Secondary hyperparathyroidism occurs in a larg number of patients whith chronic renal failure as a result of biochemical abnormalities such as hypocalcemia, hyperphosphatemia, and decreased vitamin D blood levels. In the initial phase of the renal disease, the parathyroid glands equally stimulated, are equally enlarged with single cell components, maintaining still the ability to be functionally suppressed by increased serum calcium and for calcitriol. In the late phase of chronic renal failure, each gland grows differently in size, weight and cell component. Some of the glands may exhibit nodularities with higher proliferation activity than diffuse hyperplasia as demostrated by studies using proliferating cell nuclear antigen.¹³ Nodular hyperplasia shows more severely disturbed suppression for PTH secretion and decreased density of vitamin D₃ and calcium sensor receptorr.^14,16 Functional in vitro studies, demonstrated a so called autonomous secretory disorder in these nodules. ^17,18 The clonal analyses of diffuse and nodular hyperplasia by Tominaga¹⁴ et al, demostrated that diffuse hyperplastic glands were polyclonal in origin, whereas nodules in nodular hyperplasia were monoclonal, therefore in each case polyclonal diffuse hyperplasia and monoclonal nodular hyperplasia coexist.

In recent years considerable efforts have been devoted to developing and improving imaging of abnormal parathyroid glands.

Recently, Ishibashi and Pons^6,19, have observed setamibi imaging was more sensitive for localizing abnormal parathyroid glands than ultrasonography or MR imaging. Tecnetium-99m-Sestamibi (MIBI) is now to be the radionuclide of reference for parathyroid gland scanning.¹

However, it is widely accepted the poor results of all scanning techniques in the detection of hyperplastic parathyroid glands and the high failure to recognize all the glands involved in patients with secondary hyperparathyroidism. The reasons why all hyperplastic parathyroid glands are unable to concentrate MIBI remain to be clarified.

MIBI, is a monovalent lipophilic cation which diffuses passively through cell membranes and accumulates almost exclusively in mitochondria following negative membrane potentials.²

The exact mechanism of its elective uptake in abnormal parathyroid glands remains debatable. ³ The size of abnormal parathyroid glands does not represent the only determinant for MIBI-uptake. Among the various pathological criteria, hypervascularity and mitochondrial richness of the parathyroid specimen are significantly related to the positive MIBI-uptake.³ The role of p – glycoprotein a membrane transport protein is under investigation in patients with false – negative scans.⁴ In patients with multiglandular disease hardly more than 55 percent of abnormal parathyroid glands are detected with sestamibi scanning.^1,5,6 Preoperative detection of all pathological glands occurs in less than one-third of patients.⁶ Piga⁵ et al, have suggested in patients with secondary hyperparathyroidism, a correlation of MIBI-uptake in parathyroid tissue with its autonomous hyperfunction.

Subtotal parathyroidectomy,⁷ and, total parathyroidectomy with auto-transplantation,⁸ have become the most widely accepted procedures for secondary hyperparathyroidism. Reoperation, is necessary in up to 15 percent of cases.⁹ In patients who do not undergo renal transplantation the remnant or the engrafted tissue is subject to hypersecretion and a high incidence of recurrent hyperplasia can be expected despite the most careful surgical technique.^10,11,12 The selection of the parathyroid tissue for preservation is an important issue and several morphologic markers have been described.^13,14

Our results²⁰ with a total of 27 patients operated on for severe secondary hyperparathyroidism ( mean iPTH 1.154 + 660 pg/ml ). (Table I ) whom a double – phase parathyroid technetium 99m-MIBI was performed showed a postitive double-phase MIBi sicintigraphy in twenty-four patients ( 88.8% ). However, the visualitation of 4 parathyroid hyperplastic glands was not observed in any of the patients included in this study. Focal sestamibi-uptake of only 1, 2 and 3 glands were oberved in six, eleven and eight patients respectively. (Table II)

Intraoperative PTH levels during parathyroidectomy were determined in all patients. Subtotal parathyroidectomy was carried out by completly identifying four glands initially. Once all four glands were found, one gland was selected for partial excision, leaving approximately 60 mg of parathyroid tissue.. A total of 78 parathyroid glands were removed from the operation. All specimen were weighted and the size of the glands was calculated. A total of 64 hyperplastic parathyroid glands were studied and in them, parathyroid cell cycle was analyzed using the method described by Vindelov and Christensen¹⁵.

In this study, blood levels drawn from the jugular veins after subtotal parathyroidectomy in comparison to the recorded before glandular excision. (Table III)

In all patients, we correlated the highest focal MIBI-uptake and the iPTH blood levels drawn from the ipsolateral jugular vein, in one side of the neck, with the opposite side. We found a significant correlation ( r: 0.6 ; < 0.001 ), the highest focal MIBI-uptake in one side had the highest iPTH concentration at the ipsolateral side.(Table IV) Furthermore, a significant positive correlation was found between parathyroid volume and the intensity of focal MIBI-uptake ( r: 0.5 ; p < 0.05). (Table V) Also, a positive correlation was observed between the intensity of focal MIBI-uptake and the phases of cell cycle. Low grade of intensity focal uptake correlated with G_o phase and the highest intensity of focal uptake with G₂ + S phase (r: 0.7; p < 0.01 ). (Figure 1) No correlation was found between focal MIBI-uptake and the weight of the glands.(Table VI). The intensity of focal MIBI-uptake was also correlated with both the iPTH blood concentration drawn from the ipsolateral jugular vein and the phases of cell cycle of parathyroid glands removed after parathyroidectomy.

Our results show that MIBI has little place for preoperative parathyroid scanning as a tool to localize all abnormal parathyroid glands before surgery. However, our data indicate the ability of sestamibi scintigraphy in recognizing hyperplastic glands when have reached a high degree of cell activity or proliferation. Moreover, the glands exhibiting a high intensity of focal MIBI-uptake, associated more elevated iPTH concentration in the ipsolateral jugular vein than glands with slight or absence of focal MIBI-uptake. These results suggest a positive correlation between the morphologic alterations with the functional status of the hyperplastic glands.

Intraoperative measurements of intact parathyroid hormone (iPTH ) using a rapid assay technique, may help roughly where the parathyroid hormone levels are highest indicating the presence of hyperfuntioning autonomous glands. In addition, intraoperative PTH monitoring may predict a successful parathyroidectomy when a relevant decrease in PTH levels has achieved after parathyroidectomy. The average decline in our study was 86% and was associated with symptomatic improvements and low PTH levels in follow-up. However, the ability to detect inadequate degrees of parathyroid resection during parathyroidectomy in secondary hyperparathyroidism remains to be proven in long-term follow-up.

In our investigation a positive correlation was found between the intensity of focal sestamiby-uptake and the volume of the glands. We believe, Tc-99m-MIBI do not reveal only parathyroid enlargement rather identified hyperfunctioning glands. Those glands should be resected and not used for remnant tissue in cases of subtotal parathyroidectomy or for engraftment in cases of total parathyroidectomy and autotransplantation. Using the latter procedure, several investigators have observed more often graft - dependent recurrence when grafted nodular tissue was chosen for inmediate autotransplantation. Niederle¹⁷ et al have suggested to separate B regions ( monoclonal, characterized by an abscence of fat cells, a follicular arrangement of chief or oxyphilic cells or both, with an increased mitotic index indicating a lack of in vitro suppressibility ) from A regions ( polyclonal, containing stroma fat cells and showing a high supression of PTH, in vitro studies ). These authors proposed to select only fragments from A regions for autotransplantion. However, these investigations may not be of practical use as standard technique at the time of parathyroidectomy.

In our opinion, Tc-99m-Sestamibi should be used in patients with secondary hyperparathyroidism to determine when patients have reach a point of no return in their response to medical treatment including calcitriol pulsed therapy. Surgical treatment is then indicated, to remove autonomous hyperplastic glands, clinically identified by high intensity focal MIBI-uptake and enlarged glands associated with local high blood levels of iPTH. Parathyroid glands with focal negative focal MIBI-uptake, suggest that hyperplastic cells still maintain the ability to be functionally suppressed by increased serun calcium or calcitriol therapy, and should be preserved as remnant tissue after subtotal parathyroidectomy or chosen as graft tissue after total parathyroidectomy with autografting.

Long-term follow-up and increasing number of patients will be crucial in defining the role of MIBI – uptake in the selection of the autonomous glands suitable for surgical resection and the identification of those hyperplastic parathyroids glands still maintaining the ability to be supressed with medical treatment.