When Diagnosis Doesn’t Help: Non-Responsive Celiac Disease

The gluten-free diet should resolve symptoms for those who have celiac disease within about 6 months. But sometimes symptoms continue or they come back after a long period of good health. If either of these describe you and you are wondering why you’re not getting well, it’s possible that you may be suffering from a problem called non-responsive celiac disease.

Non-responsive celiac disease is the medical term used to describe those with celiac disease who have continued symptoms after the first 6 to 12 months on the gluten-free diet or who have a relapse of symptoms after being well for a long stretch of time.  Daniel Leffler, M.D., the director of research at the Celiac Center at Beth Israel Deaconess Medical Center and an expert on non-responsive celiac disease, said up to 30 percent of patients with celiac disease experience celiac-related symptoms on a regular basis.

When the gluten-free diet isn’t working

 Non-responsive celiac disease should be considered in anyone who has been on the gluten-free diet for at least 6 months and experiences any of the following problems:

  • Persistent or recurrent gastrointestinal symptoms
  • Blood tests showing a continued elevation of celiac antibodies (TTG IgA or DGP IgG)
  • Nutritional abnormalities that do not improve after a significant amount of time on the gluten-free diet, including iron deficiency anemia, Vitamin B12 deficiency and/or Vitamin D deficiency.

A study by Patrick S. Daugherty, Ph.D., at the University of California, Santa Barbara, found that continued elevation of the IgG antibodies in patients on the gluten-free diet may be a good indicator of non-responsive celiac disease.

The most common symptoms include abdominal pain, diarrhea, weight loss and fatigue. Celiac disease-associated diarrhea should resolve after the first 60 to 90 days of being on the gluten-free diet, according to Alberto Rubio-Tapia, M.D., assistant professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic. If the diarrhea persists, it could be an indication that non-responsive celiac disease exists. 

The three most common causes of non-responsive celiac disease are unintentional gluten ingestion, a misdiagnosis of celiac disease and a second disease or condition, in addition to celiac disease, that is causing gastrointestinal symptoms.

Irritable bowel syndrome, lactose intolerance, fructose malabsorption, microscopic colitis, and small intestinal bacterial overgrowth are common secondary conditions that can occur in those who have celiac disease and lead to ongoing digestive symptoms. Less-common causes include eating disorders, inflammatory bowel disease (i.e. Crohn’s disease), pancreatic exocrine insufficiency, GI motility disturbances and food allergies or intolerances. 

Establishing the cause

Before a doctor can determine whether a patient has a non-responsive case of celiac disease, he or she has to verify that the patient actually has celiac disease in the first place.

Red flags for an initial celiac disease misdiagnosis include negative celiac antibody tests and/or a normal small intestinal biopsy prior to going on the gluten-free diet. In some cases of celiac disease misdiagnosis, patients have negative celiac disease antibodies but flattening of the villi, nutrient-absorbing fingerlike projections in the small intestine. 

Although this flattening, called villous atrophy, is the pathologic hallmark of celiac disease, it sometimes seen in non-celiac disease conditions. These include autoimmune enteropathy, Crohn’s disease, common variable immunodeficiency, Giardia infection (a parasite), milk and soy protein intolerances and tropical sprue (a diarrheal illness found only in parts of the world near the equator).

 If there is any question or doubt as to an original diagnosis of celiac disease, repeat testing may be necessary. In many cases this repeat testing may require undergoing a gluten challenge for a period of time to get a definitive answer as to whether or not gluten is causing damage.

Diet review

If the original celiac diagnosis is correct, then the patient’s gluten-free diet needs to be reviewed to determine if it still contains gluten. Research has shown that up to 70 percent of those who have celiac disease continue to be exposed to gluten while following the gluten-free diet. Approximately 50 percent of cases of non-responsive celiac disease can be attributed to accidental and intentional gluten ingestion. 

That’s why it is important to have a dietitian with special training and knowledge about celiac disease do the nutritional evaluation in cases of non-responsive celiac disease.  

Potential sources of gluten include medications, unrecognized gluten-containing ingredients in processed food, and cross-contamination of food thought to be gluten free. Cross-contamination can also occur in home kitchens and when dining out. Avoiding cross-contamination while traveling can be especially challenging.

If a detailed nutritional evaluation does not reveal any apparent sources of gluten contamination, someone thought to have non-responsive celiac disease should be evaluated for secondary disorders that may be contributing to ongoing symptoms. It is not unusual for patients with celiac disease to develop additional problems, of which irritable bowel syndrome, lactose intolerance, fructose malabsorption, microscopic colitis and small bowel bacterial overgrowth are the most common.

Between 10 to 20 percent of cases of non-responsive celiac disease can be attributed to irritable bowel syndrome. In many cases a patient’s small bowel biopsy will be either normal or almost normal, if ongoing symptoms are due to a secondary problem, such as irritable bowel syndrome.

Refractory celiac disease, which is more serious, affects 1 percent of those who have celiac disease but up to 10 percent of those with non-responsive celiac disease.

Refractory celiac disease is associated with persistent, severe villous atrophy, malabsorption and weight loss. Patients with refractory celiac disease have abnormal types and numbers of immune cells in their small bowel mucosa that can be detected with special pathology stains and tests.

Patients who develop refractory disease require close monitoring of their nutritional status and in some cases medications to suppress the immune system, such as steroids. Although in the vast majority of cases ongoing celiac symptoms are not due to refractory celiac disease, it is important that a diagnosis is not missed.

Bottom line

If you have been consistently following a gluten-free diet but still have persistent symptoms, you should know this is not normal after 6 to 12 months. The presence of ongoing symptoms indicates that you need a comprehensive evaluation of your diet to look for possible gluten cross-contamination. 

The evaluation should also investigate whether another disease might be the cause of your symptoms.  If possible, the evaluation should be done at a center that specializes in celiac disease with a team that includes a doctor and a dietician. 

In many cases ongoing symptoms will improve once any unknown source of gluten is identified and eliminated, and treatment for any secondary disease begins. In the future, medications might be coupled with the gluten-free diet to ensure good health and eliminate ongoing symptoms. 

This article was originally published in the July/August 2014 issue of Gluten-Free Living.

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