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In 2011 the three major Italian gastroenterological scientific societies (AIGO, the Italian Society of Hospital Gastroenterologists and Endoscopists; SIED, the Italian Society of Endoscopy; SIGE, the Italian Society of Gastroenterology) prepared their official document aimed at analysing medical care for digestive diseases in Italy, on the basis of national and regional data (Health Ministry and Lombardia, Veneto, Emilia-Romagna databases) and to make proposals for planning of care. Digestive diseases were the first or second cause of hospitalizations in Italy in 1999–2009, with more than 1,500,000 admissions/year; however only 5–9% of these admissions was in specialized Gastroenterology units. Reported data show a better outcome in Gastroenterology Units than in non-specialized units: shorter average length of stay, in particular for admissions with ICD-9-CM codes proxying for emergency conditions (6.7 days versus 8.4 days); better case mix (higher average diagnosis-related groups weight in Gastroenterology Units: 1 vs 0.97 in Internal Medicine units and 0.76 in Surgery units); lower inappropriateness of admissions (16–25% versus 29–87%); lower in-hospital mortality in urgent admissions (2.2% versus 5.1%); for patients with urgent admissions due to gastrointestinnal haemorrhage, in-hospital mortality was 2.3% in Gastroenterology units versus 4.0% in others. The present document summarizes the scientific societies’ official report, which constitutes the “White paper of Italian Gastroenterology”

Background and aims. Colorectal cancer is a major health problem. Colonoscopic colorectal cancer screening is cumbersome and expensive. Identification of genetic risk of colorectal cancer may help to select the subjects who could benefit from colonoscopy. The immune system plays a fundamental role in the human–environment interaction, and the carcinogenic effects of many environmental factors are mediated by the chronic activation of the immune system in a genetic-controlled fashion. Cytotoxic T lymphocyte associated antigen 4 (CTLA4) plays an inhibitory role in regulating lymphocyte functions. The loss of CTLA4 function is responsible for loss of mucosal lymphocyte tolerance. The G allele at position +49 of exon 1 of the CTLA4 gene affects the CTLA4 function. We evaluated in an association study the role of CTLA4 A+49G polymorphism as a risk factor for colorectal neoplasm. Patients and methods. Five hundred and fifty-six patients (male 295; female 261) who underwent colonoscopy at our Centre were enrolled in the study and divided into three groups: Colorectal cancer (132 patients, M/F 68/64, mean age 66 ± 11 years); Colorectal adenoma (186 patients, M/F 110/76, mean age 65 ± 11 years); Healthy controls (238 patients, M/F 117/121, mean age 63 ± 10 years). DNA was extracted from peripheral blood, CTLA4 gene was amplified by using specific primers, and A+49G polymorphism was analysed by restriction enzyme digestion. Results. No statistically significant differences in the genotype distribution among Control and Adenoma groups (p = 0.93), Control and Carcinoma groups (p = 0.52), and Adenoma and Carcinoma groups (p = 0.53) were observed. Conclusion. There is no significant correlation between CTLA4 A+49G polymorphism and the risk of colorectal neoplasm among Italian Caucasians.

Background & Aims Sympathetic nervous system (SNS) activation decreases response to diuretics, but both α1-adrenoceptor agonists and sympatholytic α2-adrenoceptor agonists are recommended in the management of ascitic cirrhosis. We intend to compare the effects of increasing doses of clonidine (α2-agonist) vs. midodrine (α1-agonist) in advanced cirrhosis. Methods Renal function, mean arterial pressure (MAP), and hormonal status were measured in rats with ascitic cirrhosis due to 13-week CCl4 administration (groups G1-G5), in control rats (Gc), and in rats with ascitic cirrhosis untreated (G6) or treated with daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate during the 11th–13th weeks of CCl4) (G7). G1–G5 cirrhotic rats received daily, during the 11th–13th CCl4 weeks: clonidine 0.3 μg only (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3) or 1 μg (G4), and diuretics + midodrine 1 mg/kg b.w. (G5). Results Cirrhotic rats in G1 or G2 had higher glomerular filtration rate, renal plasma flow and natriuresis than cirrhotic rats treated with diuretics (G7) (all P

OBJECTIVES: Several studies in human cirrhosis have demonstrated increased nitric oxide (NO) production. In experimental animals, intracerebroventricular administration of NO donors causes a marked depression of the endogenous dopaminergic activity, a function known to be physiologically recruited and exerting a natriuretic function in patients with compensated cirrhosis. The aim of this study is to evaluate the interaction between the systemic plasma levels of NO, the endogenous dopaminergic activity and the main parameters of renal function in patients with liver cirrhosis of differing degrees of severity. METHODS: A total of 21 patients (11 with preascitic and 10 with nonazotemic diuretic-free ascitic cirrhosis) and 10 healthy control subjects underwent the following tests: a) basal plasma renin activity (PRA) and aldosterone levels; b) renal clearances of sodium, potassium, inulin, para-minohippurate and lithium (the latter being a measure of the fluid delivery to the distal nephron); c) NO systemic plasma levels measured through paramagnetic resonance spectroscopy as nitrosylhemoglobin complexes; d) endogenous dopaminergic activity, evaluated by means of the incremental prolactin and aldosterone plasma levels after dopaminergic blockade with i.v. metoclopramide. RESULTS: NO plasma values and endogenous dopaminergic activity, although significantly increased with respect to healthy controls, were not different in the two groups of patients. The plasma NO/PRA ratio was significantly higher in the group of compensated patients with respect to ascitic cirrhotics (respectively, 18.3 ± 11.8 vs 3.5 ± 2.6 A.U./ng/ml/h, p < 0.001). Compared with compensated cirrhotics, patients with ascites showed significantly lower values of glomerular filtration rate (GFR) and renal plasma flow (RPF). Interestingly, GFR values were substantially the same in the ascitic patients and the control subjects. Compensated patients displayed a significant positive correlation between metoclopramide-induced incremental aldosterone plasma levels (i.e., endogenous dopaminergic tone) and fractional excretion of sodium (r = 0.58; p < 0.05). In the group of compensated patients, NO levels correlated inversely with creatinine plasma concentrations (r = −0.85; p < 0.001) and directly with inulin clearance (r = 0.65; p < 0.05). CONCLUSIONS: These data show that, at least in compensated cirrhotic patients, the stimulation of systemic NO production and the increased dopaminergic function may be mechanisms preventing renal perfusion, GFR, and fractional excretion of sodium from precocious reductions.

Background The activity of epithelial lactase ( LCT ) associates with a polymorphism 13910 bp upstream the LCT -encoding gene ( LCT-13910C > T ). The relationship between LCT-13910C > T polymorphism and risk for colorectal cancer is unclear. Aims We examined the relationship between the LCT-13910C > T polymorphism causing lactose intolerance and risk for colorectal cancer/polyps onset in the Italian population. Patients and methods 793 subjects (306 with colorectal cancer, 176 with polyps and 311 controls) were genotyped for the LCT-13910C > T variant by TaqMan real time-PCR. Results Lactose malabsorption linked to the CC genotype did not associate with an increased risk for either colorectal cancer (OR = 1.041; 95% CI = 0.751–1.442; p = 0.868) or polyps (OR = 0.927; 95% CI = 0.630–1.363; p = 0.769). There was no association with colorectal cancer/polyps site. 60% of the subjects overall bore the CC genotype. Conclusion In the Italian population the LCT-13910C > T polymorphism is not associated to the risk for colorectal cancer or polyps.

Extracellular Ca(++) activates cell membrane calcium-sensing receptors (CaRs), leading to renal tubule production of prostaglandins E(2) (PGE(2)), which decrease both sodium reabsorption in the thick ascending limb of Henle's loop and free-water reabsorption in collecting ducts.To assess the activity of this diuretic system in experimental cirrhosis, we evaluated renal function, hormonal status, PGE(2) urinary excretion, and renal tissue concentrations of Na(+)-K(+)-2Cl(-) co-transporters (BSC-1) and CaRs in three groups of rats: one group of controls receiving 5% glucose solution (vehicle) intravenously and two groups of rats with CCl(4)-induced preascitic cirrhosis receiving either vehicle or 0.5mg i.v. Poly-l-Arginine (PolyAg), a CaR-selective agonist.Compared to controls, cirrhotic rats showed reduced urine volume and sodium excretion (p0.05). Western blot analysis revealed reduced CaRs and increased BSC-1 protein content in kidneys of cirrhotic rats compared with controls (all p0.01). PolyAg-treated cirrhotic rats had their urine and sodium excretion returned to normal; PolyAg also increased renal plasma flow, PGE(2) urinary excretion, and free-water clearance in cirrhotic rats (all p0.01 v. untreated cirrhotic animals).In preascitic cirrhosis, sodium retention may be linked to down-regulation of renal CaRs and up-regulation of tubular sodium-retaining channels. Calcimimetic drugs normalize preascitic sodium retention.

P0206 PREVENTION OF BLEEDING FOLLOWING INVASIVE PROCEDURES IN CIRRHOTIC PATIENTS: A SINGLE CENTER EXPERIENCE F. Invernizzi, G. Tosetti, V. La Mura, A. Aghemo, M. Primignani, A. Sanvgiovanni, M.F. Donato, A. Nicolini, M. Iavarone, M. Colombo. Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Universita degli Studi di Milano, Division of Radiology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Milan, Italy E-mail: massimo.colombo@unimi.it

In liver cirrhosis atrial natriuretic peptide (ANP) decreases portal vascular resistance and tributary flow. The enzyme neutral endopeptidase (NEP) degrades ANP and bradykinin and generates endothelin-1 from big-endothelin. We determined the effects of NEP inhibition by candoxatrilat on hormonal status, liver function and arterial and portal pressures in rats with CCl4-induced cirrhosis.Two groups of seven control rats received 1 ml 5% glucose solution alone or containing 10 mg/kg candoxatrilat; three groups of 10 ascitic cirrhotic rats received placebo, 5 or 10 mg/kg candoxatrilat. NEP protein concentration and immunostaining were analyzed in normal and cirrhotic livers.In cirrhotic rats 10 mg/kg candoxatrilat significantly increased steady-state indocyanine green clearance (a parameter reflecting liver plasma flow) (P0.01), decreased portal pressure (P0.01), had no effect on arterial pressure and plasma renin activity but increased ANP plasma levels (P0.05) and urinary excretions (P0.01) of ANP and cGMP. In the cytosol fraction of rat cirrhotic livers a 280% increase in NEP content was found (P0.01), chiefly localized in desmin-positive myofibroblast-like cells of fibrous septa.Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance.

Angiotensin II contributes to the post-glomerular arteriolar vasoconstriction which maintains the glomerular filtration rate (GFR) in renal hypoperfusion. To explore whether depressed angiotensin II generation, due to reduced angiotensinogen production or low angiotensin-converting enzyme (ACE) levels, could impair kidney function in advanced cirrhosis.We studied and prospectively followed up 21 diuretic-free ascitic cirrhotic patients, through these determinations: plasma levels of active renin (AR), renin activity (PRA), angiotensin II, ACE and aldosterone; renal clearances of sodium, inulin and para-aminohippurate; antipyrine clearance. Fifteen healthy subjects were also studied.GFR distribution was bimodal, 10 patients had low GFR values (l-GFR group) and 11 had normal-GFR values (n-GFR group) (below and above 105 ml/min per 1.73 m(2) body surface area). Antipyrine clearance and Child-Pugh score did not differ in the two patient groups. l-GFR group had higher AR and PRA values, lower ACE levels and a significantly higher AR/Angiotensin II ratio than n-GFR group (all P0.01). All 21 patients showed increased values of the AR/PRA ratio, i.e. subnormal angiotensinogen levels (P0.03). The 18-month survival rates of l-GFR and n-GFR groups were 20 and 81% (P0.02).Low-GFR cirrhotic patients had a worse survival rate associated with more severe contraction of the effective arterial blood volume, higher AR/Angiotensin II ratio and lower ACE levels.

Dipyridamole is a vasodilator that inhibits the cellular uptake of adenosine, which physiologically reduces the resistance to hepatic arterial flow inside the liver. This study aims at assessing the acute effect of dipyridamole on functional liver plasma flow (measured as the extrarenal sorbitol clearance) and on the Doppler US Congestion Index of the portal vein (the ratio between the cross-sectional area of this vein and the mean velocity of portal flow), which correlates with the severity of portal hypertension.We have determined the extrarenal sorbitol clearance (14 cases) and the Congestion Index (seven cases) before and at 30, 60, and 90 min after the oral administration of 25 mg dipyridamole in patients with liver cirrhosis. We also measured the effect of dipyridamole on functional liver plasma flow in six healthy subjects.Dipyridamole increased the extrarenal sorbitol clearance in controls (+17%, p0.01) and in cirrhotic patients (+15%, p0.01). The drug decreased the portal Congestion Index in all patients, averaging -24% (p0.05) 90 min after its oral administration.This result was due both to a mean decrease of the portal sectional area and to a mean increase in portal flow velocity. In conclusion, these data suggest that dipyridamole should decrease the vascular resistance to portal flow in cirrhosis; this effect may be mediated by an adenosine-dependent vasodilation in the intrahepatic site or along the portosystemic collaterals.

Background: Carcinoid tumors are rare but considered to be one of the commonest tumors in the appendix. Their incidence has been shown to vary in different studies. Aims, setting & design: This seminal study was carried out to determine the incidence and clinico-pathological profile of appendiceal carcinoids in a cohort of patients undergoing emergency appendicectomies for clinically suspected acute appendicitis in Emirate of Sharjah. Material and methods: The study included the retrospective data of 964 patients operated for clinically suspected appendicitis, the resected specimens of whom were received in the Pathology laboratory of Al-Qasmi hospital Sharjah from January 2010 to December 2010. Results: Out of the 964 patients 9 (0.93%) were found to have appendiceal carcinoids. The mean age was 28.7 years with a male to female ratio of 2 :1. Eight tumors were located near the tip of appendix with mean diameter of 3.3 mm. All tumors were found to be positive for chromogranin A, synaptophysin and neuron-specific enolase on immunohistochemistry (IHC). None of the patients had recurrence or any reportable complications in the short follow up period (12–26 months). Conclusions: Our study found higher incidence of appendiceal carcinoids in patients undergoing emergency appendectomy for acute appendicitis in Emirate of Sharjah compared to two previous studies from the same geographical region. Moreover, tumors were found more commonly in young males in contrary to previous studies and all the tumors were positive for common neuroendocrine markers.

117 GENE DELIVERY OF DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 REDUCES PORTAL PRESSURE IN BILE DUCT-LIGATED RATS G. Mehta, V. Sharma, A. Habtesion, V. Balasubramaniyan, N.A. Davies, R. Jalan, V.S. Budhram-Mahadeo, R.P. Mookerjee. UCL Institute of Hepatology, Royal Free Hospital, Royal Free Hampstead NHS Trust and UCL, Medical Molecular Biology Unit, Rayne Institute, UCL, London, UK E-mail: gautam.mehta@ucl.ac.uk

Extracellular Ca stimulates membrane-bound calcium-sensing receptors (CaRs). In turn, CaRs stimulation leads to PGE2-mediated decrease in protein content of Na-K-2Cl co-transporters (BSC-1) in the thick ascending limb (TAL) of Henle’s loop and of aquaporin 2 (AQP2) water channels in collecting ducts. Parathyroid hormone (PTH) increases CaRs expression and, consequently, decreases BSC-1 and AQP2 content. To assess this Ca-dependent diuretic system in preascitic cirrhosis we evaluated renal function, hormonal status, PGE2 urinary excretion, renal content of BSC-1 and CaRs in three groups of rats: one group of controls receiving s.c. 5% glucose solution and two groups of rats with CCl4-induced preascitic cirrhosis receiving either glucose solution or five s.c. doses of 10 mcg/kg PTH (one dose every 12h) prior to study. The amount of fluid administered to each group was the same. Compared to controls, cirrhotic rats showed reduced urine volume and sodium excretion (P < 0.05); western blot analysis revealed reduced CaRs and increased BSC-1 protein content in cirrhotic rat kidneys (all P < 0.01). PTH-treated cirrhotic rats had urine and sodium excretion normalized; s.c. PTH increased also renal plasma flow, PGE2 urinary excretion, free-water clearance, reduced BSC-1 and augmented CaRs content in cirrhotic rat kidneys (all P < 0.01 v. untreated cirrhosis). In conclusion, in preascitic cirrhosis sodium retention is linked to downregulation of renal CaRs and upregulation of tubular Na-K-2Cl co-transporters. PTH returns these biomolecular alterations and sodium and urine excretions to normality. Therefore, exaggerated sodium reabsorption in Henle’s loop is largely responsible for sodium retention in preascitic cirrhosis.

s A.I.S.F. Annual Meeting (Rome, February 25th−26th, 2010) / Digestive and Liver Disease 42 Suppl. 1 (2010) S1–S51 S17 T.N.6 INTRAHEPATIC RENIN-ANGIOTENSIN SYSTEM AND LIVER CIRRHOSIS: AN UPDATED REAPPRAISAL G. Sansoe1, M. Aragno2, C. Tomasinelli2, R. Mastrocola2, M. Parola2. Division of Gastroenterology, Gradenigo Hospital, Torino, Italy.; Department of Experimental Medicine and Oncology, University of Torino, Italy The concentrations of angiotensin II are 100-fold higher in renal, hepatic and myocardial tissue fluids than in the systemic circulation, due to local production of this hormone. 90% of this huge amount of tissue angiotensin II is not produced by ACE. Instead, angiotensin II in the above organs is produced by means of chymase (a membrane-bound enzyme) from circulating angiotensin I [1]. Another newly described enzyme (ACE2) degrades angiotensin II (composed of 8 aminoacids) into angiotensin-(1−7). Angiotensin II is a vasoconstrictor and stimulates fibrogenesis, but angiotensin-(1−7) is a strong vasodilator and inhibits fibrogenesis [2]. Moreover, chymase generates also endothelin-1 from precursors (big-endothelin and endothelin1−31) and activates TGF-beta. Both endothelin-1 and TGFbeta are fibrogenic agents in the cirrhotic liver. This study aims at evaluating the content of chymase, ACE and ACE2 inside the livers of normal rats (n = 5) and rats with CCl4-induced liver cirrhosis (n = 5) by means of quantitative western blotting. Normal and cirrhotic liver slices were also submitted to immuno-histochemistry studies in order to identify the location of these enzymes. Finally, normal and cirrhotic liver samples were studied by means of HPLC in order to determine tissue fluid concentrations of angiotensin II and angiotensin-(1−7). In cirrhotic liver samples we found out a marked over-expression of chymase and ACE (all P< 0.01) and, to a lesser extent, also of ACE2 (P< 0.05). In normal liver, concentrations of angiotensin II and angiotensin-(1−7) were similar (below 50 pg/ml); conversely, cirrhotic liver tissue showed increased concentrations of angiotensin II (1400±380 pg/ml) and of angiotensin-(1−7) (260±110 pg/ml). In other words, in cirrhotic liver the ratio between angiotensin II and angiotensin-(1−7) was five times higher than in control liver, arguably contributing to fibrogenesis. The reason for a preferential production of tissue angiotensin II inside the cirrhotic liver is the concurrently increased content of ACE and chymase, with respect to a smaller over-expression of the sole ACE2. These data indicate modulation of the chymase/ACE2 system seems promising in order to alter the process of fibrogenesis in chronic liver diseases.