EAL

CD: Villous Atrophy (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To report data on the control of celiac disease and on its correlates in a large cohort of celiac adults during long-term treatment with gluten-free diet.

Inclusion Criteria:

Patients with complete records for data collected at time of diagnosis of celiac disease (baseline).

Exclusion Criteria:

Patients known to have severe complication of celiac disease such as T cell lymphoma, ulcerative jejunoileitis, refractory sprue, or cancer.

Description of Study Protocol:

Recruitment

Patients of target cohort were invited to undergo a follow-up visit for data collection as in the baseline visit and to monitor dietary compliance to a gluten-free diet.

Design

Cohort study.

Blinding used (if applicable)

Physician assessing compliance was unaware of laboratory and histological findings.

Intervention (if applicable)

Gluten-free diet for at least 2 years.

Statistical Analysis

For statistical analyses on intestinal damage, 3 groups were defined: absent intestinal damage = normal villous height and normal crypt depth and IEL count <40/100 enterocytes (type 0 according to Marsh-Oberhuber), mild intestinal damage = IEL count > 40/100 enterocytes and/or crypt elongation (types 1 and 2 according to Marsh-Oberhuber) and severe intestinal damage = villous shortening to flat mucosa plus crypt hyperplasia (types 3a, 3b and 3c according to Marsh-Oberhuber). Statistical procedures included ANOVA, chi-square analysis, and Spearman correlation analysis. In some analyses, intestinal damage and dietary compliance were coded as a numerical variable. For intestinal damage, the score was 0 for absent, 1 for mild, and 2 for severe, for dietary compliance, the score was 0 for very low, 1 for low, and 2 for good. For each variable, the change value was calculated as the follow-up minus the baseline value. Age differences between baseline and follow-up were used to calculate the duration of follow-up.

Data Collection Summary:

Timing of Measurements

Data collection at baseline medical exam included gender, age, years of education, occupation, height, weight, bowel habit, blood hemoglobin, plasma albumin and cholesterol, serum antiendomysium antibodies, dietary compliance to gluten-free diet, and intestinal damage at biopsy (absent, mild, or severe). At baseline and follow-up visits, 3 separate histological samples were collected.

Dependent Variables

Histological samples collected by intestinal biopsy obtained by upper endoscopy, which were analyzed according to Oberhuber modification of the Marsh classification. Sample with most severe damage used for analysis.
Medical exam at follow-up included: age, weight, height, bowel habit, intestinal biopsy, blood hemoglobin, plasma albumin, plasma cholesterol, serum EmA, and dietary compliance
Assay for serum EmA was performed using immunofluorescence
Blood hemoglobin, plasma cholesterol and albumin measured by automated biochemistry

Independent Variables

Gluten-free diet: yearly follow-up visit includes evaluation of dietary compliance. Patients were accurately interviewed by a trained physician to assess habitual intake of gluten-containing food per week. Compliance defined as good (no gluten-containing foods), low (up to 1 gluten-containing food/week), or very low (more than 1 serving of gluten-containing food/week).

Control Variables

Description of Actual Data Sample:

Initial N: 860 adults were followed-up for at least 2 years during treatment. 744 patients had complete records.

Attrition (final N): 390 patients, 91 men and 299 women.

Age: Mean age 27.9 +/- 10.9 years at baseline

Ethnicity: Not mentioned

Other relevant demographics: Not mentioned.

Anthropometrics: Of target cohort, differences between those who did and those who did not participate in follow-up were not significant by chi-square analysis or ANOVA.

Location: Italy

Summary of Results:

Percent Prevalence of Follow-Up Damage

Baseline	N	0	1	2	3a	3b	3c
Grade 1	6	50%	0%	16.7%	0%	16.7%	16.7%
Grade 2	12	41.7%	8.3%	25.0%	16.7%	8.3%	0%
Grade 3a	90	44.4%	8.9%	31.1%	3.3%	8.9%	3.3%
Grade 3b	162	43.2%	9.3%	19.8%	5.6%	13.6%	8.6%
Grade 3c	120	43.3%	10.8%	21.7%	5.0%	11.7%	7.5%
All Grades	390	43.6%	9.5%	23.1%	5.1%	11.8%	6.9%

Other Findings

The duration of follow-up was 6.9 +/- 7.5 years (range 2 - 22 years). At follow-up visit, intestinal damage was absent in 170 patients (43.6%), mild in 127 (32.6%) and severe in 93 (23.8%).

At follow-up, intestinal damage was significantly associated with dietary compliance (p < 0.001), EmA (p < 0.001), and plasma albumin (p < 0.001).

The duration of follow-up was inversely related to the score of dietary compliance (Spearman r = -0.125, p = 0.013), not of intestinal damage ( r = -0.081, p = 0.110).

Low or very low compliance to gluten-free diet had a positive predictive value for detection of intestinal damage of 92.8%, good compliance had a negative predictive value of 92.2%. Serum EmA had a positive predictive value of 96.8% and a negative predictive value of 56.6%.

Baseline education significantly predicted dietary compliance and intestinal damage at follow-up.

Author Conclusion:

Celiac disease is often poorly controlled in the majority of patients on long-term treatment with a gluten-free diet as demonstrated by signs of mild to severe intestinal damage at biopsy. Lack of adherence to strict gluten-free diet is the main reason of poorly controlled disease in adults. Laboratory and clinical information have a high positive predictive value and low negative predictive value for intestinal damage on long-term treatment. Dietary compliance as assessed by interview is the best marker of celiac disease control due to low cost, noninvasivity and strong correlation with intestinal damage.

Funding Source:

University/Hospital:

Federico II University of Naples, Northwestern University

Reviewer Comments:

Dietary compliance well monitored. Large sample size.

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?	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?	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?		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?	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?	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?	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