Francesco Valitutti

The anti-deamidated gliadin peptide antibodies unmask celiac disease in small children with chronic diarrhoea

OBJECTIVES To assess the usefulness of a new class of antibodies, the anti-deamidated gliadin peptides, in the diagnostic approach to children less than 2 years with suspected celiac disease. PATIENTS AND METHODS We investigated 40 children (median age: 16.8 months; age range: 4-24 months), with symptoms and signs of chronic enteropathy and high serum levels of conventional anti-gliadin antibodies, but normal values of anti-transglutaminase and anti-endomysial antibodies; all underwent measurement of anti-deamidated gliadin peptides serum levels, upper gastrointestinal endoscopy with biopsies and HLA typing; 40 subjects served as controls. RESULTS In 29 patients (group A) serum levels of anti-deamidated gliadin peptides were normal and duodenal histology showed a spectrum of abnormalities ranging from mucosal inflammatory infiltrates to villous damage (in almost all cases compatible with Marsh 1-to-2 lesions). All improved on a cows and soy milk free diet containing gluten. In 11 patients (group B) there were high serum levels of anti-deamidated gliadin peptides and histology showed features suggestive of celiac disease (Marsh 2-to-3 lesions) in all; furthermore, human leucocyte antigen typing was consistent with a celiac disease genetic pattern in all. Group B patients significantly improved on a gluten free diet containing cows and soy milk proteins. None of the control group was anti-deamidated gliadin peptides positive. CONCLUSIONS In children younger than 2 years with signs of chronic enteropathy and normal values of classical serum markers of celiac disease, the latter can be predicted by high serum levels of anti-deamidated gliadin peptides.

Autoimmune enteropathy in a 13-year-old celiac girl successfully treated with infliximab.

Autoimmune enteropathy (AIE) is a rare cause of small bowel villous atrophy, characterized by malabsorption, unresponsiveness to dietary restriction, circulating autoantibodies to enterocytes, and an overall predisposition to autoimmunity. Albeit mainly regarded as a disease of early childhood, several adult-onset AIE cases have been identified. This report describes for the first time the life-threatening clinical presentation and the management of overlapping AIE in a compliant-to-diet young celiac girl. A 13-year-old celiac girl was admitted because of vomiting, weight loss, diarrhea, hypoproteinemia, and neurological disturbances such as head tremors, vertical nystagmus, and lower limb hyperesthesia. Before this, she had always been compliant on a strict gluten-free diet and her medical history was unremarkable. The diagnosis of AIE was established on histologic findings and on the presence of antienterocyte antibodies. She was initially treated with high-dose Methylprednisolone and Azathioprine. However, only Infliximab proved itself as a highly effective tool for achieving clinical remission and restoring small bowel villous architecture.

Are ESPGHAN “Biopsy-Sparing” Guidelines for Celiac Disease also Suitable for Asymptomatic Patients?

OBJECTIVES:In 2012, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published novel guidelines on celiac disease (CD) diagnosis. Symptomatic children with serum anti-transglutaminase (anti-tTG) antibody levels ≥10 times upper limit of normal (ULN) could avoid duodenal biopsies after positive HLA test and serum anti-endomysial antibodies (EMAs). So far, both asymptomatic and symptomatic patients with anti-tTG titer <10 times ULN should undergo upper endoscopy with duodenal biopsies to confirm diagnosis. The aim of this study was to assess the accuracy of serological tests to diagnose CD in asymptomatic patients.METHODS:We retrospectively reviewed data of 286 patients (age range: 10 months to 17 years) with CD diagnosis based on elevated titer of anti-tTG, EMA positivity, and histology. All patients were distinguished between symptomatic and asymptomatic; histological lesions were graded according to the Marsh–Oberhuber (MO) criteria. Fisher exact test was applied to analyze both groups in terms of diagnostic reliability of serological markers.RESULTS:A total of 196 patients (68.53%) had anti-tTG titers ≥10 times ULN. Among them, a group of 156 patients (79.59%) also had symptoms suggestive of CD (“high-titer” symptomatic); of these, 142 patients (91.02%) showed severe lesion degree (3a, 3b, 3c MO). Conversely, 40 out of 196 patients (20.40%) were asymptomatic (“high-titer” asymptomatic) and 37 patients (92.5%) of them showed severe lesion degree (3a, 3b, 3c MO). No difference in histological damage was found between “high-titer” symptomatic and “high-titer” asymptomatic children (Fisher exact test, P=1.000).CONCLUSIONS:If confirmed in large multicenter prospective studies, the “biopsy-sparing” protocol seems to be applicable to both symptomatic and asymptomatic patients with anti-tTG titer ≥10 times ULN, positive EMA, and HLA-DQ2/DQ8.

Lack of clinical predictors for low mineral density in children with celiac disease

Objectives: Metabolic bone disease remains a significant and common complication of celiac disease (CD). Several studies have demonstrated low bone mineral density (BMD) at the time of CD diagnosis in both children and adults. Low BMD in children and adolescents is defined as an areal BMD <2 SD below the age-adjusted mean value (z score <−2 SD). The aim of the study was to evaluate the BMD in a pediatric population with CD at diagnosis and to correlate z score value, anti–tissue transglutaminase type 2 antibody (anti-tTG2) titer, symptoms, and Marsh-Oberhuber (MO) grading. Methods: We enrolled 99 patients with celiac disease (male 35, female 64) ages 4 to 15 years at the diagnosis. All of the patients had positive test results for anti-tTG2 antibodies and histological lesions graded according to MO classification, and underwent lumbar dual-energy x-ray absorptiometry. BMD was estimated by z score. Results: Low BMD (z score ⩽−2 SD) was found in 13 (13.13%) patients; 22 (22.22%) patients with CD showed −2 < z score ⩽ −1; −1 < z score < 0 was found in 41 (41.41%) patients. z score ≥ 0 was detected only in 23 (23.23%) patients with CD. Mean BMD value in patients with CD is z score −0.68. No correlations were found between z score value and anti-tTG2 titer (Spearman &rgr; 0.13), between z score value and MO degree (Spearman &rgr; −0.17), and between z score and symptoms (Spearman &rgr; −0.10). Conclusions: BMD of patients with CD at diagnosis does not seem to correlate with MO degree, anti-tTG2 titer, and symptoms. At the moment, we do not have clinical predictors for low mineral density in children with CD.

Exposure assessment to mycotoxins in gluten-free diet for celiac patients

Mycotoxins are low molecular weight secondary metabolites produced by certain strains of filamentous fungi such as Aspergillus, Penicillium and Fusarium, which attack crops in the field, and grow on foods also during storage under favorable conditions of temperature and humidity. Foods mainly contributing to the intake of mycotoxins with diet are cereals, maize being the most risky commodity due to the potential co-occurrence of more than one mycotoxin, this can be of particular concern especially for vulnerable group of population such as celiac patients that show increased maize-based products consumption. In this study the exposure of celiac patients to fumonisins (FBs) and zearalenone (ZON) has been assessed. The higher exposures, for all the matrices and for both the selected mycotoxins, were for children age group. The lower and upper bound exposure ranged between 348-582 ng/kg bw/day for FBs and 22-83 ng/kg bw/day for ZON; these values result well below the TDI for the selected mycotoxins, representing the 17-29% and 9-33% of the TDI set for FBs and ZON, respectively. Even considering the worst scenario the exposure values reported for children were lower, namely 1385 ng/kg bw/day for FBs and 237 ng/kg bw/day for ZON, than the corresponding toxicological thresholds.

Size and dynamics of mucosal and peripheral IL-17A+ T-cell pools in pediatric age, and their disturbance in celiac disease

Mucosal interleukin (IL)-17A–producing T cells contribute to protective antimicrobial responses and to epithelial barrier integrity; their role in celiac disease (CD) is debated. We analyzed the frequency and developmental dynamics of mucosal (intraepithelial lymphocytes (IEL)) and circulating (peripheral blood (PB)) IL-17A (T17) and/or interferon (IFN)-γ–producing (T1, T1/T17) T-cell populations in 86 pediatric controls and 116 age-matched CD patients upon phorbol myristate acetate/ionomycin or CD3/CD28 stimulation. T17 and T1/17 are physiologically present among IEL and PB populations, and their frequency is selectively and significantly reduced in CD IEL. The physiological age-dependent increase of Th17 IEL is also absent in CD, while IFN-γ–producing PB-T cells significantly accumulate with patients age. Finally, the amplitude of IL-17A+ and IFN-γ+ T-cell pools are significantly correlated in different individuals; this relationship only applies to CD4+ T cells in controls, while it involves also the CD4− counterpart in CD patients. In conclusion, both size and dynamics of mucosa-associated and circulating IL-17A+ T-cell pools are finely regulated in human pediatric subjects, and severely disturbed in CD. The impaired IL-17A+ IEL-T pool may negatively impact on epithelial barrier efficiency, and contribute to CD mucosa damage; the disturbed dynamics of circulating IL-17A+ and IFN-γ+ T-cell pools may be involved in the extraintestinal autoimmune manifestations associated with CD.

Cereal Consumption among Subjects with Celiac Disease: A Snapshot for Nutritional Considerations

Background: To our knowledge no study has focused on the pattern of cereal-based products (CBP) consumption among people with celiac disease (CD). Our study aimed at evaluating the dietary intake of CBP among patients with CD and comparing it with a control population. Methods: Eighty-two volunteers with CD and 77 non-CD volunteers enrolled throughout Italy were asked to register their consumption of CBP on specific diaries for three days. Results: CD patients’ median three-day intake of biscuits and crackers was higher compared to controls (65.8 g vs. 22.7 g and 44.7 g vs. 10.6 g, p < 0.05 respectively, Mann–Whitney test). A significant difference was observed also comparing the two groups for median three-day bread consumption, with the CD group consuming less bread than controls (109.5 g vs. 150.7 g, p < 0.05, Mann–Whitney test). When assessing regional and gender-related CBP consumption patterns, significantly higher rice consumption was found among CD women from Northern Italy compared to CD women from Central and Southern Italy (p = 0.006 and p = 0.002 respectively, Fisher’s exact test). No other significant differences were observed. Conclusions: Our results provide a snapshot of the overall consumption of CBP among Italian subjects with CD. Altogether, these data show that, despite minor differences, dietary consumption of CBP among CD patients is similar to the general population.

Pediatric Celiac Disease: Follow-Up in the Spotlight.

The follow-up of celiac disease (CD) is challenging due to the scarcity of published data and the lack of standardized evidence-based protocols. The worldwide frequency and methods of CD follow-up appear to be heavily influenced by expert opinions of the individual physicians who assess children with CD. The aim of this review was to summarize the available studies on CD follow-up in children. We conducted a literature search with the use of PubMed, Medline, and Embase (from 1900 to 15 December 2016) for terms relevant to this review, including CD, follow-up, dietary adherence or dietary compliance, nutrition, comorbidities, complications, and quality of life. The aims of follow-up are as follows: to ensure strict adherence to a gluten-free diet, to ensure nutritional adequacy, to improve quality of life, and to prevent disease complications. For the correct evaluation of children with CD at follow-up, a clinical and biochemical evaluation is necessary on a regular basis. It is advisable to assess compliance, nutrition, comorbidities, or possible complications once a year at the referral center. Laboratory tests might be useful for a thorough evaluation of any patient with CD to rule out a micronutrient deficiency (full blood count, ferritin, folic acid, vitamin B-6, and vitamin B-12) and possible cardiovascular risk factors (glucose, LDL cholesterol, triglycerides). Biochemical evaluation is essential when there are clinical problems and should be customized on the basis of the specific clinical suspicion. Associated autoimmune thyroiditis should also be screened for yearly by measuring thyroid-stimulating hormone and thyroid autoantibody concentrations, regardless of symptoms, because hypothyroidism is often subtle and methods for early treatment are available and desirable. Although evidence-based recommendations for follow-up of pediatric patients with CD have not yet been established, we advise a yearly follow-up visit as the safest approach.

Letter: atherosclerosis and coeliac disease – another feature of the changing paradigm?

SIRS, We welcome the paper by De Marchi et al. describing a possible increased risk of atherosclerosis in young adults with coeliac disease. The authors aimed to evaluate features of early atherosclerosis in 20 adults with coeliac disease (CD) at the time of diagnosis, and after 6–8 months of a gluten-free diet. All patients were studied for total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, C-reactive protein, plasma concentration of folic acid, vitamin B12 and homocysteine; moreover, study participants underwent colour doppler ultrasound measurement of carotid intima-media thickness (IMT) and endothelium-dependent dilatation (EDD) evaluation of the humeral artery. According to their results, coeliac patients at diagnosis showed an increased IMT and a decreased EDD, suggesting early vascular dysfunction; surprisingly, both these parameters returned within the normal ranges after only 6–8 months on a gluten-free diet. However, some limitations of the study should be taken into account. First, the authors clearly stated that the study had a small size and lacked a power calculation, both features requiring a high degree of caution when interpreting clinical data. Moreover, some doubts arise with regard to the control group: the choice of health providers as controls does not seem appropriate, as it has been demonstrated that this group might be scarcely representative of the overall population and introduces a selection bias in observational studies. Secondly, the excellent rate of mucosal healing after only 6–8 months of strict gluten avoidance in the coeliac group has not been so commonly reported, especially among adults. It could be speculated that these patients perhaps had a relatively recent onset of disease, thus questioning whether the study findings are generalisable for the whole Italian coeliac population prior to diagnosis, who may theoretically have a better lipid profile – regardless of the inflammation markers – and both normal IMT and EDD. In conclusion, the possibility of an increased risk of early atherosclerosis in young adults with coeliac disease underscores once more the ‘changing paradigm’ of coeliac disease, previously labelled as a mere enteropathy with malabsorption and nowadays fully considered as a systemic immune disorder. However, these findings need to be confirmed in larger and unbiased studies.

C. difficile and celiac disease: the “difficile” to tell association

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