Inflammatory bowel disease (IBD) could be associated with several extra-intestinal manifestations... more Inflammatory bowel disease (IBD) could be associated with several extra-intestinal manifestations (EIMs) involving musculoskeletal, hepatopancreatobiliary, ocular, renal, and pulmonary systems, as well as the skin. In the last years, hidradenitis suppurativa (HS) is acquiring an increasing interest. IBD, especially Crohn's disease (CD), is among the most reported associated diseases in HS patients. The aim of this paper is to give a brief overview of data showing a possible epidemiologic and pathogenetic association between IBD and HS. We performed a pooled-data analysis of four studies and pooled prevalence of HS in IBD patients was 12.8%, with a 95%CI of 11.7%-13.9%. HS was present in 17.3% of subjects with CD (95%CI: 15.5%-19.1%) and in 8.5% of UC patients (95%CI: 7.0%-9.9%). Some items, especially altered immune imbalance, are generally involved in IBD pathogenesis as well as invoked by HS. Smoking is one of the most relevant risk factors for both disorders, representing a predictor of their severity, despite, actually, there being a lack of studies analyzing a possible shared pathway. A role for inheritance in HS and CD pathogenesis has been supposed. Despite a genetic susceptibility having been demonstrated for both diseases, further studies are needed to investigate a genetic mutual route. Although the pathogenesis of IBD and HS is generally linked to alterations of the immune response, recent findings suggest a role for intestinal and skin microbiota, respectively. In detail, the frequent finding of Staphylococcus aureus and coagulase-negative staphylococci on HS cutaneous lesions suggests a bacterial involvement in disease pathogenesis. Moreover, microflora varies in the different cutaneous regions of the body and, consequently, two different profiles of HS patients have been identified on these bases. On the other hand, it is well-known that intestinal microbiota may be considered as "the explosive mixture" at the origin of IBD despite the exact relationship having not been completely clarified yet. A better comprehension of the role that some bacterial species play in the IBD pathogenesis may be essential to develop appropriate management strategies in the near future. A final point is represented by some similarities in the therapeutic management of HS and IBD, since they may be controlled by immunomodulatory drugs. In conclusion, an unregulated inflammation may cause the lesions typical of both HS and IBD, particularly when they coexist. However, this is still a largely unexplored field.
There are overwhelming reports and descriptions about celiac associated disorders. Although there... more There are overwhelming reports and descriptions about celiac associated disorders. Although there is a clear genetic association between celiac disease (CD) and some gastrointestinal disorders, there are controversial reports claiming an association between CD and Helicobacter pylori (H. pylori) infection. Different studies indicated the possible association between lymphocytic gastritis and both CD and H. pylori infection, although this evidence is not consistently accepted. Also it was shown that an increase in intraepithelial lymphocytes count is associated with both H. pylori infection and celiac disease. Therefore the following questions may raise: how far is this infection actually related to CD?, which are the underlying patho-mechanisms for these associations? what are the clinical implications? what is the management? and what would be the role of gluten free diet in treating these conditions? PubMed (PubMed Central), Ovid, ISI of web knowledge, and Google scholar were searched for full text articles published between 1985 and 2015. The associated keywords were used, and papers described particularly the impact of pathological and clinical correlation between CD and H. pylori infection were identified. In this review we tried to answer the above questions and discussed some of the recent developments in the pathological and clinical aspects of CD and H. pylori infection.
To investigate estrogen receptors expression in duodenal familial adenomatous polyposis (FAP) and... more To investigate estrogen receptors expression in duodenal familial adenomatous polyposis (FAP) and any relationship with epithelial proliferation/apoptosis markers. Twenty-two patients affected by FAP undergoing duodenal resection for malignancies were recruited. Controls were 15 healthy subjects undergoing endoscopy for dyspeptic symptoms. ER-α, ER-α, Ki-67, TUNEL and caspase 3 expression (labeling index: percentage of positive cells) were evaluated by immunohistochemistry or immunofluorescence and examined by light or confocal microscopy. Samples were assigned to four groups: normal tissue, low (LGD) and high-grade dysplasia (HGD), adenocarcinoma (AC). One-way analysis of variance, corrected by Bonferroni's test, and Pearson's correlation test were applied for statistical analysis. ER-beta showed a progressive decline: normal tissue (23.5 ± 4.9), LGD (21.1 ± 4.8), HGD (9.3 ± 3.5), AC (7.1 ± 3.1). The normal tissue of FAP subjects expressed ER-beta like the controls (23.9 ± 6.2). Conversely, ER-α showed a progressive increase from normal tissue (24.8 ± 5.6) to AC (52.0 ± 8.2); the expression in normal tissue was similar to controls (22.5 ± 5.3). Ki67 demonstrated a statistically significant progressive increase at each disease stage up to AC. TUNEL did not reveal differences between controls and normal tissue of FAP subjects, but progressive decreases were observed in LGD, through HGD to AC. Pearson's correlation test showed a direct relationship between ER-β and TUNEL LI (r = 0.8088, P < 0.0001). Conversely, ER-α was inversely correlated with TUNEL LI (r = - 0.7257, P < 0.0001). The co-expression of ER-β and caspase 3 declined progressively from normal to neoplastic tissue. This study confirmed that ER-β is strongly decreased in duodenal FAP carcinomas, declining in a multiple step fashion, thereby suggesting a putative anti-carcinogenic effect. ER-α showed the opposite trend. ER-β/caspase 3 co-expression suggests this hormone's possible involvement in apoptosis. Hormonal influences in FAP duodenal tumorigenesis, and modulation of these as a possible chemoprevention strategy, may be a promising approach.
Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflamma... more Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflammation. Several studies have also emphasized its pro-carcinogenic effect in colorectal cancer (CRC). In fact, increased histamine levels have been observed in CRC and a decreased catabolism of this molecule is typical of colorectal adenomas. Additional data have demonstrated that CRC is characterized by an altered balance of histamine receptors (HRs); in fact, HR1 and HR4 are down-regulated in CRC, while HR2 is overexpressed. Based on this evidence, several studies investigating the role of HR2 antagonists (HR2A), such as cimetidine, have been performed in CRC. From a clinical point of view, HR2A may prolong the survival rates of patients with CRC, and a recent meta-analysis seems to confirm this finding. From a biological perspective, it has been demonstrated that HR2A could have a beneficial effect on CRC for many reasons: i) promotion of peri-tumoral lymphocyte growth and improvement of immune response against the tumor, ii) suppression of adhesion molecules which might favor metastasis, iii) anti-angiogenetic activity (reduction of VEGF), iv) increased production of some cytokines which may counteract tumor growth, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-10 and IL-15. On the contrary, HR1 antagonists did not demonstrate any beneficial effect on CRC. Therefore, it is presumable that histamine could be an important player in the development of CRC, but its effect might be mediated by an imperfect homeostasis of its receptors. In this scenario, HR2A could inhibit carcinogenesis whereas HR2 might act as a pro-carcinogenetic, while HR1 and HR4, being suppressed in CRC, may antagonize neoplastic development.
We report an update of current methods for colorectal cancer (CRC) screening based on fecal sampl... more We report an update of current methods for colorectal cancer (CRC) screening based on fecal sample analysis. A systematic review of the literature was performed in MEDLINE, EMBASE, and Science Direct electronic databases. Blood in the stools is the first and most used strategy. Fecal occult blood test (FOBT) and fecal immunochemical test (FIT) are the main methods. Both are economic, easy to perform with high specificity, and low sensitivity. Based on CRC multi-step process with genetic and epigenetic alterations in large bowel cell DNA, single mutations or panels of alterations have been detected. These tests have the advantage of a marked improvement of the sensitivity when compared to fecal blood. However, high costs, poor availability, and correct choice of marker panel represent the major limits. A specific sDNA panel including aberrantly methylated BMP3 and NDRG4 promoter regions, mutant k-ras and β-actin (a reference gene for human DNA quantity), and an immunochemical assay for human hemoglobin has been recently approved by Food and Drug Administration. Novel promising biomarkers for CRC screening are represented by microRNAs (miRNAs), a group of 18-25 nucleotide non-coding RNA molecules that regulate gene expression. Reports on these fecal biomarkers are case-control studies, and each of them evaluates single miRNAs or multi-target panels. On the other hand, some fecal proteins have been studied as possible CRC screening markers, even though they demonstrated poor results. Finally, alterations of estrogen receptor-beta (i.e., dramatic reduction in the early stage of CRC) have been demonstrated in tissue samples. Specific investigations are warranted in order to add further noninvasive markers to the panel of CRC screening tools.
Acute pancreatitis (AP) in elderly may have an aggressive course due to co-morbidity high rate an... more Acute pancreatitis (AP) in elderly may have an aggressive course due to co-morbidity high rate and severe presentation. We retrospectively evaluated AP severity and its underlying factors in a group of elderly patients compared with an adult population sample. Forty-two elderly patients (65-102years) and 48 controls (19-64years) admitted at our Unit for biliary or alcoholic AP were retrospectively enrolled. AP severity was evaluated by the Atlanta classification and Ransom score. Laboratory investigations and demographic data were collected. Comparison between the two groups was performed by t-test, ANOVA or Fisher's exact test. A multinomial logistic regression was used to determine factors affecting AP severity. Elderly patients showed more severe Atlanta (1.81±0.75 vs 1.29±0.46; p=0.007) and higher Ransom (2.52±1.57 vs 0.75±0.73; p<0.0001) scores. No death was observed. Elderly patients consumed more drugs than controls, had higher rates of cardiovascular, pulmonary and renal co-morbidity, showed higher creatinine (1.09±0.41 vs 0.81±0.18; p=0.004) and lower calcium levels (8.43±0.48 vs 8.88±0.44; p=0.002). We observed only one case of fluid necrosis in an old patient. Non-necrotic fluid collections were more common in the elderly (40.5% vs 12.5%; p=0.003). At multivariate analysis, AP severity was influenced by white blood cell-count (WBC: OR=1.94; p=0.048), aspartate-transaminase-levels (AST: OR=1.97; p=0.02), serum lactate-dehydrogenase (LDH: OR=1.07; p=0.047) and Ransom score (OR=70.4; p=0.036) in elderly, while only Ransom score correlated in controls (OR=66.04; p<0.001). The etiology (biliary/alcoholic) did not influence the severity. Elderly patients usually undergo a severe AP course, but without increase of mortality. High WBC, LDH, AST and Ransom score at the onset may predict AP severity.
Journal of gastrointestinal and liver diseases : JGLD, 2015
Escherichia coli Nissle 1917 (EcN) has been recommended as a therapeutic tool for ulcerative coli... more Escherichia coli Nissle 1917 (EcN) has been recommended as a therapeutic tool for ulcerative colitis (UC) treatment. However, to date, no meta-analysis has been performed on this topic. We performed a literature search on PubMed, MEDLINE, Science Direct and EMBASE. We evaluated success rates for induction of remission, relapse rates and side effects, expressed as Intention-To-Treat. Odd ratios (OR), pooled OR and 95% confidence intervals (CI) were calculated, based on the Mantel-Haenszel method. Heterogeneity was assessed by using the χ2 and I2 statistics and, if present, a random-effects model was adopted. We selected six eligible trials, with 719 patients, 390 assigned to the study group and 329 to the control group. EcN induced remission in 61.6% of cases, while in the control group (mesalazine) the remission was achieved in 69.5% of cases, with a mean difference of 7.9%. The pooled OR was 0.92 (95% CI 0.15-9.66, p=0.93). A single study showed a better performance of EcN than the...
In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and inte... more In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNg). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNg-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs). Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 mm sections were used for the extraction and assay of tTG and IFNg coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change. Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15-25 (26 patients: group B), and 0-15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNg-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4. Our results suggest that tTG- and IFNγ-mRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15-25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders.
Obesity is a multifactorial disorder with a possible microbiota derangement in its pathogenesis. ... more Obesity is a multifactorial disorder with a possible microbiota derangement in its pathogenesis. Moreover, in obese patients the likelihood of small intestinal bacterial overgrowth (SIBO) is greater than in controls, although few studies are currently available. This study investigates the prevalence of SIBO and the possible role of dietary macronutrients in obesity. Sixty obese patients and normal lean controls were enrolled for SIBO detection. Diagnosis of SIBO was performed by a glucose breath test. A 24-hour recall questionnaire was administered to investigate macronutrient daily intake between the two obese patient subgroups (with/without SIBO). The presence of SIBO in obese and controls was respectively 23.3% and 6.6% (p = 0.02, OR = 4.26, 95% Confidence interval = 1.31-13.84). Obese patients with SIBO ingested more carbohydrates (252.75 ± 30.53 vs 201 ± 70.76 g/day, p = 0.01), more refined sugars (104.15 ± 28.69 vs 73.32 ± 44.93 g/day, p = 0.02) and less total and insoluble fibers (9.6 ± 1.97 vs 14.65 ± 8.80 g/day, p = 0.04 and 4.7 ± 1.11 vs 8.82 ± 5.80 g/day, p = 0.01, respectively). There were no significant differences in lipid and protein intake between the two groups. SIBO is widespread in obese subjects. Carbohydrates might promote the development of SIBO in obesity and fibers provide a protective function. Our results suggest a close relationship between diet and SIBO in obesity, thus supporting a possible role for intestinal microbiota.
In the present narrative review, we analyzed the relationship between seronegative celiac disease... more In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten "challenge" are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs' range of 15-25/100 enterocytes, suggesting that there may be a "grey zone" of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association.
Journal of gastrointestinal and liver diseases : JGLD, 2015
Infliximab (IFX) is an anti-tumor necrosis factor alpha agent used in inflammatory bowel diseases... more Infliximab (IFX) is an anti-tumor necrosis factor alpha agent used in inflammatory bowel diseases (IBD) therapy. Usually, it is administered over a 2-hour intravenous infusion. However, shortening the infusion duration to 1 hour has proved to be feasible and safe. In the present study we evaluated whether shortening the IFX infusion could affect the patients' quality of life (QoL) compared to the standard protocol. Subjects affected by IBD receiving IFX were prospectively recruited. The main criterion to shorten the infusion was the absence of IFX-related adverse reactions during the previous three 2-h infusions. For each patient, demographic, clinical and anthropometric data were collected. A questionnaire investigating their overall/job/social/sexual QoL was administered. Ordinal regression was performed with odds ratios (OR) for significant independent variables. Eighty-one patients were included (46 with ulcerative colitis - UC, 35 with Crohn's disease - CD). Sixteen rec...
Intestinal microbiota is a "dynamic organ" influencing host metabolism, nutrition, phys... more Intestinal microbiota is a "dynamic organ" influencing host metabolism, nutrition, physiology and immune system. Among its several interactions, the role of a phosphatidylcholine metabolite derived by gut flora activity, i.e., trimethylamine-N-oxide (TMAO), allows perceiving a novel insight in the cardiovascular risk scenario, being a strong predictor of this condition. Based on current reports, including the paper of Tang et al., we describe here: the possible role of intestinal microbiota in cardiovascular risk as well as potential interventions to reduce gut flora TMAO production by diet, probiotics and antibiotics. Finally, we highlight the possibility of evaluating, monitoring and modulating TMAO in order to use its serum levels as a marker of cardiovascular risk in the next future, when the need of controlled studies on large series will be satisfied.
Gastroenterology and hepatology from bed to bench, 2015
The diagnosis of Celiac Disease (CD) relies on the concordance of pathological, serological, gene... more The diagnosis of Celiac Disease (CD) relies on the concordance of pathological, serological, genetic and clinical features. For this reason, the diagnosis of CD is often a challenge. Seronegative celiac disease (SNCD) is defined by the negativity of anti-tissue transglutaminase antibodies in the presence of a positive histology on duodenal biopsy samples, i.e. inflammatory infiltrate of intra-epithelial lymphocytes (IELs > 25/100 enterocytes), mild villous atrophy and uneven brush border associated to human leukocyte antigen (HLA) haplotype DQ2 and/or DQ8. SNCD is characterized by mucosal deposits of tissue transglutaminase (tTG)/anti-tTG immuno-complexes. These may counteract the passage of anti-tTG into the bloodstream, thus explaining seronegativity. Another reason for seronegativity may be found in an incomplete maturation of plasma cells with a consequent failure of antibodies production. This condition often characterizes immunoglobulin deficiencies, and, indeed, SNCD is co...
Inflammatory bowel disease (IBD) could be associated with several extra-intestinal manifestations... more Inflammatory bowel disease (IBD) could be associated with several extra-intestinal manifestations (EIMs) involving musculoskeletal, hepatopancreatobiliary, ocular, renal, and pulmonary systems, as well as the skin. In the last years, hidradenitis suppurativa (HS) is acquiring an increasing interest. IBD, especially Crohn's disease (CD), is among the most reported associated diseases in HS patients. The aim of this paper is to give a brief overview of data showing a possible epidemiologic and pathogenetic association between IBD and HS. We performed a pooled-data analysis of four studies and pooled prevalence of HS in IBD patients was 12.8%, with a 95%CI of 11.7%-13.9%. HS was present in 17.3% of subjects with CD (95%CI: 15.5%-19.1%) and in 8.5% of UC patients (95%CI: 7.0%-9.9%). Some items, especially altered immune imbalance, are generally involved in IBD pathogenesis as well as invoked by HS. Smoking is one of the most relevant risk factors for both disorders, representing a predictor of their severity, despite, actually, there being a lack of studies analyzing a possible shared pathway. A role for inheritance in HS and CD pathogenesis has been supposed. Despite a genetic susceptibility having been demonstrated for both diseases, further studies are needed to investigate a genetic mutual route. Although the pathogenesis of IBD and HS is generally linked to alterations of the immune response, recent findings suggest a role for intestinal and skin microbiota, respectively. In detail, the frequent finding of Staphylococcus aureus and coagulase-negative staphylococci on HS cutaneous lesions suggests a bacterial involvement in disease pathogenesis. Moreover, microflora varies in the different cutaneous regions of the body and, consequently, two different profiles of HS patients have been identified on these bases. On the other hand, it is well-known that intestinal microbiota may be considered as "the explosive mixture" at the origin of IBD despite the exact relationship having not been completely clarified yet. A better comprehension of the role that some bacterial species play in the IBD pathogenesis may be essential to develop appropriate management strategies in the near future. A final point is represented by some similarities in the therapeutic management of HS and IBD, since they may be controlled by immunomodulatory drugs. In conclusion, an unregulated inflammation may cause the lesions typical of both HS and IBD, particularly when they coexist. However, this is still a largely unexplored field.
There are overwhelming reports and descriptions about celiac associated disorders. Although there... more There are overwhelming reports and descriptions about celiac associated disorders. Although there is a clear genetic association between celiac disease (CD) and some gastrointestinal disorders, there are controversial reports claiming an association between CD and Helicobacter pylori (H. pylori) infection. Different studies indicated the possible association between lymphocytic gastritis and both CD and H. pylori infection, although this evidence is not consistently accepted. Also it was shown that an increase in intraepithelial lymphocytes count is associated with both H. pylori infection and celiac disease. Therefore the following questions may raise: how far is this infection actually related to CD?, which are the underlying patho-mechanisms for these associations? what are the clinical implications? what is the management? and what would be the role of gluten free diet in treating these conditions? PubMed (PubMed Central), Ovid, ISI of web knowledge, and Google scholar were searched for full text articles published between 1985 and 2015. The associated keywords were used, and papers described particularly the impact of pathological and clinical correlation between CD and H. pylori infection were identified. In this review we tried to answer the above questions and discussed some of the recent developments in the pathological and clinical aspects of CD and H. pylori infection.
To investigate estrogen receptors expression in duodenal familial adenomatous polyposis (FAP) and... more To investigate estrogen receptors expression in duodenal familial adenomatous polyposis (FAP) and any relationship with epithelial proliferation/apoptosis markers. Twenty-two patients affected by FAP undergoing duodenal resection for malignancies were recruited. Controls were 15 healthy subjects undergoing endoscopy for dyspeptic symptoms. ER-α, ER-α, Ki-67, TUNEL and caspase 3 expression (labeling index: percentage of positive cells) were evaluated by immunohistochemistry or immunofluorescence and examined by light or confocal microscopy. Samples were assigned to four groups: normal tissue, low (LGD) and high-grade dysplasia (HGD), adenocarcinoma (AC). One-way analysis of variance, corrected by Bonferroni's test, and Pearson's correlation test were applied for statistical analysis. ER-beta showed a progressive decline: normal tissue (23.5 ± 4.9), LGD (21.1 ± 4.8), HGD (9.3 ± 3.5), AC (7.1 ± 3.1). The normal tissue of FAP subjects expressed ER-beta like the controls (23.9 ± 6.2). Conversely, ER-α showed a progressive increase from normal tissue (24.8 ± 5.6) to AC (52.0 ± 8.2); the expression in normal tissue was similar to controls (22.5 ± 5.3). Ki67 demonstrated a statistically significant progressive increase at each disease stage up to AC. TUNEL did not reveal differences between controls and normal tissue of FAP subjects, but progressive decreases were observed in LGD, through HGD to AC. Pearson's correlation test showed a direct relationship between ER-β and TUNEL LI (r = 0.8088, P < 0.0001). Conversely, ER-α was inversely correlated with TUNEL LI (r = - 0.7257, P < 0.0001). The co-expression of ER-β and caspase 3 declined progressively from normal to neoplastic tissue. This study confirmed that ER-β is strongly decreased in duodenal FAP carcinomas, declining in a multiple step fashion, thereby suggesting a putative anti-carcinogenic effect. ER-α showed the opposite trend. ER-β/caspase 3 co-expression suggests this hormone's possible involvement in apoptosis. Hormonal influences in FAP duodenal tumorigenesis, and modulation of these as a possible chemoprevention strategy, may be a promising approach.
Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflamma... more Histamine is an imidazolic compound performing a crucial function in the pathogenesis of inflammation. Several studies have also emphasized its pro-carcinogenic effect in colorectal cancer (CRC). In fact, increased histamine levels have been observed in CRC and a decreased catabolism of this molecule is typical of colorectal adenomas. Additional data have demonstrated that CRC is characterized by an altered balance of histamine receptors (HRs); in fact, HR1 and HR4 are down-regulated in CRC, while HR2 is overexpressed. Based on this evidence, several studies investigating the role of HR2 antagonists (HR2A), such as cimetidine, have been performed in CRC. From a clinical point of view, HR2A may prolong the survival rates of patients with CRC, and a recent meta-analysis seems to confirm this finding. From a biological perspective, it has been demonstrated that HR2A could have a beneficial effect on CRC for many reasons: i) promotion of peri-tumoral lymphocyte growth and improvement of immune response against the tumor, ii) suppression of adhesion molecules which might favor metastasis, iii) anti-angiogenetic activity (reduction of VEGF), iv) increased production of some cytokines which may counteract tumor growth, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-10 and IL-15. On the contrary, HR1 antagonists did not demonstrate any beneficial effect on CRC. Therefore, it is presumable that histamine could be an important player in the development of CRC, but its effect might be mediated by an imperfect homeostasis of its receptors. In this scenario, HR2A could inhibit carcinogenesis whereas HR2 might act as a pro-carcinogenetic, while HR1 and HR4, being suppressed in CRC, may antagonize neoplastic development.
We report an update of current methods for colorectal cancer (CRC) screening based on fecal sampl... more We report an update of current methods for colorectal cancer (CRC) screening based on fecal sample analysis. A systematic review of the literature was performed in MEDLINE, EMBASE, and Science Direct electronic databases. Blood in the stools is the first and most used strategy. Fecal occult blood test (FOBT) and fecal immunochemical test (FIT) are the main methods. Both are economic, easy to perform with high specificity, and low sensitivity. Based on CRC multi-step process with genetic and epigenetic alterations in large bowel cell DNA, single mutations or panels of alterations have been detected. These tests have the advantage of a marked improvement of the sensitivity when compared to fecal blood. However, high costs, poor availability, and correct choice of marker panel represent the major limits. A specific sDNA panel including aberrantly methylated BMP3 and NDRG4 promoter regions, mutant k-ras and β-actin (a reference gene for human DNA quantity), and an immunochemical assay for human hemoglobin has been recently approved by Food and Drug Administration. Novel promising biomarkers for CRC screening are represented by microRNAs (miRNAs), a group of 18-25 nucleotide non-coding RNA molecules that regulate gene expression. Reports on these fecal biomarkers are case-control studies, and each of them evaluates single miRNAs or multi-target panels. On the other hand, some fecal proteins have been studied as possible CRC screening markers, even though they demonstrated poor results. Finally, alterations of estrogen receptor-beta (i.e., dramatic reduction in the early stage of CRC) have been demonstrated in tissue samples. Specific investigations are warranted in order to add further noninvasive markers to the panel of CRC screening tools.
Acute pancreatitis (AP) in elderly may have an aggressive course due to co-morbidity high rate an... more Acute pancreatitis (AP) in elderly may have an aggressive course due to co-morbidity high rate and severe presentation. We retrospectively evaluated AP severity and its underlying factors in a group of elderly patients compared with an adult population sample. Forty-two elderly patients (65-102years) and 48 controls (19-64years) admitted at our Unit for biliary or alcoholic AP were retrospectively enrolled. AP severity was evaluated by the Atlanta classification and Ransom score. Laboratory investigations and demographic data were collected. Comparison between the two groups was performed by t-test, ANOVA or Fisher's exact test. A multinomial logistic regression was used to determine factors affecting AP severity. Elderly patients showed more severe Atlanta (1.81±0.75 vs 1.29±0.46; p=0.007) and higher Ransom (2.52±1.57 vs 0.75±0.73; p<0.0001) scores. No death was observed. Elderly patients consumed more drugs than controls, had higher rates of cardiovascular, pulmonary and renal co-morbidity, showed higher creatinine (1.09±0.41 vs 0.81±0.18; p=0.004) and lower calcium levels (8.43±0.48 vs 8.88±0.44; p=0.002). We observed only one case of fluid necrosis in an old patient. Non-necrotic fluid collections were more common in the elderly (40.5% vs 12.5%; p=0.003). At multivariate analysis, AP severity was influenced by white blood cell-count (WBC: OR=1.94; p=0.048), aspartate-transaminase-levels (AST: OR=1.97; p=0.02), serum lactate-dehydrogenase (LDH: OR=1.07; p=0.047) and Ransom score (OR=70.4; p=0.036) in elderly, while only Ransom score correlated in controls (OR=66.04; p<0.001). The etiology (biliary/alcoholic) did not influence the severity. Elderly patients usually undergo a severe AP course, but without increase of mortality. High WBC, LDH, AST and Ransom score at the onset may predict AP severity.
Journal of gastrointestinal and liver diseases : JGLD, 2015
Escherichia coli Nissle 1917 (EcN) has been recommended as a therapeutic tool for ulcerative coli... more Escherichia coli Nissle 1917 (EcN) has been recommended as a therapeutic tool for ulcerative colitis (UC) treatment. However, to date, no meta-analysis has been performed on this topic. We performed a literature search on PubMed, MEDLINE, Science Direct and EMBASE. We evaluated success rates for induction of remission, relapse rates and side effects, expressed as Intention-To-Treat. Odd ratios (OR), pooled OR and 95% confidence intervals (CI) were calculated, based on the Mantel-Haenszel method. Heterogeneity was assessed by using the χ2 and I2 statistics and, if present, a random-effects model was adopted. We selected six eligible trials, with 719 patients, 390 assigned to the study group and 329 to the control group. EcN induced remission in 61.6% of cases, while in the control group (mesalazine) the remission was achieved in 69.5% of cases, with a mean difference of 7.9%. The pooled OR was 0.92 (95% CI 0.15-9.66, p=0.93). A single study showed a better performance of EcN than the...
In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and inte... more In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNg). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNg-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs). Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 mm sections were used for the extraction and assay of tTG and IFNg coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change. Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15-25 (26 patients: group B), and 0-15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNg-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4. Our results suggest that tTG- and IFNγ-mRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15-25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders.
Obesity is a multifactorial disorder with a possible microbiota derangement in its pathogenesis. ... more Obesity is a multifactorial disorder with a possible microbiota derangement in its pathogenesis. Moreover, in obese patients the likelihood of small intestinal bacterial overgrowth (SIBO) is greater than in controls, although few studies are currently available. This study investigates the prevalence of SIBO and the possible role of dietary macronutrients in obesity. Sixty obese patients and normal lean controls were enrolled for SIBO detection. Diagnosis of SIBO was performed by a glucose breath test. A 24-hour recall questionnaire was administered to investigate macronutrient daily intake between the two obese patient subgroups (with/without SIBO). The presence of SIBO in obese and controls was respectively 23.3% and 6.6% (p = 0.02, OR = 4.26, 95% Confidence interval = 1.31-13.84). Obese patients with SIBO ingested more carbohydrates (252.75 ± 30.53 vs 201 ± 70.76 g/day, p = 0.01), more refined sugars (104.15 ± 28.69 vs 73.32 ± 44.93 g/day, p = 0.02) and less total and insoluble fibers (9.6 ± 1.97 vs 14.65 ± 8.80 g/day, p = 0.04 and 4.7 ± 1.11 vs 8.82 ± 5.80 g/day, p = 0.01, respectively). There were no significant differences in lipid and protein intake between the two groups. SIBO is widespread in obese subjects. Carbohydrates might promote the development of SIBO in obesity and fibers provide a protective function. Our results suggest a close relationship between diet and SIBO in obesity, thus supporting a possible role for intestinal microbiota.
In the present narrative review, we analyzed the relationship between seronegative celiac disease... more In the present narrative review, we analyzed the relationship between seronegative celiac disease (SNCD) and immunoglobulin deficiencies. For this purpose, we conducted a literature search on the main medical databases. SNCD poses a diagnostic dilemma. Villous blunting, intraepithelial lymphocytes (IELs) count and gluten "challenge" are the most reliable markers. Immunohistochemistry/immunofluorescence tissue transglutaminase (tTG)-targeted mucosal immunoglobulin A (IgA) immune complexes in the intestinal mucosa of SNCD patients may be useful. In our experience, tTG-mRNA was similarly increased in seropositive celiac disease (CD) and suspected SNCD, and strongly correlated with the IELs count. This increase is found even in the IELs' range of 15-25/100 enterocytes, suggesting that there may be a "grey zone" of gluten-related disorders. An immune deregulation (severely lacking B-cell differentiation) underlies the association of SNCD with immunoglobulin deficiencies. Therefore, CD may be linked to autoimmune disorders and immune deficits (common variable immunodeficiency (CVID)/IgA selective deficiency). CVID is a heterogeneous group of antibodies dysfunction, whose association with CD is demonstrated only by the response to a gluten-free diet (GFD). We hypothesized a familial inheritance between CD and CVID. Selective IgA deficiency, commonly associated with CD, accounts for IgA-tTG seronegativity. Selective IgM deficiency (sIgMD) is rare (<300 cases) and associated to CD in 5% of cases. We diagnosed SNCD in a patient affected by sIgMD using the tTG-mRNA assay. One-year GFD induced IgM restoration. This evidence, supporting a link between SNCD and immunoglobulin deficiencies, suggests that we should take a closer look at this association.
Journal of gastrointestinal and liver diseases : JGLD, 2015
Infliximab (IFX) is an anti-tumor necrosis factor alpha agent used in inflammatory bowel diseases... more Infliximab (IFX) is an anti-tumor necrosis factor alpha agent used in inflammatory bowel diseases (IBD) therapy. Usually, it is administered over a 2-hour intravenous infusion. However, shortening the infusion duration to 1 hour has proved to be feasible and safe. In the present study we evaluated whether shortening the IFX infusion could affect the patients' quality of life (QoL) compared to the standard protocol. Subjects affected by IBD receiving IFX were prospectively recruited. The main criterion to shorten the infusion was the absence of IFX-related adverse reactions during the previous three 2-h infusions. For each patient, demographic, clinical and anthropometric data were collected. A questionnaire investigating their overall/job/social/sexual QoL was administered. Ordinal regression was performed with odds ratios (OR) for significant independent variables. Eighty-one patients were included (46 with ulcerative colitis - UC, 35 with Crohn's disease - CD). Sixteen rec...
Intestinal microbiota is a "dynamic organ" influencing host metabolism, nutrition, phys... more Intestinal microbiota is a "dynamic organ" influencing host metabolism, nutrition, physiology and immune system. Among its several interactions, the role of a phosphatidylcholine metabolite derived by gut flora activity, i.e., trimethylamine-N-oxide (TMAO), allows perceiving a novel insight in the cardiovascular risk scenario, being a strong predictor of this condition. Based on current reports, including the paper of Tang et al., we describe here: the possible role of intestinal microbiota in cardiovascular risk as well as potential interventions to reduce gut flora TMAO production by diet, probiotics and antibiotics. Finally, we highlight the possibility of evaluating, monitoring and modulating TMAO in order to use its serum levels as a marker of cardiovascular risk in the next future, when the need of controlled studies on large series will be satisfied.
Gastroenterology and hepatology from bed to bench, 2015
The diagnosis of Celiac Disease (CD) relies on the concordance of pathological, serological, gene... more The diagnosis of Celiac Disease (CD) relies on the concordance of pathological, serological, genetic and clinical features. For this reason, the diagnosis of CD is often a challenge. Seronegative celiac disease (SNCD) is defined by the negativity of anti-tissue transglutaminase antibodies in the presence of a positive histology on duodenal biopsy samples, i.e. inflammatory infiltrate of intra-epithelial lymphocytes (IELs > 25/100 enterocytes), mild villous atrophy and uneven brush border associated to human leukocyte antigen (HLA) haplotype DQ2 and/or DQ8. SNCD is characterized by mucosal deposits of tissue transglutaminase (tTG)/anti-tTG immuno-complexes. These may counteract the passage of anti-tTG into the bloodstream, thus explaining seronegativity. Another reason for seronegativity may be found in an incomplete maturation of plasma cells with a consequent failure of antibodies production. This condition often characterizes immunoglobulin deficiencies, and, indeed, SNCD is co...
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