Tag Archives: refractory celiac disease

What To Do For Pediatric Patients with Non-Responsive Celiac Disease

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AA Ibrahim et al. JPGN 2022; 75: 616-622. Budesonide and the Gluten Containing Elimination Diet as Treatments for Non-responsive Celiac Disease in Children

Background: Non-responsive celiac disease (NRCD) may affect up to 15% of children with CD. A Gluten Containing Elimination Diet (GCED) is a more stringent diet consisting of fresh, whole, and unprocessed naturally gluten-free foods (MM Leonard et al. Nutrients 2017; 9: 1129. Open Access! Indications and Use of the Gluten Contamination Elimination Diet for Patients with Non-Responsive Celiac Disease).

Methods: In this 5-year retrospective study, the authors identified 22 patients with NRCD; they were following a gluten-free diet for at least 12 months but had persistent symptoms and enteropathy (Marsh 3). Treatments for NRCD were either a GCED (n=13), budesonide (n=9) or both (n=4). Four patients were lost to follow-up and did not receive either treatment.

Key findings:

  • Thirteen were treated with the GCED for 3 months with 46% achieving both histological and symptomatic resolution
  • Nine patients were treated with budesonide (6–9 mg daily), with 89% achieving both symptomatic and histologic resolution after a median 3-month treatment course
  • 67% of patients who responded to the GCED and 100% of patients who responded to budesonide remained in remission for at least 6 months following treatment transition back to exclusive GFD

My take: This important article shows that many patients thought to be receiving a GFD can respond to a more stringent approach. In addition, it offers an alternative strategy with budesonide which had a high response rate.

Related article: PHR Green et al. Gastroenterol 2022; 163: 1461-1469. Open Access! AGA Clinical Practice Update on Management of Refractory Celiac Disease: Expert Review These recommendations are for adults with refractory celiac disease.

Best Practice Advice 1

In patients believed to have celiac disease who have persistent or recurrent symptoms or signs, the initial diagnosis of celiac disease should be confirmed by review of prior diagnostic testing, including serologies, endoscopies, and histologic findings.

Best Practice Advice 2

In patients with confirmed celiac disease with persistent or recurrent symptoms or signs (nonresponsive celiac disease), ongoing gluten ingestion should be excluded as a cause of these symptoms with serologic testing, dietitian review, and detection of immunogenic peptides in stool or urine. Esophagogastroduodenoscopy with small bowel biopsies should be performed to look for villous atrophy. If villous atrophy persists or the initial diagnosis of celiac disease was not confirmed, consider other causes of villous atrophy, including common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy.

Best Practice Advice 3

For patients with nonresponsive celiac disease, after exclusion of gluten ingestion, perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, lactose or fructose intolerance, and small intestinal bacterial overgrowth.

Best Practice Advice 4

Use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies to distinguish between subtypes of refractory celiac disease and to exclude enteropathy-associated T-cell lymphoma. Type 1 refractory celiac disease is characterized by a normal intraepithelial lymphocyte population and type 2 is defined by the presence of an aberrant, clonal intraepithelial lymphocyte population. Consultation with an expert hematopathologist is necessary to interpret these studies.

Best Practice Advice 5

Perform small bowel imaging with capsule endoscopy and computed tomography or magnetic resonance enterography to exclude enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis at initial diagnosis of type 2 refractory celiac disease.

Best Practice Advice 6

Complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies in patients diagnosed with refractory celiac disease. Check albumin as an independent prognostic factor.

Best Practice Advice 7

Correct deficiencies in macro- and micronutrients using oral supplements and/or enteral support. Consider parenteral nutrition for patients with severe malnutrition due to malabsorption.

Best Practice Advice 8

Corticosteroids, most commonly open-capsule budesonide or, if unavailable, prednisone, are the medication of choice and should be used as first-line therapy in either type 1 or type 2 refractory celiac disease.

Best Practice Advice 9

Patients with refractory celiac disease require regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy. Identify local experts with expertise in celiac disease to assist with management.

Best Practice Advice 10

Patients with refractory celiac disease without response to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials.

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Unrelated article: NPR (12/11/22) Authorities are urging indoor masking in major cities as the ‘tripledemic’ rages

Link: CDC Covid Weekly Tracker -lots of interesting data and information

Canyon Road Artwork in Santa Fe

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Treatment of Refractory Celiac Symptoms with a Low FODMAP Diet

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F van Megen et al. Clin Gastroenterol Hepatol 2022; 20: 2258-2266. Open Access! A Low FODMAP Diet Reduces Symptoms in Treated Celiac Patients With Ongoing Symptoms–A Randomized Controlled Trial

Methods: A randomized controlled trial was performed from 2018 to 2019 in 70 adults with biopsy-proven celiac disease. Inclusion criteria were as follows: persistent gastrointestinal symptoms defined by a Gastrointestinal Symptom Rating Scale (GSRS)–IBS version score of 30 or higher, gluten-free diet adherence for 12 months or longer, and serologic and mucosal remission. 

Key findings:

  • Compared to placebo-treated patients, there was significant improvement in pain, bloating, diarrhea and satiety, based on GSRS-IBS scores, in those assigned to a low FODMAPs diet (see below)

While this a low FODMAP diet can be helpful, the authors offer this cautionary advice:

  • “Following 2 complex diets increases the risk of inadequate nutritional intake, and patients should be followed up carefully. A low FODMAP diet should not be recommended to patients at nutritional risk or to patients at risk of developing an eating disorder.”
Figure 2 in Article

My take: Asking patients with celiac disease to further restrict their diet is akin to running the Peachtree Road Race in a fireman’s outfit. It can be done but doesn’t look like much fun.

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Celiac Disease: “Ten Things That Every Gastroenterologist Should Know”

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Turns out that a recent review (AS Oxentenko, JA Murray. Clin Gastroenterol Hepatol 2015; 13: 1396-1404) is a succinct summary on celiac disease with questions focused on diagnosis, endoscopy, genetics/HLA typing, at risk groups, management, adherence, non responsive celiac patient, and refractory patients.  Most of these topics have been addressed previously on this blog.

However, here are a few pointers:

  • “Histologic improvement is slow in adults…Mucosal recovery, defined by a villous:crypt ratio of 3:1, was present in 34% at 2 years and 66% at 5 years, with healing complete in 90% by 9 years.”
  • “Mucosal recovery is faster and more complete in children, with 95% recovery in 2 years and 100% recovery long-term in children following a GFD.”
  • With nonresponsive celiac disease, “defined as a lack of response to 6 months on a GFD or a recurrence of celiac-related features despite compliance,” the authors recommend reviewing serology and biopsies.  Other etiologies to consider include bacterial overgrowth, autoimmune enteropathy, tropical sprue, Crohn’s disease, combined variable immunodeficiency, collagenous sprue, and eosinophilic gastroenteritis.
  • For refractory celiac disease with ongoing villous atrophy, this “should prompt immunophenotyping and T-cell rearrangement studies” of duodenal biopsies.

Briefly noted: ET Jensen et al. Clin Gastroenterol Hepatol 2015; 13: 1426-31.  The authors examined 88,517 patients who had undergone both esophageal and duodenal biopsies.  “Odds of EoE (eosinophilic esophagitis) were 26% higher in patients with celiac disease than in patients without celiac disease” (adjusted odds ratio 1.26).

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From the High Line, NYC

From the High Line, NYC

Can an Altered Microbiome Explain Persistent Symptoms in Treated Celiac Disease?

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A recent study (Am J Gastroenterol dii:10.1038/ajg.2014.355) from Helsinki examined 177 patients with celiac disease.  Their goal was to investigate whether altered intestinal microbiota may be associated with persisting gastrointestinal symptoms in celiac patients who had been following a strict gluten-free diet (GFD) for at least 3 years.

After administering a questionnaire (Gastrointestinal Symptom Rating Scale or GSRS) to those with negative celiac antibodies and normal small bowel mucosa (n=164), the researchers identified the 18 subjects with the highest total score (persistent symptom group) and compared them to the 18 subjects with the lowest total score.  Three duodenal biopsies during endoscopy had been frozen and were subsequently analyzed for their microbial DNA.  In each group, one microbial profile was unsuccessful.

Key findings:

  • In the persistent symptom group, there was lower relative abundance of Bacteroidetes (15% vs. 25%, P=0.01), lower Firmicutes (33% vs 46%, P=0.05) and higher relative abundance of Proteobacteria (40% vs 21%, P=0.04).
  • The “microbial richness,” measured as a number of detected genera or operational taxonomic units (OTUs), was reduced in patients with persistent symptoms.  On average, patients with persistent symptoms had 32 genera and 72 OTUs per sample; in contrast, those without symptoms, on average had 37 genera and 106 OTUs.

Some of the strengths of this study include the normal villous architecture for all of the patients; this helps exclude refractory celiac disease as an etiology for the persistent symptoms.  In the discussion, the authors note that the “intestinal microbiota composition in healthy adults is relatively stable and can tolerate normal stress in the intestine caused by, e.g. daily changes in diet.” The speculate that long-term untreated celiac disease “may disrupt a stable intestinal microbiota community that, in some patients, could then reform in a dysbiotic state.”

The limitations of this study include the difficulty of excluding small intestinal bacterial overgrowth which could be related and the difficulty of excluding coexisting irritable bowel syndrome.  Like most studies regarding the micro biome, this study cannot “show causality or distinguish the effects of different bacteria to the persistent symptoms.”

Bottomline: Treated celiac patients with persistent symptoms have a different duodenal microbiome compared to treated celiac patients whose symptoms resolved with a gluten-free diet.

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“Gluten-Related Disorders” (Part 2)

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Non-celiac Gluten Sensitivity NCGS -Focused discussion in Section III
  • No biologically measurable response has been found – these are people with normal celiac serology (neg ttg/ema) and normal biopsies.
  • Specific discussions regarding autism and schizophrenia.  On page 44, authors note that a 2008 Cochrane review concluded the evidence for a gluten-free diet for autism was poor.  In 2012, a two-stage RCT (Whiteley et al) of gluten-free casein-free diet reported significant group improvements after 8 and 12 months on diet. Thus, diet may be helpful.
  • Other chapters allude to NCGS as well.  Page 124: “There are no epidemiologic studies assessing the prevalence of NCGS. Bizzaro et al estimated that for every one person with CD, there are at least six to seven with gluten sensitivity.”
Wheat Allergy -Section IV
  • Forms include oral food allergy, “wheat-dependent, exercise-induced anaphylaxis,” and Baker’s asthma (aerosolized exposure).
  • Skin prick tests or RAST’s are notorious for providing a high rate of false-positive results.  Low rate of false negative results, though, are noted.

Treatment -Section VI:

  • This section provides a number of tables to assist with diet and hidden sources of gluten.
  • GFD may lead to specific nutrient deficiencies: fiber, iron, folate, niacin, zinc, vitamins B12, A, D, E, and K; also, GFD may be higher in fat.

Psychological Aspects -Section VII:

 “The family has to buy gluten-free foods and all members have to learn how to avoid contaminating gluten-free foods, dishes, toasters, and so on.” Parents have to read all food labels and prepare special meals while attending social events.
A nice sample letter is included on page 129 –should make a good EPIC smartphrase.
Difficult Cases -Section VIII:
  • Labs to check in sick CD patient (Table 2 -page 133).
  • Causes of Nonresponse to GFD: poor compliance, accidental ingestions, nonceliac disease causing symptoms.
  • While some of the authors state that true refractory disease is “rare in adults,extremely rare in children,” in other parts of the book it is noted that complete histologic response is not seen in all patients (some with apparently good adherence).

IgA deficiency (page 139).

  • 85-90% of IgA deficient patients have no clinical symptoms.  Occurs in about 1 in 300.  For those with symptoms, manifestations could include sinopulmonary disease, allergy/atopy, autoimmune diseases, giardiasis/infections, and transfusion reactions (against IgA) (see Table 8 on page 143).
  • Transiently low IgA is common in children <4 years.
  • For IgA deficient patients, risk of CD is 10-20 times general population.
  • In true deficiency, level is typically <7 mg/dL.  More often, there is a partial deficiency which is ‘almost always asymptomatic.’  In partial IgA deficiency, IgA assays identify about 90% of CD cases.
Also, in the difficult cases section an algorithm for follow-up of newly diagnosed CD is presented and discussed (page 154).  Recommendations include nutritional counseling, resource identification, family screening, and celiac education.  Consider checking iron status, vitamin D, folate, zinc, copper and DEXA.  Recommends followup serology 6 months following diagnosis and if normal, then on a yearly basis.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.