CELIAC DISEASE AND DIABETES MELLITUS

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1 1 Department of Medicine, Nova Gradiška General Hospital, Strossmayerova 17, HR Nova Gradiška, Croatia 2 Vuk Vrhovac University Clinic, Dugi dol 4a, HR Zagreb, Croatia Review CELIAC DISEASE AND DIABETES MELLITUS Franjka Po gaj Metelko 2 Key words: diabetes mellitus, celiac disease, screening SUMMARY It is known that type 1 diabetes mellitus and celiac disease have a similar genetic background associated with HLA DQ2 or 8, and similar trigger mechanisms for autoimmune process. Celiac disease typically presents with malabsorption but in recent years there is an increasing number of atypical or silent form. Untreated celiac disease may be associated with long-term health risks. The institution of gluten-free diets may result in rapid and often dramatic improvement of symptoms. Extended monitoring is needed due to documentation of the clinical benefits of screening and treatment in diabetic patients. INTRODUCTION Diabetes mellitus (DM) is one of the most common endocrine diseases in all populations and all age groups. It is a syndrome of disturbed intermediary metabolism caused by inadequate insulin secretion, or impaired insulin action, or both. Etiologic classification of DM (American Diabetes Association, 1997) defines two types of DM: type 1, beginning as destruction of ß- cells of Langerhans islets, which can be autoimmune or rarely idiopathic. DM type 1 is characterized by total lack of insulin and classic symptoms of hyperglycemia with polyuria and loss of body mass. Due to accelerated lipolysis as an effect of insulin insufficiency there is ketoacidosis with lethal outcome. Insulin therapy is necessary for the control of hyperglycemia, metabolism regulation and support of life; and type 2 (the most common type of DM) beginning as insulin resistance, which is more or less related to inadequate secretion of ß-cells. The clinical symptoms are in the beginning milder than in DM type 1, and ketoacidosis does not occur. In treating DM type 2 dietary and oral hypoglycemic therapy have an important role, while insulin therapy is not always necessary and depends on the level of hyperglycemia (1,2). CELIAC DISEASE Celiac disease is a chronic disease of the gastrointestinal system, in which characteristic atrophy of the small intestinal mucosa occurs in genetically predisposed people in response to the presence of gluten in food. It is a continuous intolerance of gluten, gliadin and responsive prolamins that are present in wheat, rye and barley. The major characteristic of the disease is intestinal damage due to an immune defect (autoimmune disease) that occurs in people with a genetic background. Celiac disease is a chronic disease of the proximal segment of the small intestine. The most important characteristics of celiac disease are: permanent intolerance of gluten (a constituent of some cereals); typical mucosal findings in jejunal biopsy specimen; 157

2 typical presentation (malabsorption); and subsequent improvement on a gluten-free diet with complete histologic and clinical remission, and recurrence of the disease when the diet is broken (3). The disease can clinically manifest at any age, most commonly in the first few years of life, a few months of introducing gluten in diet. The prevalence of celiac disease in Europe is about 1:200. It is the most common genetic disease in Europe; in Italy 1:250 and in Ireland 1:300 (4). Etiology and pathogenesis Currently, the onset of celiac disease is considered to result from interaction between environmental factors, gluten as most important, genetic predisposition, and immune system hyperactivity (3). Gluten is a constituent of endosperm in cereal grains and serves as a source of nitrogen on germination. It is built of a number of polypeptides called prolamins. They are found in wheat, rye and barley. Some studies have demonstrated the individuals suffering from celiac disease to have a higher rate of infection with adenovirus type 12. Viral infection has been postulated to possibly stimulate the transfer of hypersensitivity by molecular mimicry (3,5,6). The predisposition to celiac disease is deeply connected with HLA DQ2 heterodimer, which is present in 90% of patients with celiac disease. It is encoded by DQ A and DQ B alleles, located on the same chromosome in people with DR 3 haplotype and on opposite chromosomes in heterozygotes with DR5/DR7 haplotype. Ten percent of patients with celiac disease do not have HLA DQ2 heterodimer but HLA DR 4 haplotype and DQ8 molecules encoded by DQ A and DQ B alleles (3,5). Celiac disease was found to correlate with HLA DQ antigens (96.55%) and a high presence of HLA DR 3 (84.48%) in Croatian children (7). The small intestinal mucosa contains a high level of T lymphocytes. The expression of HLA DQ molecules is necessary for the activation of T lymphocytes. These molecules are found in a greater number on mononuclear cells of lamina propria, such as macrophages and lymphocytes, in patients with active disease and after gluten exposure. These patients have IgA and IgG antibodies to gliadin. Antiendomysium and antireticulum antibodies, which are highly specific and have an almost 100% positive predictive value, are found in the sera of celiac disease patients. Endomysium antibody in celiac disease reacts with autoantigen tissue transglutaminase. Gluten from food is a substrate for transglutaminase. Tissue transglutaminase changes the structure of gluten from food and binds with it into a stable complex acting as a complex hapten carrier in immunocompetence. Deamination of gluten permits binding to DQ2 molecules on presenting cells and results in specific clones of CD 4 lymphocytes of lamina propria. CD 4 lymphocytes express anti-inflammatory cytokines, cause inflammatory changes of the mucosa, activate autoreactive B lymphocytes and produce antibodies to the transglutaminase neoepitope, which is the result of transglutaminase binding to deaminated gluten (3,5). Symptoms of celiac disease Most patients have a typical malabsorption syndrome characterized by weight loss, abdominal distention, swelling, diarrhea, steatorea, and abnormal functional test of intestinal absorption. Retarded growth is an important feature in children with celiac disease. In recent years, an increasing number of cases with atypical symptoms have also been diagnosed at older ages. These symptoms are iron deficiency anemia without transparent loss of blood, or caused by hypoprothrombinemia, and metabolic bone disorder. Extraintestinal disorders include dermatitis herpetiformis, neuropsychiatric disorders, and fertility problems (3,5). Screening programs in apparently healthy individuals have identified the category of silent and latent celiac disease, characterized by the absence of clinical symptoms but with the presence of typical immunologic and histologic findings compatible with celiac disease. Silent celiac disease is as a rule detected on the screening for celiac disease. It is found in the people on normal diet (with gluten). The biopsy finding of intestinal mucosa corresponds to celiac disease, serologic tests are positive, gastrointestinal symptoms are not present, however, anemia, retarded growth, prolonged puberty and aphthous stomatitis may be observed. The clinical signs disappear upon switching to a gluten-free diet. 158

3 Latent (potential) celiac disease is a condition found in people on normal diet (with gluten). Serologic tests and HLA are positive, the architecture of intestinal mucosa is normal, with an increased number of intraepithelial T lymphocytes. Later on, atrophy of the small intestinal lobules and hyperplasia of the intestinal crypt may occur. Controls on normal diet are usually needed (3,5,6). Treatment Once celiac disease has been diagnosed, physicians should explain to patients the lifelong nature of the condition and the necessity of adhering to a gluten-free diet. Patients often react with grief and many have a hard time understanding or accepting that something so fundamental to their diet could be injuring them. Patients may have blamed other food substances such as lactose for their symptoms and may find it hard to accept the identity of the culprit. The institution of gluten-free diets should result in prompt and often dramatic improvements in symptoms. Recovery is more rapid and complete in children than in adults. Resolution of symptoms may take 3 6 months; complete healing of the intestine may, however, take longer time, especially in the elderly. Consistent observance of gluten-free diet can moderate the risk of malignant disease and after five years of strict glutenfree diet the risk is comparable to that in the general population (3,5,6). Associated diseases Associated diseases are congenital deficit of immunoglobulin A (in 2%-3% of celiac disease patients), Down syndrome (16-fold prevalence), and autoimmune disorders. About 90% of celiac disease patients have B8-Dr3-DQ2 haplotype, which is common in other autoimmune disorders. The autoimmune disorders most commonly associated with celiac disease are DM type 1, autoimmune thyroiditis and Sjögren s syndrome. The rate of malignant diseases is higher in patients with celiac disease, according to different authors ranging from 3% to 11%. The most common of these are non-hodgkin lymphoma, esophageal carcinoma and laryngeal carcinoma (3). Association of celiac disease with diabetes mellitus In type 1 diabetes, the coexistence of other endocrine diseases and organ-specific autoantibodies has been frequently reported, leading to the concept of autoimmune polyendocrine syndrome (8). There is ample and convincing evidence for the autoimmune pathogenesis of type 1 diabetes, e.g., inflammatory infiltration of the pancreas with T lymphocytes (insulitis), association with other autoimmune disorders, antibodies (ICA, IAA, GAD), and changes in cellular immunity (9). In addition, an association of type 1 diabetes with celiac disease has been described. The concurrence of the two diseases may be explained by a similar genetic background associated with HLA DQ2 or 8, and similar trigger mechanisms for autoimmune process. More than 90% of celiac disease patients and about 60% to 70% of diabetics carry the HLA heterodimer DQA1*05DQb1*0201 (10). Screening for specific antibodies allows for an early diagnosis of these disorders. It is recommended that, in an active case-finding strategy, the recent onset type 1 diabetic patients be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their firstdegree relatives should at least include the search for thyroid autoimmunity in addition to screening for pretype 1 diabetes. The prevalence of celiac disease in patients with type 1 diabetes is approximately 20-fold that in the general population, ranging between 2% and 6%, mean 4.5% (11-15). CD IgA antibodies to endomysium or tissue transglutaminase were found in 1.0%-6.5% of unselected patients with type 1 DM (16). In 60% of cases they are already present at diabetes onset, mostly undetected, whereas 40% of patients develop celiac disease a few years after diabetes onset. Extending screening programs for celiac disease after the onset of type 1 DM is recommended in the absence of clinical symptoms (17). Untreated patients with celiac disease have been found to have a higher prevalence of organ-specific autoantibodies than expected. In a prospective study of 90 patients with celiac disease, the prevalence of diabetes serum antibodies was 11.1% (16). These organ-specific antibodies seem to be gluten-dependent and tend to disappear with a gluten-free diet. Another 159

4 report is in contrast to what has been reported in patients with islet autoantibodies and celiac disease, in whom disappearance of these antibodies was observed after the introduction of gluten-free diet (18). It is concluded that, although diabetes can be delayed by avoiding dietary gluten in NOD mice and removal of gluten may result in a reduction of diabetes-associated autoantibodies in patients with celiac disease, gluten does not drive the production of islet autoantibodies in type 1 diabetes as it does in celiac disease. Another study indicates that the risk of developing DM is only minimally higher in patients with celiac disease than in the normal population, thus general screening cannot be recommended at present (19). Amin et al. noted that BMI and hemoglobin A1c were lower in diabetic patients with celiac disease before a gluten-free diet (20). Both body mass index and hemoglobin A1c improved on the gluten-free diet, suggesting that such a diet is necessary for normoglycemia in diabetic patients with celiac disease. Additional studies are needed to prove the relationship between celiac disease and DM type 1, and to recommend appropriate screening, diagnosis and therapy. In DM type 2 no AGA increase was found although IgA-GA were more frequent in all diabetics. There is no evidence for celiac disease to be associated with DM type 2. It seems that the prevalence of celiac disease in type 2 diabetics is the same as in the normal population. The overall prevalence of celiac disease in adult patients with type 1 DM was 1:50 compared with 1:340 in type 2 (21,22). On the other hand, gluten intolerance can disrupt glucose regulation and lead to a greater risk of hypoglycemia. Gastroparesis, constipation, diarrhea, and fecal incontinence occur frequently in diabetics with longstanding and often poorly controlled diabetes. The diagnosis of diabetic diarrhea depends on careful and judicious assessment, which allows for the distinction of this condition from other causes of diarrhea such as celiac disease (14). However, longterm monitoring is needed to document the clinical benefit of screening for celiac disease and use of gluten-free diet in diabetic patients. CONCLUSION The association between DM type 1 and celiac disease has been thoroughly investigated. It is recommended to do serologic screening for celiac disease in all patients with DM type 1. There are ever more patients with atypical, silent and latent celiac disease. In those with positive test results it is necessary to perform small intestinal biopsy to confirm the diagnosis. At present, there are only few institutions in Croatia where determination of endomysium and antigliadin antibodies is available, thus it obviously cannot be performed in all type 1 diabetics. However, screening for endomysium and antigliadin antibodies should be done in those patients with typical celiac disease manifestations or unknown anemia, in children with growth retardation, in patients with arthritis, metabolic bone disorders, unknown hepatitis and in those with poor DM control. Also, noncompliance with the correct dietary regimen will have adverse effects on both diseases. It is very hard to persuade a diabetic to accept the gluten-free diet, however, it is possible in cooperation with a specialist. The choice of food is now considerably greater and more variable than before (soya meal, corn meal, and rice). In patients with DM type 2 it is necessary to do the screening for celiac disease when the patient exhibits respective symptoms, although the rate of celiac disease is the same as in the normal population. Obviously, additional studies are needed to prove the relationship between celiac disease and DM type 1, and to recommend proper screening, diagnosis and therapy. 160

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