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.
The causes of hypocalcemia can be divided into three broad categories:
Pseudohypocalcemia- Serum calcium is normally bound to protiens 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 is usually recommended for every 1gm drop in serum albumin below normal (4 gm/dL)
Acidosis/Aklalosis- Calcium binding to albumin is dependent on the serum pH and thus in states of severe acidosis ionized calcium is increased and viceversa in sever 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.
Acute pancreatitis- Hypocalcemia is often seen in the setting of acute pancreatitis due to calcium deposition in abdominal cavity as a result of ongoing inflamation.
Severe sepsis- Severe sepsis can also lead to hypocalcemia through unclear mechanisms. Impaired PTH secretion, dysregulation of magnesium metabolism, impaired calcitriol secretion have all been outlines as potential mechanisms but none have been definitely proven as yet.
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 thorough a decreased sensitivity of calcium-sensing receptors.
Acute hyperphosphatemia- An uncommon cause of hypocalcemia which is likely precipitated because of extravascular deposition of calcium.
Drugs- Bisphosphonates, cinacalcet, Denosumab, Foscarnet can all cause hypocalcemia.
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.
PTH DEFECIENCY (low or low normal serum PTH)
Post thyroidectomy- It's not uncommon after thyroid or other head and neck surgeries to get transient or permanent hypoparathyroidism leading to hypocalcemis. This can be a result of unintentional removal of parathyroid hormones or a loss of blood supply in some cases.
Autoimmune- Auto antibodies against the parathyroid gland or activating antibodies against Calcium-sensing receptors can both cause hypocalcemia. Hypoparathyroidism can also occur as a part of MEN sydromes.
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.
Absolute or relative Vitamin D defeciency- This includes lack of active metabolite of vitamin D due to inadequate sun exposure or liver disease or kidney disease. Also, included in this category are familial causes of vitamin D resistance.
Pseudohypoparathyroidism-This category refers to end organ resistance to the action of PTH. Its a hereditary genetic disorder.
There is no literature on 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 by far remains the most common cause of hypocalcemia followed by vitamin D deficiency, magnesium deficiency, acute pancreatitis, etc.
History and Physical
The history and physical exam of patients with suspected hypocalcemia should be conducted with two underlying principles in mind. First, to uncover the potential manifestations of hypocalcemia like:
Seizures- Can be the sole manifestation or a part of the whole myriad of clinical presentation.
Tetany- 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.
Paresthesias- can be perioral or otherwise
Psychiatric manifestations- Can be associated with anxiety/depression/emotional lability
Carpopedal spasm- Also referred to 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 BP check.
Chvostek's sign- 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.
QTc prolongation- Can lead to Torsades de pointes although extremely rare, it can be fatal.
The second part of history and physical 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.
Work up of hypocalcemia can be thought of in following parts:
Confirming the hypocalcemia: First part of 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). 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.
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 eg. serum lipase in suspected pancreatitis.
Treatment / Management
Management of Hypocalcemia can be divided into two broad categories:
Symptomatic hypocalcemia: intravenous calcium is recommended for rapid repletion if there is any 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 and can be given over 10-30 minutes depending on the severity of symptoms. Calcium chloride can be used if central venous access is available. Alkaline solution like bicarbonate and phosphorus containing solution need to be avoided through the same iv to avoid precipitation of calcium salts.
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 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-exiting electrolyte disturbances eg. hypomagnesemia.
Pearls and Other Issues
Check a magnesium level when faced with hypocalcemia since its an important and easily correctable cause of hypocalcemia.
Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia., Edafe O,Antakia R,Laskar N,Uttley L,Balasubramanian SP,, The British journal of surgery, 2014 Mar [PubMed PMID: 24402815]