EAL

CD: Villous Atrophy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess histologic recovery in response to gluten withdrawal in patients with celiac disease.

Inclusion Criteria:

All initially had signs and symptoms of malabsorption. Small intestine biopsies revealed celiac-related pathology, i.e. intraepithelial infiltration with lymphocytes, crypthyperplasia, and partial, subtotal or total villous atrophy.

Exclusion Criteria:

Inflammatory bowel disease, bacterial overgrowth, Crohn's disease, giardiasis, amyloidosis, intestinal lymphangiectasia, Whipple disease, hypogammaglobulinemia, eosinophilic enteritis, and lymphoma were excluded.

Description of Study Protocol:

Recruitment

Patients seen in hospital during 15 year period, from January 1985 to December 2000.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

Biopsies interpreted by 2 researchers uninformed about clinical status of patients.

Intervention (if applicable)

Gluten-free diet.

Statistical Analysis

Chi-square tests used for significance tests.

Data Collection Summary:

Timing of Measurements

Patients underwent follow-up small intestine biopsies within 2 years after starting a gluten-free diet. Further biopsies were done if villous atrophy was present or if symptoms of relapse occurred. Biopsies categorized into time intervals of 1 - 2 years, 2 - 5 years, and more than 5 years.

Dependent Variables

Small intestine biopsies done using an endoscopic-guided Crosby capsule, with or without large forceps biopsies of the distal duodenum. Histologic features interpreted by 2 researchers according to modified Marsh classification (IIIA - partial villous atrophy, IIIB - subtotal villous atrophy, IIIC - total villous atrophy).

Independent Variables

Gluten-free diet: all received dietay counseling from their gastroenterologist and a dietitian. Diet was not defined nor monitored.

Control Variables

Description of Actual Data Sample:

Initial N: 158 celiac patients, 114 female, 44 male. 22 additional patients with symptoms and signs of malabsorption also studied, 13 women, 9 men - these patients had gluten-sensitive enteropathy with lymphocytic enteritis with crypt hyperplasia (Marsh II)at diagnosis.

Attrition (final N): See above.

Age: Celiac patients: mean age 44 years, range 0 - 74 years. Gluten-sensitive enteropathy patients: mean age 42 years, range 19 - 76 years.

Ethnicity: Not mentioned.

Other relevant demographics: Not mentioned.

Anthropometrics: Not mentioned.

Location: Netherlands

Summary of Results:

Other Findings

Of patients with Marsh IIIA, IIIB or IIIC lesions, histologic remission was seen in 65.0% within 2 years, 85.3% within 5 years, and 89.9% in long-term follow-up.

Of 59 Marsh IIIC patients: 30 (51%) recovered within 2 years, 48 (81%) within 5 years, and 51 (86%) in long-term follow-up.

Of 59 Marsh IIIB patients: 34 (58%) recovered within 2 years, 46 (78%) within 5 years, and 52 (88%) in long-term follow-up.

Of 40 Marsh IIIA patients: 35 (88%) recovered within 2 years, 39 (98%) within 5 years, and 39 (98%) in long-term follow-up.

End-stage histologic score of 142 of 158 patients: 41.3% Marsh 0, 23.8% Marsh I, and 25.9% Marsh II.

11 patients (7.0% of all patients) with persisting partial villous atrophy had symptoms and signs of malabsorption and were considered to have refractory celiac disease; 5 of them developed an enteropathy-associated T-cell lymphoma.

Patients with gluten-sensitive enteropathy: 18 (82%) recovered to Marsh 0 within 2 years, 4 (18%) recovered to Marsh I within 2 years.

In subgroup of 25 children (17 girls, 8 boys, mean age 3 years, range 1 - 16), 24 (96%) showed histologic recovery within 2 years, and 100% recovered in long-term follow-up. Recovery was faster in children than in adults (p < 0.01) and tended to be more complete in children (p < 0.20).

Author Conclusion:

In a long-term follow-up study of 158 patients with celiac disease in our hospital, the histologic recovery in gluten-sensitive sprue after starting a gluten-free diet takes time (more than 2 years in 35.4% of patients) and is incomplete or absent in a substantial subgroup of patients (10.1% villous atrophy after 5 years). Considering the morbidity of the malabsorption condition and the risk for secondary complications such as osteopenia and malignant neoplasm, these results imply the need for a systematic follow-up of patients with celiac disease, including small intestine biopsies.

Funding Source:

University/Hospital:

Rinjstate Hospital Arnhem (Netherlands)

Reviewer Comments:

Gluten-free diet not defined or monitored. Statistics not well described. Small group of children for analysis.

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?		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
	3.3.	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
	3.5.	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?	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%.)	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
	4.5.	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?		???
	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?	No
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	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?	No
	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?		???
	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?	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)?	???
	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