April 19, 2022
9 min read
Source: Healio interviews
Disclosures: Fahey, Lebovits and Oxentenko report no relevant financial disclosures. Lebwohl reports serving as a consultant for Takeda and serving on a medical advisory board for Innovate Biopharmaceuticals. Rubio Tapia reports serving on the celiac disease advisory board for Takeda.
Celiac disease is a chronic, autoimmune digestive disease that damages small intestinal villi and interferes with absorption of nutrients. While much is known about the development of the disease and its effect on the body, questions remain about screening, diagnosis and patient care now and in the years ahead.
“Celiac disease pathogenesis is very well known and complex,” Alberto Rubio Tapia, MD, director of the Celiac Disease Program at the Cleveland Clinic and assistant professor of medicine at the Mayo Clinic, told Healio Gastroenterology. “In brief, celiac disease starts with the ingestion of gluten. Gluten activates the innate immune system at the epithelial level and finds its way across the epithelial barrier to reach the DQ2 or DQ8 antigen-presenting molecules in the antigen-presenting cells. That leads to activation of the immune system and production of several cytokines responsible for the injury of the intestine.”
If left untreated, celiac disease can cause a plethora of complications, including malnutrition, bone weakening, infertility and miscarriage, nervous system problems and more.
“It’s a really fascinating disease because it’s one of the few diseases that can be treated by strictly removing a particular type of food from the diet,” Lisa M. Fahey, MD, attending physician and co-director of the Celiac Center at the Children’s Hospital of Philadelphia, said.
Healio Gastroenterology spoke with experts in the field about the best care for patients with celiac disease, the present and future state of disease management and pearls for treating this special subset of patients.
Who is at Risk?
Celiac disease affects 1% of the U.S. population and is in part genetically mediated — patients who have a first-degree relative with the disease have a higher risk for development compared with the general population (10% vs. 1%). Specific genetic disorders such as Down syndrome, Turner syndrome and selective IgA deficiency, as well as certain autoimmune conditions, can also put patients at heightened risk for celiac disease, as can the presence of certain variants of the human leukocyte antigen (HLA) complex.
“We know this disease occurs in those patients who are genetically susceptible, meaning they have to carry either HLA-DQ2 or DQ8,” Amy S. Oxentenko, MD, FACP, FACG, AGAF, chair of the department of medicine at the Mayo Clinic Arizona, said during a presentation at the American College of Gastroenterology Annual Scientific Meeting 2021. “They also have to be taking gluten in their diet. What we don’t know is there has to be something else that triggers this, either an environmental or an additional genetic factor.
“There’s lots of data on whether this can be due to the timing of when we take wheat in our diet, how wheat is processed, our route of delivery at birth, infections that we may have that alter our microbiome — all of these probably play some capacity in different individuals to trigger this immune response.”
In a systematic review and meta-analysis of studies published from January 1991 to March 2016, Prashant Singh, MD, and colleagues found that pooled global seroprevalence of celiac disease was 1.4% (95% CI, 1.1-1.7) and pooled global prevalence of biopsy-confirmed celiac disease was 0.7% (95% CI, 0.5-0.9). The disease was nearly twice as common in children vs. adults, and women were 1.5 times more likely than men to have celiac disease. Prevalence also varied based on geographic location, with the highest values reported in Europe (0.8%) and the lowest in South America (0.4%). Further, prevalence has increased over time from 0.6% between 1991 to 2000 to 0.8% between 2001 and 2016.
Additional systematic review and meta-analysis data from James A. King, MSc, and colleagues supported Singh’s findings and showed that the pooled average annual percent changes increased by 7.5% (95% CI, 5.8-9.3) per year over the last several decades with a higher pooled incidence per 100,000 person-years among women compared with men (17.4; 95% CI, 13.7-21.1 vs. 7.8; 95% CI, 6.3-9.2) and children compared with adults (21.3; 95% CI, 15.9-26.7 vs. 12.9; 95% CI, 7.6-18.2).
Data from Aynur Unalp-Arida, MD, PhD, et al. also revealed that celiac disease was more prevalent among individuals living in the U.S. at latitudes of 40° north or more (OR = 5.4; 95% CI, 2.611.3).
“What’s encouraging is that the prevalence of undiagnosed celiac disease is decreased, meaning we’re probably doing a better job of thinking about testing patients for celiac disease when we think it might be appropriate,” Oxentenko said.
When it comes to screening for celiac disease, the question of whom to test remains largely unresolved and is one of the more “interesting debates,” Benjamin Lebwohl, MD, MS, director of clinical research at the Celiac Disease Center at Columbia University, said.
Because celiac disease is associated with varying clinical signs and symptoms, one side of the debate calls for routine screening of the whole patient population. However, this is problematic because there is no consensus on the age at which a one-time screening would capture those who may have or may develop celiac disease. Further, there is uncertainty in treating patients who feel fine because, while it may result in symptom resolution and improved quality of life, a gluten-free diet can be burdensome and difficult.
“In adults, screening the asymptomatic individual remains controversial,” Lebwohl said. “Instead, the general approach that’s recommended by most [adult] guidelines is a case-finding approach. That means that the physician should think to test for celiac disease if the patient is presenting with one of the many symptoms that people with celiac disease have.”
In the pediatric population, guidelines recommend screening all high-risk individuals even if they are asymptomatic, Fahey added.
For people with celiac disease, exposure to gluten can trigger a myriad of intestinal GI symptoms ranging from diarrhea to abdominal pain and bloating, as well as extra-intestinal complications such as headaches, peripheral neuropathy and dermatitis herpetiformis.
“It can also result in malabsorption, which can lead to things like osteopenia, osteoporosis or iron deficiency anemia,” Jessica Lebovits, RD, CDN, CNSC, clinical dietitian at the Celiac Disease Center at Columbia University, said. “We do know celiac disease is also associated with an increased risk for certain cancers.”
In addition to screening patients with specific symptoms, Fahey recommended periodically screening patients who fall into one of the high-risk groups discussed before. At the Celiac Center at the Children’s Hospital of Philadelphia, providers advise annual or biennial blood-based screening of first-degree relatives of individuals with celiac disease until puberty and every 3 to 5 years thereafter. Other high-risk children, such as patients with type 1 diabetes or Down syndrome, are screened annually.
“Screening for [adult] diagnosis requires testing serum for celiac antibodies, especially transglutaminase immunoglobin A (IgA) and/or deaminated gliadin peptide IgA (among adult patients),” Rubio Tapia said. “Confirmation of the diagnosis requires a duodenal biopsy looking for celiac injury characterized by villous atrophy and intraepithelial lymphocytosis.”
Fahey discussed screening modalities among younger patients: “They will similarly send a tissue transglutaminase IgA, total IgA and then they may send the endomysial antibody IgA as well. Additionally, we also send another marker called a deaminated gliadin immunoglobin G (IgG) in very young children.”
As in adults, an upper endoscopy with biopsy confirms whether a pediatric patient has celiac disease after a positive test result.
“When we do that scope in children, we make sure that we get at least six duodenal biopsies: at least one or two of them from the duodenal bulb then the rest from the more distal duodenum,” Fahey said. “That’s because not all areas of the small intestine are equally affected in celiac disease, so if you just took one or two biopsies you might miss it.”
An interesting characteristic of celiac disease is that although most people develop the condition during childhood or adolescence, many are not diagnosed until later in life.
“The most common age of diagnosis in the U.S. is in one’s 20s or 30s, but many of those people may have had celiac disease for quite some time without knowing it,” Lebwohl said. “You can have celiac disease and have no symptoms or minimal symptoms or you can have many symptoms, but no one thinks to check for celiac disease because the symptoms don’t directly point to the intestine or to gluten.”
Further, both underdiagnosis and misdiagnosis are common in this subset of patients.
“A frequent cause of misdiagnosis is accepting a ‘definitive’ diagnosis based only on clinical response to gluten-free diet or serology without confirmation with a duodenal biopsy,” Rubio Tapia said. “Testing after starting a gluten-free diet increases the possibility of missing a true celiac disease, because serology is unreliable in that scenario.”
IgA deficiency may also result in misdiagnosis when testing is based solely on IgA serology.
“Clinical implications of misdiagnosis are serious and relevant, as the underlying condition to explain patient symptoms may be misdiagnosed in these circumstances and a lifelong gluten-free diet may not be necessary,” Rubio Tapia said.
Management in 2022
Following a GI-confirmed diagnosis of celiac disease, the gold standard for management remains lifelong adherence to a gluten-free diet.
“The most important thing is for someone with celiac disease to meet with an expert dietitian who’s knowledgeable in the gluten-free diet, because learning how to avoid gluten from online resources alone can cause confusion and contradiction and, in some cases, hypervigilance,” Lebwohl said.
At the Celiac Disease Center at Columbia University, diagnosis and management go beyond simply educating patients on how to avoid gluten.
“I really try to go beyond ‘what is gluten,’ because a lot of people can figure that out,” Lebovits said. “It’s the quality of life, emotional and mental aspects that go along with it that can be the most difficult.
“I try to investigate their acceptance of the diagnosis, their feelings toward the gluten-free diet and their readiness to make changes. Understanding all these intricacies helps us to find a balance between minimizing gluten exposure and maximizing their quality of life in order to promote long-term adherence.”
Rubio Tapia added that the basic strategy for management, though simple, can be difficult to maintain in real life.
“I strongly believe the best option in terms of health care delivery for celiac patients is a multidisciplinary approach for screening, diagnosis and management,” he said, explaining that includes not only a gastroenterologist, but also expert dietitians, GI pathologists and psychologists, and several other supporting specialists such as neurologists, dermatologists and endocrinologists.
Like the disease management strategy in adults, children and adolescents with celiac disease must adhere to a gluten-free diet to manage their symptoms with an emphasis on disease education. However, unique to this younger population are the important advocacy skills taught by a multidisciplinary team that will benefit them as they mature into adults.
“Making sure that both the patient and the caregivers are educated on the nuances of how to execute a gluten-free diet is key,” Fahey said. “When a patient is first diagnosed, we teach the family and the child, depending on the age, how to read food labels so that they can avoid gluten in their general daily life. When we see them for our follow-up visits over time, that education continues, and we’re reinforcing and encouraging them to become advocates for themselves so that they can safely eat gluten-free when their parents aren’t with them.”
Access to a GI dietitian is especially pertinent for youths to ensure all nutrient requirements and growth parameters are being met at each life stage.
New Therapies on the Horizon
Although knowledge of the pathogenesis and management of celiac disease has existed for many decades, barriers to care — such as regulatory uncertainty, access to specialists, awareness, expense and lack of research — remain.
“Funding for research is always a challenge,” Fahey said. “There are so many providers that are interested in doing research, but celiac needs support in order to do that. Ultimately, how we are going to find a cure is by doing more research.”
For these reasons, as well as the difficult, expensive and socially isolating nature of a gluten-free diet, patients with celiac disease are constantly seeking alternatives. And according to Rubio Tapia, several therapies are under active investigation at different stages of development, including engineered enzymes for gluten degradation, probiotics, gluten-sequestering polymers, gliadin nanoparticles to induce gluten tolerance, tight junction modulators, HLA-DQ2 blockers, transglutaminase 2 inhibitors and immune-cell targeted therapies.
“The most important piece of advice I would give is the relationship does not end with a diagnosis,” Lebwohl concluded. “While most patients feel substantially better when they start the gluten-free diet, it can pose many challenges both short and long-term. “This is a marathon, not a sprint.”
- Choung RS, et al. Mayo Clin Proc. 2016;doi:10.1016/j.mayocp.2016.10.012.
- King JA, et al. Am J Gastroenterol. 2020;doi:10.14309/ajg.0000000000000523.
- Lebwohl B, et al. Gastroenterology. 2020;doi:10.1053/j.gastro.2020.06.098.
- Lebwohl B. What’s on the horizon for celiac disease and non-celiac gluten sensitivity. Presented at: ACG Annual Scientific Meeting; Oct. 22-27, 2021; Las Vegas (hybrid meeting).
- Oxentenko AS. Celiac disease: From disease understanding to management strategies. Presented at: ACG Annual Scientific Meeting; Oct. 22-27, 2021; Las Vegas (hybrid meeting).
- Singh P, et al. Clin Gastroenterol Hepatol. 2018;doi:10.1016/j.cgh.2017.06.037.
- Unalp-Arida A, et al. Gastroenterology. 2017;doi:10.1053/j.gastro.2017.02.012.
- U.S. Food & Drug Administration. Gastroenterology regulatory endpoints and the advancement of therapeutics VI (GREAT VI): Workshop on celiac disease. Available at: www.fda.gov/media/151697/download. Accessed: March 10, 2022.