> Table of Contents > Hyperparathyroidism
Hyperparathyroidism
Aleta Paschal, MD
Cassandra White, MD
image BASICS
DESCRIPTION
A dysfunction of the body's normal regulatory feedback mechanisms resulting in excess production of parathyroid hormone (PTH)
  • Primary hyperparathyroidism (HPT): intrinsic parathyroid gland dysfunction resulting in excessive secretions of PTH with a lack of response to feedback inhibition by elevated calcium
  • Secondary HPT: excessive secretion of PTH in response to hypocalcemia, which can be caused by vitamin D deficiency or renal failure
  • Tertiary HPT: autonomous hyperfunction of the parathyroid gland in the setting of long-standing secondary HPT
EPIDEMIOLOGY
Incidence
Predominant sex: female > male (2:1)
Prevalence
Primary HPT: 1/1,000 in the United States
ETIOLOGY AND PATHOPHYSIOLOGY
  • PTH is synthesized by the four parathyroid glands, which are located behind the four poles of the thyroid gland (locations can vary).
  • Ectopic (abnormal locations and most common is the thymus) or supernumerary glands (more than four glands) (1)
  • Blood supply: inferior thyroid artery
  • PTH releases calcium from bone by osteoclastic stimulation (bone resorption).
  • PTH increases reabsorption of calcium in the distal tubules of the kidneys.
  • PTH stimulates conversion of 25-hydroxycholecalciferol (25[OH]D) to 1,25-dihydroxycholecalciferol (1,25[OH]2D or active vitamin D) in the kidneys.
    • 1,25(OH)2D increases calcium absorption from the GI tract, increases calcium and phosphate reabsorption in the kidneys, and stimulates osteoclastic activity and bone resorption.
  • Primary HPT: unregulated PTH production and release, causing increase in serum calcium
    • Solitary adenoma (89%)
    • Double adenomas (5%)
    • Diffuse hyperplasia (6%) caused by multiple adenomas, multiple endocrine neoplasia (MEN) types 1 and 2a, and familial hypocalciuric hypercalcemia
    • Parathyroid carcinoma (<2%)
  • Secondary HPT: adaptive parathyroid gland hyperplasia and hyperfunction
    • Dietary: vitamin D or calcium deficiency
    • Chronic renal disease resulting in the following:
      • Renal parenchymal loss causing hyperphosphatemia
      • Impaired calcitriol production causing hypocalcemia
      • General skeletal and renal resistance to PTH
  • Tertiary HPT: autonomous oversecretion of PTH following prolonged parathyroid stimulation
Genetics
  • MEN types 1 and 2a: Patients with multiple gland hyperplasia in the absence of renal disease should be screened for MEN-1 gene mutation.
  • Neonatal severe primary HPT
  • HPT—jaw tumor syndrome
  • Familial hypocalciuric hypercalcemia (FHH): autosomal dominant
  • Familial isolated HPT
RISK FACTORS
Chronic kidney disease, increasing age, poor nutrition, radiation, and/or family history
GENERAL PREVENTION
Adequate intake of calcium and vitamin D may help prevent secondary HPT.
COMMONLY ASSOCIATED CONDITIONS
  • MEN syndromes types 1 and 2a
  • Chronic renal failure
image DIAGNOSIS
PHYSICAL EXAM
Limited usefulness; 70-80% of patients have no obvious symptoms or signs of disease.
  • Physical findings may found related to underlying cause of HPT.
DIFFERENTIAL DIAGNOSIS
  • Increased PTH: ectopic PTH production
  • Nonparathyroid causes
    • Malignancy: lung (squamous cell) carcinoma, breast carcinoma, multiple myeloma, lymphoma, leukemia, prostate cancer, Paget disease
    • Granulomatous disease: sarcoidosis, tuberculosis, berylliosis, histoplasmosis, coccidioidomycosis
    • Drugs: thiazide diuretics, vitamin D intoxication, vitamin A excess, lithium, milk-alkali syndrome, exogenous calcium intake
    • Endocrine: hyperthyroidism, acute adrenal insufficiency
    • Familial: hypocalciuric hypercalcemia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Disease is often detected by an incidental finding of hypercalcemia.
  • Order serum calcium level and albumin
    • Calculate serum calcium on 2 occasions using: (0.8 × [Normal Albumin - Pt's Albumin]) + Serum Ca. If corrected calcium is above your lab's normal range (normally >2.65 mmol/L), consider this true hypercalcemia which is consistent with hyperparathyroidism.
  • If hypercalcemia is confirmed, follow with intact PTH level (2)[B].
    • High PTH (>3.0 pmol/L) suggests primary HPT.
    • Low PTH (<3.0 pmol/L) suggests non-PTH-mediated hypercalcemia.
  • If elevated calcium is inconsistent, elevated ionized serum calcium in the setting of high PTH confirms diagnosis. Other findings may include low serum phosphate, elevated serum chloride, decreased serum CO2, and abnormal 24-hour urine calcium excretion.
  • Normocalcemic primary HPT found in 2009; consistent with normal calcium, low bone mineral density, and elevated PTH(must r/o secondary HPT) (3)
  • In secondary HPT, an elevated phosphorus suggests chronic renal failure; a low phosphorus suggests another cause, most commonly vitamin D deficiency.
Follow-Up Tests & Special Considerations
  • A 24-hour urine calcium concentration to creatinine clearance ratio >0.02 suggests primary HPT; a ratio <0.01 may be normal or indicate FHH; important because FHH does not require surgery (2)[C]
  • Routine measurement of 25(OH)D levels is recommended in all patients with primary HPT. In case of vitamin D deficiency (<20 ng/mL or <50 nmol/L), defer management decisions until levels are maintained >20 ng/mL (50 nmol/L) (4)[C].
  • Intraoperative measurement of intact PTH and/or &ggr;-probe localization of abnormal glands with technetium-99m sestamibi scan has aided focused resections for patients with single-gland etiology (5)[C].
  • Screening for kidney stones is not recommended in patients without a history of nephrolithiasis (5)[B].
Diagnostic Procedures/Other
  • Consider EKG to assess for short QT interval.
  • Imaging is not required for diagnosis. It is required for surgical planning, especially for minimally invasive parathyroidectomy (MIP) (6)[C].
    • Imaging is also indicated to localize hyperplasia or an ectopic parathyroid gland in repeat surgery.
  • Imaging options for presurgical localization
    • Technetium-99m sestamibi with single-photon emission computed tomography (SPECT)
      • Has had the greatest reported success in localizing single parathyroid adenomas (7)[B]
    • US
      • Painless, noninvasive, inexpensive, and does not expose the patient to radiation; however, its accuracy is very operator-dependent (8)[C].
    • P.513

    • Positron emission tomography (PET) using C-methionine (MET-PET) is comparable to US and technetium-99m sestamibi with SPECT in terms of diagnostic use (6)[B].
    • Four-dimensional CT (4D-CT) may be more effective for primary localization than both US and sestamibi-SPECT (9)[B].
    • CT and MRI are mostly used to localize ectopic mediastinal glands.
    • Comprehensive cervical US (CCU) used for further localization following a negative sestamibi scan often reveals a single adenoma (10)[C].
      • A negative sestamibi scan likely indicates parathyroid hyperplasia/multiglandular disease and thus requires open neck exploratory surgery.
      • CCU after negative sestamibi result allows more patients who were previously excluded to be candidates for MIP.
image TREATMENT
MEDICATION
  • Primary HPT: Operative management is curative. For those awaiting or unable to have surgery
    • Bisphosphonates (alendronate): reduces bone turnover and helps to maintain bone density; avoid in kidney disease.
    • Calcimimetics (cinacalcet): Further studies needed to establish long-term benefit in primary HPT.
    • Selective estrogen receptor modulator therapy (raloxifene)
    • Hormone replacement therapy with estrogens is not recommended as first-line treatment; must weigh benefit with risks of known systemic effects
      • Can be used in postmenopausal women who do not undergo or refuse surgery
  • Secondary HPT
    • Calcium replacement
    • Vitamin D analogues (paricalcitol and calcitriol)
    • Phosphorus-binding agents (sevelamer)
    • Calcimimetic (cinacalcet) (2,11)[A]: activates calcium-sensing receptor in parathyroid gland thereby inhibiting PTH secretion
  • Tertiary HPT
    • Medical treatment is not curative and generally not indicated.
SURGERY/OTHER PROCEDURES
  • Operative management is curative for patients with primary HPT in 95-98% of patients.
  • Indications for parathyroidectomy
    • Symptomatic primary HPT
      • Nephrolithiasis
      • Nephrocalcinosis
      • Osteitis fibrosa cystica
    • Asymptomatic primary HPT
      • Serum Ca+ level >1 mg/dL above normal
      • Age <50 years
      • GFR <60 mL/min/1.73 m2 or creatinine clearance reduced to <60 mL/min
      • Bone density loss with a T score ≤ -2.5 at the lumbar spine, femoral neck, total hip, or 33% radius
  • Tertiary HPT
  • Surgical removal of diseased gland or tissue is only proven curative therapy for HPT.
  • Surgical options include the following:
    • Bilateral open neck exploratory surgery
    • MIP using preoperative sestamibi scan with SPECT/US and intraoperative PTH levels (high sensitivity 79-95% to predict location of single parathyroid adenoma) (11) which result in decreased pain, smaller incisions, improved cosmetic results, lower morbidity, and decreased length of hospital stay when compared with open neck exploratory surgery.
  • Follow postoperative serum calcium level (hypocalcemia in “hungry bone” syndrome); patients also at risk for bleeding and airway compromise; keep injectable calcium and seizure medications at bedside.
  • Monitor renal function closely.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Critical hypercalcemia requires IV fluid rehydration, IV bisphosphonate therapy, and SC calcitonin (4 U/kg q12h) for severe symptoms.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Asymptomatic patients with primary HPT require serial monitoring of calcium and PTH.
Patient Monitoring
In patients with primary HPT who are asymptomatic, measurements of serum calcium and creatinine annually and bone density scan every 1 to 2 years is sufficient.
DIET
  • In the presence of hypercalciuria or elevated 1,25(OH)2D levels, dietary calcium restriction is recommended. Otherwise, daily calcium intake should be maintained at up to 1,000 mg.
  • Restrict dietary phosphate in secondary HPT.
PATIENT EDUCATION
  • Importance of periodic lab testing
  • Signs of severe hypercalcemia
PROGNOSIS
Prognosis after surgery is excellent in primary HPT, with resolution of many of the preoperative symptoms.
REFERENCES
1. Bliss RD, Gauger PG, Delbridge LW. Surgeon's approach to the thyroid gland: surgical anatomy and the importance of technique. World J Surg. 2000;24(8):891-897.
2. Fraser WD. Hyperparathyroidism. Lancet. 2009;374(9684):145-158.
3. Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92(8):3001-3005.
4. Eastell R, Arnold A, Brandi ML, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2):340-350.
5. Bilezikian JP, Khan AA, Potts JT Jr, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.
6. Caldarella C, Treglia G, Isgrò MA, et al. Diagnostic performance of positron emission tomography using 11C-methionine in patients with suspected parathyroid adenoma: a meta-analysis. Endocrine. 2013;43(1):78-83.
7. Caldarella C, Treglia G, Pontecorvi A, et al. Diagnostic performance of planar scintigraphy using 99mTc-MIBI in patients with secondary hyperparathyroidism: a meta-analysis. Ann Nucl Med. 2012;26(10):794-803.
8. Udelsman R, Pasieka JL, Sturgeon C, et al. Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2):366-372.
9. Cheung K, Wang TS, Farrokhyar F, et al. A meta-analysis of preoperative localization techniques for patients with primary hyperparathyroidism. Ann Surg Oncol. 2012;19(2):577-583.
10. Kandil E, Malazai AJ, Alrasheedi S, et al. Minimally invasive/focused parathyroidectomy in patients with negative sestamibi scan results. Arch Otolaryngol Head Neck Surg. 2012;138(3):223-225.
11. Kunstman JW, Kirsch JD, Mahajan A, et al. Clinical review: parathyroid localization and implications for clinical management. J Clin Endocrinol Metab. 2013;98(3):902-912.
Codes
&NA;
ICD10
  • E21.3 Hyperparathyroidism, unspecified
  • E21.0 Primary hyperparathyroidism
  • E21.1 Secondary hyperparathyroidism, not elsewhere classified
Clinical Pearls
&NA;
  • 50% of patients with primary HPT are asymptomatic.
  • HPT is often detected by an incidental finding of hypercalcemia on a routine serum chemistry analysis.
  • Classic symptoms of hypercalcemia include painful bones, renal stones, abdominal pains, and behavioral changes (“stones, bones, moans, and groans”).
  • Repeat calcium (elevated), correct for serum albumin, and obtain intact PTH levels to make an initial diagnosis.
  • The two most commonly used imaging modalities in HPT are technetium-99m sestamibi scan and US.
  • Surgery is curative for most cases of primary HPT.