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:
    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 reabsorptionhypophosphatemia.
    • 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).

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