What Is Celiac Disease? Gluten, Diagnosis, and the Gluten-Free Diet

What Is Gluten and Why Does It Trigger Celiac Disease?

Gluten is a family of storage proteins found in wheat (gliadin), barley (hordein), and rye (secalin). These proteins are resistant to complete digestion by human gastrointestinal enzymes, leaving peptide fragments in the small intestine. In most people, these fragments are harmless. In individuals with celiac disease, however, certain gliadin peptides—particularly a 33-amino-acid fragment called alpha-2-gliadin 33-mer—cross the intestinal epithelium and trigger an abnormal immune response.

Celiac disease is driven by both adaptive and innate immune mechanisms. Tissue transglutaminase (tTG), an enzyme in the intestinal lining, modifies gliadin peptides through a process called deamidation, making them bind more strongly to HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells. This activates gluten-specific CD4+ T-cells, which trigger inflammation, and also stimulates intraepithelial lymphocytes that directly damage the intestinal lining. The result is a destructive autoimmune reaction that flattens the intestinal villi.

Villous Atrophy and Malabsorption

The small intestine is lined with finger-like projections called villi, which dramatically increase the surface area available for nutrient absorption. In untreated celiac disease, chronic immune-mediated inflammation destroys these villi—a process called villous atrophy—and causes the crypts (the pits between villi) to deepen in a compensatory response called crypt hyperplasia. The net result is a dramatically reduced absorptive surface, leading to malabsorption of nutrients including iron, folate, calcium, and fat-soluble vitamins (A, D, E, K).

The clinical consequences of this malabsorption are wide-ranging. Classic presentation includes chronic diarrhea, steatorrhea (fatty, foul-smelling stools), bloating, and weight loss. Iron deficiency anemia is one of the most common presenting features, particularly in adults. Calcium and vitamin D malabsorption leads to low bone mineral density and osteoporosis. Neurological manifestations—including peripheral neuropathy and cerebellar ataxia—can occur even without prominent gastrointestinal symptoms. Dermatitis herpetiformis, a blistering skin rash, is a cutaneous form of celiac disease caused by IgA antibody deposits in the skin.

Diagnosis: Blood Tests and Biopsy

Diagnosis requires the patient to be eating a gluten-containing diet, as eliminating gluten before testing produces false-negative results. The initial diagnostic workup involves serological (blood) tests measuring antibodies produced in celiac disease. The most sensitive and specific are the IgA anti-tissue transglutaminase (tTG-IgA) antibody and the IgA anti-endomysial antibody (EMA). Total serum IgA must also be measured to rule out IgA deficiency, which would falsely lower these test results; if IgA deficiency is present, IgG-class antibodies are tested instead.

Positive serology is followed by endoscopic small intestinal biopsy for histological confirmation—the gold standard for diagnosis. Biopsies are typically taken from the second part of the duodenum and graded using the Marsh classification: Marsh 1 (increased intraepithelial lymphocytes), Marsh 2 (crypt hyperplasia), and Marsh 3a–c (partial to complete villous atrophy). HLA typing for DQ2/DQ8 can be useful to exclude celiac disease in ambiguous cases, as virtually all patients carry one of these alleles.

The Gluten-Free Diet as Treatment

Currently, the only effective treatment for celiac disease is strict, lifelong adherence to a gluten-free diet. This means completely eliminating wheat, barley, rye, and their derivatives from the diet. Foods must be checked for hidden gluten in sauces, processed foods, seasonings, and medications. Cross-contamination during food preparation is a significant concern even for trace amounts of gluten (as little as 10 mg per day can trigger intestinal damage in sensitive individuals).

Naturally gluten-free grains and starches that are safe include rice, corn (maize), potato, oats (if certified gluten-free and produced without cross-contamination), quinoa, millet, buckwheat, and amaranth. Following diagnosis, a supervised gluten-free diet results in mucosal healing of the intestine, usually within 1–2 years in adults (faster in children), resolution of symptoms, normalization of antibodies, and reduction in long-term complications such as osteoporosis and intestinal lymphoma. A registered dietitian with expertise in celiac disease is an invaluable resource for navigating dietary changes.

Non-Celiac Gluten Sensitivity

Non-celiac gluten sensitivity (NCGS) is a condition in which individuals experience symptoms similar to celiac disease upon gluten ingestion—including bloating, abdominal pain, fatigue, and brain fog—but lack the autoimmune markers (negative serology) and intestinal damage (normal biopsy) of celiac disease. They also do not have wheat allergy. The mechanism is not fully understood but may involve the innate immune system and, importantly, may partly relate to non-gluten components of wheat such as fermentable oligosaccharides (FODMAPs) or amylase-trypsin inhibitors (ATIs).

NCGS is diagnosed by exclusion after ruling out celiac disease and wheat allergy, followed by a double-blind, placebo-controlled gluten challenge. Its true prevalence is difficult to estimate due to the lack of validated biomarkers, and some researchers believe a substantial portion of reported cases may actually be FODMAP sensitivity. Wheat allergy—an IgE-mediated immune reaction to wheat proteins—is a separate condition managed by wheat avoidance and carrying epinephrine for anaphylaxis.