Can you give me a comprehensive overview of hyperparathyroidism, including its types, pathophysiology, clinical features, diagnosis, imaging, and treatment options?

Hyperparathyroidism: Comprehensive Overview

Types and Pathophysiology

Hyperparathyroidism is classified into three distinct forms based on the underlying mechanism: primary (autonomous PTH overproduction), secondary (compensatory PTH elevation), and tertiary (autonomous hyperfunction after prolonged secondary disease). 1

Primary Hyperparathyroidism (PHPT)

• Parathyroid adenomas cause 80% of PHPT cases, resulting in autonomous PTH secretion that elevates serum calcium without appropriate suppression. 2
• The disease is characterized by elevated or inappropriately normal PTH levels in the presence of hypercalcemia. 3
• PHPT is more common in women (66 per 100,000 person-years) than men (25 per 100,000 person-years). 4
• In countries with routine biochemical screening, up to 80% of patients present asymptomatically with incidental discovery on laboratory testing. 4

Secondary Hyperparathyroidism

• Develops as a compensatory response to chronic hypocalcemia, most commonly from chronic kidney disease, vitamin D deficiency, or malabsorption disorders. 1, 5
• The parathyroid glands appropriately increase PTH secretion in response to hyperphosphatemia, hypocalcemia, and low vitamin D levels. 6
• Unlike primary disease, calcium levels are typically low or normal. 1

Tertiary Hyperparathyroidism

• Occurs when chronically stimulated parathyroid glands become autonomously hyperplastic and continue oversecreating PTH even after correction of the underlying disorder (typically after renal transplantation). 7
• The hypertrophied parathyroid tissue fails to involute and may become resistant to calcimimetic treatment. 7
• Biochemically, hypercalcemia persists in 1-5% of transplant recipients despite restoration of renal function. 4

Clinical Features

Symptomatic Presentations

When symptomatic, PHPT manifests through target organ damage affecting bone, kidney, neuromuscular, and neuropsychiatric systems. 4

Skeletal Manifestations

• Bone demineralization, osteoporosis, and pathological fractures occur from increased osteoclastic bone resorption. 4
• Severe hyperparathyroid bone disease with bone pain and skeletal deformities develops when PTH exceeds 10 times the upper normal limit. 4
• Progressive skeletal pain can occur at moderately elevated PTH levels (500-800 pg/mL). 4
• Elevated alkaline phosphatase reflects increased osteoblastic activity attempting to compensate for PTH-driven bone resorption. 4

Renal Manifestations

• Recurrent nephrolithiasis (kidney stones) and nephrocalcinosis are classic presentations. 4, 5
• Persistent hypercalcemia causes progressive renal damage. 4
• Hypercalciuria may be present even without frank hypercalcemia. 8

Neuromuscular and Neuropsychiatric Features

• Muscle weakness, neurocognitive disorders, and psychological disturbances occur with chronic disease. 4
• Intractable pruritus becomes debilitating in secondary hyperparathyroidism, often requiring surgical intervention when PTH exceeds 500 pg/mL. 4

Acute Hypercalcemic Crisis

• Calcium levels >12-13.5 mg/dL cause anorexia, asthenia, and persistent constipation. 1
• Severely elevated concentrations >13.5 mg/dL produce nausea, vomiting, osmotic polyuria with dehydration, and progressive lethargy, stupor, and coma. 1

Cardiovascular Associations

• PHPT is recognized as a secondary cause of hypertension in ACC and Circulation guidelines, though considered rare. 2
• Primary hyperparathyroidism should be considered in the differential diagnosis of resistant hypertension. 2
• Progressive vascular calcification occurs with persistent hypercalcemia and hyperphosphatemia, contributing to cardiovascular morbidity. 4

Diagnosis

Biochemical Diagnosis

PHPT is diagnosed by demonstrating elevated or inappropriately normal intact PTH levels in the setting of elevated total or ionized calcium. 4

Essential Laboratory Tests

• Measure serum calcium and intact PTH simultaneously to confirm diagnosis before treatment. 6
• Check serum phosphate (typically low in PHPT due to PTH-induced phosphaturia). 3
• Assess 25-hydroxyvitamin D status, as deficiency can complicate PTH interpretation and cause secondary hyperparathyroidism. 6, 8
• Calculate estimated glomerular filtration rate (eGFR) to exclude renal insufficiency as a cause of secondary hyperparathyroidism. 8
• Measure 24-hour urinary calcium excretion to differentiate from familial hypocalciuric hypercalcemia. 3

Critical Diagnostic Pitfalls

• PTH assays vary significantly between laboratories; always use assay-specific reference values. 6
• Vitamin D deficiency must be corrected before definitively diagnosing PHPT, as deficiency can elevate PTH and mask primary disease. 8
• Exclude iatrogenic causes: diuretics, lithium, excessive vitamin D or calcium supplementation, corticosteroids. 8
• Assess calcium intake adequacy and screen for malabsorption (inflammatory bowel disease, celiac disease, bariatric surgery). 8

Differential Diagnosis

Hypercalcemia with Non-Elevated PTH

• Malignancy (most common alternative cause of hypercalcemia). 8
• Hypervitaminosis D (excessive intake, production, or impaired catabolism). 8
• Prolonged immobilization. 8
• Other endocrine causes (thyrotoxicosis, adrenal insufficiency). 8

Elevated PTH without Hypercalcemia

• Normocalcemic hyperparathyroidism (early or mild PHPT variant). 8
• Secondary hyperparathyroidism from chronic kidney disease, vitamin D deficiency, or malabsorption. 5
• PTH-resistant states. 8
• Hypophosphatemic tubulopathies (X-linked hypophosphatemia). 8
• Hypercalciuric tubulopathies, metabolic syndrome, loop diuretics. 8

Hypercalcemia with Hypocalciuria

• Familial hypocalciuric hypercalcemia (genetic calcium-sensing receptor mutation). 8
• Measure calcium-to-creatinine clearance ratio to differentiate. 3

Imaging

Role of Imaging in PHPT

Imaging has no role in diagnosing hyperparathyroidism—diagnosis is purely biochemical—but is specifically indicated for preoperative parathyroid gland localization when surgery is planned. 2

Preoperative Localization Studies

The American College of Radiology recommends preoperative localization using sestamibi scintigraphy and/or neck ultrasound to enable focused, minimally invasive parathyroidectomy. 2, 6

Available Imaging Modalities

• 99Tc-sestamibi scan (parathyroid scintigraphy). 6
• Neck ultrasound. 6
• 4D-parathyroid CT. 6
• MRI. 6
• Selection depends on surgeon and radiologist preference, regional expertise, and patient characteristics. 6

Reoperative Cases

For persistent or recurrent hyperparathyroidism, preoperative imaging is mandatory prior to re-exploration, as reoperations have lower cure rates and higher complication rates. 6

Treatment

Surgical Management

Surgery is the only curative treatment for primary hyperparathyroidism, and parathyroidectomy should be performed in patients with hypercalcemia and elevated PTH. 6

Indications for Parathyroidectomy

Surgery is typically indicated even when asymptomatic, given potential negative effects of long-term hypercalcemia. 2, 4

Specific indications include: 5

• Presence of symptoms (bone pain, nephrolithiasis, neurocognitive changes)
• Age ≤50 years
• Serum calcium >1 mg/dL above upper limit of normal
• Osteoporosis (T-score ≤-2.5)
• Creatinine clearance <60 mL/min/1.73 m²
• Nephrolithiasis or nephrocalcinosis
• Hypercalciuria (>400 mg/24 hours)

Surgical Approach Selection

Minimally invasive parathyroidectomy (MIP) is the preferred approach when preoperative imaging confidently localizes a single parathyroid adenoma (80-85% of cases). 6

• MIP offers shorter operating times, faster recovery, and decreased perioperative costs compared to bilateral neck exploration. 6
• Requires intraoperative PTH monitoring to confirm removal of hyperfunctioning tissue. 2, 6

Bilateral neck exploration (BNE) is necessary when: 6

• Preoperative imaging is discordant or nonlocalizing
• Multigland disease is suspected
• PTH ≤50 pg/mL (58.9% have multigland disease)

Surgical Considerations for Tertiary Hyperparathyroidism

Three procedures are performed: total parathyroidectomy with or without autotransplantation, subtotal parathyroidectomy, and limited parathyroidectomy. 7

• Remove superior parts of thymus during surgery. 7
• The most appropriate extent of surgery remains controversial. 7

Postoperative Management

Calcium Monitoring Protocol

Monitor ionized calcium every 4-6 hours for the first 48-72 hours postoperatively. 2

If ionized calcium falls below 0.9 mmol/L (corrected total calcium <7.2 mg/dL), initiate calcium gluconate infusion at 1-2 mg elemental calcium/kg/hour. 2

Transition to oral calcium carbonate 1-2 g three times daily plus calcitriol up to 2 μg/day when oral intake is possible. 2

Hungry Bone Syndrome Prevention

• Review serum phosphorus levels and discontinue or reduce phosphate binders when phosphorus falls toward lower normal range. 2
• This prevents exacerbating postoperative hypocalcemia. 2

Medical Management

Acute Hypercalcemic Crisis

Emergency treatment is required when calcium >13.5-14 mg/dL due to risk of cardiac, CNS, gastrointestinal, and renal injury. 1

Four cardinal treatment points: 1

1. Aggressive hydration
2. Forced calciuresis
3. Inhibition of bone calcium resorption (bisphosphonates, calcitonin)
4. Treatment of underlying hyperparathyroidism

Contraindications

Increased calcium diet is completely contraindicated in hypercalcemia, as it worsens already elevated calcium levels. 2

Secondary Hyperparathyroidism Management

• Calcium and vitamin D replacement. 5
• Reduction of high phosphate levels through dietary restriction and phosphate binders. 5
• Limited evidence supports calcimimetics and vitamin D analogues for persistently elevated PTH. 5
• Avoid total parathyroidectomy in patients who may subsequently receive kidney transplant, as calcium control becomes problematic. 6

Screening in Hypertensive Patients

Screen for PHPT in hypertensive patients by measuring serum calcium levels, with follow-up PTH testing if calcium is elevated. 2