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Use of Computer Tomography/Ultrasonographyto Assess Parathyroid Gland Size responded to Cinacalcet in Secondary Hyperparathyroidism : To predict responsiveness to cinacalcet

  • 조유선 (Yoo Sun Cho, 의학전문대학원 의학과)

초록/요약

Abstract Background/Aim: We examined whether the response of cinacalcet on secondary hyperparathyroidism (SHPT) could be expected by gland size measured on computed tomography (CT) and ultrasonography (US). Methods: Patients with SHPT received cinacalcet for 1-4 months of titration and 3 months of maintenance period. Before cinacalcet trial, the largest gland volume on US and longest gland length on US and CT from each patient were measured. Based on intact PTH (iPTH <33 pmol/L), the patients were divided into group R and group NR. Clinical and laboratory variables before/after trial were evaluated. We analyzed the patients with number of gland(s) greater than or equal to cut off values estimated from ROC curve. Results: 26 patients completed the study; 17 in group R and 9 in group NR. Their clinical characteristics did not differ significantly except age (p=0.055). The use of phosphate binders and VDRA did not significantly influence on the study. In laboratory variables, differences in basal iPTH, calcium, and corrected calcium levels were significant (p=0.002, p=0.027, p=0.049). After the trial, post iPTH levels with gland length greater than or equal to the cut off values on CT (≥11.2 mm) were significantly different (p=0.019) and considerably different (p=0.065) on US with gland volume (≥475 mm3). There was different distribution of patients in group R and NR with the number of parathyroid gland(s) on CT (≥11.2 mm) (0.054). Conclusion: In our study, CT length (≥11.2 mm) was significantly predictable to determine the effect of cinacalcet on SHPT.

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Introduction
Secondary hyperparathyroidism (SHPT) is a typical complication of chronic kidney disease. Therapeutic modality, vitamin D receptor activator (VDRA), has been mostly used for treating patients of SHPT. Not only a baseline intact PTH (iPTH) or serum calcium level, but the importance of initial parathyroid gland size has been also emphasized to predict the efficacy of the therapy. The relationship between parathyroid gland volume measured by ultrasonography (US) and the gland weight measured at operation was investigated by Tominaga et al [1]. They reported that 500 mm3 on US was equal to an actual parathyroid gland weight of 500 mg and most of glands weighing >500 mg showed nodular hyperplasia [1]. According to several clinical studies, the parathyroid gland volume in 500 mm3 from US is an important indicator to determine the responsiveness to the VDRA therapy [2,3]. Surgically removed parathyroid glands weighting ≥500 mg usually showed nodular hyperplasia and the patients of SHPT with nodular hyperplasia had some resistance to the VDRA therapy [2,3]. The same could apply to cinacalcet, one of calcimimetics recently wide spread. One study reported that the percentage reduction of parathyroid gland size of the patients with nodular hyperplasia was significantly smaller after cinacalcet therapy [2]. Cinacalcet treatment in patients with SHPT reduced the parathyroid gland volume in a short 6-month period [3,4], but the correlation between parathyroid gland size and responsiveness to cinacalcet is still controversial.
Thus, in present study, we tried to find an effective way to predict the responsiveness of cinacalcet before administration. We used two different modalities in measuring parathyroid gland size, US and computed tomography (CT), whereas color doppler US was solely used in other studies, and analyzed the gland sizes by the cut off values estimated from ROC curve. We also analyzed whether the number of parathyroid gland a patient initially owns correlates to the responsiveness to cinacalcet treatment and whether the presence of parathyroid gland with cut-off value is related to the responsiveness to that. We tried to know adverse effects of cinacalcet use. For patients responding cinacalcet, we tried to determine the average time period of cinacalcet administration and dosage at which patients mostly responded.

Methods
Patients
From 2010 to 2011, we conducted a cinacalcet trial to patients with SHPT at Korea University Guro Hospital. We got the approval of IRB and the written informed consent from all the patients. The patients were enrolled for the study if they were 20 years of age or older and had required hemo/peritoneal dialysis for at least 3 months. Cinacalcet was administered for the treatment of the SHPT patients in whom the iPTH levels were ≥33 pmol/L over two consecutive laboratory data and the serum corrected calcium was ≥9.0 mg/dl.
Cinacalcet trial
We adjusted the dose titration of cinacalcet in accordance with the serum calcium or albumin measured every two weeks and iPTH measured every four weeks. The initial dose of cinacalcet was 25 mg/day. The dose of cinacalcet could be increased to the next dose level; 50, 75, and 100 mg after a 4-week interval until the iPTH level would decrease to ≤33 pmol/L. After 1-4 months of titration period, we kept administering the adjusted dose to the patients for 3 months (maintenance period) and also kept measuring the serum calcium, alkaline phosphatase (ALP), albumin, and iPTH levels. Only if the serum calcium levels were ＜8.0 mg/dl or iPTH levels were ≤16.4 pmol/L, the dose of cinacalcet could be hold or reduced. The administration of phosphate binders and calcitriols was permitted. We analyzed the following four points.
1. Clinical and laboratory data analysis:
We divided patients into two groups according to the iPTH levels after cinacalcet treatment; responded patients (group R) whose iPTH level reached ＜33 pmol/L at least once during the study period and non-responded patients (group NR) whose iPTH level remained ≥33 pmol/L constantly. We firstly investigated baseline clinical characteristics of all patients including group R and group NR. Information of the patient’s age, gender, dialysis duration in months, and use of P binders or VDRA was gathered. Serum levels of iPTH, calcium, albumin, ALP, phosphate, and hemoglobin were measured. A standard dose of phosphate binders (calcium carbonate, calcium acetate, sevelamer hydrochloride, lanthanum carbonate, or aluminum hydroxide) was administered. VDRA was strictly allowed to the patients; calcitriol was administered according to serum calcium level.
2. Measurement of parathyroid gland size:
US and CT in measurement of the parathyroid gland size were performed before starting cinacalcet administration. The images of glands are shown on figure 1. We earned 3-dimensional image of the gland from US and measured gland volume and length with the position. The gland length was also measured by CT. One expert worked for US findings whereas two experts worked for CT findings and the data from them got averaged. We chose the greatest value for basal gland size (volume and length) if a patient had a multiple number of glands could be measured.
3. Effect of cinacalcet on parathyroid gland size:
We estimated sum of sensitivity and specificity of each patient's gland size and chose the greatest value as the optimal standard of classification using ROC curve from IBM SPSS Statistics 12. We investigated how many parathyroid glands all patients had, which were greater than or equal to mean standardized values of gland volumes, and gland lengths measured by US and gland lengths measured by CT. We analyzed the patients with the number of gland(s) greater than or equal to the cut off values estimated from ROC curve previously. For each group, we estimated laboratory variables including basal iPTH and post iPTH values to know if there was a significant difference in iPTH levels among patients with at least one gland greater than or equal to the cut off values versus patients with no parathyroid gland greater or equal to the cut off values. We also estimated the difference in distribution of patients in group R and NR with number of parathyroid glands greater than or equal to the cut off values.
4. Responded group (group R) analysis and safety:
For group R, we evaluated how many patients’ iPTH levels dropped ≤33 pmol/L along the time period of cinacalcet treatment and the dose of cinacalcet. Former we evaluated the patients according to four time periods; 4-8, 8-12, 12-16, 16≤ weeks, latter we evaluated the patients according to four cinacalcet doses; 25, 50, 75 and 100 mg/day. We evaluated how many patients had adverse effects against the cinacalcet use, and how many among them failed or kept continued the study.
Statistical analysis
All values are expressed as mean±SD. We collected data for clinical and laboratory variables and parathyroid gland size. Appropriate statistical test, Mann-Whitney U test, Fisher’s exact test, or Kruskal-Wallis test, was used when assessing differences between groups. Statistical analysis was performed with SPSS ver.12.0.1. Finding of p value <0.05 was considered significant.

Results
Study population
A total of 26 patients were enrolled in the prospective trial: 17 in group R and 9 in group NR. Mean titration period of group R was 10.6±7.4 -week and the maintenance period of patients was 3-month. Demographic characteristic and basal laboratory variables of the patient are demonstrated in table 1. The clinical and basal laboratory values of two groups were not significantly different except for iPTH levels, calcium levels, and corrected calcium levels before cinacalcet treatment (p=0.002, 0.0027, 0.049). Patients in group NR had higher iPTH and calcium levels compared with those in group R. Patients in group R had less gland size measured by US and CT but it was not significantly different between the groups (p ≥0.05).
Doses of VDRA and phosphate binders in both groups were shown before and after cinacalcet therapy in suppl. table 1. Calcitriol was orally administered to most patients except for two (intravenously administered). The dosage of calcitriol and number of patients administered with tended to increase for both groups. We used oral phosphate binders; calcium carbonate, calcium acetate, sevelamer hydrochloride, lanthanum carbonate, or aluminum hydroxide. The dose of the phosphate binder tended to decrease in group R whereas it was variable in group NR.
The number of parathyroid glands, gland size, and iPTH
A total of 26 patients were checked on CT and 24 patients were checked on US at screening period (Table 1). The mean ± SD volume of the largest parathyroid gland of each patient on US was 821.9±942.0 mm3. The mean ± SD length of the longest parathyroid gland of each patient on US was 14.0±5.7 mm, and it was 16.0±4.5 mm on CT. The difference of size on US and CT was not significant in group R and NR (Table 1).
Using ROC curve, we determined the cut off value of gland volume/length on US and gland length on CT, whose sum of specificity and sensitivity is at maximum. The cut off value for gland volume on US was 475 mm3, for gland length on US was 16.4 mm, and for gland length on CT was 11.2 mm. For each patient, we figured out how many parathyroid glands larger than or equal to the cut off value s/he had initially, and analyzed the patients with the number of parathyroid gland; 0, 1, 2 or more (Table 2-1).
We compared iPTH level, calcium, albumin, ALP, P, and Hb in the point of the number of parathyroid gland, however those levels did not statically differ among the five groups in each image modality (p＞0.05). The iPTH levels after cinacalcet treatment (post iPTH) were statically different on CT gland length (p=0.029) (Table 2-2).
We evaluated the patients with existence of parathyroid gland greater than or equal to the cut off values on CT/ US, and estimated mean of post iPTH for each stratum (Table 3-1, Table 3-2). With the image modality of CT, the iPTH level after cinacalcet treatment was significantly different in the number of parathyroid gland; one with no parathyroid glands larger than the cut off value and the other with one or more parathyroid gland(s) larger than the cut off value (P=0.019) (Table 3-1). There was a not significant but considerable difference in post PTH levels divided by parathyroid gland volume on US (p=0.065) (Table 3-1). Though it was at borderline, the proportion of patients was different between group R and group NR (P=0.054) with the number of parathyroid glands on CT (Table 3-2). The result of this study would be statistically more significant if it could be conducted with greater number of patients later on.
Responded group analysis and safety
Effect of cinacalcet treatment depending on administration period and dosage
To determine the effective time interval period and dose of cinacalcet treatment, we evaluated the patients of group R according to period of cinacalcet treatment and dosage. In group R, responsiveness to cinacalcet was the highest at 4-8 weeks administration period; the iPTH levels dropped to ≤33 pmol/L among 8 out of 17 patients. The cinacalcet dosage at which most patients (7 out of 17) in group R responded was 25 mg/day. There was only one who responded with maximum dose of cinacalcet, 100 mg/day (Table 4, Suppl. fig. 2-1, and Suppl. fig. 2-2).
Safety
Adverse effects caused by cinacalcet treatment are demonstrated in suppl. table 2. 11 out of total 26 patients presented gastrointestinal troubles; 6 from group R and 5 from group NR. The mean cinacalcet dosage the symptoms of GI troubles just occurred at was 62.5±20.9 mg for group R and 60.0±13.7 mg for group NR. In group R, all six patients with GI troubles continued cinacalcet therapy, whereas 3 out of 5 patients failed to continue treatment in group NR.

Discussion
Our study suggests that the measurement of parathyroid gland by CT may be more reliable than US for predicting the responsiveness of cinacalcet for our SHPT patients. Several studies reported the standard value of parathyroid gland volume or length in US, evaluating the effect of cinacalcet in reducing parathyroid gland size. The role of US in detecting the parathyroid glands has been emphasized to diagnose SHPT and to evaluate response to medical therapy. Okada et al [5] concluded that a severely enlarged parathyroid gland which length was >1 cm detected on US may resist to cinacalcet treatment (n=5). Komaba et al [6] demonstrated that a reduction of parathyroid gland size could occur even in enlarged gland volume, >500 mm3 (total n=81; group S of gland volume <500 mm3=56, group L of at least one gland volume ≥500 mm3=25). One study [7] reported that parathyroid glands with a baseline volume ≥500 mm3 measured by US had a decrease in glandular volume in most cases with cystic degeneration and hypovascularization, and more remarkably, there were significant changes in volume after cinacalcet treatment (hyperplastic gland n=28, patient n=9, reduction in 68 % of baseline gland volume <500 mm3 and 54 % of baseline gland volume ≥500 mm3). However, the standard value for parathyroid gland size refractory to cinacalcet is still controversial. We checked gland volumes and lengths on US in 16 patients after trial, but we did not get significant size reduction (data are not shown).
To find out more specific and accurate way to predict the efficacy of cinacalcet before the therapy, we conducted the study with a different image modality. Since CT images did not depend on operators contrary to US, and scanned by CT with both sagittal and coronal views, we had attention on CT examinations. Sumida et al [8] established that more than one nodular hyperplastic gland would be resistant to cinacalcet treatment, which study was conducted with US (hyperplastic parathyroid gland n=96, patient n=24; 12 with cinacalcet showed higher reduction in gland size). We observed, in the present study, a similar finding; the patients with at least one enlarged gland on CT, which was greater or equal to the cut off length, had significantly less reduction in iPTH than the patients with no parathyroid gland greater or equal to the cut off value.
Reporting that cinacalcet might induce qualitative changes on parathyroid glands in patients and also pathological changes, another study [9] reported that color doppler US has an advantage to estimate the change of gland volume with morphologic and vascular changes, which would take an essential role in determining medical treatment strategies.
We also tried with US and found a difference in less significant reduction between the groups; our cut off value of US volume (≥475 mm3) was less than the previous study (≥500 mm3) whereas our cut off US length was larger (≥16.4 mm) than the previous study (≥10 mm). In our study, we would mention that CT length (≥11.2 mm) could be more predictable in detecting parathyroid glands to evaluate the responsiveness to cinacalcet than US volume (≥475 mm3) and US length (≥16.4 mm). The limitations of this study were small number of patients and missed data for parathyroid gland volume/length on US from two patients. If a further study could be conducted with more sample data, the result would be more influential.

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