Chiara Maruggi, MD

Affecting approximately 1% of the population in the United States, celiac disease, an immune response due to the ingestion of gluten in genetically susceptible individuals, is the most common enteropathy.

 Studies have estimated approximately 93% of patients with duodenal villous atrophy have seropositive celiac disease, defined as the serologic presence of IgA tissue transglutaminase and/or endomysial antibodies.

When villous atrophy is found in the context of negative celiac serology testing, it presents a clinical challenge. The aim of this single-center retrospective study was to characterize the differential diagnosis of seronegative villous atrophy by reviewing clinical and histological criteria.

Conducted at a large academic medical center, this study included patients with seronegative villous atrophy seen between 2000 and 2023. Inclusion criteria were adult patients with seronegative villous atrophy, defined as histologic evidence of duodenal villous atrophy and a negative tissue transglutaminase antibody with normal total IgA. Of note, patients with positive gliadin peptide antibody and/or endomysial antibody were excluded.

Medical records were reviewed for clinical and pathological data. Patients were classified according to nomenclature proposed by the Paris consensus using predefined criteria and physician consensus.

Among 2924 patients with confirmed duodenal villous atrophy, 720 with normal total IgA and negative tissue transglutaminase antibody were included. Among this cohort, the median age was 52 years, 67% of patients were female, and 81% were White.

This abstract, presented at Digestive Disease Week in Washington, DC, in May 2024, was based on the analysis of approximately the first half of those patients with seronegative villous atrophy. Among these 376 patients, the median age was 53 years, 69% were female, and 84% were White.

After chart review, 27 (7%) patients were excluded for a prior diagnosis of seropositive celiac disease. Additionally, classification according to Paris consensus was not possible for 259 (69%) patients, primarily due to a lack of systematic evaluation and/or clinical follow-up.

Among the remaining 90 (24%) patients with enough information for classification by Paris consensus, the most common diagnoses were seronegative celiac disease (SNCD) (n = 29; 32%), Crohn’s disease (n = 17; 19%), and medication-induced, commonly immunosuppressants and olmesartan (n = 13, 14%). Other diagnoses included CVID (n = 3), HIV (n = 4), H. pylori enteritis (n = 7), eosinophilic enteritis (n = 4), idiopathic (n = 4), SIBO (n = 3), and radiation enteritis (n = 2) (Figure 1).

This study demonstrates the heterogeneous makeup of seronegative enteropathies previously described in the Paris consensus. Of the patients reviewed, only 26% could be classified using current definitions. This highlights the need for systematic evaluation and clinical follow-up for patients with villous atrophy and negative celiac serologic testing to ensure adequate diagnosis. Further studies in this field are needed to help guide clinicians on this systematic evaluation and understand the clinical implications of the various enteropathies.

Figure 1. Etiologies of seronegative enteropathies according to Paris consensus (n = 90)

Lebwohl B, Rubio-Tapia A. Epidemiology, Presentation, and Diagnosis of Celiac Disease.

. 2021;160(1):63-75. doi:10.1053/j.gastro.2020.06.098

Makharia GK, Singh P, Catassi C, et al. The global burden of coeliac disease: opportunities and challenges. 

. 2022;19(5):313-327. doi:10.1038/s41575-021-00552-z

Aziz I, Peerally MF, Barnes JH, et al. The clinical and phenotypical assessment of seronegative villous atrophy; a prospective UK centre experience evaluating 200 adult cases over a 15-year period (2000-2015).

. 2017;66(9):1563-1572. doi:10.1136/gutjnl-2016-312271

Schiepatti A, Sanders DS, Baiardi P, et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus.

. 2022;71(11):2218-2225. doi:10.1136/gutjnl-2021-326645

Articles

Findings suggest a heterogeneous makeup of seronegative enteropathies, presenting difficulty in diagnosing patients with villous atrophy and negative celiac serologic testing.

The Clinical Challenge of Seronegative Villous Atrophy: A Preview 

Almost a quarter of the population in the United States has 

. Due to its prevalence, it is important for clinicians to understand the management of GERD and its most common complication, erosive esophagitis.

 Current guidelines recommend the use of proton pump inhibitors (PPIs) as the first-line treatment of erosive esophagitis; however, up to 30% of patients with severe esophagitis may not respond to PPI therapy alone.

 Previous studies conducted in Asia have identified vonoprazan, a potassium-competitive acid blocker (PCAB), as an alternative, potentially superior treatment for erosive esophagitis. Not only did vonoprazan lead to higher rates of healing, but also negated the need for dosing around meals—a well-known restriction of PPI therapy due to their short half-life.

In this randomized, double-blind, parallel-group, non-inferiority multicenter trial conducted at 111 sites in the United States and Europe from November 2019 to November 2020, vonoprazan was compared to the approved doses of lansoprazole for healing and maintenance of healing in patients with erosive esophagitis over a 32-week period. All adult patients with endoscopic evidence of erosive esophagitis, without 

 infection, Barrett’s esophagus, or COVID-19 infection were included. A total of 1027 patients with erosive esophagitis, 351 (34.3%) of which had Los Angeles Classification (LA) Grade C/D esophagitis, were first randomized to vonoprazan 20 mg (n = 514) or lansoprazole 30 mg (n = 513) for the healing phase of the study, which lasted up to 8 weeks.

The 893 subjects who achieved healing during this phase (confirmed by endoscopy at week 2 or 8 if no healing achieved at week 2) entered the maintenance phase and were randomized to either vonoprazan 20mg (N=298), vonoprazan 10mg (N=298), or lansoprazole 15mg (N=297) for 24 weeks. At the end of the maintenance phase, a final endoscopy was done. Patients recorded symptom severity and attended regular follow-up visits throughout the study period.

For the healing phase, vonoprazan was not only shown to be noninferior but also superior to lansoprazole for the primary endpoint of healing by week 8 (92.9% vs 84.6%; 

<.0001) The treatment effect was even greater with a 20% difference in healing at week 8 in LA Grade C/D patients. In addition, secondary endpoints showed vonoprazan to be noninferior to lansoprazole in mean 24-hour heartburn-free days (81.3% vs 78.3%). For the maintenance phase, both doses of vonoprazan were noninferior to lansoprazole for the primary endpoint of maintenance of healing at week 24 (vonoprazan 20 mg, 80.7%, vonoprazan 10 mg, 79.2%, lansoprazole, 72.0%; 

<.0001 or both) and both doses of vonoprazan were superior to lansoprazole for maintenance of healing at week 24 with a 16% and 13% difference, respectively, in LA Grade C/D esophagitis.

When looking at the safety of the study medications, vonoprazan was found to induce a higher gastrin level compared to lansoprazole—an important consideration given the concern that hypergastrinemia can potentially lead to gastric and/or esophageal malignancy. Comparison of the gastric histology amongst the study groups, however, did not show significant changes except for a slightly higher proportion of patients in the vonoprazan 20 mg group (compared to the lansoprazole group) having enterochromaffin-like cell hyperplasia at the end of maintenance therapy (4.9% vs 1.2%).

Overall, this large, multicenter double-blind randomized trial showed vonoprazan to be superior to lansoprazole in the healing and maintenance of healing in patients with erosive esophagitis without H

 infection. While more studies are needed to ensure the safety of long-term therapy with PCABs, this study establishes a role for the use of vonoprazan in the healing and maintenance of healing in patients with erosive esophagitis, particularly those with LA Grade C/D esophagitis.

Nirwan JS, Hasan SS, Babar ZU, Conway BR, Ghori MU. Global Prevalence and Risk Factors of Gastro-oesophageal Reflux Disease (GORD): Systematic Review with Meta-analysis. 

. 2020;10(1):5814. Published 2020 Apr 2. doi:10.1038/s41598-020-62795-1

Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. 

. 2022;117(1):27-56. doi:10.14309/ajg.0000000000001538

Lightdale CJ, Schmitt C, Hwang C, Hamelin B. A multicenter, randomized, double-blind, 8-week comparative trial of low-dose esomeprazole (20 mg) and standard-dose omeprazole (20 mg) in patients with erosive esophagitis [published correction appears in Dig Dis Sci. 2006 May;51(5):851. Dosage error in article text]. Dig Dis Sci. 2006;51(5):852-857. doi:10.1007/s10620-005-9071-3

Ashida K, Sakurai Y, Nishimura A, et al. Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis. Aliment Pharmacol Ther. 2015;42(6):685-695. doi:10.1111/apt.13331

While more studies are needed to ensure the safety of long-term therapy with PCABs, this study establishes a role for the use of vonoprazan in the healing and maintenance of healing in patients with erosive esophagitis.

Vonoprazan for the Treatment of Erosive Esophagitis: A Randomized Controlled Trial

While colorectal cancer remains the third leading cause of death in the United States, mortality rates have been declining in the past several years.

This decline has largely been attributed to the effectiveness of preventive and early-detection screening strategies advocated for by the US Preventive Services Task Force (USPTF) and other medical societies and including colonoscopy, flexible sigmoidoscopy, fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), and computed colonography.

While the most robust evidence exists for screening using FOBT and flexible sigmoidoscopy testing, colonoscopy has become the leading endoscopic screening in the United States partially due to its inferred benefit in reducing colorectal cancer mortality by increasing detection and removal of polyps throughout the colon.

Other countries, however, have not adopted this screening modality partially due to the lack of strong evidence to support this practice.

In the Nordic-European Initiative on Colorectal Cancer (NordICC) study, Bretthauer et al. aimed to study the effects of population-based colonoscopy screening on the risks of colorectal cancer and related death at 10 years through a large, multicenter randomized trial in geographic areas where colorectal cancer screening programs were not available at the time of study enrollment.

Investigators enrolled 84,585 participants aged 55 – 64 years old from Poland, Norway, and Sweden in this pragmatic study and randomly assigned them in a 1:2 ratio to either receive an invitation for first-time colonoscopy screening or no invitation, respectively. 

The primary end points for the trial were the risk of colorectal cancer and death from the disease (median follow-up, 10 years) and the secondary end point was death from any cause.

Of the cohort randomized to invitation for first-time colonoscopy screening, participation ranged widely across different countries (from 33% in Poland to 60.7% in Norway) as well as across different genders and age groups, with screening being more likely to be completed by older individuals and males. Further, while the bowel preparation was noted to be adequate in >90% of colonoscopies in all regions, the adenoma detection rates (ADR) ranged from 14.4% (Sweden) to 35.2% (Poland). 

These rates are in comparison to the 25% ADR benchmark recommended by the American College of Gastroenterology (ACG) and American Society of Gastrointestinal Endoscopy (ASGE) for a high-quality endoscopist.

Using an intention-to-treat analysis and Kaplan-Meier estimator, cumulative 10-year risks of colorectal cancer and colorectal cancer-related death in the 2 cohorts were calculated.The risk of colorectal cancer at 10 years was 0.98% in the invited group (95% confidence interval [CI], 0.86 - 1.90) vs. 1.20% in the usual-care group (95% CI, 1.10 - 1.29) with a calculated risk ratio of 0.82 (95% CI, 0.70 - 0.93).

Surprisingly, neither colorectal cancer-related death at 10 years (screening group, 0.28% vs usual care group, 0.31%) nor all-cause mortality (11.03% vs 11.04%) were found to be statistically different between the 2 groups.

But regarding the per-protocol adjusted analyses for the 42% of participants that did undergo colonoscopy screening, there was a significant 31% reduction in the risk of colorectal cancer and 50% reduction in colorectal cancer-related death in the screening group as compared to the usual-care group. These findings would appear to support the notion that completed colonoscopies do in fact significantly reduce the risk of colorectal cancer and mortality from this disease as previously shown, in even greater degrees, in previous studies.

While the well-designed, population-based NordICC study does pose some questions of the success of a colonoscopy screening program in reducing incidence and mortality of colorectal cancer, there are several limitations. In addition to the low ADR noted earlier, these limitations include the unclear baseline characterists of this seemingly homogenous population, as well as the low participation rate in the colonoscopy screening—which stands in contrast to the >80% screening participation rate seen in a previous randomized controlled trial showing a mortality benefit of colorectal cancer screening via FOBT.

Finally, focusing on the length of follow-up time, perhaps the largest limitation in the study is the relatively small length of follow-up—defined by initial enrollment and randomization rather than screening completion—placing this trial at risk of being under-powered to detect a difference in the primary end points, particularly in mortality from colorectal cancer.

Despite these limitations, an overall important takeaway of this project is the importance for clinicians to ensure patient colonoscopy screening, and to continue to work in furthering community awareness of colorectal cancer screening and removing barriers to its access. Further randomized control trials will be needed to guide colorectal cancer screening recommendations.

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022 Jan;72(1):7-33. doi: 10.3322/caac.21708. Epub 2022 Jan 12. PMID: 35020204.

Ladabaum U, Dominitz JA, Kahi C, Schoen RE. Strategies for Colorectal Cancer Screening. Gastroenterology. 2020 Jan;158(2):418-432. doi: 10.1053/j.gastro.2019.06.043. Epub 2019 Aug 5. PMID: 31394083.

Helsingen LM, Kalager M. Colorectal cancer screening — approach, evidence, and Future Directions. NEJM Evidence. 2022 Jan;1(1). doi: 

Bretthauer M, Løberg M, Wieszczy P, Kalager M, Emilsson L, Garborg K, Rupinski M, Dekker E, Spaander M, Bugajski M, Holme Ø, Zauber AG, Pilonis ND, Mroz A, Kuipers EJ, Shi J, Hernán MA, Adami HO, Regula J, Hoff G, Kaminski MF; NordICC Study Group. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022 Oct 27;387(17):1547-1556. doi: 10.1056/NEJMoa2208375. Epub 2022 Oct 9. PMID: 36214590.

Anderson JC, Butterly LF. Colonoscopy: quality indicators. Clin Transl Gastroenterol. 2015 Feb 26;6(2):e77. doi: 10.1038/ctg.2015.5. PMID: 25716302; PMCID: PMC4418496.

Shaukat A, Mongin SJ, Geisser MS, Lederle FA, Bond JH, Mandel JS, Church TR. Long-term mortality after screening for colorectal cancer. N Engl J Med. 2013 Sep 19;369(12):1106-14. doi: 10.1056/NEJMoa1300720. PMID: 24047060.

A northern Europe-based trial highlights the potential impact of streamlined and community-supported colonoscopy screening for cancer.