Continuing Education Activity

Disorders of calcium metabolism are frequently encountered. Though hypocalcemia is not encountered as frequently as hypercalcemia, it can be life-threatening if not appropriately recognized and promptly treated. This activity reviews the evaluation and management of hypocalcemia and highlights the role of the interprofessional team in educating patients with this condition about follow-up care.

Objectives:

• Examine the differential diagnosis of hypocalcemia.
• Analyze the risk factors of developing hypocalcemia.
• Review the pathophysiology of hypocalcemia.
• Explain the interprofessional team strategies for improving care coordination and communication regarding the management of patients with hypocalcemia.

Introduction

Calcium homeostasis in the body is a complex interplay between several different hormones and other factors. The main factors that regulate calcium homeostasis in the body are parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23 (FGF23), and calcitonin. Serum calcium concentration is maintained within a very narrow range. Approximately 45% of the body's calcium is bound to plasma proteins, notably albumin. Approximately 15% is bound to small anions such as phosphate and citrate. Approximately 40% is in the free or ionized state. Most laboratories report total serum calcium concentration, which usually ranges between 8.5 to 10.5 mg/dL (2.12 to 2.62 mmol/L). Ionized calcium can also be measured by some laboratories, and the normal range is 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L). Any level below this range is considered hypocalcemia. Because the majority of body calcium is bound to albumin, total calcium should always be corrected for albumin level before the diagnosis of hypocalcemia is made. There is an approximately 0.8 mg/dL (0.25 mmol/L) drop in serum total calcium concentration for every 1 g/dL (10 g/L) reduction in the serum albumin concentration.

Disorders of calcium metabolism are encountered pretty frequently in routine clinical practice. Hypocalcemia is not as frequently seen as hypercalcemia is, but it can be potentially life-threatening if not appropriately recognized and promptly treated. Most hypocalcemia problems are acquired, but some are inherited. The clinical presentation can vary from asymptomatic to a life-threatening state. Hypocalcemia is commonly seen in hospitalized patients, and for the most part, it is mild that only requires supportive treatment.

Etiology

The causes of hypocalcemia can be divided into three broad categories:

• PTH deficiency
• High PTH
• Other causes

PTH Deficiency (low or low normal serum PTH)

This occurs as a result of decreased PTH secretion, which can be due to destruction of the parathyroid glands (postsurgical or autoimmune), abnormal regulation of PTH production and secretion, or abnormal development of the parathyroid gland. Post-surgical is the most common cause of hypoparathyroidism.

1. Post-surgical: This is the most common cause of hypoparathyroidism. It can occur after thyroidectomy, parathyroidectomy, or radical neck surgery. The normal parathyroid gland is made up of about 30% capillary cells. This makes the parathyroid gland very sensitive to disruption of arterial blood supply or venous drainage, which can result from mechanical, thermal, or electrical injury during thyroidectomy. The resulting hypoparathyroidism is usually transient but can also be permanent with subsequent transient or permanent hypocalcemia. Accidental removal of all 4 parathyroid glands during thyroidectomy, though not common, is also a major cause of hypoparathyroidism. Hypoparathyroidism after parathyroidectomy is usually a result of suppression of the remaining parathyroid glands by hypercalcemia from parathyroid adenoma before surgery. This is also transient in most cases but is usually permanent if all 4 glands are removed without autotransplantation of the parathyroid gland. In cases of severe hyperparathyroidism with significantly elevated PTH levels before surgery, as in tertiary hyperparathyroidism in kidney disease, the abrupt drop in PTH levels after surgery can lead to severe hypocalcemia due to unopposed osteoblast activity causing significant calcium uptake into the bones. This condition is termed “hungry bone syndrome.” [1][2][3]
2. Autoimmune: Autoantibodies against the parathyroid gland are the main cause of autoimmune hypoparathyroidism which can be a manifestation of polyglandular autoimmune syndrome type I along with chronic mucocutaneous candidiasis and adrenal insufficiency.
3. Abnormal parathyroid gland development: X-linked or autosomal recessive hypoparathyroidism causes abnormal parathyroid gland development. This can be isolated or associated with complex congenital syndromes like DiGeorge syndrome.
4. Parathyroid gland destruction: This can also be due to rare causes such as infiltrative diseases of the parathyroid glands like granulomatous diseases, hemochromatosis, Wilson disease, or irradiation. Human immunodeficiency virus (HIV) infection is also a rare cause of symptomatic hypoparathyroidism. Lastly, activating mutation of calcium-sensing receptors (CaSR) decreases the setpoint of CaSR, causing hypoparathyroidism and hypocalcemia.

High PTH Levels

1. Absolute or relative vitamin D deficiency: Vitamin D maintains normal calcium by enhancing intestinal calcium absorption and bone resorption. Vitamin D deficiency could be from decreased intake or malabsorption, inadequate sun exposure, liver disease, kidney disease results, and decrease conversion to its active metabolite (1,25-dihydroxy vitamin D). This can lead to decreased calcium absorption and bone resorption. The resulting hypocalcemia leads to a compensatory increase in PTH secretion (secondary hyperparathyroidism).
2. Chronic kidney disease (CKD): CKD leads to impaired phosphate excretion and impaired hydroxylation of 25 hydroxyvitamin D to 1,25-dihydroxy vitamin D. This drives PTH secretion and can cause secondary hyperparathyroidism. However, due to impaired vitamin D metabolism and high phosphorus level, the serum calcium remains low despite the high PTH
3. Pseudohypoparathyroidism (PHP): This is a genetic disorder that causes end-organ resistance to the action of PTH and is characterized by hypocalcemia, hyperphosphatemia, and elevated PTH concentration.

Other Causes

1. Pseudohypocalcemia: Serum calcium is normally bound to proteins in the blood, most prominently albumin, and therefore low albumin states can give a falsely low total serum calcium level. Ionized calcium level is usually normal in these states, and thus a correction of adding 0.8 mg/dL to serum calcium level for every 1gm drop in serum albumin below normal (4 gm/dL) is recommended.
2. Acidosis/alkalosis: Calcium binding to albumin is dependent on the serum pH, and thus in states of severe acidosis, ionized calcium is increased and vice-versa decreased in severe alkalosis. There is no reliable correction factor to estimate this shift in ionized calcium level, so direct measurement of ionized calcium is recommended in these cases to guide therapy.
3. Acute pancreatitis: Hypocalcemia is often seen in the setting of acute pancreatitis due to calcium deposition in the abdominal cavity as a result of ongoing inflammation.[4]
4. Severe sepsis/critical illness: Severe sepsis can lead to hypocalcemia through unclear mechanisms. Impaired PTH secretion, dysregulation of magnesium metabolism, and impaired calcitriol secretion have been identified as potential mechanisms, but none have been proven as of yet.[5] More recent reports also indicated hypocalcemia related to severe Covid-19 infection.[6]
5. Hypomagnesemia/hypermagnesemia: Low serum magnesium can cause hypocalcemia due to induced PTH resistance. This usually occurs when the serum magnesium level drops below 0.8 mEq/L (1 mg/dL or 0.4 mmol/L). Decreased PTH secretion can occur in more severe hypomagnesemia[7]. Severe hypermagnesemia, although rare, can also cause hypocalcemia by suppressing PTH secretion through a decreased sensitivity of calcium-sensing receptors.
6. Acute hyperphosphatemia: This is an uncommon cause of hypocalcemia which is likely precipitated because of extravascular deposition of calcium phosphate products.
7. Drugs: Bisphosphonates and denosumab both inhibit osteoclastic bone resorption, which can cause hypocalcemia which can be severe in some cases. Concomitant vitamin D deficiency makes hypocalcemia more likely to occur in patients treated with those drugs. Patients being treated with these agents should have their calcium and vitamin D levels checked, and low levels should be corrected before initiation of treatment. Cinacalcet is a calcimimetic agent that works by stimulating the CaSR and thus decreasing PTH secretion. It is used in the treatment of both primary and secondary hyperparathyroidism. The resulting decrease in PTH secretion can cause hypocalcemia. Cisplatin, a chemotherapeutic drug, can also cause hypocalcemia through hypomagnesemia. Foscarnet can cause hypocalcemia by forming complexes with ionized calcium, thereby reducing levels of ionized calcium. It is therefore important to regularly monitor calcium levels during treatment with all of the above-mentioned drugs.[8][9]
8. Massive blood transfusion: Massive blood transfusion can cause an acute decline in ionized calcium due to calcium binding with citrate, which is used as an anticoagulant in the stored blood.[10]
9. Pregnancy: There are reports of hypocalcemia during pregnancy, mostly related to poor diet, hyperemesis gravidarum, or underline diseases.[11]

Osteoblastic metastasis, as in prostate cancer, can cause hypocalcemia which can be severe in rare cases. This is a result of increased calcium uptake into the bones from increased osteoblastic activity.

Epidemiology

There is no literature on the incidence and prevalence of hypocalcemia in general. However, the reported prevalence of transient hypocalcemia after thyroidectomy varies between 6.9 to 49% and between 0.4 to 33% for permanent hypocalcemia.[8] In general, renal failure remains by far the most common cause of hypocalcemia, followed by vitamin D deficiency, magnesium deficiency, acute pancreatitis, etc.

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.

History and Physical

The clinical manifestations of hypocalcemia can range from no symptoms if it is mild to life-threatening symptoms like seizures, heart failure, or laryngospasm if it is severe. Also, the clinical manifestation depends on the rate of development of hypocalcemia and its chronicity. The history and physical exam of patients with hypocalcemia should focus on identifying the symptoms present, as these may not be apparent in some patients, and also conducting provocation exams. Symptoms of hypocalcemia include:

1. Seizures: Usually present in very severe hypocalcemia. It can be the sole manifestation or a part of the myriad of clinical presentations.[12]
2. Tetany: Is generally induced by a rapid decline in serum ionized calcium. Tetany is usually more dangerous and most commonly seen in the presence of respiratory alkalosis causing hypocalcemia.
3. Paresthesias: Can be perioral or in the extremities.
4. Psychiatric manifestations such as anxiety, depression, or emotional lability: can occasionally present in some cases of hypocalcemia.
5. Carpopedal spasm: This is also referred to as Trousseau's sign. It represents increased neuromuscular excitability which may be related to the gating function of calcium ions for ion channels at a cellular level (particularly in neurons). It manifests as a spasm of the hand characterized by adduction of the thumb, flexion of the metacarpophalangeal joints, an extension of the interphalangeal joints, and flexion of the wrist when a sphygmomanometer is inflated above systolic blood pressure for three minutes.
6. Chvostek's sign: This is another manifestation of heightened neuromuscular excitability. Tapping of the facial nerve in front of the ear causes ipsilateral contraction of the facial muscles.
7. QTc prolongation: This can lead to Torsades de pointes that, although extremely rare, can be fatal.

The second part of the history and physical exam should focus on determining the cause of hypocalcemia such as recent head and neck surgery, family history of similar problems, history of kidney disease, alcohol abuse (hypomagnesemia), psychiatric history, etc.

Evaluation

Work up of hypocalcemia can be thought of in the following parts:

1. Confirming the hypocalcemia: The first part of the evaluation should focus on confirming the hypocalcemia and require checking a serum albumin level to correct the total calcium or directly measure the ionized calcium level (where available).To correct hypoalbuminemia, add 0.8 mg/dl to the total serum calcium for each 1 g/dl decrease in albumin below 4 g/dl.
2. An EKG should be obtained to look for QTc prolongation, which, if present, is a risk factor for Torsades de pointes.[13]
3. Etiology of hypocalcemia: Once hypocalcemia is confirmed, further testing should be done to determine the cause of hypocalcemia. That entails checking electrolytes such as serum magnesium and phosphorus levels, intact PTH, and vitamin D levels. Some causes are obvious, as in patients post thyroidectomy or parathyroidectomy. Other biomarkers may be obtained as indicated by history and physical exam, e.g., serum lipase in suspected pancreatitis.
4. Imaging the bones may reveal osteomalacia, rickets, or even metastatic disease.

Treatment / Management

Treatment of hypocalcemia depends on the presence and severity of symptoms, degree of hypocalcemia, and etiology of hypocalcemia. Management of hypocalcemia can be divided into different categories:

1. Intravenous (IV) calcium is recommended for use in patients with severe symptoms, prolonged QTC intervals, or in asymptomatic patients who develop acute hypocalcemia in a short period. This can be given as calcium gluconate 1 to 2 g (equivalent to 90 to 180 mg elemental calcium) or 1 g of calcium chloride (equivalent to 270 mg elemental calcium) as a short infusion over 10 to 20 minutes. This should be followed by a continuous infusion if hypocalcemia persists. Calcium gluconate is generally preferred over calcium chloride as it is less likely to cause tissue necrosis if extravasation occurs. An alkaline solution like bicarbonate and phosphorus-containing solution needs to be avoided through the same IV to avoid precipitation of calcium salts.                                                                                                                                                    
2. If the symptoms are mild such as paresthesias, or in asymptomatic patients, oral calcium can be given. Calcium carbonate (40% elemental calcium) or calcium citrate (21% elemental calcium) are the most commonly used calcium preparations. The goal is to administer 1500 to 2000 mg elemental calcium per day divided into 2 to 3 doses. Calcium carbonate needs an acidic medium to be absorbed, so this should be avoided in patients taking proton pump inhibitors (PPI). Vitamin D supplementation is often recommended with calcium to promote better absorption and because vitamin D deficiency is commonly encountered in most clinical scenarios leading to hypocalcemia. 
3. Disease-specific treatment:                             
• Postsurgical hypoparathyroidism: Most patients will develop hypocalcemia after thyroidectomy or parathyroidectomy due to hypoparathyroidism, which is usually transient. Prophylactic treatment with calcium after surgery is recommended. This usually prevents severe symptomatic hypocalcemia in most cases.[14] Calcium levels should be monitored closely after surgery, and the dose of calcium tapered off as indicated. 
• Hypomagnesemia: It should be corrected first as hypocalcemia will be difficult to correct without correcting serum magnesium.
• CKD: Hypocalcemia in CKD is usually a result of vitamin D deficiency. This can be corrected with vitamin D or its active metabolite, calcitriol. Patients with significant vitamin D deficiency should be given ergocalciferol 50,000 units weekly for 8 to 12 weeks followed by cholecalciferol at lower doses of 1000 to 5000 units daily.
• Vitamin D deficiency: Hypocalcemia due to vitamin D deficiency cannot be corrected unless vitamin D is repleted first.[15]

Differential Diagnosis

• Acute pancreatitis
• Acute renal failure
• Hyperphosphatemia
• Hypomagnesemia
• Hypoparathyroidism

Prognosis

The overall prognosis of hypocalcemia is good as it can be easily corrected. In rare cases, patients with complete parathyroidectomy require very high doses of calcium and vitamin D supplements to maintain calcium in the normal range. Patients who have undergone gastric bypass surgery usually have malabsorption and may also require very high doses of calcium and vitamin D to correct hypocalcemia.

Complications

Patients with severe hypocalcemia of less than 7 mg/dl and those with an acute drop in calcium level can develop seizures or life-threatening arrhythmia. It is therefore imperative to check ECG and the calcium be corrected aggressively in these patients.

Deterrence and Patient Education

Patients with hypocalcemia or those who are at risk of developing hypocalcemia, like after thyroidectomy or parathyroidectomy, should be educated on symptoms of hypocalcemia and the importance of adherence to replacement therapy so they can avoid life-threatening symptoms.

Pearls and Other Issues

Always repeat calcium levels and check albumin levels to confirm hypocalcemia by correcting calcium levels for low albumin. Also, remember to check a magnesium level when faced with hypocalcemia since it is an important and easily correctable cause of hypocalcemia. Vitamin D deficiency should always be addressed as correction of hypocalcemia will be difficult in patients with untreated vitamin D deficiency.

Enhancing Healthcare Team Outcomes

Because there are so many causes, the diagnosis and management of hypocalcemia are best done with an interdisciplinary team. Consultation with different specialists is sometimes required because of the diverse causes and effects. In each case, one needs to treat hypocalcemia and the primary disorder responsible for it. An endocrinologist and an internist should always be involved. While the condition can be managed in an outpatient setting, close follow-up is required. The pharmacist has to make sure that the patient is not on any medications aggravating this electrolyte disorder. A dietary consult is often beneficial for patients with renal failure and hypocalcemia to help improve adequate calcium intake. Patients have to be educated about the symptoms of hypocalcemia like muscle weakness and paresthesias so that they can seek treatment when needed. Open communication between the team members is vital to prevent the morbidity of hypocalcemia.