Lecture 9 + 10 - 2018/2017

Question 1

What is PTH?

Answer 1

Parathyroid hormone.

Question 2

What makes PTH?

Answer 2

Chief cells of parathyroid gland.

Question 3

Why is PTH made?

Answer 3

In response to low calcium levels in serum (ECF - blood).

Question 4

How does PTH restore calcium levels back to normal?

Answer 4

1. Stimulation of renal tubular reabsorption of calcium - rapid action.
2. Stimulates osteoclastic bone resorption - there is an increase in osteoclasts, so there is an increase in bone being broken down and consequently calcium is released in the blood (intermediate action).
3. Stimulates renal 1-hydroxylation of 25(OH)D - there is stimulation on the intestine to promote calcium absorption cia 1-hydroxylation of 25()H)D -> 1,23 (OH)2D.

Question 5

What is PTH regulated by?

Answer 5

1. Serum ionised calcium.
2. Serum phosphate.
3. Serum 1,25 Dihdroxy vitamin D.

Question 6

How does calcium regulate PTH?

Answer 6

If we increase calcium then there will be a decrease in PTH. This acts as a negative feedback.

Question 7

How does phosphate regulate PTH?

Answer 7

If we increase phosphate there will be an increase in PTH.

N.B. PTH will cause a decrease in absorption of phosphate via the kidney.

Question 8

How does 1,25 Dihydroxy Vitamin D regulate PTH?

Answer 8

If we increase 1,25 dihydroxy vitamin D there will be a decrease in PTH.

Question 9

What is CaR?

Answer 9

It is a specific calcium receptor at the parathyroid gland - sits at the membrane of the cell and binds to calcium.

Question 10

What happens when there is a decrease in calcium?

Answer 10

The lack of calcium means that there is no calcium bound to the receptors. The CaR will then activate a gene transcription for production of PTH. PTH is then released into the ECF.

Question 11

What happens when there is an increase in calcium?

Answer 11

Calcium binds to CaR on the ECF side of the renal tubule - CaR activates processes which switch of reabsorption of calcium from the urine.

Question 12

What is PTHrP?

Answer 12

Parathryoid Horomone-Related Peptide.

Question 13

What does PTHrP do?

Answer 13

Paracrine regulator of bone and breast development - it is NOT a physiological regulator of serum calcium. it acts like PTH and cause an increase in calcium.

Question 14

What produces PTHrP?

Answer 14

It is produced in excess by neoplasms especially those derived from epithelial tissues e.g. humoral hypercalcemiia of malignancy (HHM).

Question 15

What does PTHrP do in bone?

Answer 15

Stimulates calcium release.

Question 16

What does PTHrP do in kidney?

Answer 16

1. Increases renal tubular reabsorption of calcium.

2. Decreases renal tubular reabsorption of phosphate - lowers plasma phosphate.

Question 17

What are the signs of PTH dependent hypercalcemia?

Answer 17

1. Increase in calcium.

2. Increase in PTH (inappropriately normal).

Question 18

What causes PTH dependent hypercalcemia?

Answer 18

1. Primary hyperparathyroidism - 85% solitary adenoma, 10-15% parathyroid gland hyperplasia.
2. Familial benign hypercalcemia (FHH/FBH) - there is inactivating CaSR mutations (calcium sensing receptors - basically the receptors are inactive and sense less calcium then there really is, this means that PTH detects this and will make more calcium hence hypercalcemia).

Question 19

What are the signs of PTH independent hypercalcemia?

Answer 19

1. Increase in calcium.

2. Decrease in PTH.

Question 20

What causes PTH independent hypercalcemia?

Answer 20

1. Cancer.

2. Vitamin D toxicity.

Question 21

How does cancer cause PTH independent hypercalcemia?

Answer 21

1. Tumours secrete PTHrP.
2. Extensive lytic bone disease (bone resorption) e.g. multiple myeloma (bone marrow malignancy) - increase in breakdown of bone so increase in calcium.
3. Tumour expression of 1-alpha hydroxylase which leads to an increase in 1,25 (OH)2D.

Question 22

How does vitamin d toxicity cause PTH independent hypercalcemia?

Answer 22

1. Endogenous - granulomatous disease (sarcoidosis).

2. Exogenous - iatrogenic (vitamin d intoxication).

Question 23

What are the causes of hypocalcemia?

Answer 23

1. Hypoparathyroidism.
2. Parathyroid hormone resistance.
3. Abnormalities of vitamin D metabolism.

Question 24

How does hypoparathyroidism cause hypocalcemia?

Answer 24

1. Post surgical e.g. post neck irradiation.
2. Genetic e.g. CaSR mutations - receptor is always active (the parathyroid is told that there is an increase in calcium than there really is, so there is a decrease in PTH so there is a decrease in calcium).
3. Severe hypomagnesaemia.
4. Autoimmune.
5. Infiltrative e.g. beta-thalassaemia, wilson’s disease.

Question 25

How does parathyroid hormone resistance cause hypocalcemia?

Answer 25

1. Pseudohypoparathyroidism (types 1a, 1b, 1c).

Question 26

How does abnormalities of vitamin d metabolism cause hypocalcemia?

Answer 26

1. Vitamin D deficiency - can't make enough 1,25 Vit D thus decrease in calcium absorption in gut. 2. Deficient in 1-alpha hydroxylation - can't convert vitamin D. 3. Renal failure. 4. Vitamin D resistance.

Question 27

What is autosomal dominant hypercalciuric hypocalcemia?

Answer 27

The CaSR sense more calcium than there really is so there is a decrease in PTH so there will be a decrease in calcium.

Question 28

What are the features of autosomal dominant hypercalciuric hypocalcemia?

Answer 28

1. Autosomal dominant inheritance. 2. Hypocalcemia - usually asymptomatic. 3. Mild hypomagnesemia (0.5-0.7). 4. Higher urinary calcium excretion - this is because the CaR regulates renal tubular calcium handling therefore it tells the cells to not reabsorb calcium into the blood therefore calciums tays in the urine hence increase in urine calcium.

Question 29

What is familial hypocalciuric hypercalcemia (FHH)?

Answer 29

The CaSR sense less calcium than there really is so there is an increase in PTH so there will be an increase in calcium.

Question 30

How do you diagnose FHH?

Answer 30

1. Screening immediate relatives (AD inheritance). 2. Ratio of fasting urine calcium to creatinine clearance. 3. Family testing (serum calcium).

Question 31

Where is phosphate found?

Answer 31

1. Cell membranes. 2. Intracellular organelles. 3. Nucleic acids. 4. Enzyme co-factors and glycolytic intermediates.

Question 32

What regulates phosphate metabolism?

Answer 32

1. PTH. | 2. Calcitriol.

Question 33

How does PTH regulate phosphate levels?

Answer 33

It decreases serum phosphate.

Question 34

How does calcitriol regulate phosphate levels?

Answer 34

It increases serum phosphate by increasing intestinal absorption of phosphate and decreasing urinary phosphate excretion.

Question 35

What effect does phosphate have on PTH?

Answer 35

Low levels of phosphate will inhibit PTH production and increase calcitriol production.

Question 36

What are phosphatonins?

Answer 36

Family of hormones that regulate serum phosphate levels by modulating the expression of phosphate-transporting proteins in the renal tubule and thereby urinary phosphate excretion.

Question 37

Where do phosphatonins come from?

Answer 37

The main source is the skeleton, specifically osteoblasts and osteocytes.

Question 38

What is FGF23?

Answer 38

It is a phosphatonin that is the main regulator of phosphate.

Question 39

How does FGF23 regulate phosphate?

Answer 39

When there is an increase in phosphate, FGF23 (phosphatonin) is released from the bone. It acts on: 1. The kidney (reduce NaPi-2a,2c) to reduce phosphate reabsorption. 2. The gut (reduce 1,25 (OH)2D) to reduce phosphate reabsorption. By doing the above FGF23 will cause there to be a decrease in serum phosphate levels.

Question 40

What causes hyperphosphatemia?

Answer 40

1. Increased input of phosphate - IV phosphate, cell death. 2. Decreased excretion of phosphate - renal failure, PTH deficiency or resistance.

Question 41

What causes hypophosphatemia?

Answer 41

1. Inadequate GI absorption - vitamin d deficiency. 2. Intracellular shift - acute flux of phosphate from extracellular space to intracellular. 3. Renal loss - increase in PTH (PTH producing adenoma) or increase in phosphatonins.

Question 42

What causes an intracellular shift in phosphate (which can cause hypophosphatemia)?

Answer 42

1. Respiratory alkalosis - illness, pain (usually self-limiting). 2. Prolonged intense exercise. 3. Re-feeding malnourished patients.