Approach to hypocalcemia (pediatrics): Clinical sciences

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Introduction0:00–0:35

Hypocalcemia refers to a serum calcium level that is below the lower limit of normal, which is often considered below 8.5 mg/dL.
Calcium plays a vital role in various body functions, such as cardiac muscle function and nerve signaling, so hypocalcemia can result in abnormal cardiac rhythm and neurologic dysfunction.
The evaluation of hypocalcemia depends on whether a patient is a newborn or an older infant or child.Now, if a pediatric patient presents with a chief complaint suggesting hypocalcemia, you should first perform an ABCDE assessment to determine if your patient is unstable or stable.

Unstable Patient0:35–1:40

If unstable, stabilize the airway, breathing, and circulation. Next, obtain IV access and put your patient on continuous vital sign monitoring, including blood pressure, heart rate, and pulse oximetry.
Finally, if needed, provide supplemental oxygen.Now, here’s a clinical pearl to keep in mind! Hypocalcemia can occur in the setting of critical illness.
In cases where hypocalcemia is severe or develops rapidly, your patient might have stridor secondary to laryngospasm, as well as seizures or a prolonged QT interval on an ECG.
In such cases, you should administer intravenous calcium gluconate to restore blood calcium levels. Also, don’t forget that hypomagnesemia often occurs along with hypocalcemia, so consider giving IV magnesium as well.
Okay, let’s go back to the ABCDE assessment and discuss the stable patients. If your patient is stable, first obtain a focused history and physical examination, and order a serum calcium level.

Stable Patient1:40–2:30

Your patient may report weakness, paresthesias of the fingers and toes, and muscle cramps. Additionally, the physical exam might reveal positive Chvostek or Trousseau signs.
The Chvostek sign is positive if tapping over the muscles overlying the facial nerve causes facial muscle spasms. On the other hand, the Trousseau sign occurs when inflating a blood pressure cuff over a patient’s arm causes a spasm of their hand.
You can easily remember them as Chvostek for Cheek, and Trousseau for Triceps! Finally, labs will be notable for a serum calcium that is below reference range.At this point, you should consider hypocalcemia so your next step is to order serum albumin and magnesium.

Consider hypocalcemia2:30–2:38

Now, if both serum albumin and magnesium are normal you can diagnose hypocalcemia! However, if the serum albumin is normal but the serum magnesium level is low, you can diagnose hypocalcemia secondary to magnesium deficiency.

Hypocalcemia2:38–2:44

Magnesium deficiency2:44–3:14

Keep in mind that magnesium is required for the production of parathyroid hormone, or PTH, and low levels of PTH lead to hypocalcemia.
However, correcting magnesium levels can restore normal PTH production, eventually bringing serum calcium levels back to normal.Now, let’s go back and discuss cases where the serum albumin is low and the serum magnesium level is normal.

Pseudohypocalcemia3:14–4:21

Here, you should consider pseudohypocalcemia, meaning the low albumin level is causing a false result. This is because approximately half of the calcium in the blood is bound to plasma proteins, mainly albumin, while the other half circulates as ionized calcium.
So, when you’re measuring serum calcium in the setting of low serum albumin, there's a chance of getting false results since the albumin-bound calcium is also affected.
In this case, you should calculate a corrected serum calcium level. Do this by subtracting the patient's serum albumin level from 4 and multiplying the difference by 0.8.
Next, add the product to the measured serum calcium, and you will get the corrected calcium level. If the corrected serum calcium is normal, your patient does not have true hypocalcemia, and you can diagnose pseudohypocalcemia.
Finally, if the corrected serum calcium is low, again diagnose hypocalcemia. Now, once you diagnose hypocalcemia, the next step is to assess your patient’s age.

Corrected calcium - Hypocalcemia4:21–4:29

Assess age: 4 days and younger4:29–5:21

If your patient is a newborn, you’ll need to assess the onset of hypocalcemia. Hypocalcemia within four days of life is usually transient and associated with conditions such as birth asphyxia, prematurity, fetal growth restriction, maternal diabetes, or sepsis.
In this case, you should consider early-onset neonatal hypocalcemia, which typically resolves spontaneously; but you can also consider oral calcium supplementation!
Next, repeat a serum calcium level. If serum calcium is normal, you can confirm the diagnosis of early-onset neonatal hypocalcemia.On the flip side, if the hypocalcemia began after the fourth day of life, you should consider genetic causes of hypocalcemia, like DiGeorge syndrome.

> 4 days, DiGeorge5:21–5:59

In these individuals, prenatal ultrasound might reveal conotruncal heart defect, or cleft lip and palate, with hypertelorism or ear anomalies.
If you suspect DiGeorge syndrome, order a fluorescent in-situ hybridization test, or FISH for short. The finding of 22q11.2 microdeletion confirms the diagnosis of DiGeorge Syndrome.Alright, now let’s switch gears and discuss hypocalcemia in infants and older children.

Assess age: infants and older children5:59–6:36

In this case, your next step is to order additional labs, including a basic metabolic panel or BMP and serum phosphate level; as well as a serum PTH level.
Additionally, check levels of 25-hydroxyvitamin D, which is the inactive form of vitamin D; and 1,25-dihydroxyvitamin D, which is the active form of vitamin D.
Finally, send a urine sample to assess the calcium-to-creatinine ratio.First, let’s take a look at the urine calcium-to-creatinine ratio.

Autosomal dominant hypocalcemia type I6:36–7:24

An elevated ratio is suggestive of a calcium-sensing receptor, or CaSR, mutation, so order a genetic mutation analysis. The presence of a gain-of-function mutation in the calcium-sensing receptor confirms a diagnosis of autosomal dominant hypocalcemia type I.
In this particular disorder, a mutation in the calcium-sensing receptor makes cells more sensitive to calcium levels, resulting in abnormally low PTH secretion.
Less PTH means that there’s less reabsorption of calcium within the kidneys and that osteoclasts are not releasing the calcium from bones, which eventually results in hypocalcemia.On the other hand, if the urine calcium-to-creatinine ratio is normal, you’ll need to assess the serum PTH.

Primary hypoparathyroidism7:24–7:55

If the PTH is low or normal, diagnose primary hypoparathyroidism, which is most commonly iatrogenic, resulting from parathyroid gland damage after surgery or radiation treatment.
Occasionally, the parathyroids can be damaged by autoimmune disorders, such as polyglandular autoimmune syndrome.On the flip side, if the PTH is elevated, your patient has secondary hyperparathyroidism, so your next step is to check 25-hydroxy- and 1, 25-dihydroxyvitamin D levels.

Secondary hyperparathyroidism7:55–8:08

If 25-hydroxyvitamin D is normal and 1, 25-dihydroxyvitamin D is low, consider the possibility of impaired conversion of vitamin D to its active form.

Renal failure8:08–8:55

Next, assess the serum BUN, creatinine, and phosphate levels, and if they are all elevated, you can diagnose renal failure.
Normally, the kidneys convert vitamin D from its inactive to its active form, but when renal function is impaired, the conversion process is also affected, leading to lower serum calcium levels.
Hyperphosphatemia resulting from reduced glomerular filtration and low renal responsiveness to PTH also contribute to hypocalcemia.On the flip side, if the serum BUN and creatinine are normal, but the serum phosphate level is low, consider the possibility of vitamin D-dependent rickets type 1.

Type I vitamin D-dependent rickets8:55–10:12

In this case, order a genetic mutation analysis, and if you identify a CYP mutation, confirm the diagnosis of vitamin D-dependent rickets type 1.
This form of rickets is caused by a defect in the enzyme called 1-alpha hydroxylase that converts 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D.Now here’s a clinical pearl to keep in mind!
Rickets refers to a group of disorders of bone mineralization, all of which involve a disruption of calcium and phosphate homeostasis.
While vitamin D deficiency is the most common form of rickets, there are other subtypes, such as vitamin D-dependent rickets, which is caused by defects in vitamin D metabolism; renal rickets, which is caused by reduced kidney function; and hypophosphatemic rickets, which is caused by renal phosphate wasting.
All forms of rickets can lead to poor linear growth, bowing of the lower extremities, frontal bossing of the skull, and hypotonia.On the other hand, if both the 25-hydroxy- and 1,25-dihydroxyvitamin D levels are low, diagnose vitamin D deficiency.

Vitamin D deficiency10:12–10:41

This commonly occurs in the setting of low dietary vitamin D intake, or UVB light exposure, but it can also be caused by liver failure; as well as conditions associated with fat malabsorption, such as inflammatory bowel disease, celiac disease, or cystic fibrosis.
Finally, if both forms of vitamin D are within the normal range, consider pseudohypoparathyroidism, which is a rare genetic condition associated with end-organ resistance to PTH.

Pseudohypoparathyroidism10:41–11:35

To confirm the diagnosis, order genetic mutation analysis, and if you identify the GNAS mutation, diagnose pseudohypoparathyroidism.
Now here’s one last clinical pearl! In some cases hypocalcemia can be iatrogenic, such as with the use of medications like loop diuretics, phenytoin, or oral phosphate preparations.
Additionally, transfusion of citrated blood products can cause chelation of calcium in the blood, leading to hypocalcemia.
Always be sure to review your patient’s recent medications and medical interventions, to determine whether their hypocalcemia has an iatrogenic cause.Alright, as a quick recap… If you suspect hypocalcemia, obtain a focused history and physical exam, and order serum calcium and magnesium levels.

Review11:35–12:49

Once you rule out hypomagnesemia and pseudohypocalcemia, assess your patient's age. Early-onset hypocalcemia in newborns usually results from an underlying cause such as prematurity or maternal diabetes, while later onset neonatal hypocalcemia could be due to a genetic condition such as DiGeorge Syndrome.
On the other hand, infants and older children with hypocalcemia should have additional labs to identify an underlying cause.
Elevated urine calcium to creatinine ratio suggests autosomal dominant hypocalcemia. A low or normal PTH level indicates primary hypoparathyroidism, whereas an elevated PTH indicates secondary hyperparathyroidism.
Important causes of secondary hyperparathyroidism include renal failure, autosomal dominant hypocalcemia, vitamin D deficiency, vitamin D-dependent rickets type I, and pseudohypoparathyroidism.