AGA Clinical Practice Update on Diagnosis and Monitoring of Celiac Disease—Changing Utility of Serology and Histologic Measures: Expert Review (S Husby et al. Gastroenterol 2019; 156: 885-89)
Best Practice Advice 1: Serology is a crucial component of the detection and diagnosis of CD, particularly tissue transglutaminase–immunoglobulin A (TG2-IgA), IgA testing, and less frequently, endomysial IgA testing.
Best Practice Advice 2: Thorough histological analysis of duodenal biopsies with Marsh classification, counting of lymphocytes per high-power field, and morphometry is important for diagnosis as well as for differential diagnosis.
Best Practice Advice 2a: TG2-IgA, at high levels (> ×10 upper normal limit) is a reliable and accurate test for diagnosing active CD. When such a strongly positive TG2-IgA is combined with a positive endomysial antibody in a second blood sample, the positive predictive value for CD is virtually 100%. In adults, esophagogastroduodenoscopy (EGD) and duodenal biopsies may then be performed for purposes of differential diagnosis.
Best Practice Advice 3: IgA deficiency is an infrequent but important explanation for why patients with CD may be negative on IgA isotype testing despite strong suspicion. Measuring total IgA levels, IgG deamidated gliadin antibody tests, and TG2-IgG testing in that circumstance is recommended.
Best Practice Advice 4: IgG isotype testing for TG2 antibody is not specific in the absence of IgA deficiency.
Best Practice Advice 5: In patients found to have CD first by intestinal biopsies, celiac-specific serology should be undertaken as a confirmatory test before initiation of a gluten-free diet (GFD).
Best Practice Advice 6: In patients in whom CD is strongly suspected in the face of negative biopsies, TG2-IgA should still be performed and, if positive, repeat biopsies might be considered either at that time or sometime in the future.
Best Practice Advice 7: Reduction or avoidance of gluten before diagnostic testing is discouraged, as it may reduce the sensitivity of both serology and biopsy testing.
Best Practice Advice 8: When patients have already started on a GFD before diagnosis, we suggest that the patient go back on a normal diet with 3 slices of wheat bread daily preferably for 1 to 3 months before repeat determination of TG2-IgA.
Best Practice Advice 9: Determination of HLA-DQ2/DQ8 has a limited role in the diagnosis of CD. Its value is largely related to its negative predictive value to rule out CD in patients who are seronegative in the face of histologic changes, in patients who did not have serologic confirmation at the time of diagnosis, and in those patients with a historic diagnosis of CD; especially as very young children before the introduction of celiac-specific serology.
Best Practice Advice 10: Celiac serology has a guarded role in the detection of continued intestinal injury, in particular as to sensitivity, as negative serology in a treated patient does not guarantee that the intestinal mucosa has healed. Persistently positive serology usually indicates ongoing intestinal damage and gluten exposure. Follow-up serology should be performed 6 and 12 months after diagnosis, and yearly thereafter.
Best Practice Advice 11: Patients with persistent or relapsing symptoms, without other obvious explanations for those symptoms, should undergo endoscopic biopsies to determine healing even in the presence of negative TG2-IgA.
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A recent retrospective study (E Benelli et al. JPGN 2019; 68: 547-51) examines a large cohort of patients (=700) who were diagnosed with celiac disease (CD) from 2010-2016 and had available liver transaminases.
- ALT values >40 U/L were elevated in only 3.9% (27/700)
- Younger age (<4.27 years) correlated with a higher risk of liver involvement with OR 3.73
- Of these 27 patients with elevated ALT, 18 had adequate followup. All but 3 patients normalized ALT values after at least 1 year; of these, 1 was diagnosed with sclerosing cholangitis. In the other two, one was thought to be nonadherent with gluten-free diet and one had dropped ALT to 47 U/L.
- Thus, definitive autoimmune liver disease was identified in only one patient
My take: This study shows a lower rate of liver involvement than previous studies.
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A recent study (AS Faye et al. Clin Gastroenterol Hepatol 2019; 17: 463-8) finds a weak link in the screening guidelines for celiac disease. Generally, guidelines recommend screening all symptomatic first degree relatives and consider screening of asymptomatic first-degree relatives. Yet, little is known about adherence to these guidelines.
The authors utilized emergency contact information from the electronic records of 2081 patients with biospy-diagnosed celiac disease to assess how commonly celiac disease testing occurs in patients who are first-degree relatives.
- Of the 539 relatives identified, 212 (39.3%) were tested for celiac disease including 193 of 383 (50.4%) of first-degree relatives and 118 of 165 (71.5%) of symptomatic first-degree relatives.
- Of the 383 first-degree relatives, only 116 (30.3%) had a documented family history of celiac disease.
Thus, this study shows that ~30% of symptomatic first degree relatives have not received celiac testing and that ~70% of all first-degree relatives do not have a documented family history.
My take: If a family history of celiac disease is not conveyed to health care providers, this greatly reduces the likelihood that symptomatic first degree relatives will undergo recommended screening. This weakness in screening could be overcome by either:
- changing to a policy which encourages screening all first degree relatives, whether symptomatic or asymptomatic
- leveraging technology (when feasible) to assure that family history is documented in all at risk patients
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A recent study (RS Choung et al. Gastroenterol 156: 582-91) showed that synthetic neoepitopes of the transglutaminase-deamidated gliadin complex are better noninvasive biomarkers for detecting celiac disease and for monitoring mucosal healing.
Link to Graphical Abstract and Abstract: Synthetic Neoepitopes of the Transglutaminase–Deamidated Gliadin Complex as Biomarkers for Diagnosing and Monitoring Celiac Disease
The authors studied the serum samples from 90 patients with Celiac disease (CD) and from 79 healthy controls and developed a fluorescent peptide microarray platform Then, the authors validated their findings in 82 patients with newly diagnosed CD and 217 controls.
- 7% of patients with treated (with gluten free diet [GFD]) and healed CD had positive TTG-IgA and 27% of patients treated but unhealed CD mucosa had positive TTG IgA
- With the synthetic neoepitopes, CD was identified with 99% sensitivity and 100% specificity. The assay identified patients with CD with healed mucosa with an 84% sensitivity and 95% specificity.
My take: More precise noninvasive markers like these should help identify individuals with celiac disease and those who have responded (or not) to the recommended gluten free diet.
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Unrelated but important —NPR reports on another large study showing that MMR does not cause autism -Link: A Large Study Provides More Evidence That MMR Vaccines Don’t Cause Autism
Related blog post: “Too many vaccines and autism” debunked
Link to full text of study from Annals of Internal Medicine: Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study
The blog post alludes to the ‘lost boys of Sudan.’ Between 1987-2005, there were more than 20,000 Sudanese boys displaced by the civil wars in Sudan.
With regard to Celiac disease (CD), the problem is no where near as dire. However, the authors of a recent abstract note poor follow-up for pediatric celiac disease and speculate that this could lead to worsened outcomes (NAPSGHAN Annual Meeting 2018; abstract 105 cited in gastroendonews.com: Clinicians Fumbling Follow-up For Celiac Kids). Those without followup may have suboptimally-treated CD which could lead to vitamin deficiencies, and autoimmune diseases.
- “We lost 25% in the first year and half within three years.” Patients were considered lost to follow-up if they did not attend a visit with a celiac specialist for 18 months.
There has been data documenting even higher rates of poor follow-up among adults with celiac disease: Closer followup for Celiac disease & pediatric guidelines (2012)
My take: Celiac disease may have higher rates of poor follow-up than other GI conditions since symptoms may be minimal in many; however, poor followup is commonplace throughout medicine and contributes to worsened outcomes
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A recent multicenter retrospective study (MJ Gould et al. JPGN 2019; 68: 20-5) shows that deamidated gliadin peptide (DGP) is rarely helpful in screening for celiac disease when tissue transglutaminase IgA is negative. The study identified 40 patients who had a mean age of 6.5 years at time of intestinal biopsy.
- Of the 40 patients with DGP (IgG) positivity, only 1 patient (2.5%) had celiac disease; this patient was IgA deficient.
- Among the five IgA deficient patients, only 1 with DGP positivity had celiac disease.
- The cohort included 6 patients with DGP levels >250 U/mL (refernece <12).
- Only 5 patients in this DGP positive cohort were younger than 2 years. None had celiac disease
My take: This retrospective study indicates that DGP is rarely helpful in patients with negative TTG IgA results. However, this study had too few patients who were <2 years of age and/or IgA-deficient patients to determine its utility in these groups..
Related study: AK Verma et al. JPGN 2019; 68: 26-29. This study from Italy examined oral hygiene products and determined that 62 (94%) were gluten-free (gluten level <20 ppm). Among the 4 with detectable gluten, 3 were toothpastes and 1 lipstick with values between 20.7 adn 35 ppm. My take: Oral hygiene products have very low rates of gluten contamination.
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Here’s a link to a well-described case report. Her Searing Gut Pain Suggested Celiac Disease. Why Didn’t Cutting Out Gluten Help?
This 57 year old with ‘presumptive’ celiac disease did not improve with a gluten-free diet. After an initial self-diagnosis and subsequently an endoscopy that also suggested celiac disease, she did not improve. While the doctors involved in her care had labeled her ‘noncompliant,’ it turns out she did NOT have celiac disease and improved after the right diagnosis (diagnosis noted at bottom of this post).
My take: There are several entities that can mimic celiac disease (even histologically), including Crohn’s disease, Autoimmune enteropathy, CTLA4 deficiency, and Whipple’s disease (the diagnosis in this case). When someone is not getting better, the diagnosis needs to be reconsidered.