Secondary Hyperparathyroidism

Definition, Etiology, PathogenesisTop

Secondary hyperparathyroidism refers to parathyroid hormone (PTH) hypersecretion by hypertrophic parathyroid glands, mainly due to reduced influx of calcium ions to parathyroid cells. It is usually accompanied by low or normal calcium level. On occasions, long-standing chronic kidney disease (CKD), the most common cause of secondary hyperparathyroidism, leads to persistent parathyroid stimulation, PTH hypersecretion, and parathyroid gland hypertrophy and hyperplasia accompanied by elevation of serum calcium and worsening symptoms requiring treatment. Over time, the function of the hypertrophic parathyroid glands may become autonomous and could be defined as advanced secondary hyperparathyroidism. We choose this label over the more traditionally used tertiary hyperparathyroidism, as this situation represents a continuum of the pathophysiologic process. It is also distinct from a situation which evolves after causes of secondary hyperparathyroidism are removed but hypersecretion of PTH persists (see Tertiary Hyperparathyroidism).

Causes: CKD (the most frequent cause; hyperparathyroidism develops at a glomerular filtration rate [GFR] ≤45 mL/min/1.73 m2), acute kidney injury, diseases associated with chronic hypocalcemia, vitamin D deficiency (hereditary or acquired), gastrointestinal malabsorption syndromes, malnutrition, and hypermagnesemia.

Clinical Features and Natural HistoryTop

Signs and symptoms depend on the underlying condition that causes chronic hypocalcemia, its duration, and prior treatment. Advanced secondary hyperparathyroidism in patients with CKD leads to the development of renal osteodystrophy associated with high bone turnover (see Chronic Kidney Disease). These patients have significant bone pain, which is most noticeable in the legs, and marked weakness. They can develop severe osteodystrophy, soft tissue calcification, persistent pruritus and, in extreme cases, calciphylaxis or spontaneous rupture of tendons.

DiagnosisTop

Diagnostic Tests

1. Biochemical tests: High serum PTH levels, frequently with hypocalcemia or serum calcium levels in the lower range of the normal limits. With progression to advanced secondary hyperparathyroidism and autonomous parathyroid functioning, calcium level becomes high-normal or elevated. Other abnormalities are related to the underlying condition (most frequently elevated serum creatinine and phosphate levels in patients with CKD), usually low 25(OH)D levels, and diminished 1-25(OH)2D3 levels.

2. Imaging studies may reveal enlarged parathyroid glands (best seen on computed tomography [CT] scans) and various bone lesions similar to those found in primary hyperparathyroidism.

Diagnostic Criteria

Elevated serum PTH levels and hypocalcemia or, more commonly, normal serum calcium levels in a patient with an underlying disease known to cause secondary hyperparathyroidism (eg, CKD or low 25[OH]D levels). Hypercalcemia may develop gradually with progression to autonomously functioning parathyroid glands (advanced secondary hyperparathyroidism).

TreatmentTop

Treatment of the underlying condition. If this is not feasible, use symptomatic treatment, which involves:

1) Correction of hyperphosphatemia (see Hyperphosphatemia).

2) Correction of hypocalcemia (see Hypocalcemia).

3) Active vitamin D metabolites (calcitriol), precursors that require no renal hydroxylation (alfacalcidol), or analogues (eg, IV paricalcitol administered via a central venous catheter during hemodialysis at doses calculated on the basis of serum PTH levels).

4) If the above treatment is ineffective in lowering PTH, use a calcimimetic: cinacalcet 30 to 90 mg/d (unless the patient has hypocalcemia).

5) Surgical treatment of secondary hyperparathyroidism may be required when failure of the above measures results in persistent elevation of PTH and ongoing or worsening symptoms. Despite advances in medical treatment, 10% of patients with end-stage renal disease will require parathyroid surgery that is tailored to renal disease and the likelihood of renal transplant: subtotal parathyroidectomy is preferred in patients in whom renal transplant is anticipated, and total parathyroidectomy with parathyroid transplant in those with no immediate plan for renal transplant.

Management of secondary hyperparathyroidism in patients with CKD: see Chronic Kidney Disease.