Additional Evaluation to Determine Management of the 5% of Patients with Primary Hyperparathyoidism that a Truly Asymptomatic

• For patients diagnosed with asymptomatic primary hyperparathyroidism (PHPT – 5% of the cases):
  • Additional evaluation is necessary to make subsequent management decisions
• In order to make management recommendations for patients with asymptomatic PHPT, I usually send the following studies:
  • Urinary calcium excretion
  • Serum 25-hydroxyvitamin D
  • Serum creatinine and estimated glomerular filtration rate (eGFR):
    • To assess for renal compromise
  • Bone density to determine if it is low
  • I some situations I will also get the following imaging studies:
    • Ultrasound of the kidneys to assess for occult kidney stones
    • Spine to assess for asymptomatic vertebral compression fracture
• The Fourth International Workshop guidelines recommended further assessment to help in the decision regarding surgery for PHPT:
  • This includes renal imaging (plain radiographs or ultrasound) to determine if the patient has a clinically silent kidney stone and vertebral imaging (spine radiograph or vertebral fracture assessment [VFA] of dual-energy x-ray absorptiometry [DXA] image) for subclinical vertebral fracture
  • Urinary stone risk profile is also recommended:
    • But only if urinary calcium excretion is extremely elevated (> 400 mg/day) and a patient is unsure about parathyroid surgery
      • However, these tests are more expensive, may not be readily available to all clinicians, and there are few data to support their role in managing patients with PHPT
• Urinary calcium excretion:
  • In asymptomatic patients:
    • The urinary calcium excretion is helpful to assess the risk of renal complications (when urine calcium is high) and thus determine subsequent management
  • The Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines recommended surgical intervention as opposed to observation in asymptomatic patients who have:
    • A 24-hour urinary calcium excretion greater than 400 mg/day (> 10 mmol/day)
      • It should be noted that urinary calcium levels are considered to be elevated at a significantly lower level of excretion (250 mg/24 hours in women and 300 mg/24 hours in men):
        • There are no specific data assessing the cut-point of 400 mg calcium excretion daily
          • This particular recommendation reflected expert opinion regarding a level above which there is consensus that patients should be sent for surgery even in the absence of other criteria
• Serum vitamin D:
  • I measure serum 25(OH)D in all patients with suspected or diagnosed PHPT
  • Measurement of 25(OH)D is important:
    • To identify patients with PHPT and vitamin D deficiency (which is a significant proportion of patients)
  • Due to the significant prevalence of vitamin D insufficiency in individuals with PHPT:
    • The Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism recommended measuring 25(OH)D in all patients with the disease and repleting those with low levels (defined as ≤ 20 ng/mL [50 nmol/L]) prior to making any management decisions:
      • Specially if calcium levels are within the normal range
      • In some cases, the decision regarding surgery will be clear despite the low vitamin D level:
        • In such patients, it is still advisable to replete vitamin D if this can be done safely:
          • In order to mitigate postoperative hypocalcemia
• Serum creatinine:
  • The serum creatinine concentration provides information about renal function:
    • Which can be diminished by hypercalcemia
  • Rather than using serum creatinine alone, the eGFR can be estimated in patients with a stable serum creatinine concentration:
    • An eGFR of 60 mL/min is the threshold of chronic kidney disease for deciding:
      • Which asymptomatic individuals with PHPT may benefit from early surgical treatment
• Renal imaging:
  • In several studies, clinically silent kidney stones were reported in 7%to 21% of patients with PHPT:
    • Patients with undiagnosed (subclinical) nephrocalcinosis or calcium kidney stones:
      • Are regarded as having symptomatic disease:
        • Regardless of the absence of symptoms
      • Thus, these patients meet criteria for surgical intervention
  • For the few patients who do not have other overt indications for surgery:
    • Obtaining renal imaging (ultrasound, computed tomography [CT], or abdominal radiograph):
      • To look for nephrocalcinosis or asymptomatic nephrolithiasis at the time of the original evaluation for PHPT
        • Ultrasound is typically the imaging modality used
• Bone mineral density:
  • Patients with PHPT may have decreased bone mineral density (BMD):
    • In particular at more cortical sites (forearm and hip) as compared with more trabecular (cancellous) sites (spine)
  • Although measurement of BMD is not required for the diagnosis of PHPT:
    • It is an essential part of the management of the disease:
      • BMD must be measured at the:
        • Spine, hip, and distal one-third forearm sites
  • The degree of bone loss:
    • Is reflective of the severity of hyperparathyroidism and is useful for making recommendations for parathyroid surgery or observation with monitoring in asymptomatic patients (minority of the cases)
• Assessment for vertebral fracture:
  • Patients with subclinical, idiopathic vertebral compression fractures are regarded as having osteoporosis:
    • Independent of BMD findings
  • Vertebral compression fractures are underdiagnosed in all populations:
    • Many studies have demonstrated an increased risk of asymptomatic vertebral fractures in patients with PHPT
  • In order to diagnose asymptomatic vertebral compression fractures:
    • The Fourth International Workshop guidelines recommended imaging to assess for vertebral fracture in asymptomatic patients who do not have osteoporosis on BMD testing (patients with clinical osteoporotic fractures or with BMD in the osteoporosis range already meet criteria for surgery):
      • If a vertebral fracture is present by VFA or radiograph:
        • Parathyroidectomy is recommended
      • Vertebral assessment can be performed with plain radiographs or with VFA by DXA:
        • The latter can be done at the time of BMD testing, at greater patient convenience, less cost, and lower radiation exposure than conventional radiography of the spine
• Other tests:
  • Biochemical renal stone prediction:
    • For asymptomatic patients with hypercalciuria (> 400 mg/day [10 mmol/day]):
      • The Fourth International Workshop Guidelines on the Management of Asymptomatic Primary Hyperparathyroidism recommended:
        • Assessment of the urine composition to identify patients at highest risk for nephrolithiasis [32]:
          • There are no specific data to suggest that urine stone risk profiling can predict risk of nephrolithiasis in patients with PHPT
          • Some experts believe that urinary calcium excretion > 400 mg/day alone raises sufficient enough concern about long-term renal complications to warrant a recommendation for parathyroidectomy
    • If an asymptomatic patient with a urinary calcium >400 mg/day is unsure about proceeding to surgery, a stone risk profile might provide useful information for making a decision about surgery. (See “The first kidney stone and asymptomatic nephrolithiasis in adults”.)

For asymptomatic patients at high risk for nephrolithiasis (24-hour urinary calcium >400 mg and high-risk urinary biochemical profile), the Fourth International Workshop guidelines recommended parathyroidectomy [32]. (See “Primary hyperparathyroidism: Management”, section on ‘Candidates for surgery’.)

Serum phosphorus — The serum phosphorus concentration may be decreased but typically is in the lower range of normal. Some patients have mild hyperchloremic acidosis. (See “Primary hyperparathyroidism: Clinical manifestations”.)

Markers of bone turnover — Biochemical markers of bone turnover (collagen crosslinks, osteocalcin, bone-specific alkaline phosphatase) are often at the upper end of normal or mildly elevated in asymptomatic PHPT (see “Bone physiology and biochemical markers of bone turnover”). In those with more severe disease, they are typically high. They are only occasionally helpful in the management of hyperparathyroidism and should not be routinely measured [8].

Localization studies — The diagnosis of PHPT is established by appropriate biochemical testing. Localization studies with ultrasonography, technetium-99m sestamibi, CT, or magnetic resonance imaging (MRI) scanning should not be used to establish the diagnosis of PHPT or to determine management. Localization studies should be performed only after a decision for surgery has been made. Their utility is questionable when bilateral neck exploration is planned. However, they are commonly used now, along with intraoperative parathyroid hormone (PTH) monitoring, to facilitate unilateral exploration and minimally invasive surgery in those with probable single gland disease. (See “Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism”.)