Auteur Topic: Voll.art.: Diagnose/management Celiac in Engeland + 7 andere landen  (gelezen 10343 keer)

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Copyright © 2014 BMJ Publishing Group Ltd & British Society of Gastroenterology.
 

BMJ Open Gastroenterology
Gut doi:10.1136/gutjnl-2013-306578
Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology


1.   Fabiana Zingone23,
2.   David S Sanders24,
3.   Authors of the BSG Coeliac Disease Guidelines Development Group
+ Author Affiliations
1.   Correspondence to
David S Sanders, Gastroenterology and Liver Unit, Royal Hallamshire Hospital & University of Sheffield, Sheffield S10 2JF, UK; david.sanders@sth.nhs.uk
    Received 12 December 2013
    Revised 23 April 2014
    Accepted 25 April 2014
    Published Online First 10 June 2014




Abstract
A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD).

This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.


Objective
The aim was to create updated guidelines for the management of adult coeliac disease (CD), but non-coeliac gluten sensitivity (NCGS) was not considered.
Recommendations
▸ Diagnosis of CD requires duodenal biopsy when the patient is on a gluten-containing diet and for the vast majority of adult patients also positive serology. (Grade B)
▸ Biopsy remains essential for the diagnosis of adult CD and cannot be replaced by serology. Follow-up should aim at strict adherence to a gluten-free diet. (Grade B)


Diagnostics
Table 1
An algorithm for the diagnosis of coeliac disease
http://gut.bmj.com/content/early/2014/06/10/gutjnl-2013-306578/T1.expansion.html

Endoscopy in seronegative individuals
Recommendation
    In individuals undergoing an upper endoscopy in whom laboratory tests or symptoms or endoscopic features suggest CD, duodenal biopsy should be considered. (Grade C


Specific use of HLA typing
Recommendations
    HLA typing should be used to rule out CD. A positive DQ2.5 or DQ8 can never confirm the diagnosis. (Grade B)
    HLA typing should be used in individuals who are self-treated on a GFD and never had appropriate testing for CD before changing their diet. (Grade B)
    HLA typing can be used to rule out CD, and minimise future testing, in high-risk individuals with CD, for example, first-degree relatives. (Grade B)


Biopsy and endoscopy in CD
Recommendations
    The diagnosis of CD requires duodenal biopsy when the patient is on a gluten-containing diet and for the vast majority of adult patients also positive serology. (Grade B)
    Duodenal biopsy should be retained as the mainstay for the diagnosis of adult CD and cannot be replaced by serology. (Grade B)
    At endoscopy, if there is suspicion of CD, then at least four biopsy specimens should be obtained, including a duodenal bulb biopsy. (Grade C)
    In serologically negative patients showing signs of malabsorption (such as anaemia or diarrhoea) or a family history of CD, a duodenal biopsy should be considered. (Grade C)


Histopathology diagnosis of CD

Table 2
Histological mimics of CD in seronegative patients—conditions to be considered for investigation in an appropriate clinical context
http://gut.bmj.com/content/early/2014/06/10/gutjnl-2013-306578/T2.expansion.html

Figure 1
Relationship between villous height and crypt depth. CD, crypt depth; IEL, intraepithelial lymphocyte; LD, lymphocytic duodenosis; PVA, partial villous atrophy; TVA, total villous atrophy; VH, villous height. The dots represent IELs.
The following features should be stated in the report:
    Number of biopsies (including those from the duodenal bulb)113 and orientation.
    The architectural features (normal, partial, sub-total or total villous atrophy).
    Comment on the content of the lamina propria (in CD these are lymphocytes, plasma cells and eosinophils, and occasionally neutrophils, but cryptitis and crypt abscesses should suggest other pathology).
    Presence of Brunner's glands.
    Presence of crypt hyperplasia, villous height: crypt depth ratio (3:1).112 The absence of plasma cells suggests common variable immunodeficiency.
    Evaluation of IELs (with immunocytochemical staining for T cells (CD3) in equivocal cases114) is vital. Counting IELs should be time efficient—simply counting IELs/20 enterocytes at the tips of five villi,115 ,116 or IELs per 50 enterocytes in two villi and summing these111 are both reliable and sensitive methods using H&E staining methods. The normal count has been variably cited; however, in evidence-based practice111 and in recent classifications,109 ,112 <25IELs/100 enterocytes should be taken as the norm.
    Use of a simple classification system greatly enhances intra-observer agreement

Other causes of lymphocytic duodenosis and villous atrophy

Novel diagnostic methods

Dermatitis herpetiformis


Follow-up
Recommendations
    Follow-up biopsies may be considered in patients with CD, and are potentially helpful in identifying patients at increased risk of lymphoma. (Grade B)
    Follow-up biopsies are not mandatory if the patient with CD is asymptomatic on a GFD, and has no other features that suggest an increased risk of complications. (Grade C)
    Follow-up biopsies should be undertaken in patients with CD whose condition does not respond to a GFD. (Grade C)

Assessing adherence to the GFD
Table 3
Histological recovery of duodenal mucosa in CD
http://gut.bmj.com/content/early/2014/06/10/gutjnl-2013-306578/T3.expansion.html


Histological recovery of duodenal mucosa in adult patients with CD
Recommendations
    When adherence is questioned, it should be reviewed by a dietitian. (Grade C)
    Symptomatic patients should be evaluated more thoroughly than asymptomatic patients. (Grade C)



Gluten challenge
To perform a gluten challenge, a recent study recommends a 14-day gluten intake at ≥3 g of gluten/day (two slices of wheat bread per day) to induce histological and serological changes in the majority of adults with CD.176 The challenge can be prolonged to 8 weeks if serology remains negative at 2 weeks (in the Leffler et al176 study, serology was negative after 2 weeks in all cases, but positive after another 2 weeks).


Medical management during follow-up
Recommendations
    Newly diagnosed patients should have vaccination for Pneumococcus. (Grade C)
    Bone density should be measured after 1 year of diet in patients who have additional risk factors for osteoporosis or if over the age of 55 years. (Grade D)
    Adult patients with CD should have a calcium intake of at least 1000 mg per day. (Grade D)
    Patients with CD require follow-up by a dietitian and/or clinician with an interest or expertise in this field. (Grade D)
    Patients should have annual haematological and biochemical profiles. (Grade D)
    A GFD is the core management strategy for prevention of osteoporosis. (Grade D)


Screening for CD
Table 4 lists the WHO criteria for general population screening
http://gut.bmj.com/content/early/2014/06/10/gutjnl-2013-306578/T4.expansion.html
Recommendations
    There is insufficient evidence to recommend population screening for CD, however there should be a low threshold for case finding in clinical practice as per National Institute for Health and Care Excellence guidelines.3 (Grade B)
    Symptomatic first-degree relatives of patients with CD should undergo CD testing. (Grade C)



Quality of life
Gluten-free diet
Safe gluten intake?

Recommendations
    Patients should adhere to a GFD and have an intake of less than 10 mg gluten per day. (Grade B)
    Gluten challenge is not recommended in the ordinary patient with CD, but in patients in whom the diagnosis remains unclear despite a follow-up biopsy, gluten challenge should be performed. (Grade C)
    Patients may commence gluten-free oats at diagnosis. (Grade D)
    A GFD is recommended to decrease the excess risk of adverse foetal outcome and of lymphoma among patients with CD. (Grade C)


Patient information and support
Recommendation
    At diagnosis, patients should be encouraged to join their national coeliac support group. In the UK, patients should be advised about gluten-free items on prescription (FP10), details of which are available from http://www.coeliac.org.uk


Non-responsive CD
Very occasionally a state refractory to gluten withdrawal occurs, referred to as RCD. Figure 2 suggests an outline for investigating patients with NRCD.
Figure 2
Investigation of the patient with non-responsive coeliac disease (NRCD). Based on a figure by Mooney et al.305 FODMAPs, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; GI, gastrointestinal; HLA, human leucocyte antigen; RCD, refractory coeliac disease; SIBO, small intestine bacterial overgrowth.
http://gut.bmj.com/content/early/2014/06/10/gutjnl-2013-306578/F2.large.jpg
Recommendations
    Patients with persistent symptoms despite a GFD should have a follow-up biopsy. (Grade B)
    In symptomatic patients with ongoing enteropathy and RCD, coeliac-related malignancies and disorders that mimic CD must be excluded. (Grade C)
    Small bowel imaging should be performed in any patient with abdominal pain, fever, obstruction, anaemia, gastrointestinal bleeding or unexplained weight loss. (Grade D)
    Patients with RCD should be referred to a tertiary centre to optimise their management. (Grade D)


Novel treatment
Table 5 contains a list of potential novel treatments. None of the available novel treatments can as yet (January 2014) be recommended for use outside clinical trials.
Cereal genomics   The high copy numbers in gliadin genes have so far limited attempts to genetically modify cultivars incapable of expressing immunotoxic peptides292
RNA interference of protein translation may reduce gliadin expression, with evidence of reduced proliferation of lymphocytes challenged in vitro293
Prolyl endopeptidases (PEPs)   These endopeptidases have been isolated from microbial sources and may be capable of enzymatic cleavage of the immunotoxic gluten peptides ex vivo.294 295 296 A combination of a glutamine-specific endoprotease (EP-B2 from barley) and a prolyl endopeptidase (subcutaneous PEP from Sphingomonas capsulata)297 acts synergistically and has been evaluated in a 6-week phase IIA clinical trial against 2 g gluten taken daily298
Larazotide acetate   Larazotide is a tight junction regulator299 and maintains intestinal barrier function after gluten challenge.299 300 Phase IIA clinical trials have demonstrated limited effects on intestinal permeability after gluten ingestion, but beneficial effects on symptoms and signs.301
TG2 inhibitors   Candidate peptidomimetic blockers are currently entering clinical trials but no data are available yet.302 A potential limitation of this drug candidate is that TG2 activity occurs in a number of diseases and a TG2 inhibitor may therefore have unwanted side effects
Blocking of the antigen presenting groove of HLA-DQ molecules   No trials yet. Regarded as unpredictable
Subcutaneous injection of dominant immunotoxic gliadin peptides65   Stimulates an immunoregulatory T-cell response or deplete or anergise antigen specific memory T cells. Responses would be specific to the HLA haplotype DQ2 or 8. Ongoing phase II trials.
Polymer binding agents303   No clinical trials performed yet
http://gut.bmj.com/content/early/2014/06/10/gutjnl-2013-306578/T5.expansion.html
Recommendation
    None of the available novel treatments can as yet be recommended for use outside clinical trials. (Grade D)

Discussion



We recommend a duodenal biopsy before the diagnosis of CD. This contrasts with the recent ESPGHAN recommendations where a duodenal biopsy is optional in symptomatic paediatric patients in whom the IgA-TG2 level exceeds 10 times the upper limit of normal, EMA antibodies are positive on a separately taken blood sample and HLA typing is positive for DQ2 or DQ8.1 CD has been linked to a large number of symptoms (table 1 in the ESPGHAN review on paediatric CD lists 16 such symptoms and signs with additional symptoms in the text).1 There is a risk that all symptoms, independent of their origin, may be taken as a sign of CD when the sensitivity and specificity of even gastrointestinal symptoms are moderate in CD.304 Other reasons to require a small intestinal biopsy prior to diagnosis is that not all commercial IgA-TG2 kits are of high quality,78 and that alternative diagnoses may be more common, and sometimes serious, in adults with suspected CD. Finally, an initial biopsy is important for the follow-up of patients, especially those whose condition is non-responsive to a GFD


Areas for future research
The panel of experts recognise that the main challenge in the future is to allocate available resources effectively to reduce the burden of disease from CD.
Future research should focus on the following areas:
    how to induce long-term remission without a GFD, that is, novel therapies and vaccine;
    better understanding of the disease processes, including genetics and antigen presentation;
    prevent and cure extra-intestinal manifestation and complications, including infections;
    be able to assess tolerable amount of gluten for individual patients;
    define the role of duodenal biopsy, serology and point of care testing at diagnosis and follow-up;
    find a robust and valid blood marker for diagnosis and monitoring of the disease;
    understand the pathogenesis of RCDI and II.



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