What controls blood calcium levels?
Calcium is the fifth most abundant element in the body. It is vital for several biological processes including neurotransmission, muscle contraction, hormone secretion and the clotting cascade.
Normal adjusted calcium level is 2.2.-2.6 mmol/L.
Forms of calcium
The average young adult has around 1200g of calcium in their body, 99% of which is stored in bone, 0.99% in blood and 0.01% inside cells.
Calcium in the blood exists in three forms:
- Free-ionised – diffusible, biologically active
- Bound to anions e.g. phosphate – diffusible, not biologically active
- Bound to proteins (mainly albumin) – not diffusible, not biologically active.
So. What controls blood calcium levels?
There are three molecules which regulate the amount of calcium in the blood and ensure it is maintained within the normal range. These are calcitriol (vitamin D), parathyroid hormone and calcitonin.
The synthesis of calcitriol is completed in the kidneys, parathyroid hormone (PTH) is secreted by the parathyroid glands, and calcitonin is secreted by the thyroid glands.
Vitamin D
Vitamin D’s (calcitriol) main function is to increase the intestinal absorption of calcium.
It can be ingested, or synthesised from a cholesterol precursor as follows:
- 7-dehydrocholesterol is converted into vitamin D3 under the influence of UV radiation
- In the liver, vitamin D3 is converted into 25-hydroxyvitamin-D by 25-hydroxylase. This is relatively inactive
- In the kidney, 1-α-hydroxylase converts 25-hydroxyvitamin-D into 1,25-dihydroxyvitamin-D, otherwise known as calcitriol. This is metabolically active.
If levels of calcitriol become excessive, it is converted to 24,25-dihydroxycholecalciferol, which is less active. This prevents toxicity.
Parathyroid hormone (PTH)
When the amount of calcium in the blood falls below the normal range, additional PTH is secreted.
PTH raises blood calcium levels by:
- Increasing bone resorption – PTH causes osteoclasts to resorb bone and release calcium into the bloodstream
- Increasing renal reabsorption of calcium – PTH acts on the distal convoluted tubule (DCT). This leads to increased reabsorption of calcium into the blood and also increases the excretion of phosphate
- Increasing synthesis of calcitriol – also in the kidney, PTH stimulates the production of 1-α-hydroxylase. This enzyme catalyses the conversion of the relatively inactive 25-hydroxycholecalciferol into calcitriol.
Additionally, PTH and calcitriol inhibit the secretion of PTH from the parathyroid gland.
This negative feedback loop ensures blood calcium levels do not continue to rise and go beyond the normal range.
Calcitonin
When the amount of calcium in the blood rises above the normal range, parafollicular cells in the thyroid gland secrete calcitonin.
Calcitonin decreases calcium levels by inhibiting osteoclasts, thus reducing bone resorption.
Calcitonin has a less significant role in calcium homeostasis than PTH and calcitriol.
Low calcium level (hypocalcaemia)
Hypocalcaemia is defined as an adjusted calcium level of <2.2 mmol/L.
Patients who develop hypocalcaemia acutely tend to be more symptomatic compared to patients who develop hypocalcaemia over a long period of time (chronic hypocalcaemia).
The symptoms of hypocalcaemia include peri-oral and peripheral numbness or tingling, cardiac arrhythmia (prolonged QT interval on ECG), muscle spasms, and fits (seizures).
Causes of hypocalcaemia include:
- Hypoparathyroidism
- Vitamin D deficiency
- Hyperphosphatemia – phosphate binds to calcium to form calcium phosphate, reducing free calcium
- Chronic kidney disease (CKD) – reduced calcitriol synthesis
- Acute pancreatitis – free fatty acids bind calcium, reducing levels of free calcium.
- Respiratory alkalosis – in alkalosis, calcium ions associate with albumin with greater affinity, thus reducing free and active calcium.
High calcium level (hypercalcaemia)
Hypercalcaemia is defined as an adjusted calcium level of >2.6 mmol/L.
Patients with mild hypercalcaemia tend to be asymptomatic, but when levels exceed 3 mmol/L, symptoms include muscle weakness, cardiac arrhythmias (short QT interval), constipation, kidney stones and depression. If the calcium is above 3.5 mmol/L, confusion and drowsiness can occur – and eventually coma and fits (seizures).
Causes of hypercalcaemia include:
- Hyperparathyroidism
- Myeloma
- Malignant tumour – some tumours secrete parathyroid-hormone-related peptide (PTHrP). This mimics PTH, leading to hypercalcaemia
- Vitamin D intoxication – excess vitamin D causing increased intestinal absorption of calcium
- Thiazide diuretics – increase renal reabsorption of calcium causing excess calcium in the blood
- Other: Milk-alkali syndrome (excess calcium consumption, usually due to calcium carbonate), Paget’s disease, sarcoidosis.
Summary
We have described what controls blood calcium levels. We hope it has been helpful.
