MBD - Biochemistry (Prof Meeran)

Question 1

If you have a low calcium, the parathyroid glands detect this with the calcium receptor

They try to improve the calcium by releasing PTH

What is this called?

Answer 1

Secondary hyperparathyroidism

Can lead to osteomalacia

Question 2

What enzyme is released into the circulation which bones make?

Answer 2

Alkaline phosphatase

Question 3

Describe the process of bone remodelling.

Answer 3

• Activation occurs
• Microcrack crosses canaliculi –> severing octesocyte processes–> osteocyte apoptosis
• This acts as a signal to the connected surface lining cells (of osteoblast lineage) to release local factors that attract cells from blood and marrow to the remodelling compartment
• For resoprtion to start, osteoclasts are generated locally and resorb matrix and the offending microckrack
• Then successive teams of osteoblasts deposit new lamellar bone
• Osteoblasts that are trapped in the matrix–> osteocytes. Others die or form new osteoblast lining cells

Question 4

What are normal Ca levels?

Answer 4

2.2 -2.6 mM

Question 5

What does RANK stand for? Where is RANK found?

Answer 5

Receptor Activator of a Nuclear Factor-kappa

This is found on OSTEOCLASTS

Question 6

What activates osteoclasts?

Answer 6

RANK-ligand

Question 7

What is the dummy receptor of RANKL called?

Answer 7

Osteoprogerin OPG

Question 8

How is PTH linked to the RANK system?

Answer 8

Activates the RANK system to cause activation of osteoclasts to resorb bone

Question 9

How does PTH increase calcium?

Answer 9

• Osteoclast activation to release Ca from bone
• Kidney - stimulates absorption of calcium
• Activates enzyme 1-alpha hydroxylase (kidney)

Question 10

What is the primary cause of secodary hyperparathyroidism?

Answer 10

Low Vitamin D

Bone develops osteomalacia

Question 11

What is resorbed more in primary hyperparathyroidism, cortical or cancellous/trabercular bone?

Answer 11

Cortical bone –> increased fracture risk

Question 12

What are the names for secondary hyperparathyroidism in terms of bone?

Answer 12

Rickets and osteomalacia

Question 13

What is the difference between osteomalacia and osteoporosis?

Answer 13

Ca is normal in osteoporosis. This is a normal process that happens whith aging. Not a disorder of bone metabolism - diagram below shows that you should normally have about 65% (2 thirds) inorganic content/calcium in bone. In a bone biopsy in osteoporosis this is what will be seen but you just have less bone denisty.

In osteomalacia there is low calcium in bone.This is something that can be prevented by taking vitamin D.

The green shows how strong the bone is too.

Question 14

What are the differences between teh causes of osteomalacia and osteoporosis?

Answer 14

Question 15

How do you assess osteoporosis?

Answer 15

Single best predictor of fracture risk

BMD represents 70% of total risk

Measured using X-rays “DEXA” bone scan

Question 16

What is the difference between a Z score and a T score?

Answer 16

T score compares you to a person of 25 at peak bone mass. A T score of -2.5 below that is osteoporosis. 0 is normal for a 25 year old.

Z score is comparing you to people of the same age but this isn’t very helpful because everyone gets osteoporosis as they age.

Question 17

What is primary hyperparathyroidism? What are the phosphate levels?

Answer 17

Tumour of parathyroid glands making too much PTH (adenoma) causing high Ca inappropriately.

Phosphate levels are low - renal excretion in proximal tubule. Urine Ca will also be increased so may cause renal colic.

Question 18

What are the features of primary hyperparathyroidism?

Answer 18

• Calcium leaks out of bone (fractures)
• Extra calcium gets stuck in kidneys
• Causes psychiatric symptoms
• Causes abdominal pain and constipation

Others:

Pepper pot skull

Question 19

Describe the pathophysiology of renal osteodystrophy.

Answer 19

Renal failure - so less 1-alpha hydroxylase and plasma calcium falls

When Ca falls you try to compensate by producing PTH BUT you then end up with high phosphate too because you cannot excrete it.

Question 20

What are the biochemical features of renal osteodystrophy? What about Vit D?

Answer 20

• Low ca
• High phosphate
• HIGH PTH - THIS IS THE MAIN DIFFERENCE BETWEEN THIS AND OSTEOMALACIA

Vitamin D is not working because there is no 1-alpha hydroxylase.

Question 21

What do you see in long standing renal osteodystrophy?

Answer 21

You eventually develop tertiary hyperparathyroidism(a bit like primary) - the parathyroid gland becomes autonomous. This is due to parathyroid hyperplasia.

If you removed the kidneys and transplanted new ones then you still have a high PTH release even if the kidneys are working.

Question 22

Describe the pathyphysiology of CKD.

Answer 22

• Nephron loss –> phosphate retention (hyperphosphataemia), reduced calcitriol (causes a low Ca and osteomalacia)
• Acidosis also contributes to bone loss.
• Low Ca– > secondary increase PTH.
• Because of the high phosphate the calcium phosphate can become crystallisted all around the body –> METASTATIC CALCIFICATION

Question 23

Describe Paget’s disease pathophysiology.

Answer 23

• ·Bone has increased turnover
• ·Increased osteoblast and osteoclast
• ·Bone pain
• ·High alkaline phosphatase
• ·Normal calcium handling

Question 24

Which type of bone is metabolically active?

Answer 24

Cancellous (trabercular) - 5% is remodelling at any one time

Question 25

What percentage of Ca is free in the blood and what happens in alkalosis? What is the equation for corrected calcium?

Answer 25

* 47% FREE ionised * 7% complexed * More is released in alkalosis * 46% protein bound Corrected calcium = [calcium] + 0.02( 45 – [albumin])

Question 26

Describe the structure of PTH, half life and the ion it is dependant on.

Answer 26

MAGNESIUM dependant 84 amino acid peptide but N1-34 active Half life - 8 min

Question 27

What part of the kidney does PTH cause Ca absorption?

Answer 27

Distal tubule

Question 28

What is the effect of high serum Ca on kidneys?

Answer 28

* Causes diuresis * Increases stone risk

Question 29

What is the effect of Vitamin D on the gut and kidney? Which receptors does it induce?

Answer 29

Increases Ca and phosphate absorption by inducing TRPV6 and calbindin In the kidney it induces TRPV5 and calcinding to FACILITATE PTH action.

Question 30

In rickets "inadequate...leads to ... before .."

Answer 30

inadequate Vitamin D activity leads to defective mineralisation of the cartilagenous growth plate (before a low calcium)

Question 31

What is the function of FGF-23? What conditions is FGF-23 high in?

Answer 31

* Produced by osteoblast lineage cells, long bones * LIKE PTH causes P loss; UNLIKE PTH inhibits activation of Vit D by 1α OH ase * This aids in **phosphate excretion** (since when Ca has risen PTH is supressed) High FGF-23 can lead to hypophosphataemic rickets. Can be high in oscogenic osteomalacia.

Question 32

Why would chronic alcoholics have hypoparathyroidism?

Answer 32

Mg is low causing low PTH