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MNT: Gastrointestinal Disorders (2015

Citation:

Hollon JR, Cureton PA, Martin ML, Leonard Puppa EL, Fasano A. Trace gluten contamination may play a role in mucosal and clinical recovery in a subgroup of diet-adherent non-responsive celiac disease patients. BMC Gastroenterol. 2013; 13 (40): 13-40.

PubMed ID: 23448408
 
Study Design:
Retrospective Cohort Study
Class:
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:
To evaluate the use of the Gluten Contamination Elimination Diet (GCED) to treat non-responsive celiac disease (NRCD) patients that have failed a strict gluten-free diet (GFD).
Inclusion Criteria:
  • NRCD patients: Biopsy-proven celiac disease with persistence or relapse of symptoms or villous atrophy, despite being on a gluten-free diet for at least 12 months
  • Strictly adherent to the GFD, with no identifiable source of continued gluten exposure
  • Instructed on the GCED
  • Completed at least three months of GCED.
Exclusion Criteria:
  • Responsive to GFD
  • Non-adherent to GFD
  • Patients who did not follow up in clinic after diet education.
Description of Study Protocol:

Recruitment

The list of patients was drawn from the celiac dietitian database.

Design
  • In this single-center retrospective chart review, the charts of all patients cared for in the University of Maryland Center for Celiac Research from 2005 through 2011 who were instructed on the GCED and met the criteria for NRCD on a well-documented strict GFD were reviewed
  • Dietary compliance was assessed by an experienced dietitian with expertise in celiac disease
  • The study evaluated the effects of the GCED on clinical symptoms, mucosal pathology and celiac serology in these patients.

Intervention

  • Three to six months of the GCED, which allows: Brown and white rice; all fresh (no frozen, canned or dried) fruits, vegetables and herbs; fresh meats, poultry, fish and other non-processed protein sources
  • Unflavored, unseasoned dairy products are introduced in Week Four
  • Allowed condiments are oils, vinegar (excluding flavored and malt vinegars), honey and salt
  • Allowed beverages are 100% fruit or vegetable juices, Gatorade, milk, water and gluten-free supplemental formulas such as Boost and Ensure
  • All cereal grains aside from rice are prohibited
  • A gluten-free multi-vitamin/mineral supplement is recommended.

Statistical Analysis

Not reported.

Data Collection Summary:

Timing of Measurements

Symptoms, celiac serology and histology were evaluated prior to and after initiation of the GCED.

Dependent Variables

  • Clinical symptoms 
  • Histological changes: Duodenal biopsies were staged according to the Marsh Oberhuber classification
  • Celiac serology: IgA antibodies to tissue transglutaminase (tTG) or anti-endomysial antibodies (EMA), defined using cutoffs provided by the ELISA kit manufacturer.

Independent Variables

The GCED.

Control Variables

  • Diet adherence
  • Gluten-free prescription medication.
Description of Actual Data Sample:
Initial N

17 (15 female, two male).

Attrition (Final N)

17.

Age

  • Median age at diagnosis of CD (range): 30 years (1.6 years to 52 years) [Note: Five pediatric patients (under 21 years)]
  • Median age at start of GCED (range): 42 years (six years to 73 years).

Ethnicity

Not described.

Other Relevant Demographics

Not described.

Anthropometrics

  • Primary non-responsive: 14; mean years since start of GFD, three years (range 1.1 years to 4.6 years)
  • Secondary non-responsive or relapsed: Three; mean years since relapse while on GFD, two years (range, one year to three years)
  • Asymptomatic: One
  • Symptomatic: 16
    • Diarrhea: Eight
    • Fatigue: Five
    • Abdominal pain: Five
    • Bloating: Three
    • Constipation: Two
    • Inadequate weight gain: Two
    • Weight loss: One
    • Persistent hypertransaminasemia: One
    • Anxiety: One
    • Multiple symptoms: Nine.

Location

Baltimore, MD.
Summary of Results:

Key Findings

  • Response rate of the GCED was 82%, with 14 of the 17 compliant patients responding to the diet. Response defined as being asymptomatic after the diet with normal villous architecture on repeat biopsy, if performed. Eleven (79%) of these patients successsfully returned to their previous traditional GFD without resurgence of symptoms or elevated serology.
  • Six patients met criteria for RCD prior to the GCED; five (83%) were asymptomatic after the GCED and no longer meet RCD criteria.
  Pre-Diet
N (%)

Post-Diet
N (%)

Symptoms Asymptomatic 1 (6%) 14 (82%)
Symptomatic 16 (94%) 3 (18%)
Histology Biopsy obtained 12 (71%) 5 (29%)
Marsh 3 7 1
Marsh 2 2  
Marsh 0-1 3 4
Celiac Serology High  10 (59%) 2 (12%)
Weak positive 3 (18%) 5 (30%)
Negative 4 (24%) 10 (59%)

Marsh 3: Villous atrophy
Marsh 2: Normal villi but elevated serology
Marsh 1: Histologic remission
Marsh 0: Normal histology.

Author Conclusion:
  • The GCED may be an effective therapeutic option for NRCD patients that have already failed a well-documented GFD and may aid in differentiating those patients reacting to trace amounts of gluten contamination from those who truly have refractory celiac disease type 1 (RCD1)
  • Authors provided a proposed diagnostic algorithm to avoid patient misclassification, un-necessary testing and immunotherapy
  • The authors recommend the first step is assessment of dietary compliance by a dietitian experienced with celiac disease.
Funding Source:
Reviewer Comments:
  • Dietary compliance ensured by comprehensive interview and evaluation by an experienced dietitian
  • Diet modification carries some degree of placebo effect
  • A major limitation of this study is the absence of repeat biopsies in some patients
  • Study limited by lack of information on NRCD patients that were not started on the GCED. There is a possibility of a selection bias toward expected response to the GCED among study subjects.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? No
  8.1. Were statistical analyses adequately described and the results reported appropriately? No
  8.2. Were correct statistical tests used and assumptions of test not violated? ???
  8.3. Were statistics reported with levels of significance and/or confidence intervals? No
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes