3rd April 2024

The Parathyroid Gland

Background

The four parathyroid endocrine glands are located close to, but functionally separate from, the thyroid gland. Given their location, they are at risk of damage during neck dissection or thyroidectomy. Parathyroid hormone (PTH) secreted by the parathyroid gland, regulates serum calcium and phosphate levels and is involved in bone metabolism. 

Hyperparathyroidism

This occurs when there is excessive PTH secretion from the parathyroid glands. The aetiology can be primary, secondary or tertiary. Most patients with primary hyperparathyroidism are asymptomatic and the condition is detected on routine laboratory screening. Other patients may present with clinical and biochemical abnormalities related to hypercalcaemia, such as renal stones and pancreatitis.  

Clinical manifestations are non-specific with fatigue, myalgia, anxiety, and poor sleep the most common. Gastrointestinal symptoms such as constipation and nausea occur less frequently. The classical triad in MCQs is a patient with polyuria, polydipsia, and bony pain. A consequence of extremely high levels of PTH is abnormal bone turnover and/or mineralisation, which increases the risk of developing fragility fractures.

Aetiology

Primary hyperparathyroidism occurs when there is autonomous overproduction of PTH. It is a common condition, predominantly affecting older and post-menopausal women. Most cases (80%) are caused by a single parathyroid adenoma, with multiple gland hyperplasia responsible for the remaining 10-20%. Parathyroid carcinoma occurs in around 1% of cases. Inherited conditions such as multiple endocrine neoplasia (MEN) 1 and 2 can predispose to gland hyper-productivity, with hyperparathyroidism the presenting feature of 90% of patients with MEN1. 

Secondary hyperparathyroidism is the result of increased PTH production in response to hypocalcaemia. Commonly due to chronic kidney disease (eGFR ≤ 45 ml/min/1.73m2) or vitamin D deficiency, hypocalcaemia, combined with calcitriol deficiency and phosphate retention, leads to a compensatory rise in parathyroid hormone to maintain homeostasis. In patients with end-stage renal failure (ESRF), hypocalcaemia commonly occurs due to 1a-hydroxylase deficiency, a renal enzyme responsible for the conversion of 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D (calcitriol). 

Tertiary hyperparathyroidism occurs when there is parathyroid gland hyperplasia due to chronic hypocalcaemia.

Untreated chronic hypocalcaemia in patients with advanced or dialysis-dependent kidney failure can lead to autonomous PTH secretion, irrespective of calcium concentrations, caused by gland hyperplasia.

Diagnostics

Diagnosis is by blood sampling looking at calcium, phosphate, parathyroid hormone, alkaline phosphatase and vitamin D levels. Other causes of hypercalcaemia, such as familial hypocalciuric hypercalcaemia, should be excluded. Table 1 shows the typical biochemical findings in primary, secondary and tertiary hyperparathyroidism. Whilst imaging is not necessary for diagnosis, CT neck or cervical ultrasonography may be useful for planning surgery and identifying concomitant thyroid disease. 

Table 1: Typical biochemistry in primary, secondary and tertiary hyperparathyroidism

Management

Curative treatment centres around elective parathyroidectomy, with pre-operative vitamin D repletion advised if deficient. Successful kidney transplantation removes the driving force for tertiary hyperparathyroidism and leads to spontaneous resolution in around 60% of patients after 2 years.

In patients with resistant hypercalcaemia, second line treatments such as intravenous bisphosphonates may be given, with an onset of action in 2-4 days; or denosumab, calcitonin or calcimimetics such as cinacalcet. Cinacalcet increases the sensitivity of calcium receptors on the parathyroid gland to serum calcium and thus reduces PTH secretion, with particular use in secondary hyperparathyroidism.

Emergency treatment centres around symptomatic management of hypercalcaemia and treatment of the underlying cause. Restoration of circulating volume via aggressive rehydration, occasionally requiring up to 10 litres of fluid in the first 24 hours, is key to emergency management. Patients with hypercalcaemia-induced renal failure may require dialysis.

Hypoparathyroidism

This is characterised by hypocalcaemia, hyperphosphatemia and low/inappropriately normal levels of PTH. In pseudohypoparathyroidism, the findings are similar but PTH is raised due to resistance. Some patients remain asymptomatic with low serum calcium levels. Symptoms related to hypocalcaemia include:

• Tetany: muscle twitches, cramps, or spasms
• Perioral, hand and feet paraesthesia
• Altered mental state 
• Generalised seizures: may indicate acute or severe hypocalcaemia
• Trousseau’s sign: painful clasping of fingers and hands when blood pressure cuff is inflated
• Chvostek’s sign: tapping the facial nerve in front of the ear elicits ipsilateral facial muscle contraction

Aetiology

Primary hypoparathyroidism is a result of relative or absolute PTH deficiency and occurs most commonly post-neck surgery. Rare causes include infiltrative or destructive diseases such as tumours, autoimmune destruction, heavy metal deposition (iron/copper), or genetic syndromes such as Di George syndrome.

Pseudohypoparathyroidism occurs due to defective PTH receptors or resistance to PTH. It is an autosomal dominant condition characteristically associated with a short stature, round face, dental hypoplasia and short 4th and 5th metacarpals. PTH levels are intact or highly elevated, distinguishing it from primary hypoparathyroidism. 

In pseudopseudohypoparathyroidism patients have the characteristic phenotype of pseudohypoparathyroidism (known as Albright’s hereditary osteodystrophy) with normal biochemistry.

Diagnostics

Diagnosis requires confirmed hypocalcaemia with low levels of PTH and the absence of hypomagnesaemia. Reversible causes of hypoparathyroidism include hypomagnesaemia, iron or copper overload. Investigations for specific causes of hypoparathyroidism, as mentioned above, may be considered. Table 2 shows the typical biochemical findings in primary, pseudohypoparathyroidism and pseudopseudohypoparathyroidism. 

Table 2: Typical biochemistry findings in hypoparathyroidism

Management

Acute, symptomatic hypocalcaemia is a medical emergency, therefore immediate intravenous replacement with close ECG monitoring is crucial as severe hypocalcaemia can cause prolonged QT interval and tachyarrhythmias.  Investigation for and treatment of hypomagnesemia (which may exacerbate hypocalcaemia) should also be commenced.

In patients with minimal symptoms, oral supplementation and ensuring vitamin D stores are replete, may be suitable. The signalling defect in pseudohypoparathyroidism is incurable, therefore maintenance of normal calcium and phosphate through supplementation is key. 

Patients undergoing neck surgery with a risk of parathyroid gland interference should have serum calcium levels checked immediately postoperatively and prior to discharge, with initial supplementation recommended.

Paraneoplastic syndromes affecting the parathyroid gland

Hypercalcaemia occurs in approximately one-quarter of patients with cancer. Of these patients, the majority (80%) are caused by secretion of parathyroid hormone-related peptide (PTHrP), which leads to hypercalcemia via osteoclastic bone resorption. PTHrP is not detected on classical assays and thus, patients present with suppressed PTH (distinguishing patients from those with primary hyperparathyroidism).

References

• Mannstadt, M. (2021) Parathyroid hormone secretion and action. UpToDate.  https://www.uptodate.com/contents/parathyroid-hormone-secretion-and-action
• BMJ Best Practice (2021). Primary hyperparathyroidism. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/133
• Shoback, D., Duh, Q. (2018) Hypoparathyroidism. BMJ Best Practice.
  https://bestpractice.bmj.com/topics/en-gb/132
• Horwitz, M. (2020) Hypercalcaemia of malignancy: Mechanisms. UpToDate. https://www.uptodate.com/contents/hypercalcemia-of-malignancy-mechanisms