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
- Multiple Endocrine Neoplasia (MEN) type 1
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
- Bone: Stimulates osteoclasts (indirectly via osteoblast signals) → release of Ca²⁺ & phosphate.
- 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).
- 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:
- ↑Bone resorption of Ca²⁺ & phosphate.
- ↑Intestinal Ca²⁺ absorption (via more calcitriol).
- ↑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.
- Excess PTH → chronic hypercalcemia via:
- 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”).
- “Bones, Stones, Abdominal Moans, and Groans”
- 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
- Elevated serum total & ionized calcium.
- Decreased serum phosphate (due to PTH-mediated renal phosphate loss).
- High or inappropriately normal PTH (given hypercalcemia).
- Increased 1,25(OH)₂ vitamin D (calcitriol) from PTH-induced 1α-hydroxylation.
- Hypercalciuria (high filtered load of Ca²⁺).
- Possible mild elevated serum creatinine in chronic disease or nephrocalcinosis.
- 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).