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Endocrine Week 1 > ICL 6.1: Hormones and Disorders of Calcium and Phosphate > Flashcards

ICL 6.1: Hormones and Disorders of Calcium and Phosphate Flashcards

1
Q

what physiologic roles does calcium play?

A
  1. bone mineral
  2. blood coagulation
  3. membrane excitability
  4. neuron activation
  5. hormone secretion
  6. cell division
  7. enzyme activity
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2
Q

what physiologic roles does phosphate play?

A
  1. bone mineral
  2. acid-base buffering
  3. structural role; phospholipids in cell membranes
  4. cell signaling; kinases add phosphates
  5. high energy bonds
  6. enzyme activity regulation
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3
Q

where is most phosphate and calcium found in the body?

A

bones

99% of calcium and 85% of phosphate is in the bones

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4
Q

how much of calcium and phosphate is in the blood?

A

.1% of calcium is in the blood and of that 50% is free ionzed while the rest is bound to globulin, complexed with anions or bound to albumin

of the phosphate in the blood, 10% is protein bound while 35% is complexed with cations and 55% is free

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5
Q

what 3 hormones regulate calcium and phosphate metabolism?

A
  1. PTH
  2. 1,25 vitamin D
  3. FGF23

calcitonin has an unclear role in humans

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6
Q

what is the effect of PTH on calcium and phosphate?

A

increases calcium and decreases serum phosphate

induces renal phosphate wasting

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7
Q

what is the effect of 1,25 vitamin D on calcium and phosphate?

A

increases both serum calcium and phosphate

increases absorption of both from the intestines

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8
Q

what is the effect of FGF23 on calcium and phosphate?

A

decreases serum phosphate

no effect on calcium serum concentration

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9
Q

what is the function of PTH?

A

PTH is the peptide hormone that controls the minute-to-minute level of ionized calcium in ECF

PTH binds to cell surface receptors in bone and kidney, thereby triggering response that increase blood calcium

PTH also increases renal synthesis of 1,25(OH)2D3 which then acts on the intestine to augment absorption of dietary calcium

the resulting increase in blood calcium (and in 1,25(OH)2D3) feeds back on the parathyroid glands to decrease the secretion of PTH

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10
Q

what is the PTH-calcium feedback loop that controls calcium homeostasis?

A

if the parathyroid gland senses low serum Ca+2 then the parathyroid will secrete PTH

PTH:

  1. increasing bone resorption
  2. causes the DCT in the kidney to increase Ca reabsorption and increase phosphate excretion
  3. activates 1-alpha-hydroxylase in the kidney to form active 1,25 vitamin D which increases Ca absorption in the intestines

this increased Ca serum will ten negatively feedback to the parathyroid to decrease PTH secretion

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11
Q

what is the relationship between PTH secretion and plasma calcium concentration?

A

the parathyroid gland is poised to respond to a fall of calcium much more readily than to a rise in calcium!

you body can tolerate hypercalcemium to a certain degree but it can’t handle hypokalemia very well; it effects conduction and heart conductions which can lead to arrhythmias and respiratory failure

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12
Q

where does the parathyroid galdn develop from?

A

3rd pharyngeal pouches: thymus and inferior parathyroid glands

4th pharyngeal pouches: superior parathyroid glands

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13
Q

what is the function of the parathyroid chief cells?

A
  1. rapidly secrete PTH in response to changes in blood calcium
  2. synthesize, process, and store large amounts of PTH
  3. replicate when chronically stimulated by hypocalcemia
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14
Q

what are the calcium sensing receptors? what happens when

A

CaSR a member of the G protein–coupled family of receptors

  1. inactivating mutations cause familial hypocalciuric hypercalcemia (FHH)
  2. activating mutations cause familial hypoparathyroidism with hypercalciuria
  3. calcimimetic compounds inhibit PTH secretion

so if CaSR is activated it will suppress PTH secretion because Ca is binding appropriately but if it’s inhibited then it will secrete lots of PTH since calcium can’t bind to it and it will think there’s low calcium

the CaSR is expressed widely in renal tubules, small intestine, thyroid C-cell, osteoblasts, brain, oviduct etc. which points to multiple roles of calcium signaling

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15
Q

what is the signaling pathway of the calcium-sensing receptor?

A

it’s a G-protein coupled receptor

when calcium binds through Gq pathway, it activates PLC which then induces IP3

IP3 then goes to the IP3 receptor on the ER of the chief cells and calcium is released from the ER

the increased Ca intracellularly is going to be sensed by the parathyroid chief cells which will decrease PTH secretion

on the other hand, if calcium doesn’t bind to he chief cells then Ca stays in the ER of the chief cells and intracellular Ca levels decrease and PTH secretion is decreased

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16
Q

how does PTH effect the kidney?

A
  1. stimulation of calcium reabsorption inthe distal nephron
  2. inhibition of phosphate transport in both proximal and distal tubules
  3. stimulation of the synthesis of 1,25(OH)2D in the proximal tubule
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17
Q

how does PTH effect the bone?

A
  1. increases bone formation

2. increases bone resorption

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18
Q

what part of the kidney is regulated by PTH?

A

DCT

PTH receptors are in the DCT and can regulate Ca reabsorption via TRPV5 protein receptor

Ca is reabsorbed in the PCT and TAC but it’s not PTH regulated

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19
Q

what pathway results in increased Ca when PTH binds to the bone?

A

when PTH binds to osteoblasts, it increases RANKL and M-CSF

RANKL and M-CSF stimulates formation of osteoclast formation and they then breakdown bone to release Ca and phosphate into the ECF

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20
Q

how is active vitamin D synthesized?

A

vitamin D comes from food or the

first activation happens in the liver and becomes 25(OH)D and then in the kidney it’s activated again into 1,25(OH)D aka calcitriol which is active vitamin D

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21
Q

what are the actions of vitamin D?

A

D receptor is a nuclear receptor that regulates transcription and when vitamin D binds to it:

  1. increase intestinal calcium and phosphate absorption
  2. regulate gene transcription and cell proliferation in the parathyroids
  3. increases osteoclastic bone resorption in high doses
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22
Q

which 3 hormones effect phosphate metabolism?

A
  1. cacitriol aka active vitamin D helps with phosphate absorption in the GI tract
  2. PTH releases phosphate from the bone and increases renal excretion of phosphate
  3. FGF23 increases phosphate excretion in the kidney
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23
Q

which segment plays a major role in the phosphate reabsorption in the kidney?

A

PCT 65%

loop of hence 15%

DCT 5%

24
Q

how is phosphate absorbed in the GI tract?

A

2Na/HPO4 symporter brings in sodium and phosphate into the intestines under the control of 1,25(OH)D

25
Q

how is phosphate excreted in the kidney?

A

under the control of PTH and FGF23, phosphate reabsorption is inhibited by inhibiting the Na/HPO4 symporter

26
Q

where is FGF23 produced?

A

osteocytes and osteoblasts

it down regulates Na/HPO4 cotransporter in the PCT which results in renal phosphate wasting

27
Q

what are PTH and calcium levels in secondary hyperparathyroidism?

A

PTH levels are high but calcium levels are low

this could be due to a vitamin D deficiency, Celiac’s or CKD where something else could be causing the low Ca despite appropriate PTH levels

28
Q

what are PTH and calcium levels in PTH-independent hypercalcemia?

A

high calcium despite low PTH levels

could be due to hypercalcemia of malignancy

29
Q

what are the causes of PTH-dependent hypercalcemia?

A
  1. primary hyperparathyroidism
  2. tertiary hyperparthyroidism; usually due to ESRD when patients are exposed to chronic hypocalcemia resulting in parathyroid hyperplasia and disregulation
  3. familial hypocalciuric hypercalcemia(FHH) due to inactivated calcium sensing receptor which leads to constant PTH release and subsequent hypercalcemia
  4. lithium associated hypercalcemia
  5. antagonistic autoantibodies to the CaSR
30
Q

what are the causes of PTH-independent hypercalcemia?

A
  1. noplasms: PTHrP/Other humoral syndromes/Local osteolytic disease (including metastases)
  2. PTHrP excess (non-neoplastic)
  3. excess vitamin D action: vitamin D toxicity/Granulomatous disease/Williams syndrome
  4. thyrotoxicosis
  5. adrenal insufficiency
  6. renal failure: ARF/ CRF with aplastic bone disease
  7. immobilization
  8. drugs: vitamin A intoxication/ Milk-alkali syndrome/Thiazide diuretics/Theophylline
31
Q

why is it important to distinguish primary hyperparathyroidism and familial hypocalciuric hypercalcemia?

A

treatment is totally different!

with PHPT, a parathyroidectomy may be needed since the primary abnormality is the parathyroid inappropriately secreting PTH resulting in excessive renal Ca reabsorption, phosphaturia, bone resorption and 1,25(OH) synthesis

with FHH the mutation CaSR is inactivated so it can’t sense calcium levels and releases PTH since it thinks there’s low Ca – patients will be hypercalcemic at birth and a parathyroidectomy is CONTRAINDICATED!! Ca is slightly high but it’s not going to cause damage, most people are symptom free

32
Q

how do you distinguish primary hyperparathyroidism and familial hypocalciuric hypercalcemia?

A

measure 24 hr creatinine clearance

PHPT constantly stimulates the kidney to reabsorb Ca and eventually overwhelmed the kidney leading to hypercalciuria

FHH has mild Ca elevation and PTH will stimulate kidney to increase Ca reabsorption and patient has hypocalciuria

so if there’s more than 0.2 calcium in the urine then it’s probably PHTP and if it’s less than 0.01 then it’s probably FHH

33
Q

what is the clinical presentation of primary hyperparatyroidism?

A
  1. decreased bone mineral density; osteoporosis related fractures
  2. nephrolithiasis
  3. nephrocalcinosis

nonclassic symptoms too

34
Q

how do you monitor asymptomatic PHTP who do not undergo surgery?

A

monitor serum calcium annually

every 1-2 year, take x-rays of the spine

GFR and creatinine annually

35
Q

what causes hypercalcemia in granulomatous disease?

A

in diseases like TB or sarcoidosis, there is production of extra-renal 1-alpha-hydroxylase by macropahges in the granulomas

this can increase the conversion of circulating 25(OH)D3 to 1,25(OH)D3

when it’s really high, it results in really high Ca absorption in the GI tract and bone resorption which bone increase Ca serum levels

this can cause hypercalciuria since the kidney will be overcome by the elevated

36
Q

how do you evaluate the cause of PTH-indepedent hypercalcemia?

A

so if there’s low PTH but high calcium when the PTHrP

if it’s elevated then check for malignancies like neuroendocrine tumors that could be secreting PTHrP

if PTHrP is normal then test 1,25(OH)D levels – if they’re elevated then look for lymphomas or granulomas

if they’re normal then check 25(OH)D levels and if it’s increased then evaluate for vitamin D intoxication but if it’s normal then evaluate for multiply myeloma or other stuff

37
Q

what are the clinical features of severe hypercalcemia?

A
  1. fatigue, weakness, lethargy, confusion, coma
  2. anorexia, nausea, abdominal pain, constipation
  3. polyuria, nocturne, polydipsia
38
Q

how do you manage severe hypercalcemia?

A
  1. volume repletion to help kidney remove Ca
  2. inhibition of bone resorption
  3. calciuresis: loop diuretics only after volume repletion
  4. glucocorticoids for vitamin D-dependent hypercalcemia
  5. dialysis if renal failure
39
Q

what are the clinical features of hypocalcemia?

A
  1. neuromuscular irritability like Trousseau’s sign, paresthesias, seizures, muscle cramps
  2. neurological signs and symptoms
  3. prolonged QT intervals, CHD, cardiomyopathy y
  4. dysphagia, abdominal pain, dyspnea, wheezing
  5. subcapsular cataracts
40
Q

what are the causes of hypocalcemia?

A
  1. congenital hypoparathyroidism like in DiGeroge syndrome
  2. post surgical hypoparathyroidism
  3. vitamin D deficiency
  4. hypomagnesemia (Mg helps with PTH secretion)
  5. impaired 1-alpha-hydroxylation in renal failure
  6. other
41
Q

what genetic conditions can cause hypoparathyroidism?

A
  1. AD CaSR activation mutation
  2. DigGeorge syndrome
  3. autoimmune polyendocrine syndrome type 1 which produces antibodies against the parathyroid
  4. parathyroid resistance syndrome – pTH secretion is fine but there’s receptor resistance
42
Q

what is pseudohypoparathyroidism?

A

PHP labs include:
1. low Ca and high PO4

  1. high PTH
  2. low 1,25(OH)D
43
Q

what is albright hereditary osteodystrophy?

A
  1. rough facies
  2. low nasal bridge
  3. short neck
  4. short stature
  5. malocclusion of teeth/crwoded teeth
  6. obesity
  7. developmental delay
  8. subcutaneous calcifications
  9. short 4th and 5th digits and metacarapals/metaatarsals
44
Q

what is the acute treatment of severe hypocalcmiea?

A

If symptoms of neuromuscular irritability are present and carpopedal spasm is elicited on PE, intravenous calcium gluconate is indicated

the goal is to raise the serum ionized calcium into the low normal range, maintain it there and control the patient’s symptoms.

note: the calcium-phosphate product should not exceed 55 or else soft tissue calcium phosphate deposition

45
Q

what is the long term treatment of severe hypocalcmiea?

A

the overall goal of therapy is to maintain serum calcium in the low normal range, especially in patients with hypoparathyroidism

  1. oral calcium carbonate TID or QID with food
  2. vit D2/D3
  3. calcitriol (1,25-(OH)2 Vit D)
  4. thiazide diuretics: increase calcium reabsorption in hypoparathyroidism
  5. recombinant human PTH(1-84) subcutaneous injection for hypoparathyrodiism
46
Q

what are the causes of hyperphosphatemia?

A
  1. renal insufficiency!!!!
47
Q

what are the therapeutic options for hyperphosphatemia?

A
  1. volume expansion to help improve GFR in acute ysndrome
  2. removal of any exogenous sources of phosphate
  3. hemodialysis is the most effective approach
48
Q

what is x-linked hypophophatemic rickets?

A

x-linked dominant

patients present with ickets, osteomalacia, short stature, poor linear growth often despite adequate Tx, and frequent dental abscesses, enthesopathy (calcification of tendons and ligaments)

it’s due to inactivating mutations in PHEX which increases FGF23 levels resulting in
decreased phosphate reabsorption and 1,25(OH)2D

49
Q

what happens to phosphate levels after renal traplsnt?

A

hypophosphatemia after renal transplant

during ESRD there’s excess FGF23 and after the transplant this elevated FGF23 that acts on the kidney and can cause hypophosphatemia

but this excess GFG23 production gradually resolves over time

50
Q

what non-FGF23 mediated renal conditions can cause hypocalcemia?

A
  1. hereditary hypophosphatemic rickets with hypercelciuria

mutation in Na/P transporter in the PCT which reuslts in phosphate wsating

bu’t there’s increase in 1,25(OH) dehydroxylase activity in the PCT so GI absorption of calcium and phosphate so they’re maintained

  1. Fanconi
51
Q

what are the non-renal causes of hypophosphatemia?

A
  1. impaired phosphate intake or GI absorption
  2. referring syndrome
  3. DKA
  4. respiratory alkalosis
  5. drugs/toxins
52
Q

what are the lab is the most important when evaluating the cause of hypophosphatemia?

A

measure TmP/GFR: ratios of the maximum rate of tubular phosphate reabsorption to the GFR – this tells you if the phosphate wasting is due to renal or non-renal origin

53
Q

how do you treat fanconi syndrome?

A

replace Ca and phosphate

54
Q

how do you treat hereditary hypophosphatemic rickets with hypercelciuria?

A

treat HHRH with phosphate but no calcitriol

55
Q

how do you treat FGF-mediated disorders?

A

phosphate and calcitriol

56
Q

what are the 2 main cause of hypercalcemia?

A
  1. primary hyperparathyroidism

2. malignano hypercalcemia

Endocrine Week 1 (11 decks)

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