Low PTH
High PTH
Others
Destruction of parathyroid glands by surgery or radioactive iodine
Vitamin D deficiency or resistance
Hypomagnesaemia
Autoimmune destruction of parathyroid glands
Chronic kidney disease
Drugs
Irradiation or infiltration of parathyroid glands
PTH resistance
Spurious hypocalcaemia
(assay interference)
Abnormal parathyroid gland development
Extravascular calcium deposition
Abnormal PTH regulation
Severe sepsis or pancreatitis
HIV infection
Tumour lysis syndrome
Hungry bone syndrome (post parathyroidectomy)
Malabsorption
Is the problem acute or chronic?
If the problem seems to be of acute onset in adult life it is more likely to be acquired. Acquired hypoparathyroidism tends to be the consequence of postsurgical or autoimmune damage. Other acute causes may be related to change in medications or recent new illness.
Is there evidence of malabsorption?
Ask specifically about symptoms of gastrointestinal disease consistent with malabsorption, lactose intolerance or a history of coeliac disease may be a predisposing factor to hypocalcaemia. Patients with gastro-oesophageal reflux disease or peptic ulcer disease tend to be on proton pump inhibitor therapy which has been associated with hypomagnesaemia, which in turn may cause hypocalcaemia.
Is there a deficiency in calcium intake?
If poor dietary intake of calcium is suspected, using a calcium calculator to calculate daily intake of calcium may be useful as part of the history. Poor calcium intake with concurrent vitamin D deficiency or coeliac disease can present with clinically significant hypocalcaemia.
Is there a history of other autoimmune conditions?
The presence of other autoimmune conditions, such as thyroid disease, adrenal insufficiency, coeliac disease, would point towards an autoimmune cause of hypocalcaemia.
What is the past medical history?
Conditions such as chronic kidney disease, cancer (particularly with bone metastases), pancreatitis, rhabdomyolysis, recent severe illness and HIV may predispose towards hypocalcaemia. Is there a history of granulomatous disorders or infiltrative disease (e.g., haemochromatosis, Wilson’s disease)?
Is there a history of surgery, irradiation or cancer in head or neck?
Recent parathyroidectomy, or previous operations on thyroid or head and neck cancers in the past may have led to postsurgical parathyroid damage leading to hypocalcaemia.
Is there a family history?
A family history of hypocalcaemia may suggest a genetic cause such as an activating mutation of the calcium sensing receptor (CaSR), parathyroid hormone resistance or polyglandular autoimmune syndrome type 1. The presence of chronic mucocutaneous candidiasis and adrenal insufficiency would support a diagnosis of polyglandular autoimmune syndrome type 1.
What medication does the patient take?
Drugs associated with hypocalcaemia include, calcium chelators (citrate given during plasma exchange or large volume blood transfusion), cinacalcet, denosumab, phenytoin and bisphosphonates. Use of chemotherapy, especially cisplatin or leucovorin with 5-fluouracil is associated with hypocalcaemia. Foscarnet, an antiviral drug used in cytomegalovirus infections, may also cause symptomatic hypocalcaemia.
The patient denied any further symptoms. His chemotherapy regimen had used cisplatin, but he did not have symptoms consistent with hypocalcaemia at the time. Interestingly, he had been started on a proton pump inhibitor following oesophageal surgery. He was taking calcium carbonate supplements infrequently.
What Signs to Look Out For?
On examination the patient was of slim build with a BMI 21.3 kg/m2. There was evidence of laryngectomy and stoma, with assisted speech. No neck masses or lymphadenopathy were evident. The patient was alert and orientated to time, place and person. Carpopedal spasm was provoked with inflation of a sphygmomanometer cuff (Trousseau’s sign). Chvostek’s sign was negative. There were no dental or bone abnormalities. An ECG did not show evidence of prolonged QT interval.
The symptoms and signs of hypocalcaemia are dependent on the severity, duration and rate of development of hypocalcaemia. Some patients may have no neuromuscular symptoms, and others may have non-specific symptoms such as fatigue, anxiety and low mood. A corrected calcium level of <1.9 mmol/L may lead to the acute symptoms described below.
Acute Symptoms and Signs
Acute hypocalcaemia leads to hyperexcitability of neurones and the development of tetany. Initially mild symptoms may predominate, such as peri-oral numbness, paraesthesia of the extremities and muscle spasms. Hyperventilation may result, which leads to alkalosis, which can exacerbate tetany.
More severe tetany may manifest as carpopedal spasm, seizures and laryngospasm. Carpopedal spasm involves flexion of the metacarpophalangeal joints and wrists with associated extension of the fingers and adduction of the thumb.
If the onset of hypocalcaemia is gradual, the patient is likely to have fewer symptoms.
The classical signs of hypocalcaemia are Trousseau’s sign and Chvostek’s sign. However, both may be negative, even in significant acute hypocalcaemia.
Trousseau’s sign is the induction of carpopedal spasm by inflation of a sphygmomanometer above systolic blood pressure for 3 min.
Chvostek’s sign is a contraction of facial muscles caused by tapping the facial nerve in front of the ear.
The cardiovascular system is highly sensitive to changes in calcium concentrations. Decreased cardiac output, heart failure and hypotension have all been associated with hypocalcaemia. This impairment of myocardial function seems to be reversible with correction of hypocalcaemia. Hypocalcaemia is also associated with prolongation of the QT interval on the electrocardiograph. This may be associated with the onset of arrhythmias, particularly Torsade de Pointes.
Psychiatric symptoms such as acute confusional states, hallucinations and psychosis are rarely associated with severe hypocalcaemia.
Another sign of severe, acute hypocalcaemia is papilloedema. This again is usually reversible with correction of serum calcium concentration.
Chronic Hypocalcaemia
Chronic hypocalcaemia has multiple effects and is often specific to the underlying cause.
Dry, coarse skin, brittle nails, and sparse hair with alopecia may all be manifestations of chronic hypocalcaemia.
Longstanding hypoparathyroidism may lead to basal ganglia calcification (detectable on CT scan), which can then lead to movement disorders or Parkinsonism.
If hypocalcaemia is particularly longstanding, dental abnormalities such as dental hypoplasia and defective enamel and root formation may occur. PTH resistance is often associated with numerous developmental skeletal abnormalities.
Diffuse bone pain, muscle weakness and bone tenderness as a result of chronic hypocalcaemia secondary to osteomalacia is possible.
What Tests are Needed to Reach a Diagnosis?
Initial investigations showed that the patient had an adjusted calcium of 1.83 mmol/L (2.2–2.6 mmol/L). PTH was undetectable, total hydroxy-vitamin D levels were low at 25 nmol/L (50–100 nmol/L), magnesium levels were also below the reference range at 0.53 mmol/L (0.7–1.0 mmol/L). Renal function and albumin were normal. Serum phosphate levels were marginally elevated.
The first step in establishing the diagnosis is to recheck calcium levels with measurement of the serum albumin concentration. Calcium is bound to proteins, mainly albumin. Therefore, total serum calcium concentrations in patients with abnormal albumin levels may not be representative of ionised (or free) calcium concentrations. Most labs will provide a corrected calcium concentration which takes this into account. Each 1 g/dL reduction in serum albumin concentration will lower total calcium concentration by approximately 0.2 mmol/L.
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