Hyperparathyroidism

Aka: Hyperparathyroidism, Primary Hyperparathyroidism

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II. Epidemiology

  1. Primary Hyperparathyroidism is the most common cause of Hyperparathyroidism and mild Hypercalcemia
    1. Often found in asymptomatic patients with a incidental High Serum Calcium
  2. Prevalence
    1. Women: 2-3 cases per 1000 women over age 65 years
    2. Men: 1 case per 1000 men over age 65 years
  3. Ages
    1. Range: 40-70 years old
    2. Mean: 55 years old

III. Pathophysiology

  1. Overactive Parathyroid Glands (>=1 of 4 glands)
  2. Produce excessive Parathyroid Hormone (PTH)
  3. Results in disorder of bone metabolism

IV. Causes: Primary Hyperparathyroidism

  1. Single Parathyroid Adenoma (82 to 85%)
  2. Parathyroid Gland Hyperplasia or hypertrophy (15%)
  3. Parathyroid Malignancy (rare, accounts for 0.5 to 3% of Primary Hyperparathyroidism)
    1. Presents with severe Hypercalcemia, cervical Neck Mass, Laryngeal Nerve Palsy
  4. Familial Hyperparathyroidism (10-20%): Younger patients
    1. Multiple Endocrine Neoplasia Type I (MEN I)
    2. Multiple Endocrine Neoplasia Type II (MEN II)
    3. Familial Hypocalciuric Hypercalcemia
    4. Hyperparathyroidism-Jaw Tumor Syndrome
    5. Neonatal severe Primary Hyperparathyroidism
  5. Other Parathyroid related causes
    1. Lithium Therapy
    2. External neck radiation exposure
    3. Neck surgery with Parathyroid injury or resection
  6. Tertiary Hyperparathyroidism
    1. Accelerated response to chronic Hypocalcemia (in advanced Renal Failure)
    2. Parathyroid over-produces PTH causing Hypercalcemia

V. Causes: Secondary Hyperparathyroidism

  1. Vitamin D Deficiency
  2. Decreased Calcium intake
  3. Renal Osteodystrophy
    1. Chronic Kidney Disease stage 4 or stage 5 and
    2. Decreased 1,25 dihydroxyvitamin D
    3. Hyperphosphatemia
    4. Hypocalcemia
  4. Normocalcemic Hyperparathyroidism (associated with Osteoporosis)
    1. Diagnosis of exclusion after ruling-out Vitamin D Deficiency and Chronic Kidney Disease

VI. Symptoms

  1. See Hypercalcemia
  2. Asymptomatic Hypercalcemia (up to 80% of cases)

VII. Diagnosis

  1. Mnemonic (classic presentation is uncommon)
    1. Stones
    2. Bones
    3. Abdominal groans
    4. Psychic moans
  2. Constellation of findings
    1. See Hypercalcemia
    2. Calcium oxalate renal stones (Nephrolithiasis)
    3. Bony changes
      1. Osteitis fibrosa
      2. Salt and pepper skull
      3. Bone resorption
    4. Acute Pancreatitis
    5. Psychosis and depression

VIII. Labs

  1. See Hypercalcemia for evaluation protocol
  2. Parathyroid Hormone (PTH) Level elevated
    1. Measure Intact PTH
    2. See Parathyroid Hormone for algorithm
  3. Serum Electrolyte abnormalities
    1. Hypercalcemia (Use Corrected Serum Calcium for Serum Albumin or Ionized Calcium)
      1. Draw Fasting with minimal Occlusion
      2. Discontinue Thiazide Diuretics for 2 weeks before
      3. Repeat serum testing in 2 weeks if normal
    2. Hyperchloremia
    3. Hypophosphatemia
    4. Hypokalemia
  4. Urine Calcium
    1. Hypercalciuria (24 hour Urine Calcium and Urine Creatinine)
    2. If Urine Calcium low, consider Familial Hypocalciuric Hypercalcemia (rare) instead
  5. Renal Function tests
    1. Serum Creatinine
  6. Miscellaneous
    1. 25 Hydroxyvitamin D
    2. 1,25 Dihydroxyvitamin D3
    3. Genetic Testing indications
      1. CASR Gene Mutation
      2. Primary Hyperparathyroidism in age <40 years
      3. Familial Hypocalciuric Hypercalcemia
      4. Multiglandular disease (multiple Parathyroid Glands involved)
      5. Multiple Endocrine Neoplasia

IX. Imaging: Primary Hyperparathyroidism

  1. Classic XRay Findings
    1. Skull XRay
      1. "Salt and pepper" skull
    2. Chest XRay
      1. Distal Clavicle resorption
    3. Hand XRay
      1. Second and third middle phalange bone resorption
    4. Dental XRay
      1. Bone resorption of Lamina dura around teeth
  2. Sestamibi Technetium Tc 99mParathyroid Scan
    1. Test Sensitivity for localizing adenoma: 95%
    2. Causes of non-localizing scan
      1. Ectopic PTH production
      2. Diagnostic error
      3. Four-gland hyperplasia
  3. End-organ evaluation
    1. Renal Ultrasound
    2. Bone Densitometry (DEXA Scan, Bone Mineral Density)
      1. Lumbar Spine
      2. Hip
      3. Forearm

X. Differential Diagnosis

  1. See Hypercalcemia
  2. Familial Benign Hypocalciuric Hypercalcemia
    1. Does not improve with surgery, unlike primary disease
    2. Calcium to Creatinine ratio <0.01

XI. Management: Medical for Primary Hyperparathyroidism

  1. See Renal Osteodystrophy (Secondary Hyperparathyroidism)
  2. Hypercalcemic Crisis (Serum Calcium >14 mg/dl)
    1. See Hypercalcemia for emergent management
  3. Indications for Non-surgical Management
    1. Asymptomatic patients without surgical indications
    2. Serum Calcium level only mildly increased
    3. No prior life-threatening Hypercalcemia
    4. Normal Renal Function
      1. Creatinine Clearance >70%
      2. No Nephrolithiasis
      3. No Nephrocalcinosis
    5. Normal Bone Mineral Density (Osteopenia or better)
  4. Avoid provocative factors
    1. Thiazide Diuretics (although may be used in Nephrolithiasis prevention as below)
    2. Avoid Lithium
    3. Avoid Volume depletion (maintain hydration)
    4. Avoid prolonged bedrest or inactivity
    5. Avoid High Calcium diet
  5. Encourage moderate Physical Activity
    1. Minimize bone resorption
  6. Encourage 64 ounces non-caffeinated fluid per day
    1. Minimize risk of Nephrolithiasis
  7. Encourage moderate Calcium intake (1000 mg/day)
    1. Low Calcium diet may surge Parathyroid Hormone
  8. Medications
    1. Calcium Lowering Therapy
      1. See Hypercalcemia for emergent Calcium lowering
      2. Calcimimetics
        1. Cinacalcet (Senispar)
        2. Etelcalcetide (Parsabiv)
    2. Reduce bone resorption and increase Bone Mineral Density
      1. Hormonal Therapy in Women (Postmenopausal)
        1. Estrogen Replacement
        2. Selective Estrogen Receptor Modulators (SERM)
      2. Bisphosphonates
        1. Alendronate (Fosamax)
        2. Pamidronate
        3. Risedronate
        4. Zoledronic Acid
      3. Vitamin D Supplementation (400 to 800 IU/day, keep Vitamin D levels >20-30 ng/ml)
        1. Cholecalciferol (Vitamin D3)
        2. Ergocalciferol (Vitamin D2)
      4. Monoclonal Antibody
        1. Denosumab (also used in Hypercalcemic Crisis to emergently lower Serum Calcium)
    3. Nephrolithiasis Prevention
      1. Thiazide Diuretics (Chlorthalidone, Hydrochlorothiazide)
        1. Decreases urinary Calcium and may reduce Nephrolithiasis risk
  9. Monitoring of medically managed patients
    1. Every 12 month labs
      1. Serum Calcium
      2. Serum Creatinine with estimated GFR
      3. Other annual testing if history or Nephrolithiasis
        1. 24 hour Urine Calcium and Urine Creatinine
        2. Renal imaging
    2. Every 1-2 years
      1. Bone Density (DEXA Scan)

XII. Management: Surgery (Parathyroidectomy) for Primary Hyperparathyroidism

  1. Precautions
    1. Re-evaluate on a periodic basis
    2. Up to 15% of originally asymptomatic Hyperparathyroidism cases develop a surgical indication within 4.7 years
      1. Yu (2011) QJM 104(6): 513-21 [PubMed]
  2. Indications in Primary Hyperparathyroidism
    1. Serum Calcium >12 mg/dl (or >1 mg/dl above the upper limit of normal)
    2. Hypercalcemic Crisis (Serum Calcium >14 mg/dl)
    3. Hypercalciuria (24 hour Urine Calcium >400 mg/dl/day)
    4. Osteoporosis (or T-Score <-2.5 at hip, spine or wrist)
    5. Osteitis fibrosa cystica
    6. Nephrolithiasis (including Incidental Imaging Findings)
    7. Nephrocalcinosis
    8. Young patient age (e.g. age <50 years)
    9. Exacerbating factors
      1. Dehydration
      2. Immobile patient
    10. Creatinine Clearance <60 ml/min/1.73m2 or 30% below age-matched peers
    11. Persistent symptomatic Hypercalcemia (esp. neuromuscular)
  3. Efficacy
    1. Successful in up to 95% of cases
    2. Few complications (up to 3.6% risk of Hypoparathyroidism)
    3. Normalizes PTH and Calcium levels
    4. Decreases Nephrolithiasis risk
    5. Decreases risk of worsening Renal Function
    6. Improves Bone Mineral Density
  4. Single Parathyroid Adenoma
    1. Surgery to locate and remove adenoma
    2. Biopsy a second gland to rule out atrophy
  5. Parathyroid hyperplasia or hypertrophy
    1. Remove 3.5 glands
    2. Autotransplant tissue into arm Muscle

XIII. Complications

  1. See Hypercalcemia
  2. Untreated Primary Hyperparathyroidism
    1. Increased mortality
    2. Increased risk of cardiovaascular disease and Cerebrovascular Disease
    3. Increased risk of Nephrolithiasis and Renal Failure
    4. Increased Osteoporosis risk with decreased Bone Mineral Density

XIV. References

  1. Spiegel in Goldman (2000) Cecil Medicine, p. 1402-5
  2. (1991) Ann Intern Med 114:593-7 [PubMed]
  3. Bilezikian (2002) J Clin Endocrinol Metab 87:5353-61 [PubMed]
  4. Khan (2017) Osteoporos Int 28(1): 1-19 [PubMed]
  5. Sell (2022) Am Fam Physician 105(3): 289-98 [PubMed]
  6. Taniegra (2004) Am Fam Physician 69(2):333-40 [PubMed]
  7. Michels (2013) Am Fam Physician 88(4): 249-57 [PubMed]

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