Endocrinology: Calcium Roles and Regulation Flashcards
Roles of calcium
- Excitability of nerves
- Control of Ca2+ channels (both voltage and ligand gated)
- Cardiac, skeletal, and smooth muscle contractility (excitation-contraction coupling and cross bridge cycling)
- Neurotransmitter release and hormone secretion (stimulus-secretion coupling)
- Blood clotting
- Maintenance of cellular integrity
- Bone and teeth structure and strength
Why do plasma calcium levels need to be maintained within narrow limits?
Maintaining narrow limits for plasma calcium is essential for the normal functioning of various physiological processes, e.g., listed above. Imbalances can lead to various problems for health.
How is free plasma [Ca2+] controlled?
- Slow: absorption/ excretion (involving intestines and kidneys
- Fast: exchange between fixed and free pools (transfer from bone to plasma)
Endocrine regulation of plasma [Ca2+]
- Three hormones regulate plasma concentration of Ca2+ (and hence PO43-)
- Parathyroid hormone (PTH)
- Calcitonin
- Vitamin D/ calcitriol
The parathyroid glands
4 rice grain-sized glands located on the posterior surface of the thyroid
Sensing and responding to changes in plasma [Ca2+]
- Most Ca2+ (99%) is locked up in an insoluble form, e.g., calcium hydroxyapatite
- The free (unbound) [Ca2+] in the ECF is biologically active and subject to regulation in a narrow range
- Calcium sensing receptors in the parathyroid gland are sensitive to free [Ca2+]
Parathyroid hormone
- Primary hormone responsible for maintenance of Ca2+
- PTH promotes transfer of Ca2+ from bone fluid into circulation
- In addition to enhancing bone dissolution (slow), PTH also stimulates transfer of Ca2+ from bone fluid (labile pool) across both osteocytes and osteoblasts into central canal and circulation (rapid
- PTH raises plasma Ca2+ by withdrawing Ca2+ from the ‘bone bank’
- Effects on kidneys: conserves Ca2+ (by promoting Ca2+ reabsorption in distal tubule) and increases removal of PO43- (by blocking reabsorption
- Enhances activation of vitamin D
Calcitonin
- Produced by the C cells of the thyroid
- Protective against hypercalcaemia (plays little to no role in the normal control of calcium metabolism; as evidenced by thyroid removal/ calcitonin secreting tumours)
- May play a role in protecting skeletal integrity when there is a high Ca2+ demand (e.g., pregnancy and breastfeeding)
- Decreases the movement of Ca2+ from the labile pool and inhibits osteoclast activity in bones (decreasing bone resorption/ dissolution)
- Decreases reabsorption of both Ca2+ and PO43- form the kidney tubules, thereby decreasing plasma [Ca2+] and [PO43-]
Vitamin D
calcitriol
- Synthesised from cholesterol derivative when exposed to sunlight
- Levels supplemented by dietary intake
- Must be activated to calcitriol by liver and kidneys before it can exert its effect on intestines
- Increase Ca2+ and PO43- absorption from the intestine
- Increases responsiveness of bone to PTH
- Vitamin D is a steroid hormone
- The vitamin D receptor is a nuclear receptor
- Active vitamin D binds to the receptor which forms a heterodimer with the retinoid-X receptor
- This then binds to hormone response elements on DNA resulting in expression of specific gene products
- This ultimately increases Ca2+ uptake and translocation across intestinal epithelium
PTH role in bone remodelling
PTH is secreted by the parathyroid glands and is the primary hormone responsible for maintenance of Ca2+.
Bone remodelling
- Osteoclasts: secrete acids which dissolve Ca3(PO4)2 crystals and break down organic matrix
- Osteoblasts secrete organic matrix in which Ca3(PO4)2 precipitates, RANK ligand (RANKL) to increase osteoclast action, osteoprotegerin (OPG) to decrease osteoclast action
- PTH stimulates osteoclasts indirectly by binding to osteoblasts: increases RANKL expression, decreases OPG, increases osteoclast maturation
- More osteoclasts = more bone resorption
How do disorders of calcium metabolism arise?
can arise from abnormal levels of PTH or vitamin D
Hyperparathyroidsm
Hyperparathyroidism: stones, bones, abdominal groans, and psychic moans
- Predominant cause (80%) is adenoma or the parathyroid
- Overproduction of PTH leads to hypercalcemia and hypophosphatemia
- Bone disease (osteitis fibrosa cystica) – high bone turnover due to increased osteoclast number; bone pain. Osteoporosis
- Kidney disease – kidney stone and loss of normal kidney function
- CNS dysfunction – stupor/ coma, fatigue, depression, difficulty in concentrating, personality changes
Hypoparathyroidism
Hypoparathyroidism: CATS go numb – convulsions, arrhythmias, tetany and numbness/ paraesthesia in hands, feet, around mouth and lips
- Surgical: removal/ destruction of parathyroid glands; failure to secrete PTH
- Idiopathic: autoimmune diseases (mostly in girls aged 5-10 years)
- PTH or vitamin D deficiency or insensitivity
- Familial – rare; failure to produce PTH
- Neuromuscular effects: increased neuromuscular excitability and tetany (severe muscle contractions of the hands and face)
- Cardiac effects: prolongation of the QT interval and impaired excitation-contraction coupling
- Ophthalmologic effects: cataracts
- Dermatologic effects: dry flaky skin and brittle nails
Chvostek’s sign
- A clinical sign of nerve hyperexcitability and tetany seen in hypocalcaemia associated with hypoparathyroidism
- When the facial nerve is tapped at the angle of the jaw (I.e., masseter muscle), the facial muscles on the same side of the face will contract momentarily (typically a twitch of the nose or lips): over responds to stimulus
- May also be encountered in respiratory alkalosis (decreased free plasma Ca2+ as more becomes bound to plasma proteins) and hypomagnesemia
- Not sensitive nor specific for hypocalcaemia, since it is absent in about one third of patients with hypocalcaemia, and present in approximately 10% of people with normal calcium levels
Trousseau’s sign
- A clinical sign of nerve hyperexcitability and tetany seen in hypocalcaemia associated with hypoparathyroidism
- Blood pressure cuff is placed around the arm and inflated over the systolic blood pressure (to occlude brachial artery) and held in place for 3 minutes
- In the absence of blood flow spasm of the muscles of the hand and forearm will be induced
- Flexure and extension of wrist and finger joints and adduction of fingers
- More sensitive and specific than Chvostek’s for hypocalcaemia: present in 94% of patients with hypocalcaemia and only 1% of people with normal calcium levels
