No-Biopsy Approach to Celiac Disease Diagnosis and Positive Predictive Value (Based on Population)

Posted on May 29, 2024 by gutsandgrowth

In medical school, I distinctly remember my anatomy professor discussing how a test’s accuracy was affected by the underlying population tested. He said, ‘Well if you do an RPR test for syphilis among prostitutes and it is abnormal, then it is likely accurate as the test performs better in a population with a higher risk of the condition. Whereas if you run the same test on the faculty, the test would perform with much less accuracy. Well, actually, may be the faculty here are not the best example…’

This discussion comes to mind with the recent publication regarding the No-Biopsy Approach for Celiac disease in adults:

MG Shiha et al. Gastroenterol 2024; 166: 620-630. Open Access! Accuracy of the No-Biopsy Approach for the Diagnosis of Celiac Disease in Adults: A Systematic Review and Meta-Analysis

In this systematic review and meta-analysis with 12,103 adult patients from 18 studies, the key findings:

The pooled prevalence of biopsy-proven celiac disease in the included studies was 62%.The proportion of patients with IgA-tTG ≥10×ULN was 32%.
The summary sensitivity of IgA-tTG ≥10×ULN was 51%, and the summary specificity was 100%
However, the positive predictive value of the no-biopsy approach to identify patients with celiac disease was 65%, 88%, 95%, and 99% if celiac disease prevalence was 1%, 4%, 10%, and 40%, respectively in hypothetical cohorts.

The associated editorial (B Lebwhol, pg 557: Moving Away From Biopsy Confirmation of Celiac Disease) notes the following:

The duodenal biopsy, long the cornerstone of a celiac disease diagnosis, has lost some of its luster in recent years. As data emerged that the specificity of tissue transglutaminase (TTG) IgA for duodenal villus atrophy increases in accordance with the degree of antibody elevation in children, in 2012 the European Society for Pediatric Gastroenterology and Nutrition adopted a biopsy-free pathway for the diagnosis of celiac disease in symptomatic children who met stringent criteria, including a ≥10-fold TTG IgA elevation and an elevated endomysial antibody on a separate blood draw.¹ With further data supporting the positive predictive value of a highly elevated TTG IgA² these guidelines were modified in 2020 to now include asymptomatic children.³

..the specificity of an elevated TTG IgA seems to be lower in people with type 1 diabetes.⁸

Studies employing a serial serology strategy, such as a ≥10-fold TTG IgA elevation that persists over a number of months, might yield specificities that are so high that that they are impervious to decreases in positive predictive values wrought by low underlying prevalences…

Most patients with celiac disease do not mount a sufficiently high TTG IgA to rely exclusively on a serological diagnosis. And the minority who do meet the stringent criteria of a biopsy-free diagnosis might wisely choose to confirm their life-long diagnosis with a biopsy.

My take: Ironically, this study, which showed that a TTG IgA ≥10 x ULN was highly indicative of celiac disease in adult patients with a 100% specificity and a positive predictive value of 98%, makes an argument for ongoing duodenal biopsies in those at lower risk for celiac disease. However, the lower positive predictive values (in some groups) are based on hypothetical cohorts. Shared decision-making is important and relying on a single elevated lab test is particularly problematic.

Related blog posts:

Does The Degree of Villous Atrophy Affect Long-Term Outcomes with Celiac Disease? Plus One

Posted on July 23, 2020 by gutsandgrowth

S Kroger et al. JPGN 2020; 71: 71-7. This study, conducted from 1966-2014, examined long-term outcomes of individuals diagnosed with celiac disease in childhood. This study examined 906 children and sent questionnaires to 503 adults (212 responded) who were diagnosed in childhood.

Key findings:

More recent diagnosis (after 2006) has been associated with children having milder lesions, more often diagnosis due to screening (rather than symptoms) 30% vs. 25%, less anemia (16% vs 21%), less growth disturbances (22% vs. 36%), and lower TTG-2 titers (mean 64 U/L vs 120 U/L.
Among adults completing questionnaire, severity of villous atrophy at childhood diagnosis did not predict complications, persistent symptoms, quality of life, or adherence with glute-free diet

RV Lopez et al. JPGN 2020; 71: 59-63. Influence of the 2012 European Guidelines in Diagnosis and Follow-up of Coeliac Children With Selective IgA Deficiency. This study showed that the guidelines were used incorrectly for individuals with selective IgA deficiency, using a 10-fold elevation of TTG IgG instead of TTG IgA. The associated editorial (pg 2 by P Gillett) recommends “we should perform endoscopy in all sIgAD patients.” In addition, this population may merit followup endoscopy at much lower threshold due to difficulty using serology for follow-up.

My take: Children with severe villous atrophy due to celiac disease can respond fully to a gluten-free diet. In the small subset of individuals with selective IgA deficiency, a no-biopsy diagnosis is not recommended.

Related blog posts:

The Non-Biopsy Diagnosis of Pediatric Celiac Disease

Posted on October 3, 2017 by gutsandgrowth

In some corners, experts have suggested the need for a followup intestinal biopsy to assure that celiac disease is responding to a gluten-free diet (Related blog post: Are followup biopsies necessary in celiac disease? Look beyond the headlines). Meanwhile, many are looking at performing zero biopsies –at diagnosis or later. A recent study (J Wolf et al. Gastroenterol 2017; 153: 410-9) involved a prospective enrollment of 898 children undergoing duodenal biopsy to confirm or rule out celiac disease (CD). Patients had tissue transglutaminase IgA (TTG IgA), total IgA and deamidated gliadin IgG (DGL-IgG) measured.

Key findings:

592 had CD and 345 did not have CD. 24 did not have a final diagnosis.
In examining non-IgA deficient patients that had either TTG IgA >10 times ULN or normal (<1 times ULN), the positive predictive value for CD was 0.988 and the negative predictive value was 0.934.
In examining patients with both TTG IgA elevation (>10 times ULN) and DGP-IgG (>10 times ULN) or normal labs, the positive predictive value (PPV) for CD was also 0.988 and the negative predictive value (NPV) was 0.958. The authors estimated that the PPV and NPV would remain >0.95 even at disease prevalence rates as low as 4%.
In this high prevalence population, the authors note that only 23% would have required an endoscopy to confirm or exclude CD; however, they note that in another study using consecutive serologic data, a much higher proportion (57%) needed biopsies due to serology that was <10 times ULN.
The authors note that HLA status genotyping, which has been recommended as needed in non-biopsy diagnosis, is not helpful. Compatible HLA status was noted in all 277 cases of TTG-IgA >10 times ULN and was deemed “unnecessary” by the study authors in those with high titers.

The ESPGHAN guidelines for non-biopsy diagnosis indicate that a repeat serologic study should be performed to exclude a sample mix-up and to only forego biopsies in symptomatic patients.

My take: This study show\ed that individuals with high celiac serology titers have celiac disease >98% of the time. This information should be discussed with families in determining whether endoscopic biopsy is needed. Among those who pursue a non-biopsy approach, some individuals could have competing etiologies for their symptoms; thus, a low threshold for evaluation is needed in those who do not respond to a gluten free diet

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

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