What are the causes and treatment of normocalcemic hyperparathyroidism?

Causes and Treatment of Normocalcemic Hyperparathyroidism

Normocalcemic hyperparathyroidism should be treated with active vitamin D without phosphate supplements in adult patients, and switching to burosumab therapy when possible is recommended for optimal management of morbidity and mortality outcomes. 1

Definition and Diagnosis

• Normocalcemic hyperparathyroidism is characterized by persistently elevated parathyroid hormone (PTH) levels with normal serum calcium concentrations 2, 3
• Diagnosis requires exclusion of secondary causes of PTH elevation, including vitamin D deficiency, renal insufficiency, medication effects (thiazides, lithium), and gastrointestinal disorders 2, 4
• A calcium challenge test can help differentiate between primary and secondary forms - approximately 55% of patients normalize their PTH levels with calcium supplementation, confirming secondary hyperparathyroidism due to insufficient calcium intake 2

Causes

Primary Normocalcemic Hyperparathyroidism

• Parathyroid adenomas (single or multiple glands) 5
• Parathyroid hyperplasia 5
• Early or mild form of classic primary hyperparathyroidism that may progress to hypercalcemia (19% of cases) 2

Secondary Causes (must be excluded for diagnosis)

• Vitamin D deficiency (25-OH vitamin D <20 ng/ml) 1
• Calcium deficiency or inadequate dietary calcium intake 1, 2
• Chronic kidney disease (eGFR <60 ml/min/1.73m²) 2, 4
• Medications (loop diuretics, lithium, bisphosphonates, denosumab) 2, 4
• History of bariatric surgery (gastric bypass, sleeve gastrectomy) 2

Clinical Manifestations

• Bone disorders (osteoporosis, osteopenia, fractures) 5, 3
• Nephrolithiasis and occult renal calcifications (present in 26.5% of asymptomatic patients) 5, 4
• Gastrointestinal symptoms 3
• May be asymptomatic in some patients 6
• Clinical manifestations and complications are similar to hypercalcemic hyperparathyroidism despite more favorable biochemical profile 3

Evaluation

• Measure serum calcium (corrected for albumin), PTH, and 25-OH vitamin D simultaneously 7
• Assess 24-hour urinary calcium excretion 4
• Evaluate renal function (eGFR) 2, 4
• Screen for vitamin D deficiency 1
• Assess dietary calcium intake 1
• Consider calcium challenge test to differentiate primary from secondary hyperparathyroidism 2
• Imaging studies (ultrasound, sestamibi scan, 4D-CT) for surgical candidates 8, 7

Treatment Recommendations

For Normocalcemic Hyperparathyroidism in X-Linked Hypophosphatemia

• Active vitamin D should be given without phosphate supplements if careful follow-up is guaranteed 1
• When possible, switch patients to burosumab therapy 1

For Secondary Hyperparathyroidism

• Correct vitamin D deficiency to achieve 25-OH vitamin D levels >20 ng/ml 1
• Ensure adequate dietary calcium intake according to age-related recommendations 1
• Calcium supplementation for patients with insufficient intake 2

For Primary Normocalcemic Hyperparathyroidism

• Surgical management (parathyroidectomy) for patients with:
  • Symptomatic disease (nephrolithiasis, bone disease) 5
  • Progressive disease with rising PTH levels 6
  • Development of hypercalcemia 2
• Bilateral neck exploration is the standard approach when preoperative localization studies are negative 8
• Intraoperative PTH monitoring may help increase surgical success rates 5

For Severe or Refractory Cases

• Treatment with calcimimetics (cinacalcet) may be considered for severe hyperparathyroidism despite normocalcemia 1
• Use cinacalcet with caution due to potential adverse effects including hypocalcemia and increased QT interval 1
• Parathyroidectomy should be considered for persistent hypercalcemic hyperparathyroidism 1

Follow-up and Monitoring

• Regular monitoring of serum calcium, phosphorus, PTH, and vitamin D levels 7
• Assess for development of hypercalcemia, which occurs in approximately 19% of patients with normocalcemic hyperparathyroidism 2
• Monitor for complications including renal calcifications, bone loss, and fractures 4, 3
• Patients with higher PTH values, elevated 1,25(OH)₂D, and increased urinary calcium excretion are at higher risk for renal calcifications 4

Pitfalls and Caveats

• Failure to exclude secondary causes of hyperparathyroidism can lead to unnecessary surgery 2
• Normocalcemic hyperparathyroidism may be a heterogeneous disease with high rates of multigland disease, which can complicate surgical management 5
• Occult renal calcifications are common (26.5%) even in asymptomatic patients 4
• Some patients may progress from normocalcemic to hypercalcemic hyperparathyroidism over time 2
• Advanced imaging techniques may be necessary when standard imaging is negative 8