hyperparathyroidism

Etiology

• primary hyperparathyroidism
  • most common cause of hypercalcemia in ambulatory patients
  • hyperfunctioning solitary parathyroid adenoma (80%)
  • parathyroid carcinoma
  • multiple endocrine neoplasia-1 (MEN1)
    • hyperparathyoidism is the most common manifestation of MEN1
  • multiple endocrine neoplasia-2A (MEN2A)
  • hypercalcemia in ambulatory patient taking thiazide diuretic
• secondary hyperparathyroidism
  • renal failure is associated with a high phosphorus & low calcium & stimulates PTH production
  • diminished Ca+2 absorption stimulates PTH secretion
    • vitamin D deficiency
    • malabsorption syndromes
• tertiary hyperparathyroidism
  • in renal failure, PTH secretion may become independent of serum Ca+2
  • ectopic secretion of PTH by non-parathyroid tumors (rare)
• risk factor
  • low calcium diet may induce production of PTH, thus promote formation of parathyroid adenomas

Epidemiology

• 2-4 times more common in women than men
• increased incidence after age 50
• incidence of 30/100,000 in USA
• most common cause of hypercalcemia in outpatients

Genetics

• familial forms associated with mutations in parafibromin gene

History

• psychiatric disease, lithium carbonate use
• thiazide diuretic use
• calcium supplementation, vitamin D supplementation

Clinical manifestations

• often asymptomatic, detected during routine laboratory screening
• general: weakness, fatigue
• musculoskeletal:
  • bone tenderness/pain
  • arthralgia/ joint effusion
  • soft tissue calcification
  • osteitis fibrosa cystica (uncommon)
  • osteopenia, osteoporosis
• neurologic: memory impairment, confusion, depression
• GI: nausea/vomiting, peptic ulcer, constipation
• GU: renal colic (nephrolithiasis), polyuria
• abdominal pain
• hypertension
• corneal bands
• pseudogout (calcium pyrophosphate dihydrate deposition)
• 'stones, bones & moans' a mneumonic developed in the 1930's by Fuller Albright
• symptoms do not correlate with degree of hypercalcemia

Laboratory

• hypercalcemia: serum calcium is generally < 12 mg/dL
• increased serum ionized calcium (unnecessary if serum albumin is normal)
• elevated intact parathyroid hormone (fasting) (< 5X normal)
  • may be inappropriately normal in patient with hypercalcemia
    • upper 1/2 of reference interval
• mild to moderate decrease in serum phosphate
• serum chloride: chloride:phosphate ratio is generally > 33:1 (need to use same units for chloride & phosphorus)
• non anion gap metabolic acidosis
• azotemia may be observed
• urinalysis (24-hour urine calcium)*
  • increased urinary excretion of Ca+2 & phosphate (24 hour urinary Ca+2 > 4 mg/kg or > 200 mg/day is significant)
  • increased biochemical markers of bone turnover
    • osteocalcin
    • collagen-cross-linked peptides
    • alkaline phosphatase derived from bone
  • diminished urinary excretion of Ca+2 suggests
    • vitamin D deficiency
    • malabsorption syndrome
    • familial hypocalciuric hypercalcemia
• serum 25-hydroxyvitamin D3 (all patients)
  • 50% of patients with primary hyperparathyroidism have coexisting vitamin D deficiency
    • hypocalcemia, hypophosphatemia, & increased serum PYH may be due to secondary to vitamin D deficiency (GRS11)
    • severe vitamin D deficiency if prolonged may lead to osteomalacia
  • target serum 25-hydroxyvitamin D3: > 30 ng/dL
• serum 1,25 dihydroxyvitamin D level may be high

* rule out secondary causes of secondary hyperparathyroidism including familial hypocalciuric hypercalcemia, idiopathic hypercalciuria & absorptive hypercalciuria before diagnosing hyperparathyroidism

Radiology

• routine radiographs rarely helpful unless symptomatic
  • chondrocalcinosis
  • subperiosteal bone resorption of the digits & sternoclavicular joints
  • osteitis fibrosa cystica (bone cysts)
  • renal calcifications
  • pathologic fractures
  • osteolytic "brown tumor" (rare)
• bone density measurement
  • osteoporosis generally manifests at cortical sites
  • assessment of the distal forearm or hip better than the lumbar spine
    • include distal 3rd of radius
• imaging procedures to localize the parathyroid glands
  • if indications for parathyroidectomy (see Management: below
  • ultrasound (lacks sensitivity)
  • computed tomography
  • magnetic resonance imaging (MRI)
  • choline PET-CT is the best preoperative imaging modality for localization of primary hyperparathyroidism
  • thallium scan or technetium-99m sestamibi scan
  • angiography
  • selective venous catheterization with intact PTH measurement to localize parathyroid gland

Complications

• nephrolithiasis
• hypertension
• osteoporosis (bone fractures)
• band keratopathy

Differential diagnosis

(see also hypercalcemia)

• primary vs secondary vs tertiary hyperparathyroidism
• hypercalcemia of malignancy
• familial hypocalciuric hypercalcemia
  • generally normal PTH, but may be elevated
  • low urinary calcium
• granulomatous disease may be associated with hypercalcemia with suppressed serum PTH
  • tuberculosis
  • sarcoidosis

Management

medical management

• criteria
  • contraindications to surgery (surgery generally treatment of choice)
  • serum Ca+2 < 11.5 mg/dL
  • compliance with regular follow-up
  • bone density should be normal
  • no evidence of renal insufficiency
  • frail elderly
• semiannual follow-up
  • blood pressure
  • serum calcium
  • bone mass
• avoid dehydration, immobilization & thiazide diuretics
• bisphosphonates 1st line therapy if osteoporosis or meets FRAX criteria for treatment
  • may temporarily mitigate effects of excess PTH on bone loss
  • prolonged efficacy has not been demonstrated
  • increases bone mineral density, but also increases risk of hip fracture in primary hyperparathyroidism relative to observation (RR=1.5)
• postmenopausal women
  • estrogen therapy
  • selective estrogen receptor modulators (SERMs)
  • progestins
• cinacalcet (Sensipar) for patients who decline surgery & not at risk for fracture
  • expensive, mulitple drug interactions
• treat vitamin D deficiency
  • target serum 25-hydroxyvitamin D3 > 30 ng/dL
  • calcitriol for secondary hyperparathyroidism due to chronic renal failure
• treat hyperphosphatemia in patients with chronic renal failure (1st line)
  • sevelamer rather than calcium carbonate

parathyroidectomy

• treatment of choice
  • underutilized in the elderly
• indications (or logic, any of the following)
  • age < 50 years
  • serum calcium > 11.0 mg/dL; > 11.5 mg/dL
    • >= 1 mg/dL higher than upper limit of normal
  • osteoporosis
    • T-score <= -2.5 at hip, lumbar spine, or distal radius
  • minimal trauma fracture
  • nephrolithiasis
  • 24-hour urine calcium > 400 mg
  • elevated serum creatinine
    • creatinine clearance < 60 mL/min
  • GERD or peptic ulcer disease
  • significant bone, renal, GI or neuromuscular symptoms
  • previous episodes of hypercalcemic crisis
• preserves bone density in patients with mild hyperparathyroidism
• minimally invasive surgery
  • may be treatment of choice if imaging suggests solitary adenoma
  • excision of adenoma through a small unilateral incision with the patient under local cervical block anesthesia
  • may be combined with rapid serum PTH assays
    • intraoperatively assess success of surgery
    • serum PTH levels diminish within minutes after excision of PTH-secreting adenoma
• otherwise,surgical exploration requires identification of all 4 parathyroid glands
• in 4 gland hyperplasia (MEN syndromes), 3 glands are removed & portions of the 4th are implanted in the forearm
• glands may be aberrant in location, especially within the thyroid or mediastinal in location
• initial success of surgery is about 90%
• complications of surgery
  • vocal cord paralysis (recurrent laryngeal nerve)
  • hypocalcemia
    • inadvertant removal of all 4 parathyroid glands
    • hungry bone syndrome
  • hematoma formation
• surgical follow-up
  • hypocalcemia & tetany
  • flare-ups of gout & pseudogout
  • decreased renal function
  • monitor serum calcium
  • recurrent hyperparathyroidism implies previously undiagnosed hyperplasia or carcinoma
• repeat surgeries difficult due to scar tissue & higher likihood of ectopic thyroid tissue

familial form

• periodic monitoring of family members
• genetic screening for MEN syndromes is available

More general terms

• parathyroid disease
• bone disease; osteopathia
• sign/symptom

More specific terms

• osteitis fibrosa cystica; von Recklinghausen's disease of bone
• primary hyperparathyroidism
• secondary hyperparathyroidism
• tertiary hyperparathyroidism

Additional terms

• hypercalcemia
• hypoparathyroidism
• multiple endocrine neoplasia (MEN)

Patient information

hyperparathyroidism patient information

Database

• OMIM: https://mirror.omim.org/entry/145000
• OMIM: https://mirror.omim.org/entry/145001
• OMIM: https://mirror.omim.org/entry/239200
• OMIM: https://mirror.omim.org/entry/607393