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 have 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.
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.