EAL

CD: Wheat Starch (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To study a group of subjects with CD who were still experiencing symptoms on a Codex-GFD, and to examine the role of intolerance to foods or food chemicals other than gluten in those patients whose symptoms persisted despite changing from a Codex-GFD to a NDG-GFD and in those already on a NDG-GFD.

Inclusion Criteria:

Eligible subjects required to have persistent bowel symptoms despite consuming a GFD. Symptoms were usually multiple and included diarrhea, urgency, bloating, abdominal pain and flatulence. Diagnosis of CD must have been made by small bowel biopsy, with improvement on a follow-up biopsy at least six months later after following a GFD.

Exclusion Criteria:

Pregnant or lactating women, those with dermatitis herpetiformis only, and those with other serious medical conditions.

Description of Study Protocol:

Recruitment

Volunteers sought from The Coeliac Society of New South Wales. Recruitment began in April 1994 and was completed in September 1995.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

Blinding used for subjects on elimination diet.

Intervention (if applicable)

All subjects required to follow a NDG-GFD during study. Those in whom symptoms persisted after changing from a Codex-GFD, and those already on NDG-GFD, began an elimination diet to identify specific non-gluten food or food chemical intolerances.

Statistical Analysis

Data analysis was descriptive in nature.

Data Collection Summary:

Timing of Measurements

Detailed medical history and small bowel biopsies obtained at initial visit, as well as dietary analysis, food questionnaire and one-week food diary to classify them into one of three groups: NDG-GFD consumers commencing to take elimination diet; Codex-GFD consumers with normal biopsy asked to follow NDG-GFD for three to 12 weeks and elimination diet if symptoms persisted; Codex-GFD consumers with abnormal biopsy asked to follow NDG-GFD for three months followed by second biopsy and elimination diet if symptoms persisted. Elimination diet followed for two to six weeks. If 50% improvement experienced, subjects moved to challenge phase with foods reintroduced after three symptom-free days.

Dependent Variables

Small bowel biopsies: Endoscopic biopsy from distal duodenum.
Symptom diaries also kept daily, recorded as mild, moderate, marked or severe.

Independent Variables

Dietary intake and compliance determined through use of daily food diaries. Elimination diet excluded foods containing natural salicylates, amines or glutamate, and those with added colorings, preservatives, MSG and lactose. Dairy products, soy and millet-containing foods also excluded.

Description of Actual Data Sample:

Initial N: 50 volunteers fulfilled entry requirements. Eight decided to not proceed based on perceived difficulties in dietary adherence, two others became pregnant, one withdrew based on diagnosis of cancer.
Attrition (final N): 39 subjects, 37 female and two male. Several subjects dropped out at various points in the study based on improvement in symptoms.
Age: Median 42 years (19-75 years).
Ethnicity: Not mentioned.
Other relevant demographics: Median age at diagnosis of CD was 37 years (three to 62 years). Median duration of disease was six years (one to 29 years).
Location: Sydney, Australia.

Summary of Results:

Number of Positive Responses to Whole Food and Chemical Challenges

Challenge	Number of Subjects	Number Positive	Percentage
Soy	24	12	50
Millet	22	9	41
Milk	24	11	46
Amine	19	11	58
Salicylate	20	10	50
Glutamate	19	9	47
Propionic Acid	19	9	47
Antioxidant	19	8	42
Preservative	19	8	42
Coloring	19	8	42
Lactose	18	6	33
Nitrate	19	5	26
Sucrose	19	4	21
Potato Starch	19	3	16

Other Findings

Dietary analysis indicated that 22 (56%) were consuming a GFD as defined by the WHO/FAO Codex Alimentarius (Codex-GFD), in which foods containing up to 0.3% of protein from gluten-containing grains can be labelled as "gluten-free." The duodenal biopsy was normal in seven subjects and abnormal in 15.
The remaining 17 were following a no detectable gluten diet (NDG-GFD), as defined by Food Standards Australia. In seven, the duodenal biopsy was normal and in 10 there were various degrees of villous atrophy.
Of the 22 patients switching to a NDG-GFD, symptoms resolved in five (23%) and were reduced in 10 others (45%).
31 subjects commenced the elimination diet. Symptomatic improvement was experienced in 24 (77%). Subsequent food or food chemical challenges resulted in a mean of five positive challenges per individual. Diarrhea was the most commonly provoked symptom, followed by headache, nausea and flatulence. Symptoms were especially provoked by amine, salicylate and soy.

Author Conclusion:

Patients who remain symptomatic on a "gluten-free diet" are generally suspected of poor compliance or inadvertent ingestion of gluten, although careful and thorough dietary analysis using three methods in this study showed that this was not always the case. Our findings indicate that intolerance to other foods or food chemicals should be considered. The consumption of trace amounts of gluten, traditionally allowed in a Codex-GFD, may be responsible for the continuing symptoms seen in some patients with CD. On the basis of the findings presented here, we suggest the following practical approach in coeliac patients whose symptoms persist despite adherence to a GFD. First, a careful dietary analysis should ensure that all trace amounts of gluten are removed from the diet. If this fails to relieve the symptoms after a period of approximately three months, the possible coexistence of non-gluten food intolerances should be investigated with a suitably designed elimination diet administered for four to six weeks.

Funding Source:

University/Hospital:

Royal Prince Albert Hospital

Reviewer Comments:

Interesting that majority of subjects were female and that, for seven out of 17 subjects already following NDG-GFD, there were abnormal biopsies.

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.)	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?	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?	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?		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?	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?		???
	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?	???
	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?		No
	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?	No
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	No
	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
	8.6.	Was clinical significance as well as statistical significance reported?	No
	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