Jess Madden

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.

Why some people with celiac disease may not be getting better on the gluten-free diet

The gluten-free diet should resolve symptoms for those who have celiac disease within about six 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 nonresponsive celiac disease.

Nonresponsive celiac disease is the medical term used to describe those with celiac disease who have continued symptoms after the first six 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 nonresponsive celiac disease, says up to 30 percent of patients with celiac disease experience celiac-related symptoms on a regular basis.

This phenomenon was discussed at the recent International Celiac Disease Symposium, a gathering of worldwide experts in celiac disease. Daniel Adelman, M.D., chief medical officer of Alvine Pharmaceuticals, discussed research suggesting that more than 50 percent of celiac patients have continued symptoms after eight to 12 years of being on the gluten-free diet.

Researchers are asking why and what can be done about it. Alvine Pharmaceuticals is one of several companies working on a pill to treat celiac disease in conjunction with the gluten-free diet.

When the gluten-free diet isn’t working

Nonresponsive celiac disease should be considered in anyone who has been on the gluten-free diet for at least six 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 or Vitamin D deficiency.

The three most common causes of nonresponsive 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.

Refractory celiac disease is a serious condition that can sometimes be behind nonresponsive celiac disease. It can be associated with the development of gastrointestinal lymphomas and other cancers, but it is very rare.

Establishing the cause

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

Research by David Dewar, M.D., of King’s College, London, in 2012 found that about 10 percent of 112 patients who presented to a British celiac clinic with nonresponsive celiac disease had actually been misdiagnosed with celiac disease. The patients had no improvement on the gluten-free diet, and doctors were able to find alternate explanations for digestive symptoms in all 12 patients. These included irritable bowel syndrome, small bowel bacterial overgrowth and a wheat allergy.

Red flags for an initial celiac disease misdiagnosis include negative celiac antibody tests 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.

Olmesartan, a blood pressure medication, can also cause damage in the lining of the intestines that mimics that of celiac disease. 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 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 nonresponsive 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 nonresponsive 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.

“Staying 100 percent gluten free is impossible,” Leffler said.

If a detailed nutritional evaluation does not reveal any apparent sources of gluten contamination, someone thought to have nonresponsive 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, with irritable bowel syndrome, lactose intolerance, fructose malabsorption, microscopic colitis and small bowel bacterial overgrowth being the most common.

Between 10 percent and 20 percent of cases of nonresponsive 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 nonresponsive celiac disease.

Even refractory celiac disease varies in how treatable it can be. The milder form has a good prognosis, but the more severe type is associated with both ulcerative jejunitis and the development of intestinal cancer.

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.

New treatments

Researchers are currently working on developing medications to reduce symptoms and damage from gluten cross-contamination and treat nonresponsive celiac disease.

Although these drugs will not replace the gluten-free diet, the hope is that taking them will minimize the damage from ingesting small amounts of gluten. The medications will be targeted at those who still have symptoms despite trying to do their best on the gluten-free diet, with a goal of both improving symptoms and promoting healing of the small bowel.

Alvine Pharmaceuticals is working on ALV003. The drug consists of two enzymes that hydrolyze, or break down, the gluten protein into non-toxic fragments. Early research has shown that ALV003 hydrolyzes 95 percent of gluten in the stomach, preventing intact gluten proteins from reaching the small intestine and causing damage. Subjects in early studies have tolerated the drug well, without adverse side effects.

The CeliAction Study is a drug trial specifically investigating the use of ALV003 in those who have nonresponsive celiac disease. Patients are currently being recruited for the CeliAction Study at centers across the United States. To participate in the study, you have to have been diagnosed with celiac disease by a healthcare professional via blood tests or a small bowel biopsy. You also have to be on a gluten-free diet and have at least one moderate to severe symptom of celiac disease in the previous month.

Participants in the study maintain their normal gluten-free diet and receive the treatment medication or a placebo for 12 weeks. The study is expected to be completed by the end of 2014. The overall goal of the CeliAction Study is to see if there may be a way to manage celiac disease in addition to the gluten-free diet.

Alba Therapeutics has developed larazotide acetate, another drug that is being researched to augment the gluten-free diet in those with nonresponsive celiac disease.

Gluten exposure leads to an increase in small intestinal permeability—so-called “leaky gut”—in patients with celiac disease through the release of a protein called zonulin. Larozotide acetate blocks the zonulin receptors and prevents zonulin-induced changes in intestinal permeability from occurring. Early studies showed a significant decrease in symptoms from gluten ingestion when subjects with celiac disease were given the drug.

A recently completed trial in patients with nonresponsive celiac disease showed a significant decrease in symptoms over a 12-week period in those who took the drug compared with a placebo. The FDA has granted “fast track” approval for this drug. The important next phase of trials to determine if it’s safe and produces the desired effect will soon be underway.

It appears promising that both ALV003 and larazotide acetate may be future options for those who have celiac disease and are not improving on the gluten-free diet.

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 six 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 dietitian.

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.