Continuing Education Activity

Disorders of calcium metabolism are frequently encountered. Though hypocalcemia is encountered as frequently as hypercalcemia, it can be potentially life-threatening if not appropriately recognized and treated promptly. 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 factor 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 or hormone-like substances, such as parathyroid hormone (PTH), Vitamin D, and calcitonin. Disorders of calcium metabolism are encountered pretty frequently in routine clinical practice. Hypocalcemia is not as frequently encountered as hypercalcemia, but it can be potentially life-threatening if not appropriately recognized and treated promptly. Hypocalcemia is said to be present when the total serum calcium concentration is less than 8.8 mg/dl. The disorder may be acquired or inherited but its presentation can vary from asymptomatic to life-threatening state. Hypocalcemia is commonly seen in hospitalized patients and for the most part, is mild in nature that only requires supportive treatment.

Etiology

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

• Miscellaneous
• PTH deficiency
• High PTH

Miscellaneous

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 usually 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 in severe alkalosis. There is no reliable correction factor to estimate this shift in ionized calcium level and 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. Severe sepsis/Critical illness: Severe sepsis can also lead to hypocalcemia through unclear mechanisms. Impaired PTH secretion, dysregulation of magnesium metabolism, impaired calcitriol secretion have all outlined as potential mechanisms but none have been definitely proven as of yet[1]. Most recent reports indicated hypocalcemia related to severe Covid-19 infection[2].
5. Hypomagnesemia/hypermagnesemia: Low serum magnesium can be commonly associated with hypocalcemia due to induced PTH resistance. It is uncommon above a serum magnesium level of 1mg/dL. 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.
7. Drugs: Bisphosphonates, cinacalcet, Denosumab, Foscarnet can all cause hypocalcemia[3][4][3].
8. Massive Blood transfusion: Massive blood transfusion can cause an acute decline in ionized calcium due to calcium binding with citrate which is used to prevent the stored blood from clotting[5].
9. Pregnancy: There are reports of hypocalcemia during pregnancy, mostly related to poor diet or underline diseases[6].

PTH deficiency (low or low normal serum PTH)

1. Post thyroidectomy: It's not uncommon after thyroid or other head and neck surgeries to get transient or permanent hypoparathyroidism leading to hypocalcemia. This can be a result of unintentional removal of parathyroid glands or a loss of blood supply in some cases[7][8][9][8].
2. Autoimmune: Autoantibodies against the parathyroid gland or activating antibodies against calcium-sensing receptors can both cause hypocalcemia.

High PTH levels

1. Chronic Kidney Disease (CKD): CKD leads to impaired phosphate excretion which 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.
2. Absolute or relative Vitamin D deficiency: This includes lack of active metabolite of vitamin D due to inadequate sun exposure, liver disease or kidney disease. Also, included in this category are familial causes of vitamin D resistance.
3. Pseudohypoparathyroidism: This category refers to end-organ resistance to the action of PTH. It is a hereditary genetic disorder.

Epidemiology

There is no literature on the quantification 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. 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 by renal excretion. The levels of calcium are rigidly controlled by vitamin D, parathyroid hormone and calcitonin. Parathyroid hormone enhances osteoclastic bone resorption and distal tubular reabsorption of calcium. In addition, it mediates absorption of calcium from the intestine. Vitamin D is known to regulate PTH release, intestinal absorption of calcium and also medicares PTH stimulated bone reabsorption. Calcitonin on the other hand lowers levels of calcium. Hypocalcemia is a common cause of tetany and neuromuscular irritability. An alkaline environment lowers calcium levels and induces tetany, whereas an acidic envirionment is protective.

History and Physical

The history and physical exam of patients with suspected hypocalcemia should be conducted with two underlying principles in mind. First one is to uncover the potential manifestations of hypocalcemia like:

1. Seizures: Can be the sole manifestation or a part of the whole myriad of clinical presentation.
2. Tetany: Is generally induced by a rapid decline in serum ionized calcium. Tetany is usually most dangerous and most commonly seen in the presence of respiratory alkalosis causing hypocalcemia.
3. Paresthesias: Can be perioral or otherwise.
4. Psychiatric manifestations: Can be associated with anxiety, depression, or emotional lability.
5. Carpopedal spasm: I also referred as Trousseau's sign. It represents increased neuromuscular excitability which may be related to the gating function of calcium ion for ion channels at a cellular level (particularly in neurons). This manifests as a spasm of hand upon routine blood pressure check.
6. Chvostek's sign: Is another manifestation of heightened neuromuscular excitability. It is the spasm of facial muscles in response to tapping the facial nerve near the angle of the jaw.
7. QTc prolongation: Can lead to Torsades de pointes that although extremely rare, it can be fatal.

The second part of 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: First part of the evaluation should focus on confirming the hypocalcemia and requires checking a serum albumin level to correct the total calcium or measuring directly the ionized calcium level (where available).To correct for hypoalbuminemia, add 0.8 mg/dl to the total serum calcium for each 1 g/dl decreased in albumin below 4 g/dl.
2. An EKG should also be obtained for all suspected cases of hypocalcemia to look for QTc prolongation which, if present, is a risk factor for Torsades de pointes[10].
3. Etiology of hypocalcemia: This part can be driven by the clinical picture obtained during previous steps. Usually entails checking electrolytes such as serum magnesium and phosphorus levels and at least a serum PTH level. If suspicion for vitamin D deficiency is high based on history, then Vitamin D2 level should be measured as vitamin D3 can be affected by PTH levels. Other biomarkers may be obtained as indicated by history and physical exam, eg. serum lipase in suspected pancreatitis.
4. Imaging of the bones may reveal osteomalacia, rickets or even metastatic disease.

Treatment / Management

Management of hypocalcemia can be divided into two broad categories:

1. Symptomatic hypocalcemia: Intravenous (IV) calcium is recommended for rapid repletion, when there is evidence of neuromuscular excitability. If the symptoms are mild such as paresthesias or psychiatric, oral calcium can be attempted. Calcium gluconate is the preferred solution IV and can be given over 10-30 minutes depending on the severity of symptoms. Calcium chloride can be used IV only if central venous access is available. An alkaline solution like bicarbonate and phosphorus containing solution need to be avoided through the same IV to avoid precipitation of calcium salts. 
2. Asymptomatic hypocalcemia: If corrected total serum calcium is below 7.5mg/dL, IV calcium should still be the preferred method. However, if corrected serum calcium is >7.5 mg/dL and the patient is asymptomatic oral calcium can be used. Vitamin D supplementation is often recommended with calcium to promote absorption and because vitamin D deficiency is commonly encountered in most clinical scenarios leading to hypocalcemia. It is also important to address disease-specific problems and correct co-existing electrolyte disturbances eg. hypomagnesemia[11].
3. Patients with ECG changes need monitoring during calcium supplementation.
4. In some patients, ultraviolet or sunlight exposure may help to increase the serum calcium levels.
5. In patients with chronic hypocalcemia and renal failure, at least 1 g/day of dietary calcium is necessary.

Differential Diagnosis

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

Pearls and Other Issues

Check a magnesium level when faced with hypocalcemia since it is an important and easily correctable cause of hypocalcemia.

Enhancing Healthcare Team Outcomes

Because there are many causes, the diagnosis and management of hypocalcemia is best done with an interprofessional team. Consultations from many specialists are 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 that are aggravating the electrolyte disorder. A dietary consult should be ordered for patients with renal failure and hypocalcemia in order to prevent the symptoms. Patients need to be educated about the symptoms of hypocalcemia like muscle weakness and paresthesias, so that they can seek treatment. Open communication between the team members is vital to prevent the morbidity of hypocalcemia.