What is secondary hyperparathyroidism?

Secondary Hyperparathyroidism: Definition, Pathophysiology, and Management

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease characterized by compensatory parathyroid gland hyperplasia and increased parathyroid hormone secretion in response to disturbances in calcium and phosphate metabolism. 1

Pathophysiology

Secondary hyperparathyroidism develops through several interrelated mechanisms:

1. Initial Trigger: Early in chronic kidney disease (CKD), even with moderate loss of kidney function, phosphate retention occurs. While patients may appear normophosphatemic, transient increases in serum phosphorus directly decrease ionized calcium, stimulating parathyroid hormone (PTH) release. 1

2. Compensatory Response: The parathyroid glands undergo hyperplasia, resulting in increased PTH secretion to normalize calcium levels. This adaptive mechanism becomes maladaptive over time. 1

3. Progression Factors:

   • Decreased vitamin D receptor (VDR) expression in parathyroid glands
   • Reduced calcium-sensing receptor (CaR) expression
   • Persistent hyperphosphatemia
   • Vitamin D deficiency 1, 2

4. Role of FGF-23: Fibroblast growth factor 23 plays a central role in phosphate-vitamin D homeostasis and increases in CKD, contributing to SHPT progression. 2

Clinical Manifestations

SHPT manifests with:

• High PTH levels
• Hyper- or hypocalcemia
• Persistently elevated phosphorus levels
• Skeletal complications (bone pain, fractures, deformities)
• Cardiovascular complications (vascular calcification)
• Neurological disturbances
• Hematological abnormalities 1, 3

These complications contribute to increased mortality and cardiovascular morbidity in CKD patients. 4

Diagnosis

SHPT is diagnosed based on:

• Elevated PTH levels with a clear underlying cause (most commonly CKD)
• Normal or low serum calcium (distinguishing it from primary hyperparathyroidism)
• Elevated phosphorus levels (particularly in advanced CKD)
• Evidence of bone disease on imaging 5, 6

Unlike primary hyperparathyroidism, where imaging is used to localize adenomas, in SHPT imaging is primarily used to identify all parathyroid glands when surgical intervention is planned. 1

Management

Management of SHPT follows a stepwise approach:

1. Dietary Modifications:

   • Low-phosphorus diet
   • Adequate calcium intake 1, 4

2. Pharmacological Treatment:

   • Phosphate binders: To reduce phosphate absorption
   • Vitamin D and analogs: To suppress PTH secretion
   • Calcimimetics (e.g., cinacalcet): Activate calcium-sensing receptors, reducing PTH secretion without increasing calcium and phosphorus levels 7, 2

3. Surgical Intervention: For refractory or progressive SHPT, surgical options include:

   • Total parathyroidectomy (TPTX)
   • Total parathyroidectomy with autotransplantation (TPTX+AT)
   • Subtotal parathyroidectomy (SPTX) 1

Clinical trials comparing TPTX and TPTX+AT have shown that TPTX may have advantages in reducing SHPT relapse, while concerns about persistent hypocalcemia appear to be largely unfounded. 1

Treatment Efficacy

Cinacalcet has demonstrated significant efficacy in clinical trials:

• 40% of patients achieved iPTH ≤250 pg/mL (vs. 5% with placebo)
• Reduced calcium-phosphorus product
• Lowered serum calcium and phosphorus levels 7

However, common adverse effects include nausea (31%), vomiting (27%), and diarrhea (21%). 7

Monitoring

Patients with SHPT should have regular monitoring of:

• Serum calcium
• Phosphorus
• PTH levels
• Bone mineral density when appropriate 1

Special Considerations

Tertiary hyperparathyroidism may develop in patients with long-standing SHPT, particularly after kidney transplantation. This condition is characterized by autonomous PTH secretion despite rising calcium levels, often requiring surgical intervention. 1, 6