Celiac Diagnosis: Progress & Challenges

Increasing Awareness of Celiac Disease

The estimated prevalence of celiac disease is 1% though estimates vary around the world as researchers improve their understanding of who should be screened for celiac disease and as testing methods improve [1]. Interestingly, after controlling for variations in diagnosis rates, prevalence may vary by geographic region. For example, a higher rate of celiac disease has been observed in those who live in Northern regions of the United States (above a 35° latitude) compared to Southern [2]. Among all population groups, there is widespread acknowledgement that those with a first degree or second degree relative who has celiac disease are at increased risk and should undergo screening. Though research is ongoing, the pathogenesis of celiac disease may be connected to other autoimmune conditions, such as type 1 diabetes, autoimmune hepatitis, autoimmune thyroid disease, Down syndrome and Turner syndrome [3]. 

An estimated 30-40% of the population carries the genes that are associated with celiac disease onset (HLA-DQ2 or HLA-DQ8) and 97% of those with celiac disease do have these genes [4]. However, since this 30-40% of the population never goes on to develop celiac disease, environmental factors are considered necessary for its onset. Hypotheses around triggers that may contribute to development of celiac disease include antibiotic use, history of gastroenteritis, viral infection, Campylobacter infection, use of proton pump inhibitors, a Cesarean birth, pregnancy or even severe stress. Still, much remains unknown on celiac disease’s onset and on why, even after controlling for increased diagnosis rates, prevalence rates appear to be increasing [4].

Diagnosis Challenges

While roughly 1% of the population has celiac disease, only an estimated 17% of cases in the United States are diagnosed [3]. Among cases that are, the average time to diagnosis is 11 years [3]. 

Celiac disease has over 300 known symptoms and can impact every system in the body, not just the digestive tract. GI symptoms include abdominal bloating and pain, distention, chronic diarrhea, constipation, vomiting, malabsorption, anorexia and malabsorption, while extra-intestinal symptoms can manifest in dozens of ways, including anemia, vitamin deficiencies, neurological issues, chronic fatigue, fertility and psychiatric disorders, skin rashes (Dermatitis Herpetiformis), and osteoporosis or osteopenia [5]. 

This diverse picture of celiac disease means that some people with celiac disease never show signs or symptoms, though they have the same risk for long-term complications that symptomatic patients face. Unfortunately, symptoms are not an accurate measure of disease severity, risk of long term complications, or adherence to a gluten-free diet. While a gluten-free diet is important to control symptoms, improve quality of life and decrease the risk of complications, mucosal healing is considered the best way to monitor celiac disease management [1]. 

In the United States, physicians rarely consider celiac disease as part of their differential diagnosis, meaning celiac disease testing is not often part of the work-up for patients presenting with celiac symptoms. This lack of standardized work-up contributes to missed or delayed diagnoses. 

Celiac disease can present at any life stage, from childhood to late adulthood. Among children, failure to thrive often leads physicians to screen and test for celiac disease, which accounts for the vast majority of diagnoses in children.The widespread adoption of a gluten-free diet by personal choice can further contribute to challenges, as accurate diagnosis requires that patients follow a gluten-containing diet both before and during the diagnostic procedure.

The Gold Standard in the US: Intestinal Biopsy

Blood tests can be used to screen for celiac disease, but are not accurate in children under

three years old and can provide false negative results. A small intestinal biopsy, performed while a patient is still consuming gluten, is recommended to confirm or rule out celiac diagnosis based on the severity of duodenal villous atrophy [6]. Both blood and biopsy results can also be used to monitor response to a gluten-free diet and assess how the small intestine may be healing. 

Celiac disease can present in patches along the intestine, meaning the location and number of samples taken during intestinal biopsy matters. Multiple samples from various regions along the intestinal tract can increase accuracy of diagnosis [7,8]. While it’s considered minimally invasive and pain-free, a biopsy can come with expense and small risks. Controversy around the importance of a biopsy’s role in accurate diagnosis stems partly from the risk that false positive tissue transglutaminase test results may occur following a temporary gluten autoimmunity, which would lead to an incorrect diagnosis of celiac disease. 

Still, an intestinal biopsy provides baseline diagnosis data for evaluation following implementation of a gluten-free diet, which can be particularly useful among patients who may continue to experience symptoms despite gluten elimination. Recent studies point toward the validity of antibody-based celiac disease diagnosis without an intestinal biopsy, contributing to updated guidelines on celiac diagnosis [9,10].

Updated Guidelines in Europe & the United States

In 2019, the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition updated its celiac diagnosis guidelines for children with the HLA-DQ2 or HLA-DQ8 haplotypes. Guidelines now recommend that symptomatic children with greater than 10 times the normal transglutaminase antibody levels and who have a positive endomysial antibody (EMA) test result from a different blood sample can be diagnosed with celiac disease without pathologic confirmation, meaning they do not need to undergo an intestinal biopsy [11]. European guidelines recommend diagnosis be confirmed by a decline in antibodies and clinical response to the gluten-free diet. 

The United States also released new guidelines in January of 2023 on the diagnosis of celiac disease in both adults and children. The new guidelines emphasize the importance of multiple intestinal biopsies for accurate diagnosis. However, they also acknowledge that a combination of high tissue transglutaminase IgA levels along with positive EMA results from a second blood sample may be used to diagnose pediatric patients and symptomatic adults unwilling or unable to undergo upper gastrointestinal endoscopies [1]. The new guidelines also set a goal of intestinal healing as an end point, shifting the focus from clinical and serological measures of remission. Other recommendations include suggestions against the use of gluten detection devices and inclusion of gluten-free oats in patients who do not show an immune reaction to the oat protein avenin. They also discuss the prevalence of dysbiosis in celiac disease and its potential role in pathogenesis and symptomatology, but emphasize there is insufficient evidence to recommend for or against the use of probiotics as treatment [1]. 

A strict gluten-free diet remains a lifelong requirement for those with celiac disease. Fortunately, a gluten elimination will prevent symptoms and help avoid long-term complications of celiac disease in most patients. While diagnosis of celiac disease remains a challenge, the intestine can begin to heal within months following gluten elimination and symptoms can resolve even sooner.

Still, an individualized approach to celiac disease management is important. Patients may react differently to various levels of gluten-exposure based on their own immune-response and other co-existing conditions. There are a wealth of delicious products and resources (like our Gluten-Free Life booklet) to help patients follow a diverse, balanced gluten-free diet.