regulation of ca and PO4 metabolism - chapter 9 Flashcards
normal total ca concentration in blood
about 10 mg/mL
40% bound to plasma proteins
60% not protein-bound - ultrafilterable
- some complexed to anions but most free - 50% free - only form that’s biologically active
hypocalcemia symptoms
spontaneous twitching muscle cramps tingling numbness chvostek sign and trousseau sign
chvostek sign
twitching of the facial muscles elicited by tapping on the facial nerve
used to diagnose hypocalcemia
trousseau sign
carpopedal spasm upon inflation of a blood pressure cuff
used to detect hypocalcemia
low extracellular ca causes:
1: increased excitability of excitable cells => lower threshold potential, less inward current needed to depolarize => tingling and numbness and spontaneous muscle twitches
hypercalcemia symptoms
constipation polyuria polydipsia neurologic signs of hyporeflexia lethargy coma death
changes in anion concentration on ca concentration
change the fraction of ca complexed with anions
if plasma phosphate concentration increases => fraction of ca that is complexed increases => decreased ionized ca concentration
acidemia
excess H+ in blood => more H+ bound to albumin => fewer sites for Ca => increase in free ca
alkalemia
deficit of H+ in blood => less H+ bound to albumin => more sites for Ca to bind => hypocalcemia
vitamin D,1,25-dihydroxycholecalciferol
stimulates absorption of Ca in GI tract
chief cells of parathyroid gland
synthesize and secrete PTH
PTH
secreted by chief cells of parathyroid gland
single-chain with 84 AA
biologic activity resides in N-terminal 34 AA
synthesis of PTH
1: synthesized as preproPTH on ribosomes (115 AA)
2: 25 AA signal sequence cleaved off => 90 AA pro-PTH
3: pro-PTH transported to golgi
4: 6 AA cleaved => PTH
5: packaged into secretory granules for release
short-term regulation of PTH secretion
by plasma ionized ca concentration
secreted at basal level when ca levels normal
reaches maximal rates when ca levels at 7.5
response within seconds
mg levels also regulate
mechanism of PTH secretion
1: parathyroid cell membrane has Ca sensing receptors linked via Gq to phospholipase C
2: extracellular ca concentration increased
3: Ca binds to receptor
4: phospholipase C activated
5: increased levels of IP3/Ca2+
6: inhibits PTH secretion
if amounts of ca binding receptor decrease, inhibition of PTH secretion is decreased so more PTH secreted
long-term regulation of PTH secretion
chronic changes in plasma Ca concentration alter transcription of gene for preproPTH, synthesis and storage of PTH, and growth of parathyroid glands
therefore, chronic hypocalcemia => secondary hyperparathyroidism => increased synthesis and storage of pTH and hyperplasia of parathyroid glands
chronic hypercalcemia => decreased synthesis and storage of PTH, increased breakdown of PTH, and release of inactive PTH fragments
secondary hyperparathyroidism
due to chronic hypocalcemia
increased synthesis and storage of PTH
hyperplasia of parathyroid glands
Mg on PTH secretion
hypomagnesia stimulates PTH
hypermagnesia inhibits
except with severe hypomagnesia associated with chronic Mg depletion (alcoholism) => inhibition of PTH synthesis, storage, secretion
mechanisms of action of PTH
on bone and kidney, direct, mediated by cAMP
on intestine, indirect via activation of vitamin d
mechanism of PTH action on kidney
1: PTH binds receptor
2: receptor coupled to adenylyl cyclase via Gs protein
3: adenylyl cyclase catalyzes conversion of ATP to cAMP
4: cAMP activates protein kinases
5: protein kinases phosphorylate intracellular proteins
6: these proteins inhibit Na/phosphate cotransport at luminal membrane
PTH on bone
increased bone resorption
1: PTH receptors on osteoblasts, not osteoclasts - direct action on osteoblasts initially creates increase in bone formation
2: long-term, causes increase in bone resorption via indirect action on osteoclasts mediated by cytokines released by osteoblasts => release of both Ca and P to ECF - also release of hydroxyproline, which is excreted in urine
not enough to explain entire increase in ca due to PTH, though - other mechanisms
PTH on kidney
decreased phosphate reabsorption (phosphaturia)
increased ca reabsorption
increased urinary cAMP
1: inhibits phosphate reabsorption by inhibiting Na-phosphate cotransport in PCT => phosphaturia - prevents phosphate released along with ca by resorption of bone from complexing with ca in ECF
cAMP generated in PT cells also excreted in urine
2: stimulates Ca reabsorption - on DCT
actions of PTH of intestine
increase ca absorption (indirectly via 1,25-dihydroxycholechalciferol)
stimulates renal 1alpha-hydroxylase => conversion of 25-hydroxycholecalciferol to active form = 1,25-dihyroxycholecaliferol => stimulates intestinal ca absorption
hyperparathyroidism
rater of bone resorption elevated => increased serum Ca concentration
1alpha-hydroxylase
renal enxyme that is stimulated by PTH
converts 25-hydroxycholecalciferol to active form 1,25-dihydroxycholecalciferl
(activates vitamin D)
therefore stimulates intestinal ca absorption
primary hyperparathyroidism (table)
increased PTH
increased 1,25-dihydroxyholecalciferol (because of PTH’s effect on 1alpha-hydroxylase)
increased bone resorption
increase urine phosphate concentration adn ca
increase urine cAMP
increased serum ca
decreased serum phos
surgical hypoparathyroidsm (table)
decreased PTH decreased 1,25-dihydroxyholecalciferol (because of PTH's effect on 1alpha-hydroxylase) decreased bone resorption decrease urine phosphate concentration decreased urine cAMP decreased serum ca increased serum phos
pseudohypoparathyroidism (table)
increased PTH decreased 1,25-dihydroxyholecalciferol (because of PTH's effect on 1alpha-hydroxylase) decreased bone resorption (defective Gs) decrease urine phosphate concentration decrease urine cAMP decreased serum ca increased serum phos
humoral hypercalcemia of malignancy (increase PTH-rp) (table)
decrease PTH increases 1,25-dihydroxyholecalciferol increase bone resoprtion increase urine posphate increase urine ca because of high filtered load increase urine cAMP increase serum ca decrease serum phos
chronic renal failure (table)
increase PTH (secondary)
decrease 1,25-dihydroxyholecalciferol
osteomalacia due to decreased 1,25-dihydroxyholecalciferol
increased bone resorption due to increased PTH
decreased urine phosphate due to decreased GFR
decreased serum ca due to decreased 1,25-dihydroxyholecalciferol
decreased serum phos due to decreased urine phos
primary hyperparathyroidism
most commonly caused by parathyroid adenomas => secretion of excessive amounts of PTH
increased PTH
hypercalcemia due to increased bone resorption, increased renal ca reabsorption and increased intestinal ca absorption
hypophosphatemia due to decreased renal phosphate reabsorption and phosphaturia
get “stones, bones, and groans” = stones from hypercalcemia, bones from increased bone resorption, groans from constipation
treat with parathyroidectomy
secondary hyperparathyroidism
parathyroid glands are normal but are stimulated to secrete excess PTH secondary to hypocalcemia - can be due to vitamin D deficiency or chronic renal failure
blood levels of ca low or normal but never high
circulating PTH levels elevated
hypoparathyroidism
inadvertent consequence of thyroid surgery or parathyroid surgery
can also be autoimmune or congenital
low circulating pTH, hopcalcemia due to decreased bone resorption, decreased renal Ca reabsorption and decreased intestinal ca absorption
hyperphosphatemia due to increased phosphate reabsorption
treat with oral ca supplement and active form of vitamin D
pseudohypoparathyroidism - albright’s hereditary osteodystrophy
hypocalcemia, hyperphosphatemia, short stature, short neck, obesity, subcuateneous calcification, shortened fourth metatarsals and metacarpals
administration of endogenous PTH produces no phosphaturic response and no increase in cAMP
inherited autosomal dominant disorder in which Gs protein for PTH in kidney and bone is defective
humoral hypercalcemia of malignancy
when malignant tumors (lung, breast) secrete PTH-related peptide (PTH-rp) = structurally homogenous to PTH - has all actions of PTH
=> hypercalcemia and hypophosphatemia despite low circulating levels of PTH
treat with furosemide and etridronate
furosemide
used to treat humoral hypercalcemia of malignancy
inhibits renal ca reabsorption and increases ca excretion
etidronate
used to treat humoral hypercalcemia of malignancy
inhibits bone resorption
familial hypocalciuric hypercalcemia (FHH)
autosomal dominiant
decreased urinary ca excretion
increased serum ca concentration
due to inactivation mutations of the ca sensing receptors in parathyroid glands adn parallele recptors in the thick AL of kidney
defective renal receptors => high serum ca concentration incorrectly sensed as normal so PTH secretion not inhibited as it should be
clinical presentation of primary hyperthyroidism
generalized weakness easy fatigability loss of appetite occasional vomiting higher urine output unusually thirsty lab tests show: hypercalcemia and hypophosphatemia and phosphaturia, elevated PTH
calcitonin
secreted by parafollicular cells of thyroid gland
straight-chain peptide with 32 AA
stimuli for calcitonin release
increased plasma Ca
actions of calcitonin
inhibits osteoclastic bone resorption => decreased plasma ca concentration
doesn’t participate in minute-to-minute regulation
vitamin D versus PTH
PTH maintains plasma ca concentration - actions coordinated to increase ionized ca concentration toward normal
vitamin D - promotes mineralization of new bone - actions coordinate to increase both ca and phosphate concentrations in plasma so they can be used in bone
synthesis of vitamin D
1a: 7-dehydrocholesterol is converted in the skin by UV light to cholecalciferol
1b: cholecalciferol is acquired through dietary intake
2: liver converts cholecalcifero to 25-OH-cholecalciferol - in ER, requires NADPH, O2, Mg2+ but not cytochrome P450
3: bound to an alpha-globulin in plasma
4a: 25-OH-cholecalciferol is converted in kidney to 1,25-(OH)2-cholecalciferol by 1alpha-hydroxylase
4b: 25-OH-cholecalciferol is converted to 24,25-(OH2-cholecalciferol (inactive)
1alpha-hydroxylase
in kidney mitochondria
requires NADPH, O2, Mg, and cytochrome P450
converts 25-OH-cholecalciferol to active form = 1,25-(OH)2-cholecalciferol
activated by:
1: decreased ca
2: increased PTH
3: decreased phosphate
regulation of vitamin D synthesis
can go to step 4a or 4b depending on status of ca in body - when sufficient, 4b
actions of vitamin D on intestine
increases both ca and phosphate absorption
induces synthesis of vitamin-d dependent ca binding protein = calbindin D-28 D
calbindin D-28 K
cytosolic protein in intestine
synthesis stimulated by vitamin D
binds four ca ions
exact role uncertain
mechanism of intestinal ca absorption
1: ca diffuses from the lumen into the cell, down its electrochemical gradient
2: ca is bound to calbindin D-28K
3: ca is pumped across the basolateral membrane by ca atpase
actions of vitamin D in kidney
parallel to actions on intestine
stimulates ca and p reabsorption
(PTH stimulates ca reabsorption but INHIBITS p reabsorption)
actions of vitamin D in bone
acts synergistically with PTH to stimulate osteoclast activity and bone resorption
allows for mineralized old bone to be resorbed to provide more ca and p to ecf so that new bone can be made
rickets
due to vitamin d deficiency in children
not enough ca and p to mineralize bone
growth failure and skeletal deformities
osteomalacia
due to vitamin d deficiency in adults
new bone fails to mineralize, resulting in bending and softening of weight-bearing bones
vitamin d resistance
when kidney unable to produce ative metabolite (1,25…)
can be due to congenital absence of 1alpha-hydroxylase or chronic renal failure
