Parathyroid Disorders. Группа авторов

calcium levels <1.0 mg/dL above the upper end of the normal range [18]. Most of these cases lack classical skeletal features, including osteitis fibrosa cystica or osteoporosis. Bone disease is currently diagnosed in <5% of patients with PHPT [19, 20]. Bone density of the 1/3 distal radius increases the detection rate of osteoporosis in patients with PHPT by 11% [21]. Renal disease, including nephrocalcinosis, calcium-containing nephrolithiasis, or renal insufficiency, may be found in up to 20% of patients [22]. Hypercalciuria is reported in up to 30% of patients [23].

Asymptomatic patients do not complain of mild fatigue, weakness, or subtle cognitive impairment [24]. Other classical abnormalities of PHPT, such as gout or pseudogout, anemia, band keratopathy, or loosened teeth due to lamina densa resorption, are rarely seen in patients with asymptomatic PHPT.

      Laboratory Findings

Patients with asymptomatic PHPT typically have laboratory values similar to, but somewhat milder, than those with symptomatic PHPT. Serum total and ionized calcium may be high-normal or mildly increased [25]. The serum phosphate level is usually low-normal or mildly decreased, in conjunction with normal serum creatinine. Intact PTH, measured by the second generation 2-site immunoradiometric assay or immunochemiluminometric assays, or the newer third generation intact assay, is mildly increased or inappropriately high-normal for the level of serum calcium [25]. Serum 1,25-dihydroxyvitamin D levels may be high-normal or mildly increased, with serum 25-hydroxyvitamin D levels usually low-normal. In up to 30% of patients, 24-h urinary calcium excretion may be increased.

      Imaging

      Some patients with asymptomatic PHPT have positive imaging with a parathyroid sestamibi scan, but because they do not meet other criteria for surgery, surgery is delayed. However, some asymptomatic patients will eventually become symptomatic or meet the criteria for surgery. Most centers prefer to use ^99mTc-sestamibi scanning first to localize parathyroid adenomas, but there is variability, and some prefer to use ultrasound, 4D-CT scans, or MRI as the imaging method of choice.

In a small series, Cheng et al. [26] assessed whether a positive ^99mTc-sestamibi scan could predict future surgical eligibility in patients with asymptomatic PHPT. In a retrospective study of 94 asymptomatic patients who had PHPT and underwent a ^99mTc-sestamibi scan with SPECT/CT imaging, 35 patients had scan results and follow-up for at least 1 year. Of these 35 patients, 12 had positive scans and 23 had negative scans at baseline, and did not meet criteria for surgery at the time of imaging. At a median follow-up of 2.4 years (range 1–4 years), 6 of 12 patients with a positive scan at baseline became eligible for surgery later, whereas 20 of 23 patients with negative scans remained asymptomatic and did not meet the criteria for surgery. The authors concluded that a positive parathyroid ^99mTc-sestamibi scan with SPECT/CT imaging predicted a higher possibility of meeting the surgical criteria later in patients with asymptomatic PHPT who do not meet criteria for surgery when they initially present.

      Natural History

Sun et al. [27] reviewed the experience with PHPT at a single regional hospital in China between 2005 and 2016, and reported that 73.1% of the 260 patients documented remained symptomatic, but that 27.9% were asymptomatic. The number of patients with symptomatic PHPT increased by 2.5-fold from 2005 to 2016, whereas the number of patients with asymptomatic PHPT increased by up to 3-fold over the same interval.

      Therapeutic Management

      Surgical Treatment

Surgical decisions about patients with asymptomatic PHPT depend on the presence of hypercalcemia or complications. Approximately 100,000 new cases of PHPT are diagnosed each year in the USA. Most of these patients are asymptomatic and have a relatively mild form of the disease, and present with few if any obvious signs or symptoms. Recent consensus indicates that asymptomatic patients with PHPT may have improved outcomes after curative surgery [28].

Table 1. Guidelines for surgery in asymptomatic PHPT: a comparison of current and previous recommendations

Four 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