What is nonresponsive celiac disease?

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By Carol Semrad, MD

Celiac disease is unique among intestinal inflammatory diseases in that the trigger for inflammation, gluten, is known. This allows effective dietary treatment. Fortunately, most individuals with celiac disease have improvement in symptoms and signs (diarrhea or constipation, abdominal gas/ bloating/cramps, fatigue and anemia) within two weeks of starting a gluten-free diet. Others improve more slowly due to inadequate dietary education, inability to give up favorite gluten-containing foods, or cost. In adults, complete recovery of inflammation on intestinal biopsy may take five years or longer.

Carol Semrad, MD

Approximately 10% of adults never completely recover, however, unlike children who have near 100% recovery of intestinal inflammation in the long term. The reason for this slow recovery of intestinal inflammation in adults with celiac disease and whether it has any clinical consequence is unknown. In two studies, persistent intestinal inflammation carried no mortality risk, one study reported a higher risk for lymphoproliferative disorders.

So what is Nonresponsive Celiac Disease? This term applies to the approximately 20% of individuals diagnosed with celiac disease who have persistent symptoms or anemia with or without a positive tissue transglutaminase antibody (a molecular marker indicating celiac). The term is somewhat of a misnomer: The most common cause of Nonresponsive Celiac Disease is failure to completely exclude gluten from the diet, and most of these individuals do have improvement in intestinal inflammation compared to their baseline biopsy, suggesting at least partial diet response. In addition, upon careful review, some are found to have an incorrect diagnosis of celiac disease.

Therefore, the first step in assessment for persistent symptoms is evaluation by a registered dietitian knowledgeable in the gluten-free diet. The most common hidden culprits include medications, processed gluten-free food, gluten-contaminated oats, and restaurant meals. If, despite a stricter gluten-free diet, gastrointestinal symptoms persist, further evaluation is warranted. This usually includes a repeat endoscopy with duodenal biopsy, with further testing based on three different categories of patients.

  1. Persistent symptoms, intestinal biopsy normal: This indicates that celiac disease is well controlled on diet and either the diagnosis is incorrect or there is another cause of symptoms. The most common other causes include IBS, constipation due to low fiber in a gluten-free diet, lactose or fructose intolerance and microscopic colitis in those with predominant diarrhea. In patients who have suffered weight loss, superior mesenteric artery (SMA) syndrome should be considered due to loss of fat around the artery that can then compress the duodenum and cause obstruction.
  2. Persistent symptoms, mild inflammation/villous atrophy on intestinal biopsy: This may indicate high sensitivity to even trace amounts of gluten and may warrant a trial of a naked gluten-free diet (no oats and no processed or restaurant food). Occasionally it is due to other diseases that can cause intestinal inflammation, such as non-steroidal anti-inflammatory drugs, small intestinal bacterial overgrowth, infection, or co-existent Crohn’s Disease. Sometimes, no other cause is found and depending on symptoms and degree of inflammation, immunosuppression treatment is considered.
  3. Severe symptoms with weight loss and severe intestinal inflammation/ villous atrophy: This situation is rare, and involves 5% or less of adults with Nonresponsive Celiac Disease. These individuals have severe malabsorption and often require intravenous nutrition. Special studies of intestinal lymphocytes are needed to determine the risk for development of T-cell lymphoma. Treatment is with drugs that suppress the immune system or in the latter case chemotherapy/ bone marrow transplant. It is important in older adults to assess for the use of sartan drugs (olmesartan) used to treat hypertension. These drugs can cause severe intestinal inflammation similar to celiac disease, and these patients are often misdiagnosed as having celiac disease.

The good news is that most individuals with celiac disease have resolution of their symptoms and recovery of intestinal inflammation. Even in the Nonresponsive Celiac Disease group of adults, a stricter diet and time was favorable for complete improvement in symptoms and recovery of intestinal inflammation to normal. In the group with persistent mild inflammation and/or villous atrophy, there was no decrease in mortality in follow up for over 10 years. Little is known regarding persistent mild intestinal inflammation and the risk for bone mass loss, other autoimmune diseases, and cancers. Therefore, the goal in therapy remains recovery in symptoms and intestinal inflammation on a strict gluten-free diet. At present, there is no other effective therapy.

Carol Semrad, MD, is a gastroenterologist, specializing in small bowel diseases (celiac disease, diarrhea, malabsorption) and nutrition. She is a leader in the use of small bowel endoscopy (video capsule endoscopy and double balloon enteroscopy) for management of small bowel bleeding, ulcers, and tumors, and is member of the medical leadership team at the University of Chicago Celiac Disease Center.

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