4/20/2015. The Neck xt Exploration: Intraoperative Parathyroid Hormone (IOPTH) Testing During Surgical Parathyroidectomy. Learning Objectives

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1 The Neck xt Exploration: Intraoperative Parathyroid Hormone (IOPTH) Testing During Surgical Parathyroidectomy Nichole Korpi-Steiner, PhD, DABCC, FACB University of North Carolina Chapel Hill, NC Learning Objectives Describe the physiological regulation and biological actions of parathyroid hormone (PTH) Understand the clinical utility of intraoperative PTH testing during surgical parathyroidectomy Diagram the test methodology used in 2 nd versus 3 rd generation PTH assays Discuss differences in performance characteristics between the various generations of PTH assays Patient Case JF is a 76 year old male who presents to an endocrinologist with symptoms of chronic constipation, abdominal pain, and newly diagnosed osteoporosis. Lab findings: Patient Result Reference Range PTH pg/ml (ng/l) Calcium 10.6 (2.7) mg/dl ( mmol/l) Diagnosis: Primary Hyperparathyroidism Treatment Plan: Surgical parathyroidectomy o Neck ultrasound is performed indicating a hypoechoic nodule suggestive of left inferior parathyroid adenoma o Lab is notified of the scheduled surgery to perform intraoperative parathyroid hormone (IOPTH) testing 1

2 Parathyroid Hormone (PTH) Biosynthesis PTH is a primary regulator of calcium homeostasis Parathyroid Chief Cells Pre ProPTH ProPTH PTH PTH (1 84) T 1/2 ~ 5 min Typically 4 parathyroid glands near thyroid glands Parathyroid chief cells produce, store and secrete PTH o 115 amino acid Pre-proPTH polypeptide o Intracellular cleavage to 84 amino acid mature PTH PTH Physiological Regulation Synthesis and secretion o Free Ca 2+ is primary acute regulator of PTH o Free Ca 2+ is sensed by Ca 2+ -sensing receptor (CaSR) Ca 2+ Ca 2+ Target Tissues Ca 2+ CaSR PTH Chief Cells ( ) ( ) PTH gene Chen and Goodman. Am J Physiol Renal Physiol. 2004; 286: F1005 F1011 PTH Physiological Regulation Synthesis and secretion o Free Ca 2+ is primary acute regulator of PTH o Free Ca 2+ is sensed by Ca 2+ -sensing receptor (CaSR) Ca 2+ Target Tissues Ca 2+ Chief Cells CaSR PTH (+) PTH gene Chen and Goodman. Am J Physiol Renal Physiol. 2004; 286: F1005 F1011 2

3 PTH Physiological Regulation Narrow Ca 2+ reference range Inverse relationship between Ca 2+ and PTH o Parathyroid glands respond rapidly to small changes in Ca 2+ AACE/AAES Position Statement, Endocr Pract. 2005;11(No. 1) PTH Biological Actions PTH is the primary regulator of calcium homeostasis Taniegra. Am Fam Physician 2004; 69: Hyperparathroidism Primary Secondary Tertiary Hypercalcemia with inappropriate elevation of PTH ~85% single adenoma ~10 15% multiple gland adenomas ~1% carcinoma Elevated PTH in response to hypocalcemia and hyperphosphatemia Common with chronic renal failure Hyperplasia of parathyroid glands Development of autonomous PTH hypersecretion Long standing secondary hyperparathyroidism Hyperplasia of parathyroid glands Pitt et al. World J Surg. 2010; 34(6): Udelsman et al. J Clin Endocrinol Metab. 2014; 99:

4 Symptoms of Untreated Hyperparathyroidism Overt symptoms: Stones, bones, abdominal groans, and psychiatric moans o Stones Nephrolithiasis, nephrocalcinosis o Bones Accelerated bone remodeling, osteopenia, osteoporosis, osteitis fibrosa cystica o Abdominal groans Loss of appetite, nausea, constipation o Psychiatric moans Lethargy, changes in cognition, depression Bilizekian. Endocr Pract. 2012;18: Parathyroidectomy Potential cureable treatment for patients with PHPT o Cure rate of 95-98% Indications: o Symptomatic patients with hyperparathyroidism o Asymptomatic PHPT patients meeting 1 of the following criteria: Criterion Surgery Recommended* Serum Calcium > 1.0 mg/dl (0.25 mmol/l) above URL Skeletal BMD by DXA: T score < 2.5 Vertebral fracture Renal Creatinine clearance < 60 ml/min 24 h urinary Ca2+ > 400 mg/d (> 10 mmol/d) and abnormal biochemical stone risk analysis Nephrolithiasis or nephrocalcinosis Age < 50 years *If any 1 of these criteria is met Bilezikian et al. J Clin Endocrinol Metab. 2014; 99: Udelsman et al. J Clin Endocrinol Metab. 2014; 99: Parathyroidectomy Classic bilateral cervical exploration o Visualize all 4 parathyroid glands o Use morphologic criteria (frozen section analysis) o Low complication rates and cure rate of 95-98% Caveats o In-hospital patient procedure o General anesthesia o Large incision and cost (patient dissatisfaction) Udelsman et al. J Clin Endocrinol Metab. 2014; 99:

5 Minimally Invasive Parathyroidectomy Adjunct tools support limited exploration parathyroidectomy o Ultrasound or 99m Tc-sestamibi CT scan Lacks sensitivity to reliably detect multi-glandular disease o Intraoperative PTH (IOPTH) testing PTH (1-84) half-life ~5 minutes Miami criteria PTH decrease by 50% supports successful resection of abnormal tissue Rule in/out multi-glandular disease Biochemical cure rate 98% Advantages o In-hospital or outpatient procedure o Local anesthesia o Smaller incision and reduced cost (patient satisfaction) Greene et al. JAmColl Surg 2009;209: Udelsman et al. J Clin Endocrinol Metab. 2014; 99: Paradigm Shift: Parathyroidectomy Trends Limited exploration parathyroidectomy favored in U.S Greene et al. JAmColl Surg 2009;209: Udelsman et al. J Clin Endocrinol Metab. 2014; 99: Patient Case Continued Patient JF presents for parathyroidectomy surgery o Limited exploration: left inferior nodule identified by ultrasound PTH (pg/ml) Pre incision baseline Left inferior nodule identified Pre excision baseline 11:10 12:05 12:10 12:15 13:25 13:36 13:41 Time Bilateral neck exploration Right superior parathyroid gland excised Surgical Pathology confirmed benign thyroid tissue & hypercellular parathyroid IOPTH testing is useful for guiding parathyroidectomy surgery o Rapid IOPTH turn-around-time is needed 5

6 PTH Assays Specimen type: plasma (EDTA) or serum PTH assays o Historically competitive immunoradiometric methodology o Most PTH assays use (2-site, sandwich) immunometric methodology Anti PTH Signal Ab* Radiolabel IRMA Chemiluminescent compound ICMA Enzyme ELISA PTH (1 84) *Antibodies (Ab) in excess Anti PTH Capture Ab* Detection signal increases with increasing concentration of PTH PTH Testing: Inter assay Variability Lack of PTH assay standardization remains a concern Cantor et al. Clin Chem. 2006; 52(9): IOPTH Testing: Inter assay Variability PTH inter-assay variability during parathyroidectomy Mean % Decrease Mean Baseline PTH Mean Post-op n = 20 in PTH from (pg/ml) PTH (pg/ml) Baseline Roche Stat PTH % DPC Stat PTH % p < p = p < Korpi Steiner et al. Clin Chem 2008; 54(6): A117 6

7 PTH Test Standardization / Harmonization World Health Organization developed 1 st International Standard for PTH (WHO IS 95/646) International Federation of Clinical Chemistry (IFCC) has established a Parathyroid Hormone Working Group o Develop a PTH reference measurement system o Evaluate commutability of PTH WHO IS 95/646 o Encourage worldwide implementation of PTH WHO IS 95/646 and to assess the effect of this on inter-assay agreement scientific division/sd working groups/parathyroid hormone wg pth/ Circulating PTH Heterogeneity Biological variability in PTH Intact PTH (1 84) T 1/2 ~ 5 min N truncated PTH Non(1 84) or (7 84) C terminal fragments Patients with chronic renal failure have clearance of PTH fragments PTH Assays: Cross Reactivity 1 7 N Terminal C Terminal 84 Mid or C Terminal 1 st Generation aa 1 4 N Terminal Mid or C Terminal Mid or C Terminal 2 nd Generation Intact 3 rd Generation Intact PTH assays may cross-react with non(1-84) PTH 7

8 Patient Case EB is a 54 year old female who presents to an endocrinologist with symptoms of chronic constipation, bone pain in her back and lower extremities, and history of nephrolithiasis. Lab findings: Patient Result Reference Range PTH pg/ml (ng/l) Calcium 10.8 (2.7) mg/dl ( mmol/l) Diagnosis: Primary Hyperparathyroidism Treatment Plan: Parathyroidectomy surgery o Neck ultrasound is performed indicating a small (5X3 mm) hypoechoic nodule suggestive of left inferior parathyroid adenoma o Lab is notified of the scheduled surgery to perform intraoperative parathyroid hormone (IOPTH) testing Patient Case Continued Patient EB presents for parathyroidectomy surgery o Minimally invasive surgery- left inferior nodule identified by ultrasound PTH (pg/ml) Pre incision baseline Left inferior nodule identified Pre excision baseline 0 7:56 8:26 8:35 8:40 8:58 Time Surgical manipulation of gland(s) can cause a PTH spike o IOPTH increase (> 50 pg/ml) before gland excision o May occur in 10-15% parathyroidectomy patient cases o Which PTH baseline value to use, pre-incision or pre-excision? IOPTH Testing: What Baseline Value to Use? No consensus in IOPTH interpretive criteria o Miami (Irvin) criterion*: 50% in PTH concentration compared with highest PTH baseline value (pre-incision or pre-excision) o Vienna criterion*: 50% in PTH concentration compared with pre-incision PTH baseline value * within 10 min after removal of hyperfunctioning gland(s) Clinical interpretation challenges with PTH spike o Missed multiglandular disease: PTH decline from elevated PTH artifact or from the removal of hyperfunctioning tissue o Extended exploration: PTH spike may delay 50% reduction from pre-incision PTH baseline concentration Riss et al. Langenbecks Arch Surg. 2013; 398: Riss et al. Langenbecks Arch Surg. 2007; 392:

9 Patient Case Continued Patient EB exhibited a PTH spike during parathyroidectomy PTH (pg/ml) Pre incision baseline 0% 61% (Vienna) (Miami) 7:56 8:26 8:35 8:40 8:58 Time Clinical interpretations can be challenging o Surgeon expertise is essential Patient follow-up (1 month post-surgery): o Concern for persistent hyperparathyroidism Left inferior nodule identified Pre excision baseline Surgical Pathology confirmed hypercellular parathyroid PTH Calcium 177 pg/ml 10.1 mg/dl IOPTH Testing: Timing of Post Excision Samples Timing of post-excision sample collection is not clearly defined o Generally 5 and/or 10 min post-excision Bilateral neck exploration: 6 cases post operative normocalcemia & PTH 4 cases post operative hypercalcemia & PTH 10 cases additional pathological gland removed o For patients with < 50% decrease in PTH after 10 min, measuring PTH at 20 min post-excision may avoid unnecessary bilateral neck exploration Calò et al. BMC Surgery 2013, 13:36 Summary PTH is comprised of heterogeneous molecular forms o 1-84 PTH is a primary regulator of calcium homeostasis IOPTH testing is clinical useful in the biochemical evaluation of surgical parathyroidectomy procedures PTH assays continue to evolve Be aware of potential cross-reactivity limitations 9

10 Assessment Question Which process is not directly mediated by PTH? A. Increased Ca2+ reabsorption in distal convoluted tubules B. Increased Ca2+ mobilization from bones C. Increased Ca2+ absorption from gastrointestinal tract D. Increased expression of 1-alpha hydroxylase in renal cells Assessment Questions Which best describes 3 rd generation PTH immunometric assays? A. Pan-anti-PTH antibodies detect all PTH fragments B. Analytical specificity for 1-84 PTH C. Analytical specificity for 7-84 PTH D. Equimolar detection of both 1-84 and 7-84 PTH Assessment Question Patient TK is a 37 year old female recently diagnosed with primary hyperparathyroidism and presents to the hospital for surgical parathyroidectomy. IOPTH testing was performed at preincision, prexcision and 10 min postexcision of a parathyroid gland, indicating the following values: Preincision Preexcision 10 min Postexcision PTH (pg/ml) Which best describes the surgical parathyroidectomy procedure? A. Successful biochemical cure per Miami criterion B. Unsuccessful biochemical cure per Miami criterion C. Indeterminate, additional IOPTH testing needed D. Complete removal of hypercellular parathyroid ademona 10