Updated AGA Practice Guideline on Evaluating and Managing Seronegative Enteropathies

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To improve the assessment and management of patients with seronegative enteropathies, the AGA reviewed studies that reported on the management of patients with suspected celiac disease or other enteropathies not related to gluten who had received negative results from serologic tests.

In an update to their clinical practice guideline on the evaluation and management of seronegative enteropathies, the American Gastroenterological Association (AGA) provides 8 best practice recommendations on appropriate tests for the diagnosis of celiac disease, assessment of dietary patterns at time of serologic testing, and medication therapy for seronegative patients with celiac disease refractory to dietary intervention. The new AGA practice update was published in a recent edition of Gastroenterology.

Seronegative enteropathy, which is frequently encountered by gastroenterologists in clinical practice, is typically represented by some level of villous atrophy (often caused by celiac disease) as well as negative tissue transglutaminase (tTG), anti-endomysial antibody (EMA), and deamidated gliadin peptide (DGP).

To improve the assessment and management of patients with seronegative enteropathies, the AGA performed a review of cohort studies, case-control studies, cross-sectional studies, case series, and descriptive studies that reported on the management of patients with suspected celiac disease or other enteropathies not related to gluten who had received negative results from serologic tests. A review of these studies yielded 8 recommendations for best practices.

  • Join forces with specialized pathologists. The AGA recommends gastroenterologists review histologic findings of patients with seronegative enteropathies with pathologists specialized in gastroenterology. These specialized pathologists should be able to confirm the presence of villous atrophy. The guideline recommends clinicians consider describing histologic findings in the duodenum by using the Corazza-Villanacci classification. Also, the AGA update suggests clinicians consult with experienced pathologists to confirm orientation of the duodenal tissue and to examine for signs of other enteropathy etiologies in patients with seronegative enteropathy.
  • Use serologic tests for accurate celiac disease diagnosis. Clinicians should measure total immunoglobulin A (IgA) in patients who describe and demonstrate classic signs and symptoms of celiac disease but who test negative on serologic tests, the guideline states. In addition, anti-tTG, IgA against deamidated gliadin peptide, and EMA (IgA) should also be tested. A diagnosis of celiac disease with selective IgA deficiency should be considered for patients with total IgA levels below the lower limit of detection and IgG against tTG, DGP, or EMA.
  • Evaluate diets and analyze duodenal biopsies. The guideline recommends that the dietary patterns of patients with suspected celiac disease be evaluated in conjunction with collection and examination of duodenal biopsy samples at time of serologic testing. This will help determine gluten exposure. Patients should not refrain from consuming gluten before diagnostic testing, and clinicians should discourage reducing gluten beyond the patient’s normal levels of intake. Reducing or eliminating gluten prior to testing will reduce the accuracy of histologic and serologic results.
  • Collect thorough medication histories. A detailed medication history should be obtained from patients with seronegative enteropathy. Specific focus should be placed on past and/or current use of angiotensin 2 receptor blockers, such as olmesartan. Additionally, clinicians are encouraged to conduct a thorough review of the patient’s travel history to identify possible etiologies of villous atrophy. The results of these reviews may guide additional testing.
  • Analyze for disease-associated genetic variants. Disease-associated variants in human leukocyte antigen genes should be assessed in seronegative individuals. Negative results, if carefully evaluated, can be used to rule out the possibility of celiac disease in patients who are seronegative.
  • Use endoscopic evaluation after a long-term gluten-free diet. An endoscopic evaluation should be performed in seronegative patients with suspected celiac disease who have villous atrophy and genetic risk factors. The endoscopic evaluation should be performed after the patient has adhered to a gluten-free diet for 1 to 3 years, as this will help in the evaluation of atrophy improvements. Clinical and histologic markers of these improvements can be used to confirm a diagnosis of seronegative celiac disease.
  • Treat the patient accordingly. Consultation with a dietitian should be encouraged for seronegative patients with a confirmed celiac disease diagnosis. In addition to regular follow-up appointments, the dietitian should be consulted prior to a repeat endoscopy to ensure the gluten-free diet is being followed correctly.
  • Initiate budesonide in cases of nonresponse to dietary changes. For patients who do not respond to a gluten-free diet, who continue to demonstrate persistent signs and symptoms of celiac disease, and for whom no etiology of the enteropathy is identified, the AGA guideline recommends initiating budesonide. An open-capsule protocol starting at 9 mg daily should be considered as the first-line treatment for refractory celiac disease. Budesonide should be slowly tapered over 9 months, depending on the patient’s symptoms.

In addition, the AGA guideline concluded that clinicians may consider following budesonide with “prednisone or azathioprine based on the patient’s clinical status and response to treatment.”

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Leonard MM, Lebwohl B, Rubio-Tapia A, Biagi F. AGA clinical practice update on the evaluation and management of seronegative enteropathies. Published online September 30, 2020. Gastroenterology. doi: 10.1053/j.gastro.2020.08.061