EAL

CD: Villous Atrophy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To compare the clinical, histological and serological response to a wheat-starch-based or natural GFD in patients with newly detected CD.

Inclusion Criteria:

Newly diagnosed CD patients. Diagnosis based on severe partial or subtotal small bowel villous atrophy with crypt hyperplasia.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

Consecutive adults diagnosed with CD at Tampere University Hospital between April 1998 and February 2000.

Design

Randomized controlled trial.

Blinding used (if applicable)

Patient entered trial before random treatment assignment revealed.

Intervention (if applicable)

Subjects randomized to wheat-starch-based or natural GFD for one year.

Statistical Analysis

Quantitative data expressed as means and 95% confidence intervals. A two tailed t test used to compare laboratory values between groups. Cross-tabulations were carried out by Fisher's exact test. The required number of participants was determined to achieve statistical power.

Data Collection Summary:

Timing of Measurements

Dietary analysis at three and nine months after diet adoption. Clinical response, small bowel mucosal morphology, CD3+, alpha-beta+ and gamma-delta+ intraepithelial lymphocytes, mucosal human leucocyte antigen-DR expression and serum endomysial, transglutaminase and gliadin antibodies measured before and after 12 months diet. Quality of life and bone mineral density also measured.

Dependent Variables

Three to five small bowel biopsy specimens taken by upper GI endoscopy from distal part of duodenum, morphometric analysis, villous height:crypt depth ratio, enterocyte cell height and IEL density performed
Mucosal human leucocyte antigen (HLA)-DR expression was detected with monoclonal HLA-DR antibody
Serum IgA endomysial antibodies determined through indirect immunofluorescence
Serum IgA gliadin and tissue transglutaminase antibodies investigated by ELISA
Blood Hgb, serum iron, calcium, vitamin B12 and RBC folate measured using routine lab methods
GI symptoms evaluated by total score on Gastrointestinal Symptom Rating Scale
Quality of life assessed by Psychological General Well-Being Questionnaire
Bone Mineral Density measured by DEXA.

Independent Variables

Detailed dietary analysis and history assessed through interview and four-day food record. Dietitian evaluated the daily consumption of gluten-free flours (either natural or wheat-starch-based).

Description of Actual Data Sample:

Initial N: 65 adults originally diagnosed with CD. Eight refused to participate. 57 consecutive adults entered study. Natural GFD (n=29), 23 females, six males. Wheat-starch-based GFD (n=28), 22 females, six males.
Attrition (final N): 49 patients completed the study with a proper diet, 23 in the natural GFD and 26 in wheat-starch-based GFD. Two patients in the natural GFD discontinued the study after two months since they found the diet too convoluted. Four patients in natural GFD and two patients in wheat-starch-based GFD did not follow strict GFD.
Age: Natural GFD, mean age 47 years (24-68 years). Wheat-starch-based GFD, mean age 44 years (22-69 years).
Ethnicity: Not mentioned.
Anthropometrics: The groups were similar with respect to age, gender and symptoms.
Location: Department of Medicine, Tampere University Hospital, Finland.

Summary of Results:

	Natural GFD (n=23) Before GFD	Natural GFD (n=23) On GFD	Wheat-Starch-Based GFD (n=26) Before GFD	Wheat-Starch-Based GFD (n=26) On GFD
Hgb, mean	12.6 (10.9-14.4)	12.7 (11.1-14.5)	12.9 (9.8-15.3)	13.3 (10.8-14.9)
Serum Calcium, mean	2.3 (2.12-2.45)	2.3 (2.13-2.51)	2.3 (2.08-2.54)	2.3 (2.2-2.6)
Serum Vit B12, mean	301 (166-597)	363 (191-661)	271 (148-441)	316 (127-602)
RBC Folate, mean	398 (138-847)	499 (293-1050)	433 (120-632)	585 (163-1200)
Serum Iron, mean	16.8 (3.6-46.2)	19.0 (7.0-31.1)	14.6 (3.3-22.8)	17.4 (6.2-29.4)
Serum AGA, number of abnormal levels	14/23 (61%)	2/23 (9%)	18/26 (70%)	4/26 (15%)
Serum EmA, number of abnormal levels	18/23 (78%)	1/23 (4%)	17/26 (65%)	2/26 (8%)
Serum tTg-ab, number of abnormal levels	22/23 (96%)	5/23 (22%)	23/26 (88%)	3/26 (12%)

Other Findings

Mean consumption of gluten-free flours after three months was 79 g/day (20-186 g/day) in natural GFD and 82 g/day (35-184 g/day) in wheat-starch-based GFD. After nine months, mean consumption was 77 g/day (20-186 g/day) for natural GFD and 81 g/day (37-173 g/day) for wheat-starch-based GFD.
The villous height to crypt depth ratio and enterocyte cell height increased and the density of IELs decreased equally in the groups on natural and wheat-starch-based GFD. In both groups, abdominal symptoms were alleviated equally by a strict diet.
There were no differences between the groups in mucosal morphology, the density of IELs, epithelial HLA-DR expression, serum antibodies, bone mineral density or quality of life tests at the end of the study.
Four patients on the natural GFD and two on the wheat-starch-based GFD had dietary lapses and had indequate mucosal, serological and clinical recovery.

Author Conclusion:

We have shown, for the first time, in a randomized prospective study that a natural gluten-free diet and a wheat-starch-based gluten-free diet produce a similar histological and clinical recovery in patients with newly detected celiac disease. Repetitive dietary transgressions resulted in incomplete small bowel mucosal recovery, and this may clearly expose patients to health risks. It thus appears that the overall compliance with diet is much more important than the trace amounts of gluten possibly present in wheat-starch-based gluten-free products.

Funding Source:

University/Hospital:

Tampere University Hospital (Finland)

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Authors note the possibility that patients in natural GFD consumed products that may have been contaminated.

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)	Yes
	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.)	Yes
	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?	N/A
	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?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	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%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	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?	Yes
	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?	N/A
	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?	N/A
	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?	N/A
	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?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	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)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	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