Hyperparathyroidism

See Also

Epidemiology

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

Pathophysiology

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

Causes
Primary Hyperparathyroidism

Single Parathyroid Adenoma (82 to 85%)
Parathyroid Gland Hyperplasia or hypertrophy (15%)
Parathyroid Malignancy (rare, accounts for 0.5 to 3% of Primary Hyperparathyroidism)
1. Presents with severe Hypercalcemia, cervical Neck Mass, Laryngeal Nerve Palsy
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
Other Parathyroid related causes
1. Lithium Therapy
2. External neck radiation exposure
3. Neck surgery with Parathyroid injury or resection
Tertiary Hyperparathyroidism
1. Accelerated response to chronic Hypocalcemia (in advanced Renal Failure)
2. Parathyroid over-produces PTH causing Hypercalcemia

Causes
Secondary Hyperparathyroidism

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

Symptoms

See Hypercalcemia
Asymptomatic Hypercalcemia (up to 80% of cases)

Diagnosis

Mnemonic (classic presentation is uncommon)
1. Stones
2. Bones
3. Abdominal groans
4. Psychic moans
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

Labs

See Hypercalcemia for evaluation protocol
Parathyroid Hormone (PTH) Level elevated
1. Measure Intact PTH
2. See Parathyroid Hormone for algorithm
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
Urine Calcium
1. Hypercalciuria (24 hour Urine Calcium and Urine Creatinine)
2. If Urine Calcium low, consider Familial Hypocalciuric Hypercalcemia (rare) instead
Renal Function tests
1. Serum Creatinine
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

Imaging
Primary Hyperparathyroidism

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
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
End-organ evaluation
1. Renal Ultrasound
2. Bone Densitometry (DEXA Scan, Bone Mineral Density)
  1. Lumbar Spine
  2. Hip
  3. Forearm

Differential Diagnosis

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

Management
Medical for Primary Hyperparathyroidism

See Renal Osteodystrophy (Secondary Hyperparathyroidism)
Hypercalcemic Crisis (Serum Calcium >14 mg/dl)
1. See Hypercalcemia for emergent management
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)
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
Encourage moderate Physical Activity
1. Minimize bone resorption
Encourage 64 ounces non-caffeinated fluid per day
1. Minimize risk of Nephrolithiasis
Encourage moderate Calcium intake (1000 mg/day)
1. Low Calcium diet may surge Parathyroid Hormone
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
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)

Management
Surgery (Parathyroidectomy) for Primary Hyperparathyroidism

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]
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)
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
Single Parathyroid Adenoma
1. Surgery to locate and remove adenoma
2. Biopsy a second gland to rule out atrophy
Parathyroid hyperplasia or hypertrophy
1. Remove 3.5 glands
2. Autotransplant tissue into arm Muscle

Complications

See Hypercalcemia
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

References

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