Seronegative Villous Atrophy in Children

Abstract

Objectives: Villous atrophy (VA) is not pathognomonic of celiac disease (CD). We aimed at reporting distribution, clinical, and immunohistochemical features of seronegative VA (SNVA) in a pediatric population. Methods: We retrospectively collected data from patients who underwent intestinal biopsies between 2010 and 2017 and showed VA without serum CD-associated autoantibodies. Marsh-Oberhuber grading was used. Density of intraepithelial lymphocytes (IELs) expressing CD3 or TCRγδ+ receptor and of lamina propria CD25+ cells was assessed by immunohistochemistry. Intestinal deposits of anti-tissue tranglutaminase2 (anti-TG2) were also investigated by double immunofluorescence. Results: Over a 7-year period, 64 out of 1282 patients with VA had negative serum CD serology. Diagnoses were: inflammatory bowel diseases (IBD) (21/64), Gastro-Esophageal Reflux Disease (GERD) (12/64), food allergy (8/64), infections (7/64, of which 3 HIV infections), immune deficiency (3/64), short bowel syndrome (3/64), congenital diarrhea (2/64), other/inconclusive diagnosis (8/64). Forty-four, 15, and 5 showed Marsh 3a, 3b, and 3c lesion, respectively. The latter category included 2 patients with Crohn disease, 2 with immunodeficiencies, 1 with lymphohistiocytosis. In 41/46 (89%) patients, mononuclear CD25+ cells were above the cut-off, indicating mucosal inflammation but only 18/46 (39%) had IELs and TCRγδ + IELs above limits of normality. In 10 of 46 (22%) patients, a positive immunofluorescence indicated the presence of anti-TG2 mucosal antibodies. Conclusions: SNVA is not rare representing up to 5% of the cases of VA. Most patients have a Marsh 3a lesion. Immunohistochemical analysis may be helpful in excluding CD, whereas the finding of mucosal anti-TG2, particularly with a weak staining, shows no absolute specificity for CD.

The Role of the Gluten-Free Diet in the Management of Seronegative Enteropathy

“…Autoimmune and immune-mediated diseases Autoimmune enteropathy [16] Crohn's disease [17] Collagenous sprue [18] Common variable immune deficiency (CVID) [19] Infectious or probably infectious diseases Giardia lamblia infection [20] Helicobacter pylori infection [17] Post-viral enteropathy [21] Tuberculosis [22] Small intestinal bacterial overgrowth [23] HIV-enteropathy [24] Whipple disease [25] Tropical sprue [26] Iatrogenic causes Medication (angiotensin II receptor blockers [27], mefenamic acid [28], azathioprine [29], methotrexate [30], mycophenolate mofetil [31]) Chemotherapy [32] Radiotherapy [33] Graft versus host disease [34] Inflammatory disease Peptic duodenitis [35] Eosinophilic gastroenteritis [36] Neoplastic Small intestinal lymphoma [37] Other Amyloidosis [38] Malnutrition [39] Food allergy (cow's milk, soy) [20] According to the few studies available on the subject, the frequency of occurrence of SNVA varies considerably, particularly between adult and child populations. CD is diagnosed in 28-45% of adults with SNVA [5,13,40]; among the remainder, the most common causes of non-CD SNVA are believed to be inter alia medication-related enteropathy and infectious causes, including giardiasis and small intestinal bacterial overgrowth, peptic duodenitis, and collagenous sprue [5,13,40,41].…”

“…CD is diagnosed in 28-45% of adults with SNVA [5,13,40]; among the remainder, the most common causes of non-CD SNVA are believed to be inter alia medication-related enteropathy and infectious causes, including giardiasis and small intestinal bacterial overgrowth, peptic duodenitis, and collagenous sprue [5,13,40,41]. In the paediatric population, the most common causes of SNVA are believed to be inflammatory bowel disease and infections, such as Giardia lamblia and Helicobacter pylori [12,17]. In up to 1/3 of patients, the cause of SNVA cannot be determined [5,12,13,17,40,41].…”

“…In the paediatric population, the most common causes of SNVA are believed to be inflammatory bowel disease and infections, such as Giardia lamblia and Helicobacter pylori [12,17]. In up to 1/3 of patients, the cause of SNVA cannot be determined [5,12,13,17,40,41]. The main causes of SNVA in children and adults are summarised in Table 3.…”

“…In addition, the presence of dense mucosal eosinophilia, often with sheets of eosinophils and usually not accompanied by epithelial lymphocytosis, especially in children may indicate food allergy or Giardia lamblia infection [20,51]. On rare occasions, some grade of villous atrophy with prominent neutrophilic inflammation, but with a normal lymphocyte count, may be seen in peptic duodenitis in both Helicobacter pylori-positive and -negative patients; this is often accompanied by gastric metaplasia and Brunner's gland hyperplasia [17].…”