2 - Calcium Pathology Flashcards
Hyperparathyroidism is a condition of what?
Excess PTH secretion
What two types of hyperparathyroidism are there?
Primary - within parathyroid gland
Secondary - elsewhere i.e. Chronic renal failure / rickets
What is a common cause of primary hyperthyroidism?
Monoclonal parathyroid adenoma (hyperplasia)
What two serum findings result from primary hyperparathyroidism?
1) Hypercalcaemia
2) HYPOphosphataemia
What are 2 complications of primary hyperparathyroidism? (bone/kidney)
Bone demineralisation - loss of calcium and phosphate.
Renal calculi from hypercalciuria - concentrations get so high it comes out of solution.
What are the most common type of calcium kidney stones?
Calcium oxalate
What is a complication of chronic bone demineralisation?
Multiple bone cysts
osteitis fibrosa cystica
What are 3 genetic causes of primary HPT?
1) Vitamin-D receptor mutation
2) MEN1 mutation
3) Over-expression of cyclin D1
What’s the pathophysiology of a vitamin-D receptor mutation leading to Primary HPT?
Vitamin D-R provides negative feedback to parathyroid gland, inhibiting gene expression of PTH.
Mutation = loss of -ve feedback.
What’s the pathophysiology of MEN1 mutation causing primary HPT?
MEN1 is a tumour suppressor gene. Mutation results in neoplasia.
What’s the pathophysiology of cyclin D1 over-expression causing primary HPT?
Cyclin D1 is a cell-cycle regulator.
Overexpression favours cell division = sporadic parathyroid adenoma.
What other symptoms occurs with hyperparathyroidism?
‘Stones, bones, abdominal groans and psychic moans’
Muscle weakness, depression, GI upset, lethargy, aches.
What is tetany?
Muscular spasms, caused by a deficiency in calcium (Parathyroid dysfunction)
What is the treatment for primary HPT?
Surgery - parathyroidectomy
What is the main complication of a parathyroidectomy?
Nephrolithiasis
How do you best avoid nephrolithiasis following a parathyroidectomy?
Hydration
Moderate calcium intake
What scan is used to detect parathyroid tumours?
Sestamibi
What radioactive isotope is used in the sestamibi scan?
Technetium 99
What is the full name of the modern parathyroidectomy?
Minimally invasive radio-guided parathyroidectomy (MIRP)
During the MIRP, how does the surgeon confirm excised tissue is a tumour and that they’ve got it all?
Radiation-sensitive probe can detect the presence of Technetium 99.
What two pathologies occur in the kidney that can augment secondary hyperparathyroidism?
1) Increase phosphate reabsorption (inability to excrete)
2) Decreased 1alpha hydroxylation (less vitamin D)
What 4 factors (2 direct, 2 indirect) therefore, increase the level of PTH secretion?
1) High plasma phosphate
1b) Low free calcium
2) Low vitamin D
2b) Decrease calcium GUT absorption
Chronic renal failure results in what area of the kidney being unresponsive to PTH levels?
Proximal convoluted tubule
In the non-affected PCT cells, what two proteins are affected by PTH?
1) PTH inhibits the NaPi transporter
2) PTH increases activity of 1-alpha-OHase
In chronic renal failure, what three consequences occur in the PCT as a result of a lack of response to PTH?
1) Hyperphosphataemia
2) Hypocalcaemia
3) Acidosis
What 3 pharmaceutical agents can be used for secondary hyperthyroidism?
1) Vitamin D supplementation
2) Calcimimetics
3) Phosphate binders
How does Vitamin D work in the context of secondary HPT?
Increases serum calcium and phosphate levels.
What are the issues with using Vitamin D as a treatment of secondary HPT?
Increases phosphate - already high because kidneys can’t get rid of it.
Slow onset.
Does nothing to reverse hyperplasia.
Give an example of a calcimimetic?
Cinacalcet
How often is cinacalcet taken?
1x daily
How does it work?
Positive allosteric modulators - activating the calcium receptor to inhibit PTH secretion.
(chemical parathyroidectomy)
Which cohort of patients can receive calcimimetics?
As a result of what risk?
Dialysis patients
Risk of hypocalcaemia
Which two medications for secondary HPT are usually combined together?
Why?
Vit D + Cinacalcet
vitamin D sustains calcium levels that cinacalcet drops
Give one example of a phosphate binder?
Renagel
How do phosphate binders work?
They bind to phosphate within the GI tract and stop its uptake - decreasing total PTH secretion.
What are the two clinical signs of HYPOcalcaemia?
Chvostek’s sign
Trousseaus sign
What is Chvostek’s sign?
Muscular tremor elicited by tapping the facial nerve resulting in mouth spasm.
What is Trousseau’s sign?
Hand contortion when taking blood pressure
What is Vitamin D-dependent Rickets Type 1?
An issue in vitamin D synthesis.
What is an example of an affected enzyme in the vitamin D pathway in VDDR1?
1-alpha hydroxylase
Where is 1-alpha-hydroxylase found?
Proximal tubule of the nephron
What is the pathophysiology of rickets?
Growth occuring, but long bone strength is poor - gravity takes its effect by bowing on the femur.
What is the definition of osteoporosis?
Bone mineral density of >2.5 S.D. below healthy controls.
What is the underlying cause of osteoporosis?
Imbalance of bone remodelling.
Increase resorption, decrease formation.
What is osteopenia?
<2.5 S.D. below health controls - en route to osteoporosis.
What two changes occur from osteoporosis?
1) Reduced bone mass
2) Microarchitectural deterioration
Which cohort is the most common to get osteoporosis?
Menopausal women
Which bones are most commonly fractured in osteoporosis?
Hips, pelvis, spine, wrists, shoulder.
In women, losing oestrogen has what effect on osteoclasts and osteoblasts?
Increase osteoblast apoptosis.
Decrease osteoclast apoptosis.
Epidemiology of osteoporosis:
- Prevalence (women / men)
- Cost to NHS
Over 50:
Men: 1/12
Women: 1/3
£2 billion / year
What two factors determine adult bone health?
1) Peak bone mass (puberty)
2) Rate of bone loss
How do estrogens maintain bone mineral density - what do they bind to ?
ERalpha (ERbeta?) on osteoblasts
K/o studies of ERalpha have what effect on bone?
Decreases BMD.
Ovarectomy also results in what effect on bone?
Decreases BMD
What pharmaceutical agents can be used for post-menopausal women who haven’t had a fracture?
Bisphosphonates
Strontium ranelate
Raloxifene
What hormone, in men, in linked more closely to bone demineralisation?
Oestrogen (not testosterone)
What pharmaceutical agents can be used for post-menopausal women that have had a fracture?
Bisphosphonates
Strontium ranelate
Raloxifene
+ Teriparatide
How do bisphosphonates work?
Inhibit osteoblast action - slowing bone loss.
What needs to be done after taking bisphosphonates?
Sit upright for 30 mins - causes heartburn.
What class of drug is raloxifene?
Selective estrogen-receptor modulator. (SERM)
What does teriparatide do? Who’s it given to?
Drives bone formation
Post-menopausal women with previous fracture.
Loss of function calcium-receptor mutations results in what shift on the calcium-PTH curve?
Rightward shift.
i.e. more calcium is required to elicit the same amount of suppression
What effect do loss-of-function calcium receptor mutations have on PTH levels?
Increased PTH levels (because less suppression)
What are two genetic types of calcium-receptor mutations?
1) Heterozygous
2) Homozygous
A heterozygous calcium-receptor mutation is also called what?
Familial hypercalcaemia hypocalciuria
What is a homozygous calcium-receptor mutation called?
Neonatal severe hyperparathyroidsm
Familial hypercalcaemia hypocalciuria presents like what other condition?
What’s the difference?
Primary hyperparathyroidism
Hypocalciuria (in Primary HPT, you get hypercalciuria)
What is the role of the calcium receptor in the nephron?
Reduce calcium reuptake
In FHH, what change occurs in the nephron?
Becomes less sensitive to calcium, so begins to reabsorb it
What two effects does FHH have then?
1) Increased PTH secretion because CaR not inhibiting.
2) Increased Ca reabsorption because less sensitive to high concentrations.
What finding after a parathyroidectomy would make you think FHH?
Persistent hypercalcaemia.
what pharmacological agent is used to treat FHH?
Calcimimetics (reintroduce calcium sensitivity)
What is the treatment for neonatal severe hyperparathyroidism?
Early PTX
Lifelong calcium + vitamin D supplementation.
What is a gain of function CaR mutation disease called?
Autosomal dominant hypocalcaemia
Why should you NOT given vitamin D supplements to ADH patients?
Increases calcium
Hypercalciuria
= Kidney stones / nephrogenic diabetes insipidus
