A 36-Year-Old Woman With Flatulence and Memory Problems

Alexander Potashinsky, MD; John W. Birk, MD


April 19, 2022

NCGS is a condition in which consumption of gluten leads to symptoms similar to those of celiac disease. It is nonallergic and nonautoimmune in nature. It is termed "sensitivity" because symptoms are relieved by gluten withdrawal and reappear with reintroduction of gluten to the diet, which triggers a constellation of GI and extraintestinal symptoms.[5]

Typical GI symptoms of NCGS include postprandial abdominal pain, bloating, diarrhea, and/or constipation. Extraintestinal symptoms can be diverse and include peripheral neuropathy, eczema, joint and muscle aches, anxiety, and headaches. A prominent feature is the feeling of a "foggy brain," which manifests as slowed thinking and memory issues. These extraintestinal features are in major contrast with irritable bowel syndrome (IBS) symptoms, which are primarily GI symptoms.

Unlike in celiac disease, other systemic features are absent, including iron deficiency anemia, weight loss, and dermatitis herpetiformis rash. Because NCGS does not cause malabsorption, no nutrient deficiencies (eg, folic acid, fat-soluble vitamins) are noted. Whereas in celiac disease, symptoms may take weeks to manifest and subside, the associated symptoms in NCGS generally increase and diminish within hours to days of gluten exposure. As in the patient in this case, many patients often notice the association of gluten-containing foods with their symptoms.[1,2,3]

The pathophysiology of NCGS is still under investigation. The main antigen present in gluten is a protein called "gliadin." When gluten is partially digested, gliadin binds to gut wall receptors, leading to increased intestinal permeability. This allows gluten to be mistakenly recognized as a pathogen by the immune system. In celiac disease, the adaptive immune response leads to gluten molecules being cross-linked by tissue transglutaminase. This then binds to human leukocyte antigen (HLA) DQ2 or DQ8 on antigen-presenting cells. This interacts with CD+ T cells in the lamina propria and activates a proinflammatory cascade, which leads to the systemic response to gluten and secretory diarrhea due to increased gut permeability.[3,5]

In NCGS, unlike in celiac disease, the innate immune response is thought to play a larger role, with local cytokine release leading to recruitment of intraepithelial lymphocytes.[4] The reaction is expressed by decreased gut permeability and an increased epithelial barrier, causing osmotic diarrhea. Although a systemic effect is observed, it is much less robust compared with the adaptive immune system cascade.

In addition to celiac disease and NCGS, wheat allergy is another important acute reaction. This is a true food allergy, with an immunoglobulin E (IgE)-mediated response that activates basophils and mast cells. The cascade releases histamine and causes rapid onset of symptoms, including flushing, diarrhea, and potentially anaphylaxis. Unlike celiac disease and NCGS, the onset of symptoms occurs within minutes to hours of ingestion of the wheat-containing food. Testing for wheat allergy is performed via skin prick testing or with a food challenge. Patients with wheat allergy must carry epinephrine pens in case of accidental exposure.[2]

The testing algorithms for celiac disease have been well described. The initial test of a patient consuming a gluten-rich diet is checking serology with tissue transglutaminase antibodies. If positive, this is validated by EGD duodenal biopsies that reveal villous blunting, crypt hyperplasia, and intraepithelial lymphocytes.[6] Unfortunately, NCGS is much more difficult to pinpoint because no serologic or histologic markers have been validated. Diagnosis is based on clinical symptoms after celiac disease and other potential causes have been ruled out and with resolution of symptoms when a gluten/wheat-free diet is adhered to for at least 3 weeks.[3,7]

In 2015, a group of experts met in Salerno, Italy, to describe a standard way of testing for NCGS. Their consensus statement describes a double-blind, placebo-controlled gluten challenge. The first step is to rule out celiac disease while a patient is consuming a gluten-rich diet. The patient is given a questionnaire to assess their baseline symptoms while consuming gluten.

The patient is then placed on a 6-week gluten-free diet, and the questionnaire is repeated. If symptoms improvement is less than 30%, NCGS is ruled out. If a larger improvement is noted, the patient is then moved to phase 2, where they are introduced to either a placebo or gluten-containing pill. The gluten dose is standardized to 8 g, which is equivalent to about two pieces of bread. This is given over the course of a week, followed by a 1-week washout period with a gluten-free diet. The other pill is then given for another week. Symptoms are reassessed at each step.

The goal is to determine whether gluten is associated with at least a 30% change in symptoms.[8] In clinical practice, where standardized gluten and placebo pills may be hard to come by, this can be done with gluten-containing or gluten-free bread.


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