As I discuss in my article Celiac Disease: A Clinical Chameleon, celiac disease can be vexing in how it presents in clinical practice. In this article, my goal is to cover current conditions and diseases that have been linked to celiac disease in multiple studies in peer-reviewed literature. Take a moment to review the list below.
|Diseases & Conditions Linked to Celiac Disease|
|Budd Chiari syndrome|
|Cancers - gliomas, breast, lung, lymphomas, ovarian, pancreatic|
|Chronic inflammatory demyelinating polyneuropathy (CIDP)|
|Immune thrombocytopenia purpura|
|Juvenile idiopathic arthritis|
|Nonalcoholic fatty liver disease|
|Primary biliary cirrhosis|
|Systemic lupus erythematosus|
|Type 1 Diabetes|
While the above list is not exhaustive, it is a representation of the most common associated conditions and if you or a loved one are experiencing one of the aforementioned, please draw their attention to my article What do you do if you think you may have celiac disease? and hopefully start the diagnostic process. Let’s briefly examine a pathway between celiac disease and other diseases, particularly autoimmune diseases.
The equilibrium between tolerance and immunity to non-self-antigens is dependent upon the tight junctions of the intestinal epithelial barrier, which, like a conductor, directs the orchestra of the gut-associated lymphoid tissue and the neuroendocrine network of the intestines. A physiological modulator that regulates the tolerance and immune response balance by controlling the flux of macromolecules across the intestinal barrier is the protein zonulin.
Fasano discovered that small intestine exposure to gliadin is a powerful trigger of zonulin release. While Drago and colleagues noted zonulin release by enteric bacterial infection of the small intestine, gliadin remains the most powerful zonulin stimulant. Lammers and colleagues have shown that the chemokine receptor CXCR3, which is overexpressed in celiac disease patients, co-localizes with gliadin, recruiting the adaptor protein MyD88, resulting in the release of zonulin and subsequent increase in intestinal permeability. This is critical information as numerous diseases are recognized to involve alterations in intestinal permeability due to impaired tight junctions of the small intestine.
In various autoimmune diseases such as multiple sclerosis, type 1 diabetes and rheumatoid arthritis, what is shared with celiac disease is a breach of the tight junctions of the small intestine that allows antigens to pass through the intestinal lumen, provoking an immune system response that can then target any organ, tissue or gland. Zonulin is over expressed in tissues of individuals with autoimmune diseases. Fasano and colleagues have shown that within minutes of gliadin exposure, human intestinal cells secrete large amounts of zonulin. Moreover, this breaching of the intestinal tight junction of the small intestine allows gliadin to translocate to the lamina propria, triggering the proinflammatory interleukin 15 (IL-15) and interleukin 8 (IL-8) as well as keratinocyte growth factor.
While this is transpiring, the Toll like receptor 4-MD2-CD14 complex results in the presence of proinflammatory cytokines. Continued immune system response mechanisms ensue.
Rodrigo and colleagues noted an increased prevalence of celiac disease in multiple sclerosis patients suggesting a rate of gluten intolerance 11 times higher than the general population. Mormile agrees with Rodrigo and recommends celiac disease patients be evaluated for multiple sclerosis and vice versa. Mormile states that celiac disease and multiple sclerosis may share osteopontin gene splice variants, acting as inducers toward a multiple sclerosis diagnosis in celiac disease patients. Fasano has linked various neurological diseases such as multiple sclerosis to zonulin release in celiac disease patients.
Asleh and colleagues have associated gliadin and the stimulation of zonulin to type 1 diabetes autoimmunity in human studies. Yachyshyn and colleagues discovered an increase in serum zonulin in multiple sclerosis patients. Celiac disease and the autoimmune thyroid diseases Grave’s disease, Hashimoto’s thyroiditis and idiopathic myxedema, share the DQ2 allele, which explains why there is a higher incidence of such endocrinopathies in celiac disease. Celiac disease has also been implicated in hypo and hyper primary and secondary parathyroidism. Heneghan and colleagues have found a 100-fold increase in Addison’s disease among celiac disease patients and suggest that Addison’s disease patients should be screened for celiac disease. The suspected connection is via the HLA-DQ8 allele.
Zhernakova and colleagues have established a shared genetic basis between rheumatoid arthritis and celiac disease, with an overrepresentation of T-cell signaling. Fourteen loci were identified that are shared between celiac disease and rheumatoid arthritis, indicating an overlapping genetic basis for both diseases and implicating altered T-cell activation and differentiation as a similar stimulating matter of autoimmunity.
Using an autoimmune comorbidity model, we can see how consumption of gluten in the celiac patient can lead to a compromise of the intestinal tight junctions via zonulin release, with continued hyperpermeability from the presence of zonulin occludens toxin, resulting in circulating immune complexes, creating a secondary autoimmune presentation. If the celiac patient falls into the obese category, inflammasome activation continues this autoimmune cascade. Using pathology as an example, a celiac disease patient may present with a diagnosis of rheumatoid arthritis, multiple sclerosis, type 1 diabetes, ankylosing spondylitis, or another disease due to the circulating autoimmune complexes that may infiltrate through the intestinal lumen. This creates a different viewpoint of the diagnosis of celiac disease. Individuals with celiac disease should be tested for the aforementioned diseases and vice versa.