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Endo/Repro Exam 1 > 8. Regulation of Calcium and Phosphate Metabolism > Flashcards

8. Regulation of Calcium and Phosphate Metabolism Flashcards

1
Q

Calcium homeostasis is TIGHTLY regulated. Calcium is stored in __________.

A

Bones

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2
Q

The concentration of Ca2+ outside of the cell has a big effect on what?

A

the excitability of cells.

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3
Q

How does Ca2+ homeostasis change as we age?

A
  • As we age, there is a decrease in the amount of Ca2+ absorbed from dietary intake and in dietary intake.
  • Existing bone cells are reabsorbed faster than our body can make them. Thus, as we age, we are more likely to develop osteopenia or osteoporosis.
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4
Q

Calcium is stored mostly in _________. The majority of total Ca2+ in the body is what type?

A
  • Bone and teeth (99%).
  • Free, ionized Ca2+ (which is the biological active form)
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5
Q

What are our blood Ca2+ levels as we age?

A

For the most part, there is little deviation of Ca2+ levels as we age.

We stay in between 9-10 mg/dL.

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6
Q

What is hypocalcemia and what are the symptoms?

A

Hypocalcemia is a decrease in the plasma Ca2+ concentration.

Sx: hyperreflexia, twitching, tingling and numbness.

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7
Q

What signs can we use during a physican exam to tell us our patient may have hypocalcemia?

A
  • Chvostek sign- tap on facial nerve causes face muscles to twitch.
  • Trousseau sign- inflate BP cuff causes carpopedal spasm
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8
Q

What is hypercalcemia and what are assx symptoms?

A

Hypercalcemia is an increase in Ca2+ concentration.

Symptoms: decreased QT interval, constipation, polyuria, polydipsia, lack of appeptide, muscle weakness, lethargy, hyporeflexia.

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9
Q

How exactly does hypocalcemia cause twitching, numbness, tingling, tetany?

A

Plasma Ca2+ influences membrane excitability!

Hypocalcemia -> reduces the activation threshold for Na+ channels -> increase membrane excitability (spontaneous AP) -> easier to elicit an AP.

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10
Q

How exactly does hypercalciuma depress our NS and reflex responses?

A

Plasma Ca2+ concentration influences membrane excitability!

Hypercalcemia -> high extracellular Ca2+ -> decrease membrane excitability.

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11
Q

What 3 ways can we alter forms of Ca2+ in the plasma.

A
  • 1. Change the plasma protein concentration
  • 2. Changes in anion concentration
  • 3. Acid base abnormalities.

These will only be significant if they. alter ionized Ca2+ concentration becuse it is biologically actibve.

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12
Q

The forms of Ca2+ in the plasma can be changed by

  1. Change the plasma protein concentration
  2. Changes in anion concentration
  3. Acid base abnormalities.

Describe.

A
    1. Increase in plasma protein concentration -> increase total Ca2+ concentration.
      * Decrease in plasma protein concentration -> decrease total Ca2+ concentration.
      * The amount of ionized Ca2+ will NOT change: GOOD!
    1. Changes in anion concentration are going to change the fraction of Ca2+ complexed with anions. For example. if plasma phosphate concentration increases, the fraction of Ca2+ that. is complexed incerases-> decrease the ionized Ca2+.
    1. Acid base abnormalities change the ionized concentration by changing the fraction of Ca2+ bound to albumin.
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13
Q

How will acidemia and alkalemia affect our concentration of ionized Ca2+?

A

Ca2+ will compete with H+ for binding onto albumin.

  • In cases of acidemia-> H+ preferentially binds to albumin -> increase in free ionized Ca2+ concentration because less is bound to albumin (hypercalcinemia)
  • In cases of alkelemia-> not alot of H+ so Ca2+ will bind to albumin and we will have decreased free ionized Ca2+ (hypocalcemia)
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14
Q

Calcium homeostasis is VERY controlled. In involves the action of what organs and hormones?

A
  • Bone, intestines and kidneys.
  • Calcitonin, PTH and vitamin D.
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15
Q

Our overall goal is to maintain a homeostasis of ECF Ca2+ of ________.

A

10 mg/dL of Ca2+.

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16
Q

Ca2+ homeostasis in intestines and kidneys.

A

Net absorption of Ca2+ from the GI tract.

  • If a person ingests 1000mg. of Ca2+ a day, Vitamin D absorbs 350 mg of Ca2+ from the intestines -> ECF via 1,25 Vit D.
  • 150 mg is then secreted back. Net absorption is 200mg and 800 are excreted in the feces.
  • To maintain Ca2+ balance, the kidneys must excrete the SAME amount of Ca2+ that is absorbed by the intestines (200mg)
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17
Q

Is there a net gain or loss of Ca2+ from bone?

A

Due to bone remodeling, there is not a net gain or a net loss of Ca2+.

New bone is deposited and old bone is resorbed (d/t PTH and Vitamin D).

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18
Q

What stimulates bone resorption and what inhibits bone resorption?

A

Stimulated by: PTH & Vitamin D (1, 25-dihydroxycholecalciferol)

Inhibited by: Calcitonin

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19
Q

How is extracellular Pi** related to **Ca2+ levels?

A

Pi is inversely related to Ca2+

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20
Q

What regulates extracellular concentration of Pi?

A

the same hormones that regulate Ca2+ concentration.

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21
Q

Normal range of extracellular Pi is _____.

A

2.5-4.5 mg/dL

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22
Q

Where is Pi located?

A

85% of it is located in the bone.

1% is in the plasma and 84% is ionized.

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23
Q

What makes PTH?

A

Chief cells of the parathyroid gland.

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24
Q

Describe what PTH looks like and how it is made.

A

PTH is a peptide hormone that is 84 AA. However, the first 34 have the biological activity.

  1. It is made on ribosomes as preproPTH
  2. Cleaved to form proPTH
  3. Goes to golgi where it is further cleaved to PTH and packaged into secretory. vesicles.
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25
Q

PTH regulates the concentration of what in the plasma?

A
  1. Ca2+
  2. Pi
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26
Q

PTH secretion is regulated by plasma Ca2+ levels.

  • total plasma Ca2+ concentration is normal or higher: _____ PTH
  • total plasma Ca2+ concentration is low (below 10 mg/dL): ____ PTH
A
  • low
  • high
  • Know that it is the ionized Ca2+ concentration that regulates secretion.
  • Response is fast and the faster the ionized Ca2+ falls, the greater the PTH secretory response!
27
Q

Discuss how a chief cell of the PTH gland knows how to secrete PTH.

A
  1. PTH cell will have CaSR (Ca2+ sensing receptor), that are linked bia Gq and Gi pathways.
  2. When Ca2+ levels are high, extracellular Ca2+ binds to the receptor and activates both pathways
  3. Inhibits PTH secretion.

When extracellular Ca2+ is decreased, there is decreaesd Ca2+ binding to the receptor, which causes PTH secretion.

28
Q

How does 1,25 vitamin D affect the Chief cell?

A

Inhibits PTH secretion (via a neg feedback system bc PTH is needed to + vitD)

and promotes the expression of CaSR.

29
Q

What can we see in a patient with chronic hypercalcemia?

A
  • Decrease synthesis and storage of PTH.
  • Increase breakdown of stored PTH.
  • Release of inactive PTH into the circulation
30
Q

What can we see in a patient with chronic hypocalcemia?

A

Causes secondary hyperparathyroidism, which is characterized by:

  1. Increase synthesis and storage of PTH
  2. Hyperplasia of the parathyroid glands.
31
Q

What affects does Magnesium have on PTH secretion?

A
  • Hypomagnesia -> + PTH secretion
  • Hypermagnesia -> - PTH secretion.

However, when one has severe hypomagnesia d/t chronic Mg2+ depletion (alcoholism), it will i_nhibit PTH synthesis, storage and secretion by the parathyroid glands._

32
Q

What is the MOA of PTH on bone and kidney?

A

PTH binds to receptor, which is coupled with a Gs protein to AC.

AC: ATP -> cAMP.

33
Q

What is everything that happens when we have low plasma Ca2+ levels?

A
34
Q

What is the purpose of vitamin D?

A
  • Vit. D will increase Ca2+ and Pi plasma concentrations-> promote mineralization of new bone.
  • Vit. D has actions in the intestine, kidney and bone.
35
Q

The roles of PTH and vitamin D can be distinguished as follows:

The role of PTH is to maintain the plasma Ca2+ concentration, and its actions are coordinated to increase the ionized Ca2+ concentration toward normal.

The role of vitamin D is to promote mineralization of new bone, and its actions are coordinated to do what?

A
  • _increase both Ca2+ and Pi concentrations i_n plasma so these elements can be deposited in new bone.
36
Q

Vitamin D as cholecalciferol is a what?

A
  • a prohormone, thus, physiologically inactive, that we get from our diet and made in the skin d/t UV light.
  • It must be hydroxylated to an active metabolite, which is regulated by - feedback.
37
Q

How do we activate Choleciferol?

A
  • In the liver, 25-hydroxylase will activate it and form 25-OH-cholecalciferol, which is the main circulating form but has VERY low activity.
  • In the kidney, it can undergo two routes of hydroxylation
    • ​1. In the renal proximal tubule, 1-alpha-hydroxylase (aka CYP1alpha) can make it become 1,25 OH2-cholecalciferol, our active steriod hormone.
      1. 24-hydroxylase will make it into our 24,25 (OH)-cholecalciferol inactivte protein.
38
Q

What are stimuli for the formation of active vitamin D?

A
  1. low Ca2+
  2. Low Pi
  3. High PTH
39
Q

The overall goal of vitamin D is to increase the plasma concentration of both Ca2+ and phosphate and to increase the Ca2+ X Pi product to promote mineralization of new bone.

Kidney 1-alpha-hydroxylase is TIGHTLY regulated. Describe how PTH, high Ca2+ levels 1,25 Vit D and 25 Vit D affect it.

A
  1. PTH will increase synthesis of 1-alpha-hydroxylase (CYP-1) via Gs pathway.
  2. High levels of Ca2+ will inhibit synthesis of CYP-1 via Gq/Gi pathway.
  3. High 1,25 Vit. D will inhibit synthesis of CYP 1 activate synthesis of 24-hydroxlase.
40
Q

Where are PTH receptors located on the bone?

A

OsteoBLASTS

41
Q

PTH has two types of action on the bone. What. are they?

A
  • Short-term action of PTH is to lead to the formation of bone by action on osteoblast. This is why we give PTH to those with osteoporosis.
  • Long-term action is to increase bone resorption by indirect action of osteblasts releasing cytokines -> osteoclasts.

THUS: bone forming cells, osteoblasts are required for the bone-resorbing action of PTH on osteoclasts. Overall effect is to promote bone resorption, increasing Ca2+ and P.

*

42
Q

Vitamin D works synergistically with PTH to do what?

A

+ osteoclasts -> + bone resorption.

we need both to
+RANKL

43
Q

Describe the synergestic effects of PTH and Vit D on b_one formation and absorption_

A
  • M-CSF (macrophage colony stimulating factor): causes stem cells -> osteoclast precursors, mononuclear osteoclasts and mature multinucleated osteoclasts
  • RANKL (receptor activator for NF-kB L)- primary. mediator for osteoclast formation
  • RANK Receptor- cell-surface receptor on osteoclasts and osteoclast precursors.
  • OPG (osteoprotegerin): soluble protein made by osteoblasts that stops bone resorption by competing with RANKL for binding on RANK.
44
Q

What are the SPECIFIC actions of PTH and Vit D. on bone formation and absorption?

A
  • PTH: + RANKL and - OPG
  • Vitamin D: + RANKL
45
Q

What is the MOA for PTH on the kidney?

A
    1. PTH binds to GCPR with a Gs protein on BL membrane of proximal tubule cell.
    1. AC: ATP -> cAMP (which is excreted in urine as urinary cAMP)
      • PKA
    1. Phosphorylation of proteins
    1. Inhibit Na+/Phosphate co-transporter (NPT) on the apical lumen.

–> Decreased phospate reabsorption and phosphaturia (increase excretion of Pi)

In the distal convulted tubule:

  • PTH complements the _increase in plasma [Ca2+] t_hat resulted from the combo of bone resorption and phosphaturia.
46
Q

What do PTH and Vitamin D do on the kidneys?

A
    1. PTH: decrease phosphate reabsoprtion and cause phosphateuria (increase Pi in urine) and increase Ca2+ reabsorption
    1. Vit D: stimulate Ca2+ and P reabsorption
47
Q

What are the MOA of Vitamin D (a steroid hormone) on the absorption of Ca2+ in the intestines?

A

Vitamin D will increase Ca2+ and Pi absorption by

  • Increasing calbindin, which shuttles Ca2+ from apical side of cell -> BL.
  • Increasing Na+/Ca2+ transporter
  • Increasing H+/Ca2+ ATPase transporter
48
Q

Whenever we have low blood Ca2+, PTH is secreted.

PTH has rapid responses and slower responses, that could take hrs-days. What are they?

A
  1. Rapid reponses:
  • Increase CYP1alpha
  • Increase bone turnover
  • Increase Ca2+ reabsorption and Pi excretion by kidneys.
  1. Slower responses:
    * Increase 1,25 (OH) Vit D, which increases dietary Ca2+ absorption by the SI.
49
Q

What are the actions of Calcitonin?

A
  • Primary axn: kidney and bone.
  • Released when we have HIGH plasma Ca2+.
  • Inhibits bone resorption by binding to receptors on the osteoclasts -> decrease number and activity of osteoclasts -> decrease plasma levels of Ca2+ and Pi.
50
Q

Calcitonin does/does not help to regulate our plasma Ca2+ levels minute-by-minute.

Thus, what happens if we have a thyroidectomy a thyroid tumor?

A

DOES NOT.

Thyroidectomy: decrease calcitonin but NO effect on Ca2+ metabolism

Thyroid tumor: increase calcitonin but NO effect on Ca2+ metabolism.

51
Q

What is primary hyperparathyroidism?

____ PTH

____ Ca2+

____ Pi

____ Vit. D

A

High PTH

High Ca2+ (hypercalcemia), d/t high filtered load.

Low Pi (hypophosphatemia)

High Vit. D

Parathyroid adenmoa that secretes alot. of PTH, cAMP and Ca2+. Sx are stones, bones and groans.

  • Hypercalcenemia leads to hypercalcuria stones.
  • Increased bone absorption
  • Constipation (groans)

Tx: parathyroidectomy.

52
Q

What is secondary hyperparathyroidism?

____ PTH

____ Ca2+

____ Pi

____ Vit. D

A
  • Disorder IN parathyroid gland that leads to excessive secretion of PTH, secondary to hypocalcemia (low Ca2+ in blood) which is caused by vit D def or chronic renal failure.

If Vit D deficiency

high PTH

low Ca2+

low Pi (bc kidney is normal)

low Vit. D

If Chronic renal failure

high PTH

low Ca2+

high Pi (kidney is not working; cant excrete)

low Vit. D

53
Q

What causes hypoparathyroidism?

A

thyroid/parathyroid surgery, autoimmune or congenital

54
Q

What is hypoparathyroidism?

____ PTH

____ Ca2+

____ Pi

____ Vit. D

Sx:

Tx:

A

low PTH

low Ca2+ (hypocalcemia)

high Pi (hyperphosphatemia)

low Vit. D

Sx: Sx are mostly d/t hypocalemia: muscle spasms, numbness, tingling around mouth and fingers, seizures. In kids; poor teetch development and mental

Tx: oral Ca2+ and active form of Vit D

55
Q

Pseudohypoparathyroidism (Albright hereditary osteodystrophy)

____ PTH

____ Ca2+

____ Pi

____ Vit. D

If we give a pt exegenous PTH, will it work?

A

High PTH

Low Ca2+ (hypocalcemia)

High Pi (hyperphosphatemia)

Low Vit. D

  • We have low Ca2+ levels, so we need PTH, however PTH does not exert its effects bc there is a mutation in Gs Gprotein on the PTHR in the bone and kidney. Thus, AC does not activate and AC -> cAMP. Thus, it just SEEMS like we have no PTH.
  • No, it will not work. No response and no increase in urinary cAMP.
56
Q

phenotype of someone with Albright hereditary osteodystropghy

A
  • short stature
  • short neck
  • obesity
  • subcutaneous calcification
  • shorted metatarsals and metacarpals.
57
Q

Humoral hypercalcemia of malignancy

____ PTH

____ Ca2+

____ Pi

____ Vit. D

Similar to ___________.

A

low PTH

high Ca2+ (hypercalcemia)

low Pi (hypophophatemia- bc high exceretion)

low Vit. D

Some malignancies can produce PTH-rp (PTH-related peptide) that mimics PTH and binds to the same receptor.

Produces similar sx to primary hyperparathyroidism: high urinary Ca2+, urinary Pi, cAMP, blood Ca2+ and low blood Pi.

Different in that it has: Low PTH and VitD (d/t cancer).

58
Q

How do we tx

Humoral hypercalcemia of malignancy

A
  1. Furosemide, which inhibits renal Ca2+ reabsorption and increases Ca2+ excretion
  2. Etidronate (inhibitor of bone resorption).
59
Q

Familial Hypocalciuric Hypercalemia (FHH)

___ PTH

____ serum Ca2+

_____ urine Ca2+

____ Pi

____ Vit. D

A

normal to high PTH

high serum Ca2+

low urine Ca2+

normal Pi

normal Vit. D

Autosomal dominant disorder where there is a defect in CaSR in PT gland and parallel Ca2+ receptors in TAL of kidney. When renal receptors are defective, a high serum Ca2+ is sensed as normal and Ca2+ reabsoprtion in increased, leading to decreased urinary Ca2+ excretion). Bc the Ca2+ receptors in the PTH are defectibe. they inccorectly think they high serum Ca2+ is normal and PTH seceretion is not inhibited. Thus, it cannot sense high levels of Ca2+.

60
Q

What is rickets?

___ PTH

____ Ca2+

_____ Pi

____ urine Pi and cAMP

____ vitamin D

________ bone

A

high PTH (2º)

normal or low Ca2+

low Pi

high urine Pi and cAMP

low vitamin D

osteomalacia (high resorption) bone

Not enough Ca2+ and Pi are available to mineralize growing bone. Thus, kids will have growth failure and skeletal deformities. .

61
Q

What can cause impaired vit. D metabolism?

A
  1. Dietary deficiency of vitD
  2. Vit D resistance d/t deficit in synthesis of active vit D or mutations in Vit D receptor
62
Q

what are the two kinds of rickets

A
  • Pseudovitamin D deficient rickets or Vit D dependent rickets type 1 (decrease in 1-alpha-hydroxylase)
  • Pseudovitamin D deficient rickets or Vit D dependent rickets type II (decrease in vit D Receptor)
63
Q

What is osteomalacia

A

Vit D def in adults that causes new bones to fail to mineralize and weight-bearing bones bend and soften

64
Q

Who is more likely to develop osteoporosis?

A

Decrease in bone mass is more likely in F as they age (like over 45) d/t loss of estrogen

Endo/Repro Exam 1 (14 decks)

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