Table of Contents
Definition of Hypocalcemia
Hypocalcemia is the condition in which the serum calcium level in the blood is low. The normal calcium level in the body is between 2.2–2.6 mmol/L.
Etiology of Hypocalcemia
The causes of hypocalcemia include, besides inadequate oral intake of calcium, the following.
Kidney or liver disease
Especially in the end stages, these are the most common causes of hypocalcemia. Both the kidney and the liver are paramount in the regulation of calcium levels. They are essential for the activation of vitamin D, which is a major enzyme that controls the levels of calcium. In end-stage kidney and liver disease, there will be dysfunction of both these organs that would lead to reduced activation of vitamin D3 and, therefore, reduced calcium levels.
Hypoparathyroidism is a condition in which the body does not produce the adequate parathyroid hormone. Parathyroid hormone (PTH) is a hormone produced by the parathyroid glands. These are four glands which, as their name suggests, lie parallel to the thyroid gland. PTH plays a key role in the regulation of calcium levels. PTH results in elevated levels of calcium in the blood. This is usually achieved by:
Mobilization of calcium as well as phosphate from the bone into the extracellular fluid, then into the blood.
Reduction of calcium excretion from the kidney, thus retention of calcium in the blood.
Increased activation of inactive vitamin D3, which is another hormone that is important in the maintenance of normal calcium levels in the blood.
In cases where hypoparathyroidism is present, these functions performed by PTH are absent or insufficient, resulting in hypocalcemia.
Hypoparathyroidism can occur following a variety of causes, which are described in the following.
Damage to the parathyroid glands. This can occur during thyroid surgery, which happens to be the most common cause of hypoparathyroidism. Hypoparathyroidism is, however, not that common a complication of thyroidectomies, as only a small percentage of patients present with hypoparathyroidism in the post-thyroidectomy period.
Damage to the parathyroid glands can also occur in surgery aimed at treating laryngeal malignancies or other neck tumors. It can also result following extensive irradiation to the neck region, as well as the face and mediastinum.
Congenital causes of hypoparathyroidism are relatively rare. These include autoimmune poly-endocrine syndrome type 1, which is a rare disorder that results in multiple endocrine glands demonstrating insufficient functioning.
Another more common congenital cause of hypoparathyroidism, which is still rare, is DiGeorge syndrome. This is one of several common conditions that are principally characterized by a deletion of a part of chromosome 22, more specifically at chromosome 22q11.2.
DiGeorge syndrome may manifest most commonly as neonatal hypocalcemia and congenital heart defects coupled with a cleft palate. Patients may also present with abnormal faces characterized by micrognathia, broad nasal bridges, and a long face.
There may be evidence of immune dysfunction, with increased susceptibility to infections, especially those caused by fungi and bacteria.
This immune deficiency may be due to the absence of or insufficient functioning of the thymus as DiGeorge syndrome tends to have manifestations involving multiple glands and organs. An absent or poorly functioning thymus would result in poor development and maturation of T lymphocytes – a key component of the immune system – which would explain the susceptibility to infectious diseases.
These patients may also present with learning difficulties such as autism, psychiatric conditions like schizophrenia as well as behavioral abnormalities.
Another cause of hypoparathyroidism that may be congenital, although presentation may be seen in adulthood, is autosomal dominant familial hypoparathyroidism. Not surprisingly, this condition has been associated with other congenital abnormalities, among them DiGeorge syndrome.
Affected patients may present with hypoparathyroidism, deafness – usually sensorineural –, and may demonstrate symptoms associated with other conditions, for example diabetes mellitus.
Parathyroid gland infiltration. This may be seen in hemochromatosis, which is an accumulation of abnormal levels of iron in several glands, including the parathyroid glands.
It may also occur in Wilson’s disease, in which there are abnormal accumulation and deposition of copper. Both these conditions result in poor function of the parathyroid glands, which results in hypoparathyroidism.
Patients with hypoparathyroidism may often complain of numbness especially at the toes, fingertips and the perioral area, fatigue and anxiety, dyspnea, and psychiatric symptoms, especially those affecting mood and personality.
Clinically, the attending physician may note tetany, which is more common in severe cases of hypocalcemia. Hypocalcemia may also result in there being more neuromuscular irritability. This may be demonstrated by the Trousseau sign and the Chvostek’s sign. These are described in detail later.
There may also be cardiac manifestations including congestive cardiac failure and QT prolongation. There may also be signs of glandular insufficiency, for example, adrenal insufficiency, following particular causes of hypoparathyroidism, for example, autoimmune poly-endocrine syndrome.
There may also be high serum levels of phosphate. On plain radiographs, there may be abnormal visible thickening of bone. This is termed osteosclerosis.
This is a syndrome of end organ resistance to parathyroid hormone owing to a mutation in a G protein (GNAS). This disorder is inherited in an autosomal recessive fashion.
Pseudohypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia and raised serum concentration of parathyroid hormone.
Although many types of pseudohypoparathyroidism exist, the most common is type 1a, also called Albright’s Hereditary Osteodystrophy. Affected patients present with obesity, short stature, rounded face, short 4th and 5th metatarsals and metacarpals, and subcutaneous calcification.
There is no symptomatic relief upon administration of PTH.
Vitamin D deficiency
Vitamin D deficiency can be a result of several causes such as renal failure, severe liver disease and intestinal malabsorption. In renal failure, hydroxylation of vitamin D at the 1st site does not occur as usual. This results in decreased production of calcitriol, which eventually leads to reduced absorption of calcium from the small intestine.
In severe liver disease, hydroxylation of vitamin D at the 25th position fails, ultimately resulting in decreased calcitriol levels and therefore reduced calcium absorption. However, hypocalcemia from severe liver disease rarely occurs.
Calcium is absorbed passively throughout the intestine, and actively at the duodenum and jejunum. It therefore stands to reason that any interference in the absorption of calcium may have a direct effect on its concentration in the blood.
In diseases such as celiac disease and chronic pancreatitis, calcium will not be absorbed into the body as usual.
Large blood transfusions
Most blood products including fresh frozen plasma and platelets contain high concentrations of citric acid. The reason for adding citrate into blood is to prevent coagulation. During blood transfusions, this citrate binds to calcium in the serum thus lowering the ionized plasma calcium concentration.
Magnesium depletion, hypomagnesemia, usually results in PTH-dependent hypocalcemia. It has been demonstrated that in the setting of hypomagnesemia, there is reduced release of and reduced sensitivity to PTH. This is what results in the hypocalcemia observed.
Hypomagnesemia also results in improper working of the liver and kidney, both of which are important in calcium homeostasis. This hypocalcemia is rapidly corrected following administration of magnesium.
In all cases of hypocalcemia, magnesium levels should be checked because the body needs adequate levels of magnesium for…
- …normal secretions of parathyroid hormone to take place.
- …parathyroid hormones to work on osteoclast receptors to basically activate these receptors.
Pancreatitis causes a release of pancreatic enzymes including lipase into the circulation. Lipase normally breaks down triglycerides into free fatty acids to aid in absorption of fatty acid.
Some of these enzymes damage the blood vessels and lipases manage to leak into the extravascular compartment. Here, the lipases begin to digest the triglycerides that were released as a result of fat necrosis. Calcium binds to these fatty acids thus resulting in hypocalcemia.
Acute respiratory alkalosis
In alkalosis following hyperventilation, there may be a decrease in the levels of ionized calcium in the blood.
Excessive tissue breakdown
Hypocalcemia due to excessive tissue breakdown is best demonstrated by rhabdomyolysis, the breakdown of skeletal muscle cells. On lysis, these cells result in the release of enzymes that chelate calcium, thus resulting in reduced levels of calcium.
Clinical Features of Hypocalcemia
Most cases of mild reductions in calcium levels are usually asymptomatic, although the exact concentration at which symptoms appear is yet to be determined.
A normal calcium level is important to maintain a normal neuromuscular function. Most severe forms of hypocalcemia present with tetany and laryngospasms. Symptoms of tetany can be mild or severe.
While both adults and children can be affected, this is most common in children and often presents with a classical triad of convulsions, stridor – due to spasms affecting the glottis – and carpopedal spasms.
In carpopedal spasms, the hand attains a characteristic posture commonly referred to as ‘main d’accoucheur’, which involves adduction of the thumb and flexion at the metacarpal phalangeal joints. While adults can also experience carpopedal spasms, the other components of the triad are rare in adults who instead experience tingling around the mouth, in the feet and hands.
Paresthesia, numbness especially in the perioral region, and muscle cramps are all mild symptoms of tetany whereas carpopedal spasms, seizures and laryngospasms indicate severe tetany. Bronchospasms, hypotension and reduced cardiac contractility are other features of neuromuscular irritability. Two signs of hypocalcemia are:
Chvostek sign – If you tap over the facial nerve, the patient develops twitching of the ipsilateral facial muscles.
- Trousseau’s sign – A sphygmomanometer cuff is applied and inflated above the systolic pressure for 3 minutes. This will induce a tetanic spasm of the fingers and wrist.
Both these signs are evident of latent tetany.
The patients may also be prone to ventricular arrhythmias with ECG changes observed including QT elongation as a typical finding.
Skeletal abnormalities in pseudohypoparathyroidism
Pseudohypoparathyroidism presents skeletal abnormalities such as shortened 4th and 5th metacarpals and metatarsals and short stature.
There are also other features observed in cases of hypocalcemia. These include rickets, seen in children and osteomalacia, seen in adults. These are usually seen in cases of combined hypocalcemia and hypophosphatemia, which can also predispose to seizures, psychotic symptoms and basal ganglia disorders following basal ganglia calcification.
There may also be ocular defects including papilledema and cataracts.
Differential Diagnosis of Hypocalcemia
Parathyroid hormone absent
- Hereditary hypoparathyroidism
- Idiopathic hypoparathyroidism
- Syndromes associated with hypoparathyroidism (DiGeorge’s syndrome, Kenney Caffey syndrome, etc.)
- Acquired hypoparathyroidism (surgery, radiation)
Ineffective parathyroid hormone
- Chronic renal failure
- Vitamin D deficiency (decreased dietary intake, decreased exposure to sunlight, intestinal malabsorption)
Overwhelmed parathyroid hormone
- Severe acute hyperphosphatemia
- Tumor lysis
- Acute renal failure
Investigations for Hypocalcemia
The clinical history and the presentation are often diagnostic of hypocalcemia and it is confirmed by low serum calcium levels. However the investigations that can be done are:
- Serum calcium levels
- Check albumin levels
This is the first thing that should be done when a patient with hypocalcemia presents. When we measure calcium, the total calcium level is usually measured and about 40 % of calcium is bound to albumin. So, the first thing is to check if this is true hypocalcemia or is it an effect from the low albumin levels.
If the albumin levels are low in this patient, then it is not true hypocalcemia. Therefore check the albumin and correct the levels and if the hypocalcemia levels are correct, then the patient does not have true hypocalcemia and the patient should be treated for low albumin instead.
The correction is: for every decrease in albumin by 1g, there is a decrease in calcium by 0.8 mg/dL.
- Serum phosphate levels – This will be raised in hypocalcemia patients.
- Serum magnesium levels – To exclude hypomagnesemia; severe hypomagnesemia will result in reduced secretion and activity of the parathyroid hormones which will be reversed by magnesium replacement.
- Parathyroid hormone levels in the serum – If the parathyroid hormone levels are low in the serum, then it could be hypoparathyroidism. If it is high then the hypocalcemia could be due to other causes such as vitamin D deficiency.
- 25-hydroxy vitamin D serum levels – Vitamin D levels will be low in vitamin D deficiency.
- Serum and urine creatinine – To exclude any renal diseases.
- X-rays of metacarpals – Shows short 4th and 5th metacarpals in pseudohypoparathyroidism.
Treatment of Hypocalcemia
If the patient has any evidence of tetany, latent tetany, laryngospasms or muscle cramps, the patient should be given intravenous calcium gluconate or calcium chloride. It will readjust the calcium in serum as quickly as possible.
If the patient has very mild symptoms then only maintenance therapy is needed. These patients should be given oral calcium carbonate 2–4 g/day or calcium citrate. This is usually given in conjunction with vitamin D if they are missing it.
The best way to give vitamin D is in the active form because now the patient doesn’t have to hydroxylate it. Thus 1,25 hydroxycholecalciferol is given since it is the easiest way and has the quickest action. However, during the treatment these patient’s serum calcium levels should be monitored regularly for hypercalcemia.
Patients especially with end stage kidney disease develop hyperphosphatemia as a result of low or no urine output. When the phosphate levels increase, the calcium levels go down further. Therefore, these patients should have a restricted diet and phosphate binders such as calcium carbonate and aluminum hydroxide should be given to reduce the phosphate levels in the blood.