IntroductionBy as disease severity (1). Gluten proteins contain an

IntroductionBy definition, Coeliac disease (CD) is an immune-mediated enteropathy (chronic inflammation and damage of the intestine) precipitated in response to dietary gluten in genetically predisposed individuals (1). Gluten is a mixture of storage proteins found in rye, wheat, barley and related species which following ingestion by coeliacs, leads to abnormal absorption of nutrients due to an impaired mucosal surface (2). Adults with untreated or late diagnosed CD may be burdened with several complications which may be severe. Among them, anaemia, osteoporosis, infertility, ulcerative jejunoileitis, and some types of malignancies including Non-Hodgkin lymphoma, small bowel adenocarcinoma and enteropathy-associated intestinal T cell lymphoma (2). A strict gluten-free diet remains to be the only treatment and is effective in most patients however, it may be burdensome and impact quality of life (5). It is estimated that in the UK, 1 in 100 people are affected by CD, and a worldwide incidence of approximately 1% (3). Although CD is one of the cheapest long term conditions to treat on the NHS (owing to a gluten-free diet as the only treatment), annual prescriptions for gluten-free foods in England cost the NHS £25.7 million in 2016. Ongoing debate suggests this as an easy target for clinical commissioning groups to try and make savings, due to the unprecedented financial pressures on the NHS (4). Miss B, a 25 year old female with recent unexplained weight loss and anaemia, presented to her general practitioner. She was recommended dietary advice and vitamin replacement which later at her second visit, proved to be of no benefit. She was also suffering from mouth ulcers and gastrointestinal symptoms. After various tests, Miss B was referred to a gastrointestinal specialist whom diagnosed coeliac disease. This report will provide an evidence based approach into the management of CD and more specifically addressing this patient’s actual and potential health needs.PathophysiologyCoeliac disease arises from the interaction of environmental factors, mainly gluten, immunological factors and predisposing genes (HLA-DQ2 and HLA-DQ8 haplotypes)(5). Found in 95% of CD patients, the HLA DQ2/DQ8 molecules, are integral in the development of CD, playing a major role in the risk of disease development, as well as disease severity (1). Gluten proteins contain an abundance of glutamines that are not completely digested by peptidases. This leaves large gliadin peptides that must pass through the intestinal epithelial barrier via transcellular (through the cells) or paracellular (between the cells) transport pathways (5). At the small intestinal epithelium, the immune response to gluten leads to activation of distinctive autoantibodies (TTG and EMA), production of cytokines, histological changes (villous atrophy and intraepithelial lymphocytosis), resulting in clinical symptoms such as diarrhoea, constipation and absorption issues (5). Tissue transglutaminase (TTG) is an enzyme that is released from cells during inflammation and is thought to have two critical roles in CD. One role as a deamidating enzyme that can enhance the immunostimulatory effect of gluten, and the second role as a target autoantigen in the immune response. Gliadin peptides are excellent substrates for TTG and the resulting deamidated gliadin, has a much higher affinity for the HLA-DQ2/DQ8 molecules. Following activation of the HLA-DQ2/DQ8 molecules, the inflammatory cascade leads to formation of TTG autoantibodies and accompanying endomysial antibodies (EMA) and as mentioned earlier, these form the basis of the adaptive immune response to gluten. The activity of TTG is therefore thought to be instrumental in the pathogenesis of CD. Tests, Investigations and Definitive diagnosisPatients with malabsorption, unexplained iron and vitamin D deficiency, unexplained weight loss, recurrent mouth ulcers and persistent, unexplained abdominal or gastrointestinal symptoms such as indigestion, diarrhoea, abdominal bloating and constipation, should be considered for CD serological testing (1,3). In addition, there is an increased suspicion of CD in patients who have one of the following which are associated with CD: Type 1 Diabetes Mellitus, autoimmune thyroid disease and a first degree relative with diagnosed CD. Incidence of CD in relatives of the first degree, is between 2.8% and 17.2% (1, 3) and 5-7% of patients with type 1 diabetes also have CD (6). Before serological testing, it is essential to confirm that the patient suffering from the above symptoms has been eating gluten containing foods in more than one meal a day for at least 6 weeks, as recommended by NICE guidelines (3). Once confirmed, health care professionals should request laboratory tests for total IgA and IgA TTG as first line (for adults and children). If IgA TTG is weakly positive, then IgA EMA is used. If the patient is IgA deficient, then IgG EMA, IgG deamidated gliadin peptide (DGP) or IgG TTG is used. Positive test results are defined as unambiguously positive IgA TTG alone, or both weakly positive IgA TTG with positive IgA EMA.  Patients with positive serological test results should be referred to a gastrointestinal specialist for endoscopic intestinal biopsy (3).In support of the presence of CD-associated antibodies (TTG and EMA) and their return to normal after undertaking the gluten-free diet, definitive diagnosis of CD is made when there are typical small-intestinal histopathological abnormalities. Such abnormalities may be seen with a duodenal biopsy, as a spectrum of gluten-sensitive enteropathy ranging from mild, involving only an increase in inflammation in the surface epithelium (intraepithelial lymphocytosis) to severe, with total villous atrophy (1). Villous height and width can be measured to assess the degree of structural change as well as villous cross-sectional area which is useful to judge the degree of recovery in patients following the strict gluten-free diet. A straightforward diagnosis is made when patients have positive serology and histological changes that are consistent with CD. However, a small cohort of patients may represent a diagnostic dilemma when they produce positive serology but negative biopsies. These patients may be subject to more complex tests such as HLA DQ2/DQ8 genetic tests (1, 3).Case PresentationMiss B presents with a range of medical problems. Firstly, she was seen by the general practitioner with general fatigue, weight loss and a BMI of 17. According to NICE guidelines, these are red flag symptoms that must be investigated to rule out sinister causes such as malignancy. This was, however, not done for Miss B. Her initial blood tests showed Hb 10g/dl, low ferritin and B12 levels, which is strongly suggestive of anaemia. She was given dietary advice and vitamin replacement. It is difficult to predict the type of anaemia for Miss B without more specific tests such as mean cell volume (MCV).  This would have guided the GP’s decisions on different treatment options for the different types of anaemia.After one-month, Miss B re-presents with no improvement and is now suffering from diarrhoea, bloating and recurrent mouth ulcers. Patients presenting with gastrointestinal symptoms and malabsorption pose diagnostic difficulties given their non-specificity and similarities among a range of conditions, such as Crohn’s Disease, Ulcerative Colitis, malignancy and IBS. However, her mouth ulcers may have been the characteristic difference in Miss B’s case, which deterred the GP from querying these differential diagnoses, and requesting serological testing for coeliac disease. The patient showed a weak positive IgA TTG and a positive IgA EMA test result, which prompted referral to gastrointestinal specialist for endoscopy, as per NICE guidelines (3). Miss B’s duodenal endoscopic biopsy showed villi still present but shortened, which may be staged under the simplified marsh classification as Marsh 3 in the spectrum of changes in symptomatic CD (8,9).As outlined earlier, positive serology test results, in addition to villous atrophy consistent with CD, confirms the diagnosis of CD with little uncertainty.Management PlanIntroductory paragraph stating goals of treatment  to prevent long and short term complications (actual and potential health needs) – The gluten-free diet and clinical responseFollowing a diagnosis, it is well recognized that life-long adherence to a gluten-free diet is the only effective treatment for CD, with a large range of gluten-free products available on the NHS (3). A gluten-free diet involves complete avoidance of foods based on wheat (and wheat varieties), barley and rye. Common foods containing gluten include bread, flour, cakes, pastries and biscuits. Some foods may also contain wheat, barley or rye as fillers or flavouring, such a sausages, soups and sauces. Patients must also be aware that some foods may become contaminated with gluten during processing, packaging and even when fried in the same oil as used to fry gluten-containing food. In addition, malt containing dietary items such as most beers, may still contain gluten as the malting process does not completely remove it.A clinical response to the diet is observed as a normalization of symptoms, with a mean resolution time in most patients of four weeks (5). While Miss B should expect to see an improvement in her diarrhoea and bloating reasonably quickly, it may take months to more than a year for normalization of TTG antibodies and eventually intestinal mucosa (11). In a retrospective data analysis study of 241 adults who underwent follow-up biopsy, the median time to achieve a normal villous height was 3.8 years (11). In the same study, 75% of patients with good compliance to the gluten-free diet achieved mucosal recovery, compared to only 4% who were poorly compliant (11). Intestinal mucosal recovery is therefore a gradual process and is significantly dependent on patient’s strict adherence to the gluten-free diet. Miss B will need extensive advice and information regarding the gluten-free diet and nutrition, with ongoing support. If needed, she may benefit more intensive education with a dietician, which has been shown to improve histological outcomes, especially in patients with persistent villous atrophy. Miss B’s nutritional status is expected to improve once controlled on the gluten-free diet, however should she require it, specific supplements such as calcium and vitamin D may be required (3).  In addition to improvement of her symptoms, Miss B should expect to see an increase in the BMI, which is of concern. As per the world health organisation, a BMI of 17 is considered as underweight. It is well documented that BMI in CD is significantly lower than BMI in healthy individuals and in one study where BMI was measured at diagnosis and after 2.8 years on the gluten-free diet, 66% of underweight patients gained weight (12, 13).

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