BASICSChristina Kelly, MD, FAAFP
BASICS
DESCRIPTION
• Deficient secretion of parathyroid hormone (PTH)
• Usually asymptomatic
• Acute hypoparathyroidism: tetany that is mild (muscle cramps, perioral numbness, paresthesias of hands and feet) or severe (carpopedal spasm, laryngospasm, heart failure, seizures, stridor)
• Chronic: lethargy, anxiety/depression, urolithiasis and renal impairment, dementia, blurry vision from cataracts or keratoconjunctivitis, parkinsonism or other movement disorders, mental retardation, dental abnormalities, and dry, puffy, coarse skin
• System(s) affected: endocrine/metabolic, musculoskeletal, nervous, opthomalogic, renal
Pediatric Considerations
• 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 (75% of all cases). 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 or 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 (GCMB)
• 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
• Bartter 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.
• Cardinal clinical feature: neuromuscular irritability
• Also includes: fatigue, circumoral or distal extremity paresthesias, muscle spasm, 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 above 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 or ectopic calcifications
• Tooth enamel defects
• Vitiligo
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); how to distinguish from pseudohypoparathyroidism or secondary causes.
• 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, and 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
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 per kg body weight per hour (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 carbonate: calcium salts: Start with 1 to 3 g/day PO but dose varies. For geriatric patients, those on a PPI or those who have constipation on the carbonate form, consider using calcium citrate instead (3)[B].
– Calcitriol: (vitamin D 1, 25-dihydroxycholecalciferol): 0.25 μg/day. Doses 0.5 to 2.0 μg/day are usually required (2)[A].
– Either parental form of vitamin D (D2 ergocalciferol or D3 cholecalciferol) for tissues to generate their own 1,25 form
– For hypercalciuria, consider a thiazide diuretic.
– For phosphate level well above normal (>6.5 mg/dL), use low phosphate diet or phospate binder.
• Children
– Oral elemental calcium: 25 to 50 mg/kg daily
– Calcitriol: 0.25 μg daily for age >1 year
ISSUES FOR REFERRAL
Endocrinologist, nephrologist, ophthalmologist
ADDITIONAL THERAPIES
PTH peptides 1-34 and 1-84 SC
• rhPTH 1-84—FDA approved, 50 μg SC daily
• For patients who with frequent episodes of hyper- and hypocalcemia, nephrolithiasis, nephrocalcinosis, GFR <60 mL/min, persistently high phosphate (3)[B]
• Treatment goal: Eliminate use of active vitamin D3, reduce supplemental calcium to 500 mg daily; maintain consistent Ca level in low normal range.
• Improved well-being and increased bone mineral density have been shown for these patients.
SURGERY/OTHER PROCEDURES
Autotransplantation of cryopreserved parathyroid tissue: restores normocalcemia in 23% of cases
ADMISSION, INPATIENT, AND NURSING 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. If Ca <2.0 mmol/L or <8.0 mg/dL, then treat even if asymptomatic (3)[B].
• 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 6 months (3)[B].
• 24-hour urine for calcium and Cr secretion yearly
• If symptoms of renal stone disease or increasing Cr, get renal imaging every 5 years (3)[B].
• Annual slit-lamp and ophthalmologic evaluations are recommended.
• DEXA scan: standard monitoring recommended (3)[B]
DIET
Low-phosphate diet in patients with hyperphosphatemia
PATIENT EDUCATION
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
1. Al-Azem H, Khan A. Hypoparathyroidism. Best Pract Res Clin Endocrinol Metab. 2012;26(4):517–522.
2. Bilezikian JP, Khan A, Potts JT Jr, 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.
3. Brandi M, Bilezikian D, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. 2016;101(6):2273–2283.
ADDITIONAL READING
• 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.
• 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 practitioners. https://www.nichd.nih.gov/health/topics/hypopara/resources/pages/providers.aspx. Accessed December 7, 2016.
• Stack BC Jr, Bimston DN, Bodenner DL, et al. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management. Endocr Pract. 2015;21(6):674–685.
CODES
ICD10
• E20.9 Hypoparathyroidism, unspecified
• P71.4 Transitory neonatal hypoparathyroidism
• E89.2 Postprocedural hypoparathyroidism
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.
• Distinguish hypoparathyroidism from pseudohypoparathyroidism and secondary causes by PTH level.
• Not much clinical difference between 2nd- and 3rd-generation PTH assays
• Serum levels of magnesium and 25-OH should be measured to rule out deficiency that could contribute to reduced serum calcium levels.