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May occur in premature infants
Neonates born to hypercalcemic mothers may experience suppression of developing parathyroid glands.
Congenital absence of parathyroids
May appear later in childhood as autoimmune or APS-1
Geriatric Considerations
Hypocalcemia is fairly common in elderly; however, rarely secondary to hypoparathyroidism
Pregnancy Considerations
Use of magnesium as a tocolytic may induce functional hypoparathyroidism.
For women with hypoparathyroidism, calcitriol requirements decrease during lactation.
EPIDEMIOLOGY
More common in women; affects all ages
Incidence
Most common after surgical procedure of the anterior neck. Transient hyperparathyroidism is seen after 6.9-46% of thyroidectomies, whereas permanent hypoparathyroidism, 0.9-1.6% at experienced centers.
Prevalence
Wide variation. Autosomal dominant hypocalcemia with hypercalciuria (ADHH): 1/70,000 typically in infancy with hypocalcemic seizures
ETIOLOGY AND PATHOPHYSIOLOGY
- PTH is involved in the control of serum-ionized calcium levels:
- Mobilizes calcium and phosphorus from bone stores
- Stimulates formation of 1,25-dihydroxy-vitamin D
- Stimulates reabsorption of calcium in the distal convoluted tubule and phosphate excretion in proximal tubule
- Loss of PTH action results in hypocalcemia, hyperphosphatemia, and hypercalciuria.
- Magnesium is crucial for PTH secretion and activation of the PTH receptor; hypo- or hypermagnesemia may result in functional hypoparathyroidism.
- Acquired hypoparathyroidism
- Surgical: removal or damage to parathyroid glands or their blood supply; thyroid, parathyroid, or radical neck surgery for head and neck cancers (1)
- Autoimmune: isolated or combined with other endocrine deficiencies in polyglandular autoimmune (PGA) syndrome
- Deposition of heavy metals in gland: copper (Wilson disease) or iron (hemochromatosis, thalassemias), radiation-induced destruction, and metastatic infiltration
- Functional hypoparathyroidism: associated with hypomagnesemia; hypermagnesemia
- Congenital
- Calcium-sensing receptor (CaSR) abnormalities: hypocalcemia with hypercalciuria
- HDR or Barakat syndrome: deafness, renal dysplasia
- Familial: mutations of the TBCE gene; abnormal PTH secretions
- 22q11.2 deletion syndrome
- Autoimmune: genetic gain-of-function mutation in CaSR
- Infiltrative: metastatic carcinoma, hemochromatosis, Wilson disease, granulomas
- Hypo- (alcoholics) or hypermagnesemia: chronic iron overloads
Genetics
- Genetic defects may result in X-linked or in autosomal recessive hypoparathyroidism due to abnormal parathyroid gland development; associated with mutations in the transcription factor glial cell missing B (BCMB)
- Mutations in transcription factors or regulators of parathyroid gland development
- Component of a larger genetic syndrome (APS-1 or DiGeorge syndrome) or in isolation (X-linked hypoparathyroidism) (2)
- May be autosomal dominant (DiGeorge), autosomal recessive (APS-1), or X-linked recessive (X-linked hypoparathyroidism) (2)
- Congenital syndromes
- 22q11.2 deletion syndrome, familial hypomagnesemia, hypoparathyroidism with lymphedema (2)
- Hypoparathyroidism with sensorineural deafness
- ADHH: mutations gain-of-function of the CaSR gene suppressing the parathyroid gland, without elevation of PTH
- PGA syndrome type I: mucocutaneous candidiasis, hypoparathyroidism, and Addison disease
RISK FACTORS
Neck surgery and neck trauma, neck malignancies, family history of hypocalcemia, PGA syndrome
GENERAL PREVENTION
Intraoperative identification and preservation of parathyroid tissue
COMMONLY ASSOCIATED CONDITIONS
- DiGeorge syndrome
- PGA syndrome type I
- Multiple endocrine deficiency autoimmune candidiasis (MEDAC) syndrome
- Juvenile familial endocrinopathy
- Addison disease
- Moniliasis (HAM) syndrome: a polyglandular deficiency syndrome, possibly genetic, characterized by hypoparathyroidism
DIAGNOSIS
HISTORY
Often asymptomatic; ask about previous neck trauma or surgery, head or neck irradiation, family history of hypocalcemia, or presence of other autoimmune endocrinopathies.
- Fatigue, circumoral or distal extremity paresthesias
- Muscle cramps, seizures, neuropsychiatric symptoms
PHYSICAL EXAM
- Surgical scar on neck
- Chvostek sign: ipsilateral twitching of the upper lip on tapping the facial nerve on the cheek. 10% of normal people have positive Chvostek sign.
- Trousseau sign: painful carpal spasm after 3-minute occlusion of brachial artery with BP cuff. BP cuff inflated to > systolic BP for 3 minutes leads to carpal spasm (flexion of metacarpophalangeal [MCP] joints, extension of interphalangeal [IP] joints, adduction of fingers and thumb).
- Tetany, laryngo- or bronchospasm, cardiac arrhythmias, refractory heart failure, dyspnea, edema
- Dry, coarse, puffy hair; brittle nails
- Loss of deep tendon reflexes
- Dysrhythmias (secondary hypocalcemia)
- Cataracts
- Tooth enamel defects
DIFFERENTIAL DIAGNOSIS
- Vitamin D deficiency/resistance
- Pseudohypoparathyroidism, which presents in childhood, kidney and bone unresponsiveness to PTH; characterized by hypocalcemia, hyperphosphatemia, and, in contrast to hypoparathyroidism, elevated rather than reduced PTH concentrations
- Hypoalbuminemia, renal failure, malabsorption, familial hypocalcemia, hypomagnesemia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Calcium: ionized (low) and total (low) (correct serum calcium level for albumin)
- Corrected serum calcium = total serum calcium + 0.8 (4 - serum albumin)
- Phosphorus (high)
- Intact or "whole" PTH (low or inappropriately normal)
- Magnesium (low may be cause of hypoparathyroidism; may also be normal)
- BUN, creatinine, 25-OH vitamin D level (especially in elderly)
- Urinary calcium (normal or high)
- Calcium should be monitored after thyroid or parathyroid surgery.
- Radiographs may show absent tooth roots, calcification of cerebellum, choroid plexus, or cerebral basal ganglia.
Follow-Up Tests & Special Considerations
- ECG: prolongation of ST and QTc intervals nonspecific repolarization changes, dysrhythmias
- Urine calcium: Creatinine ratio (normal 0.1 to 0.2) may be low before treatment but should be monitored to prevent stones due to hypercalciuria.
- Gene sequencing: Evaluation of other hormone levels may be required to diagnose APS-1.
- Hungry bone syndrome (transient hypoparathyroidism after parathyroid surgery)
- Hypocalcemia due to hungry bone syndrome may persist despite recovery of PTH secretion from the remaining normal glands. Thus, serum PTH concentrations may be low, normal, or even elevated.
- Infiltrative: osteoblastic metastasis of prostate, breast, or lung cancer
- Metabolic/nutritional: renal failure, neonatal hypocalcemia, hypoalbuminemia, malabsorption, calcium (Ca++) chelators, hypomagnesemia
- Familial hypocalcemia, acute hyperphosphatemia (rare), vitamin D deficiency
- Autoantibodies against NACHT leucine-rich-repeat protein 5(NALPS) found in 49% of 73 patients with APS-1 and hypoparathyroidisms
Test Interpretation
Parathyroid gland parenchymal tissue completely or almost completely replaced by fat
TREATMENT
GENERAL MEASURES
- Monitor ECG during calcium repletion.
- Maintenance therapy: may require lifelong treatment with calcium and calcitriol
- Maintain serum calcium in low normal range: 8 to 8.5 mg/dL (2 to 2.12 mmol/L).
- If hypercalcemia occurs, hold therapy until calcium returns to normal. Treat magnesium deficiency if present.
- Phosphate binders are required if high calcium-phosphate product.
- Thiazide diuretics combined with a low-salt diet may be used to prevent hypercalciuria, nephrocalcinosis, and nephrolithiasis.
- Oral calcium administration and vitamin D supplementation after thyroidectomy may reduce the risk for symptomatic hypocalcemia after surgery.
MEDICATION
Acute Hypoparathyroidism
- Hypoparathyroid with severe symptoms (tetany, seizures, cardiac failure, laryngospasm, bronchospasm)
- IV calcium gluconate: 1 or 2 g, each infused over a period of 10 minutes. Central venous catheter is preferred because calcium-containing solutions can irritate surrounding tissues. Follow with infusion of 10 g calcium gluconate in 1 L 5% dextrose water at a rate of 1 to 3 mg calcium gluconate/kg body weight/hr (1)[B].
- Hypomagnesemia: acutely: 1 to 2 g IV q6h. Long-term magnesium oxide tablets (600 mg) once or twice per day
- Maintenance: See "First Line" treatment for chronic hypoparathyroidism.
Chronic Hypoparathyroidism
First Line
- Adults
- Oral calcium: calcium salts: 1 to 3 g/day PO. For geriatric patients, consider using calcium citrate instead of calcium carbonate.
- Calcitriol: (vitamin D 1, 25-dihydroxycholecalciferol): 0.25 Ī¼g/day. Doses 0.5 to 2.0 Ī¼g/day are usually required (2)[A].
- Children
- Oral elemental calcium: 25 to 50 mg/kg daily
- Calcitriol: 0.25 Ī¼g daily for age >1 year
Second Line
Cholecalciferol 10,000 to 50,000 U duration of action 4 to 8 weeks
ISSUES FOR REFERRAL
Endocrinologist, nephrologist, ophthalmologist
ADDITIONAL THERAPIES
Parathyroid hormone 1 to 34 and 1 to 84 SC
- Improved well-being and increased bone mineral density have been shown with PTH therapy, but other long-term benefits have not (3).
SURGERY/OTHER PROCEDURES
Autotransplantation of cryopreserved parathyroid tissue: restores normocalcemia in 23% of cases
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Laryngospasm, seizures, tetany, QT prolongation
Discharge Criteria
Resolution of hypocalcemic symptoms, patient educated on hypoparathyroidism and treatment
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Goal is a total corrected serum calcium level in low normal range (8 to 8.5 mg/dL or 2 to 2.12 mmol/L), 24-hour urine calcium <300 mg, and calcium-phosphate product <55.
- Outpatient measurement of serum calcium, phosphate, magnesium, and creatinine weekly to monthly during initial management; for changes in medication, check weekly or every other week; when stable, measure every 3 to 6 months (3)[A].
- Measure 24-hour urinary calcium secretion yearly.
- If symptoms of renal stone disease or increasing Cr, get renal imaging (3)[A].
- Annual slit-lamp and ophthalmologic evaluations are recommended.
- DEXA scan (2)[A]
DIET
Low-phosphate diet in patients with hyperphosphatemia
PATIENT EDUCATION
https://www.hypopara.org/
PROGNOSIS
Hypoparathyroidism following neck surgery is often transient. Length of required treatment may vary depending on origin.
COMPLICATIONS
- Reversible: due to low calcium levels, most likely to improve with adequate treatment
- Neuromuscular symptoms: Paresthesias (circumoral, fingers, toes), tetany, seizures, parkinsonian symptoms; pseudotumor cerebri has been described.
- Renal: hypercalciuria, nephrocalcinosis, nephrolithiasis
- Cardiovascular: heart failure, arrhythmias
- Irreversible: when condition starts early in childhood and will not improve with calcium and vitamin D treatment
- Stunting of growth
- Enamel defects and hypoplasia of teeth
- Atrophy, brittleness, and ridging of nails
- Cataracts and basal ganglia calcifications
REFERENCES
11 Al-Azem H, Khan A. Hypoparathyroidism. Best Pract Res Clin Endocrinol Metab. 2012;26(4):517-522.22 Bilezikian JP, Khan A, Potts JTJr, et al. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res. 2011;26(10):2317-2337.33 Bollerslev J, Rejnmark L, Marcocci C, et al. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173(2):G1-G20.
ADDITIONAL READING
- Michels TC, Kelly KM. Parathyroid disorders. Am Fam Physician. 2013;88(4):249-257.
- National Institute of Child Health and Human Development. Hypoparathyroidism: For researchers and health care practictioners. https://www.nichd.nih.gov/health/topics/hypopara/resources/pages/providers.aspx
CODES
ICD10
- E20.9 Hypoparathyroidism, unspecified
- P71.4 Transitory neonatal hypoparathyroidism
- E89.2 Postprocedural hypoparathyroidism
- E20.1 Pseudohypoparathyroidism
- E20.0 Idiopathic hypoparathyroidism
- E20.8 Other hypoparathyroidism
ICD9
- 252.1 Hypoparathyroidism
- 775.4 Hypocalcemia and hypomagnesemia of newborn
SNOMED
- 36976004 Hypoparathyroidism (disorder)
- 63981007 Neonatal hypoparathyroidism (disorder)
- 190455009 Post-surgical hypoparathyroidism (disorder)
- 58976002 Pseudohypoparathyroidism (disorder)
CLINICAL PEARLS
Often asymptomatic; consider if hypocalcemic with fatigue and circumoral or distal extremity paresthesias.
- Correct the serum calcium level for albumin level.
- Monitor calcium after thyroid or parathyroid surgery.
- Serum levels of magnesium and 25-OH should be measured to rule out deficiency that could contribute to reduced serum calcium levels.