Publications by authors named "Francesco Lanzarotto"

32 Publications

Topographical distribution of microscopic colitis and the importance of orientation of paraffin-embedded biopsies.

Hum Pathol 2020 09 13;103:63-71. Epub 2020 Jul 13.

Institute of Pathology, ASST Spedali Civili of Brescia, 25123 Brescia BS, Italy. Electronic address:

The diagnosis of microscopic colitis (MC) relies on specific histopathological findings in colon biopsies. The number of biopsies needed to diagnose MC remains disputed. The aim of the study was to determine the number and site of biopsies necessary for the diagnosis and the effect of perpendicular orientation when embedding the biopsies. This retrospective multicenter European study included 42 patients with a consensus diagnosis of collagenous colitis (CC), 51 patients with lymphocytic colitis (LC), and three patients with incomplete LC (LCi). The number of individual diagnostic biopsies from each patient was determined. The diagnostic rate of 744 individual biopsies from 96 patients with MC was 69.5% for the specific MC subgroup, 79.4% for MC and 93.4% for MC plus incomplete MC (MCi). The risk of missing a diagnosis of the specific subgroup of MC when analyzing four biopsies was 0.87%, decreasing to 0.18% for MC and 0.0019% for MC plus MCi. More biopsies from the right colon were diagnostic of the specific MC subgroup (76.3% vs. 64.0%, p = 0.0014). Perpendicular orientation of biopsies increased the diagnostic rate of the specific MC subgroup (73.1% vs. 65.0%, p = 0.0201). Histological changes diagnostic of MC were present in almost all biopsies from the right colon, with orientated biopsies more often being diagnostic of the specific MC subgroup. The results of this study indicate that four biopsies from the colon, rectum excluded, are sufficient to diagnose MC.
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September 2020

Elderly-onset vs adult-onset ulcerative colitis: a different natural history?

BMC Gastroenterol 2020 May 12;20(1):147. Epub 2020 May 12.

Gastroenterology Unit, Spedali Civili Hospital - University of Brescia, Viale Europa, 11, 25123, Brescia, Italy.

Background: Incidence of ulcerative colitis (UC) in elderly population is increasing because of ageing and because of its minimal impact on life span. Data on natural history, outcomes and therapeutic strategies are limited. Our aim is to characterize UC in elderly-onset patients followed at our Inflammatory Bowel Disease outpatient clinic and compare with adult-onset UC.

Methods: From January 2000 to June 2019, 94 patients with UC diagnosed after the age of 65 years (elderly group, E-O) were identified and matched 1-1 according to gender and calendar year of diagnosis with patients diagnosed with UC at age between 40 and 64 years (adult age, A-O).

Results: Comorbidity Index (3.8 vs 1.6, p < 0.0005) was higher for elderly UC patients. Symptoms at presentation were similar between the two groups, although abdominal pain was more common in adults, and weight loss was more common in the elderly. At diagnosis, left colitis (61% vs 39%) and proctitis (14% vs 26%) (p = 0.011) were more frequent in the elderly. Therapy and clinical behaviour were similar. Surgery was more frequently performed in the elderly (20% vs 9%, p = 0.02), while biological therapy was less used (2.1% vs 22%, p < 0.0005). Complications were more frequent in the elderly. Extraintestinal manifestations were lower in elderly patients (9.6% vs 19.2%, p = 0.061). Time to first relapse was similar between the two groups. Mortality (p < 0.0005) was higher in elderly patients.

Conclusions: Ulcerative Colitis has similar presentation and behaviour in elderly and adults patients. However, the elderly are more fragile because of comorbidities, increased risk of infections and disease-related complications.
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May 2020

A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1).

Clin Immunol 2019 03 9;200:31-34. Epub 2019 Jan 9.

Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili of Brescia, Brescia, Italy.

This study reports on a novel activating p110δ mutation causing adult-onset hypogammaglobulinemia with lymphopenia without the classical presentation of atypical Activated phosphoinositide 3-kinase δ syndrome (ADPS-1), underlining thus the heterogeneous clinical and immunological presentation of p110δ mutated individuals and offers additional data on the role of p110δ in early and late B cell development in humans.
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March 2019

Localization of TNF alpha in ileocolonic biopsies of patients with inflammatory bowel disease.

Ann Diagn Pathol 2019 Feb 27;38:20-25. Epub 2018 Oct 27.

Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia School of Medicine, Perugia, Italy.

Background: Although antitumor necrosis factor alfa (TNFα) agents are widely used to treat patients with inflammatory bowel diseases (IBD) - both Crohn's disease (CD) and ulcerative colitis (UC) - there is still some uncertainty in the cell type expressing TNFα in human ileo-colonic segments.

Aims: We investigated the immunohistochemical (IHC) expression of TNFα in the ileo-colonic segments of patients with both active CD and UC, to establish its anatomic and cellular localization in the inflamed sites. Our aim was to identify patients potentially resistant to anti TNFα agents.

Patients And Methods: Ileo-colonic slides of complete histological mapping of patients with CD and UC before any treatment was started were obtained, and serial sections assessed for TNFα expression, together with IHC markers for lymphocytes, macrophages, and plasma cells.

Results: TNFα was expressed in almost all inflamed segments of IBD patients, albeit with different strength, and was present, in addition to lymphocytes and, to a lesser extent, to macrophages, in plasma cells, where it had a strong positivity, as also demonstrated by colocalization of specific IHC staining. The expression of TNFα was mostly focal in CD patients and more diffuse in UC patients, likely due to the different patterns of inflammation (transmural and mucosal) of the two entities.

Conclusions: In IBD, TNFα is strongly expressed also in plasma cells, and it is easily evidenced by conventional IHC techniques. It remains to be established whether this observation might be useful in future to establish in routine biopsy samples whether patients may be responsive to treatments toward this cytokine.
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February 2019

Novel steps forward in the histopathology of non-celiac gluten sensitivity, authors' reply.

Virchows Arch 2018 10 27;473(4):525. Epub 2018 Jun 27.

Gastroenterology Unit, Department of Clinical and Experimental Science, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

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October 2018

Duodenal histological features in suspected non-celiac gluten sensitivity: new insights into a still undefined condition.

Virchows Arch 2018 08 4;473(2):229-234. Epub 2018 Apr 4.

Gastroenterology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

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August 2018

Ulcerative colitis and the aging-related development of colonic diverticula.

Int J Colorectal Dis 2018 Sep 30;33(9):1277-1283. Epub 2018 Mar 30.

Endoscopy, ASST Spedali Civili di Brescia, Brescia, Italy.

Purpose: Aim of this observational case-control study was to assess the prevalence, features, and risk factors of colonic diverticula in patients with ulcerative colitis (UC).

Methods: The data of 896 UC patients aged ≥ 30 years from Brescia IBD database were retrospectively analyzed. Individuals with colonic diverticula were identified and prevalence was compared with that of control patients undergoing screening colonoscopy after gender/age matching. A nested cohort study was then conducted among UC patients in order to define eventual association of diverticula with specific clinico-pathologic parameters.

Results: Prevalence of subjects with diverticula was 11.4% among 465 UC patients aged 49 years and older, significantly lower than 35.1% prevalence in control patients of same age and gender (p < 0.001). Advancing age was a significant risk factor for diverticula development in both groups. Among UC patients, a short duration and a late onset of UC were both significantly associated to the presence of diverticula. Moreover, UC patients with diverticula had a significantly lower frequency of flares per year, even if maximal flare severity and frequency of hospital admission were similar to those of subjects without diverticula. UC patients with diverticula had a trend toward more frequent extension of UC to the left colon, possibly because of their older age. The majority of those patients had few sigmoid diverticula without symptoms.

Conclusions: Development of colonic diverticula is substantially reduced in patients with UC, markedly among those with an early onset, a long history of inflammatory disease, and a high flare frequency. This study reinforces the hypothesis sustaining a protective role of UC against colonic diverticula.
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September 2018

Usefulness of Different Pathological Scores to Assess Healing of the Mucosa in Inflammatory Bowel Diseases: A Real Life Study.

Sci Rep 2017 07 28;7(1):6839. Epub 2017 Jul 28.

Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia School of Medicine, Perugia, Italy.

The concept of remission for patients with inflammatory bowel diseases has recently evolved, and should also include histological healing of the mucosa, difficult to evaluate since there is no agreement on pathological scores and those available are quite complex to use in the daily routine. We evaluated the possible usefulness of a simplified pathological score to assess histological healing of the mucosa in inflammatory bowel diseases patients compared with four commonly proposed pathological scores. Slides from 24 patients (12 Crohn's disease, 12 ulcerative colitis, age range 24-62 years), pre- and post-treatment with biological agents and displaying endoscopic remission were assessed by two pathologists. Pre- and post-treatment results and the time employed to calculate the various scores were obtained. All scores were useful to document highly significant post-treatment decreases of histological activity. However, the simplified score needed significant less time to be calculated for each slide, had high inter-rater agreement, and avoided subjectivity from the pathologists. The simplified score is easy to calculate and seems apt to document histological healing of the mucosa, in a manner similar to the more complex scores. It remains to be established whether this score could simplify the daily routinary practice in this context.
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July 2017

Autoimmune gastritis: relationships with anemia and Helicobacter pylori status.

Scand J Gastroenterol 2017 Jun - Jul;52(6-7):674-677. Epub 2017 Feb 17.

h Gastroenterology and Hepatology Section, Department of Medicine , University of Perugia School of Medicine , Perugia , Italy.

Background: Autoimmune gastritis (AIG) is a gastric pathologic condition affecting the mucosa of the fundus and the body and eventually leading to hypo-achlorhydria.

Aims: We report our clinical and pathological experience with AIG.

Methods: Data from patients with a diagnosis of AIG seen in the period January 2002-December 2012 were retrieved. Only patients with complete sets of biopsies were analyzed.

Results: Data from 138 patients were available for analysis. Pernicious anemia was present in 25% of patients, iron deficiency anemia was found in 29.7% of patients, hypothyroidism in 23% of patients, type 1 diabetes in 7.9% of patients, and vitiligo in 2.8% of patients. Parietal cell antibodies were positive in 65% of patients, and no patient had serology positive for celiac disease. All gastric biopsies showed glandular atrophy associated with enterochromaffin-like (ECL)-cells hyperplasia, features limited to the mucosa of the fundus and body, and focal glandular intestinal metaplasia. Helicobacter pylori was negative in all cases.

Conclusions: AIG was strongly associated with anemia; atrophy, intestinal metaplasia and ECL hyperplasia in the gastric fundus and body are hallmarks of this condition.
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October 2017

Persistent Intraepithelial Lymphocytosis in Celiac Patients Adhering to Gluten-Free Diet Is Not Abolished Despite a Gluten Contamination Elimination Diet.

Nutrients 2016 Aug 26;8(9). Epub 2016 Aug 26.

Gastroenterology Unit, University and Spedali Civili of Brescia, Piazzale Spedali Civili, Brescia I-25123, Italy.

The gluten-free diet (GFD) is the only validated treatment for celiac disease (CD), but despite strict adherence, complete mucosal recovery is rarely obtained. The aim of our study was to assess whether complete restitutio ad integrum could be achieved by adopting a restrictive diet (Gluten Contamination Elimination Diet, GCED) or may depend on time of exposure to GFD. Two cohorts of CD patients, with persisting Marsh II/Grade A lesion at duodenal biopsy after 12-18 months of GFD (early control) were identified. Patients in Cohort A were re-biopsied after a three-month GCED (GCED control) and patients in Cohort B were re-biopsied after a minimum of two years on a standard GFD subsequent to early control (late control). Ten patients in Cohort A and 19 in Cohort B completed the study protocol. There was no change in the classification of duodenal biopsies in both cohorts. The number of intraepithelial lymphocytes, TCRγδ+ (T-Cell Receptor gamma delta) T cell and eosinophils significantly decreased at GCED control (Cohort A) and at late control (Cohort B), compared to early control. Duodenal intraepithelial lymphocytosis persisting in CD patients during GFD is not eliminated by a GCED and is independent of the length of GFD. [NCT 02711696].
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August 2016

Subclinical cardiac involvement in Crohn's disease and ulcerative colitis: an echocardiographic case-control study.

Panminerva Med 2016 Jun 10;58(2):115-20. Epub 2016 Mar 10.

Section of Cardiovascular Diseases, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy -

Background: Cardiovascular manifestations of inflammatory bowel disease (IBD) are considered rare. The aim of the present study was to assess cardiac structure and function by means of traditional Doppler echocardiography and tissue Doppler imaging in order to better appreciate myocardial subclinical alterations and their future implications for these kind of patients.

Methods: Twenty-seven patients affected by Crohn's disease (CD) and 43 suffering from ulcerative colitis (UC) were enrolled. They were selected without cardiovascular diseases nor risk factors. They were compared with 24 healthy subjects matched for sex and age. Everyone underwent transthoracic echocardiography.

Results: IBD patients had larger left atrial anterior-posterior dimension (34±7 vs. 31±2 mm; P=0.001) and volume (46±7 vs. 41±6; P=0.002), reduced left ventricular (LV) ejection fraction (59±6 vs. 63±5%; P=0.006) and higher pulmonary artery systolic pressure (26±6 vs. 22±2 mmHg; P<0.001) than healthy volunteers. Moreover, LV diastolic function was slightly altered in patients in respect of controls. Atrioventricular valve regurgitation was prevalent in IBD. Finally, we found that 18 (25.7%) patients had mitral valve prolapse, 35 (50.0%) mitral valve leaflets thickening and 3 (4.3%) pericardial effusion. We did not find differences in echocardiographic parameters between CD and UC.

Conclusions: Our study suggests that subclinical cardiac involvement is frequent among IBD patients. The underlying mechanisms require further evaluation, but might be due to a systemic increase in cytokines and profibrotic factors.
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June 2016

Gastrointestinal Pathologic Abnormalities in Pediatric- and Adult-Onset Common Variable Immunodeficiency.

Dig Dis Sci 2015 Aug 28;60(8):2384-9. Epub 2015 Mar 28.

Pediatrics Clinic, Department of Clinical and Experimental Sciences, Spedali Civili, University of Brescia, Brescia, Italy.

Background: Common variable immunodeficiency is the most common form of primary symptomatic immunodeficiency. Gastrointestinal manifestations, such as gastritis, diarrhea, gastrointestinal infections, and malabsorption, may complicate the clinical history in almost 50 % of patients.

Aim: To evaluate gastrointestinal histopathological findings in pediatric- and in adult-onset common variable immunodeficiency patients.

Methods: Twenty-two patients with common variable immunodeficiency (13 children, nine adults) were retrospectively studied from a clinical and histopathological point of view.

Results: Increased T lymphocyte infiltrate and the absence of plasma cells in duodenal lamina propria and submucosa were the most frequent findings, independently from onset age, whereas follicular lymphoid hyperplasia and polymorphonuclear infiltrate, as well as parasitic and viral infections, were only present in the adult group. Common variable immunodeficiency patients with minor gastrointestinal symptoms also presented pathological findings, mainly the absence of plasma cells, T cell infiltrate, and infections, independently of age.

Conclusions: Gastrointestinal pathological abnormalities are common in both pediatric- and adult-onset common variable immunodeficiency patients. Histological alterations may vary depending upon the age of onset, possibly due to duration of disease. Minor gastrointestinal symptoms are also associated with pathological findings; therefore, these should be searched in all symptomatic patients.
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August 2015

Clinical expression of lymphocytic duodenosis in "mild enteropathy" celiac disease and in functional gastrointestinal syndromes.

Scand J Gastroenterol 2014 Jul 18;49(7):794-800. Epub 2014 Jun 18.

Gastroenterology Unit, University and Spedali Civili , Brescia , Italy.

Objective: Abnormally high number of duodenal intraepithelial lymphocytes is frequently found in many conditions including mild enteropathy celiac disease (CD) and functional gastrointestinal syndromes, but is unclear whether lymphocytosis affects the clinical phenotype particularly in functional syndromes.

Materials And Methods: We compared clinical characteristics of celiac patients with lymphocytic duodenosis and normal villous structure with those of patients with functional gastrointestinal syndromes with and without lymphocytic duodenosis. We retrospectively identified 3 cohorts among patients referred for suspected CD: (1) "CoelD", 135 patients (age 36 ± 14 years) with mild enteropathy CD; (2) "LymD", 245 patients (38 ± 12 years) with functional gastrointestinal syndromes and lymphocytic duodenosis; and (3) "NorD", 147 patients (37 ± 15 years) with functional syndromes and normal duodenal histology.

Results: Prevalence of gastrointestinal symptoms was similar in the three cohorts, but prevalence of extra-intestinal manifestations (42% vs. 27% vs. 18%, p < 0.003) and of associated diseases (35% vs. 15% vs. 14%, p < 0.0001) was higher in "CoelD" than in "LymD" and "NorD", respectively. Prevalence of Helicobacter pylori infection was similar in the three cohorts. The proportion of patients with final diagnosis of irritable bowel syndrome-diarrhea (38% vs. 37%), dyspepsia (31% vs. 27%), functional pain (14% vs. 19%), and functional diarrhoea (14% vs. 11%) was virtually the same in the cohorts with (LymD) and without (NorD) lymphocytic duodenosis.

Conclusions: Lymphocytic duodenosis has different clinical presentation in patients with mild enteropathy CD than those with functional gastrointestinal syndromes, and is not specific for any particular functional syndrome.
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July 2014

Quantitative analysis of contrast-enhanced ultrasonography of the bowel wall can predict disease activity in inflammatory bowel disease.

Eur J Radiol 2014 Aug 16;83(8):1317-23. Epub 2014 May 16.

Department of Radiology, University of Brescia, P.le Spedali Civili, 1, 25123 Brescia, Italy. Electronic address:

Purpose: To evaluate the accuracy of quantitative analysis of bowel wall enhancement in inflammatory bowel disease (IBD) with contrast enhanced ultrasound (CEUS) by comparing the results with vascular density in a biopsy sample from the same area of the intestinal tract, and to determine the usefulness of this analysis for the prediction of disease activity.

Materials And Methods: This prospective study was approved by our institute's ethics committee and all patients gave written informed consent. We enrolled 33 consecutive adult patients undergoing colonoscopy and biopsy for IBD. All patients underwent CEUS and the results were quantitatively analyzed. Vessel count per high-power field on biopsy specimens was compared with colonoscopy, baseline ultrasonography, and CEUS findings, and with analysis of peak intensity, time to peak, regional blood volume, mean transit time, and regional blood flow. Results in patients with high and low vascular density were compared using Fisher's test, t-test, Pearson's correlation test, and receiver operating characteristic curve (ROC) analysis. Cutoff values were determined using ROC analysis, and sensitivity and specificity were calculated.

Results: High vascular density (>265 vessels per field) on histological examination was significantly correlated with active disease on colonoscopy, baseline ultrasonography, and CEUS (p<.0001). Quantitative analysis showed a higher enhancement peak, a shorter time to peak enhancement, a higher regional blood flow and regional blood volume in patients with high vascular density than in those with low vascular density. Cutoff values to distinguish between active and inactive disease were identified for peak enhancement (>40.5%), and regional blood flow (>54.8 ml/min).

Conclusion: Quantitative analysis of CEUS data correlates with disease activity as determined by vascular density. Quantitative parameters of CEUS can be used to predict active disease with high sensitivity and specificity.
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August 2014

Factors that contribute to hypertransaminasemia in patients with celiac disease or functional gastrointestinal syndromes.

Clin Gastroenterol Hepatol 2014 May 7;12(5):804-810.e2. Epub 2013 Nov 7.

Gastroenterology Unit, University and Spedali Civili, Piazza Spedali Civili, Brescia, Italy. Electronic address:

Background & Aims: Transaminasemia develops via different pathways in patients with celiac disease; no information is available on risk factors specifically attributable to celiac disease.

Methods: We analyzed data collected from consecutive patients referred from January 1997 through December 2009 to the celiac disease clinic at the Spedali Civili of Brescia, Italy. We assessed the factors affecting hypertransaminasemia in 683 patients with celiac disease (based on serologic and biopsy analysis, cohort A; 34 ± 14 years of age) and 304 with functional syndromes (cohort B; 37 ± 13 years of age).

Results: Hypertransaminasemia was detected in 138 patients in cohort A (20%). It was associated with malabsorption (odds ratio [OR], 2.22; P = .004), diarrhea (OR, 1.72; P = .005), and increasing severity of mucosal lesion (Marsh-Oberhuber class; OR, 1.46; P = .001) but not with body mass index (BMI) or the serum level of tissue-transglutaminase antibodies (tTG). Hypertransaminasemia was detected in 22 patients in cohort B (7%) and was associated with the World Health Organization's BMI categories (OR, 7.9; P < .001). In subsets of patients studied with the same analytical method (313 of cohort A and 188 of cohort B), the level of tTG was significantly higher in cohort A at baseline (25.2 ± 16.9 U/L aspartate aminotransferase [AST]) than in cohort B (20.6 ± 9.9 U/L AST, P < .0001) and was related to BMI in cohort B (P = .0012) but not cohort A. When patients were placed on gluten-free diets, the levels of AST decreased from 25.2 ± 16.9 U/L to 19.9 ± 6.6 U/L (P < .0001), independently of the changes of duodenal histology and tTG and correlated with BMI (P = .0007); the prevalence of hypertransaminasemia decreased from 13% to 4%.

Conclusions: Patients with celiac disease have a higher prevalence of hypertransaminasemia than controls (patients with functional syndromes). Hypertransaminasemia is related to the severity of the duodenal lesion and malabsorption but not BMI. By contrast, there was a positive correlation between the levels of AST and BMI in controls; this relationship was restored when patients with celiac disease were placed on gluten-free diets.
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May 2014

Anti-TCR gamma antibody in celiac disease: the value of count on formalin-fixed paraffin-embedded biopsies.

Virchows Arch 2013 Sep 17;463(3):409-13. Epub 2013 Jul 17.

Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Italy.

Small bowel intraepithelial lymphocytosis (IL) may depend from different causes, including celiac disease (CD). Demonstration of increased number of duodenal T cell receptor gamma-delta (TCRγδ) positive intraepithelial lymphocytes (IELs) has been used to support CD diagnosis on frozen material. This work evaluates a new commercially available anti-TCRγ antibody on formalin-fixed paraffin embedded (FFPE) small bowel biopsies. Anti-CD3 and anti-TCR CγM1 (clone γ3.20) from Thermo Scientific were applied by immunohistochemistry on 59 FFPE biopsies from 18 cases of CD with mild/severe atrophy, 19 cases of IL in CD patients on gluten-free diet (IL-GFD), 14 cases of IL (6/14 with positive CD-related serology), and 8 controls (CTR) with mild duodenitis and negative CD serology and genotyping. IELs/100 epithelial cells were counted in at least six high power fields. CD3+ and TCRγ+ IELs were significantly higher in CD, IL-GFD, and IL compared with CTR, but in contrast to CD3+ IELs, TCRγ+ IELs were significantly increased in CD and IL-GFD compared with IL. Furthermore, TCRγ+ IELs discriminated between IL with negative and positive CD-related serology (p = 0.02). TCRγ+ IELs can be identified on FFPE samples and their evaluation adds useful information for the work-up of small bowel biopsies in CD diagnosis. In fact, TCRγ staining coupled with CD3, may represent an additional tool to recognize cases of latent/potential CD when serology and clinical data are not conclusive or when the histological diagnosis remains equivocal.
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September 2013

Search for atoxic cereals: a single blind, cross-over study on the safety of a single dose of Triticum monococcum, in patients with celiac disease.

BMC Gastroenterol 2013 May 24;13:92. Epub 2013 May 24.

Background: Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and ex-vivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD.

Methods: We performed a single blind, cross-over study involving 12 CD patients who had been on a GFD for at least 12 months, challenged on day 0, 14 and 28 with a single fixed dose of 2.5 grams of the following (random order): Tm, rice (as reference atoxic protein) and Amygluten (as reference toxic protein) dispersed in a gluten-free pudding. The primary end-point of the study was the change in intestinal permeability, as assessed by changes in the urinary lactulose/rhamnose ratio (L/R ratio) measured by High Pressure Liquid Chromatography. We also assessed the occurrence of adverse gastrointestinal events, graded for intensity and duration according to the WHO scale. Variables were expressed as mean ± SD; paired t-test and χ² test were used as appropriate.

Results: The urinary L/R ratio did not change significantly upon challenge with the 3 cereals, and was 0.055 ± 0.026 for Tm Vs 0.058 ± 0.035 for rice (p = 0.6736) and Vs 0.063 ± 0.054 with Amygluten (p = 0.6071). Adverse gastrointestinal events were 8 for Tm, Vs 11 for rice (p = 0.6321) and Vs 31 for Amygluten p = 0.0016), and, in all cases events were graded as "mild" or "moderate" with TM and rice, and as "severe" or "disabling" in 4 cases during Amygluten.

Conclusions: No definite conclusion can be drawn on the safety of Tm, based on no change in urinary L/R because even Amygluten, a toxic wheat protein, did not cause a significant change in urinary L/R indicating low sensitivity of this methodology in studies on acute toxicity. Tm was, however, well tolerated by all patients providing the rationale for further investigation on the safety of this cereal for CD patients.

Trial Registration: EudraCT-AIFA n2008-000697-20.
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May 2013

Impact of gluten-free diet on cardiovascular risk factors. A retrospective analysis in a large cohort of coeliac patients.

Dig Liver Dis 2013 Oct 18;45(10):810-5. Epub 2013 May 18.

Gastroenterology Unit, University and Spedali Civili, Brescia, Italy.

Background: Concerns have been raised on whether a gluten-free diet affects the cardiovascular risk profile of coeliac patients.

Aims: To assess changes of multiple cardiovascular risk factors in coeliac patients evaluated before and during a gluten-free diet.

Methods: Retrospective analysis of the effects of 1-5 years of gluten-free diet on indicators of cardiovascular risk and on distribution in cardiovascular risk categories in 715 coeliac patients.

Results: Compared to baseline, significant increases were found in body mass index (21.4±3.4 vs. 22.5±3.5; p<0.0001), total cholesterol (171.2±37.4mg/dL vs. 181.4±35.1mg/dL; p<0.0001), and γ-glutamyl transpeptidase (16.5±14.9 vs. 19.5±19.2U/L; p<0.0001). Significant reductions were found in serum triglycerides (87.9±49.5 vs. 80.2±42.8mg/dL; p<0.0001) and homocysteine (16.9±9.6 vs. 13.3±8.0μmol/L; p=0.018) during gluten-free diet. The proportion of patients included in an arbitrarily defined category of "lowest cardiovascular risk profile" decreased from 58% at baseline to 47% during gluten-free diet.

Conclusions: A gluten-free diet significantly affects cardiovascular risk factors in coeliac patients, but changes do not consistently point towards worse or better risk profiles, thus suggesting that the diet is unlikely to be atherogenic.
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October 2013

Altered expression of type-1 and type-2 cannabinoid receptors in celiac disease.

PLoS One 2013 19;8(4):e62078. Epub 2013 Apr 19.

Department of Biomedical Sciences, University of Teramo, Teramo, Italy.

Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.
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November 2013

Celiac disease with mild enteropathy is not mild disease.

Clin Gastroenterol Hepatol 2013 Mar 27;11(3):253-8. Epub 2012 Sep 27.

Gastroenterology Unit, University of Brescia, Brescia, Italy.

Background & Aims: Patients with celiac disease have varying degrees of damage to the small intestinal mucosa, ranging from lymphocytic duodenosis with normal villous structure to severe villous atrophy. We assessed whether the severity of mucosal lesions was associated with clinical and laboratory features of celiac disease.

Methods: We compared demographic, clinical, and laboratory characteristics among patients with celiac disease who were classified based on the severity of duodenal lesions. We analyzed data from 1408 adult patients seen consecutively at a tertiary referral center since 1990. Patients were classified as having villous atrophy (n = 1249) or as having mild enteropathy (n = 159) in the presence or absence of villous atrophy.

Results: Similar percentages of patients with villous atrophy, vs mild enteropathy, experienced weight loss (17% vs 17%), gastrointestinal manifestations (70% vs 70%), extraintestinal manifestations (66% vs 57%), and other associated conditions (19% vs 23%). More patients with villous atrophy than patients with mild enteropathy developed osteopenia or osteoporosis (22% vs 5%; P = .0005). Greater percentages of patients with villous atrophy than those with mild enteropathy also had anemia (42% vs 29%; P = .002), folate deficiency (75% vs 64%; P = .02), hypocholesterolemia (7% vs 2%; P = .02), hypocalcemia (26% vs 13%; P = .004), or hyperparathyroidism (45% vs 29%; P = .004).

Conclusions: Although osteopenia, osteoporosis, and alterations in laboratory parameters are prevalent among patients with celiac disease with mild enteropathy, they are more prevalent and severe in those with villous atrophy. The prevalence of associated conditions is similar between these groups. These results indicate that celiac disease with mild enteropathy is not mild disease, but requires treatment with a gluten-free diet.
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March 2013

Celiac disease in elderly adults: clinical, serological, and histological characteristics and the effect of a gluten-free diet.

J Am Geriatr Soc 2012 Jun;60(6):1064-9

Gastroenterology Unit, University and Spedali Civili Hospital, Brescia, Italy.

Objectives: To compare celiac disease (CD) in older and younger adults and to assess the effects of a gluten-free diet (GFD).

Design: Retrospective retrieval of information prospectively entered into a structured database.

Setting: CD clinic, University and Spedali Civili, Brescia, Italy.

Participants: Two cohorts were identified (older, Group A, n = 59, >65; younger, Group B, n = 1,166, 18-64), and Group B was subgrouped (B1, n = 600, 18-34; B2, n = 440, 35-49; and B3, n = 26, 50-64).

Measurements: Clinical, serological, and histological characteristics of individuals with CD studied before and during a GFD.

Results: At presentation, weight loss (37% vs 21%, P = .005) and dyspepsia (22% vs 12%, P = .04) were more frequent in older than younger participants. Incidence at diagnosis of non-Hodgkin's lymphoma (NHL) was much higher in older (5%) than younger participants (0.3%, P = .003). Prevalence of osteoporosis was 67% in older and 14% in younger male participants and 70% in older and 9% in younger female participants ( P < .001). During treatment, adherence to a GFD was 90%, normal villous structure was reconstituted, and t-transglutaminase antibodies were negative in 80% of older and younger participants. Lumbar-sacral and femoral T scores increased significantly during a GFD in pooled results of 48 older and younger participants studied before and during GFD.

Conclusion: NHL is already present at CD diagnosis in most cases in individuals aged 50 and older, emphasizing the importance of early diagnosis. Older and younger individuals are equally adherent and equally benefit from a GFD, indicating that older age is not a barrier to dietary treatment.
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June 2012

Cognitive performance is impaired in coeliac patients on gluten free diet: a case-control study in patients older than 65 years of age.

Dig Liver Dis 2012 Sep 7;44(9):729-35. Epub 2012 Apr 7.

Gastroenterology Unit, Department of Medicine, University and Spedali Civili, Brescia, Italy.

Introduction: Retrospective studies and case reports suggest an association between coeliac disease and impaired cognitive function.

Aim: To evaluate functional and cognitive performances in coeliac disease vs. control patients older than 65 years.

Method: Eighteen coeliac disease patients (75±4 years, group A) on gluten free diet since 5.5±3 years and 18 age-sex matched controls (76±4 years, group B) were studied using a battery of neuropsychological tests. Results of functional and cognitive tests are expressed as "row scores" and as "equivalent scores" by relating "raw scores" to reference rank categories.

Results: Barthel Index of functional performance was similar in the 2 groups. "Raw score" was significantly lower in coeliac disease than controls for Mini Mental Test Examination (p=0.02), Trail Making Test (p=0.001), Semantic Fluency (p=0.03), Digit Symbol Test (p=0.007), Ideo-motor apraxia (p<0.001) and Bucco-facial apraxia (p<0.002). "Equivalent score" was also lower in coeliac disease than controls for Semantic memory (p<0.01) and for Ideo-motor apraxia (p=0.007).

Conclusion: Cognitive performance is worse in elderly coeliac disease than control patients, despite prolonged gluten avoidance in coeliacs. Awareness on the increasing phenomenon of late-onset coeliac disease is important to minimize diagnostic delay and prolonged exposure to gluten that may adversely and irreversibly affect cognitive function.
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September 2012

High tissue-transglutaminase antibody level predicts small intestinal villous atrophy in adult patients at high risk of celiac disease.

Dig Liver Dis 2012 Apr 25;44(4):280-5. Epub 2011 Nov 25.

Gastroenterology Unit University and Spedali Civili, Brescia, Italy.

Background: Duodenal biopsy may be unnecessary to confirm celiac disease in patients with high tissue-transglutaminase antibody level.

Aims: To define a cut-off value of tissue-transglutaminase antibody with high positive likelihood ratio for duodenal atrophy in patients with suspected celiac disease.

Methods: We retrospectively identified 945 patients with suspected celiac disease and classified according to the method used for tissue-transglutaminase antibody assay: Group A (n=393, Eu-tTG® Eurospital), Group B (n=263; Eu-tTG® Eurospital) and Group C (n=289; Celikey® Phadia). Duodenal histology was graded according to Marsh. Sensitivity, specificity, and positive likelihood ratio were used to evaluate cut-off points of tissue-transglutaminase antibody as predictor of villous atrophy.

Results: 100% specificity and ∞ positive likelihood ratio for duodenal atrophy was observed at a cut-off value of tissue-transglutaminase antibody 5 times higher than the upper limit of normal. CD diagnosis was confirmed by concordance with antiendomysial antibodies, and by reduction of t-TG titre in all patients and improvement of duodenal histology in 80% during gluten-free diet.

Conclusions: Tissue-transglutaminase antibody level 5-folds the upper limit of normal is 100% specific for duodenal atrophy and using this cut-off biopsy could by avoided in 1/3 of patients. Diagnostic criteria of celiac disease in adults need revision.
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April 2012

Bio-physical characteristics of gastrointestinal mucosa of celiac patients: comparison with control subjects and effect of gluten free diet-.

BMC Gastroenterol 2011 Nov 7;11:119. Epub 2011 Nov 7.

Gastroenterology Unit, Spedali Civili and University, Piazzale Spedali Civili 1, 25123 Brescia, Italy.

Background: Intestinal mucosa is leaky in celiac disease (CD), and this alteration may involve changes in hydrophobicity of the mucus surface barrier in addition to alteration of the epithelial barrier. The aims of our study were i) to compare duodenal hydrophobicity as an index of mucus barrier integrity in CD patients studied before (n = 38) and during gluten- free diet (GFD, n = 68), and in control subjects (n = 90), and ii) to check for regional differences of hydrophobicity in the gastro-intestinal tract.

Methods: Hydrophobicity was assessed by measurement of contact angle (CA) (Rame Hart 100/10 goniometer) generated by a drop of water placed on intestinal mucosal biopsies.

Results: CA (mean ± SD) of distal duodenum was significantly lower in CD patients (56° ± 10°)) than in control subjects (69° ± 9°, p < 0.0001), and persisted abnormal in patients studied during gluten free diet (56° ± 9°; p < 0.005). CA was significantly higher (62° ± 9°) in histologically normal duodenal biopsies than in biopsies with Marsh 1-2 (58° ± 10°; p < 0.02) and Marsh 3 lesions (57° ± 10°; p < 0.02) in pooled results of all patients and controls studied. The order of hydrofobicity along the gastrointestinal tract in control subjects follows the pattern: gastric antrum > corpus > rectum > duodenum > oesophagus > ileum.

Conclusions: We conclude that the hydrophobicity of duodenal mucous layer is reduced in CD patients, and that the resulting decreased capacity to repel luminal contents may contribute to the increased intestinal permeability of CD. This alteration mirrors the severity of the mucosal lesions and is not completely reverted by gluten-free diet. Intestinal hydrophobicity exhibits regional differences in the human intestinal tract.
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November 2011

Five year time course of celiac disease serology during gluten free diet: results of a community based "CD-Watch" program.

Dig Liver Dis 2010 Dec 2;42(12):865-70. Epub 2010 Jul 2.

Gastroenterology Unit, University and Spedali Civili of Brescia, Italy.

Background: Little information is available on the effect of a follow-up strategy in celiac disease patients during gluten-free diet.

Aims: To assess 5 year time course of t-transglutaminase antibodies (t-TG) in celiac disease patients enrolled in a community based follow-up program.

Methods: Annual t-TG testing and periodical clinic visit in 2245 patients.

Results: Proportion of patients with negative t-TG progressively increased from 83% to 93% during the 5-year follow-up: poor adherence to gluten-free diet (HR 4.764), long duration of gluten-free diet (HR 0.929) and female gender (HR 1.472) were independently associated with serological outcome. In individual patients, 69% tested t-TG "persistently negative", 1% "persistently positive" and 30% "intermittently negative or positive". By applying mathematical modelling to t-TG conversion rates observed in this latter group at beginning and end of the follow-up program, the predicted proportion of t-TG negative population increased from 90% to 95% over 5 years.

Conclusions: Time-course of t-TG serology in the community fluctuates in 1/3 of celiac disease patients suggesting inconstant adherence to gluten-free diet and need of follow-up strategy. Periodical serological and clinical follow-up is a viable and efficacious strategy to promote adherence to gluten-free diet as inferred from time-course of t-TG serology.
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December 2010

[Extraintestinal manifestations in Crohn's disease: risk factors and influence of intestinal surgery].

Ann Ital Chir 2009 Jul-Aug;80(4):293-8

Università degli Studi di Brescia, Italia.

Background: Extraintestinal manifestations significantly affect the quality of life of patients with Crohn's disease. The aim of the present study is to define the risk factors for extraintestinal manifestations and the relative influence of intestinal surgery.

Patients And Methods: In a cohort of 223 patients with Crohn's disease we analyzed the association between demographic/clinico-pathological factors and extraintestinal manifestations. In addition, we evaluated their association with the timing of appearance of the extraintestinal manifestations with respect to the intestinal surgery.

Results: Fifty-seven patients (25.6%) developed 91 extraintestinal manifestations. Demographic and clinico-pathological variables significantly associated with extraintestinal manifestations were: female gender (OR 2.84, 95% CI: 1.37-5.90) and colonic involvement (OR 2.68, 95% CI: 1.06-6.76). In patients not undergoing surgery and in patients with extraintestinal manifestations present only before surgery, the latency period between the onset of Crohn'S disease and extraintestinal manifestations were 3.7 +/-8.2 and 2.1 +/- 6.3 years, respectively. In patients developed extraintestinal manifestations only after surgery, the latency between surgery and extraintestinal manifestations was 12.0 +/-10.0 years. In 5 patients with early onset of extraintestinal manifestations, these did not regress or recur after surgery.

Conclusion: Female gender and colonic involvement are confirmed as risk factors for the development of extraintestinal manifestations in Crohn's disease. Surgical treatment of the intestinal disease represents a therapeutic option for patients with extraintestinal manifestations, as it seems to prevent or delay these manifestations in most cases.
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January 2010

Lack of association of coeliac disease with idiopathic and ischaemic dilated cardiomyopathies.

Scand J Clin Lab Invest 2008 ;68(8):692-5

Department of Cardiology, University and Spedali Civili of Brescia, Brescia, Italy.

Objective: A prevalence of coeliac disease higher than in the general population has been reported not only in patients with idiopathic dilated cardiomyopathy, a presumable autoimmune disease, but also in patients with ischaemic or valvular cardiomyopathy. The evidence is controversial, however, and the concept itself of an association unrelated to aetiology is intriguing and warrants further testing. The aim of our study was to assess the prevalence of coeliac disease in a cohort of patients with dilated cardiomyopathy screened for the presence of serum anti-transglutaminase antibodies. We provisionally assessed the sensitivity and specificity of two commercially available kits for tissue transglutaminase antibodies detection.

Material And Methods: We screened for anti-transglutaminase antibodies in 350 consecutive patients with idiopathic (n = 182) and with ischaemic (n = 168) dilated cardiomyopathy using the previously validated method for anti-transglutaminase antibody assay. Coeliac disease diagnosis has been confirmed by duodenal histopathology in patients testing positive at serological screening.

Results: Two coeliac patients (0.6% prevalence) have been identified, one with idiopathic and one with ischaemic dilated cardiomyopathy. They presented with iron deficiency anaemia and with recurrent abdominal pain and diarrhoea, respectively, and both had villous atrophy at histopathology. After 1 year on a gluten-free diet, the echocardiographic parameters did not improve in either patient.

Conclusions: Our results indicate that the prevalence of coeliac disease in patients with dilated cardiomyopathies is similar to that reported for the Italian general population. The confounding factor of conditions associated with both coeliac disease and dilated cardiomyopathies may explain the association unrelated to aetiology reported in previous studies mostly based on small sample size.
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January 2009

Is TCRgamma clonality assay useful to detect early celiac disease?

J Clin Gastroenterol 2007 Mar;41(3):275-9

Second Pathology Unit, Spedali Civili, Brescia, Italy.

Background: Although histology is considered the gold standard for the diagnosis of celiac disease, the early stages (latent or potential) of this disease are difficult to diagnose, because of the negativity of laboratory tests and the lack of villous atrophy. Thus, markers of early disease are needed.

Aims: We investigated the possibility to detect latent or potential celiac disease by means of TCRgamma clonality assay in intraepithelial T cells in patients with suspected disease, negative laboratory tests, and an increased number of intraepithelial lymphocytes.

Patients And Methods: Duodenal biopsies were obtained from 35 patients with nonspecific duodenitis (controls), 13 latent or potential celiac disease subjects, 28 well-defined celiac patients, and 8 celiac patients in gluten-free diet. Histologic and immunohistochemical quantification of intraepithelial lymphocytes, as well as TCRgamma clonality assay, were carried out in all subjects by means of standard techniques.

Results: Intraepithelial lymphocytes and TCRgamma clonality were significantly increased in potential and defined celiac patients with respect to the controls, even though the increase in TCRgamma clonality was lesser with respect to that of intraepithelial lymphocytes. No significant differences were found concerning this variable between the potential and defined celiac subjects.

Conclusions: TCRgamma clonality does not represent a marker of early disease. However, it might be useful to help in distinguishing celiac disease from other causes of nonspecific duodenitis.
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March 2007

Novel treatment options for inflammatory bowel disease: targeting alpha 4 integrin.

Drugs 2006 ;66(9):1179-89

Imperial College London, Hammersmith Hospital, London, UK.

The aetiology of inflammatory bowel disease (IBD) is complex and many aspects still remain unclear. However, significant progress has been made in understanding the pathogenesis of chronic inflammation in the intestine, and new insights have been gained recently. A better understanding of the immunopathology of IBD has led to the development of novel biological agents to target crucial molecules and processes in the inflammatory cascade. The development of novel therapies in the management of IBD has moved from empirical to scientific rational translation from bench to bedside. Lymphocyte infiltration into the intestinal tract in Crohn's disease (CD) is mediated by interaction between alpha4 integrin expressed on lymphocytes and its specific ligand mucosal vascular addressin cell adhesion molecule-1, expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against alpha4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, a recombinant humanised monoclonal antibody against alpha4 integrin, was effective in CD in a phase II randomised controlled trial. The highest response rate and remission rate were 71% and 44%, respectively, at 6 weeks after two infusions of natalizumab 3mg administered 4 weeks apart. Natalizumab was well tolerated in this trial. The phase III trial results are encouraging, although the primary efficacy endpoint of response at week 10 was not achieved. The maintenance of response and remission trial, ENACT (Evaluation of Natalizumab as Continuous Therapy)-2, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT-1) trial. This was associated with an improvement in quality-of-life parameters. A second humanised monoclonal antibody, MLN-02 (LDP-02), developed against alpha4beta7 has also shown evidence of efficacy in ulcerative colitis and CD. Although the clinical trials showed that inhibition of alpha4 integrin was well tolerated, use of natalizumab in multiple sclerosis and CD has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML) in a small number of patients, and the drug has been withdrawn from the market pending further safety evaluation. PML is caused by polyoma JC virus infection, is progressive and generally fatal, and is recognised to occur in patients with severe immunosuppression. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with CD receiving open-label natalizumab treatment.
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December 2006