Lecture 2 - Clinical mineral dysfunction

Question 1

Primary vs secondary hyperthyroidism

Answer 1

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

Question 2

HPT

Answer 2

Hyperthyroidism

1deg vs 2deg

Excess secretion of PTH

Question 3

1oHPT

Answer 3

Primary hyperparathyroidism

∙ A common endocrinopathy generally caused by a monoclonal parathyroid adenoma (Hyperplasia).

Hypercalcaemia
Hypophosphatemia
Bone demineralisation
Hypercalciuria → kidney stones
Multiple bone cysts (osteitis fibrosa cystica)

• 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.

Question 4

Treatment of primary HPT

Answer 4

Parathyroidectomy (PTx):
rel. inexpensive & curative.
Long-term medical follow-up
Ca2+/vit D replacement for life.
∙ W/o Ca2+ replacement, steady drop in serum Ca2+ → hypocalcaemic tetany. Tetany after thyroid surgery indicates inadvertent PTX.
Since main 1oHPT complication is nephrolithiasis:
Hydration, Moderate Ca2+ intake

Question 5

Parathyroidectomy

Answer 5

Traditional surgical approach for PTx:
bilateral neck exploration, gland visualisation, excision
However, most 1oHPT cases result from solitary
parathyroid adenoma. Thus, improved methods employ
pre-operative parathyroid localisation techniques inc.
High-resolution neck ultrasonography (US)
Radio-guided MIRP.
Less invasive due to pre-operative localisation.
Can be performed under local anaesthetic (+ sedative)

Answer 5

http://www.parathyroid.com/

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

Question 5

2oHPT

Answer 5

Secondary hyperparathyroidism (2oHPT)

∙ PTH secretion ↑ by ↓ in serum Ca2+ or a prolonged ↑ in serum phosphate (Pi).

∙ In chronic kidney disease (CKD), the kidney fails to excrete sufficient PO4 or generate sufficient calcitriol

Question 6

(1) Treatment of 2oHPT

Answer 6

Phosphate binders

Vitamin D:
No reversal of PT hyperplasia.
↑ serum Ca2+ and Pi
Slow onset ↓ in PTH secretion.
Calcimimetics:
Cinacalcet (1 dose daily - oral) gives rapid
↓ in PTH secretion (nadir in 2-4h)
Stably reduced even after many years.
Effectively a chemical PTx.
Only for dialysis patients (hypocalcaemia)
Combined Vit D / Cinacalcet:
Different mechanisms – potentiation of PTH↓ ?
Vitamin D supports Ca2+ levels

Question 7

Phosphate binders

Answer 7

bind Pi in the GI tract → insoluble compound
usually taken with meals to bind ingested Pi

Renagel (sevelamer hydrochloride) for the control
of hyperphosphataemia in adult dialysis patients.
Weak effect on ↓PTH - used in conjunction with Vit D.

Calcichew, Titralac (Ca carbonate) and Phosex (Ca acetate) bind Pi - Can increase blood Ca levels

Question 8

Osteoporosis

Answer 8

Osteoporosis: Defined as –
Bone Mineral Density (BMD)
> 2.5 S.D. below healthy controls.
(< 2.5 S.D. = “Osteopenia”)
Imbalance in bone remodelling
i.e. ↑ resorption +/- ↓ formation.
Prevalent in post-menopausal ♀. Fractures
of the hip, spine, wrist, shoulder & pelvis.

● Hip fractures associated with 20% mortality
& 50% permanent disability (>90k pa UK)

Question 9

Oestrogen deficiency

Answer 9

Drops after menopause

Oestrogens bind osteoblastic
estrogen receptors, ERα & ERβ

• leads to ↑ bone turnover
• Lack of leads to bone loss
• induces remodeling imbalance by ↑ resorption phase (↓ OC apoptosis ) & ↓ formation phase (↑ OB apoptosis)

Question 10

PBM

Answer 10

Adult bone health is determined by
a) peak bone mass (PBM)
b) 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.

Question 11

Treatment of Postmenopausal Osteoporosis

Answer 11

∙ Bisphosphonates: Alendronate, etidronate, risedronate for ↓ fractures in postmenopausal women with osteo-porosis who have not had a fracture. NICE guidelines
* P-C-P backbone resembles P-O-P
pyrophosphate. Binds to bone,
inhibits osteoclast action.
* Severe heartburn – remain
upright 30-mins post drug

Question 12

Treatment of Post-fracture Osteoporosis

Answer 12

Teriparatide (forteo) PTH 1-34

• ↓ Vertebral & non-vertebral fractures in postmenopausal ♀ with osteoporosis. Anabolic for bone. Insufficient hip fracture data.
• Contraindicated with hypercalcaemia, and small, transient ↑ serum calcium possible. Injected s.c. 20 μg/day for 24 months max.
• Recommended where alendronate / risedronate not tolerated or following unsatisfactory response.
• Can be self-injected with training (Thigh/Abdomen). £3.5k p.a.

Question 13

Loss-of-function CaR mutations

Answer 13

↑ PTH secretion and thus cause hypercalcaemia

Heterozygous - Mild-to-Moderate Familial Hypercalcaemia Hypocalciuria (FHH)
Homozygous - Neonatal Severe Hyperparathyroidism (NSHPT)

Question 14

FHH

Answer 14

FHH1
FHH2
FHH3

Question 15

Familial Hypocalciuric Hypercalcemia (FHH)

Question 16

NSHPT, Neonatal Severe Hyperparathyroidism

Question 17

Gain-of-function CaR mutations

Answer 17

↓ PTH secretion and thus cause hypocalcaemia

Autosomal Dominant Hypocalcaemia (ADH)

Question 18

ADH

Answer 18

Autosomal Dominant Hypocalcaemia

ADH1
ADH2

Activating mutation: i.e. CaR more sensitive to Ca2+

• Hypocalcaemia, relative hypercalciuria & low serum PTH levels. Also hypomagnesaemia and hyperphosphataemia.
• Can be asymptomatic - but in some cases results in nephrocalcinosis, nephrolithiasis and renal insufficiency.
• Vit D treatment to ↑ serum calcium can cause significant hypercalciuria → nephrocalcinosis as well as nephrogenic diabetes insipidus.

Answer 19

Lumen of thick limb becomes poristive charged- Ca2+ and MG2+ reabsorption decreases

2Cl- and Na+ are moved, resulting in the thick limb becoming positively charged as K+ ions are recycled - result in more Ca2+ being reabosrbed as the positivity causes it to move through gaps between cells

This can be turned off

LOF means this isn’t turned off

idk ngl go over this again