Wheat-related disorders reviewed: making a grain of sense

Abstract

Wheat-related disorders have become a growing area of clinical and scientific interest and can be categorized broadly as: autoimmune-mediated; allergic; and non-autoimmune/non-allergic conditions. Non-celiac gluten sensitivity (NCGS) and non-celiac wheat sensitivity (NCWS) present on this spectrum as disorders associated with adverse gastrointestinal and extra-intestinal manifestations following exposure to gluten and/or other wheat-related constituents. NCGS/NCWS is increasingly considered in patients with unexplained symptoms after the exclusions of celiac disease and wheat allergy. As objective diagnostic data and specific biomarkers are lacking, response to a gluten-free/wheat-free diet can confirm the presence of NCGS/NCWS. An association with irritable bowel syndrome has been detected, and the effects of other food components, such as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, may contribute. Our organization and synthesis of extant knowledge pertaining to wheat-related disorders may advance current practice and research efforts toward an improved understanding of NCGS/NCWS as an evolving clinical entity.

Keywords:

• gluten-free diet
• gluten intolerance
• non-celiac gluten sensitivity
• wheat sensitivity
• wheat allergy

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Non-celiac gluten sensitivity (NCGS)/non-celiac wheat sensitivity (NCWS) is an emerging clinical entity that manifests on a spectrum and may be considered after excluding celiac disease (CD) and wheat allergy.

• CD is based on a combination of factors, including clinical evaluation, celiac-specific serology, and histopathologic features of duodenal biopsy samples (i.e., increased intraepithelial lymphocytes, crypt hyperplasia and villous atrophy). HLA-DQ2/8 testing can be useful for its negative predictive value in eliminating CD but not NCGS/NCWS. The treatment for CD is lifelong, strict avoidance of gluten-containing products. The distinction between CD and NCGS/NCWS is critical in identifying CD patients who are at risk for specific nutritional deficiencies, complications including intestinal lymphoma, and associated familial disorders.

• In vivo skin prick testing and specific IgE are first-line tests in consideration of IgE-mediated food allergy, although they are not definitively diagnostic. The clinical relevance of positive testing is determined by elimination diet (usually 2–4 weeks) for diagnostic purposes with oral food challenge as the gold standard. Similarly, with suspected non-IgE-mediated food allergy, elimination of the proposed allergen (typically 2–6 weeks) can be undertaken, ideally with food reintroduction after the trial period. Avoidance of the implicated trigger(s) is the mainstay of food allergy treatment.

• Multi-systemic NCGS features have been more commonly described in adult patients. Gastrointestinal manifestations include abdominal pain, nausea, bloating, diarrhea and constipation. Extra-intestinal manifestations include fatigue, lethargy, depression, anxiety, headache, dermatitis and joint/muscle pain. Neuropsychiatric conditions have also been associated. Symptoms classically improve with gluten/wheat avoidance and reappear with substance rechallenge.

• NCGS/NCWS patients demonstrate gluten/wheat adversity favoring an innate and/or adaptive immune response. HLA status and serologic markers appear to be variable. Duodenal histology in NCGS generally shows preserved villous architecture, although CD3+ intraepithelial lymphocytosis may be seen. Mucosal gene expression studies related to intestinal barrier function favor an innate immune activation in NCGS/NCWS and an adaptive immune involvement in CD.

• There are currently no recognized discriminative clinical or biochemical markers for NCGS/NCWS. Diagnostic and therapeutic indicators of disease presence include notable negative effects induced by gluten/wheat, followed by perceived improvements with gluten/wheat elimination. A formal double-blind, placebo-controlled food challenge may confirm gluten/wheat sensitivity.

• Other Conditions responsive to wheat-exclusion, such as IBS and FODMAP-sensitivity, should be considered in the assessment of NCGS/NCWS patients.

• The detection of gluten or wheat traces in food and other products is important in safeguarding patients with CD, wheat allergy and gluten/wheat sensitivity.

• As a symptom-based condition, NCGS/NCWS requires an individualized management strategy in a multidisciplinary approach embracing medical, dietary, nutritional and psychological facets.

• Patients with NCGS/NCWS can potentially embrace a more liberal dietary approach and may be able to titrate gluten/wheat exposure to symptomatology. The low-FODMAP diet may be a useful clinical alternative or adjunct.

• Given the potential overlap and evolving knowledge of gluten/wheat-related conditions, periodic patient reassessments, with dietary tracking and possible modifications over time, are recommended.