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Celiac.com 11/04/2024 - Celiac disease is an autoimmune disorder that primarily affects the digestive system, but its influence extends far beyond the gut. When individuals with celiac disease consume gluten, an immune response is triggered that can damage the small intestine and lead to a wide array of health problems. Recent research has been exploring the potential connection between celiac disease and other organ systems, including the kidneys. This study focuses on whether there is a causal relationship between celiac disease and various forms of kidney disease, specifically through genetic predisposition. The researchers used a method called Mendelian randomization to assess this potential link, which helps reduce the chance of bias in observational studies. Methods: Using Genetics to Explore Connections To investigate the possible connection between celiac disease and kidney disease, the researchers used data from European populations. They applied a technique known as Mendelian randomization, which analyzes genetic data to identify potential causal relationships. This method reduces the impact of confounding factors and helps establish whether genetic susceptibility to celiac disease might lead to an increased risk of kidney-related issues. Specifically, they looked at 10 different kidney traits, such as immunoglobulin A nephropathy (a kidney disorder involving deposits in the kidneys), chronic glomerulonephritis (a condition where the kidney’s filtering units become inflamed), and a decline in estimated glomerular filtration rate, which measures kidney function. Key Findings: Increased Risk of Kidney Disease The study found that individuals with a genetic predisposition to celiac disease have a higher risk of developing certain kidney diseases. The data showed a significant increase in the risk of immunoglobulin A nephropathy, with a 44% higher likelihood for those genetically inclined toward celiac disease. Additionally, the study noted a 15% increased risk of chronic glomerulonephritis. A decline in kidney function, as measured by a decrease in the estimated glomerular filtration rate, was also observed. Interestingly, the study also hinted at a potential connection between celiac disease and membranous nephropathy, a type of kidney disease where the immune system attacks the membranes in the kidneys. Although this relationship was not as strong as others, it remains a possibility that requires further investigation. Mechanisms: How Celiac Disease Might Affect the Kidneys One proposed mechanism for this connection is that in individuals with celiac disease, gluten triggers an immune response that does not remain confined to the gut. Instead, this response may cross-react with other tissues, including the kidneys. Specifically, circulating antibodies, which are produced in response to gluten, may end up targeting kidney tissues. These immune reactions and the associated inflammation could damage the kidneys over time, leading to the development of kidney disease. In particular, the study draws attention to the similarity between the damage caused to the intestinal barrier in celiac disease and the type of damage seen in certain kidney diseases, such as immunoglobulin A nephropathy. Some research has shown that antibodies produced in response to gluten can be found in the kidneys of people with this condition, which strengthens the idea that the immune system’s misdirected response in celiac disease can have broader consequences for other organs. Contradictory Evidence: No Clear Link with All Kidney Conditions While the study highlights the increased risk for certain kidney conditions, it also shows that not all kidney diseases are strongly associated with celiac disease. For instance, the research found no significant correlation between celiac disease and diabetic nephropathy, a type of kidney damage commonly seen in people with diabetes. This suggests that the connection between celiac disease and kidney disease may depend on the specific type of kidney condition in question, and not all kidney issues share the same underlying mechanisms with celiac disease. Implications for Individuals with Celiac Disease For individuals diagnosed with celiac disease, the findings of this study underscore the importance of monitoring kidney health. Although kidney problems may not be a common or immediate concern for all celiac patients, there is enough evidence to suggest that people with this condition should be aware of their potential risk for certain types of kidney disease. Regular screenings, such as urine tests or blood tests to assess kidney function, could help detect any early signs of kidney issues before they progress. Moreover, adopting a strict gluten-free diet remains crucial for people with celiac disease. While this study did not directly address the impact of a gluten-free diet on kidney health, other research has suggested that reducing gluten intake can have a positive effect on various health outcomes in celiac patients. Maintaining a gluten-free diet may help minimize the immune response that could contribute to kidney damage. Valuable Insights into the Relationship Between Celiac Disease and Kidney Health This study adds valuable insight into the relationship between celiac disease and kidney health. By using genetic data, the researchers were able to show that individuals with a genetic predisposition to celiac disease may be at a higher risk of developing certain kidney diseases, such as immunoglobulin A nephropathy and chronic glomerulonephritis. While not all kidney diseases are linked to celiac disease, the findings highlight the need for continued research into how autoimmune responses triggered by gluten can affect other organs beyond the gut. For those with celiac disease, understanding this potential link to kidney health could help improve long-term outcomes through early detection and prevention. If future research confirms these findings, routine kidney screenings could become an important part of managing celiac disease, ultimately reducing the risk of serious kidney complications. Read more at: journals.lww.com

Celiac.com 08/13/2022 - Celiac disease is an autoimmune gastrointestinal disorder that may occur in genetically susceptible individuals triggered by the ingestion of gluten-containing grains such as wheat, barley and rye. Of the many autoimmune disorders, celiac disease represents one of the few where the etiological agent is known and the disease subsides and goes in remission once the etiological agent is withdrawn from the diet. Celiac disease is characterized by malabsorption resulting from inflammatory injury to the small intestinal mucosa, which, when prolonged, can cause malnutrition. The classic symptoms of celiac disease include diarrhea, weight loss and malnutrition. However, only a small percentage of patients with celiac disease present with the classic symptoms. Consequently, the clinical spectrum of celiac disease has grown much broader to include patients without classic symptoms. It is not uncommon for the initial symptoms to be non-gastrointestinal or for gastrointestinal symptoms, if present, to be mild or intermittent. Some of the common non-gastrointestinal manifestations include short stature, iron and folate deficiency, anemia, bone loss, aphthous stomatitis, arthralgia, dental enamel defects, etc. The inclusion of a wider range of clinical presentation has led to greater numbers of individuals diagnosed with celiac disease later in life than ever before. Adults may present with iron deficiency, macrocytic anemia and hypocalcaemia. Studies have found the prevalence of celiac disease to be highly variable from population to population (1) and the true prevalence has been difficult to ascertain. The disparate criteria used in the diagnosis of celiac disease are often the cause. If only the clinical criteria are used in determining prevalence, the incidence of celiac disease is much lower as compared with incidence established by serological methods (2) . Using serological methods of diagnosis, the incidence of celiac disease in the general population is approximately one in 200. Diagnosis of celiac disease based on clinical criteria can therefore be misleading and may lead to serious delays in proper diagnosis. Frequently, delays in diagnosis extend 10-13 years from the first clinical presentation of symptoms. Failure to diagnose celiac disease early on may predispose an individual to long-term complications such as splenic atrophy and intestinal lymphoma. The incidence of lymphoma arising in the context of celiac disease is difficult to ascertain. One study has shown incidence of lymphoma involving the gastrointestinal tract in patients with celiac disease to range from 3.6 percent to 40 percent (3) . In another recent study, celiac disease was found to be associated with significantly elevated risk for intestinal lymphoma, especially for non-Hodgkin’s (4) . A gluten-free diet normalizes the mucosa and helps reduce the malignant potential. Histological examination of the small intestinal biopsy is considered to be the gold standard for diagnosing celiac disease, but it has its own limitations. Certain studies have shown some patients with latent or even active celiac disease that may have normal histopathology(5). Serological Methods of Detecting Celiac Disease The revised European Society of Pediatric Gastroenterology and Nutrition (ESPGAN) criteria for diagnosis of celiac disease include only a single biopsy with clear-cut remission of clinical symptoms on a gluten-free diet (6). Positive serology at the time of diagnosis with a decline in antibody levels on a gluten-free diet contributes to the diagnosis. The various serological tests employed in the work-up of patients suspected to have celiac disease include anti-gliadin antibody (AGA), anti-endomysial antibody (EMA), anti-reticulin antibody (ARA) and anti-tissue transglutaminase (tTG) antibody tests. Antibodies to gliadin and tTG are detected by the ELISA method, whereas endomysial and reticulin antibodies are detected by indirect immunofluorescence. EMA are very specific indicators of celiac disease. One study (7) concludes that “EmA-IgA is 100 percent sensitive and specific in active, untreated IgA-sufficient celiac disease patients when performed by an established laboratory.” tTG has been identified as the endomysial antigen. This discovery has enabled development of automatable ELISA methods for detecting antibodies in the sera of patients with celiac disease. Many laboratories have opted to use the tTG antibody method in screening for celiac disease. In these laboratories, it may be the only assay used for detection of celiac disease cases. Various studies on the efficacy of the tTG antibody method for screening have found the specificity and sensitivity of this method to range from 90 percent to 95 percent (8). Assays using human tTG have been described to improve the sensitivity of detection of tTG antibodies. Surprisingly, in a recent report by the Medicines and Healthcare Products Regulatory Agency (MHRAM) on various anti-tTG IgA isotype assays the specificities were found to be good but assay sensitivity was often poor, indicating considerable variation in reliability of detection. One limitation of existing serological methods is that, with the exception of IgG–gliadin, they detect only the IgA isotype of the antibodies; hence, IgA deficient celiac disease patients may yield false negative serology (9) . This may compromise the utility of the serum antibody methods in detecting all celiac disease cases (10). What is IgA deficiency? In the blood there are proteins called immunoglobulins that generally provide immunological protection. There are five types of immunoglobulins, known as IgG, IgA, IgM, IgE, and IgD. IgG and IgM provide protection in the circulatory system whereas IgA is transported to the surface of mucosal surfaces such as in the gastrointestinal tract and oral mucosa, safeguarding these mucosal surfaces from infection. Certain individuals that fail to produce the IgA immunoglobulin are referred to have selective IgA deficiency. The cause of this selective IgA deficiency is not known. What is known is that patients with selective IgA deficiency have a defect in differentiating B cells (one of the white cell types) into cells that manufacture immunoglobulins called plasma cells. The concentration of IgA in the plasma of normal individuals is about 300 mg/dl. In individuals with selective IgA deficiency the IgA levels are less than 0.05 mg/dl. IgA deficiency is one of the most common immunodeficiencies, found in one in 500-700 healthy blood donors (11). In most situations, these IgA deficient individuals are healthy. Those who develop symptoms suffer from sino-pulmonary infections, allergies, and autoimmune disorders, especially celiac disease (12). The incidence of IgA deficiency in celiac disease patients is between 2-3% representing a 10-15 fold increase over the general population. Familial inheritance of IgA deficiency occurs in 20% of cases. While the selective defect of B cells limits the number of IgA secreting plasma cells, IgA deficient individuals have normal function of IgG and other immunoglobulin secreting plasma cells. Celiac disease patients with IgA deficiency produce IgG immunoglobulin normally, and the antibodies to EMA, tTG and gliadin are of the IgG isotype rather than IgA. To prevent false negative results in IgA deficient cases of celiac disease, it is necessary to include serological methods that can detect antibodies of IgG isotype. How can we detect Celiac Disease in patients with IgA deficiency? In patients with known selective IgA deficiency, the IgG antibody levels for EMA, tTG and gliadin can be measured and are very effective in identifying patients with celiac disease. However, one generally does not know if the individual is IgA deficient. Until specific tests for IgA levels are performed, the IgA status of an individual may never be known. As IgA deficiency is more prevalent in the celiac population than the general population, it has been proposed that all patients who are considered for celiac disease be tested for IgA levels to identify cases of IgA deficiency. Checking all routine samples referred to a laboratory for celiac disease testing, Lock and Unsworth found that testing for IgA levels in identifying IgA deficient celiac disease patients is excessive and more likely to identify non-celiac disease cases (13). They concluded that testing of IgA levels is not cost effective. Testing for IgG antibodies to EMA, tTG or AGA, however, is cost effective. Detection of these antibodies either individually or in combination helps to identify all cases of IgA deficient celiac disease on normal diets. Using this method, we reported the first IgA deficient celiac disease case in 1989. Since then, others have reported on large populations of IgA deficient celiac disease and non-celiac disease cases and found the serological methods to be effective (see table on pg. 17). The levels of these antibodies are also of interest, as antibody level tends to correlate with the severity of the disease. When a patient is on a gluten free diet, the levels of these antibodies will decrease and eventually disappear, suggesting that the patient is in remission. Thereafter, tests for antibody levels could be checked annually or bi-annually to ensure the individual’s dietary compliance. Intake of gluten in individuals who are in remission will result in the re-appearance or increase of these antibodies in the serum (see figure below).

Celiac.com 10/04/2021 - How symptoms and antibodies related to SARS-CoV-2 infection develop in patients with celiac disease is unclear. Is it similar to non-celiacs? A team of researchers recently set out to investigate the impact of SARS-CoV-2 infection in celiac patients. The team asked celiac disease patients about how their COVID-19 symptoms developed, how they were complying with anti-virus measures and, how strictly they were following a gluten-free diet. The team compared data on the rates of anti-SARS-CoV-2 IgG and IgA (anti-RBD and N proteins) in celiacs with data for non-celiacs. They also looked at expression of the duodenal ACE2 receptor. Where possible, they analyzed data on duodenal histology, anti-tissue transglutaminase IgA (tTGA), comorbidities and GFD adherence. The team looked at a total of 362 celiac patients, 42 of which reported COVID-19 symptoms (12%), with 21% of these symptomatic patients testing positive for anti-SARS-CoV-2 Ig. Overall, 18% of celiac patients showed anti-SARS-CoV-2 Ig compared with 25% of the control group. Celiac patients had significantly lower levels of anti-N IgA. Symptoms and/or antibodies were not affected by tTGA, duodenal atrophy, gluten-free diet adherence, or other comorbidities. They did detect ACE2 receptor in the non-atrophic duodenal mucosa of patients; which, is associated with atrophy at lower levels. Except for anti-N IgA, celiac disease patients have an anti-SARS-CoV-2 Ig profile similar to non-celiacs. The team found no risk factors tied to celiac disease parameters or gluten-free diet adherence. Read more in Digestive and Liver Disease The research team included Luca Elli; Federica Facciotti; Vincenza Lombardo; Alice Scricciolo; David S. Sanders; Valentina Vaira; Donatella Barisani; Maurizio Vecchi; Andrea Costantino; Lucia Scaramella; Bernardo dell'Osso; Luisa Doneda; and Leda Roncoroni. They are variously affiliated with the Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; the European Institute of Oncology IRCCS; the Centre for Prevention and Diagnosis of Celiac Disease; the Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; the Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, United Kingdom; the School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; the Pathology Unit, and the Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; and the Centre for Prevention and Diagnosis of Celiac Disease.

Celiac.com 11/04/2015 - A research team that conducted an analysis of the relationship between seronegative celiac disease and immunoglobulin deficiencies also conducted a literature search on the main medical databases, which revealed that seronegative celiac disease poses a diagnostic dilemma. The research team included F. Giorgio, M. Principi, G. Losurdo, D. Piscitelli, A. Iannone, M. Barone, A. Amoruso, E. Ierardi, and A. Di Leo. They are variously affiliated with the Section of Gastroenterology at University Hospital Policlinico, Department of Emergency and Organ Transplantation at University of Bari in Bari, Italy. They note that villous blunting, intraepithelial lymphocytes (IELs) count and gluten "challenge" are the most reliable markers in addressing seronegative celiac disease. They also note that immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of seronegative celiac disease patients may be useful. In the team's view, tTG-mRNA was similarly increased in seropositive celiac disease and suspected seronegative celiac disease, and strongly correlated with the IELs count. This increase is found even in the IELs' range of 15-25/100 enterocytes, suggesting that there may be a "grey zone" of gluten-related disorders. An immune deregulation, severely lacking B-cell differentiatio, underlies the association of seronegative celiac disease with immunoglobulin deficiencies. Therefore, celiac disease may be linked to autoimmune disorders and immune deficits, known as common variable immunodeficiency (CVID)/IgA selective deficiency. CVID is a heterogeneous group of antibody dysfunction, whose association with celiac disease revealed only by a positive response to a gluten-free diet. The research team suggests a possible familial inheritance between celiac disease and CVID. Selective IgA deficiency, commonly associated with celiac disease, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare, with less than 300 documented cases, and is connected to celiac disease in 5% of cases. The team diagnosed seronegative celiac disease in a patient affected by sIgMD using the tTG-mRNA assay. One-year on a gluten-free diet restored IgM levels. This study data support a link between seronegative celiac disease and immunoglobulin deficiencies, and invites researchers to take a closer look at this connection. Source: Nutrients. 2015 Sep 8;7(9):7486-504. doi: 10.3390/nu7095350