Quality of life in celiac disease patients: prospective analysis on the importance of clinical severity at diagnosis and the impact of treatment.

BACKGROUND/AIMS: Celiac disease (CD) patients are affected in their quality of life (QoL). Our objectives were to assess differences in quality of life of patients according to the clinical presentation at diagnosis, and to determine the time-course impact of a gluten-free diet. PATIENTS/METHODS: We prospectively evaluated 132 newly diagnosed adult CD patients and 70 healthy controls using self-administered questionnaires: the Short Form-36 health survey, the Gastrointestinal Symptoms Rating Scale; the Beck Depression Inventory both, at diagnosis and at 3-, 6- and 12-months on treatment. RESULTS: At diagnosis, patients with classical symptoms (n=97) exhibited a significantly more pronounced alteration of all items of the three questionnaires than atypical/silent cases (n=35) (p<0.01 to <0.00001). Silent CD patients had even better baseline scores (p<0.05 to <0.00001). Treatment produced a substantial and rapid (3-month) improvement of most outcome measures in classical and atypical patients but not in asymptomatic cases. Both subgroups attained comparable final scores with no differences comparing strictly adherents with partially compliant. CONCLUSIONS: Atypical/silent celiac disease patients have a significantly better baseline quality of life than those with classical symptoms. Treatment induces a rapid and significant improvement in symptomatic cases but not in silent patients with all subgroups having similar 1-year scores comparable to healthy controls.

The IL-1 gene family and bone involvement in celiac disease.

Celiac disease (CD) is associated with decreased bone mineral mass. Its pathogenesis is multifactorial since both systemic and local mechanisms may play a role. Our objective was to determine whether single-nucleotide polymorphisms in genes encoding members of the interleukin-1 family are associated with bone damage measured by densitometry in a series of 71 adult CD patients assessed at diagnosis. When compared with non-carrier CD patients, carriers of allele T of the interleukin-1beta gene (IL1B-511T) had a significantly lower bone mass at the total skeleton level (p = 0.0484) and a greater prevalence of osteopenia/osteoporosis (p = 0.0102). To our knowledge, this is the first evidence on the association between a genetic predisposition and low bone mass in CD patients. This finding supports the postulated inflammation-associated bone loss pathogenesis as one of the causes of bone weakness in CD.

Significance of smooth muscle/anti-actin autoantibodies in celiac disease / Significado de los anticuerpos anti-músculo liso/anti-actina en la enfermedad celíaca

BACKGROUND/AIM: Smooth muscle antibody (SMA) specific for the protein actin, a major component of the cytoskeleton of epithelial cells, is one of the most prevalent non-organ specific autoantibodies in the serum of celiac disease (CD) patients. Our aim was to explore the clinical relevance of the presence of IgA type anti-actin antibody (AAA) and SMA in a series of patients with CD. METHODS: We evaluated frozen serum samples collected at diagnosis from 92 adult patients with CD and 52 control individuals in whom CD was excluded. Patients were re-evaluated a median time of 5 yr after treatment. IgA type AAA was detected using a modified commercial ELISA assay and IgA SMA was detected using indirect immunofluorescence on primate esophagus substrate. RESULTS: At diagnosis, samples from CD patients had significantly higher AAA values than controls (p<0.00001). While all active CD patients had serum AAA values over the cut-off for healthy controls, we observed a very significant reduction of these antibodies after treatment (p>0.0001). AAA had a highly significant correlation with both, tissue, transglutaminase (r=0.62) and antigliadin (r=0.60, p<0.00001) antibodies as well as the severity of the intestinal injury (p<0.05). SMA was detected in sera of 35 consecutive CD patients. At diagnosis, SMA positive patients had significantly higher values of AAA (p<0.0002), increased number of autoimmune disorders (p<0.04), delayed menarche (p<0.04), lower hemoglobin levels (p<0.01), increased fecal a-I antitrypsin clearance (p<0.01) and more severe diarrhea (p<0.06). We also detected a trend to more severe complications at follow-up (p=0.059). CONCLUSIONS: Based on our findings we suggest that the presence of increased IgA AAA serum levels is a highly sensitive marker of the disturbed architecture of intestinal epithelial cells of CD patients with a potential relevance to diagnosis and follow-up. The presence of SMA seems to define a distinct subset of CD patients with ...

Introduccion/objetivo: El anticuerpo anti-musculo liso (SMA) dirigido contra la proteína actina, un componente mayor del citoesqueleto de las células epiteliales, es el anticuerpo no-órgano específico más prevalente en enfermedad celíaca (EC). Nuestro objetivo fue explorar la importancia clínica de los anticuerpos anti-actina (AAA) y SMA en una serie de pacientes con EC. Métodos: Evaluamos 92 muestras serológicas de pacientes celíacos adultos recolectadas al momento del diagnóstico y la de 52 individuos controles no celíacos. Los pacientes fueron re-evaluados luego de un tiempo medio de 5 años en tratamiento. Evaluamos AAA tipoIgA mediante ELISA empleando un equipo commercial modificado y SMA IgA por inmunofluorescencia indirecta sobre sustrato de esófago de mono. Resultados: Al momento del diagnóstico, los pacientes celíacos tuvieron valores de AAA significativamente más elevados que los controles (p<0.00001). Todos los pacientes con EC activa presentaron niveles de AAA por encima del valor de corte determinado para el grupo control sano y se evidenció una reducción significativa de los nivelesluego del tratamiento (p>0.0001). Los AAA presentaron una correlación significativa con los anticuerpos anti-transglutaminasa tisular (r=0.62) y anti-gliadina (r=0.60) (p<0.00001), de igual modo que con la severidad del daño intestinal (p<0.05). Al momento del diagnóstico, se detectó SMA en el suero de 35 pacientes no controles. Los pacientes SMA positivos tuvieron valores significativamente mayores de AAA (p<0.002), un incremento del número de enfermedades autoinmunes asociadas (p<0.04), menarca tardía (p<0.04), niveles bajos de hemoglobina (p<0.01), incremento del clearance de a-1 antitripsina fecal (p<0.01) y mayor severidad de la diarrea (p<0.06).En ellos se evidenció una tendencia al desarrollo de complicaciones más severas durante el seguimiento (p=0.059). Conclusiones: Sugerimos que la presencia de un valor sérico aumentado de AAA tipo IgA...

Significance of smooth muscle/anti-actin autoantibodies in celiac disease

BACKGROUND/AIM: Smooth muscle antibody (SMA) specific for the protein actin, a major component of the cytoskeleton of epithelial cells, is one of the most prevalent non-organ specific autoantibodies in the serum of celiac disease (CD) patients. Our aim was to explore the clinical relevance of the presence of IgA type anti-actin antibody (AAA) and SMA in a series of patients with CD. METHODS: We evaluated frozen serum samples collected at diagnosis from 92 adult patients with CD and 52 control individuals in whom CD was excluded. Patients were re-evaluated a median time of 5 yr after treatment. IgA type AAA was detected using a modified commercial ELISA assay and IgA SMA was detected using indirect immunofluorescence on primate esophagus substrate. RESULTS: At diagnosis, samples from CD patients had significantly higher AAA values than controls (p<0.00001). While all active CD patients had serum AAA values over the cut-off for healthy controls, we observed a very significant reduction of these antibodies after treatment (p>0.0001). AAA had a highly significant correlation with both, tissue, transglutaminase (r=0.62) and antigliadin (r=0.60, p<0.00001) antibodies as well as the severity of the intestinal injury (p<0.05). SMA was detected in sera of 35 consecutive CD patients. At diagnosis, SMA positive patients had significantly higher values of AAA (p<0.0002), increased number of autoimmune disorders (p<0.04), delayed menarche (p<0.04), lower hemoglobin levels (p<0.01), increased fecal a-I antitrypsin clearance (p<0.01) and more severe diarrhea (p<0.06). We also detected a trend to more severe complications at follow-up (p=0.059). CONCLUSIONS: Based on our findings we suggest that the presence of increased IgA AAA serum levels is a highly sensitive marker of the disturbed architecture of intestinal epithelial cells of CD patients with a potential relevance to diagnosis and follow-up. The presence of SMA seems to define a distinct subset of CD patients with ...(AU)

Introduccion/objetivo: El anticuerpo anti-musculo liso (SMA) dirigido contra la proteína actina, un componente mayor del citoesqueleto de las células epiteliales, es el anticuerpo no-órgano específico más prevalente en enfermedad celíaca (EC). Nuestro objetivo fue explorar la importancia clínica de los anticuerpos anti-actina (AAA) y SMA en una serie de pacientes con EC. Métodos: Evaluamos 92 muestras serológicas de pacientes celíacos adultos recolectadas al momento del diagnóstico y la de 52 individuos controles no celíacos. Los pacientes fueron re-evaluados luego de un tiempo medio de 5 años en tratamiento. Evaluamos AAA tipoIgA mediante ELISA empleando un equipo commercial modificado y SMA IgA por inmunofluorescencia indirecta sobre sustrato de esófago de mono. Resultados: Al momento del diagnóstico, los pacientes celíacos tuvieron valores de AAA significativamente más elevados que los controles (p<0.00001). Todos los pacientes con EC activa presentaron niveles de AAA por encima del valor de corte determinado para el grupo control sano y se evidenció una reducción significativa de los nivelesluego del tratamiento (p>0.0001). Los AAA presentaron una correlación significativa con los anticuerpos anti-transglutaminasa tisular (r=0.62) y anti-gliadina (r=0.60) (p<0.00001), de igual modo que con la severidad del daño intestinal (p<0.05). Al momento del diagnóstico, se detectó SMA en el suero de 35 pacientes no controles. Los pacientes SMA positivos tuvieron valores significativamente mayores de AAA (p<0.002), un incremento del número de enfermedades autoinmunes asociadas (p<0.04), menarca tardía (p<0.04), niveles bajos de hemoglobina (p<0.01), incremento del clearance de a-1 antitripsina fecal (p<0.01) y mayor severidad de la diarrea (p<0.06).En ellos se evidenció una tendencia al desarrollo de complicaciones más severas durante el seguimiento (p=0.059). Conclusiones: Sugerimos que la presencia de un valor sérico aumentado de AAA tipo IgA...(AU)

Antibodies to human recombinant tissue transglutaminase may detect coeliac disease patients undiagnosed by endomysial antibodies.

BACKGROUND: The screening and diagnosis of coeliac disease have been simplified by the advent of new serological tools. AIM: To assess the clinical utility of a newly developed kit for antibodies to human recombinant tissue transglutaminase (hu-anti-tTG) in a large population of patients undergoing intestinal biopsy for suspected intestinal disorders. METHODS: We evaluated 426 serum samples from consecutive adult patients (250 from untreated coeliac disease patients and 176 from individuals in whom a diagnosis of coeliac disease had been excluded), obtained at the time of intestinal biopsy. Samples were tested for immunoglobulin A (IgA) hu-anti-tTG by enzyme-linked immunoabsorbent assay, IgA endomysial antibodies (EmA) by indirect immunofluorescence and IgA and IgG antigliadin antibodies by enzyme-linked immunoabsorbent assay. A sub-group of samples was also assessed for a guinea-pig-based anti-tissue transglutaminase. RESULTS: According to the cut-off for hu-anti-tTG, the sensitivity, specificity and positive and negative predictive values were 91%, 96%, 97% and 87%, respectively. Simultaneous determination of EmA showed values of 86%, 100%, 100% and 83% for the same parameters. Although 19 coeliac disease patients (7.6%) were negative for EmA and hu-anti-tTG, both tests rendered superior statistical values to antigliadin antibody tests. At diagnosis, IgA deficiency was detected in 11 patients, but both assays were able to detect samples with mild to moderate deficiency. The comparison of hu-anti-tTG with EmA showed excellent concordance between the tests (kappa statistic, 0.85). Discordance was observed in 20 samples from coeliac disease patients (8%) and in nine samples from controls (5%). Fifteen samples had an EmA-negative but hu-anti-tTG-positive serology, and five showed the converse pattern. Comparison of human recombinant and guinea-pig tests showed concordant results in 96% of cases. CONCLUSIONS: The quantitative determination of hu-anti-tTG type IgA using a commercial enzyme-linked immunoabsorbent assay kit was highly sensitive and specific for the detection of coeliac disease. Our results in a large population of patients with a clinical condition suggestive of the disorder demonstrated that the test can be used to detect a substantial number of patients otherwise unrecognized by IgA EmA.

Is it necessary to screen for celiac disease in postmenopausal osteoporotic women?

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.

Budesonide enema in pouchitis--a double-blind, double-dummy, controlled trial.

BACKGROUND: Pouchitis has been suggested to be a recurrence of ulcerative colitis in a colon-like mucosa. Topical steroids are a valid therapeutic alternative for distal forms of ulcerative colitis. AIM: To investigate the efficacy and tolerability of budesonide enema in the treatment of pouchitis compared with oral metronidazole. MATERIALS AND METHODS: Twenty-six patients with an active episode of pouchitis (defined as a pouchitis disease activity index score >or= 7) and no treatment during the previous month were randomized to receive either budesonide enema (2 mg/100 mL at bedtime) plus placebo tablets or oral metronidazole (0.5 g b.d.) plus placebo enema in a prospective, double-blind, double-dummy, 6-week, controlled trial. RESULTS: Based on the intention-to-treat principle, we detected a significant improvement in disease activity at the end of the first week with both drugs (P < 0.01). After that, improvement was moderated until stabilization at 4 weeks in both treatments. The per protocol analysis showed that both drugs had similar efficacy in terms of disease activity, clinical and endoscopic findings. Fifty-eight per cent and 50% of patients improved (decrease in pouchitis disease activity index >or= 3) with budesonide enema and metronidazole, respectively (odds ratio, 1.4; confidence interval, 0.2-8.9). Adverse effects were observed in 57% of patients given metronidazole and in 25% of patients given budesonide. CONCLUSIONS: Budesonide enemas are an alternative treatment for active pouchitis, with similar efficacy but better tolerability than oral metronidazole.

Acute gastrointestinal permeability responses to different non-steroidal anti-inflammatory drugs.

BACKGROUND AND AIMS: Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage both in the upper and lower gastrointestinal tract. New anti-inflammatory drugs have been developed in an attempt to improve their gastrointestinal side effect profile. Our objective was to compare the effect on gastrointestinal permeability of acute equieffective doses of four different NSAIDs; three were designed to reduce gastrointestinal mucosal injury. MATERIALS: Healthy volunteers underwent sugar tests in a randomised fashion, 15 days apart, at: (1) baseline; (2) after two days of 75 mg slow release (microspheres) indomethacin; (3) after two days of 7.5 mg oral meloxicam which preferentially inhibits cyclooxygenase 2; and (4) after two days of 750 mg naproxen. A subgroup of subjects was tested after two days of 200 mg celecoxib. In each test, subjects ingested a solution containing sucrose, lactulose, and mannitol and sucralose, to evaluate gastroduodenal, intestinal, and colonic permeability, respectively. RESULTS: Gastric permeability was significantly affected by naproxen (p<0.05) but not by slow release indomethacin, meloxicam, or celecoxib. Intestinal permeability was significantly increased by the first three NSAIDs (p<0.05) but not by celecoxib. Abnormal lactulose/mannitol ratios were observed in 42% of meloxicam treatments, in 62% during indomethacin, and in 75% of subjects treated with naproxen. Finally, colonic permeability, as measured by sucralose, was not significantly increased by any of the four drugs. CONCLUSION: Our study provides evidence that the newly developed NSAIDs reduce gastric mucosal permeability significantly. However, most produced significant alteration of small intestinal permeability. In contrast, our results suggest that celecoxib seems to exhibit the most desirable gastrointestinal side effect profile.

Prevalence of celiac disease in Argentina: screening of an adult population in the La Plata area.

OBJECTIVES: Up to now, the epidemiological characteristic of celiac disease among adults in South America remains unknown. The present prospective screening was designed to determine the prevalence of celiac disease in adults from the general population in an urban area of Argentina. METHODS: Between January. 1998, and May, 2000, all couples attending a centralized laboratory for an obligatory prenuptial examination in the La Plata area were offered participation in a screening program for celiac disease. The study included 2000 subjects (996 women; median age 29 yr, range 16-79 yr). All individuals completed a clinical questionnaire at the time that serum samples were obtained. A three-step screening protocol was used, as follows: 1) all samples were tested for antigliadin antibodies (AGAs) (type IgA and IgG); 2) samples that were IgA AGA positive were tested for antiendomysial antibody (EmA type IgA); samples that were positive for AGA-G but negative for IgA AGAs were tested for total IgA serum levels and EmA type IgG; and 3) subjects who were EmA-positive were referred for intestinal biopsy. RESULTS: At the end of the screening we detected 10 subjects who were EmA-A positive and two others who were IgA-deficient (both were EmA-G positive). Up to now, 11 of the 12 subjects (including nine EmA-positive and two IgA-deficient subjects) had endoscopic intestinal biopsies showing the characteristic celiac histology. The remaining EmA-positive individual was considered to be affected by celiac disease. The overall prevalence assessed was 1:167 (6.0 x 1000 subjects; 95% CI = 3.1-10.5). Eight of the 12 (67%) subjects were female (1:124; 8.0 x 1000; 95% CI = 3.5-15.8) and four (33%) were male (1:251; 4.0 x 1000; 95% Cl = 1.1-10.2). Although eight new patients were considered to be asymptomatic, three presented with a subclinical course and one was classically symptomatic. Only one patient had been previously diagnosed with celiac disease. CONCLUSIONS: Our screening protocol showed a very high prevalence of celiac disease for an urban area of Argentina that is ethnically similar to 90% of the general population of the country. The prevalence among women was double that for men, and the heterogeneous clinical picture of new patients showed predominance of asymptomatic cases.

Serum transforming growth factor-beta1 levels increase in response to successful anti-inflammatory therapy in ulcerative colitis.

OBJECTIVE: To investigate serum levels of transforming growth factor-beta1 and interferon-gamma in active ulcerative colitis and to assess changes during treatment. METHODS: We prospectively evaluated serum from 25 patients with untreated active ulcerative colitis and 19 healthy controls. Disease activity score (DAI), serum transforming growth factor-beta1 and interferon-gamma levels were measured at baseline and after 7 days of conventional treatment. Disease activity score and transforming growth factor-beta1 were also assessed at 42 days. RESULTS: Baseline transforming growth factor-beta1 levels were significantly higher in patients than in controls (P < 0.02). On the 7th day, transforming growth factor-beta1 levels increased only in patients who responded (P < 0. 01); variations in transforming growth factor-beta1 levels and disease activity score were inversely correlated (r=- 0.72, P < 0. 001). At day 42, serum transforming growth factor-beta1 decreased significantly compared with the 7th day (P < 0.05). While in controls, interferon-gamma was undetectable; untreated patients had higher, widely variable, levels. At day 7, responders had higher interferon-gamma values than unresponsive cases. Variations in interferon-gamma correlated moderately with changes in transforming growth factor-beta1 (r=0.53, P < 0.05). Cytokine response did not depend upon the type of treatment. CONCLUSIONS: Both transforming growth factor-beta1 and interferon-gamma may play a role in the injury-repair process in active ulcerative colitis. Variations in circulating transforming growth factor-beta1 levels in the first week of treatment seem to be related to the therapeutic response.

Tissue transglutaminase antibodies in celiac disease: assessment of a commercial kit.

OBJECTIVE: Tissue transglutaminase was identified as the autoantigen eliciting endomysial antibody. A homemade enzyme-linked immunosorbent assay (ELISA)-based test was recently developed to determine quantitative titers of IgA antitissue transglutaminase antibody. Our objective in this study was to assess the suitability of a newly developed commercial kit for quantitative determination of antibody in patients with untreated celiac disease. MATERIALS: We tested serum samples from 79 untreated celiac patients, 42 healthy blood donors, and 18 patients with nonceliac intestinal disorders evaluated in two different centers. Samples were tested for antitissue transglutaminase, and antiendomysial and antigliadin antibodies in the center where diagnosis was performed. To assess interlaboratory variability of methods, 24 samples randomly selected were blindly tested in both centers. Antitissue transglutaminase antibodies were determined using a commercial kit (INOVA Diagnostics, Inc., San Diego, CA). RESULTS: Untreated celiac patients had significantly higher titers of antitissue transglutaminase than healthy and disease controls (p < 0.00001). According to the cut-off provided by the manufacturers (20 AU/mL), overall sensitivity was 92% (85% for one center and 100% for the other) and specificity was 98% (100% and 95%, respectively). Antiendomysial antibody was 86% sensitive and 100% specific. Discordance between antitissue transglutaminase and antiendomysial antibodies was detected in 13% of patients. Although two antitissue transglutaminase-negative cases had a positive antiendomysial antibody, the inverse situation was found in eight cases. A blind determination of antitissue transglutaminase on the same samples evidenced a good agreement (kappa statistic: 0.66) between both centers when assessment was qualitative (based on the decision of positive or negative). Although correlation of titers for both determinations was highly significant (r: 0.902, p < 0.00001), a very wide interlaboratory variability (median: 50%) was detected when absolute values were considered. CONCLUSIONS: The quantitative determination of antitissue transglutaminase using a commercial kit was highly sensitive and specific for detection of celiac disease. We observed an incomplete overlapping with antiendomysial antibody. The very high variability of values between laboratories still remains to be solved so as to propose the commercial ELISA assay for the screening of celiac disease.

The natural history of gluten sensitivity: report of two new celiac disease patients resulting from a long-term follow-up of nonatrophic, first-degree relatives.

OBJECTIVE: Early studies revealed that up to 50% of non-atrophic, first-degree relatives of celiac disease patients exhibit features of gluten sensitivity. However, whether these features progress to a fully expressed celiac disease remain partially known. Our aim was to report two new patients resulting from a prospective, long-term surveillance of relatives who were nonatrophic at initial assessment. METHODS: After a median time of 86 months (range: 42-102 months) from the baseline assessment, we re-evaluated 44 first-degree relatives of propositi who had taken part in family studies and in whom baseline small intestinal biopsies were normal. At the baseline screening, 21 relatives had positive serum antigliadin antibodies and/or increased intraepithelial lymphocyte infiltration, and 23 did not. In addition, 11 of 18 had a celiac-like response to rectal gluten challenge and 16 of 34 possessed the characteristic HLA DQ2 haplotype (DQA1 0501 DQB1 0201). Re-evaluation was based on celiac-related serology antigliadin (AGA) and endomysial (EmA) antibodies. EmA-positive subjects underwent intestinal biopsy. RESULTS: At the end of the study, EmA was positive in only two subjects. Histological examination revealed flat small bowel mucosa in both. At baseline, both cases were EmA-negative and no minor histological changes were observed. One was a woman with positive baseline IgA and IgG AGA and a rectal gluten challenge with a celiac-like response; the other patient has presented only with a positive IgG AGA. In both cases, progression was detected in a clinically silent context. Both new patients had the characteristic HLA DQ2 haplotype. CONCLUSIONS: Our data suggest the need to re-evaluate relatives who have been negative on initial screening for celiac disease. Up to now, the progression to severe enteropathy was only observed in relatives who had presented some evidence of gluten sensitivity and the characteristic HLA DQ2 haplotype. Longer longitudinal studies are necessary to obtain definitive conclusions.

Sugar tests detect celiac disease among first-degree relatives.

OBJECTIVES: First-degree relatives of patients with celiac disease are at high risk for developing the disease themselves. Detection of serum antibodies and intestinal permeability tests have been useful to identify candidates for intestinal biopsies. Recently it was demonstrated that abnormal sucrose permeability is a very sensitive marker of active disease. Our objectives in this prospective study were (1) to assess the screening value of permeability tests, and (2) to compare the usefulness of these markers with that of the celiac disease-related serology in screening for celiac disease in a cohort of first-degree relatives of well-known patients. METHODS: We performed sugar tests in 66 first-degree relatives of probands. Subjects ingested 450 ml of a solution containing sucrose (100 g), lactulose (5 g), and mannitol (2 g). Subsequently, a complete overnight urine collection was obtained. Measurement of sugars was performed by high-performance liquid chromatography. All relatives were evaluated for antigliadin (type IgA and IgG) and endomysial antibodies and subjects positive for any test underwent intestinal biopsy. RESULTS: Twelve relatives were diagnosed as having small intestinal mucosal atrophy. Increased sucrose permeability was detected in 9 (75%) of these patients. Four false-positive determinations were found but all had gastric erosions, which is known to increase sucrose permeability independently of duodenal damage. Increased lactulose/mannitol ratios were observed in all new celiac patients. An additional nine relatives had positive results; however, four of them did not accept intestinal biopsy and the remaining five did not seem to have histological evidence of disease. Endomysial antibodies were detected in 11 of 12 patients and no false-positive cases were observed. Antigliadin antibodies were 75% sensitive and 88% specific. CONCLUSIONS: Our study demonstrated that screening using the endomysial antibody test is highly sensitive and specific for detecting celiac disease; however, almost 10% can be missed. The addition of lactulose/mannitol permeability testing to the screening protocol allowed us to detect all relatives who actually presented with evidence of gluten sensitivity. Sucrose permeability exhibited a lower sensitivity; however, it did detect other endoscopically visible lesions.

Gluten sensitivity in patients with primary biliary cirrhosis.

OBJECTIVE: Whereas celiac disease and primary biliary cirrhosis have been reported to coexist in the same patient, the frequency of this relationship has not been clarified. Nowadays, the concept of celiac disease has been extended from that of a severe enteropathy to a broader concept of gluten-driven intestinal immunological response. In this study we assessed features of gluten sensitivity in a cohort of patients with primary biliary cirrhosis. METHODS: Ten patients with primary biliary cirrhosis were evaluated a mean of 2 yr after diagnosis. The following features of gluten sensitivity were assessed: serum antigliadin and endomysial antibodies, small bowel histology (degree of atrophy and quantitative histological parameters), the presence of the typical celiac HLA genotype (DQ2), and intraepithelial lymphocyte response in the rectal mucosa after local gluten instillation (rectal gluten challenge). RESULTS: Overall, three patients presented evidence of gluten sensitivity. All three had abnormal titers of antigliadin antibody type IgA and one was positive for endomysial antibody. Two patients had partial villous atrophy. The rectal gluten challenge showed a celiac-like response, evidenced by an increase in intraepithelial lymphocyte infiltration after gluten exposure, in the three patients. The characteristic celiac HLA genotypes (DQA1 0501 and DQB1 0201) were identified in three patients. One of them also exhibited other features of gluten sensitivity. However, despite evidence of gluten intolerance, patients had minimal or no symptoms characteristic of celiac disease. CONCLUSION: We detected features of gluten sensitivity in a high proportion of patients with primary biliary cirrhosis. Further studies should be performed to elucidate the clinical significance of this association.

Pre- and post-treatment serum levels of cytokines IL-1beta, IL-6, and IL-1 receptor antagonist in celiac disease. Are they related to the associated osteopenia?

OBJECTIVE: Decreased bone mineral density is a common finding in untreated celiac disease patients. However, the precise pathophysiology of osteopenia remains incompletely understood. Pathological features of gluten sensitivity are associated with local release of proinflammatory and antiinflammatory cytokines. We investigated the serum levels of IL-1beta, IL-6, and IL-1 receptor antagonist in celiac patients and correlated them with bone density measurements. METHODS: We assessed serum samples of 16 female patients at the time of diagnosis (on an unrestricted diet) and after a mean time of 37 months on a gluten-free diet. At the same time, bone mineral density in the lumbar spine and total skeleton was determined by DEXA. RESULTS: Untreated patients had high serum levels of IL-1beta and IL-6 and normal IL-1-RA. Treatment produced a decrease in median IL-1beta levels (p = NS) and a significant diminution of IL-6 (p < 0.05). On the contrary, IL-1-RA increased significantly after treatment (p < 0.05). Baseline lumbar spine Z-score and IL-6 levels exhibited a significant inverse correlation (r = -0.61; p < 0.01). Patients with more severe baseline osteopenia (< -2 Z-scores) had a significantly lower IL-1-RA than those with less bone compromise (> -2 Z-scores). CONCLUSIONS: Our data demonstrate that the inflammatory process observed in active celiac disease is associated with high serum levels of IL-1beta and IL-6 and normal levels of IL-1-RA. Treatment significantly reduces both proinflammatory cytokines and significantly increases the antiinflammatory one. We also suggest that these cytokines might have a role in the osteopenia associated with celiac disease.

Gluten sensitivity in the rectal mucosa of first-degree relatives of celiac disease patients.

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.

Splenic hypofunction in cirrhosis is not associated with increased risk for infections.

BACKGROUND/AIM: Pitted cell count has been described as a sensitive marker of splenic function. Recently, pitted cell count was shown to be increased in patients with alcoholic liver disease, and also to be associated with an increased susceptibility to infection. Therefore, our aim in the present study was to assess splenic function in a group of patients with cirrhosis and to determine its possible role in the development of infections. METHODS: Splenic function was assessed during hospitalization in 44 patients diagnosed as having cirrhosis, and was compared to 18 healthy subjects. Function was evaluated by counting the number of pitted cells in peripheral blood films. Results were the mean value of two independent counts and were expressed as number of pitted cells/100 erythrocytes. RESULTS: The mean percentage of pitted cells in peripheral blood of cirrhotic patients was significantly greater than that assessed in controls (3.5 +/- 3.7% vs. 1.6 +/- 0.9%, P < 0.01, Mann-Whitney U test). Eighteen patients with cirrhosis (36%) had counts greater than 3.4% (mean + 2 SD of the control group). There were no significant differences between patients with counts above or below 3.4% in terms of liver tests, platelet and reticulocyte counts, the presence of complications, Child-Pugh score and the prevalence of infections. There was no difference in pitted cell count between alcoholic and non-alcoholic cirrhotic patients (3.8 +/- 3.4% vs. 3.1 +/- 2.8% respectively, P, NS). Moreover, the mortality rate and the occurrence of infections were similar in patients with normal and increased pitted cell counts during 1-year follow-up. CONCLUSION: The increased number of pitted cells in patients with cirrhosis is not related to heptic function and does not represent a risk factor for infections.

Serological markers identify histologically latent coeliac disease among first-degree relatives.

BACKGROUND AND AIM: Serological markers detect asymptomatic coeliac disease among first-degree relatives of patients with sprue. However, some relatives with coeliac disease-related antibodies have 'normal' jejunal mucosa by conventional histology. Whether these serological abnormalities represent false-positives or are consequences of gluten sensitivity is not known. Our aim was to evaluate, through quantitative histology, intestinal biopsies of asymptomatic relatives of probands seeking abnormalities consistent with latent coeliac disease. MATERIALS: Fifty-nine intestinal biopsies obtained from asymptomatic relatives were evaluated; 40 samples were suitable for histological quantification. Seven samples showed severe mucosal atrophy (coeliac disease) and 33 were considered as 'normals'. In the 'normal' group, nine samples were obtained from patients with one or more positive serological tests and 24 from those with negative tests. Morphometry was compared for samples obtained from healthy control individuals (n = 10) and for those from coeliac patients (n = 7). METHODS: Serological tests used were: antigliadin antibodies type immunoglobulin (Ig)A and IgG (enzyme-linked immunosorbent assay), antirrecticulin antibody (immuno-fluorescence) and endomysial antibody (immunofluorescence). Biopsy samples were obtained with endoscopic forceps from the distal duodenum (second portion). Quantitative histology of duodenal biopsies was performed with a computerized image analysis system. RESULTS: Relatives with positive serology showed shorter villi (P < 0.05) and higher number (P < 0.01) and numerical density (P < 0.01) of intraepithelial lymphocytes in crypts than healthy controls. Numerical density of intraepithelial lymphocytes in crypts in antibody-positive patients was significantly higher than that observed in relatives with negative serology (P < 0.03). Four of nine (44%) relatives with positive serology had a number of intraepithelial lymphocytes in crypts within the range of coeliac disease patients. However, only one patient with negative serology (4%) was in this range. CONCLUSION: Our study shows quantitative histological evidence that relatives of probands with positive coeliac disease-related serology are not false-positives, and that they should be considered as individuals with latent coeliac sprue.

Screening for asymptomatic celiac sprue in families.

We evaluated the reliability of IgA and IgG antigliadin antibodies (AGA-A, AGA-G), antireticulin antibody (ARA), endomysial antibodies (EmA), and alpha 1-antitrypsin clearance (alpha 1-AT CL) in the detection of celiac sprue (CS) in 59 first-degree asymptomatic relatives of celiac patients who had duodenal biopsy. Twenty-four relatives who had normal results of screening tests were selected at random for biopsy; 35 relatives with at least one abnormal test result were biopsied. Eleven relatives were noted to have villous atrophy at biopsy; the diagnosis of celiac sprue was confirmed by histological improvement after gluten-free diet in six. AGA-G, alpha 1-AT CL, and EmA had sensitivities of 73%, 73%, and 64%, respectively, with very high levels of specificity. Sensitivity was improved by the combination of two serological markers (AGA-G + alpha 1-AT CL = 91%; AGA-G + EmA = 82%; EmA + ARA = 82%). Furthermore, combination of EmA and ARA has shown the best specificity and positive predictive value. AGA-G, alpha 1-AT CL, and EmA are reliable individual markers for the detection of asymptomatic celiac sprue. However, a combination of two of them, including ARA, was more sensitive than the individual tests.

Faecal alpha 1-antitrypsin concentration in the diagnosis and management of patients with pouchitis.

OBJECTIVE: To investigate the role of faecal alpha 1-antitrypsin concentration in the diagnosis and management of patients with ileal pouch-anal anastomosis. DESIGN: Prospective study. METHODS: Fifty-two measurements of faecal alpha 1-antitrypsin concentration were taken from 33 patients operated on for ulcerative colitis. RESULTS: Patients with active pouchitis (44.4 +/- 7.1 mg%) had a three-fold higher mean faecal alpha 1-antitrypsin concentration than patients in remission (13.7 +/- 1.3 mg%; P < 0.0001), than patients who had never had pouchitis (14.4 +/- 2.3 mg%; P < 0.003) and than patients with incontinent ileostomies (12.7 +/- 1.3 mg%; P < 0.004). Faecal alpha 1-antitrypsin measurements were 80% sensitive and 97% specific for active pouchitis. A significant positive correlation between the pouchitis disease activity index and faecal protein loss was observed (r = 0.702; P < 0.0001). The correlations between protein loss and other parameters were weaker (protein loss versus clinical score, r = 0.309; versus endoscopic score, r = 0.583; and versus histologic score, r = 0.558). CONCLUSION: Faecal alpha 1-antitrypsin concentration is a good indicator of the degree of intestinal inflammation in pouchitis and may be useful as a quantitative index of disease activity in prospective studies.