Anaemia and Iron Deficiency in Paediatric Gastrointestinal Diseases: A Focus on Coeliac Disease

Anaemia is a common finding in children, and besides tiredness, pallor, and other well-known acute symptoms, it can cause long-lasting disabilities such as impairment in cognitive development and in the immune system. Therefore, the reason underlying anaemia should always be investigated. Most often anaemia is caused by iron deficiency, which in low-income countries is most often dietary, but in developed countries in particular is also often secondary to a gastrointestinal disease. In fact, international guidelines advise gastrointestinal endoscopy for all children with obscure anaemia to rule out alimentary tract diseases, but the evidence behind this recommendation remains scarce.

In the variety of symptoms and findings caused by coeliac disease, anaemia and iron deficiency are among the most common. Coeliac disease is an autoimmune- mediated disorder where dietary gluten induces inflammation and gradual destruction of the small bowel mucosal structure. The ensuing reduction of the absorption area of iron has traditionally been suggested to be the cause of anaemia in coeliac disease, but since seropositive patients with only mild or even normal villous morphology (potential coeliac disease) have also been shown to present with anaemia, other factors seem to play a part. Changes in levels of iron regulatory hormone hepcidin or in expressions of duodenal iron transporter proteins have been proposed as possible explanations.

In the present dissertation, the diagnostic yield of gastrointestinal endoscopies in anaemic children was investigated in Study I, while Studies II-IV examined anaemia and iron deficiency in children with coeliac disease from different perspectives.

In Study I, the diagnostic outcomes were evaluated in 864 children who underwent endoscopies in the Paediatric Department of Tampere University Hospital during the years 2007-2014. Besides possibly obtained diagnoses, demographic and clinical characteristics as well as laboratory and histology results were collected from the patient records and compared between children with and without anaemia. Additionally, the associations between different findings and diagnoses set were evaluated. Anaemia was found to increase the probability of being given a diagnosis, especially when presented with bloody stools, growth failure, diarrhoea, positive coeliac antibodies, high faecal calprotectin, high erythrocyte sedimentation rate or hypoalbuminemia. However, anaemia in patients without additional findings seldom improved the diagnostic yield of endoscopies. Thus, in these children a short period of observation with possible iron supplementation should be considered before proceeding to invasive investigations.

The impact of anaemia on the clinical and histopathological presentation of coeliac disease in children was investigated in Study II. Again, comprehensive clinical data was collected systemically from the medical records of a total of 455 children and compared between children with and without anaemia at coeliac disease diagnosis. The results showed anaemia to be associated with more severe clinical, serological and histological disease. Additionally, the haemoglobin levels did not fully recover after one year of follow-up on a well-maintained gluten-free diet.

In Study III, the prevalence of anaemia and iron deficiency were evaluated in potential coeliac disease and in coeliac disease with different levels of mucosal atrophy at diagnosis. Iron parameters, including hepcidin, were measured in altogether 125 children. The prevalence of anaemia and iron deficiency were shown to increase along with the severity of mucosal damage. Additionally, abnormal iron parameters were more common in potential coeliac patients than in healthy controls, suggesting altered iron metabolism in the early stage of the disease.

In Study IV, the aim was to evaluate the role of iron transporter proteins in the pathogenesis of anaemia in coeliac disease. This was done by measuring their expression semi-quantitatively in the epithelium of 43 immunohistochemically stained duodenal biopsies from children with coeliac disease and controls. No differences in the expressions between anaemic and non-anaemic patients were seen. However, possibly reflecting the atrophic disease state, the stainings of ferroportin and hephaestin differed between coeliac patients and healthy controls.

To conclude, this dissertation highlights the high frequency of anaemia in gastrointestinal diseases, as well as its importance as an alarm symptom (I). In children with coeliac disease anaemia was shown to be associated with more severe presentation and to occur in even the histologically early stages of the disease, supporting early diagnosis and dietary treatment (I, II). In future, the aetiology of anaemia in coeliac disease needs further research, as it seems that neither hepcidin nor altered iron transporter expression offers an explanation (IV).