EAL

CD: Villous Atrophy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the small-bowel mucosal condition in a large group of patients with CD and dermatitis herpetiformis who had ingested wheat starch-based gluten-free flour products for many years.

Inclusion Criteria:

All patients with CD fulfilled the diagnostic criteria of the European Society of Pediatric Gastroenterology and Nutrition. The diagnosis of dermatitis herpetiformis was based on the typical rash and on the finding of granular IgA deposits in the uninvolved skin.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

58 patients who had been on a GFD for many years were asked to undergo a follow-up small bowel biopsy; 41 patients with CD and 11 patients with dermatitis herpetiformis agreed to participate.

Design

Cross-sectional.

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Children and adults with CD and adults with dermatitis herpetiformis adhering to a GFD.

Statistical Analysis

Results for villous height/crypt depth ratio and enterocyte height given as mean with 95% confidence intervals. Fisher's exact test was used in cross-tables, in comparisons of IELs the unpaired t-test was used.

Data Collection Summary:

Timing of Measurements

Daily dietary gluten and wheat starch intake calculated. Small bowel villous architecture, CD3+, alpha/beta +, and gamma/delta + intraepithelial lymphocytes, mucosal HLA-DR expression, and serum endomysial, reticulin, and gliadin antibodies investigated.

Dependent Variables

Seven forceps biopsy specimens taken from the distal part of the duodenum at upper GI endoscopy, morphometric studies including villous height/crypt depth ratio, enterocyte height completed, IEL counts
HLA-DR expression detected by staining biopsy specimens with monoclonal antibody HLA-DR
Serum IgA endomysial and reticulin antibodies determined by indirect immunofluorescence
Serum gliadin antibodies investigated with ELISA.

Independent Variables

Consumption of gluten-containing products assessed by a dietitian and four-day food record.

Description of Actual Data Sample:

Initial N: 41 children and adults with CD and 11 adults with dermatitis herpetiformis. 35 newly diagnosed CD and dermatitis herpetiformis patients at diagnosis and six to 24 months after start of GFD and 27 non-CD patients with dyspepsia investigated for comparison.
Attrition (final N): 41 children and adults with CD, 11 adults with DH, 21 newly diagnosed CD patients, 14 newly diagnosed DH patients, 27 non-CD controls.
Age: CD children, 12 years (seven to 18 years); CD adults, 50 years (43-67 years); DH adults, 43 years (31-62 years); untreated CD patients, 40 years (22- 66 years); untreated DH patients, 32 years (23-84 years); controls, 45 years (22-81 years).
Ethnicity: Not mentioned.
Location: Tampere University Hospital, Tampere, Finland.

Summary of Results:

	Number with enhanced HLA-DR expression	% with enhanced HLA-DR expression	P compared with patients on wheat starch-based diet
Long-term treated CD and DH, all	21/52	40%
Wheat starch-based diet	15/40	37%
Naturally GFD	1/6	17%	0.2434
Occasional dietary lapses	5/6	80%	0.0430
Short-term treated CD	13/21	62%	0.0427
Untreated CD	19/21	90%	<0.001
Non-CD controls	3/27	11%	0.0126

Other Findings

40 of 52 long-term treated patients (76%) adhered to a strict wheat starch-based diet, with mean daily intake of gluten from wheat starch-containing flour products of 34 mg (5-150 mg) and six (12%) to a strict naturally GFD. Six patients had dietary lapses.
None of the 16 children with CD had GI complaints and their growth was normal. Four of the 25 (18%) adult patients with long-term treated CD admitted to mild GI symptoms, but none had dietary lapses.
All 11 patients with dermatitis herpetiformis were asymptomatic and did not require dapsone.
In the 46 patients on a strict diet, the villous architecture, enterocyte height and density of alpha/beta + IELs were similar to those in non-coeliac subjects and better than in short-term-treated coeliac patients. The density of gamma/delta + cells was higher, but they seemed to decrease over time with the GFD.
An enhanced mucosal HLA-DR expression was not significantly more common in patients on a strict wheat starch-based diet than in those taking a natural GFD.
The mucosal integrity was not dependent on the daily intake of wheat starch in all patients on a strict diet, whereas two of the six patients with dietary lapses had villous atrophy and positive serology.

Author Conclusion:

We conclude that wheat starch-based gluten-free flour products are well tolerated among patients with coeliac disease and dermatitis herpetiformis, and they do not cause small bowel mucosal inflammation even during long-term ingestion. They provide an alternative in the treatment of coeliac disease, in which overall dietary compliance is essential.

Funding Source:

Government:

Academy of Finland,

University/Hospital:

Tampere University Hospital (Finland)

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Author notes assumption that gluten content was no more than maximum allowed by Codex Alimentarius standard, it is possible that the daily gluten intake was less. Obvious that patients who have tolerated wheat/starch-based products for years would not be significantly different.

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
	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
	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
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	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
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	???
2.	Was the selection of study subjects/patients free from bias?		???
	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?	No
	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?	No
	2.2.	Were criteria applied equally to all study groups?	???
	2.2.	Were criteria applied equally to all study groups?	???
	2.3.	Were health, demographics, and other characteristics of subjects described?	???
	2.3.	Were health, demographics, and other characteristics of subjects described?	???
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
	3.	Were study groups comparable?	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
	3.1.	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
	3.2.	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
	3.3.	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?	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?	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
	3.5.	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
	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.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	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
	4.2.	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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	N/A
	4.4.	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
	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?	N/A
5.	Was blinding used to prevent introduction of bias?		N/A
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	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.)	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.)	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	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
	5.4.	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
	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.	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
	6.1.	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
	6.2.	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
	6.3.	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
	6.4.	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
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments 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
	6.7.	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
	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?	???
7.	Were outcomes clearly defined and the measurements valid and reliable?		???
	7.1.	Were primary and secondary endpoints described and relevant to the question?	???
	7.1.	Were primary and secondary endpoints described and relevant to the question?	???
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	???
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	???
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	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?	???
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	???
	7.5.	Was the measurement of effect at an appropriate level of precision?	???
	7.5.	Was the measurement of effect at an appropriate level of precision?	???
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.7.	Were the measurements conducted consistently across groups?	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.	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
	8.1.	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
	8.2.	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
	8.3.	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
	8.4.	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)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	N/A
	8.6.	Was clinical significance as well as statistical significance reported?	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
	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.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	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.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes