Hypocalcemia

Etiology

The causes of hypocalcemia can be divided into 3 broad categories: PTH deficiency, high PTH, and other causes. Each of these categories is detailed below. 

PTH Deficiency 

Decreased PTH levels (low or low normal serum PTH) can be due to the destruction of the parathyroid glands (postsurgical or autoimmune), abnormal regulation of PTH production and secretion, or abnormal parathyroid gland development. Postsurgical loss is the most common cause of hypoparathyroidism. Low PTH as a cause of hypocalcemia is determined by 2 calcium levels at least 2 weeks apart accompanied by inappropriately low PTH levels.[3]

• Postsurgical: This is the most common cause of hypoparathyroidism (about 75% of cases) occurring after thyroidectomy, parathyroidectomy, or radical neck surgery.[2][4][5] About 70% to 80% of patients undergoing parathyroidectomy will recover PTH function within one month. In cases of severe hyperparathyroidism with presurgical highly elevated PTH levels, such as 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.[6][7][8] It is characterized by marked hypocalcemia in response to a sudden PTH drop and can also be associated with low phosphorus and magnesium levels.[9] 
• Autoimmune: Autoantibodies against the parathyroid gland are the leading cause of autoimmune hyperparathyroidism. A common hereditary cause is autoimmune polyglandular syndrome type I, which manifests as a triad of hyperparathyroidism, chronic mucocutaneous candidiasis, and adrenal insufficiency. This syndrome is also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED).[10]
• Abnormal parathyroid gland development: Several genetic disorders are linked with hyperparathyroidism, which can be isolated or associated with complex congenital syndromes. Some of these syndromes are DiGeorge syndrome, Charge Syndrome, Gracile bone dysplasia, Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), and Medium-chain acyl COA dehydrogenase deficiency.[3]
• Parathyroid gland destruction: This can be due to rare causes such as infiltrative diseases of the parathyroid glands like granulomatous diseases, hemochromatosis, Wilson disease, amyloidosis, aluminum-containing phosphate binders, or irradiation. HIV infection is rarely associated with immune cell infiltration of the parathyroid gland. The chemotherapeutic agents nivolumab and l-asparaginase are also associated with destroying the parathyroid gland.[2] 

High PTH Levels

• 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 (more common in those with dark skin), liver disease, kidney disease, and decreased conversion to its active metabolite (1,25-dihydroxy vitamin D). Active 1,25-dihydroxy vitamin D (calcitriol) is the principal regulator of intestinal calcium absorption.[11] The resulting hypocalcemia leads to a compensatory increase in PTH secretion (secondary hyperparathyroidism). Low vitamin D levels before neck surgeries can also increase the risk of hypocalcemia and hypoparathyroidism postoperatively.[12][13] 
• Chronic kidney disease (CKD): CKD leads to impaired phosphate excretion and 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 levels, the serum calcium remains low despite the high PTH.
• Pseudohypoparathyroidism (PHP): This genetic disorder causes end-organ resistance to the action of PTH and is characterized by hypocalcemia, hyperphosphatemia, and elevated PTH concentration.[3]

Other Causes

• Pseudohypocalcemia: Serum calcium is usually 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 levels are usually normal in these states. 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.
• Acidosis/alkalosis: Calcium binding to albumin is dependent on the serum pH. Therefore, ionized calcium is increased in severe acidosis due to less albumin binding and vice-versa in severe alkalosis. There is no reliable correction factor to estimate this shift, so direct measurement of ionized calcium is recommended in these cases.
• Acute pancreatitis: Hypocalcemia is often seen in the setting of acute pancreatitis due to calcium combining with free fatty acids released during pancreatic autodigestion of mesenteric fat, leading to saponification and calcium precipitation. Hypocalcemia is part of Ranson's criteria and is associated with poor prognosis.[14][15]
• Severe sepsis/critical illness/trauma: Severe sepsis can lead to hypocalcemia through various mechanisms. Impaired PTH secretion, dysregulation of magnesium metabolism, catecholamine release shifting calcium intracellularly, and impaired calcitriol secretion have been suggested as potential causative factors.[15][16] More recent reports also indicate hypocalcemia can be caused by severe COVID-19 infection.[17][18] Hypocalcemia is also frequently observed in patients after severe trauma and shock, often due to administering blood transfusions containing citrate, which binds to calcium.[17][19][20]
• 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).[21] Decreased PTH secretion can occur in more severe hypomagnesemia.[22] Severe hypermagnesemia, often in the setting of renal impairment, can also cause hypocalcemia by suppressing PTH secretion through decreased sensitivity of calcium-sensing receptors (CaSRs).[23]
• Acute hyperphosphatemia: This is an uncommon cause of hypocalcemia that results from extravascular deposition of calcium phosphate products. This is most common when the calcium-phosphate product is greater than 60 mg²/dL².[24]
• Drugs: Bisphosphonates and denosumab both inhibit osteoclastic bone resorption, which can cause hypocalcemia.[25] Concomitant vitamin D deficiency worsens hypocalcemia in patients treated with those drugs, so vitamin D and calcium levels should be corrected before initiating these treatments. Cinacalcet is a calcimimetic agent that works by stimulating the CaSR and thus decreases 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 physiologically active calcium. It is important to regularly monitor calcium levels (and ionized calcium with foscarnet) during treatment with the drugs mentioned above.[26][27]
• 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.[19][20]
• Pregnancy: There are reports of hypocalcemia during pregnancy, mainly related to poor diet, hyperemesis gravidarum, or underlying diseases.[28]
• Osteoblastic metastasis: Similar to hungry bone syndrome, certain metastatic cancers, such as prostate cancer, can cause hypocalcemia. This results from increased calcium uptake into the bones from increased osteoblastic activity.[29]

Epidemiology

The literature lacks comprehensive data regarding the incidence and prevalence of hypocalcemia in the general population. However, the reported prevalence of transient hypocalcemia after thyroidectomy varies between 6.9% to 49% and between 0.4% to 33% for permanent hypocalcemia.[26] The most common causes of hypocalcemia are surgical, chronic kidney disease, vitamin D deficiency, magnesium deficiency, and acute pancreatitis. Smoking is thought to decrease PTH and increase calcitonin levels, but the effects on calcium levels are unknown.[1]

Pathophysiology

Calcium is vital for many body functions, such as cell function, nerve transmission, bone structure, intracellular signaling, and blood coagulation. Neurons and cardiac cells are susceptible to fluctuations in calcium levels. The amount of calcium absorbed from the GI tract is usually matched with renal excretion. Calcium levels are rigidly controlled by PTH, vitamin D, calcitonin, and FGF23.

PTH enhances osteoclastic bone resorption and distal tubular reabsorption of calcium. PTH also stimulates renal excretion of phosphorus and the hydroxylation of 25 hydroxyvitamin D to the active form 1,25-dihydroxy vitamin D. Activated vitamin D stimulates intestinal absorption of calcium, renal absorption of calcium and phosphate, and bone reabsorption.

Calcitonin, on the other hand, lowers calcium levels 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 calcium binding to albumin, causing increased ionized calcium levels, while an alkaline environment has the opposite effect. An acidic environment also promotes the exchange of extracellular hydrogen ions for intracellular calcium, increasing ionized calcium levels and vice-versa for alkaline environments.

History and Physical

The clinical manifestations of hypocalcemia can range from asymptomatic at mild deficiency to life-threatening symptoms like seizures, heart failure, or laryngospasm if severe. Also, the clinical manifestations depend on the rate of development and chronicity of hypocalcemia. The history and physical exam of patients with hypocalcemia should include provocation exams. Symptoms of hypocalcemia include the following:[30][31]

1. Seizures: Usually present in very severe hypocalcemia. They can be the sole manifestation or part of many clinical presentations.
2. Tetany: 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: Anxiety, depression, or emotional lability are less frequently noted symptoms.
5. Carpopedal spasm: This is also referred to as Trousseau's sign. It represents increased neuromuscular excitability and manifests as a spasm of the hand characterized by flexion of the thumb, wrist, and metacarpophalangeal joints with extension of the fingers when a sphygmomanometer is inflated above systolic blood pressure for 2 to 3 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 pointe, a ventricular tachycardia that can be fatal.

The second part of the history and physical exam should focus on determining the etiology of hypocalcemia, such as recent head and neck surgery, family history of hypocalcemia, gastrointestinal or kidney disease, or alcohol use causing hypomagnesemia.

Evaluation

The workup of hypocalcemia can be broken down into the following steps:

• Confirmation of hypocalcemia: The first part of the evaluation should focus on confirming the hypocalcemia by checking a serum albumin level to correct the total calcium or directly measuring the ionized calcium level. For each 1 g/dL decrease in albumin below 4 g/dl, 0.8 mg/dL should be added to the total serum calcium level.
• Checking cardiac stability: An ECG should be obtained to look for QTc prolongation, which, if present, is a risk factor for torsades de pointes. This is often treated with IV magnesium.[31]
• Determining the etiology of hypocalcemia: Once hypocalcemia is confirmed, further testing should be done to determine the etiology. This entails checking other electrolytes, such as serum magnesium and phosphorus levels, intact PTH, and vitamin D levels. Some causes are apparent, as in patients post-thyroidectomy or parathyroidectomy. Other biomarkers may be obtained as indicated by history and physical exam (eg, serum lipase in suspected pancreatitis.)

Imaging of skeletal system: Appropriate studies may reveal osteomalacia, rickets, or metastatic disease.

Treatment / Management

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

Intravenous calcium: IV calcium is recommended in patients with severe symptoms or prolonged QTC intervals and those who are asymptomatic and acutely develop hypocalcemia. 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) can be administered as a short infusion over 10 to 20 minutes. A continuous infusion should follow this if hypocalcemia persists. Calcium gluconate is generally preferred over calcium chloride as it is less likely to cause tissue necrosis if extravasation occurs. Alkaline solutions like bicarbonate and phosphorus-containing solutions should be avoided through the same IV to prevent the precipitation of calcium salts.                                                                                                                                                  

Oral calcium: If the symptoms are mild, 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 of elemental calcium daily, divided into 2 to 3 doses. Doses are divided to avoid gastrointestinal and renal losses that can occur when large boluses are given. Calcium carbonate needs an acidic medium to be absorbed, so it should be avoided in patients taking proton pump inhibitors. Vitamin D supplementation is often recommended with calcium to promote better absorption and because vitamin D deficiency is commonly encountered in clinical scenarios leading to hypocalcemia.                                                                                                                       

Recombinant human parathyroid hormone: For the treatment of chronic hypoparathyroidism and certain genetic diseases related to low PTH levels, recombinant human parathyroid hormone has been approved by the FDA, but its use is limited by cost and availability. There are also concerns for long-term adverse effects such as bone pain and iatrogenic hyperparathyroidism.[32] Other parathyroid hormone preparations are in development and are expected to be approved for treating chronic hypocalcemia due to hypoparathyroidism.[5][33]                                                                                                                                                 

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 sometimes recommended. This usually prevents severe symptomatic hypocalcemia.[34] Calcium levels should be monitored closely after surgery, and replacement calcium should be tapered off as indicated. 
• Hypomagnesemia: Serum magnesium should be corrected before correcting hypocalcemia.
• Vitamin D deficiency: Hypocalcemia due to vitamin D deficiency cannot be corrected unless vitamin D is repleted first.[35]
• CKD: Hypocalcemia in CKD is usually a result of vitamin D deficiency. This is usually corrected by activated vitamin D (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. Patients with a history of nephrolithiasis should be counseled about the increased risk of nephrolithiasis and methods to decrease this risk (eg, increasing water consumption, lowering sodium and animal protein in the diet).
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Differential Diagnosis

The differential for hypocalcemia includes hypoalbuminemia, acute pancreatitis or sepsis, acute kidney injury, hyperphosphatemia, hypomagnesemia, and hyperparathyroidism. These conditions are interrelated, so it can be challenging to differentiate the cause and effect of these metabolic abnormalities.

Prognosis

The overall prognosis of hypocalcemia is usually 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 a normal calcium level. Patients who have undergone gastric bypass surgery often have malabsorption and may also require very high doses of calcium and vitamin D to correct hypocalcemia. High doses of vitamin D supplementation are commonly linked to nephrolithiasis and nephrocalcinosis.

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 arrhythmias. Checking an ECG and aggressively correcting calcium levels in these situations is imperative. Patients with poorly controlled hypoparathyroidism are at increased risk of developing kidney problems, including kidney stones and chronic kidney disease, and overall decreased quality of life.[36][37]