EAL

CD: Iron Deficiency Anemia (2006)

Citation:

Annibale B, Severi C, Chistolini A, Antonelli G, Lahner E, Marcheggiano A, Iannoni C, Monarca B, Delle Fave G. Efficacy of gluten-free diet alone on recovery from iron deficiency anemia in adult celiac patients. Am J Gastroenterol 2001; 96: 132-137.

PubMed ID: 11197242

Study Design:

Non-Randomized Controlled Trial

Class:

C - Click here for explanation of classification scheme.

Quality Rating:

POSITIVE: See Quality Criteria Checklist below.

Research Purpose:

The first aim of this study was to assess the prevalence of celiac disease in adult patients with iron deficiency anemia, and the second aim was to verify in the newly diagnosed patients the efficacy of and time course of recovery from anemia by a gluten-free diet alone (without oral iron replacement).

Inclusion Criteria:

Iron deficiency anemia, defined as a hemoglobin concentration <14 g/dL for men (normal range 14 - 18 g/dL) and <12 g/dL for women (normal range 12 - 16 g/dL), mean corpuscular volume <80 fl (normal range 80 - 100 fl), low serum iron (normal range 50 - 150 micrograms/dL) and low serum ferritin (normal range 20 - 180 ng/ml). Some subjects had previously been treated with iron supplementation therapy. Celiac disease was defined as having villous flattening, crypt hypertrophy, as well as evident regrowth of the villi after at least 6 months on a gluten-free diet.

Exclusion Criteria:

Obvious causes of blood loss (heavy menstrual loss, active GI hemorrhage) and other conditions that could justify microcytic anemia (positive fecal occult blood tests, liver cirrhosis, hemolytic disease, renal failure, thalassemia, malignancies). To exclude gastric causes of iron malabsorption, 2 antral and 2 fundic biopsies were performed. To exclude lower GI bleeding, fecal occult blood tests were done and those over 40 years of age underwent either double contrast barium enema or colonoscopy.

Description of Study Protocol:

Recruitment

190 consecutive adult patients with iron deficiency anemia referred from Hematology Dept to Gastroenterology Dept from January 1994 - May 1997.

Design

Nonrandomized Clinical Trial.

Blinding used (if applicable)

No blinding used.

Intervention (if applicable)

Screened for celiac disease by upper GI endoscopy with duodenal biopsies. Gluten-free diet without iron supplementation.

Statistical Analysis

Data expressed as median (range) or number/total (percentage). Statistical analysis performed using the Wilcoxon test for nonpaired parametric data. Correlation between variables was assessed by using the Spearman rank correlation test.

Data Collection Summary:

Timing of Measurements

After 6 months of gluten-free diet, duodenal biopsies were performed and hematological tests repeated at 6, 12 and 24 months.

Dependent Variables

2 biopsy specimens taken during upper endoscopy in the second duodenal portion of each subject. Degree of atrophy and chronic inflammatory infiltration classified according to Marsh's classification system
Hemoglobin concentrations, mean corpuscular volume, red cell distribution width and lymphocyte count were determined by an automated Coulter counter
Serum ferritin levels measured by commercial kits (chemiluminescence assay)
Serum iron, glucose, cholesterol, triglycerides, proteins, albumin also measured
IgA antiendomysium antibodies detected using immunofluorescence

Independent Variables

Gluten free diet was not defined but compliance was monitored through EmA values.

Description of Actual Data Sample:

Initial N: 190 adult patients with iron deficiency anemia screened for celiac disease, which was diagnosed in 26 adults (24 women, 2 men).

Attrition (final N): 20 of the 26 diagnosed (18 women, 2 men) were followed for 24 months. 5 subjects lost during follow up. 1 patient was not compliant based on positive EmA values at 6 months and was excluded from statistical evaluation.

Age: Median age 31.3 years (20 - 72 years)

Ethnicity: Not mentioned

Other relevant demographics: Median onset of iron deficiency anemia was 3 years (1 - 20 years) before diagnosis of celiac disease.

Location: Italy

Summary of Results:

Hematological Features of 18 CD Women with Iron Deficiency Anemia

	Hemoglobin (normal range 12 -16)	Mean Corpuscular Volume (normal range 80 - 100)	Red Cell Distribution Width (normal range 11.5 - 15.5)	Serum Iron (normal range 50 - 150)	Ferritin (normal range 20 - 180)
Before GFD	10.7 (6.1 - 11.9)	73 (54.2 - 95.1)	18 (12.9 - 22.8)	17 (3 - 41)	4 (1 -10)
6 months GFD	12.5 (8.3 - 14.4), p < 0.0001 compared to before GFD	83.3 (65 - 90), p < 0.0005 compared to before GFD	13.1 (10.5 - 28.3)	56.5 (20 - 113), p < 0.0001 compared to before GFD	11.5 (3 - 82), p < 0.0001 compared to before GFD
12 months GFD	13.3 (9.7 - 15.3), p < 0.005 compared to 6 months	85.1 (67 - 95), p < 0.005 compared to 6 months	14.2 (11.7 - 17.2)	68.5 (30 - 135), p < 0.01 compared to 6 months	19 (5.1 - 63)
24 months GFD	13.8 (10.4 - 14.7)	85.5 (76 - 99)	13.7 (11.9 - 17.1)	67.5 (20 - 132)	21 (4 - 58)

Other Findings

At beginning of study, histological score of duodenitis was A3 (total villous atrophy and severe chronic inflammatory infiltration) in 20 patients (76.9%) and A2 (subtotal villous atrophy and moderate chronic inflammatory infiltration) in 6 patients (23.1%). 8 patients had diarrhea, 1 had constipation, 4 had dermatological symptoms.

After 6 months of gluten-free diet, 14/18 (77.8%) of female patients recovered from iron deficiency anemia (defined as normalization of hemoglobin concentrations), but only 5/18 (27.8%) reversed from iron deficiency (defined as normalization of serum ferritin levels). In the 2 male patients, only 1 recovered from anemia but not iron deficiency. GI symptoms were no longer present in those 8 patients.

At 12 months, all but one patient (94.4%) recovered from anemia and 9 patients (50%) from iron deficiency. Both males had reversed from iron deficiency.

After 24 months, only the patient who did not recover from anemia at 12 months was still anemic, whereas 10 patients (55.5%) reversed from iron deficiency.

The patient who did not recover from iron deficiency anemia was a 72 year old woman with a 20 year history of iron deficiency anemia. Colonoscopy was negative.

A significant inverse correlation (r = -0.7141, p = 0.0003) between increase of hemoglobin concentrations and decrease of individual histological scores of duodenitis was observed.

Author Conclusion:

This prospective study shows that celiac disease is a frequent cause of iron deficiency anemia in adults and that the resolution of duodenal histological alterations obtained by a gluten-free diet is able to restore dietary iron absorption and thus to recover from anemia in celiac disease patients. In conclusion, an active screening for occult celiac disease should be completed in adult patients with iron deficiency anemia, in particular those refractory to iron therapy or iron dependent. Recovery from anemia occurs between 6 and 12 months on a gluten-free diet alone as a consequence of normalization of the histological alterations of the intestinal mucosa, but reversal from iron deficiency (defined as normalization of serum ferritin levels) occurs in only 50% of these patients and requires at least 1 year.

Funding Source:

Government:

Italian Ministry for the University, FIMAD (Italy)

Reviewer Comments:

Compliance to gluten-free diet measured and subject excluded from results.

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?	N/A
	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?	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?		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
	5.3.	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?	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
	6.8.	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?	N/A
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)?	N/A
	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