2016 Guidelines: Primary Hyperparathyroidism

Primary hyperparathyroidism is a common disorder that arises from autonomous overproduction of parathyroid hormone by abnormal parathyroid glands. The disease is characterized by the persistent elevation of total serum calcium levels with corresponding elevated or inappropriately normal PTH levels.

The diagnosis of pHPT is biochemical. The clinical presentation is heterogeneous, and the associated symptoms overlap with those of aging and disease. Patients with symptomatic pHPT have overt signs and symptoms; however, the definition of symptomatic disease is still evolving. Patients with asymptomatic pHPT have no disease-specific symptoms.

Normocalcemic pHPT is a recently recognized, incompletely characterized variant that presents with high PTH levels and normal total and ionized serum calcium levels. Some, but not all, patients may progress over time to hypercalcemic pHPT.

JAMA


J A M A

AAES Guidelines

October 2016

Because the surgical treatment of pHPT has undergone extensive change in the last 2 decades, the AAES determined the need to develop evidence-based clinical guidelines to enhance the safe, definitive treatment of pHPT. These evidence-based guidelines provide a broad-based approach to the clinical spectrum of pHPT and, although they do not represent the only acceptable approach, serve as a sound template for the effective surgical management of pHPT to achieve cure as safely and efficiently as possible.

 

Diagnosis and Evaluation

  • The biochemical evaluation of suspected pHPT should include serum total calcium, PTH, Creatinine, and D25 levels (strong recommendation; moderate-quality evidence).

  • A 24-hour urinary calcium and creatinine measurements should be considered in patients undergoing evaluation for possible pHPT (strong recommendation; moderate-quality evidence).

  • In patients with suspected pHPT, a personal and family history should be taken (strong recommendation; moderate-quality evidence).

  • In patients with asymptomatic pHPT, abdominal imaging should be performed for detection of nephrocalcinosis or nephrolithiasis (weak recommendation; low-quality evidence).

  • Bone mineral density should be measured at the lumbar spine, hip, and distal radius, preferably using DXA (strong recommendation; high-quality evidence).

  • Genetic counseling should be performed for patients younger than 40 years with pHPT and multigland disease (MGD) and considered for those with a family history or syndromic manifestations (strong recommendation; low-quality evidence).

 

Epidemiology and Pathogenesis

  • Multigland disease affects approximately 15% of patients with pHPT and should be routinely considered in preoperative planning (strong recommendation; moderate-quality evidence).

  • Exposure-related and genotype-phenotype correlations are predictive of parathyroid anatomical and pathophysiologic features and should be considered because they may affect the planning and conduct of surgery (strong recommendation; moderate-quality evidence).

 

Indications and Outcomes of Intervention

  • Parathyroidectomy is indicated, and is the preferred treatment, for ALL patients with symptomatic pHPT (strong recommendation; high-quality evidence).

  1. Parathyroidectomy is indicated when the serum calcium level is greater than 1 mg/dL above normal, regardless of whether objective symptoms are present or absent (strong recommendation; low-quality evidence).

  2. Parathyroidectomy is indicated for objective evidence of renal involvement, including silent nephrolithiasis on renal imaging, nephrocalcinosis, hypercalciuria (24-hour urine calcium level >400 mg/dL) with increased stone risk, or impaired renal function (glomerular filtration rate <60 mL/min) (weak recommendation; low-quality evidence).

  3. Parathyroidectomy is indicated in patients with pHPT and osteoporosis, fragility fracture, or evidence of vertebral compression fracture on spine imaging (strong recommendation; high-quality evidence).

  4. Parathyroidectomy is indicated when pHPT is diagnosed at 50 years or younger regardless of whether objective or subjective features are present or absent (strong recommendation; moderate-quality evidence).

  5. Parathyroidectomy is recommended for patients with neurocognitive and/or neuropsychiatric symptoms that are attributable to pHPT (strong recommendation; low-quality evidence) -- [difficult to establish biochemical-clinical causality. GT]

  6. Operative management is more effective and cost-effective than long-term observation or pharmacologic therapy (strong recommendation; moderate-quality evidence).

  • Parathyroidectomy is indicated when the clinical or biochemical evidence is consistent with Parathyroid Carcinoma (strong recommendation; high-quality evidence).
  • Parathyroidectomy is the preferred treatment for patients who are unable or unwilling to comply with observation protocols (strong recommendation; low-quality evidence).

  • Parathyroidectomy may be offered to surgical candidates with cardiovascular disease who might benefit from mitigation of potential cardiovascular sequelae other than hypertension (weak recommendation; low-quality evidence).

  • The nontraditional symptoms of muscle weakness, functional capacity, and abnormal sleep patterns should be considered in the decision for parathyroidectomy (weak recommendation; moderate-quality evidence).

  • The nontraditional features of gastroesophageal reflux and fibromyalgia symptoms may be considered in the decision for parathyroidectomy (insufficient evidence).

  • Parathyroidectomy should be conducted by surgeons with adequate training and experience in pHPT management (strong recommendation; moderate-quality evidence).

 

Parathyroid Localization Modalities: What Imaging to Perform and When

  • Cervical ultrasonography is recommended to localize parathyroid disease and assess for concomitant thyroid disease (strong recommendation; low-quality evidence).

  • Preoperative parathyroid fine-needle aspiration biopsy is not recommended except in unusual, difficult cases of pHPT and should not be performed if PCA is suspected (insufficient evidence).

  • MRI and venous sampling can be considered in cases of subsequent operation, difficult localization, or ionizing radiation contraindication (weak recommendation; low-quality evidence).

 

Preoperative Management

  • Most patients with pHPT should follow Institute of Medicine guidelines for calcium intake (strong recommendation; moderate-quality evidence).

  • Before parathyroidectomy, patients with pHPT who are vitamin D deficient can safely begin vitamin D supplementation (weak recommendation; low-quality evidence).

  • Preoperative voice evaluation should include specific inquiry about subjective voice changes, with additional evaluation for significant voice changes or a history of prior at-risk surgery (strong recommendation; low-quality evidence).

  • Patients with pHPT who present with hypercalcemic crisis should be medically managed, followed by parathyroidectomy (strong recommendation; low-quality evidence).

 

Intraoperative PTH Monitoring (IPM)

  • When image-guided focused parathyroidectomy is planned, IPM is suggested to avoid higher operative failure rates (strong recommendation; moderate-quality evidence).

  • Surgeons who use IPM should use a sampling protocol that is reliable in the local environment and should be familiar with the interpretation of PTH decay dynamics (strong recommendation; low-quality evidence).

 

Minimally Invasive Parathyroidectomy

  • Defined as a focused dissection, MIP is ideally used in patients who appear clinically and by imaging to have a single parathyroid adenoma. It is not routinely recommended in patients with known or suspected high risk of MGD (strong recommendation; high-quality evidence).

  • Ex vivo PTH aspiration or frozen section analysis may be used to confirm the resection of parathyroid tissue (weak recommendation; low-quality evidence).

  • During MIP, the discovery of MGD, the inability to identify an abnormal gland, or the failure to achieve an appropriate IPM decrease should prompt conversion to bilateral exploration (strong recommendation; high-quality evidence).

 

Bilateral Exploration (BE)

  • Planned BE is the preferred operative strategy in situations of discordant or nonlocalizing preoperative imaging, when there is a high suspicion of MGD, when IPM is not available, or at the discretion of the surgeon (strong recommendation; moderate-quality evidence).

  • Bilateral exploration is defined by a standard technique in which all parathyroid glands are identified with exploration of expected and, if necessary, ectopic cervical locations (strong recommendation; moderate-quality evidence).

  • In lithium-induced pHPT, the surgical approach may be BE or MIP guided by imaging and IPM (weak recommendation; low-quality evidence).

 

Familial pHPT

  • In patients with multiple endocrine neoplasia type 1(MEN1–associated pHPT, subtotal parathyroidectomy is recommended as the index operation (strong recommendation; moderate-quality evidence).

  • In multiple endocrine neoplasia type 2A (MEN 2A–associated pHPT, resection of only visibly enlarged glands is recommended (weak recommendation; low-quality evidence).

 

Concurrent Thyroidectomy

  • Patients undergoing parathyroidectomy should have preoperative thyroid evaluation because of the high rate of concomitant disease, which may require thyroid resection (strong recommendation; moderate-quality evidence).

  • In patients with concomitant pHPT and thyroid disease that requires resection, thyroid resection should be performed at the time of parathyroidectomy (strong recommendation; moderate-quality evidence).

  • Evaluation for concomitant thyroid disease in patients undergoing parathyroidectomy for pHPT should follow evidence-based guidelines (strong recommendation; high-quality evidence).

  • The indications for thyroidectomy for concomitant thyroid disease during parathyroidectomy for pHPT are the same as those for patients with isolated thyroid disease and should follow evidence-based guidelines (strong recommendation; high-quality evidence).

 

Parathyroid Carcinoma

  • The diagnosis of PCA should be considered in patients with pHPT with markedly elevated PTH levels and severe hypercalcemia (strong recommendation; low-quality evidence).

  • With intraoperative suspicion of parathyroid carcinoma, complete resection avoiding capsular disruption improves the likelihood of cure and may require en bloc resection of adherent tissues (strong recommendation; low-quality evidence).

  • Prophylactic central or lateral neck dissection should not be performed for parathyroid carcinoma (insufficient evidence).

  • The histologic diagnosis of PCA relies on identification of unequivocal angioinvasion and can be assisted by biomarkers (strong recommendation; moderate-quality evidence).

  • Adjuvant external beam radiotherapy should not be routinely performed after surgical resection of PCA and is reserved as a palliative option (strong recommendation; low-quality evidence).

  • Patients with functional PCA should undergo regular surveillance by testing serum calcium and PTH levels (strong recommendation; low-quality evidence).

 

Autotransplantation and Cryopreservation

  • Immediate autotransplantation is recommended for normal parathyroid glands that appear devascularized (strong recommendation; low-quality evidence).

 

Immediate Postoperative Care

  • After parathyroidectomy, patients should be observed in a monitored setting for the development of cervical hematoma. Evidence of compressive hematoma after parathyroidectomy should prompt emergency decompression (strong recommendation; low-quality evidence).

  • Short-term calcium and/or vitamin D supplementation for prophylaxis against hypocalcemia should be considered after parathyroidectomy (weak recommendation; low-quality evidence).

  • Outpatient parathyroid surgery can be considered in selected patients (weak recommendation; low-quality evidence).

  • After apparently successful parathyroidectomy, calcium intake should follow the Institute of Medicine Dietary Reference Intakes (strong recommendation; moderate-quality evidence).

  • Patients who are vitamin D deficient should receive vitamin D supplementation after apparently successful parathyroidectomy (strong recommendation; moderate-quality evidence).

  • At 6 months, surgeons individually or in conjunction with the multidisciplinary care team should assess postparathyroidectomy patients for cure and evidence of long-term complications (strong recommendation; low-quality evidence).

Cure and Failure

  • Cure after parathyroidectomy is defined as the reestablishment of normal calcium homeostasis lasting a minimum of 6 months (strong recommendation; high-quality evidence).

  • Patients with normocalcemic pHPT who have persistently elevated PTH levels after parathyroidectomy should be evaluated and treated for causes of secondary HPT and, if none are present, monitored for recurrent disease (strong recommendation; low-quality evidence).

  • Surgeons should choose an operative approach that in their hands carries a high cure rate, low-risk profile, and cost comparable to other available techniques (strong recommendation; low-quality evidence).

  • In normocalcemic pHPT, the definition of cure must include normal calcium and PTH levels more than 6 months after surgery (insufficient evidence).

  • Persistent pHPT should be defined as a failure to achieve normocalcemia within 6 months of parathyroidectomy. Recurrent pHPT is defined by recurrence of hypercalcemia after a normocalcemic interval at more than 6 months after parathyroidectomy (strong recommendation; high-quality evidence).

 

Management of Other Complications

  • When RLN transection is recognized during parathyroidectomy, a reinnervation procedure should be attempted (strong recommendation; low-quality evidence).

  • Patients with transient hypoparathyroidism after surgery should be treated with calcium and, if necessary, calcitriol supplements, which should be weaned as tolerated. Patients with prolonged hypoparathyroidism may be considered for recombinant PTH therapy (weak recommendation; low-quality evidence).

  • The evaluation of persistent or recurrent pHPT should include confirmation of biochemical diagnosis, assessment of indications for surgery, review of prior records if available, and evaluation of RLN function (strong recommendation; low-quality evidence).

  • Patients with persistent or recurrent pHPT should be evaluated by an experienced parathyroid surgeon before the decision to proceed with surgery or nonoperative management (strong recommendation; low-quality evidence).

  • Intraoperative PTH monitoring should be considered in patients undergoing reoperative parathyroidectomy for pHPT (strong recommendation; low-quality evidence).