[99mTc]-Sestamibi parathyroid scintigraphy in chronic haemodialysis patients: static and dynamic explorations

Ines Olaizola1, Johanna Zingraff2, Carlos Heuguerot1, Laura Fajardo1, Aubène Léger3, Juan Lopez1, Gonzalo Acuña1, Alicia Petraglia1, Asuncion Alvarez1, Hena Caorsi1, Tilman Drüeke2, and Pablo Ambrosoni1

1 Servicio de Nefrologia and Servicio de Medicina Nuclear, Hospital de Clinicas ‘Manuel Quintela’, Montevideo, Uruguay, 2 Unités 90 and 507 de l'INSERM and Division of Nephrology and 3 Service des Radio-Isotopes, Hôpital Necker, Paris, France



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
>Background. The place of parathyroid gland imaging by [99mTc](technetium)-sestamibi scintigraphy in uraemic patients with secondary hyperparathyroidism remains a matter of debate. The purpose of the present study was (i) to assess its value with respect to plasma intact parathyroid hormone (iPTH) levels and to surgical parathyroidectomy (PTx), and (ii) to explore the possibility of suppressing parathyroid [99mTc]-sestamibi uptake by calcitriol.

Methods. In a first cross-sectional, static study 52 chronic haemodialysis (HD) patients with plasma iPTH levels between 14 and 2791 pg/ml (normal, 10–65 pg/ml) had a [99mTc]-sestamibi scan, and 21 of them underwent surgical PTx. In a second longitudinal, dynamic study 14 chronic HD patients with advanced secondary hyperparathyroidism received short-term calcitriol treatment in an attempt to suppress [99mTc]-sestamibi imaging of parathyroid glands. Calcitriol was given intravenously for 2 weeks, 2 µg after each haemodialysis session. Scintigraphy was carried out before and at the end of this inhibition test.

Results. [99mTc]-Sestamibi scan led to imaging of one or more (maximum three) parathyroid glands in most, but not all, HD patients with plasma iPTH values >600 pg/ml. Based on surgical findings, overall sensitivity of [99mTc]-sestamibi scan in correctly locating parathyroid glands was only 50%, whereas specificity was 100%. In contrast, its sensitivity was 100% in locating single glands in the subgroup of five patients with recurrent hyperparathyroidism. The calcitriol inhibition test showed suppression of [99mTc]-sestamibi uptake by at least one parathyroid gland in eight patients (57%), with complete suppression in five of them (36%). Basal plasma iPTH or decrease of plasma iPTH in response to calcitriol was not predictive of suppressible [99mTc]-sestamibi uptake in the individual case, although mean iPTH was markedly higher in patients with non-suppressible parathyroid glands.

Conclusion. Because of its relatively low sensitivity the [99mTc]-sestamibi scan is of limited help in the exploration of uraemic patients with severe secondary hyperparathyroidism before a first surgical PTx. However, it is very useful in locating the remaining parathyroid gland(s) in case of reoperation. The novel calcitriol inhibition test of [99mTc]-sestamibi uptake could help to better distinguish parathyroid glands with non-suppressible, autonomous activity from glands whose activity might be amenable to long-term suppression.

Keywords: haemodialysis; hyperparathyroidism; imaging; parathyroid scintigraphy; parathyroidectomy; sestamibi



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The treatment and prevention of the secondary hyperparathyroidism of chronic renal failure have greatly improved during the last decade. However, in a minority of uraemic patients parathyroid overfunction persists, progressively escapes medical control, and eventually becomes extremely severe, requiring surgical correction [1,2]. This escape probably occurs because of an alteration in parathyroid tissue growth pattern, consisting of a switch from polyclonal to monoclonal or multiclonal proliferation [3,4].

In case of severe secondary hyperparathyroidism, it appears useful to assess the location of each hyperplastic gland, using one or more of the presently available imaging techniques. Ultrasound evaluation has become the standard method and is of relatively low cost. The sensitivity of this technique is almost 80% when performed by experienced radiologists; specificity is much lower [5], but reproducibility is excellent [6]. CT scan and magnetic resonance imaging are costly methods; the latter may be especially useful in localizing ectopic glands not detected by other methods [6].

Among radioisotopic techniques double subtraction with 201Tl (thallium) and 99mTc (technetium) or 123I (iodine) is no longer used in clinical routine [6]. A relatively promising radionuclide technique has been introduced more recently, using cationic isoalkylonitrile complex radiolabelled with 99mTc, namely [99mTc]-sestamibi. This compound enters the intracellular and intramitochondrial space, depending on respective membrane potential differences [7]. It is taken up by cells in activity phase and therefore has been used as a tumour marker. Its uptake by benign tumours is not the rule, but primary adenomas of the parathyroid have been shown to exhibit a demonstrable uptake of the radiomarker in most instances [810].

The value of [99mTc]-sestamibi scintigraphy in uraemic patients with secondary hyperparathyroidism remains inconclusive at present, although subtraction by another isotope has been shown to improve sensitivity [1114].

We thought it might be of interest to evaluate the suppressibility of [99mTc]-sestamibi uptake by hyperplastic, overactive parathyroid glands of uraemic patients in response to calcitriol administration, using repeat scintigraphy. We hypothesized that the result of such a test might be helpful in the choice between medical treatment and surgical parathyroidectomy (PTx).

The aim of the present study was (i) to reassess the usefulness of [99mTc]-sestamibi scintigraphy in a large group of uraemic patients with various degrees of secondary hyperparathyroidism; (ii) to re-examine the place of this technique with respect to surgical findings; and (iii) to test the hypothesis that inhibition of parathyroid [99mTc]-sestamibi uptake after short-term, high-dose calcitriol administration can distinguish between autonomous and suppressible gland function.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Static exploration
In this cross-sectional study we explored 52 chronic haemodialysis patients with plasma intact parathyroid hormone (iPTH) levels varying from 14 to 2791 pg/ml in order to determine the usefulness of sestamibi scan in locating parathyroid glands. Patients have been recruited for study partly in Montevideo, Uruguay, and partly in Paris, France.

Patients were subdivided into three groups, based on plasma iPTH levels (Table 1Go): group A, plasma iPTH <600 pg/ml (n=11); group B, plasma iPTH between 601 and 1000 pg/ml (n=21); and group C, plasma iPTH >1000 pg/ml (n=20). Table 1Go also shows patients' age, gender, and length of haemodialysis treatment, as well as plasma biochemistry.


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Table 1. Characteristics of 52 haemodialysis patients with sestamibi scintigraphy

 
Sestamibi scan findings were compared with surgical findings in the 21 patients who underwent parathyroidectomy. Five of them had recurrent hyperparathyroidism after previous neck surgery. Table 2Go shows the clinical and biochemical data of these 21 patients.


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Table 2. Characteristics of all 21 haemodialysis patients with both sestamibi scintigraphy and surgical parathyroidectomy

 

Dynamic exploration
In this longitudinal study, 14 chronic haemodialysis patients with various degrees of secondary hyperparathyroidism underwent a functional test to explore the possibility of suppressing a positive sestamibi image of the parathyroid glands by the administration of calcitriol. Calcitriol was administered intravenously, 2 µg after each haemodialysis session, thrice weekly for 2 weeks. This time period was chosen because the patients in the Uruguayan centre were usually given calcitriol for 2 weeks before parathyroidectomy to decrease the risk of hungry bone syndrome and profound hypocalcaemia after surgery. Only patients with a CaxPO4 product below 80 mg2/dl2 were asked to participate at the test. Plasma total calcium and phosphorus concentration was monitored at days 5 and 10 to verify that the CaxPO4 product did not exceed this level. Sestamibi scintigraphy was performed and plasma iPTH determined immediately before (basal study) and at the end (repeat study) of the inhibition test period.

Methods
Sestamibi scintigraphy was performed using i.v. administration of [99mTc]-sestamibi, 700 MBq/70 kg body weight, with a projected radiation dose to the thyroid of 0.0063 mGy/MBq. Dynamic images were obtained in scintillation camera (SOPHA Computer DSX), taken up to 30 min and then at 2 h following injection [8].

Sestamibi images were considered as ‘positive’ when one or more clearly defined focal areas of abnormal uptake in the thyroid area, with respect to the surrounding tissue, were visible on early images and persisted on late images (washout). Scintigraphic imaging was considered ‘negative’ when these criteria were not fulfilled [8].

The calcitriol inhibition test was considered positive when at least one area of tracer uptake persistent on the late sestamibi scan images at basal study could no longer be identified on the sestamibi scan at repeat study.

Plasma total calcium and phosphorus were determined by standard methods. Plasma iPTH was measured with Allegro immunoradiometric assay (Nichols Institute Diagnostics, Paris, France), with normal values comprised between 10 and 65 pg/ml.

The study project was approved by the local hospital ethical committee, and informed consent was obtained from each patient.

Statistical analysis
Statistical analysis was performed using Student's paired or unpaired t-test, or Wilcoxon test, as appropriate. A P value <0.05 was considered significant. Results have been expressed as means±SD throughout.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Static exploration
In group A, five of 11 patients exhibited positive tracer uptake in one area. The lowest iPTH value associated with a positive scan was 268 pg/ml. Only one of group A patients had PTx because of recurrent hyperparathyroidism. In this patient, the parathyroid gland removed corresponded to the one identified by [99mTc]-sestamibi scan.

In group B, 17 of 21 patients exhibited positive tracer uptake in 1–3 areas, corresponding to a total of 29 glands. In fact, three glands were found in only three patients, and in no patient could four glands be identified. Eight of the 21 patients underwent PTx, leading to the removal of 22 glands. One of these eight patients had recurrent hyperparathyroidism with only one gland identified by both sestamibi and surgery. The comparison between [99mTc]-sestamibi and surgical findings in this group showed a sensitivity of 59% and a specificity of 100%.

In group C, 19 of 20 patients exhibited positive tracer uptake in 1–3 areas, corresponding to a total of 29 glands. Three glands were found in only one patient, and again four glands in none of them. Twelve of the 20 patients underwent PTx, leading to the removal of 35 glands. Three of these 12 patients had recurrent hyperparathyroidism with only one gland identified by both [99mTc]-sestamibi and surgery. The comparison between sestamibi and surgical findings in group C showed a sensitivity of 46% and a specificity of 100%.

When considering the value of [99mTc]-sestamibi scan vs surgical findings in the three groups together a total of 58 hyperplastic glands were identified by surgery in the 21 operated upon whereas 29 were correctly located by scintigraphy. This corresponded to an overall sensitivity of 50%. No false-positive result was obtained, indicating an excellent specificity (100%). In the five patients with recurrent hyperparathyroidism, a single gland was correctly identified by both procedures (sensitivity and specificity of 100%).

In 18 PTx patients we obtained the weight of their 52 parathyroid glands removed at surgery. In glands weighing <300 mg [99mTc]-sestamibi study showed a sensitivity of 50%. In glands weighing between 300 and 999 mg sensitivity was 36%. Finally, for parathyroid gland weights >1000 mg sensitivity was 90%.

Dynamic exploration
In the 14 patients studied, basal [99mTc]-sestamibi scan revealed 1–3 glands with focal tracer uptake. In five of them, subjects 10–15 (36%), the repeat test after calcitriol treatment showed an entire disappearance of tracer uptake, whereas in the other nine patients, subjects 1–9, one or two glands remained positive (Table 3Go). In three of these latter patients, subjects 6–8, calcitriol treatment led to the disappearance of one in three glands at repeat examination. Mean basal plasma iPTH level was not significantly different between the group with persistent [99mTc]-sestamibi-positive glands and the group in which focal uptake was entirely negative at repeat study. In both groups, plasma iPTH levels decreased significantly in response to calcitriol administration.


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Table 3. Change of sestamibi uptake by parathyroid glands in response to calcitriol treatment

 
We then compared all those patients with plasma iPTH measurements at basal and repeat study who had at least a partial scintigraphic response to calcitriol (positive inhibition test), namely one or more parathyroid glands being no longer visible on repeat sestamibi scan, with the patients who had no response at all (negative inhibition test). Basal plasma iPTH levels were twofold higher in the latter than in the former, although the difference was only of borderline significance (Table 4Go). Similarly, plasma iPTH was more than twofold higher at repeat examination in the patients with a negative than in those with a positive inhibition test.


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Table 4. Change of plasma iPTH levels as a function of sestamibi uptake inhibition in response to calcitriol treatment

 
Interestingly, the majority of positive, non-inhibitable glands proved to exhibit nodular type hyperplasia on light microscopy examination after surgery (data not shown).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the last decade, considerable progress has been made in the biochemical diagnosis of primary and secondary hyperparathyroidism, due to the development of highly sensitive and clinically reliable assays to measure plasma iPTH. However, absolute plasma iPTH values are probably not the best means of assessing parathyroid gland hyperplasia precisely. Therefore functional tests have been developed. The increase in plasma PTH in response to hypocalcaemia provides a much better correlation with parathyroid gland mass than does basal plasma PTH [15]. A more elaborate way to illustrate this relationship, at least theoretically, is the definition of the sigmoidal relationship between plasma Ca and PTH and derived parameters such as maximal stimulation and suppression, set-point, and slope [16,17]. However interesting from a pathophysiological point of view, the practical significance of the sigmoidal relationship and derived variables for patient management has remained limited.

The importance of assessing parathyroid tissue growth and gland size in uraemic patients, in addition to PTH oversecretion, has been re-emphasized recently [1,2]. In particular, the recognition of tumour-like, clonal parathyroid growth in advanced stages of hyperplasia with the transformation from diffuse to nodular tissue hyperplasia [3,4] has stimulated general interest in more precise knowledge of the anatomy and the growth pattern of each parathyroid gland. Whereas at present information on the latter is still mainly limited to the analysis of surgically removed tissue, the study of the former has become possible with the advent of specific radionuclide methods.

Parathyroid imaging by [99mTc]-sestamibi scintigraphy has been shown to be useful in the preoperative location of parathyroid glands in primary hyperparathyroidism. However, its usefulness in assessing the size and location of parathyroid glands of uraemic patients and in managing secondary hyperparathyroidism surgically remains a matter of debate, especially in case of a first intervention [1113].

In the first part of the present work (static study) we have evaluated the place of the [99mTc]-sestamibi scan in the detection of parathyroid gland hyperplasia (normal parathyroid tissue not being visualized by this technique) and in the preoperative location of hyperplastic glands in severe forms of secondary hyperparathyroidism, compared with subsequent surgical findings. In the group of patients with a plasma iPTH <600 pg/ml, one gland could be visualized in five patients. In the remaining six, no gland was detected, despite plasma iPTH values >200 pg/ml in three of them. In the two other groups with plasma iPTH values >600 pg/ml, a greater number of parathyroid glands was detected, mostly one or two glands per patient, but never more than three. There was no correlation between plasma iPTH and gland number (data not shown). Compared with surgical findings, the overall sensitivity of the [99mTc]-sestamibi scan in locating parathyroid glands was 50%, whereas the specificity was 100%. Thus this scintigraphic method fails to identify one in two glands, compared with surgery performed by experts in the field.

However, the performance of [99mTc]-sestamibi scan is much better in uraemic patients with recurrent or persistent secondary hyperparathyroidism with only one hyperplastic gland in the cervical region. In the five cases of this study with recurrence, sensitivity increased to 100%, with specificity remaining at 100%. Obviously, the [99mTc]-sestamibi scan is also helpful in the detection of ectopic glands, as found by others [913] as well as ourselves (unpublished data).

In the second part of our work (dynamic study) we evaluated for the first time the question of whether parathyroid gland imaging by the [99mTc]-sestamibi scan might be acutely inhibitable by i.v. calcitriol administered for 14 days, and if so, whether such an inhibition test might be of help in the management of uraemic patients with hyperparathyroidism. Scintigraphic visualization became negative for at least one gland in 57% of patients at repeat study. None of the glands exhibited [99mTc]-sestamibi uptake at repeat examination in 36% of them. Plasma iPTH levels decreased to a similar degree in response to calcitriol in patients with persistent vs lost parathyroid [99mTc]-sestamibi imaging at repeat study, although mean hormone values were nearly twofold higher in the former than in the latter, both before and after inhibition by calcitriol. When comparing all those patients who had at least a partial scintigraphic response to calcitriol (positive inhibition test) with those having no response at all (negative inhibition test) we again found that basal plasma iPTH levels were twice as high in the latter than in the former, both before and after calcitriol administration. In fact, mean plasma iPTH at repeat study in patients with a negative inhibition test became similar to basal plasma iPTH in patients with a positive inhibition test.

What can be learnt from this dynamic study? Firstly, the results show that parathyroid gland imaging can be suppressed by pulse calcitriol administration for 2 weeks. This indicates that some activity of the hyperplastic parathyroid cell involved in [99mTc]-sestamibi uptake can be rapidly inhibited by vitamin D, possibly via an increase in P-glycoprotein mediated efflux from the cell membrane [7,18,19], although this latter mechanism remains controversial. Secondly, our results demonstrate that in uraemic patients with severe parathyroid overfunction, imaging may be suppressed in some glands, but not in others. This could indicate a more or less marked autonomy of parathyroid cell function from one gland to another, in keeping with varying parathyroid gland size and anatomy and with monoclonal vs polyclonal growth of different glands removed at surgery from same patient. This finding is also in keeping with the observation by Canella et al. [20] that after 8 months of calcitriol therapy the intensity of radiotracer uptake by parathyroid glands using 201Tl–99Tc subtraction scintigraphy remained unchanged in three dialysis patients, whereas it decreased in five others. Thirdly, the response to calcitriol in terms of [99mTc]-sestamibi uptake might be of help in deciding which gland to use for autotransplantation in cases of total PTx followed by immediate autografting, or which gland to destroy when ethanol injection is considered. Such hypotheses clearly require further study.

In conclusion, static imaging by [99mTc]-sestamibi scintigraphy generally does not visualize all enlarged parathyroid glands in uraemic patients with advanced secondary hyperparathyroidism, in the absence of prior surgical PTx. It may only reveal those glands that exhibit high secretory activity, the remaining glands being functionally less active or inactive. However, it has recently been shown that simultaneous recording of [99mTc]-sestamibi and 123I subtraction scanning substantially improved the imaging of parathyroid glands in secondary uraemic hyperparathyroidism, compared with single [99mTc]-sestamibi scintigraphy [21]. The technique could also identify ectopic and supernumerary parathyroid glands with a higher degree of reliability.

Based on our dynamic study in response to short-term calcitriol administration, we propose that the suppression of [99mTc]-sestamibi imaging could indicate whether glands are amenable to medical inhibition of secretory and/or proliferative overactivity. Conversely, non-suppressible glands may be the ones which in case of severe hyperparathyroidism should be removed preferentially, either by surgery or by other means such as ethanol injection. Persistent imaging could be particularly useful in cases of ectopic location. It remains to be seen whether our hypothesis can be confirmed in prospective, long-term studies aimed at exploring the efficacy of various treatment modalities, including novel phosphate binders, vitamin D derivatives, and calcimimetic agents.



   Acknowledgments
 
The authors wish to thank the surgeons who have operated on our patients, namely Drs Raul Morelli and Sonia Boudrandi, Montevideo, and Dr Emile Sarfati, Paris. They also gratefully acknowledge the assistance in translation of Ms Pauline Davies and Dr Celia Herrera. Part of the present study has been presented at the XIIIth International Congress of Nephrology (Symposium on ‘Renal Osteodystrophy’, Seville, Spain, 1995), the XIVth ALASBIMN Congress (San Salvador, Bahia, Brazil, 1996), and the 2nd Symposium on ‘Advances in Renal Osteodystrophy’ (Oviedo, Spain, 1996), and a preliminary part of this work has been published in a Supplement to Nephrology Dialysis Transplantation (Ambrosoni et al., Nephrol Dial Transplant 1998; 12 [Suppl 3]: 33–36). The collaborative work between Montevideo and Paris has been kindly supported by ECOS-Sud.



   Notes
 
Correspondence and offprint requests to: Tilman B. Drüeke MD, INSERM Unité 507 and Service de Néphrologie, Hôpital Necker, 161 rue de Sèvres, F-75743 Paris Cedex 15, France. Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 17. 6.99
Revision received 16. 3.00.