For years, the standard diagnostic pathway for celiac disease in adults within the United States has included an intestinal biopsy. This invasive procedure, typically performed during an endoscopy, is used to confirm the damage to the small intestine characteristic of celiac disease. However, a recent international study is challenging this long-held practice, suggesting that a biopsy might not be essential in numerous cases.
This groundbreaking study highlights the reliability of highly positive anti-tissue transglutaminase immunoglobulin A (TTG) blood tests. Researchers discovered that when individuals exhibited TTG levels ten times greater than the upper limit of normal, they almost invariably presented with the intestinal damage indicative of celiac disease. This finding opens the door to the possibility of diagnosing celiac disease without the need for an endoscopy and biopsy in a significant portion of adult patients.
Despite these compelling results, it’s important to note that some celiac disease experts in the US, including authors involved in the study, advocate for cautious interpretation. While the study strengthens the evidence supporting the predictive power of the TTG test, they argue that it doesn’t yet fully negate the crucial role of the biopsy in definitively diagnosing celiac disease.
The necessity of biopsy in celiac disease diagnosis remains a topic of ongoing debate and active research within the medical community.
Reliability of Blood Tests in Predicting Celiac Disease
“My personal opinion is that these results should inform future guidelines,” states Dr. Benjamin Lebwohl, a study author and the Director of Clinical Research at the Celiac Disease Center at Columbia University. While acknowledging the study’s significance, Dr. Lebwohl cautions against immediate changes in diagnostic protocols. “But I believe it’s premature to adopt a non-biopsy approach based on these data.” He also points out that while his stance is more conservative, other researchers involved in the study are more inclined towards embracing diagnosis methods that forgo biopsy.
The study itself underscores the “strong predictive” nature of highly elevated TTG blood test results, asserting that this evidence supports a “no-biopsy” approach for diagnosing celiac disease in adult patients. This comprehensive research involved collaborators from eight countries, including the United Kingdom, the United States, and Italy, and was published in the esteemed medical journal Gut.
Interestingly, European pediatric guidelines have already incorporated a no-biopsy diagnostic pathway for children with highly positive TTG blood test results. However, these guidelines have not yet been adopted within the United States.
Dr. Joseph Murray, a renowned celiac disease expert from the Mayo Clinic, who was not directly involved in the recent study, emphasizes the evolving landscape of celiac disease diagnosis. He acknowledges the growing body of evidence supporting a no-biopsy approach but stresses the importance of adhering to a meticulous set of procedures. The European guidelines for children, established by the European Society for the Study of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), include not only highly positive TTG results but also a confirmatory second blood test for anti-endomysial antibodies (EMA).
“The key thing is, the study is encouraging,” Dr. Murray concludes. “But following all the details is critical.”
Examining the Study’s Findings on TTG Test Accuracy
The recent study analyzed data from approximately 1400 adults. Within this group, 431 participants, representing 30 percent, exhibited TTG test results that were at least ten times the upper limit of normal. Remarkably, 424 of these individuals, or 98 percent, demonstrated significant intestinal damage during biopsy, confirming a diagnosis of celiac disease.
Dr. Lebwohl highlights that the study assessed the TTG test’s performance across diverse settings. While in some settings, a highly elevated TTG level showed 100 percent predictive accuracy for celiac disease, in others, this figure was slightly lower at 95 percent.
“Ninety-five percent sounds like a near-certain diagnosis,” Dr. Lebwohl acknowledges. However, he also points out the implications of this statistic. “But in reality, that means if we were to rely on antibody testing exclusively, one in 20 people with this highly-elevated antibody level would be erroneously diagnosed with celiac disease and prescribed a potentially unnecessary gluten-free diet.”
Dr. Lebwohl expresses concern about this potential false-positive rate, deeming it unacceptable. He also worries that adopting a no-biopsy approach could lead to a relaxation of the strict 10-times cutoff, potentially increasing diagnostic errors if less stringent criteria are used for diagnosis.
Currently, no medical guidelines in the United States advocate for diagnosing celiac disease in adults without a biopsy. Nevertheless, Dr. Lebwohl suggests that some individuals undergoing celiac disease testing might find the high reliability of a significantly elevated TTG test result sufficient for diagnosis, particularly in situations where a biopsy poses specific risks, such as in patients with bleeding disorders.
The study participants were categorized into three groups:
- 740 individuals from a UK celiac center with a high pre-test suspicion of celiac disease.
- 532 patients with general gastrointestinal symptoms referred for endoscopy with a low suspicion of celiac disease.
- 175 individuals with positive blood tests and biopsies from multiple centers across eight countries.
This study design was specifically intended to address concerns raised by adult gastroenterologists regarding a no-biopsy approach. Gastroenterologists have emphasized the need for robust international, multi-center data, including data from populations with varying prevalence rates of celiac disease.
Across all three study groups, the research revealed that “almost all individuals” with sufficiently high TTG test results displayed the intestinal changes characteristic of celiac disease. This consistency held true regardless of whether participants were initially considered at high or low risk for celiac disease. The study authors emphasize that these findings build upon previous research and demonstrate the potential applicability of a no-biopsy approach across diverse adult populations with varying celiac disease risk levels.
Weighing the Pros and Cons: Biopsy vs. Non-Invasive Diagnosis
The study highlights several drawbacks associated with upper endoscopy and biopsy. These include the significant cost of the procedure, encompassing both the procedure itself and the processing and analysis of biopsy samples. Furthermore, endoscopy can be poorly tolerated by patients due to its invasive nature and associated risks. Finally, the accuracy of biopsy results is dependent on the interpretation of the samples by a pathologist, which introduces the possibility of diagnostic errors and missed cases. These factors contribute to the growing interest in developing non-invasive diagnostic methods for celiac disease.
However, Dr. Murray points out the advantages of maintaining endoscopy and biopsy as part of the standard diagnostic process. In older adults, endoscopy can detect other gastrointestinal conditions, such as ulcers and malignancies, which might be missed by blood tests alone. Additionally, an initial biopsy at diagnosis provides a baseline against which future biopsies can be compared to monitor intestinal healing in response to a gluten-free diet. Dr. Murray routinely performs follow-up biopsies for his celiac disease patients as part of their ongoing disease management.
Dr. Lebwohl concurs, noting, “If a patient has symptoms that mandate examination for additional conditions, for example, a suspected ulcer, that is all the more reason not to skip an endoscopy.”
Addressing Variability in Blood Test Results
One of the primary hurdles in implementing a widespread no-biopsy approach is the variability and lack of standardization in TTG test analysis across different laboratories and assays. The study emphasizes that “The inability to compare TTG results accurately between different assays increases the chances of misdiagnosis if a uniform threshold is used.” This concern is highlighted by the observed decrease in the test’s predictive accuracy, from 99 percent to 95 percent, when comparing two of the study groups to the multi-center international group. “This raises the concern that sole reliance on [10 times the upper limit of normal TTG results] will lead to a false positive diagnosis in around 1 in 20 cases,” the study authors caution.
“As a gastroenterologist who sees adults, I will continue to advocate for a biopsy as the default in all cases since I do not think it is acceptable to prescribe a long-term gluten-free diet if there is a 5 percent chance it is unnecessary,” Dr. Lebwohl states.
European pediatric guidelines recommend a confirmatory EMA test in conjunction with a highly positive TTG test. However, the recent study did not incorporate EMA testing for all participants due to its higher cost, labor-intensive nature, and potential for subjective interpretation of results. The authors acknowledge that including EMA testing could hinder the adoption of a no-biopsy approach. They suggest that testing for deamidated gliadin peptides in conjunction with TTG testing could be a viable alternative to EMA.
Current Diagnostic Guidelines in the United States
Current guidelines from the American College of Gastroenterology and the American Gastroenterological Association for celiac disease diagnosis recommend endoscopy with biopsy. An AGA practice update, co-authored by Dr. Murray, also advises biopsy but acknowledges that a TTG result ten times above the upper limit of normal is a “reliable and accurate test for diagnosing active celiac disease at high levels.” It’s important to note that practice updates reflect emerging processes but do not formally change established guidelines.
Similarly, the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), a leading organization of pediatric gastroenterologists in the US, Mexico, and Canada, stipulates that intestinal biopsy is required for celiac disease diagnosis in children in all cases.
A NASPGHAN clinical report published in 2016 emphasizes the risks associated with forgoing biopsy, despite the desirability of a no-biopsy diagnostic approach. The report cites the lack of standardized blood tests and significant variability in test analysis as potential factors that could lead to misdiagnosis and unnecessary gluten-free diets for some children. “Because a strict gluten-free diet is cumbersome, expensive, and has an adverse impact on the quality of life of the individual, it is important to confirm the diagnosis before recommending such a lifelong dietary change,” the report underscores.
Conclusion: The Future of Celiac Disease Diagnosis
The recent study concludes that a no-biopsy approach holds the potential to reduce the cost, risks, and procedural burden associated with endoscopy and biopsy in adults with celiac disease. The evidence strongly indicates that at significantly elevated levels, the TTG test is highly effective in identifying adults with celiac disease. However, the study emphasizes that standardization and validation of TTG test analysis are crucial to maximize the impact and reliability of a no-biopsy diagnostic strategy for adults.
Dr. Murray points out that the no-biopsy approach still faces “spirited defense of the biopsy” within the medical community.
Dr. Lebwohl summarizes the ongoing debate: “A highly elevated tissue transglutaminase antibody means that it is highly like that someone has celiac disease,” he acknowledges. “We can now estimate that ‘highly likely’ is 95 percent. Is that high enough? This will be a matter of debate.”
