EM@3AM: Hyper- and HypoCa

Author: Dustin Taliaferro, DO (Emergency Medicine Resident, UT Southwestern, Dallas, TX) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

A 59-year-old male presents to the emergency department with left sided flank pain. He was sitting in a chair 4 hours ago when the pain suddenly started. The pain has been constant since onset. He endorses radiation of the pain into the LLQ of his abdomen and slightly into the left inguinal region. This problem has never happened before. His last bowel movement was earlier in the morning. He has been nauseous but has not vomited. He denies any urinary symptoms. His only medical problem is CML.

Initial vital signs: BP 132/80, HR 100, T 98.2 Oral, RR 20, SpO2 98% on RA.

Physical exam reveals a patient who appears uncomfortable laying on the bed in moderate distress. He is A&OX3. His lungs and heart are normal. There is mild TTP in the LLQ with no guarding or rebound. Testicular exam is normal.

What is your presumed diagnosis, and what is the most likely contributor?

Answer: Renal calculi secondary to hypercalcemia

From Dr. Katy Hanson at Hanson’s Anatomy:

Background: Calcium is the most abundant mineral in the body, comprised of 50% active ionized Ca and 50% calcium bound to albumin in extracellular fluid. One of calcium’s primary roles is stabilizing the resting membrane potential of cells.


  • Normal total serum (corrected) calcium is 2.1-2.6 mmol/L (8.5-10.5 mg/dL)
  • Normal ionized calcium is 1.1-1.3 mmol/L (4.65-5.25 mg/dL)
    • Generally, people become symptomatic at levels corrected total calcium levels of >3.0 mmol/L.
    • Levels of corrected total calcium >3.4 mmol/L can be emergent.
  • Calcium/Albumin relationship
    • Total serum calcium is directly related to serum albumin, while ionized calcium is inversely related to serum albumin.
    • Total serum calcium is adjusted by 0.8 mg/dL for every 1g/dL change in serum albumin.
  • Ionized calcium is pH dependent
    • Alkalotic environment causes increased binding to albumin, thus lowering levels of active ionized calcium.
    • Acidotic environment causes dissociation from albumin, thus increasing levels of active ionized calcium.

Signs and Symptoms of Hypercalcemia

  • Most patients are asymptomatic and will be found hypercalcemic incidentally during workup for other complaints. However, symptoms of early hypercalcemia can be very vague and be mistaken for other diseases. The typical phrase used to remember symptoms of hypercalcemia is “Bones, stones, groans, and psychic moans”
  • Constitutional: weakness, lethargy, malaise, polyuria, and polydipsia
  • Neurologic: muscle weakness and paresis; hypotonia and hyporeflexia may mimic focal lesions
  • Cardiovascular: arrhythmias, hypertension
  • Bones: bone pain complaints will usually be generalized and nonspecific but may also be present in the setting of Paget’s or metastatic disease. Pathologic fractures may also be the source of “bone pain” secondary to osteoporosis.
  • GI: anorexia, constipation, pancreatitis, PUD (due to increased gastrin production), nausea, and vomiting
  • Renal: Colic, nephrolithiasis, nephrocalcinosis from chronic hypercalcemia
  • Psychiatric: anxiety, depression, hallucinations, CNS depression

Causes of Hypercalcemia

  • More than 90% of symptomatic hypercalcemia cases are due to hyperparathyroidism or malignancy.
  • Primary Hyperparathyroidism
    • Almost always due to a functioning parathyroid adenoma. PTH directly stimulates calcium reabsorption in the distal tubules of the kidney. PTH also indirectly stimulates osteoclasts to release calcium and phosphate from bones. Increased active vitamin D (calcitriol) from excess PTH leads to increased absorption of calcium from the GI tract, renal tubules, and bones.
  • Malignancy
    • Mainly due to 3 causes: paraneoplastic production of PTHrP, osteolytic metastases, and paraneoplastic production of calcitriol. PTHrP is the most common malignant source and functions identical to PTH. Malignancies that produce PTHrP are SCC, lymphoma, leukemia, renal/bladder/breast/ovarian cancers. Origins of osteolytic metastases include multiple myeloma, renal and prostate cancer, lymphoma, and leukemia. Origins of malignant calcitriol production include lymphoma and ovarian dysgerminoma.
  • Sarcoidosis and TB
    • Hydroxylase activity in activated mononuclear cells produces extrarenal calcitriol.
  • Drug Related
    • Vitamin D or calcium supplement intoxication.
    • Thiazide diuretics-reduce renal calcium excretion.
    • Thyroxine-supratherapeutic levels of thyroxine can cause increased bone turnover.
    • Lithium-lithium toxicity results in excessive PTH.
  • Renal Failure
    • CKD causes secondary hyperparathyroidism in response to chronically low calcium levels. The parathyroid glands proliferate until one may become autonomous. This autonomous gland produces an excess amount of PTH leading to hypercalcemia (ultimately transitioning to tertiary hyperparathyroidism).
  • Other causes include endocrine (Addison’s, pheochromocytoma, hyperthyroidism), immobilization, and milk-alkali syndrome.


  • EKG Changes
    • Levels of total Ca >4 mmol/L are associated with bradyarrhythmias and VF arrest. Osborn Waves are also seen at critically high levels. The most common change seen is shortened QT interval. Other changes include depressed ST segments, widened T waves, and shortened ST segments. As calcium levels increase, the QRS will widen and evolve into a complete heart block.
  • Hypercalcemic Crisis
    • Occurs at total Ca levels >3.5 mmol/L or an ionized Ca level >2.5 mmol/L. Symptoms include dehydration, nausea, vomiting, fever, psychosis, and somnolence.

History and Exam

  • Many patients present with vague, nonspecific symptoms. Patients may present with a myriad of symptoms suggestive of hypercalcemia thus warranting a thorough history. Common complaints include weakness, muscle paresis, “bone pain” due to pathologic fractures, renal colic, abdominal pain, N/V, constipation, and neuropsychiatric disturbances. If hypercalcemia secondary to another disease process is suspected, information will need to be obtained related to the suspected underlying process.
  • Most patients suspected of having hypercalcemia warrant a thorough exam. Neurologic exam may show extremity weakness, hypotonia, and hyporeflexia. If a pathologic fracture is suspected, then neurovascular evaluation of the limb is needed. Primary GI conditions need to be considered (appendicitis, cholecystitis, etc.). Pancreatitis can also occur due to Ca abnormalities.


  • A basic chemistry panel will provide the level of the total calcium level. To confirm this number, an ionized calcium level can be ordered, or use serum albumin to find the level of corrected calcium. MDCalc makes this easy. Creatinine can give a clue on whether the patient may have hypercalcemia secondary to CKD. Lipase is useful for evaluation of suspected pancreatitis.
  • ECG should be obtained all patients to look for changes related to calcium levels.
  • Any suspected pathologic fractures or metastases warrant films for evaluation. If patient has suspected nephrolithiasis, the appropriate imaging included US vs CT.


  • Symptomatic and corrected total Ca >3.5 mmol/L (14 mg/dL)
  • Mainstay to treatment is volume expansion with diuresis. 500 to 1000 mL/h of 0.9% NS should be given in the first 2-4 hours. 3-4 total liters should be given over the first 24 hours to achieve a urine output of 2 liters per day. Magnesium and potassium will need to be monitored due to being excreted in the urine. The rate of fluid resuscitation will have to be tailored to the patient’s cardiovascular status (CHF, CKD/ESRD).
  • Furosemide has historically been given after fluid resuscitation. This has become controversial due to unproved efficacy and possible worsening hypercalcemia through furosemide possibly promoting bone reuptake[2]. Recent recommendations have suggested mainstay in treatment should be fluids and bisphosphonates. DO NOT administer thiazide diuretics as this will worsen the hypercalcemia.
  • Bisphosphonates block bone resorption by osteoclasts. They are typically indicated in malignancy associated hypercalcemia and are prophylactically used in known bony metastases. Effects from bisphosphonates are usually seen in 24-48 hours with effects lasting up to 15 days. Zoledronic acid 4 mg IV given over 15 minutes is the recommended choice.
  • Calcitonin 4u/kg IM or SC works faster than bisphosphonates. It works by increasing renal excretion of calcium and blocking osteoclast activity. Typical onset is 4-6 hours, and it is usually given in conjunction with bisphosphonates.
  • Corticosteroids decrease osteoclast activity and can be given in Addison’s disease and steroid responsive malignancies. Initial dose of hydrocortisone 200-300 mg IV or prednisone 1-2 mg/kg can be given, though the onset of action is delayed.
  • Cinacalcet works by sensitizing the parathyroid to circulating calcium levels. This increases the negative feedback loop and decreases PTH release. Indications for this are secondary hyperparathyroidism in renal failure and primary hyperparathyroidism when surgery is not an option.


  • In patients with symptomatic and severe disease, admission is warranted for further fluid resuscitation and electrolyte monitoring. Further work up targeting underlying cause is needed.
  • Patients that are mild to moderately hypercalcemic may be discharged home with close follow up. Instructions should be given to avoid dehydration, high calcium diets and prolonged bed rest or inactivity.



  • Defined by total corrected calcium levels drop below 2.1 mmol/L or ionized levels are below 1.1 mmol/L.
  • Severity of signs and symptoms depend on rate of decrease in serum calcium.

Signs & Symptoms

  • Neuromuscular excitability-perioral numbness, paresthesia, cramps, seizures, tetany
  • Ventricular dysrhythmias
  • Abdominal cramping and diarrhea
  • Osteodystrophy, osteomalacia
  • Hyperpigmentation, coarse and brittle hair, dry skin
  • Neuropsychiatric symptoms


  • Decreased intake/absorption
    • Oral calcium and vitamin D
    • Malabsorption syndromes such as celiac disease and tropical sprue
  • Redistribution and increased excretion/bone resorption
    • Alkalosis, citrate toxicity (massive transfusions), pancreatitis, hyperphosphatemia, tumor lysis syndrome, hypoparathyroidism (post-surgical or autoimmune), drugs (bisphosphonates, loop diuretics, phenytoin, antibiotics), hemorrhage, plasmapheresis, hydrofluoric acid, burns, DiGeorge’s Syndrome


  • May show signs of tetany such as Chvostek’s or Trosseau’s sign
  • Hypotension, long QT interval, heart failure
  • Patient may have other signs relating to underlying cause of hypocalcemia


  • Chemistry panel will give calcium level. Ionized calcium may be obtained or corrected calcium level can be calculated.
  • In malabsorption or alcoholism, magnesium will be decreased.
  • Phosphate will be elevated in hypoparathyroidism, pseudohypoparathyroidism (Albright Syndrome), and CKD; will be normal to decreased in Vitamin D deficiency.
  • Other tests to identify underlying cause such as lipase, creatinine, and CK.
  • ECG will show prolonged QT. Hypocalcemia has also been associated with ventricular arrhythmias such as Torsades.


  • In asymptomatic patients or not severely low (ionized Ca >1 mmol/L), the patient should be provided oral calcium 500 to 3000 mg a day with Vitamin D.
  • IV calcium is indicated if patient is symptomatic and ionized Ca <1 mmol/L. Give 10% calcium chloride 10 mL or 10% calcium gluconate 10-30 mL over 20 minutes. Can repeat until symptoms resolve or initiate an infusion of 10% calcium chloride .02 to .08 mL/kg/h.
  • Magnesium will need to be replaced along with calcium.
  • Do not give patients calcium taking cardiac glycosides.
  • If the cause is due to loop diuretic, change patient to thiazide diuretics.


  • Patients with asymptomatic or only slightly decreased levels can be discharged on home oral calcium.
  • If severe disease, admission for electrolyte monitoring and investigation of underlying cause.

A 45-year-old woman with a history of breast cancer presents to the emergency department with weakness, confusion and constipation. She is found to have a serum calcium concentration of 15 mg/dL. What is the most appropriate initial treatment?

A) Furosemide

B) Normal saline

C) Pamidronate

D) Prednisone



Answer: B

Hypercalcemia is usually mild (< 12 mg/dL), asymptomatic and typically does not require emergent treatment. Hypercalcemic crisis, however, occurs in a subset of patients where the serum calcium concentration is usually greater than 14 mg/dL and requires emergent treatment. Hypercalcemic crisis occurs most often in patients with primary hyperparathyroidism, malignant disease or secondary to medications (e.g. thiazide diuretics, lithium, estrogens). The clinical manifestations are nonspecific, vary widely, and can include neurologic (fatigue, lethargy) cardiovascular (shortening of the QT interval on ECG, bradycardia), renal (dehydration, nephrolithiasis) and gastrointestinal (nausea, vomiting, constipation) findings. Goals of therapy include a stepwise process of volume repletion, renal calcium elimination, osteoclast inhibition and treatment of the primary disorder. Initial treatment is the administration of normal saline to increase intravascular volume.

Furosemide (A) is a loop diuretic that inhibits the resorption of calcium in the ascending loop of Henle. As intravascular volume is repleted with normal saline initially, furosemide then adds to the calciuric effect by blocking the resorption of calcium. Pamidronate (C) is a bisphosphonate that inhibits osteoclastic activity, thus reducing calcium mobilization from bone. Prednisone (D) is a glucocorticoid that inhibits the action of vitamin D. The active form of vitamin D enhances intestinal absorption of calcium. Prednisone is effective in primary disorders that led to excess vitamin D, such as granulomatous disorders or vitamin D intoxication.

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LITFL Hypercalcemia

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  1. Body, Jean-Jacques, et al. “Hypercalcaemia and Hypocalcaemia: Finding the Balance.” Supportive Care in Cancer, vol. 25, no. 5, 2017, pp. 1639–1649., doi:10.1007/s00520-016-3543-1.
  2. Legrand, Susan B., et al. “Narrative Review: Furosemide for Hypercalcemia: An Unproven Yet Common Practice.” Annals of Internal Medicine, vol. 149, no. 4, 2008, p. 259., doi:10.7326/0003-4819-149-4-200808190-00007.
  3. Mirrakhimov, Aibeke. “Hypercalcemia of Malignancy: An Update on Pathogenesis and Management.” North American Journal of Medical Sciences, vol. 7, no. 11, 2015, p. 483., doi:10.4103/1947-2714.170600.
  4. Tintinalli, Judith E., et al. Tintinallis Emergency Medicine: a Comprehensive Study Guide. 8th ed., McGraw-Hill Education, 2016.
  5. Walls, Ron, et al. Rosen’s Emergency Medicine: Concepts and Clinical Practice. 9th ed., Elsevier, 2017.

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