Gastroenterology Today Spring 2022

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NEWS GASTROENTEROLOGY TODAY - SPRING 2022 Go with the Flow! How the Rare Disease Collaborative Network can support you in diagnosis and management of refractory coeliac disease Woodward JM 1 , Soilleux E 1 , Passmore R 2 , Sanders D 3 Coeliac disease that is refractory to the withdrawal of gluten from the diet is rare, and as a result prone to both over and under diagnosis. Two types are described: ‘Type 1’ is indistinguishable from non-responsive coeliac disease (1) and may be due to the individual being highly sensitized to trace amounts of gluten remaining in the diet that would not affect most people with the condition. ‘Type 2’ refractory coeliac disease (RCD2) progresses to an aggressive T-cell lymphoma in as many as 67% of cases over 5 years (2). RCD2 is distinguished from non-responsive coeliac disease or RCD1 by the abnormal clonal increase of an unusual population of intestinal intra-epithelial lymphocytes (IELs) characterized by the presence of the T-cell marker CD3 within the cytoplasm but not on the surface of the cell (3). These cells also usually lack the normal expression of another surface marker, CD8. However, immunohistochemistry for T-cell markers or polymerase chain reaction (PCR) for T-cell receptor clonality are unreliable diagnostic tests for RCD2 (3,4), whereas flow cytometry to identify individual IELs isolated from fresh intestinal biopsies is definitive (figure 1a). It is important to distinguish RCD1 from other causes of non-responsive coeliac disease and from RCD2 as specific treatments exist – for instance, the use of topical steroids or azathioprine for RCD1 and cladribine and autologous stem cell transplantation for RCD2. In 2018, NHS England designated Sheffield and Cambridge as the two national centres in the first ever UK Rare Disease Collaborative network in order to refine diagnostic and therapeutic techniques, and to develop a national database in order to further the understanding of the conditions and facilitate trials of treatment (5,6). The ongoing development of flow cytometry of intra-epithelial lymphocytes in the network has unexpectedly also demonstrated the utility of this technique in the diagnosis of coeliac disease itself (7). A characteristic change in the IEL composition occurs following the development of coeliac disease (8) and remains regardless of normalization of duodenal histology and serological tests on institution of a gluten free diet. Hence IEL flow cytometry is the only existing accessible test capable of confirming or refuting the diagnosis of coeliac disease in a patient following a strict gluten free diet. Referrals to the national centres remain lower than the expected prevalence of RCD (6) and indicates ongoing failure to recognize the condition. The following case studies demonstrate the utility of referral to the specialist national centres. Coeliac UK have developed resources on refractory and non-responsive coeliac disease to support you and your patients, scan the QR code to find out more. Case 1. Misdiagnosis of coeliac disease. A 20-year old woman contacted Coeliac UK for advice. Following a period of chronic fatigue she presented to her GP who found a very high anti-TTG antibody titre in her serum. Indirect immunofluorescence was negative for anti-endomysial antibodies. Following referral to her local gastroenterologist she underwent a gastroscopy and duodenal biopsies which were reported as showing equivocal features but consistent with coeliac disease. She was commenced on a gluten free diet which marginally improved her symptoms, however on follow up her anti-TTG titres remained high and she was repeatedly told by her hospital team that this meant that she was continuing to ingest gluten, which was a cause of significant anxiety for her and contributed to her fatigue. The patient was advised to request a second opinion from a tertiary centre. Further blood tests at the national centre revealed a negative anti-TTG titre and non-compatible HLA (human leucocyte antigen) haplotype for coeliac disease (9). Duodenal biopsies were reported as showing mild peptic duodenitis and flow cytometry revealed no evidence of coeliac disease (fig 1a). Following reassurance that she did not have coeliac disease she was able to tolerate a normal diet without symptoms. This case demonstrates the variability of anti-TTG assays between laboratories, and the potential flaws of current diagnostic techniques. Case 2. Delayed diagnosis of RCD2. A previously fit and well 56-year old man presented via his GP to the local hospital following a business trip to the tropics with diarrhoea. A strong family history of coeliac disease was elicited, and duodenal biopsies at gastroscopy demonstrated sub-total villous atrophy, however anti-TTG antibodies were negative. He was therefore considered not to have coeliac disease and was treated empirically for tropical parasitic infections. However, his symptoms progressed and 12 months later he was reinvestigated and found to have ongoing severe villous atrophy in the duodenum with thickening of the distal jejunum on magnetic resonance enterography. He was referred to one of the national tertiary centres for enteroscopy and biopsy of the thickened jejunum in order to make a diagnosis. An experienced clinician considered the possibility of RCD2 and lymphoma and instead carried out a gastroscopy and duodenal biopsy with flow cytometry the day after receiving the referral. The flow cytometry demonstrated a large population of atypical IELs lacking surface CD3 (fig 1b) in keeping with RCD2 and a presumptive diagnosis of enteropathy associated lymphoma was made. Within 3 weeks of referral he was admitted for establishment of home parenteral nutrition and underwent laparotomy and resection of the tumour, which was confirmed as a T cell lymphoma. He subsequently underwent CHOP chemotherapy and autologous haematopoeitic stem cell transplant. In his case earlier consideration of the diagnosis of RCD and referral to a national centre could have led to preventative treatment prior to developing lymphoma. Case 3. Overdiagnosis and overtreatment. A 37-year old woman presented to her GP in 2013 with diarrhoea and weight loss. A positive anti-tissue transglutaminase (TTG) antibody titre led to referral to the local gastroenterologist and a diagnosis was confirmed by the presence of sub-total villous atrophy on duodenal biopsy. She was commenced on a gluten free diet. However, in 2016 the presence of ongoing symptoms led to a repeat endoscopy which demonstrated persistent villous atrophy in the duodenal biopsies. She was told by her local gastroenterologist that she had refractory coeliac disease and that she needed to start on steroids and azathioprine as she was otherwise at risk of developing lymphoma. At this stage she sought a referral for a second 28
NEWS Figure 1a Figure 1b Figure 1c opinion through one of the national tertiary centres. An experienced clinician elicited a history of a shared kitchen with potential for gluten contamination during food preparation, and that the patient was consuming foods that were labelled as ‘may contain traces of gluten’. It was recommended that she did not start steroids or azathioprine but made the necessary changes to her lifestyle and attend for a repeat duodenal biopsy after a further 9 months. At endoscopy the patient reported complete resolution of her symptoms, biopsies were reported as entirely normal while flow cytometry confirmed the underlying diagnosis of coeliac disease (figure 1c). She therefore avoided potentially harmful treatment, considerable health anxiety and achieved rapid resolution of her condition following referral. Notably the referral came from herself via her GP, not the local gastroenterologist. Figure 1. Typical duodenal IEL flow cytometry plots for a non-coeliac individual (a), a patient with RCD2 (b), and a patient with coeliac disease (c). Each dot on the plot represents a separate cell, immunostained for surface CD3 (y-axis) and cytoplasmic CD3 (x-axis). In addition, CD3+ T cells bearing the gamma-delta type of TCR are in dark blue, those with the alpha-beta TCR are in light blue. Clearly defined population of IELs are apparent based on the lack of expression of CD3 (green), the expression of surface and cytoplasmic CD3 (light and dark blue), or just cytoplasmic CD3 (orange). Note that RCD1 is not distinguishable from coeliac disease using any available diagnostic tests (including flow cytometry) (reference 2), whereas populations of CD3+ and gamma delta TCR positive cells are clearly increased in coeliac disease compared to normal. References 1. Rubio-Tapia A, Murray JA. Classification and management of refractory coeliac disease. Gut 2010 Apr;59(4):547-57. 2. Nijeboer P, van Wanrooij, van Gils T, et al. Lymphoma development and survival in refractory coeliac disease type II: histological response as a prognostic factor. United European Gastroenterol J 2017; 5(2): 208-217 3. Woodward JM. Improving outcomes of refractory Celiac Disease: current and emerging treatment strategies. Clinical and Experimental Gastroenterology 2016; 9: 225-236 4. Liu H, Brais R, Lavergne-Slove A, et al. Continual monitoring of intraepithelial lymphocyte immunophenotype and clonality is more important than snapshot analysis in the surveillance of refractory coeliac disease. Gut. 2010 Apr;59(4):452-60. 5. https://www.coeliac.org.uk/about-us/ media-centre/news/first-rare-diseasecollaborative-network-on-refractorycoeliac/ 6. Baggus E, Urwin H, Watson S, Woodward JM, Sanders DS. How to manage adult coeliac disease: The perspective from the NHS England Rare Diseases Collaborative Network for Non-Responsive and Refractory Coeliac Disease. Frontline Gastroenterol. 2019 Aug 8;11(3):235-242 7. Basu K, Creasey H, Bruggemann N, Stevens J, Bloxham DM, Woodward JM. The diagnosis of coeliac disease by flow cytometry of intraepithelial lymphocytes – a new ‘gold standard’? Frontline Gastroenterology 2021 epub ahead of print http://dx.doi.org/10.1136/ flgastro-2021-101838 8. Mayassi T, Ladell K, Gudjonson H, et al. Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease. Cell 2019;176:967–81. 9. Abadie V, Sollid LM, Barreiro LB, et al. Integration of genetic and immunological insights into a model of celiac disease pathogenesis. Annu Rev Immunol. 2011;29:493-525 1 NHS Refractory Coeliac Disease Rare Disease Collaborative Network Box 133 Addenbrooke’s Hospital Hills Road Cambridge CB2 0QQ 01223-596231 (jeremy.woodward@nhs.net) *Corresponding author 2 Coeliac UK Apollo Centre, Desborough Road High Wycombe HP11 2QW 3 NHS Refractory Coeliac Disease Rare Disease Collaborative Network Academic unit of gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF (david.sanders1@nhs.net) GASTROENTEROLOGY TODAY - SPRING 2022 29
Page 1 and 2: Volume 32 No. 1 Spring 2022 The Per
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Page 7 and 8: FEATURE All cases of gastric polyps
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