How to diagnose and treat primary hyperparathyroidism?

Diagnosis and Treatment of Primary Hyperparathyroidism

Primary hyperparathyroidism (PHPT) is diagnosed through biochemical testing and treated primarily with surgical excision of abnormal parathyroid tissue, even in asymptomatic patients, due to the potential negative effects of long-term hypercalcemia. 1

Diagnosis

Biochemical Diagnosis

• PHPT is characterized by:
  • Elevated or inappropriately normal parathyroid hormone (PTH) levels
  • Hypercalcemia (or high-normal calcium)
  • Imaging has no utility in confirming or excluding the diagnosis 1

Key Laboratory Tests:

1. Serum calcium (total calcium corrected for albumin) - elevated or high-normal
2. Intact PTH (iPTH) - elevated or inappropriately normal relative to calcium level
3. Phosphate - typically low or low-normal
4. Chloride - often elevated (high chloride-to-phosphate ratio)
5. 25-hydroxyvitamin D - to exclude vitamin D deficiency as a secondary cause
6. Calcium-to-creatinine clearance ratio - to rule out familial hypocalciuric hypercalcemia (ratio <0.01)

Ionized calcium measurements may provide additional benefit in certain cases as they correlate better with PTH levels and adenoma size, and may be more sensitive markers of disease severity than serum calcium. 2

Differential Diagnosis

• Familial benign hypocalciuric hypercalcemia
• Medication-induced hypercalcemia (lithium, thiazides)
• Secondary hyperparathyroidism due to vitamin D deficiency
• Malignancy-associated hypercalcemia (suppressed PTH)
• Other endocrinopathies (hyperthyroidism, adrenal insufficiency)

Imaging for Localization (Not for Diagnosis)

Once PHPT is biochemically confirmed, imaging is used to localize abnormal glands before surgery:

1. First-line imaging options:

   • Ultrasound of the neck
   • 99mTc-sestamibi scintigraphy with SPECT/CT ("parathyroid scan") 1

2. The combination of these two tests provides high sensitivity for localization of parathyroid adenomas 1

Treatment

Surgical Management

Surgery is the only curative treatment for PHPT and is recommended for:

• Symptomatic patients
• Asymptomatic patients at risk of progression
• Patients with subclinical evidence of end-organ damage 3

Surgical Approaches:

1. Minimally Invasive Parathyroidectomy (MIP)

   • Unilateral operation with limited dissection
   • Requires confident preoperative localization
   • Benefits: shorter operating times, faster recovery, decreased costs
   • Typically used for single adenomas (80% of PHPT cases) 1

2. Bilateral Neck Exploration (BNE)

   • All parathyroid glands are identified and examined
   • Necessary for:
     • Discordant or non-localizing preoperative imaging
     • High suspicion for multigland disease (15-20% of cases)
     • Failed minimally invasive approach 1

3. Intraoperative PTH monitoring is used to confirm removal of hyperfunctioning tissue 1

Medical Management

For patients unable to undergo surgery:

1. Cinacalcet

   • Indicated for hypercalcemia in patients with primary HPT who cannot undergo parathyroidectomy 4
   • Reduces serum calcium but does not improve bone mineral density

2. Bisphosphonates

   • Can improve bone mineral density but have limited effect on serum calcium

Monitoring Recommendations

• For patients under observation:
  • Serum calcium every 6 months
  • Annual PTH measurement
  • Bone mineral density assessment every 1-2 years
  • Renal imaging if history of kidney stones

Special Considerations

Normocalcemic PHPT

• Elevated PTH with consistently normal serum calcium
• Requires exclusion of secondary causes of hyperparathyroidism
• May represent an early form of PHPT

Genetic Forms

• Consider genetic testing in young patients (<40 years)
• Associated with Multiple Endocrine Neoplasia (MEN) types 1 and 2A
• Familial hyperparathyroidism may require different surgical approaches 1

Common Pitfalls

1. Misdiagnosis of secondary hyperparathyroidism - Always check vitamin D status
2. Missing familial hypocalciuric hypercalcemia - Check urinary calcium excretion
3. Relying on imaging for diagnosis - Diagnosis is biochemical, imaging is only for localization 1
4. Inadequate preoperative localization - Can lead to failed surgery or conversion to bilateral exploration
5. Failure to recognize multigland disease - May result in persistent hyperparathyroidism after surgery

Primary hyperparathyroidism is a common endocrine disorder that is often asymptomatic but can lead to significant complications if left untreated. Early recognition, proper diagnosis, and appropriate treatment can prevent long-term sequelae and improve quality of life.