Calcium Phosphate Metabolism

Question 1

What are the 3 important hormones of Calcium Homeostasis?

And what are the 3 important organs for calcium homeostasis?

Answer 1

Hormones:

1. Calcium: one of the most tightly regulated minerals
2. Parathyroid Hormone
3. 1,25 (oh)₂D (bioactive form of vitamin D)

Organs:

1. Intestines: where you absorb calcium and phosphate from diet
2. Bone: huge reservoir for Ca²⁺ and phosphate
3. Kidney: does the regulation of these minerals

Question 2

So what is Parathyroid Hormone release regulated by?

Answer 2

1. Serum Ionised Ca²⁺ (-)
2. Serum phosphate (+) : slightly less potent
3. Serum 1,25 dihydroxyvitamin D (-) : also less potent

Question 3

What is Parathyroid Hormone

Answer 3

Main ‘defender’ of the serum calcium

• 84aa hormone, chief cells of parathyroid gland and binds to PTH receptor 1
• Released within minutes of decreased serum Ca²⁺​
• It restores serum Ca²⁺ by acting on all effector organs
  
  • Bone and Kidney → directly
  • Intestine → indirectly

Question 4

What are the three main actions of PTH?

Describe the difference in action on Ca²⁺ and Phosphate

Answer 4

1. ​Stimulates osteoclastic bone resorption (pulls Ca2+ from bone)
2. Stimulates renal tubular reabsorbtion of Ca2+ **
3. Stimulates renal 1-hydroxylation of 25(OH)D (1-25(OH)D increases gut absorbtion of Ca2+)

• 1 and 2 are rapid, 3 takes longer*
• Whilst PTH increases phosphate concentration via bone resorption and indirectly via intestinal absorption, it actually _decreases renal tubular absorption**_*

Question 5

ECF Calcium?

Answer 5

What we are trying to regulate, and what has massive impact on PTH levels.

• 45-50% ionized, bioactive** what parathyroid gland receptors see
• 5-10% complexed with anions eg HCO₃
• 45-50% protein-bound, albumin and globulins: “not available”

Question 6

Describe specifically how the Parathyroid receptor detects Ca²⁺ levels and how it responds

Answer 6

• If Ca²⁺ levels are low, then the receptor is ‘unliganded’ and that activates gene transcription for production and release of PTH

and vice versa:

• If Ca²⁺ levels are reasonably high, the receptor switches these processes off → Decreased PTH

These Ca²⁺ sensitive receptors are also present elsewhere, eg the renal tubules

Question 7

Describe how the CaR handles Renal Tubular Calcium Handling

Answer 7

1. ECF Ca²⁺ binds to the receptor in the ECF lumen side of the and switch off reabsorbtion processes in the tubule → increased excretion of Ca²⁺ and Mg²⁺

Question 8

Vitamin D and it’s metabolism ( know the pathway)

Answer 8

It’s actually a hormone!! Retained from the effects of UV radiation on the skin.

Calciferol →(liver)→ Calcidiol (25OH D) →(kidneys)→ Calcitriol (1,25 (OH)₂D)

Calcitriol is formed by a 1-alpha hydroxylase step and is what is regulated by PTH. Stimulates calcium and phosphate reabsorption in the gut.

Question 9

Just as a note know that Calcitonin is NOT ________.

Answer 9

Clacitonin is not a physiological regulator of serum calcium.

But it does have an unclear seemingly opposing effect on Calcium levels

Question 10

What is Parathyroid hormone-related peptide (PTHrP)

Answer 10

• Important paracrine/local regulator of development (breast, bone and skin)
• Acts very similarly to PTH as it signals via PTHR1
• NOT a physiological regulator of serum calcium
• Produced in excess by some cancers; especially epithelial tumours → humoral hypercalcemia of malignancy (HHM)
• Most common cause of cancer-associated hypercalcemia (severe and life-threatening issue)

Question 11

What are the two types of Causes of Hypercalcemia

Answer 11

1. PTH-dependent: increased PTH, increased sCa²⁺
2. PTH-independent: Decreased PTH, Increased sCa²⁺

Question 12

Describe PTH-dependent Hypercalcemia

Answer 12

• Most Common form of hypercalcemia
• Primary Hyperparathyroidism: due to benign tumour/adenoma to 1 of the 4 glands
• FHH/inactivating Ca²⁺ Sensing Receptor (G_a11, APS2) mutations: Gland sees a lower Ca²⁺ level then is there and produces too much PTH → hypercalcemia

Question 13

Describe PTH-independent Hypercalcemia

Answer 13

• Normal Parathyroid function: appropriately low PTH levels due to the Hypercalcemia.
• Usually due to cancer

1. Cancer
   
   • PTHrP
   • Extensive lytic bone disease (myeloma)
   • 1,25 dihydroxyvitamin D (v rare)
2. Vitamin-D dependent
   
   1. Sarcoidosis: granulomatous disease can convert the 25 to 1,25
   2. Vitamin-D intoxication

Question 14

Causes of Hypocalcemia are?

Answer 14

1. Hypoparathyroidism
   
   • post surgical, post neck irradiation
2. Parathyroid Hormone Resistant
   
   • Pseudohypoparathyroidism
3. Abnormalities in Vitamin D metabolism
   
   • Vitamin D deficiency
   • Renal Failure

Question 15

Phosphate Metabolism.

Main three organs involved.

Main three hormones

Answer 15

Organs:

1. Gut: we absorb phosphate
2. Bone: store phosphate in bone
3. Kidney: regulates excretion/retention

Hormones:

1. Vitamin D (1,25(OH)₂D): key player in gut absorbtion, (also too much Vit D drives bone resorption)
2. PTH:
   
   • stimulates bone resorbtion
   • Phosphoturic; stimulates renal excretion of Phosphate
3. Phosphatonins

Question 16

What are Phosphotonins?

Answer 16

Hormones made in skeletal tissue that are transported via blood to target organs.

Also Phosphoturic so help us to get rid of Phosphate via renal excretion by acting on the kidneys.

Therefore Low phosphate could be attributed to too much of a Phosphotonin.

Main Phosphotonin in phosphate regulation = FGF-23 (Fibroblast Growth Factor)

Question 17

How does pH impact Phosphate rgulation

Answer 17

Has a big impact on extracellular phosphate regulation.

• Phosphates mainly extracellular, but in the face of alkalosis (inc. pH) this drives phosphate into cells and out of the ECF
• **Many sick people get a respiratory alkalosis from hyperventilation, which will attribute to a moderately low serum phosphate level. (when they get better the system will restore itself!)

Question 18

What are some causes of Hyperphosphatemia?

Answer 18

• increased Phosphate input: IV phosphate, cell death
• Decreased Excretion: renal failure (most advanced renal failure patients have this), PTH deficiency or resistence

Question 19

Causes of Hypophosphatemia?

Answer 19

1. Inadequate GI absorption: eg from a vit D deficiency in elderly that don’t see the sun enough! Can lead to osteomalacia from hypocalcemic and hypophosphatemic
2. Intracellular Shift
   
   • Respiratory Alkalosis (from illness/pain) usually self-limiting
   • Prolonged intense exercise
   • Refeeding malnourished patients
3. ​Renal Loss (excretion)
   
   • ​​inc PTH
   • inc Phosphatonins (FGF-23)

Question 20

What are FGF-23 phosphotonins two main roles and where is it derived from?

Answer 20

Derived from Bone.

1. inhibits production and activity of phosphate transporting proteins in the renal tubule → more phosphate gets peed out
2. Potent inhibitor of 1-dihydroxate enzyme → less 1,25 (OH)₂D → less phosphate absorption

These develop Hypophosphatemia!

Which will eventually cause osteomalacia (not enough phosphate to mineralize bone)

Question 21

Describe the mechanism of FGF-23 and some acquired and genetic conditions related to it that can lead to phosphate loss!

Answer 21

• FGF-23 comes out of osetcytes in bone
• **FGF-23 can be inhibited by PHEX from osteoblasts in bone*
• FGF-23 inhibits renal tubular phosphate reabsorption → increased phosphate loss inhbits NaPi2c
• FGF23 through acting on 1,25(OH)₂D decreases phosphate gut absorbtion → dereased serum phosphate inhibits 1aOHase

These can be acquired (older) and genetic (younger)

a) Fanconi’s Syndrome: defective Pi transport in renal tubule

a) Oncogenic osteomalacia: Tissue that’s making too much FGF23. Have to remove tumour.

g) Abnormal FGF23 (ADHR): that is resistant to PHEX inhibiting enzyme, so net effect is igher.

g) Abnormal PHEX (XLH): where PHEX enzyme is inactive