Peter H. Green

The Oslo definitions for coeliac disease and related terms

Objective The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten. Design A multidisciplinary task force of 16 physicians from seven countries used the electronic database PubMed to review the literature for CD-related terms up to January 2011. Teams of physicians then suggested a definition for each term, followed by feedback of these definitions through a web survey on definitions, discussions during a meeting in Oslo and phone conferences. In addition to ‘CD’, the following descriptors of CD were evaluated (in alphabetical order): asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity and gliadin-specific antibodies. Results CD was defined as ‘a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals’. Classical CD was defined as ‘CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.’ ‘Gluten-related disorders’ is the suggested umbrella term for all diseases triggered by gluten and the term gluten intolerance should not to be used. Other definitions are presented in the paper. Conclusion This paper presents the Oslo definitions for CD-related terms.

Human Apolipoprotein A-IV: INTESTINAL ORIGIN AND DISTRIBUTION IN PLASMA

The role of the human intestine has been explored as a site of synthesis of apoA-IV, a major apoprotein of human intestinal triglyceride-rich lipoproteins. Intestinal biopsies were performed on normal volunteers while fasting and after lipid ingestion. Indirect immunofluorescence demonstrated a marked increase in immunofluorescence for apoA-IV during lipid absorption consistent with an increased intracellular content. ApoA-IV comprised 10-13% of chylomicron apoprotein and 24-30% of intestinal very low density lipoprotein (VLDL) as assessed by densitometry of sodium dodecyl sulfate gels of lipoproteins from chylous urine (mesenteric lymphatic-urinary fistula) and thoracic duct lymph (postoperative fistula). After one subject with chyluria ingested 40 g of corn oil, triglyceride excretion in urine was accompanied by an increased excretion of apoA-IV. 11.5 g of triglyceride and 81 mg of apoA-IV were recovered in the urine. In chylous urine 56% of apoA-IV was in the triglyceride-rich lipoproteins (chylomicrons and intestinal VLDL) and 44% in the d > 1.006-g/ml fraction. Normal plasma apoA-IV was 15.7+/-0.9 mg/dl (n = 14) whereas four subjects with abetalipoproteinemia had reduced levels 1.2, 7.6, 9.6, and 8.3 mg/dl, respectively. Lipid feeding in normal volunteers resulted in a rise in plasma apoA-IV (16.1+/-0.7 mg/dl to 18.5+/-0.7 mg/dl, n = 5, P < 0.01). In fasting plasma, 98% of apoA-IV was in the d > 1.21-g/ml fraction. In lipemic plasma, 10% of apoA-IV was associated with triglyceride-rich lipoproteins and 90% with the d > 1.21-g/ml fraction. Agarose column chromatography of fasting plasma confirmed that the bulk of plasma apoA-IV is free, unassociated with lipoproteins. These results demonstrate that apoA-IV is present in human intestinal epithelial cells and is secreted as a chylomicron and VLDL apoprotein. Within fasting plasma most of the apoA-IV is found free, unassociated with lipoproteins. After lipid ingestion apoA-IV is also found in plasma chylomicrons indicating that some apoA-IV remains associated with chylomicrons in plasma during chylomicron metabolism, although some may be transferred from the chylomicron surface.

Spectrum of gluten-related disorders: consensus on new nomenclature and classification

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching

Characteristics of adult celiac disease in the USA: results of a national survey

2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications.

Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology

OBJECTIVE:The clinical spectrum of adults with celiac disease in the United States, where the disease is considered rare, is not known. We sought this information by distributing a survey.METHODS:A questionnaire was distributed by way of a celiac newsletter, directly to celiac support groups, and through the Internet.RESULTS:Respondents (1612) were from all United States except one. Seventy-five percent (1138) were biopsy proven. Women predominated (2.9:1). The majority of respondents were diagnosed in their fourth to sixth decades. Symptoms were present a mean of 11 yr before diagnosis. Diarrhea was present in 85%. Diagnosis was considered prompt by only 52% and 31% had consulted two or more gastroenterologists. Improved quality of life after diagnosis was reported by 77%. Those diagnosed at age ≥60 yr also reported improved quality of life. Five respondents had small intestinal malignancies (carcinoma 2, lymphoma 3) accounting for a relative risk of 300 (60–876) for the development of lymphoma and 67 (7–240) for adenocarcinoma.CONCLUSIONS:Patients with celiac disease in the United States have a long duration of symptoms and consider their diagnosis delayed. Improved quality of life after diagnosis is common. An increased risk of developing small intestine malignancies is present.

Risk of malignancy in patients with celiac disease

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders

PURPOSE Studies from Europe have demonstrated an increased risk of malignancy, especially non-Hodgkins lymphoma, in patients with celiac disease. However, there are no data on the risk for similar patients in the United States. Our aim was to estimate the risk of malignancy in a cohort of patients with celiac disease compared with the general U.S. population and to determine if a gluten-free diet is protective. METHODS Patients with celiac disease seen between July 1981 and January 2000 at a referral center were included. Standardized morbidity ratios (SMRs) (ratio of observed to expected) and corresponding 95% confidence intervals (CI) were calculated, using data from the National Cancer Institutes Surveillance, Epidemiology, and End Results Program. RESULTS Forty-three (11%) of 381 celiac disease patients had a diagnosis of cancer; 9 were after the diagnosis of celiac disease, 7 were simultaneous (during same month or admission), and 27 were before the diagnosis. The standardized morbidity ratio for all cancers combined was 1.5 (95% CI: 0.3 to 7.5), with significantly increased values for small bowel cancer (SMR = 34; 95% CI: 24 to 42), esophageal cancer (SMR = 12; 95% CI: 6.5 to 21), non-Hodgkins lymphoma (SMR = 9.1; 95% CI: 4.7 to 13), and melanoma (SMR = 5.0; 95% CI: 2.1 to 12). Following the diagnosis of celiac disease, patients were at increased risk of non-Hodgkins lymphoma only (SMR = 6.2; 95% CI: 2.9 to 14), despite adherence to a gluten-free diet. The non-Hodgkins lymphoma included both T-cell and B-cell types and occurred in both gastrointestinal (n = 5) and extraintestinal sites (n = 4). CONCLUSION In this cohort of patients with celiac disease, we observed increased risks of small intestinal adenocarcinoma, esophageal cancer, melanoma, and non-Hodgkins lymphoma. The risk of non-Hodgkins lymphoma persisted despite a gluten-free diet.

Narrative review : Celiac disease: understanding a complex autoimmune disorder

Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.

Human Intestinal Lipoproteins: STUDIES IN CHYLURIC SUBJECTS

Once considered a rare childhood disorder, celiac disease is now known to be a common condition that may have multiple complications. Nevertheless, the disease remains widely underrecognized. Use of new serologic markers in the diagnosis of celiac disease, in particular antitransglutaminase antibody, has resulted in more efficient screening. Information on the pathogenic mechanism of the autoimmune response in celiac disease is emerging, although many aspects remain unclear. We discuss current concepts in the clinical presentation and diagnosis of celiac disease; the usefulness of serologic markers, including the sensitivity and specificity of available tests; the pathogenesis of the disease; and the association of celiac disease with other disorders. Celiac disease is one of the most common immune-mediated disorders. Its presence has been documented in North and South America, Europe, north Africa, south and west Asia, and Australia (1, 2). Large studies in the United States and Europe show the prevalence of the disease to approach 1% (3-6). Celiac disease is triggered by ingestion of wheat gluten and related cereal proteins, particularly those in rye and barley. These molecules induce an inflammatory response in the small intestine, resulting in villous atrophy, crypt hyperplasia, and lymphocytic infiltration (2). Elimination of gluten and related proteins from the diet leads to clinical and histologic improvement. A strong genetic susceptibility is demonstrated by a 75% concordance rate among monozygotic twins (7). This relationship is due in part to close genetic linkage to specific class II human leukocyte antigens (HLA). Human leukocyte antigen-DQ2 is expressed in about 95% of patients with celiac disease, and HLA-DQ8 is found in most of the remainder (2). The DQ2 and DQ8 molecules confer susceptibility to celiac disease by presenting specific gluten peptides to T cells of the immune system in the intestine (8-10). Celiac disease is also strongly associated with the presence of antibodies against gluten proteins and of autoantibodies to connective tissue components, the main target of which is transglutaminase 2 (also known as tissue transglutaminase). Clinical Presentation The clinical presentation of celiac disease varies greatly and ranges from asymptomatic to severe malnutrition. The most common manifestations of celiac disease include abdominal pain, increased frequency of bowel movements, weight loss, bone disease, anemia, and weakness. Celiac disease is sometimes divided into clinical subtypes. The terms symptomatic or classic apply to cases that meet the classic features of celiac disease, which include chronic diarrhea, abdominal distention and pain, weakness, and sometimes malabsorption. In contrast, in the now-common atypical form of the disease, gastrointestinal symptoms may be absent or less pronounced; instead, extraintestinal features, such as anemia, osteoporosis, short stature, infertility, and neurologic problems, are more prominent (11-41) (Table 1). Patients with asymptomatic or silent celiac disease lack classic or atypical symptoms but have villous atrophy that may be discovered during endoscopy or intestinal biopsy for other reasons, or as a result of serologic screening. Because atypical presentations are increasingly found to predominate, celiac disease is now considered to resemble a multisystem disorder rather than a mainly gastrointestinal one (42, 43). Table 1. Disorders Associated with Celiac Disease Diagnosis and Management Current diagnostic criteria for celiac disease in clinical practice are based on revised guidelines proposed by the European Society for Paediatric Gastroenterology and Nutrition, which have been extrapolated to adults (44). According to these guidelines, celiac disease is present if histologic changes are found on intestinal biopsy while the patient consumes a gluten-containing diet and unequivocal clinical improvement occurs while he or she consumes a gluten-free diet. Figure 1 shows a possible algorithm for diagnosing celiac disease that is based on the European Society for Paediatric Gastroenterology and Nutrition criteria (44) and on recommendations from the National Institutes of Health Consensus Development Conference on Celiac Disease (45). Patients usually undergo tests for serologic markers once celiac disease is suspected, either because characteristic symptoms are present or because they are in an at-risk group, such as having disorders associated with celiac disease (Table 1) or being a first-degree relative of a person with the disease. Measurement of antitransglutaminase 2 (or antiendomysial) antibodies of the IgA isotype is more sensitive and specific for celiac disease than is the IgG isotype and is recommended for initial screening. However, IgA deficiency occurs in 1.7% to 2.6% of patients with celiac disease, which is a 10- to 16-fold increase over that in the general population (35). It is therefore helpful to also measure total IgA. If IgA deficiency is found, measurement of IgG class antitransglutaminase 2 (or antiendomysial) and antigliadin antibodies is recommended. Figure 1. Proposed algorithm for evaluation of patients in whom celiac disease is suspected. If results of testing for IgA antitransglutaminase 2 or antiendomysial antibodies is positive, if IgA deficiency is found and results of testing for IgG antibody (antitransglutaminase 2, antiendomysial, or antigliadin antibodies) is positive, or if results of serologic testing are negative but clinical suspicion is high, intestinal biopsy should be performed (Figure 1). Because the disease may be patchy, as seen on chromoendoscopy and magnification endoscopy (46, 47), an adequate number of tissue samples (4 to 6 pieces) must be obtained (48, 49). Such sampling will further ensure that some sections will be oriented correctly to determine the degree of villous atrophy needed to make the diagnosis, whereas other pieces allow assessment of intraepithelial lymphocytosis, epithelial disarray, and degree of inflammation. Biopsy samples obtained with standard-size forceps from the descending duodenum at the level of the ampulla of Vater are sufficient for diagnosis (50). Interest is increasing in video capsule endoscopy for assessment of small-intestinal diseases, although use of this technique in patients with celiac disease has not been studied. Characteristic histologic features of celiac disease include varying degrees of villous atrophy, with hyperplasia of the crypts and increased intraepithelial lymphocyte count. The criteria proposed by Marsh are often used to grade the disease (from 0 to 4) in terms of these features (51). Most symptomatic patients have partial, subtotal, or total villous atrophy, which are Marsh type 3 lesions. Positive identification of these abnormalities leads to a presumptive diagnosis of celiac disease and institution of a gluten-free diet. Clear clinical improvement while the patient is following the diet yields a definitive diagnosis. The serum antibodies generally disappear by 6 to 12 months, although they are not necessarily reliable indicators of the mucosal response (52, 53). When patients do not present with the classic clinical symptoms of celiac disease, a second biopsy that shows histologic improvement confirms the diagnosis. Gluten challenge is not considered necessary for diagnosis, except in patients for whom no initial diagnostic biopsy was done or results of biopsy are unclear or uncharacteristic of celiac disease. In such cases, biopsy is repeated after clinical relapse subsequent to gluten challenge, or after 3 to 6 months if gluten challenge does not lead to symptoms (44). Patients should be told that they may have a severe reaction to the gluten challenge. Of note, diagnosis of celiac disease based solely on serologic markers is not yet accepted, and identification of the characteristic mucosal abnormalities on intestinal biopsy is required. However, intestinal biopsy can also yield false-negative results, either because the intestinal damage is patchy or because mucosal changes are not detectable on light microscopy (2, 54). If results of biopsy are negative but serologic tests are positive and celiac disease is strongly suspected, the results of the biopsy should be reviewed with an expert gastrointestinal pathologist before additional biopsy is considered. In addition, if histologic examination yields equivocal results, it is useful to proceed with HLA typing. Although about 30% of the general population has the HLA-DQ2 or HLA-DQ8 markers, nearly all patients with celiac disease have them (55). Therefore, a negative result for both markers has an excellent negative predictive value for the disease (56). Table 2 summarizes issues that clinicians often face in diagnosing celiac disease and ways to manage them. Table 2. Common Pitfalls in Diagnosis of Celiac Disease The mainstay of treatment of celiac disease is strict lifelong adherence to a gluten-free diet, in which the patient avoids food products containing wheat, rye, or barley. Even though various studies have found oat to be generally well tolerated (57), some patients appear to be sensitive to it, and the presence of oat-specific intestinal T cells has been demonstrated in persons with celiac disease (58). More important, concern about contamination from the above-mentioned cereals in commercial preparations of oat has led to reluctance in recommending it (57, 59). Commonly substituted grains in the gluten-free diet include rice, corn, quinoa, and buckwheat. Although use of a gluten-free diet safely and effectively manages celiac disease, adherence is not a trivial task in an age in which wheat flour is nearly ubiquitous in foods. Patients whose disease does not respond to dietary therapy should undergo a systematic evaluation (60, 61). The 2 most important points to clarify are whether the patient actually has the disease and whether the patient is truly consuming a gluten

Reprogramming of CTLs into natural killer-like cells in celiac disease

To explore the role of the human intestine as a source of apolipoproteins, we have studied intestinal lipoproteins and apoprotein secretion in two subjects with chyluria (mesenteric lymphatic-urinary fistulae). After oral corn oil, apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) output in urine increased in parallel to urinary triglyceride. One subject, on two occasions, after 40 g of corn oil, excreted 8.4 and 8.6 g of triglyceride together with 196 and 199 mg apoA-I and on one occasion, 56 mg apoA-II. The other subject, after 40 g corn oil, excreted 0.3 g triglyceride and 17.5 mg apoA-I, and, after 100 g of corn oil, excreted 44.8 mg apoA-I and 5.8 mg apoA-II. 14.5+/-2.1% of apoA-I and 17.7+/-4.3% of apoA-II in chylous urine was in the d < 1.006 fraction (chylomicrons and very low density lipoprotein). Calculations based on the amount of apoA-I and apoA-II excreted on triglyceride-rich lipoproteins revealed that for these lipid loads, intestinal secretion could account for 50 and 33% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Similarly, subject 2 excreted 48-70% and 14% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Chylous urine contained chylomicrons, very low density lipoproteins and high density lipoproteins, all of which contained apoA-I. Chylomicrons and very low density lipoproteins contained a previously unreported human apoprotein of 46,000 mol wt. We have called this apoprotein apoA-IV because of the similarity of its molecular weight and amino acid composition to rat apoA-IV. In sodium dodecyl sulfate gels, chylomicron apoproteins consisted of apoB 3.4+/-0.7%, apoA-IV 10.0+/-3.3%, apoE 4.4+/-0.3%, apoA-I 15.0+/-1.8%, and apoC and apoA-II 43.3+/-11.3%. Very low density lipoprotein contained more apoB and apoA-IV and less apoC than chylomicrons. Ouchterlony immunodiffusion of chylomicron apoproteins revealed the presence of apoC-I, apoC-II, and apoC-III. In contrast, plasma chylomicrons isolated during a nonchyluric phase revealed a markedly altered chylomicron apoprotein pattern when compared with urinary chylomicrons. The major apoproteins in plasma chylomicrons were apoB, apoE, and the C peptides: no apoA-I or apoA-IV were present in sodium dodecyl sulfate gels indicating that major changes in chylomicron apoproteins occur during chylomicron metabolism. When incubated in vitro with plasma, urinary chylomicrons lost apoA-I and apoA-IV and gained apoE and apoC. Loss of apoA-I and apoA-IV was dependent upon the concentration of high density lipoproteins in the incubation mixture. These studies demonstrate that the human intestine secretes significant amounts of apoA-I and apoA-II during lipid absorption. Subsequent transfer of apoproteins from triglyceride-rich lipoproteins to other plasma lipoproteins may represent a mechanism whereby the intestine contributes to plasma apoprotein levels.