Metabolic bone disease: Biochemistry Flashcards
symptoms of MBD
Metabolic
- Hypocalacaemia
- Hypercalcaemia
- Hypo/Hyper phosphataemia
Specific to bone
- Bone pain –> deformity and fractures
What are the biochemical investigations in bone disease? What are the biochemical changes in bone disease?
See slides 16 and 17
Bone calcium
Is in the form of hydroxyapatite
Cancellous bone is metabolically active:
- 5% is remodelling at anytime total
- the whole skeleton is remodelled over 7 years
- Continuous exchange of ECF with bone fluid reserve
Calcium balance
See endocrinology
Bone acts as the compensatory mechanism when everything goes wrong in the calcium homeostasis.
Post menopausal women are less efficient at getting Ca because lack of oestrogen
What are the serum levels of calcium and how are they corrected?
46% protein bound (to albumin)
47% Free ionized
7% complexed (to P and citrate)
So the corrected calcium a lab gives you compensates for the protein level; if protein levels are HIGH they compensate down; o.o2 for each g/l of albumin
Corrected calcium = [calcium] + 0.02(45 - [albumin])
Alkalosis changes ionized to protein bound –> more Ca binds to protein so free levels of Ca2+ drop = tingling sensation.
What is the role of PTH?
Acts on 2 systems
- Bone acute release of available calcium; not in hydroxyapatite crystals
more chronically INCREASED osteoclast activity to reabsorb bone - Kidney increased Ca reabsorption in the distal conv tubule. Also activates renal 1-alpha hydroxylase
What are the clinically relevant points about PTH?
See slides
1 - 84 amino acid peptide but N1-34 active
- Mg dependent
- plsma half life 1/2 8 mins
- PTH1 receptor is actvated by…
What are the clinically relevant points about PTH?
- 84 amino acid peptide
but N1-34 active - Mg dependent
- T 1/2 8 min
- PTH receptor is activated
also by PTHrP
What does PTH drive in terms of the kidney?
It drives active calcium absorption in the distal tubule of the kidney.
How does PTH affect bone reabsopriton?
Causes bone reaborption through the RANK ligand system
What are the causes of HPT?
- Parathyroid adenoma
- Parathyroid hyperplasia
- Parathryoid cancer
- Familial syndrome (under age 40 –> higher chance of familial syndrome)
How do you diagnose primary HPT?
Primary hyperthryoidism is diaignosed by:
An elevated total/ionised calcium with PTH levels fankly elevated or in the upper half of the normal range.
What are the clinical features of hyperthyroidism?
These features are mainly due to the high calcium - hypercalcaemia
Thirst, polyuria, tiredness, fatigue, muscle weakness.
Stones, adbominal moans and psychic groans.
1) Renal colic, nephrocalcinosis, CRF
2) Dyspepsia, pancreatitis, constipation, nausea, anorexia
3) Depression , impaired concentration, drowsy and coma
Patients may also supper fractures secondary to bone resorption.
Why does hypercalcaemia cause diuresis?
Na/Cl/K co transporter transports these ions into cells of the ascending loop. K+ is then recycled out.
High levels of Ca2+ –> shuts down the counter current system. The K+ transport stops moving K+ out of the cell which means the co transporter can not bring ions in. Water moves out by osmosis. Viscous cycle
The diuresis results in hypercalciuria
What does chronic elevated PTH cause?
Causes increased cortical bone resorption
Increased bone turnover
The cortical bone > cancellous
Increases fracture risk
What are the biochemical findings in primary HPT?
1) Increased serum calcium
2) Decreased serum phosphate
3) PTH in the upper half
4) Creatinine may be elevated
Describe the metabolism of the vitamin D
See slides and endocrinology
How do you define vitamin D deficiency?
You define it as the level where PTH starts to rise
See slides
Define rickets?
Inadequate vitamin D activity leads to defective mineralisation of the cartilagenous growth plate (before a low calcium)
Severe rickets may have hypocalcaemia (this is serious because hypocalcaemia has many neuromuscular problems) chovestek sign + Trousseaus’s sign
See slides for symptoms and signs
Causes of rickets/osteomalacia?
Vitamin D related
1) Dietary
2) GI - small bowel malabsorption/bypass, pancreatic insufficiency, liver/biliary disturbance, drugs
3) Renal - Chronic renal failure
4) Rare hereditary - Vitamin D dependent rickets
Type I = Deficiency of 1 alpha hydroxylase
Type II = Defective vitamin D receptor for calcitriol
Describe the biochemistry of rickets?
Serum:
- calcium = N/low
- Phosphate = N/low
- 25(OH) Vita D = low
- PTH = high
- Alk phos = high
Urine:
- phosphate = high
Bone and phosphate?
see slide
If phosphate levels are low and they have rickets there are probably problems with the kidney
The PCT is where phosphate resorption occurs with Na+PO4^3- cotransporter. Damage to the PCT results in phosphaturia and stops the 1 alpha hydroxylation of vitamin D.
Fanconi syndrome = see slides
What is FGF-23
See endocrinology - from osteocytes
- Inhibits calcitriol = less phosphate resorption in the gut
- Inhibits Na+/PO4^3- co-transporter = more phosphate excretion like PTH
What can FGF-23 cause?
Excess can cause rickets/osteomalacia as normal phosphate levels are required for bone and cartilage mineralisation.
Kidneys are forced to lose phosphate. Isolated hypophophataemia: X linked mutations in PHEX = high levels of FGF-23. Autosomal dominant: Mutation of FGF-23 cleavage site = high FGF-2
Oncogenic osteomalacia - mesenchymal tumours produce FGF-23
Describe the effect of the menopause on bone?
Menopause results in an estrogen deficiency which:
Increases the number of remodelling units
- Causes remodelling imbalance with increased bone resorption (90%) compared to bone formation (45%) Enhanced osteoclast survival and activity
- Remodelling errors. Deeper and more resorption pits lead to
1) Trabecular perforation
2) Cortical excess excavation - Decreased osteocyte sensing
