guidelines have been published since 1991 to help guide recommendations for surgery in patients with PHPT (Table 1). The 1991 National Institutes of Health consensus development conference recommended surgical management for patients with serum calcium levels >1.0 mg/dL above the upper limit of normal, recognized complications such as nephrolithiasis or overt bone disease, acute PHPT with life-threatening hypercalcemia, 24-h urinary calcium excretion in excess of 400 mg, distal 1/3 radial bone density Z-score of <–2.0, or age younger than 50 years [29]. The 2002 National Institutes of Health consensus development conference [30] modified these recommendations to advise surgery for patients with serum calcium >1.0 mg/dL above the upper limit of normal, creatinine clearance reduced by 30% or more, recognized complications such as nephrolithiasis or overt bone disease, acute PHPT with life-threatening hypercalcemia, 24-h urinary calcium excretion in excess of 400 mg, bone mineral density T-score below –2.5 at any skeletal site, or age younger than 50 years. The 2009 Third International Workshop conference affirmed and further refined the previous recommendations for management of asymptomatic PHPT, and dropped the recommendation for surgery based on 24-h urinary calcium excretion in excess of 400 mg due to a lack of convincing evidence [31]. The 2013 Fourth International Workshop revised guidelines for management, including the addition of: (1) recommendations for more extensive evaluation of the skeletal and renal systems, (2) skeletal and/or renal involvement as determined by further evaluation were included in the guidelines for surgery, and (3) more specific guidelines for monitoring those who do not meet guidelines for parathyroid surgery [32]. These guidelines have helped direct endocrinologists and surgeons caring for patients with asymptomatic PHPT.
A blueprint for future research is proposed to foster additional investigation into issues that remain uncertain or controversial. Approximately half the patients diagnosed with PHPT fulfill at least one of the criteria for surgery, and of these patients most are asymptomatic but have high serum or urine calcium or low bone density. Patients not requiring surgical treatment generally have stable mild hypercalcemia without progression, although about 25% of patients may develop a complication requiring surgery, such as osteoporosis, over 15 years of follow-up [33].
Elderly patients undergoing surgery for PHPT generally do well. Polistena et al. [34] retrospectively analyzed 898 patients undergoing surgery for PHPT, including 135 elderly patients and 763 patients younger than 65 years. PHPT was asymptomatic in 31.2% of the patients over 65 years and in 18.4% of the younger patients. Unilateral temporary recurrent laryngeal nerve injury was observed in 0.9% of the elderly patients and in 0.1% of the younger patients (p > 0.05). No differences were seen in cervical hematomas, mortality, or major cardiovascular, neurological, respiratory or metabolic postoperative complications. All the patients reported improvement in their quality of life. Bone mineral density increased after surgery in 85.6% of the elderly and 79.8% of the younger patients, without significant differences between symptomatic and asymptomatic patients. The study concluded that parathyroidectomy in elderly patients with PHPT is safe, with benefits and morbidity similar to what is seen in younger patients.
Parathyroid surgery is best performed by experienced surgeons because of variability in location of the abnormal gland(s). In major medical centers, preoperative localization of parathyroid adenomas before initial neck exploration may be considered unnecessary because of extremely high cure rates (95–98%) with standard neck exploration. Patient or physician interest in minimally invasive parathyroidectomy typically leads to parathyroid imaging studies, including ultrasonography, 99mTc-sestamibi scanning, 99mTc-sestamibi-123I subtraction scanning, 4D-CT scanning, MRI, or 18F-choline-PET/CT scanning [35] of the neck before surgery. 99mTc-sestamibi subtraction scanning is capable of detecting as many as 90% of single parathyroid adenomas before surgery. False-negative and false-positive imaging results, however, are relatively common. During standard neck exploration, patients with single or more adenomas should undergo resection of the tumor or tumors and identification of the remaining normal glands. Patients with 4-gland hyperplasia should typically undergo removal of 3.5 glands, with an alternative approach being removal of all 4 parathyroid glands, followed by auto-transplantation of part of 1 gland in the forearm, neck, or chest wall.
In patients cured of their hyperparathyroidism, the serum calcium concentration promptly normalizes, often after a brief period of asymptomatic relative hypocalcemia. “Hungry bones” syndrome, with rapid skeletal mineral uptake postoperatively, may develop in patients with bone disease [36].
Reoperation for persistent or recurrent PHPT is technically difficult. Most surgeons require preoperative imaging as described above to attempt to localize the parathyroid tumor before a second surgery.
The American Association of Endocrine Surgeons developed evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy [37]. Based on a literature review, these guidelines recommend that initial evaluation include the measurement of serum 25-hydroxyvitamin D and 24-h urine calcium, dual-energy X-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is recommended for all symptomatic patients, and should be considered for most asymptomatic patients, as surgery is more cost-effective than observation or pharmacologic therapy. These evidence-based recommendations were created to assist clinicians in the optimal management of patients with persistent or recurrent PHPT.
Nonsurgical Management
Medical options are limited for patients with asymptomatic hypercalcemia who are unable or unwilling to undergo a surgical procedure [38]. Patients not undergoing surgery should maintain adequate hydration and remain physically active. Use of thiazides and lithium should be avoided. Dietary calcium intake of 800–1,000 mg/day is advised to minimize bone loss and avoid aggravation of hypercalcemia or hypercalciuria. Dietary calcium intake of less than 600 mg/day may stimulate physiologic hyperparathyroidism. Oral or intravenous administration of phosphate should be avoided because of the risk of precipitation of ectopic calcification. Estrogen replacement therapy may help normalize serum calcium levels and prevent bone loss in postmenopausal women, although PTH and phosphate levels do not change [39]. Orally and intravenously administered bisphosphonates may be beneficial, but oral etidronate and intravenous clodronate and pamidronate infusions have not shown any long-term benefit. Alendronate, risedronate, raloxifene, and salmon calcitonin administered by nasal spray or injection have not been extensively investigated for this indication, although reports indicate that alendronate [40] or raloxifene [41] may help decrease serum calcium levels. The CaSR agonist (calcimimetic) cinacalcet HCl has been shown to decrease serum calcium and maintain normal levels of serum calcium for as long as 5 years without changing bone mineral density [42], and to improve serum calcium levels in patients with intractable PHPT or parathyroid carcinoma. Asymptomatic patients with PHPT who do not have parathyroidectomy tend to do well, although as many as a quarter of these patients may develop progression of disease, defined as development of at least one new indication for surgery, over 15 years of follow-up, and younger patients less than 50 years old tend to have a higher incidence of progressive disease.
