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:

• Early hypocalcemia. This happens in the first 2 to 3 days of a baby’s life. To some degree it’s part of a normal developmental process. It’s more likely to go away with nutrition support.
• Late hypocalcemia. This starts in the first week or weeks after birth and is less likely to go away.

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).

• Parathyroid hormone (PTH) enhances bone resorption and reabsorption of calcium. PTH also stimulates the conversion of Vitamin D (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 bone resorption.
• FGF23 inhibits the conversion of Vitamin D to its active form, thus reducing intestinal calcium absorption.

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

•  Parathyroid hormone (PTH) deficiency
•  High parathyroid hormone (PTH)
•  Other causes

Other causes

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

• Acute pancreatitis: Hypocalcemia is often associated with acute pancreatitis as inflammation of pancreas leads to calcium deposition in the abdominal cavity.
• Hypoproteinemia: Refers to lower-than-normal levels of protein in the body. This reduces the protein-bound fraction of serum calcium.
• Magnesium depletion: This can cause relative PTH deficiency and end-organ resistance to PTH action, usually when serum magnesium concentrations are < 1.0 mg/dL [< 0.5 mmol/L] leading to lower calcium levels.
• Severe sepsis or critical illness: Severe sepsis can lead to hypocalcemia through ways that are not clear. Proposed mechanisms include impaired PTH secretion, dysregulation of magnesium metabolism, and impaired calcitriol secretion. Recent reports also indicate that hypocalcemia is associated with severe Covid-19 infection.
• Hyperphosphatemia: This is an uncommon cause of hypocalcemia which is mostly caused by extravascular (outside a blood or lymph vessel) deposition of calcium phosphate products.
• Massive blood transfusion: Transfusion of >10 units of citrate-anticoagulated blood can cause hypocalcemia. Citrate binds with calcium leading to an acute decline in ionized calcium.
• Radiocontrast agents: These contain the chelating agent ethylenediaminetetraacetate (EDTA) which can decrease the concentration of bioavailable ionized calcium while total serum calcium concentrations remain unchanged.
• Pregnancy: Hypocalcemia is seen during pregnancy, mostly related to poor diet, extreme and persistent nausea, vomiting, or any underlying diseases.

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:

• Irritability
• Muscle twitches
• Jitteriness
• Tremors
• Poor feeding
• Lethargy
• Seizures
• Difficulty breathing
• Difficult walking or using the hands

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:

• Parathyroid problems and surgery
• Previous thyroid surgery
• Immune system problems
• Certain types of brain cancer
• Certain inherited disorders

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

• Lack of vitamin D in the diet or through sunlight exposure
• Lack of magnesium in the diet
• Digestive problems such as inflammatory bowel disease
• Certain medicines such as diuretics or laxatives
• Inflammation of the pancreas—pancreatitis
• Kidney disease or failure
• Medicines such as bisphosphonates—move calcium to bone

Complications

Calcium deficiency has been linked to:

• Dental problems
• Depression
• Various skin conditions
• Chronic joint and muscle pain
• Fractures
• Seizures
• Disability

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:

• Other blood tests: Your healthcare provider may do more blood tests to check your levels of magnesium, phosphorus, parathyroid hormone (PTH) and/or vitamin D.
• ECG (electrocardiogram): An EKG is a procedure that uses electrodes attached to your chest to measure your heart rhythm. Hypocalcemia can cause an abnormal heart rhythm.
• Bone imaging tests: Bone imaging tests could be used to see if you have calcium issues in your bones, such as osteomalacia or rickets.

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.