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Assessment of the clinico-anamnestic and morphofunctional parameters in children with celiac disease made it possible to define criteria for the acuity of the pathological process, enabling the diagnosis of the disease phase. The data obtained as a result of morphometric examination of the biopsy material withdrawn from the small intestinal mucosa turned out to be of paramount importance.
Previous studies on celiac patients demonstrated that exposure to gliadin alters the motility of the upper gastrointestinal tract, leading to increased acid reflux. No literature is available regarding the possible presence of specialized intestinal metaplasia of the esophagus as a consequence of chronic reflux in adult celiac patients. Our purpose was to evaluate endoscopically and histologically the esophagi of a group of untreated celiac patients. We studied 60 celiac patients, 13 men and 47 women (mean age, 40 +/- 14 [SD] years; range, 18-80 years), at their first endoscopy (following a normal diet). The distal esophagus was evaluated and multiple biopsies were taken. Hematoxylin-eosin and alcian blue stainings were performed. A group of nonceliac, age- and sex-matched patients was used as a control. We found intestinal metaplasia in the distal esophagus of 16 of 60 (26.6%) celiacs (mean age, 45 +/- 13 years; range, 27-75 years), in comparison with a control-group prevalence of 10.9% (OR, 3.9; 95% CI, 1.4-11.2%). Among the celiac group with metaplasia, only one patient had reflux-like symptoms. None had esophagitis. In conclusion, we observed an increased prevalence of esophageal metaplasia in patients with celiac disease. This finding could be the result of motor abnormalities leading to chronic acid reflux, combined with a mucosa which is sensitive to gliadin.
BACKGROUND/AIMS: Rectal gluten challenge is a simple, sensitive, and specific test of mucosal gluten sensitivity. Our aims in this study were to evaluate gluten sensitivity in a group of relatives of celiac patients and to compare these findings with those obtained on small bowel histology, celiac disease-related serology, and HLA typing. METHODS: A 4-h rectal gluten challenge was performed with 6 g of crude gluten in saline solution in 29 first-degree relatives, 20 well-diagnosed celiac patients, and 10 subjects in whom celiac disease had been excluded. The number of intraepithelial lymphocytes in pre- and postchallenge frozen rectal biopsies (pan T-cell immunocytochemistry) was quantified by computerized image analysis. RESULTS: The intraepithelial lymphocyte response after gluten instillation was significantly higher in celiac disease patients (median, 126% increase above the baseline count; 95% confidence interval: 61-213%) compared with control subjects (median, -5%; 95% confidence interval: -29-5%). Using a cut-off of 20% change in intraepithelial lymphocyte count, 14 relatives (48%) showed a celiac-like response. Two of these subjects had partial villous atrophy and increased lymphocyte counts in the small bowel mucosa. One of them also exhibited a positive celiac disease-related serology and the typical celiac human lymphocyte antibody (HLA) DQ2. The remaining 12, and all those relatives with a negative challenge, had normal small bowel mucosa and were negative for antigliadin and endomysial antibodies. The characteristic celiac HLA (DQA1 0501 DQB1 0201 heterodimer) was identified in five relatives with positive challenge (including the patient with more severe mucosal atrophy) but was also present in eight relatives with no evidence of gluten sensitivity in the rectal mucosa. CONCLUSIONS: Our study characterizes a subgroup of relatives of celiac patients who show mucosal evidence of sensitization after local instillation of gluten in the rectum but who have no other features of celiac disease.
The possibility that genetic susceptibility to celiac disease (CD) might be influenced by tumor necrosis factor (TNF) genes polymorphism has repeatedly been put forward. To date, this has only been investigated in case-control studies and results have been contradictory. In order to avoid any possible ethnic mismatching between patients and controls, we have approached this problem studying 71 celiac families, establishing the parental haplotypes and comparing CD versus control haplotypes (the so-called AFBAC or affected family-based controls). We used DNA-based methods to screen for HLA-DRB1, -DQA1, and -DQB1 alleles, TNFalpha promoter polymorphims and TNFa and b microsatellites. The guanine-to-adenine polymorphism at position -308 of the TNFalpha gene promoter region was found associated with CD as the TNF-308A allele appeared significantly increased in frequency in CD haplotypes, and this was shown to be independent of the association between CD and the DRB1*0301,DQA1*0501,DQB1*0201 alleles. Our results indicate that at least another gene, in addition to the known association of CD with HLA class II, has a susceptibility role in this disease. This should be either TNFalpha or another polymorphic gene in the telomeric end of the HLA class III region.
OBJECTIVES: Screening for celiac disease (CD) in the apparently healthy members of 107 nuclear families with two affected siblings (sib pair) and estimating the risk of CD in siblings and parents. METHODS: One hundred seven families from Sweden and southern Norway with at least two affected children were investigated. Frozen sera from 187 of the 192 healthy parents and from 94 of 95 siblings without diagnosed CD were examined for total immunoglobulin A (IgA) and anti-endomysial antibodies (EMA). Individuals with positive antibody titers underwent small intestinal biopsy. RESULTS: Positive test for EMA was found in 6 of 94 (6.3%) siblings without previously diagnosed CD and in 8 of 189 (4.2%) parents. CD was confirmed by small intestinal biopsy in all siblings and seven parents. The estimated risk for CD in multiply affected families was 26.3% for siblings and 12.9% for parents. An unexpected male preponderance was found among the new CD cases (10 males, 3 females). CONCLUSION: The risk of CD in the members of nuclear families with two affected children is approximately three times higher than that when only one child is affected. The high male preponderance of new cases is unexpected and could not be explained fully by more silent disease in males as compared with females. Considering the high level of knowledge about CD in these families, the number of undiagnosed cases is surprisingly high. The authors suggest that serologic screening should be offered to all first-degree relatives of patients with CD.
BACKGROUND: In adults, the relation between celiac disease (CD) and cancer has been long recognized. In children, only four cases of CD and cancer have been described in Europe. We made a new inventory of cases with CD and cancer in children that were known by the members of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition between 1989 and 1999. METHODS: Postal inquiry was made of all European Society for Paediatric Gastroenterology, Hepatology and Nutrition members mentioned on the society's web page. The members were asked if they had seen a child with CD and cancer between 1989 and 1999 and if so, to supply additional clinical data. Also, information on working place, experience, and number of celiac patients under their care was requested. RESULTS: Fifty-six percent of the members responded. Sixteen members reported 22 cases of cancer and CD in children. One case had been reported in the literature previously. The tumors that were reported originated from the brain, thyroid, larynx, liver, small bowel, adrenal, lymphoreticular system, and the musculoskeletal system. There were no differences between members reporting a case and those who did not. CONCLUSIONS: Twenty-one new cases of cancer and CD in children in Europe were found. Cancer and CD in children are underreported. A remarkable number of thyroid and small bowel cancers were found, suggesting a possible relation with CD. It is important to evaluate whether these findings are coincidental. All cases of cancer and CD in children should be reported to the literature.
AIM: To address the role of CD209 in celiac disease (CD) patients. Non-human leukocyte antigen (HLA) genetic factors in CD predisposition are poorly understood, and environmental factors like infectious pathogens may play a role. CD209 is a dendritic and macrophage surface molecule involved in pathogen recognition and immune activation. Recently, a functional variant in the promoter of the CD209 gene (-336A/G) has been shown to affect the transcriptional CD209 activity in vitro and it has been associated with a higher susceptibility to/or severity of infection. METHODS: The study population was composed of two case-control cohorts of 103 and 386 CD patients and 312 y 419 healthy controls as well as a panel of 257 celiac families. Genotyping for the -336A/G CD209 promoter polymorphism was performed using a TaqMan 5' allelic discrimination assay. HLA-DQ was determined by hybridization with allele specific probes. RESULTS: Initially, the case-control and familial studies did not find any association of the -336 A/G CD209 genetic variant with CD susceptibility. However, the stratification by HLA-DQ2 did reveal a significant association of CD209 promoter polymorphism in the HLA-DQ2 (-) group (carrier A vs GG in DQ2 (-) vs DQ2 (+) patients (P = 0.026, OR = 3.71). CONCLUSION: The -336G CD209 allele seems to be involved in CD susceptibility in HLA-DQ2 (-) patients. Our results might suggest a possible role of pathogens in the onset of a minor group of CD patients.
In this 54 year old woman with celiac disease, osteomalacia developed while she was on a gluten-free diet which had caused regression of her steatorrhea. She was not responsive to large doses of parenterally administered dihydrotachysterol and calcium, but she was responsive to the oral administration of 25-hydroxyvitamin D3 (25-OHD3). The data suggest that 25-OHD3 is the treatment of choice for patients with vitamin D deficiency due to intestinal malabsorption.
In this paper we consider recent new data on the pathological features of gluten sensitivity and on the disease-associated antigens, in the context of a multistage hypothesis that we have been developing for the last five years. This incorporates concepts of oral tolerance induction, mucosal T-cell and antibody-mediated injury, and genetic contributions. Until now, there has been complete agreement that the diagnosis of celiac disease must be based on small bowel histology. There are patients with low-grade gluten-sensitive enteropathy, in whom the only morphological abnormality is a high count of intraepithelial lymphocytes (IEL). Some, but not all, also have positive serum IgA anti-endomysium antibody (AEA). With good techniques, in a properly accredited laboratory, in a patient suspected on clinical grounds to have celiac disease, a positive serum IgA AEA test (perhaps, alternatively, high-titer anti-transglutaminase by ELISA), is virtually diagnostic of the condition. Our hypothesis of a stepwise pathogenesis of severe gluten-sensitive enteropathy is re-examined in the light of these new data. It is evident that there are at least five different levels at which genetic influences may operate.
We report the case of a 57-year-old woman with celiac disease of long standing, who developed episodes of intestinal obstruction during two months. They were misdiagnosed as intestinal obstructions caused by adhesions. The barium meal and follow-through examination disclosed several jejunal stenoses. Therefore, the patient underwent early surgery where an intestinal resection was carried out. The histological examination showed the presence of benign ulcers at the stenoses. After surgery, the patient began to gain weight and her nutritional state improved remarkably.
A 74-year-old female patient with therapy-resistant sprue (celiac disease) and a new IgA autoantibody is presented. This autoantibody was demonstrated by immunofluorescence and differs from the conventional antibody against type 3 connective tissue (so-called endomysium antibody). It reacts predominantly with the muscularis and less strongly with the muscularis mucosae of the monkey esophagus. The reaction is not retiform but punctiform; the typical reaction sites of the antibody against type 3 connective tissue are negative. Especially on esophageal sections the antibody can be mistaken for the characteristic antibody directed against tissue transglutaminase, in particular at low magnification. The antigen of the new antibody is as yet unknown.
Decreased bone mass is a frequent finding in celiac patients, and subclinical celiac disease (CD) appears to be unusually overrepresented among patients with idiopathic osteoporosis. Since silent CD may be more common than previously believed, it has been suggested that all osteoporotic patients should be checked for occult CD. The aim of this study was to explore the prevalence of CD in a well-defined population of postmenopausal osteoporotic women. We evaluated 127 consecutive postmenopausal patients (mean age: 68 years; range: 50-82 years) with verified osteoporosis. The observed prevalence of CD in this group was compared to that observed in a group of 747 women recruited for a population-based study. The screening algorithm used to diagnose CD was based on a 3-level screening using type IgA and IgG antigliadin antibodies (AGA) in all the patients (1st level) followed by antiendomysial antibodies (EmA) and total IgA (2nd level) of samples testing positive, and intestinal biopsy of positive cases (3rd level). At the end of the serological screening, only 1 of 127 osteoporotic women was eligible for jejunal biopsy showing a characteristic celiac flat mucosa (prevalence 7.9 x 1,000; 95% CI 0.2-43.1). In addition, CD was diagnosed in 6 of 747 women of the population-based study (prevalence: 8.0 x 1,000; 95% CI 3.3-18.3). There was no significant difference between the two groups. Therefore, our study showed that the prevalence of CD in postmenopausal osteoporotic women was lower than that reported in previous studies and similar to that of the general population. In conclusion, although the relatively small size of the group tested does not allow us to be conclusive, the results suggest that a case finding policy in postmenopausal osteoporosis would have a high cost/benefit ratio except for patients not responding to conventional therapies, or presenting borderline laboratory results.
We studied DQA1, DQB1, and DPB1 alleles in 31 Finnish families with celiac disease (CD). All healthy first-degree relatives underwent clinical investigation, including in most cases biopsy, to establish whether clinically silent CD was present. Our results indicate that all patients, having either full clinical CD or its silent form, had the susceptibility alleles DQA1*0501 and DQB1*0201. The different clinical outcomes of CD were therefore not directly determined by the DQ alleles. The frequency of DPB1*0101 was also higher in CD patients, but the association appeared secondary to those of DQA1*0501 and DQB1*0201 (DQ2). The primary association of CD with the DQA1*0501 and DQB1*0201 alleles, rather than with HLA haplotypes, was confirmed in multiplex families.
The role of histopathology for diagnosing celiac disease (CD) has been recently challenged. However, based in our experience with roughly 4,600 distal duodenal and jejunal biopsies in children it is apparent that appropriate biopsy site, handling, processing, and microscopic evaluation result in a consistent pattern of microscopic changes which allows strong clinical-pathologic correlation. A simple way for establishing the villous/crypt (V/C) ratio is proposed. Normal mucosa displays a V/C ratio of 2.5 or more. Villous atrophy is then graded according to the V/C ratio as follows: Grade 1: 2.5-2; Grade 2: 1-2; Grade 3: 1-0.5, and Grade 4: less than 0.5. The grading should be done in areas of the biopsy where at least 2 to 3 crypts are present in almost its full length. CD disease was consistently associated with villous atrophy grades 3 and 4, which fully recovered or maintained Grade 1 after gluten-free diet. Grade 2 biopsies were rare and related to incomplete gluten-free diet. Patchy lesions were never seen as were patients with normal biopsies later developing mucosal atrophy. Histopathologic evaluation of mucosal biopsies to rule out CD requires adequate biopsy site (distal duodenum or proximal jejunum), and proper handling (oriented material), processing (cutting on edge) and interpretation. The proposed villous atrophy grading may help to adequately compare experiences from different centers as well as to reconcile apparent different findings in separate biopsies. In children histopathology keeps on having a central role for CD diagnosis.
The efficacy of the treatment with an agluten diet of celiac disease of the adults was studied in 45 patients over time, the observation periods ranging from 6 months to 6 years. The results were assessed from the patients' clinical examination that included study of absorption function of the small intestine (daily mass and fat loss with feces, absorption of D-xylose), determination of hemoglobin, total protein in blood serum, and morphological study of the jejunum mucosa obtained on aspiration enterobiopsy. Analysis of the data has shown that the patients who strictly observed the agluten diet noted a clinical remission with a tendency towards morphological improvement of the structure of small intestinal mucosa. No such an improvement was recorded in patients given gluten on a periodic basis.
The highest diamine oxidase activity is contained in small-bowel mucosa and, after heparin administration, the enzyme is released by the intestine into the plasma. Previous experimental studies showed that measurement of plasma postheparin diamine oxidase activity is a sensitive test for quantitating the length and severity of small-bowel mucosal injury. On this basis, we measured plasma diamine oxidase activity in celiac disease, a condition characterized by a loss of mature enterocyte mass. Twenty-five untreated celiac patients, 21 celiac patients on a gluten-free diet, 16 patients with small-bowel diseases other than celiac disease (abnormal controls), and 18 healthy controls were studied. Diamine oxidase activity was measured using [14C]putrescine as substrate and expressed as units per milliliter of plasma. Basal diamine oxidase levels in controls and patients were too low for significant differences between the groups to be detected. After preliminary experiments in which, on separate occasions, heparin was intravenously administered at doses of 75 and 150 units/kg and in which the second blood sample was taken 10 and 30 min after heparin injection, it was decided to use the 150 unit/kg dose and to measure plasma diamine oxidase activity in the blood sample taken 10 min after heparin stimulation in all the remaining subjects taking part in the study. Postheparin diamine oxidase levels were significantly lower in untreated celiac patients (mean 1.53 units/ml) than in healthy controls (mean 5.85), treated celiac patients (mean 4.82), and abnormal controls (mean 2.62). Except in three patients, no overlap between healthy controls and untreated celiac patients was observed. No significant difference was detected between healthy controls and treated celiac patients.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Light microscopy of jejunal biopsy specimens is routinely used to diagnose celiac disease. Confocal laser scanning microscopy offers research advantages, since thin optical sectioning can be performed without mechanical damage to the specimen. Fixed as well as non-fixed specimens can be studied. METHODS: Confocal laser scanning microscopy was used to study the stanining of wheat germ agglutinin, which binds to glycoconjugates of the enterocyte, and rhodamine phalloidin, which binds to the F-actin of the cells. RESULTS: In healthy mucosa the wheat germ agglutinin labeling showed a strong and punctate staining of microvilli, which outlined a convoluted surface. Phalloidin-labeled actin formed a three-dimensional cage at the cell membrane. In the crypt-hyperplastic mucosa, both staining patterns were irregular, and the cytoskeleton was disorganized. CONCLUSIONS: Confocal laser scanning microscopy offers the possibility to study the distribution of surface and cytoskeleton markers in thick, structurally intact specimens.
Association between Myosin IXB (MYO9B) gene polymorphisms and celiac disease (CD) was recently detected by a case-control association study in the Dutch, but not confirmed in the British and Swedish/Norwegian populations. We tested the association between CD and the three most associated single nucleotide polymorphisms (SNPs) in the Dutch study by the transmission disequilibrium test in the Italian population. A total of 252 pediatric patients and 504 parents were genotyped. No transmission distortion was detected either for the single SNPs or for their haplotypic combinations. Control allele frequencies, calculated from untransmitted alleles, were significantly different from those of the Dutch control population. Conversely, allele frequencies were very similar in Italian, British, Swedish/Norwegian and Dutch patients. In conclusion, MYO9B is not involved in CD susceptibility in the Italian population. The difference with the Dutch result might be explained by an imperfect selection of the Dutch controls.