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Celiac.com 06/01/2021 - Villous atrophy not caused by celiac disease is called "non-celiac enteropathy." In many cases, the symptoms mirror the classic symptoms of celiac disease: diarrhea, weight loss, abdominal pain, and fatigue. Spotting the difference between celiac disease and non-celiac enteropathy can be challenging. That's why physicians recommend celiac disease blood tests, which are used to find adverse immune reactions to the gluten protein in the foods you eat. Just as it's possible to have damaged villi without celiac disease, it's possible to have celiac disease, and villi damage, even with negative blood antibody tests. People with celiac disease usually improve on a gluten-free diet. While some may not, many folks with non-celiac enteropathy do not respond to a gluten-free diet. People who do not see symptom improvement on a gluten-free diet may need to consider alternative causes for their symptoms and villous atrophy. Non-Celiac Causes of Villous Atrophy Non-celiac causes of villous atrophy include: Benicar (olmesartan) In some patients, taking this blood pressure medication leads to villous atrophy combined with diarrhea and weight loss. The U.S. Food and Drug Administration issued a warning about this in 2013. Common Variable Immune Deficiency, or CVID CVID is a condition that leaves people vulnerable to recurrent infections. Crohn's disease Villous atrophy is unusual in Crohn's disease, but can happen. Lymphoma One study found two different types of lymphoma could cause villous atrophy: small intestinal T-cell lymphoma, and enteropathy-associated T-cell lymphoma. Enteropathy-associated T-cell lymphoma is closely linked to celiac disease. Casein/Cow's Milk Intolerance Research has shown that flattened villi can also be caused by casein intolerance. For more info see "Mucosal reactivity to cow's milk protein in C(o)eliac disease," which states "A mucosal inflammatory response similar to that elicited by gluten was produced by CM (Cows Milk) protein in about 50% of the patients with coeliac disease. Casein, in particular, seems to be involved in this reaction." Certain Drugs Drugs that suppress your immune system (such as Imuran and CellCept), the antibiotic neomycin, and the anti-inflammatory medication Colcrys, also have been linked to reports of medication-induced villous atrophy. Small intestine Bacterial Overgrowth, or SIBO Symptoms of SIBO can mimic those of celiac disease. Other possible causes of villous atrophy, including infection with parasites or with the ulcer-causing bacteria Helicobacter pylori, also have been reported. Thiamine Deficiency and/or Beri Beri Both can cause thinning of the villi, leading to both casein/lactose intolerance and in time possibly a celiac disease or non-celiac gluten sensitivity (NCGS) diagnosis. Not all Villous Atrophy is From Celiac Disease Most, but not all, cases of villous atrophy are caused by celiac disease. Patients with negative blood test, who do not see symptoms improve on a gluten-free diet, should consult with a doctor about other possible causes of villous atrophy.

Celiac.com 06/12/2024 - A recent study presented at the Digestive Disease Week (DDW) Annual Meeting 2024 has sparked a significant conversation around the relationship between celiac disease and obesity. Traditionally, celiac disease was understood primarily as a condition affecting malnourished children with chronic diarrhea. However, recent findings suggest that the clinical presentation of celiac disease has evolved, with obesity now emerging as a noteworthy symptom among affected adults. Study Objectives and Methodology The primary goal of the study was to evaluate how prevalent obesity is among patients with celiac disease. To achieve this, researchers utilized data from the All of Us Research Program, a comprehensive national database. They examined a large sample size, consisting of 407,333 patients with celiac disease and an equal number of control individuals without the disease. These groups were matched by age and analyzed using health survey data. The main focus was to compare the prevalence of obesity between these two groups. Key Findings: Obesity Rates in Celiac Disease The results were striking: nearly one-third (32.6%) of patients with celiac disease were found to be obese, compared to only 18.4% of the control group. This substantial difference indicates that individuals with celiac disease are significantly more likely to be obese. The study reported an odds ratio of 2.111, underscoring the strong association between celiac disease and obesity. Demographic Insights When the data was broken down by sex, it was observed that women with celiac disease had the highest rates of obesity. However, men with celiac disease also exhibited a higher prevalence of obesity compared to their counterparts in the control group. Additionally, age stratification revealed that obesity was more common among individuals over the age of 65 with celiac disease. These demographic insights highlight that the relationship between celiac disease and obesity is consistent across different segments of the population. The Role of the Gut Microbiome One of the most intriguing aspects of this study is the suggested role of the gut microbiome in linking celiac disease and obesity. The researchers speculated that changes in the gut microbiota might contribute to the increased obesity rates observed in patients with celiac disease. This idea is supported by the notion that maintaining a strict gluten-free diet, which is essential for managing celiac disease, can be challenging for some patients. The resulting gut dysbiosis, or microbial imbalance, might therefore play a role in both celiac disease and obesity. Implications for Treatment and Future Research The study authors emphasized that their findings highlight the need for further investigation into how microbial changes and dietary exposures influence the development and progression of both celiac disease and obesity. Understanding these connections could pave the way for new therapeutic approaches that target gut dysbiosis. This could be particularly beneficial for patients struggling to adhere to a gluten-free diet or those experiencing obesity as a direct symptom of celiac disease. Conclusion This study's findings are particularly meaningful for individuals with celiac disease as they challenge the traditional understanding of the disease and expand its clinical spectrum to include obesity. For patients and healthcare providers alike, recognizing obesity as a potential symptom of celiac disease can lead to more comprehensive management strategies that address both dietary and microbiome-related aspects of the condition. By acknowledging and investigating the link between celiac disease and obesity, there is potential to improve patient outcomes and develop more effective, targeted treatments in the future. Read more: infectiousdiseaseadvisor.com

Celiac.com 02/10/2024 - Villous atrophy, a condition marked by the blunting or flattening of the microscopic structures called villi in the small intestine, is most commonly associated with celiac disease. However, emerging research and clinical observations have unveiled a spectrum of diverse conditions beyond celiac disease that can lead to villous atrophy. This article explores the lesser-known contributors to villous atrophy, shedding light on various health conditions that may present with similar histological changes in the small intestine. While celiac disease remains a prominent cause, understanding these alternative pathways to villous atrophy is crucial for accurate diagnosis, appropriate management, and a comprehensive approach to gastrointestinal health. From autoimmune disorders to infections and drug-induced reactions, exploring the multifaceted nature of villous atrophy enhances our grasp of gastrointestinal pathology and guides clinicians toward more nuanced and personalized patient care. Other Conditions Associated with Villous Atrophy In the following sections, we delve into a comprehensive exploration of diverse health conditions intricately linked to villous atrophy, shedding light on their unique associations and implications for gastrointestinal health. Eosinophilic Enteritis Eosinophilic enteritis is an inflammatory disorder characterized by an increased presence of eosinophils in the gastrointestinal tract. Eosinophils are a type of white blood cell involved in the immune response. In eosinophilic enteritis, these cells infiltrate the walls of the intestines, causing inflammation and damage. This inflammatory process can lead to various symptoms, including abdominal pain, diarrhea, and malabsorption. In some cases, the inflammation may result in villous atrophy, affecting the absorptive capacity of the small intestine. Diagnosis often involves endoscopic procedures with tissue biopsy to evaluate the extent of inflammation and associated damage. Crohn's Disease Crohn's disease is a chronic inflammatory bowel disease that can affect any part of the gastrointestinal tract, from the mouth to the anus. In the small intestine, Crohn's disease can cause inflammation and damage to the intestinal lining, leading to complications such as strictures and fistulas. In some cases, individuals with Crohn's disease may experience villous atrophy, particularly in areas of the small intestine affected by inflammation. The severity of villous atrophy can vary among patients with Crohn's disease, and its presence may contribute to malabsorption issues and nutritional deficiencies. Management often involves anti-inflammatory medications, immunosuppressants, and, in severe cases, surgical intervention to address complications. Giardiasis Giardiasis is an intestinal infection caused by the parasite Giardia lamblia. This parasitic infection can lead to symptoms such as diarrhea, abdominal cramps, and bloating. In addition to the acute phase of the infection, chronic giardiasis has been associated with villous atrophy in some cases. The mechanisms by which Giardia lamblia causes villous atrophy are not fully understood, but it is believed to involve both direct damage to the intestinal lining and an immune response triggered by the presence of the parasite. Diagnosis typically involves stool tests to detect the parasite, and treatment includes antiparasitic medications. Common Variable Immunodeficiency (CVID) Common Variable Immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by impaired antibody production, leading to increased susceptibility to infections. Some individuals with CVID may experience gastrointestinal symptoms, including chronic diarrhea and malabsorption. In severe cases, villous atrophy can occur, impacting the absorption of nutrients in the small intestine. The association between CVID and villous atrophy underscores the complex interplay between the immune system and the intestinal mucosa. Management involves immunoglobulin replacement therapy to address the immune deficiency and supportive measures for gastrointestinal symptoms. Autoimmune Enteropathy Autoimmune enteropathy is a rare autoimmune disorder that primarily affects the small intestine. In this condition, the immune system mistakenly attacks the cells of the intestinal lining, leading to severe inflammation and damage. Villous atrophy is a characteristic feature of autoimmune enteropathy, affecting the absorptive surface area of the small intestine. Individuals with autoimmune enteropathy often present with persistent diarrhea, malabsorption, and failure to thrive. Diagnosis requires extensive evaluation, including endoscopic procedures and tissue biopsy. Treatment involves immunosuppressive medications to modulate the autoimmune response and manage symptoms. Human Immunodeficiency Virus (HIV) Advanced Human Immunodeficiency Virus (HIV) infection can result in various gastrointestinal complications, affecting both the upper and lower parts of the digestive tract. HIV-associated enteropathy may involve villous atrophy, contributing to malabsorption and nutritional deficiencies. The mechanisms leading to villous atrophy in HIV infection are multifactorial, involving both direct viral effects and immune-mediated processes. Additionally, opportunistic infections and other HIV-related complications can further impact the gastrointestinal mucosa. Management includes antiretroviral therapy to control HIV replication and supportive measures to address nutritional deficiencies and associated symptoms. Regular monitoring and a multidisciplinary approach are crucial in the care of individuals with HIV-associated gastrointestinal conditions. Dermatitis Herpetiformis (DH) Dermatitis herpetiformis is a chronic skin condition characterized by intensely itchy, blistering skin lesions. While DH primarily manifests as a skin disorder, its connection to celiac disease is well-established. Both conditions share a common trigger: gluten ingestion. DH is considered the skin manifestation of celiac disease, and individuals with DH often have underlying gluten sensitivity. The immune response triggered by gluten in susceptible individuals leads to the formation of IgA antibodies, which deposit in the skin, causing the characteristic skin lesions. While DH predominantly affects the skin, it is crucial to recognize its association with celiac disease, as individuals with DH may also experience villous atrophy in the small intestine. Therefore, a gluten-free diet is not only essential for managing skin symptoms but also for addressing the underlying celiac disease and preventing intestinal damage. Diagnosis involves skin biopsy for characteristic IgA deposits and, in some cases, intestinal biopsy to assess the extent of villous atrophy. Treatment primarily revolves around strict adherence to a gluten-free diet, often complemented by medications to control skin symptoms. Managing DH effectively requires a multidisciplinary approach, involving dermatologists, gastroenterologists, and dietitians to address both the skin manifestations and the underlying celiac disease. Idiopathic Sprue Idiopathic sprue is a term used for cases of sprue (malabsorption syndrome) where the cause is unknown. It may include cases that do not fit the criteria for celiac disease or other known causes of malabsorption. It shares some features with celiac disease, such as malabsorption and damage to the small intestine, but it lacks specific diagnostic markers for celiac disease. Diagnosis may involve excluding other causes of malabsorption, and it may be considered when typical celiac disease markers are absent. Tropical Sprue Tropical sprue is a malabsorption syndrome that occurs in tropical regions, and its exact cause is not fully understood. It is thought to be associated with infections or environmental factors. It presents with symptoms of malabsorption, such as diarrhea, weight loss, and nutritional deficiencies. It is more commonly observed in tropical regions but can occur in non-tropical areas as well. Collagenous Sprue Collagenous sprue is a rare disorder characterized by collagen deposition in the small intestine. The cause is not well-established. It leads to malabsorption and features similar to celiac disease but is distinguished by the characteristic collagen band in the intestinal lining. Diagnosis involves histological examination of small intestinal biopsies. The management of collagenous sprue may involve a combination of treatments, including a gluten-free diet and immunosuppressive medications. Corticosteroids or other immunosuppressants may be prescribed. Peptic Duodenitis Peptic duodenitis, a condition characterized by inflammation of the duodenal lining due to exposure to stomach acid, shares a commonality with celiac disease in its potential to induce villous atrophy. In peptic duodenitis, the inflammatory response triggered by gastric acid can extend into the duodenum, disrupting the delicate balance of the intestinal mucosa. This sustained inflammation may lead to changes in the architecture of the small intestine, including the villi, finger-like projections crucial for nutrient absorption. The damage incurred can result in villous atrophy, akin to the characteristic intestinal changes observed in celiac disease. Helicobacter Pylori Helicobacter pylori, a bacterium known for its association with gastric ulcers and gastritis, has been implicated in gastrointestinal conditions that extend beyond the stomach, including potential involvement in villous atrophy akin to celiac disease. The presence of H. pylori in the duodenum and small intestine has been linked to chronic inflammation and alterations in mucosal architecture. The bacterium's ability to induce immune responses may contribute to the damage of the intestinal villi, compromising their structure and functionality. This shared consequence of villous atrophy highlights the interconnectedness of various gastrointestinal disorders and underscores the need for comprehensive investigations to discern the specific triggers and mechanisms at play. While celiac disease and H. pylori-related duodenal changes differ in their etiology, understanding the potential overlap in their impact on intestinal health is crucial for accurate diagnosis and tailored therapeutic interventions. Small Intestinal Bacterial Overgrowth (SIBO) Small intestinal bacterial overgrowth (SIBO) is recognized for its capacity to disrupt the normal balance of microorganisms in the small intestine, leading to various gastrointestinal manifestations. In some cases, SIBO has been associated with mucosal damage, mirroring the villous atrophy observed in conditions like celiac disease. The overgrowth of bacteria in the small intestine can interfere with nutrient absorption and trigger an inflammatory response, potentially contributing to the erosion of the intestinal villi. While the mechanisms differ from those in celiac disease, the shared outcome of villous atrophy underscores the intricate relationship between dysbiosis and intestinal health. Lymphoma Lymphoma, a form of cancer that originates in the lymphatic system, can exhibit parallels with celiac disease in terms of inducing villous atrophy. In some cases, individuals with longstanding untreated celiac disease may face an elevated risk of developing enteropathy-associated T-cell lymphoma (EATL), a rare but serious complication. EATL is characterized by the infiltration of malignant T lymphocytes into the intestinal mucosa, leading to structural changes reminiscent of villous atrophy. While lymphoma and celiac disease differ fundamentally, the shared manifestation of villous atrophy underscores the intricate interplay between chronic inflammation and the potential oncogenic transformations within the gastrointestinal milieu. Thiamine (Vitamin B1) Deficiency There is some old research that indicates that prolonged low thiamine (vitamin B1) may cause thinning of the microvillus membrane. While these conditions may share some clinical features with celiac disease, the differences in their etiology, histopathology, and diagnostic criteria make them distinct entities. Accurate diagnosis and differentiation often require a thorough clinical evaluation, including serological tests, histopathological examination, and consideration of geographic or idiopathic factors. Consulting with a gastroenterologist or healthcare professional is essential for proper diagnosis and management. Drug-Associated Enteropathy: Medications Associated with Villous Atrophy Understanding the intricate interplay between medications and intestinal well-being is paramount for individuals managing chronic health conditions. While medications play a pivotal role in alleviating symptoms and improving overall health, certain drugs may harbor the potential to influence the delicate environment of the small intestine. This section delves into the impact of various medications on the intestinal villi, focusing on conditions that may lead to villous atrophy. From common pain relievers to immunosuppressive drugs, the discussion aims to shed light on the nuanced relationship between medications and gastrointestinal health. It underscores the importance of informed healthcare decisions, proactive monitoring, and open communication between patients and healthcare providers to mitigate potential complications and ensure optimal intestinal function during the course of medical treatments. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used to alleviate pain and inflammation, but prolonged and excessive use has been associated with adverse effects on the gastrointestinal (GI) tract. NSAIDs can cause irritation and inflammation in the small intestine, potentially leading to villous atrophy. The mechanism involves the inhibition of cyclooxygenase enzymes, which play a role in maintaining the integrity of the GI mucosa. Individuals relying on NSAIDs for chronic pain management should be cautious and work closely with healthcare providers to monitor and mitigate potential GI complications. Immunosuppressive Drugs Immunosuppressive drugs, such as methotrexate and mycophenolate mofetil, are crucial in managing autoimmune conditions and preventing organ rejection after transplantation. While these medications target the immune system to curb excessive responses, they may also impact the gastrointestinal lining. Long-term use could lead to intestinal complications, including villous atrophy. Healthcare providers prescribing immunosuppressive drugs carefully assess the risk-benefit profile for each patient and monitor closely for potential adverse effects on the GI tract. Chemotherapy Drugs Chemotherapy, a cornerstone in cancer treatment, aims to eradicate rapidly dividing cells, including cancerous ones. However, the impact isn't limited to tumors, and normal, healthy cells may also be affected. The rapidly renewing cells in the small intestine are particularly susceptible, potentially resulting in damage to the villi and compromising the absorptive capacity of the intestines. Individuals undergoing chemotherapy should discuss potential gastrointestinal side effects with their oncologist to address and manage any complications that may arise. Some Antibiotics Certain antibiotics, such as tetracycline and ampicillin, may disrupt the balance of the gut microbiota, leading to gastrointestinal disturbances. While these antibiotics target harmful bacteria, they can also affect beneficial microbes, influencing the overall health of the intestinal lining. The intricate relationship between antibiotics and the gut underscores the importance of judicious antibiotic use and, when necessary, the simultaneous administration of probiotics to support a healthy gut environment. Proton Pump Inhibitors (PPIs) Proton Pump Inhibitors (PPIs), commonly prescribed for acid reflux and gastroesophageal reflux disease (GERD), reduce stomach acid production. Prolonged use of PPIs has been linked to changes in the small intestine, potentially impacting the structure and function of the villi. Individuals relying on PPIs for an extended period should collaborate with healthcare providers to assess the necessity of continued use and explore alternative approaches to manage acid-related conditions. Opioid Pain Medications Opioid pain medications, including morphine and oxycodone, are known for their analgesic properties but are also associated with side effects such as constipation. Chronic use of opioids may lead to intestinal issues, affecting the normal functioning of the small intestine. It is crucial for healthcare providers to carefully manage opioid prescriptions, considering the potential impact on the gastrointestinal tract, and to explore alternative pain management strategies whenever possible. Patients should communicate openly with their healthcare team about any digestive issues experienced during opioid therapy to ensure timely intervention and support. Conclusion In conclusion, the journey through conditions associated with villous atrophy extends far beyond the realms of celiac disease. This exploration has highlighted the intricate interplay of various factors that can impact the health of the small intestine, leading to structural changes in the form of villous atrophy. Recognizing these diverse contributors is pivotal for healthcare professionals navigating the complexities of gastrointestinal disorders. As we deepen our understanding of the nuanced manifestations of villous atrophy, we pave the way for improved diagnostic accuracy and tailored treatment strategies. The heterogeneity of conditions linked to villous atrophy underscores the need for a holistic and individualized approach to patient care, ensuring that the intricacies of each case are addressed with precision and empathy. Through continued research and clinical vigilance, we strive to unravel the mysteries of these conditions and enhance the well-being of individuals facing the challenges of villous atrophy. Further reading on the topic of other causes of villous atrophy: Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies

Celiac.com 01/19/2023 - Is gluten sensitivity celiac disease? You might not believe that gluten sensitivity could be celiac disease if you still believe the world is flat. By definition, celiac disease is still clinically diagnosed in the presence of villous atrophy, whereby the absorptive villi, tiny-fingerlike projections of the intestinal surface lining, are blunted to varying degrees by the actions of lymphocytes (a type of white blood cell) responding to gluten(1) . In 1992, Marsh introduced the gluten sensitive spectrum to give wider recognition of the types of intestinal lesions seen in gluten sensitivity, in addition to the classic celiac lesion(2) . In the Marsh I lesions, lymphocytes are found in increased numbers in the villi. Marsh II lesions are comparable to Marsh I lesions with the addition of increased cellular growth in the crypts (the bottom of the valleys in the intestinal lining where new cells are produced). In the classic celiac lesion, villous atrophy is present and is graded as partial, subtotal, and total flattening of the villi (Marsh IIIa, IIIb, and IIIc lesions, respectively)(3). Normal villi architecture with no increased lymphocytic infiltration is sometimes referred to as Marsh 04 . Researchers studying milder Marsh lesions are providing corroboration to the gluten sensitivity of such patients and describing them as having borderline, silent, and subclinical celiac disease. Some gluten-sensitive patients with normal villi architecture are being described as having either latent or potential celiac disease. Borderline Celiac Disease Patients with borderline celiac disease have clinical symptoms of celiac disease with demonstrated intestinal abnormality but no villous atrophy(5) . To determine which patients have borderline celiac disease, a trial of a gluten-free diet can demonstrate if such patients respond favorably in symptomatic terms with biopsy improvement. Another approach is the use of a gluten challenge to aid in the diagnosis of patients with initially only mild intestinal damage. In a study by Wahab et al, 38 patients, who had Marsh I lesions along with signs and symptoms of malabsorption, were subjected to a gluten challenge for two months(4) . Five of the 38 patients worsened to Marsh II and seven worsened to Marsh III with villous atrophy. Of the 12 patients whose intestinal lesions had worsened, all had improved symptomatically and histologically (Marsh 0 in seven patients) after six to12 months on a gluten-free diet. In another study, 23 of 35 patients with gastrointestinal symptoms of unknown origin agreed to an eight to 12 month trial of a gluten-free diet(5) . Of seven who were initially found to have Marsh I lesions, six normalized (Marsh 0) and one still had a Marsh I lesion. Of 16 patients who initially had Marsh II lesions, seven normalized, six improved to Marsh I, and three still had Marsh II lesions. All of the patients on a gluten-free diet experienced substantial or complete resolution of clinical symptoms (i.e., diarrhea, weight loss, fatigue, slow gastric emptying, epilepsy, and abdominal pain). Conversely, seven of 12 patients (five lost to follow-up) who refused a gluten-free diet had persistent lesions and symptoms while one progressed from Marsh I to Marsh IIIa lesion and experienced a worsening of symptoms. The response to gluten was clear. Patients with gluten sensitivity who were given a gluten-free diet found relief in their symptoms and improvement or normalization in their biopsies, while those who were gluten challenged had to endure a further provocation of their symptoms and lesions. Silent and Subclinical Celiac Disease With the acceptance of the broader spectrum of celiac disease, some researchers are making the case for the diagnosis of celiac disease in the presence of mild intestinal lesions. In a recent study of 115 silent and subclinical celiac patients, 13% of each form were identified with the presence of mild intestinal damage (Marsh I or II lesions) due to gluten sensitivity(6) . Patients with subclinical celiac disease had extra-intestinal symptoms (i.e., iron deficiency anemia, dental enamel defects, epilepsy, and hair loss) but no gastrointestinal symptoms. Subclinical celiac patients without villous atrophy were detected by antibody testing only 33% of the time. Patients were classified as having silent celiac disease because they had no symptoms and were high-risk for celiac disease due to their status as first degree relatives of celiac patients or as having type I diabetes. Silent celiac patients without villous atrophy were not detected by antibody testing. In practice, the recognition of the silent and subclinical forms of celiac disease will be more accurately diagnosed through the alertness of gastroenterologists and other specialists. Gluten Sensitivity in Patients with Normal Intestinal Villi The expression of gluten-sensitive symptoms is exhibited in patients even with normal intestinal villi. Identifying patients with gluten sensitivity involves exclusion of all other possible causes and utilizing various ways of detection. Also, a finding of increased lymphocytes just as villous atrophy is not always a prerequisite for gluten sensitivity. In a study by Picarelli et al, ten patients with celiac-like symptoms and normal villi architecture at some stage during their illness were found to have positivity to anti-endomysial antibodies which disappeared on a gluten-free diet(7) . Only four of the ten patients had an increased lymphocyte infiltrative (Marsh I) lesion in addition to normal villi architecture. Also, six of these patients did not have the common HLA genes associated with celiac disease. Cells cultured from biopsies were challenged with gliadin peptides resulting in immune activation. Challenge with similar corn peptides did not have evidence of immune activation. Also, the patients themselves showed signs of immune activation on a normal diet which went away after the removal of gluten and came back in three patients on a four month gluten challenge. Similarly, latent celiac disease was found in another study of seven children with normal biopsies who were positive for anti-endomysial antibodies and were later found to develop villous atrophy by three years(8) . These studies highlight a need for better diagnosis of non-atrophic celiac disease patients. Antibody Detection of Mild Intestinal Damage Although blood antibody testing is useful in predicting the degree of villous atrophy, it can often fail to detect patients with milder intestinal lesions as well as partial villous atrophy (Marsh I-IIIa). A study confirmed that the largest percentage of patients with positive antibody results were found with the most severe intestinal damage(6) . 78% of patients with total villous atrophy were positive for anti-gliadin antibodies while 89% of patients with total villous atrophy were positive for anti-endomysium antibodies. None of the patients with Marsh I lesions or silent celiac disease patients with Marsh II lesions were positive for anti-gliadin or anti-endomysial antibodies. A study of 119 adult celiac patients found a poor correlation between slight intestinal damage and antitissue transglutaminase (anti-tTG) positivity(9) . Only one of 13 patients with Marsh I lesions and eight of 24 patients with Marsh II lesions were anti-tTG positive. Even in the presence of villous atrophy, only 56% of those patients with partial villous atrophy (Marsh IIIa) while 96% of those with total villous atrophy (Marsh IIIc) were positive for anti-tTG. As a method of detecting patients with the potential to develop villous atrophy ('potential' celiac disease), celiac disease patient biopsies were challenged in culture with gliadin peptides while the patients were on a gluten-free diet(8) . Such biopsies were found to produce anti-endomysial antibodies. Therefore, biopsy culture production of anti-endomysial antibodies may be more sensitive than blood anti-endomysial antibodies which fail to detect less severe intestinal damage. Current research reviewed here demonstrates that patients with non-classical forms of celiac disease can go on to develop the classic diagnostic celiac lesion when they continue on a gluten-containing diet. Conversely, patients with these non-classical forms of celiac disease can heal when given the treatment of a gluten-free diet. Thus, these studies highlight the need for doctors and pathologists to be alert to celiac disease in all its forms in order to recognize it. “(J)ust as Christopher Columbus sailed past an apparently flat horizon to help prove the world is round, the time has come to broaden the horizons of the histologic diagnosis of celiac disease”(10). References: Kennedy NP. 2000. Clinical features of coeliac disease today. Biomed & Pharmacother 54:373-80. Marsh MN, 1992. Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterol 102:330-54. Rostami K, et al. 1997. SAT and serology in adult coeliacs, seronegative coeliac disease seems a reality. Neth J Med 53:15-19. Wahab P, et al. 2001. Gluten challenge in borderline gluten-sensitive enteropathy. Am JGastroenterol 96:1464 - 69. Tursi A, and Brandimarte G. 2003. The symptomatic and histologic response to a gluten-free diet in patients with borderline enteropathy. J Clin Gastroenterol 36:13-17. Tursi A, et al 2001. Low prevalence of antigliadin and anti-endomysium antibodies in subclinical/silent celiac disease. Am J Gastroenterol 96:1507-10. Picarelli A, et al 1996. Gluten-sensitive disease with mild enteropathy. Gastroenterol 111:608-16. Holmes G, 2001. Potential and latent coeliac disease. Eur J Gastroenterol Hepatol 13:1057-60. Tursi A, et al. 2003. Prevalence of antitissue tranglutaminase antibodies in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol 36:219-21. Moskaluk C, 2001. The histologic diagnosis of celiac disease in "nonflat" intestinal mucosa. Am J Clin Pathol 116:7-9.

Celiac.com 05/27/2022 - Among the many symptoms associated with celiac disease, some of the commonest fall into the broad category of “dyspepsia”. These are symptoms more usually attributed to acid reflux from the stomach into the esophagus (heartburn, regurgitation, even difficulty swallowing a.k.a. dysphagia) or to peptic ulcer disease (upper abdominal pain, indigestion, fullness). While we are not entirely sure why celiac disease causes these, often in the absence of typical “bowel” symptoms, we do know how(1) . Studies of the upper gut in celiac disease patients frequently show abnormal motility and peristalsis: the conveyor belt isn’t working properly (The constipation that is often paradoxically a symptom of celiac disease probably has the same basis). So many celiac patients are going to be referred not for small bowel investigation but for upper GI endoscopy, and the gastroenterologist is expecting not celiac disease, but reflux esophagitis, hiatus hernia, gastritis or peptic ulcer disease. Wouldn’t it be nice—and wouldn’t it make life a lot simpler for the so far undiagnosed celiac patient—if the gastroenterologist could spot villous atrophy like these other conditions? The good news is that you can see villous atrophy down an endoscope. Well, some of the time (but more of that later). One of the most exciting developments in my career as a celiac diagnostician was when our museum piece fiberoptic endoscopes were replaced by full color videoscopes. Endoscopy was no longer an uncomfortable (for the endoscopist!) and hurried foray into the upper gut, hunched over with one eye peering down a clouded eyepiece, frantically trying to see everything and get the heck out before the disinfectant fumes wafting up the scope dissolved the glue holding my spectacles together. Instead it became a civilized stroll which ended in a duodenum filling a ten inch TV picture in glorious color. And it became clear to me and many other celiac specialists that the duodenums of celiac patients didn’t look quite right when they were up close and magnified in this way. Abnormalities seen in our patients with villous atrophy(2) include mosaic mucosa (53%), scalloped folds (50%), fold loss (15%) and nodular mucosa (6%) and erosions (small ulcers) in the second part of duodenum in 7%. Occasionally the mucosa is so thin that blood vessels can be seen through it. Although uncommon in celiac disease, the finding of erosions in the second part of duodenum is of particular interest as clinicians may simply flag it up as peptic ulcer disease, even though peptic ulcers usually only affect the first part of duodenum. I’ve seen a few patients who had previously been wrongly diagnosed “peptic” because of this endoscopic feature. So how have these endoscopic markers changed my practice? Around half of my new celiac patients present with dyspepsia and are recognized at endoscopy(3) . One in 60 (twice the background prevalence of celiac disease) patients referred for endoscopy from primary care with dyspepsia are diagnosed celiac because of these markers(4). Often the story is of dyspeptic symptoms which have not responded to ulcer healing drugs—while on a gluten-free diet they disappear magically. There are two caveats regarding endoscopic markers. While villous atrophy in adults is pretty much synonymous with celiac disease in Western Europe, elsewhere it may sometimes indicate other disease, as reported by the New York Group(5) . Secondly, the bad news is that villous atrophy can’t always be spotted. We found that only 74% of villous atrophy cases had endoscopic markers(2) , and as many patients had endoscopy for biopsy because we were expecting to find celiac disease, that figure may be an overestimate of routine practice. The Mayo Clinic found markers in only 59% of celiac patients from a group of anemic patients having endoscopy(6). While 82% of our patients with subtotal or total villous atrophy had one or more endoscopic markers, the yield fell to 58% for partial villous atrophy(7). And as you might expect, I have never seen endoscopic markers in gluten-sensitive patients with milder (Marsh I, Marsh II) histologic abnormalities which have not yet progressed to villous atrophy. So lack of markers does not mean that there is no need to biopsy, particularly in high risk groups like patients with anemia and insulin dependent diabetes. In an ideal world, duodenal biopsy would be a routine part of every upper GI endoscopy, as already proposed by Peter Green and Joe Murray(8). In practice, particularly in the good ol’ underfunded UK National Health Service that I work for, this would have very significant resource implications. I suspect such a policy—duodenal biopsies taken at every endoscopy— implemented without a major funding initiative on my side of the Atlantic might find our already overworked and undervalued histopathologists under the cars of gastroenterologists furiously cutting through their brake lines. In the meantime, and until the New Jerusalem of routine duodenal biopsy during endoscopy is constructed, recognition of the endoscopic markers of celiac disease, while not foolproof, represents a pragmatic way of diagnosing celiac patients who present with dyspepsia. References: Bassotti G, Castellucci G, Betti C et al. Abnormal gastrointestinal motility in patients with celiac sprue. Dig Dis Sci 1994; 39: 1947-54. Dickey W, Hughes DF. Erosions of the second part of duodenum in patients with villous atrophy. Gastrointestinal Endoscopy 2004; 59: 116-118. Dickey W. Diagnosis of coeliac disease at open access endoscopy. Scandinavian Journal of Gastroenterology 1998; 33: 612- 5. Dickey W, Hughes DF. Prevalence of celiac disease and its endoscopic markers among patients undergoing routine endoscopy. American Journal of Gastroenterology: 1999; 94: 2182-6. Shah VH, Rotterdam H, Kotler DP, Fasano A, Green PHR. All that scallops is not celiac disease. Gastrointest Endosc 2000; 51: 717-20. Oxentenko AS, Grisolano SW, Murray JA et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002; 97: 933-8. Dickey W, Hughes DF. Disappointing sensitivity of endoscopic markers for villous atrophy in a high-risk population: implications for celiac disease diagnosis during routine endoscopy. Am J Gastroenterol 2001; 96: 2126-8. Green PHR, Murray JA. Routine duodenal biopsies to exclude celiac disease? Am J Gastroenterol 2003; 58: 92-5.

Celiac.com 01/08/2022 - Celiac disease is a chronic inflammatory disease of the gut occurring in genetically susceptible individuals after ingestion of gluten. It is characterized by a flattened mucosa, villous atrophy and crypt hyperplasia in the small intestine and by the classic malabsorption syndrome (diarrhea, steatorrhea, and weight-loss) or by minor apparently unrelated symptoms such as iron-deficiency anaemia, osteopenic bone disease, amenorrhea and infertility(1). The diagnostic algorithm of this disease demand a screening approach based on anti-endomysium (EmA) and anti-tissue transglutaminase (anti-tTG) and, in case of antibodies-positivity, patients should undergo intestinal biopsy to confirm the presence of small bowel lesions according to celiac disease. Unfortunately, this approach is rarely effective in clinical practice, especially in patients with mild to moderate histological lesions. In fact several recent studies have shown that 5-10% of patients affected by mild to moderate lesions of the small bowel typically seen in celiac disease actually lack EmA and anti-tTG antibodies(2-5). In light of these scientific results, should all patients who are suspected to have, or who are at risk for celiac disease—including first degree relatives of celiacs, those with Down’s syndrome or autoimmune thyroid disease, patients whose stories indicate celiac disease, etc.—undergo intestinal biopsy? This does not seem like a very reliable approach—perhaps other more non-invasive tests should be done in conjunction with serological testing to help determine which patients should undergo a biopsy. The sorbitol H2 -breath test (H2 -BT) could be exactly what is needed. Sorbitol is a hexahydroxy alcohol that is present in many fruits such as peaches6 . It is used as a sugar substitute in dietetic foods and as a drug vehicle. At low doses (5 grams/day) sorbitol is completely absorbed by the small bowel, and low dose ingestion does not typically produce any symptoms. However, we know that celiac disease patients often experience sugar malabsorption (as lactose malabsorption)(7), which prompted us to hypothesize that the same may be true for sorbitol. In general terms, sugar malabsorption could be primary— congenital enzymatic/ carrier deficiency, or acquired—developing after intestinal damage caused by acute gastroenteritis, medications, Crohn’s disease, celiac disease, etc.(8) In the normal individual, gut bacteria are primarily located in the colon and in the distal small intestine. When sugar malabsorption is present, unabsorbed sugars in excess are available in the distal small bowel and colon for bacterial fermentation, with air excretion of H2 and CH4 9 . This mechanism occurs for all sugars— lactose, fructose, glucose, sorbitol—and H2 lactose, fructose and sorbitol breath tests are commonly used to detect specific sugar malabsorption issues. Sorbitol H2-BT Methods This is a simple, non invasive, repeatable, and cheap test. To minimize basal hydrogen excretion, subjects are asked to have a carbohydrate-restricted dinner on the day before the test (for example, a meal of rice and meat) and are studied after an overnight fasting for at least 12 hours. On the testing days, patients do a mouthwash with 20 ml of chlorhexidine 0.05%; smoking and physical exercise are not allowed for 30 minutes before and during the test. End expiratory samples are collected before the patients drink the test solution— 5g of sorbitol in 150/200 ml of tap water—and every 30 minutes for 4 hours using a two-bag system. The two-bag system is a device consisting of a mouthpiece, a T-valve and two collapsible bags, for collection of dead space and alveolar air. From this system, the breath sample is aspirated into a 20 ml plastic syringe. Samples are generally evaluated for H2 using a model DP Quintron Gas Cromatograph (Quintron Instrument Company, Milwakee, WI). It is also possible to measure the hydrogen concentration in each collected sample by a portable breath-hydrogen analyzer (for example, EC60 Gastrolyzer Breath Hydrogen Monitor, Bedfont Scientific Ltd, Upchurch – Kent, England [U.K.]). An increase in H2 concentration of at least 20 ppm over fasting baseline is considered positive for sorbitol malabsorption. The cut-off for calculating the validity of the test is shifted every 30 minutes, and a Response Operating Characteristics (ROC) curve is plotted on the basis of the obtained results. Results are expressed as parts per million (ppm). Sorbitol H2-BT and Celiac Disease The first study assessing the effectiveness of sorbitol in detecting intestinal damage in celiac disease was performed by Corazza, et al. in 1988. They showed for the first time that low dose concentrations of sorbitol (5 grams at 2%) are malabsorbed in almost all celiac disease patients(10), and these results were confirmed in a more recent study(11). These provocative results led to the idea that it could be used as a screening tool in celiac disease, in addition to serological tests. However, these results have not been completely considered by investigators, and using sorbitol H2 -BT to screen for celiac disease was not investigated further for another four years. In the 2001 we published a paper about the low-prevalence of anti-gliadin and anti-endomysium antibodies in a sub-clinical/silent form of celiac disease. We found that 5-20% of celiac disease patients affected by this form of the disease lack these antibodies according to histological damage4 , and we found the same results using anti-tTG12. Based on this research it was apparent that there was a risk of not properly diagnosing a very high percentage of celiac disease patients if their screening is based solely on serological tests. At this point we tried to use the sorbitol H2 -BT as screening tool to obtain more information on patients’ intestinal absorption, and to help select patients who should undergo intestinal biopsy. Sorbitol H2-BT in Detecting the Sub-clinical/Silent Form of Celiac Disease Sub-clinical celiac disease is defined by the presence of a gluten sensitive enteropathy with extra-intestinal symptoms (iron-deficiency anemia, alopecia, recurrent abortion, Breath Test, continued “there was a risk of not properly diagnosing a very high percentage of celiac disease patients if their screening is based solely on serological tests” etc.) but without gastrointestinal symptoms, whereas silent celiac disease is defined by the presence of a gluten-sensitive enteropathy not accompanied by any symptoms, but identified during the course of screening of high-risk groups such as first-degree relatives of celiac patients, patients with insulin-dependent diabetes, Down’s syndrome, IgA deficiency and thyroid disorders. In detecting silent celiac disease sorbitol H2 -BT seems to be better than serological tests. We found that EmA were positive in 77/96 (80.80%) and sorbitol H2 -BT was positive in 94/96 (97.91%) of patients with sub-clinical celiac disease, whereas EmA were positive in 17/27 (62.96%) and sorbitol H2 -BT was positive in 26/ 27 (96.29%) of patients with silent celiac disease (p<0.001 in both forms of celiac disease). The best cut-off value in ppm and minutes in both forms of celiac disease are higher and shorter in the severe form rather than in the mild form of intestinal damage respectively (p<0.001 in both forms)13. Therefore sorbitol excretion seems to be closely correlated with the severity of histological lesions. Sorbitol H2-BT as Screening Test in Relatives of Celiac Disease Patients The prevalence of celiac disease among first-degree relatives has been reported to be about 10- 20%, and approximately 50% of the newly diagnosed cases are asymptomatic(14,15). It is known that lymphoma and cancer deaths(16,17) occur more frequently in first-degree relatives of celiac disease patients, and it is also known that gluten withdrawal has a protective role in the complications associated with the disease(18). However, up to 50% of celiac disease relatives show mild histological damage without evident mucosal atrophy(19-21). Since several recent studies showed that serological tests are ineffective in detecting celiac disease in patients with mild histological damage, there is a concrete risk that a significant proportion of celiacs among relatives may be missed. Since a routine intestinal biopsy in all family members is, however, unfeasible—asymptomatic individuals would rarely accept such an approach—it is very important to identify an optimal non-invasive method of screening first-degree relatives. In this regard sorbitol H2 -BT screening seems to be better than serological tests. In my experience, sorbitol H2 -BT is extremely effective at detecting histological damage in relatives of those with celiac disease. We found that AGA, EmA and anti-tTG showed strong positivity only when there was severe intestinal damage (Marsh IIIb-c lesions—but overall positivity was 36.73%, 38.78%, and 44.89% for AGA, EmA and anti-tTG respectively), whereas sorbitol H2 -BT showed a strong positivity in patients with only mild histological damage (Marsh I - IIIa—overall positivity was 83.67%). A significant proportion of celiac disease patients will be missed if relatives of those with celiac disease are screened only via serology(22). Sorbitol H2-BT in Assessing Histological Recovery after a Gluten-free Diet Currently the only effective therapeutic approach to celiac disease is the gluten-free diet, and the result of a proper gluten-free diet is clinical and histological improvement. In particular, the gluten-free diet plays a key role in preventing nutritional deficiency, especially of micronutrients, and in reducing the risk of the development of intestinal malignancies. There is great demand for highly sensitive, non-invasive tests that can be done to determine histological recovery in patients after the start of a gluten-free diet—with the ultimate goal of reducing or eliminating the need of follow-up endoscopies and biopsies. If we consider EMA an indicator of small bowel damage, it would be expected to persist until histological recovery occurs. However, several recent studies failed to show a positive relationship between EMA and histological improvement after a gluten-free diet(23-26). Our study confirmed these experiences, since microscopic damage persists at histological examination during the follow-up despite EMA negativity. It is difficult to explain the poor predictor value of EMA in assessing histological recovery. EMA positivity seems to be related not only to the length of intestinal involvement but also to the grade of histologic damage(4) . Thus, when histological damage improves we can note a false EMA negativity, since histological lesions improve more slowly than EMA seroconversion. Moreover, EMA are a marker of the immunological activity related to the gluten sensitivity, it is therefore hypothesized that after a period of gluten restriction the immunological process can be quite inactive and thus EMA will subside. Similarly, anti-tTG do not seem effective to assess histological recovery in the follow-up of celiac patients after they have started a gluten-free diet due to its poor correlation with histological damage. Anti-tTG is generated in genetically predisposed individuals by complexes formed between anti-tTG and gluten(27). So, it is hypothesize that anti-tTG should disappear soon after gluten withdrawal, and these findings have been frequently recognized in our clinical practice, for example we sometimes see a quick subsiding of anti-tTG values soon after patients begin a gluten-free diet—in some cases within few weeks. In my experience, sorbitol H2-BT seems to be very effective even in assessing histological recovery after gluten-free diet. We found a strict correlation between cut-off values (in ppm and minutes) of H2 excretion and the patients’ histological lesions. In particular, maximal cut-off values (in ppm and in minutes) correlate statistically with a more severe degree of intestinal damage—patients with more severe histological lesions had higher cut-off value H2 levels and earlier peaks (in minutes). Likewise, we found that progressive histological recovery correlated significantly with decrease of maximal cut-off values (in ppm) and with the later appearance of the peak (in minutes). This is a very important finding, since it permits us to observe and to monitor the progressive improvement of the histological damage of small bowel after a gluten-free diet—without any small bowel biopsy(28, 29). Sorbitol H2 -BT in Borderline Entheropathy A clinical problem arises when patients present with symptoms suggestive of gluten sensitivity (diarrhea, weight loss, unresponsive iron-deficiency anemia, etc.) but small intestinal biopsies reveal only minor abnormalities, particularly lymphocytosis with or without crypt hyperplasia (Marsh I-II lesions). It is hypothesized that some of these patients have borderline celiac disease. A gluten challenge may be a good choice in these patients, as it may provoke a significant worsening of the mucosal lesions, which could lead to a correct diagnosis. This approach, however, may not be necessary if we have a sensitive non-invasive method to detect such mild intestinal lesions. Serological tests are insufficient in this area. We recently found that AGA, EmA and anti-tTG were positive in 0-20% of patients showing Marsh I-II lesions, whereas sorbitol H2 -BT was positive in 18- 41% of such cases(30). Clearly this data shows that it makes sense to use Sorbitol H2 -BT to detect cases of borderline entheropathy. Factors Affecting Sorbitol H2-BT in Clinical Practice Unfortunately, several factors may affect the results of sorbitol H2 -BT. First of all, sorbitol H2 -BT shows high sensitivity but low specificity. Several small bowel disorders, including Crohn’s disease, are associated with excessive rates of H2 breath excretion and then with sorbitol H2 -BT positivity(31). Moreover, the breath tests will be positive in the setting of not only small bowel mucosal injury, but also in cases of rapid intestinal transit and small bowel bacterial overgrowth(32). Finally, despite its low cost, the breath test is quite cumbersome, since it requires an overnight fast followed by at least 4 hours of the patient’s time for testing. Conclusion Sorbitol H2 -BT is a simple, feasible, repeatable, cheap, non-invasive test that can accurately assess intestinal absorption. Unfortunately low specificity may affect the results and may make it difficult for us to distinguish the different causes of malabsorption using only the sorbitol H2 -BT results. On the other hand, sorbitol H2 -BT may be very helpful and seems to be very promising in the following areas: Identifying patients suspected of having celiac disease with mild intestinal damage, who are serologically negative for celiac disease; Screening relatives of patients with celiac disease; Monitoring dietary compliance to the gluten-free diet Although intestinal biopsies will remain the “gold standard” for assessing the state of small bowel, sorbitol H2 -BT is a very interesting and non-invasive test that has the potential to reveal just how large the current “black hole” in celiac disease diagnosis is. At the very least it can help diagnose patients whose complaints cause us to suspect celiac disease but who have negative blood tests, and it is an excellent method to monitor the recovery of patients who are on a gluten-free diet. It is a key part of my medical practice in the treatment of celiac disease. References: Martucci S, Biagi F, Di Sabatino A, Corazza GR. Coeliac disease. Dig Liver Dis 2002; 34(suppl. 2): S150-3. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg ME, Meijer JWR, Mulder CJJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol 1999;94: 888-94. Dickey W, Hughes DF, McMillan SA. Reliance on serum endomysial antibody testing underestimates the true prevalence of coeliac disease by one fifth. Scand J Gastroenterol 2000;35: 181-3. Tursi A, Brandimarte G, Giorgetti GM, Gigliobianco G, Lombardi D, Gasbarrini G. Low prevalence of antigliadin (AGA) and anti-endomysium (EMA) antibodies in subclinical/silent celiac disease. Am J Gastroenterol 2001;96: 1507-10. Abrams JA, Diamone B, Rotterdam H, Green PHR. Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Dig Dis Sci 2004;49: 546-50. Washüttl J, Reiderer P, Baucher E. A qualitative and quantitativestudy of sugar-alcohols in several foods. J Food Sci 1973;38: 1262-3. Ojetti V, Nucera G, Migneco A et al. High prevalence of celiac disease in patients with lactose intolerance. Digestion 2005;71: 106-10. wagerty DL Jr, Walling AD, Klein RM. Lactose intolerance. Am Fam Physician 2002;65: 1845-50. Strocchi A, Ellis C, Levitt MD. Reproducibility of measurement of trace gas concentrations in expired air. Gastroenterology 1991;101: 175-9. Corazza GR, Strocchi A, Rossi R, Sirola D, Gasbarrini G. Sorbitol malabsorption in normal volunteers and in patients with coeliac disease. Gut 1988;29: 44-8. Pelli MA, Capodicasa E, De Angelis V, Morelli A, Bassotti G. Sorbitol H2-breath test in celiac disease. Importance of early positivity. Gastroenterol Int 1998;11: 65-8. Tursi A, Brandimarte G, Giorgetti G. Prevalence of anti-tissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol 2003; 36(3): 219-221. Tursi A, Brandimarte G, Giorgetti GM. Sorbitol H2- breath test versus anti-endomysium antibodies for the diagnosis of subclinical/ silent coeliac disease. Scand J Gastroenterol 2001;36: 1170-2. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992;102: 330-54. Auricchio S, Mazzacca G, Tosi R, Visakorpi J, Maki M, Polanco I. Coeliac disease as familial condition: identification of asymptomatic patients within family groups. Gastroenterol Int 1988;1: 25-31. Barry RE, Morris JS, Kenwright S, Read AE. Coeliac disease and malignancy. The possible importance of familial involvement. Scand J Gastroenterol 1971;6: 205-207. Stokes PL, Prior P, Sorahan TM, McWalter RJ, Waterhouse JA, Cooke WT. Malignancy in relatives of patients with coeliac disease. Br J Prev Soc Med 1976;30: 27-21. Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease – effect of gluted free diet. Gut 1989;30: 333-8. Corazza GR, Valentini RA, Frisoni M ETAL. Gliadin immune reactivity is associated with overt and latent enteropathy in relatives of celiac patients. Gastroenterology 1992; 103: 1517-22. Maki M, Holm K, Lipsaen V, Hallstrom O, Viander M, Collin P et al. Serological markers and HLA genes among healthy first-degree relatives of patients with coeliac disease. Lancet 1991;338: 1350-3. Vazquez H, Cabanne A, Sugai E, Fiorini A, Pedreira S, Maurino E et al. Serological markers identify latent coeliac disease among first-degree relatives. Eur J Gastroenterol Hepatol 1996;8: 15-21. A. Tursi, G. Brandimarte, G.M. Giorgetti, C.D. Inchingolo. Effectiveness of sorbitol H2 breath test in detecting histological damage among relatives of coeliacs. Scand J Gastroenterol 2003;38: 727-31. Bardella MT, Trovato C, Cesana BM, Pagliari C, Gebbia C, Peracchi M. Serological markers of celiac disease: is it time to change? Digest Liver Dis 2001;33: 426-31. Valentini RA, Andreani ML, Corazza GR, Gasbarrini G. IgA endomysium antibody. A valuable tool in the screening of coeliac disease but not its follow-up. Ital J Gastroenterol 1994;26: 279-82. Sategna-Guidetti C, Grosso SB, Bruno M, Grosso S. Is human umbilical cord the most suitable substrate for the detection of endomysium antibodies in the screening and follow-up of coeliac disease? Eur J Gastroenterol Hepatol 1997;9: 657-60. Dickey W, Hughes DF, McMillan SA. Disappearance of endomysial antibodies in treated celiac disease does not indicate histological recovery. Am J Gastroenterol 2001;95: 712-4. Dieterich W, Ehnis T, Bauer M et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3: 797-801. Tursi A, Brandimarte G, Giorgetti GM. Sorbitol H2- breath test versus antiendomysium (EMA) antibodies to assess histological recovery after gluten-free diet in coeliac disease. Dig Liver Dis 2002;34: 846-50. Tursi A, Brandimarte G, Giorgetti GM. Lack of effectiveness of anti-transglutaminase antibodies in assessing histological recovery after gluten-free diet in celiac disease. J Clin Gastroenterol 2003;37: 381-5. Tursi A, Brandimarte G. The symptomatic and histological response to a gluten-free diet in patients with borderline enteropathy. J Clin Gastroenterol 2003;36: 13-7. Tursi A, Giorgetti GM, Brandimarte G, Elisei W. High prevalence of celiac disease among patients affected by Crohn’s disease. Inflamm Bowel Dis 2005;11: 662-6. Nucera G, Gabrielli M, Lupascu A et al. Abnormal breath test to lactose, fructose and sorbitol in irritable bowel syndrome may be explained by small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2005;21: 1391-5.

Celiac.com 06/19/2020 (Revised 06/24/2020) - It is not uncommon to have received blood testing from your doctor to see if you have celiac disease, and it comes back negative, when in fact your body is actually having a problem and you are on the celiac spectrum. The tests most doctors use to determine whether or not someone has celiac disease are very accurate for end stage celiac disease-after you have total villous atrophy, but not earlier stages of the disease (1). In those earlier situations, these tests often come back negative, even though you truly have a problem and are reacting to wheat moving towards total villous atrophy (1, 2, 3, 4, 5). It’s the wrong test. If you have an earlier stage in terms of the amount of damage incurred, the standard blood tests can be wrong over 70% of the time giving false negatives Standard blood tests for celiac disease have been extremely accurate and dependable if a person has total villous atrophy celiac disease. However, the accuracy of the blood test results for the two accepted blood markers (Endomysium and Tissue Transglutaminase) with anything less than total villous atrophy drops tremendously (to as low as being wrong 7 out of 10 times) (8,9). The reason these tests are often wrong in some people is that the research to validate the test used subjects who all had been diagnosed with celiac disease which by definition was total villous atrophy (Marsh IIIa,b,c). The earlier stages, Marsh 1 and 2 by most are considered ‘potential celiac disease’. So, when researchers were looking to validate if their blood tests were accurate in diagnosing celiac disease, they tested the blood of people diagnosed with celiac disease (total villous atrophy). And in that scenario, endomysium and tissue transglutaminase are highly accurate. from Lerner A, Jeremias P, Neidhöfer S, Matthias T (2017) Comparison of the Reliability of 17 Celiac Disease Associated Bio-Markers to Reflect Intestinal Damage. J Clin Cell Immunol 8: 486. from Lerner A, Jeremias P, Neidhöfer S, Matthias T (2017) Comparison of the Reliability of 17 Celiac Disease Associated Bio-Markers to Reflect Intestinal Damage. J Clin Cell Immunol 8: 486. Why? Celiac disease is defined as total villous atrophy. However, you don’t just magically go to sleep one night fine and wake up the next morning with total villous atrophy celiac disease. This disease, like all diseases, needs to be looked at more as a spectrum. That’s why Prof. Michael Marsh identified the spectrum of celiac disease development (Marsh I, II, III a, b, c). Bottom line? The test for total villous atrophy celiac disease (Marsh III a, b, c) are not the tests to rely on for earlier phases of the spectrum (Marsh I, II). The end result is many people have been told they do not have celiac disease and wheat is not a problem continue eating this food that is leading them further down the path of autoimmune disease. And of course, the tests for celiac disease are NOT the tests for the spectrum of Wheat Related Disorders (9). Predictive autoimmunity can tell you what areas of your body are under attack. Identifying an autoimmune mechanism early in the spectrum of development gives an opportunity to address it before there is so much tissue damage, now you have an autoimmune disease. Autoimmunity is the number 3 cause of death and highly preventable. If you could peek inside and determine what is going on before it does irreparable damage, it gives you a window of opportunity to address the problem early on and change the course of your health. This is called Predictive Autoimmunity (30). Identifying that you are on the celiac spectrum at Marsh I, gives you the opportunity to take action (gluten-free diet) and prevent progressing to Marsh III total villous atrophy. So the tests that are highly accurate for Marsh III are the wrong tests for Marsh I and II. They may be helpful and they may be misleading Gluten, Autoimmunity, and Your Gut Dr. Alessio Fasano is the chair of pediatric gastroenterology at Mass. General Hospital, Harvard, and director of Mucosal Immunology and Biology Research Center at Mass General Hospital for Children. He has done extensive research in the area of mucosal lining of the gut. He discovered, in the early 2000’s, a trilogy present in the development of autoimmunity: genetics, triggers, and intestinal permeability. (10) With celiac, we all know this – DQ2/DQ8, gluten, leaky gut = vulnerability to developing celiac disease. In the last 15 years, research has continued to expand to include two more features - thus a total of 5 components in the development of autoimmune diseases. In addition to genetics, environmental triggers and intestinal permeability, we now know that a dysbiotic microbiome and a systemic inflammatory immune response are involved. (11) This is important in our understanding of treatment. You can arrest the development of autoimmunity by healing the gut and addressing intestinal permeability. The majority of people with leaky gut do not show symptoms in the gut. A leaky gut spews out macromolecules into the blood stream that travel throughout your body that are considered foreign objects that your immune system will protect you from. And the resulting systemic inflammation from a leaky gut can affect any area of your body. And what are the most common triggers that will trigger a leaky gut? Gluten and small intestinalal bacteria overload. (11) Dangers of a Gluten-Free Diet Now this is a ‘Big Picture’ concept, but when you read the science it is clear that no one can fully digest the proteins in wheat (11, 12, 13, 14). It is indigestible to all humans, and in every single person causes a transient state of intestinal permeability (12, 13). Having said that, not everything about wheat is bad. Wheat (78%) and barley (3%) account for 78 - 81% of total prebiotics in the Western diet (14, 15, 16). When you remove wheat from your diet, a large percentage of the good bacteria will likely starve. This may be a contributing factor to the jaw-dropping statistic from the largest study ever done on mortality and celiac disease, that being diagnosed with celiac disease is associated with an 86% increased risk of mortality from a cardiovascular incident within 1 year (18). Just by being diagnosed. As far as I know, no one has pursued further research on this fact. What is different after diagnosis? People go on a gluten-free diet. What else? For most people, nothing else-they just stat eating gluten-free foods. You MUST be conscious of replacing the loss of prebiotics in your diet. Replacing wheat-based products with gluten-free products is a landmine. The vast majority of gluten-free products do not have prebiotic fibre, are not enriched, and are just tasty white paste. There’s nothing wrong with a gluten-free blueberry muffin once in a while, or gluten-free pasta on occasion. But these products are not healthy for you and can NOT be the cornerstone of your new diet. Be mindful of this at the onset of starting your gluten-free diet, so that you replenish your body with the necessary prebiotic nutrients your microbiome needs to increase diversity and balance. (14) So many people make the same newbie mistakes of just shopping in the gluten-free aisle and walk away with gluten-free cookies and snacks. I’m sorry to say that those are pretty much just as unhealthy, or worse, than the gluten versions. They just lack the antigen gluten. You need to look towards the produce aisle, vary your food choices from day to day, eat a wide variety in colour and types of organic fruits and vegetables, eat fermented foods rich in probiotics, and feed that good bacteria in your gut with foods that are prebiotics (root vegetables daily). I highly recommend finding a Certified Gluten-free Practitioner (CGP) who has received extensive training in celiac disease, gluten sensitivities, wheat-related disorders and autoimmunity. That is the most comprehensive training out there in this area. Find a CGP in your area-they’re all over the world, and most do on-line private consults. Addressing the intestinal permeability that has been developing with every exposure to wheat (12), within 5 minutes of wheat coming out of the stomach into the small intestine (20), is a game-changer in your overall health. There are over 300 autoimmune conditions. With the ‘Gateway’ in the development of autoimmune diseases being intestinal permeability, addressing this, and focusing on healing the gut can bring big rewards. Heal the Gut Identify and eliminate your triggers. Reduce inflammation. Reduce stress. The following supplements all have many studies showing their value in addressing intestinal permeability: Glutamine (21), Fish oils (22), Vitamin D (23), Colostrum (24), Turmeric (25), Pre (26) and Probiotics (27). Each of these basic nutrients modulates (has their hands on the steering wheel) of genes to reduce inflammation achieving a similar end goal, but they each work in different ways. Using a pleiotropic approach ensures success (great scrabble word-pleiotropic-means ‘all roads lead to Rome’. When you have a gluten-related disorder, the treatment is a strict gluten-free diet - without exception. Don’t let the treatment be the trigger for more problems. I’m known for the saying “You can’t be a little pregnant, you can’t have a little gluten” (if your immune system is activated fighting any of the peptides of wheat). Cheating once-per-month increases your risk of early death 6-fold! (19) Take measures to protect yourself against nutritional and vitamin deficiencies associated with a gluten-free diet. The benefits of a ‘Coach’ to learn the correct basics through this transition cannot be overemphasized (28, 29). A CGP, Nutritionist, trained Registered Dietician, Health Coach, … are invaluable in you learning the basics of this transition into a new way of eating. Eat different colors of the rainbow at every meal, every day. It will help restore balance to your gut health and rebalance your immune system. If you’re going to do this alone, avoid wheat (gluten), dairy, and added sugar for a month. Eat nutrient dense organic foods, such as quinoa, amaranth, vegetables, and quality meats. Gauge how you feel. Is your weight better managed? Do your hands and feet no longer feel cold? Are you able to think more clearly? If so, continue to eliminate those offending foods and eat a varied diet rich in nutrients. If you reintroduce and notice a problem, now you know those were foods that are inflammatory to you. And be careful of your tricky mind. Humans are the only species on the planet that finds something that works, and they stop doing it! References: Lerner A, Jeremias P, Neidhöfer S, Matthias T (2017) Comparison of the Reliability of 17 Celiac Disease Associated Bio-Markers to Reflect Intestinal Damage. J Clin Cell Immunol 8: 486 Immunoglobulin A autoantibodies against transglutaminase 2 in the small intestinal mucosa predict forthcoming coeliac disease. Salmi TT, Collin P, Järvinen O, Haimila K, Partanen J, Laurila K, Korponay-Szabo IR, Huhtala H, Reunala T, Mäki M, Kaukinen K.Aliment Pharmacol Ther. 2006 Aug 1;24(3):541-52 Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease. Brar P, Kwon GY, Egbuna II, Holleran S, Ramakrishnan R, Bhagat G, Green PH.Dig Liver Dis. 2007 Jan;39(1):26-9 Seronegative celiac disease: increased prevalence with lesser degrees of villous atrophy. Abrams JA, Diamond B, Rotterdam H, Green PH.Dig Dis Sci. 2004 Apr;49(4):546-50 Utility in clinical practice of immunoglobulin a anti-tissue transglutaminase antibody for the diagnosis of celiac disease. Abrams JA, Brar P, Diamond B, Rotterdam H, Green PH.Clin Gastroenterol Hepatol. 2006 Jun;4(6):726-30 Tests for Serum Transglutaminase and Endomysial Antibodies Do Not Detect Most Patients With Celiac Disease and Persistent Villous Atrophy on Gluten-free Diets: a Meta-analysis. Silvester JA, Kurada S, Szwajcer A, Kelly CP, Leffler DA, Duerksen DR.Gastroenterology. 2017 Sep;153(3):689-701 Screening for celiac disease.Lebwohl B, Green PH.N Engl J Med. 2003 Oct 23;349 (17):1673-4 Joint BAPEN and British Society of Gastroenterology Symposium on 'Coeliac disease: basics and controversies'. Coeliac disease in the twenty-first century. Dickey W. Proc Nutr Soc. 2009 Aug;68(3):234-41. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Fasano A, Shea-Donohue T. Nat Clin Pract Gastroenterol Hepatol. 2005 Sep;2(9):416-22. Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020;9:F1000 Faculty Rev-69. Published 2020 Jan 31. doi:10.12688/f1000research.20510.1. Celiac Disease and Nonceliac Gluten Sensitivity: A Review. Leonard MM, Sapone A, Catassi C, Fasano A. JAMA. 2017 Aug 15;318(7):647-656. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Hollon J, Puppa EL, Greenwald B, Goldberg E, Guerrerio A, Fasano A.Nutrients. 2015 Feb 27;7(3):1565-76. Lerner A, O'Bryan T, Matthias T. Navigating the Gluten-Free Boom: The Dark Side of Gluten Free Diet. Front Pediatr. 2019;7:414. Published 2019 Oct 15. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult Human subjects - comment by Jackson. Jackson FW. Br J Nutr. 2010 Sep;104(5):773. On the presence of Inulin and Oligofructose as natural ingredients in the western diet Jan Van Loo , Paul Coussement , Leen De Leenheer , Hubert Hoebregs & Georges Smits Critical Reviews in Food Science and Nutrition, Volume 35, 1995 - Issue 6. Prebiotic effects of wheat arabinoxylan related to the increase in bifidobacteria, Roseburia and Bacteroides/Prevotella in diet-induced obese mice. Neyrinck AM, Possemiers S, Druart C, Van de Wiele T, De Backer F, Cani PD, Larondelle Y, Delzenne NM. PLoS One. 2011;6(6):e20944. Small-intestinal histopathology and mortality risk in celiac disease. Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F., JAMA. 2009 Sep 16;302(11):1171-8. Mortality in patients with coeliac disease and their relatives: a cohort study. Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, Sategna Guidetti C, Usai P, Cesari P, Pelli MA, Loperfido S, Volta U, Calabró A, Certo M; Club del Tenue Study Group.Lancet. 2001 Aug 4;358(9279):356-61. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Fritscher-Ravens A, Schuppan D, Ellrichmann M, Schoch S, Röcken C, Brasch J, Bethge J, Böttner M, Klose J, Milla. PJ.Gastroenterology. 2014 Nov;147(5):1012-20. Glutamine and the regulation of intestinal permeability: from bench to bedside. Achamrah N, Déchelotte P, Coëffier M.Curr Opin Clin Nutr Metab Care. 2017. Jan;20(1):86-91 Potential of Omega-3 Polyunsaturated Fatty Acids in Managing Chemotherapy- or Radiotherapy-Related Intestinal Microbial Dysbiosis. Zhang Y, Zhang B, Dong L, Chang P.Adv Nutr. 2019 Jan 1;10(1):133-147. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Kong J, Zhang Z, Musch MW, Ning G, Sun J, Hart J, Bissonnette M, Li YC.Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G208-16. Peptide Immunotherapy: Colostrum, A Physician's Reference Guide Hardcover, Keech A., AKS Publishing; 1St Edition edition (2009) ISBN-10: 0692002421. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Aggarwal BB, Harikumar KB.Int J Biochem Cell Biol. 2009 Jan;41(1):40-59. Modulation of the gut microbiota by nutrients with prebiotic properties: consequences for host health in the context of obesity and metabolic syndrome. Delzenne NM, Neyrinck AM, Cani PD.Microb Cell Fact. 2011 Aug 30;10 Suppl 1(Suppl 1):S10 Gut Microbiota in Celiac Disease: Is There Any Role for Probiotics? Pecora F, Persico F, Gismondi P, Fornaroli F, Iuliano S, de'Angelis GL, Esposito S.Front Immunol. 2020 May 15;11:957. Factors that influence adherence to a gluten-free diet in adults with celiac disease. Leffler DA, Edwards-George J, Dennis M, Schuppan D, Cook F, Franko DL, Blom-Hoffman J, Kelly CP.Dig Dis Sci. 2008 Jun;53(6):1573-81. Gluten-free diet: the medical and nutrition management of celiac disease. See J, Murray JA.Nutr Clin Pract. 2006 Feb;21(1):1-15. Predicting and preventing autoimmunity, myth or reality? Harel M, Shoenfeld Y.Ann N Y Acad Sci. 2006 Jun;1069:322-45.

Celiac.com 01/07/2020 - Everyone with celiac disease needs to follow a gluten-free diet. However, celiac patients on a gluten-free diet often suffer from villous atrophy, which might point to regular accidental gluten ingestion. A group of international researchers called the Doggie Bag Study group, has found that gluten ingestion is common even among those who make a concerted effort to avoid gluten. The study group included Jocelyn A. Silvester, Isabel Comino. Ciarán P. Kelly, Carolina Sousa, and Donald R. Duerksen. The group's analysis found that antibody tests on celiac patients who report good or excellent gluten-free dietary practices show that most patients had ingested measurable amounts of gluten in the 10-days before biopsy. These findings indicate that most people with celiac disease are not as gluten-free as they might think, and would likely benefit from treatments other than the simple gluten-free diet, according to Jocelyn A. Silvester, MD, PhD, a pediatrician at Boston Children's Hospital and Harvard Medical School, Massachusetts, and colleagues. Silvester and her colleagues write that their findings indicate that a completely "gluten-free diet may be more aspirational than achievable, even by highly committed and knowledgeable individuals." In their study, which appears in Gastroenterology, the researchers report on 12 female and 6 male asymptomatic celiac patients who had not intentionally consumed gluten. All patients reported diligently following a gluten-free diet and avoiding gluten. Patients were recruited from the Manitoba Celiac Disease Inception Cohort study for the purpose of assessing potential gluten exposure in patients who were supposedly gluten-free. More than three out of four participants self-reported accidental gluten exposure on the Gluten-Free Eating Assessment. For 7 days, study participants allowed testing on a representative 25% portion of food they ate, including sauces, dressings, and flavored drinks, but excluding naturally gluten-free whole foods, such as fruits, vegetables, and wine. Using food testing and gluten-related antibody tests to detect gluten in both the food samples, and in stool and urine samples, of adults with celiac disease who claimed to strictly follow a gluten-free diet, the investigators found substantial evidence that these "gluten-free" diets still included gluten in various amounts. In food testing samples from nine participants, 40% contained detectable gluten over 20 ppm, while 20% contained contained detectable gluten over 200 ppm. In excretory assays, gluten immunogenic peptides were detectable in 30 of 519 (6%) samples from eight participants and in 8 of 75 (11%) stool samples from five participants. Positive samples were distributed throughout the day. Read more at Sciencedirect.com

Celiac.com 05/16/2019 - People with potential celiac disease show positive results from blood tests for tissue transglutaminase antibodies (anti-TG2), but show no damage to the intestinal lining. Such patients are all Marsh stage 0 or 1, meaning they have healthy, normal gut mucosa. Clinicians are still sorting out the best way to treat these patients. To provide some answers, a team of researchers recently set out to assess risk factors for villous atrophy in children with potential celiac disease. The team included R. Auricchio, R. Mandile, M.R. Del Vecchio, S. Scapaticci, M. Galatola, M.A. Maglio, V. Discepolo, E. Miele, D. Cielo, R. Troncone, and L. Greco. They are variously affiliated with the Department of Translation Medical Science, Section of Pediatric, and European Laboratory for the Investigation of Food Induced Disease (ELFID), University Federico II, Naples, Italy, and the Department of Medicine, University of Chicago, Chicago, IL, USA. For children with "potential" celiac disease who do not follow gluten-free diets, possible risk factors for villous atrophy include age at diagnosis, gamma delta lymphocytes and HLA haplotype, researchers say. The team conducted a prospective study of 280 children between 2–18 years old in Italy who had suspected celiac disease, and followed the children from 18 months to 12 years. Each participant had two consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of IgA in the normal range, normal Marsh 0–1 duodenal condition in 5 biopsies, and HLA DQ2- or DQ8-positive haplotypes. The children underwent serologic tests and clinical analyses every 6 months and a small bowel biopsy every 2 years. Two hundred ten patients of the original group were checked after 9-years. The team conducted multivariate analyses of clinical, genetic, and histologic data to spot factors associated with villous atrophy. The team's long-term study showed 43% cumulative rates of progression to villous atrophy over the 12-year study. The team identified factors that can be used to spot children with the highest risk for villous atrophy. This approach might be used to assess whether children with suspected celiac disease should immediately start a gluten-free diet or be monitored on their regular diet. The takeaway, Dr. Auriccio told reporters, is that potential celiac disease affects "a very heterogenous group of patients [who]...have to be carefully managed by expert pediatric gastroenterologists." Studies like this one by Dr. Auriccio and his team are highly valuable, because diagnosing and properly treating celiac disease as early as possible is important in helping to prevent the development of associated conditions later on. Read more at Gastrojournal.org

Celiac.com 04/12/2019 - In this 4-part Series, we’re going to look at the world of gluten sensitivity, what the current science tells us, the frustrations gluten sensitive and celiac patients often experience, and how to use the science in getting healthier. Part 1: Why the Tests are Often Wrong Part 2: Why Don’t I Feel Great on a gluten-free diet: Cross-Reactive foods Part 3: Why Don’t I Feel Great on a gluten-free diet: the Intestinal Milieu Part 4: Why Don’t I Feel Great on a gluten-free diet: Invaders in the House Many of us believe that the toxic peptides of gluten found in wheat, rye and barley may detrimentally affect any tissue in the body and are not restricted to the intestines. As a matter-of-fact, one of the ‘mantras’ of the Gluten Sensitivity Network comes from an 8-year old article: “That gluten sensitivity is regarded as principally a disease of the small bowel is a historical misconception.(1)” There is a key word in this statement which I suspect emphasizes the Author’s message and sets the tone for this article (and this network movement). That key word is ‘principally’. Is Gluten sensitivity ‘principally’ a disease of the small intestine? Point-blank answer-no, it is not. For every Gluten sensitive patient with the symptoms of an enteropathy (classic celiac disease), there are 8 more with no GI symptoms(2, 3). And the importance of recognizing this? Unfortunately, too many doctors will tell their patients that if the intestinal symptoms are not severe, or if there is no advanced intestinal damage (total villous atrophy), then the patient does not need to be vigilant in avoiding gluten exposure at all costs(4). Many patients are advised to follow the World Health Organization or Food and Agricultural Organization Codex Alimentarius gluten-free diet, which allow up to 0.3% of gluten per 100 g of protein in foods, whereas others follow a strict GFD with no detectable gluten. However, trace amounts of gluten may be responsible for persistent symptoms in some patients with celiac disease. Up to 75% of patients with persistent symptoms despite a World Health Organization or Food and Agricultural Organization Codex Alimentarius gluten-free diet will improve when put on a ‘‘no detectable gluten’’ diet(5). We know that for gluten-sensitive patients, eating gluten will cause inflammation in the intestines, and often in other parts of the body(6, 7, 8, 9). The importance of ‘quieting down’ the inflammatory cascade from gluten exposure? Mortality in celiac patients is highest (6-fold higher) in those not adherent to a gluten-free diet. Non-adherence to a gluten-free diet was defined as eating gluten once-per-month(10). Vigilance is paramount. You can’t be a little pregnant. There is no convincing evidence that you can have a little gluten if you have gluten sensitivity. The ‘conundrum of gluten sensitivity’ is when patients know they have a problem with wheat, their doctors run the standard blood profile, and one of two things happens: -IgA anti-transglutaminase or anti-endomysial antibodies come back negative(11), or; -IgA anti-transglutaminase or anti-endomysial antibodies come back negative and anti-gliadin, or anti-deamidated gliadin antibodies come back positive and the doctor tells the patient “it’s okay to eat wheat because the tissue antibodies are negative”. The patient is left in a state of confusion. They don’t WANT to give up wheat. After all, they believe it’s a staple of life. And their doctor says it’s okay to eat it. Yet they know they don’t feel as well when they eat it. So many will rationalize “Oh well, it must be the stress of my life making me feel bad”, and they order their bagel. That’s the conundrum. Where’s the problem? The problem is the test. Gluten sensitivity is a systemic autoimmune disease with diverse manifestations(12). Celiac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. And yet, this enteropathy, ‘one of the most common lifelong disorders in both the U.S. and Europe(13), receives the lion’s share of focus to the point of ignoring other manifestations. Auto-immune disease, the 3rd leading cause of morbidity and mortality in the industrialized world(14), is ten times more common in a gluten sensitive enteropathy than in the general population(15). The correlation is undeniable. The exact mechanisms of how this correlation manifests is being investigated intensively. What we can say, with a good deal of research behind us, is that the toxic peptides of gluten may act as a trigger in the development of the auto-immune mechanism (the immune system attacking our own tissues). Traditionally, doctors do not recognize this connection and wait for the accumulated damage from the immune system attacking our tissue (our thyroid, or our brains, or our skin, or…), they wait until the damage is extensive enough that there are obvious symptoms, and then we receive a diagnosis of an auto-immune disease (celiac disease, Hashimoto’s thyroiditis, type 1 diabetes, systemic lupus, inflammatory bowel disease, inflammatory skin diseases, ….)(16). Thus, the burden on society imposed by gluten sensitivity is difficult to overestimate. Earlier identification might result in earlier treatment, better quality of life and an improved prognosis for these patients(17). The diagnosis of gluten sensitivity has been proposed to include not just intestinal damage (celiac disease), but also gluten-reactive patients without intestinal lesions. From the skin (dermatitis herpetiformis, psoriatic arthritis, alopecia areata, dermatomyositis, cutaneous vasculitis,), to the muscles (inflammatory myopathies), to the brain (gluten ataxia, altered neurotransmitter production, schizophrenia, anxiety, depression, attention deficit disorders,…) to the nerves (peripheral neuralgias, carpal tunnel syndrome, idiopathic neuropathies,…), and beyond. Pathology in response to gluten exposure can occur in multiple systems without evidence of intestinal damage(18-27). Now, what about this conundrum? The tests are negative, yet the person feels better when they do not eat gluten. Many studies have validated the sensitivity and specificity using anti-endomysial and/or anti-transglutaminase antibody testing to identify celiac disease(28, 29). This means that the science says these tests are very, very accurate. Then how is there a conundrum? Here’s the problem: the definition of celiac disease requires total villous atrophy(30). Not partial villous atrophy; not increased inflammation without any visible atrophy. The definition of celiac disease requires total villous atrophy. Thus, when researchers look at populations who have celiac disease confirmed by biopsy, and look to see how accurate the blood tests are, they come up with percentages above 95%, because they’re only including people who have total villous atrophy in their study group-because that’s the definition of celiac disease. If we were to expand the definition of celiac disease to include those with partial villous atrophy, or include those who currently show only the mechanism that wears down the villi (increased intraepithelial lymphocytes), then the sensitivity and specificity of anti-endomysial or anti-transglutaminase goes down, in some studies dramatically down, to as low as 27-32%(31, 32, 33, 34). So do we want to base our health guidance and decisions on blood tests that are limited to identifying celiac disease at its end stage of intestinal deterioration (total villous atrophy)(35, 36)? Or would we want to include testing that has a much bigger picture in mind and identifies gluten sensitivity inside and outside the intestines and at earlier stages? If we recognize the fact that gluten sensitivity may manifest as celiac disease, or it may manifest outside of the intestines(37), one of the ways of expanding our diagnostic range is to focus on whether or not our immune system is saying that gluten is a problem. We may know where the problem is manifesting, or we may not. But if our immune system is saying “We’ve got a problem here”, it is likely worth listening to. As a comparison, if your car is running fine on the highway at 60 miles per hour, do you listen when the immune system of the car (the dashboard gauges) says “we’ve got a problem here”, and the hot light has lit up, or do we say “the car’s running fine-I don’t see or feel any problem”, and keep driving? I think most would agree that is not a very wise move. The same is true for your body. You may ‘feel’ a problem; you may not. We’ll talk more about that in a future article. For now, the point I want to make is that we will benefit from ‘listening’ to what our immune system is saying to us. We just have to be able to hear what it’s trying to say. The problem is accurate communication The current blood test that every laboratory offers in looking for an immune reaction to the gluten fraction of wheat is elevated antibodies to gliadin or deamidated gliadin - every laboratory. And there are many studies that have shown that looking for elevated antibodies to gliadin is not as accurate in identifying celiac disease as looking for elevated antibodies to transglutaminase or endomysial antibodies. Why? Because sometimes the antibodies to gliadin are positive and the biopsy shows there is no celiac disease. And sometimes the gliadin antibodies are negative and the biopsy shows there is celiac disease. Thus, the consensus in the scientific community is that looking for antibodies to wheat (gliadin) is not sensitive enough when looking for celiac disease. You can’t rely on it. Now that doesn’t make much sense, does it? If the gluten peptide is the problem, why can’t we measure the immune reaction to it when other gauges on the dashboard are hot? Two reasons: Researchers tell us it is “inappropriate” to compare gliadin antibodies against transglutaminase or endomysial antibodies because gluten sensitivity can exist without villous atrophy. Thus the gliadin antibodies may be elevated (and often are) without recognizable celiac disease. It’s showing us a bigger problem than just Celiac disease. They’re not ‘false positives’. It’s the immune system saying “we’ve got a problem here” that is not currently manifesting in the intestines-it is likely manifesting somewhere else, such as in the brain or the nervous system(38). Identifying antibodies just against the fraction of gluten called gliadin is not thorough enough in looking for an immune reaction to gluten(39). Amino acids are the building blocks of protein. When we eat protein, any protein, it’s the job of the digestive system to break down that protein into 1, 2, or at most 3 amino acid peptides that are easily absorbed into the blood stream through the ‘cheesecloth’ of the intestines. When someone has gluten sensitivity, the gluten molecules in wheat, barley and rye are not digested into small enough molecules to easily fit through the cheesecloth, be absorbed into the blood stream, and they remain in larger peptides, sometimes very large peptides. These large peptides, called macromolecules, trigger the immune system to say “these are not good for me(40, 41)”. An exposure to a large peptide on a rare occasion would not likely have initially been a problem. But with pancakes for breakfast, a sandwich for lunch, pasta for dinner, toast for breakfast, a sandwich for lunch, croutons on the salad at dinner, day in and day out, eventually you’ve got a hot light on the dashboard that is reaching the critical stage(42). Then ‘boom’ your engine overheats and you begin to notice symptoms-perhaps in the intestines, perhaps in the joints, perhaps in the skin, perhaps in the skull (depression, anxiety, headaches), perhaps fatigue,….. So let’s get back to the large peptides left in the intestines due to an inability to digest the gluten molecule. We know there are many peptides of gluten result from poor digestion(43). One study identified over 60 putative peptides of gluten(44). Yet the current blood tests only test for one - gliadin. Studies have said that gliadin is the primary toxic peptide. But, only about 50% of celiac patients have antibodies to the gliadin peptide of gluten(39). The rest of the celiacs don’t. They have antibodies to other peptides of gluten(45). This is the reason for the conundrum-you test for it, the test only looks for antibodies to gliadin, the test comes back negative, and yet you ‘know’ you feel better off of gluten. It’s the test! In that example, the person does not react to the gliadin peptide-they are likely to be reacting to a different peptide of gluten. Why don’t laboratories test for other peptides of gluten? Good question. I do not know the answer to that. Some of the studies on this go back to the mid 1990’s. Probably a supply and demand issue for commercial laboratories. Well, no longer. There is a new blood test, looking at 12 different peptides of gluten-not just Gliadin. You can go to www.cyrexlabs.com or to my web site www.theDr.com to read more about this test. Looking at antibodies to 12 different peptides of gluten (including gliadin) will certainly increase the detection rate of the immune system saying “we’ve got a problem here with gluten”. We know celiac disease is due to sensitivity to the peptides of gluten found in wheat, barley and rye, many of the peptides in gluten-not just to gliadin. And now, another diagnostic tool has been added to your doctor’s repertoire assisting in accurately identifying gluten sensitivity with or without the serious end-stage of tissue destruction-total villous atrophy. And my personal prayer is that as a result of this expanded test looking for a reaction to gluten, we no longer miss those with earlier stages of celiac disease and gluten sensitivity thus being able to calm down the ‘fire in the belly’, the hot light on the dashboard, before the engine blows up. Before the diagnosis of attention deficit hyperactivity disorder, before the diagnosis of autoimmune thyroid disease, before the diagnosis of type 1 diabetes, before the diagnosis of migraines, before the loss of a pregnancy,…. and doctors will have the tools to truly guide their patients in increasing their health - tuning the engine before it blows up with a diagnosable disease. So our bodies can carry us through life purring instead of rumbling along. References: 1. Hadjavassilios, M., Gluten sensitivity as a Neurological illness, J Neurol Neurosurg Psychiatry 2002;72:560–563 2. van Heel D., West J, Recent Advances in Coeliac Disease, Gut 2006;55:1037–1046 3. Fasano A, Catassi C., Current Approaches to Diagnosis and Treatment of Celiac disease: An Evolving Spectrum Gastroenterology 2001;120:636-651 4. Goddard CJ., Gillett H R., Complications of coeliac disease: are all patients at risk? Postgrad. Med. J. 2006;82;705-712 5. Green PHR, Stavropoulos SN, Panagi SG, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gasroenterol 2001;96:126–31. 6. Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Microscopic colitis: a common diarrhoeal disease. An epidemiological study in Orebro, Sweden, 1993-1998. Gut, 2004; 53:346-350. 7. Gillet HR, Freeman HJ. Prevalence of celiac disease in collagenous and lymphocytic colitis. Can J Gastroenterol, 2000; 14: 919-921. 8. Koskela RM, Niemelä SE, Karttunen TJ, Lehtola JK. Clinical characteristics of collagenous and lymphocytic colitis. Scand J Gastroenterol, 2004;39: 837-845. 9. Dickey W, Celiac disease and the Colon, PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2008 10. Corrao G, Corrazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358:356–61. 11. Hill I Salem W, Dirks M, Liptak G, Colletti R , Fasano A, Guandalini S, Hoffenberg E, Horvath K, Murray J, Pivor M, Salem W, Seidman E, Guideline for the Diagnosis and Treatment of Celiac disease in Children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, J Pediatr Gastroenterol Nutr, Vol. 40, No. 1, January 2005 12. Hadjavassilios, M, Gluten sensitivity: from Gut to Brain. Lancet Neurol 2010; 9: 318–30 13. Fasano, A, Celiac disease-How to handle a Clinical Chameleon, NEJM 348;25 June 19,2003 14. Arnson Y, Amital H, and Shoenfeld Y, Vitamin D and autoimmunity: new aetiological and therapeutic considerations, J of Immunology, 2005, 175: 4119–4126. 15. Alaedini A, Okamoto H, Briani, C, Wollenberg K, Shill H, Bushara K, Sander H, Green P, Hallett M, Latov N, Immune Cross-Reactivity in Celiac disease: Anti-Gliadin Antibodies Bind to Neuronal Synapsin I, The Journal of Immunology, 2007, 178: 6590–6595. 16. Bland J., Understanding the Origins and Applying Advanced Nutritional Strategies for Autoimmune Disease, Metagenics Seminar Series, 2006 17. Green P, Alaedini A, Sander HW, Brannagan III TH, Latov N, Chin R, Mechanisms underlying celiac disease and its Neurologic Manifestations Cell. Mol. Life Sci. 62 (2005) 791–799 18. Marietta E, Black K, Camilleri M, Krause P, Rogers RS 3rd, David C, Pittelkow MR, Murray JA., A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice, J Clin Invest. 2004 Oct;114(8):1090-7 19. 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