Benefits of a Gluten-Free Diet for Asymptomatic Patients With Serologic Markers of Celiac Disease
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Gastroenterology 2014;147:610–617
Benefits of a Gluten-Free Diet for Asymptomatic Patients
With Serologic Markers of Celiac Disease
Kalle Kurppa,1 Aku Paavola,2 Pekka Collin,2 Harri Sievänen,3 Kaija Laurila,1 Heini Huhtala,4
Päivi Saavalainen,5 Markku Mäki,1 and Katri Kaukinen2,6
1
Tampere Center for Child Health Research, 4Tampere School of Health Sciences, University of Tampere and Tampere
CLINICAL AT
University Hospital, Tampere, Finland; 2Department of Gastroenterology and Alimentary Tract Surgery, Tampere University
Hospital and School of Medicine, University of Tampere, Tampere, Finland; 3UKK Institute, Tampere, Finland; 5Research
Program Unit, Immunobiology and Haartman Institute, Department of Medical Genetics, University of Helsinki, Helsinki,
Finland; 6Seinäjoki Central Hospital, Seinäjoki, Finland
and endomysial antibodies (EmA) are used widely in first-line
See Covering the Cover synopsis on page 548; case-finding for further endoscopic studies, but demonstration
see editorial on page 557. of small-bowel mucosal damage still is required for the diag-
nosis in adults.1,6 Since celiac disease is common but difficult to
detect because of the heterogeneous clinical picture, a wide-
BACKGROUND & AIMS: We investigated whether screen-
detected and apparently asymptomatic adults with endomy- scale screening of the whole population with noninvasive
sial antibodies (EmA) benefit from a gluten-free diet (GFD). serologic tests frequently has been suggested.7,8 However, the
METHODS: We performed a prospective trial of 3031 in- only current treatment of the condition, a lifelong strict gluten-
dividuals at risk for celiac disease based on screens for EmA. Of free diet (GFD), is restrictive and difficult to maintain and thus
148 seropositive individuals, 40 fulfilled inclusion criteria and the positive effects of the screening are not straightforward.9
were assigned randomly to groups placed on a GFD or gluten- There have been some previous studies exploring the bene-
containing diets. We evaluated ratios of small-bowel mucosal fits of a GFD in screening-detected celiac disease patients, but
villous height:crypt depth, serology and laboratory test results, the results have been somewhat inconsistent, in particular with
gastrointestinal symptom scores, physiologic well-being, asymptomatic subjects10–14; hitherto randomized studies have
perception of health by a visual analog scale, bone mineral been lacking. A further problem is that wide-scale screening
density, and body composition at baseline and after 1 year. frequently detects seropositive subjects who are apparently
Thereafter, the group on the gluten-containing diet started a asymptomatic and evince only mild enteropathy or even
GFD and was evaluated a third time; subjects in the GFD group normal small-bowel mucosa; it has been unclear whether all
remained on this diet. RESULTS: After 1 year on the GFD, the such individuals in fact suffer from a true gluten-induced
mean mucosal villous height:crypt depth values increased clinical disease.15
(P < .001), levels of celiac-associated antibodies decreased The aim of this randomized trial was to establish whether
(P < .003), and gastrointestinal symptoms improved to a greater asymptomatic adults with positive EmA benefit from a sero-
extent than in patients on gluten-containing diets (P ¼ .003). The logic screening and subsequent GFD. Because celiac disease is
GFD group also had reduced indigestion (P ¼ .006), reflux (P ¼
known to run in families, recruitment was executed by
.05), and anxiety (P ¼ .025), and better health, based on the
screening at-risk relatives of celiac patients. By reason of its
visual analog scale (P ¼ .017), than the gluten-containing diet
high specificity, EmA was selected as the inclusion criterion.1
group. Only social function scores improved more in the gluten-
containing diet group than in the GFD group (P ¼ .031). There
were no differences between groups in laboratory test results, Patients and Methods
bone mineral density, or body composition. Most measured
parameters improved when patients in the gluten-containing Patients
diet group were placed on GFDs. No subjects considered their This study was conducted at the Department of Gastro-
experience to be negative and most expected to remain on GFDs. enterology and Alimentary Tract Surgery and the Tampere
CONCLUSIONS: GFDs benefit asymptomatic EmA-positive pa- Center for Child Health Research, the University of Tampere,
tients. The results support active screening of patients at risk for and Tampere University Hospital. Relatives of celiac patients
celiac disease. Clinicaltrials.gov no: NCT01116505. were recruited using newspaper advertisements and by
Keywords: VAS; Gastrointestinal Endoscopy; Serology Test; GSRS. Abbreviations used in this paper: BMD, bone mineral density; BMI, body
mass index; DGPab, antibodies to deamidated gliadin; EmA, endomysial
antibody; GFD, gluten-free diet; GSRS, Gastrointestinal Symptom Rating
Scale; IEL, intraepithelial lymphocyte; PGWB, Physiological General Well-
C eliac disease is a lifelong disorder caused by inges-
ted cereal-derived gluten in predisposed individuals.1
Screening studies have shown the prevalence in the European
Being; SF-36, Short-Form 36; TG2ab, transglutaminase 2 antibodies; VAS,
visual analogue scale; Vh/CrD, villous height/crypt depth ratio.
© 2014 by the AGA Institute
and North American population to be 1%–2%, and to be 0016-5085/$36.00
increasing over time.2–5 Serum transglutaminase 2 (TG2ab) http://dx.doi.org/10.1053/j.gastro.2014.05.003September 2014 Diagnosis of Celiac Disease Without Biopsy 611
contacting patient support groups. Altogether, 3031 in- subjects would have remained unrecognized and continued on
dividuals volunteered for evaluation of serum celiac antibodies a gluten-containing diet.
(Supplementary Figure 1). Exclusion criteria were a previous All authors had access to the study data, and reviewed and
diagnosis of celiac disease, age younger than 18 years, evident approved the final manuscript. This study has been registered
clinical symptoms, dietary gluten restriction, severe contem- at clinicaltrials.gov; identification number NCT01116505.
porary illness or immunosuppressive medication, ongoing or
planned pregnancy, and study refusal. EmA-positive adults
(age, 18–75 y) who considered themselves asymptomatic and Measurements
had no exclusion criteria were invited to participate in a Serology and genetics. IgA class EmA were determined
further prospective study. The symptoms were interviewed by an indirect immunofluorescence method using human
systemically with similar questions each time by a study umbilical cord as substrate.16 A serum dilution of 1:5 was
physician and asymptomatic patients were defined as those considered positive15,16 and further diluted to 1:50–1:4000.
CLINICAL AT
with an absence of abdominal pain (>3 pain episodes over at IgA-class TG2ab (Celikey; Phadia, Freiburg, Germany) and
least 3 months interfering with function), constipation (612 Kurppa et al Gastroenterology Vol. 147, No. 3
X-ray absorptiometry (Lunar Prodigy Advance, GE Healthcare, Table 1.Baseline Characteristics of the Study Patients
Waukesha, WI). BMD values were expressed as T-scores and as
age- and sex-matched Z-scores. Changes in BMD were calcu- Gluten group GFD group
lated as g/cm2. BMI was determined as weight (kg)/height Characteristic (n ¼ 20) (n ¼ 20)
(m)2; a value less than 18.5 was considered underweight,
Age, y
18.5–24.9 was considered normal, 25.0–29.9 was considered
Median 42 42
overweight, and 30.0 or higher was considered obese. Range 23–62 21–74
Small-bowel mucosal morphology and inflamma- Female sex, n (%) 5 (25) 9 (45)
tion. At each visit (at baseline, after 1 year, and after 2 years), Hypothyroidism, n (%) 2 (10) 1 (5)
an upper gastrointestinal endoscopy with 6 biopsy specimens Other chronic condition, n (%)a 7 (35) 7 (35)
taken from the duodenum was performed and the samples Osteoporotic fracture, n (%) 0 (0) 0 (0)
were coded and stored. Upon completion of the study (after the Infertility or frequent 1 (20) 1 (11)
CLINICAL AT
2-year visit) the biopsy results were read and villous height miscarriages, n (%)b
crypt/depth ratio (Vh/CrD) was measured, and the density of Age at menarche, yb
CD3þ and gdþ intraepithelial lymphocytes (IEL) were counted Median 13 13
Range 13–15 9–14
as previously described.22 Reference values were as follows:
Vh/CrD greater than 2.0, CD3þ IEL less than 37 cells/mm, and
gdþ IEL less than 4.3 cells/mm.22 a
Asthma, endometriosis, diverticulosis, allergies.
Other evaluations. At each study visit, the subjects’ b
Females.
health and medications were registered. After 1 year on a GFD
they were asked about their dietary adherence, difficulties in
maintaining the diet, and willingness to continue the diet in the
future. Thereafter, they also were asked what they now thought HLA Typing and Serology
about their celiac disease screening. All subjects had the celiac disease–associated HLA DQ2
or DQ8. The median EmA titer was 1:200 (range,
Statistical Analyses 1:5–1:2000) in the GFD and 1:100 (1:5–1:4000) in the
The primary outcome of the study defined a priori was a
gluten group. On intervention, the titers decreased signifi-
change in the Vh/CrD. Previous results have shown a standard cantly in favor of the GFD group (Figure 1A). The titers also
deviation of 0.5 for Vh/CrD and a similar change in this value subsequently decreased in all but 2 patients in the gluten
has been considered clinically relevant.15,23 Consequently, to group when they started a GFD. At baseline, TG2ab was
provide 80% statistical power at a significance level of 0.05, 17 positive in 88% of the EmA-positive participants. All 5
patients would be needed. Based on an estimated attrition rate subjects who were negative for TG2ab had EmA titers of
of 15%, we enrolled 20 subjects in each group. The chi-square 1:5–1:50. Similar to EmA, there was a significant decrease in
test in cross-tabulations and a 2-sided Student t test or the TG2ab in favor of GFD (Figure 1B). DGPab was positive in
Mann–Whitney U test were used to compare differences be- 80% of the subjects, with mean values of 69 62 U in the
tween the groups, and a paired t test or the Wilcoxon signed- GFD group and 70 58 U in the gluten group, and changes
rank test as used to compare changes within a group. A after 1 year of -54 59 U and 11 38 U, respectively
P value less than .05 was considered significant. If a subject (P < .001).
failed to answer 1 item in the questionnaire the missing answer
was replaced by the median value of the other scores. If 2 or
more items were missing the questionnaire was rejected. An- Gastrointestinal Symptoms and Quality of Life
alyses were conducted on an intention-to-treat principle. Cor- The baseline mean GSRS total score was 1.8 0.6 in the
rections for multiple comparisons were not made here because GFD group and 1.7 0.6 in the gluten group. After inter-
we had one predefined primary outcome and the rest were vention, the total, indigestion, and reflux symptoms were
secondary outcomes; in addition, no subgroup analyses were reduced significantly in the GFD group (Figure 2A). Subse-
performed.24 All analyses were conducted in cooperation with quently, the total score (P ¼ .049) and indigestion
an experienced statistician. (P ¼ .016) also decreased within the gluten group after
starting a GFD. The PGWB total score was 112.2 12.0 in
the GFD group and 111.3 11.0 in the gluten group at
Results baseline, and anxiety was alleviated in the GFD group
The randomized study groups were comparable with (Figure 2B). On intervention, the SF-36 social functioning
respect to age, sex, medical history, and associated condi- was reduced in the gluten group (Figure 2C). Perception of
tions (Table 1). One subject in the gluten group started a current health as evaluated by the VAS improved in the GFD
GFD after randomization and 2 patients refused the 2-year group (Figure 1D).
endoscopy. None of the patients in the GFD group was
willing to restart gluten, and none was withdrawn as a
result of major symptoms or complications. Because sub- Laboratory Parameters
jects in the GFD group already had adhered to the diet for The mean laboratory values were within the reference
1 year at the time of the second endoscopy, it was consid- range and no significant differences were observed in the
ered unnecessary or even unethical to perform a biopsy for changes between the groups during the intervention
a third time after 2 years on the diet. (Table 2). Although there was no difference between theSeptember 2014 Diagnosis of Celiac Disease Without Biopsy 613
CLINICAL AT
Figure 1. (A and B) Serum EmA and TG2ab antibodies, (C)
VAS, and (D) small-bowel mucosal Vh/CrD. The results are
shown at baseline and after 1 and 2 years of study enroll-
ment. The solid line denotes the GFD group on a gluten-free
diet and the dashed line shows the gluten group on a gluten-
containing (from baseline to 1 year) or on a gluten-free diet
(from 1 to 2 years). The dotted line denotes (A and B) upper or
(D) lower reference limits for normal. The values are Figure 2. Absolute differences between the study groups in
expressed as the (A) unadjusted median and quartiles or changes in the (A) GSRS, (B) PGWB, and (C) SF-36 scores.
(B–D) means and 95% confidence intervals. There was a The differences in changes between the intervention group
significant difference in the changes between the randomi- (GFD) and the normal diet group (gluten) are shown after 1
zation groups after 1 year in EmA (P ¼ .003) and TG2ab year of study enrollment and are expressed as means and
(P ¼ .003), in the perception of health by VAS (P ¼ .017), and 95% confidence intervals. On the GSRS, higher scores
in the Vh/CrD (P < .001). On the VAS, the scale ranges from denote more severe gastrointestinal symptoms, on the
0 to 100 mm and higher values indicate better subjective PGWB higher scores denote better self-perceived quality of
perception of current health. In Vh/CrD ratios, greater than 2.0 life, and on the SF-36 higher scores denote better health
indicates normal small-bowel mucosal morphology. status and quality of life. Values in each subdimension scores
are calculated as a mean of the relevant items. EP, emotional
problems; PP, physical problems.
groups, within the GFD group the red blood cell folate
(P < .001) and vitamin B12 values improved (P < .001); this
in the gluten group; no subject was underweight but 55%
also was seen later in the gluten group upon adaption of a
were overweight or obese. There were no differences in BMI
GFD (P ¼ .005 and P ¼ .018, respectively).
changes during the intervention (Table 3). The mean body
fat percentage was 34.0 8.9 in the GFD group and 28.9
Bone Mineral Density and Body Composition 8.2 in the gluten group, and changes in body fat percentage
In the GFD group the baseline mean T-score for the did not significantly diverge between the groups (Table 3).
lumbar spine was -0.2 1.5, and for the femur neck was
-0.5 1.2; the corresponding Z-scores were -0.1 1.5 and
-0.2 1.0, respectively. In the gluten group the T-scores Small-Bowel Mucosal Morphology and
were -0.2 1.7 and -0.3 1.0, and the Z-scores were -0.3 Inflammation
1.7 and -0.1 1.0, respectively. Differences in BMD changes At the end of the study (after 2 years) the small-bowel
between the groups were not significant (Table 3). The mucosal biopsy results were opened. At baseline, the
mean BMI was 27.0 6.8 in the GFD group and 26.4 3.7 mean Vh/CrD was 1.0 0.9 in the GFD group and 0.8 0.8614 Kurppa et al Gastroenterology Vol. 147, No. 3
Table 2.Laboratory Parameters at Baseline and After 1 Year Table 3.Body Mass Index, Total Body Fat, BMD, and Density
on Study of Small-Bowel Mucosal IELs at Baseline and After
1 Year on Study
Gluten group GFD group P valuea
Gluten group GFD group P valuea
Blood hemoglobin level, g/dL
Baseline 14.3 1.4 14.4 1.6 Body mass index, kg/m2
Change -0.2 0.6 -0.2 0.7 Baseline 26.4 3.7 27.0 6.8
Difference 0.0 (-0.4 to 0.4) .902 Change -0.3 1.0 0.0 1.2
Plasma albumin level, g/dL Difference 0.3 (-0.5 to 1.0) .451
Baseline 4.1 0.3 4.0 0.4 Total body fat, %
Change 0.2 0.3 0.2 0.4 Baseline 28.9 8.2 34.0 8.9
Difference 0.0 (-0.2 to 0.2) .859 Change -0.6 2.4 -1.2 3.4
CLINICAL AT
Serum ionized calcium level, mmol/L Difference -0.5 (-2.4 to 1.4) .600
Baseline 1.28 0.03 1.26 0.03 Lumbar spine BMD, g/cm2
Change -0.01 0.03 0.00 0.04 Baseline 1.17 0.21 1.17 0.19
Difference 0.00 (-0.02 to 0.03) .687 Change -0.01 0.03 0.00 0.02
Plasma intact parathormone level, pmol/L Difference 0.01 (-0.01 to 0.02) .338
Baseline 5.4 2.0 4.7 1.8 Femur neck BMD, g/cm2
Change -0.3 1.1 -0.3 0.9 Baseline 1.00 0.12 0.97 0.14
Difference 0.0 (-0.7 to 0.6) .916 Change -0.01 0.03 0.00 0.02
Serum total iron level, mmol/L Difference 0.01 (-0.01 to 0.03) .182
Baseline 17.3 5.7 20.0 8.6 Density of mucosal CD3þ IELs, cells/mm epithelium
Change 2.8 6.8 0.3 7.2 Baseline 78.5 38.1 75.9 30.2
Difference -2.5 (-7.0 to 2.1) .288 Change -0.4 45.2 -12.9 34.1
Red blood cell folate level, nmol/L Difference -12.5 (-39.5 to 14.4) .351
Baseline 497 193 477 187 Density of mucosal gdþ IELs, cells/mm epithelium
Change 183 215 300 260 Baseline 29.8 19.3 24.7 12.9
Difference 117 (-39 to 272) .136 Change -2.0 20.6 -1.7 10.1
Serum vitamin B12 level, pmol/L Difference 0.4 (-10.4 to 11.2) .945
Baseline 366 108 316 72
Change 18 63 45 54
Difference 27 (-11 to 65) .158 NOTE. The values are expressed as means SD, except
Serum alanine amino transferase level, U/L differences in the changes between the groups, which are
Baseline 28.8 11.6 32.2 20.0 expressed as means with the 95% confidence interval.
a
Change 0.2 10.4 -5.1 13.9 Calculated with the Student t test.
Difference -5.2 (-13.2 to 2.8) .196
by definition asymptomatic, subjects at baseline and after
NOTE. The values are expressed as means SD, except being on a GFD.
differences in the changes between the groups, which are
expressed as means with the 95% confidence interval.
a
Calculated with the Student t test. Other Clinical Evaluations
After 2 years, when the trial was completed, 92% of the
subjects reported adherence to the GFD, and 8% reported
in the gluten group. On intervention, a significant dietary transgressions; 85% expected to remain on the diet
improvement in Vh/CrD was seen after 1 year on a GFD in the future; 15% were not sure. Maintaining the GFD was
(Figure 1D), and the ratio also increased within the gluten considered “easy” by 5%, “goes by itself” by 67%, and
group when they started the diet. At baseline, mucosal “difficult” by 13%; 15% could not say. Finally, 58% expe-
CD3þ IELs were greater than the reference value in 90% rienced their celiac disease screening and diagnosis as
and dgþ IELs in all but one subject; differences in IEL positive or very positive, 42% were indifferent, and none
changes between the groups were not significant (Table 3). were negative.
The Vh/CrD was considered normal (>2.0) in 2 cases in
both groups at baseline (Table 4). Despite having morpho-
logically normal small-bowel mucosal villi, these 4 subjects Discussion
showed mucosal inflammation as measured by increased The results of this randomized study showed that
IELs; none of the study participants had completely normal screen-detected and even apparently asymptomatic EmA-
mucosa at baseline. The 2 subjects with normal Vh/CrD in positive patients benefit from a GFD as measured by
the GFD group evinced beneficial histologic, serologic, and extensive clinical, serologic, and histologic parameters.
clinical responses comparable with those with evident There was some previous evidence indicating improvement
villous damage. Results in the gluten group were inconsis- in the well being of screen-detected celiac disease patients
tent because the other subject experienced unfavorable re- on a GFD,10–14 and we showed this now by a vigorous
sponses while the other beneficial responses while on randomized approach. Here, the greatest differences be-
gluten (Table 4). Table 4 also shows examples of the tween the groups on dietary intervention could be seen in
symptom-specific GSRS total, diarrhea, and pain scores in 2, serology and in mucosal morphology. For ethical reasons noSeptember 2014 Diagnosis of Celiac Disease Without Biopsy 615
Table 4.Data on the 4 Subjects With Positive EmA but GSRS scores on GFD, suggest that the patients may in fact
Normal (>2.0) Vh/CrD at Baseline have accepted mild symptoms as normal and recognized
them as abnormal only later when on the diet. It is likely
GFD group Gluten group
that the changes would have been more evident in the
Patient 1 Patient 2 Patient 1 Patient 2 symptomatic subjects who were excluded here but
commonly are found by active screening.11,14 In clinical
Age, y 30 36 48 34 settings many screen-detected patients also may suffer from
Sex Female Female Female Male atypical symptoms not being recognized as celiac disease.13
EmA, titer Until now, active screening of celiac disease has been a
Baseline 1:500 1:5 1:50 1:5
After 1 year 1:100 Negative 1:100 Negative
subject of controversy. Because of the high prevalence and
TG2ab, U/L ambiguous clinical picture and existence of effective treat-
CLINICAL AT
Baseline 84.1 4.7 8.2 5.6 ment, screening of at-risk groups or even the whole popu-
After 1 year 7.6 0.0 19.5 0.0 lation has been suggested.7,8,13,25 Nevertheless, treatment
DGPab, U/L benefit in apparently asymptomatic patients has remained
Baseline 125 45 16 10 unsolved. Notwithstanding the known positive effects of a
After 1 year 24 8 65 12
GFD, it is expensive and socially isolating and may be
Vh/CrD
Baseline 3.4 2.6 3.1 2.2
detrimental to quality of life. Furthermore, availability of the
After 1 year 2.8 3.5 0.3 2.7 products is limited and they may have lower nutritional
CD3þIEL,a cells/mm epithelium value and palatability than their gluten-containing coun-
Baseline 79 95 173 81 terparts. Here, indeed, the SF-36 social functioning score
After 1 year 76 56 92 72 decreased in the GFD group. Then again, besides objective
GSRS,b total score serologic and histologic parameters, self-perceived GSRS
Baseline 2.1 1.9 2.5 1.8
scores and anxiety also improved and the majority of sub-
After 1 year 1.5 1.0 2.9 2.0
GSRS, diarrhea score jects showed excellent dietary adherence and were willing
Baseline 1.3 2.0 1.7 1.7 to continue on the diet, indicating that it was not considered
After 1 year 1.3 1.0 3.0 2.0 harmful. There also has been concern that obese celiac pa-
GSRS, pain score tients might gain more weight on a GFD26; however, the
Baseline 2.7 1.7 2.0 1.3 present and other recent results do not support this
After 1 year 1.7 1.0 1.3 1.7 concept.27,28 Furthermore, although not as apparent here,
PGWB,c total score
Baseline 117 102 104 102
there is evidence that screen-detected patients may have a
After 1 year 120 122 83 107 decreased quality of life and BMD that improves on a
VAS,d mm GFD.10–13 Nevertheless, besides the decrease in social
Baseline 91 81 72 91 functioning seen here, in some screen-detected patients the
After 1 year 94 96 46 89 celiac disease diagnosis may lead to increased anxiety and
health concerns.10 Given that unrecognized celiac disease
NOTE. Results are shown at baseline and after 1 year on a
may not necessarily increase the risk of malignancy or
GFD (GFD group) or on a normal, gluten-containing diet mortality,29–31 the consequences of possible screening must
(gluten group). be weighed carefully in advance on an individual basis.
a
Density of intraepithelial lymphocytes; reference value < 37 Furthermore, because the present study was conducted in
cells/mm epithelium. individuals belonging to an at-risk group, the question of
b
Higher scores indicate more severe self-perceived gastro- population-based mass screening remains a subject for
intestinal symptoms. future studies.
c
Higher scores indicate better self-perceived health-related
quality of life. As a result of increasing celiac disease screening, a
d
Higher scores indicate better self-perceived general health. substantial number of seropositive individuals manifest
with only mild enteropathy (ie, Marsh grades I–II).15 Thus
far, strict criteria with the demonstration of villous atrophy
(Marsh III) have been necessary to ensure a reliable diag-
subjects with evident symptoms were randomized and, in nosis of this lifelong and restrictive disorder. However, the
fact, the mean baseline quality of life was even better than modern biomarkers, particularly EmA, have shown almost
previously observed in healthy controls.10 Likewise, the 100% specificity for celiac disease.1 Furthermore, we
mean laboratory parameters and BMD were within normal previously showed that most false-positive cases with
range; one cannot expect major improvements in in- initially morphologically normal villi (Marsh I–II) eventu-
dividuals at such an early stage in celiac disease. Nonethe- ally will develop mucosal atrophy if they continue on
less, in favor of a GFD, there were also significant differences gluten.32 Moreover, a randomized trial showed that these
in the GSRS and quality-of-life scores. This randomized EmA-positive subjects already benefit from a GFD before
approach showed that subjects who thought they were villous atrophy (the end stage of the histologic damage)
asymptomatic experienced improvement in several objec- develops.15 Accordingly, the latest diagnostic criteria of
tive disease scores upon adopting a GFD. These findings, as celiac disease have begun to accept milder forms of en-
exemplified in Table 4 by a marked decrease in most of the teropathy as diagnostic in seropositive patients.17 These616 Kurppa et al Gastroenterology Vol. 147, No. 3
findings suggest that the hitherto used grouped classifica- Supplementary Material
tions are no longer optimal in the diagnosis of celiac dis- Note: To access the supplementary material accompanying
ease. Nevertheless, because serology and symptoms have this article, visit the online version of Gastroenterology at
been shown to be unreliable markers for the mucosal www.gastrojournal.org, and at http://dx.doi.org/10.1053/
improvement and dietary adherence in celiac disease,6 we j.gastro.2014.05.003.
considered it necessary to use histology as the primary
outcome in this study; this is likely even more important in
screen-detected subjects with mild clinical presentation. To
detect even minor changes in morphology, validated and References
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CLINICAL AT
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Author names in bold designate shared co-first authors.
serology and gastrointestinal symptoms. Am J Gastro-
enterol 2011;106:1333–1339. Received August 15, 2013. Accepted May 6, 2014.
26. Dickey W, Kearney N. Overweight in celiac disease: Reprint requests
prevalence, clinical characteristics, and effect of a gluten- Address requests for reprints to: Katri Kaukinen, MD, University of Tampere,
free diet. Am J Gastroenterol 2006;101:2356–2359. School of Medicine, FIN-33014, Tampere, Finland. e-mail: katri.kaukinen@uta.fi;
fax: (358) 3-3551-8402.
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The authors disclose no conflicts.
J Clin Gastroenterol 2010;44:267–271.
28. Ukkola A, Mäki M, Kurppa K, et al. Changes in body Funding
mass index on a gluten-free diet in coeliac disease: a This work was supported by the Academy of Finland Research Council for
Health, the Competitive Research Funding of the Pirkanmaa Hospital District
nationwide study. Eur J Intern Med 2012;23:384–388. (Grants 9R034 and 9R018), the Sigrid Juselius Foundation, the Finnish
29. Lohi S, Mäki M, Rissanen H, et al. Prognosis of unrecog- Foundation for Gastroenterological Research, the Yrjö Jahnsson Foundation,
the Finnish Medical Foundation, the Foundation for Pediatric Research and
nized coeliac disease as regards mortality: a population- the Finnish Celiac Society. The sponsors had no role in the contents of the
based cohort study. Ann Med 2009;41:508–515. article or the decision to submit the manuscript for publication.617.e1 Kurppa et al Gastroenterology Vol. 147, No. 3 Supplementary Figure 1. Enrollment, randomization, and follow-up evaluation of the study patients. *Exclusion criteria of the study were as follows: previous diagnosis of celiac disease, age younger than 18 years, evident clinical symptoms, dietary gluten restriction, severe contemporary illness, pregnancy, immunosuppressive medication, and study refusal. †One subject started a gluten-free diet soon after randomization, but was assigned to the gluten group according to an intention-to-treat principle. ‡The subjects remained on a gluten-free diet.
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