I. Problem/Condition.

Hypocalcemia is a frequently encountered phenomenon in the hospitalized patient. It can range from asymptomatic to life-threatening in presentation. An understanding of the physiology of calcium metabolism is critical to determining the appropriate differential diagnosis and management.

The serum calcium level is maintained by the activity of parathyroid hormone (PTH) and vitamin D on the gastrointestinal (GI) tract, kidneys and bones. Vitamin D is mainly obtained through exposure to ultraviolet light with a lesser portion from the diet. PTH stimulates calcium resorption in the kidney and calcium release from bone. PTH also promotes the production of 1,25-dihydroxyvitamin D (calcitriol) from 25-hydroxyvitamin D in the kidney. Calcitriol acts on the GI tract to increase calcium absorption.

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II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

Most common

Vitamin D deficiency due to:

  • Lack of exposure to ultraviolet light (Vitamin D 1,25)

  • Malabsorption or poor diet intake (Vitamin D)

  • Renal disease (Vitamin D1)

Hypoparathyroidism due to:

  • Surgery

  • Autoimmune disease

Less common
  • Vitamin D resistance

  • PTH resistance (pseudo-hypoparathryoidism)

  • Hypomagnesemia

  • Osteoblastic metastases–prostate, breast, lung cancer

  • Pancreatitis

  • Loop diuretics (promote calcium excretion in the kidney)

  • Antiepileptic drugs (increased vitamin D metabolism)

  • Large volume blood transfusions (citrate is a calcium chelator)

  • Hereditary (autosomal dominant hypocalcemia)

  • High dose intravenous (IV) bisphosphonates in vitamin D deficient patients (blocks bone resorption)

B. Describe a diagnostic approach/method to the patient with hypocalcemia

  • History/presentation

  • Physical examination

  • Laboratory evaluation

1. Historical information important in the diagnosis of hypocalcemia

  • Have you experienced any muscle twitching, tingling, numbness, or spasms?

  • Is there demonstrated tetany, seizure activity, or cardiac dysrhythmias?

  • Any difficulty breathing?

  • Any change in skin or nails?

  • Amount and duration of exposure to ultraviolet light?

  • Diarrhea or other symptomatology to suggest malabsorption?

  • History of chronic renal disease?

  • History of head and neck surgery?

  • Personal or family history of autoimmune disease?

  • History of metastatic cancer (prostate, breast, lung)?

  • Medications (e.g., loop diuretics, antiepileptic drugs, IV bisphosphonates)?

2. Physical Examination maneuvers that are likely to be useful in diagnosing hypocalcemia.

Trousseau’s sign is the most specific provocative maneuver for hypocalcemia. This is accomplished by inflating a blood pressure cuff above the patient’s systolic blood pressure and leaving it in place for 3 minutes. The absence of blood flow and hypocalcemia will result in spasms of the muscles of the hand and forearm.

Chvostek’s sign is positive when tapping of the parotid gland over the facial nerve results in facial muscle spasms. However, this maneuver is not very sensitive.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing hypocalcemia.

A stepwise approach can be considered in the evaluation of hypocalcemia. The most important laboratory testing is illustrated below and include: ionized or adjusted calcium, serum PTH, 25 hydroxyvitamin D level, assessment of renal function, and a magnesium level (Figure 1).

An alkaline phosphatase can be obtained if osteomalacia (in the setting of vitamin D deficiency) or sclerotic metastases is suspected. The level will be elevated with these disease states, but can also be elevated in renal disease or hungry bone syndrome after parathyroidectomy (for hyperparathyroidism).

An electrocardiogram can show a prolonged QT interval.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

The above figure illustrates how the most common diagnoses can be determined using laboratory testing. A thorough history will uncover most additional etiologies. The table below shows the biochemical profile for a number of common etiologies (Figure 2).

Figure 2.

Laboratory work-up of hypocaclemia.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of hypocalcemia

  • 1,25 Vitamin D levels should not be obtained.

  • Unless chronic renal failure is the etiology, obtaining a phosphate level has questionable value given the diurnal variability and swings with dietary intake.

III. Management while the Diagnostic Process is Proceeding

A. Management of hypocalcemia

Symptomatic hypocalcemia or severely low calcium – less than 1.9 millimole/Liter (mmol/L) or ionized calcium less than 1 mmol/L – of indeterminate etiology:
  • Correct levels over minutes to hours.

  • Place patient on a cardiac monitor to observe for dysrhythmias and obtain electrocardiography (EKG) to evaluate QT-interval.

  • Support hemodynamics as needed.

  • Calcium gluconate is preferred over calcium chloride, unless a central line is in place.

    Give 10 milliliter (ml) of a 10% solution of calcium gluconate intravenously (intramuscular [IM] is contraindicated) over 10 minutes.

    Treatment should be repeated until symptoms have resolved and/or level is satisfactory.

    A continuous infusion of calcium gluconate may be necessary. It should be infused at a rate of 50 milliliters/hour (ml/hr) with the expectation that a 10 milliliter/kilogram (ml/kg) solution will increase the serum calcium by 0.3-0.5 mmol/liter over 4-6 hours.

    Therapy should be monitored with serial serum calcium levels until symptoms have resolved and values are within the reference range. Initially, serum calcium levels should be obtained every 1-2 hours while the infusion is adjusted every 4-6 hours thereafter to ensure stability. The calcium infusion should be slowly tapered over 24-48 hours, dependent on the severity of the patient’s presentation and duration ongoing symptoms.

  • Give calcitriol, under the direction of and endocrinologist, if parathyroid hormone (PTH) is normal or low.

  • If the patient is able to take medications orally, start oral calcium supplementation concurrently with the intravenous administration.

  • Search for and treat the underlying cause (e.g., gluten-free diet in celiac disease).

  • Replace magnesium aggressively, if determined to be low.

Asymptomatic or moderate hypocalcemia
  • Search for and treat the underlying cause.

  • Correct levels over days to weeks.

  • Oral supplementation is acceptable. Calcium acetate or carbonate are preferred in renal patients. 1.5-2g of elemental calcium may be required.

  • In vitamin D deficiency, treat with 50.000 international units (IU) of either ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) once a week for 8 weeks to achieve a blood level of 25 (OH) D above 30 nanograms/milliter (ng/ml), then the patient can be transitioned to 800 to 1500 IU daily with periodic monitoring of levels of vitamin D and calcium. Obese, patients with severe deficiency, with malabsorption syndrome or taking anticonvulsants or glucocorticoids should be treated with higher doses such as 50,000 IU orally two times a week and may also require higher maintenance doses once normal levels are achieved.

  • If there is hypoparathyroidism, standard vitamin D supplementation will not work. Therefore, calcitriol should be given to the patient under the direction of an endocrinologist. A typical starting dose is 0.5 micrograms (mcg) of calcitriol with dosage increases every 4-7 days until serum calcium is in the lower part of the reference range.

  • Replace magnesium as needed.

Recommended dosages
  • Calcitriol: 0.25-2 mcg orally or intravenously under the direction of an endocrinologist.

  • Calcium acetate: Start with 2 tabs/capsules orally with each meal.

  • Calcium chloride: Use a central line. Calcium gluconate is preferred. 500-1000 mg slow IV every 1-3 days.

  • Calcium gluconate: 10% (1000 mg/10ml, 4.65 mEq/10ml). 10 ml over 10 minutes intravenously in symptomatic hypocalcemia. A continuous infusion of calcium gluconate may be necessary. It should be infused at a rate of 50 ml/hour with the expectation that a 10 ml/kg solution will increase the serum calcium by 0.3-0.5 mmol/liter over 4-6 hours.

  • Calcium carbonate or citrate: 1-2g elemental calcium daily or more, orally with meals, divided 2-4 times a day.

  • Ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3): Severe deficiency: 50,000-200,000 units orally daily.

  • Osteoporosis prevention and treatment: 800-1,000 units orally daily ergocalciferol or cholecalciferol.

  • Magnesium sulfate: 1 gram (g) of 20% solution IM every 6 hours for 4 doses or 2g IV over 1 hour. May need repeat doses or more aggressive replacement dependent on the severity of the hypomagnesemia.

B. Common Pitfalls in the Diagnosis and Management of hypocalcemia

  • Lack of recognition of the clinical consequences of hypocalcemia.

  • Inadequate history or work-up to determine etiology.

  • Failure to use a central line with calcium chloride.

  • Failure to aggressively replete vitamin D in the setting of severe deficiency.

  • Failure to aggressively replete magnesium in the setting of severe deficiency.

  • Failure to consult endocrinology early when hypoparathyroidism is suspected or diagnosed.

  • Lack of adequate monitoring to prevent recurrence, morbidity, or mortality.

What's the evidence?

Cooper, MS, Gittoes, NJ. “Diagnosis and managment of hypocalcemia”. BMJ. vol. 336. 2008. pp. 1298-302l.

Shoback, D. “Clinical Practice. Hypoparathyroidism”. N Engl J Med. vol. 359. 2008. pp. 391-403.

Fukumoto, S, Namba, N, Ozono, K. “Causes and differential diagnosis of hypocalcemia-recommendation proposed by expert panel supported by ministry of health, labour, and welfare, Japan”. Endocr J. vol. 55. 2008. pp. 787-94.

Bilezikian, JP, Khan, A, Potts, JT. “Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for futre research”. J Bone Miner Res. vol. 26. 2011. pp. 2317-37.

Khan, A, Fong, J. “Hypocalcemia: updates in diagnosis and managment for primary care”. Can Fam Physician. vol. 58. 2012. pp. 158-62.

Holick, MF, Binkley, NC, Bischoff-Ferrari, HA, Gordon, CM, Hanley, DA, Heaney, RP, Murad, MH, Weaver, CM. “Endocrine Society: Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 96. 2011. pp. 1911