Should Celiac Disease Biopsy Be the Gold Standard for Diagnosis?

According to many sources, small bowel biopsy is the “gold standard” test for celiac disease diagnosis. But is this really the case when there is no single test (including biopsy) that can diagnose celiac disease with 100% sensitivity and specificity? In this article, we propose synoptic (comprehensive) reporting of the celiac testing triad (biopsy, antibodies, and genetics) as the gold standard for diagnosing celiac disease.

About Celiac Disease

Celiac disease is one of the few autoimmune diseases for which the root cause (genetics) and the trigger (gluten) have been well-defined. All individuals who develop celiac disease have inherited at least one of the celiac gene variants (HLA-DQ2, HLA-DQ8) and are regularly eating gluten-containing foods. However, not all gluten-consuming individuals with positive genetics develop celiac disease. Thus, genetics and gluten are necessary but not sufficient for causing this unique autoimmune illness. Other genes and environmental factors determine which at-risk individuals will (or will not) develop celiac disease.

Individuals at high risk for celiac disease share the following factors:

• Positive for celiac genes DQ2 and/or DQ8
•  Consuming gluten in their diet
• Have first-degree relatives (parents, siblings, children) with celiac disease (whether they’ve been diagnosed or not)

Genetically positive individuals on a gluten-containing diet who have family members diagnosed with celiac disease are at a particularly high level of risk. This is because families share many genes associated with celiac disease, including DQ2 and/or DQ8. In addition, families share lifestyle and other factors contributing to disease development. A recent Mayo Clinic study revealed over 40% of celiac disease patient family members who were screened by antibody testing already had the disease.

Think you may have celiac disease?

If you are experiencing symptoms of celiac disease and looking for diagnostic testing, antibody testing is the least invasive option for celiac disease diagnosis. If positive, the next step is generally an upper endoscopy procedure to collect a small intestinal biopsy sample. However, if you prefer starting with a screening method for celiac risk before moving straight to diagnostic testing, then celiac genetic health risk (GHR) testing is the best option. Genetic testing can be performed from a non-invasive collection of cheek swabs which are sent to the lab for DNA extraction and testing. Positive genetic results support moving ahead with follow-up diagnostic testing, whereas negative results completely rule out celiac disease.

Before undergoing a celiac disease biopsy, here are FIVE facts to know:

1.    Biopsy results will be falsely negative if you have started on a gluten-free diet, even if you have celiac disease.

2.    Biopsy results will be falsely negative if tissue samples are collected outside small intestine regions harboring autoimmune damage. 

3.    If you have not inherited DQ2 and/or DQ8 genetics, biopsy results are not necessary to rule out celiac disease because genetically negative individuals cannot develop celiac disease.

4.    For children, the American College of Gastroenterology supports celiac diagnosis with positive antibody and genetic testing with (or without) biopsy.

5.    Biopsy alone is not the gold standard, but biopsy interpreted in conjunction with antibody and genetic testing results is the pillar of making a celiac disease diagnosis.

Biopsy in the treatment of adult celiac disease

Biopsy results alone cannot make the diagnosis of celiac disease even if the pathologist reading the biopsy detects characteristic celiac “flattening” of the small intestinal villi. The villi are fingerlike projections in the small intestine exquisitely designed to capture nutrients from the food we eat. When villi are attacked by the immune system in celiac disease, the villi lose the capability to absorb nutrients. This explains the anemia and vitamin deficiencies commonly seen in celiac disease. However, flattened intestinal villi and the accompanying signs/symptoms are not diagnostic of celiac disease. Many other diseases, including parasite infections, drugs, and inflammatory bowel diseases (IBD) such as Crohn’s and ulcerative colitis, can also have this finding. Thus biopsy is an essential part of the diagnostic workup, but a gold standard celiac disease diagnosis also requires testing for positive genetics and celiac antibodies.

Can children have a celiac disease biopsy?

Many experts, including the European Society for Pediatric Gastroenterology, Hepatology, Nutrition (ESP-GHAN) and American College of Gastroenterology (ACG) agree that children with celiac disease symptoms, positive genetics, and high levels of celiac specific antibodies do not need small bowel biopsy, particularly those with celiac disease family members.  However, this recommendation is not routinely followed in the United States. The decision whether to perform small bowel biopsy on a child is ultimately up to the treating physician and the child’s parents. Although the chances of complications are low, all endoscopy procedures are associated with some level of risk. Performing the least invasive tests first (genetics followed by antibody testing) can be adequate for establishing the diagnosis or determining which children would benefit from more invasive testing.

How to Prepare for an Endoscopy and/or Biopsy

The most important preparation for small bowel biopsy is daily consumption of large quantities of gluten for at least six weeks prior to the biopsy. This is not a problem for individuals on a gluten containing diet. However, people who are on a gluten free diet will need to re-introduce gluten into their diet for at least six weeks before having a small bowel biopsy. This is because the small intestine begins repairing the villi when gluten is eliminated from the diet because the immune reaction ceases in the absence of gluten. In some instances celiac disease family members who already adopted a gluten free diet are offered a small intestine biopsy for disease screening. This raises the dilemma of whether or not to reintroduce gluten into their diet even if they are thriving on a gluten free diet. In these cases, the best approach is genetic risk testing which can either rule out celiac disease completely or support further screening by biopsy.

How Accurate Is a Biopsy For Celiac Disease?

Celiac biopsy is only highly accurate for celiac disease diagnosis when interpreted in the context of the patient’s other clinical findings and test results. When interpreted without other clinical data, celiac biopsy alone is not a gold standard test for celiac disease. This is because the biopsy has high sensitivity (> 90%) but very low specificity (< 70%) for celiac disease. 

Why an Intestinal Biopsy? 

Small intestinal biopsies are the most common for celiac disease because this is the location of the initial celiac immune reaction. When wheat, rye, barley products are ingested the gluten proteins are broken down into smaller pieces recognized by immune cells only in genetically susceptible individuals. People without celiac risk genes can digest gluten proteins without triggering an immune reaction. In celiac disease, the immune cells triggered by gluten proteins attack tissues of the small intestine and other organs. The damage to small intestinal villi is well recognized by pathologists reading small bowel biopsies and can help make the diagnosis of celiac disease.

What Does the Intestinal Biopsy Show?

Intestinal biopsy results are most often reported by the pathologist using the Marsh Scoring Classification. A negative small bowel biopsy will show normal intestinal villi capable of absorbing nutrients from food. This result is called a Marsh Score of I (image). Positive results represent Marsh Scores from II-IV, with 4 being the most severe damage. The majority of celiac disease patients fall into the Marsh III category.

After the Endoscopy

You should not resume a gluten free diet until all biopsy results have been received. Your doctor may need to order further testing which requires an activated immune system to give accurate results. Starting on a gluten free diet will quiet the immune system resulting in false negative results. Once a comprehensive assessment of all test results has been performed, dietary planning based on the findings can begin. If your results are positive for celiac disease, it is best to consult with your primary care provider, a genetics counselor, and a nutritionist to plan next steps.

What Does a Negative Biopsy Test Result Mean?

A negative biopsy test result cannot rule out celiac disease. This is because there is the potential for false negative results caused by tissue sampling outside the inflammation zone and inadequate dietary gluten. The only way to rule out celiac disease with close to 100% certainty is with celiac genetic risk testing. If genetic results are negative, then celiac disease testing can be discontinued. If genetic and antibody test results are positive but the biopsy is negative, then the diagnosis is called “Potential Celiac Disease.”

What Some Celiac Disease Experts Are Saying About Potential Celiac Disease

The potential celiac disease represents about 10% of all individuals diagnosed with celiac disease. In this situation, the intestinal biopsy shows normal results, but genetics, antibodies, and symptoms are positive. The criteria for diagnosing Potential Celiac Disease is most clearly presented using a “synoptic” (comprehensive) reporting strategy of the three essential laboratory tests. This means that the biopsy, antibody, and genetic results are all evaluated and reported by the same clinical pathologist. Synoptic reporting gives the patient and their treating physician a comprehensive evaluation of all the test results with a final unequivocal diagnosis stating the presence or absence of celiac disease.

For those patients positive for celiac disease, the diagnosis is further classified into the following variants:

• Celiac Disease: Positive antibodies, Positive biopsy, Positive genetics
• Potential Celiac Disease: Positive antibodies, Positive genetics, Negative biopsy
• Seronegative celiac Disease: Negative antibodies, Positive genetics, Positive Biopsy

Accurate and timely diagnosis of potential and seronegative celiac disease is critical because the longer an individual lives with an inflamed immune system, the greater their risk for the development of other autoimmune diseases and malignancies. Therefore, comprehensive reporting of the celiac testing triad (biopsy, antibodies, and genetics) should be the gold standard for diagnosing celiac disease.