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Celiac.com 10/26/2017 - Making an accurate count of intraepithelial lymphocytes (IEL) is important to making an accurate diagnosis of celiac disease, but so far, researchers have not been able to establish a definitive 'normal' IEL range. In a recent multi-center study, a team of researchers set out to do just that. The research team included Kamran Rostami, Michael N Marsh, Matt W Johnson, Hamid Mohaghegh, Calvin Heal, Geoffrey Holmes, Arzu Ensari, David Aldulaimi, Brigitte Bancel, Gabrio Bassotti, Adrian Bateman, Gabriel Becheanu, Anna Bozzola, Antonio Carroccio, Carlo Catassi, Carolina Ciacci, Alexandra Ciobanu, Mihai Danciu, Mohammad H Derakhshan, Luca Elli, Stefano Ferrero, Michelangelo Fiorentino, Marilena Fiorino, Azita Ganji, Kamran Ghaffarzadehgan, James J Going, Sauid Ishaq, Alessandra Mandolesi, Sherly Mathews, Roxana Maxim, Chris J Mulde, Andra Neefjes-Borst, Marie Robert, Ilaria Russo, Mohammad Rostami-Nejad, Angelo Sidoni, Masoud Sotoudeh, Vincenzo Villanacci, Umberto Volta, Mohammad R Zali, Amitabh Srivastava. They are variously affiliated with the twenty-eight institutions listed below. The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centers in eight countries on three continents, recruited 198 patients with Marsh III histology, and another 203 control subjects. They used a single agreed upon protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. They also collected demographic and serological data. The research team used receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off between normal and celiac disease (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. The average ages of celiac and control groups were 45.5 and 38.3 years, respectively. They found that mean IEL count was 54±18/100 enterocytes in celiac disease and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the sub-classification of the Marsh III lesion. Their ROC curve analyses show that a cut-off of 25 IEL/100 enterocytes for Marsh III lesions provides the best way to distinguish between normal control and celiac disease biopsies. They saw no differences in IEL counts between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental gluten antigenic influence. Source: GUT Affiliations: The team members for this study are affiliated with the Department of Gastroenterology and Pathology, Milton Keynes University Hospital, Milton Keynes, UK; the Department of Gastroenterology, Luton and Dunstable University Hospital, Luton, UK; the Wolfson College, University of Oxford, Oxford, UK; the Gastroenterology and Liver Diseases Research Centre, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, The Islamic Republic of Iran; the Centre for Biostatistics, Faculty of Biology, Academic Health Science Centre, University of Manchester, Manchester, UK; the Department of Gastroenterology, Royal Derby Hospital, Derby, UK; the Department of Pathology, Ankara University Medical School, Ankara, Turkey; the Department of Gastroenterology, Warwick Hospital, Warwick, UK; the Service de Pathologie, Centre de Biologie et Pathologie Groupe Hospitalier du Nord, Hospices Civils de Lyon, Lyon, France; University of Perugia Medical School, Perugia, Italy; the Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Department of Pathology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Institute of Pathology Spedali Civili, Brescia, Italy; Internal Medicine and Pathology Unit, University of Palermo, Giovanni Paolo II Hospital, Sciacca, Italy; Department of Pediatrics and Surgical Pathology, Università Politecnica delle Marche, Ancona, Italy; Department of Medicine and Surgery, Scuola Medica Salernitana, University of Salerno, Salerno, Italy; Departments of Gastroenterology and Pathology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania; College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran; Center for Prevention and Diagnosis of Coeliac Disease and Pathology Unit, Fondazione IRCCS Ca' granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Medical and Surgical Sciences, University of Bologna and Diagnostic and Experimental, University of Bologna, Bologna, Italy; Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University 0f Medical Sciences, Mashhad, Iran; Pathology department, Razavi hospital, Mashhad, Iran; Department of Pathology, Southern General Hospital, Lanarkshire, UK; Department of Hepatogastroenterology and Pathology, Free University Medical Centre, Amsterdam, The Netherlands; Department of Pathology and Medicine, Yale University School of Medicine, New Haven, USA; Digestive Disease Research Center, Tehran University Medical Science, Tehran, Iran; Department of Pathology, Brigham & Women's Hospital, Boston, USA.
Celiac.com 11/10/2016 - Seronegative villous atrophy (SNVA) is commonly attributed to celiac disease. However, celiac is not the sole cause of SNVA. Recent reports have pointed to a connection with angiotensin-2-receptor-blockers (A2RBs), but data on such cases of SNVA was limited to centers dealing with complex case referrals, and not SNVA in general. A team of researchers recently completed a clinical and phenotypical assessment of SNVA over a 15-year period. The research team included I Aziz, MF Peerally, JH Barnes, V Kandasamy, JC Whiteley, D Partridge, P Vergani, SS Cross, PH Green, DS Sanders. They are variously affiliated with the Academic Department of Gastroenterology, the Department of Microbiology, the Department of Histopathology at the Royal Hallamshire Hospital in Sheffield, UK, and with the Department of Medicine, Columbia University College of Physicians and Surgeons, Celiac Disease Center, New York, New York, USA. Over a 15-year period (2000-2015) the team assessed 200 adult patients with SNVA. Patients were diagnosed with either seronegative celiac disease (SNCD) or seronegative non-celiac disease (SN-non-celiac disease). The team then made baseline comparisons between the groups, with 343 seropositive celiac disease patients serving as controls. Of the 200 SNVA cases, SNCD represented 31% (n=62) and SN-non-celiac disease 69% (n=138). The human leucocyte antigen (HLA)-DQ2 and/or DQ8 genotype was present in 61%, with a 51% positive predictive value for SNCD. The breakdown of identifiable causes in the SN-non-celiac disease group comprised infections (27%), inflammatory/immune-mediated disorders (17.5%) and drugs (6.5%; two cases related to A2RBs). However, the researchers found no obvious cause in 18%, while duodenal histology spontaneously normalized in 72% of SNVA patients, while those patients were consuming a gluten-enriched diet. Following multivariable logistic regression analysis, the only independent factor associated with SN-non-celiac disease was non-white ethnicity (OR 10.8, 95% CI 2.2 to 52.8); in fact, 66% of non-white patients showed GI infections. On immuno-histochemistry all groups stained positive for CD8-T-cytotoxic intraepithelial lymphocytes. However, additional CD4-T helper intraepithelial lymphocytes were occasionally seen in SN-non-celiac disease mimicking the changes associated with refractory celiac disease. Most patients with SNVA, especially non-white patients, do not have celiac disease. Furthermore, a subgroup of patients with no obvious cause for their SNVA will show spontaneous histological resolution while consuming gluten. Based on these findings, the researchers encourage doctors to investigate patient condition before prescribing a gluten-free diet. Source: Gut. 2016 Sep 7. pii: gutjnl-2016-312271. doi: 10.1136/gutjnl-2016-312271.
Dr. Peter Green is a gastroenterologist and the director of the GI Endoscopy Unit at Columbia-Presbyterian Medical Center in New York City. He has a large celiac patient base. On September 29th, Dr. Green spoke to the Westchester Celiac Sprue Support Group and presented an excellent review of the medical care an adult Celiac patient should receive. What follows is a summary of Dr. Greens presentation, compiled by Sue Goldstein, a past president of the Westchester group. Initial Assessment Dr. Green sees a lot of patients who, either through their own frustration or because of physician advice, have started a gluten-free (gluten-free) diet without obtaining a biopsy-proven diagnosis of celiac disease (celiac disease). However, the need for a biopsy to establish a diagnosis of celiac disease must be emphasized. celiac disease is a lifelong illness with serious potential implications. In addition, sensitivity to gluten doesnt go away, and a radical lifestyle change is involved. You also need to be certain of the diagnosis because celiac patients families should be screened. The initial biopsy is also needed to serve as a baseline because one doesnt know what the future may involve. Basic blood work is also included in the initial assessment. Such things as anemia and liver function need to be looked for. But its very important to go further than that, and knowledge of the physiology of the small intestine should lead a physician to measure those nutrients that could be malabsorbed. celiac disease involves the small intestine, where iron, folic acid, calcium, fat soluble vitamins (K, A, D, and E) and zinc are absorbed. These nutrients should be measured in the initial assessment and also during the course of the illness. Physicians will see patients who present with malabsorption of just one of these nutrients. If they are aware of the consequences of all these nutrient deficiencies, it will help them consider celiac disease as a possible diagnosis. The patient should also have the celiac antibodies blood testing, but the diagnosis is still established on the biopsy pathology. In Dr. Greens experience, about 30% of celiacs have negative antibodies at diagnosis, so positive antibodies are not required to make the diagnosis. Antibodies testing often helps establish the need for a biopsy, but they also have great value in establishing a baseline so that an assessment can be made on how the patient is doing later on. All the antibodies should normalize, in time, when gluten is eliminated from the diet. What about the patient who seeks a diagnosis, but has already eliminated gluten from the diet? It is very difficult for many patients to go back on a gluten-containing diet to secure a biopsy-proven diagnosis. This can often take three to six months or longer. Columbia-Presbyterian has been talking about setting up alternative means of securing a diagnosis, such as a rectal challenge. The physician can take a biopsy of rectal tissue, and then instill gliadin extract into the rectum and do a repeat biopsy a certain number of hours afterward to demonstrate an inflammatory response similar to that in the small bowel. However, interpreting the results of the gluten challenge would require a pathologist who is very experienced, and sophisticated immunology on the cells of the rectal biopsy may be needed. Follow-up Care Soon after diagnosis and adhering to a gluten-free diet, patients will often report an increased feeling of well-being. How well they feel--and how quickly--will also depend on what the manifestations of their disease were. For example, if the patient was iron-deficient, it will take time for the iron stores to be restored. An assessment of vitamin and mineral levels should be part of the follow-up care. Specific deficiencies need to be addressed, treated, and monitored. Patients have been seen who have been ingesting too much of the fat-soluble vitamins, with resulting problems such as liver disease (from vitamin A toxicity), and hypercalcemia (from vitamin D toxicity) which can cause confusion, constipation, and kidney problems. Certain vitamins and minerals may need to be administered, but the patient should be under a physicians guidance as to how much should be taken. After a diagnosis of celiac disease, a bone mineral density test should be performed to assess the condition of the bones. Reports have shown that between 50-100% of people at initial diagnosis of celiac disease will have osteopenia or osteoporosis. Ostopenia is thinner bones, usually less than 2 standard deviations from normal. Osteoporosis involves an even greater deviation from normal.. In Dr. Greens experience, nearly 100% of the celiac patients at diagnosis will have osteoporosis. Surveys of celiac patients have shown an increased incidence of fractures prior to diagnosis and after diagnosis. If the bone mineral density is low, the patient should be referred to a bone mineral expert for assessment and specific individual treatment. For example, calcium and vitamin D needs will be addressed and monitored, and exercise and hormone replacement (in post-menopausal women) will be considered. At diagnosis, patients should get a Pneumovax, because it is very common for celiacs to have poor splenic function, which puts them at risk of developing certain bacterial infections such as pneumoccal pneumonia and meningitis. Since there is a genetic predisposition to celiac disease, another important issue in the follow-up is screening family members for celiac disease. Children and other first-degree relatives should have their antibodies status measured. About 10-15% of first-degree relatives have positive antibodies, and the bulk of the people with positive antibodies will have the disease, even though 50% of those people will be asymptomatic, even with a flat biopsy. What annual follow-up care should the celiac patient be getting? The most important thing is a good physical examination. Blood work, x-rays, CAT scans, mammograms and PSA tests, while valuable, do not replace a physical examination. The physical exam should include a breast exam for women, prostate exam for men, and a rectal exam for everyone. Blood work should include measurements of folic acid, calcium, and iron, and antibodies testing. Bone mineral density testing should be repeated annually for those with abnormal results, and every several years for those with normal results. Finally, patients with celiac disease should have at least one follow-up biopsy to confirm response--normalization of the biopsy sample. Patients who are non-responders, or whose clinical situation is somewhat confusing, may need more repeated biopsies at intervals. Non-responders What about the non-responders or people who relapse? The first thing is to check the diet with antibodies testing. People may be ingesting gluten, such as in medications, and not be aware of it. They may be getting gluten from licking stamps or envelopes. They may have misinformation from food labels or manufacturers. However, the antibodies can normalize and the biopsy still look quite flat, so once again, the antibodies have only a limited value--but they are still important to measure. It is also important to check the original biopsy to make sure of the diagnosis. Not all pathologists are experienced enough to properly diagnose celiac disease. Pathology departments, by law, have to keep the biopsies for a lengthy period of time--some keep them for 50 years. So it is important for the physician to review the biopsy sample with a pathologist who understands the spectrum of celiac disease. The pathologist needs to know, for example, how to identify latent celiac disease and different subtle aspects of the biopsy, such as increased intraepithelial lymphocytes. A problem that comes up in non-responders is other food sensitivities. Its very rare for people with celiac disease to also have sensitivities to other foods that result in the abnormal biopsy. There are, however, reports of ingestion of soy protein or egg or some kind of meats that cause the biopsy not to normalize. There are other conditions that can co-exist with celiac disease and confuse physicians. For example, pancreatic insufficiency can cause diarrhea and steatorrhea (malabsorption of fat), and bacterial overgrowth can affect absorption of nutrients. Patients may have colonic pathology. Having one disease doesnt mean you cant have another disease, and other conditions need to be investigated in the celiac disease patient who is not doing well. When there is no improvement in the biopsies, patients remain at the risk of developing or maintaining bone disease and vitamin deficiencies, and they are at a higher risk for malignancy. Patients who are refractory may need other therapies such as corticosteroids or immunosuppressent drugs such as cyclosporin. One doesnt engage in these therapies lightly (for example, steroids will thin the bones); being closely evaluated while on these drugs is important. Prognosis for the Celiac Patient The studies that have indicated increased mortality in celiac disease are from other countries where people have different smoking and dietary habits. It is hard to extrapolate these studies to our patient population. Dr. Green believes existing studies indicate that the mortality rate among adult celiacs is about two to three times that of the general population, and the increased mortality is found mainly in the first five years after diagnosis. After that, the mortality rate approaches that of the normal population. That tends to suggest that it is the continued ingestion of gluten that is responsible for the increased mortality. This is especially so in regard to malignancies, where the risk of diagnosis of malignancy such as lymphoma is usually highest in the first year after diagnosis, and then decreases in incidence downward until it equals that of the normal population after about five years. There is certainly the suggestion that adhering to a gluten-free diet reduces the risk of developing a malignancy. A Final Word--Looking For Celiac Disease Traditionally, the incidence of celiac disease in this country, based upon epidemiological work, suggests that celiac disease occurs in about 1 in 4,600 people. Certainly its much more common than that. Serology testing of blood donors by Dr. Fasano suggests the same prevalence as in European countries, about 1 in 300 people. Dr. Green, who does a lot of endoscopies, has found an incidence of celiac disease in about 1 in 280 patients who were having endoscopies for reasons other than suspicion of celiac disease. It is important, therefore, for the gastroenterologist to have a higher suspicion for the possibility of celiac disease, and for physicians to screen for celiac disease, particularly among their patients who have associated diseases such as Insulin Dependent Diabetes, Sjogrens, and Autoimmune Thyroid Disease.
Celiac.com 12/28/2009 - A team of researchers recently set out to compare continual monitoring of intraepithelial lymphocyte immunophenotype and clonality against snapshot analysis in the surveillance of refractory celiac disease. The research team was made up of H. Liu, R. Brais, A. Lavergne-Slove, Q. Jeng, K. Payne K, H. Ye, Z. Liu, J. Carreras, Y. Huang, C. M. Bacon, R. Hamoudi, V. Save, L. Venkatraman, P. G. Isaacson, J. Woodward, and M. Q. Du of Addenbrooke's Hospital, Cambridge, UK. Often, people with refractory celiac disease suffer from abnormal immunophenotype and monoclonality of intraepithelial lymphocytes (IELs). No good studies have been done to compare the utility of continual monitoring of IEL immunophenotype and clonality in monitoring refractory celiac disease (RCD). To address this deficiency, and to gather some data for comparison, the team used CD3e/CD8 double immunohistochemistry and PCR-based clonality analysis of the rearranged TCR genes to evaluate diagnostic and follow-up biopsies from 33 people with proven celiac disease, 7 with suspected refractory celiac disease, 41 with proven refractory celiac disease, and 20 with enteropathy associated T-cell lymphoma (including 11 evolved from RCD). The team found aberrant immunophenotype (CD3epsilon(+)CD8(-) IEL >/=40%) and monoclonality in occasional celiac disease biopsies, either transiently in celiac patients not following a gluten free diet, or in those who later developed refractory celiac disease, suspected RCD, or enteropathy associated T-cell lymphoma (EATL). By comparison, they found aberrant immunophenotype and monoclonality respectively in 30 of 41 (73%) and 24 of 37 (65%) biopsies at the time of diagnosis for refractory celiac disease. Among the patients with refractory celiac disease showed no such abnormalities in their diagnostic biopsies, 8 of 10 (80%) and 5 of 11 (45%) cases showed aberrant immunophenotype and monoclonality respectively upon follow-up. Whether found in initial or follow-up biopsies, the ongoing development of both aberrant immunophenotype and monoclonality is a common facet of refractory celiac disease. One key point was that the presence of both persistent monoclonality and aberrant immunophenotype, especially <>/=>80% CD3epsilon(+)CD8(-) IEL, was a strong predictor of enteropathy associated T-cell lymphoma development in patients with RCD (P=0.001). From these findings, the team found concludes that the continual monitoring of both immunophenotype and clonality of IEL is superior to snapshot analysis for diagnosis and follow-up of refractory celiac disease, and could provide a useful tool for surveillance of patients at risk of developing EATL. Source: Gut. 2009 Dec 8.