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Rapid parathyroid hormone measurement during venous localization
Clinica Chimica Acta 295 (2000) 193–198 www.elsevier.com / locate / clinchim
Case report
Rapid parathyroid hormone measurement during venous localization a,
b
c
c
Robert Udelsman *, Floyd Osterman , Lori J. Sokoll , Helen Drew , Michael A. Levine d , Daniel W. Chan c a
Division of Endocrine and Oncologic Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA b Cardiovascular Diagnostic Laboratory, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA c Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA d Division of Endocrinology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA Received 17 September 1999; received in revised form 17 December 1999; accepted 21 December 1999
Abstract The development of a rapid format for intact parathyroid hormone (PTH) immunometric assays has facilitated the use of these assays intraoperatively as a guide to parathyroid surgery. The near real-time characteristics of this rapid PTH assay led us to evaluate its utility in the angiography suite in a patient who underwent venous localization for persistent primary hyperparathyroidism. The assay provided the angiographers with almost immediate feedback and thereby facilitated accurate parathyroid adenoma localization. We conclude that the performance characteristics of the rapid PTH assay extend its diagnostic utility to near real-time analysis of plasma PTH levels in patients undergoing venous catheterization for parathyroid localization. 2000 Elsevier Science B.V. All rights reserved. Keywords: Parathyroid hormone; Venous localization; Hyperparathyroidism
1. Introduction Patients who require reexploration for primary hyperparathyroidism pose *Corresponding author. Tel.: 1 1-410-955-1658; fax: 1 1-410-614-2913. 0009-8981 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0009-8981( 00 )00184-4
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R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
difficult management problems. Due to fibrosis and scarring, repeat parathyroid surgery is inherently difficult and associated with higher failure and complication rates compared to initial exploration [1]. It has therefore become the standard of care for these patients to undertake studies designed to localize the abnormal parathyroid tissue prior to surgical reexploration [2]. Typically, one or more noninvasive imaging procedures are performed; these include Sestamibi scans often in combination with single photon emission computed tomography (SPECT), ultrasonography, CT, and MRI scans [3]. Unfortunately, a subset of these patients who require reexploration will have negative, discordant, or nonconvincing noninvasive localization studies. Current guidelines recommend that these patients undergo invasive localization procedures in the form of selective arteriography in conjunction with venous sampling for parathyroid hormone (PTH). Venous localization with measurement of serum PTH levels has proven to be the most sensitive means for parathyroid localization. This technique requires catheterization of multiple veins in the neck and mediastinum from which blood samples are obtained. In the past, the samples were collected, stored on ice, sent to the laboratory, and the serum was subsequently separated and analyzed using an immunoradiometric (IRMA) assay for intact PTH. Unfortunately, this process results in a significant delay between specimen retrieval and PTH measurement. Therefore, the angiographer could only obtain the PTH levels in retrospect and then determine which, if any, samples could provide proof of a significant venous gradient. This information delay obviated the ability of the radiologist to obtain additional samples from a region in which a subtle, but potentially significant, PTH gradient was detected. Recent modifications of immunometric assays for intact PTH have resulted in a marked decrease in time from specimen retrieval to assay interpretation [4]. A turnaround time of , 15 min is now possible. The rapid format of the intact PTH assay has resulted in the ability to measure PTH directly in the operating room during surgical exploration, and has led to the use of the rapid PTH assay by some surgeons during exploration for primary and secondary hyperparathyroidism [5,6]. Based on the performance characteristics of the rapid PTH assay we hypothesized that this assay might also have clinical utility in the angiography suite. In this report, we describe the use of this assay in a patient who underwent venous localization to identify the site of persistent primary hyperparathyroidism.
2. Case report A 41-year-old woman was diagnosed with primary hyperparathyroidism in April of 1996. She underwent a neck exploration at another institution and in
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
195
spite of a detailed search the surgeon was unable to identify an enlarged parathyroid gland. She had persistent hypercalcemia after surgery and experienced progressive lethargy, as well as diffuse body aches and polydypsia. A month after her initial parathyroid exploration biochemical evaluation demonstrated a total serum calcium level of 3 mmol / l (2.1–2.6 mmol / l), phosphorus of 0.84 mmol / l (0.87–1.45 mmol / l), an intact PTH concentration of 185 ng / l (10–65 ng / l) and a urinary calcium excretion of 17 mmol / 24 h (normal , 6.25 mmol / 24 h). She underwent noninvasive localization studies including sonography, a Sestamibi scan and a MRI scan. These studies were discordant and inconclusive. Accordingly, the patient underwent angiography and venous sampling.
3. Results During the late phase of a selective arterial injection an elliptical mass consistent with a parathyroid adenoma was noted in the left paratracheal position (Fig. 1). Venous samples were obtained and analyzed employing the rapid PTH assay. Due to the extensive previous surgery there were very few small to medium sized veins available for catheterization. Accordingly, multiple samples were obtained from larger vessels. The samples were collected in EDTA tubes and centrifuged immediately on site. The plasma was analyzed using the QuiCk-IntraOperative intact PTH assay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA), which is a modified version of a chemiluminescent assay. A 15 min assay time was achieved by employing vibratory shaking at 458C to reduce the incubation time to 7 min. Duplicate blood samples were obtained and sent to the chemistry laboratory where the plasma was subsequently analyzed for intact PTH by a conventional IRMA assay (Nichols Institute Diagnostics). The PTH levels obtained by the rapid assay presented in Table 1 are compared to the results obtained in the standard IRMA. There was an obvious gradient on the left side with the exception of one sample obtained from the right internal jugular vein ( . 1250 ng / l, specimen 6 in Table 1). Accordingly, an additional sample was obtained from the right internal jugular vein, which demonstrated a PTH concentration of 429 ng / l (specimen 13). These findings confirmed a left side gradient and were consistent with the blush seen on arteriography. A subsequent PTH IRMA performed on duplicate specimens demonstrated that the one aberrant sample from the right internal jugular vein represented a likely error in sample identification (Table 1, specimen 6). The results of the rapid PTH assay are depicted in the anatomic locations from which the specimens were obtained in Fig. 2. The left sided gradient is demonstrated. The patient later underwent surgical exploration via a left-side lateral approach and a 670 mg parathyroid adenoma was readily identified in the left
196
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
Fig. 1. Selective angiography injection demonstrating arterial phase tumor blush in the left tracheoesophageal groove (arrows).
tracheoesophageal groove and was resected. Intraoperative use of the PTH assay demonstrated in Table 2 shows a marked diminution in peripheral plasma PTH levels following tumor removal. Postoperatively the patient experienced normalization of both serum PTH and calcium levels accompanied by a marked resolution of her symptoms. At last follow-up on no medications, her ionized serum calcium was 1.19 mmol / l (1.13–1.32 mmol / l). Her total serum calcium was 2.3 mmol / l (2.1–2.6 mmol / l), with an intact PTH of 4 ng / l (10–65 ng / l).
4. Discussion To our knowledge this is the first reported use of the rapid PTH assay to provide near real-time analysis of plasma PTH concentrations during parathyroid
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
197
Table 1 Plasma PTH concentrations measured from venous samples in both the rapid and standard assays Specimen location
Rapid PTH (ng / l)
Standard PTH (ng / l)
Left axillary vein Left midsubclavian vein Left subclavian vein Left proximal innominate vein Left innominate vein Left innominate vein Left distal innominate vein Central inferior thyroidal vein Left internal jugular vein Superior vena cava Right subclavian vein Right internal jugular vein Right internal jugular vein
231 209 641 477 1229 1016 . 1250 547 328 612 390 . 1250 429
233 214 446 665 1077 1003 1489 427 298 406 252 279 216
Fig. 2. Venous localization PTH measurements using the rapid PTH assay. A left sided gradient is suggested. The single value of . 1250 ng / l from the right internal jugular vein was not confirmed on repeat measurement (429 ng / l). The same sample was subsequently reanalyzed on the standard IRMA assay. Normal PTH range 10–65 ng / l.
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R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
Table 2 Rapid intraoperative PTH (ng / l) measurements Baseline Baseline 1 10 min after tumor removed 1 20 min after tumor removed
177 160 35 16
venous sampling. Real-time information was particularly useful as it alerted us to the discordant value of a single sample, which appears to have been caused by an identification error. Thus, additional samples were obtained that confirmed the presence of a unilateral PTH gradient. The fact that the duplicate sample of the discordant specimen demonstrated a background PTH level when analyzed in the standard IRMA strongly supports the probability of an identification error. The potential for this type of error is increased in the angiography suite where multiple samples are obtained in rapid succession. We have now used this rapid assay in over 200 patients in the operating room and have never encountered a similar problem. Although intraoperative analysis is an attractive utilization of the rapid PTH assay, especially in reoperative cases, the use of this technique during angiographic localization for persistent parathyroid disease may prove to be its most beneficial application.
Acknowledgements Assay kits for this study were provided by Nichols Institute Diagnostics (San Juan Capistrano, CA, USA).
References [1] Brennan MF, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1987;153:241–54. [2] Udelsman R. Primary hyperparathyroidism. In: Cameron JL, editor, Current surgical therapy, 5th ed, St. Louis: Mosby, 1995, pp. 525–9. [3] Udelsman R. Parathyroid imaging: the myth and the reality. Radiology 1996;47:501–3. [4] Irvin GI, Dembrow V, Prudhomme D. Clinical usefulness of an intraoperative ‘‘quick’’ parathyroid hormone assay. Surgery 1993;14:1019–23. [5] Carty EC, Worsey MJ, Virji MA, Brown ML, Watson CG. Concise parathyroidectomy: the impact of preoperative SPECT 99m Tc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122:1106–7. [6] Clary BM, Garner SC, Leight Jr GS. Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism. Surgery 1997;122:1034–9.
Case report
Rapid parathyroid hormone measurement during venous localization a,
b
c
c
Robert Udelsman *, Floyd Osterman , Lori J. Sokoll , Helen Drew , Michael A. Levine d , Daniel W. Chan c a
Division of Endocrine and Oncologic Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA b Cardiovascular Diagnostic Laboratory, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA c Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA d Division of Endocrinology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA Received 17 September 1999; received in revised form 17 December 1999; accepted 21 December 1999
Abstract The development of a rapid format for intact parathyroid hormone (PTH) immunometric assays has facilitated the use of these assays intraoperatively as a guide to parathyroid surgery. The near real-time characteristics of this rapid PTH assay led us to evaluate its utility in the angiography suite in a patient who underwent venous localization for persistent primary hyperparathyroidism. The assay provided the angiographers with almost immediate feedback and thereby facilitated accurate parathyroid adenoma localization. We conclude that the performance characteristics of the rapid PTH assay extend its diagnostic utility to near real-time analysis of plasma PTH levels in patients undergoing venous catheterization for parathyroid localization. 2000 Elsevier Science B.V. All rights reserved. Keywords: Parathyroid hormone; Venous localization; Hyperparathyroidism
1. Introduction Patients who require reexploration for primary hyperparathyroidism pose *Corresponding author. Tel.: 1 1-410-955-1658; fax: 1 1-410-614-2913. 0009-8981 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0009-8981( 00 )00184-4
194
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
difficult management problems. Due to fibrosis and scarring, repeat parathyroid surgery is inherently difficult and associated with higher failure and complication rates compared to initial exploration [1]. It has therefore become the standard of care for these patients to undertake studies designed to localize the abnormal parathyroid tissue prior to surgical reexploration [2]. Typically, one or more noninvasive imaging procedures are performed; these include Sestamibi scans often in combination with single photon emission computed tomography (SPECT), ultrasonography, CT, and MRI scans [3]. Unfortunately, a subset of these patients who require reexploration will have negative, discordant, or nonconvincing noninvasive localization studies. Current guidelines recommend that these patients undergo invasive localization procedures in the form of selective arteriography in conjunction with venous sampling for parathyroid hormone (PTH). Venous localization with measurement of serum PTH levels has proven to be the most sensitive means for parathyroid localization. This technique requires catheterization of multiple veins in the neck and mediastinum from which blood samples are obtained. In the past, the samples were collected, stored on ice, sent to the laboratory, and the serum was subsequently separated and analyzed using an immunoradiometric (IRMA) assay for intact PTH. Unfortunately, this process results in a significant delay between specimen retrieval and PTH measurement. Therefore, the angiographer could only obtain the PTH levels in retrospect and then determine which, if any, samples could provide proof of a significant venous gradient. This information delay obviated the ability of the radiologist to obtain additional samples from a region in which a subtle, but potentially significant, PTH gradient was detected. Recent modifications of immunometric assays for intact PTH have resulted in a marked decrease in time from specimen retrieval to assay interpretation [4]. A turnaround time of , 15 min is now possible. The rapid format of the intact PTH assay has resulted in the ability to measure PTH directly in the operating room during surgical exploration, and has led to the use of the rapid PTH assay by some surgeons during exploration for primary and secondary hyperparathyroidism [5,6]. Based on the performance characteristics of the rapid PTH assay we hypothesized that this assay might also have clinical utility in the angiography suite. In this report, we describe the use of this assay in a patient who underwent venous localization to identify the site of persistent primary hyperparathyroidism.
2. Case report A 41-year-old woman was diagnosed with primary hyperparathyroidism in April of 1996. She underwent a neck exploration at another institution and in
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
195
spite of a detailed search the surgeon was unable to identify an enlarged parathyroid gland. She had persistent hypercalcemia after surgery and experienced progressive lethargy, as well as diffuse body aches and polydypsia. A month after her initial parathyroid exploration biochemical evaluation demonstrated a total serum calcium level of 3 mmol / l (2.1–2.6 mmol / l), phosphorus of 0.84 mmol / l (0.87–1.45 mmol / l), an intact PTH concentration of 185 ng / l (10–65 ng / l) and a urinary calcium excretion of 17 mmol / 24 h (normal , 6.25 mmol / 24 h). She underwent noninvasive localization studies including sonography, a Sestamibi scan and a MRI scan. These studies were discordant and inconclusive. Accordingly, the patient underwent angiography and venous sampling.
3. Results During the late phase of a selective arterial injection an elliptical mass consistent with a parathyroid adenoma was noted in the left paratracheal position (Fig. 1). Venous samples were obtained and analyzed employing the rapid PTH assay. Due to the extensive previous surgery there were very few small to medium sized veins available for catheterization. Accordingly, multiple samples were obtained from larger vessels. The samples were collected in EDTA tubes and centrifuged immediately on site. The plasma was analyzed using the QuiCk-IntraOperative intact PTH assay (Nichols Institute Diagnostics, San Juan Capistrano, CA, USA), which is a modified version of a chemiluminescent assay. A 15 min assay time was achieved by employing vibratory shaking at 458C to reduce the incubation time to 7 min. Duplicate blood samples were obtained and sent to the chemistry laboratory where the plasma was subsequently analyzed for intact PTH by a conventional IRMA assay (Nichols Institute Diagnostics). The PTH levels obtained by the rapid assay presented in Table 1 are compared to the results obtained in the standard IRMA. There was an obvious gradient on the left side with the exception of one sample obtained from the right internal jugular vein ( . 1250 ng / l, specimen 6 in Table 1). Accordingly, an additional sample was obtained from the right internal jugular vein, which demonstrated a PTH concentration of 429 ng / l (specimen 13). These findings confirmed a left side gradient and were consistent with the blush seen on arteriography. A subsequent PTH IRMA performed on duplicate specimens demonstrated that the one aberrant sample from the right internal jugular vein represented a likely error in sample identification (Table 1, specimen 6). The results of the rapid PTH assay are depicted in the anatomic locations from which the specimens were obtained in Fig. 2. The left sided gradient is demonstrated. The patient later underwent surgical exploration via a left-side lateral approach and a 670 mg parathyroid adenoma was readily identified in the left
196
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
Fig. 1. Selective angiography injection demonstrating arterial phase tumor blush in the left tracheoesophageal groove (arrows).
tracheoesophageal groove and was resected. Intraoperative use of the PTH assay demonstrated in Table 2 shows a marked diminution in peripheral plasma PTH levels following tumor removal. Postoperatively the patient experienced normalization of both serum PTH and calcium levels accompanied by a marked resolution of her symptoms. At last follow-up on no medications, her ionized serum calcium was 1.19 mmol / l (1.13–1.32 mmol / l). Her total serum calcium was 2.3 mmol / l (2.1–2.6 mmol / l), with an intact PTH of 4 ng / l (10–65 ng / l).
4. Discussion To our knowledge this is the first reported use of the rapid PTH assay to provide near real-time analysis of plasma PTH concentrations during parathyroid
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
197
Table 1 Plasma PTH concentrations measured from venous samples in both the rapid and standard assays Specimen location
Rapid PTH (ng / l)
Standard PTH (ng / l)
Left axillary vein Left midsubclavian vein Left subclavian vein Left proximal innominate vein Left innominate vein Left innominate vein Left distal innominate vein Central inferior thyroidal vein Left internal jugular vein Superior vena cava Right subclavian vein Right internal jugular vein Right internal jugular vein
231 209 641 477 1229 1016 . 1250 547 328 612 390 . 1250 429
233 214 446 665 1077 1003 1489 427 298 406 252 279 216
Fig. 2. Venous localization PTH measurements using the rapid PTH assay. A left sided gradient is suggested. The single value of . 1250 ng / l from the right internal jugular vein was not confirmed on repeat measurement (429 ng / l). The same sample was subsequently reanalyzed on the standard IRMA assay. Normal PTH range 10–65 ng / l.
198
R. Udelsman et al. / Clinica Chimica Acta 295 (2000) 193 – 198
Table 2 Rapid intraoperative PTH (ng / l) measurements Baseline Baseline 1 10 min after tumor removed 1 20 min after tumor removed
177 160 35 16
venous sampling. Real-time information was particularly useful as it alerted us to the discordant value of a single sample, which appears to have been caused by an identification error. Thus, additional samples were obtained that confirmed the presence of a unilateral PTH gradient. The fact that the duplicate sample of the discordant specimen demonstrated a background PTH level when analyzed in the standard IRMA strongly supports the probability of an identification error. The potential for this type of error is increased in the angiography suite where multiple samples are obtained in rapid succession. We have now used this rapid assay in over 200 patients in the operating room and have never encountered a similar problem. Although intraoperative analysis is an attractive utilization of the rapid PTH assay, especially in reoperative cases, the use of this technique during angiographic localization for persistent parathyroid disease may prove to be its most beneficial application.
Acknowledgements Assay kits for this study were provided by Nichols Institute Diagnostics (San Juan Capistrano, CA, USA).
References [1] Brennan MF, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1987;153:241–54. [2] Udelsman R. Primary hyperparathyroidism. In: Cameron JL, editor, Current surgical therapy, 5th ed, St. Louis: Mosby, 1995, pp. 525–9. [3] Udelsman R. Parathyroid imaging: the myth and the reality. Radiology 1996;47:501–3. [4] Irvin GI, Dembrow V, Prudhomme D. Clinical usefulness of an intraoperative ‘‘quick’’ parathyroid hormone assay. Surgery 1993;14:1019–23. [5] Carty EC, Worsey MJ, Virji MA, Brown ML, Watson CG. Concise parathyroidectomy: the impact of preoperative SPECT 99m Tc sestamibi scanning and intraoperative quick parathormone assay. Surgery 1997;122:1106–7. [6] Clary BM, Garner SC, Leight Jr GS. Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism. Surgery 1997;122:1034–9.