Hypocalcemia

Hypocalcemia that develops gradually is most likely to be asymptomatic, but acute hypocalcemia can result in severe symptoms requiring hospitalization. Some of the symptoms of hypocalcemia include:

• Paresthesia (burning or prickling sensation)
• Tetany (involuntary muscle contractions)
• Cramps
• Circumoral numbness (absent or reduced sensory perception around the mouth)
• Seizures
• Twitching in your hands, face, and feet
• Numbness
• Tingling
• Depression
• Memory loss
• Scaly skin
• Changes in the nails
• Rough hair texture
• Delayed tooth eruption
• Increased dental caries
• Dysphagia (difficulty in swallowing)
• Abdominal pain
• Dyspnea (shortness of breath)
• Wheezing
• Subcapsular cataracts (a type of cataract)
• Papilledema (swelling of the optic nerve)

Often, treating hypocalcemia may relieve these symptoms immediately. If hypocalcemia is caused by another condition, there might be additional symptoms such as:

• Laryngospasm (spasm of the vocal cords)
• Trouble remembering, learning new things, or concentrating
• Electrocardiographic changes that resemble a heart attack
• Prolonged QT intervals on ECG
• Personality disturbances
• Heart failure

Heart failure can be prevented by leading a healthy life. Read about tips that every cardiologist wants you to know.

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 of hypocalcemia can be divided into three broad categories:

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

1. Parathyroid hormone (PTH) deficiency

Hypoparathyroidism or low normal serum PTH occurs as a result of decreased PTH secretion, which can be due to the following reasons:

• Post-surgical: This is the most common cause of hypoparathyroidism. It can occur after removal of the thyroid gland (thyroidectomy), removal of parathyroid glands (parathyroidectomy), or radical neck surgery. The resulting hypoparathyroidism is usually transient but can also be permanent, leading to transient or permanent hypocalcemia. In cases where surgery is required for severe hyperparathyroidism with significantly elevated PTH levels, the abrupt drop in PTH levels after surgery can lead to severe hypocalcemia, causing significant calcium uptake into the bones. This condition is termed ‘Hungry Bone Syndrome.'
• Autoimmune: Autoantibodies against the parathyroid gland are the main cause of autoimmune hypoparathyroidism, eventually leading to hypocalcemia.
• Abnormal development of the parathyroid gland: Some genetic aberrations can cause abnormal parathyroid gland development. This can be isolated or associated with complex hereditary syndromes like DiGeorge syndrome.
• Parathyroid gland destruction: This can occur due to rare diseases of the parathyroid gland like hemochromatosis (excess iron absorption), Wilson disease (excess copper accumulation in the liver), or irradiation. Human immunodeficiency virus (HIV) infection is also a rare cause of symptomatic hypoparathyroidism.

2. High PTH levels

Causes include:

• Absolute or relative Vitamin D deficiency: Vitamin D deficiency or resistance can occur due to lack of sun exposure, inadequate dietary intake, intestinal malabsorption (steatorrhea), liver or kidney disease, osteomalacia, and rickets. Certain medications such as phenytoin, phenobarbital, and rifampin can also alter Vitamin D metabolism. Vitamin D dependency results from the inability to convert Vitamin D to its active form or decreased responsiveness of end-organs to adequate levels of the active vitamin, leading to decreased calcium absorption and bone resorption. The resulting hypocalcemia leads to a compensatory increase in PTH secretion (secondary hyperparathyroidism).
• Chronic kidney disease: Long-term kidney diseases can cause severe hypocalcemia due to abnormal renal loss of calcium and decreased renal conversion of Vitamin D to its active form, driving PTH secretion and causing secondary hyperparathyroidism. However, due to impaired Vitamin D metabolism and high phosphorus levels, serum calcium remains low despite high PTH.
• Pseudohypoparathyroidism (PHP): This is an uncommon group of genetic disorders characterized not by hormone deficiency but by end-organ resistance to PTH, leading to hypocalcemia, hyperphosphatemia, and elevated PTH concentration.

3. Other causes

Other causes that can lead to hypocalcemia include:

• Acute pancreatitis: Hypocalcemia is often associated with acute pancreatitis as inflammation of the pancreas leads to calcium deposition in the abdominal cavity.
• Hypoproteinemia: Refers to lower-than-normal levels of protein in the body, reducing 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 mechanisms that are not fully understood. 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, mostly caused by extravascular deposition of calcium phosphate products.
• Massive blood transfusion: Transfusion of more than 10 units of citrate-anticoagulated blood can cause hypocalcemia, as 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 observed during pregnancy, mostly related to poor diet, extreme and persistent nausea, vomiting, or any underlying diseases.

Hypocalcemia can be due to environmental or genetic factors. Some of the common risk factors in the development of hypocalcemia include:

• Vitamin D deficiency
• Parathyroid hormone (PTH) deficiency
• Hypomagnesemia
• Hypoalbuminemia
• Hyperphosphatemia
• Newborn babies with diabetic mothers
• Family history of parathyroid disorders

Less common risk factors in the development of hypocalcemia include:

• Surgical removal of parathyroid glands
• Side effects of medications
• Anion chelation (binding of negatively charged ions)
• Pseudohypoparathyroidism
• Hepatic (liver) disease
• Acute pancreatitis
• Increased protein binding
• Critical illness
• Severe sepsis
• History of gastrointestinal disorders
• Tumor lysis syndrome (TLS) is when a large number of cancer cells die within a short period, releasing their contents into the blood
• Osteoblastic metastases (characterized by deposition of new bone, seen in certain types of cancers)
• Anxiety disorders

If the cause of hypocalcemia is not clinically obvious, the most important investigation is to measure serum parathyroid hormone. A standard biochemical profile, a parathyroid hormone measurement, and a clinical history will usually provide the likely cause of hypocalcemia. The tests required to confirm the diagnosis include:

Laboratory tests

• Calcium: Hypocalcemia is diagnosed by a total serum calcium concentration < 8.8 mg/dL (< 2.2 mmol/L). However, because low plasma protein can lower total, but not ionized, serum calcium, ionized calcium should be estimated based on serum albumin concentration.
• Parathyroid hormone: In true hypocalcemia, intact parathyroid hormone concentrations should be high in case of reduced negative feedback of calcium by parathyroids or low if these glands are the cause of the problem. A high concentration of parathyroid hormone in the presence of normal renal function suggests a deficiency of Vitamin D or calcium malabsorption.
• Alkaline phosphatase: A raised serum alkaline phosphatase suggests osteomalacia as a result of Vitamin D deficiency. Parathyroid hormone stimulates clearance of phosphate through the kidneys, so serum phosphate should be low in non-parathyroid disease but high in parathyroid hormone deficiency.
• Vitamin D: Vitamin D concentrations are useful in confirming Vitamin D deficiency when it presents atypically, and it should be assessed in patients with possible pseudohypoparathyroidism. Vitamin D helps our body absorb calcium and phosphorus. Diagnosing Vitamin D deficiency is very important and may require a complete workup.
• Magnesium: Serum magnesium is important to estimate the normal functioning of the parathyroid gland. In hypomagnesemia, the release of parathyroid hormone is inhibited, leading to potentially severe hypocalcemia. Recognition of hypomagnesemia is important because it is difficult to reverse hypocalcemia without normalizing magnesium levels.
• Phosphate: Low to low normal serum phosphate levels can be due to deficient actions of Vitamin D, loss of calcium in the urine, and deposition of calcium in bone. Hypocalcemia with high normal to high serum phosphate levels includes chronic renal failure and hypoparathyroidism.

Imaging

• Plain radiography: Radiographs can diagnose bone disorders like rickets or osteomalacia. It can also disclose the spread of certain tumors to the bones (e.g., breast, prostate, and lungs), which can cause hypocalcemia.
• Computed tomography (CT): CT scans of the head may show calcification of basal ganglia (structures linked to the thalamus of the brain).
• Echocardiogram (ECG): The ECG hallmarks of hypocalcemia can be used to determine the degree of hypocalcemia.

The main cause of hypocalcemia is the deficiency of calcium and Vitamin D. This can be prevented by:

• Eating foods rich in calcium such as dairy products.
• Choosing low-fat or fat-free options to reduce your risk of heart disease.
• Including calcium in the diet every day. The dietary need for calcium is as follows:
• 2,000 mg per day for men and women 51 years of age and above.
• 2,500 mg per day for men and women 19 to 50 years of age.
• Adding multivitamin supplements along with the diet.
• Understanding the Vitamin D need by consulting a doctor.
• Increasing your calcium intake by adding foods rich in Vitamin D to the diet. These include:
• Fatty fish like salmon and tuna.
• Fortified orange juice.
• Fortified milk.
• Mushrooms.
• Eggs.
• Exposing oneself to enough sunlight to boost Vitamin D levels.
• Making certain lifestyle changes like:
• Maintaining a healthy body weight.
• Exercising regularly.
• Limiting alcohol intake.
• Restricting tobacco use.

The treatment and management of hypocalcemia can be divided into acute and chronic (long-term) management. They are as follows:

Acute management of hypocalcemia

Acute hypocalcemia can result in severe symptoms requiring hospitalization. The treatment consists of:

• Intravenous calcium if serum calcium levels are below 1.9 mmol/L, ionized calcium levels are less than 1 mmol/L, or if patients are symptomatic.
• Oral calcium supplements and calcitriol (0.25 to 1 μg/day) as needed.
• Correction of magnesium deficiency or alkalosis.
• Cardiac monitoring during intravenous calcium supplementation is necessary, especially for patients taking digoxin therapy.

Chronic management of hypocalcemia

Hypocalcemia that develops gradually is more likely to be asymptomatic, but some common symptoms include paresthesia (burning or prickling sensation), tetany (involuntary muscle contractions), cramps, muscle spasms, circumoral numbness (absent or reduced sensory perception around the mouth), and seizures. Its management consists of:

• Calcium carbonate and calcium citrate supplements as they have the greatest proportion of elemental calcium (40% and 28% respectively) and are easily absorbed.
• Calcium supplement dosages are 1 to 2 g of elemental calcium 3 times daily.
• Elemental calcium supplements can be started at 500 mg to 1000 mg 3 times daily and titrated upward.
• Asymptomatic electrocardiography changes usually normalize with calcium and calcitriol supplementation.
• Magnesium supplementation corrects hypomagnesemia-related hypocalcemia.
• Thiazide diuretics decrease urinary calcium excretion by increasing distal renal tubular calcium reabsorption.
• Combining diuretics with a low-salt, low-phosphate diet, and phosphate binders is beneficial.
• Serum calcium, phosphorus, and creatinine should be measured weekly to monthly during initial dose adjustments, with quarterly or twice-yearly measurements once the therapy protocol has stabilized.

Correcting Vitamin D inadequacy

If hypocalcemia is due to malabsorption of Vitamin D, physicians should treat the underlying cause (e.g., implementing a gluten-free diet for patients with celiac disease). It consists of:

• Correcting the deficiency with ergocalciferol (Vitamin D2) or cholecalciferol (Vitamin D3).
• Ergocalciferol can be given in doses of 50,000 IU weekly or twice a week with an assessment of levels 3 months later, titrating up until a normal Vitamin D level is reached.
• Alternatively, 300,000 IU of ergocalciferol can be administered intramuscularly, with the first 2 injections spaced 3 months apart, followed by regular injections every 6 months.
• Administering 100,000 IU of Vitamin D3 once every 3 months is also effective in maintaining adequate Vitamin D levels.
• Vitamin D analogs, particularly calcitriol or alfacalcidol, can be used.

Replacement with PTH for hypoparathyroidism

Replacement therapy with PTH is optional, as it corrects hypercalciuria (decreased amount of calcium in the urine) and potentially reduces the risk of nephrocalcinosis (too much calcium deposited in the kidneys), nephrolithiasis (mineral and salt deposition in the kidneys), and renal insufficiency. It also reduces the wide fluctuation in serum calcium. Additionally, PTH reduces urinary calcium excretion, which can help in the reduction of the dose of calcium and Vitamin D. PTH has also been studied and might become a valuable addition to current treatment options.

Calcium plays a vital role in strengthening bones and teeth. It also helps in the proper functioning of nerves and muscles. Mild cases of hypocalcemia can be managed by adding foods rich in calcium and certain lifestyle modifications. They are as follows:

• Add milk or yogurt to fruit smoothies.
• Add greens to soups or pasta dishes.
• Increase vegetable intake in every meal.
• Include nuts and seeds such as almonds and sesame seeds in the diet.
• Use yogurt instead of vegetable dips.
• Take Vitamin D and calcium supplements.
• Expose the skin to natural sunlight.
• Choose appropriate clothing and sunscreen to avoid complete blockage of sunlight.
• Consider using UV lamps, as exposure to UV-B helps the skin produce its own Vitamin D.
• Consume fortified foods.
• Exercise regularly.
• Consult a doctor about medications that can cause hypocalcemia and avoid them.
• Include egg yolks in the diet.

Hypocalcemia can be asymptomatic in mild cases to presenting as an acute life-threatening crisis. It is important to detect calcium-regulating hormones like parathyroid hormone (PTH), Vitamin D, and calcitonin through their specific effects on the bowel, kidneys, and skeleton. The complications are as follows:

Neurological Complications

Neurological complications occur due to the presence of co-morbidities and other electrolyte imbalances. They include:

• Seizures: Hypocalcemia can cause seizures because low ionized calcium concentrations in the cerebrospinal fluid (CSF) can lead to increased excitability in the central nervous system.
• Status epilepticus: A seizure that lasts longer than 5 minutes or having more than one seizure within a 5-minute period, without returning to a normal level of consciousness between episodes.
• Uremic encephalopathy: Cerebral dysfunction due to the accumulation of toxins resulting from acute or chronic renal failure. Studies have shown that this can be a complication of hypocalcemia.
• Cerebral edema: Swelling of the brain, which is a relatively common phenomenon with numerous etiologies including hypocalcemia.
• Coma: A Glasgow coma scale score of less than 9/15 is seen in severe cases.

Cardiac Complications

Numerous case reports associate hypocalcemia with life-threatening cardiac complications such as:

• Reversible heart failure: Hypocalcemia caused by hypoparathyroidism and hypomagnesemia can lead to heart failure in severe cases that can be reversed.
• Torsades de pointes: A specific type of fast heart rhythm (heart rate over 100 beats per minute) that begins in the ventricles of the heart.
• Arrhythmias: Severe hypocalcemia can predispose individuals to life-threatening arrhythmias. In such cases, rapid admission to the hospital and correction of electrolyte imbalance are necessary.

An arrhythmia is a condition in which the heartbeat is irregular. Arrhythmias can occur with a regular or an irregular heart rate. Read more about its signs, symptoms, causes, risk factors, and treatment.

There is no alternative treatment for hypocalcemia, but mild symptoms can be managed by incorporating food substances that are rich in calcium and Vitamin D. Some of these include:

• Dairy products: Increase your intake (in moderation) of milk, cheese, cottage cheese, yogurt, and ice cream as they are rich in calcium.
• Nuts: Seeds and nuts, including almonds and sesame seeds, serve as vegan dietary sources of calcium.
• Beans: In addition to being rich in fiber and protein, beans and lentils are also good sources of calcium.
• Broccoli: It provides a generous amount of calcium along with other minerals like beta-carotene (the precursor to Vitamin A) and Vitamins C and K.
• Black-eyed peas (lobia): A half-cup serving of black-eyed peas contains 8 percent of the daily recommended intake of calcium.
• Figs (anjeer): They are a good source of both calcium and potassium, which can work together to improve bone density.
• Oranges: They help boost the immune system and are rich in calcium and Vitamin D.
• Salmon: Fatty fish and seafood are among the richest natural food sources of Vitamin D.

Hypocalcemia is a metabolic disorder that can be asymptomatic or cause mild symptoms. In rare cases, it can lead to a severe life-threatening crisis. The treatment of hypocalcemia depends on the cause, severity, presence of symptoms, and the rate of development (acute or chronic). Most cases of hypocalcemia are clinically mild and require only supportive treatment and further laboratory evaluation. Some tips that can help manage mild cases include:

• Eating calcium-rich foods
• Avoiding foods that are high in trans fat
• Reducing alcohol intake
• Ensuring adequate sun exposure
• Avoiding prolonged indoor activities
• Choosing sunscreens and clothing that do not completely block sun exposure
• Incorporating foods rich in Vitamin D into the diet
• Exercising regularly
• Quitting smoking
• Maintaining a healthy weight
• Taking Vitamin D and calcium supplements
• Consulting a doctor to understand any underlying causes