Coeliac disease is an immune-mediated inflammatory disorder of the small intestines induced by the prolamins of certain cereals causing loss of villous height, crypt hypertrophy leading to malabsorption. There is functional and histological reversal towards normalcy, with elimination and reappearance on luminal challenge to noxious prolamins. It is one of the most common lifelong disorders in Europe and the USA.1 2
During the Second world war period, in Holland, with the elimination of bread from children's diet due to rationing, Paediatrician WK Dicke noted clinical improvement in children with previously diagnosed coeliac disease. Together with JH van Kamer and HA Weijers, using different dietary challenges and measuring faecal fat as an indicator of malabsorption, he went on to identify gliadin as the causative agent of coeliac disease.3
Coeliac disease is a condition more common in Caucasians. It is more frequent in those with HLA BQ- DR3-DQ2, with 90% of people with the condition having HLA-DQ2. There is a familial increase with 10% of first-degree relative being affected by the condition and a monozygotic concordance of 70%. Interplay between genes and environment lead to intestinal damage that is characteristic of the disease. Aberrancy in gut permeability induced by a protein involved in tight junction regulation is thought to allow gluten into the lamina propria where it is deaminidated by tissue transglutaminase, recognised by antigen presenting cells bearing DQ2 or DQ8 leading to an autoimmune reaction that is characteristic of the early stages of coeliac disease.4
Malabsorption occurs from loss of absorptive area and the presence of a population of immature surface epithelial cells whose absorptive and secretory functions may be additionally impaired by cytokines and inflammatory mediators. About 30 years ago, the use of intestinal biopsy was reserved for patients with symptoms of overt malabsorption, and, consequently, the prevalence of malabsorption among patients with coeliac disease was very high.5
Awareness of the disease and lowered threshold for its investigation, followed by the advent of serology, now means that the number of patients with minor symptoms is twice the number of people with overt malabsorption. This observation was accompanied by a significant rise in the rate of diagnosis and a progressive lowering of patients’ age at diagnosis.6
In adults, presentation of coeliac disease varies from asymptomatic to severely symptomatic, depending on the severity and the extent of mucosal involvement. Gastrointestinal symptoms are more common and include other conditions such as diarrhoea, weight loss, malaise, lethargy and abdominal pain.7
Although less common, presentation with hypocalcaemia, osteomalacia, myopathy and coagulapathy as a first presentation of coeliac disease has been described and can occur without gastrointestinal symptoms.8–12
In a study of 47 patients with osteomalacia due to gastrointestinal causes, 26% of cases were due to coeliac disease.13
Studies have found significantly decreased bone-mineral density (BMD) in the lumbar spine and femoral neck in coeliac patients compared to controls.14
In adults, these changes may persist in the peripheral skeleton despite normalisation in the axial skeleton after patients are on a gluten-free diet. In a Swedish study looking at vitamin D and BMD in coeliac patients, a low vitamin D concentration was a typical biochemical abnormality (64% of men and 71% of women). Prevalence of osteopenia and osteoporosis was highest in newly diagnosed coeliac patients and in patients with disease not in remission.15
Osteomalacia refers to defective mineralisation of bone matrix due to deficiency or resistances to vitamin D. Severe vitamin D deficiency, with osteomalacia and hypocalcaemia, is rare unless vitamin D levels are below 12 nmol/l. Clinical features include bone pain, tenderness, skeletal deformity and proximal muscle weakness. Decreased physical activity secondary to pain with secondary hyperparathyroidism and hypocalcaemia also contribute to decreased BMD.16
An association between coeliac disease and osteomalacia was first reported in 1953.17
In coeliac disease, intestinal malabsorption of vitamin D contributes to plasma and urine calcium levels being lower than normal and defective absorption of phosphate consequently leads to hypophosphataemia. Hypocalcaemia stimulates PTH to correct for low calcium level. Secondary hyperparathyroidism occurs due to vitamin D and calcium malabsorption as well as increased bone turnover.
Hypocalcaemia in coeliac disease is thought to occur due to the following causes: There is a negative calcium balance, due to loss of villous surface area,18
with unabsorbed calcium binding to excess fatty acids in the intestinal lumen as a result of fat malabsorption.19
There is impairment of active intestinal calcium transport mechanisms because of depletion of calbindin from enterocytes.20
Decreased vitamin D also contributes to decreased calcium absorption.
Hypocalcaemia as a feature of coeliac disease is well described.21 22
A screening study in the UK found serum calcium to be on average 0.02 mmol/l lower in asymptomatic coeliac patients that the general population.23
In an observational case series of 15 patients with coeliac disease, hypocalcaemia was present in 11 patients, with average corrected calcium of 1.800.30 mmol/l.22
In another case series of 42 patients with coeliac disease, symptoms of tetany was present in 10%.24
Hypocalcaemia induced by medicines that are not commonly noted to do so should raise awareness for possible vitamin D deficiency and malabsorption. In one case, hypocalcaemia induced by bisphosphonates was the basis for the diagnosis of coeliac disease.25
In another, symptomatic hypocalcaemia was induced by oral phosphosoda during the work-up of malabsorption in a patient subsequently diagnosed on histology as having coeliac disease.26
In our patient, initial correction of calcium was with intravenous calcium gluconate. Replacement of calcium with intravenous calcium is recommended for patients who are symptomatic or have very low calcium levels. Replacement should be with cardiac monitoring, as intravenous calcium may cause a sinus bradycardia. Intravenous calcium is sclerosing to veins and should be administered through a central vein if possible. Once calcium is corrected to safer levels, oral calcium supplementation is sufficient. In the acute management of severe hypocalcaemia associated with coeliac disease, it is important to identify other possible factors, in addition to malabsorption, which might be contributing to the hypocalcaemia. Coeliac disease may cause hypomagnesemic hypocalcaemia and hypokalaemia.27
Severe magnesium deficiency can cause defective secretion and action of PTH, which leads to functional hypocalcaemia.28
Initial replacement of calcium in these patients requires higher doses of oral calcium supplementation.
Activated vitamin D (alfacalcidol) was used along with intravenous calcium to treat our patient's hypocalcaemia initially. However, once vitamin D deficiency was confirmed biochemically and the diagnosis apparent, intramuscular cholecalciferol was administered to replace vitamin D stores in the body. Activated vitamin D was not continued as treatment for his vitamin D deficiency, as malabsorption was present and levels may not have responded adequately to oral replacement alone.
In our patient on discharge from hospital, the calcium level was still below normal range despite vitamin D and high-level calcium supplementation. This was likely due to decreased calcium absorption from ongoing damaged intestinal mucosa. At follow-up, however, calcium levels had normalised allowing a decrease in calcium supplementation.
During the initial recovery phase, it is important to follow patients closely to assess for improvement in calcium absorption as continued high-dose calcium and vitamin D supplementation may lead to hypercalcaemia.
- Hypocalcaemia may be a manifestation of coeliac disease due to malabsorption of both or either vitamin D and calcium.
- Correction of low vitamin D alone may not be sufficient if absorption of calcium is also reduced due to malabsorption.
- Treating hypocalcaemia associated with coeliac disease requires close follow-up so that calcium supplementation can be adjusted as malabsorption improves.