Primary Hyperparathyroidism

PATHOPHYSIOLOGY OF PRIMARY HYPERPARATHYROIDISM

• Incidence and Demographics
  • Annual incidence: ~4 per 100,000
  • More common in women (2:1 ratio)
  • Typically diagnosed after age 45
• Underlying Pathology
  • Single parathyroid adenoma (~89%)
  • Multiple (“double”) parathyroid adenomas (~4%)
  • Multigland parathyroid hyperplasia (~6%)
  • Parathyroid carcinoma (~1%)
  • Correctly identifying each pathologic form is crucial for determining the surgical approach.

Parathyroid Adenomas

• Gross & Histology
  • Usually encapsulated, arising from chief cells (some from oxyphilic cells).
  • Typically located in the neck, but ectopic sites can occur in anterior/posterior mediastinum.
• Clonal Mutations
  • Arise from somatic mutations in growth regulatory genes.
  • ~30% show cyclin D1 (CCND1) overexpression.
  • MEN1 gene (tumor suppressor) mutations found in ~15% of sporadic adenomas.

Parathyroid Hyperplasia

• General
  • May involve all four glands (“multigland disease”).
  • Typically chief cell hyperplasia (rarely clear cell hyperplasia).
  • Pathologically: less fat within hyperplastic glands, and they appear enlarged.
• Sporadic or part of familial syndromes:
  • Multiple Endocrine Neoplasia (MEN) type 1
    • HPT occurs in almost all MEN 1 patients; hypercalcemia evident by 3rd decade.
  • MEN 2A
    • Only ∼10% develop hyperparathyroidism, usually later in life.
  • HPT–jaw tumor syndrome
    • Often multiple, cystic adenomas; associated jaw tumor is typically fibrous.
  • Familial Isolated Hyperparathyroidism

Parathyroid Carcinoma

• Incidence: ~1% in primary HPT.
• Diagnosis: confirmed by local tissue invasion or metastases (lymph nodes or distant).
• Germline inactivating mutations in CDC73/HRPT2 gene:
  • Associated with HPT–jaw tumor syndrome and increased risk of parathyroid carcinoma.

NORMAL CALCIUM–PTH HOMEOSTASIS

• Calcium-Sensing Mechanism
  • Serum ionized calcium tightly regulated (8.9–10.1 mg/dL total Ca²⁺).
  • Hypocalcemia → stimulates parathyroid PTH secretion.
  • Hypercalcemia → suppresses PTH secretion.
  • Calcium-sensing receptor (CaSR) in parathyroid glands modulates PTH release.
• Actions of PTH
  1. Bone: Stimulates osteoclasts (indirectly via osteoblast signals) → release of Ca²⁺ & phosphate.
  2. Kidney:
     • ↓Renal calcium excretion by promoting distal tubular reabsorption of Ca²⁺.
     • ↑Phosphate excretion by inhibiting proximal tubular phosphate reabsorption.
     • ↑Renal 1α-hydroxylation → more 1,25(OH)₂ vitamin D (calcitriol).
  3. GI Tract: Enhanced calcium absorption indirectly via calcitriol.

PRIMARY HYPERPARATHYROIDISM: DISRUPTED REGULATION

• Elevated Set Point
  • In primary HPT, feedback suppression of PTH by calcium is abnormal.
  • The “set point” (threshold for PTH suppression) is raised ~15–30% above normal.
  • PTH not fully autonomous; can be partially suppressed by very high Ca²⁺.
• Consequences
  • Excess PTH → chronic hypercalcemia via:
    1. ↑Bone resorption of Ca²⁺ & phosphate.
    2. ↑Intestinal Ca²⁺ absorption (via more calcitriol).
    3. ↑Renal Ca²⁺ reabsorption.
  • Concurrently, PTH inhibits phosphate reabsorption → hypophosphatemia.
  • Excess urinary excretion of Ca²⁺ and phosphate → predisposes to calcium phosphate or calcium oxalate stones.
  • Nephrocalcinosis can occur from calcium deposits in kidney tissue.
• Bone Disease
  • ~25% with primary HPT have notable skeletal involvement.
  • Marked osteoclast activity plus a compensatory rise in osteoblast activity.
  • Bone mineral = hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂) with minor carbonate, Mg²⁺, Na⁺, K⁺.

CLINICAL MANIFESTATIONS & LABORATORY FINDINGS

• Asymptomatic & Mild Forms
  • ~80% are asymptomatic, discovered incidentally on routine labs revealing hypercalcemia.
  • Subtle manifestations: fatigue, mild depression, musculoskeletal aches.
• Classic Symptoms
  • “Bones, Stones, Abdominal Moans, and Groans”
    • Stones: Nephrolithiasis (20% of primary HPT) from hypercalciuria & calcium oxalate/phosphate stones.
    • Bone: Osteopenia/osteoporosis most common; severe forms include subperiosteal bone resorption, salt-and-pepper skull, brown tumors, osteitis fibrosa cystica.
    • Abdominal: Anorexia, nausea, constipation, peptic ulcer, pancreatitis.
    • Neuro: Confusion, depression, potential coma if very severe (“parathyroid crisis”).
• Physical Examination
  • Typically no specific findings unless a large parathyroid tumor is palpable (suggestive of carcinoma).
  • Band keratopathy: Calcium deposits in corneal limbus on slit-lamp exam.
• Laboratory Abnormalities
  1. Elevated serum total & ionized calcium.
  2. Decreased serum phosphate (due to PTH-mediated renal phosphate loss).
  3. High or inappropriately normal PTH (given hypercalcemia).
  4. Increased 1,25(OH)₂ vitamin D (calcitriol) from PTH-induced 1α-hydroxylation.
  5. Hypercalciuria (high filtered load of Ca²⁺).
  6. Possible mild elevated serum creatinine in chronic disease or nephrocalcinosis.
  7. May see normocytic, normochromic anemia in severe cases.
• Vitamin D Deficiency
  • Often coexists; can mask severity of hypercalcemia.
  • Correcting deficiency can worsen hypercalcemia/hypercalciuria.

MANAGEMENT

• Definitive Treatment
  • Surgical removal of the overactive gland(s).
  • For single adenoma, resection of that adenoma.
  • For hyperplasia (e.g., MEN 1), often 3½ gland resection is performed.
• Parathyroid Crisis (Calcium >15 mg/dL)
  • Urgent IV saline rehydration + medications to reduce bone resorption (e.g., bisphosphonates).