Renal management of phosphate is impaired in secondary hyperparathyroidism which results in hyperphosphatemia.Primary hyperplasia of the parathyroid gland, results from both hypocalcaemia and increased phosphate levels by decreasing expression of calcium sensing receptors and vitamin D receptors at the parathyroid gland. These decreases in receptor expression lead to hyperfunctioning of the parathyroid. Hyperfunction of the parathyroid gland is thought to exacerbate primary hyperplasia which evolves further to a secondary more aggressive hyperplasia. Histologically, these hyperplasic glands can be either diffuse or nodular. Primary hyperplasia, usually resulting in diffuse polyclonal growth is manly related to reversible secondary hyperparathyroidism. Secondary hyperplasia of the parathyroid gland is more often a nodular, monoclonal growth that sustains secondary hyperparathyroidism and is the catalyst in the progression to tertiary hyperparathyroidism. Nodular hyperplastic glands in tertiary hyperparathyroidism are distinctly larger in both absolute size and weight up to 20-40-fold increases have been reported. Parathyroid glands are normally composed of chief cells, adipocytes and scattered oxyphil cells. Chief cells are thought to be responsible for the production, storage and secretion of parathyroid hormone. These cells appear light and dark with a prominent Golgi body and endoplasmic reticulum. In electron micrographs, secretory vesicles can be seen in and around the Golgi and at the cell membrane. These cells also contain prominent cytoplasmic adipose. Upon onset of hyperplasia these cells are described as having a nodular pattern with enlargement of protein synthesis machinery such as the endoplasmic reticulum and Golgi. Increased secretory vesicles are seen and decreased intercellular fat is characteristic.
Oxyphil cells also appear hyperplasic however, these cells are much less prominent. Biochemically, there are changes in function between normal and nodular hyperplastic parathyroid glands. These changes involve proto-oncogene expression and activation of proliferative pathways while inactivating apoptotic pathways. In nodular parathyroid tissue increased expression of TGF-a, a growth factor, and EGFR, its receptor, results in aggressive proliferation and further downregulation of vitamin D receptors, which act to suppress hormone secretions. Furthermore, the proliferative marker, Ki67 is seen to be highly expressed in the secondary nodular hyperplastic state. Tumour suppressor genes have also been highlighted as being silenced or degraded in nodular hyperplastic parathyroid tissue. One such gene, p53, has been shown to regulate multiple tumour suppressor pathways and in tumorigenesis can be degraded by b-catenin. This pathway, in some aspect, is mediated by CACYBP, which is highly expressed in nodular parathyroid hyperplasia. Treatment
Early pharmaceutical treatment for tertiary hyperparathyroidism may include supplementing vitamin D and the use of cinacalcet. Cinacalcet acts to increase the sensitivity of the calcium sensing receptors to calcium leading to a reduction in parathyroid hormone release, however, its use has limited impact in those with tertiary hyperparathyroidism. These treatments are more likely only transient therapies before parathyroidectomy is performed. Indications for surgery in tertiary hyperparathyroidism commonly involve the development of chronic, severe conditions including osteopenia, persistent severe hypercalcemia, bone pain and pathologic fracture. Other indications include development of conditions such calciphylaxis.