The global prevalence of celiac disease has been calculated to be 1.4%. Studies have shown that the rate of new diagnoses of celiac disease has increased by 7.5% annually for the last few decades in the industrialized Western world. This dramatic rise in disease incidence has been attributed, in part, to the development of more accurate, cost-effective, and non-invasive testing methods. (9) 

Still, only 24% of patients with celiac disease are thought to be diagnosed. Undiagnosed and untreated celiac disease has severe implications for health outcomes, which may include poorer quality of life and higher risk of osteoporosis, infertility, and small intestinal cancer. As such, early and accurate diagnosis is critical. While small intestinal biopsy remains the gold standard for celiac disease diagnosis, serological testing has emerged as an important diagnostic tool in gastroenterology. 

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Overview of Celiac Disease

Celiac disease, often called gluten-sensitive enteropathy or celiac sprue, is a chronic autoimmune disorder triggered by ingesting gluten, a protein found in wheat, barley, and rye. In individuals with celiac disease, the immune system reacts abnormally to gluten, leading to the production of immune proteins that attack and damage the small intestinal lining. This damage causes intestinal inflammation and impairs the absorption of essential nutrients, leading to a wide range of symptoms, including abdominal pain, diarrhea, fatigue, and weight loss. (14) 

However, the impact of celiac disease extends beyond the digestive system. If left untreated or undiagnosed, the systemic implications can be severe. Malabsorption of nutrients may lead to nutritional deficiencies, osteoporosis, infertility, and an increased risk of other autoimmune disorders and certain cancers. Additionally, celiac disease has been linked to neurological disorders and gallbladder, liver, and heart diseases. Therefore, understanding the basics of celiac disease is crucial for both healthcare professionals and individuals, enabling timely diagnosis and early therapeutic intervention to prevent irreversible damage and improve the quality of life for those affected. (3)

Common Celiac Blood Tests

A definitive diagnosis of celiac disease requires a duodenal biopsy, performed via endoscopy, to visualize characteristic histological features of celiac disease. However, most doctors order serological testing for celiac disease before a duodenal biopsy because these blood tests serve as a non-invasive and cost-effective initial screening method. Elevated levels of these antibodies indicate an immune response to gluten and suggest the presence of celiac disease. Doctors will then proceed with a biopsy to confirm the diagnosis and assess the extent of intestinal damage. 

By conducting celiac blood tests first, doctors can identify individuals who are likely to have celiac disease without subjecting them to the discomfort and risks associated with a duodenal biopsy. This approach allows for a more efficient diagnostic process, minimizing unnecessary invasive procedures for individuals less likely to have celiac disease based on negative serological test results, while ensuring that those with positive results receive appropriate follow-up for confirmation and management.

Let's discuss the various blood markers that are commonly ordered as part of a comprehensive celiac profile for diagnosing and monitoring celiac disease:

tTG-IgA

When people with celiac disease are exposed to gluten, the immune system produces antibodies against an enzyme called tissue transglutaminase. The tissue transglutaminase IgA (tTG-IgA) measures the amount of circulating tTG antibodies and is the preferred celiac disease serologic test. Research shows that this test has a sensitivity of 78-100% and specificity of 90-100% (2). The American College of Gastroenterology (ACG) recommends using tTG-IgA as the first-line test for patients older than two years old with suspected celiac disease. 

EMA-IgA

The serum endomysial antibodies (EMA) IgA detects antibodies targeting the endomysium, a layer of connective tissue surrounding muscle fibers. The EMA-IgA test has a sensitivity of 86-100% and a specificity of 97-100%. It is less preferred to tTG-IgA because it is more expensive and time-consuming. Additionally, the EMA-IgA results are qualitative rather than quantitative, making them more subjective than tTG-IgA results. Healthcare providers often reserve this test as a follow-up to tTG-IgA to make a celiac diagnosis more certain. (2)

DGP-IgA

Deamidated gliadin peptides are gluten fragments. The serum deamidated gliadin peptide IgA (DGP-IgA) test measures the presence of antibodies to these peptides. This test is less sensitive and specific than the tTG-IgA test. It is commonly utilized in conventional algorithms when there is a suspicion of celiac disease, but the tTG and EMA IgA tests are inconclusive. (2)

Total Serum IgA

IgA deficiency is more common in patients with celiac disease than in the general population. Because many of the serologic celiac disease tests rely on the presence of IgA antibodies, it is recommended to measure total serum IgA to rule out IgA deficiency and increase the accuracy of IgA test results. 

How to Interpret Your Celiac Blood Test Results: Beyond the Numbers

Interpreting celiac blood test results correctly is crucial for diagnosing celiac disease. A moderate to strong positive result indicates the presence of specific antibodies and correlates with the degree of mucosal damage. Borderline or weak positive results are less conclusive and may result from external factors interfering with the test or may indicate a lesser degree of mucosal damage. Regardless, a small intestinal biopsy should be considered to confirm the diagnosis.

A negative result means these antibodies are undetected, indicating a lower probability of celiac disease. However, a negative result does not entirely rule out the condition, especially if the individual is IgA deficient or following a gluten-free diet. 

False Positives and False Negatives: Navigating the Gray Areas 

Celiac serologic tests, while valuable, are not foolproof and can yield false positives or false negatives in certain scenarios. 

False Positives

Some autoimmune disorders, such as rheumatoid arthritis or lupus, can cause elevated tTG antibody levels, leading to a false positive celiac serology result. Examples include rheumatoid arthritis, lupus, connective tissue disease, inflammatory bowel disease, and type 1 diabetes. (6, 13)

False Negatives

Individuals with IgA deficiency might not produce enough IgA antibodies for the standard celiac serologic tests to detect, leading to false negative results. In such cases, IgG-based tests are more appropriate. (6) 

For accurate results, the individual being tested must be consuming gluten. If someone has already started a gluten-free diet before testing, it can lead to false negative results as the immune response might not be active enough for detection. (6) 

Next Steps After Blood Test Results

Individuals with positive or borderline results should be promptly referred to a gastroenterologist for a consultation and an endoscopic biopsy. This referral may also be warranted for symptomatic patients with negative celiac results when clinical suspicion remains high. An endoscopic biopsy is essential for confirming the diagnosis, assessing the extent of intestinal damage, and guiding appropriate treatment. Additional testing may also be recommended to screen for nutrient deficiencies (e.g., iron, vitamin B12) and comorbid conditions associated with celiac disease (4, 5). 

The only treatment for celiac disease is a gluten-free diet. Generally, clinical improvement is achieved within a few weeks of dietary elimination, and mucosal damage is reversed within 1-2 years. Continuous monitoring of celiac antibodies can confirm compliance with strict gluten avoidance. Serum EMA-IgA often becomes undetectable after 6-12 months of gluten withdrawal. Persistent elevations of EMA and tTG antibodies after one year indicate poor compliance to a gluten-free diet or unintended environmental exposure to gluten (4). 

Non-celiac patients who experience similar gastrointestinal symptoms when consuming gluten may have non-celiac gluten sensitivity (NCGS). The diagnosis of NCGS can be supported by symptom improvement with gluten elimination, followed by symptom recurrence with reintroduction of gluten-containing foods.

The Role of Genetics: HLA Testing for Celiac Risk

Celiac disease has a strong genetic component, and certain genetic markers, specifically human leukocyte antigen (HLA) genes, play a key role in its development. Most individuals with celiac disease carry specific HLA-DQ2 or HLA-DQ8 gene variants, which are closely linked to the disease. However, having these genetic markers does not guarantee the development of celiac disease; it merely increases the risk. Conversely, individuals without these markers are at an extremely low risk for developing celiac disease. (4, 8) 

HLA testing is valuable in several scenarios related to celiac disease. Firstly, it is particularly useful in cases where celiac serologic test results are ambiguous, especially when symptoms are present but standard tests are inconclusive. If a person tests negative for the common HLA-DQ2 and HLA-DQ8 variants, the likelihood of celiac disease is significantly reduced, which can guide healthcare providers in exploring other potential causes for the symptoms. Secondly, HLA testing is beneficial for family members of individuals diagnosed with celiac disease. It helps identify at-risk individuals, enabling early monitoring and intervention, if necessary. Moreover, in scenarios where celiac disease diagnosis is challenging, HLA testing can be part of a comprehensive diagnostic approach, providing valuable genetic information that contributes to a more accurate assessment of celiac risk and overall patient care. (10) 

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Summary

Mastering celiac blood test interpretation is paramount for healthcare practitioners to ensure accurate diagnosis and effective management of celiac disease. A comprehensive understanding of these tests empowers healthcare professionals to make informed decisions. This knowledge equips healthcare providers to confidently order celiac serology, interpret test results, differentiate between false positives and negatives, and consider the broader clinical context, ultimately leading to timely and accurate diagnoses. By pursuing continuous education and expertise in celiac blood test interpretation, healthcare practitioners can significantly enhance the quality of care provided to individuals suspected of having celiac disease, ensuring appropriate interventions and improved patient outcomes.