This review focuses on the autoimmune connective tissue diseases, endocrine, and dermatologic conditions associated with celiac disease, as well as the related gut inflammatory disorders of refractory celiac disease, autoimmune enteropathy, collagenous enteritis, and collagenous colitis.
Celiac disease is a common immune-mediated enteropathy with a prevalence of approximately 1% within the US and European populations. There is a worldwide disease distribution including Mexico, South America, the Middle East, parts of India, and specific regions of Africa. Although the classic and usually obvious consequences of the enteropathy are malabsorption with diarrhea, weight loss, and nutritional deficiencies, the difficulty in diagnosis is due in large part to the silent form of the disease which affects the majority of patients. Overall mild clinical symptoms with nonspecific complaints such as fatigue, headaches, and arthralgias are common and can delay diagnosis. A large multicenter study in the United States showed an increased disease prevalence in high-risk groups, including patients with autoimmune insulin-dependent diabetes mellitus (AIDDM), Sjogren’s syndrome, osteoporosis, and first-degree relatives of patients with celiac disease. In addition to diarrhea, abdominal pain and constipation were among the most highly reported symptoms . Because of the diagnostic difficulties inherent in this often mild or clinically silent presentation, the identification of high-risk groups for serologic screening may decrease the time to diagnosis and lessen the complications of untreated disease.
Several studies have demonstrated the cost-effectiveness of screening the population with irritable bowel syndrome for celiac disease. The results from one recent study addressed the possibility of immunologically based mechanisms following gluten exposure contributing to irritable bowel syndrome symptoms that may represent a celiac-like disorder. This study showed decreases in stool frequency and improvement in the gastrointestinal symptoms score among 60% of patients with diarrhea-predominant irritable bowel syndrome who carried the celiac disease–associated HLA type (DQ2) but lacked fully developed celiac disease .
Various autoimmune diseases have been historically associated with celiac disease . These findings raise interesting questions as to whether abnormal immune responses at the level of the gut mucosa, when exposed to environmental antigens, have a role in systemic autoimmune disease, or whether these associations reflect more an underlying genetic predisposition. Proposed mechanisms of association include abnormal regulation of intestinal permeability and increased autoantibody production in the setting of chronic gut inflammation.
This review focuses on the autoimmune connective tissue diseases, endocrine, and dermatologic conditions associated with celiac disease, as well as the related gut inflammatory disorders of refractory celiac disease, autoimmune enteropathy, collagenous enteritis, and collagenous colitis.
Gut Immunogenesis of Celiac Disease
Celiac disease is the result of an unchecked immune reaction to gluten. This unchecked response results in inflammation of the proximal small intestine where the partially digested gluten proteins contact the gut immune system. This immune response extends beyond just a direct response to the exogenous substance, also including a potent and multifaceted immune response to autoantigens that results in substantial damage to the structure and function of the gut and other organs. The clinical manifestations are heterogeneous, including the complete absence of gastrointestinal complaints, a myriad of extraintestinal manifestations, signs of overt malabsorption, and, in rare cases, the development of ulcerative jejunitis and enteropathy associated T-cell lymphoma (EATL). In the small intestinal mucosa, CD4+ T cells are stimulated by gliadin peptides only when presented by DQ2 or DQ8 MHC molecules on the surface of antigen-presenting cells. This binding triggers a proliferation of pathogenic gluten-specific T cells, a potent Th1 inflammatory response characterized by high levels of interferon-γ, and subsequent villous atrophy. In addition to this response to gluten, there is a potent and almost universal humoral response to autoantigen tissue transglutaminase (tTg) in the gut. The role and, indeed, the production of tTg autoantibodies are not fully understood. What is truly curious is the ability of cell surface tTg to bind and deamidate gliadin peptides . These deamidated peptides subsequently bind tightly to DQ2/DQ8 molecules, potentiating CD4+ T-cell activation and proliferation. What the antibodies that are directed against the active site of the transglutaminase are doing is uncertain from a pathologic perspective. Both T- and B-cell responses diminish upon withdrawal of gluten, and normal villous architecture is restored.
Although antibodies directed against wheat proteins have been pursued for many years, the recognition of more specific antibodies directed against extracellular antigens revolutionized the detection of celiac disease. Given the high specificity of positive anti-endomysial antibody (EMA) titers and the high sensitivity of IgA tTg, both tests in conjunction have a high positive predictive value. Because EMA testing increases expense and is prone to interpretation errors, tTg antibody testing alone is recommended for screening. Subsequent tTg antibody titers can be followed to assess occult gluten exposure or dietary indiscretion. The time to normalization of IgA tTg titers in the setting of a strict gluten-free diet is variable, ranging from weeks to months.
Although it has been widely hypothesized that there may be environmental triggers for many autoimmune diseases, celiac disease is unique in that we know the major and necessary precipitating factors. Additionally, celiac disease is different from most autoimmune diseases in that the environmental triggers need to be there all of the time or the disease and the autoantibodies regress. Most people with the known genetic predisposition (DQ2 or 8) who eat gluten do not get celiac disease; therefore, there must be other factors. These additional factors contributing to disease development are less well understood but likely include stimulation of an innate immune response to some environmental factor derived from gluten or some other factor present in the intestinal lumen.
Environmental Factors
The timing or amount of gluten exposure may be important factors in disease development. The data to support this comes largely from observational studies. In the 1980s, the incidence of celiac disease among Swedish children increased significantly and remained high for approximately 10 years. Subsequently, with nationwide changes in infant feeding practices to reduce gluten exposure and to alter its timing, the incidence of celiac disease dropped back to pre-epidemic levels. This “Swedish epidemic” generated the hypothesis that the introduction of large quantities of gluten after the cessation of breastfeeding was responsible for the failure of development of immune tolerance to gluten in these young children. Breastfeeding as a single factor did not appear to be the major risk factor. Dietary gluten exposure earlier than 3 months or later than 6 months of age was found to be a risk factor in a longitudinal follow-up study of a cohort of children in Denver, Colorado . These studies taken together suggest that there is a crucial window when tolerance to gluten occurs, and that overlapping the introduction of gluten with breastfeeding may provide the best protection against childhood celiac disease. Whether such a practice will ultimately prevent the lifetime development of celiac disease or another autoimmune disease is not known.
Ivarsson and colleagues found that the risk of the development of celiac disease increases with the number of gastrointestinal infections before 6 months of age and among infants born between the months of March and July. This seasonal risk was consistently shown year to year throughout the 10-year epidemic . Significant interest in rotavirus as a possible infectious trigger was generated following a study by Stene and colleagues showing that frequent rotavirus infections increased the risk of celiac disease in 54 children under 4 years of age. Additional case reports of the development of celiac disease in children following rotavirus infection have been published. Of recent interest are the roles of interleukin-15 and gastrointestinal flora in the proximal small bowel in relation to precipitating disease . The dysregulation of immune mechanisms in response to food and microbial antigens and how these mechanisms relate to gastrointestinal and systemic autoimmune diseases are the focus of ongoing research.
Environmental Factors
The timing or amount of gluten exposure may be important factors in disease development. The data to support this comes largely from observational studies. In the 1980s, the incidence of celiac disease among Swedish children increased significantly and remained high for approximately 10 years. Subsequently, with nationwide changes in infant feeding practices to reduce gluten exposure and to alter its timing, the incidence of celiac disease dropped back to pre-epidemic levels. This “Swedish epidemic” generated the hypothesis that the introduction of large quantities of gluten after the cessation of breastfeeding was responsible for the failure of development of immune tolerance to gluten in these young children. Breastfeeding as a single factor did not appear to be the major risk factor. Dietary gluten exposure earlier than 3 months or later than 6 months of age was found to be a risk factor in a longitudinal follow-up study of a cohort of children in Denver, Colorado . These studies taken together suggest that there is a crucial window when tolerance to gluten occurs, and that overlapping the introduction of gluten with breastfeeding may provide the best protection against childhood celiac disease. Whether such a practice will ultimately prevent the lifetime development of celiac disease or another autoimmune disease is not known.
Ivarsson and colleagues found that the risk of the development of celiac disease increases with the number of gastrointestinal infections before 6 months of age and among infants born between the months of March and July. This seasonal risk was consistently shown year to year throughout the 10-year epidemic . Significant interest in rotavirus as a possible infectious trigger was generated following a study by Stene and colleagues showing that frequent rotavirus infections increased the risk of celiac disease in 54 children under 4 years of age. Additional case reports of the development of celiac disease in children following rotavirus infection have been published. Of recent interest are the roles of interleukin-15 and gastrointestinal flora in the proximal small bowel in relation to precipitating disease . The dysregulation of immune mechanisms in response to food and microbial antigens and how these mechanisms relate to gastrointestinal and systemic autoimmune diseases are the focus of ongoing research.
Risk of Autoimmune Disease
A 1999 study by Ventura and colleagues demonstrated an increased prevalence rate of autoimmune disease among 909 patients who had celiac disease when compared with controls, although no significant difference was found in a comparison with 163 patients with Crohn’s disease. Logistic regression analysis showed that the age at diagnosis of celiac disease was a significant predictor of autoimmune disease development later in life. Follow-up studies addressing the length of gluten exposure as a predictor of autoimmune disease by Sategna-Guidetti and colleagues and Biagi and colleagues did not confirm these findings. Cataldo and Marino showed a higher prevalence of autoimmune disease (4.8%) among the first-degree relatives of celiac patients when compared with the first-degree relatives of healthy controls (0.86%). A subset of these first-degree relatives of patients with celiac disease was diagnosed with silent disease. A higher prevalence of autoimmune disease among this group was found in a comparison with healthy first-degree relatives of celiac disease patients (20% versus 3.8%, respectively). They suggested that this increased risk relates to the higher prevalence of silent celiac disease. Whether untreated celiac disease is responsible for an incremental incidence in autoimmune disease is unknown, although it is worthwhile for the clinician to be aware of these associations lest they occur. Generally, patients with newly diagnosed celiac disease can be reassured that their risk of developing another autoimmune disease is not greatly elevated after diagnosis and treatment.
Associations with Autoimmune Disease
Sjogren’s Syndrome
Several studies have revealed a high prevalence of celiac disease among patients with Sjogren’s syndrome. Iltanen and colleagues showed that 14.7% of 34 patients with Sjogren’s syndrome had celiac disease confirmed by small bowel biopsy. A more recent study from Hungary of 111 patients with Sjogren’s syndrome found the prevalence rate of celiac disease to be 4.5 cases per 100 persons confirmed by small bowel biopsy . Luft and colleagues measured levels of tTg autoantibodies in the sera of patients who had systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis. Twelve percent of patients with Sjogren’s syndrome were positive for IgA tTg autoantibodies versus 4% of controls. Five of six patients with positive IgA tTg titers had villous atrophy on small bowel biopsy, confirming the diagnosis of celiac disease. Significantly lower levels of tTg autoantibodies were found in patients who had systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.
Inflammatory Arthritis
Several studies have looked for celiac disease in cohorts with arthritis. Stagi and colleagues found an increased prevalence of celiac disease among 151 children with juvenile idiopathic arthritis (6.7% versus 0.6% in controls). Prevalence rates reported by Lepore and colleagues demonstrated an increased prevalence of biopsy-confirmed celiac disease (2.5%) among 119 children with juvenile chronic arthritis. This association does not extend to adult rheumatoid arthritis ( Table 1 ) .
| Study | Autoimmune disorder (number of patients) | Age (years) | Prevalence of celiac disease | Celiac disease diagnosis confirmation |
|---|---|---|---|---|
| Stagi, et al | Juvenile idiopathic arthritis (151) | 2.4 to 16.9 (median, 8.3) | 6.7% | Positive anti-EMA and IgA tTg serology, SBBx |
| Lepore, et al | Juvenile chronic arthritis (119) | 2 to 16 (mean, 11.5) | 2.5% | Positive anti-EMA serology, SBBx |
| Francis, et al | Rheumatoid arthritis (60) | 20 to 84 (mean, 61) | 0.63% | Positive anti-EMA serology; SBBx not reported |
| Study | Autoimmune disorder (number of patients) | Age (years) | Prevalence of non-erosive arthritis | Effect of gluten-free diet |
|---|---|---|---|---|
| Lubrano, et al | Previously diagnosed celiac disease patients (200) | 18 to 65 (mean, 32.8) | 26% | Higher prevalence of arthritis on regular diet 41% versus 21% on gluten-free diet |
The prevalence of rheumatologic conditions is not convincingly elevated in the celiac disease population as a whole. Several small case series show that treatment with a gluten-free diet may be helpful in some patients with musculoskeletal symptoms. Lubrano and colleagues demonstrated a 26% prevalence rate of arthritis among 200 adult patients with celiac disease. The prevalence of arthritis was significantly higher and more severe among the group on a regular diet as yet untreated when compared with patients already established on a gluten-free diet for an average of 58 months. This finding confirmed the observations in an earlier small case series that showed improvement of the joint symptoms in newly diagnosed celiac disease patients following treatment with a gluten-free diet . The mechanisms underlying these arthritic complaints in celiac disease are unknown, although the alterations in intestinal permeability in untreated celiac disease may be a factor.
There have been a few case reports of clinically overt celiac disease in patients who have systemic lupus erythematosus . The diagnosis of celiac disease consistently preceded that of systemic lupus erythematosus by an average 15 years in the pediatric cases, whereas in the adults, the diagnosis of celiac disease consistently followed the diagnosis of systemic lupus erythematosus by an average of 3.8 years . The association of systemic lupus erythematosus with celiac disease is likely rare, because one study did not find hidden cases in 103 patients with systemic lupus erythematosus . A more recent study from Northern Ireland did not reveal clinical evidence of systemic lupus erythematosus among a cohort of 60 patients with celiac disease . Although gastrointestinal manifestations of systemic lupus erythematosus are common in both adults and children , celiac disease is relatively rare among this patient population but should be considered in the setting of malabsorption symptoms. False-positive antinuclear antibody tests may be found in patients with untreated celiac disease.
Associated Autoimmune Endocrine Diseases
Addison’s Disease
European studies estimate the prevalence of celiac disease among patients with autoimmune Addison’s disease to be between 1.2% and 8% . More recent studies have demonstrated higher prevalence rates. A study from Ireland found five cases of celiac disease among 41 patients who had Addison’s disease . A recent large Italian study showed a 5.4% prevalence of celiac disease among 109 patients with autoimmune Addison’s disease versus 0.06% among controls . This association was confirmed by the analysis of more than 14,000 celiac disease patients from the Swedish national register, showing an increased risk for Addison’s disease among celiac patients . Table 2 summarizes these recent studies.
| Study | Addison’s disease (number of patients) | Age (years) | Prevalence of celiac disease | Celiac disease diagnosis confirmation |
|---|---|---|---|---|
| O’Leary, et al | 41 | 7 to 66 (mean, 37) | 12.2% | Positive IgA tTg and anti-EMA serology; SBBx confirmation |
| Myhre, et al | 76 | 6 to 85 (mean, 45.6) | 7.9% (6 of 76, 1 patient with known celiac disease) | Positive IgA tTg and anti-EMA serology; SBBx confirmation |
| Biagi, et al | 17 | 26 to 79(mean, 53.9) | 5.9% | Positive anti-EMA serology; SBBx confirmation |
| Betterle, et al | 109 | 11 to 87 (mean, 42.7) | 5.4% (6 of 109, 2 patients with known celiac disease) | Positive tTg IgA, 3 of 4 patients confirmed by SBBx (1 silent celiac disease, 2 latent celiac disease) |
| Study | Celiac disease (number of patients) | Age (years) | Risk (hazard ratio) | |
| Efstrom, et al | Previously diagnosed celiac disease patients (14,366) | 18 to 65 (mean, 32.8) | 11-fold increased risk of developing Addison’s disease | — |
Autoimmune Insulin-Dependent Diabetes Mellitus
AIDDM has a high prevalence rate among the patient population with celiac disease. Serologic screening for celiac disease in AIDDM populations showed a median prevalence of 4.1% among 40 studies; these studies included primarily European centers as well as six centers from the United States and United Kingdom . Gastrointestinal symptoms attributed to celiac disease among AIDDM patients are generally mild. Active malabsorption may lead to unreliable carbohydrate absorption and unpredictable glucose responses to meals. This problem can lead to some degree of brittleness in diabetic controls. Folate and iron deficiency are also commonly seen. The diagnosis of celiac disease often follows within 1 year of the diagnosis of AIDDM .
It is has not been universally accepted that all patients who have AIDDM should be screened for celiac disease, although some advocate screening for celiac disease at intervals in children with AIDDM due primarily to the prevalence and the potential consequences of delayed diagnosis . Although it is rational to expect that early treatment would prevent the complications of celiac disease in this population, few data document such benefit. There may be a slight increase in the insulin total dose with improved absorption that comes with correction of the intestinal malabsorption. Certainly, physicians caring for patients with AIDDM should have a low threshold for celiac disease testing.
Thyroid Disease
A recent review of thyroid disease studies revealed a high prevalence of celiac disease among patients with autoimmune thyroid disease, Hashimoto’s disease, Graves’ disease, and pediatric autoimmune thyroid disease ranging from 2% to 7.8% (average, 4.1%) . The occurrence of hyperthyroidism in adult patients with celiac disease ranges from 0.1% to 5.2% (average, 2.3%), whereas the occurrence of hypothyroidism ranges from 0% to 5.8% (average, 2.6%) . Although there are insufficient data to advocate screening for celiac disease in patients with thyroid disease, a much greater awareness should lead to a low threshold for testing. An awareness of the converse relationship is also crucial, because thyroid disease may explain fatigue and additional constitutional symptoms in treated celiac disease.
Associated Autoimmune Liver Disease
Mild transaminitis in the absence of primary liver disease can occur in the setting of untreated celiac disease. Patients are often asymptomatic and develop mild periportal inflammation that resolves with a gluten-free diet. Multiple studies and case reports have demonstrated variable associations among primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, and celiac disease. With the exception of two negative studies, a consistent association between primary biliary cirrhosis and celiac disease has been shown . In a recent review of celiac and liver disease, the percentage of biopsy-confirmed cases of celiac disease among the primary biliary cirrhosis population ranged from 1.3% to 7% . The largest study included greater than 13,800 patients with celiac disease from the Swedish national register and confirmed the association .
Prevalence rates of celiac disease among patients with autoimmune hepatitis range from 4% to 6.4% . Several other autoimmune diseases are more commonly associated with autoimmune hepatitis, including rheumatoid arthritis, synovitis, Graves’ disease, autoimmune thyroiditis, and ulcerative colitis . The association between autoimmune hepatitis and celiac disease appears to be less common in children than adults .
Initially reported in 1988, the association between celiac disease and primary sclerosing cholangitis has been investigated in a few large-scale studies. Ludvigsson and colleagues recently published one of the largest studies using the Swedish national register with the same cohort of greater than 13,800 patients with celiac disease, showing a fourfold to eightfold increased risk of primary sclerosing cholangitis.
Testing for celiac disease should be included in strategies for investigating elevated transaminases. False-positive tTg autoantibodies may occur in the setting of liver disease; however, a positive anti-EMA titer is quite specific even in this setting and may be a preferable way to detect celiac disease in this regard.
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Functional Gastrointestinal Disorders and the Potential Role of Eosinophils
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