LONG-TERM INTRAVENOUS CALCITRIOL IN SECONDARY HYPERPARATHYROIDISM: THE ROLE OF TECHNETIUM-99M-MIBI SCINTIGRAPHY IN PREDICTING THE RESPONSE TO TREATMENT

Abstract

Background: Despite the effectiveness of intravenous calcitriol in suppressing parathyroid hormone secretion in patients with uremic hyperparathyroidism, 50% of the patients remain refractory to this treatment. There are conflicting reports regarding the factors that can predict the response to treatment. Technetium-99m-MIBI scintigraphy was found to be correlated with functional activity of the parathyroid gland. Methods: We, retrospectively, evaluated 16 chronic hemodialysis patients, who were maintained on i.v. calcitriol for 36 months or longer, and who had MIBI scan either at the start of, or within the first 6 months of starting calcitriol. Nine patients had a positive uptake (+ve group), and 7 patients had a negative uptake (−ve group). All patients had an elevated iPTH (iPTH>300 pg/ml) at the start of treatment. Results: The percentage reduction of iPTH in the (−ve) and the (+ve) groups was 65% versus 45% at 12 months, and 65% versus 10% at 36 months respectively. In long-term follow-up of 36 months, all the patients in the (−ve) group responded to calcitriol; while 8 of the 9 patients (89%) in the (+ve) group didn’t respond. The difference in response between the 2 groups was statistically significant (p ≤ 0.001). Conclusion: We conclude that MIBI scan is a reliable technique in predicting the response to treatment with i.v. calcitriol in patients with secondary hyperparathyroidism.

• Secondary hyperparathyroidism
• Technetium-99m-MIBI
• Calcitriol
• Hemodialysis

INTRODUCTION

Secondary hyperparathyroidism in chronic dialysis patients remain high with a prevalence of 50% despite the wide spread use of intravenous calcitriol [[1]]. There are few studies that investigated the predictors of the response to calcitriol; gland volume [[2]] and gland size [[3]], [[4]] were suggested as predictors with conflicting results.

Technetium-99-m methoxyisobutylisonitrile (MIBI) scintigraphy was described by O′Doherty et al. [[5]] in 1992. MIBI is a lipophilic material that passes easily across membranes due to its hydrated structure. In addition, it is sequestered in the mitochondria [[6]]. Its uptake was found by Piga et al. [[7]] to be correlated to the functional parathyroid activity, and this was further demonstrated by Ambrossoni et al. [[8]] who suggested that therapeutic decision could be made on the basis of the pattern of uptake.

The aim of this study was to assess whether the MIBI scintigraphy uptake pattern could predict the response to calcitriol.

SUBJECTS AND METHODS

Patients and Treatment

The study group included 16 adult patients (11 women, and 5 men) with a mean age of 46 ± 12. All the patients were on regular 3 sessions/week hemodialysis for a mean of 69 ± 27 months receiving 3–4 h/session and had an intact parathyroid hormone (iPTH) of >300 pg/ml at the time of commencement of calcitriol. None of the patients were on steroid, phenytoin or phenobarbitone. The patients’ characteristics are shown in Table 1.

Table 1. Characteristics of the Patients

	−ve MIBI Group (n = 7)	+ve MIBI Group (n = 9)	P
Cause of ESRF
Chronic interstitial nephritis	1	1
Unknown (small kidneys)	4	6
Diabetic nephropathy	1	1
ADPKD	1	1
Sex
Male	2	3
Female	5	6
Age (years) mean ± S.D.	45.4 ± 17.8	47.1 ± 5.3	0.791*
Duration of dialysis (months) mean ± S.D.	70 ± 27	68.7 ± 27.8	0.931*

*Statistically not significant.

Correction of hyperphosphatemia is done by diet restricted in phosphate to a maximum of 900 g/day and a protein intake of 1 g/kg/day. Calcium carbonate was the sole phosphate binder and the dose was titrated according to the phosphate level in increments up to a total daily dose of 6.25 g (2.5 g of elemental calcium). The patients were kept on standard dialysate calcium of 2.5 mmol/l. Boluses i.v. calcitriol were given at the end of each dialysis in initial dose of 1–2 µg commensurate with the iPTH. Response was assessed by measurement of serum calcium (Ca⁺⁺) and phosphate (Po₄) (measured every 2 weeks) and iPTH (measured monthly). If the iPTH is unchanged or increasing, the dose was titrated by 1 µg increment per dialysis to a maximum of 4 µg/dialysis depending on the response. Once the iPTH was in a decreasing trend, the dose of calcitriol was maintained. Calcitriol was temporarily discontinued if Ca⁺⁺ ≥ 3 mmol/l, Po₄ ≥ 2.26 mmol/l or Ca⁺⁺ × Po₄ product was ≥6 mmol/l.

Patients were considered responders if the iPTH was reduced to 140–225 pg/ml (i.e., to level between 2 to 3 times the upper limit of the normal range).

Measurements

Calcium, phosphate and alkaline phosphatase were measured by a standard autoanalyzer. The intact PTH was measured by a commercial kit (reference range 12–72 pg/ml).

MIBI Scan

This was obtained either at the beginning or during the 1st 6 months of starting calcitriol. 400 MBq of technetium-99m-MIBI were injected into an antecubital vein. The patient was then placed supine, with the neck extended, under an IGE 300 small field of view gamma camera fitted with a pinhole collimator and a 4 mm insert. Planar images of the thyroid region, on a 128 × 128 matrix were acquired at 10 min and at 1–2 h post administration. After the second images, a further planar image was acquired using a high-resolution parallel hole collimator, covering the area from the upper neck to the lower thorax, for detection of any ectopic parathyroid tissue.

Statistics

Results are expressed as Mean ± S.D.; unpaired student's t-test was used to analyze the difference between means. Fisher's exact test was used to analyze the difference in response to treatment. Probability values of <0.05 were considered significant. SPSS 8.0 statistical package (SPSS Inc.) computer software was used.

RESULTS

MIBI scintigraphy was positive in 9 patients (+ve group) with one or more glands taking-up the radiotracer, while 7 patients had a negative scan (−ve group). The age, sex, duration of dialysis and the cause of ESRF in our study population are shown in Table 1.

There was no statistically significant difference between the 2 groups in age or time on dialysis. Intact PTH was slightly higher in the +ve scan compared to the −ve scan group at the start of the study (mean of 635 versus 535), however this was not statistically significant (P = 0.42, confidence interval −360 to 160).

There was no statistical difference between the two groups in the levels of calcium, phosphate or alkaline phosphatase at baseline or throughout the study period as is shown in Tables 345.

Table 2. Reduction in iPTH

	−ve MIBI Group iPTH2^∞ Mean±S.D. (% Reduction)	+ve MIBI Group iPTH2^∞ Mean±S.D. (% Reduction)	p (of the Mean)	95% C.I.
0 Month	535±180	635±278	0.4243*	−360 to 160
12 Months	198±111 (65%)	303±150 (45%)	0.1463*	−250 to 41
24 Months	122±62 (77%)	330±149 (48%)	0.0034^†	−329 to −87
36 Months	170±47 (65%)	501±322 (10%)	0.0184^†	−596 to −65

^∞iPTH (pg/ml);

*Statistically not significant;

^†Statistically significant.

Table 3. Level of Serum Calcium (mmol/l)

	−ve MIBI Group (Mean ± S.D.)	+ve MIBI Group (Mean ± S.D.)	p
0 Month	2.11 ± 0.36	2.24 ± 0.17	0.3225*
12 Months	2.40 ± 0.11	2.57 ± 0.27	0.1355*
24 Months	2.52 ± 0.15	2.50 ± 0.23	0.8315*
36 Months	2.50 ± 0.23	2.57 ± 0.28	0.605*

*Statistically not significant.

Table 4. Level of Serum Phosphate (mmol/l)

	−ve MIBI Group (Mean ± S.D.)	+ve MIBI Group (Mean ± S.D.)	p
0 Month	1.96 ± 0.46	1.84 ± 0.57	0.6756*
12 Months	1.97 ± 0.31	1.83 ± 0.37	0.4756*
24 Months	1.94 ± 0.44	1.97 ± 0.51	0.9326*
36 Months	2.26 ± 0.41	1.93 ± 0.45	0.1596*

*Statistically not significant.

Table 5. Level of Alkaline Phosphatase (IU/l)

	−ve MIBI Group (Mean±S.D.)	+ve MIBI Group (Mean±S.D.)	p
0 Month	478±286	425±225	0.6817*
12 Months	208±103	188±47	0.6127*
24 Months	215±135	298±108	0.1927*
36 Months	236±203	250±80	0.8517*

*Statistically not significant.

All patients with −ve scan showed response to treatment compared to only 1 patient out of 9 in the +ve scan group on long-term follow-up, which was statistically highly significant (P ≤ 0.001).

Patients with −ve scan showed steady response throughout the duration of the treatment period of 36 months or longer, with a mean percentage reduction of 65% at 12 and 36 months. In contrast, in those with a +ve scan, 7 patients had a response in the 1st 12 months, however, by 36 months, a clear non-response curve was obtained in 8 patients despite the continued treatment with i.v. calcitriol; the percentage reduction of iPTH was 45 and 10% at 12 and 36 months, respectively (Figures 1 and 2). The mean iPTH is shown in Table 2 and Figure 3.

Figure 1. Response to calcitriol in −ve scan patients.

Figure 2. Response to calcitriol in +ve scan patients.

Figure 3. Mean iPTH in the 2 groups.

In the +ve scan group, 2 patients underwent parathyroidectomy at the conclusion of the observation period, and 5 are scheduled to have it, giving a complete medical treatment failure of 78%.

One patient who had an initial negative scan showed a non response during the 1st year of treatment, and a repeat scan was positive and he had severe hyperparathyroidism with iPTH reaching 1200 pg/ml, hypercalcemia and metabolic bone disease; he underwent parathyroidectomy (patient 9, Figure 2).

DISCUSSION

We have demonstrated previously the value of high dose i.v. calcitriol in reducing the PTH in dialysis patients with secondary hyperparathyroidism [[9]], which was also demonstrated by an earlier report by Slatopolsky [[10]] and confirmed further by other subsequent studies [[11]], [[12]], [[13]], [[14]], [[15]]. However, the duration of follow-up in these studies was short (weeks to few months). In this present study, we found a reduction of iPTH in the first year of treatment in 14 patients (88% of all patients), but by 3 years, this number had declined, with only 8 patients maintaining this response (50% of all patients), this in keeping with a recent survey among 612 hemodialysis patients from Mississippi [[1]], in which the prevalence of hyperparathyroidism (PTH>195 pg/ml) was found to be 50% despite the widespread use of calcium and vitamin D. This refractoriness to treatment has been described in various studies [[2]], [[3]], [[4]], [[13]], [[14]].

Nodular hyperplasia, as opposed to diffuse hyperplasia, is a severe form of parathyroid hyperplasia and is associated with decreased Vitamin D receptor density (VDR), rendering these glands unresponsive to Vitamin D treatment [[16]]. There are few studies that investigated the factors that predict the response to calcitriol and, hence, differentiating nodular (non-responsive) from diffuse (responsive) hyperplasia. Fukagawa has found an inverse relation between gland volume and responsiveness to calcitriol [[3]], which was further confirmed by Malberti's [[2]], who found a gland volume greater than 1cm to be associated with non-responsiveness, and this was thought to be related to the fact that larger glands tend to show nodular hyperplasia rather than diffuse hyperplasia.

Technetium-99m-MIBI scintigraphy was introduced in 1992 [[5]]. Its sensitivity in detecting parathyroid hyperplasia has ranged from (44%) [[7]] to 82% [[17]]. This difference is related to the fact that MIBI is taken up by metabolically hyperfunctioning gland [[7]], [[8]], [[18]], as it has been shown that positive MIBI has corresponded to increased concentration of PTH, severe bone disease, and nodular hyperplasia. Furthermore, Piga [[7]] did not find a correlation between gland size and function, parathyroid gland size was significantly correlated with serum PTH in MIBI positive glands only. In a MIBI negative gland, the parathyroid size did not correlate with PTH concentration.

In our study, we found that all patients with negative MIBI responded to i.v. calcitriol, and that the response was maintained throughout the duration of treatment of 36 months or longer. On the other hand, in those with a positive MIBI scan, there was an initial response, which was seen in the first year of treatment. This response was lost possibly due to increased parathyroid suppression threshold due to VDR loss as the disease has progressed. On long term treatment of 36 months or longer, all patients with +ve MIBI, except one, expressed unresponsiveness, this in accordance with the previously mentioned observations, in that a positive scan can detect a hyperfunctioning autonomous nodular gland.

Though a large prospective study is needed; we conclude that MIBI is a reliable method to predict the response to i.v. calcitriol in patients with moderate to severe hyperparathyroidism. By virtue of its ability to detect nodular hyperplasia and hence refractoriness to treatment, patients can be selected for treatment on the basis of the MIBI scan results. Patients with negative scan should be selected for calcitriol treatment. Those with positive scans should be considered for surgical management from the outset, thus avoiding unnecessary prolonged course of secondary hyperparathyroidism with its metabolic consequences. More over there will be a reduction in the cost incurred in the large doses of calcitriol used and the need for frequent biochemical monitoring of these patients.

ACKNOWLEDGMENT

The authors would like to thank Mrs. Geraldine G. delor Santos for the help with the data collection, and Dr. Jamal H. Mohamed for the statistical analysis.