Hypocalcemia

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. Hypocalcemia is commonly seen in hospitalized patients and for the most part, is mild in nature and only requires supportive treatment.

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 is usually recommended for every 1gm drop in serum albumin below normal (4 gm/dL)
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- 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 yet.
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 thorough a decreased sensitivity of calcium-sensing receptors.
6. Acute hyperphosphatemia- 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.
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.

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 hormones or a loss of blood supply in some cases[1][2].
2. Autoimmune- Autoantibodies against the parathyroid gland or activating antibodies against calcium-sensing receptors can both cause hypocalcemia. Hypoparathyroidism can also occur as a part of MEN syndromes.

High PTH

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 or 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's a hereditary genetic disorder.

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 by far remains the most common cause of hypocalcemia followed by vitamin D deficiency, magnesium deficiency, acute pancreatitis, etc.

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.