EAL

CD: Villous Atrophy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To examine the frequency of histologic abnormalities in small bowel biopsy specimens and investigate whether these could be related to trace amounts of gluten in "gluten-free" foods as defined by the WHO/FAO Codex Alimentarius or to any other factors.

Inclusion Criteria:

All subjects were adhering to a GFD, either the Codex-GFD or NDG-GFD. Entry not influenced by which type of GFD consumed. All subjects had experienced a clinical response to gluten withdrawal.

Exclusion Criteria:

None specifically mentioned.

Description of Study Protocol:

Recruitment

Recruitment through The Coeliac Society of New South Wales. 42 were enrolled in a study of non-gluten food intolerances (April 1994 to March 1995), eight acted as asymptomatic controls and 39 were enrolled in a long-term assessment of the histologic and metabolic findings in CD (June 1996 to May 1997).

Design

Cross-sectional

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Duodenal biopsy specimens were examined and correlated with their form of GFD.

Statistical Analysis

Number of subjects with normal biopsy specimen or villous atrophy in each dietary group was compared by means of the chi-square test for 2x2 tables. Mean values for each of the dietary groups were compared with each other and with controls using the Student t-test. Results are expressed as mean ± standard deviation.

Data Collection Summary:

Timing of Measurements

Detailed medical and diet history obtained at initial visit. Small bowel biopsy specimens and serum IgA and EmA also investigated.

Dependent Variables

Three small bowel biopsy specimens taken from third part of duodenum by upper GI endoscopy, analyzed for overall assessment for normal/showing villous atrophy, villous/crypt ratio, IEL count, activities of lactase, sucrase and maltase
Serum IgA AGA assayed by ELISA in 42 subjects
IgA EmA assessed by indirect immunofluorescence in 37 subjects.

Independent Variables

Dietary assessment through dietitian interview, food intake questionnaire and one-week food diary. Dietary compliance confirmed and diet classified as either Codex-GFD or NDG-GFD.

Description of Actual Data Sample:

Initial N: 89 subjects with proven CD, 73 women and 16 men. 62 control patients undergoing small-bowel biopsy for diarrhea, weight loss or suspected CD, 48 women and 14 men.
Attrition (final N): 89 study subjects, 62 controls.
Age: Mean age at study entry was 47.2±13.6 years (20-75 years). Controls, mean age 45.4±12.4 years (23-62 years).
Ethnicity: Not mentioned
Other relevant demographics: Mean age at CD diagnosis was 38.9±14.2 years (three to 70 years).
Location: Australia.

Summary of Results:

	Codex-GFD Subjects	NDG-GFD Subjects	Codex-GFD IEL Count	NDG-GFD IEL Count	Codex-GFD Lactase	NDG-GFD Lactase
Normal (%)	21 (41)	30 (59)	99.5±25.8, P<0.05	99.2±34.3, P<0.05	22.6±16.5	18.9±12.5
Villous Atrophy (%)	18 (47)	20 (53)	165.1±59.8, P<0.001	180.4±95.2, P<0.001	4.6±4.0, P<0.001	7.4±6.2, P<0.001
Controls	62		80.9±38.3		17.3±16.1

Other Findings

39 subjects (43.8%) were consuming a Codex-GFD and 50 (56.2%) were consuming a NDG-GFD.
In 51 subjects, the duodenal specimen was histologically normal, whereas in 38 there was villous atrophy (partial: 28, subtotal: eight, total: two). As expected, patients with villous atrophy had significantly higher IEL counts (173.2±79.7) than patients with normal biopsy specimens (99.3±30.8, P<0.001) or controls (80.9±38.6, P<0.001). The number of IEL in patients with normal biopsy specimens was also slightly higher than in controls (P<0.01).
For those with villous atrophy, age on study entry was higher (52.2±14.0 years, P<0.005) than in those with normal biopsies (43.4±12.2 years) and controls (45.4±12.4 years). In addition, for those with villous atrophy, age at diagnosis was higher (44.3±14.4 years, P<0.005) than in those with normal biopsies (34.9±13.0 years).
Lactase levels in patients with villous atrophy were significantly lower (6.1±5.4 U) than in those with a normal specimen (20.5±14.3 U, P<0.001) or controls (17.5±16.2 U, P<0.001). Results similar for lactase were found for sucrase and maltase.
There was no relationship between the presence or absence of villous atrophy and ingestion of either a GFD as defined by the Codex Alimentarius (Codex-GFD; 39 patients) or a GFD that contained no detectable gluten (NDG diet; 50 patients).
IEL counts were higher and lactase levels lower in subjects with an abnormal biopsy specimen than in those in whom it was normal. However, within each of these biopsy groups there was no difference in these variables between patients on a Codex-GFD and those on a NDG-GFD.
IgA AGA was detected in four of 29 patients on a Codex-GFD and in three of 13 on a NDG-GFD. Two of these had a normal biopsy specimen, two had partial villous atrophy, two had subtotal villous atrophy and one had total villous atrophy. Four were consuming a Codex-GFD and three consuming a NDG-GFD. EmA was positive in one of 37 patients; this subject had subtotal villous atrophy and was consuming a NDG-GFD.

Author Conclusion:

This study confirms that even after an average of eight years on a GFD, persisting mucosal abnormalities are found in many patients with CD. In 32%, there was partial villous atrophy; in 9%, subtotal villous atrophy; in 2%, total villous atrophy. These histological abnormalities were associated with the expected increase in the number of IEL and reduction in disaccharidase activity. The results of the current study confirm that the small amount of gluten found in wheat starch and malt in the Codex-GFD is not responsible for the villous atrophy, increased IEL counts and low lactase levels found in many of the subjects. The occurrence of symptoms and of mucosal damage appears to be independent phenomena in these patients.

Funding Source:

University/Hospital:

Royal Prince Albert Hospital (Sidney Australia)

Reviewer Comments:

Authors note that patients with villous atrophy were on average 9.4 years older at the time of diagnosis than those with normal biopsy results. Younger patients might be able to make a more swift mucosal recovery, but evidence is sparse.

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?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	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?	N/A
3.	Were study groups comparable?		N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.1.	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?	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	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?	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?	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
	3.5.	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?	Yes
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
	7.1.	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
	7.2.	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
	7.3.	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
	7.4.	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
	7.5.	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
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	N/A
	7.7.	Were the measurements conducted consistently across groups?	N/A
	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