Patients and Methods
Patients attending the Adult Coeliac clinic at Addenbrooke's Hospital have been routinely followed up by serology and re-biopsy. In 2006, practice was consolidated in a clinical care pathway. The Cambridge Coeliac Pathway is outlined in Figure 1. This retrospective observational cohort study of 595 cases includes 298 cases diagnosed after the initiation of the pathway in March 2006. Patients were excluded from analysis if they were previously excluding gluten and diagnosed on the basis of a gluten challenge biopsy, or if initial biopsies did not show evidence of villous atrophy, even if subsequently diagnosed with CD.
Serological Testing
Immunoglobulin (Ig) A Anti-tissue transglutaminase antibody (Anti-TTG) is measured by ELISA (Phadia) along with total IgA levels. IgA anti-EMA (Endomysial Antibody) indirect immunofluorescence is not tested routinely following an internal audit in 2002 of nearly 1400 samples, showing no additional diagnostic benefit in testing for anti-EMA antibodies as well as TTG. The subsequent cost saving allowed testing of total IgA alongside TTG. Deamidated gliadin antibody tests were not available during the time course of this study and were not therefore tested. Serology is measured prior to every clinic visit, usually within 4 weeks of the visit.
Small Intestinal Biopsy
Standard practice is to perform oesophagogastroduodenoscopy (OGD) and obtain four biopsies from the second part of the duodenum, in different quadrants because of the frequent patchy nature of the disease. Duodenal bulb biopsy had not become a recommendation during the time course of this study and was therefore not routinely practised. Biopsies were analysed by dedicated gastrointestinal pathologists and a descriptive result using the terms used in the modified Marsh criteria was given. Any degree of villous atrophy was considered Marsh 3 or above or Corazza grade B1 (for Marsh grade 3a and 3b, partial or subtotal villous atrophy) or Corazza grade B2 (for Marsh grade 3c, total villous atrophy). Isolated duodenal intraepithelial lymphocytosis was considered Marsh 1 and additional lamina propria infiltrate was considered Marsh 2; both of these correspond to Corazza A. Biopsies were obtained at initial referral to confirm the diagnosis and, according to the Cambridge Coeliac Pathway, after 9–12 months of gluten-free diet to assess histological response. Re-biopsy was not performed on patients who were deliberately non-adherent to the diet, but persisting raised antibody titres to tissue transglutaminase did not prevent or delay repeat biopsy.
Dietetic Intervention
Patients are given a group introductory talk by a consultant gastroenterologist and specialist dietitian at diagnosis, and are then given an appointment to see the doctor and dietitian in clinic afterwards. Dietitians give introductory verbal and written information to patients (and their partners or relatives to include those involved in shopping, cooking and preparing their food) on a gluten-free diet, including suitable and unsuitable foods, the Codex standard, current labelling laws and reading food labels, cross-contamination, prescribable and nonprescribable gluten-free substitute products, common pitfalls of the diet and advice for when eating out and travelling abroad. Gluten-free food samples are provided and it is recommended that they join Coeliac UK (represented in clinic by local volunteers). Patients are provided with contact details for further specialist dietetic advice if required. The GP is asked to provide gluten-free foods on prescription. We do not recommend exclusion of pure oats at diagnosis. Initial follow-up dietary review is then scheduled 2 months later with further dietetic appointments scheduled on an individual basis.
Review After Follow-up Biopsy
Patients are seen in clinic by both a clinician and dietitian after their follow-up biopsy. If histological recovery has occurred (defined as an absence of villous atrophy, Marsh grade 0, 1, 2 or Corazza Grade A changes were acceptable), then no specific changes are recommended. If the biopsy shows persisting villous atrophy, regardless of serology or symptoms, they undergo dietetic review by clinic consultation. At this point, if non-adherence or a potential source of gluten ingestion (above the Codex standard) is identified, patients are given appropriate advice. If there is uncertainty, patients are asked to keep a detailed food diary for 1–2 weeks followed by a further Dietetic review to identify sources of gluten. If no contamination can be identified, a recommendation for a supersensitive diet (SSD) is made. In addition to the strict GFD the patient is already adhering to, this diet excludes foods deemed gluten-free based on Codex Alimentarius Standards. The current standards, defining gluten-free food as containing less than 20 parts per million (20 ppm), were introduced in 2008 and became European law in 2012. Therefore, the majority of cases reported in this study were subject initially to less stringent standards (up to 200 ppm). The SSD thereby excludes Codex wheat starch and barley malt extract and pure oats in view of the controversial possibility of avenin immunotoxicity.
Further Biopsy After Second-line Intervention
Following any of the above measures (dietary review, food diary, SSD), a third biopsy is considered to assess response.
Discharge From Secondary Care
An agreed shared care pathway has been developed with regional primary care providers to ensure annual follow-up appointments for patients discharged from the Coeliac clinic. Definitive discharge takes place if the patient is compliant with diet, has no ongoing symptoms or complications and has made an adequate histological response to diet. Normalisation of the biopsy prior to discharge is not a prerequisite if there is further evidence of improved dietary adherence following a biopsy showing only minor villous architectural changes.
Statistical Analysis
Data analysis for serological accuracy was performed using standard techniques. Comparison of biopsy results at varying time periods was performed by chi-squared test and comparison of outcomes was performed using Fisher's exact test.
No patient-identifiable data were recorded in the analysis and, as a review of clinical practice, formal ethical permission was not considered necessary.