77 Parathyroid Disease
The parathyroid gland is the last major endocrine gland to be discovered in the human body and was first described in 1862 by Richard Owen. Parathyroid hormone or parathormone (PTH) has the physiological effects of mobilising calcium from bone, enhancing absorption of calcium from the small intestine and suppressing excretion of calcium in the urine. Primary hyperparathyroidism (pHPT) results from excessive secretion of PTH and is the commonest cause of hypercalcemia in the outpatient population and second only to malignancy in the inpatient population. It is characterised by hypercalcemia with unsuppressed PTH levels.
Parathyroid neoplasia is the commonest cause of hypercalcemia and is benign in over 99% cases, and over 80% are single-gland adenomas. Over 80% are asymptomatic on presentation but may have complications of hypercalcemia as indications for surgery. High-frequency ultrasound and radioactive sestamibi scans are the main imaging modalities for localisation. Minimal access single-gland exploration is the procedure of choice for the majority of pHPT cases. Secondary hyperparathyroidism is usually due to chronic renal failure and may require subtotal/total parathyroidectomy. Parathyroid carcinoma is a rare occurrence and has an acute metabolic onset.
The incidence of pHPT is estimated to be between 0.5 and 5 per 1,000 and is commoner in patients over 45 years of age with a male to female ratio of 1:3. The incidence of pHPT is increasing due to the advent of more readily available blood tests showing up hypercalcemia in asymptomatic patients. In 80% of patients with pHPT, the symptoms of hypercalcemia are mild or absent at the time of diagnosis.
The vast majority of pHPT (95%) are sporadic of which 80 to 90% are solitary, 4 to 6% are double adenomas and 5 to 10% are due to four-gland hyperplasia. The remaining 5% are hereditary, associated with endocrine syndromes such as multiple endocrine neoplasia types 1 and 2A (MEN1 and MEN2A).
77.2 Surgical Anatomy
Normally there are two pairs of parathyroid glands, each about 5 to 7 mm in size, with an average weight of 30 to 40 mg. They are usually bean shaped and in younger patients the colour is reddish brown, while in the older patient it may be yellowish due to the increased fat content and of oxyphil cells. They are positioned as a superior and inferior pair on the posterolateral aspect of each thyroid lobe with the upper pair being more constant in position. Supernumerary fifth glands have been reported in 5% of cases and are often found in the thymus.
The inferior glands receive their blood supply from the inferior thyroid artery. In 50% of cases, the inferior glands are found within 1 cm of the lower pole of the thyroid lobe. They are superficial to the recurrent laryngeal nerve and caudal to the inferior thyroid artery. In 25% of cases, the inferior parathyroid gland may be found within the thymic tissue. In the remaining 25% of cases, their position is variable, lateral to the thyroid (12%), ectopically in the mediastinum or at the carotid bifurcation, and rarely it may be intra-thyroidal (0.5–4%).
The superior parathyroid gland is deeper to the recurrent laryngeal nerve in the coronal plane and is more symmetrical in position and shape. In 80% of cases, the superior parathyroid gland is found adjacent to the cricothyroid junction, 1 cm cephalic to the junction of the recurrent laryngeal nerve and the inferior thyroid artery. The main blood supply is from the inferior thyroid artery while in some cases it may also be from the superior thyroid artery. In 3% of cases, the superior parathyroid glands may be ectopic in a retropharyngeal, retrolaryngeal or tracheo-oesophageal position.
Parathyroid glands have a fine capsule with multiple septa that divide them into lobules. The stroma consists of islands of secretory cells interspersed with fat cells and a rich sinusoidal capillary network.
There are two cell types:
1. Chief cells are the predominant cell type in children and synthesise PTH.
2. Oxyphil cells are larger and their number increases with age, their actual function is not known.
The adenomatous portion of the parathyroid may consist predominantly of chief cells with a suppressed rim of normal parathyroid tissue differentiating it from a hyperplastic gland.
• Primary hyperparathyroidism (high PTH, high calcium)
The excess PTH is produced by either neoplastic or hyperplastic parathyroid parenchymal cells.
• Secondary hyperparathyroidism (high PTH, low calcium)
The chronic stimulation of the parathyroid gland leads to parathyroid cell proliferation and usually reverts to normal once the stimulus is removed. In chronic renal failure, low-calcium and a high-phosphate burden causes parathyroid proliferation. There is also reduced responsiveness of calcium receptors to PTH secretion due to metabolic acidosis during renal failure. Prolonged use of lithium and vitamin D deficiency are also related to secondary hyperparathyroidism.
• Tertiary hyperparathyroidism (high PTH, high calcium)
Follows prolonged stimulus in chronic renal failure. The hyperplastic gland may become autonomous and may not revert to its normal state after the stimulus ceases.
77.5 Clinical Assessment
Usually the referring endocrinologists will have identified patients with pHPT from other causes of hypercalcemia. It is important to ask about risk factors for hyperparathyroidism (such as lithium therapy and neck irradiation). The majority of patients with pHPT are asymptomatic (80%) and their hypercalcemia is picked up incidentally on biochemical screening for other reasons. Most symptomatic patients have non-specific complaints such as fatigue, lethargy, depression, lack of concentration and joint and bone pain. The neurocognitive symptoms can mimic dementia in the elderly population. Gastrointestinal symptoms may include abdominal pain, chronic constipation, peptic ulceration and pancreatitis. Renal involvement includes nephrolithiasis and hypercalciuria and occurs in 20% and 40% respectively of all patients with pHPT. These patients are then further evaluated with PTH assay, 24-hour urinary collection for calcium level and creatinine clearance/glomerular filtration rate (GFR). A raised PTH assay, hypercalcemia and hypercalciuria confirm the diagnosis of pHPT. In young patients with pHPT, family history of MEN should be investigated. The surgical mnemonic to help aid memory of these symptoms is ‘Bones, Stones, Groans and psychic Moans’.
In the majority of patients, there are no specific physical signs. The occasional giant adenoma may present as neck fullness. In suspected cases of parathyroid malignancy, patients may present with palpable nodes or vocal cord paresis.
77.7.1 Biochemical Variations
A small number of primary hyperparathyroid patients may present with normocalcemia and elevated PTH. As part of the investigations, these patients should be assessed for vitamin D deficiency, low calcium intake and gastrointestinal and renal disorders, which lead to secondary hyper-parathyroidism. An elevated parathyroid hormone level with an elevated ionised serum calcium level is diagnostic of primary hyperparathyroidism and must be repeated. A 24-hour urine calcium measurement is necessary to rule out familial benign (hypocalciuric) hypercalcemia.