Guideline sources The following summarized guidelines for the evaluation and management of primary hyperparathyroidism are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2021), the Canadian Task Force on Hyperparathyroidism (CTFH 2017), the American Association of Endocrine Surgeons (AAES 2016), and the International Workshop on the Management of Asymptomatic PHPT (IWMAP 2014). 1 2 3 4 5 5 6 7 8 9 Definition Primary hyperparathyroidism is an endocrine disorder of calcium metabolism resulting from an abnormal increase in the secretion of PTH from one or more of the parathyroid glands. 5 Epidemiology Primary hyperparathyroidism is primarily caused by a solitary parathyroid adenoma (80%), four- gland hyperplasia (10-15%), multiple adenomas (5%), and parathyroid cancer (<1%). 7 Pathophysiology https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 1/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway The average incidence of primary hyperparathyroidism in the United States men and women is 24.7 and 65.5 cases per 100,000 person-years, respectively. The age-adjusted prevalence in men and women is 85.2 and 232.7 per 100,000 individuals, respectively. 6 Disease course The loss of homeostatic control of PTH synthesis and secretion causes an increase in PTH secretion by either single cell or parathyroid hyperplasia. Normally, there is an inverse sigmoid relationship between calcium concentration and parathyroid secretion; however, in primary hyperparathyroidism, parathyroid cells in adenomas become less sensitive to the inhibitory action of calcium resulting in hypercalcemia. Since PTH plays an important role in bone homeostasis and calcium reabsorption in kidneys, the disease is characterized by skeletal deformities, pathological fractures, kidney stones, and may also lead to cardiac and neurocognitive manifestations. 8 Prognosis and risk of recurrence Parathyroidectomies have >98% cure rates. The recurrence rates of double parathyroid adenoma, hyperplasia, and single adenoma are 4.0%, 2.2%, and 1.3%, respectively. 5 9 Guidelines 1. Screening and diagnosis Clinical presentation: Recognize that approximately 85% of patients in developed countries present with asymptomatic disease, and 20% present with renal complications (kidney stones, nephrocalcinosis), skeletal complications (fracture, osteitis fibrosa cystica, bone pain) or symptomatic hypercalcemia. E Recognize that the majority of patients in developing countries present with symptomatic disease. E Diagnosis: Confirm the diagnosis of primary hyperparathyroidism if serum calcium is elevated (total calcium corrected for albumin or elevated ionized calcium) in the presence of an elevated or inappropriately normal PTH in the absence of conditions mimicking primary hyperparathyroidism (thiazide diuretics or lithium) and familial hypocalciuric hypercalcemia. E Suspect familial hypocalciuric hypercalcemia if Ca/Cr clearance ratio is < 0.01, recognizing that in 20% of familial hypocalciuric hypercalcemia cases Ca/Cr clearance ratio overlap with primary hyperparathyroidism and is 0.01-0.02. E 2. Diagnostic investigations Clinical history: elicit a personal and family history in patients with suspected primary hyperparathyroidism. B https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 2/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway Laboratory tests: As per AAES 2016 guidelines: Obtain the following laboratory tests in patients with suspected primary hyperparathyroidism: serum total calcium PTH creatinine 25-hydroxyvitamin D. B Consider obtaining a 24-hour urine measurement of calcium and creatinine in patients undergoing evaluation for possible primary hyperparathyroidism. B As per IWMAP 2014 guidelines: Obtain the following laboratory tests for the evaluation of patients with asymptomatic primary hyperparathyroidism: PTH (by second- or third-generation immunoassay) biochemistry panel (calcium, phosphate, ALP activity, BUN, creatinine) 25-hydroxyvitamin D 24-hour urine for calcium, creatinine, CrCl, stone risk profile. E Consider obtaining the following laboratory tests for the evaluation of patients with asymptomatic primary hyperparathyroidism: fractional excretion of calcium on timed urine sample bone turnover markers (bone-specific ALP activity, osteocalcin, procollagen type I N- propeptide, C-telopeptide cross-linked collagen type I, urinary N-telopeptide of type I collagen). E Genetic testing: As per CTFH 2017 guidelines: Consider obtaining a deoxyRNA analysis of MEN1, HRPT2 genes, and RET oncogene for familial primary hyperparathyroidism in pediatric and < 35 years old adult patients with any of the following: family history of hypercalcemia prior unsuccessful parathyroid surgery in the patient or a relative hypercalcemia identified at a young age (< 25 years) in patient or relative absence of symptoms of hypercalcemia ca/Cr clearance ratio < 0.02. E Obtain a deoxyRNA analysis of CaSR, GNA11, or AP2S1 genes to confirm the diagnosis of familial hypocalciuric hypercalcemia. E As per AAES 2016 guidelines: Offer genetic counseling in < 40 years old patients with primary hyperparathyroidism and multigland disease. B Consider offering genetic counseling in patients with primary hyperparathyroidism and a family history or syndromic manifestations. B https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 3/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway As per IWMAP 2014 guidelines, consider obtaining deoxyRNA testing if genetic basis for primary hyperparathyroidism is suspected. E Parathyroid imaging: As per ACR 2021 guidelines, obtain any of the following (these are typically equivalent alternatives - obtain only one modality to provide the clinical information to effectively manage the patient's care - although they may be used in a complementary manner to maximize the accuracy and confidence of parathyroid localization via concordant imaging results) as the initial imaging in patients with primary hyperparathyroidism and in patients with recurrent or persistent primary hyperparathyroidism after parathyroid surgery: parathyroid ultrasound neck CT without and with IV contrast neck sestamibi dual-phase scan neck sestamibi dual-phase scan with SPECT or SPECT/CT neck sestamibi scan and I-123 thyroid scan neck sestamibi scan and I-123 thyroid scan with SPECT or SPECT/CT neck sestamibi scan and pertechnetate thyroid scan neck sestamibi scan and pertechnetate thyroid scan with SPECT or SPECT/CT. B As per CTFH 2017 guidelines: Do not use imaging for the diagnosis of primary hyperparathyroidism, which is based on biochemical profile. D Recognize that: identification of abnormal parathyroid tissue is enhanced with SPECT in combination with CT and is particularly valuable in repeat surgical cases ultrasound, (99m)Tc-sestamibi scintigraphy continue to be useful localization tools, however, they can miss small adenomas and hyperplasia additional imaging or localization tools for patients failing surgery or suspected of having an ectopic parathyroid gland include CT, MRI, C-methionine positron emission tomography/CT, parathyroid scintigraphy; obtain selective venous sampling only when required for remedial exploration. E As per AAES 2016 guidelines, refer candidates for parathyroidectomy to an expert clinician B to decide between imaging studies based on their knowledge of regional imaging capabilities. B Show 3 more Abdominal imaging: obtain abdominal imaging for the detection of nephrocalcinosis or nephrolithiasis in patients with asymptomatic primary hyperparathyroidism. B Bone mineral density testing: As per AAES 2016 guidelines, measure bone mineral density at the lumbar spine, hip, and distal radius, preferably using DEXA. A As per IWMAP 2014 guidelines: Obtain the following investigations for the evaluation of patients with asymptomatic primary hyperparathyroidism https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 4/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway bone mineral density measurement by DEXA at the lumbar spine, hip, and distal 1/3 radius vertebral spine assessment by X-ray vertebral fracture assessment by DEXA. E Consider obtaining the following investigations for the evaluation of patients with asymptomatic primary hyperparathyroidism: high resolution peripheral quantitative CT trabecular bone score measurement by DEXA. E 3. Diagnostic procedures Parathyroid biopsy: Do not perform preoperative parathyroid FNA biopsy except in unusual, difficult cases of primary hyperparathyroidism. D Do not perform preoperative parathyroid FNA biopsy in patients with suspected parathyroid cancer. D 4. Medical management Indications for medical management: As per CTFH 2017 guidelines, insufficient evidence to recommend medical therapy currently as an alternative to surgery. I As per AAES 2016 guidelines, initiate medical management before parathyroidectomy in patients with primary hyperparathyroidism presenting with hypercalcemic crisis. B Bisphosphonates: Consider administering amino-bisphosphonates to prevent decreases in bone mineral density and to lower bone remodelling. E Consider administering amino-bisphosphonates in combination with cinacalcet in selected patients. E Cinacalcet: consider administering cinacalcet to lower serum calcium in patients with symptomatic primary hyperparathyroidism when surgery is not an option. E Vitamin D supplementation: correct any vitamin D deficiency/insufficiency to lower serum PTH without further elevating serum calcium. Correct serum 25-hydroxyvitamin D to > 50 nmol/L. E 5. Perioperative care Preoperative planning: Take into account the following in the preoperative planning: multigland disease, as it affects approximately 15% of patients with primary hyperparathyroidism exposure-related and genotype-phenotype correlations (these are predictive of parathyroid anatomical and pathophysiologic features), as they may affect the planning and conduct of https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 5/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway surgery. B Preoperative thyroid evaluation: Obtain preoperative thyroid evaluation in patients undergoing parathyroidectomy because of the high rate of concomitant disease, which may require thyroid resection. B Follow evidence-based guidelines for the evaluation of concomitant thyroid disease in patients undergoing parathyroidectomy for primary hyperparathyroidism. A Preoperative voice evaluation: obtain preoperative voice evaluation including specific inquiry about subjective voice changes and additional evaluation in patients with significant voice changes or a history of prior at-risk surgery. B Preoperative vitamin D/calcium supplementation: Initiate vitamin D supplementation before parathyroidectomy in patients with primary hyperparathyroidism and vitamin D deficiency. B Follow the IOM guidelines for calcium intake in most patients with primary hyperparathyroidism. B Intraoperative PTH monitoring: Consider obtaining intraoperative PTH monitoring to avoid higher operative failure rates when image-guided focused parathyroidectomy is planned. B Use a sampling protocol reliable in the local environment and be aware of the interpretation of PTH decay dynamics. B Postoperative monitoring: monitor patients for the development of cervical hematoma after parathyroidectomy. Perform emergency decompression in patients with evidence of compressive hematoma after parathyroidectomy. B 6. Surgical interventions Parathyroidectomy (general principles): recognize that surgical management is more effective and cost-effective than long-term observation or pharmacologic therapy. B Show 3 more Parathyroidectomy, indications: As per CTFH 2017 guidelines: Perform parathyroidectomy in all patients with symptomatic primary hyperparathyroidism. E Consider performing parathyroidectomy in patients with asymptomatic primary hyperparathyroidism meeting criteria for surgical intervention. E As per AAES 2016 guidelines, perform parathyroidectomy as the preferred treatment in all patients with symptomatic primary hyperparathyroidism. A Show 9 more Parathyroidectomy (bilateral exploration): recognize that bilateral exploration provides a time-tested standard of efficacy and safety in the definitive treatment of primary hyperparathyroidism. A Show 3 more https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 6/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway Parathyroidectomy (minimally invasive surgery): perform minimally invasive parathyroidectomy, defined as a focused dissection, ideally in patients with a single parathyroid adenoma (clinically and by imaging). A Show 4 more Parathyroidectomy (autotransplantation): perform immediate autotransplantation of normal parathyroid glands appearing devascularized. B Concomitant thyroidectomy: Perform thyroid resection at the time of parathyroidectomy in patients with concomitant primary hyperparathyroidism and thyroid disease requiring resection. B Follow evidence-based guidelines for thyroidectomy in concomitant thyroid disease during parathyroidectomy for primary hyperparathyroidism, recognizing that the indications for thyroidectomy are the same as in patients with isolated thyroid disease. A Recurrent laryngeal nerve reinnervation: attempt a reinnervation procedure when recurrent laryngeal nerve transection is recognized during parathyroidectomy. B 7. Specific circumstances Patients with multiple endocrine neoplasia: Perform subtotal parathyroidectomy as the index surgery in patients with MEN1-associated primary hyperparathyroidism. B Perform resection of only visibly enlarged glands in patients with MEN2A-associated primary hyperparathyroidism. B Patients with parathyroid carcinoma: suspect parathyroid cancer in patients with primary hyperparathyroidism with markedly elevated PTH and severe hypercalcemia. B Show 6 more 8. Follow-up and surveillance Postoperative vitamin D/calcium supplementation: consider administering short-term calcium and/or vitamin D supplementation for prophylaxis against hypocalcemia after parathyroidectomy. C Show 2 more Management of postoperative hypoparathyroidism: Initiate calcium and, if necessary, calcitriol supplements (weaned as tolerated) in patients with transient hypoparathyroidism after surgery. B Consider initiating recombinant PTH in patients with prolonged hypoparathyroidism. C Follow-up: define cure after parathyroidectomy as the reestablishment of normal calcium homeostasis lasting a minimum of 6 months. A Show 3 more Management of persistent or recurrent disease: define persistent primary hyperparathyroidism as a failure to achieve normocalcemia within 6 months of parathyroidectomy. A https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 7/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway Show 4 more Clinical findings Patient demographics Symptoms Age > 50 Anxiety Bone pain Past medical history Constipation Depression Dementia Fatigue Fragility fracture Joint pain Kidney stones Loss of appetite MEN2A Muscle weakness Osteoporosis Poorly localized abdominal pain Pancreatitis Sleeping disorder Parathyroid cancer Thirst Peptic ulcer disease Urinary frequency Vital signs Family history Hypertension MEN1 Musculoskeletal exam Neurological exam Muscle atrophy Lethargy Hematological findings Proximal muscle weakness Anemia Lab findings serum ALP serum PTH serum calcium urine calcium serum 25-hydroxyvitamin D serum anion gap serum phosphate Imaging findings Diastolic dysfunction LV hypertrophy Myocardial calcification Nephrocalcinosis Osteitis fibrosa cystica Parathyroid adenoma References https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 8/9 6/29/23, 11:29 PM Primary hyperparathyroidism Pathway 1. Khan AA, Hanley DA, Rizzoli R et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int. 2017 Jan;28 1 1 19. Open 2. Scott M Wilhelm, Tracy S Wang, Daniel T Ruan et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016 Oct 1;151 10 959 968. Open 3. Bilezikian JP, Brandi ML, Eastell R et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct;99 10 3561 9. Open 4. Expert Panel on Neurological Imaging, David Zander, Paul M Bunch et al. ACR Appropriateness Criteria Parathyroid Adenoma. J Am Coll Radiol. 2021 Nov;18 11S S406 S422. Open 5. Bilezikian JP, Bandeira L, Khan A et al. Hyperparathyroidism. Lancet. 2018 Jan 13;391 10116 168 178. Open 6. Yeh MW, Ituarte PH, Zhou HC et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab. 2013 Mar;98 3 1122 9. Open 7. Walker MD, Silverberg SJ. Primary hyperparathyroidism. Nat Rev Endocrinol. 2018 Feb;14 2 115 125. Open 8. Bilezikian JP, Cusano NE, Khan AA et al. Primary hyperparathyroidism. Nat Rev Dis Primers. 2016 May 19;2 16033. Open 9. Khan AA, Hanley DA, Rizzoli R et al. Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int. 2017 Jan;28 1 1 19. Open https://web.pathway.md/diseases/recWWZLxLJV9RhSCu 9/9