where conventional investigations have failed [18]. Magnetic resonance imagines may identify adenomas missed by sestamibi analysis. CT after contrast injection is a valuable imaging tool of particular benefit in localizing ectopic mediastinal parathyroid glands [18]. CT imaging allows the rapid assessment of the parathyroids. Disadvantages include the exposure to radiation, cost, and need for iodinated contrast [18].
Classical and Nonclassical Clinical Manifestations
Classically, PHPT targets the kidney and the skeleton. The extent to which a patient will present with overt involvement of these target organs varies depending on the availability of multichannel screening in a given country [18].
Skeletal Involvement
Radiographic signs of the PHPT include a salt-and-pepper pattern skull demineralization, distal clavicle tapering, subperiosteal bone resorption, cysts, and brown tumors. Together, these features are described as osteitis fibrosa cystica and are rarely seen in developed countries where more subtle forms of skeletal involvement are observed. A BMD measured by DXA (dual-energy X-ray absorptiometry) is usually low at the distal 1/3 radius and BMD should be measured at the 1/3 radius site in all individuals with PHPT [23]. An increase in fracture risk at all skeletal sites has been described [24]. High-resolution peripheral quantitative tomography has shown that both trabecular and cortical bone compartments are affected in patients with PHPT [18, 23]. The trabecular bone score, or TBS, which is able to predict the fracture risk independent of BMD [21], is consistent with a deteriorated trabecular microstructure and increased fracture risk [18, 25] in patients with PHPT.
Renal Involvement
Renal stones are a major complication of PHPT. Generally, patients with PHPT who develop renal stones are younger and more often male [18]. Hypercalciuria likely contributes to an increased risk of renal stones. The pathogenesis of increased renal stone formation in PHPT has not yet been fully elucidated. Hypercalciuria by itself does not fully explain the increased risk, and only limited data are currently available on the potential impact of other biochemical abnormalities, such as renal acidification abnormalities on the risk of stones in PHPT [18].
Nonclassical Clinical Manifestations
General symptoms – in particular, fatigue, weakness, anxiety, and mood alterations – along with impairment in quality of life may affect patients with PHPT and may or may not improve after surgical cure [4].
Peptic ulcer disease, which used to be considered a frequent complication of PHPT, is now rarely seen and is almost exclusively detected in patients with MEN1 or MEN4 syndromes, who can develop gastrin-producing tumors [4]. With regard to cardiovascular health, hypertension, premature atherosclerosis, valve calcification, left ventricular hypertrophy, and arrhythmias have been reported in patients with PHPT.
Table 2. Spectrum of clinical signs of hyperparathyroidism according to organ systems
| Central nervous systemFatigueDepressionMemory impairmentDementiaPsychosisComa |
| GastrointestinalPeptic ulcer diseaseCholelithiasisPancreatitisConstipation |
| SkeletalOsteopenia – osteoporosisFracturesBone cysts – brown tumors |
| Neuromuscular and articularMyopathyGout – pseudogoutChondrocalcinosisErosive arthritis |
| CardiovascularHypertension – left ventricular hypertrophyShortened QT intervalArterial stiffnessArrhythmiasVascular and cardiac calcifications |
| RenalPolyuriaUrine concentrating defectNephrolithiasisRenal tubular acidosis |
| OcularCataractsBand keratopathy |
Severe PHPT characterized by higher serum calcium levels (calcium ≥11.2 mg/dL) has been associated with an increased risk of cardiovascular mortality [18]. Table 2 shows the spectrum of clinical features of hyperparathyroidism according to the organ system.
Table 3. Indication for surgery in PHPT
| Age <50 years |
| Serum calcium >1 mg/dL or >0.25 mmol/L of the upper limit of the reference interval for total calcium and >0.12 mmol/L for ion calcium |
| BMD T-score <–2.5 SD at the lumbar spine, femoral neck, total hip, 1/3 radius for postmenopausal women or males >50 years, or a prevalent low-energy fracture |
| GFR <60 mL/min. Evaluation of asymptomatic patients with renal imaging: X-ray, CT, or ultrasound Evaluation of stone risk profile in patients with urinary calcium excretion >400 mg/day If stone or nephrocalcinosis, surgery should be recommended |
Surgical Management
Patients with symptomatic PHPT as well as asymptomatic patients who meet any one of the guideline criteria should be advised to undergo parathyroidectomy [4, 24]. Table 3 shows the indication of surgery in PHPT. Surgical consultation can be offered to those who do not meet guidelines for surgery.
Genetic testing is advised for patients suspected of having a genetic disorder, such as young patients (<30 years of age), patients with syndromic findings and/or a positive family history of syndromic PHPT, and patients with multiglandular disease, such as parathyroid carcinoma [4]. The surgical approach for patients with a genetic etiology may differ from those with a sporadic parathyroid adenoma, in that multiglandular disease is more common when there is a genetic etiology. Preoperative localization studies are recommended with ultrasound, 99mTc-sestamibi nuclear scintigraphy, CT, MRI, or PET scans. The choice of preoperative imaging depends on the experience of the surgical center.
Medical Therapies
Adequate hydration and avoidance of dehydration is always recommended. Calcium intake should not be restricted and should follow national guidelines. 25-hydroxyvitamin D levels >20 ng/mL are recommended, although some experts continue to recommend levels of >30 ng/mL. Concerning supplied vitamin D when needed, initial doses of 600–1,000 IU daily are recommended, and serum calcium