Lecture 9 and 10: Calcium Metabolism I and II Flashcards
ECF ca2+ levels are _____
Tightly controlled, which suggests that it’s an important physiolgoical phenomenon
What form of Ca2+ regulates PTH?
Ionised/free form
In the ECF, ECF, about 50% of calcium is in the free/ionised/bioactive form
What organs are closely related to Ca2+ and phosphate?
Bone acts as a major reservoir for calcium and phosphate
The kidney regulates the excretion of calcium. It is an important contributor for regulation of rapid response and serum calcium
How does the PTH stimulate release of Ca2+?
- Stimulates osteoclastic bone resorption
- Stimulates renal tubular reabsorption of Ca++
- Stimulates _renal 1-hydroxylation of 25(OH)D (_long loop effect)- form bioactive form of vitamin D. This stimulate intestine Ca2 and K absorption
So directly or indirectly Restores serum Ca++ by acting on all effector organs
_____ is the main regulator of serum calcium
Parathyroid hormone is the main defender of serum calcium
So directly or indirectly Restores serum Ca++ by acting on all effector organs
Describe the effect of plasma Ca2+ on PTH
1) Decrease in plasma Ca2+
2) Calcium sensing receptor in the Parathyroids (chief cells) increase production of Parathyroid
3a) Increases Bone reabsorption of Ca2+ and Phosphate
3b) Increases renal tubular reabsorption of Ca2+. This decreases reabsorption of phosphate
3c) Stimulates renal 1-hydroxylation of 25(OH)D (long loop effect)- form bioactive form of vitamin D. This s_timulate intestine Ca2 and K absorption_
What are parathyroid hormones?
Hormone secreted by the parathyroid glands that is important in bone remodeling, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time.
PTH is secreted in response to low blood serum calcium(Ca2+) levels.
What is Parathyroid hormone release regulated by? (3)
1) Release is most importantly regulated by Serum ionized calcium level. (negative regulator)
2) Also regulated in some extent by serum phosphate, so that high levels of serum phosphate as a pharmacologic agent can stimulate PTH production (not major)
3) Also 1,25 dihydroxyvitamin D (negative regulator)
Describe the composition of ECF calcium
45-50% ionized, bioactive
5-10% complexed with anions eg HCO3
45-50% protein-bound, albumin and globulins
What happens if the Ca2+ levels are high
Schematic to reinforce the idea that there are specific cell membrane-bound receptor for ionised-calcium at the membrane of PTH chief cells.
In such a way that if the level of cA2+ is high, the receptor conformation changes and signals to the cells to switch off parathyroid hormone production and secretion.
Subsequent reduction in PTH
If the receptor function is disordered, (constantly switched off or switch off), will result in perdubation of Ca2+/PTH axis.
Describe the DIRECT renal-handling of Ca2+
Another place (independent of PTH). CaR is expressed is the renal tubule
Basolateral membrane of renal tubular cells
ECF Ca2+ levels can module the reabsorption of Ca2+ from the urine back into the body
The receptor will signal to reduce further reabsorption of CA2+ into the ECF
Describe Vit D and Ca2+
Vit D is technically a hormone (we produce it due to UVB exposure)
Through a series of steps, you produce calidiol (25OD H) then hydroxylation to 1,25(OH2)D (1,25 vitamin D)
Vitamin D then i_ncreases absorption of Ca2+ and Pi (fractionally)_
Is Calcitonin is a physiological regulator of serum calcium?
NO
Is the Parathyroid hormone-related peptide a regulator of serum calcium?
No, it is NOT a physiological regulator of serum calcium
It is an important paracrine regulator of breast, skin and bone development
What is PTHrP?
Parathyroid hormone-related peptide (PTHrP)
- Important paracrine regulator of breast, skin and bone development
-
NOT a physiological regulator of serum calcium
- PTH is usually suppressed due to elevated serum calcium concentrations.
- A variety of other mechanisms lead to inappropriate hypercalcemia in hypercalcemia of malignancy. These include:
- -Impaired renal function due to a tumor or its treatment
- -Osteolytic activity within bony metastases
- -Release of calcemic cytokines by non-osteolytic bony metastases
- -Secretion of humoral factors mimicking PTH action (humoral hypercalcemia of malignancy: HHM), usually associated with secretion of parathyroid hormone-related peptide (PTHrP) by the primary tumor (or more commonly its metastases)
- -Other as yet unknown factors
- Produced in excess by some cancers, esp epithelial cell tumours → humoral hypercalcemia of malignancy (HHM)
- Most c_ommon cause of cancer-associated hypercalcemia_
- Acts v similarly to PTH, signals via PTHR1
- Hypercalcemia can be severe and life-threatening
What is produced in excess by some cancers, esp epithelial cell tumours?
Parathyroid hormone-related peptide (PTHrP)
What are the causes of hypercalcemia?
PTH-dependent, ↑sCa++, ↑/N PTH (due to excess of PTH)
- Primary hyperparathyroidism
- Bengin Familial Hypercalcemia: FHH/inactivating CaSR mutations (tricked into thinking Ca2+ concentration is lower than it is)
- High Ca2+, High PTH, Low Ca2+ excreted in urine
PTH-independent, ↑sCa++, ↓ PTH
- a_. Cancer_
- almost always releated to increased PTHrP (parathyroid hormone-related peptide)
- increased bone reabsorption: extensive lytic bone disease (myeloma)
- 1,25 dihydroxyvitamin D dependent hypercalcemia (v rare)
-
b. Vitamin D-dependent
- Sarcoidosis
- Vitamin D intoxication
If someone comes in with hypercalcemia, what should you do?
Do a PTH test to determine whether the cause is PTH-dependent or PTH-independent
Raised PTH= PTH-dependent diseases
Decreased PTH = PTH-independent diseases
How does PThRP cause hypercalcemia?
NOT a physiological regulator of serum calcium
Hypercalcemia of malignancy is typically not due to excess parathyroid hormone (PTH). In these disorders, PTH is usually suppressed due to elevated serum calcium concentrations. A variety of other mechanisms lead to inappropriate hypercalcemia in hypercalcemia of malignancy. These include:
- Impaired renal function due to a tumor or its treatment
- Osteolytic activity within bony metastases
- Release of calcemic cytokines by non-osteolytic bony metastases
- Ectopic 1-alpha hydroxylase activity in tumor tissues
- Secretion of humoral factors mimicking PTH action (humoral hypercalcemia of malignancy: HHM), usually associated with secretion of parathyroid hormone-related peptide (PTHrP) by the primary tumor (or more commonly its metastases)
- Other as yet unknown factors
What are the causes of hypocalcemia?
1) Hypoparathyroidsim
- due to postsurgical, post neck irradiation
- autoimmune disease
- genetic, including activating CaSR mutations (even though serum calcium levels are low, it mimics )
- severe hypomagnesaemia
2) Parathyroid hormone resistance
-High parathyroid, but the receptors are resistant.
3) Abnormaltieis of vitamin D metabolism
- Vitamin D deficiency (deficient 1a-hydroxylation)
- Renal failure (vit D resistance)