Hyperparathyroidism — Signs & Symptoms

"Painful bones, renal stones, abdominal groans, and psychic moans"

Overview

Signs & Symptoms by System

🦴 Skeletal ("Painful Bones")

🫘 Renal ("Renal Stones")

🫁 Gastrointestinal ("Abdominal Groans")

• Nausea, vomiting, constipation — common early symptoms
• Peptic ulcer disease — hypercalcemia stimulates gastrin secretion
• Pancreatitis — acute or chronic
• Gallstones — increased calcium in bile

🧠 Neuropsychiatric ("Psychic Moans")

• Depression, anxiety, emotional lability
• Lethargy, cognitive dysfunction ("brain fog")
• Weakness and fatigue — neuromuscular
• Seizures — in severe/prolonged hypercalcemia

❤️ Cardiovascular

• Shortened QT interval on ECG (hallmark of hypercalcemia)
• Hypertension — PTH directly elevates BP
• Left ventricular hypertrophy
• Valvular / mitral / aortic calcifications
• Cardiac arrhythmias
• Heart failure — with severe or chronic disease
• Shortening of QT, blunting of T wave, occasional ST changes mimicking ischemia

Asymptomatic Hyperparathyroidism

Key Lab Findings

Secondary Hyperparathyroidism

Diagnostic Tests for Hyperparathyroidism

Step 1 — Biochemical Confirmation (Always First)

Core Blood Tests

Key rule from Harrison's (2025): If PTH is elevated (or inappropriately normal) in the setting of elevated calcium + low/low-normal phosphorus → diagnosis is almost always primary hyperparathyroidism (PHPT).

Urine Tests

Familial Hypocalciuric Hypercalcemia (FHH) must be excluded — it mimics PHPT (elevated Ca, non-suppressed PTH) but surgery is ineffective. Low urinary Ca excretion (ratio <0.01) and/or genetic testing of CASR, GNA11, AP2S1 genes confirms FHH.

Secondary Hyperparathyroidism Labs

Step 2 — Bone Assessment

• DEXA scan (dual-energy X-ray absorptiometry) — Measures bone mineral density at lumbar spine, hip, and distal 1/3 radius. The distal radius is most sensitive in PHPT (cortical bone is preferentially lost).
• X-rays — May show subperiosteal resorption (radial aspect of middle phalanges), "salt and pepper" skull, brown tumors, or osteitis fibrosa cystica in advanced disease.

Step 3 — Renal Assessment

• Renal ultrasound or CT — Evaluate for nephrolithiasis and nephrocalcinosis.
• 24-hour urine calcium/creatinine — Assess hypercalciuria.

Step 4 — Localization Imaging (Pre-operative Only)

Intraoperative Confirmation

• Intraoperative PTH monitoring (ioPTH): PTH half-life = 3–5 minutes. A >50% drop in PTH at 10 minutes after gland removal confirms successful excision of the hyperfunctioning tissue. This is the intraoperative gold standard.

Diagnostic Summary

Elevated serum calcium (confirmed × 2)
         ↓
Intact PTH (two-site assay)
    ↑ or inappropriately normal  →  PRIMARY PHPT
    Suppressed (<20 pg/mL)       →  Non-PTH-mediated hypercalcemia
                                     (malignancy, vitamin D toxicity, sarcoidosis)
         ↓
Exclude FHH (urine Ca/Cr ratio; CASR gene testing)
         ↓
Assess complications (DEXA, renal ultrasound, 24hr urine Ca)
         ↓
Localization imaging ONLY if surgery planned
(Sestamibi + Ultrasound ± 4D-CT)

Treatment of Hyperparathyroidism

SURGICAL TREATMENT

Parathyroidectomy — The Only Curative Option

Indications for Surgery

Symptomatic Patients

Asymptomatic Patients (4th International Workshop Guidelines)

Types of Surgical Procedures

1. Focused/Minimally Invasive Parathyroidectomy (MIP)

• Standard of care for single-gland disease (adenoma, ~85% of cases)
• Uses preoperative localization (sestamibi/ultrasound/4D-CT) to target only the abnormal gland
• Smaller incision, shorter operative time, lower complication rate (1–3%)
• Intraoperative PTH monitoring confirms cure: >50% drop in PTH at 10 minutes post-excision

2. Bilateral Neck Exploration

• Used when localization fails, when multigland disease is suspected, or in MEN syndromes
• Higher complication rate (~4%) but allows inspection of all four glands
• Recommended in MEN1 (subtotal parathyroidectomy — removal of 3.5 glands)

3. Subtotal Parathyroidectomy

• Removal of 3.5 of 4 glands
• Used in parathyroid hyperplasia (MEN1, MEN2A, secondary/tertiary HPT)
• A remnant is left in situ, marked with surgical clips

4. Total Parathyroidectomy + Autotransplantation

• All 4 glands removed; parathyroid tissue implanted into forearm (brachioradialis muscle)
• Preferred for secondary HPT in ESKD and some MEN1 cases
• Recurrence ~10%; if recurrent, forearm implant can be removed under local anesthesia

5. Alternative (Scarless) Approaches

• Transaxillo-breast, facelift (postauricular), transoral vestibular approaches
• Limited to well-localized single-gland disease
• Additional specific nerve injury risks; requires expert surgeons

6. Thermal Ablation

• Ultrasound-guided; ~90% cure rate
• Option for patients who are not candidates for general anesthesia or open surgery

Operative Complications

NON-SURGICAL TREATMENT

1. Watchful Waiting (Active Surveillance)

• Serum calcium, PTH, 25-OH vitamin D
• Serum creatinine / creatinine clearance
• 24-hour urine calcium
• DEXA bone mineral density
• Spinal imaging if height loss or back pain
• Renal imaging if nephrolithiasis suspected

2. Calcimimetics — Cinacalcet (Sensipar)

3. Bisphosphonates

• Inhibit osteoclast-mediated bone resorption
• Do not alter serum calcium or PTH levels
• Best chosen when the primary goal is preserving/improving bone density
• Can be combined with cinacalcet — combination normalizes hypercalcemia and improves bone density

4. Vitamin D Supplementation

• Paradoxically, vitamin D deficiency is common in PHPT (PTH-driven conversion to 1,25-OH₂D depletes 25-OH-D)
• Correction with cholecalciferol (vitamin D₃) cautiously → can decrease PTH and improve bone density
• Target 25-OH-D >50 nmol/L (20 ng/mL)

5. Secondary HPT — Additional Medical Options

• Phosphate binders (calcium-based or non-calcium-based) — reduce phosphate-driven PTH stimulation
• Active vitamin D analogues (calcitriol, paricalcitol, doxercalciferol) — suppress PTH directly; limited by risk of hypercalcemia/hyperphosphatemia
• Calcimimetics (cinacalcet or etelcalcetide) — preferred when PTH is the primary concern

Summary: Surgical vs. Non-Surgical Decision

Symptomatic OR meets any surgical criterion?
    YES → Parathyroidectomy (98% curative)
    NO  → Active surveillance ± medical therapy

Medical therapy goals:
  Reduce calcium     → Cinacalcet
  Protect bone       → Bisphosphonate (alendronate)
  Both               → Cinacalcet + Alendronate combination
  Vitamin D deficient → Cholecalciferol (cautious replacement)