Hyperparathyroidism

Essentials of Diagnosis

• Often found incidentally by routine blood testing.

• Renal calculi, polyuria, hypertension, constipation, fatigue, mental changes.

• Bone pain; rarely, cystic lesions and pathologic fractures.

• Elevated serum PTH, serum and urine calcium, and urine phosphate

• Serum phosphate low to normal

• Alkaline phosphatase normal to elevated

General Considerations

• Primary hyperparathyroidism

  • PTH hypersecretion usually due to parathyroid adenoma, less commonly, to hyperplasia or carcinoma (rare)

  • If age < 30 years, higher incidence of multiglandular disease (36%) and parathyroid carcinoma (5%) responsible for hyperparathyroidism

• Secondary or tertiary hyperparathyroidism

  • Chronic kidney disease (CKD): hyperphosphatemia and diminished renal vitamin D production decrease serum ionized calcium, thus stimulating the parathyroids

  • Renal osteodystrophy: bone disease of secondary hyperparathyroidism and CKD

• Multiple endocrine neoplasia (MEN)

  • Hyperparathyroidism is familial in about 5–10% of cases; parathyroid hyperplasia may arise in MEN types 1, 2A, and 2B

  • In MEN 1, multiglandular hyperparathyroidism is usually the initial manifestation and ultimately occurs in over 90% of affected individuals

  • Hyperparathyroidism in MEN 2A is less frequent than in MEN 1 and is usually milder

• Hyperparathyroidism-jaw tumor syndrome: a familial autosomal dominant condition with parathyroid adenomas or carcinomas that are associated with tumors of the jaw and renal lesions

• Familial isolated hyperparathyroidism: familial hyperparathyroidism without the characteristic extraparathyroid features of more complex hyperparathyroid syndromes

Demographics

• Most common cause of hypercalcemia, with a prevalence of 0.1 to 0.4% of the population

• Occurs at all ages but most commonly in the seventh decade and in women (74%)

• Before age 45, the prevalence is similar in men and women

• More prevalent in blacks, followed by whites, then other races

Symptoms and Signs

• Skeletal manifestations

  • Low bone density: most prominent at the distal third of the radius

  • Postmenopausal women are prone to asymptomatic vertebral fractures

  • Severe bone demineralization is uncommon in mild cases

  • Arthralgias and bone pain, particularly involving the legs, are more common than severe bone demineralization

  • Osteitis fibrosa cystica

    • Seen in severe chronic hyperparathyroidism

    • Calcified bone matrix is replaced with fibrous tissue forming cystic brown tumors of bone that can be palpable in the jaw

    • The skeleton become weaker with bowing of the long bones and pathologic fractures

• Hypercalcemia manifestations

  • Level of serum calcium or PTH may not reliably predict severity of symptoms

  • Mild cases may be asymptomatic or manifest significant symptoms, particularly

    • Depression

    • Constipation

    • Bone and joint pain

  • Neuromuscular manifestations

    • Paresthesias

    • Muscle cramps and weakness

    • Diminished deep tendon reflexes

  • Neuropsychiatric manifestations

    • Malaise, fatigue, insomnia

    • Headache

    • Irritability, depression

    • Cognitive impairment can vary from intellectual weariness to more severe disorientation, psychosis, or stupor

  • Cardiovascular manifestations

    • Hypertension

    • Palpitations

    • Prolonged P-R interval, shortened Q-T interval

    • Bradyarrhythmias, heart block, asystole

    • Sensitivity to digitalis

  • Renal manifestations

    • Polyuria and polydipsia

    • Calcium-containing renal calculi

  • Gastrointestinal symptoms

    • Anorexia, nausea, vomiting

    • Heartburn

    • Abdominal pain

    • Weight loss

    • Constipation, obstipation

    • Pancreatitis (occurs in 3%)

  • Dermatologic symptoms: Pruritus

• Normocalcemic primary hyperparathyroidism

  • Patients generally have few symptoms or very subtle symptoms, such as mild fatigue, that may not be appreciated as abnormal

  • Usually slightly atherogenic lipid panel

  • Higher blood pressures (typically systolic blood pressure 10 mm Hg higher and diastolic blood pressure 7 mm Hg higher) than controls

• Pregnancy

  • Mild maternal hyperparathyroidism

    • Serum calcium < 11.0 mg/dL (< 2.75 mmol/L)

    • Women generally tolerate pregnancy well and have normal outcomes

  • Severe maternal hypercalcemia can cause complications

    • Nephrolithiasis

    • Hyperemesis

    • Pancreatitis

    • Muscle weakness

    • Cognitive changes

    • Hypercalcemic crisis, especially postpartum

    • Preelampsia; about 30% of affected women have preeclampsia and two-thirds of eclamptic women have preterm delivery

    • Fetal effects; about 80% of fetuses have fetal demise, preterm delivery, or low birth weight

• Presence of a large neck mass, or vocal fold paralysis from recurrent laryngeal nerve palsy, raises concern for parathyroid carcinoma

Differential Diagnosis

• Artefactual hypercalcemia

• Hypercalcemia of malignancy

• Plasma cell myeloma

• Vitamin D intoxication

• Granulomatous diseases (sarcoidosis, tuberculosis)

• Familial benign hypocalciuric hypercalcemia

• Immobilization

• Hyperthyroidism

• Vitamin D deficiency (serum 25-OH vitamin D < 20 ng/mL) can cause high serum PTH with normal serum calcium

• High-dose corticosteroid therapy in patients taking thiazide diuretics

• Hypercalcemia due to other conditions (eg, milk-alkali syndrome)

Laboratory Tests

• In hyperparathyroidism, hallmark finding is serum adjusted total calcium > 10.5 mg/dL

• Elevated or high-normal PTH confirms the diagnosis; immunoradiometric assay (IRMA) for PTH is most specific and sensitive

• Serum phosphate is often < 2.5 mg/dL

• Serum phosphate is high in secondary hyperparathyroidism (CKD)

• Serum ionized calcium levels are elevated (above 1.36 mmol/L)

• Urine calcium excretion is normal (100–300 mg/day [25–75 mmol/day])

• Urine phosphate is high despite low to low normal serum phosphate

• Serum alkaline phosphatase is elevated only if bone disease present

• A serum calcium:phosphate (Ca/P) ratio above 2.5 (mg/dL) or above 2.17 (mmol/L) helps confirm the diagnosis of primary hyperparathyroidism

• Plasma chloride and uric acid may be elevated

• Screen for familial benign hypocalciuric hypercalcemia with 24-h urine for calcium and creatinine. Discontinue thiazide diuretics prior to urine collection

Imaging Studies

• Ultrasound of the neck

  • Should be performed with a high-resolution transducer (5–15 MHz) and should scan the neck from the mandible to the superior mediastinum in an effort to locate ectopic parathyroid adenomas

  • Has a sensitivity of 79% for single adenomas but only 35% for multiglandular disease

• Sestamibi scintigraphy can help locate parathyroid adenomas preoperatively

• CT and MRI are not usually required prior to a first neck surgery

  • However, 4-dimensional CT has been developed and is useful for preoperative imaging in patients who have had prior neck surgery and in those with ectopic glands

  • MRI may also be useful for repeat neck operations and when ectopic parathyroid glands are suspected; it does not deliver radiation and shows better soft tissue contrast than CT

• Noncontrast-enhanced CT scanning of the kidneys is recommended for all patients to determine whether calcium-containing stones are present

• ¹⁸F-flurocholine PET/MRI

  • Useful scan for patients with primary hyperparathyroidism and negative or discordant localization imaging on neck ultrasound and sestamibi scanning

  • A small study showed the sensitivity of this scan to be 90% with a 100% positive predictive value

• Bone radiographs

  • Usually normal and not required

  • However, may show demineralization, subperiosteal bone resorption, loss of lamina dura of the teeth, cysts throughout skeleton, mottling of skull, or pathologic fractures

  • Articular cartilage calcification (chondrocalcinosis) is sometimes found

• In renal osteodystrophy, bone radiographs may show

  • Ectopic calcifications around joints or soft tissue

  • Osteopenia

  • Osteitis fibrosa

  • Osteosclerosis

• Bone densitometry of wrist, hip, and spine may reveal low bone mineral density

Diagnostic Studies

• Recommendations for genetic testing

  • Documented primary hyperparathyroidism

  • Age younger than age 40

  • Presence of multiglandular disease

  • Family history of hyperparathyroidism

Medications

• Bisphosphonates

  • Pamidronate, 30–90 mg (in 0.9% saline) intravenously over 2–4 hours

  • Zoledronate, 5 mg intravenously over 15–20 minutes; it is quite effective but also very expensive

  • Oral bisphosphonates, such as alendronate, are not effective for treating the hypercalcemia or hypercalciuria of hyperparathyroidism

  • However, oral alendronate has been shown to improve bone mineral density in the lumbar spine and hip (not distal radius) and may be used for asymptomatic patients with hyperparathyroidism who have a low bone mineral density

• Cinacalcet (calcium sensing receptor activator [CaSR])

  • Given to patients with severe hypercalcemia due to parathyroid carcinoma

    • Initial dose is 30 mg twice daily orally

    • Dose is increased progressively to 60 mg twice daily, then 90 mg twice daily, then to a maximum of 90 mg every 6–8 hours

  • Usually well tolerated but may cause nausea and vomiting, which are usually transient

• Etelcalcetide (CaSR)

  • Activates the parathyroid glands' CaSR

  • Reduces hypercalcemia in dialysis patients

  • Given intravenously at the end of hemodialysis sessions, thereby avoiding the gastrointestinal side effects of cinacalcet

• Vitamin D replacement, 800–2000 units daily for patients with vitamin D deficiency

• Calcitriol

  • Used in secondary and tertiary hyperparathyroidism associated with azotemia

  • Given orally or intravenously after dialysis, suppresses parathyroid hyperplasia of CKD

  • For patients with near-normal serum calcium levels, it is given orally in starting at doses of 0.25 mcg on alternate days or daily

• Doxercalciferol

  • Used in secondary or tertiary hyperparathyroidism associated with azotemia

  • Administer intravenously three times weekly during hemodialysis to patients with secondary hyperparathyroidism due to CKD

    • Starting dose: 4 mcg three times weekly to maximum dose of 18 mcg three times weekly

    • Alternatively, administered orally three times weekly at dialysis, starting with 10 mcg at each dialysis to a maximum of 60 mcg/wk

• Denosumab

  • Used in severe hypercalcemia due to parathyroid carcinoma

  • Dose of 120 mcg subcutaneously monthly may be effective

  • However, high doses increase the risk of jaw osteonecrosis and serious infections

• Paricalcitol

  • Used in secondary or tertiary hyperparathyroidism associated with azotemia

  • Administer intravenously during dialysis three times weekly in starting doses of 0.04–0.1 mcg/kg body weight to a maximum dose of 0.24 mcg/kg three times weekly

• Estrogen replacement, reduces hypercalcemia slightly in postmenopausal women with hyperparathyroidism

• Oral raloxifene 60 mg/day

  • May be given to postmenopausal women with hyperparathyroidism

  • Reduces serum calcium an average of 0.4 mg/dL (0.1 mmol/L), while having an anti-estrogenic effect on breast tissue

• Beta-blockers, such as propranolol, may prevent adverse cardiac effects of hypercalcemia

Surgery

• Parathyroidectomy is indicated for patients with symptomatic hyperparathyroidism, nephrolithiasis, or parathyroid bone disease

• Consider parathyroidectomy for asymptomatic patients if

  • Serum calcium 1 mg/dL (0.25 mmol/L) above upper limit of normal if urine calcium excretion > 50 mg/24 h (off thiazide diuretics)

  • Urine calcium > 400 mg/24 h (> 10 mmol/day)

  • Creatinine clearance < 60 mL/min

  • Nephrolithiasis or nephrocalcinosis

  • Cortical bone density (wrist, hip) indicating osteoporosis (T score < –2.5) or previous fragility bone fracture

  • Age < 50 years

  • Difficulty ensuring medical follow-up

  • Pregnancy (second trimester)

• Minimally invasive parathyroid surgery usually sufficient if adenoma identified preoperatively

• Subtotal parathyroidectomy (3½ glands removed) is done for patients with resistant parathyroid hyperplasia

Therapeutic Procedures

• Patients with mild, asymptomatic hyperparathyroidism are advised to

  • Keep active

  • Drink adequate fluids

  • Avoid immobilization

  • Avoid thiazides, large doses of vitamin A, calcium-containing antacids or supplements

Follow-Up

• In mild, asymptomatic hyperparathyroidism, check

  • Serum calcium and albumin twice yearly

  • Kidney function and urine calcium once yearly

  • Bone density (distal radius) every 2 years

• Postoperatively

  • Keep patients hospitalized overnight

  • Monitor serum calcium and PTH

  • Oral calcium and calcitriol, 0.25 mg/day orally for 2 weeks, helps prevent tetany

  • Treat symptomatic hypocalcemia with oral calcium carbonate and calcitriol, 0.25–1.0 mcg once daily orally

  • Secondary hyperparathyroidism occurs in ~12% and is treated with calcium and vitamin D, usually for 3–6 months

  • Hyperthyroidism immediately following parathyroid surgery may require short-term propranolol

Complications

• Pathologic long bone fractures

• Urinary tract infection due to obstruction by stones

• Confusion, acute kidney injury, and soft tissue calcinosis from rapidly rising serum calcium

• Renal osteodystrophy from hyperphosphatemia

• Peptic ulcer disease

• Pancreatitis

• Pseudogout before or after surgery

• Disseminated calcification in skin, soft tissues, and arteries (calciphylaxis) can result in gangrene, arrhythmias, and respiratory failure

• Nephrolithiasis, hyperemesis, pancreatitis, muscle weakness, cognitive changes, and hypercalcemic crisis seen in some pregnant women

• About 80% of fetuses experience complications of maternal hyperparathyroidism, including

  • Fetal demise

  • Preterm delivery

  • Low birth weight

  • Postpartum neonatal tetany

  • Permanent hypoparathyroidism

Prognosis

• Asymptomatic mild hypercalcemia

  • Remains stable with follow-up

  • However, worsening hypercalcemia, hypercalciuria and reductions in cortical bone mineral density may develop in one-third of patients

  • Must be monitored and treated with oral hydration and mobilization

• Overall cardiovascular mortality is increased in patients with chronic moderate to severe hypercalcemia

• Resection of sporadic parathyroid adenoma generally results in cure

• Despite severe cyst formation or fracture, bones heal if parathyroid tumor removed

• Occurrence of pancreatitis increases mortality rate

• Significant kidney damage may progress even after adenoma removal

• Parathyroid carcinoma

  • Associated with 5- and 10-year survival rates of 78% and 49%, respectively

  • A better prognosis is associated with clear surgical margins and no detectable metastases postoperatively

  • Positive surgical margins or metastases predict a very poor 5-year survival

  • Prognosis is also poorer for nonfunctioning parathyroid carcinoma and those tumors that carry a CDC73 mutation, loss of fibromin, or loss of CaSR expression

  • Repeat surgical debulking procedures may improve survival

  • Aggressive medical management can also prolong life

When to Refer

• Refer to parathyroid surgeon for parathyroidectomy

When to Admit

• Patients with severe hypercalcemia for intravenous hydration