What Is Known
- The prevalence of celiac disease is on the rise.
- Celiac disease has a wide range of presenting features depending on the stage of the disease and the age of the patient at the time of diagnosis.
- Diagnosing celiac disease is important to prevent serious potential complications.
What Is New
- The presenting features of celiac disease and the age of diagnosis differ from the original descriptions of the disease.
- Abdominal pain and constipation are the most frequent presenting features for celiac disease in western New York.
- Disaccharidase deficiency correlates with Marsh score.
Celiac disease (CD) is a lifelong autoimmune disease (AID) in genetically susceptible individuals. If left untreated, it has been associated with serious complications such as impaired nutritional status and growth, secondary to malabsorption and chronic inflammation (1).
CD is associated with an increased risk of AIDs such as thyroid, liver, and skin diseases; mental health issues; others. An increased risk of malignancy has been described in untreated CD. More recent data, however, are ambiguous. It shows the highest risk for an increase in lymphoproliferative disease, especially if there is a persistence of villous atrophy (2,3). Strict adherence to gluten-free diet is shown to reduce this risk (4).
With the development of sensitive serologic tests, safe endoscopy, and increased awareness of primary care providers, more children are diagnosed as having CD. The aim of this study is to evaluate the pattern of the presentation of CD in pediatric patients during 10 years in western New York and to compare this presentation to the historical descriptions of the disease.
The study was approved by the Children and Youth Institutional Review Board of the State University of New York at Buffalo. Both sexes from all ethnic backgrounds of newly diagnosed patients with CD with biopsy-proven CD up to 18 years of age seen at the Digestive Disease and Nutrition Center from January 2003 to March 2013 were included. Patients without a biopsy-proven diagnosis of CD were excluded.
A retrospective chart review of 177 pediatric patients diagnosed as having CD was undertaken. Two patients were totally excluded because of incomplete records. Ten patients could not be included in the analysis of presenting features because of incomplete data. Thus, 165 patients were included in the analysis for presenting features.
The following data were extracted from the records for analysis: date of diagnosis, age at diagnosis, weight, height, Body Mass Index (BMI), BMI z score, the presenting features, serum immunoglobulin (Ig) A level, tissue transglutaminase (tTG) IgA and IgG, anti-endomysial antibody IgA (EMA) and anti-gliadin antibody IgA and IgG level, tissue disaccharidase assay (DA), and Marsh score at the time of diagnosis. Data were statistically analyzed by a biostatistician using SAS 9.3 (Cary, NC) software.
By protocol in our unit, each endoscopist obtains the following samples: 1 to 2 biopsies for DA from the second portion of the duodenum. Four biopsies from the second part of the duodenum and 2 from the bulb for histopathology. In addition, we also obtain gastric antral and body biopsies and esophageal biopsies. All of the biopsies are interpreted by a board-certified pathologist. In the case of CD, the small bowel biopsies are histologically assessed using modified Marsh classification as 0 = normal small bowel, 1 = normal villi with increased intraepithelial lymphocytes (>25 lymphocytes per 100 epithelial cells), 2 = normal villi with crypt hyperplasia, 3A = mild villous atrophy, 3B = subtotal villous atrophy, and 3C = total villous atrophy (2). In this study, we have included patients with CD with histopathologic Marsh score of 2 and higher.
Table 1 shows the characteristics of the 175 patients diagnosed as having CD during the study's 10-year period. Note that the average age at diagnosis was 10.68 years, and >95% of patients were white, non-Hispanic. All of the patients had elevated serum tTG IgA antibody level except 2 patients (1.1%). One of the patients had elevated EMA level only, and the other one had negative celiac serology. Both patients were stage Marsh 3A.
Excluding the 10 patients with no recorded presenting feature, the 165 patients had multiple presenting features (Fig. 1). The 2 most frequent ones are abdominal pain (52.7%) and constipation (38.9%).
Using Pearson correlation coefficient we found a negative correlation between Marsh histopathologic score and DA of sucrase, maltase, and palatinase (P < 0.05) but not with lactase (Fig. 2). We found no correlation between Marsh histopathologic score and serum tTG IgA level at the time of diagnosis and no correlation between tissue DA and serum tTG IgA level. Using Student t test, we found no correlation between the presenting feature and tTG IgA level, presenting feature and Marsh histopathologic score, serum tTG IgA level and DA, or between the age and the presenting feature.
Quantitation of disaccharidases is not necessary for the diagnosis of CD. At our institution, we have elected to measure disaccharidases on all of the patients who undergo a small bowel biopsy. Table 2 shows that more than two thirds of the patients had pandisaccharidase deficiency and >90% of patients had lactase deficiency at the time of diagnosis.
CD is thought to be caused by a failure of oral tolerance toward prolamins, which represent the alcohol-soluble fractions of cereals and are called gliadins (wheat), hordeins (barley), secalins (rye), and avenins (oat). Human leukocyte antigen class DQ2/8 mediates antigen presentation of toxic cereal peptides by dendritic cells of the lamina propria to gluten-sensitive mucosal T cells (5–7). The only available treatment is lifelong strict adherence to a gluten-free diet (8).
The prevalence of CD is estimated to range between 0.3% and 1.3% among Americans. This has increased during the recent years (9–14). The increased recognition of the wide distribution of CD, the low threshold for screening, and improved screening tools has led to diagnosing patients who would not have been diagnosed in the past (15–17). Unlike the “classic” description of CD in which most children are diagnosed in the first 2 years of life with diarrhea and failure to thrive (FTT), we found the average age at diagnosis to be much higher (10.7 years), and most of them had “nonclassic” presentation.
CD has a wide range of presenting features depending on the stage of the disease and the age of the patient at the time of diagnosis. It has been noted that diarrhea, FTT, and abdominal pain are more common in early ages, whereas systemic symptoms such as, fatigue, thyroid disease, osteoporosis, neurologic manifestations, anemia, dermatitis herpetiformis, and elevated liver enzymes occur more commonly in adolescents (8,18).
In this study, we did not find any subject <1 year of age at the time of diagnosis. We found that abdominal pain was the most common presenting feature of patients (52.7%). The second most frequent feature was constipation, whereas, features generally associated with CD, such as diarrhea, failure to grow, and weight loss, ranked lower. This observation leads us to suggest that in western New York, at least, the pattern of presenting features and perhaps even the natural history of the disease may be different from the initial descriptions in the early 20th century. There are various factors that could influence this. First and foremost, public awareness, dietary habits, rapid westernization globally, and the easy availability of highly processed food materials may contribute to exposure to the gliadin antigens. It is possible that in our patients, the long-term outcome and the risks associated with CD may differ from those of the original descriptions of patients with CD.
The fact that we could not identify a correlation between the serum tTG-IgA level and Marsh score suggests that tTG-IgA levels may not accurately reflect the disease severity.
Disaccharidases are membrane-bound glycoproteins, which function to hydrolyze carbohydrate and include lactase, sucrase, maltase, and palatinase. Their maximal expression is at the lower and mid villus and is decreased at the villus tips and the crypts (4,5). A high proportion of our patients had ≥1 disaccharidase deficiency (92.5%). The strong correlation between Marsh score and disaccharidase deficiency we found can be explained by the degree of damage to the intestinal brush border.
The explanation for these findings could be that with increasing damage to the intestinal brush border, (and thus higher Marsh score) disaccharidase levels decrease. The fact that lactase did not follow this pattern could be explained by the high prevalence of lactase deficiency in the general population (6–9), or lactase could be so severely affected that even at lower Marsh scores lactase was decreased. This latter explanation is in agreement with what has been found by other groups (19).
This study is unique in that it describes the presenting features for CD during a 10-year period, and it makes correlations among CD parameters that have not been previously described. This single-center analysis and the findings may not be entirely applicable to other geographic areas or a different genetic background.
Children newly diagnosed as having CD in western New York presented most frequently with abdominal pain and constipation and were older at the time of diagnosis than those described in the classical presentation of CD. We speculate that our patients may have different long-term natural history and different risk factors than the original descriptions of patients with CD.
The authors thank Changxing Ma, PhD, for assistance in the statistical analysis of the data.
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