Lecture 2 - Clinical mineral dysfunction Flashcards
Primary vs secondary hyperthyroidism
1 - parathyroid gland itself
2 - something else is telling the PT gland to secrete more PTH
HPT: what is it, what are the types, and what does it cause?
Hyperthyroidism
- 1°HPT
- 2°HPT
Excess secretion of PTH
1°HPT: what is it, what is it caused by, and what does it cause?
Primary hyperparathyroidism - a common endocrinopathy
Generally by hyperplasia - a monoclonal parathyroid adenoma caused by:
* Mutation of Vitamin D receptor gene (VDR)
* Mutation of MEN1 (multiple endocrine neoplasia) tumour suppressor gene
* Overexpression of cyclin D1 (cell cycle regulator); implicated in 20-40% sporadic PT adenomas.
- Hypercalcaemia
- Hypophosphatemia
- Bone demineralisation
- Hypercalciuria - kidney stones
- Multiple bone cysts (osteitis fibrosa cystica)
1°HPT: what are the statistics?
Incidence in the UK is ~1/1000
Accounts for 54% of all cases of hypercalcaemia
Treatments of primary HPT: what is the main and easiest option, what is the main primary HPT complication, and what treatments are suggested for this?
Parathyroidectomy (PTx) - removing the gland with the tumour
Main complication - nephrolithiasis
- Hydration
- Moderate Ca²⁺ intake
PTx: what is it, what are the benefits, and what are the disadvantages?
Parathyroidectomy - removing the gland with the tumour
- Relatively inexpensive & curative
- Long-term medical follow-up
- Ca²⁺/vit D replacement for life.
- If all four glands need to be removed, with no PTH, there is a steady drop in serum Ca²⁺, causing hypocalcaemic tetany
Tetany after thyroid surgery: what may it be caused by?
Iatrogenic (doctor-caused) hyperparathyroidism
Parathyroidectomy: what is it and what is the standard process?
PTx - removing the gland with the tumour
- Bilateral neck exploration
- Gland visualisation
- Excision
Parathyroidectomy: what are the current employed methods and why are these methods preferred?
- Pre-operative parathyroid localisation techniques (including High-resolution neck ultrasonography (US), Radio-guided MIRP)
- Surgery to remove the localised tumour
- Most 1°HPT cases result from solitary parathyroid adenoma
- Less invasive due to pre-operative localisation
- Can be performed under local anaesthetic (+ sedative)
Parathyroidectomy video
http://www.parathyroid.com/
https://www.google.com/url?q=http://www.parathyroid.com/&sa=D&source=editors&ust=1730823065350244&usg=AOvVaw2vJTm_73AhdZm7cWCuXi3B
2°HPT: what is it, what may it be caused by, what does it cause?
Secondary hyperparathyroidism (2°HPT)
Increased PTH secretion caused by:
* Decrease in serum Ca²⁺
* Prolonged serum phosphate (Pᵢ) increase (may be due to CKD)
* Vitamin D deficiency (may be due to kidney damage) - no PTH negative feedback
CKD: what is it, what happens in it, and how does it relate to hyperthyroidism?
Chronic kidney disease
Damage to the kidneys
Renal cells fail to react to PTH, meaning the Kidney fails to excrete sufficient PO₄ or generate sufficient calcitriol, resulting in secondary HPT
Standard movement of sodium, phosphate, and PTH in the proximal tubule
- NaPᵢ brings sodium and phosphate in but is inhibited by PTH
- NHE - sodium, proton exchange pump brings Na⁺ in and H⁺ out
- 1αOHase hydroxylates calcifediol into calcitriol, stimulated by PTH
Movement of sodium, phosphate, and PTH in the proximal tubule in CKD
Proximal tubule fails to respond to PTH
- NaPᵢ brings too much sodium and phosphate in due to lack of PTH inhibition
- NHE brings less Na⁺ in and H⁺ out
- 1αOHase hydroxylates produces less calcitriol
Effects:
Acidosis, hyperphosphataemia, and hypercalcaemia, etc
2°HPT treatment
- Phosphate binders
- Vitamin D
- Calcimimetics
- Combined Vit D/Cinacalcet:
Vitamin D treatment for 2°HPT: what does it result in and what is a disadvantage of this treatment?
- Increase in serum Ca²⁺ and Pᵢ
- Slow onset decrease in PTH secretion
No reversal of PT hyperplasia
Calcimimetics treatment for 2°HPT: what is it, what does it do, when is it used?
Cinacalcet - 1 oral dose daily
- Gives rapid decrease in PTH secretion (nadir in 2-4h)
- PTH levels are stably reduced even after many years
- Effectively a chemical PTx.
Only for dialysis patients, prone to causing hypocalcaemia
Combined Vit D/cinacalcet treatment for 2°HPT: how does it work and what does it result in?
Different mechanisms – decrease the potentiation of PTH
Vitamin D supports Ca²⁺ levels
Phosphate binders: what are they, what do they do, when are they taken, what are some examples, and what do they do?
Compounds that bind Pᵢ in the GI tract - insoluble compounds
Usually taken with meals to bind ingested Pᵢ
- Renagel (sevelamer hydrochloride) - used for the control of hyperphosphataemia in adult dialysis patients, has a weak effect on decreasing PTH - used in conjunction with Vit D
- Calcichew - Can increase blood Ca²⁺ levels
- Titralac (Ca²⁺ carbonate) - Can increase blood Ca²⁺ levels
- Phosex (Ca²⁺ acetate) bind Pᵢ - Can increase blood Ca²⁺ levels
Osteoporosis: what is it defined as, what is it caused by, what does it cause, what is an example of a case where it is prevalent, and why is it so significant?
Bone Mineral Density (BMD) > 2.5 S.D. below healthy controls
Imbalance in bone remodelling (i.e. an increase in resorption and a decrease in formation) - resulting in microfracture of the connections between bones, reducing overall bone integrity and strength
Fractures of the hip, spine, wrist, shoulder & pelvis
Prevalent in post-menopausal women.
Hip fractures associated with 20% mortality & 50% permanent disability (>90k pa UK)
Osteopenia: what is it?
Bone Mineral Density (BMD) <2.5 S.D. below healthy controls
Oestrogen deficiency: when does it occur, what relation does it have to osteoperosis, and what does it do to bones?
After menopause
Oestrogens bind osteoblastic
estrogen receptors, ERα & ERβ, affecting bone turnover
- Leads to an increase in bone turnover - leads to bone loss
- induces remodeling imbalance by increasing resorption phase (decreasing osteoclast apoptosis) and decreasing formation phase (increasing osteoblast apoptosis)
PBM: what is it and what is it used for?
Peak bone mass (PBM)
Determining adult bone health along with the rate of bone loss with age
Adult bone health: what is it determined by and what activities are beneficial/detrimental to skeletal health
Adult bone health is determined by:
* Peak bone mass (PBM)
* The rate of bone loss with age.
Weight-bearing exercise is generally beneficial to the skeleton
Excessive exercise/dieting leading to amenorrhoea would be detrimental
Treatment of post-menopausal osteoporosis: what are they and what do they do?
- 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)
Treatment of post-fracture osteoporosis: what are they and what do they do?
- 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)
Teriparatide: what is it, what is its structure, what does it do, what should be kept in mind when using it, how is it used, and when is it used?
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
Loss-of-function Ca²⁺ receptor mutations: what do they result in, why, and what are the types?
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)
FHH: what is it, what does it result in, how significant is it, how is it treated, what are the types, and what are they caused by?
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
FHH and 1°HPT: how do they relate, how can you differentiate between them, and how is hypercalcemia treatment affected by them?
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
NSHPT: what is it, what does it do, how dangerous is it, how is it treated, and are there any follow-ups required after treatment?
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
Gain-of-function Ca²⁺ receptor mutations: what do they result in and what is an example?
Results in a decrease in PTH secretion and thus causes hypocalcaemia
Autosomal Dominant Hypocalcaemia (ADH)
ADH: what is it, what does it result in, what effects does it cause, what are the types, and what are they caused by?
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
Vitamin D treatment for ADH: what effects can it cause?
- Hypercalciuria
- Nephrocalcinosis
- Nephrogenic diabetes insipidus.
Renal Ca²⁺ reabsorption: how does it work and how is it regulated?
- 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
CaSR LOF: how does it affect Ca²⁺ reabsorption?
LOF means its effects don’t occur - no K⁺ channel inhibition and no claudin-14 expression
Na⁺/K⁺/2Cl⁻ cotransporter: what is it and what does it do?
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
