Supplementary Online Content Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. Published online August 10, 2016. doi:10.1001/jamasurg.2016.2310. eAppendix. The American Association of Endocrine Surgeons (AAES) Guidelines for Definitive Management of Primary Hyperparathyroidism eTable 1. Table of Contents: The American Association of Endocrine Surgeons (AAES) Guidelines for Definitive Management of Primary Hyperparathyroidism eTable 2. Common Secondary Causes of Elevated PTH Levels eTable 3. Selected Results of the Two Most Commonly Utilized IPM Protocols eTable 4. Parathyroid Carcinoma in Large Retrospective Series This supplementary material has been provided by the authors to give readers additional information about their work. © 2016 American Medical Association. All rights reserved. 1 eAppendix. The American Association of Endocrine Surgeons (AAES) Guidelines for Definitive Management of Primary Hyperparathyroidism ABSTRACT Importance Primary hyperparathyroidism (pHPT) is a common clinical problem for which the only definitive management is surgery. Surgical management has evolved considerably during the last several decades. Objective To develop evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy. Evidence Review A multidisciplinary panel used PubMed to reviewed the medical literature from January 1, 1985, to July 1, 2015. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Findings Initial evaluation should include 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacologic therapy. Cervical ultrasonography or other high-resolution imaging is recommended for operative planning. Patients with nonlocalizing imaging remain surgical candidates. Preoperative parathyroid biopsy should be avoided. Surgeons who perform a high volume of operations have better outcomes. The possibility of multigland disease should be routinely considered. Both focused, image-guided surgery (minimally invasive parathyroidectomy) and bilateral exploration are appropriate operations that achieve high cure rates. For minimally invasive parathyroidectomy, intraoperative parathyroid hormone monitoring via a reliable protocol is recommended. Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. Ex vivo aspiration of resected parathyroid tissue may be used to confirm parathyroid tissue intraoperatively. Clinically relevant thyroid disease © 2016 American Medical Association. All rights reserved. 2 should be assessed preoperatively and managed during parathyroidectomy. Devascularized normal parathyroid tissue should be autotransplanted. Patients should be observed postoperatively for hematoma, evaluated for hypocalcemia and symptoms of hypocalcemia, and followed up to assess for cure defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated postoperatively. Familial pHPT, reoperative parathyroidectomy, and parathyroid carcinoma are challenging entities that require special consideration and expertise. Conclusions and Relevance Evidence-based recommendations were created to assist clinicians in the optimal treatment of patients with pHPT. INTRODUCTION The surgical treatment of primary hyperparathyroidism (pHPT) has undergone extensive change in the last two decades. Laboratory testing, point of care access, radiographic imaging, operative techniques, intraoperative adjuncts, and other areas of surgical care have all rapidly evolved. With these transformations has come significant potential for subjective interpretation and variable management. Recognizing these innovations and challenges, the American Association of Endocrine Surgeons (AAES) determined the need to develop evidence-based clinical guidelines to enhance the safe and effective practice of surgery to achieve definitive treatment of pHPT. Intended for surgeons who perform parathyroidectomy, as well as their team members, these guidelines supply a broad medical update on the clinical spectrum of pHPT and in addition specifically aim to: 1) Provide surgical caregivers with a current background understanding of the epidemiology and pathogenesis of pHPT. 2) Outline the process for diagnosis of pHPT by laboratory studies and clinical manifestations (both subjective and objective) and once a diagnosis is established, examine the indications for surgical intervention. © 2016 American Medical Association. All rights reserved. 3 3) Detail the pre- and intra-operative management of pHPT including creation of a patient-specific operative plan based on available resources, surgeon experience, and patient characteristics. 4) Delineate methods for safe and effective postoperative management including a definition of cure and an algorithm for managing operative failure. pHPT is a common clinical problem for which the only definitive management is surgical intervention. The presentation, diagnosis and medical management have recently been addressed in several influential statements including the National Institutes of Health (NIH) consensus development conference on diagnosis and management of asymptomatic primary hyperparathyroidism1, the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons guidelines for the diagnosis and management of primary hyperparathyroidism2, and several international workshops3-5, which offer selected surgical suggestions as a portion of their content. The guidelines presented here specifically focus on the surgical management of pHPT with the goal of achieving cure as safely and efficiently as possible. METHODS Writing Group, Topics, and Analysis of Literature Evidence With the approval of the AAES Council at the project’s inception, a multidisciplinary panel of endocrinologists, pathologists, surgeons and radiologists was appointed by the AAES President to include broad-based complementary expertise. Eleven of the 16 writing group members have been AAES presidents, officers or council members. In January 2014, individual writing subcommittees were established for each of 17 topics and were comprised of 2-5 coauthors. Topic outlines were vigorously discussed to consensus. Search parameters for the worldwide medical literature were set from January 1985 to July 1, 2015 (30 years of the most recent data and research available in the field). At the discretion of the authors, this time frame was expanded to allow for inclusion of “classic literature” i.e. large and/or landmark articles to give historical reference or to illustrate time-tested principles of management. For each topic, the primary co-author then conducted a PubMed Medical Subject Heading (MESH) search using Boolean logic for MESH terms. Limitations were applied to select publications containing an abstract (English Language) and published in © 2016 American Medical Association. All rights reserved. 4 abridged index medicus (AIM), otherwise known as core clinical journals in PubMed. Results yielded a broad category of publication types which were then critically appraised to generate a pertinent bibliography. Particular value was assigned to study design (e.g. randomized controlled trials (RCT), meta-analyses and large single-center reports). Text and Recommendations To craft the specific content, all topics went through a rigorous process of determining the quality of the evidence, drafting text and recommendations supported by evidence, and amending that material in discussion to consensus. The draft document was discussed in detail during regular teleconferences as well as by email and in person. Expert opinion was vigorously examined. Editing to eliminate redundancy, verify referenced data, and ensure that the material met the guiding principles was performed by 5 committee members (SMW, TSW, DTR, JAL, and SEC). Grading of Practice Recommendations The writing group adopted the American College of Physicians (ACP) grading system for evidence- based clinical guidelines, which employs a validated scale to critically interpret and evaluate the strength and quality of the evidence 6. The ACP writing guidelines were drafted in 1981 and have undergone periodic revisions; the most recent version from 2010 was utilized. In brief, the ACP system applies the designations “Strong” when benefits clearly outweigh risks and/or the recommendation should be applied to all or most patients without reservation, “Weak” when benefits are finely balanced with risks or appreciable uncertainty exists, and “Insufficient” when the evidence to support a recommendation is conflicting, lacking, or of poor quality; in these circumstances the writing group provided recommendations based on expert interpretation of the available data. Quality assessment is followed by a formal interpretation about the evidence strength to provide guidance on how to best apply the recommendation to individual patients; evidence quality is graded “High” for well-done RCT or overwhelming evidence, “Moderate” for RCT with important limitations, well- designed cohort or case-control studies, or large observational studies, and