Celiac disease (CD) is an autoimmune disorder triggered by consuming gluten, a protein found in wheat, barley, and rye. In individuals with CD, gluten ingestion causes the immune system to attack and damage the lining of the small intestine. This damage hinders the body’s ability to absorb nutrients, leading to various health complications. To confirm this condition, an upper endoscopy with a biopsy of the small intestine remains the primary diagnostic procedure.
The Gold Standard: Endoscopy and Biopsy Criteria
Celiac disease is diagnosed using an upper gastrointestinal endoscopy, often called an esophagogastroduodenoscopy (EGD). During this procedure, a flexible tube with a camera is passed into the duodenum, the first part of the small intestine. The lining of the small intestine features millions of tiny, finger-like projections called villi, which are responsible for nutrient absorption.
The gastroenterologist takes multiple tissue samples, typically four to six, from different areas of the duodenum for examination. Pathologists examine these samples for three microscopic changes characteristic of active celiac disease. The most definitive sign is villous atrophy, which is the flattening or blunting of the villi, severely reducing the surface area for absorption.
The pathologist also looks for crypt hyperplasia, the overgrowth of glandular structures at the base of the villi, indicating the body’s attempt to repair the damage. The third feature is an increase in intraepithelial lymphocytes (IELs), inflammatory immune cells found within the intestinal lining. These findings are graded using a standardized system, such as the Marsh classification, to assess the severity of the intestinal damage. A confirmed diagnosis of active celiac disease is usually associated with the more advanced Marsh III changes, which include definite villous atrophy.
The Critical Impact of Gluten Consumption Before Testing
The single most common reason an endoscopy might fail to diagnose celiac disease is that the patient stopped eating gluten before the procedure. For the diagnostic changes to be present in the small intestine, the tissue must be actively inflamed by the immune reaction to gluten. If a patient begins a gluten-free diet (GFD) prior to testing, the small intestine begins to heal, sometimes within weeks.
This healing process, known as mucosal recovery, can reverse the characteristic damage, leading to a false-negative biopsy result, even if the person has celiac disease. The immune response subsides when the trigger is removed, making the microscopic changes undetectable. This scenario often results in a diagnosis of “potential” celiac disease if the patient’s blood tests (serology) were positive before the diet change but the biopsy was negative.
Patients who have already adopted a GFD must undergo a “gluten challenge” before accurate testing can be performed. This involves consuming a defined amount of gluten daily, typically equivalent to two slices of bread, for several weeks (usually six to twelve). The challenge must be long enough to re-induce the intestinal inflammation necessary for the biopsy to capture villous atrophy. Patients should always consult with a physician to determine the appropriate length and quantity of the challenge, as it can cause a return of symptoms.
Technical and Pathological Reasons for a Missed Diagnosis
Sampling Errors
Celiac disease damage is not always uniform throughout the small intestine; sometimes, the lesions are localized or “patchy.” This patchy distribution means a sampling error can occur if the biopsies are taken only from healthy, undamaged sections of the duodenum. To mitigate this, medical guidelines recommend taking a minimum of four to six biopsies from different sites in the duodenum, including at least one from the duodenal bulb. Taking an insufficient number of samples significantly increases the likelihood of missing localized damage.
Interpretation Challenges
If the tissue samples are not properly oriented when mounted on a slide, the pathologist may be unable to accurately assess the height of the villi, leading to an underestimation of the damage. Early-stage celiac disease presents a separate challenge, as the damage may be mild (Marsh I or Marsh II), involving increased immune cells but no clear villous atrophy. These early stages can be overlooked or misinterpreted by the pathologist. Mild damage can also be caused by other conditions, such as certain infections or medications. The diagnosis relies on the pathologist’s trained eye to distinguish subtle inflammatory changes from normal tissue, which requires specialized expertise.
Follow-Up Steps When Symptoms Persist
If an endoscopy comes back negative but digestive symptoms continue, it is prudent to review the initial celiac blood markers, or serology. Blood tests, such as those for tissue transglutaminase (tTG-IgA) antibodies, can be highly suggestive of celiac disease. If the tTG-IgA test was negative, a second test for total Immunoglobulin A (IgA) should be checked, as a common IgA deficiency can lead to a false-negative result on the tTG-IgA test.
Genetic testing for the HLA-DQ2 and HLA-DQ8 genes can offer additional clarity. Nearly all individuals with celiac disease carry one or both of these genes. A negative genetic test provides a high negative predictive value, meaning it can almost entirely rule out the possibility of celiac disease. A positive result, however, is not diagnostic, as these genes are common in the general population, but it does support the need for further investigation.
It is important to consider other conditions that can mimic celiac disease symptoms, a process known as differential diagnosis. Conditions like Non-Celiac Gluten Sensitivity, Irritable Bowel Syndrome (IBS), or Small Intestinal Bacterial Overgrowth (SIBO) can cause similar digestive distress. Continuing to work with a gastroenterologist is advisable to explore these other possibilities and ensure that the persistent symptoms are not being overlooked.