The incidence of chronic renal failure (CRF) continues at a relatively high rate of about one in ten thousand population per year in China. However the primary cause of CRF has changed from glomerulo-nephritis to chronic diseases such as diabetes or hypertension. These patients are seldom suitable for renal transplantation. Due to the continuous development and widespread availability of dialysis, the survival time of the patients with CRF is being obviously extended. As a result the rate of secondary hyperparathyroidism (sHPT) is increasing as well, usually in those patients undergoing long-term dialysis. Moreover, the clinical effects of sHPT may be more severe than CRF per se. It can directly affect the quality of life of patients and cause reduced time of survival. No satisfactory pharmaceutical therapy for those with refractory sHPT has been established. The classical surgical treatment for sHPT is to resect the majority of the parathyroid tissue, i.e., to remove three and half parathyroid glands. But it is very difficult to determine the volume of gland that should be retained. Furthermore, once recurrence occurs, it is very hard to perform re-operation on the neck because of tissue adhesion, and the resultant total parathyroid removal may cause a more bothersome problem such as complete hypopara-thyroidism.
Therefore, we wought to evaluate the feasibility and effectiveness of surgical treatment using total parathy-roidectomy combined with forearm autotransplantation of parathyroid tissue on patients with sHPT. We have successfully conducted these surgical procedures on 20 cases of sHPT from September 1999 through September 2006. This is the largest study of such cases reported until now in China. This study presents the outcome and experience of these patients.
Twenty-two operations were conducted on 20 sHPT patients. Amongst these patients, one case had re-operation on transplant side forearm because of the development of autograft hyperplasia, and another patient required re-operation on the neck to remove the remnant of cervical parathyroid glands.
There were 7 males and 13 females and their average age was 52.4 years old (range, 35-74 years old). 19 cases underwent hemodialysis for an average 9.1 years (range 1-18 years), and 1 case had peritoneal dialysis for 8 years. The serum intact parathyroid hormone (iPTH) measurement showed an average of (1554.24±393.06) ng/L, with the highest of (1852.92±491.88) ng/L. In accordance with the diagnostic criteria of sHPT (serum iPTH >500 ng/L), the mean course of the disease in these patients was 9.7 months (range, 0.5-36 months).
After stosstherapy with calcimimetic agent Rocaltrol (Calcitriol) 2 μg, twice per week, all symptoms such as pruritus, bony pain, movement disorder, weakness, anorexia, depression and kyphosis were getting progressively worse, with serum iPTH and calcium level exceeding the normal range. Surgical treatment was determined when the serum test presented an average of (1615.86±372.48) ng/L for iPTH, (2.926 ±0.289) mmol/L for calcium, (1.975±0.470) mmol/L for phosphorus, and (854.35±294.97) μmol/L for creatinine.
Sixty five hyperplastic parathyroid glands were detected by B-ultrasonography in 20 cases, 2 to 4 enlarged parathyroid glands in each case. Two patients had an additional focus located in the thyroid gland, which was in accordance with the characteristic of parathyroid hyperplasia approved by ultrasonography. Thus a total of 67 hyperplastic parathyroid glands were detected. Four patients experienced ECT scanning, and two of them showed three or four radionuclide dense areas in the neck. Another two cases had cervical CT scanning and two or three hyperplastic parathyroid glands were discovered in each.
In addition to routine preoperative tests including complete blood counts, serum electrolytes, urinalysis, chest x-ray, electrocardiogram, and coagulation screening, all patients were ordered pulmonary function tests and echocardiography for evaluating cardiopulmonary function. Hemodialysis or peritoneal dialysis was performed the day before operation. Quite importantly, specialists surgeons attended the ultrasonography examination, which was helpful to get an exact localization of parathyroid glands and made clear their relationship with the surrounding tissues.
The operation was performed under general anesthesia. Briefly, a frontal cervical transverse incision was made two finger’s-breadth above the sternal notch, tissues from skin to muscles were dissected layer by layer until the thyroid gland was exposed. Then the middle thyroid veins were isolated and ligated, the thyroid gland was turned over medially. By the combination of preoperative ultrasonography and intraoperative exploration, almost all of the parathyroid tissues were carefully discovered and removed. An average of two to four glands in each case were resected. A total of 71 glands were removed from 20 patients. In two patients who had 3 lesions inferred by preoperative ultrasonography, one more hyperplastic parathyroid was discovered by intraoperative exploration. In three patients who had two lesions inferred by preoperative ultrasonography, two more hyperplastic parathyroids were discovered by intraoperative exploration. In another two cases with preoperative ultrasonography indicating additional suspicious parathyroid gland located in thyroid glands, the intrathyroid lesions were resected as well. A suction drainage tube was inserted into the operative field at the end of surgical procedure.
The resected tissues were kept in sterilized iced saline, and parts of the glands were taken for the immediate frozen section pathological examination. Upon completion of the cervical operation, the confirmed diffused hyperplastic parathyroid tissues with relatively normal appearance were cut into thirty granules with 1 mm3 size and transplanted individually into the muscular bed of the patients’ forearm without an previous artery-vein fistula formation. Finally, the local muscle fasciae were sutured with unabsorbable threads as markers for re-operation if necessary.
The vital signs of all patients were monitored carefully after operation. The patient’s voice along with the quantity and quality of the drained liquids were specially observed.
In view of the risk of transient hypocalcemia which might occur subsequent to the removal of parathyroid glands, every patient was given calcium supplement postoperatively through a deep vein infusion pump to maintain adequate calcium levels. The serum calcium concentration was monitored four to six times per day. The protocol for calcium administration after parathyroidectomy was as follows. Calcium gluconate 16-20 g per 24 hours was administered for one to two weeks, then, the rate and times of calcium infusion were adjusted according to the results of serum calcium measurement to maintain the serum concentration within the range of 1.8-2.4 mmol/L and until the serum calcium was stabilized (usually in one to two weeks). Afterwards, oral calcium administration (calcium carbonate 3-12 g per day) was prescribed. Meanwhile, postoperative oral Calcitriol was administrated with the dose of 1 μg per day for one to two weeks, gradually diminished to 0.25 μg per day.
Hemodialysis was resumed for every patient, 24 hours postoperatively.
All statistical analyses were performed using SAS version 8.2. For continuous variables, two-sample t test was used to test the difference between timepoints at significance level 0.05. Statistically significant difference will be claimed only when a P value is less than 0.05.
Discoveries by ultrasonography and operation
A total of 71 hyperplastic parathyroids in 20 patients were resected. 67 of these were detected correctly by preoperative B-ultrasonography including 2 suspicious parathyroid glands located in the thyroid tissues. The undetected lesions were mainly located at the left or right lower pole of the thyroids. The average value of the maximal diameter of the lesions under B-ultrasonography was (17.1±6.1) mm, with the biggest one 30 mm in diameter. In 12 cases with 4 glands detected by preoperative B-ultrasonography individually, 10 were confirmed by surgical exploration. One had the thyroid tissue resected instead of parathyroid gland; recurrent secondary hyperparathyroidism had happened in this case. The other patient had only 2 glands discovered by operation and the postoperative iPTH for this case was elevated all the time. In 3 cases with 3 glands detected by ultrasonography, one had another hyperplastic parathyroid gland discovered by surgical exploration. Finally, in those 5 cases with 2 glands detected by ultrasonography individually, 3 had the other two parathyroid glands found intraoperatively. In total, 71 glands in 20 cases had been discovered by surgical exploration. Among them: 4 glands in 14 cases; 3 glands in 3 cases; 2 glands in 3 cases (Table). The undiscovered glands were also located in the left or right lower pole of the thyroid. The accordance rate of parathyroid localization between B-ultrasonography and intraoperative exploration was 94.4% (67/71). The average value of the maximal diameter of the resected gland was (18.3±7.6) mm, with the biggest one 35 mm in diameter. No significant difference was found between ultrasonography and surgical exploration for the volumes of the glands (P>0.05). The average value of the weight of a single parathyroid gland was (1.35±1.00)g, with the biggest one 4 g. All glands were confirmed as parathyroid hyperplasia by pathological diagnosis.
Serum iPTH and calcium measurement
Blood samples were collected intraoperatively for iPTH measurement after removing 1, 2, 3, and 4 parathyroid glands individually. The values of iPTH decreased after each gland was resected, which were listed as follows: (913.85±111.22) ng/L, (633.93±570.97) ng/L, (635.05±472.74) ng/L, and (197.61±133.25) ng/L in 1, 2, 3 and 4 glands resected respectively. All values significantly decreased (P<.0001) as compared to those preoperatively, except the ‘1 gland resected’ group (P=0.2634), and reduced to the levels within the normal range after 4 glands resected.
The values of intraoperative serum calcium concentration were as follows: (2.843±0.254) mmol/L, (2.894±0.412) mmol/L, (2.766±0.316) mmol/L, and (2.619±0.336) mmol/L, in 1, 2, 3 and 4 glands resected respectively. All values reduced slightly (not statistically significant) as compared to those preoperatively, except the 4 glands resected (P=0.0014), but their values remained within the normal range.
The postoperative serum iPTH were tested at 1, 2, 3, 7, and 30 days after operation. The values declined as compared to those preoperatively, as (110.90±67.42) ng/L, (433.80±243.72) ng/L, (48.80±42.69) ng/L, (229.04±172.68) ng/L, and (232.39±224.05) ng/L in 1, 2, 3, 7 and 30 days after operation respectively (Fig.). The lowest level appeared at the third day postoperatively (P=0.0029 vs preoperatively).
Meanwhile, postoperative serum calcium concentrations tested at 1, 2, 3, 7, 30 days were maintained within a normal range, which was 2.206-2.444 mmol/L, noting that calcium supplements was given in accordance with the protocol described above (Fig.).
After operation, all clinical symptoms including anorexia and anemia were ameliorated, especially the bony pain and pruritus were greatly diminished and even disappeared. Two cases with movement disorder were able to walk without a stick. In all cases, the average value of the hematocrit significantly increased 3 months postoperatively compared to those preoperatively ((30.6±5.8)% vs (26.48±4.89)%, P<0.05).
Serum iPTH were kept constantly below 300 ng/L in 13 cases. In one case whose serum iPTH rose to higher than 500 ng/L 6 months after the operation, the iPTH value decreased to lower than 300 ng/L after the stosstherapy of Rocaltrol. At most recent follow up, the values of serum calcium and iPTH were (2.000±0.223) mmol/L and (454.40±455.94) ng/L respectively. Seven cases continue to require Rocaltrol adminisatration.
In our first case, a 2 cm × 2 cm × 2 cm mass appeared in the transplantation area of the right forearm 4 years after the operation, accompanied by a high serum iPTH level exceeding 2000 ng/L, and ultrasonography showed an hypo-echo area in the transplanted area, which presented dense radioactivity under ECT scanning. These findings indicated a recurrence of hyperparathyroidism caused by the hyperplasia of transplant tissue. Thus, a further operation was required to resect the mass of about 3 g in weight under brachial plexus blockade. Parathyroid hyperplasia was confirmed by pathological examination, and the value of serum iPTH level decreased to lower than 300 ng/L after the re-operation. In another case, only three glands were discovered intraoperatively, the fourth one was confirmed as thyroid tissue instead of parathyroid, the recurrence appeared 3 years after operation and iPTH rose to 1146 ng/L. An enlarged parathyroid gland at the back of the middle pole of the left thyroid was detected by ultrasonography and was resected surgically and confirmed as hyperplastic parathyroid. Postoperatively the serum iPTH decreased to lower than 300 ng/L.
No serious intraoperative or postoperative complications, such as recurrent laryngeal nerve damage, wound infection, massive hemorrhage occurred in any of these cases.
Drug treatment for secondary hyperparathyroidism caused by CRF may be available at the early stage of the disease, but it is not as effective for the severe patients. Once complications including skeletal malformation, fracture and extensive metastatic calcification in cardiovascular system appear, the quality of life of the patients may be influenced and life expectancy reduced. According to the reported surgical guidelines,1-4 the indications for surgical treatment in serious sHPT patients include as follows: (1)obvious iPTH level higher than 500-1000 ng/L; (2) enlarged parathyroids (the largest gland>0.5 mm3) showed by imaging examination; (3) fibrocystic osteitis inferred by radiology; (4) three indications mentioned above plus at least one of the following: hypercalcemia, uncontrolled high serum phosphate, progressive heterotopic ossification, severe clinical symptoms, severe fibrous osteitis proved by imaging, skeleton deformation, progressive loss of bony volume, anemia inefficacy to erythropoiesis therapy, etc. Surgical procedures such as parathyroidectomy should be considered in the conditions described above. All the patients reported in the current study exhibited the above indications.
There are several types of operations for sHPT: (1)Subtotal parathyroidectomy. Early in 1960, Stanbury et al5 was the first to use subtotal parathyroidectomy to treat sHPT, since then it had been regarded as the standard surgical procedure. Briefly, almost all of the parathyroids are resected with only 30-60 mg tissue chosen from the smallest gland remained (about half volume of a gland), together with bilateral removal of the thymus glands. The main defect of this surgical procedure is that it is very difficult to recognize whether nodular tissue exists in the remaining gland by observation with the naked eye. This may cause recurrence of hyperparathyroidism. Once recurrence occurs, re-operation on the cervical area may have a high risk, because tissue adhesion may make it more difficult to find the recurrent gland and accidental injury of the recurrent laryngeal nerve may occur. This method is less frequently used today. (2)Total parathyroidectomy, presents a risk of life-long hypoparathyroidism, which is hard to treat. (3)Total parathyroidectomy combined with autotransplantation which is advocated by some scholars represented by Wells.6 The hyperplastic parathyroid glands should be completely resected with about 60 mg gland tissue left and cut into granules of 1-2 mm3 in size, which is implanted in the radiohumerous muscular bed of the forearm without previous arterial-venous fistula formation. Because the recurrence occurs more frequently in nodulated than diffused hyperplastic glands, as reported by Gasparri et al,7 Giangrande et al,8 and Neonakis et al,9 it is important to make sure that the transplanted gland should be non-nodular tissues type. Recently, this surgical procedure has been widely preferred due to its safety, efficacy, low recurrence rate and convenient re-operation for forearm transplants, as in the current study.10-11 Our results demonstrated that all clinical symptoms had been significantly ameliorated by the successful surgery. Even in that one case who presented recurrence of hyperparathyroidism 4 years after operation, the simple re-operation for the forearm transplant obtained a satisfactory outcome.
Besides the postoperative hyperplasia of transplanted tissues, the remnant gland is the main source of recurrence, so one of the key points for the successful operation is whether the parathyroids would be completely removed. The current opinion is that preoperative imaging examination and localization should be essential to achieve this purpose. The most frequently used imaging techniques include cervical ECT scanning, B-ultrasonography and CT scanning. According to Liu et al,12 B-ultrasonography exhibited a high sensitivity of 73%, but showed less effectiveness in detecting some heterotopic lession. The result of our study was consistent with the report. Among the 71 hyperplastic parathyroid glands in 20 patients, 67 were detected by preoperative B-ultrasonography, the detection rate was as high as 94.4% (67/71). Even allowing for the normal four glands in every person, the detection rate was 83.8% (67/80). Based on our experiences, B-ultrasonography can produce an exact anatomic localization for hyperplastic parathyroids, especially for those with diameters exceeding 0.5 cm. Furthermore, it should be more convenient for the surgical specialists to precisely explore lesions intraoperatively if they attend the preoperative ultrasonographic examination. It has been reported that cervical ECT scanning holds high value in clinical application.13 Malhotra et al14 reported that 99mTcMIBI nuclide scanning could discover adenoma as small as 80 mg in weight, which was regarded as the most effective form of noninvasive examination. The sensitivity of ECT scanning in detecting parathyroids was 80%-87%.15 It showed better effect in localization for some heterotrophic glands that were hard to be located with ultrasonography. So, the combination of ultrasonography and MIBI scanning may improve the detection rate. However, in our study, in the four cases who underwent preoperative cervical ECT scanning, only 7 hyperplastic glands were detected from 16 expected, another case of hyperplastic implant was indicated as radioactivity dense area on the forearm. So, the value of ECT scanning should be further investigated in future research.
The intraoperative exploration is another principal method to ensure successful operation. In our patients, there were 4 cases with 7 parathyroid glands of about 0.5 cm size undetected by preoperative ultrasonography but discovered by careful and thorough surgical exploration. According to embryogenesis, normally there are four parathyroid glands divided into two pairs distributed symmetrically at the two sides of thyroid. The upper pairs are usually located in relatively invariable places, while the lower pairs often present in various positions due to the descending course along with thymus during the fetation period. It has been reported that the frequency of heterotopic parathyroids was 14%-30%.16-18 Our data indicated that the theoretically existing parathyroids which were undiscovered by preoperative ultrasonography or intraoperative exploration, were also located at the left or right lower pole of the thyroid. The completely removal of heterotopic parathyroids is important for avoiding postoperative recurrence. However, we did not explore the mediastinum routinely because our patients were all suffered from renal failure. Parathyroid glands were rarely embedded in thyroid tissues.19 In two cases hyperplastic parathyroid glands were located in thyroid tissues which were detected by preoperative ultrasonography and were successfully resected, and thus the recurrence was avoided. One case recurred due to the thyroid tissue was resected instead of a parathyroid gland, the re-operation was much more difficult than that on forearm. Thus, again, the total parathyroidectomy combined with partial auto-transplantation in the forearm presented its predominant advantage.
The intraoperative iPTH test could be a useful tool to assess an inadequate resection. The half life of iPTH is very short, only about (1.68±0.94) minutes, as reported by Libutti et al.20 Theoretically, during the resection period, iPTH should be supposed to decline progressively. The unobvious decline or partial decline of iPTH followed by secondary elevation could be a suggestion to the surgeon to be aware of incomplete removal of the glands or existence of heterotopia. Vignali et al21 estimated that the accuracy of iPHT on predicting the outcome of surgery was 97.5%. Our study showed that intraoperative iPTH decreased after resecting each parathyroid gland and reached the lowest value when all the glands had been completely removed. Although the instant iPTH monitor was not viable in the current study, our results still had significance as a guidance for intraoperative exploration in a further study. During the follow-up period it was found that iPTH reduced to low level three days after surgery and increased gradually after then, this result indicated that the implant parathyroid had been alive and begun to play its function. The values of iPTH in all our cases were all kept below 800 ng/L during follow-up, except in three cases. Two of them were proved recurrent. Another case had four glands detected by preoperative ultrasonography but only had two glands discovered intraoperatively. Postoperative iPTH was also higher than 1000 ng/L, but was closely followed due to no obvious symptoms.
The values of intraoperative serum calcium concentration were slightly reduced but still within the normal range so calcium supplements were not given during operation. Thus it is not essential to emphasize intraoperative calcium administration. To avoid “bone hungry syndrome” occurred after the operation, which may cause serious hypocalcemia and rigid muscle spasm, we monitored serum calcium concentration intensively and offered postoperative calcium supplements promptly. It proved to be a successful management strategy in all our patients. Up to now the serum calcium concentrations in all our cases have remained within the normal range.
Whether the patients with chronic renal failure would be able to tolerate operation under general anesthesia was an important problem of concern before the study. Indeed, by the close cooperation with physicians and anesthetists, all our patients went through the peri-operative periods fluently. Although we could not predict voice problem under general anesthesia, no surgical related complications such as recurrent laryngeal nerve damage happened, other anesthesia related complications were also avoided, which indicated that the operation should be safety and feasibly performed. In particular, tissues of CRF patients are more friable and often have dilated vessels distributed on the surface of the swollen glands, special care should be given throughout the operation.
In conclusion, the total parathyroidectomy with forearm autotransplantation is feasible, safe and effective for the patients with secondary hyperparathyroidism, while its long-term effect will be further investigated after obtaining more samples and much longer follow-up.
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