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Nephrol Dial Transplant (2003) 18: III65-III70
© 2003 European Renal Association-European Dialysis and Transplant Association

Original Article

Re-operation is frequently required when parathyroid glands remain after initial parathyroidectomy for advanced secondary hyperparathyroidism in uraemic patients

Yoshihiro Tominaga1,, Akio Katayama1, Tetsuhiko Sato1, Susumu Matsuoka1, Norihiko Goto1, Toshihito Haba1, Yatsuka Hibi2, Masahiro Numano3, Toshihiro Ichimori4 and Kazuharu Uchida1

1 Department of Surgery, Renal Center, Nagoya Second Red Cross Hospital, Nagoya, 2 Department of Surgery II, Nagoya University School of Medicine, Nagoya, 3 Department of Transplant Surgery, Kakegawa General Hospital, Kakegawa and 4 Department of Surgery, Tokushima Red Cross Hospital, Tokushima, Japan



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Parathyroidectomy (PTx) is the most successful treatment for advanced secondary hyperparathyroidism (2HPT) not responsive to medical treatment. However, persistent HPT remains problematic after PTx if some glands remain. The clinical course in patients with persistent 2HPT was evaluated to clarify the risk for re-operation after PTx.

Methods. Between March 1981 and December 2001, initial total PTx with forearm autograft were performed in 1156 uraemic patients. Persistent HPT cases were defined as those in which the lowest post-operative intact parathyroid hormone (i-PTH) concentration was >60 pg/ml, and patients were classified into groups A, B and C, with i-PTH concentrations of >=500, 300–500 and 60–300 pg/ml, respectively. These patients were followed for 7–234 months after PTx.

Results. Persistent HPT was identified in 49/1156 patients (4.2%), with nine cases in group A, 10 in group B and 30 in group C. Re-operation was required in 21/49 (42.8%) cases, and in seven of these the last i-PTH concentration was >=500 pg/ml. All cases in group A required re-operation. In group C, 11/30 (36.7%) patients required re-operation. The missed glands removed at re-operation were supernumerary in 14 cases, and located in the mediastinum in 13 cases. The frequency of advanced HPT and re-operation was not negligible.

Conclusions. To prevent persistent 2HPT, all parathyroid glands must be found and resected during the initial operation. Even if small parathyroid glands remain, there is a risk of progression. Complete PTx is the first treatment choice for advanced 2HPT.

Keywords: chronic renal failure; mediastinal parathyroid gland; parathyroidectomy; persistent hyperparathyroidism; secondary hyperparathyroidism; supernumerary gland



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Secondary hyperparathyroidism (2HPT) induced by chronic renal failure is a serious problem for uraemic patients because it induces osteitis fibrosa and cardiovascular complications associated with a high mortality risk [1–5]. Despite advances in medical prophylaxis and treatment, in many patients 2HPT is refractory to medical treatment, and parathyroidectomy (PTx) is required [6]. The incidence of advanced 2HPT gradually increases with the duration of haemodialysis (HD) treatment and, in Japan, >10% of patients treated with HD for >10 years require PTx [7].

PTx is the most successful treatment for advanced 2HPT and has a positive effects on symptoms and biochemistry. Skeletal deformity, progressive bone loss and vessel calcification leading to high mortality risk remain, however, even after successful PTx; therefore, to prevent the cardiovascular complications, surgery should be performed at an early stage of 2HPT [8]. The size of the parathyroid glands is an important factor in deciding whether surgery is indicated. If the ultrasonographic estimation of parathyroid volume exceeds 500 mm3, this suggests that nodular hyperplasia is present and that control of 2HPT is unlikely with medical treatment [6,8,9]. For uraemic patients, total PTx with forearm autograft is the treatment of choice for 2HPT, especially in Japan, because, if patients require long-term HD after PTx, the risk of recurrent HPT is significant. Recurrent 2HPT caused by the autograft can be treated non-invasively under local anaesthesia by removing the enlarged autografted parathyroid tissue from the forearm [6,8,10,11]. In some cases, it is impossible to remove all the parathyroid glands during the initial operation because of their ectopic location or the existence of supernumerary glands, which leads to persistent HPT developing into 2HPT after PTx [10,12,13].

To clarify the risk of progression of HPT and the requirement for re-operation, the present study evaluated the clinical course of patients who had residual parathyroid glands after initial surgery. The information obtained may be useful in evaluating the efficacy of other treatments such as percutaneous ethanol injection therapy (PEIT), percutaneous calcitriol injection therapy (PCIT) and percutaneous maxacalcitol injection therapy (PMIT) for advanced 2HPT refractory to medical treatment. With these treatments, enlarged parathyroid glands are not completely destroyed, and other small glands remain intact [14,15].



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Between March 1981 and December 2001, we performed total PTx with forearm autograft in 1156 uraemic patients with advanced 2HPT refractory to medical treatment. Our surgical indications and strategy have been described previously [8–10]. To avoid missed glands, we proceed as follows.

  1. The patient undergoes diagnostic imaging with 201TlCl or 99mTc MIBI scintigraphy, ultrasonography, computed tomography and magnetic resonance imaging. At operation, all parathyroid glands shown by these procedures are found and removed.
  2. As supernumerary glands are often found in thymic tissue, this is routinely excised through a cervical incision [12].
  3. Routine bilateral opening of the carotid sheath exposes any supernumerary glands around the carotid and in the paraoesophageal and paratracheal area.
  4. Because rudimentary or split supernumerary glands are sometimes located in fat lobules covering the glands, they are also extirpated [12].
  5. Part of each resected gland is sent for histopathological confirmation during operation.

After PTx, active vitamin D and calcium salts in dosages estimated to avoid hypoparathyroidism and recurrence of HPT are administered [8,10]. Patients attend the out-patient clinic for evaluation of parathyroid function six times in the first year, and then twice per year during the follow-up period. The follow-up period for this series was 7–243 months. If the intact parathyroid hormone (i-PTH) concentration (measured by Allegro Kit; normal range <=60 pg/ml) exceeded 100 pg/ml, active vitamin D was given. If the i-PTH concentration was >=300 pg/ml, intensive treatment, such as oral or intravenous calcitriol pulse therapy or maxacalcitol injection, was given. When the i-PTH concentration exceeded 500 pg/ml, and 2HPT was refractory to medical treatment, two types of diagnostic imaging were again performed and, if missed glands were detected, they were removed by re-operation [16].

Persistent HPT was identified if the lowest post-operative i-PTH concentration was still higher than the upper normal limit (>60 pg/ml) measured after initial PTx on post-operative day 1 or 2, and this indicated that at least one parathyroid gland remained in situ. Recurrent HPT was identified when the minimal i-PTH concentration just after initial PTx was <=60 pg/ml, after which the i-PTH concentration rose and re-operation was required. To evaluate the clinical course of patients with persistent HPT, we classified them into three groups based on the minimal i-PTH concentration: group A comprised patients whose minimal PTH concentration was >=500 pg/ml, which is one of the factors indicating PTx; group B comprised patients whose minimal i-PTH concentration was between 300 and 500 pg/ml (i-PTH >=300 pg/ml suggesting clinically advanced 2HPT, and being an indication for calcitriol or maxacalcitol pulse therapy); and group C comprised patients whose minimal i-PTH concentration was between 60 and 300 pg/ml.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The number of parathyroid glands removed at initial PTx varied: one patient (0.1%) had seven glands removed; in 14 cases (1.2%), six glands were resected; in 135 cases (11.7%), five glands were resected; in 971 cases (84.4%), four glands were resected; in 28 cases (2.4%), three glands were resected; and two glands were removed from two patients (0.2%). At the initial PTx, four or more glands were identified in 97.4% of explorations. In 13.0% of patients, supernumerary glands were resected at initial operation, but in a few cases the PTH concentration did not drop under the normal upper limit for i-PTH.

The total incidence of persistent 2HPT was 49/1156 patients (4.2%); nine patients (0.8%) were in group A, 10 (0.9%) in group B, and 30 (2.6%) in group C. The number of glands removed at initial PTx in each group is presented in Table 1Go. In only 11/49 cases (22.4%) were fewer than four glands resected. In 34 cases (69.3%), four glands were removed, and in four cases (8.5%) supernumerary glands were removed at initial PTx; however, persistent HPT occurred.


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  		Table 1.  Number of parathyroid glands removed in each group at the initial parathyroidectomy (PTx) in patients with persistent hyperparathyroidism (HPT)

 
Of these 49 cases, 22 were women; the mean age was 50±5.5 years (±SD); duration of HD before PTx was 142±27.5 months; serum calcium concentration was 10.2±0.5 mg/dl, phosphorus 6.0±0.7 mg/dl, alkaline phosphatase 491±267 IU/l, i-PTH 1232±744 pg/ml and the mean total glandular weight resected at initial operation was 2466±717 mg. There were no significant differences between the three groups, also in a comparison with patients without persistent HPT, except that the total glandular weight in group A was less than that of the other groups (1635±410 mg in group A, 2309±2107 mg in group B and 2740±616 mg in group C).

In group A, eight of nine patients required re-operation between 5 and 25 months after initial PTx and, in seven of these cases, the supernumerary gland affected was removed from the mediastinum; in the other case, the gland resected from the left paratracheal area was affected. In the remaining case, the i-PTH level of >=500 pg/ml persisted but, as a missed gland could not be detected by any imaging methods, follow-up of that patient continued. In all cases, the PTH concentration dropped after re-operation; however, one patient underwent removal of the autograft from the forearm because of graft-dependent recurrence after re-operation. One patient died of arterial valve stenosis 142 months after the first PTx, and another died of renal cell carcinoma 116 months after the initial operation (Figure 1Go).



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  		Fig. 1.  Clinical course of patients in group A.

 
In group B, two of 10 cases (20%) underwent removal of a supernumerary gland from the mediastinum at 9 and 28 months after their initial operation, which resulted in control of HPT. One patient died of cerebral bleeding 9 months after the initial operation. In the remaining seven cases, HPT was medically controlled; however, in three patients, the i-PTH concentration was very high (>=500 pg/ml) and re-operation will be required in the future (Figure 2Go).



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  		Fig. 2.  Clinical course of patients in group B.

 
A summary of the clinical course of the patients in group C is shown in Figure 3Go. Eleven of the 30 patients (36.7%) underwent re-operation between 19 and 136 months after initial PTx. In five cases, the missed parathyroid gland was supernumerary, removed from the mediastinum in four cases, and from the neck in one case. In three of four cases in which the supernumerary gland was resected from the mediastinum, the PTH concentration dropped, but in the remaining case a high PTH concentration persisted after re-operation, and HPT was controlled by successful renal transplantation. In three cases of initial PTx in our early experience, a missed fourth gland was removed from the neck. In two cases, histopathological confirmation of parathyroid tissue resected during operation was not available and a thyroid nodule was mistaken for a parathyroid gland. The remaining parathyroid glands located in the area around the thyroid lobe were removed, but the PTH concentration rose again. These patients required removal of the forearm autograft. In another case, we missed an undescended parathyroid gland initially and it was removed 68 months after the first operation. Later, the PTH concentration was re-elevated, and the patient required removal of the autograft from the forearm and removal of a fifth gland from the thymic tissue. In three cases, missed glands could not be detected in the neck or mediastinum by imaging diagnosis, and HPT improved with removal of autografted parathyroid tissue. One patient in group C had an interesting clinical course. After the initial operation, the PTH concentration gradually rose and a missed gland was detected around the aortic arch by imaging, and re-operation was scheduled. At 36 months after the first operation, the patient had a sudden onset of hypocalcaemic symptoms and the PTH concentration dropped. A shrunken parathyroid gland was detected by diagnostic imaging at the same location. The HPT improved and re-operation was avoided; we speculated that infarction of the gland induced spontaneous remission of HPT. The patient finally died of a cerebrovascular episode during the follow-up period. In the remaining 18 cases, HPT was managed medically. However, in three cases, the i-PTH concentration gradually increased to >=500 pg/ml, and re-operations will be necessary in the near future. One patient died of heart failure at 52 months after the initial PTx.



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  		Fig. 3.  Clinical course of patients in group C.

 
In summary, 21 of 49 cases (42.8%) with persistent HPT needed re-operation because medical treatment was insufficient. In seven cases, the last PTH concentration exceeded 500 pg/ml and re-operation will be needed in the near future. In total, the HPT of 28 (57.1%) patients could not be controlled medically. If the PTH concentration immediately following PTx did not drop below 500 pg/ml, re-operation within 3 years of the first operation was required. Even when the i-PTH concentration dropped below 300 pg/ml, HPT in approximately half of the patients was progressive, and 11/30 of these patients (36.7%) required re-operation. The missed glands in these patients were supernumerary in 14 cases (66.6%), located in the mediastinum in 13 cases (61.9%), and in the neck in five cases (23.8%). In three cases, missed glands could not be detected and the swollen autograft was resected. In some patients, persistent HPT could be controlled by medical treatment; however, the frequency of advanced HPT and the requirement for re-operation increased significantly.

To prevent persistent HPT and avoid re-operation, it is important to identify and resect all parathyroid glands, including supernumerary glands, during the initial operation. However, it was difficult to avoid persistent HPT caused by supernumerary parathyroid glands located in the mediastinum. If parathyroid glands were missed during the initial operation, re-operation frequently was required.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The aim of parathyroid interventional therapy, such as PEIT, PCIT and PMIT, including PTx, is mass reduction of pathological and enlarged parathyroid tissue. With PEIT, PCIT and PMIT, it is impossible to destroy small diffuse hyperplastic parathyroid glands, and to reduce all parathyroid cells of nodular hyperplastic glands completely [14,15]. We wanted to understand the reasons for incomplete improvement of HPT and re-elevation of PTH concentration during long-term follow-up, even when adequate and intensive medical treatment was provided.

PTx is the most successful treatment for mass reduction of parathyroid glands, but even the most skilled surgeon will miss a few glands during initial PTx because (i) it is not always easy to detect normal sized parathyroid glands that are small and have a fat-like macroscopic appearance; (ii) parathyroid glands are sometimes located ectopically [i.e. in the mediastinum or in a thyroid lobe (intrathyroidal) in an upper area of the upper pole (undescended gland)] [13,17–19]; and (iii) they can be supernumerary. The incidence of supernumerary glands has been reported to be 2.5–12.5% in autopsy series [13,17,18] and 10–30% in patients who underwent PTx for 2HPT [12,20]. Detecting supernumerary glands is important in 2HPT because all parathyroid glands, including those that are supernumerary, are fundamentally hyperplastic in uraemic patients.

In the present study, we evaluated the incidence of re-elevation of PTH concentration, and the requirement for re-operation for missed parathyroid glands during initial PTx. We diagnosed the existence of remaining glands and persistent HPT when the i-PTH concentration did not drop under the normal upper limit (60 pg/ml) following PTx. In >97% of patients, four or more parathyroid glands were removed, and our assumption is that the frequency of persistent 2HPT was 49/1156 (4.2%). If the i-PTH concentration was >500 pg/ml, re-operation was unavoidable. Even when the concentration was between 300 and 500 pg/ml, the frequency of re-operation was 2/10. In group C, in which the i-PTH was between 60 and 300 pg/ml, 11/30 patients underwent re-operation between 19 and 136 months after the initial PTx. Moreover, during the same period, 19/1156 (1.6%) patients required a second neck exploration for recurrent HPT, even when the i-PTH concentration decreased to <60 pg/ml following PTx. This indicates that small, usually supernumerary glands were not detected macroscopically at initial operation. These glands gradually enlarged, and removal was required during the long-term follow-up period [21]. The incidence of removal of autograft for graft-dependent recurrent HPT during the same period was 97/1156 (8.4%) [21]. The incidence gradually increased after operation to 10% in the third year, 20% in the fifth year, and 30% in the seventh year after PTx [10,21]. This indicates that even if small parathyroid glands or tissue remain, re-progression of HPT and requirement for re-operation cannot be avoided in many patients. Grafted parathyroid tissue can be removed non-invasively from forearm muscle; however, re-exploration of the neck entails a high risk of injury to the laryngeal recurrent nerve [22]. Following PEIT, we found adhesions surrounding the parathyroid glands at PTx. A number of patients who underwent PTx at other institutes were referred for re-operation because of persistent/recurrent HPT. In these cases, it is often difficult to detect the responsible parathyroid glands or tissue at surgery, and multiple surgery is needed because of incomplete improvement in the high PTH concentration after re-operation. We recommend complete removal of all parathyroid tissue and adequate transplantation of tissue at initial PTx as the most effective treatment for cases of advanced HPT, refractory to medical treatment. Follow-up with adequate medical treatment is also important.

We previously evaluated the clinical course of 21 patients in whom fewer than four glands were detected macroscopically and removed at the initial PTx [23]. In five cases, microscopic examination confirmed that a fourth gland was removed without macroscopic affirmation. In seven cases, the i-PTH concentration dropped below 60 pg/ml following PTx. Only 3/21 (14.2%) patients required removal of a fourth gland for persistent/recurrent HPT. We have found that parathyroid glands responsible for persistent HPT are usually supernumerary and located in the mediastinum [8]. Although the ideal procedure is to remove all parathyroid glands, including supernumerary glands, this is difficult to achieve, and persistent HPT from the missed mediastinal parathyroid glands is hard to avoid except when large mediastinal parathyroid glands are detected by MIBI scintigraphy before operation.

Possible reasons for progression of HPT after PTx include (i) the small chance of having a renal transplantation in Japan; unfortunately, almost all patients must continue HD treatment for a long period after PTx and so the stimuli to the parathyroid glands or tissue (i.e. hypocalcaemia, phosphate retention and deficiency of active vitamin D) persist in the long term; (ii) the hyperplastic nature of all parathyroid glands, including supernumerary glands, in uraemic patients; (iii) the residual parathyroid glands or tissue retaining physiological abnormalities [i.e. less expression of the vitamin D receptor (VDR) and calcium-sensing receptor] [24,25]; (iv) the possibility that the genotype of the VDR and PTH genes influences the progression of 2HPT [26–30]; patients who require PTx may have genetic factors that induce progression of HPT; and (iv) poor drug compliance, which makes it hard to control phosphate retention after PTx.

Even if the missed glands are small, the risk of progressive HPT and the requirement for re-operation will probably be unavoidable during long-term follow-up. Therefore, patients who require intervention, including PTx, for advanced 2HPT have a high risk for progression after treatment.

We therefore conclude that adequate PTx should be the first choice of treatment for advanced 2HPT refractory to medical treatment, and that it should be performed before progression to irreversible ectopic calcification.



   Notes
 
Correspondence and offprint requests to: Yoshihiro Tominaga, MD, Department of Surgery, Renal Center, Nagoya 2nd Red Cross Hospital, 2–9 Myoken-cho, Showa-ku, Nagoya 466-8650, Japan. Email: ytomi{at}nagoya2.jrc.or.jp Back



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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