Hypoparathyroidism: Comprehensive Management
Definition and Diagnostic Criteria
Hypoparathyroidism is definitively diagnosed by the triad of hypocalcemia (corrected calcium <8.6 mg/dL), hyperphosphatemia, and low or inappropriately normal PTH levels (<20 pg/mL), after excluding renal failure and magnesium disorders. 1, 2
Key Diagnostic Laboratory Panel
- Serum calcium (corrected for albumin) or ionized calcium (normal 4.65-5.28 mg/dL) 3
- Intact PTH – will be low or inappropriately normal (<20 pg/mL) despite hypocalcemia 1, 2
- Serum phosphorus – elevated (>4.6 mg/dL) 1
- Serum magnesium – must be checked, as both hypomagnesemia and hypermagnesemia impair PTH secretion 1
- Serum creatinine and eGFR – to exclude renal failure as cause of hyperphosphatemia 3
- 25-hydroxyvitamin D – assess vitamin D status 4
Critical Measurement Considerations
- Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C 3
- PTH assays vary by up to 47% between different generations; always use assay-specific reference values 5, 3
Etiology: Causes of Hypoparathyroidism
Most Common Cause
Iatrogenic hypoparathyroidism following anterior neck surgery (thyroidectomy or parathyroidectomy) is the most frequent etiology. 1
Other Causes
- Autoimmune destruction of parathyroid glands 1
- Genetic abnormalities (DiGeorge syndrome, activating mutations of calcium-sensing receptor) 1
- Infiltrative disorders (hemochromatosis, Wilson's disease, metastatic disease) 1
- Magnesium disorders – hypomagnesemia or hypermagnesemia impair PTH secretion 1
- Congenital absence or dysgenesis of parathyroid glands 1
Clinical Presentation
Acute Symptomatic Hypocalcemia
- Neuromuscular irritability: perioral numbness, paresthesias (hands/feet), muscle cramps, tetany 1, 4
- Seizures (generalized or focal) 1
- Bronchospasm and laryngospasm 1
- Cardiac manifestations: prolonged QT interval on ECG, arrhythmias 6
- Chvostek's sign (facial twitching with tapping facial nerve) and Trousseau's sign (carpopedal spasm with blood pressure cuff inflation) 4
Chronic Hypocalcemia
- May be asymptomatic and detected only on routine biochemical screening 1
- Chronic symptoms include fatigue, cognitive impairment, cataracts, basal ganglia calcifications 4
Acute Management of Symptomatic or Severe Hypocalcemia
For symptomatic hypocalcemia or corrected calcium <7.2 mg/dL (ionized calcium <0.9 mmol/L), initiate immediate intravenous calcium gluconate infusion at 1-2 mg elemental calcium per kg per hour. 6
Step-by-Step Acute Protocol
- Start IV calcium gluconate infusion immediately at 1-2 mg elemental calcium/kg/hour 6
- Measure ionized calcium every 4-6 hours for the first 48-72 hours, then twice daily until stable 6
- Begin oral calcium carbonate 1-2 g three times daily as soon as oral intake is possible 6
- Add calcitriol up to 2 μg/day when oral intake tolerated 6
- Gradually reduce IV infusion when ionized calcium stabilizes in normal range 6
- Check and correct magnesium if low, as hypomagnesemia worsens hypocalcemia 6
- Monitor ECG for QT prolongation 6
Critical Pitfall to Avoid
Never use calcimimetics (cinacalcet) in hypoparathyroidism—they are absolutely contraindicated and will cause severe worsening of hypocalcemia and QT prolongation. 6
Chronic Management of Hypoparathyroidism
Standard Conventional Therapy
The cornerstone of chronic management is oral calcium supplementation (1-2 g elemental calcium three times daily) combined with active vitamin D metabolites (calcitriol 0.25-2 μg/day). 1, 4
Calcium Supplementation
- Calcium carbonate 1-2 g three times daily with meals (provides dual benefit as phosphate binder) 7, 1
- Total elemental calcium intake should not exceed 2000 mg/day 3
Active Vitamin D Therapy
- Calcitriol (1,25-dihydroxyvitamin D) is the preferred active metabolite 1, 4
- Starting dose: 0.25-0.5 μg twice daily, titrate up to 2 μg/day as needed 6, 1
- Calcitriol increases intestinal calcium absorption and helps maintain serum calcium 4
Thiazide Diuretics
- Add thiazide diuretics (hydrochlorothiazide 25-50 mg daily) to enhance renal calcium reabsorption and reduce urinary calcium losses 1
- Particularly beneficial in patients with activating mutations of calcium-sensing receptor 1
- Helps reduce hypercalciuria, a common complication of conventional therapy 1
Monitoring During Chronic Therapy
Laboratory Monitoring Schedule
- Serum calcium and phosphorus: measure within 1 week of initiating therapy, then monthly for first 3 months, then every 3 months 7, 3
- 24-hour urinary calcium or spot urine calcium/creatinine ratio: monitor for hypercalciuria (goal <300 mg/24hr) 3
- Serum creatinine and eGFR: monitor renal function regularly 3
- Serum magnesium: check periodically, as deficiency impairs PTH secretion 6, 1
Therapeutic Targets
- Serum calcium: maintain in low-normal range (8.0-9.0 mg/dL), not fully normal 1, 4
- Avoid hypercalcemia (>10.2 mg/dL): discontinue all vitamin D therapy immediately if calcium exceeds this threshold 7, 3
- Urinary calcium: keep <300 mg/24hr to prevent nephrolithiasis and nephrocalcinosis 3
- Serum phosphorus: aim for normal range (2.7-4.6 mg/dL) 7
Critical Pitfall
Do not target fully normal serum calcium levels (>9.5 mg/dL), as this often requires excessive calcium and calcitriol doses that cause hypercalciuria, nephrolithiasis, and nephrocalcinosis. 1, 4
Recombinant Human Parathyroid Hormone (Natpara®)
Natpara® [rhPTH(1-84)] is FDA-approved for chronic hypoparathyroidism inadequately controlled with conventional therapy (calcium and active vitamin D alone). 8
Indications for rhPTH(1-84)
- Refractory hypoparathyroidism: patients unable to maintain stable serum calcium despite optimized conventional therapy 8
- Persistent hypercalciuria (>300 mg/24hr) despite thiazide diuretics 1
- Requirement for excessively high doses of calcium (>2500 mg/day) or calcitriol (>1.5 μg/day) 8
- Nephrolithiasis or nephrocalcinosis developing on conventional therapy 8
Benefits of rhPTH(1-84) Therapy
- Increases serum calcium and reduces need for calcium and calcitriol supplementation 1, 9, 8
- Lowers serum phosphate by increasing renal phosphate excretion 1, 9
- Reduces urinary calcium losses, decreasing risk of nephrolithiasis 1, 8
- Restores more physiologic calcium-phosphate homeostasis compared to conventional therapy 8
Dosing and Administration
- Starting dose: 50 μg subcutaneously once daily 8
- Titration: adjust dose every 4 weeks based on serum calcium and urinary calcium 8
- Maintenance dose range: typically 50-100 μg daily 8
- Administered as subcutaneous injection in the thigh, rotating injection sites 8
Monitoring on rhPTH(1-84)
- Serum calcium: measure within 1 week of starting, then every 3-4 weeks during titration 8
- 24-hour urinary calcium: monitor every 3-6 months 8
- Serum phosphorus: check every 3 months 8
- Gradually reduce calcium and calcitriol doses as serum calcium stabilizes 8
Safety Considerations
- Long-term safety data are still limited, as this is a relatively new therapy 8
- Hypercalcemia risk: monitor closely during dose titration 8
- Not approved for use in patients with increased baseline risk of osteosarcoma 8
Alternative: rhPTH(1-34) (Teriparatide)
- Teriparatide is off-label for hypoparathyroidism and has no established safety or efficacy data in this population 7
- Causes hypercalcemia and hyperuricemia, making it problematic in hypocalcemic patients 7
- No published studies in hypoparathyroidism patients 7
Special Clinical Scenarios
Post-Parathyroidectomy "Hungry Bone Syndrome"
After parathyroidectomy for severe hyperparathyroidism, anticipate rapid calcium decline ("hungry bone syndrome") due to avid bone uptake of calcium and phosphate. 6, 3
- Measure ionized calcium every 4-6 hours for first 48-72 hours post-operatively 6, 3
- If ionized calcium drops below 0.9 mmol/L, start IV calcium gluconate infusion at 1-2 mg/kg/hour 6, 3
- Begin oral calcium carbonate 1-2 g three times daily plus calcitriol up to 2 μg/day as soon as oral intake possible 6, 3
- May require phosphate supplements as hungry bone syndrome involves uptake of both calcium and phosphate 6
Hypomagnesemia-Induced Hypoparathyroidism
- Correct magnesium first before expecting PTH secretion to normalize 6, 1
- Magnesium replacement: IV magnesium sulfate 1-2 g over 15-60 minutes for severe deficiency 6
- Oral magnesium supplementation: 400-800 mg elemental magnesium daily for chronic deficiency 1
When Conventional Therapy Fails
Criteria for "Refractory" Hypoparathyroidism
- Inability to maintain serum calcium >8.0 mg/dL despite calcium >2500 mg/day and calcitriol >1.5 μg/day 8
- Persistent hypercalciuria (>300 mg/24hr) despite thiazide diuretics 1, 8
- Development of nephrolithiasis or nephrocalcinosis on conventional therapy 8
- Frequent symptomatic hypocalcemic episodes requiring emergency care 8