Lecture 2 - Clinical mineral dysfunction Flashcards

Question

Treatment of post-menopausal osteoporosis: what are they and what do they do?

Answer 1

* Bisphosphonates: Alendronate, etidronate, risedronate for decrease in fractures in postmenopausal women with osteoporosis who have not had a fracture (NICE guidelines) * P-C-P backbone resembles P-O-P pyrophosphate - binds to bone, inhibits osteoclast action, may cause severe heartburn – remain upright 30-mins post drug * Calcium/vitamin D (NICE guidelines)

Answer 2

* Teriparatide (Forteo) - anabolic for bone, reduces (non)vertebral postmenopausal fractures in those with osteoporosis * Bisphosphonates: Alendronate, etidronate, risedronate for decrease in fractures in postmenopausal women with osteoporosis who have not had a fracture (NICE guidelines) * P-C-P backbone resembles P-O-P pyrophosphate - binds to bone, inhibits osteoclast action, may cause severe heartburn – remain upright 30-mins post drug * Calcium/vitamin D (NICE guidelines)

Answer 3

Forteo - the first 1-34 aa's of PTH * Anabolic for bones * Causes a decrease in (non)vertebral fractures in postmenopausal women with osteoporosis Also contraindicated with hypercalcemia as a small, transient increase in calcium is possible Injected (may be self-administered) in thigh/abdomen s.c. 20 μg/day for 24 months max (£3.5k p.a.) Recommended where alendronate/risedronate not tolerated or following unsatisfactory response

Answer 4

Results in an increase in PTH secretion and thus causes hypercalcemia - this is because receptor activation indicates the presence of Ca²⁺ and so PTH secretion is decreased to decrease renal reabsorption so a LoF mutation results in uninhibited PTH secretion * Heterozygous - Mild-to-Moderate Familial Hypercalcaemia Hypocalciuria (FHH) * Homozygous - Neonatal Severe Hyperparathyroidism (NSHPT)

Answer 5

Familial Hypocalciuric Hypercalcemia (FHH) Inactivating mutation (i.e. CaR less sensitive to Ca²⁺) - resulting in high PTH levels, causing hypercalcemia * Lifelong, mild-to-moderate hypercalcemia * Usually asymptomatic * Inappropriate hypocalciuria * Easily confused with more serious 1°HPT Calcimimetic treatment - by increasing the CaR sensitivity FHH1 - CaR mutation (most frequent) FHH2 - Gα₁₁ mutation FHH3 - adaptor-protein-2 sigma-2 (AP2σ2) mutation

Answer 6

FHH - less severe, mostly asymptomatic 1°HPT - severe cause of hypercalcemia with various lethal effects Urinary Ca²⁺ levels: - In 1°HPT the kidneys are fine so release high amounts in the urine - During FHH, the renal and PT Ca²⁺ receptors result in urinary Ca²⁺ reabsorption, resulting in hypocalciuria * FHH must be ruled out prior to PTX for 1°HPT * Persistence of hypercalcaemia post-PTX suggests FHH

Answer 7

Neonatal Severe Hyperparathyroidism - the homozygous form of FHH (both alleles mutated) * Bone demineralisation with long bone & rib fractures * Failure to thrive * Constipation * Substantial hypercalcaemia with inappropriately high PTH levels Lethal without PTx early in life Parathyroidectomy required - after PTx, life-long calcium & Vit D required

Answer 8

Results in a decrease in PTH secretion and thus causes hypocalcaemia Autosomal Dominant Hypocalcaemia (ADH)

Answer 9

Autosomal Dominant Hypocalcaemia - activating mutation, calcium receptor is more sensitive to Ca²⁺, resulting in hypocalcemia - activation of the CaSR results in a decrease in PTH secretion and therefore a decrease in renal Ca²⁺ reabsorption * Hypocalcaemia * Low serum PTH levels * Relative hypercalciuria * Hyperphosphataemia * Hypomagnesaemia * Can be asymptomatic - but in some cases results in nephrocalcinosis, nephrolithiasis and renal insufficiency. ADH1 - CaR mutation ADH2 - Gα₁₁ mutation

Answer 10

* Hypercalciuria * Nephrocalcinosis * Nephrogenic diabetes insipidus.

Answer 11

* Action of the Na⁺/K⁺/2Cl⁻ cotransporter causes the reabsorption of Na⁺, K⁺, and 2Cl⁻ ions * Na⁺ ions move through the cells through their Na⁺/K⁺ ATPase channel proteins, the 2Cl⁻ ions move straight through to the blood through its channel protein, and K⁺ ions get recycled back into the lumen of the thick limb * This all results in the generation of a positively charged lumen of the thick limb, * Ca²⁺ and Mg²⁺ ions repel the charge of the thick limb and travel paracellularly into the bloodstream The CaSR detects systemic/reabsorbed Ca²⁺ and when Ca²⁺ levels are high, it inhibits the action of the K⁺ channel as well as promotes the expression of claudin-14, a protein that blocks the path of Ca²⁺ and Mg²⁺ ions from travelling paracellularly

Answer 12

LOF means its effects don't occur - no K⁺ channel inhibition and no claudin-14 expression

Answer 13

Generates a positive charge within the lumen of the thick limb along with the K⁺ channel protein Results in reabsorption of Ca²⁺ and Mg²⁺ ions