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Hypocalcemia – Pathophysiology, Causes, and Treatment

Definition

Hypocalcemia is a condition where blood levels of calcium are low. Hypocalcemia is a total serum calcium concentration < 8.5 mg/dL (< 2.13 mmol/L) in the presence of normal plasma protein concentrations or a serum ionized calcium concentration < 4.7 mg/dL (< 1.17 mmol/L). Normal calcium values range from 8.5 to 10.2 mg/dL (2.13 to 2.55 millimol/L). Symptoms of hypocalcemia include numbness and tingling in the fingers, muscle cramps, convulsions, lethargy, poor appetite, and abnormal heart rhythms.

In a baby, some common causes of hypocalcemia are premature birth, infections, maternal diabetes and some medications. Hypocalcemia can be caused by vitamin D deficiency, which can occur in breastfed babies who are not given vitamin D supplements. Hypocalcemia is frequently encountered in patients who are hospitalized. Depending on the cause, unrecognized or poorly treated hypocalcemic emergencies can lead to significant morbidity or death.

Types

There are 2 types of hypocalcemia in newborns:

Epidemiology

Incidence and prevalence are difficult to estimate because hypocalcemia is a multifactorial diagnosis. Hypocalcemia is particularly a problem for people who are hospitalized. A 2018 study found 27.72% of inpatients had Hypocalcemia.

Pathophysiology

Calcium is vital for many body functions like cell function, nerve transmission, bone structure, intracellular signaling, and blood coagulation. The amount of calcium absorbed from the GI tract is usually matched with renal excretion. The levels of calcium are rigidly controlled by vitamin D, parathyroid hormone, calcitonin, and FGF23. Parathyroid hormone enhances osteoclastic bone resorption and distal tubular reabsorption of calcium. PTH also stimulates the hydroxylation of 25 hydroxyvitamin D to the active form 1,25-dihydroxy vitamin D and renal excretion of phosphate. Vitamin D stimulates intestinal absorption of calcium, renal absorption of calcium and phosphate, and also bone reabsorption. Calcitonin, on the other hand, lowers levels of calcium by inhibiting osteoclast activity.

FGF23 inhibits the conversion of vitamin D to its active form, 1,25-dihydroxy vitamin D, thus reducing intestinal calcium absorption. Acid-base disturbances alter the binding capacity of calcium to albumin and affect the exchange of calcium and hydrogen ions between the intracellular and extracellular space. Acidosis reduces, and alkalosis increases the binding of calcium to albumin, causing increased or decreased levels of ionized calcium, respectively. An alkaline environment lowers ionized calcium levels by exchanging calcium for hydrogen ions, while an acidic environment increases ionized calcium levels by exchanging hydrogen ions for calcium.

Feedback mechanisms maintaining extracellular calcium concentrations within a narrow, physiologic range [8.9–10.1 mg/dL (2.2–2.5 mM)]. A decrease in extracellular (ECF) ionized calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via activation of the calcium sensor receptor on parathyroid cells. PTH, in turn, results in increased tubular reabsorption of calcium by the kidney (2) and resorption of calcium from bone (2) and also stimulates renal 1,25(OH)2 D production (3). 1,25(OH)2 D, in turn, acts principally on the intestine to increase calcium absorption (4). Collectively, these homeostatic mechanisms serve to restore serum calcium levels to normal.

Causes of Hypocalcemia

The levels of calcium are controlled by Vitamin D, parathyroid hormone, calcitonin, and fibroblast growth factor-23 (FGF23).

A number of causes that can cause hypocalcemia are divided into three broad categories:

Other causes

Apart from the above-mentioned causes, other causes that can lead to hypocalcemia include:

Symptoms of hypocalcemia

Symptoms depend on the age of the child; how low the serum calcium level is and how quickly hypocalcemia has occurred.

The following are the most common symptoms of hypocalcemia. However, each child may experience symptoms differently. Symptoms may include:

Hypocalcemia may not be obvious in new-born babies and may only be identified by laboratory tests. The spectrum of clinical features can range from few (if any) if hypocalcemia is mild to life-threatening related to seizures, if more severe. Children are more likely to have symptoms if calcium levels drop suddenly, and symptoms may lessen over time as the body becomes used to hypocalcemia.

Characteristic physical signs may be observed, including Chvostek sign, which is poorly sensitive and specific of hypocalcemia, and Trousseau sign.

Hypocalcemia risk factors

Low calcium levels are more common in those who are very ill. It is also more common in new-born babies who are premature. Other things that raise the risk are:

Problems that interfere with hormones, such as:

Things that make it hard to get enough calcium, such as:

Complications

Calcium deficiency has been linked to:

Diagnosing hypocalcemia

You have hypocalcemia if your total serum (blood) calcium concentration is less than 8.8 mg/dL. Your healthcare provider may find mild hypocalcemia incidentally (by chance) from routine blood tests or by testing for other conditions.

What tests will be done to diagnose the cause of hypocalcemia?

Healthcare providers use a calcium concentration blood test to diagnose hypocalcemia. Figuring out and diagnosing the cause of hypocalcemia is just as important as diagnosing the hypocalcemia itself.

Your healthcare provider may perform the following tests or procedures to try to determine the cause of your hypocalcemia or to be sure your hypocalcemia isn’t affecting other parts of your body:

Treatment for Hypocalcemia

As hypocalcemia is most commonly caused by an underlying condition, treating that condition often resolves the hypocalcemia. This includes correction of magnesium or vitamin D levels with supplementation, correction of nutritional status, correction of acid-base disorder, and treatment of underlying liver or kidney disease.

Acute treatments

IV Calcium Gluconate

Patients with severely acute or symptomatic hypocalcemia require emergent treatment to raise calcium levels. Acute drop to below 7.5 mg/dL should be treated, with or without symptoms. Initially, 1-2 g of IV calcium gluconate in dextrose should be infused over 10-20 minutes. Calcium chloride can also be used; however, calcium gluconate is preferred because it is less likely to cause tissue necrosis if extravasated. This initial bolus must be followed by a slow infusion of 10% calcium in normal saline or dextrose.

Cardioprotective

Calcium has a direct effect on cardiac membrane potential and excitability, acting to stabilize the cardiac membrane. This effect can be cardioprotective in cases of impaired neuromuscular transmission and alterations in membrane potential, such as hyperkalemia. On the other side, an excess of calcium can also cause cardiac dysfunction. For this reason, IV calcium must be given slowly due to the risk of serious cardiac dysfunction and arrest with more rapid infusion.

Chronic treatments

Calcium Carbonate

Mild or chronic hypocalcemia is defined as a total serum corrected concentration of 7.5-8.0 mg/dL, or an ionized calcium level above 3.0mg/dL, with little to no symptoms. In these cases, oral calcium repletion is preferred. Initially, 1500-2000 mg of elemental calcium given as calcium carbonate or calcium citrate is given daily.

Calcium Citrate

Calcium citrate is a more expensive supplement than calcium carbonate, but it is better tolerated by patients when taken on an empty stomach. Both are equally efficacious as oral medications.

Vitamin D Supplements

Vitamin D is often needed in conjunction with calcium supplementation. Correction of vitamin D deficiency will correct hypocalcemia if it is the sole underlying cause. Treatment consists of 50,000 international units of ergocalciferol (vitamin D2) or calcitriol (vitamin D3) given once per week for six to eight weeks. In the case of impaired vitamin D metabolism (renal or hepatic dysfunction), calcitriol must be used as the body cannot activate the vitamin D precursors itself.

Hypocalcemia prevention

Implementing dietary measures is still the most effective form of prevention.

Dietary Recommendations for Calcium Intake in Children

The dietary recommendations for children according to the health experts from HHS and USDA are mentioned below:

Age Group (in years) Female Male
1-3 700 700
4-8 1000 1000
9-13 1300 1300
14-18 1300 1300

As the ability to absorb calcium (which is as high as 60% in infants) drops, there is a need to increase calcium intake with age. This explains the recommendations.

Dietary Recommendations for Calcium Intake in Adults

According to the health experts from USDA and HHS, the dietary recommendations for the intake of calcium in adults are:

Age Group (in years) Female Male
19-30 1000 1000
31-50 1000 1000
51+ 1200 1000

There is a drop in recommended calcium intake because the bone formation is near complete by the age of 19 and over, and therefore a steady intake of 1000 mg is recommended. With the increase in age beyond 50, however, in women, the risk of osteoporosis is higher and therefore the increased intake suggested for women.

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