Hyperparathyroidism: Diagnosis and Treatment
Diagnose hyperparathyroidism by measuring serum calcium and PTH simultaneously—the hallmark is elevated or inappropriately normal PTH in the setting of hypercalcemia, with fractional calcium excretion >2% to exclude familial hypocalciuric hypercalcemia. 1
Diagnostic Approach
Biochemical Confirmation
The diagnosis rests on demonstrating inappropriate PTH secretion relative to calcium levels 1:
Typical presentation:
- Elevated serum calcium
- Elevated PTH
- Increased urinary calcium or fractional calcium excretion (FeCa) >2%
Atypical presentations requiring additional workup:
- Hypercalcemia with normal PTH (still inappropriate for calcium level)
- Normocalcemic hyperparathyroidism (normal calcium with elevated PTH)
Critical Differential Diagnosis Step
Before confirming primary hyperparathyroidism, you must:
- Calculate fractional calcium excretion: FeCa = (urinary calcium × plasma creatinine)/(urinary creatinine × plasma calcium)
- If FeCa ≤2%, suspect familial hypocalciuric hypercalcemia (FHH) and consider genetic testing 1
- Ensure vitamin D sufficiency for >6 months and exclude secondary causes (renal disease, malabsorption) 1
- Consider oral calcium loading test in ambiguous cases 1
This is a common pitfall—missing FHH leads to unnecessary surgery on patients who don't need it.
Mandatory Workup After Diagnosis
Assess target-organ damage systematically 1:
Renal assessment (Grade A++):
- Glomerular filtration rate
- 24-hour urinary calcium
- Fasting calcium/creatinine ratio
- Renal imaging: non-contrast CT is more sensitive than ultrasound for detecting asymptomatic stones and nephrocalcinosis 1
Bone assessment:
- DEXA scan of spine, femur, AND radius (distal radius is critical—cortical bone is preferentially affected) 1
- Spine imaging to detect asymptomatic vertebral fractures 1
Genetic screening indications:
- Age <40 years
- Family history of hyperparathyroidism
- Multi-glandular disease
- Recurrent disease
- Associated endocrine tumors 1
In children, genetic mutations are found in 50% of cases (70% in infants, 40% in older children), making genetic testing mandatory 1.
Treatment Algorithm
Surgical Indications
Surgery is the only curative treatment and should be performed when any of the following are present 1:
- Symptomatic disease (kidney stones, fractures, severe hypercalcemia)
- Serum calcium >1 mg/dL above upper limit of normal
- GFR <60 mL/min
- Kidney stones or nephrocalcinosis on imaging
- T-score ≤-2.5 at any site or history of fragility fracture
- Age <50 years
- 24-hour urinary calcium >400 mg
Preoperative Localization
Perform imaging to enable minimally invasive parathyroidectomy 1:
- Cervical ultrasound (first-line)
- 99mTc-sestamibi scintigraphy with SPECT/CT
- Four-dimensional CT for difficult cases
- Consider 18F-fluorocholine PET/CT for persistent/recurrent disease 2
The 2025 French consensus emphasizes that advances in targeted imaging have revolutionized surgical approach, allowing focused procedures rather than routine four-gland exploration 1.
Surgical Approach
Minimally invasive parathyroidectomy is preferred when preoperative imaging successfully localizes a single adenoma 1, 3. Intraoperative PTH monitoring confirms adequate resection (>50% drop from baseline) 4, 3.
Special Populations
Pregnancy (Grade A++) 1:
- Imaging limited to ultrasound and 4D MRI (no nuclear medicine)
- Conservative management for mild hypercalcemia
- Surgery in second trimester if symptomatic
- Monitor newborn for hypocalcemia due to suppressed fetal parathyroid glands
Children (Grade A++) 1:
- Genetic testing is mandatory
- Higher likelihood of syndromic disease
Parathyroid carcinoma (1% of cases) 1:
- Requires en bloc resection with thyroid lobectomy if needed
- Manage only in specialized centers
- Screen for CDC73 germline mutations
- Consider adjuvant radiotherapy for R1 resection
Non-Surgical Management
When surgery is contraindicated or declined, the 2025 guidelines acknowledge therapeutic alternatives exist 1, though surgery remains definitive. Medical management focuses on monitoring calcium, bone density, and renal function, with bisphosphonates for osteoporosis and calcimimetics to lower calcium in selected cases.
Key Clinical Pitfalls
- Missing FHH: Always calculate fractional calcium excretion—operating on FHH patients is futile and harmful
- Inadequate vitamin D repletion: Correct deficiency for >6 months before diagnosing primary hyperparathyroidism 1
- Skipping radius DEXA: Cortical bone loss at distal radius may be the only finding
- Overlooking genetic syndromes: Young patients and those with multiglandular disease need genetic evaluation
- Inadequate preoperative imaging: Poor localization leads to failed minimally invasive surgery and need for bilateral exploration
No systematic population screening is recommended despite disease frequency, given heterogeneous morbidity 1.