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Background: The Inflammatory Bowel Disease-Disk (IBD-Disk) is a physician-administered tool that evaluates the functional status of patients with Inflammatory Bowel Disease (IBD). The aim of our study was to validate the content of the IBD-Disk in a Greek cohort of IBD patients. Methods: Two questionnaires [the IBD Disk and the IBD-Disability Index (IBD-DI)] were translated into Greek and administered to IBD patients at baseline visit, after 4 weeks and 6 months. Validation of the IBD Disk included measuring of concurrent validity, reproducibility, and internal consistency. Results: A total of 300 patients were included at baseline and 269 at follow-up. There was a good correlation between the total scores of the IBD-Disk and IBD-DI at baseline (Pearson correlation 0.87, p < 0.001). Reproducibility of the total IBD-Disk score was very good [intra-class correlation coefficient (ICC), 95% confidence interval (CI) 0.89 (0.86–0.91)]. Cronbach’s coefficient alpha for all items achieved 0.90 (95%CI 0.88–0.92), demonstrating a very good homogeneity of the IBD-Disk items. Female gender and extraintestinal manifestations were significantly associated with a higher IBD-Disk total score. Conclusions: The Greek version of the IBD-Disk proved to be a reliable and valid tool in detecting and assessing IBD-related disability in a Greek cohort of IBD patients.

Background Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been associated with improved outcomes in inflammatory bowel disease. We aimed to investigate any possible effect of antihypertensive medications on inflammatory bowel disease course. Methods One hundred and fifty inflammatory bowel disease patients with hypertension were compared using a 1:1 ratio with age- and gender-matched control patients with inflammatory bowel disease. The class of antihypertensive medication, traditional risk factors for atherosclerosis, inflammatory bowel disease characteristics, and history (surgery, hospitalizations, and treatment) were retrospectively analyzed. Results Of 150 (44.7% Crohn's disease) patients with hypertension, 46.7% were on angiotensin receptor blockers, 30.6% on angiotensin-converting enzyme inhibitors, 40% on β-blockers, and 40.7% on calcium channel blockers. Univariate analysis revealed significantly higher rates of traditional risk factors for atherosclerosis among antihypertensive users. When analyzing by class of antihypertensive medication, angiotensin receptor blockers were significantly associated with milder course as indicated by less frequent immunomodulator (P = 0.039) and steroid use (P = 0.041). Rates of lifetime steroids were statistically significantly lower among angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (odds ratio = 1.191, 95% confidence interval, 1.005-1.411). After adjustment with confounding factors, only angiotensin receptor blockers were associated with milder inflammatory bowel disease course (P = 0.037) and lower rates of immunomodulator use (P = 0.038). Conclusions Our study suggests a possible protective effect of angiotensin receptor blockers on overall inflammatory bowel disease course by targeting the renin-angiotensin system. Their effect on inflammatory bowel disease needs to be studied in larger cohorts.

Objectives Chronic inflammation has been implicated in the pathogenesis of atherosclerosis and cardiovascular disease. Data linking the severity of inflammatory bowel disease to coexisting cardiovascular disease are scarce. The aim of the present study was to investigate whether inflammatory bowel disease patients with coexistent cardiovascular disease have more severe disease. Methods We included 103 inflammatory bowel disease patients with coexisting cardiovascular disease compared to 206 age- and sex-matched inflammatory bowel disease patients without cardiovascular disease derived from three referral inflammatory bowel disease Centers. Traditional cardiovascular disease factors and parameters of inflammatory bowel disease severity were compared between the two groups. Results Cardiovascular disease was diagnosed after the inflammatory bowel disease diagnosis in 56.6% of cases. No significant difference was found in the prevalence of surrogate markers of severity (inflammatory bowel disease-related surgeries, hospitalizations, biologics or immunosuppressants' use, and persistent CRP elevation) between inflammatory bowel disease patients with and without cardiovascular disease. There was no difference between cardiovascular disease patients diagnosed before and after inflammatory bowel disease onset. All traditional risk factors (hypertension, dyslipidemia, smoking, obesity, diabetes mellitus) were significantly more common in cardiovascular disease patients. Cardiovascular disease patients had a trend for lower rates of multiple hospitalizations (16.5% vs. 24.3%, P = 0.05) and inflammatory bowel disease-related surgeries (P = 0.09). Conclusion The inflammatory burden possibly plays a less important role in the development of cardiovascular disease in inflammatory bowel disease patients but future larger prospective studies are needed.

Εισαγωγή: Η Π.Χ.Κ. είναι μια όργανο-ειδική αυτοάνοση νόσος αγνώστου αιτιολογίας. Χημικές ουσίες, λοιμώδεις παράγοντες, ορμονοθεραπεία, το αναπαραγωγικό ιστορικό και οι χειρουργικές επεμβάσεις συνιστούν παράγοντες οι οποίοι έχουν συνδεθεί με πιθανή επίδραση στην εμφάνιση της νόσου. Ενδοοικογενειακή εμφάνιση της Π.Χ.Κ. έχει αναφερθεί σε συγγενείς Α βαθμού ασθενών.Σε μελέτη που διεξήχθη στο εργαστήριο Γαστρεντερολογίας της Ιατρικής σχολής Κρήτης βρέθηκε ότι τα επίπεδα των ενδοθηλινών που παράγονται από τα ενδοθηλιακά κύτταρα του ήπατος είναι αυξημένα στην Π.Χ.Κ. και πιθανά να έχουν κάποιο ρόλο στην παθογένεση της νόσου, ενισχύοντας το ρόλο του γενετικού παράγοντα.Σε συνάρτηση με τα παραπάνω, ο επιπολασμός της Π.Χ.Κ. ποικίλλει σε διαφορετικές γεωγραφικές περιοχές, γεγονός το οποίο πιθανά αντανακλά την επίδραση γενετικών ή περιβαλλοντικών παραγόντων στην εμφάνιση της νόσου.Σκοπός: Οι περισσότερες μελέτες ομάδων (cohort), είναι γενετικά ετερογενείς. Σκοπός της μελέτης μας είναι α) να καθοριστεί πιθανή συσχέτιση της Π.Χ.Κ. με παράγοντες από τις συνήθειες και τον τρόπο ζωής των ασθενών, με άλλα νοσήματα καθώς και να υπολογιστεί το ποσοστό ενδοοικογενειακής Π.Χ.Κ. σε ένα πληθυσμό γενετικά ομοιογενή και γεωγραφικά περιορισμένο όπως είναι ο Κρητικός, β) να μελετηθούν γενετικοί πολυμορφισμοί οι οποίοι σχετίζονται με τα ενδοθηλιακά κύτταρα (γονίδια eNOS, EDN-1 ) και, να διερευνηθεί εάν η συσχέτιση των πολυμορφισμών του γονιδίου CTLA4 αναπαράγεται και στον γενετικά ομοιογενή Ελληνικό πληθυσμό της Κρήτης και γ) να καθοριστεί η επίπτωση και ο επιπολασμός της Π.Χ.Κ. στην Κρήτη, να περιγραφεί η γεωεπιδημιολογική κατανομή των ασθενών στο νησί, να δημιουργηθούν χάρτες πρόβλεψης ύπαρξης της νόσου και να ανιχνευθεί πιθανή χώρο-χρονική πορεία της Π.Χ.Κ. στην Κρήτη, στην Ελλάδα.Μεθοδολογία: Στο διάστημα 1990-2010, από τους 245 ασθενείς με Π.Χ.Κ. που διαγνώστηκαν και παρακολουθούνται στη Γαστρεντερολογική κλινική του Πανεπιστημιακού Νοσοκομείου Κρήτης και των Περιφερειακών νοσοκομείων του νησιού, οι 222 συμπεριελήφθησαν στην χώρο-χρονική ανάλυση. 111 εξ αυτών συναίνεσαν να συμμετάσχουν στην κλινική μελέτη συμπληρώνοντας ένα ερωτηματολόγιο με στοιχεία δημογραφικά, τρόπου ζωής, ιατρικό, χειρουργικό και αναπαραγωγικό ιστορικό. Οι ασθενείς αυτοί συγκριθήκαν με 115 συγγενείς Α βαθμού και 149 υγιείς εθελοντές αντίστοιχης ηλικίας, φύλου, Κρητικής καταγωγής και διαμονής. Οι στατιστικά σημαντικές μεταβλητές στην μονοπαραγοντική ανάλυση χρησιμοποιήθηκαν περαιτέρω σε πολυπαραγοντική, με τη χρήση μοντέλου βηματικής λογιστικής παλινδρόμησης προς τα εμπρός. Επιπλέον εκατό από το σύνολο των ασθενών με Π.Χ.Κ. (83 θήλεα, 93% AMA+, 74/100 σταδίου Ludwig I–II) και 158 υγιείς εθελοντές συναίνεσαν για την εξαγωγή γενομικού DNA προκειμένου να ανιχνευθούν οι πολυμορφισμοί των γονίδιων eNOS, CTLA4 και ET1 με τη χρήση PCR–RFLP.Πιο συγκεκριμένα, για να γίνει η χαρτογράφηση της χώρο-χρονικής κατανομής των 222 ασθενών ανά 5ετια, εφαρμόστηκαν γεωχωρικά μοντέλα στο λογισμικό Gis–ArcMap 9.3. Η μέθοδος χωρικής παρεμβολής Kriging χρησιμοποιήθηκε για τη δημιουργία χάρτη πρόβλεψης της Π.Χ.Κ. στην Κρήτη. Οι περιοχές υψηλής ή χαμηλής πιθανότητας για εμφάνιση της νόσου υπολογίστηκαν με πολυπαραγοντικό μοντέλο. Το Arc map’s toolbox λογισμικό εφαρμόστηκε, ώστε να χαραχθεί η χώρο-χρονική πορεία της ΠΧΚ στην Κρήτη.Αποτελέσματα: Όσον αφορά στη μελέτη των συνοσηροτήτων, δυσλιπιδαιμία βρέθηκε στο 69.4% των ασθενών με Π.Χ.Κ., στο 60% των συγγενών Α βαθμού και στο 40.9% της ομάδας ελέγχου(p < 0.0001 και p = 0.003 αντίστοιχα), συνοδά αυτοάνοσα νοσήματα στο 36.9% των ασθενών, στο 30.4% των συγγενών Α βαθμού και στο 13.4% της ομάδας ελέγχου(p < 0.0001 και p = 0.011 αντίστοιχα). Η θυρεοειδίτιδα Hashimoto(p = 0.003), το σύνδρομο Raynaud(p = 0.023) και Sjögren(p = 0.044) είχαν στατιστικά σημαντική συσχέτιση με την Π.Χ.Κ. Στην πολυπαραγοντική ανάλυση βρέθηκαν στατιστικά σημαντικές συσχετίσεις της νόσου με την πρωτοβάθμια εκπαίδευση (χαμηλό επίπεδο εκπαίδευσης) (AOR 2.304, 95% CI 1.024-5.181), με τη χολοκυστεκτομή(AOR 2.927, 95% CI 1.347-6.362) και με τη συνύπαρξη τουλάχιστον ενός άλλου αυτοανοσου νοσήματος (AOR 3.318, 95% CI 1.177-6.22). Ιστορικό κακοήθειας βρέθηκε με μεγαλύτερη συχνότητα στους ασθενείς με Π.Χ.Κ. σε σύγκριση με τους υγιείς εθελοντές(p = 0.033). Η ενδοοικογενειακή εμφάνιση Π.Χ.Κ. στην Κρήτη υπολογίστηκε σε 9.9%. Από τη μελέτη των γενετικών πολυμορφισμών τόσο το eNOS intron4 VNTR όσο και το eNOS exon7 G894T SNP βρέθηκε ότι σχετίζονται σημαντικά με αυξημένο κίνδυνο εμφάνισης Π.Χ.Κ. Τα αλληλομορφα EDN-1 rs2071942 ‘‘A’’ και rs5370 ‘‘T’’ έδειξαν μια τάση για συσχέτιση με το στάδιο της νόσου. Καμία συσχέτιση δεν βρέθηκε ανάμεσα στην Π.Χ.Κ. και στους πολυμορφισμούς CTLA4 που μελετήθηκαν. Ο επιπολασμός της Π.Χ.Κ. στην Κρήτη προσδιορίστηκε στις 365 περιπτώσεις ανά 1.000.000 πληθυσμού και η μέση επίπτωση 20.88(εύρος 3.79-35.99). Οι χάρτες πρόβλεψης υπολογίζουν από 1.22 έως 11 ασθενείς ανά 50 km2 στην Κρήτη. Οι περιοχές υψηλού κινδύνου για εμφάνιση της νόσου βρίσκονται στο ανατολικό τμήμα του νησιού, ενώ οι χαμηλού κινδύνου στο δυτικό τμήμα.Συμπεράσματα: Η δυσλιπιδαιμία και τα συνοδά αυτοάνοσα νοσήματα ήταν σημαντικά αυξημένα όχι μόνο στους ασθενείς με Π.Χ. Κ. όπως αναμενόταν, αλλά και στους συγγενείς Α βαθμού. Επιπλέον, αυξημένα ποσοστά κακοηθειών είχαν οι ασθενείς με Π.Χ. Κ. Ως πιθανοί παράγοντες κινδύνου για τη νόσο βρέθηκαν η πρωτοβάθμια εκπαίδευση, η χολοκυστεκτομή και η παρουσία τουλάχιστον ενός άλλου αυτοάνοσου νοσήματος. Δεν διεπιστώθη συσχέτιση της Π.Χ.Κ. με το κάπνισμα, τις λοιμώξεις ουροποιητικού ή το αναπαραγωγικό ιστορικό. Λόγω των υψηλών ποσοστών ενδοοικογενειακής εμφάνισης της νόσου στην Κρήτη προτείνεται προληπτικός έλεγχος AMA στους συγγενείς Α βαθμού στους οποίους συνυπάρχει τουλάχιστον ένα άλλο αυτοάνοσο νόσημα.Επίσης δείξαμε ότι το γονίδιο eNOS, το οποίο επιδρά στη λειτουργία του ενδοθηλίου του ήπατος σχετίζεται με την εμφάνιση PBC στον Κρητικό πληθυσμό, όχι όμως και το σχετιζόμενο με την επίκτητη ανοσία γονίδιο CTLA4. Η επίπτωση και ο επιπολασμός της Π.Χ.Κ. στην Κρήτη είναι από τους μεγαλύτερους στην Ευρωπαϊκή βιβλιογραφία. Με δεδομένο την ομοιογένεια του υπό μελέτη πληθυσμού και τα γεωπολιτικά χαρακτηριστικά του νησιού, η παρατηρηθείσα ετερογένεια στην χώρο-χρονική κατανομή και στην πορεία της νόσου, ενισχύει την υπόθεση της επίδρασης περιβαλλοντικών παραγόντων στην αιτιολογία της Π.Χ.Κ.

Chronic inflammation of the intestinal mucosa has been associated with the appearance of inflammatory polyps or pseudopolyps. Among the distinct categories of inflammatory polyps are inflammatory myoglandular polyps (IMGP) usually found in the colorectum. Only one case of IMGP in the terminal ileus has been described since their first description. We report the first case of an inflammatory polyp with both hyperplastic and myoglandular histological characteristics, in the terminal ileum of a patient with quiescent Crohn’s disease, causing recurrent intussusception.

Objectives Agents targeting the epidermal growth factor receptor (EGFR)-mediated signalling pathway are increasingly being used for the treatment of advanced lung, pancreatic, colorectal and head and neck cancers. Case presentation Here, we report the first case of eruptive seborrhoeic keratosis following panitumumab treatment, an anti-EGFR monoclonal antibody, in a 73-year-old patient with stage 4 (IV) colorectal cancer with hepatic metastasis. Conclusion While panitumumab is an emerging therapy for RAS wild-type metastatic colorectal cancer, physicians should consider panitumumab as a potential cause of eruptive seborrhoeic keratosis. LEARNING POINTS Panitumumab is a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), indicated for the treatment of wild-type RAS metastatic colorectal cancer. Dermatologic toxicity of all grades occurs in more than 90% of patients treated with EGFR inhibitors. To the best of our knowledge, we have reported here a rare side effect; panitumumab-induced eruptive seborrhoeic keratosis.

Background No evidence is available on the natural history of grade 1 ascites and its progression to grade 2/3 in patients with liver cirrhosis. The aim of the current study was to address this issue, to assess the development of main comorbid disorders closely related to ascites progression, and to identify the predictive factors for survival in this setting. Methods Consecutive Caucasian cirrhotic patients with grade 1 ascites were retrospectively analyzed. None of patients was under treatment with diuretics at diagnosis. Control groups consisted of 145 cirrhotics with grade 2/3 ascites and 175 cirrhotics without ascites. Results Diuretics were initiated in 58 patients with grade 1 ascites at baseline by the attending physician. At the last follow up, 29 patients had no ascites, 33 patients had grade 1 and 38 patients had grade 2/3 ascites. No variable was found to be an independent predictor of grade 2/3 ascites. Seven patients developed spontaneous bacterial peritonitis while under treatment with diuretics; at that time only 1 patient had grade 1 ascites. The mortality rate was similar among all examined groups. Conclusions This study suggests that the presence of grade 1 ascites does not constitute a precursor of grade 2/3 ascites in patients with cirrhosis. Thus, patients with grade 1 ascites do not require specific treatment with diuretics.

Background The outcome of primary biliary cholangitis (PBC) is affected by both genetic and environmental factors. Objective The aim of this study was to study the effect of smoking on liver histology and mortality in a genetically homogeneous population having PBC. Patients and methods Smoking and drinking habits at diagnosis (based on standard criteria) were recorded in 171 Cretan patients with PBC (163 women). A total of 148 patients had a liver biopsy. Odds ratios were calculated with logistic regression analysis. Kaplan-Meier curves were used for mortality estimation. Results Smoking was associated with alcohol consumption of more than 20 g/day [adjusted odds ratio (AOR)=2.20, 95% CI: 1.029-4.099], severe steatosis (AOR=5.31, 95% CI: 2.019-9.919), and fibrosis stage F3-F4 (AOR=1.21, 95% CI: 1.015-3.031). Heavy smoking, years of passive smoking, and serious necroinflammatiοn were independent factors associated with advanced fibrosis after adjustment for sex, age, BMI, and alcohol consumption in multivariate analysis. For every pack-year increase in smoking intensity, there was a 3.2 times higher likelihood of advanced fibrosis (95% CI: 2.018-6.294). Increased mortality was found in smokers with advanced PBC. Conclusion There is an association between smoking, whether active or passive, and advanced fibrosis in PBC. Mortality is increased in smokers with advanced disease at presentation.

Portal vein thrombosis (PVT) is a frequent complication in cirrhosis and its prevalence increases with disease severity. Several factors are involved in the development and progression of PVT. The challenge for the management of PVT is the precise evaluation of the bleeding risk as opposed to life-threatening extension of thrombosis. Nevertheless, the impact on the progression and outcome of liver disease is unclear. A critical evaluation of the available data discloses that treating PVT in cirrhotics is safe and effective. However, there are open issues, such as which anticoagulant could represent a safer therapeutic option, and when and for how long this treatment should be administered to cirrhotic patients with PVT.

Background No sequential long-term data exist for Greece on the etiological evolution and incidence of cirrhosis and hepatocellular carcinoma. Therefore, we studied their etiological evolution over a period of 25 years in the island of Crete. Methods We studied 812 cases of cirrhosis (561 male, median age 69 years) and 321 cases of hepatocellular carcinoma (234 male, median age 70 years) from the database of our Center. Cases were classified into five-year periods according to incidence and etiology (hepatitis B, hepatitis C, alcohol, alcohol plus viral, and non-alcoholic fatty liver disease). Results Overall, there was an increase in the incidence of hepatocellular carcinoma. A significant fourfold reduction in the incidence of hepatitis C-related cirrhosis was observed, which was degraded from first to third place as a risk factor for cirrhosis. Alcohol gradually became the first risk factor in cirrhosis (1990-94: 36.1%, 2010-14: 52.3%) and carcinoma, while the steepest increase in incidence of cirrhosis and carcinoma was associated with non-alcoholic fatty liver disease. Conclusions The incidence of cirrhosis remained constant over the years, but the incidence of hepatocellular carcinoma increased during the last decade. Risk factors for cirrhosis and hepatocellular carcinoma have changed over the past 25 years in Crete. The initial high hepatitis C virus association has significantly decreased, with alcohol now ranking first among risk factors. Non-alcoholic fatty liver disease is continually increasing and is a prominent risk factor for cirrhosis and hepatocellular carcinoma. Keywords Hepatocellular carcinoma, cirrhosis, non-alcoholic fatty liver disease, HCV, hepatocellular carcinoma Ann Gastroenterol 2017; 30 (3): 357-363

Background & Aims The prevalence of Primary biliary cirrhosis varies in different geographical areas. This might reflect genetic or environmental risk factors. We aimed to define Primary biliary cirrhosis prevalence and incidence, describe patient's spatial distribution, generate prediction maps and detect any possible routing pattern of time-spatial appearance of the disease in Crete, Greece. Methods From 1990–2010, 245 Primary biliary cirrhosis patients diagnosed and followed up at the Gastroenterology Department of the University Hospital and the District Hospitals of the island, were contacted and 222 were included in the time–spatial analysis. To map their spatial distribution per 5-year periods, geospatial models were applied in Gis–ArcMap 9.3 software. Kriging Interpolation methods were used to generate prediction maps for the disease in Crete. Areas of high and low probability of disease occurrence were estimated through multicriteria modelling. The disease route was defined by Gis-ArcMap's toolbox. Results Prevalence was found to be 365 cases per million, with a mean incidence of 20.88 (range 3.79–35.99). Prediction map estimates from 1.22 to 11 patients per 50 km2 all over Crete. Areas of high risk of disease occurrence are located in the Eastern part, while low risk in the Western part of the island. Discussion Prevalence and incidence of Primary biliary cirrhosis in Crete are among the higher published in Europe. Given the homogeneous and stable study population and the geopolitics of the island, the heterogeneity in the time-spatial distribution and the route of disease appearance strongly suggest a role for environmental causative agents.

Background Primary biliary cirrhosis (PBC) is a disease with genetic and environmental pathogenetic background. Chemicals, infectious agents, hormone therapy, reproductive history and surgical interventions have been implicated in the induction of PBC. Familial PBC has been documented in first degree relatives (FDR). Most cohort studies are genetically heterogeneous. Our study aimed to determine eventual lifestyle or disease associations and familial occurrence rates in a genetically homogeneous and geographically defined population of PBC patients. Methods 111 consenting PBC patients, were compared with 115 FDR and 149 controls matched for age, sex, Cretan origin and residence. All participants completed a questionnaire regarding demographics, lifestyle, medical, surgical and reproductive history. Significant variables on the univariate analysis were analyzed by multivariate analysis using a forward step-wise logistic regression model. Results Dyslipidaemia was found in 69.4% of patients, 60% of FDR and 40.9% of controls (p Conclusions Dyslipidaemia and autoimmune diseases were significantly increased not only in patients as expected but also in their FDR. An increased prevalence of malignancies was found in patients. Primary educational level, cholecystectomy and the presence of at least another autoimmune disease were found as putative risk factors for PBC. No association was found with smoking, urinary tract infection or reproductive history. The reported high familial occurrence of PBC could imply screening with AMA of FDR with at least another autoimmune disease.

Introduction and background Twin and family studies suggest that there is a significant heritable component to PBC. It has been suggested that increased nitric oxide (NO) synthesis may contribute to the development of the hyperdynamic circulation observed in cirrhotic patients, while total NO circulating levels are enhanced in PBC. Aims The authors examined two endothelial nitric oxide synthase (eNOS) gene polymorphisms, a 27-bp repeat in intron 4 and a Glu298Asp in exon 7, to assess a possible association with the development of PBC in a genetically homogenous Cretan population. Methods Genomic DNA was extracted from 91 PBC patients (77 female), 82 AMA+, median age 68 years (41–84 years), 48/91 Ludwig stage I–II and 101 FDR (63 female), median age 41 (age range 18–80 years), 3/101 AMA+ and 20/101 ANA+ of Cretan origin. 100 sex, age and geography matched healthy controls (76 female), median age 69 years (39–86 years), 9/100 ANA+. Exon7 polymorphism was determined by PCR–restriction fragment–length polymorphism analysis. Intron4 polymorphism was determined using PCR amplification with oligonucleotide primers. Distribution of genotypes and alleles was compared by x 2 test or Fisher9s exact test. Conclusions In Cretan PBC patients both eNOs intron 4 VNTR and Glu298Asp in exon 7 eNOs polymorphism are not associated with disease occurrence or disease stage.

Aikaterini N. Mantaka, Dimitrios N. Samonakis, Michail Liontiris andIoannis E. Koutroubakis, Department of Gastroenterology, University Hospitalof Heraklion, Crete, GreeceCorrespondence to Ioannis E. Koutroubakis, MD, PhD, Department ofGastroenterology, University Hospital of Heraklion, PO Box 1352, 71110Heraklion, Crete, GreeceTel: +30 281 039 2253; fax: +30 281 054 2085; e-mail: ikoutroub@med.uoc.grReceived 30 June 2014 Accepted 9 July 2014

Introduction Conflicting data for the role that cigarette smoking may play in Primary Biliary Cirrhosis (PBC) have been reported. Some studies have suggested an association of smoking with a more advanced fibrotic stage. The aim of the present study therefore was to assess the association between smoking and a) the severity of histological findings at the time of diagnosis, b) the immunological features of a genetically homogeneous and geographically defined population of PBC patients. Methods Smoking history data were collected from 171 PBC patients of Cretan origin (163 female) using a standardised questionnaire. Diagnosis was based on standard biochemical, Immunological and histological criteria. Liver biopsy was performed in 148 patients at diagnosis. Liver fibrosis and histological inflammatory activity were semi-quantified according to a METAVIR-based classification system. Odds ratios (OR) were assessed using logistic regression analysis. Results Smoking history prior to diagnosis was reported in 56 patients (32,7%%). Twenty-six patients (15,2%) were active smokers at diagnosis. Male gender (AOR 8.19, 95% CI: 3.014–11.937), alcohol intake >20 g/d (AOR, 2.20, 95% CI: 1.029–4.099), severe steatosis (AOR, 5.31, 95% CI: 2.019–9.919)), and F3–F4 fibrosis stage (AOR 1.21 95% CI: 1.015–3.031), but not piecemeal necrosis grade, bile duct paucity and cholangitis, or immunological laboratory data, were associated with smoking history. Multiple logistic regression analysis identified smoking intensity, years of passive smoking and significant necroinflammatory histological activity as independent risk factors of advanced liver fibrosis (F3–F4 stage) at diagnosis, adjusted for age, gender, BMI and alcohol consumption. For every pack-year increase in smoking intensity there was a 3.2 times higher likelihood of advanced fibrosis (95% CI: 2.018–6.294). Conclusion Our study results confirm the previously reported link between smoking history and the risk of advanced liver fibrosis at diagnosis in PBC. The mechanism by which smoking may accelerate the histological progression of PBC is unknown and larger studies are needed to define it. Disclosure of Interest None Declared.

Introduction and background Cytotoxic T lymphocyte antigen 4 (CTLA4) encodes a coinhibitory immunoreceptor that is a key regulator of self tolerance with established genetic associations to multiple autoimmune diseases. Studies of CTLA4 in PBC identified an association with the G allele of 49AG in Chinese and French patients, but not in the USA, Brazil, UK, Italy and Germany ones. Aims To examine whether CTLA-4 CT60 and/or +49A/G polymorphisms are involved in the genetic predisposition to PBC in a genetically homogeneous Cretan population. Methods The authors studied 91 PBC patients (77 female, 9 AMA-), median age 68 years (41–84 years), Ludwig stage III –IV: 43/91, 101 first degree relatives (FDR, 63 females), median age 40 years (18–80 years), 3/101 AMA + and 100 healthy controls (76 female), median age 69 years (39–86 years), 16/100 ANA+, all of Cretan origin. After the isolation of genomic DNA from peripheral blood mononuclear cells, CTLA-4 CT60 and +49A/G polymorphisms were genotyped by restriction fragment length polymorphism with the use of Bbv I (+49A/G) and Nla III (CT60). Distribution of genotypes and alleles were compared by x 2 test. Results The genotypes AA, AG and GG of the polymorphism rs231775 of CTLA4 gene were 41 (45.1%), 47 (51.6%) and 3 (3.3%) in the PBC patients, 58 (57.4%), 39 (38.6%) and 4 (4%) in the FDR and 46 (46%), 47 (47%) and 7 (7%) in the control group. No statistical differences were found among groups (PBC vs controls p=0.48, FDR vs controls p=0.23) and no association of the genotypes with disease stage (p=0.178). The genotypes AA, AG and GG of the genetic polymorphism rs3087243 of CTLA4 gene were 22 (24.1%), 39 (42.9%) and 30 (33%) in the PBC patients, 25 (24.8%), 59 (58.4%) and 17 (16.8%) in the FDR and 24 (24%), 52 (52%) and 24 (24%) in the control group. No statistical differences of the genotypes were found among groups (PBC vs controls p=0.334, FDR vs controls p=0.438) and no association with disease stage (p=0.316). Conclusions rs3087243 and rs231775 CTLA4 gene polymorphisms have no association with either susceptibility to PBC or disease stage in a genetically homogeneous population of Cretan origin.