Session 9: Endocrine Control of Calcium Homeostasis Flashcards
What is the role of calcium in our diet?
- Micronutrient = essential in our diet
- Macromineral = 0.7g/day
What minerals are stored in bones?
Calcium and phosphate
What are the cellular functions of calcium?
1) Hormone secretion
2) Exocytosis
3) Cell proliferation
4) Muscle contraction
5) Nerve conduction
What are the bodily functions of calcium?
1) Blood clotting
2) Blood pressure
3) Sleep
What are the THREE forms of serum calcium found in the blood?
1) Free ionised calcium = biologically active (50% of total serum calcium)
2) Calcium bound to anionic sites on serum proteins e.g., albumin (40% of total serum calcium)
3) Calcium complexed with low molecular weight organic anions e.g., phosphate, citrate and oxalate (10% of total serum calcium)
What is the biologically active serum calcium found in blood?
Free ionised calcium (50% of total serum calcium)
What is the normal range of total serum calcium?
2.2 - 2.6 mmol/L
What is the normal range of free ionised calcium in serum?
1.3 - 1.5 mmol/L
What is the intracellular calcium concentration kept very low at?
10^-4 mmol/L
Why is it important that there is a low intracellular calcium concentration maintained?
Excessive calcium influx can lead to loss of regulation and cell death - fatal
How is low calcium levels maintained within cells, despite the large inward concentration gradient?
Low intracellular calcium levels are achieved by…
- Relative** impermeability of plasma membrane to calcium**
- Calcium buffers
-** Pumping calcium out the cells (Na-Ca exchanger)**
- Calcium sequestered OUT intracellular space into organelles (e.g., ER, mitochondria)
Why does calcium enter cells?
Signalling processes e.g., excitation-contraction coupling in muscles
Why do serum calcium blood tests need to be adjusted for albumin?
50% of free ionised calcium that is biologically active is bound to albumin
The corrected calcium concentration depends on the level of albumin which determines whether free calcium is in the optimal range.
What are some sources of serum calcium and approximate quantities of each (mmol)?
1) BONE = 500mmol = exchanged between bone/ECF daily
2) KIDNEYS = 250mmol = reabsorbed into kidneys
3) GI TRACT = 15mmol = dietary calcium absorbed from gut
How is calcium lost from the body?
Calcium is lost in urine and feces
What is it called when normally calcium intake and its deposition in bone is matched by the excretion of calcium in urine and feces?
zero balance
What is positive calcium balance?
Intake > Output
Occurs during growth and increased dietary calcium intake.
What is negative calcium balance?
Intake < Output
Poor dietary calcium intake, poor absorption = role of calcitriol, Crohn’s, excessive loss = lactation, ageing.
Where is 99% of calcium in the body stored?
bone (~1kg)
What are the constituents of bone?
1) Extracellular matrix (proteins - 90% type 1 collagen)
2) Hydroxyapatite
3) Cells = osteoclasts and osteoblasts
What is the main protein found in the ECM of bone?
90% type 1 collagen
What is hydroxyapatite?
Crystalline complex of calcium and phosphate within and between collagen fibers of the matrix of bone
This mineralised matrix provides strength and stability to bone.
What type of cells does bone formation (ossification) occur via?
Osteoblast
What type of cells does bone breakdown (resorption) occur via?
Osteoclast
Osteoclasts release acids and enzymes to break down the matrix collagen and hydroxyapatite.
What two main hormones increase serum calcium levels?
1) Parathyroid hormone (PTH) released by parathyroid gland
2) 1,25-dihydroxyvitamin D (calcitriol) released by kidney
What is the short-term regulation of serum calcium level (hormonal)?
Parathyroid hormone (PTH) released by parathyroid gland
What is the medium to long-term regulation of serum calcium level (hormonal)?
1,25-dihydroxyvitamin D (calcitriol) released by kidney
What is the anatomy of the parathyroid gland?
- Four parathyroid glands (2 embedded in each thyroid gland)
- Located on posterior wall of thyroid gland
- Mainly secretes parathyroid hormone (PTH)
What is the histology of the parathyroid gland?
2 cell types:
Principal (Chief) cells = parathyroid hormone (PTH)
Oxyphil cells = unknown function
Describe some features of parathyroid hormone (PTH).
- Polypeptide hormone (84 aa)
- Half-life ~5 minutes
- Synthesised as preproPTH (115 aa) and cleaved to prePTH (90 aa) and then to PTH
What receptors found on the surface of chief cells in the parathyroid gland monitor serum calcium levels?
Calcium-sensing receptors found on the surface of chief cells in the parathyroid gland monitor serum calcium levels and respond to it accordingly
What stimulates PTH secretion?
Hypocalcemia
What inhibits PTH secretion?
- Hypercalcemia
- Increased 1,25 dihydroxyvitamin D (calcitriol)
What type of feedback loop is secretion of PTH and its regulation an example of?
Negative feedback
How does PTH act on target cells?
Via PTH1 and PTH2 receptors
What does PTH increase leading to?
Increased calcium
How does PTH increase blood calcium levels (kidneys, bone)?
KIDNEYS
1) Increased tubular reabsorption of calcium
2) Increased excretion of phosphate (which normally prevents calcium release from bone)
3) Increased synthesis of dihydroxyvitamin D (calcitriol) in kidneys
BONE
1) Stimulation of bone resorption
Indirect effect = binds to osteoblasts - which promotes secretion of cytokines that stimulate osteoclasts
Direct effect = promotes breakdown of matrix in bone
What does PTH decrease leading to?
Decreased calcium
What protein is mainly responsible for humoral hypercalcemia of malignancy?
Parathyroid Hormone Related Protein (PTHrP)
What are some normal in utero physiological functions/effects of Parathyroid Hormone Related Protein (PTHrP)?
- Growth and development of cartilage in utero
- Transport of calcium across placenta
Where is calcitriol (dihydroxyvitamin D) released from?
Kidney
How does the hormone dihydroxyvitamin D (calcitriol) increase serum calcium?
GI TRACT
- Increased absorption of calcium from diet (mediated by PTH that initially acts on kidneys to increase calcitriol synthesis)
KIDNEYS
- Increased reabsorption of calcium
BONE
- Stimulation of bone resorption
What proteins does dihydroxyvitamin D (Calcitriol) stimulate bone resorption via?
Matrix-destroying proteins e.g., alkaline phosphate
What type of hormone is vitamin D?
Steroid hormone
What are the two forms of vitamin D and their sources?
1) D3 (cholecalciferol) = sunlight, diet (oily fish, eggs, liver)
2) D2 (ergocalciferol) = yeast + fungi
What is the biologically active form of vitamin D known as?
Calcitriol
Is vitamin D fat soluble?
True
How is calcitriol synthesised from vitamin D?
1) Biologically inactive forms of vitamin D undergo hydroxylation to form active form (calcitriol)
What is vitamin D largely bound to?
Vitamin D is largely bound to vitamin D binding protein (DBP) with a small fraction in free form
What is the majority of circulating metabolite of vitamin D?
25-hydroxyvitamin D
Where is vitamin D3 (cholecalciferol) synthesised?
Keratinocytes of the deepest layer of skin (beneath cells with melanin)
How does vitamin D3 synthesis differ in people with pale skin?
People with pale skin tone
- Generate vitamin D3 under lower light conditions
- Higher risk of skin cancer (less melanin to provide sun protection)
How does vitamin D3 synthesis differ in people with darker skin?
People with darker skin tone
- Might not make enough vitamin D3 from sunlight exposure
- Lower risk of skin cancer (more melanin - providing more sun protection)
- Might need supplementation
What are the daily requirements of vitamin D for children >1 year and adults?
10 μg (400 IU)
What is the daily requirement of vitamin D for babies <1 year?
8-10 μg (240-400 IU)
How does PTH interact with calcitriol?
- PTH stimulates kidneys to convert more 25-hydroxyvitamin D to calcitriol - increasing calcitriol levels
- Increase action of calcitriol in the gut = more calcium absorbed from diet
How does calcitriol interact with PTH?
Stimulates absorption of calcium from diet (PTH-mediated)
What type of hormone is calcitonin?
Peptide hormone (32 aa)
Where is calcitonin secreted from?
Thyroid gland
Parafollicular (C) cells
What is the effect of calcitonin on calcium?
Calcitonin decreases serum calcium levels (opposes action of PTH and calcitriol)
How does calcitonin decrease serum calcium levels?
1) Inhibiting osteoclasts
2) Decrease kidney reabsorption of calcium into blood
3) Decrease gut absorption of calcium from diet
What are some other hormones involved in calcium homeostasis?
- Testosterone, oestradiol
- Glucocorticoids
- Thyroid hormones = Insulin, Insulin-like growth factor 1 (IGF-1) and growth hormone (GH)
The decline of what TWO hormones with age may lead to osteoporosis and increased bone resorption/breakdown?
Testosterone and oestradiol
The excess of which hormones may lead to osteoporosis due to increased bone resorption?
Glucocorticoids
What is the impact of insulin and insulin-growth factor 1 (IGF-1) on bone remodelling?
Stimulates bone formation
What is the impact of growth hormone on calcium homeostasis?
Stimulates calcium absorption in the gut
What are the signs and symptoms of hypercalcemia?
Stones, bones, groans, psychiatric overtones
NEUROLOGICAL - Lethargy, depression, decreased alertness, confusion, coma
GASTROINTESTINAL - Constipation, loss of appetite, abdominal pain, nausea/vomiting
RENAL - Polyuria, polydipsia, kidney stones
SKELETAL - Increased bone resorption, fracture risk, joint pain
CARDIAC - Abnormal heartbeat
What are the hormonal causes of hypercalcemia?
- Primary hyperparathyroidism = increased PTH
- Excess vitamin D action
- Malignancy (humoral hypercalcemia of malignancy)
What are the non-hormonal causes of hypercalcemia?
- Excessive calcium intake = milk alkali syndrome
- Drugs e.g, thiazides and lithium
What are the two most common causes of hypercalcemia?
Primary hyperparathyroidism
- 85% cases due to single adenoma of one of parathyroid glands
- PTH above normal range
Humoral Hypercalcemia of Malignancy
- Breast, lung and kidney tumors
- Parathyroid hormone related protein (PTHrP) above normal range
What is the management of hypercalcemia?
- Treat underlying cause (e.g., cancers)
- Fluids (0.9% NaCl)
- Parathyroidectomy
Calcium-lowering therapy
- Bisphosphonates = prevent bone resorption
- Calcitonin = prevent bone/kidney resorption
- Loop diuretics
What are the signs and symptoms of hypocalcemia?
NEUROLOGICAL
- Irritability
- Seizures
- Personality change
- Impaired cognition
NEUROMUSCULAR
- Paresthesia
- Tetany = Chvostek’s sign; Trousseau’s sign
- Paralysis
- Convulsions
CARDIAC
- Irregular heartbeat
What two signs can be seen (neuromuscular) in hypocalcemia?
1) Chvostek’s sign = tapping over facial nerve causes twitching of facial muscle
2) Trousseau’s sign = reducing blood flow in the arm (e.g., by BP cuff) causes contraction of hand muscles
What are the causes of hypocalcemia?
Hypoparathyroidism
- Post-surgery (common)
- Autoimmune
- Genetic (pseudohypoparathyroidism)
Hypovitaminosis D - low vitamin D
- Dietary deficiency
- Lack of sun exposure
- Malabsorption of vitamin D (Crohn’s)
- Defective synthesis of calcitriol (liver/kidney disease)
What is the treatment of hypocalcemia?
- Treat underlying cause
- Supplementation = vitamin D
- IV calcium gluconate or IV calcium chloride
What are the two common consequences of vitamin D deficiency?
Rickets (children) and osteomalacia (adults)
What is rickets?
Vitamin D deficiency in children
- Growth retardation
- Bone deformities
- Weak, soft, painful bones
- Bowing of long bones in legs
What is osteomalacia?
Vitamin D deficiency in adulthood
- Weak, soft, painful bones
How is rickets/osteomalacia treated?
Vitamin D and calcium supplementation
What are the risk factors of osteoporosis?
-
What is Rickets?
Vitamin D deficiency in children
Symptoms include growth retardation, bone deformities, weak, soft, painful bones, and bowing of long bones in legs.
What is Osteomalacia?
Vitamin D deficiency in adulthood
Symptoms include weak, soft, painful bones.
What are the risk factors of osteoporosis?
- Ageing
- Women > men
What causes osteoporosis?
- Low oestrodiol levels
- Low calcium intake
- Low vitamin D
- High glucocorticoids
What is the management of osteoporosis?
- Calcium supplementation
- Antiresorptive drugs = oestrogen and bisphosphonates
- Agents stimulating bone formation = vitamin D and PTH
Osteoporosis is a disease of ___ bone density due to increased bone breakdown by osteoclasts.
Low
Osteomalacia and Rickets are diseases of defective bone ___
Mineralisation
What is the physiologically active form of serum calcium?
Free ionised form
What are the three major sites of calcium metabolism?
- Bones
- Kidneys
- Gut
Name the hormone involved in the short-term regulation of serum Ca2+ level.
Parathormone
Name the hormone involved in the long-term regulation of serum Ca2+ level.
Calcitriol, 1,25-dihydroxycholecalciferol
Which tissues are target tissues for actions of parathormone in order to increase serum calcium level?
- Kidneys
- Bones
- Gut
Synthesis and secretion of PTH is stimulated by low extra-cellular calcium concentration while its high concentration inhibits the synthesis and secretion of PTH. True or false?
True
Name another hormone which is responsible for hypercalcaemia in the absence of abnormal levels of PTH.
PTH-related peptide (PTHrP)
