In celiac, immune cells fight ferociously against a crumb of bread, damaging the small intestine in the process. Gluten, normally innocuous, leaks out of the small intestines of people with celiac disease, triggering a sequence of cellular activity more appropriate for fighting off a deadly salmonella infection.
Celiac disease is not to be confused with gluten intolerance or other phrases used lightly by people seeking to eat healthily, says Alice Bast, president and CEO of the National Foundation for Celiac Awareness. “Celiac disease is a serious genetic autoimmune disease,” Bast says.
She repeats, with emphasis: “Serious. Genetic. Autoimmune.”
For years, Bast struggled with undiagnosed celiac disease, with periods of unrelenting diarrhea — “I knew where every bathroom was, everywhere” — and harmful consequences to her reproductive system: three miscarriages and a stillborn baby born at full term, followed by a baby (now healthy) born at six months, weighing only three pounds. “I was one very sick person,” says Bast, now 54.
The long-term consequences of celiac, especially if it is untreated, can be very significant. People with celiac disease bear a significantly higher-than-average risk of non-Hodgkin lymphoma (two to four times higher than average) and cancer of the small intestine (30-fold increased risk).
More common is the malabsorption of nutrients, caused by damage to cells lining the small intestine. Anemia and osteoporosis, delayed puberty, even malnutrition can ensue, especially in children.
“So many of these kids with celiac have been cramping and having pain for years, even,” says CHOP’s Hakonarson. “They don’t grow well … there are multiple stigma.”
For McCullom, whose symptoms began appearing after the birth of her first child, fatigue, presumably from lack of proper nutrition, was crippling. “I’d catch my eyes closing while I was driving,” she says. “I’d roll down the windows, drink coffee, and then more coffee.”
Today, a gluten-free diet (GFD) is the only treatment for celiac disease. McCullom and others say it works well (most of the time), but it’s a burden that can hit the waist as well as the wallet.
“If I want to eat a bagel, my gluten-free bagel is going to have at least two times the calories and carbs as yours,” says McCullom. At first, she ate the gluten-free version of everything she loved. “I gained 15 pounds and realized I just couldn’t do that.”
Her food costs more, too. The other day at the grocery store, McCullom searched desperately for a can of tomato soup that didn’t contain gluten — she was craving grilled cheese and tomato soup, and she had the gluten-free bread covered already. But most of the tomato soups looked risky: The one she eventually purchased cost more than $4 for a single serving; others were less than $1.
One of the things that has been astonishing is that in many instances, the same genes — and in some cases, the same alleles of the same genes — seem to play roles in multiple diseases.
And gluten hides, too, in products where you might least expect the molecule: lipstick and pharmaceuticals, for example, and candy. “I ate a Twizzler at work one day in the late afternoon,” McCullom says. Helping her son with his homework an hour or two later, she was suddenly overcome with nausea. She didn’t make it to the bathroom.
Today, such episodes are rare for her, and they usually follow trips to a restaurant with friends or work colleagues and clients. “I choose to take the risk,” McCullom says. “I can’t be a hermit.”
There are treatments for other autoimmune diseases, but none that cure and few that are broadly effective. McCullom’s cousin Hayden, a writer and marketing consultant, takes Rituxan (rituximab), an anti-cancer drug that targets immune system cells involved in the inflammation process and can slow or prevent joint damage. People with multiple sclerosis can take a variety of therapeutics that slow disease progression in some but not others, and that can carry serious side effects. Diabetes is managed, not cured, with insulin, healthy diets, careful blood sugar monitoring, and exercise.
Genes and the environment
One of the challenges to understanding and treating autoimmune diseases is the fact that they trigger such varied symptoms in different people. A decade or two ago, many of these diseases probably weren’t diagnosed reliably, and even today, diagnosis can take years: Celiac may present with symptoms of Crohn’s disease or lactose intolerance — even depression. Lupus can look like a rash or a kidney problem.
Several tests, including the tissue transglutaminase antibodies (tTG-IgA) screening blood test, can help confirm celiac disease or lead to an endoscopic biopsy, a procedure that allows your doctor to get a clear picture of what’s going on inside your small intestine.
In The Pipeline
ALV003, a mixture of two enzymes designed to break down gluten. During a small phase 2 trial, researchers gave a daily gluten challenge (two grams of gluten) to 41 people with celiac disease; 20 were given a placebo drug, and 21 were given ALV003 daily. Researchers took small intestine biopsies from the patients after six weeks, to evaluate damage. Patients on the placebo had measurable injury to cells lining part of the small intestine; those given the drug had none. Alvine Pharmaceuticals, Inc., in San Carlos, California, makes ALV003, which is taken orally as a liquid.
Larazotide acetate, a drug that works to effectively seal up cellular leaks that let gluten escape the gut, triggering immune system attack. In a phase 2 trial, patients given the drug reported significant improvement: Fewer gastrointestinal issues and headaches, and less fatigue, diarrhea, and stomach pain. Alba Therapeutics in Baltimore makes larazotide acetate, which is designed to be given as a capsule.
Nexvax2, a drug designed to build tolerance to gluten. As with allergy shots or desensitization, the idea of Nexvax2 is to induce immune tolerance to gluten, thereby preventing damage to the intestine. The drug is in early clinical trials to evaluate safety and tolerability.
BL-7010, in development by the Israeli company BiolineRX. BL-7010 targets a part of the gluten molecule itself, sequestering the trigger for the disease and preventing it from leaving the small intestine. Tested successfully in animals, this drug is in early clinical testing in humans.
At least half a dozen other pharmaceutical companies around the world are developing drugs that target a biological pathway involved in celiac disease. These companies include Calypso Biotech; Celimmune, LLC; Cour Pharmaceuticals; Dr. Falk Pharma; Biomedal, and more.
For more information, visit beyondceliac.org.
Increasingly powerful genetic tools are helping to sort through the complexities, but studies often raise more questions than they answer. About 95 percent of people with celiac disease have the HLA-DQ2 allele (an allele is a variant of a gene), for example, and the others have HLA-DQ8. However, many more people have those alleles and never exhibit symptoms, are never diagnosed with the disorder, or don’t get sick until adulthood. So while HLA typing, which is done through a blood test, cheek swab, or saliva sample, can be used to rule out celiac (the disease just doesn’t occur in people without one of these two HLA types), the presence of these alleles does not guarantee that a person will develop celiac.
Mass General’s Fasano has funding from the National Institutes of Health to try to sort out some of the reasons that people develop celiac, including the roles of antibiotic history and bacterial colonies in our guts (see “We are What We Eat,” on this page).
“For all these autoimmune diseases, we suspect you have to be genetically predisposed, and you have to be exposed to something in the environment — a trigger,” Fasano says. “Celiac disease is the only autoimmune disease for which we know the trigger — gluten. That makes it not only fascinating but unique. ”
In Fasano’s view of autoimmune diseases, genetic predisposition and an environmental trigger are not enough; you also need a biological connection that links the two. In celiac disease, he points to the gaps that form between the normally tightly packed cells lining a person’s small intestine. Those gaps let gluten (the trigger) through, where it stimulates an intense immune response (associated with genetic predisposition).