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Tertiary Hyperparathyroidism is a condition involving the overproduction of the hormone, parathyroid hormone, produced by the parathyroid glands. The parathyroid glands are involved in monitoring and regulating blood calcium levels and respond by either producing or ceasing to produce Parathyroid hormone. Anatomically, these glands are located in the neck, Para-lateral to the thyroid gland, which does not have any influence in the production of parathyroid hormone. Parathyroid hormone is released by the parathyroid glands in response to low blood calcium circulation. Persistent low levels of circulating calcium are thought to be the catalyst in the progressive development of adenoma in the parathyroid glands resulting in primary hyperparathyroidism. While primary hyperthyroidism is the most common form of this condition, secondary and tertiary are thought to result due to chronic kidney disease (CKD). Estimates of CKD prevalence in the global community range from 11-13% which translate to a large portion of the global population at risk of developing tertiary hyperparathyroidism. Tertiary hyperparathyroidism was first described in the late 1960s and had been misdiagnosed as primary prior to this. Unlike primary hyperparathyroidism, the tertiary form presents as a progressive stage of resolved secondary hyperparathyroidism with biochemical hallmarks that include elevated calcium ion levels in the blood, hypercalcemia, along with autonomous production of parathyroid hormone and adenoma in all four parathyroid glands. Upon diagnosis treatment of tertiary hyperparathyroidism usually leads to a surgical intervention.

Background
In 1962, Dr C.E Dent reported that autonomous hyperparathyroidism may result from malabsorption syndromes and chronic kidney disease. The term ‘tertiary hyperparathyroidism’ was first used in 1963 by Dr Walter St. Gaur to describe a case reported on at Massachusetts General hospital. This case involved a patient who had presented with autonomous parathyroid adenoma causing hypercalcemia with a background of parathyroid hyperplasia. Further reports were recorded in 1964, 65 and 67 of suspected tertiary hyperparathyroidism.

In 1968 Davies, Dent and Watson produced a historic case study where they reviewed 200 cases of previously diagnosed primary hyperparathyroidism and found the majority of these cases should be reclassified as tertiary. These were important findings as it allowed an understanding into distinguishing features of primary, secondary and tertiary hyperparathyroidism which then allows appropriate medical treatment.

It is now understood that tertiary hyperparathyroidism is defined as the presence of hypercalcemia, hyperphosphatemia and parathyroid hormone due to terminally biased parathyroid-bone-kidney feedback loop. Although there is still conjecture as to whether tertiary hyperparathyroidism is also due to adenomatous growth or hyperplasia it is clear that tertiary hyperparathyroidism presents with some form of tissue enlargement in all four parathyroid glands.

Aetiology
Hyperparathyroidism, in general, is caused by either tumorous growth in one or more parathyroid glands or a prolonged decrease in blood calcium levels or hypocalcaemia which in turn stimulates the production of parathyroid hormone release from the parathyroid gland. The parathyroid gland is located beside the thyroid gland in the neck, below and in front of the larynx and above the trachea. It is comprised of four glands in total that monitor blood calcium levels via the calcium sensing receptors, a g-coupled protein receptor. The parathyroid glands main role is calcium homeostasis. Histologically, these glands are comprised of chief cells and oxyphil cells with the chief cell primarily responsible for the storing and release of parathyroid hormone. These cells are arranged in a pseudo-follicular pattern similar to the thyroid follicles. Keratin staining is used to image the parathyroid hormone granules.

Parathyroid hormone is responsible for the induction of increased calcium absorption in the gastrointestinal tract or gut and in the kidney. It also induces calcium and phosphate resorption from the bone by osteoclasts. Parathyroid hormone also plays a role in activating vitamin D from its pro form to its active form. Vitamin D is also responsible for increased blood calcium levels and works in conjunction with parathyroid hormone. Vitamin D is also partly responsible for the inhibition of parathyroid hormone release by binding Vitamin D receptors at the parathyroid gland.

Tertiary hyperparathyroidism is defined by autonomous release of parathyroid hormone while in a hypercalcaemic state. Unlike primary hyperparathyroidism, hypercalcemia in the tertiary form is thought to be the result of resolution of secondary hyperparathyroidism rather than adenoma formation alone.

Many of the mechanisms that drive the formation of tertiary hyperparathyroidism are due to outcomes of secondary hyperparathyroidism and so the tertiary from is said to be a continued progressive hyperparathyroidism. Secondary hyperparathyroidism occurs mainly in those who suffer chronic kidney disease or vitamin D deficiencies both of which lead to malabsorption of calcium and phosphate leading to decreased blood calcium levels inducing a hyperparathyroidism. Hyperphosphatemia in secondary hyperparathyroidism, due to increased parathyroid hormone, is thought to act directly on parathyroid glands and induce a hyperplasia or increased growth of the chief cells in particular. At the same time the hyperplasic parathyroid glands have reduced fibroblast-growth-factor-23 (FGF-23) and vitamin D receptor expression. FGF-23 is partly responsible for phosphate homeostasis and provides negative feedback to the parathyroid gland as does vitamin D.

During prolonged secondary hyperparathyroidism increased blood phosphate levels drive hyperplasia of the parathyroid gland and this acts to reset calcium sensitivity at the calcium sensing receptors leading to tertiary hyperparathyroidism after resolution of the secondary form with the continued release of parathyroid hormone in the presence of hypercalcemia.

Risk Factors and genetics:
An elevated risk of developing tertiary hyperparathyroidism exists when late stage kidney disease is not corrected timely. This is due to a hyperphosphatemia acting directly on the parathyroid glands. Genetically, those who suffer an X-linked dominant disorder that disrupts phosphate transport at the renal tubules (X-Linked hypophosphatemic rickets) and are receiving oral phosphate treatment have shown to be at high risk of developing tertiary hyperparathyroidism in the absence of secondary hyperparathyroidism. Recurring tertiary hyperparathyroidism is generally seen to be caused by incomplete parathyroidectomy without renal transplant and the risk is increased when the parathyroid tissue left after surgery is that of a nodular type.

Other risk factors of tertiary hyperparathyroidism include an elevated risk of developing acute pancreatitis, mainly due to the hypercalcemia associated with the hyperparathyroidism. Other studies have shown a significant increase in the risk of developing malignancies of the urinary tract and renal system with women being more at risk. Though there is some conjecture as to the correlation between hyperparathyroidism and thyroid carcinoma development, there is however a correlation between the two, which is thought to be due to prolonged irradiation of the neck and head for parathyroid adenomas and increased parathyroid hormone.

Other studies have found some correlation in the development of renal disease following parathyroidectomy. However, the mechanism for this effect remains unknown.