Celiac Disease: Is There a Link With Environmental Chemicals and Metals?

The definition of celiac disease as found in a medical dictionary.
A team of researchers recently evaluated serum concentrations of persistent organic pollutants to determine how they may affect celiac disease.

Celiac disease (CD), also known as gluten-sensitive enteropathy, is an autoimmune condition that involves a proinflammatory state within the small bowel that is mediated by a sensitivity to gluten.1 Patients with CD can report a multitude of both gastrointestinal (GI; diarrhea, bloating, weight loss, vitamin deficiencies, and elevated transaminases) and non-GI symptoms (rash, headache, depression, infertility, and anemia).1

CD is relatively prevalent, with approximately 1% of the world and 0.7% of the US population affected.2 The underlying pathophysiology of CD is complex; however, it predominantly involves triggering of the immune system by the gluten component of wheat in patients who are genetically predisposed with the HLA-DQ2 or HLA-DA8 alleles.3 The gluten protein is not well digested in the upper GI tract, as it is not easily degraded by gastric, intestinal, or pancreatic enzymes.3 Gluten is partially digested to gliadin, which can then cross the epithelial lining of the GI tract and promote an inflammatory response with increased numbers of lymphocytes, villous blunting, and the development of antibodies.3 Subsequently, transport of gliadin across the intestinal lining is facilitated when the intestinal permeability is increased, as can be seen with certain infections or environmental factors.3 Infectious links include a possible role for rotavirus infection and the development of CD. 

Environmental factors affecting CD include the protective effects seen with breastfeeding and increased risks associated with early introduction of gluten before 4 months of age.5 Other environmental factors that have been implicated include the persistent organic pollutants (POPs) polybrominated diphenyl ethers (PBDEs), perfluoroalkyl substances (PFASs), P,p’-dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyltrichloroethane (DDT)5. POPs are synthetic organic compounds that have traditionally been used in certain manufacturing processes.

POPs have been previously linked with deleterious effects on the endocrine and immune systems. Despite the decreasing use of POPs, they can persist in the environment for prolonged amounts of time due to their resistance to degradation.5 Therefore, people can still come in contact with these agents, even at a young age. As POPs have been implicated in potentially increasing intestinal permeability, there is some research interest in determining if they play a significant role in the pathogenesis of CD. Recently, Gaylord et al evaluated serum concentrations of POPs to assess how they may affect CD.5 The findings from their pilot study were published in Environmental Research.

The authors conducted a pilot study of 88 patients younger than 21 years of age from a single outpatient center (Hassenfeld Children’s Hospital at NYU Langone) who were being evaluated for CD based on varying GI symptoms. A diagnosis of CD was made based on abnormal serologic values and duodenal biopsies. Each patient’s blood was analyzed for POPs as well as HLA-DQ genotype.

Of the 88 patients, 30 were diagnosed with CD based on serology and duodenal biopsies. The group with CD had statistically significantly more female patients (63.33% vs 39.66%, P =.04) and lower albumin levels (4.3 g/dL vs 4.7 g/dL, P =.008), but no statistically significant differences were noted in race/ethnicity, age, hemoglobin value, and body mass index. After controlling for multiple patient characteristics, patients with higher DDE concentrations were found to have 2-times greater odds ratio (OR) for being diagnosed with CD (OR 2.04; 95% CI, 1.08-3.84). When evaluating patients by sex, the authors found higher ORs for CD in female patients with greater serum concentrations of certain POPs: DDE (OR 13.0; 95% CI, 1.54-110), perfluorooctane sulfonate (OR 12.8; 95% CI, 1.17-141), and perfluorooctanoic acid (OR 20.6; 95% CI, 1.13-375). Similar findings were found in male patients with detectable BDE153 (OR 2.28; 95% CI, 1.01-5.18), a PBDE congenor. The authors concluded that certain POPs were associated with increased odds of CD.

This study had several limitations including the relatively small sample size, which contributed to the wide 95% CIs indicating a lack of precision. Also, it may be difficult to routinely screen patients for POPs at any age based on associated costs and the limited availability of the required assays. Despite these limitations, this pilot study does raise several interesting points regarding the role of environmental triggers, aside from gluten, in patients with CD. There appears to be a difference in how male and female individuals are affected by specific POPs, as seen within this study, yet the exact explanation remains to be fully elucidated.

Regardless of sex, the authors propose that POPs could lead to increased membrane permeability through disruption of tight junctions, promoting a “leaky gut” that may facilitate the transport of gliadin across the small intestine epithelium.5 In addition to this mechanism, POPs may also have a direct impact on the endocrine and immune systems by promoting dysregulation of the body’s immune response to gliadin once it has actually crossed the intestinal barrier. The impact on the endocrine system may partly explain some of the differences found between male and female individuals. Most of the research evaluating the interactions of POPs within several body systems is derived from preclinical animal studies; therefore, future studies may focus specifically on more human-based data.

Another interesting viewpoint on the role of environmental factors in CD is how a gluten-free diet (GFD) may affect exposure of these agents in patients. The GFD is the primary “treatment” for patients with CD, as there is currently a limited amount of therapeutics available, all of which are predominantly investigational.1 In addition to patients with CD following a GFD, there has been an increasing number of people without CD who choose to follow a GFD based on its purported health benefits.6 Patients following a GFD may have increased consumption of foods containing heavy metals such as fish and rice-based products.6 Raehsler et al conducted a study to assess how much exposure patients with and without CD, as well as those following a GFD, have to heavy metals and published their findings in Clinical Gastroenterology and Hepatology.6

This population-based, cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) between 2009 and 2012; after evaluating 11,354 patients, 55 were found to have CD based on serology or a reported clinical diagnosis. Subsequently, the diets of all patients were evaluated, with 115 patients found to be following a GFD. These patients had their blood and urine evaluated for several heavy metals including mercury, lead, cadmium, and arsenic.

Patients following a GFD had significantly higher total blood mercury (1.37 μg/L vs 0.93 μg/L; P =.008), lead (1.42 μg/L vs 1.13 μg/L; P =.007), and cadmium (0.42 μg/L vs 0.34 μg/L; P =.03) levels compared with those patients not following a GFD, respectively. In addition, patients following a GFD also had higher levels of urine arsenic compared with those not on a GFD (15.15 μg/L vs 8.38 μg/L; P =.002). Elevated levels of heavy metals in most patients following a GFD did not reach or exceed toxic levels, except for some limited cases of arsenic. The exact impact of a GFD on long-term accumulation of heavy metals was not assessed and will be evaluated in future studies.

The role that environmental chemicals and heavy metals play in both CD and the GFD will undoubtedly continue to be the focus of future research. As new treatments are developed for CD, it will be important to consider a patient’s exposure to these substances and how it may affect clinical outcomes.

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1. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656-676. doi:10.1038/ajg.2013.79

2. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012;107(10):1538-1544. doi:10.1038/ajg.2012.219

3. Green PHR, Cellier C. Celiac disease. N Engl J Med. 2007;357(17):1731-1743. doi:10.1056/NEJMra071600

4. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA. 2005293(19):2343-2351. doi:10.1001/jama.293.19.2343

5. Gaylord A, Trasande L, Kannan K, et al. Persistent organic pollutant exposure and celiac disease: a pilot study. Environ Res. 2020;186:109439. doi:10.1016/j.envres.2020.109439

6. Raehsler SL, Choung RS, Marietta EV, Murray JA. Accumulation of heavy metals in people on a gluten-free diet. Clin Gastroenterol Hepatol. 2018;16(2):244-251. doi:10.1016/j.cgh.2017.01.034