Hyperparathyroidism

Hyperparathyroidism

1. Introduction and Overview

Definition:

Hyperparathyroidism is a disorder characterized by excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands, leading to hypercalcemia and disturbances in calcium, phosphate, and bone metabolism.

Epidemiology:

• Prevalence: Primary hyperparathyroidism (PHPT) occurs in 0.3% of the general population and is more common in postmenopausal women.

• Age and Sex Predispositions: Most commonly diagnosed between ages 50–70; females are affected three times more often than males.

• Geographic Variations: Higher prevalence in regions with calcium and vitamin D deficiencies.

Relevance:

Hyperparathyroidism significantly impacts morbidity by causing osteoporosis, nephrolithiasis, cardiovascular complications, and neuropsychiatric disorders if left untreated.

2. Etiology

Primary Causes:

• Genetic Mutations: MEN1 (multiple endocrine neoplasia type 1) and MEN2A syndromes.

• Parathyroid Adenomas: Responsible for 80–85% of primary cases.

• Parathyroid Hyperplasia: Associated with hereditary conditions like familial hyperparathyroidism.

Secondary Causes:

• Chronic Kidney Disease (CKD): Leading to secondary hyperparathyroidism due to hypocalcemia and hyperphosphatemia.

• Vitamin D Deficiency: Reduces calcium absorption, stimulating PTH secretion.

• Malabsorption Syndromes: Such as celiac disease.

Risk Factors:

• Prolonged lithium use.

• Family history of hyperparathyroidism.

• Chronic vitamin D deficiency.

• Chronic kidney disease.

3. Pathophysiology

Normal Physiology:

• PTH regulates calcium homeostasis by:

  1. Stimulating osteoclasts for bone resorption.

  2. Increasing calcium reabsorption in the kidneys.

  3. Enhancing intestinal calcium absorption via activation of vitamin D.

Mechanisms of Disease:

1. Primary Hyperparathyroidism:

   • Autonomous overproduction of PTH due to adenomas, hyperplasia, or carcinoma.

   • Leads to hypercalcemia and hypophosphatemia.

2. Secondary Hyperparathyroidism:

   • Adaptive increase in PTH secretion due to hypocalcemia from vitamin D deficiency or CKD.

3. Tertiary Hyperparathyroidism:

   • Persistent hypersecretion of PTH after prolonged secondary hyperparathyroidism, often seen in CKD.

Key Pathways:

Chronic PTH elevation activates osteoclasts, leading to bone resorption, osteoporosis, and increased fracture risk.

4. Clinical Features

Symptoms:

• General: Fatigue, malaise, and muscle weakness.

• Skeletal: Bone pain, fractures, osteitis fibrosa cystica.

• Renal: Polyuria, nephrolithiasis, and nephrocalcinosis.

• Neurological: Depression, cognitive dysfunction, and confusion.

• Gastrointestinal: Constipation, nausea, and peptic ulcers.

Signs:

• Physical Examination Findings:

  • Subperiosteal bone resorption on X-rays.

  • Hyperreflexia or muscle hypotonia in severe cases.

• Dermatological Changes:

  • Pruritus (secondary to CKD-related phosphate disturbances).

Stages and Progression:

• Mild: Asymptomatic hypercalcemia.

• Moderate: Renal and skeletal symptoms.

• Severe: Hypercalcemic crisis (life-threatening).

Differentiating Features:

• Primary hyperparathyroidism: Hypercalcemia and low-normal phosphate.

• Secondary hyperparathyroidism: Hypocalcemia and elevated phosphate (CKD).

• Tertiary hyperparathyroidism: Persistent hypercalcemia in CKD.

5. Diagnostic Approach

Clinical Diagnosis:

• History: Symptoms of hypercalcemia, family history of MEN syndromes.

• Examination: Signs of bone deformities or nephrolithiasis.

Laboratory Investigations:

• Serum calcium: Elevated in primary and tertiary forms.

• PTH levels: Elevated or inappropriately normal in hypercalcemia.

• 25-hydroxyvitamin D: To rule out deficiency.

• Serum phosphate: Low in primary, high in secondary hyperparathyroidism.

Imaging Studies:

• Neck ultrasound: For adenoma detection.

• Sestamibi scan: Localizes hyperactive parathyroid tissue.

• CT/MRI: For complex or recurrent cases.

Functional Testing:

• Bone mineral density (DEXA scan): To assess osteoporosis risk.

Diagnostic Criteria:

• Elevated calcium with elevated PTH confirms primary hyperparathyroidism.

• Elevated PTH with normal or low calcium suggests secondary hyperparathyroidism.

6. Management

Medical Management:

1. First-Line Therapy:

   • Bisphosphonates: Alendronate for osteoporosis.

   • Calcimimetics: Cinacalcet to reduce PTH secretion.

2. Adjunctive Therapy:

   • Vitamin D and calcium supplementation in secondary hyperparathyroidism.

Surgical Management:

• Indications:

  • Symptomatic hypercalcemia.

  • Complications like osteoporosis, nephrolithiasis.

  • Parathyroid carcinoma.

• Procedure: Parathyroidectomy.

  • Minimally invasive or open surgery depending on adenoma location.

Emergency Management:

• Hypercalcemic Crisis:

  • IV fluids and loop diuretics (e.g., furosemide) for calcium reduction.

  • Hemodialysis in severe cases.

7. Prognosis

Natural History:

• Primary hyperparathyroidism progresses to complications if untreated.

• Secondary hyperparathyroidism may resolve with addressing underlying causes.

Outcomes with Treatment:

• Post-surgical remission rates exceed 95%.

• Untreated secondary hyperparathyroidism often progresses to tertiary.

Long-Term Impacts:

• Risk of recurrence in familial cases.

• Chronic bone and renal damage in untreated cases.

8. Complications

Primary Disease Complications:

• Osteoporosis and pathological fractures.

• Nephrolithiasis leading to chronic kidney disease.

• Hypercalcemic crisis.

Therapeutic Complications:

• Hypocalcemia post-parathyroidectomy.

• Hungry bone syndrome (severe hypocalcemia due to rapid bone uptake of calcium post-surgery).

9. Prevention

Primary Prevention:

• Adequate dietary calcium and vitamin D.

• Screening in at-risk populations (e.g., MEN syndromes).

Secondary Prevention:

• Early detection and management of CKD or vitamin D deficiency.

Tertiary Prevention:

• Post-surgical follow-up and monitoring of calcium levels.

10. Patient Education

Disease Understanding:

Explain that the disorder affects calcium regulation and can impact bones, kidneys, and overall health.

Self-Monitoring:

• Regular calcium and PTH monitoring.

Lifestyle Advice:

• Adequate hydration and dietary modifications to prevent nephrolithiasis.

When to Seek Help:

• Sudden worsening of symptoms like bone pain, confusion, or kidney issues.

11. Recent Research and Advances

• Novel Therapies: Development of PTH receptor antagonists.

• Clinical Trials: Investigating new calcimimetic agents.

• Guidelines: Updated surgical recommendations for minimally invasive techniques.

12. Case Studies

Example:

A 58-year-old woman with fatigue and recurrent kidney stones diagnosed with a parathyroid adenoma. Surgical removal led to symptom resolution and normalization of calcium levels.

13. References

1. Harrison’s Principles of Internal Medicine, 21st Edition.

2. Endocrine Society Guidelines on Hyperparathyroidism.

3. Recent peer-reviewed articles on hyperparathyroidism management.