D on GI?
vit D –> mRNA –> protein synthesis –> calbindin –> Ca2+ calbindin –> basolateral side
**increases Ca2+ and Pi absorption
What is the function of calbindin?
shuttle
buffer level of calcium intracellularly
What is primary hyperparathyroidism?
- mechanism
- actions
- labs
LO14
- elevated PTH –> elevated resorption, activation of vit D, elevated Pi excretion and Ca2+ reabsorption
- “stones, bones, and groans” - hypercalcuria stones, increased bone resorption - bones, constipation - groans
- treatment requires parathyroidectomy
PTH high
Ca2+ high
Pi low
vit D high
What is secondary hyperparathyroidism?
- mechanism
- actions
- labs
LO14
-increased PTH due to low calcium levels (chronic kidney disease and vit D deficiency)
both
PTH high
Ca2+ low
vit D low
renal failure - high Pi
vit D deficiency - low Pi
hypoparathyroidism
- causes
- symptoms
- treatment
LO15
causes
- thyroid surgery
- parathyroid surgery
- autoimmune or congenital (less common)
symptoms
- muscle spasms or cramping
- numbness, tingling, burning especially around mouth and fingers
- seizures
- kids: poor teeth development, mental deficiency
treatment
-oral calcium supplement and active form of vit D
hypoparathyroidism
-labs
LO15
PTH low
Ca2+ low
Pi high
vit D low
pseudohypoparathyroidism type 1a
- pathophysiology
- labs
PTH binds PTHR
defective Gs is unable to activate adenylyl cyclase
- AD disorder
- hypocalcemia and hyperphosphatemia
- high PTH
ALBRIGHT HEREDITARY OSTEODYSTROPHY
-short stature, short neck, obesity, subcutaneous calcification, shortened metatarsal and metacarpals
PTH high
Ca2+ low
Pi high
vit D low
humoral hypercalcemia of malignancy
- pathophysiology
- labs
PTH related peptide (PTHrP) produced in tumors with similar homology to PTH
-binds and activates same receptor as PTH
PTH low
Ca2+ high
Pi low
vit D low (paradoxally)
familial hypocalciuric hypercalcemia
- genetics
- cause
- labs
- AD
- mutations that inactivate CaSR in parathyroid glands and parallel calcium receptors in the kidney
PTH normal/high Ca2+ high urine Ca2+ low Pi normal vit D normal
Rickets and osteomalacia
-cause
LO19
impaired vit D metabolism
- dietary deficiency
- vit D resistance (deficit in synthesis of active form from absence of 1 alpha hydroxylase or mutations affecting vit D receptor)
Rickets
- definition
- characterizations
- types
LO19
children
- insufficient amount of calcium and phosphate are available to mineralize growing bone
- characterized by growth failure and skeletal deformities
- type I (low 1 alpha hydroxylase)
- type II (low vit D receptor)
osteomalacia
LO19
- new bone fails to mineralize
- characterized by bending and softening of weight bearing bones
labs of vit D deficiency
LO18
PTH high (secondary) Ca2+ normal/low Pi low Urine Pi high Urine cAMP high vit D low bone osteomalacia high resorption
risk factors for osteoporosis
LO20
decrease in bone mass increases with age
gender - female b/c loss of estrogen after menopause
treatment of osteoporosis
-anabolic therapy short term PTH
-antiresorptive therapy
biophsophonates
estrogen
selective estrogen receptor modulators
calcitonin
RANKL inhibitors
