Novel applications of the intraoperative parathyroid hormone assay

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J Lab Med 2005;29(4):229–234     2005 by Walter de Gruyter • Berlin • New York. DOI 10.1515/JLM.2005.031        2005/32


Point-of-Care-Testing                                                                     Redaktion: R. Junker

Novel applications of the intraoperative parathyroid hormone
assay
Neue Anwendungen des intraoperativen Parathormon-Assays



Melanie L. Richards* and Juliane Bingener                             ¨      ¨
                                                                 Schlusselworter: Hyperparathyreoidismus; Hypokalzia-¨
                                                                 mie; intraoperatives Parathormon; Parathyreoidektomie;
Department of Surgery, University of Texas Health
                                                                 Thyreoidektomie.
Science Center at San Antonio, San Antonio, USA



Abstract                                                         Introduction

The development of an accurate and rapid method to               The concept of monitoring parathyroid hormone (PTH)
measure parathyroid hormone (PTH) utilizing a two-site           levels intraoperatively was first described by Nussbaum
immunochemiluminometric assay (ICMA) has expanded                in 1988 w1x. Several years later, in 1992, the intraoperative
its use to point-of-care testing. Measuring parathyroid          parathyroid hormone (IOPTH) assay was introduced to
hormone can be utilized to determine the completeness            the clinical setting using a modified immunoradiometric
of parathyroid resection, to regionalize hypersecreting          assay (IRMA) to measure the whole molecule PTH w2x.
parathyroid glands, to identify parathyroid glands on fine-      This method was advantageous over frozen section
needle aspiration, and as a predictor of postoperative           results because it identified a biochemical cure. However,
hypocalcemia following thyroidectomy and parathyroid-            it was limited by the time it spent to obtain a result
ectomy. This review addresses the current utilization of         (60 min). In 1994, Irvin and Deriso reported their results
these techniques in patients with thyroid and parathyroid        using a two-site immunochemiluminometric assay
disease.                                                         (ICMA) to measure the active component of PTH, 1-84
                                                                 PTH, also referred to as the intact-PTH w3x. The ICMA
Keywords: hyperparathyroidism; hypocalcemia; intra-              provided IOPTH results in less than 15 min and had a
operative parathyroid hormone; parathyroidectomy;                sensitivity of 94% for predicting postoperative calcium
thyroidectomy.                                                   levels. Since that time, the IOPTH assay has undergone
                                                                 several modifications to reduce the assay’s detection of
                                                                 PTH fragments in order to improve its specificity and
Zusammenfassung                                                  sensitivity w4x. The development of this accurate and rap-
                                                                 id assay broadened its applicability to point-of-care test-
Die Entwicklung praziser und schneller Methoden zur
                     ¨                                           ing. In this setting it has been utilized to determine the
Bestimmung des Parathormons (PTH) mittels Immun-                 completeness of parathyroid resection, to regionalize
chemoluminiszenz ermoglicht die Anwendung dieser
                         ¨                                       hypersecreting parathyroid glands, to identify parathyroid
Bestimmung in der patientennahen Diagnostik. Die                 glands on fine-needle aspiration, and as a predictor of
                           ¨
Bestimmung erfolgt zur Uberprufung der vollstandigen
                                   ¨              ¨              postoperative hypocalcemia following thyroidectomy and
Resektion der Nebenschilddruse, zur Lokalisierung
                                  ¨                              parathyroidectomy. This review will discuss the current
hypersekretorischer Nebenschilddrusen, zur Kontrolle bei
                                       ¨                         utilization of these techniques in thyroid and parathyroid
Feinnadelbiopsien und zur Abschatzung einer zu erwar-
                                     ¨                           surgery.
                                     ¨
tenden postoperativen Hypokalzamie nach Resektion
von Schilddruse oder Nebenschilddrusen. Die vorliegen-
            ¨                            ¨                       Post-thyroidectomy
    ¨
de Ubersicht stellt aktuelle Einsatzgebiete der patienten-
nahen PTH-Bestimmung dar.                                        The most common complication following a total thy-
                                                                 roidectomy is hypoparathyroidism, with hypocalcemia
*Correspondence: Melanie L. Richards, MD, University of          occurring in up to 11–87% of patients w5–8x. The hypo-
Texas Health Science Center at San Antonio, 7703 Floyd Curl,     parathyroidism is transient and will resolve in the majority
San Antonio, TX 78229, USA
                                                                 (80–90%) of cases w5, 9x. However, it is the common
Tel.: q1 210-567-5730
Fax: q1 210-567-5797                                             cause for a prolonged hospitalization and readmission
E-mail: richardsm@uthscsa.edu                                    following total thyroidectomy. The onset of hypocalcemia
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230 M.L. Richards and J. Bingener: Novel applications of the intraoperative parathyroid hormone assay



Table 1 Utilization of the intraoperative parathyroid hormone assay to predict post-thyroidectomy hypocalcemia.

Reference                         Protocol                                             Predicting hypocalcemia
                                                                                       Sensitivity                Specificity
Richards 2003                     Single PTH level obtained 10 min                      80%                       100%
                                  post total thyroidectomy
                                  measured -10 pg/mL
Lindblom 2002                     Single PTH level obtained post                        71%                        81%
                                  total thyroidectomy measured
                                  below the reference level
Lo 2002                           Decline in PTH level )75%                            100%                        72%
                                  from induction to 10 min
                                  post total thyroidectomy


and its associated symptoms will usually occur within                Lindblom et al. also used the IOPTH assay immediately
6–24 h after the operation. Investigators who have eval-          following near-total or total thyroidectomy w17x. They
uated serial calcium levels to identify a downward trend          reported that an IOPTH level below the reference level
or actual hypocalcemia have found that they are usually           predicted symptomatic hypocalcemia. A comparison
not helpful until 12–24 h postoperatively w10–12x. A pro-         was made between the IOPTH level and a serum calcium
longed delay in identification of symptomatic patients will       on postoperative day one. The IOPTH had a higher sen-
prolong the length of hospitalization because earlier sup-        sitivity and specificity (71% vs. 52% and 81% vs. 76%).
plementation facilitates an earlier discharge. The short          This sensitivity may be further increased if the PTH level
half-life of PTH (on the average, less than 2 min) and the        is sent later in the postoperative period, but early enough
ability to obtain a timely result with the rapid PTH assay        to initiate supplementation prior to the development of
prompted investigators to evaluate its application to pre-        symptomatic hypocalcemia. Lam and Kerr measured a
dict post-thyroidectomy hypocalcemia w13x.                        PTH level at one hour post-thyroidectomy w18x. All pa-
                                                                  tients who had a level below 8 pg/mL developed hypo-
Single PTH measurement                                            calcemia and all patients with a level above 9 pg/mL were
                                                                  normocalcemic. The sensitivity can be further increased
Our practice over the past four years has been to mea-            by broadening the range of PTH values associated with
sure the IOPTH levels following closure of the skin inci-         hypocalcemia. Toniato et al. recommended that the rapid
sion, approximately 10 min after the thyroid has been             PTH assay should be used on postoperative day one
removed. With this technique we found that the patients           w19x. They found that a PTH level below 16 pg/mL, rather
who developed symptomatic hypocalcemia had signifi-               than 10 pg/mL, identified 8.6% more patients with hypo-
cantly lower IOPTH levels than the asymptomatic                   calcemia. The sensitivity and specificity of the IOPTH
patients (mean IOPTH 7.6"12.0 versus 55.7"31.8, p                 may also vary between assays because of differing ref-
-0.05) w9x. Overall, this method was found to be 80%              erence ranges. For example, the Elecsys 2010 assay has
sensitive and 100% specific for predicting hypocalcemia.          a reference range of 1.6–6.9 pmol/L and the Immulite
An IOPTH value -10 pg/mL had a positive predictive                assay reference range is 12–72 pg/mL. The techniques
value of 100% and a negative predictive value of 91%              of measuring sequential PTH levels have also shown to
for detecting patients at risk for symptomatic hypocal-           be useful in the clinical setting.
cemia w9x. Table 1 compares this method to several other
techniques that will be discussed.                                Sequential PTH levels
  A single post-thyroidectomy IOPTH method was cho-
sen to obviate the possible impact of fluid administration        Lo et al. evaluated 100 patients undergoing a total or
or sedative agents on the IOPTH level and its decline.            completion thyroidectomy using a method of sequential
The primary agent in question is propofol (2,6-diisopro-          IOPTH levels w5x. They obtained an IOPTH after the
pylphenol). It has been reported that propofol increases          induction of anesthesia, at zero and 10 min post-thyroid-
PTH levels in normocalcemic patients w14x. There were             ectomy, and at one day postoperatively. The 11 patients
also conflicting results in patients with primary and sec-        who developed symptomatic hypocalcemia had signifi-
ondary hyperparathyroidism (HPT). Sokoll et al. found             cantly lower immediate post-thyroidectomy PTH levels
that propofol present at dilutions of 5 to 40% resulted in        and a significantly higher percentage decline in the PTH
PTH levels that were 53 to 90% of the actual value w15x.          from the induction values (mean, 88.6% vs. 38.1%). At
Sipple et al. evaluated the effect of propofol on IOPTH           10 min post-thyroidectomy the mean percentage of
levels in patients with secondary HPT undergoing dialysis         decline was 96.3% in the patients with symptomatic
access procedures and found no significant effect on              hypocalcemia and 47.5% in the asymptomatic patients.
IOPTH levels w16x. In our own experience, propofol given          The authors found that a )75% decline at 10 min post-
at induction will increase the IOPTH level significantly          thyroidectomy was 100% sensitive, 72% specific and
above the IOPTH level obtained 10 min after induction.            75% accurate for predicting hypocalcemia. Higgins et al.
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                        M.L. Richards and J. Bingener: Novel applications of the intraoperative parathyroid hormone assay 231



measured IOPTH levels at 5, 10 and 20 min post-thy-              important to recognize that the average PTH half-life is
roidectomy w20x. There were significant differences in the       variable. In a kinetic analysis of 45 patients with HPT,
rates of decline between patients that did and did not           the PTH half-life ranged from 0.4–3.8 min (mean,
require calcium supplementation at each time period.             1.68"0.94 min) w13x. This variability led the authors to
However, the rate of decline for the IOPTH levels drawn          recommend a kinetic analysis for improved accuracy in
at 20 min post-thyroidectomy was the most predictive,            determining a curative operation.
identifying 64% of patients who would require calcium               From these studies in primary HPT it is evident that a
supplementation. These results were confirmed by other           limited parathyroid exploration in conjunction with the
investigators and it was proposed that these patients be         IOPTH assay has been shown to have equivalent suc-
considered for autotransplantation because of the ques-          cess to a four-gland exploration. In addition, it has sig-
tionable viability of the remaining parathyroid glands w21x.     nificantly reduced the cost of surgery by decreasing the
The selection of parathyroid glands for autotransplanta-         number of frozen sections, decreasing the length of hos-
tion should be undertaken with caution because the vast          pital stay, and allowing for local anesthesia w24x.
majority of patients will have reversal of their hypopara-
thyroid state.                                                   Secondary hyperparathyroidism
   The ability of sequential or early postoperative PTH
levels to predict which patients will develop symptomatic        The IOPTH assay has been controversial in secondary
hypocalcemia w5, 9x allows the clinician to initiate calcium     HPT (2HPT) because of the presence of multiglandular
and possible calcitriol supplementation prior to the onset       disease and the variability of PTH degradation kinetics in
of symptoms. It also identifies a subgroup of patients           patients with renal disease and 2HPT. This has led some
who may not be candidates for early discharge. The               investigators to conclude that there is no role for the
measurement of IOPTH levels post-thyroidectomy is the            IOPTH assay in surgery for 2HPT because there is no
earliest predictor of symptomatic hypocalcemia.                  correlation between the IOPTH and the PTH obtained on
                                                                 postoperative day one w31x. However, studies have
Primary hyperparathyroidism                                      shown that the IOPTH level in patients with 2HPT does
                                                                 degrade at a rate (85% average decline from baseline)
The ‘‘gold standard’’ operation for parathyroidectomy has        allowing for intraoperative utilization of the criterion re-
been a four-gland exploration, which in the hands of an          commended in 1HPT w32, 33x. This was confirmed when
experienced surgeon will have a success rate of 95%. In          Chou et al. demonstrated that the IOPTH at 10 min was
the mid-90s, the IOPTH assay with a limited exploration          as accurate as one obtained 30 min post-excision w34x.
in sporadic primary hyperparathyroidism (1HPT) rivaled              The two operations most commonly performed for
the four-gland exploration and became a new standard             2HPT are a subtotal parathyroidectomy and a total para-
of care.                                                         thyroidectomy. The goals of each operation are different
   The accept criterion for biochemical success is a 50%         and require separate strategies for utilizing the IOPTH
reduction from the highest pre-excision IOPTH level              assay. Theoretically, the post-excision IOPTH level in
when the sample is drawn 10 min after the abnormal               patients undergoing a subtotal parathyroidectomy should
parathyroid tissue is removed w1, 15, 22x. Cure rates            fall more than 50% from the pre-excision levels and be
range from 97 to 100% in patients who have sporadic              as close to the normal range as possible. To ensure a
1HPT and undergo a directed parathyroidectomy based              complete total parathyroidectomy, the criterion for 2HPT
on the IOPTH criterion of )50% decline from baseline             is more stringent, as a )60% reduction in IOPTH has
w23–27x. In addition, a few investigators recommend that         been recommended w34x.
the post-excision PTH should be within the normal range             The IOPTH is a useful adjunct for guiding the com-
w28x. The IOPTH assay has been a questionable predictor          pleteness of resection in 2HPT and may reduce the inci-
of multiglandular disease. In Irvin’s 2004 update, he            dence of persistent and recurrent 2HPT. However, as with
found that patients undergoing a limited exploration had         familial forms of HPT, the stimuli for hyperplasia will per-
significantly fewer rates of multiglandular disease (3% vs.      sist until the patient undergoes renal transplantation and
10%) when compared to those who had undergone a                  then they may develop autonomously functioning hyper-
four-gland exploration w23x. This was likely a result of pre-    plastic parathyroid glands and tertiary HPT (3HPT).
selection bias, as the majority of patients undergoing a
limited exploration had localization on preoperative imag-       Tertiary hyperparathyroidism
ing. Despite this finding, the incidence of recurrent HPT
was comparable between the two groups (3% and 4%).               The application of the IOPTH in 3HPT has been rarely
There have been several reports in which the drop in the         reported. In our practice we have utilized the IOPTH in
IOPTH suggested a biochemical cure, but the patient had          patients with 3HPT because the hyperplasia is generally
evidence of multiglandular disease w29, 30x. This sug-           asymmetrical and amenable to a limited exploration. We
gests that there may be pathologically confirmed hyper-          have found the PTH degradation kinetics in patients with
cellular parathyroid glands which are not hypersecreting         3HPT to be comparable to those with 1HPT. The average
PTH. When assessing the drop in IOPTH levels, it is also         PTH decrease from the baseline value was 85% in 1HPT
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232 M.L. Richards and J. Bingener: Novel applications of the intraoperative parathyroid hormone assay



Table 2 Recommendations on utilizing the intraoperative parathyroid hormone assay in hyperparathyroidism.

Clinical usage                       Reference                        IOPTH protocol                          Cure rates
Sporadic primary                     Irwin 2004                       Decline in IOPTH level                  97–100%
hyperparathyroidism                  Johnson 2001                     )50% from baseline to
                                     Vignalli 2001                    10 min post-excision
Secondary                            Chou 2002                        Decline in IOPTH level                  100%
hyperparathyroidism                                                   )60% from baseline to
                                                                      10 min post-excision
Tertiary                             Richards 2005                    Decline in IOPTH level                  100%
hyperparathyroidism                                                   )50% from baseline to                   normocalcemic
                                                                      10 min post-excision
Familial                             Carneiro 2002                    Decline in IOPTH level                  91%
hyperparathyroidism                                                   )50% from baseline to
                                                                      10 min post-excision
Multiglandular                       Gauger 2004                      Regression-based                        Identifies 54%
disease                                                               nomogram of PTH                         of patients with
                                                                      degradation kinetics at                 multiglandular
                                                                      baseline and 10 min                     disease
                                                                      post-excision


and 89% in 3HPT (unpublished data). Interestingly, at            method, it was also possible to identify more patients
10 months follow up, 50% of patients with 3HPT had               with multiglandular disease than by relying solely on a
inappropriate elevations in PTH levels and 100% of               50% drop from the baseline values (54% vs. 38%).
patients were normocalcemic. This finding may be relat-             A summary of the recommendations for utilizing the
ed to an underlying total calcium or vitamin D deficiency.       IOPTH assay in the different types of HPT is presented
Patients with this biochemical profile have been shown           in Table 2.
to have reductions of the PTH levels when they are
placed on calcium and vitamin D supplementation w35x.
Normocalcemia is the benchmark of a successful oper-
                                                                 Reoperation
ation and patients with 3HPT can be successfully treated
with a limited parathyroid exploration in conjunction with
                                                                 The other side to the 97–100% success rates in para-
the IOPTH criterion.
                                                                 thyroid surgery is the 0–3% rate of failure. The para-
                                                                 thyroidectomy for recurrent or persistent hyperpara-
Familial hyperparathyroidism-multiple gland disease
                                                                 thyroidism is a challenging operation. The success rates
The patients with familial HPT will have either a Multiple       are reduced and the morbidity is increased at reoper-
Endocrine Neoplasia (MEN 1 or MEN 2) or familial iso-            ation. To improve success, the endocrine surgeon has
lated HPT. These two distinct entities have historically         utilized a multimodality armamentarium of localizing pro-
been evaluated as one group. However, the patients with          cedures. These have included: technetium-99m sesta-
MEN 1 are at a higher risk for persistent or recurrent HPT       mibi scintigraphy with or without single-photon emission
compared to those with MEN 2 or familial isolated HPT.           computed tomography, ultrasonography, computed
This has led to a more conservative parathyroidectomy            tomography scanning, magnetic resonance imaging, and
in these latter two groups. While these groups are at risk       selective venous sampling. Ideally, the surgeon will know
for recurrent disease, a limited parathyroidectomy in            where the hyperplastic parathyroid tissue is located prior
familial isolated HPT performed with IOPTH guidance has          to surgery. However, he will not have knowledge of the
been shown to have an operative success rate of 93%              function or presence of the remaining normal parathyroid
and a short-term (less than 6 months) recurrent HPT rate         glands. The use of the parathyroid hormone testing
of 9% w36x. These results are similar to those obtained          extends throughout the care of the patient. If necessary,
with a subtotal or total parathyroidectomy with autotrans-       the rapid PTH testing allows the opportunity for the
plantation. This group of patients was also found to have        selective venous sampling in the immediate post-
a curative operation with a unilateral neck exploration          operative period. The immediate results allow for early
80% of the time. Therefore, these investigators recom-           re-exploration, which may reduce the likelihood of
mended consideration of jugular venous sampling for              encountering a severe inflammatory reaction. Intraoper-
PTH to determine which side of the neck to explore first.        atively, the surgeon can also perform jugular venous
The utilization of decay kinetics has also been applied to       sampling to assist in regionalizing the hypersecreting
patients with multiglandular 1HPT. These patients appear         parathyroid tissue to one side of the neck. In addition to
to have a more gradual decay slope compared to those             predicting a curative operation, the IOPTH can also be
patients with a sporadic adenoma w37x. By using this             utilized to predict patients at risk for severe hypocalcemia
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                         M.L. Richards and J. Bingener: Novel applications of the intraoperative parathyroid hormone assay 233



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