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Celiac Disease With Mild Enteropathy Is Not Mild Disease
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:253–258
Celiac Disease With Mild Enteropathy Is Not Mild Disease BARBARA ZANINI,* FRANCESCA CASELANI,* ALBERTO MAGNI,* DANIELE TURINI,* ALICE FERRARESI,* FRANCESCO LANZAROTTO,* VINCENZO VILLANACCI,‡ NICE CARABELLESE,§ CHIARA RICCI,* and ALBERTO LANZINI* *Gastroenterology Unit, ‡Histopathology Service, §Immunology Unit, University of Brescia, Brescia, Italy
BACKGROUND & AIMS:
Patients with celiac disease have varying degrees of damage to the small intestinal mucosa, ranging from lymphocytic duodenosis with normal villous structure to severe villous atrophy. We assessed whether the severity of mucosal lesions was associated with clinical and laboratory features of celiac disease.
METHODS:
We compared demographic, clinical, and laboratory characteristics among patients with celiac disease who were classified based on the severity of duodenal lesions. We analyzed data from 1408 adult patients seen consecutively at a tertiary referral center since 1990. Patients were classified as having villous atrophy (n ⴝ 1249) or as having mild enteropathy (n ⴝ 159) in the presence or absence of villous atrophy.
RESULTS:
Similar percentages of patients with villous atrophy, vs mild enteropathy, experienced weight loss (17% vs 17%), gastrointestinal manifestations (70% vs 70%), extraintestinal manifestations (66% vs 57%), and other associated conditions (19% vs 23%). More patients with villous atrophy than patients with mild enteropathy developed osteopenia or osteoporosis (22% vs 5%; P ⴝ .0005). Greater percentages of patients with villous atrophy than those with mild enteropathy also had anemia (42% vs 29%; P ⴝ .002), folate deficiency (75% vs 64%; P ⴝ .02), hypocholesterolemia (7% vs 2%; P ⴝ .02), hypocalcemia (26% vs 13%; P ⴝ .004), or hyperparathyroidism (45% vs 29%; P ⴝ .004).
CONCLUSIONS:
Although osteopenia, osteoporosis, and alterations in laboratory parameters are prevalent among patients with celiac disease with mild enteropathy, they are more prevalent and severe in those with villous atrophy. The prevalence of associated conditions is similar between these groups. These results indicate that celiac disease with mild enteropathy is not mild disease, but requires treatment with a gluten-free diet.
Keywords: Clinical Presentation; Bone Mineral Density; Food Allergy; Disease Progression.
See editorial on page 259.
T
he spectrum of histologic lesions of the small bowel in celiac disease (CD) has been described by Marsh1 as a continuum. The classic lesion is characterized by villous atrophy (Marsh III), usually graded A–C according to severity, and with milder lesions characterized by normal villous structure and by an increased number of intraepithelial lymphocytes (IELs, Marsh I) with crypt hyperplasia (Marsh II). Only 10%2 to 16%3 of Marsh I–II lesions, also defined as grade A in the classification by Corazza et al,4 are attributable to CD when accompanied by positive CDrelated serology. Accurate identification and counting of IELs is critically important5 and a count of 25 IELs/100 epithelial cells is the likely cut-off value of normalcy.6,7 At present, there is limited information on the natural history of this condition.8 –12 In prospective trials, deterioration of mucosal villous architecture has been reported to occur in 10 of 10 adult patients,10 and in 7 of 811 and in 12 of 36 pediatric patients12 continuing a gluten-containing diet for 1 year or
longer, and a “modestly increased” risk of death13 also has been reported in a Swedish nationwide study, confirming earlier observations.14,15 Although these observations and the gluten dependency of symptoms10,12 advocate treating these patients with a gluten-free diet (GFD), this practice is not universally adopted16 and the decision to treat with a GFD is likely to rely mainly on the clinical severity of their condition. Although it has been reported in small series of patients that mild enteropathy may be clinically relevant,11,17–21 there is little information on how they compare with patients with villous atrophy. The aim of this study was to analyze the clinical, laboratory, and genetic characteristics of a large cohort of adult celiac patients with mild enteropathy compared with patients with villous atrophy. We looked at differences in these 2 cohorts in Abbreviations used in this paper: BMI, body mass index; CD, celiac disease; GFD, gluten-free diet; IEL, intraepithelial lymphocytes; t-TG, tissue transglutaminase. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2012.09.027
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detail22 on H&E-stained sections and, after 2004, by using immunohistochemistry for CD3 identification (Dako, Glostrup, Denmark) (Figure 1). IELs were counted after counting at least 300 epithelial cells on both sides of 5 villous bodies, using a cut-off value for normality of 40 IELs/100 epithelial cells as classically described by Marsh,1 and after 2002 by using a cut-off value of 25 IELs/100 epithelial cells,6 a criteria adopted by Corazza et al4 for the definition of mild enteropathy (grade A).4 Ninety-five percent of endoscopic biopsy specimens were reviewed by the same experienced pathologist (V.V.). Tissue transglutaminase (t-TG) antibodies were measured by the enzyme-linked immunosorbent assay procedure (Eu t-Tg; Eurospital, Trieste, Italy; or Celikey; Phadia, Uppsala, Sweden). Anti-endomysial antibodies were detected by indirect immunofluorescence using monkey esophagus tissue as substrate (Antiendomysium; Eurospital). Antigliadin antibodies were measured using Antigliatest (Eurospital) when anti-endomysial antibodies and t-TG antibodies were not yet available. Information extracted from the database included demographic characteristics, CD-related serology, HLA DQ types and genotypes, reason for medical evaluation (either symptoms, family screening, screening in associated diseases, or incidental diagnosis), clinical characteristics (general, gastrointestinal, extraintestinal manifestations), and presence of associated diseases.23 Serum samples were collected at the time of endoscopic biopsy in most cases and always within 2 months before biopsy, and serologic parameters were measured using standard automated laboratory methods in use at our institution. Bone mineral density was measured as a standard procedure adopted for a limited period of time using dual-energy X-ray absorptiometry on the lumbar-sacral spine and on the femoral neck of consecutive patients. Figure 1. Duodenal histology in patients with (A) mild enteropathy (Marsh II) and with (B and C) villous atrophy CD (Marsh IIIa and IIIc). Sections stained with H&E and with anti-CD3 antibodies are shown on the left and right side of each panel.
2 ways: first, by measuring the difference in absolute values for clinical and laboratory parameters, and, second, by measuring the proportion of patients with abnormal clinical or laboratory findings.
Methods We extracted information for this cohort study from a prospectively maintained database of 1741 CD patients older than age 14 referred from January 1990 to June 2010 to our CD clinic at the Spedali Civili (Brescia, Italy). Two cohorts of patients were identified and were defined as having villous atrophy for patients with duodenal villous atrophy (Marsh III at duodenal histology) and as having mild enteropathy for patients with normal villous structure, increased IEL count (Marsh I), and crypt hyperplasia (Marsh II). All patients in both cohorts tested positive according to CD-related serology. According to our institutional protocol, a minimum of 4 endoscopic biopsy specimens were obtained in the duodenum and specimens were oriented mucosal-side up on a cellulose filter. Duodenal histology was classified according to Marsh.1 Pathology assessment was performed as reported elsewhere in
Figure 2. Identification of the study cohorts according to patient selection criteria.
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CHARACTERISTICS OF MILD ENTEROPATHY CD
Expression of Results and Statistical Analysis Body mass index (BMI) was classified according to the 4 World Health Organization categories.24 Osteopenia was defined as a t score of ⫺1 to ⫺2.5 and osteoporosis was defined as a t score of less than 2.5.25 DQA1-DQB1 genotypes were grouped into 5 groups, based on a hierarchy of relative risk of CD as described by Margaritte-Jeannin et al.26 Laboratory values were expressed both as absolute values and as a percentage of values outside the normal range for our laboratory. Results of t-TG antibodies and of osteocalcin were expressed as an index (observed value/upper limit of normal as suggested by the manufacturer) to uniform values obtained with different commercial kits. Categoric variables were expressed as numbers and proportions, and continuous variables were expressed as mean ⫾ standard deviation. Differences between the 2 cohorts were tested for continuous variables using a t test for unpaired samples, and differences for categoric variables were tested using the chi-square test or the Fisher exact test as appropriate. A P value less than .05 was considered significant to reject the null hypothesis. The statistical analysis was performed using the GraphPad Prism 5 statistical package (GraphPad Software, San Diego, CA).
Ethics The study protocol was approved by our institution’s ethical committee on December 13, 2011.
Results Of 1741 total CD patients in our database, 1408 met the selection criteria, 1249 (89%) were in the villous atrophy Table 1. Anthropometric Genetic Characteristics and Distribution of Positive CD-Related Serology in Patients in the Villous Atrophy and Mild Enteropathy Cohorts
Variable
Villous atrophy, n (%)
Mild enteropathy, n (%)
Female sex Age, y, mean ⫾ SD BMI ⬍18.5 (%) 18.5–25 (%) ⬎25 (%) Mean ⫾ SD Genetic features HLA DQ2 HLA DQ8 HLA DQ2 ⫹ DQ8 HLA genotypes groups G1 G2 G3 G4 G5 Serology t-TG⫹ EMA⫹ AGA⫹
1249 (89) 912 (73) 35.3 ⫾ 13.0 n ⫽ 967 169 (18) 681 (70) 117 (11) 21.3 ⫾ 3.4 n ⫽ 140 128 (91) 7 (5) 5 (4) n ⫽ 124 41 (33) 24 (19) 37 (30) 9 (7) 13 (10) 1249 830 (64) 730 (58) 68 (5)
159 (11) 113 (71) 36.2 ⫾ 13.6 n ⫽ 119 22 (19) 70 (59) 27 (23) 22.2 ⫾ 4.0 n ⫽ 33 29 (88) 3 (9) 1 (3) n ⫽ 23 4 (17) 7 (30) 7 (30) 0 5 (21) 159 116 (73) 98 (62) 5 (3)
n
AGA, antigliadin antibodies; EMA, antiendomysial antibodies.
P value
NS NS NS .01 .002 .007 NS
NS
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Table 2. Clinical Manifestations in Celiac Patients in the Villous Atrophy and Mild Enteropathy Cohorts
Variable n General manifestations One or more 1 2 Weight loss Fatigue Gastrointestinal manifestations One or more 1 2 3 Diarrhea Abdominal pain Abdominal distention Nausea and vomiting Aphthous stomatitis Dyspepsia Constipation Extraintestinal manifestations One or more 1 2 3 Dermatitis herpetiformis Anemia Hypertransaminasemia Osteopenia-osteoporosis Hypocalcemia Joint pain arthritis Others Associated diseases One or more 1 2 3 Thyroid disfunction Type 1 diabetes IgA deficit Autoimmune disorders Others
Villous atrophy, n (%)
Mild enteropathy, n (%)
1227
155
372 (30) 343 (92) 29 (8) 279 (23) 122 (10)
39 (25) 36 (92) 3 (8) 33 (21) 9 (6)
NS NS NS NS NS
834 (70) 365 (44) 294 (35) 175 (21) 510 (42) 375 (31) 217 (18) 70 (6) 57 (5) 148 (12) 100 (8)
108 (70) 44 (41) 38 (35) 26 (24) 63 (41) 55 (35) 25 (16) 14 (9) 12 (8) 13 (8) 16 (10)
NS NS NS NS NS NS NS NS NS NS NS
814 (66) 559 (69) 192 (24) 63 (7) 138 (12) 520 (42) 143 (12) 270 (22) 57 (5) 34 (3) 67 (6)
88 (57) 68 (77) 18 (20) 2 (3) 25 (16) 40 (26) 10 (6) 7 (5) 7 (5) 6 (4) 15 (10)
NS NS NS NS NS ⬍.0001 NS .0005 NS NS .045
227 (19) 210 (92) 16 (7) 1 (1) 165 (11) 38 (3) 16 (1) 6 (⬍1) 19 (2)
36 (23) 31 (86) 3 (8) 2 (6) 25 (13) 8 (4) 4 (2) 1 (⬍1) 5 (3)
NS NS NS NS NS NS NS NS NS
P value
IgA, immunoglobulin A.
cohort, and 159 (11%) were in the mild enteropathy cohort (Figure 2). The proportion of patients with mild enteropathy increased from 2% in 1991–1995, to 10% in 1996 –2000, to 12% in 2001– 2005 when the cut-off value for IELs was greater than 40, and to 15% thereafter with a lower cut-off value of more than 25 IELs.
Demographic Characteristics There was no statistical difference in the sex and age distribution between the 2 cohorts (Table 1). BMI was significantly lower in the classic than in the mild enteropathy cohort, and BMI distribution in the 3 main World Health Organization classes revealed a higher prevalence of overweight patients in
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the mild enteropathy cohort. The serum t-TG antibody index was higher (5.5 ⫾ 6.0 vs 2.7 ⫾ 3.9; P ⬍ .0001) in patients in the villous atrophy cohort than in patients in the mild enteropathy cohort, respectively. Results of HLA genotype were available for 173 patients. The majority of patients carried the DQ2 genotype (91% vs 88%) in the villous atrophy and mild enteropathy cohorts, and genotype distribution among the 5 HLA-related risk groups also was similar.
Reason for Medical Evaluation and Clinical Characteristics The presence of symptoms was the main reason that lead to clinical investigation in both cohorts (82% vs 83%), and the proportion of patients investigated for family screening (12% vs 9%) and for screening in associated diseases (3% vs 6%), or identified incidentally at endoscopy (3% vs 2%), was similar in the villous atrophy and in the mild enteropathy cohorts, respectively (Table 2). Weight loss accounted for 17% of cases at presentation in both cohorts (Table 2). Seventy percent of patients complained of at least 1 gastrointestinal manifestation, with diarrhea accounting for 42% vs 41% of cases in the villous atrophy and in the mild enteropathy cohorts, respectively. The prevalence of extraintestinal manifestations was, as a whole, similar in the 2 cohorts, but patients in the villous atrophy cohort presented more often with anemia (42% vs 26%; P ⬍ 00.1) and with osteopenia-osteoporosis (22% vs 5%) than patients in the mild enteropathy cohort. The prevalence of associated diseases was similar and thyroid dysfunction and type 1 diabetes mellitus were the most prevalent associated diseases in both cohorts (Table 2). Fifty-three patients (4%) in the villous atrophy and 7 patients (4%) in the mild enteropathy cohorts had no general, gastrointestinal, or extraintestinal manifestations, and no associated
Table 3. Laboratory Variables in Celiac Patients in the Villous Atrophy and Mild Enteropathy Cohorts Variable
Villous atrophy, n, mean ⫾ SD
Mild enteropathy, n, mean ⫾ SD
P value
Hemoglobin, 1093, 12.6 ⫾ 1.9 146, 13.0 ⫾ 1.9 .02 mg/dL Ferritin, ng/mL 892, 32.3 ⫾ 65.6 116, 49.9 ⫾ 74.8 .0001 B12 vitamin, 798, 352 ⫾ 206 101, 393 ⫾ 212 .01 pg/mL Folates, ng/mL 801, 3.8 ⫾ 3.2 101, 4.8 ⫾ 3.4 ⬍.0001 Total serum 939, 6.9 ⫾ 0.6 120, 6.9 ⫾ 0.5 NS proteins, g/dL Albumin, g/dL 930, 4.2 ⫾ 0.5 120, 4.4 ⫾ 0.4 .005 Calcium, mg/dL 844, 8.9 ⫾ 0.7 105, 9.0 ⫾ 0.5 .02 PTH index 740, 1.3 ⫾ 1.3 93, 0.8 ⫾ 0.5 .0009 D vitamin, ng/mL 752, 20.9 ⫾ 12.6 98, 20.6 ⫾ 11.5 NS Bone ALP, U/L 347, 49.1 ⫾ 49.1 39, 31.1 ⫾ 13.6 .0006 Osteocalcin index 347, 1.3 ⫾ 1.5 34, 0.9 ⫾ 0.5 NS Deoxypyridinoline, 344, 7.7 ⫾ 5.4 38, 6.0 ⫾ 2.3 NS nmol/L/mmol/ L Cr Ntx, nmol/L 243, 72.7 ⫾ 80.8 31, 44.6 ⫾ 21.6 .006 Homocysteine, 175, 15.5 ⫾ 8.8 24, 13.4 ⫾ 4.6 NS mol/L Cr, creatinine; Ntx, N-telopeptide of type I collagen; PTH, parathormone.
Table 4. Proportion of Celiac Patients With Abnormal Laboratory Values in the Villous Atrophy and Mild Enteropathy Cohorts
Variable Blood profile Anemia, ⬍lln Microcytosis, ⬎lln Macrocytosis, ⬍uln Piastrinosis, ⬎uln Malabsorption parameters Ferritin, ⬍lln Vitamin B12, ⬍ lln Folates, ⬍lln Serum proteins, ⬍lln Albumin, ⬍lln Triglycerides, ⬍lln Total cholesterol, ⬍lln Bone-related parameters Calcium, ⬍lln PTH, ⬎uln Vitamin D, ⬍lln Bone ALP, ⬎uln Osteocalcin, ⬎uln Deoxypiridinoline, ⬎uln Ntx, ⬎uln Hepatic parameters Alanine aminotransferase, ⬎uln ␥-glutamyltransferase, ⬎uln ALP, ⬎uln Homocysteine, ⬎uln
Villous atrophy,
Mild enteropathy,
n/d (%)
n/d (%)
461/1093 (42) 281/1080 (26) 38/1080 (4) 114/1080 (11)
42/146 (29) 26/146 (18) 1/146 (⬍1) 4/145 (3)
.002 .01 .01 .005
459/892 (51) 57/798 (7) 601/801 (75) 56/939 (6) 32/930 (3) 144/927 (16) 69/954 (7)
45/116 (39) 2/101 (2) 65/101 (64) 4/120 (3) 2/120 (1) 31/117 (27) 2/118 (2)
.01 .04 .02 NS NS .003 .02
221/844 (26) 331/740 (45) 154/752 (20) 101/342 (30) 181/347 (52) 156/342 (46) 80/243 (33)
14/105 (13) 27/93 (29) 20/98 (20) 4/38 (11) 13/34 (38) 15/36 (42) 4/31 (13)
.004 .004 NS .01 NS NS .02
162/939 (17)
9/112 (8)
25/762 (3)
5/102 (5)
NS
170/830 (20) 84/175 (48)
6/101 (6) 12/24 (50)
.0004 NS
P value
.01
ALP, alkaline phosphatase; d, denominator (total population); lln, lower limit of normal; n, numerator (number of patients with an altered parameter); PTH, parathormone; uln, upper limit of normal.
disease at the time of diagnosis. These patients were identified at family screening in 37 of 53 and 5 of 7 cases, and at incidental endoscopic finding in 16 of 53 and 2 of 7 cases in the villous atrophy and mild enteropathy CD cohorts, respectively.
Laboratory Parameters Absolute values. Hemoglobin, ferritin, vitamin B12, folate, and albumin serum levels were significantly lower in patients in the villous atrophy cohort than in those in the mild enteropathy cohort (Table 3). Moreover, serum parameters of bone remodeling were altered more severely in the villous atrophy than in the mild enteropathy cohorts as indicated by significantly lower values of calcium and higher values of parathormone, bone alkaline phosphatase, and N-telopeptide of type I collagen. Proportion of pathologic values. The proportion of patients with pathologic values of laboratory parameters in the villous atrophy and in the mild enteropathy cohorts is detailed in Table 4 and was as follows: 42% vs 29% (P ⫽ .002) for hemoglobin, 11% vs 3% (P ⫽ .005) for platelets, 51% vs 39% (P ⫽ .01) for ferritin, 7% vs 2% (P ⫽ .04) for vitamin B12, and 75% vs 64% (P ⫽ .002) for folates, respectively.
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Bone and Mineral Density Results for bone mineral density were available for 244 consecutive patients, 222 in the villous atrophy cohort and 22 in the mild enteropathy cohort. Lumbar-sacral T score was ⫺1.12 ⫾ 1.27 vs 0.47 ⫾ 1.21 (P ⫽ .01), femoral T score was ⫺0.95 ⫾ 1.07 vs 0.41 ⫾ 0.83 (P ⫽ .02), lumbar-sacral Z score was ⫺0.79 ⫾ 1.15 vs 0.23 ⫾ 1.03 (P ⫽ .02); and femoral Z score was ⫺0.71 ⫾ 0.97 vs 0.31 ⫾ 0.92 (P ⫽ .09) in the villous atrophy vs mild enteropathy cohorts, respectively.
Discussion Our results, based on large cohorts of patients, clearly indicate that extraintestinal manifestations and laboratory alterations are more prevalent and more severe in patients with villous atrophy than in those with mild enteropathy, and that the prevalence of associated diseases is similar in the 2 conditions. Interestingly, as many as 23% of CD patients with mild enteropathy were overweight at presentation as indicated by a BMI greater than 25, a proportion that was double that observed in patients with villous atrophy. This high prevalence of overweight patients in CD is consistent with previous reports21,27–29 and is worrying because although some patients may reduce BMI on a GFD,28,29 there is a risk that the high content of refined sugars and fat of the GFD30 may increase body weight further31 in these obesity-prone subjects. No difference was observed between the mild enteropathy and the villous atrophy cohorts for the prevalence of CD-associated diseases, which probably is a reflection of the common autoimmune pathogenesis. Alteration of laboratory parameters was particularly evident for the parameter expression of intestinal malabsorption (Tables 3 and 4), a phenomenon reasonably reflecting a more severe impairment of the intestinal absorptive function in patients with villous atrophy. Osteopenia and osteoporosis, well-known extraintestinal manifestations of CD32 that may even precede other symptoms of malabsorption,33 also were more prevalent in patients with villous atrophy. From a clinical perspective, however, celiac patients with mild enteropathy cannot be distinguished from those with villous atrophy on the basis of laboratory characteristics, with the one possible exception of the t-TG antibody index. We recently reported,34 as have others,35 that a very high serum t-TG antibody index predicts villous atrophy with very high specificity. Based on the observations reported earlier, it is clear that mild enteropathy is not a mild disease as indicated by the high prevalence of weight loss, anemia, hyperparathyroidism, T and Z scores less than 1, or folate deficiency. Furthermore, our results indicate that CD with mild enteropathy is accompanied by associated diseases in a large proportion of patients (23%) similar to that observed in patients with villous atrophy (19%). These latter observations suggest that celiac patients with mild enteropathy deserve treatment with GFD on clinical grounds, independently of any consideration of the natural history of the disease. The improvement of symptoms during a GFD reported in prospective studies10,12 has suggested gluten dependency of clinical manifestations in mild enteropathy. Whether mild enteropathy represents an early stage of CD or a separate entity is still unclear. Studies on genetic predisposition suggest that mild enteropathy may represent, from an immunogenic point of view, a separate entity by carrying a
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lighter HLA-related risk than patients with villous atrophy,36,37 a phenomenon confirmed as a trend in our study. Environmental factors, including differences in the amount of gluten in the diet,38 also potentially may play a role. It is of interest to note that the diagnosis of mild enteropathy CD increased in our clinic from 2% to 15% in 2 decades. Increased CD awareness and availability of highly sensitive serologic tests for CD screening has been reasonably advocated as a likely explanation.10 Furthermore, the prevalence of mild enteropathy CD is likely to be underestimated given the relatively low sensitivity of serologic testing in patients with mild histologic lesions.39 Our study had strengths and weakness. The main strengths were the large number of patients of both cohorts, and that all patients were studied according to the same clinical, laboratory, and histologic protocol. A weakness was that we had no information on factors that may have affected the severity of histologic lesions in CD, in particular the amount of gluten in the diet and the genetic background that was assessed only in a minority of patients. In our opinion, these 2 points deserve specific testing in future research. In conclusion, our study indicates that there is a gradient of clinical severity that parallels histologic severity in CD. CD with mild enteropathy is not, however, a mild disease because the prevalence of associated conditions and of alterations of laboratory parameters is high, although lower than in CD with villous atrophy. These observations support the practice of treating patients with mild enteropathy with GFD. The outcome of GFD in mild enteropathy patients, however, needs to be assessed by specific studies. References 1. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology 1992;102:330 –354. 2. Kakar S, Nehra V, Murray JA, et al. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol 2003;98:2027–2033. 3. Aziz I, Evans KE, Hopper AD, et al. A prospective study into the aetiology of lymphocytic duodenosis. Aliment Pharmacol Ther 2010;32:1392–1397. 4. Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin Gastroenterol Hepatol 2007;5:838 – 843. 5. Järvinen TT, Kaukinen K, Laurila K, et al. Intraepithelial lymphocytes in celiac disease. Am J Gastroenterol 2003;98:1332– 1337. 6. Hayat M, Cairns A, Dixon MF, et al. Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol 2002;55:393–394. 7. Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112–119. 8. Collin P, Helin H, Mäki M, et al. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small-bowel biopsy findings. Scand J Gastroenterol 1993;28:595–598. 9. Kaukinen K, Collin P, Holm K, et al. Small-bowel mucosal inflammation in reticulin or gliadin antibody-positive patients without villous atrophy. Scand J Gastroenterol 1998;33:944 –949. 10. Kurppa K, Collin P, Viljamaa M, et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology 2009;136:816 – 823.
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27. Dickey W, Kearney N. Overweight in celiac disease: prevalence, clinical characteristics, and effect of a gluten-free diet. Am J Gastroenterol 2006;101:2356 –2359. 28. Cheng J, Brar PS, Lee AR, et al. Body mass index in celiac disease: beneficial effect of a gluten-free diet. J Clin Gastroenterol 2010;44:267–271. 29. Ukkola A, Mäki M, Kurppa K, et al. Changes in body mass index on a gluten-free diet in coeliac disease: a nationwide study. Eur J Intern Med 2012;23:384 –388. 30. Wild D, Robins GG, Burley VJ, et al. Evidence of high sugar intake, and low fibre and mineral intake, in the gluten-free diet. Aliment Pharmacol Ther 2010;32:573–581. 31. Kabbani TA, Goldberg A, Kelly CP, et al. Body mass index and the risk of obesity in coeliac disease treated with the gluten-free diet. Aliment Pharmacol Ther 2012;35:723–729. 32. Bernstein CN, Leslie WD, Leboff MS. AGA technical review on osteoporosis in gastrointestinal diseases. Gastroenterology 2003;124:795– 841. 33. Mazure R, Vazquez H, Gonzalez D, et al. Bone mineral affection in asymptomatic adult patients with celiac disease. Am J Gastroenterol 1994;89:2130 –2134. 34. Zanini B, Magni A, Caselani F, et al. High tissue-transglutaminase antibody level predicts small intestinal villous atrophy in adult patients at high risk of celiac disease. Dig Liver Dis 2012;44: 280 –285. 35. Hill PG, Holmes GK. Coeliac disease: a biopsy is not always necessary for diagnosis. Aliment Pharmacol Ther 2008;27:572– 577. 36. Sperandeo MP, Tosco A, Izzo V, et al. Potential celiac patients: a model of celiac disease pathogenesis. PLoS One 2011;6: e21281. 37. Schirru E, Jores RD, Cicotto L, et al. High frequency of low-risk human leukocyte antigen class II genotypes in latent celiac disease. Hum Immunol 2011;72:179 –182. 38. Wahab PJ, Crusius JB, Meijer JW, et al. Gluten challenge in borderline gluten-sensitive enteropathy. Am J Gastroenterol 2001;96:1464 –1469. 39. Rashtak S, Ettore MW, Homburger HA, et al. Comparative usefulness of deamidated gliadin antibodies in the diagnosis of celiac disease. Clin Gastroenterol Hepatol 2008;6:426 – 432.
Reprint requests Address requests for reprints to: Alberto Lanzini, MD, PhD, Gastroenterology Unit, University of Brescia, Piazzale Spedali Civili 1, 25100 Brescia, Italy. e-mail: [email protected]; fax: (39) 030396011. Conflicts of interest The authors disclose no conflicts.
Celiac Disease With Mild Enteropathy Is Not Mild Disease BARBARA ZANINI,* FRANCESCA CASELANI,* ALBERTO MAGNI,* DANIELE TURINI,* ALICE FERRARESI,* FRANCESCO LANZAROTTO,* VINCENZO VILLANACCI,‡ NICE CARABELLESE,§ CHIARA RICCI,* and ALBERTO LANZINI* *Gastroenterology Unit, ‡Histopathology Service, §Immunology Unit, University of Brescia, Brescia, Italy
BACKGROUND & AIMS:
Patients with celiac disease have varying degrees of damage to the small intestinal mucosa, ranging from lymphocytic duodenosis with normal villous structure to severe villous atrophy. We assessed whether the severity of mucosal lesions was associated with clinical and laboratory features of celiac disease.
METHODS:
We compared demographic, clinical, and laboratory characteristics among patients with celiac disease who were classified based on the severity of duodenal lesions. We analyzed data from 1408 adult patients seen consecutively at a tertiary referral center since 1990. Patients were classified as having villous atrophy (n ⴝ 1249) or as having mild enteropathy (n ⴝ 159) in the presence or absence of villous atrophy.
RESULTS:
Similar percentages of patients with villous atrophy, vs mild enteropathy, experienced weight loss (17% vs 17%), gastrointestinal manifestations (70% vs 70%), extraintestinal manifestations (66% vs 57%), and other associated conditions (19% vs 23%). More patients with villous atrophy than patients with mild enteropathy developed osteopenia or osteoporosis (22% vs 5%; P ⴝ .0005). Greater percentages of patients with villous atrophy than those with mild enteropathy also had anemia (42% vs 29%; P ⴝ .002), folate deficiency (75% vs 64%; P ⴝ .02), hypocholesterolemia (7% vs 2%; P ⴝ .02), hypocalcemia (26% vs 13%; P ⴝ .004), or hyperparathyroidism (45% vs 29%; P ⴝ .004).
CONCLUSIONS:
Although osteopenia, osteoporosis, and alterations in laboratory parameters are prevalent among patients with celiac disease with mild enteropathy, they are more prevalent and severe in those with villous atrophy. The prevalence of associated conditions is similar between these groups. These results indicate that celiac disease with mild enteropathy is not mild disease, but requires treatment with a gluten-free diet.
Keywords: Clinical Presentation; Bone Mineral Density; Food Allergy; Disease Progression.
See editorial on page 259.
T
he spectrum of histologic lesions of the small bowel in celiac disease (CD) has been described by Marsh1 as a continuum. The classic lesion is characterized by villous atrophy (Marsh III), usually graded A–C according to severity, and with milder lesions characterized by normal villous structure and by an increased number of intraepithelial lymphocytes (IELs, Marsh I) with crypt hyperplasia (Marsh II). Only 10%2 to 16%3 of Marsh I–II lesions, also defined as grade A in the classification by Corazza et al,4 are attributable to CD when accompanied by positive CDrelated serology. Accurate identification and counting of IELs is critically important5 and a count of 25 IELs/100 epithelial cells is the likely cut-off value of normalcy.6,7 At present, there is limited information on the natural history of this condition.8 –12 In prospective trials, deterioration of mucosal villous architecture has been reported to occur in 10 of 10 adult patients,10 and in 7 of 811 and in 12 of 36 pediatric patients12 continuing a gluten-containing diet for 1 year or
longer, and a “modestly increased” risk of death13 also has been reported in a Swedish nationwide study, confirming earlier observations.14,15 Although these observations and the gluten dependency of symptoms10,12 advocate treating these patients with a gluten-free diet (GFD), this practice is not universally adopted16 and the decision to treat with a GFD is likely to rely mainly on the clinical severity of their condition. Although it has been reported in small series of patients that mild enteropathy may be clinically relevant,11,17–21 there is little information on how they compare with patients with villous atrophy. The aim of this study was to analyze the clinical, laboratory, and genetic characteristics of a large cohort of adult celiac patients with mild enteropathy compared with patients with villous atrophy. We looked at differences in these 2 cohorts in Abbreviations used in this paper: BMI, body mass index; CD, celiac disease; GFD, gluten-free diet; IEL, intraepithelial lymphocytes; t-TG, tissue transglutaminase. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2012.09.027
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detail22 on H&E-stained sections and, after 2004, by using immunohistochemistry for CD3 identification (Dako, Glostrup, Denmark) (Figure 1). IELs were counted after counting at least 300 epithelial cells on both sides of 5 villous bodies, using a cut-off value for normality of 40 IELs/100 epithelial cells as classically described by Marsh,1 and after 2002 by using a cut-off value of 25 IELs/100 epithelial cells,6 a criteria adopted by Corazza et al4 for the definition of mild enteropathy (grade A).4 Ninety-five percent of endoscopic biopsy specimens were reviewed by the same experienced pathologist (V.V.). Tissue transglutaminase (t-TG) antibodies were measured by the enzyme-linked immunosorbent assay procedure (Eu t-Tg; Eurospital, Trieste, Italy; or Celikey; Phadia, Uppsala, Sweden). Anti-endomysial antibodies were detected by indirect immunofluorescence using monkey esophagus tissue as substrate (Antiendomysium; Eurospital). Antigliadin antibodies were measured using Antigliatest (Eurospital) when anti-endomysial antibodies and t-TG antibodies were not yet available. Information extracted from the database included demographic characteristics, CD-related serology, HLA DQ types and genotypes, reason for medical evaluation (either symptoms, family screening, screening in associated diseases, or incidental diagnosis), clinical characteristics (general, gastrointestinal, extraintestinal manifestations), and presence of associated diseases.23 Serum samples were collected at the time of endoscopic biopsy in most cases and always within 2 months before biopsy, and serologic parameters were measured using standard automated laboratory methods in use at our institution. Bone mineral density was measured as a standard procedure adopted for a limited period of time using dual-energy X-ray absorptiometry on the lumbar-sacral spine and on the femoral neck of consecutive patients. Figure 1. Duodenal histology in patients with (A) mild enteropathy (Marsh II) and with (B and C) villous atrophy CD (Marsh IIIa and IIIc). Sections stained with H&E and with anti-CD3 antibodies are shown on the left and right side of each panel.
2 ways: first, by measuring the difference in absolute values for clinical and laboratory parameters, and, second, by measuring the proportion of patients with abnormal clinical or laboratory findings.
Methods We extracted information for this cohort study from a prospectively maintained database of 1741 CD patients older than age 14 referred from January 1990 to June 2010 to our CD clinic at the Spedali Civili (Brescia, Italy). Two cohorts of patients were identified and were defined as having villous atrophy for patients with duodenal villous atrophy (Marsh III at duodenal histology) and as having mild enteropathy for patients with normal villous structure, increased IEL count (Marsh I), and crypt hyperplasia (Marsh II). All patients in both cohorts tested positive according to CD-related serology. According to our institutional protocol, a minimum of 4 endoscopic biopsy specimens were obtained in the duodenum and specimens were oriented mucosal-side up on a cellulose filter. Duodenal histology was classified according to Marsh.1 Pathology assessment was performed as reported elsewhere in
Figure 2. Identification of the study cohorts according to patient selection criteria.
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CHARACTERISTICS OF MILD ENTEROPATHY CD
Expression of Results and Statistical Analysis Body mass index (BMI) was classified according to the 4 World Health Organization categories.24 Osteopenia was defined as a t score of ⫺1 to ⫺2.5 and osteoporosis was defined as a t score of less than 2.5.25 DQA1-DQB1 genotypes were grouped into 5 groups, based on a hierarchy of relative risk of CD as described by Margaritte-Jeannin et al.26 Laboratory values were expressed both as absolute values and as a percentage of values outside the normal range for our laboratory. Results of t-TG antibodies and of osteocalcin were expressed as an index (observed value/upper limit of normal as suggested by the manufacturer) to uniform values obtained with different commercial kits. Categoric variables were expressed as numbers and proportions, and continuous variables were expressed as mean ⫾ standard deviation. Differences between the 2 cohorts were tested for continuous variables using a t test for unpaired samples, and differences for categoric variables were tested using the chi-square test or the Fisher exact test as appropriate. A P value less than .05 was considered significant to reject the null hypothesis. The statistical analysis was performed using the GraphPad Prism 5 statistical package (GraphPad Software, San Diego, CA).
Ethics The study protocol was approved by our institution’s ethical committee on December 13, 2011.
Results Of 1741 total CD patients in our database, 1408 met the selection criteria, 1249 (89%) were in the villous atrophy Table 1. Anthropometric Genetic Characteristics and Distribution of Positive CD-Related Serology in Patients in the Villous Atrophy and Mild Enteropathy Cohorts
Variable
Villous atrophy, n (%)
Mild enteropathy, n (%)
Female sex Age, y, mean ⫾ SD BMI ⬍18.5 (%) 18.5–25 (%) ⬎25 (%) Mean ⫾ SD Genetic features HLA DQ2 HLA DQ8 HLA DQ2 ⫹ DQ8 HLA genotypes groups G1 G2 G3 G4 G5 Serology t-TG⫹ EMA⫹ AGA⫹
1249 (89) 912 (73) 35.3 ⫾ 13.0 n ⫽ 967 169 (18) 681 (70) 117 (11) 21.3 ⫾ 3.4 n ⫽ 140 128 (91) 7 (5) 5 (4) n ⫽ 124 41 (33) 24 (19) 37 (30) 9 (7) 13 (10) 1249 830 (64) 730 (58) 68 (5)
159 (11) 113 (71) 36.2 ⫾ 13.6 n ⫽ 119 22 (19) 70 (59) 27 (23) 22.2 ⫾ 4.0 n ⫽ 33 29 (88) 3 (9) 1 (3) n ⫽ 23 4 (17) 7 (30) 7 (30) 0 5 (21) 159 116 (73) 98 (62) 5 (3)
n
AGA, antigliadin antibodies; EMA, antiendomysial antibodies.
P value
NS NS NS .01 .002 .007 NS
NS
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Table 2. Clinical Manifestations in Celiac Patients in the Villous Atrophy and Mild Enteropathy Cohorts
Variable n General manifestations One or more 1 2 Weight loss Fatigue Gastrointestinal manifestations One or more 1 2 3 Diarrhea Abdominal pain Abdominal distention Nausea and vomiting Aphthous stomatitis Dyspepsia Constipation Extraintestinal manifestations One or more 1 2 3 Dermatitis herpetiformis Anemia Hypertransaminasemia Osteopenia-osteoporosis Hypocalcemia Joint pain arthritis Others Associated diseases One or more 1 2 3 Thyroid disfunction Type 1 diabetes IgA deficit Autoimmune disorders Others
Villous atrophy, n (%)
Mild enteropathy, n (%)
1227
155
372 (30) 343 (92) 29 (8) 279 (23) 122 (10)
39 (25) 36 (92) 3 (8) 33 (21) 9 (6)
NS NS NS NS NS
834 (70) 365 (44) 294 (35) 175 (21) 510 (42) 375 (31) 217 (18) 70 (6) 57 (5) 148 (12) 100 (8)
108 (70) 44 (41) 38 (35) 26 (24) 63 (41) 55 (35) 25 (16) 14 (9) 12 (8) 13 (8) 16 (10)
NS NS NS NS NS NS NS NS NS NS NS
814 (66) 559 (69) 192 (24) 63 (7) 138 (12) 520 (42) 143 (12) 270 (22) 57 (5) 34 (3) 67 (6)
88 (57) 68 (77) 18 (20) 2 (3) 25 (16) 40 (26) 10 (6) 7 (5) 7 (5) 6 (4) 15 (10)
NS NS NS NS NS ⬍.0001 NS .0005 NS NS .045
227 (19) 210 (92) 16 (7) 1 (1) 165 (11) 38 (3) 16 (1) 6 (⬍1) 19 (2)
36 (23) 31 (86) 3 (8) 2 (6) 25 (13) 8 (4) 4 (2) 1 (⬍1) 5 (3)
NS NS NS NS NS NS NS NS NS
P value
IgA, immunoglobulin A.
cohort, and 159 (11%) were in the mild enteropathy cohort (Figure 2). The proportion of patients with mild enteropathy increased from 2% in 1991–1995, to 10% in 1996 –2000, to 12% in 2001– 2005 when the cut-off value for IELs was greater than 40, and to 15% thereafter with a lower cut-off value of more than 25 IELs.
Demographic Characteristics There was no statistical difference in the sex and age distribution between the 2 cohorts (Table 1). BMI was significantly lower in the classic than in the mild enteropathy cohort, and BMI distribution in the 3 main World Health Organization classes revealed a higher prevalence of overweight patients in
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the mild enteropathy cohort. The serum t-TG antibody index was higher (5.5 ⫾ 6.0 vs 2.7 ⫾ 3.9; P ⬍ .0001) in patients in the villous atrophy cohort than in patients in the mild enteropathy cohort, respectively. Results of HLA genotype were available for 173 patients. The majority of patients carried the DQ2 genotype (91% vs 88%) in the villous atrophy and mild enteropathy cohorts, and genotype distribution among the 5 HLA-related risk groups also was similar.
Reason for Medical Evaluation and Clinical Characteristics The presence of symptoms was the main reason that lead to clinical investigation in both cohorts (82% vs 83%), and the proportion of patients investigated for family screening (12% vs 9%) and for screening in associated diseases (3% vs 6%), or identified incidentally at endoscopy (3% vs 2%), was similar in the villous atrophy and in the mild enteropathy cohorts, respectively (Table 2). Weight loss accounted for 17% of cases at presentation in both cohorts (Table 2). Seventy percent of patients complained of at least 1 gastrointestinal manifestation, with diarrhea accounting for 42% vs 41% of cases in the villous atrophy and in the mild enteropathy cohorts, respectively. The prevalence of extraintestinal manifestations was, as a whole, similar in the 2 cohorts, but patients in the villous atrophy cohort presented more often with anemia (42% vs 26%; P ⬍ 00.1) and with osteopenia-osteoporosis (22% vs 5%) than patients in the mild enteropathy cohort. The prevalence of associated diseases was similar and thyroid dysfunction and type 1 diabetes mellitus were the most prevalent associated diseases in both cohorts (Table 2). Fifty-three patients (4%) in the villous atrophy and 7 patients (4%) in the mild enteropathy cohorts had no general, gastrointestinal, or extraintestinal manifestations, and no associated
Table 3. Laboratory Variables in Celiac Patients in the Villous Atrophy and Mild Enteropathy Cohorts Variable
Villous atrophy, n, mean ⫾ SD
Mild enteropathy, n, mean ⫾ SD
P value
Hemoglobin, 1093, 12.6 ⫾ 1.9 146, 13.0 ⫾ 1.9 .02 mg/dL Ferritin, ng/mL 892, 32.3 ⫾ 65.6 116, 49.9 ⫾ 74.8 .0001 B12 vitamin, 798, 352 ⫾ 206 101, 393 ⫾ 212 .01 pg/mL Folates, ng/mL 801, 3.8 ⫾ 3.2 101, 4.8 ⫾ 3.4 ⬍.0001 Total serum 939, 6.9 ⫾ 0.6 120, 6.9 ⫾ 0.5 NS proteins, g/dL Albumin, g/dL 930, 4.2 ⫾ 0.5 120, 4.4 ⫾ 0.4 .005 Calcium, mg/dL 844, 8.9 ⫾ 0.7 105, 9.0 ⫾ 0.5 .02 PTH index 740, 1.3 ⫾ 1.3 93, 0.8 ⫾ 0.5 .0009 D vitamin, ng/mL 752, 20.9 ⫾ 12.6 98, 20.6 ⫾ 11.5 NS Bone ALP, U/L 347, 49.1 ⫾ 49.1 39, 31.1 ⫾ 13.6 .0006 Osteocalcin index 347, 1.3 ⫾ 1.5 34, 0.9 ⫾ 0.5 NS Deoxypyridinoline, 344, 7.7 ⫾ 5.4 38, 6.0 ⫾ 2.3 NS nmol/L/mmol/ L Cr Ntx, nmol/L 243, 72.7 ⫾ 80.8 31, 44.6 ⫾ 21.6 .006 Homocysteine, 175, 15.5 ⫾ 8.8 24, 13.4 ⫾ 4.6 NS mol/L Cr, creatinine; Ntx, N-telopeptide of type I collagen; PTH, parathormone.
Table 4. Proportion of Celiac Patients With Abnormal Laboratory Values in the Villous Atrophy and Mild Enteropathy Cohorts
Variable Blood profile Anemia, ⬍lln Microcytosis, ⬎lln Macrocytosis, ⬍uln Piastrinosis, ⬎uln Malabsorption parameters Ferritin, ⬍lln Vitamin B12, ⬍ lln Folates, ⬍lln Serum proteins, ⬍lln Albumin, ⬍lln Triglycerides, ⬍lln Total cholesterol, ⬍lln Bone-related parameters Calcium, ⬍lln PTH, ⬎uln Vitamin D, ⬍lln Bone ALP, ⬎uln Osteocalcin, ⬎uln Deoxypiridinoline, ⬎uln Ntx, ⬎uln Hepatic parameters Alanine aminotransferase, ⬎uln ␥-glutamyltransferase, ⬎uln ALP, ⬎uln Homocysteine, ⬎uln
Villous atrophy,
Mild enteropathy,
n/d (%)
n/d (%)
461/1093 (42) 281/1080 (26) 38/1080 (4) 114/1080 (11)
42/146 (29) 26/146 (18) 1/146 (⬍1) 4/145 (3)
.002 .01 .01 .005
459/892 (51) 57/798 (7) 601/801 (75) 56/939 (6) 32/930 (3) 144/927 (16) 69/954 (7)
45/116 (39) 2/101 (2) 65/101 (64) 4/120 (3) 2/120 (1) 31/117 (27) 2/118 (2)
.01 .04 .02 NS NS .003 .02
221/844 (26) 331/740 (45) 154/752 (20) 101/342 (30) 181/347 (52) 156/342 (46) 80/243 (33)
14/105 (13) 27/93 (29) 20/98 (20) 4/38 (11) 13/34 (38) 15/36 (42) 4/31 (13)
.004 .004 NS .01 NS NS .02
162/939 (17)
9/112 (8)
25/762 (3)
5/102 (5)
NS
170/830 (20) 84/175 (48)
6/101 (6) 12/24 (50)
.0004 NS
P value
.01
ALP, alkaline phosphatase; d, denominator (total population); lln, lower limit of normal; n, numerator (number of patients with an altered parameter); PTH, parathormone; uln, upper limit of normal.
disease at the time of diagnosis. These patients were identified at family screening in 37 of 53 and 5 of 7 cases, and at incidental endoscopic finding in 16 of 53 and 2 of 7 cases in the villous atrophy and mild enteropathy CD cohorts, respectively.
Laboratory Parameters Absolute values. Hemoglobin, ferritin, vitamin B12, folate, and albumin serum levels were significantly lower in patients in the villous atrophy cohort than in those in the mild enteropathy cohort (Table 3). Moreover, serum parameters of bone remodeling were altered more severely in the villous atrophy than in the mild enteropathy cohorts as indicated by significantly lower values of calcium and higher values of parathormone, bone alkaline phosphatase, and N-telopeptide of type I collagen. Proportion of pathologic values. The proportion of patients with pathologic values of laboratory parameters in the villous atrophy and in the mild enteropathy cohorts is detailed in Table 4 and was as follows: 42% vs 29% (P ⫽ .002) for hemoglobin, 11% vs 3% (P ⫽ .005) for platelets, 51% vs 39% (P ⫽ .01) for ferritin, 7% vs 2% (P ⫽ .04) for vitamin B12, and 75% vs 64% (P ⫽ .002) for folates, respectively.
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Bone and Mineral Density Results for bone mineral density were available for 244 consecutive patients, 222 in the villous atrophy cohort and 22 in the mild enteropathy cohort. Lumbar-sacral T score was ⫺1.12 ⫾ 1.27 vs 0.47 ⫾ 1.21 (P ⫽ .01), femoral T score was ⫺0.95 ⫾ 1.07 vs 0.41 ⫾ 0.83 (P ⫽ .02), lumbar-sacral Z score was ⫺0.79 ⫾ 1.15 vs 0.23 ⫾ 1.03 (P ⫽ .02); and femoral Z score was ⫺0.71 ⫾ 0.97 vs 0.31 ⫾ 0.92 (P ⫽ .09) in the villous atrophy vs mild enteropathy cohorts, respectively.
Discussion Our results, based on large cohorts of patients, clearly indicate that extraintestinal manifestations and laboratory alterations are more prevalent and more severe in patients with villous atrophy than in those with mild enteropathy, and that the prevalence of associated diseases is similar in the 2 conditions. Interestingly, as many as 23% of CD patients with mild enteropathy were overweight at presentation as indicated by a BMI greater than 25, a proportion that was double that observed in patients with villous atrophy. This high prevalence of overweight patients in CD is consistent with previous reports21,27–29 and is worrying because although some patients may reduce BMI on a GFD,28,29 there is a risk that the high content of refined sugars and fat of the GFD30 may increase body weight further31 in these obesity-prone subjects. No difference was observed between the mild enteropathy and the villous atrophy cohorts for the prevalence of CD-associated diseases, which probably is a reflection of the common autoimmune pathogenesis. Alteration of laboratory parameters was particularly evident for the parameter expression of intestinal malabsorption (Tables 3 and 4), a phenomenon reasonably reflecting a more severe impairment of the intestinal absorptive function in patients with villous atrophy. Osteopenia and osteoporosis, well-known extraintestinal manifestations of CD32 that may even precede other symptoms of malabsorption,33 also were more prevalent in patients with villous atrophy. From a clinical perspective, however, celiac patients with mild enteropathy cannot be distinguished from those with villous atrophy on the basis of laboratory characteristics, with the one possible exception of the t-TG antibody index. We recently reported,34 as have others,35 that a very high serum t-TG antibody index predicts villous atrophy with very high specificity. Based on the observations reported earlier, it is clear that mild enteropathy is not a mild disease as indicated by the high prevalence of weight loss, anemia, hyperparathyroidism, T and Z scores less than 1, or folate deficiency. Furthermore, our results indicate that CD with mild enteropathy is accompanied by associated diseases in a large proportion of patients (23%) similar to that observed in patients with villous atrophy (19%). These latter observations suggest that celiac patients with mild enteropathy deserve treatment with GFD on clinical grounds, independently of any consideration of the natural history of the disease. The improvement of symptoms during a GFD reported in prospective studies10,12 has suggested gluten dependency of clinical manifestations in mild enteropathy. Whether mild enteropathy represents an early stage of CD or a separate entity is still unclear. Studies on genetic predisposition suggest that mild enteropathy may represent, from an immunogenic point of view, a separate entity by carrying a
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lighter HLA-related risk than patients with villous atrophy,36,37 a phenomenon confirmed as a trend in our study. Environmental factors, including differences in the amount of gluten in the diet,38 also potentially may play a role. It is of interest to note that the diagnosis of mild enteropathy CD increased in our clinic from 2% to 15% in 2 decades. Increased CD awareness and availability of highly sensitive serologic tests for CD screening has been reasonably advocated as a likely explanation.10 Furthermore, the prevalence of mild enteropathy CD is likely to be underestimated given the relatively low sensitivity of serologic testing in patients with mild histologic lesions.39 Our study had strengths and weakness. The main strengths were the large number of patients of both cohorts, and that all patients were studied according to the same clinical, laboratory, and histologic protocol. A weakness was that we had no information on factors that may have affected the severity of histologic lesions in CD, in particular the amount of gluten in the diet and the genetic background that was assessed only in a minority of patients. In our opinion, these 2 points deserve specific testing in future research. In conclusion, our study indicates that there is a gradient of clinical severity that parallels histologic severity in CD. CD with mild enteropathy is not, however, a mild disease because the prevalence of associated conditions and of alterations of laboratory parameters is high, although lower than in CD with villous atrophy. These observations support the practice of treating patients with mild enteropathy with GFD. The outcome of GFD in mild enteropathy patients, however, needs to be assessed by specific studies. References 1. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology 1992;102:330 –354. 2. Kakar S, Nehra V, Murray JA, et al. Significance of intraepithelial lymphocytosis in small bowel biopsy samples with normal mucosal architecture. Am J Gastroenterol 2003;98:2027–2033. 3. Aziz I, Evans KE, Hopper AD, et al. A prospective study into the aetiology of lymphocytic duodenosis. Aliment Pharmacol Ther 2010;32:1392–1397. 4. Corazza GR, Villanacci V, Zambelli C, et al. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin Gastroenterol Hepatol 2007;5:838 – 843. 5. Järvinen TT, Kaukinen K, Laurila K, et al. Intraepithelial lymphocytes in celiac disease. Am J Gastroenterol 2003;98:1332– 1337. 6. Hayat M, Cairns A, Dixon MF, et al. Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol 2002;55:393–394. 7. Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112–119. 8. Collin P, Helin H, Mäki M, et al. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small-bowel biopsy findings. Scand J Gastroenterol 1993;28:595–598. 9. Kaukinen K, Collin P, Holm K, et al. Small-bowel mucosal inflammation in reticulin or gliadin antibody-positive patients without villous atrophy. Scand J Gastroenterol 1998;33:944 –949. 10. Kurppa K, Collin P, Viljamaa M, et al. Diagnosing mild enteropathy celiac disease: a randomized, controlled clinical study. Gastroenterology 2009;136:816 – 823.
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Reprint requests Address requests for reprints to: Alberto Lanzini, MD, PhD, Gastroenterology Unit, University of Brescia, Piazzale Spedali Civili 1, 25100 Brescia, Italy. e-mail: [email protected]; fax: (39) 030396011. Conflicts of interest The authors disclose no conflicts.