Lecture 2 - Clinical mineral dysfunction Flashcards

1
Q

Primary vs secondary hyperthyroidism

A

1 - parathyroid gland itself
2 - something else is telling the PT gland to secrete more PTH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

HPT: what is it, what are the types, and what does it cause?

A

Hyperthyroidism

  • 1°HPT
  • 2°HPT

Excess secretion of PTH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

1°HPT: what is it, what is it caused by, and what does it cause?

A

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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

1°HPT: what are the statistics?

A

Incidence in the UK is ~1/1000

Accounts for 54% of all cases of hypercalcaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

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?

A

Parathyroidectomy (PTx) - removing the gland with the tumour

Main complication - nephrolithiasis

  • Hydration
  • Moderate Ca²⁺ intake
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

PTx: what is it, what are the benefits, and what are the disadvantages?

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Tetany after thyroid surgery: what may it be caused by?

A

Iatrogenic (doctor-caused) hyperparathyroidism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Parathyroidectomy: what is it and what is the standard process?

A

PTx - removing the gland with the tumour

  • Bilateral neck exploration
  • Gland visualisation
  • Excision
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Parathyroidectomy: what are the current employed methods and why are these methods preferred?

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Parathyroidectomy video

A

http://www.parathyroid.com/

https://www.google.com/url?q=http://www.parathyroid.com/&sa=D&source=editors&ust=1730823065350244&usg=AOvVaw2vJTm_73AhdZm7cWCuXi3B

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

2°HPT: what is it, what may it be caused by, what does it cause?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

CKD: what is it, what happens in it, and how does it relate to hyperthyroidism?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Standard movement of sodium, phosphate, and PTH in the proximal tubule

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Movement of sodium, phosphate, and PTH in the proximal tubule in CKD

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

2°HPT treatment

A
  • Phosphate binders
  • Vitamin D
  • Calcimimetics
  • Combined Vit D/Cinacalcet:
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Vitamin D treatment for 2°HPT: what does it result in and what is a disadvantage of this treatment?

A
  • Increase in serum Ca²⁺ and Pᵢ
  • Slow onset decrease in PTH secretion

No reversal of PT hyperplasia

17
Q

Calcimimetics treatment for 2°HPT: what is it, what does it do, when is it used?

A

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

18
Q

Combined Vit D/cinacalcet treatment for 2°HPT: how does it work and what does it result in?

A

Different mechanisms – decrease the potentiation of PTH

Vitamin D supports Ca²⁺ levels

19
Q

Phosphate binders: what are they, what do they do, when are they taken, what are some examples, and what do they do?

A

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
20
Q

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?

A

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)

21
Q

Osteopenia: what is it?

A

Bone Mineral Density (BMD) <2.5 S.D. below healthy controls

22
Q

Oestrogen deficiency: when does it occur, what relation does it have to osteoperosis, and what does it do to bones?

A

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)
23
Q

PBM: what is it and what is it used for?

A

Peak bone mass (PBM)

Determining adult bone health along with the rate of bone loss with age

24
Q

Adult bone health: what is it determined by and what activities are beneficial/detrimental to skeletal health

A

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

25
Q

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

A
  • 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)
26
Q

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

A
  • 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)
27
Q

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?

A

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

28
Q

Loss-of-function Ca²⁺ receptor mutations: what do they result in, why, and what are the types?

A

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)
29
Q

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?

A

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

30
Q

FHH and 1°HPT: how do they relate, how can you differentiate between them, and how is hypercalcemia treatment affected by them?

A

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
31
Q

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?

A

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

32
Q

Gain-of-function Ca²⁺ receptor mutations: what do they result in and what is an example?

A

Results in a decrease in PTH secretion and thus causes hypocalcaemia

Autosomal Dominant Hypocalcaemia (ADH)

33
Q

ADH: what is it, what does it result in, what effects does it cause, what are the types, and what are they caused by?

A

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

34
Q

Vitamin D treatment for ADH: what effects can it cause?

A
  • Hypercalciuria
  • Nephrocalcinosis
  • Nephrogenic diabetes insipidus.
35
Q

Renal Ca²⁺ reabsorption: how does it work and how is it regulated?

A
  • 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

36
Q

CaSR LOF: how does it affect Ca²⁺ reabsorption?

A

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

37
Q

Na⁺/K⁺/2Cl⁻ cotransporter: what is it and what does it do?

A

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