Lecture 1 - Control of extracellular calcium homeostasis Flashcards
Hypocalcaemia: what is it, what symptoms are present with it, and what signs are medically used to detect it?
Low blood calcium levels
Increased nerve excitability - Tetany (spasms), severe forms can cause death by asphyxiation
Chvostek sign
Trousseaus sign
Chvostek’s sign: what is it?
Twitching of facial muscles in response to tapping over the facial nerve
Trousseaus sign
Involuntary contraction of the muscles in the hand and wrist (i.e., carpopedal spasm) that occurs after the compression of the upper arm with a blood pressure cuff
Hypercalcaemia: what is it and what symptoms are there for it?
Too high blood calcium levels
- Neuromuscular excitability leading to cardiac arrhythmias, lethargy, death
Calcium stores: what types are their, where are they located, and what percentage of the body’s calcium storage do they contribute to?
Insoluble - bones and teeth - 99%
Intracellular soluble - cytosol and nucleus - <0.1%
Intracellular insoluble - Plasma membrane, mitochondria, ER, and other organelles - 0.9%
Extracellular soluble - extracellular fluid - 0.1%
Ca²⁺o homeostasis is maintained by balance of Net Dietary Intake and Urinary Excretion
Primary Ca²⁺ regulating endocrine organ is
the Parathyroid Gland
Parathyroid Hormone (PTH)
Produced in Chief cells of Parathyroid gland.
∙ 84 αα hormone but synthesised as:
pre-pro PTH (115 αα)
proPTH (90 αα)
1-84 PTH (t1/2 < 20 mins)
∙ PTH elevates plasma Ca²⁺ levels by:
↑ Bone resorption
↑ Renal Ca²⁺ reabsorption i.e. ↓excretion
(but also ↑Pi excretion)
↑ Production of 1,25(OH)2D3 (Vit D)
∙ PTH secretion is inversely proportional to serum Ca²⁺
Daily pulsatile PTH secretion
Results in mineralised bone formation
Treatment of Post-fracture Osteoporosis
- Teriparatide (Forteo) PTH 1-34
- Anabolic for bone. ↓ Vertebral & non-vertebral fractures in
postmenopausal ♀ with osteoporosis. - Self-injected (Thigh/Abdomen, requires training)
s.c. 20 μg/day for 24 months max. £3.5k p.a. - Recommended where alendronate / risedronate not tolerated or
following unsatisfactory response. Contraindicated with
hypercalcaemia, and small, transient ↑ serum calcium possible.
Vitamin D
1,25(OH)2 vitamin D3
Cholesterol
Intestine (Pro-vitamin D3 (7-dehydrocholesterol))
Skin, through UV -> preVitamin D3 - vit d3
Liver (+OH) 25(OH)D3 (Calcifediol) 30ng/ml (constitutive process)
Kidney (+OH) 1,25(OH)2D3 (Calcitriol) 0.03ng/ml (PTH reliance)
The final step is catalysed by 1α- Hydroxylase primarily in the renal Proximal Tubule.
1,25(OH)2D3
1,25(OH)2D3 can ↑ net intestinal Ca²⁺ uptake from 200 to as much as 600 mg / day. It ↑ calbindin expression (D9k and D28k - see later lecture).
1,25(OH)2D3 can also ↑ serum Ca²⁺ levels by
↑ bone resorption and renal Ca²⁺ reabsorption (as for PTH).
Vit D3 (& its –OH derivatives) are lipid soluble → carried in plasma bound to specific globulin VitD binding protein (DBP).
Intestinal Ca²⁺ absorption
● 90% of dietary Ca²⁺ absorbed in duodenum, both paracellularly (passive), and, transcellularly (active) requiring 1,25(OH)2D3.
● Very similar in renal DCT except TRPV5 predominant, and calbindin-D28k replaces D9k. Again needs 1,25(OH)2D3.
Vitamin D receptors (VDRs)
Activation of nuclear vitamin D receptor (VDR) →
transcriptional regulation of vitamin D-responsive genes.
VDR knockout mice exhibit no abnormalities before
weaning but after weaning exhibit:
* Impaired bone formation
(≡vitamin D-dependent rickets type II)
* Uterine hypoplasia
* Failure to thrive
* Hypocalcaemia
* Growth retardation
* Alopoecia
* Infertility
Vitamin D sources
Dietary Sources – Lipid soluble:
Oily Fish e.g. salmon
Milk (variable)
Ocean - calcium rich environment, organisms in the ocean focus on removing calcium while terrestial focus on gaining calcium (using UVR)
Vitamin D deficiency
∙ Rickets – Vitamin D deficiency due to inadequate intake of proVit, or, sun exposure.
Chronic deficiency → 2oHPT, osteomalacia
