Investigating hypocalcaemiaBMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f2213 (Published 09 May 2013) Cite this as: BMJ 2013;346:f2213
- 1Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK
- 2Department of Clinical Biochemistry, John Radcliffe Hospital, Oxford OX3 9DU, UK
- Correspondence to: R V Thakker
To confirm hypocalcaemia, calculate serum albumin-adjusted calcium concentrations; in patients who are critically ill or have acid-base disorders, ionised calcium measurements are needed
Careful clinical assessment may show common causes of hypocalcaemia, such as post-surgical hypoparathyroidism, chronic kidney disease, or drugs
Serum parathyroid hormone measurements are central to investigating and classifying causes of hypocalcaemia; other tests include serum phosphate, magnesium, and creatinine concentrations
Serum vitamin D measurements are indicated in patients with inadequate exposure to sunlight, nutritional deficiency, or malabsorption syndrome
A 42 year old woman with active Crohn’s disease presented to her general practitioner for annual review. Serum electrolyte, renal and liver function tests were normal apart from the following: total calcium 2.04 mmol/L (normal range 2.20-2.60 mmol/L); albumin 38 g/L (35-50 g/L); phosphate 0.71 mmol/L (0.80-1.45 mmol/L); and alkaline phosphatase activity 380 U/L (80-290 U/L). She had no history of paraesthesiae, carpopedal spasms, or seizures. Subsequent investigations showed a low serum 25-hydroxyvitamin D (25(OH)D) concentration of 23 nmol/L (normal >75 nmol/L). She was therefore started on oral calcium and cholecalciferol daily. Four months later, the patient presented to the local emergency department with persistent severe diarrhoea, paraesthesiae, carpal spasms, and seizures. Investigations found no causes for the seizures other than hypocalcaemia (ionised plasma calcium 0.82 mmol/L; normal range 1.1-1.30 mmol/L).
What are the next investigations?
Confirm hypocalcaemia by measurement of serum albumin-adjusted calcium (albumin-adjusted calcium = total calcium + 0.016 × (40 − albumin)).1 At admission this patient’s serum calcium is 1.56 + 0.016 x (40 – 35) = 1.64 mmol/L
In critically ill patients or those with acid-base disorders and symptoms attributable to hypocalcaemia, measure ionised calcium on a blood sample obtained without a tourniquet
Define causes of hypocalcaemia by measuring serum parathyroid hormone concentrations.
Assess serum magnesium.
Other first line tests include serum phosphate and creatinine concentrations, and estimated glomerular filtration rate to help elucidate causes.
These tests are outlined in the figure⇓ and discussed in detail below.
The prevalence of hypocalcaemia has been reported as >15% and 85% in hospitalised and critically ill patients, respectively.2 The clinical presentation of hypocalcaemia (serum albumin-adjusted calcium <2.20 mmol/L or ionised calcium <1.1 mmol/L) ranges from an asymptomatic biochemical abnormality to a life threatening disorder.3 Patients with severe hypocalcaemia (serum albumin-adjusted calcium <1.90 mmol/L or ionised calcium <0.95 mmol/L) may develop symptoms of acute neuromuscular irritability. Paraesthesiae of the circumoral region, fingers, and toes occurs most commonly. However, patients may also develop muscle cramps, carpopedal spasms, seizures of all types, and cardiac arrhythmias associated with prolongation of the QT interval on electrocardiography. Chronic hypocalcaemia (over several years) may be associated with subcapsular cataracts; papilloedema; abnormal dentition; and ectopic calcification (such as in the basal ganglia).3
Serum albumin-adjusted calcium and ionised calcium in diagnosing hypocalcaemia
The diagnosis of hypocalcaemia should be based on the measurement of serum albumin-adjusted calcium concentrations. Serum total calcium is adjusted to the prevailing serum albumin concentration, as about half of the circulating calcium is bound mainly to albumin, and also to globulins, bicarbonate, and other anions. Thus, alterations in albumin concentrations alone will lead to changes in total calcium without affecting the biologically important ionised calcium fraction.1 3 One of the most widely used methods of adjustment is to add or subtract 0.1 mmol/L from the total calcium concentration for every 6 g/L of albumin below or above a reference value of 40 g/L, respectively, as illustrated above. However, owing to differences between assays, many laboratories derive their own adjustment equations.4
In critically ill patients, serum albumin-adjusted calcium measurements are unreliable, possibly owing to the presence of severe hypoalbuminaemia and alterations in sample pH, and use of an albumin-adjusted calcium measurement may underestimate the occurrence of hypocalcaemia.5 Moreover, disturbances of acid-base balance—such as hyperventilation induced alkalosis—may increase calcium binding by albumin, thereby leading to a reduction in ionised calcium concentrations without affecting the adjusted total calcium value.6 Thus, in some clinical situations direct measurement of ionised calcium is needed for the detection of hypocalcaemia. When a blood sample is obtained for ionised calcium analysis, it is important to minimise pH changes that affect the ionisable fraction in vitro. In particular, collect venous or arterial blood anaerobically using a blood gas syringe, ideally as an uncuffed sample, and ensure it is analysed within 15 minutes of collection.7
Serum parathyroid hormone measurement for defining cause of hypocalcaemia
Measurement of serum parathyroid hormone concentration, plus concurrent serum albumin-adjusted calcium, is central to investigating hypocalcaemia and is used to classify its causes (box).3 Circulating ionised calcium concentrations are tightly regulated by parathyroid hormone, which stimulates osteoclastic bone resorption, inhibits the renal excretion of calcium, and promotes the renal synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D), leading to enhanced intestinal absorption of calcium.3 A low or normal serum parathyroid hormone concentration linked with hypocalcaemia is consistent with hypoparathyroidism (box), whereas a raised concentration indicates secondary hyperparathyroidism, which is commonly caused by disorders such as chronic kidney disease or vitamin D deficiency (box).8 9 10
Classification of the common causes of hypocalcaemia according to serum parathyroid hormone concentrations
Low concentrations (hypoparathyroidism)
Reduced parathyroid function (reversible)—Hypomagnesaemia; drugs such as cinacalcet (decrease secretion of parathyroid hormone); neonatal hypocalcaemia (may be associated with maternal hypercalcaemia)
Parathyroid loss (irreversible)—Surgery; autoimmune disease; agenesis
High concentrations (secondary hyperparathyroidism)
Vitamin D deficiency—Elderly or living in a care home; lack of sunlight; nutritional lack (such as in exclusively breastfed infants), malabsorption syndrome, liver disease, or chronic kidney disease
Parathyroid hormone resistance—Hypomagnesaemia; pseudohypoparathyroidism
Drugs—Inhibitors of bone resorption (such as bisphosphonates, calcitonin, denusomab); inhibitors of calcium and magnesium absorption (such as proton pump inhibitors); altered vitamin D metabolism (caused by, for example, phenytoin, ketoconazole)
Chelation of circulating calcium—Acute pancreatitis; early rhabdomyolysis; massive tumour lysis; large blood transfusions
Low ionised calcium concentrations—Hyperventilation; acute severe illness
However, serum parathyroid hormone measurements may not be available on a same day basis, and appropriate clinical assessment and interpretation of more readily available serum measurements may help to uncover the cause of hypocalcaemia (figure⇑).Thus, the first step in establishing the cause of hypocalcaemia is a careful history and examination focusing on the predisposing causes, such as chronic kidney disease, neck surgery, drugs, vitamin D deficiency, autoimmune disease, malabsorption syndrome, or dysmorphic features consistent with a congenital disorder (box, figure⇑).3 9 10 11 12
Serum creatinine concentrations and estimated glomerular filtration rate
These will help to confirm renal impairment (figure⇑)—hypocalcaemia is typically observed in stage 5 of chronic kidney disease (estimated glomerular filtration rate <15 ml /min/1.73m2).13 Hypocalcaemia in chronic kidney disease is secondary to the reduced synthesis of 1,25-dihydroxyvitamin D and the occurrence of hyperphosphataemia, which leads to an increase in the calcium phosphate product and precipitation of calcium phosphate in soft tissues, thereby lowering circulating calcium concentrations.10
Serum phosphate concentrations
Measurement of serum phosphate may be helpful for diagnosing the cause of the hypocalcaemia, as hypoparathyroid disorders are associated with hyperphosphataemia, whereas low serum phosphate concentrations are associated with high parathyroid hormone concentrations as occur in secondary hyperparathyroid states such as vitamin D deficiency and osteomalacia (figure⇑). However, serum phosphate varies greatly within an individual owing to the effects of circadian variation and dietary intake.14 To minimise this variability, a fasting serum phosphate is recommended.
Serum magnesium concentrations
These are helpful as a first line investigation, as hypomagnesaemia is associated with an impairment of parathyroid hormone secretion and end-organ resistance to the effects of parathyroid hormone. Serum magnesium concentrations <0.5 mmol/L typically result in symptomatic hypocalcaemia.15 Hypomagnesaemia may occur in patients with acute or chronic diarrhoea, malabsorption syndromes, or alcoholism or in those taking proton pump inhibitors or loop or thiazide diuretics.11 15
Serum 25-hydroxyvitamin D concentrations
Vitamin D deficiency (as assessed by serum concentration of 25-hydroxyvitamin D, its major circulating form) is a major cause of hypocalcaemia and commonly affects elderly people, people living in a care home, and individuals of non-white ethnicity. The deficiency occurs as a consequence of inadequate exposure to sunlight (for example, wearing skin concealing garments, or using excessive amounts of sunscreen); nutritional deficiency (such as in exclusively breastfed infants); and malabsorption syndrome (such as those with coeliac disease, Crohn’s disease, short bowel syndrome, cystic fibrosis, or chronic pancreatic insufficiency).9 16 Vitamin D deficiency should be considered in a patient with clinical features of osteomalacia or rickets, hypophosphataemia, increased serum alkaline phosphatase activity or raised parathyroid hormone concentrations.9 Vitamin D deficiency is generally defined by a serum 25-hydroxyvitamin D concentration of <50 nmol/L, although hypocalcaemia is not usually observed until the concentration is as low as <25 nmol/L.8 9
Serum amylase concentrations
These are helpful for the detection of acute pancreatitis (figure⇑).
Serum creatine kinase concentrations
These are helpful for the detection of early rhabdomyolysis (figure⇑).
Additional history from her relatives showed that she had not taken the prescribed oral calcium and cholecalciferol. Serum biochemical investigations undertaken at the time of admission showed the following abnormal concentrations: an albumin-adjusted calcium of 1.64 mmol/L, phosphate of 0.66 mmol/L, magnesium of 0.36 mmol/L (normal range 0.75-1.05 mmol/L), and parathyroid hormone of 10.8 pmol/L (normal range 1.3-7.6 pmol/L). This patient was diagnosed with hypocalcaemia associated with secondary hyperparathyroidism, hypomagnesaemia, and vitamin D deficiency resulting from malabsorption from extensive small bowel Crohn’s disease. She was treated with intravenous infusions of calcium gluconate and magnesium and oral high dose cholecalciferol, as well as glucocorticoids for active Crohn’s disease.
Cite this as: BMJ 2013;346:f2213
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor, head of department of academic endocrinology, diabetes, and metabolism, Hull York Medical School; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at.
Contributors: FMH did the literature search and wrote the article; RVT edited and contributed to the writing. RVT is the guarantor.
Competing interests: Both authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
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