Calcium-Phosphate Homeostasis (Lopez) Flashcards
1
Q
How is calcium distributed within the body and in what forms?
A
- distribution: ECF (0.1%), plasma (<0.5%), ICF (1%), bone/teeth (~99%)
- forms: total Ca2+ > protein-bound (40%) and ultrafilterable (60%) > complexed to anions (10%) and ionized Ca2+ (50%)
- active form: free, ionized Ca2+
2
Q
Why is calcium homeostasis tightly regulated?
A
- extracellular calcium conc has dramatic effect on excitability of cells (especially nerve fibers)
- aging: decreases in amnt of calcium absorbed from dietary intake and in dietary calcium intake (existing bone cells are reabsorbed by body fasted than new bone is made, contributes to osteopenia and osteoporosis)
3
Q
- decrease plasma Ca2+ conc
- sx: hyperreflexia, spontaneous twitching, muscle cramps, tingling/numbness
- Chvostek sign: twitching of facial muscles elicited by tapping on facial nerve
- Troussea sign: carpopedal spasm upon inflation of BP cuff
- mechanism for sx: low extracellular Ca2+ reduces activation threshold for Na+ channels > easier to evoke AP; increase in membrane excitability (spontaneous AP’s) which is basis for tetany (spontaneous muscle contractions) and produces tingling/numbness (on sensory neurons) and spontaneous muscle twitches (on motorneurons and muscle)
A
hypocalcemia
4
Q
- increase plasma Ca2+ conc
- sx: decreased QT interval, constipation, lack of appetite, polyuria, polydipsia, muscle weakness, hyporeflexia, lethargy, coma
- mechanism of sx: high extracellular Ca2+ increases activation threshold and decreases membrane excitability > nervous system becomes depressed and reflex responses are slowed
A
hypercalcemia
5
Q
How do changes in the forms of Ca2+ in plasma lead to alterations in levels?
A
- changes in plasma protein conc: alter total Ca2+ conc in same direction (increase in plasma protein conc = increase in total Ca2+ conc
- change in anion conc: change the fraction of Ca2+ complexed w/ anions (increase in phosphate conc = decrease in ionized Ca2+ conc)
- acid-base abnormalities: alter ionized conc by changing fraction of Ca2+ bound to albumin
6
Q
How do acid-base abnormalities affect Ca2+ conc?
A
(alter ionized conc of Ca2+ by changing fraction of Ca2+ bound to albumin)
- acidemia: free ionized Ca2+ conc increases b/c less Ca2+ is bound to album
- alkalemia: free ionized Ca2+ conc decreases, often accompanied by hypocalcemia
7
Q
Describe the process of calcium homeostasis:
A
1000 mg of calcium ingested/day
>
350 mg absorbed by GI tract (enhanced by vitamin D)
>
sent to ECF, then to bone for deposition
>
bone resorption occurs simultaneously (inhibited by calcitonin, and activated by PTH/vitamin D)
(^ bone remodeling: no net gain/loss of Ca2+, new bone is deposited, old bone resorbed)
>
PTH also activates Ca2+ reabsorption within kidneys, with levels ECF levels being balanced by filtration of the kidneys
>
ECF maintains ~10 mg/dL Ca2+ at any given time
>
ECF secretes Ca2+ back into GI tract where 800 mg is excreted/day
>
kidneys secrete 200 mg/day
8
Q
What is the relationship between calcium and phosphate?
A
- extracellular conc of Pi is inversely related to Ca2+ conc
- regulated by same hormones that regulate Ca2+ conc
- normal range is 2.5-4.5 mg/dL
- % distribution of Pi: bone (85%), plasma <1% (ionized (84%), protein-bound (10%), complex to cations (6%)), ICF (15%)
9
Q
Where is PTH synthesized and what are the characteristics of this hormone?
A
- chief cells of parathyroid gland
- peptide hormone, single-chain polypeptide w/ 84 AA
- biological activity exists between AA 1-34
- synthesized on ribosomes as preproPTH (115 AA), then cleaved to form proPTH (90 AA), followed by transportation to golgi and further cleavage to form PTH
- packaged in secretory granules
- regulates conc of Ca2+ in plasma, stimulus for secretion is decreased Ca2+ levels
- acts via G-protein linked receptor (Gs protein specifically, aka increases intracellular cAMP)
10
Q
How is PTH gene expression and secretion regulated?
A
- increased extracellular Ca2+ conc inhibits PTH synthesis and secretion
- increased extracellular Ca2+ situation: Ca2+ binds to CaSR > Gq+Gi > downstream signaling pathway (inhibits PTH exocytosis from cell) > PTH gene inhibition (also by vitamin D) and activates CaSR gene expression > CaSR mRNA produced > preCaSR produced > CaSR upregulation
- decreased extracellular Ca2+ situation: PTH is not inhibited > PTH mRNA produced > proPTH > PTH > PTH exits cell via exocytosis
- chronic hypercalcemia: causes decreased synthesis and storage of PTH, increased breakdown of stored PTH and release of inactive PTH fragments into circulation
- chronic hypocalcemia: causes increased synthesis and storage of PTH, and hyperplasia of parathyroid glands (secondary hyperparathyroidism)
11
Q
What are the actions of PTH on bone, kidneys, and intestines?
A
decreased plasma Ca2+
>
increased PTH secretion
>
- bone: increased bone resorption
- kidneys: decreased Pi reabsorption (phosphaturia), increased Ca2+ reabsorption, increased urinary cAMP
- intestines: increased Ca2+ absorption (indirect via vitamin D)
>
increased plasma Ca2+ toward nml
12
Q
What are the affects of vitamin D in terms of regulation of Ca2+ and Pi?
A
- vitamin D promotes mineralization of new bone through coordinated actions in reg of Ca2+ and Pi
- vit D increases Ca2+ and Pi conc, which promotes mineralization
- also has actions in intestines and kidney in addition to bones
- vit D (cholecalciferol) is a prohormone (steroid, receptor within nucleus), must be successively hydroxylated to be an active metabolite, and is regulated by negative feedback mech
13
Q
How is synthesis of vitamin D regulated?
A
- obtained in 2 ways: either from UV light conversion of 7-dehydrocholesterol or from diet, which both of which yield cholecalciferol
- cholecalciferol > (25-hydroxylase in liver) > 25-OH-cholecalciferol (main circ form, low activity) > (kidney) >
>
(1α-hydroxylase in renal proximal tubule) produces 1,25-(OH)2-cholecalciferol (active)
(24-hydroxylase) produces 24,25-(OH)2-cholecalciferol (inactive)
- 1α-hydroxylase: activated by low Ca2+ and Pi conc, and elevated PTH
14
Q
How is 1α-hydroxylase regulated?
A
- at the transcriptional level within epithelial cell of proximal tubule of kidney
- inhibited by high Ca2+ conc, activated by low Ca2+ conc
- activated by PTH > Gs protein > cAMP/PKA signaling pathway > CYP1α gene enhancement
- 1,25(OH)2 vit D (active) inhibits CYP1α gene and activates CYP24 gene that codes for 24-hydroxylase which produces 24,25 (OH)2 vit D (inactive)
15
Q
Where are PTH receptors located and what are the short-term effects and long-term effects of PTH stimulation?
A
- receptors located on osteoblasts
- short-term: bone formation (via direct action on osteoblasts), basis for use of intermittent synthetic PTH administration in osteoporosis tx
- long-term actions: increased bone resorption (indirect action on osteoclasts mediated by cytokines released from osteoblasts)
(vitamin D acts synergistically w/ PTH to stim osteoclast activity and bone resorption)
16
Q
Describe the agents/factors involved in bone formation/resorption and how this process is regulated:
A
- PTH: short-term it enhances osteoblasts bone formation, long-term it enhances osteoclasts bone resorption; increases RANKL and decreases OPG
- vitamin D: acts synergistically w/ PTH to stim osteoclast activity and bone resorption; increases RANKL
- M-CSF (macrophage colony-stimulating factor): induces stem cells to differentiate into osteoclast precursors, mononuclear osteoclasts, and mature into multinucleated osteoclasts (enhanced by active osteoblasts)
- RANKL (receptor activator for NF-kβ ligand): cell surface protein produced by osteoblasts, bone lining cells, and apoptotic osteocytes; helps stimulate osteoclast maturation when bound to RANK
- RANK: cell surface protein receptor on osteoclasts and osteoclast precursors
- OPG (osteoprotegerin): soluble protein prod by osteoblasts; decoy receptor for RANKL; inhibits RANKL/RANK interaction
17
Q
What is the mechanism of action of PTH in the kidneys and what are the physiological results?
A
- in the proximal tubules, PTH binds to GCPR and activates Gs protein > cAMP production > protein kinase activation > phosphorylation inhibits NPT (Na+-Pi transporter) > phosphaturia (increased secretion of Pi in urine)
- cAMP generates in cells of proximal tubule is also excreted in urine
- in the distal convoluted tubules, PTH complements increase in plasma Ca2+ conc that results from bone resorption and phosphaturia
19
Q
What is the mechanism of action of vitamin D for intestinal calcium and phosphate reabsorption?
A
- calcium: vit D leaves interstitial space of intestines and enters into epithelial cell, binding on nuclear receptor > activates mRNA to produce protein synthesis > upregulates TRPV6 receptors on intestinal lumen to bring more Ca2+ into the cell > protein syn also upregulates calbindin which binds Ca2+ across cell > Ca2+ leaves via Na+-Ca2+ transporter
- phosphate: ? look at photo
21
Q
Summary of Ca2+ and Pi homeostasis:
A
22
Q
What effects does calcitonin have on Ca2+ and Pi homeostasis?
A
- primary actions on bone and kidneys
- decreases blood Ca2+ and Pi conc by inhibiting bone resorption (effects occurs only at high circulating levels of the hormone)
- calcitonin receptors expressed on osteoclasts, decreases activity and number of osteoclasts, major stimulus is increased Ca2+ conc
- no role in chronic (minute-to-minute) regulation of plasma conc
- thyroidectomy: decreases calcitonin but no effect on Ca2+ metabolism
- thyroid tumors: increases calcitonin but no effect on Ca2+ metabolism
24
Q
- condition labeled as “stones”, “bones”, and “groans”
- hypercalciuria causes renal stones, increased bone resorption affects bones, and constipation causes groans
- may be caused by an adenoma in the parathyroid gland
- clinical signs: hypercalcemia, hypophosphatemia, increased PTH, increased Ca2+, decreased Pi, increased vit D
- tx: parathyroidectomy
A
primary hyperparathyroidism
25
Q
- increase in PTH levels secondary to low Ca2+ in blood
- causes for low Ca2+: renal failure, vit D def
- clinical signs in renal failure: elevated PTH, low Ca2+, elevated Pi, low vit D
- clinical signs in vit D def: elevated PTH, low Ca2+, low Pi, low vit D
A
secondary hyperparathyroidism
26
Q
- decreased PTH production due to damage to parathyroid
- causes: thyroid surg, parathyroid surg, autoimmune or congenital (less common)
- sx (most a/w low Ca2+): muscle spasm/cramps, numbness/tingling (esp around mouth/fingers), seizures, in kids poor teeth dvlpmt and mental deficiency
- clinical signs: low PTH, low Ca2+, elevated Pi, low vit D
- tx: oral Ca2+ supplement and active form of vit D
A
hypoparathyroidism
27
Q
- inherited autosomal dominant disorder that causes Gs protein for PTH in bone and kidney to be defective
- hypocalcemia and hyperphosphatemia develop
- increased PTH levels leads to PTH resistance: administration of exogenous PTH produces no phosphaturic response and no increase in urinary cAMP
- phenotype: short stature, short neck, obestity, subcutaneous calcification, shortened metatarsals and metacarpals
- clinical signs: elevated PTH, low Ca2+, elevated Pi, low vit D
A
Albright hereditary osteodystrophy
(pseusohypoparathyroidism type 1a)
28
Q
What is the relationship between hypercalcemia and malignancy?
A
- PTH-related peptide (PTHrP) is produced by tumors w/ close homology in the N-terminal to PTH (product of gene duplication of PTH)
- binds and activates same receptor as PTH (type 1 PTH receptor)
- increased PTHrp levels produces similar profile to primary hyperparathyroidism: increased urinary Ca2+, urinary Pi, urinary cAMP and increased blood Ca2+ w/ low blood Pi (hypophosphatemia)
- differs from hyperparathyroidism in: low PTH levels and low vit D
29
Q
- autosomal dominant disorder that leads to decreased calciuric secretion and increased Ca2+ blood conc
- causes: mutations that inactivate CaSR in parathyroid glands and parallel Ca2+ receptors in ascending limb of kidney
- clincial signs: PTH levels are normal to elevated, elevated serum Ca2+, low urine Ca2+, normal Pi, normal vit D
A
familial hypocalciuric hypercalcemia (FHH)
30
Q
What is the pathophysiology of vitamin D deficiency and what conditions does this cause?
A
- impapired vit D metabolism: dietary def, deficit in syn of active vit D (absence of 1α- hydroxylase), vit D resistance (mutations affecting vit D receptor)
- also, GI disorders, chronic renal failure, and Pi depletion can lead to changes in vit D metabolism
- leads to: Rickets in children (insufficient Ca2+ and Pi are available to mineralize growing bone, causes growth failure/skeletal deformities) and osteomalacia in adults (new bone fails to mineralize, causes bending and softening of weight-bearing bones)
31
Q
- vit D deficiency in children that leads to failure of growing bone to mineralize causing growth failure/skeletal deformities
- congenital types: pseudovitamin D-deficient or vitamin D dependent type 1 (low 1α- hydroxylase) and pseudovitamin D-deficient or vitamin D dependent type II (low vitamin D receptor)
A
Rickets
33
Q
How does bone mass change with age/gender and what are treatment options?
A
- both male and female bone mass increases significantly in late teens-early 20’s
- male bone mass slowly declines starting in 30’s
- female bone mass stays consistent until menopause (50-60’s) where is sharply declines and continues to decline
- tx: anabolic therapy (PTH, aka Forteo), antiresorptive therapy (bisphosphonates, estrogen, selective estrogen receptor modulators (raloxifene, tamoxifen), and RANKL inhibitors (Prolia))
