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Showing results for tags 'villi'.
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Exploring Other Causes of Villous Atrophy Beyond Celiac Disease
Scott Adams posted an article in Spring 2024 Issue
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 03/04/2004 - Gluten sensitivity is the process by which the immune system reacts to gluten contained in wheat, barley, rye, and oats. The reaction begins in the intestine because that is where the inciting antigen, gluten, is present (from food). When this immunologic reaction damages the finger-like surface projections, the villi, in the small intestine (a process called villous atrophy), it is called celiac disease (or sometimes celiac sprue or gluten-sensitive enteropathy). The clinical focus of gluten-induced disease has always been on the intestine because that is the only way the syndrome was recognized before screening tests were developed. The intestinal syndrome consists mainly of diarrhea, gas, bloating, nausea, vomiting, fat in the stool, nutrient malabsorption, and even constipation. Although the small intestine is always the portal of the immune response to dietary gluten, it is not always affected in a way that results in villous atrophy. Even though recent research has shown that celiac disease is much more common than previously suspected, affecting 1 in 100-200 Americans and Europeans, past and emerging evidence indicates that it accounts for only a small portion of the broader gluten sensitive clinical spectrum (often referred to as the "Tip of the Gluten Sensitive Iceberg"). With better understanding of how gluten triggers immune and autoimmune reactions in the body under the control of various genes, and advancing techniques of detecting these reactions, it is becoming apparent that the majority of the gluten sensitive population (the submerged "mass of the iceberg") do not manifest villous atrophy in its classic, complete form and therefore do not have celiac disease. In these non-celiac, gluten sensitive individuals, the brunt of the immune reaction either affects the function of the intestine, causing symptoms without structural damage, affects other tissues of the body (and virtually all tissues have been affected in different individuals), or both. This is important because the commonly used diagnostic tests of clinically important gluten sensitivity (blood tests for certain antibodies and intestinal biopsies) are only positive when villous atrophy of the small intestine is present. But if only a small minority of gluten sensitive individuals actually develop celiac disease, the majority, who have not yet or may never develop villous atrophy, with or without symptoms, can remain undiagnosed and untreated for years. This can result in significant immune and nutritional consequences, many of which are irreversible even after treatment with a gluten-free diet. Some of these disorders include loss of hormone secretion by glands (hypothyroidism, diabetes, pancreatic insufficiency, etc), osteoporosis, short stature, cognitive impairment, and other inflammatory bowel, liver, and skin diseases, among others. Only with early diagnosis, can these problems be prevented or reversed. I am here to report on a scientific paradigm shift regarding early diagnosis of gluten sensitivity based on about 30 years of medical research by myself and others. My message is that earlier and more inclusive diagnosis of gluten sensitivity than has been allowed by blood tests and intestinal biopsies must be developed to prevent the nutritional and immune consequences of long-standing gluten sensitivity. Imagine going to a cardiologist because your blood pressure is high or you're having chest pain, and the doctor says he is going to do a biopsy of your heart to see what is wrong. If it "looks" O.K., you are told you have no problem and no treatment is prescribed because you have not yet had a heart attack showing on the biopsy. You would not think very highly of the doctor utilizing this approach because, after all, isn't it damage to the heart that you would want to prevent? But for the intestine and gluten sensitivity, current practice embraces this fallacious idea that until an intestinal biopsy shows structural damage, no diagnosis or therapeutic intervention is offered. This has to change now because with newly developed diagnostic tests, we can diagnose the problem before the end stage tissue damage has occurred, that is "before the villi are gone," with the idea of preventing all the nutritional and immune consequences that go with it. There are many misconceptions regarding the clinical presentation of gluten sensitivity or celiac disease: For example, that you cannot be gluten sensitive if you have not lost weight, are obese, have no intestinal symptoms, or are an adult or elderly. However, the most widely held and clinically troublesome misconception is that a negative screening blood test, or one only showing antigliadin antibodies (without the autoimmune antiendomysial or anti-tissue transglutaminase antibody) rules out any problem caused by gluten at that time or permanently. For some reason, the high "specificity" of these blood tests has been tightly embraced. Specificity means if the test is positive, you surely have the disease being tested for with little chance that the positive is a "false positive." But sadly, a negative test does not mean you do not have the problem. This is the biggest pitfall of all because the only thing a very specific test, like blood testing for celiac disease, can do is "rule in" the disease; it can not "rule it out." If you've got very far advanced and/or long-standing celiac disease, it is likely that the test will be positive. However, several studies have now revealed that it is only those with significant villous atrophy of the small intestine who regularly show a positive antiendomysial or anti-tissue transglutaminase antibody, the specific tests relied upon most heavily for diagnosis of gluten-induced disease. When there was only partial villous atrophy, only 30% had a positive test. More disturbing perhaps, were the results with respect to screening first degree relatives of celiacs with blood tests. Despite some biopsy-proven early inflammatory changes in the small intestine but without villi damage, all blood tests were negative. For some reason, it's been perfectly acceptable to celiac diagnosticians that a patient must have far advanced intestinal gluten sensitivity, i.e., villous atrophy, to be diagnosed and a candidate for treatment with a gluten-free diet. That means from the specific testing standpoint, there's never (or rarely) a false positive. But what about the larger majority of gluten-affected people who do not presently have or may never get this end stage, villous atrophic presentation? They are out of luck as far as blood testing is concerned. So the fact is that we have erroneously relied on specificity (always picks up gluten sensitivity after it has caused villous atrophy, never having a false positive) instead of sensitivity (doesn't miss gluten sensitive people even though they might be picked up early, even before full-blown celiac disease develops). Would a test relying on specificity rather than sensitivity be good enough for you, or your children? Consider the risk of not getting an early diagnosis versus going on a gluten free diet a few months or years prematurely. While I do not recommend anyone to have a biopsy (especially children) for diagnosis because of the shortcomings and invasive nature of this technique, I particularly do not want someone to have a biopsy showing villous atrophy, since by that time, associated bone, brain, growth, and/or gland problems are all but guaranteed. And here is another related problem: You have a positive blood test, but, if a small bowel biopsy comes back normal or nearly normal, you are told that the blood test must have been a "false positive" and that gluten is not your problem. Would you believe that, especially in light of the fact that most such people would have gotten the blood test in the first place because of a specific symptom or problem? Let's hope not. All that means (positive blood test, negative biopsy) is that the gluten sensitivity (evidenced by antibodies to gliadin in the blood) has not yet damaged your intestines severely. Evidence of this comes from a study that I performed. We tested 227 normal volunteers with blood tests for celiac disease. Twenty-five of these people (11%) had either antigliadin IgG or IgA in their blood versus only one (0.4%) that had antiendomysial, anti-tissue transglutaminase, and antigliadin IgA in the blood. So for every one person in a population that has the antibodies that have 100% specificity for celiac disease of the intestine (antiendomysial and anti-tissue transglutaminase), there are 24 that have antibodies to gliadin that may not have celiac disease. So what is going on with the 11% with antigliadin antibodies in blood? Are these false positives (rhetorically)? You're telling me that there is a disease called celiac disease and it is associated with antibodies to gliadin in the blood and sometimes it damages the intestine? But people with antigliadin antibody in their blood but no other antibodies do not have a clinically significant immunologic reaction to gluten? Do you see the problem? How can 11% be false positives? What about the 89% with none of these antibodies? You cannot equate having no antibodies at all (a negative test) with having antigliadin antibodies alone. If you have antibodies to gliadin, something is going on here. Where there's smoke there's fire. The purpose of this study was to test this hypothesis: That an antigliadin antibody alone does indicate the presence of an immune reaction to gluten that may be clinically important. Using tests for intestinal malabsorption and abnormal permeability (i.e., tests of small bowel function, unlike a biopsy which says nothing about function), we found that 45% of people with only an antigliadin IgG or IgA antibody in blood (without either antiendomysial or anti-tissue transglutaminase antibody) already had measurable intestinal dysfunction, compared to only 5% of people with no antibodies to gliadin in their blood. When we did biopsies of these people's intestines, none had villous atrophy with only a few showing some early inflammation. Thus, having an antigliadin antibody in your blood does mean something: That there is nearly a 1 in 2 chance that functional intestinal damage is already present even though it may not be visible structurally at the resolution attained by a light microscope assessment of a biopsy. As mentioned at the outset, not all gluten sensitive individuals develop villous atrophy. Evidence for this has been around for a long time. In 1980, a medical publication titled "Gluten-Sensitive Diarrhea" reported that eight people with chronic diarrhea, sometimes for as long as 20 years, that resolved completely when treated with a gluten-free diet, had mild small bowel inflammation but no villous atrophy. In 1996 in a paper called "Gluten Sensitivity with Mild Enteropathy," ten patients, who were thought to have celiac disease because of a positive antiendomysial antibody blood test, had small bowel biopsies showing no villous atrophy. But amazingly, these biopsies were shown to react to gluten when put in a Petri dish, proving the tissue immunologically reacted to gluten (which was likely anyway from their positive blood tests). Two other reports from Europe published in 2001 showed gluten sensitivity without villous atrophy (and hence without celiac disease). In one of these studies, 30% of patients with abdominal symptoms suggestive of irritable bowel syndrome having the celiac-like HLA-DQ2 gene but no antibodies to gliadin in their blood, had these antibodies detected in intestinal fluid (obtained by placing a tube down into the small intestine). Thus, in these people with intestinal symptoms, but normal blood tests and biopsies, the antigliadin antibodies were only inside the intestine (where they belong if you consider that the immune stimulating gluten also is inside the intestine), not in the blood. This is the theme we have followed in my research, as we are about to see. More proof that patients in these studies were gluten sensitive came from the fact that they all got better on a gluten-free diet, and developed recurrent symptoms when "challenged" with gluten. Although the gluten-sensitive patients in these studies did not have the villous atrophy that would yield a diagnosis of celiac disease, small bowel biopsies in many of them showed some, albeit minimal, inflammatory abnormalities. Yet, when a symptomatic patient in clinical practice is biopsied and found to have only minimal abnormalities on small bowel biopsy, clinicians do not put any stock in the possibility of their having gluten sensitivity. As much as I would like to take credit for the concept, you can see from these studies that I did not invent the idea that not all gluten sensitive patients have villous atrophy. It has been around for at least 23 years, and reported from different parts of the world. For many years there has also been proof that the intestine is not the only tissue targeted by the immune reaction to gluten. The prime example of this a disease called dermatitis herpetiformis where the gluten sensitivity manifests primarily in skin, with only mild or no intestinal involvement. Now from more recent research it seems that the almost endless number of autoimmune diseases of various tissues of the body also may have the immune response to dietary gluten and its consequent autoimmune reaction to tissue transglutaminase as the main immunologic cause. A study from Italy showed that the longer gluten sensitive people eat gluten, the more likely they are to develop autoimmune diseases. They found that in childhood celiacs, the prevalence of autoimmune disease rose from a baseline of 5% at age two to almost 35% by age 20. This is a big deal if you think of how much more complicated one's life is when one is both gluten sensitive AND has an additional autoimmune disease. So preventing autoimmune disease is one very important reason why early diagnosis and treatment of gluten sensitivity is important. Early diagnosis before celiac disease develops also holds the potential of preventing other clinical problems such as malnutrition, osteoporosis, infertility, neurologic and psychiatric disorders, neurotube defects (like spina bifida) in your children, and various forms of gastrointestinal cancer. Another reason for early diagnosis and treatment is very straightforward and that is because many gluten sensitive individuals, even if they have not yet developed celiac disease (villous atrophy), have symptoms that abate when gluten is removed from their diet. Furthermore, from a study done in Finland, a gluten sensitive individual who reports no symptoms at the time of diagnosis can improve both psychological and physical well-being after treatment for one year with a gluten-free diet. Despite the common sense and research evidence that early diagnosis of gluten sensitivity offers many health advantages over a diagnostic scheme that can only detect the minority and end-stage patients, until now, the limitation was still in the tests being employed. As mentioned above, the main tests used for primary (before symptoms develop) and secondary (after symptoms develop) screening for celiac disease, blood tests for antigliadin and antiendomysial/anti-tissue transglutaminase antibodies, are only routinely positive after extensive damage to intestinal villi. As shown in a 1990 publication, this is because unless you have full blown, untreated celiac disease, the IgA antibodies to gliadin are only INSIDE the intestine not in the blood. Measuring antigliadin antibody in blood and intestinal fluid (obtained by the laborious technique of having research subjects swallow a long tube that migrates into the upper small intestine), researchers found that in untreated celiacs, antigliadin antibody was present in the blood and inside the intestine, whereas after villous atrophy healed following a year on a gluten-free diet, the antigliadin antibody was no longer in the blood but was still measurable inside the intestine in those with ongoing mild inflammation. An important conclusion can be drawn from these results, as these researchers and myself have done: Gluten sensitive individuals who do not have villous atrophy (the mass of the iceberg), will only have evidence of their immunologic reaction to gluten by a test that assesses for antigliadin IgA antibodies where that foodstuff is located, inside the intestinal tract, not the blood. This makes sense anyway, because the immune system of the intestine, when fighting an antigen or infection inside the intestine, wages the fight right in that location in an attempt to neutralize the invading antigen, thereby preventing its penetration into the body. It does this with T cells on the surface of the epithelium, the intraepithelial lymphocytes, and with secretory IgA made with a special component called secretory piece that allows its secretion into the intestine. The excellent English researchers that made the discovery that they could detect the immunologic reaction to gluten inside the intestine before it was evident on blood tests or biopsies knew it was a breakthrough, testing it many times over in different ways, and further extending the clinical spectrum of gluten-induced disease to include a phase before the villi are damaged, so-called "latent celiac sprue". Furthermore, they developed this technique of assessing the intestinal contents for antigliadin antibodies into what they viewed as a "noninvasive screening test for early or latent celiac sprue" (what others and I would simply call "gluten sensitivity"). However, this was not exactly noninvasive, nor was it simple. It still required the patient to swallow a tube, followed by a complete lavage of all their gastrointestinal contents with many gallons of nonabsorbable fluid that had to be passed by rectum and collected into a large vat to be analyzed for the presence of antigliadin antibodies. While this was indeed a conceptual breakthrough, it practically went unnoticed by the medical community because the cumbersome procedure of washing out the intestine just could not be done in a normal clinical setting. To this day, I am not sure how many people even know that it was not me, but rather this well known celiac research group, led by the late Dr. Anne Ferguson, who pioneered the assessment of the intestinal contents as a viable and more sensitive source of testing material for the early reactions of the immune system to gluten. What we did in my research was to refine and simplify the method of collecting and measuring these intestinal IgA antigliadin antibodies before they can be detected in blood. That is, instead of washing out the antibodies from the intestine, we allow them to be excreted naturally in the stool (feces). And so with that idea, and our ability to measure these antibodies in stool, as others before us had done for fecal IgE antibodies directed to food antigens, our new gluten (and other food) sensitivity stool testing method was born. It was actually my research of microscopic colitis that led me to discover that stool analysis was the best way of assessing for gluten sensitivity before celiac disease develops. Microscopic colitis is a very common chronic diarrheal syndrome, accounting for 10% of all causes of chronic diarrhea in all patients, and is the most common cause of ongoing chronic diarrhea in a treated celiac, affecting 4% of all celiac patients. However, from my published research, despite the presence of the celiac HLA-DQ2 gene in 64% of patients with microscopic colitis, very few get positive blood tests or biopsies consistent with celiac disease. Yet, small bowel biopsies revealed some degree of inflammation sometimes with mild villous blunting in 70% of cases. According to the facts and previously discussed shortcomings of celiac blood tests, antibodies to gliadin are unlikely to be detected in the blood in these patients because they lack villous atrophy. So negative blood tests for antigliadin antibodies per se did not, in my mind, rule out the possibility that these patients with microscopic colitis, a disease that under the microscope looks like celiac disease (but of the colon), and that affects many celiac patients, were not gluten sensitive themselves. But as Dr. Ferguson's research revealed, these antibodies might be detectable inside the intestine. And since we surely were not going to perform that cumbersome intestinal lavage test in my patients, we decided to see if we could find these antibodies in the stool as a reflection of what is coming through the intestine. Here's the first set of data that we found showing the superior sensitivity of stool testing versus blood tests for antigliadin IgA antibodies. In untreated celiac disease patients, we found a 100% positivity in the stool versus only 76% in blood. In hundreds of microscopic colitis patients since tested, only 9% have antigliadin antibody in blood but 76% have it in stool. And the same is true of 79% of family members of patients with celiac disease; 77% of patients with any autoimmune disease; 57% of people with irritable bowel syndrome-like abdominal symptoms; and 50% of people with chronic diarrhea of unknown origin, all of whom have only about a 10-12% positivity rate for blood tests (like normal volunteers). Thus, when you go to the source of production of these antibodies for testing, the intestine, the percentage of any population at a higher than normal genetic and/or clinical risk of gluten sensitivity showing a positive antigliadin stool test is 5 to 7.5 times higher than would be detected using blood tests. In normal people without specific symptoms or syndromes, the stool test is just under 3 times more likely to be positive than blood (29% vs. 11%, respectively). That's a lot more people reacting to gluten than 1 in 150 who have celiac disease. 29% of the normal population of this country, almost all of whom eat gluten, showing an intestinal immunologic reaction to the most immune-stimulating of dietary proteins really is not so high or far fetched a percentage, especially in light of the fact that 11% of them display this reaction in blood, and 42% carry the HLA-DQ2 or DQ8 celiac genes. Why is this so important? Because some people with microscopic colitis never get better when they're treated, and most autoimmune syndromes only progress with time, requiring harsh and sometimes dangerous immunosuppressive drugs just for disease control. If the immune reaction to gluten is in any way at the cause of these diseases as research suggests, and if we had at our disposal a sensitive test that can diagnose this gluten sensitivity without having to wait for the intestinal villi to be damaged, then treatment with a gluten free diet might allow the affected tissues to return to normal or at least prevent progression. We now have that test in fecal antigliadin antibody. Just a few weeks ago we completed the first follow-up phase of our study: What happens when a gluten sensitive person without villous atrophy goes on a gluten-free diet for one or two years. While I am still gathering and analyzing the data, most of the subjects reported a much improved clinical status (utilizing an objective measure of symptoms and well being). Not everybody gets well, because sadly not everyone stays on a gluten-free diet (as they sometimes admit on the surveys). Some people have the misconception that if they don't have celiac disease, but "I just have gluten sensitivity" then maybe they do not have to be strict with their gluten elimination diet. I do not think that is the case. Although a gluten free diet is like anything: Less gluten is not as damaging as more gluten, but certainly no gluten is optimal if a gluten sensitive person desires optimal health. Of the first 25 people with refractory or relapsing microscopic colitis treated with a gluten-free diet, 19 resolved diarrhea completely, and another five were notably improved. Thus, a gluten-free diet helped these patients with a chronic immune disease of a tissue other than small bowel (in this case the colon), who have been shown to be gluten sensitive by a positive stool test in my lab. The same may be true of patients with chronic autoimmune diseases of any other tissue, but who do not have full-blown celiac disease. Gluten-free dietary treatment, sometimes combined with dairy-free diet as well, has been shown to help diabetes, psoriasis, inflammatory bowel disease, eczema, autism, and others. Thus, my approach (and I believe the most sensitive and most complete approach) for screening for early diagnosis and preventive diagnosis for clinically important gluten sensitivity is a stool test for antigliadin and anti-tissue transglutaminase IgA antibodies (IgG is not detectable in the intestine) and a malabsorption test. The malabsorption test we developed is special, because you no longer have to collect your stool for three days; we can find the same information with just one stool specimen. Stool testing in combination with HLA gene testing, which we do with a cotton-tipped swab rubbed inside the mouth, is the best diagnostic approach available for gluten sensitivity. Who should be screened for gluten sensitivity? Certainly family members of celiacs or gluten sensitive people being at the highest genetic risk. For the most part, all of the following patient groups have been shown to be at higher risk than normal for gluten sensitivity: Chronic diarrhea; microscopic colitis; dermatitis herpetiformis; diabetes mellitus; any autoimmune syndrome (of which there is an almost end-less number like rheumatoid arthritis, multiple sclerosis, lupus, dermatomyositis, psoriasis, thyroiditis, alopecia areata, hepatitis, etc.); Hepatitis C; asthma; chronic liver disease; osteoporosis; iron deficiency anemia; short stature in children; Down's syndrome; female infertility; peripheral neuropathy, seizures, and other neurologic syndromes; depression and other psychiatric syndromes; irritable bowel syndrome; Crohn's Disease; and people with severe gastroesophageal reflux (GERD). Autism and possibly the attention deficit disorders are emerging as syndromes that may improve with a gluten- free (and additionally casein-free) diet. A diagnosed celiac might be interested in our testing to know (after some treatment period no shorter than a year) that there is no on-going damage from malabsorption, for which we have a test. If a celiac is having ongoing symptoms or other problems, a follow-up test should be done just to be sure there's no hidden gluten in the diet, or something else that could be present, like pancreatic enzyme deficiency which often accompanies celiac disease, especially in its early stages of treatment. Historically, with respect to diagnostic methods for celiac disease, from 100 A.D., when celiac disease was first described as an emaciating, incapacitating, intestinal symptom-causing syndrome, to 1950, we had just one diagnostic test: Clinical observation for development of the end stage of the disease. Then in 1940 to 1960, when the discovery of gluten as the cause of celiac disease occurred, the best diagnostic test was removing gluten from the diet and watching for clinical improvement. It was during this period that the 72-hour fecal fat and D-xylose absorption tests were developed as measures of gluten-induced intestinal dysfunction/damage. In the mid- to late1950's, various intestinal biopsy methods were pioneered and utilized, showing total villous atrophy as the diagnostic hallmark of celiac disease. You've heard the intestinal biopsy called the "gold standard"; well as you can see, it is a 50 year-old test, and thus, the "old" standard. It was not until the 1970's and 80's (and improved upon in the 1990's) that blood tests for antigliadin and antiendomysial/anti-tissue transglutaminase were developed, but again these tests like all methods before, can reliably reveal only the "heart attack" equivalent of the intestinal celiac syndrome: Significant villous atrophy or bad celiac disease. We are in a new century, a new millennium, and I have built upon what my research predecessors have started; mostly on the work of researchers who laboriously put down tubes and sucked out intestinal fluid for testing for antigliadin antibody when it was not present in blood. We now know that a stool test for antigliadin antibody is just as good and much simpler. The wide-reaching ramifications of knowing that so many more people and patients are gluten sensitive than have ever been previously known has led me to assume a professional life of medical public service. To do so, I started a 501©3 not-for-profit institute called the Intestinal Health Institute, have brought these new diagnostic tests to the public on the internet (at http://www.enterolab.com), and volunteer my time helping people with health problems by email and by lecturing. With greater awareness and education of both the public and medical community that early diagnosis of gluten sensitivity can be achieved before the villi are gone, more of the gluten sensitive iceberg will be diagnosed and treated early, leading to far fewer gluten-related symptoms and diseases than has ever been experienced before. Dr. Fine has been an intestinal researcher and an academic and clinical gastroenterologist for 15 years. He is the Director of The Intestinal Health Institute and The www.EnteroLab.com Clinical Laboratory in Dallas Texas.
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Celiac.com 06/13/2022 - In 1992 Dr. Michael Marsh developed his "Marsh Classification" system to describe the various stages of microscopic damage to the small intestine (histological changes) seen in those with celiac disease. The original system ranged from 0 - 4, and 3 or higher meant celiac disease, but his system was modified for consistency and reproducibility between pathologists. Today, anyone who has been diagnosed with celiac disease has likely heard about the Marsh classification system. Using the Marsh Classification allows clinicians to accurately measure the full extent of the damage to the villi that line the small intestine, to determine the extent of celiac disease progress and damage. Modified Marsh Classification of histologic findings in celiac disease (Oberhuber) are measured in units of IEL/100 enterocytes, intraepithelial lymphocytes per 100 enterocytes. Current Marsh Classification Marsh Type 0 - Normal; celiac disease highly unlikely. IEL / 100 enterocytes – jejunum <40 IEL / 100 enterocytes - duodenum <30 Normal crypt hyperplasia Normal villi Marsh Type 1 - Seen in patients on gluten free diet (suggesting minimal amounts of gluten or gliadin are being ingested); patients with dermatitis herpetiformis; family members of celiac disease patients, not specific, may be seen in infections. IEL / 100 enterocytes – jejunum >40 IEL / 100 enterocytes - duodenum >30 Normal crypt hyperplasia Normal villi Marsh Type 2 - Very rare, seen occasionally in dermatitis herpetiformis. IEL / 100 enterocytes – jejunum >40 IEL / 100 enterocytes - duodenum >30 Increased crypt hyperplasia Normal villi Marsh Type 3 - Spectrum of changes seen in symptomatic celiac disease. Marsh Type 3a IEL / 100 enterocytes – jejunum >40 IEL / 100 enterocytes - duodenum >30 Increased crypt hyperplasia Mild villous atrophy Marsh Type 3b IEL / 100 enterocytes – jejunum >40 IEL / 100 enterocytes - duodenum >30 Increased crypt hyperplasia Marked villous atrophy Marsh Type 3c IEL / 100 enterocytes – jejunum >40 IEL / 100 enterocytes - duodenum >30 Increased crypt hyperplasia Complete villous atrophy In an effort to simply the Marsh Classification system, the following Simplified Celiac Classification System has been proposed by researchers Corazza, Roberts, and Ensari, which may be much easier and more reproducible. Simplified Celiac Classification System Grade A/Type 1: increased intraepithelial lymphocytes but no villous atrophy. This occurs in those on a gluten-free diet and is likely caused by patients who consume small amounts of gluten due to cross-contamination or in those who cheat on their diets, and in patients with dermatitis herpetiformis, family members of celiacs, and can also be seen in certain infections. Grade B1/Type 2: villi still present but shortened. This level of damage is accompanied by many symptoms associated with celiac disease. Grade B2/Type 3: complete villous atrophy. This level of damage is accompanied by many symptoms associated with celiac disease. To date, there has been no good study data comparing the two systems. Certainly, a simpler, more reproducible Marsh system would make the job of measuring the progress of celiac disease and the gluten-free diet in celiac patients much easier. Stay tuned for more on this and related stories. Read more at stanford.edu.
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Will Other Foods Affect the Villi? - by Kemp Randolph
Scott Adams posted an article in Allergy vs. Intolerance
The following is a March 11, 1998 post by Kemp Randolph krand@PIPELINE.COM. According to Dr. Hugh Sampson, Mt. Sinai Medical Center, at an AMA sponsored press briefing on Nutrition, in a list of Facts vs. Fictions, Fiction: Skin tests or blood tests can be used to diagnose food sensitivities. Fact: ...A positive test does not mean a person will react to a food...furthermore these tests do not tell whether a person has a non-IgE mediated sensitivity to food. He describes these tests only as useful guides and points out that diet testing is the only reliable way to identify a food allergy, preferably where the person does not know whether they have eaten the suspect food. Q: If I am sensitive to milk and eggs...could they damage my villi in the same way as gluten? A: Theres a specific note in Michael Marshs book about food allergies causing villi damage. Thats the book On Coeliac Disease, page 155. Table there shows that the Type 3 stage of intestinal response, flat destructive does occur with milk, egg, soy and chicken or fish allergies. It differs from the celiac response in that only 1 or 3 of the 5 stages of lesion connected with celiac disease occur with an allergy. Whats unclear from this reference and from Medline searches Ive made is whether food allergies in adults cause villi damage. All the references I found were for children. Villi destruction does occur in children with milk allergy, but this like other pediatric allergies, apparently is usually outgrown. -
The following abstract was submitted to celiac.com directly by William Dickey, Ph.D., a leading celiac disease researcher and gastroenterologist who practices at Altnagelvin Hospital, Londonderry, Northern Ireland. Scandinavian Journal of Gastroenterology 2005; 40: 1240-3. Dickey W, Hughes DF, McMillan SA. Celiac.com 09/27/2005 - What does a positive endomysial antibody (EmA) test mean if the biopsy does not show villous atrophy? The authors studied 35 patients where this was the case. In the authors practice, these patients account for 10% of all EmA positives. Firstly, the lack of villous atrophy did not necessarily mean a normal biopsy: 14 patients had excess inflammatory cells (lymphocytes) consistent with a mild abnormality of gluten sensitivity. Secondly, many of these patients had typical celiac features: twelve had a family history of celiac, five had dermatitis herpetiformis and thirteen had osteopenia or osteoporosis on DEXA scan. After discussion, 27 patients opted to take a gluten-free diet from the first biopsy: 26 of these had clinical improvement. Seven of eight patients who persisted with a normal diet developed villous atrophy on follow-up biopsies. The authors conclude that a positive EmA result indicates gluten sensitivity even if biopsies do not show villous atrophy. While a biopsy remains important as a baseline reference, these patients should be offered a gluten-free diet to allow clinical improvement and prevent the development of villous atrophy. There may be no such thing as a "false positive" EmA, although the authors emphasise that the same conclusion cannot yet be applied to tissue transglutaminase antibody results.
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Flattened Villi is Not Always Caused by Celiac Disease
Scott Adams posted an article in Latest Research
Am J Clin Pathol. 2004 Apr;121(4):546-50 Celiac.com 04/20/2004 – According to researchers at the Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI, the cause of flattened villi is not always celiac disease. The researchers studied seven patients who experienced several weeks of gluten-sensitivity and the same type of villi injury—"increased lymphoplasmacytic lamina propria inflammation, moderate to complete villous flattening, numerous crypt mitoses, and markedly increased villous intraepithelial lymphocytes (IELs)." All patients were diagnosed with gluten sensitivity, and all returned 9 to 38 weeks later questioning their diagnosis, as their symptoms had substantially or completely disappeared, and clinical improvement in these patients seemed unrelated to their ingestion of gluten. A follow up endoscopy and colonoscopy was performed on these patients 4 to 16 months later, and the results of each showed a normal mucosa. According to the researchers: "Diseases other than GS can cause marked villous flattening and increased villous IELs in adults. The cause of small bowel mucosal injury is unknown. A similar non-GS-associated clinicopathologic complex, assumed to be due to a protracted viral enteritis or slow regression of a virus-induced immune reaction, occurs in children. The temporal aspects of symptom improvement and mucosal restitution in these 7 patients are similar to acute self-limited colitis. An overly exuberant immune response to an infectious agent is possible." -
The following is a list of causes of flattened villi which was published in a book titled Coeliac Disease by W. T. Cooke and G. K. Holmes, published by Churchill Livingstone, Medical Division of Longman Group Limited (1984). Celiacs on a gluten-free diet (for a prolonged period) who continue to have flatten villi may be want to look for other causes to their problem. Keep in mind that some of the items listed rarely cause flatened villi, and are usually found in conjunction with Celiac Disease or immuno-deficiencies. Coeliac Disease Cows Milk Protein Intolerance Soy Protein Intolerance Refractory Sprue Collagenous Sprue Immunodefiency Synodromes Mediterranean Lymphoma Intestinal Ulceration Gastroenteritis Intractable Diarrhoea of Infancy Protein Calorie Malnutrition Kwashiorkor Tropical Sprue Parasitic Disease: Giardiasis Strongyloidiasis Coccidiosis Intestinal Capillariasis Hookworm Disease Eosinophilic Gastroenteritis Contaminated Bowel Syndrome Drug and Radiation Damage
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