Celiac disease (CD) is an autoimmune disorder where consuming gluten, a protein found in wheat, barley, and rye, triggers an immune response that damages the lining of the small intestine. This damage, known as villous atrophy, impairs the body’s ability to absorb nutrients, leading to gastrointestinal and systemic symptoms like chronic diarrhea, fatigue, and weight loss. Because these symptoms are broad and non-specific, they overlap significantly with many other common and rare conditions, making initial diagnosis complex. Understanding these mimics is an important step in navigating the diagnostic process.
Dietary Sensitivities and Functional Disorders
The most common conditions mistaken for celiac disease involve sensitivities to food components or functional gastrointestinal problems that do not cause permanent intestinal damage. Non-Celiac Gluten Sensitivity (NCGS) is a primary mimic, where individuals experience symptoms such as abdominal pain, bloating, and headache after consuming gluten, even though they test negative for the characteristic antibodies and small intestine damage seen in CD. NCGS is a diagnosis of exclusion, meaning doctors confirm it only after ruling out celiac disease and wheat allergy.
Irritable Bowel Syndrome (IBS) is another frequent mimic, a disorder of gut-brain interaction that involves chronic abdominal pain linked to altered bowel habits, such as diarrhea, constipation, or both. IBS symptoms—including severe bloating, cramping, and gas—are nearly identical to the digestive complaints of celiac disease, but unlike CD, IBS does not involve inflammation or structural damage to the intestinal lining.
Disruptions to the gut microbiome can also replicate celiac symptoms, most notably in Small Intestinal Bacterial Overgrowth (SIBO). SIBO occurs when excessive bacteria colonize the small intestine, leading to fermentation of carbohydrates and the production of gas, which causes bloating, abdominal discomfort, and malabsorption. While SIBO can sometimes cause secondary villous damage, its mechanism is distinct from the autoimmune reaction of CD. Similarly, common carbohydrate maldigestion, such as lactose or fructose intolerance, can cause gas, bloating, and diarrhea due to the inability to properly digest these specific sugars, which may lead to confusion with celiac symptoms.
Inflammatory Bowel Conditions
Chronic inflammatory conditions that affect the gut share the inflammatory nature and many systemic symptoms of celiac disease. Crohn’s disease, a type of Inflammatory Bowel Disease (IBD), can affect any part of the gastrointestinal tract, but when it impacts the small intestine, it causes inflammation, abdominal pain, diarrhea, and malabsorption that strongly resemble CD.
A key distinction lies in the pattern of damage: celiac disease primarily affects the mucosal layer (the innermost lining) of the small intestine, whereas Crohn’s disease is characterized by transmural inflammation, meaning the inflammation extends through all layers of the bowel wall. Crohn’s can also cause ulcers, strictures, and fistulas that are not typical features of uncomplicated CD. Ulcerative Colitis, another IBD, is primarily limited to the colon, but its systemic effects, such as fatigue, weight loss, and anemia, can contribute to the initial diagnostic confusion before targeted testing is performed.
A particularly challenging mimic is Autoimmune Enteropathy (AIE), a rare condition where the body’s immune system attacks the small intestine lining, resulting in severe villous atrophy and malabsorption. Differentiation relies on specific clinical features, the presence of distinct autoantibodies, and the fact that AIE symptoms do not resolve with a gluten-free diet.
Rare Diseases Causing Small Intestine Damage
Tropical Sprue is an acquired disorder, often seen in individuals from or traveling to tropical regions, that results in chronic diarrhea and severe malabsorption due to damage to the small intestine lining. While it causes villous atrophy, it is not an autoimmune reaction to gluten, and it requires different treatment, typically involving antibiotics and nutritional support.
Whipple’s disease is another rare systemic infection caused by the bacterium Tropheryma whipplei, which leads to small intestinal inflammation, malabsorption, and a range of systemic symptoms like joint pain and neurological problems. Pathologists distinguish Whipple’s disease from CD by identifying foamy macrophages containing the bacteria in the small intestine biopsy tissue. In addition, some medications can directly induce enteropathy that is histologically similar to celiac disease. The blood pressure drug olmesartan (Benicar) has been specifically linked to a condition that causes severe diarrhea and villous atrophy, which often resolves once the medication is discontinued.
How Doctors Rule Out Celiac Disease
The initial step involves serology screening, which checks for elevated levels of specific autoantibodies, primarily tissue transglutaminase immunoglobulin A (tTG-IgA) and sometimes deamidated gliadin peptide immunoglobulin G (DGP-IgG). It is crucial for the patient to be consuming gluten regularly for several weeks before these blood tests, as eliminating gluten can cause the antibody levels to drop, leading to a false-negative result.
If the serology tests are positive, the next step is a gastroscopy with a small intestinal biopsy. A gastroenterologist uses an endoscope to take tiny tissue samples from the duodenum, the first part of the small intestine. Pathologists then examine these samples under a microscope to confirm the presence and severity of villous atrophy.
The biopsy is also crucial for differentiation, as pathologists look for specific cellular markers and patterns of damage to distinguish CD-induced atrophy from damage caused by other conditions like Autoimmune Enteropathy or Whipple’s disease. If both the serology and biopsy are negative, celiac disease is effectively ruled out. At that point, the doctor may recommend targeted elimination diets, such as a trial of a gluten-free diet or a low-FODMAP diet, to assess for conditions like NCGS or IBS.