Pathogenesis And Operative Treatment For Secondary Hyperparathyroidism In Uremia

Part 1: Clinical effect of total parathyroidectomy with forearm autograft on the uremic patients suffering from parathyroidismBackgroundChanges in mineral metabolism and bone structure are an almost universal concomitant of progressive renal failure. Osteitis fibrosa in which bone turnover is increased is due to secondary hyperparathyroidism. What's more, the hyperparathyroidism affects the metabolism of lipid, cardiac function , hematological system, dermal system and so on. Though the parathyroidectomy is decreased by the use of calcitriol and good control of phosphate, the drug-resistent severe hyperparathyroidism is also commonly diagnosed in the uremic patients with prolong life profited from the development of hemodialysis technique.MethodsTo analyze the change of intact parathyroid hormone(iPTH), blood calcium and phosphate, blood haematocrit(HCT), dyslipidemia, sufficiency of hemodialysis (KT/V, UUR) on the 12 patients accepting parathyroidectomy with forearm autograft.RESULTThe orientation of the parathyroid node detected by B-ultrasonic is consistent with location observed in surgery among 11 patients. The iPTH and blood calcium and phosphate decreased after PTX; And also the operation ameliorate the HCT ,dyslipidemia and sufficiency of hemodialysis (KT/V,UUR) .Recurrent hyperparathyroidism occurred in three patients among which two patients received Vitamin D therapy with the result of remaining iPTH in the normal range and the another one patient received resection of autograft resulting in normal iPTH.CONCLUSIONPTX with forearm autograft is an effective way to treat severe hyperparathyroidism in uremic paitients. PTX can ameliorate anemia and dyslipidemia .The orientation of parathyroid node by B-ultrasonic before surgery is feasible.Part 2: Research of cyclooxygenase-2 expression on the parathyroid glands in uremic patients with secondary hyperparathyroidismBackgroundIt has long been known that a chronic increase in PTH production, characteristic of primary as well as of secondary forms of hyperparathyroidism, goes along with an increase in parathyroid gland size. The increase of parathyroid cell mass in the chronic uremic state is mainly due to enhanced parathyroid cell proliferation, characterized by an increase in cell number. Normal parathyroid cells are characterized by an extremely low turnover. However they remais the ability to proliferate when stimulated. Cyclooxygenase-2 is an enzyme which involves in the pathogenesis of inflammation and cell hyperplasia. COX2 was found to promote the cell hyperplasia in many researchs including tumor and precancerous lesion. What's more, the essence of severe secondary hyperparathyroidism is the cell hyperplasia including duffuse hyperplasia and nodular hyperplasia. This part will show us whether there is C0X2 expressed on the gland of proliferated cell from uremic patients. And whether is the COX2 expression associated with the proliferation of the cells marked by PCNA.METHODSThe parathyroid glands were collected from the uremic patients who accepted the parathyroidectomy with forearm autotransplation. According to the H.E staining the glands were divided into three groups including mild diffuse hyperplasia, severe diffuse hyperplasia and nodular hyperplasia. We dectect the expression of COX-1 , C0X2 and PCNA on the glands by Immunohistochemistry and Western Blot.RESULTAmong all the glands,eighteen glands belongs to nodular hyperplasia and eight glands belongs to diffuse hyperplasia. The immunohistochemistry staining shows little COX-1 expression on the cell with different degree of hyperplasia. The expression of COX2 is more on the severe diffuse hyperplasia glands than the nodularand mild hyperplasia glands. The expression of PCNA is more on the nodular and severe diffuse hyperplasia glands.ConclusionCOX2 exits on the glands of proliferated parathyroid cell. And the expression of COX2 is associated with the PCNA. C0X2 may participate in the development of cell hyperplasia in the early stage of secondary hyperparathyroidism.Part 3: To approach the relationship between the prostaglandins and parathyroid hormone in the blood of uremic patientsBackgroundIn part 2 we find the expression of COX2 on the parathyroid glands and suppose that COX2 prticipate the development of secongdary hyperparathyroidism. To illuminate whether the local COX2 or the systemic COX2 involves the hyperplasia , we dectect the systemic COX2 activity by its metabolites prostaglandins among the uremic patients with different level of PTH and normal adults.MethodsFour groups were estabalished. Group A represents the uremic patients whose PTH is less than 100pg/ml. Group B represents the uremic patients whose PTH is between 100pg/ml and 300 pg/ml . Group C represents the uremic patients whose PTH is more than 300pg/ml. Group D represents the normal adults. We dectect the PGE2 , 6-keto-PGF1a and TXB2 by radioimmunology.ResultsThe PGE2 and the TXB2 levels in the uremic patients are higher than the levels in normal adults. Hower there is no difference among the three groups of uremia. The 6-keto-PGF1a level in uremic patients is lower than the normal adults. And also no difference is observed among the three uremic groups.ConclusionsProstglandins disorder exit in the uremic patients. However the disorder is not concommitent with the level of parathyroid hormone.Part 4: the Phosphate can stimulate the hyperplasia of primary parathyroid cell culture in vitro through the COX2 pathwayBackgroundsSecondary hyperparathyroidism is a well known feature of chronic renal failure. It is characterized by an increase in the synthesis and secretion of parathyroid hormone (PTH), mainly due to disturbances of calcium, phosphate, and vitamin D metabolism. In addition to several long known indirect effects, they all have also been shown to act directly on the parathyroid cell, via a cell membrane receptor for calcium, a nuclear receptor for calcitriol, and a yet unknown cellular target for phosphate. The disorder of of blood calcium and vitamin D is easily adjusted by the use of oral calcium , the proper dialysate calcium and the vitamin D. However the blood phosphate is very difficult to be well controlled though many methods are explored. What's more the phosphate can stimulate the hyperplasia directly and raise the mortality of the uremic patients. So more and more attention is paid to the mechanisms how the phosphate involves in the onset of hyperparathyroidism. Unfortunately , little is known in the mechanisms in the cell while the high phosphate stimulates the cell.MethodsWe established the method of Parathyroid Cell Culture according to liturate. The cells are cultured in different culture fluid charactered with high or normal phosphate. We detect the parathyroid hormone in the two groups. And also we observe the expression of COX2 and PCNA in protein and mRAN levels by Immunohistochemistry and Real-time PCR.ResultsHigh phosphate can stimulate the cell secretion in vitro. High phosphate can raise the levels of COX2 and PCNA both in proteins and mRNA.ConclusionsThe parathyroid cell in vitro remains the ability to secrete parathyroid hormone. High phosphate can stimulate the hyperplasia of parathyroid cell in vitro through the way of raised COX2.