There are four small parathyroid glands situated in four corners of the thyroid gland. The parathyroid glands produce parathyroid hormone (PTH) in response to lower calcium in the blood. Parathyroid hormone acts to increase the serum calcium level by targeting three organs:
- Bones (increasing calcium absorption from the bones)
- Kidneys (increasing calcium reabsorption from the urine)
- Intestines (increasing vitamin D activity, which increases calcium absorption from food)
The serum calcium is ideally maintained between 2.2 – 2.6 mmol/L.
Parathyroid Hormone Physiology
Inside the parathyroid glands are the chief cells, which produce parathyroid hormone and store it inside secretory granules. Secretory granules fuse with the cell membrane and release parathyroid hormone into the circulation (exocytosis). When calcium-sensing receptors (CaSR) on the cell surface detect calcium, they set off a signalling cascade inside the cell that controls the release of parathyroid hormone. Higher serum calcium inhibits parathyroid hormone release, and lower serum calcium leads to more parathyroid hormone release.
There is a feedback loop involving serum calcium and parathyroid hormone that helps maintain normal calcium:
- When less calcium is present, more parathyroid hormone will be released to help increase the calcium level
- When more calcium is present, less parathyroid hormone will be released to allow the calcium level to fall
CLINICAL RELEVANCE
Cinacalcet is a medication used to treat certain types of hyperparathyroidism (where there is too much parathyroid hormone). It works by mimicking the action of calcium on the calcium-sensing receptors (CaSR). The chief cells of the parathyroid gland sense the cinacalcet, thinking it is calcium and that there is too much calcium in the system. They respond by reducing the production of parathyroid hormone.
In the bones, parathyroid hormone increases the activity and number of osteoclasts. The main inorganic mineral that forms bone is hydroxyapatite, containing calcium phosphate. Osteoclasts break down bone, releasing calcium and phosphate into the blood, increasing the serum calcium and phosphate.
In the kidney nephrons, parathyroid hormone acts on the distal tubule and early collecting duct to stimulate calcium reabsorption from the urine and back into the blood. Less calcium is excreted in the urine and the serum calcium (in the blood) increases.
Parathyroid hormone also acts on the proximal tubule, decreasing the phosphate reabsorption from the urine. Therefore, parathyroid hormone causes more phosphate to be excreted in the urine, lowering the serum phosphate. Phosphate ions bind to calcium ions (e.g., becoming calcium phosphate), reducing the free calcium in the blood. More phosphate excretion in the urine means less is bound to calcium, increasing the free calcium in the blood.
PTH also stimulates the kidneys to convert vitamin D into its active form, calcitriol. Calcitriol has various actions within the body, including:
- Increasing calcium and phosphate absorption in the small intestine
- Increasing calcium and phosphate reabsorption from the urine to the blood in the kidneys
- Inhibits parathyroid hormone release (providing negative feedback to the parathyroid glands)
To summarise the factors that control parathyroid hormone:
- Calcium inhibits parathyroid hormone release
- Phosphate stimulates parathyroid hormone release (by binding to calcium and lowering the free calcium level)
- Calcitriol (the active form of vitamin D) inhibits parathyroid hormone release
Calcitonin
Calcitonin is a hormone excreted by specific cells in the thyroid gland called the parafollicular cells (also known as C cells). The role of calcitonin is to reduce the calcium levels in the blood. It has the reverse effect of parathyroid hormone on the calcium level. It reduces the serum calcium by:
- Inhibiting osteoclast activity in the bone (less calcium is reabsorbed from the bones)
- Inhibiting calcium reabsorption in the kidneys (more calcium is excreted in the urine)
CLINICAL RELEVANCE
Calcitonin can be given as an intramuscular or subcutaneous injection to treat hypercalcaemia (high serum calcium) caused by malignancy (cancer).
Hypercalcaemia
The top causes of raised serum calcium (hypercalcaemia) are:
- Medications (e.g., calcium and vitamin D supplements)
- Hyperparathyroidism
- Cancer (particularly lung, breast and kidney)
- Renal failure with reduced calcium excretion
The mechanisms by which cancer can cause hypercalcaemia are:
- Parathyroid hormone-related protein (PTHrP) production by the tumour (which stimulates PTH receptors)
- Bony metastases causing increased osteoclast activity
- Calcitriol (the active form of vitamin D) production by the tumour (particularly in lymphomas)
Hyperparathyroidism
Primary hyperparathyroidism is caused by uncontrolled parathyroid hormone production by a parathyroid tumour, leading to a raised serum calcium (hypercalcaemia). Treatment is to surgically remove the tumour. Cinacalcet is a medical option where surgery is not possible.
Secondary hyperparathyroidism is where insufficient vitamin D or chronic kidney disease reduces calcium absorption from the intestines, kidneys and bones, resulting in low serum calcium (hypocalcaemia). The parathyroid glands react to the low serum calcium by excreting more parathyroid hormone. The serum calcium level will be low or normal, but the parathyroid hormone will be high. Treatment is to correct the underlying vitamin D deficiency or chronic kidney disease (e.g., renal transplant). Cinacalcet is a medical option in end-stage renal disease.
Tertiary hyperparathyroidism happens when secondary hyperparathyroidism continues for an extended period, after which the underlying cause is treated. Hyperplasia (growth) of the parathyroid glands occurs as they adapt to producing a higher baseline level of parathyroid hormone. Then, when the underlying cause of the secondary hyperparathyroidism is treated, the baseline parathyroid hormone production remains inappropriately high, leading to inappropriately high calcium absorption in the intestines, kidneys and bones, causing hypercalcaemia. Treatment is to surgically remove part of the parathyroid tissue to return the parathyroid hormone to an appropriate level.
|
Hyperparathyroidism |
Cause |
PTH |
Calcium |
|
Primary |
Tumour |
High |
High |
|
Secondary |
Low vitamin D or CKD |
High |
Low / Normal |
|
Tertiary |
Hyperplasia |
High |
High |
Last updated August 2024
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