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Hyperparathyroidism — Comprehensive Overview

Definition

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PTH Physiology — What Goes Wrong

1. Osteoclast activation — via increased RANKL expression on osteoblasts → bone resorption → calcium mobilization
2. Renal calcium resorption — increased tubular reabsorption of Ca²⁺
3. Phosphaturia — increased urinary phosphate excretion
4. Vitamin D activation — stimulates renal 1α-hydroxylase → 1,25(OH)₂D synthesis → enhanced intestinal calcium absorption

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Classification

1. Primary Hyperparathyroidism (PHPT)

Causes & Pathology

• Sporadic adenoma: Autonomous, clonal, single-gland enlargement. Associated with somatic mutations in MEN1 (chromosome 11q13) in ~15–20% of cases and overexpression of cyclin D1 (PRAD1/CCND1).
• Parathyroid hyperplasia: Multiglandular enlargement — the hallmark of MEN-1 (MEN1/MENIN tumor suppressor) and MEN-2A (Ret protooncogene gain-of-function).
• Parathyroid carcinoma: Associated with inactivating mutations in CDC73 (HRPT2 gene, chromosome 1q21-31), encoding parafibromin. Rb gene abnormalities also found. Importantly, carcinoma involves a different genetic pathway than benign adenoma — it does not evolve from adenoma through progressive mutations.
• HPT-JT syndrome: Familial hyperparathyroidism with jaw tumors — caused by germline CDC73 mutations.

Harrison's Principles of Internal Medicine 22E, 2025, p. 3318–3320

Epidemiology

• Peak incidence in middle adulthood (post-menopausal women particularly affected)
• Earlier onset in MEN-1 and MEN-2A (single germline mutation sufficient to trigger tumor)

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2. Secondary Hyperparathyroidism

• Inadequate 1,25(OH)₂D synthesis (loss of renal 1α-hydroxylase)
• Hyperphosphatemia → further lowers serum calcium
• Metabolic acidosis
• Calcium sensing receptor resistance

Robbins & Kumar Basic Pathology, p. 775

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3. Tertiary Hyperparathyroidism

Harrison's Principles of Internal Medicine 22E, p. 3325

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Skeletal Pathology (Morphology)

1. Osteoporosis

• Generalized but most severe in phalanges, vertebrae, and proximal femur
• Predisposes to fractures and joint problems

2. Dissecting Osteitis (Tunneling Resorption)

• Osteoclasts bore into and dissect along the length of trabeculae — "railroad track" appearance
• Marrow spaces replaced by fibrovascular tissue

3. Brown Tumors & Osteitis Fibrosa Cystica

• Microfractures → hemorrhage → macrophage infiltration + reparative fibrous tissue = brown tumor (named for its vascularity + hemosiderin content)
• Can undergo cystic degeneration
• Osteitis fibrosa cystica = the full triad of increased osteoclast activity + peritrabecular fibrosis + cystic brown tumors — now rarely encountered because HPT is diagnosed early

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Clinical Features

Symptoms of Hypercalcemia (general)

Symptoms are more common at calcium >2.9–3.0 mmol/L (11.6–12 mg/dL); severe manifestations at >3.2 mmol/L (12.8 mg/dL).

Asymptomatic PHPT (modern presentation)

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Diagnosis & Laboratory Findings

• Asymptomatic hypercalcemia lasting >1 year → malignancy unlikely
• Malignancy-related hypercalcemia: PTHrP elevated (not PTH), malignancy usually clinically apparent
• Familial hypocalciuric hypercalcemia (FHH): benign mutation in calcium-sensing receptor — urine calcium/creatinine ratio <0.01 distinguishes it from PHPT

Harrison's Principles of Internal Medicine 22E, p. 3317

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Indications for Surgery (PHPT)

• Age <50 years
• Serum calcium >1 mg/dL above upper limit of normal
• Bone mineral density (BMD) T-score ≤ −2.5 at any site, or vertebral fracture
• Renal involvement: CrCl <60 mL/min, 24-hour urine Ca >400 mg/day, nephrolithiasis or nephrocalcinosis on imaging
• Patient preference for surgery over surveillance

Evidence favoring surgery is growing due to concerns about skeletal, cardiovascular, and neuropsychiatric disease even in mild PHPT. — Harrison's 22E, p. 3322

Surgical Approach

• Conventional neck exploration (general anesthesia) — standard
• Minimally invasive parathyroidectomy (local anesthesia, focused approach) — gaining traction
• Preoperative imaging: Neck ultrasound, ⁹⁹ᵐTc-sestamibi SPECT, C-11 choline PET/CT, 4D-CT
• Intraoperative PTH monitoring: Rapid PTH assay; >50% fall to normal confirms successful removal
• Familial/multiglandular disease: Subtotal parathyroidectomy or total PTX with forearm autotransplantation

Post-Operative Complications

• "Hungry bone" syndrome: Rapid calcium influx into demineralized bone → hypocalcemia; requires IV calcium replacement
• Transient hypoparathyroidism: Usually resolves in days–months
• Permanent hypoparathyroidism: Risk if PTH <15 pg/mL at 12–24 h post-op
• Hypomagnesemia can complicate recovery (impairs PTH secretion)

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Medical Management of PHPT

A Scandinavian RCT of parathyroidectomy vs. observation in mild PHPT showed no difference in morbidity or mortality at 10 years. — Harrison's 22E, p. 3323

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Treatment of Secondary Hyperparathyroidism (CKD)

1. Dietary phosphate restriction
2. Phosphate binders: Calcium carbonate (avoid in hypercalcemia), sevelamer (preferred — no aluminum, no excess calcium loading)
3. Active vitamin D: Calcitriol 0.25–2 μg/day or IV pulse calcitriol/paricalcitol
4. Cinacalcet: Reduces PTH and calcium; effective in dialysis patients
5. Parathyroidectomy for tertiary HPT (autonomous, unresponsive to medical therapy)

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Special Situations

Lithium-Induced Hyperparathyroidism

• ~10% of lithium-treated patients develop hypercalcemia
• Lithium shifts the PTH secretion set-point to the right (requires higher Ca²⁺ to suppress PTH)
• Usually resolves on stopping lithium; cinacalcet effective
• Surgery only if HPT persists after lithium discontinuation

Post-Renal Transplant HPT

• Residual hyperparathyroidism is very common in the first post-transplant year
• Risk factors: degree of pre-transplant HPT, duration of dialysis
• Managed with paricalcitol or cinacalcet
• Surgery (subtotal PTX) if persistent hypercalcemia ≥12 mg/dL after >1 year, or calciphylaxis

MEN Syndromes

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Summary Table: PHPT vs Secondary HPT vs Tertiary HPT

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Recent Evidence (2024)

• A 2024 systematic review (PMID 38551756) evaluated quality of clinical practice guidelines for PHPT management — evidence base continues to be refined.
• A 2024 meta-analysis (PMID 38583772) found parathyroidectomy superior to medical treatments for secondary HPT in dialysis patients in reducing PTH, calcium, and phosphate.
• A 2024 meta-analysis (PMID 38536478) showed calcimimetics reduce fracture risk in dialysis patients with secondary HPT.

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