Hypoparathyroidism & Pseudohypoparathyroidism

Essentials of Diagnosis

• Tetany, carpopedal spasms, tingling of lips and hands, muscle cramps, irritability

• Chvostek sign and Trousseau phenomenon

• Hypocalcemia with low serum parathyroid hormone (PTH); serum phosphate high; alkaline phosphatase normal; urine calcium excretion reduced

• Serum magnesium may be low

General Considerations

• Acquired hypoparathyroidism

  • Most commonly caused by anterior neck surgery, occurring after total thyroidectomy in about 25% of patients transiently, and in about 4% of patients permanently

  • Risk is higher for patients undergoing total thyroidectomy (especially large goiters) or surgery for Graves disease, patients over age 50, and when fewer than 2 parathyroid glands are identified at surgery

  • Risk of permanent postoperative hypoparathyroidism can be reduced during thyroid surgery by taking parathyroid glands with suspected vascular damage and autotransplanting them into the sternocleidomastoid muscle

• Permanent hypoparathyroidism

  • May occur after the resection of multiple parathyroid adenomas

  • In cases of "hungry bone syndrome" (transient hypoparathyroidism after the surgical removal of a single parathyroid adenoma for primary hyperparathyroidism due to suppression of the remaining normal parathyroids and accelerated remineralization of the skeleton), hypocalcemia can be quite severe, particularly in patients with preoperative hyperparathyroid bone disease and vitamin D or magnesium deficiency

  • Neck irradiation is a rare cause

• Autoimmune hypoparathyroidism may be isolated or combined with other endocrine deficiencies

• Parathyroid deficiency may be caused by

  • Damage from heavy metals such as copper (Wilson disease) or iron (hemochromatosis, transfusion hemosiderosis)

  • Granulomas

  • Riedel thyroiditis

  • Tumors

  • Infection

• Magnesium deficiency causes functional hypoparathyroidism

• Hypomagnesemia

  • Most commonly caused by alcoholism, diuretics, and intestinal malabsorption

  • Can also be caused by

    • Certain antibiotics (aminoglycosides, amphotericin, and pentamidine)

    • Epithelial growth factor inhibitors (panitumumab, cetuximab) for colon cancer

  • Mild hypomagnesemia stimulates PTH secretion; however, more severe hypomagnesemia (< 1.2 mg/dL) inhibits PTH secretion

  • Also causes resistance to PTH in bone and renal tubules

• Symptomatic hypoparathyroidism may be precipitated by a proton pump inhibitor, since absorption of calcium decreases with reduced stomach acidity

• Congenital hypoparathyroidism

  • Causes hypocalcemia beginning in infancy; however, it may not be diagnosed for many years

  • Since hypoparathyroidism can be familial, screening is suggested for family members of any patient with idiopathic hypoparathyroidism

  • Genetic testing is suggested for the following

    • Early-onset idiopathic hypoparathyroidism

    • Hypoparathyroidism with a family history of idiopathic hypoparathyroidism

  • DiGeorge syndrome is another cause of congenital hypoparathyroidism, along with congenital cardiac and facial anomalies

Symptoms and Signs

• Depend on the severity and rate of development of hypocalcemia as well as individual factors

  • Acute hypocalcemia after parathyroidectomy

    • Symptoms may be severe despite having only mildly low or even low-normal serum calcium levels

  • Chronic severe hypocalcemia: symptoms may be few

• Neuromuscular irritability presents with

  • Perioral numbness

  • Paresthesias of the feet or hands

  • Myalgias, muscle cramping, generalized muscle spasms with tetany, hyperactive reflexes

  • Laryngospasm, which can cause respiratory stridor

  • Chvostek sign

    • Facial muscle contraction on tapping the facial nerve in front of the tragus

    • Present in 70% of patients with hypocalcemia and in about 15% of individuals who are normocalcemic

  • Trousseau sign

    • Flexion of the wrist and metacarpal-phalangeal joints with adduction of the fingers after application of a sphygmomanometer cuff inflated to over systolic blood pressure for 3 minutes

    • Present in over 90% of patients with hypocalcemia but in only about 1% of normocalcemic individuals

• Cardiovascular manifestations of acute hypocalcemia include

  • Bradycardia

  • Ventricular arrhythmias

  • Impaired ventricular ejection fraction

• CNS manifestations of hypocalcemia

  • Include seizures as well as psychiatric changes, irritability, fatigue, and cognitive impairment

  • Parkinsonian and extrapyramidal symptoms may occur

• Ophthalmic manifestations of severe hypocalcemia include papilledema and cataracts

• Renal manifestations of chronic hypoparathyroidism

  • Occur due to hypercalciuria

  • Include nephrolithiasis, nephrocalcinosis, and kidney disease

• Dermatologic manifestations include

  • Dry, rough skin

  • Dry hair

  • Scalp and eyebrow hair loss

  • Brittle fingernails with transverse grooves

• Chronic hypocalcemia with hyperphosphatemia can cause calcifications in soft tissues, such as joints, skin, and arteries

Differential Diagnosis

• Pseudohypoparathyroidism (renal resistance to PTH)

• Vitamin D deficiency

• Acute pancreatitis

• Chronic kidney disease

• Hypoalbuminemia

• Paresthesias or tetany due to respiratory alkalosis

• Familial hypocalcemia with hypercalciuria (normal serum PTH)

• Hypomagnesemia

Laboratory Tests

• Low serum calcium

  • Note: serum calcium is largely bound to albumin. If hypoalbuminemia is present, obtain ionized calcium (should be 4.6–5.3 mg/dL [1.15–1.32 mmol/L]) or correct calcium level for albumin level.

  • Corrected Ca²⁺ = serum Ca²⁺ mg/dL + [0.8 × (4.0 – albumin g/dL)]

• Serum phosphate high

• Alkaline phosphatase normal

• Urinary calcium low

• Serum PTH levels usually low or not elevated in the presence of hypocalcemia

• Serum magnesium levels should always be measured

• Serum calcium should not be determined within 24 hours following intravenous gadolinium, since gadolinium interferes with the colorimetric calcium assay, thereby causing artefactual hypocalcemia

Imaging Studies

• Brain calcification are visible on CT scanning in the basal ganglia and other areas in over 50% of patients with chronic hypocalcemia

• Bones may appear denser than normal

• Bone mineral density is usually increased, particularly in the lumbar spine

• Cutaneous calcification may occur

Diagnostic Procedures

• Slit-lamp examination may show early posterior lenticular cataract formation

• ECG may show heart block, prolonged QT interval, and ST-T changes suggestive of a myocardial infarction

Medications

Prophylaxis against severe postoperative hypocalcemia

• If the serum calcium falls below 8.0 mg/dL (2.0 mmol/L) with a serum PTH below 10–15 pg/mL (1.0–1.5 pmol/L) after thyroid or parathyroid surgery, the patient is at high risk for hypocalcemia and can be prophylactically treated with calcitriol and oral calcium

  • Calcitriol is typically given orally in doses of 0.25–1 mcg twice daily

  • Calcium carbonate (with meals) 500–1000 mg twice daily

Emergency treatment for acute hypocalcemia

• Ensure adequate airway

• Calcium gluconate

  • 10–20 mL of 10% solution intravenously, given slowly until tetany ceases

  • Add 10–50 mL of calcium gluconate 10% to 1 L of D5W or saline by slow intravenous drip

  • Titrate to serum calcium of 8–9 mg/dL (2–2.25 mmol/L)

• Oral calcium, 1 g daily as soon as possible

  • Liquid calcium carbonate, 500 mg/5 mL; contains 40% calcium

  • Dosage is 1–2 g calcium orally daily

• Vitamin D derivatives to be given with oral calcium include

  • Begin calcitriol at a dose of 0.25 mcg (1000 international units) orally each morning and titrate upward to near normocalcemia

  • Ultimately, doses of 0.5–2 mcg/day are usually required

• If hypomagnesemia (serum magnesium < 1.8 mg/dL or < 0.8 mmol/L) is present, it must be corrected to treat the resulting hypocalcemia

  • For critical hypomagnesemia (serum magnesium < 1.0 mg/dL or < 0.45 mmol/L),

    • 50% magnesium sulfate solution (5 g/10 mL) is diluted in 250 mL 0.9% saline or 5% dextrose in water

    • Give by an intravenous infusion of 5 g over 3 hours, with further dosing based on serum magnesium levels

  • Long-term oral magnesium replacement may be given as magnesium oxide 500 mg (60% elemental Mg) tablets, one to three times daily

Maintenance treatment

• Calcium (1–2 g/day) and vitamin D supplementation (see above) to achieve slightly low but asymptomatic serum calcium (8.0–8.6 mg/dL [2–2.15 mmol/L]) to minimize hypercalciuria and provide margin of safety against hypercalcemia

• Calcium supplements

  • Can be given in doses of 800–1000 mg orally daily

  • Calcium carbonate (40% elemental calcium) is best absorbed at the low gastric pH that occurs with meals

  • Calcium citrate (21% elemental calcium) is absorbed with or without meals and is a better choice for patients taking proton pump inhibitors or H₂-blockers; it causes less gastrointestinal intolerance than calcium carbonate

  • Calcium lactate contains 13% elemental calcium

  • Calcium gluconate contains 9% elemental calcium

• Calcitriol, a short acting preparation, is given in doses that range from 0.25 mcg/day to 2.0 mcg orally daily

• Alphacalcidol (1-hydroxyvitamin D) may also be given orally in doses of 0.5–4.0 mcg daily; it undergoes 25-hydroxylation in the liver

• Vitamin D analogs are generally required for patients with chronic hypoparathyroidism

  • The dosage of vitamin D preparations required to maintain target serum calcium levels can vary over time

  • Vitamin D₃ may be required in doses of 1000–5000 units daily to maintain serum 25-(OH) vitamin D levels above 30 ng/mL

• Ergocalciferol (vitamin D₂)

  • Usual dose ranges from 25,000 to 150,000 units/day

  • Has long duration of action because it is stored in fat

  • If toxicity develops, hypercalcemia—treatable with hydration and prednisone—may persist for weeks after it is discontinued

  • Despite this risk, usually produces a more stable serum calcium level than do the shorter-acting preparations

• Parathyroid hormone (PTH)

  • Is effective for treating patients with hypoparathyroidism

  • Is restricted to patients whose hypocalcemia cannot be adequately treated with calcium and vitamin D analogs

• Recombinant human parathyroid hormone (rhPTH)

  • An 84-amino acid polypeptide that is identical to native PTH

  • FDA-approved as an adjunct to calcium and vitamin D analogs to control symptomatic hypocalcemia in patients with hypoparathyroidism

• Avoid phenothiazines in hypocalcemia; may precipitate extrapyramidal symptoms

• Avoid furosemide; may worsen hypocalcemia

Surgery

• Transplantation of cryopreserved parathyroid tissue from prior surgery restores normocalcemia in ~23%

Follow-Up

• Monitor serum calcium at least every 3 months; keep serum calcium slightly low

• Monitor "spot" urine calcium to keep level < 30 mg/dL if possible

• Hypercalciuria may respond to oral hydrochlorothiazide, usually given with a potassium supplement

• Hypercalcemia developing in patients with previously stable, treated hypoparathyroidism may signal new onset of Addison disease

Complications

• Stridor, especially with vocal cord palsy, may cause respiratory obstruction requiring tracheostomy

• Seizures in untreated patients

• Hypocalcemia can also cause heart failure and dysrhythmias

• Nerve root compression due to ossification of paravertebral ligaments

• Nephrocalcinosis and impaired kidney function if overtreatment with calcium and vitamin D

• Chronic hypoparathyroidism may be associated with autoimmune diseases, eg, celiac disease, pernicious anemia, or Addison disease

Prognosis

• Prognosis reasonably good with prompt diagnosis and treatment

• Patients with moderate-to-severe hypoparathyroidism have been reported to have an overall reduced quality of life

• In patients with chronic disease

  • Calcifications in kidneys and basal ganglia frequently develop

  • Risk of calcium kidney stones and kidney dysfunction as well as seizures, mood and psychiatric disorders, and a reduced overall sense of well-being is increased

When to Refer

• Refer all patients to endocrinologist for stable regimen

When to Admit

• Any symptomatic hypocalcemia