80% of all calcium is bound to albumin in circulation. However, the biologically active form of calcium is the free, or ionized form, which is occasionally ordered as a separate test. Typically, a total serum calcium level should be used as a screening test. And if low, an ionized calcium level should be ordered prior to treatment, as the active form of calcium may actually be normal despite a low total calcium level.
Calcium plays many important biological functions, including building strong bones and teeth, clotting of blood, Sending and receiving nerve signals, muscle contraction and relaxation, cardiac contraction and in the release of many hormones from both the anterior and posterior pituitary in the brain.
Blood calcium levels are regulated to keep a total serum calcium concentration around 10 mg/dL. Serum levels are primarily controlled by 3 hormones (PTH, 1,25-dihydroxyvitamin D and Cacitonin). As blood calcium levels fall, the parathyroid gland, which are located within the thyroid, secretes the hormone parathyroid hormone, or PTH. PTH can directly stimulate Calcium uptake in the kidneys, resulting in an increased blood calcium levels. The kidney also activates Vitamin D to increase calcium uptake in the intestines, again increasing blood calcium levels. Finally, PTH also stimulates calcium reabsorption from calcium stores in bones, further increasing serum calcium levels. Calcitonin causes direct inhibition of bone resorption with increased calcium levels.
HYPERCALCEMIA
Hypercalcemia can be caused by hyperparathyroidism, where an excess amount of PTH is released, by excessive Vitamin D intake, which increases calcium reabsorption in the intestines, Thiazide diuretic use, which causes calcium sparing in the kidney, adrenal insufficiency, and certain types of cancers, such as multiple myeloma which cause hormone mediated increases in calcium similar to PTH. Patients with heartburn may take excessive amounts of calcium carbonate or tums, which increase serum calcium levels, which is known as milk-alkali syndrome.
Causes:
- Hyperparathyroidism (usually mild, < 11.2)
- Malignancy (Usually rapid rise)
- Vit. D excess
- Hyperthyroidism
- Thiazide diuretics
- Milk-alkali syndrome
- Adrenal insufficiency
Patients experience the pathomnemonic symptoms of “stones, bones, groans and psychiatric overtones.” That is, patients can experience bone loss from higher levels of calcium reabsorption and inappropriate bone remodeling, kidney stones and kidney disease from increased calcium concentrations in the renal tubules, psychiatric disturbances and abdominal pain.
Additional Labs:
Lab values can give clues into the underlying process causing hypercalcemia. Lets quickly review the key players here…
PTH – a decrease in calcium levels leads to an increase in PTH secretion, which increases bone resorption, renal and intestinal absorption as well as increased urinary phosphate excretion.
Vitamin D – a decrease in calcium leads to activation of vitamin D, which increases bone and intestinal resorption
Calcitonin – causes direct inhibition of bone resorption with increased calcium levels
- PTH
- ↑ – primary hyperparathyroidism
- If < 20 pg/mL = Consider Vit D and add on a PTH-rP (increased in some cancers)
- Vitamin D
- 25-hydroxy Vit D = ↑ with exogenous intake
- 1,25-dihydroxy Vit D = ↑ with lymphoma, sarcoid
Hypercalcemia Treatment
Treatment Goals
- Immediate therapy for corrected total > 14 mg/dL regardless of symptoms
- Asymptomatic, mild hypercalcemia does not require emergent treatment
Step 1: Restore IV volume
- 200-300 mL/hr isotonic saline (titrate to UOP 100-150/hr)
- Often need 2-5 L/day
Step 2: Renal Elimination
- After volume expansion – Give Lasix if Ca still high or if fluid overload
- Don’t use in children – may decrease GFR and worsen hypoCa
Step 3: Inhibit Osteoclastic activity
- Reduce mobilization of Ca from bone with Bisphosphonates of Calcitonin
- Likely safe in children
Admission Criteria:
- Corrected total Ca > 13
- Symptomatic or EKG changes
- ICU admit if > 14
Discharge Criteria
- Asymptomatic
- Corrected Ca < 13
HYPOCALCEMIA
Hypocalcemia is seen when ionized calcium levels drop below 4.6 mg/dL. This can occur from an increased loss of calcium or from decreased entry of calcium into circulation. Roughly half of circulating calcium is pound to proteins (mainly albumin) and roughly half is ionized, which is thee free and active form. Therefore, it should not be surprising that hypoalbuminemia is the most common cause of hypocalcemia. can be due to an underactive parathyroid gland, vitamin D deficiency, renal failure or any disease process that causes calcium sequestration such as pancreatitis.
Causes
- Hypoalbuminemia – most common
- Hypoparathyroidism
- Vitamin D deficiency
- Chronic renal failure
- Calcium sequestration (pancreatitis, citrate exess after blood transfusions, acute PO4 increase in rhabdo)
- Hypomagnesemia
- Medications – PPI, Bisphosphonates, Calcitonin, Phenytoin, Phenobaarbital, Colchicine
Symptoms of hypocalcemia typically occur when ionized calcium levels fall to < 3.2 mg/dL but are also dependent on the rate at which the level falls. These include psychiatric disturbances such as irritability, confusion, delusions, chorea and parkinsonisms. Cardiovascular disturbances include bradycardia , QT and ST prolongation that can progress to heart block and Torsades de pointes. Neurologic manifestations include paresthesias, hyperreflexia, muscle spasms, seizures and tetany.
Clinical signs such as Chvostek and Trousseau signs may be seen. Chvostek sign includes tapping your finger over the parotid gland over the facial nerve, which causes muscle spasm. Trousseau sign is when you see a slow carpopedal spasm when a blood pressure cuff is inflated over the upper arm.
Additional Labs:
Lab values can give clues into the underlying process causing hypocalcemia. Lets quickly review the key players here…
PTH – a decrease in calcium levels leads to an increase in PTH secretion, which increases bone resorption, renal and intestinal absorption as well as increased urinary phosphate excretion.
Vitamin D – a decrease in calcium leads to activation of vitamin D, which increases bone and intestinal resorption
Calcitonin – causes direct inhibition of bone resorption with increased calcium levels
- PTH
- ↑↑ – Pseudohypoparathyroidism
- ↑ – Vitamin D Deficiency
- ↓ – Hypoparathyroidism
- Phosphate
- ↑ – Hypoparathyroidism
- ↓ – Vitamin D Deficiency
Hypocalcemia Treatment
Treatment is to replace calcium. If the patient is symptomatic, this is given as calcium gluconate or calcium chloride IV.
Caution should be given to patients on Digoxin receiving IV calcium, specifically calcium gluconate, as there is a theoretical risk of causing calcium influx into myocardial cells resulting in a phenomenon known as “stone heart” resulting in malignant dysrhythmias. I will say, literature has not reproduced evidence that this is causation.
- Basis of the theory…
- Digoxin inhibits Ca transport out of myocytes AND form Ca-channels in lipid bilayers – import Ca
- Ca was found to increase digoxin toxicity in animal models
- Only 5 total case reports showing a temporal increase in mortality (all from the 1930-1950’s)
- Issues with this theory…
- Several case reports also showing no harm
- Of the 5 case reports, no report of digoxin levels and only 2 showed a temporal increase in mortality
- Animal models have not been able to reproduce early models (Hack et al, 2004)
- Early animal models were severely hypocalcemic (> 15 mM/L) prior to Digoxin administration (Noel, 1970)
- Levine et al, 2011
- Showed no dysrhythmias or increased mortality with chronic Digoxin use and IV Calcium (2020 patients)
- Only level of K associated with increased mortality (OR 1.5 for each 1 mEq/L increase in serum K)
- Only 1 case was digoxin toxic (no clear evidence to date either way if dig toxic)
Acute Treatment – Should be done with IV Calcium if symptomatic
- Bolus infusions over 20 min
- Faster rates can cause cardiac dysrhythmias
- Bolus doses only increase Ca for 1-2 hours, so patients with severe hypocalcemia should be followed with an infusion at 0.5-3 mg/kg/hr (will raise serum levels by 1.2-2 mg/dL over 4-6 hours)
- Monitor ionized Ca levels every 1-2 hours and adjust infusion rate as needed.
Which Calcium formulation should I use?
- Calcium Gluconate: 1–2 g in 50 mL D5W (1g=90mg [4.5 mEq] elemental Ca)
- Preferred form if patient is stable
- Calcium Chloride: contains 3 x the elemental Ca (13.6 vs 4.6 mEq in 10 mL of a 10% solution)
- Preferred if unstable – make sure IV is a good one
- More likely to cause tissue necrosis with extravasation (best to use a central line)
- Calcium Gluceptate: 1g in 5 mL (1g=90mg [4.5 mEq] elem Ca)
- Can be given IV or IM
Pediatric Considerations
- Calcium Gluconate 1 – 2 mL/kg not to exceed 5 mL in premature infants or 10 mL in term infants
Replace Vitamin D
- Calcitriol (1,25 dihydroxyvitamin D) is the most active vitamin D metabolite. Further, it does not require hydroxylation in liver or kidney and therefore has a rapid onset of action and can be used in patients with rental failure
- Give at a dose of 0.25-1 mcg IV or PO 1-2 times daily
- Give to all patients with severe hypocalcemia (don’t wait for PTH and Vitamin D levels to result)
Replace Magnesium
- Magnesium converts Vitamin D into its active form.
- 2g IVPB 10% solution over 10 min
- Faster rates can cause cardiac dysrhythmias
Admission Criteria:
- Symptomatic or EKG changes
- Ionized Ca < 3.2 mg/dL
- Continuous IV calcium necessary
Discharge Criteria
- Asymptomatic
- Ionized Ca > 3.2 mg/dL in healthy patients with no comorbid illnesses
Chronic Treatment – Can be done with PO Calcium if asymptomatic
- Typical starting doses are 1-2 grams of elemental calcium divided 2-3 times daily
- May need up to 4 g/day in patients with malabsorption
- Doses may need to be adjusted based on tolerance, compliance and treatment goals.
Calcium carbonate (1 g = 400 mg elem Ca)
- Should be taken with food
- GI upset and constipation can occur
- Requires acidic environment for absorption
- Do not use this form if on a PPI
Calcium citrate (1 g = 211 mg elem Ca)
- Preferred in patients on a PPI
- Less GI adverse effects
- Does not need to be taken with food
Calcium glubiomate (1 g = 65 mg elem Ca)
- Small dose of elemental Ca, would need many pills
Calcium gluconate (1 g = 90 mg elem Ca)
- Small dose of elemental Ca, would need many pills
Calcium lactate (1 g = 130 mg elem Ca)
- Small dose of elemental Ca, would need many pills
Don’t forget to supplement Vitamin D as well
- Ergocalciferol (Vitamin D2) or Cholecalciferol (Vitamin D3) if no history of hypoparathyroidism or renal failure
- 50,000 IU weekly or 6,000 IU daily for 6 weeks
- Consider increased dose 2-3 fold if obese, malabsorption syndrome or drug induced Vitamin D deficiency
- Recheck Vitamin D levels every 1-3 months to avoid toxicity
- Calcitriol if patient has a history of liver or renal failure
- Ergocalciferol (Vitamin D2) or Cholecalciferol (Vitamin D3) if no history of hypoparathyroidism or renal failure
Calcium content in food
Milk or yogurt (8 oz) = 300 mg
Cheddar cheese (1 oz) = 200 mg
Ca-fortified cereal (1 cup) = 300 mg
Ca-fortified orange juice (1 cup) = 270 mg
Shrimp (3 oz) = 50 mg
Peanuts = 130 mg
Orange = 50 mg
- Monoclonal Antibodies for COVID-19 – An evidence based update - January 18, 2022
- COVID-19 Vaccines in Pregnancy - January 6, 2022
- COVID-19 Boosters….are they necessary? - October 8, 2021