Hyperparathyroidism

Classification

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 1010
• Goldman-Cecil Medicine, p. 2642

Primary Hyperparathyroidism

Epidemiology

• One of the most common endocrine disorders; affects ~3 in 1000 adults
• Estimated annual incidence of ~25 cases per 100,000 in the US and Europe
• More common in females than males (~4:1)
• Peak incidence in the 50s and older
• ~80% are identified incidentally via routine serum electrolyte panels

Causes

• Cyclin D1 (CCND1) inversions: A pericentromeric inversion on chromosome 11 repositions CCND1 adjacent to the PTH gene, causing PTH regulatory elements to drive cyclin D1 overexpression - promoting cell proliferation. Even without gene inversion, cyclin D1 is overexpressed in up to 40% of adenomas.
• MEN1 mutations: Loss-of-function mutations in the MEN1 tumor suppressor gene.
• CDC73 mutations: Encode parafibromin; mutated in ~70% of sporadic parathyroid carcinomas.

Morphology

Parathyroid Adenoma

• Almost always solitary; 0.5-5 g; soft, tan-to-reddish-brown, well-circumscribed
• Non-neoplastic glands are normal or shrunken (feedback inhibition from hypercalcemia)
• Microscopy: sheets of uniform polygonal chief cells with small central nuclei; sparse adipose tissue; a rim of compressed normal tissue at the edge
• Bizarre/pleomorphic nuclei (endocrine atypia) may be present but are not a criterion for malignancy

Fig. Parathyroid adenoma. (A) Low-power: adenoma delineated from the fat-containing normal gland above. (B) High-power: monotonous chief cells with dark round nuclei and pale vacuolated cytoplasm. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Sestamibi Scan Imaging

Fig. Technetium-99m-sestamibi scan demonstrating an area of increased uptake at the left inferior parathyroid gland (arrow) corresponding to a parathyroid adenoma. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Parathyroid Hyperplasia

• Classically all four glands involved, but asymmetry is common - making distinction from adenoma difficult
• Combined weight rarely exceeds 1 g
• Microscopy: chief cell hyperplasia (diffuse or multinodular); less commonly water-clear cell hyperplasia; stromal fat is inconspicuous

Parathyroid Carcinoma

• Defined by invasive growth and/or metastasis (cytology alone is unreliable)
• Gray-white irregular masses, sometimes >10 g
• Local recurrence in ~1/3; more distant dissemination in another third

Pathophysiology

• Bone: increases osteoclastic resorption → releases Ca²+ into blood
• Kidney: increases Ca²+ reabsorption, decreases phosphate reabsorption (phosphaturia), stimulates 1α-hydroxylase → activates vitamin D (1,25-dihydroxycholecalciferol)
• Intestine: indirectly increases Ca²+ absorption via activated vitamin D

• Hypercalcemia
• Hypophosphatemia (phosphaturia)
• Elevated urine Ca²+, phosphate, and cAMP

• Costanzo Physiology 7th Edition, p. 383

Clinical Features

Classic Mnemonic: "Bones, Stones, Abdominal Groans, and Psychic Moans"

• Decreased bone mineral density (especially cortical bone - distal 1/3 radius)
• Osteitis fibrosa cystica (severe cases): generalized osteitis with fibrous replacement of marrow
• Brown tumors (focal collections of osteoclasts, reactive giant cells, and hemorrhagic debris - appear brown due to hemosiderin)
• Subperiosteal bone resorption - classically on radial aspect of middle phalanges
• "Salt and pepper" skull on X-ray

Fig. Hyperparathyroidism: osteoclasts boring into the center of a bone trabeculum (dissecting osteitis). - Robbins, Cotran & Kumar Pathologic Basis of Disease

• Nephrolithiasis (Ca²+-phosphate or Ca²+-oxalate)
• Nephrocalcinosis
• Polyuria and polydipsia (hypercalcemia impairs renal concentrating ability)
• Reduced creatinine clearance

• Constipation, nausea, vomiting, anorexia
• Peptic ulcer disease (hypercalcemia stimulates gastrin)
• Acute pancreatitis

• Fatigue, weakness (proximal myopathy)
• Depression, anxiety, cognitive impairment, psychosis
• Hypercalcemic crisis (Ca²+ >14 mg/dL): confusion, coma

Laboratory Diagnosis

• Serum Ca²+: elevated (or inappropriately normal for PTH level)
• Intact PTH (iPTH): elevated or inappropriately normal
• Serum phosphate: low
• Urinary Ca²+ (24-hr): elevated
• 25-OH Vitamin D: often low (must check before labeling secondary HPT)
• Alkaline phosphatase: elevated if bone disease present
• PTH vs. PTHrP: essential to distinguish primary HPT from malignancy-related hypercalcemia (PTH is suppressed in malignancy; PTHrP is elevated)

Secondary Hyperparathyroidism

1. Reduced renal 1α-hydroxylase → less activated vitamin D → decreased intestinal Ca²+ absorption
2. Phosphate retention (reduced renal excretion) → drives down ionized Ca²+
3. Both factors → hypocalcemia → stimulates PTH secretion
4. PTH tries to restore Ca²+; results in bone resorption = renal osteodystrophy

Tertiary Hyperparathyroidism

Management of Primary Hyperparathyroidism

Indications for Parathyroidectomy (2022 Guidelines)

• Any complication of primary HPT (nephrolithiasis, nephrocalcinosis, osteitis fibrosa cystica)
• Episode of life-threatening hypercalcemia
• Serum Ca²+ >1 mg/dL above the upper limit of normal
• Marked hypercalciuria (>400 mg/24hr in men; >300 mg/24hr in women) + increased nephrolithiasis risk by stone risk analysis
• Creatinine clearance <60 mL/min
• T-score below -2.5 at any site (lumbar spine, total hip, femoral neck, distal 1/3 radius) and/or prior vertebral fracture
• Age <50 years
• Surgery is also indicated when surveillance is not possible or desired

Watchful Waiting (Asymptomatic Patients)

• Serum Ca²+, PTH, 25-OH-D
• Creatinine clearance (formal, not eGFR)
• 24-hr urinary calcium
• Bone mineral density (DXA)
• Renal imaging if nephrolithiasis suspected
• Correct vitamin D deficiency cautiously (target 25-OH-D >50 nmol/L)
• Avoid thiazide diuretics, excess calcium intake, dehydration

Medical Therapy

• Goldman-Cecil Medicine, p. 2643-2644

Summary Table