Exam 2: Regulation of Ca++ and Phosphate Metabolism Flashcards
What is the average of what the total calcium conc. in the blood is?
10 mg/dl
What percentage of blood calcium is bound vs unbound?
40% bound to plasma proteins
60% unbound, therefore ultrafilterable (at kidneys)
Of the 60% of blood calcium that us unbound, what percent is complexed to anions?
10%
- like phosphate, sulfate, citrate
What percentage of calcium in the blood is ionized?
50% (therefore unbound)
= only form of calcium that is biologically active
What is the only form of calcium that is biologically active?*
ionized Calcium (~50% of it in the blood)
What is a decrease in plasma concentrations of calcium (extracellular) called?
hypocalcemia
What will occur with hypocalcemia?
- hyper-reflexia
- spontaneous twitching
- muscle cramps
- tingling
- numbness
(decrease Ca+ extracellular = increase Ca+ intracellular, therefore increase reflexes?)
What do we call twitching of the facial muscles elicited by tapping on the VII cranial nerve? What is this a sign of?
Chvostek sign
nerve hyperexcitability–> therefore indicative of hypocalcemia
What do we call the carpopedal spasm after inflation of a sphygmomanometer (blood pressure cuff)? What is this a sign of?
Trousseau sign
hypocalcemia
What is an increase in plasma calcium concentrations called?
hypercalcemia
What are signs of hypercalcemia?
Neurologic signs:
- hyporeflexia
- lethargy
- coma–> death
Constipation, polyurea, polydispsia
How are changes in calcium concentration correlate with changes in protein concentration?
changes in protein conc. are proportional to changes in Ca++ conc.
Ex: increase protein conc. are ass. with increase in total Ca++
T/F. The changes in protein concentration occur quick and therefore have a parallel change in ionized Ca++.
False–the changes tend to be chronic and develop slowly and therefore do NOT cause a parallel change in ionized Ca++
How are changes in anion concentration associated with plasma Ca++?
changes in anion concs are inversely proportional to changes in ionized Ca++
Describe what happens to plasma calcium in Acidemia (aka Acidosis).
Acidemia –> due to increase in H+ –> which increase H+ binding to albumin–> therefore displacing Ca++ –> and increasing ionized Ca++
(less Ca++ bound to albumin)
Describe what happens to plasma calcium in Alkalemia (aka Alkalosis).
Alkalemia–> due to decrease in H+ –> therefore less H+ binding to albumin –> therefore increase of Ca++ bound to albumin and lowers ionized Ca++
(hypocalcemia)
What is the effect of the acid-base alterations in blood below:
- Acidosis
- Alkalosis
- increase ionized Ca++
2. Decrease ionized Ca++
What three organ systems does overall calcium homeostasis require interaction of?
- bone
- kidney
- intestine
What three hormones does the overall calcium homeostasis require?
- PTH (parathyroid hormone)
- Calcitonin (from thyroid)
- activated Vitamin D
What hormones stimulate bone resorption? What inhibit bone resorption?
stimulate = PTH, Vit D inhibit = calcitonin
What hormone stimulates reabsoprtion in kidneys?
PTH
T/F. We are always secreting and reabsorbing Ca++ in order to raise the levels.
False– it is all done to MAINTAIN the levels
What is the role of the PTH?
to regulate calcium conc. in ECF
What will PTH do if there is a decrease in plasma Ca++?
it will increase PTH from parathyroid glands
What does PTH act on indirectly via vitamin D in order to increase plasma Ca++ back to normal?
bone, kidney, intestine
Where are the parathyroid glands located and how many are there?
4 parathyroid glands located in the neck on the back of the thyroid gland
What type of cells synthesize and secrete PTH?
chief cells in parathyroid gland
A level under what of Ca++ plasma conc. will stimulate PTH secretion? What level will it reach maximum secretion? How fast does the response occur?
< 10 mg/dl
max secretion if plasma Ca++ conc = 7.5 mg/dl
w/in seconds
What does chief cells have that help with regulation of plasma Ca++ conc.?
a Ca++ sensing receptor
What will an increase in Ca++ have on chief cells?
stimulate G protein –> activates phospholipase C –> increase IP3/Ca++
increase in IP3/Ca++ will inhibit PTH secretion
What will a decrease in Ca++ have on chief cells?
stimulate PTH secretion
What will chronic changes in plasma Ca++ conc. do?
alter gene transcription for preproPTH synthesis and growth of parathyroid glands
What will chronic hypocalcemia cause?
secondary hyperparathyroidism
What will chronic hypercalcemia cause?
decrease synthesis and storage of PTH and increase breakdown of stored PTH and release of inactive fragments in blood
What other substance has similar effects as Ca++ does on PTH secretion?*
Magnesium (Mg++), but not as pronounced
What effect will hypomagnesia have on PTH secretion?
will stimulate PTH secretion
EXCEPT– severe hypomagnesia ass. with alcoholism will inhibit PTH synthesis, storage, and secretion
What effect will hypermagnesia have of PTH secretion?
will inhibit PTH secretion
Does PTH have direct or indirect effect on the kidneys? What is the effected mediated by?
direct effect on kidney–> mediated by cAMP
What effect with PTH have on the kidneys at the Renal Proximal Tubule?*
What about the distal convoluted tubules?
proximal–> it will inhibit renal phosphate reabsorption (inhibition of Na+/phosphate cotransport in the proximal convoluted tubule)
distal–> stimulates Ca++ reabsorption
What will PTH effect on the kidneys of inhibition of renal phosphate reabsorption?
results in phosphaturia (increase phosphate in urine)
What PTH did not stimulate the excretion of phosphate in the proximal renal tubules?
if not excreted, phosphate from bone would have complexed with Ca++ in the ECF –> by NOT allowing this to happen, plasma ionized Ca++ in increased
Does PTH have an indirect or direct effect on the intestines? Via what? What will this cause?
indirect effect on intestine via activation of vit. D
increases calcium absorption via vit D
What cells in bone are PTH receptors only located on?
osteoblasts
What are the effects of PTH on bone? (recall, only osteoblasts have PTH receptors)*
initially/briefly –> PTH increases bone formation (direct)
then–> PTH causes an increase in bone resorption (indirect and longer lasting effect on osteoclasts)
If only osteoblasts have PTH receptors, then how does PTH cause a increase in bone resorption?*
osteoblasts release cytokines stimulated an indirect and longer lasting effect on osteoclasts to break down bone
(therefore why osteoblasts are required for PTH to effect its major effect on bone resorption)
What is the net effect of PTH over the long haul on bone?
is bone resorption –> therefore increasing both Ca++ and phosphate to ECF
What will the phosphate released with Ca++ from bone do?
complex with Ca++, therefore limiting the rise in ionized Ca++ –> body overcomes with PTH promoting secretion of phosphate (by inhibiting its reabsorption in the kidneys)
What effect does PTH have on vitamin D?
PTH stimulates renal 1-alpha-hydroxylase, which converts 25-hydroxycholecalciferol —> 1,25- dihydroxycholecalciferol (active form of Vit. D) —> and stimulates intestinal Ca++ absorption
How does PTH act on the intestine indireclty?
via 1,25 dihydroxycholecalciferol (activated form of vit. D.)
What is the activated form of Vitamin D?
1,25 dihydroxycholecalciferol
or called calcitriol
Pathophysiology of PTH can fall into one of what three categories?
- excess PTH
- deficiency of PTH
- target tissue resistance to PTH
What are the 6 pathophysiological of PTH we are discussing?
- Primary Hyperparathyroidism
- Secondary Hyperparathyroidism
- Hypoparathyroidism
- Pseudohypoparathyroidism
- HHM (humoral hypercalcemia or malignancy)
- FHH (familial hypocalciuric hypercalcemia)
What is most commonly caused by a parathyroid adenoma?
Primary Hyperparathyroidism
–secrete excessive amounts of PTH
What causes hypercalcemia and hypophosphatemia?
Primary hyperparathyroidism
What are kidney stones indicative of?
type of hyperparathyroidism
What does Primary Hyperparathyroidism cause?
- hypercalcemia
- hypophosphatemia
- excrete excessive amounts of Ca++, cAMP, phosphate in urine–> commonly form kidney stones as Ca++ precipitates
What phrase should we remember to have us recall what Primary Hyperparathyroidism does?
“stones, bones, groans, moans, thrones, and psychiatric overtones”
What is associated with Primary Hyperparathyroidism for the following:
- stones
- bones
- groans
- moans
- thrones
- psychiatric overtones
- kidney stones
- bone pain as PTH increases breakdown in order to increase Ca++ in blood
- lethargy and fatigue
- constipation (abdominal pain)
- polydipsia and polyuria
- confusion, depression, anxiety, hallucinations, irritability, etc.
What disease occurs when the parathyroid is normal but stimulated to secrete excessive PTH secondary to hypocalcemia?
Secondary Hyperparathyroidism
What can Hypoglycemia be due to that causes Secondary Hyperparathyroidism?
- vit D deficiency (not absorbing Ca++ well in GI tract)
2. chronic renal failure (not reabsorbing Ca++ well)
What disease will have high PTH levels, but low or normal plasma Ca++ levels?*
Secondary Hyperparathyroidism
different from primary hyperparathyroidism!!
What can a relatively common inadvertent consequence of thyroid surgery (Tx of cancer, or Graves’ disease)?
Hypoparathyroidism
Besides Tx or surgery on thyroid, what else can cause hypoparathyroism, but is less common?
autoimmune and congenital causes
When the thyroid is cut out and causes hyoparathyroidism, what are the effects?
- decrease levels of PTH
- hypocalcemia
- hyperphosphatemia
How is hypoparathyroidism treated?
with oral Ca++ or active Vit. D
What will a defective Gs protein for PTH in kidney and bone cause? Why?
Pseudohypoparathyroidism
when PTH binds to recpetor it doesn’t activate adenylyl cyclase
In Pseudohypoparathyroidsm what happens to PTH levels? How is this different that Hypoparathyroidism?**
PTH levels increase
in hypoparathyroidism PTH levels are decreased
What are the effects of Pseudohypoparaythroidism?
- hypocalcemia
- hyperphosphatemia
- short stature, short neck, obesity, subcutaneous calcificaiton, shortened 4th metacarpals/metatarsals
aka Alright’s Hereditary osteodystrophy
What disease is when some malignatn tumors (i.e. lungs and breast) secrete a peptide that is SIMILAR in structure and function to PTH?
Humoral Hypercalcemia of Malignancy (HHM)
What has similar findings to primary hyperparathyroidism. except PTH is low b/c it is suppressed by hypercalcemia?*
Humoral Hypercalcemia of Malignancy (HHM)
What are the effects of Humoral Hypercalcemia of Malignancy?
- hypercalcemia
- hypophosphatemia
- low PTH levels
What drugs are used to treat Humoral Hypercalcemia of Malignancy?
- furosemide –> inhibits renal Ca++ reabsorption
- etidronate–> inhibits bone resorption
What is an autosomal dominate disorder characterized by decrease urinary Ca++ excretion and increase in plasma Ca++ conc.?
Familial Hypocalciuric Hypercalcemia (FHH)
How are the PTH levels in someone with Familial Hypocalciuric Hypercalcemia (FHH)? Why?
PTH levels are high b/c it is not inhibited as it should be due to:
- mutation of Ca++ sensing receptors in both parathyroid glands and kidney
- therefore high plasma Ca++ levels are sensed as “normal” and reabsorption is not decreased–> leading to of high plasma Ca++ conc.
What is synthesized by parafollicular (C cells) of the thyroid gland and is stored in secretory granules until released?
Calcitonin
What are the two precursors to calcitonin?
Preprocalcitonin –> procalcitonin –> calcitonin
What will stimulate calcitonin secretion?*
increase in plasma Ca++ conc.
What will Calcitonin inhibit?
osteoclasts bone resorption and therefore decrease plasma Ca++ conc.
T/F. Neither thyroidectomy nor thyroid tumors cause a derangement of Ca++ metabolism.
True
don’t really understand, but it was a statement on a slide under calcitonin haha
What is second to PTH as a major regulatory hormones for Ca++? What does it promote?
Vitamin D; promotes mineralization of new bone
What do the actions of Vitamin D coordinate?
to increase both plasma Ca++ conc, and phosphate conc.–> so that these elements can be deposited in new bone mineral
How can we get out Vitamin D?
from the UV light via the skin or from our diet
What enzyme will decreased Ca++ conc, and phosphate conc, and increase PTH stimulate?
1alpha-hydroxylase
to make 25-OH-cholecalciferol —–to–> 1,25-dihyroxycolecalciferol (active form)
What effect does Vitamin D have on the intestine?
(major site of action)
- increases both Ca++ and phosphate absorption
- induces synthesis of calbindin D-28 K (vit D dependent calcium binding protein)
What effect does Vitamin D have on the kidney?
- increase both Ca++ and phosphate absorption
recall: PTH increase Ca++ but decreases phosphate absorption
What effect does Vitamin D have on bone?
- acts synergistically with PTH to stimulate osteoclast activity and bone resorption
(mineralized “old” bone is resorbed to provide more Ca++ and phosphate to ECF so that “new” bone can be mineralized)
What are two pathophysiologies of vitamine D?
- Rickets
2. Osteomalacia
What pathology occurs in children with a vitamin D deficiency? What occurs?
Rickets
- insufficient amounts of Ca++ and phosphate are available to mineralize growing bones
- growth failure, skeletal deformities (bowed legs)
What pathology occurs in adults with vit. D deficiency? What occurs?
Osteomalacia
- new bone fails to mineralize–> softening of weight bearing bones
- bone pain
What amount of Vit. D is required for optimal health?
When do we want to measure in the blood to get the amount of vitamin D present?*
30-40 ng/ml
**always measure 25 hydroxycholecalciferol, NOT 1,25 dihydroxycholecalciferol)
What else has a deficiency in vitamin D been associated with besides adverse effects on bone?
- Cardiovascular disease
- cancer
- infection
- MS
- childhood asthma
T/F. only certain cells in the bod express vitamin D receptors.
False– virtually every cell in the body expresses vitamin D receptors
What are 6 functions of Vitamin D?
- Directly or indirectly controls over 200 genes
- decreases cellular proliferation of both normal and cancer cells
- potent immunomodulator*
- control inflammation
- muscle strength (vit. D. def. causes ms weakness)
- blood pressure
How is Vitamin D a potent immunomodulator?
in response to TB or LPS, macrophages up-regulate genes which increases production of active Vit. D –> results in increased production of CATHELICIDIN*, which is capable of destorying TB organ and other inf. agents
What is a powerful antimicrobial peptide that activated vitamin D will increase the production of?*
cathelicidin
How does vitamin D function in blood pressure regulation?
inhibits renin secretion by the kidney
What is characterized by a decrease production of 1,25-dihydroxycholecalciferol (active Vit. D)?
Chronic Renal Failure (b/c cannot put -OH on 1 position to make 1-25 dihydroxycholecalciferol)
What will Chronic Renal Failure cause PTH levels to do?
increase PTH levels (this is a secondary response)
What effects does Chronic Renal Failure have?
- increase PTH
- increase one resportion of C++ due to increase PTH
- decrease urine phosphate due to decrease glomerular filtration, therefore increasing plasma phosphate
- decrease plasma Ca++ due to deficiency of Vit. D
- osteomalacia
What is declining with Renal Failure?*
GFR (glomerular filtration rate)
how they “test” and see what stage you are at
