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Twenty years ago, ribavirin was first used in the treatment for chronic hepatitis C. After few years, ribavirin, in combination with interferon-alpha, showed a dramatic synergistic efficacy against hepatitis C virus infection, leading to viral clearance in about 50% of patients. Recent discovery of potent inhibitors of hepatitis C virus proteases did not replace ribavirin as the mainstay of combination therapy for chronic hepatitis C. Despite this fundamental role of ribavirin, many aspects of the mechanism of action and of the optimal dose and duration of therapy remain to be discovered or settled. In the present review, the authors recall the milestones in the history of ribavirin and try to shed light on the more relevant features of ribavirin action and utilization, and on the clinical problems encountered in managing and optimizing treatment for chronic hepatitis C. Finally, some potential off-label use of this drug in most difficult-to-treat subjects is pointed out. In conclusion, even if a sort of mystery surrounds ribavirin, its efficacy against hepatitis C virus infection fortunately remains lasting and stable.

Due to the importance of intestinal transport in pharmacological studies and the emerging role of intestinal signalling activity in the gut-liver axis, we have developed a new method to investigate intestinal transport and liver signalling using cell and serum free mesenteric perfusion system in the rat. The method regarding bile acid active absorption was validated, then, the portal venous content was examined for fibroblast growth factor 15(FGF15), a putative signalling protein produced by the ileal enterocytes following bile acid absorption. After isolation and cannulation of the relevant vessels (abdominal aorta and portal vein), the abdominal aorta and the terminal ileum were infused with respectively Krebs-Ringer solution and tauroursodeoxycholate (TUDCA) and the absorption was assessed by its recovery in the portal vein. After immunoblot, liquid chromatography and mass spectrometry analysis were performed both on gel bands digestion products and on portal outflow samples in order to evaluate if negligible amounts of FGF15 were present in the portal circulation. TUDCA absorption was efficient, intestinal morphology and oxygen consumption were normal. Despite accurate analysis, we could not find FGF15. Our method proved to be reliable for studying the active bile acid absorption. It is also suitable to identify molecules produced by enterocytes and transferred to the portal circulation in response to absorption of different substances such as nutrients or drugs. Since FGF15 was not recovered we suggest the possibilities that this protein is produced in very little amounts, poorly transferred outside the cell, or that it is extremely unstable and rapidly degraded.

AIM: To evaluate the efficacy of extracorporeal shock wave lithotripsy (ESWL) for the management of refractory bile duct cholelithiasis in a third level referral centre. METHODS: The clinical records of all patients treated with a second generation electromagnetic lithotripter (Lithostar Plus, SIEMENS) from October 1990 to April 2005 were evaluated. All patients were monitored during the procedure and antibiotics were administered in case of cholangitis. The χ2 test and logistic regression analysis were performed as appropriate. RESULTS: Two hundred and fourteen patients (102 males, 112 females; mean age 74.8 ± 0.84 years - single stone 97, multiple stones 117) underwent ESWL. The mean number of sessions and shock waves were 3.5 ± 0.13 and 3477.06 ± 66.17, respectively. The maximum stone size was 5 cm. Complete stone clearance was achieved in 192 (89.7%) patients. Of the remaining patients 15 required surgery, 2 a palliative stent and in 5 patients stone fragmentation led to effective bile drainage with clinical resolution despite incomplete clearance. Age, sex and stone characteristics were not related to treatment outcome. Major complications occurred in two patients (haemobilia and rectal bleeding) and minor complications in 25 (3 vomiting, 22 arrhythmias). No procedure-related deaths occurred. CONCLUSION: ESWL is a safe and effective technique for clearance of refractory bile duct stones.

We report a case of a prompt reactivation of a quiescent Crohn's disease with pain, fever and abdominal abscess which occurred after seasonal and pandemic flu vaccinations. Based on the clinical history and the timing of the events, we could relate the relapse of CD to the double vaccinations.

Background and Aims: The knowledge of natural history is essential for disease management. We evaluated the natural history (e.g. frequency and characteristics of symptoms and clinical outcome) of gallstones (GS) in a population-based cohort study. Methods: A total of 11 229 subjects (6610 men, 4619 women, age-range: 29–69 years, mean age: 48 years) were studied. At ultrasonography, GS were present in 856 subjects (338 men, 455 women) (7.1%). GS were followed by means of a questionnaire inquiring about the characteristics of specific biliary symptoms. Results: At enrolment, 580 (73.1%) patients were asymptomatic, 94 (11.8%) had mild symptoms and 119 (15.1%) had severe symptoms. GS patients were followed up for a mean period of 8.7 years; 63 subjects (7.3%) were lost to follow up. At the end of the follow up, of the asymptomatic subjects, 453 (78.1%) remained asymptomatic; 61 (10.5%) developed mild symptoms and 66 (11.4%) developed severe symptoms. In subjects with mild symptoms, the symptoms disappeared in 55 (58.5%), became severe in 23 (24.5%), remained stable in 16 (17%); in subjects with severe symptoms, the symptoms disappeared in 62 (52.1%), became mild in 20 (16.8%) and remained stable in 37 (31.1%). A total of 189 cholecystectomies were performed: 41.3% on asymptomatic patients, 17.4% on patients with mild symptoms and 41.3% on patients with severe symptoms. Conclusions: This study indicates that: (i) asymptomatic and symptomatic GS patients have a benign natural history; (ii) the majority of GS patients with severe or mild symptoms will no longer experience biliary pain; and (iii) a significant proportion of cholecystectomies are performed in asymptomatic patients. Expectant management still represents a valid therapeutic approach in the majority of patients.

Summary Background Acute pouchitis, an idiopathic inflammatory condition of the ileal pouch anal anastomosis, is the most frequent complication after proctocolectomy for ulcerative colitis. Aim To test the hypothesis that sulfasalazine (SASP) might have a synergistic beneficial effect in acute pouchitis, by combining the anti-inflammatory activity of 5-aminosalicylic Acid and the bacteriostatic effect of sulphapyridine. Methods Twenty two patients were investigated for acute pouchitis; the Pouchitis Disease Activity Index (PDAI) was calculated and 11 patients with acute pouchitis (PDAI >7) were included in an open study, after obtaining their informed consent. Patients were treated with SASP 500 mg tablets, two tablets three times per day (3000 mg daily), for 2 months. Pouch endoscopy with biopsies was performed at the entry and at the end of the study. Results According to the PDAI score, 8/11 patients (73%) improved their clinical condition and 7/11 (63%) were in remission at the end of the treatment. At 8 weeks, the median PDAI index decreased from 11.2 ± 2.3 to 6.6 ± 4.7 P

Intestinal bile acid absorption is mediated by a sodium-dependent transporter located in the brush border apical membrane of ileocytes. The transmembrane topology and the role of individual amino acid residues in the bile acid transport process have been investigated by means of various experimental approaches, leading to multiple hypotheses. We raised a monoclonal antibody against a segment of the transporter comprising vicinal cysteine residues, in order to evaluate its functional role. A 14 amino acid peptide, corresponding to amino acids 104−117 of the transporter, was synthesized, and a monoclonal anti-peptide antibody was raised. In vitro uptake−inhibition studies in the presence of the monoclonal anti-peptide antibody were performed using ileal brush border membrane vesicles. Rabbit ileum was perfused in vivo with 5 mM taurocholic acid in the presence of the monoclonal antibody, and bile acid absorption inhibition was evaluated. The anti-peptide monoclonal antibody significantly reduced the in vitro uptake and in vivo absorption of taurocholic acid. The present data demonstrate the functional relevance of the 104−117 peptide segment and report the generation of a novel antibody against the apical sodium-dependent bile acid transporter (ASBT) that may be used as a therapeutic agent in hypercholesterolemia and in cholestatic pruritus.

AIM: To evaluate the efficacy of granulocyte colony stimulating factors (G-CSF) in liver transplanted patients with hepatitis C (HCV) recurrence and Pegylated-IFN α-2b induced neutropenia, and to evaluate the impact of G-CSF administration on virological response. METHODS: Sixty-eight patients undergoing antiviral treatment for post-liver transplantation (OLT) HCV recurrence were enrolled. All patients developing neutropenia received G-CSF. RESULTS: Twenty three (34%) received G-CSF. Mean neutrophil count at the onset of neutropenia was 700/mmc (range 400-750/mmc); after 1 mo of G-CSF it increased to 1210/mmc (range 300-5590/mmc) (P < 0.0001). Three patients did not respond to G-CSF. Treatment duration was similar in neutropenic and non-neutropenic patients. No differences in the rate of discontinuation, infections or virological response were observed between the two groups. G-CSF was protective for the onset of de novo autoimmune hepatitis (P < 0.003). CONCLUSION: G-CSF administration is effective in the case of Peg-IFN induced neutropenia increasing neutrophil count, prolonging treatment and leading to sustained virological response (SVR) rates comparable to non-neutropenic patients. It prevents the occurrence of de novo autoimmune hepatitis.

Proton pump inhibitors (PPI) are very effective in inhibiting acid secretion and are extensively used in many acid related diseases. They are also often used in patients with cirrhosis sometimes in the absence of a specific acid related disease, with the aim of preventing peptic complications in patients with variceal or hypertensive gastropathic bleeding receiving multidrug treatment. Contradicting reports support their use in cirrhosis and evidence of their efficacy in this condition is poor. Moreover there are convincing papers suggesting that acid secretion is reduced in patients with liver cirrhosis. With regard to Helicobacter pylori (H pylori) infection, its prevalence in patients with cirrhosis is largely variable among different studies, and it seems that H pylori eradication does not prevent gastro-duodenal ulcer formation and bleeding. With regard to the prevention and treatment of oesophageal complications after banding or sclerotherapy of oesophageal varices, there is little evidence for a protective role of PPI. Moreover, due to liver metabolism of PPI, the dose of most available PPIs should be reduced in cirrhotics. In conclusion, the use of this class of drugs seems more habit related than evidence-based eventually leading to an increase in health costs.

OBJECTIVE: Existing endoscopy-based data on gastro-oesophageal reflux disease (GORD) in the general population are scarce. This study aimed to evaluate typical symptoms and complications of GORD, and their associated risk factors, in a representative sample of the Italian population. METHODS: 1533 adults from two Italian villages were approached to undergo symptom assessment using a validated questionnaire and upper gastrointestinal endoscopy. Data were obtained from 1033 individuals (67.4% response rate). RESULTS: The prevalence of reflux symptoms was 44.3%; 23.7% of the population experienced such symptoms on at least 2 days per week (frequent symptoms). The prevalence rates of oesophagitis and Barrett's oesophagus in the population were 11.8% and 1.3%, respectively. Both frequent (relative risk (RR) 2.6; 95% confidence interval (CI) 1.7 to 3.9) and infrequent (RR 1.9; 95% CI 1.2 to 3.0) reflux symptoms were associated with the presence of oesophagitis. No reflux symptoms were reported by 32.8% of individuals with oesophagitis and 46.2% of those with Barrett's oesophagus. Hiatus hernia was associated with frequent reflux symptoms and oesophagitis, and was present in 76.9% of those with Barrett's oesophagus. We found no association between body mass index and reflux symptoms or oesophagitis. CONCLUSIONS: GORD is common in Italy, but the prevalence of Barrett's oesophagus in the community is lower than has been reported in selected populations. Both frequent and infrequent reflux symptoms are associated with an increased risk of oesophagitis. Individuals with oesophagitis and Barrett's oesophagus often have no reflux symptoms.

AIM: To evaluate gallstone incidence and risk factors in a large population-based study. METHODS: Gallstone incidence and risk factors, were evaluated by structured questionnaire and physical examination, respectively, in 9611 of 11 109 (86.5%) subjects who were gallstone-free at the cross-sectional study. RESULTS: Six centers throughout Italy enrolled 9611 subjects (5477 males, 4134 females, aged 30-79 years), 9517 of whom were included into analysis: 424 subjects (4.4%) had gallstones and 61 (0.6%) had been cholecystectomized yielding a cumulative incidence of 0.67% per year (0.66% in males, 0.81% in females). Increasing age, a high body mass index (BMI), a history of diabetes, peptic ulcer and angina, and low cholesterol and high triglyceride levels were identified as risk factors in men while, in females, the only risk factors were increasing age and a high BMI. Increasing age and pain in the right hypocondrium in men and increasing age in females were identified as predictors of gallstones. Pain in the epigastrium/right hypocondrium was the only symptom related to gallstones; furthermore, some characteristics of pain (forcing to rest, not relieved by bowel movements) were significantly associated with gallstones. No correlation was found between gallstone characteristics and clinical manifestations, while increasing age in men and increasing age and BMI in females were predictors of pain. CONCLUSION: Increasing age and BMI represent true risk factors for gallstone disease (GD); pain in the right hypocondrium and/or epigastrium is confirmed as the only symptom related to gallstones.

The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel diseases (IBD), are rising in western countries. The modern hygienic lifestyle is probably at the root of a disease where, in genetically susceptible hosts, the intestinal commensal flora triggers dysregulated immune and inflammatory responses. Current therapies ranging from anti-inflammatory drugs to immunosuppressive regimens, remain inadequate. Advances in our understanding of the cell populations involved in the pathogenetic processes and recent findings on the regenerative, trophic and immunoregulatory potential of stem cells open new paths in IBD therapy. Hematopoietic and mesenchymal stem cells are catalyzing the attention of IBD investigators. This review highlights the pivotal findings for stem cell-based approaches to IBD therapy and collects the encouraging results coming in from clinical trials.

To develop a new formulation with hydroxy propyl methyl cellulose and Shellac coating for extended and selective delivery of butyrate in the ileo-caecal region and colon.One-gram sodium butyrate coated tablets containing 13C-butyrate were orally administered to 12 healthy subjects and 12 Crohn's disease patients and the rate of 13C-butyrate absorption was evaluated by 13CO2 breath test analysis for eight hours. Tauroursodeoxycholic acid (500 mg) was co-administered as a biomarker of oro-ileal transit time to determine also the site of release and absorption of butyrate by the time of its serum maximum concentration.The coated formulation delayed the 13C-butyrate release by 2-3 h with respect to the uncoated tablets. Sodium butyrate was delivered in the intestine of all subjects and a more variable transit time was found in Crohn's disease patients than in healthy subjects. The variability of the peak 13CO2 in the kinetic release of butyrate was explained by the inter-subject variability in transit time. However, the coating chosen ensured an efficient release of the active compound even in patients with a short transit time.Simultaneous evaluation of breath 13CO2 and tauroursodeoxycholic acid concentration-time curves has shown that the new oral formulation consistently releases sodium butyrate in the ileo-cecal region and colon both in healthy subjects and Crohn's disease patients with variable intestinal transit time. This formulation may be of therapeutic value in inflammatory bowel disease patients due to the appropriate release of the active compound.

AIM: To comparatively evaluate the long term efficacy of Rifaximin and dietary fibers in reducing symptoms and/or complication frequency in symptomatic, uncomplicated diverticular disease. METHODS: 307 patients (118 males, 189 females, age range: 40-80 years) were enrolled in the study and randomly assigned to: Rifaximin (400 mg bid for 7 d every month) plus dietary fiber supplementation (at least 20 gr/d) or dietary fiber supplementation alone. The study duration was 24 mo; both clinical examination and symptoms’ questionnaire were performed every two months. RESULTS: Both treatments reduced symptom frequency, but Rifaximin at a greater extent, when compared to basal values. Symptomatic score declined during both treatments, but a greater reduction was evident in the Rifaximin group (6.4 ± 2.8 and 6.2 ± 2.6 at enrollment, p = NS, 1.0 ± 0.7 and 2.4 ± 1.7 after 24 mo, p < 0.001, respectively). Probability of symptom reduction was higher and complication frequency lower (Kaplan-Meyer method) in the Rifaximin group (p < 0.0001 and 0.028, respectively). CONCLUSION: In patients with symptomatic, uncomplicated diverticular disease, cyclic administration of Rifaximin plus dietary fiber supplementation is more effective in reducing both symptom and complication frequency than simple dietary fiber supplementation. Long term administration of the poorly absorbed antibiotic Rifaximin is safe and well tolerated by the patients, confirming the usefulness of this therapeutic strategy in the overall management of diverticular disease.

The identification of new biomarkers or a disease-related protein fingerprint for inflammatory bowel diseases (IBDs) represents a major task in the diagnosis, prognosis and pharmacological therapy. To address these issues, a simple and rapid analytical proteomic method for serum protein profiling based on selective beads-based solid-phase bulk extraction, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and chemometric data analysis was developed. Serum proteins from healthy subjects (22) and patients with Crohn's disease (15) and ulcerative colitis (26) were selectively extracted according to reversed-phase (C18), strong anion-exchange (SAX) and metal ion affinity (IDA-Cu(II)) principles. This approach allowed enrichment of serum proteins/peptides due to the high interaction surface between analytes and the solid phase and high recovery due to the elution step performed directly on the MALDI-target plate. The MALDI-TOF MS serum protein profiles were acquired and, after a data pre-processing step, analyzed by linear discriminant analysis (LDA), a chemometric classification technique, in order to classify serum samples among healthy subjects and patients with inflammatory bowel diseases (IBDs). Since the high number of variables in the MALDI spectra (more than 16000 m/z values) prevents the use of LDA, the variables were reduced to 10-20 by features selection, thus allowing the evaluation of a pattern of m/z values with high discriminant power. Serum protein profiles obtained by reversed-phase extraction and the selection of 20 m/z values gave the best overall prediction ability (96.9%). The recognition of these m/z values may allow the identification of protein biomarkers involved in IBDs.

BACKGROUND: Triple therapy is recommended for Helicobacter pylori eradication, yet consensus on the duration of treatment is lacking. AIM: To compare the efficacy and safety of 1- and 2-week regimens of omeprazole, amoxicillin and clarithromycin in a large, multicentre, double-blind and randomised study. METHODS: A total of 909 H pylori-positive patients with duodenal ulcer, enrolled in 81 endoscopy units in Italy, were randomised to receive omeprazole, amoxicillin and clarithromycin for either 1 week (OAC1W) or 2 weeks (OAC2W) or omeprazole and amoxicillin for 2 weeks. H pylori eradication was assessed by histological examination and carbon-13 urea breath test 4 weeks after treatment. RESULTS: Both the intention-to-treat (ITT; n = 907) and per protocol (PP; n = 661) analyses showed no significant differences between the eradication rates of OAC1W (ITT 79.7%; PP 83.6%) and OAC2W (ITT 81.7%; PP 84.9%; ITT p = 0.53; PP p = 0.71). Both triple omeprazole, amoxicillin and clarithromycin regimens gave significantly higher eradication rates compared with omeprazole and amoxicillin treatment (ITT 44.6%; PP 42.8%; p

Background. Chronic persistent cough is a common and disabling disorder and gastro-oesophageal reflux disease is considered to be the third leading cause, after asthma and postnasal drip. Therefore, patients with unexplained chronic persistent cough usually undergo a stepwise evaluation to establish the existence of a reflux disease. Aim. To identify the most cost-effective diagnostic approach to assess gastro-oesophageal reflux disease in patients with unexplained chronic persistent cough. Methods. Direct and indirect costs associated with six diagnostic strategies using 24-h oesophageal pH-metry, oesophago-gastroduodenoscopy and the proton pump inhibitors test in different sequences, were evaluated using a decision tree model. If the first test was positive, the diagnostic work-up was stopped, if negative the patient proceeded to the second test, and so on. Clinical data from an observational prospective trial conducted in 51 patients with unexplained chronic persistent cough were used in the economic model. Results. All six strategies had the same clinical effectiveness (78.4%). The diagnostic work-up with the lowest cost was the proton pump inhibitors test followed by pH-metry and then oesophago-gastroduodenoscopy with a total cost of EURO211.08 (direct EURO142.93, indirect EURO68.15). Conclusions. This study shows that the lowest cost is the strategy where proton pump inhibitors test is performed as first investigation. Implementation of this diagnostic work-up may lead to cost savings in the management of patients with chronic persistent cough. (c) 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm, the major cause of death in patients with liver cirrhosis, and the third most common cause of cancer-related death in the world. The geographic distribution of HCC varies significantly and 80% of cases occur in developing countries (Far East and South Asia) where the prevalence of viral hepatitis is higher. The treatment of HCC is difficult because most patients are diagnosed when the tumour is in an advanced stage and is not amenable to potential curative therapy, thus prevention is the key to reducing HCC and its related morbidity and mortality. HCC is unique among cancers, occurring mostly in patients with a known risk factor. Ninety percent of HCCs develop in the context of chronic liver diseases and mainly in patients with cirrhosis. Viral hepatitis is the most common cause of HCC worldwide, followed by alcoholic liver disease (ALD) and other causes such as non-alcoholic fatty liver disease (NAFLD), genetic haemocromatosis (GH) and primary biliary cirrhosis in an advanced stage (III-V). In certain areas of the People's Republic of China, exposure to aflatoxin and HBV infection are thought to be responsible for the extraordinary high risk of HCC. Substantial progresses in the prevention of virusl-related hepatitis (screening of blood units, use of disposable sanitary tools, HBV vaccination) have been achieved in developed countries, but in the same areas, alcohol- and dysmetabolism-related HCCs are emerging problems which require specific interventions in terms of public health measures. In developing countries, economic constraints limit the development of any program for the prevention of viral hepatitis transmission (including health education campaigns, healthcare politics, primary prevention and the improvement of hygienic and sanitary conditions). When viral liver disease is established, only a minority of patients are treated worldwide and benefit a possible preventive effect of medical treatment on HCC development. Thus the real contribution of medical treatment to HCC prevention in patients with chronic viral hepatitis is small. Great efforts are needed to identify more effective medical measures for primary and secondary prevention of HCC.

Autoimmune manifestations are common both in patients chronically infected by hepatitis C virus, and in patients transplanted for non-autoimmune diseases. A correlation between interferon based treatment and autoimmune diseases or the development of autoantibodies is well established in non-transplanted patients, but few data are available about transplanted patients. It is unclear whether interferon may increase the incidence of acute cellular rejection and there are few reports on the development of atypical autoimmune manifestations during post-liver transplantation interferon or pegylated interferon treatment. We describe a case of systemic lupus erythematosus following treatment with pegylated interferon alfa-2b in a transplanted patient with recurrence of chronic hepatitis C. Our experience suggest that pegylated interferon may induce autoimmune diseases in the immunosuppressed host, different from acute cellular rejection and call for a great attention to possible autoimmune disorders development during interferon based treatments in liver transplanted patients.

The incidence of invasive fungal infection is increasing especially in the field of transplantation, affecting as many as 50% of bone marrow transplant (BMT) patients with neutropenia and 5-20% of solid-organ transplant (SOT) recipients. Fusarium species are soil saprophytes and plant pathogens. They may cause superficial mycoses or important opportunistic infections in patients with bone marrow suppression and neutropenia, they have been rarely described in solid organ recipients, and up to now there have been no reports of such infection in isolated liver transplanted patients. We describe a case of disseminated Fusarium solani infection with hepatic localization in a liver transplanted patient that resolved with the administration of amphotericin B. Our observation confirms that Fusarium spp. are emerging pathogens that may most frequently affect not only BMT patients and patients with hematological malignancies, but also SOT patients. They may cause both localized and disseminated infection. In conclusion, Fusarium spp. etiology should be considered in the context of infectious diseases following liver transplantation.

AIM: To simultaneously evaluate the presence of defects in gallbladder and gastric emptying, as well as in intestinal transit in gallstone patients (GS) and the effect of chronic ursodeoxycholic acid (UDCA) administration on these parameters and on serum bile acids and clinical outcome in GS and controls (CTR). METHODS: After a standard liquid test meal, gallbla-dder and gastric emptying (by ultrasound), oroileal transit time (OITT) (by an immunoenzymatic technique) and serum bile acids (by HPLC) were evaluated before and after 3 mo of UDCA (12 mg/kg bw/d) or placebo administration in 10 symptomatic GS and 10 matched healthy CTR. RESULTS: OITT was longer in GS than in CTR (P < 0.0001); UDCA significantly reduced OITT in GS (P < 0.0001), but not in CTR. GS had longer gastric half-emptying time (t1/2) than CTR (P < 0.0044) at baseline; after UDCA, t1/2 significantly decreased (P < 0.006) in GS but not in CTR. Placebo administration had no effect on gastric emptying and intestinal transit in both GS and CTR. CONCLUSION: The gallstone patient has simultaneous multiple impairments of gallbladder and gastric emptying, as well as of intestinal transit. UDCA administration restores these defects in GS, without any effect in CTR. These results confirm the pathogenetic role of gastrointestinal motility in gallstone disease and suggest an additional mechanism of action for UDCA in reducing bile cholesterol supersaturation.

Summary Non-alcoholic fatty liver disease is a new clinicopathological condition of emerging importance, now recognized as the most common cause of abnormal liver tests. It is characterized by a wide spectrum of liver damage: simple steatosis may progress to advanced fibrosis and to cryptogenic cirrhosis through steatohepatitis, and ultimately to hepatocellular carcinoma. Obesity is the most significant single risk factor for the development of fatty liver, both in children and in adults; obesity is also predictive of the presence of fibrosis, potentially progressing to advanced liver disease. From a pathogenic point of view, insulin resistance plays a central role in the accumulation of triglycerides within the hepatocytes and in the initiation of the inflammatory cascade. Chronic hepatocellular injury, necroinflammation, stellate cell activation, progressive fibrosis and ultimately, cirrhosis may be initiated by peroxidation of hepatic lipids and injury-related cytokine release. In the last few years, several pilot studies have shown that treatment with insulin-sensitizing agents, anti-oxidants or cytoprotective drugs may be useful, but there is no evidence-based support from randomized clinical trials. Modifications in lifestyle (e.g. diet and exercise) to reduce obesity remain the mainstay of prevention and treatment of a disease, which puts a large number of individuals at risk of advanced liver disease in the near future.

SUMMARY: Beside substantial progress in treatment of chronic hepatitis C (CHC) particular patients (genotype 1/4, high viral load, previous nonresponse, cirrhosis) remain difficult to treat. The aim of our pilot randomized study was to compare efficacy and tolerability of standard doses of Peginterferon alpha-2b + ribavirin with higher doses of Peginterferon alpha-2b administered twice weekly + ribavirin. Sixty-five outpatients with CHC were subsequently enrolled. Group A (n = 22) received recommended doses of Peginterferon alpha-2b and group B (n = 43), received high doses twice weekly. Groups were comparable for baseline characteristics. All genotype 1/4 patients had high baseline viraemia. Sustained virological response (SVR) was significantly higher in group B among naïve patients (72%vs 25%, P = 0.024). A significantly higher rate of SVR was observed in group B both considering only genotype 1/4 patients, (46%vs 13%, P = 0.03) and grouping together genotype 1/4 naive and relapsers (57%vs 11%, P = 0.039). Discontinuation rate was 32% (7 of 22) in group A and 21% (9 [corrected] of 43) in group B. Our response rates are the highest reported for genotype 1/4 with high viraemia. Our pilot study supports the need of randomized studies to evaluate both viral kinetics and efficacy of high dose and twice weekly administration of Peginterferon alpha-2b in genotype 1/4 patients with high viraemia who may need personalized treatment schedules. SUMMARY: Beside substantial progress in treatment of chronic hepatitis C (CHC) particular patients (genotype 1/4, high viral load, previous nonresponse, cirrhosis) remain difficult to treat. The aim of our pilot randomized study was to compare efficacy and tolerability of standard doses of Peginterferon alpha-2b + ribavirin with higher doses of Peginterferon alpha-2b administered twice weekly + ribavirin. Sixty-five outpatients with CHC were subsequently enrolled. Group A (n = 22) received recommended doses of Peginterferon alpha-2b and group B (n = 43), received high doses twice weekly. Groups were comparable for baseline characteristics. All genotype 1/4 patients had high baseline viraemia. Sustained virological response (SVR) was significantly higher in group B among naive patients (72%vs 25%, P = 0.024). A significantly higher rate of SVR was observed in group B both considering only genotype 1/4 patients, (46%vs 13%, P = 0.03) and grouping together genotype 1/4 naive and relapsers (57%vs 11%, P = 0.039). Discontinuation rate was 32% (7 of 22) in group A and 19% (8 of 43) in group B. Our response rates are the highest reported for genotype 1/4 with high viraemia. Our pilot study supports the need of randomized studies to evaluate both viral kinetics and efficacy of high dose and twice weekly administration of Peginterferon alpha-2b in genotype 1/4 patients with high viraemia who may need personalized treatment schedules.

Functional gastrointestinal disorders can be defined as 'a variable combination of chronic or recurrent gastrointestinal symptoms not explained by structural or biochemical abnormalities'. Motor disorders are considered to be one of the pathogenetic mechanisms of these symptoms; in fact, it has been hypothesized that the smooth muscle of the whole gastrointestinal tract could be involved. Gallbladder motility has been evaluated in patients with dysmotility-like dyspepsia, irritable bowel syndrome and biliary disorders without gallstones; results of these observations are often inconclusive, conflicting and not always useful from a clinical point of view. The aim of this review is to explore the relationship between gallbladder motility and functional gastrointestinal disorders from pathogenetic and physiopathological points of view, and also to define the possible impact of these observations on clinical practice.

Diverticular disease of the colon is a common disease worldwide. Although the disease is asymptomatic in about 70-80 % of patients, it represents, at least in Western countries, one of the most important gastrointestinal diseases in terms of direct and indirect health costs. Pathogenesis of the disease is still unknown. However, it is the result of complex interactions between colonic structure, intestinal motility, diet and genetic factors. Whilst efficacious preventive strategies remain to be identified, fibre supplementation in the diet is recommended. Why symptoms develop is still unclear. Results of recent experimental studies on irritable bowel syndrome speculated that low grade inflammation of colonic mucosa, induced by changes in bacterial microflora, could affect the enteric nervous system, which is crucial for normal gut function, thus favouring symptom development. This hypothesis could be extrapolated also for diverticular disease, since bacterial overgrowth is present, at least in a subgroup of patients. These perspectives on symptom development are reviewed and new therapeutic approaches are hypothesized.

Little is known of the incidence of hepatitis C virus (HCV) infection, and the frequency of spontaneous viral clearance in the general population is unknown. We conducted an epidemiological study in two Apennine towns in northern Italy.Anti-HCV (ELISA and RIBA third generation) and HCV-RNA by polymerase chain reaction were tested in thawed sera from an adult general population of Loiano-Monghidoro in 1986 and 1996, obtained in the context of the MICOL (Multicenter Italian Study on Cholelithiasis). In 1999, anti-HCV positive subjects and sex and age matched controls were recalled in order to identify risk factors for acquiring HCV infection and to assess the family composition of anti-HCV+ subjects.For 1646 subjects, sera were available from both 1986 and 1996 (mean age in 1986 43 (0.39) years). In 1986, 57 (3.46%) subjects were HCV antibody positive (HCV-Ab+). Eight new cases were recorded in 1996: adult incidence was 50.3 cases/100 000 inhabitants/year. Fifty three of 63 (84.1%) HCV-Ab+ sera were also HCV-RNA+. Genotype 2a/2c accounted for 44% and 1b for 47.0% of cases. HCV-Ab+ subjects had higher serum levels of alanine aminotransferase with respect to controls (p0.005), as did subjects infected with genotype 1 with respect to those with genotype 2 (p0.05). Eleven of 65 (16.9%) HCV-Ab+ subjects spontaneously cleared HCV-Ab; 7/11 also lost HCV-RNA- in both serum and leucocytes. Sixteen anti-HCV+ subjects belonged to families containing more than one infected member. Married couples accounted for 10 of these 16 subjects. In four of these five married couples, HCV genotype was identical in the two spouses.In rural northern Italy, the adult incidence of HCV is approximately 50 cases/100 000 inhabitants/year. Our findings suggest that as many as 17% of infected subjects may spontaneously clear HCV-Ab. Interfamilial transmission seems to have a role in the spread of infection.

Chronic hepatitis C represents a major clinical problem after liver transplantation, but factors influencing the recurrent disease have not been well characterized. We analyzed the clinical records of all the patients transplanted for hepatitis C virus (HCV)-related liver disease in our Center between 1991 and 1997. Eighty consecutive HCV-positive (+) patients (60 men, ages 28 to 64) survived more than 1 month after transplantation and were followed for a median of 45 months. Diagnosis of recurrent chronic hepatitis C was made in 38 patients (47.5%), of whom 22 had moderate/severe chronic hepatitis. Decompensated cirrhosis occurred in six patients (7.5%). No difference in patient survival was found between patients with and without hepatitis C recurrence. No association was found between recurrent hepatitis C and presumed risk factors. The method of tapering off corticosteroids was significantly associated with both hepatitis C recurrence and the severity of hepatitis. In patients receiving a higher daily prednisone dose, 12 months after transplantation, the proportion of recurrent hepatitis C was 35.7% versus 66.6% (P = .02; odds ratio [OR], 3.6; 95% confidence interval (CI): 1.25 to 10.36), and among patients receiving a higher daily prednisone dose, 6 months after transplantation, the proportion of moderate/severe chronic hepatitis C was 40% versus 89% (P = .03; OR: 0.08, 95% CI: 0.008 to 0.84). Finally, prednisone dose at month six was significantly associated with disease-free survival of the liver graft. In conclusion, our results seem to indicate that in HCV-infected liver transplant recipients, a long-term treatment with corticosteroids, slowly tapered off over time, may prevent the more aggressive forms of recurrent liver disease.

Background. Ursodeoxycholic acid is currently used for the treatment of primary biliary cirrhosis at 13–15 mg/kg/day, but liver tests of some patients do not return to normal at this dose. Studies reported here were designed to test whether a higher dose of ursodeoxycholic acid than is currently used would induce still greater biliary enrichment of ursodeoxycholic acid and whether such enrichment would lead to still further improvement in liver tests in patients with early primary biliary cirrhosis. Methods. A total of 20 patients with histologically proven primary biliary cirrhosis were enrolled. Patients had early stage primary biliary cirrhosis as serum bilirubin levels were normal and the Mayo risk score 4.2±0.5. Group 1 received 600, 1200 and 1800 mg/day of ursodeoxycholic acid; group 2 received 900, 1500 and 2100 mg/day. The order of periods was randomized. Each treatment period lasted 3 months followed by a further 3 months during which a standard dose of ursodeoxycholic acid was given. At the end of each treatment period, liver tests were evaluated, and biliary bile acid pattern of duodenal bile was determined using high pressure liquid chromatography. Results. Biliary bile acid became enriched in ursodeoxycholic acid in direct relationship to dosage (r=0.84, p

Background: It is not established whether virological status affects the efficiency of α-fetoprotein (AFP) as a hepatocellular carcinoma (HCC) marker among patients with chronic liver disease (CLD). Methods: We enrolled in a case-control study 170 HCC and 170 CLD patients, matched for age, sex, CLD and HBsAg/anti-HCV status. The AFP sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. PPV and NPV were evaluated for three additional HCC prevalences (5, 10, and 20%). Results: The best discriminating AFP value was 16 ng/ml. A value of 20 ng/ml (above which investigations for HCC are recommended) had equivalent sensitivity (60.0 vs. 62.4%) and specificity (90.6 vs. 89.4%). PPV of 20 ng/ml was 84.6% but decreased to 25.1% at 5% tumor prevalence. NPV was 69.4% and rose to 97.7% at 5% prevalence. In the different groups of infected patients PPV ranged from 80.0 to 90.9%, falling to 17.4-34.5% at 5% prevalence. In noninfected patients PPV was 100% at any HCC prevalence. NPV ranged from 59.0 to 73.0%, reaching 96.5-98.1% at 5% prevalence. Conclusions: In CLD patients, AFP monitoring misses many HCCs and inappropriately arouses suspicion of malignancy in many patients. Its usefulness is barely affected by the infection responsible for CLD. An AFP elevation could be more indicative of HCC in non-infected patients. © 2001 European Association for the Study of the Liver.

BACKGROUND & AIMS: A direct comparison of jejunal and ileal absorption rates of bile acids has not been reported. The aim of this study was to compare the relative transport rates of different bile acids in the jejunum and ileum. METHODS: Jejunal and ileal rabbit intestinal segments were separately perfused with bile acid solutions, and dose- response curves were obtained for taurocholate, ursodeoxycholate, chenodeoxycholate, deoxycholate, and their glycoconjugates. Membrane fluidity and bile acid transport were assessed in brush border membrane vesicles. RESULTS: Taurocholate showed active transport in the ileum and no transport in the jejunum. Unconjugated bile acids showed passive diffusion in the two tracts, whereas glycoconjugated bile acids showed both components of transport in the ileum and passive diffusion in the jejunum (lower in the latter). A higher membrane fluidity and lower cholesterol-to-phospholipid ratio were found in the jejunum. Ursodeoxycholate reduced bile acid uptake into membrane vesicles from both ileum and jejunum. CONCLUSIONS: Active transport is limited to the ileum. Passive diffusion is higher through a less fluid membrane with a higher cholesterol-to-phospholipid ratio in the ileum than in the jejunum. Ursodeoxycholate inhibition may be at the level of a facilitated, sodium-independent diffusion in the jejunum. (Gastroenterology 1996 Feb;110(2):459-68)

We investigated liver morphology and biliary function in vivo in rats made porphyric by hexachlorobenzene (HCB). In one group of HCB rats we also evaluated whether S -adenosyl-l-methionine (SAMe), administered during the last 15 days of HCB treatment, attenuated liver injury and the accumulation of porphyrins (HCB + SAMe group). In HCB rats we found: (a) a 100% increase in liver weight; (b) a 500-fold increase in total liver porphyrins (TLP); (c) significantly increased serum bilirubin and cholesterol levels; (d) unchanged total bile flow (TBF) but enhanced levels of the bile acid independent fraction (BAIF); and (e) decreased excretion in bile of bile acids (BA), phospholipids (PL) and cholesterol (CHO) (58, 65 and 47%, respectively, expressed as mmol/min per kg liver). SAMe was found to partially reverse HCB-related effects. TLP levels were about 65% lower in HCB + SAMe treated rats than in HCB rats. However, while SAMe restored bile CHO excretion to control values, it did not influence bile excretion of BA, PL, or BAIF. In conclusion, HCB-induced porphyria was characterized by a complex derangement of liver morphology and biliary function that was unrelated to the extent of porphyrin accumulation in the liver.

1 Hypolipidaemic agents may increase biliary cholesterol in man, inducing a supersaturated bile. 2 To evaluate this possible side-effect, we have studied bile lipid secretion over a period of 8 h with intact enterohepatic circulation and 4 h with complete interruption in rats treated for two months with a salt of cholestyramine and 2-[4-(p-chlorobenzoyl)-phenoxy]2-methyl propionic acid (alpha-1081, 1.150 g/kg body wt., daily), cholestyramine (1.125 g/kg body wt. daily), procetofenic acid (25 mg/kg body wt. daily) and saline respectively (six rats for each group). 3 Cholesterol saturation index significantly (P less than 0.005) increased (from 0.21 +/- 0.01 to 0.39 +/- 0.09, mean +/- s.d.), in rats fed with procetofenic acid but it did not in alpha-1081- and cholestyramine-treated animals. 4 Procetofenic acid and, to a lesser extent, cholestyramine increased the bile flow. Procetofenic acid increased cholesterol secretion from 0.45 +/- 0.17 to 0.94 +/- 0.19 mumol kg-1 body wt. h-1 (mean +/- s.d.). 5 Cholestyramine increased both serum cholesterol and bile acid secretion from 0.45 +/- 0.17 to 0.68 +/- 0.10 and 25.8 +/- 9.48 to 39.96 +/- 6.68 mumol kg-1 body wt. h-1 respectively; alpha-1081, on the contrary, had no effect on bile lipid secretion. 6 These data suggest that alpha-1081 may be used as a new hypolipidaemic drug without any risk of increasing cholesterol in bile.

A series of unconjugated and taurine conjugated bile acids (BAs) differing in water solubility (SWo), critical micellar concentration (CMC), and hydrophilicity (K') were infused iv to rats at a tracer dose and a dose of 6 mumol/min/kg over a 1-h period. Bile was collected for 3 h to evaluate the role of BA structure on cholesterol, phospholipids secretions, and bile flow. The BAs studied differ in the number (2-3), position (-3, -6, -7, -12), and orientation of the hydroxyls (alpha/beta); the side chain structure was modified by shortening (C-23, nor-BA) and by lengthening (C-25, homo-BA), while maintaining the same structure of nuclear hydroxyls (3 alpha 7 beta). At a "tracer" dose, all C-24 natural BAs are efficiently recovered in bile when administered in both unconjugated and taurine conjugated forms. At a "high dose", all taurine conjugated BAs are efficiently recovered in bile (80-100%). However, a variable recovery was observed among unconjugated BAs: trihydroxy BAs are efficiently recovered (85-100%), while dihydroxy BAs are only partially recovered (25-40%). The side chain-modified BAs [i.e., C-23 nor and C-25 homo analogs of ursodeoxycholic acid (UDCA)] are partially recovered at a tracer dose (20-30%), but less at a high dose (10-20%) when administered in the unconjugated form. In contrast, the corresponding taurine conjugates are more efficiently recovered in bile (60-80%). Conjugation with taurine increases total recovery of unconjugated BAs in bile by not more than 30-40%. Highly hydrophilic and water-soluble BAs, such as ursocholic acid (SWo = 1.67 mM) and cholic acid (SWo = 0.27 mM), can also be secreted as unconjugates, and this accounts for their complete recovery. The conjugation step is rate limiting for poorly soluble BAs such as ursodeoxycholic acid (SWo = 0.009 mM) when administered at a high dose, and critical for nor and homo analogs which are poorly soluble and whose side chain modification partially suppresses their conjugation with taurine or glycine and thereby induces alternative pathways such as glucuronidation or sulfation. The induced bile flow is directly related to the hydrophilicity of the natural C-24 bile acid.(ABSTRACT TRUNCATED AT 400 WORDS)

A side chain derivative of ursodeoxycholic acid, 23-methylursodeoxycholic acid, was synthesized and the effect of i.v. infusion of the acid at different doses (0.75, 1.5, 3.0 and 6.0 μmoles per min per kg body weight over 1 hr) on bile flow, on its hepatic biotransformations and on biliary lipid secretion has been studied in bile fistula rats. The results were compared with those of ursodeoxycholic and cholic acid administered under similar conditions. 23-Methylursodeoxycholic acid is poorly secreted into bile and poorly taurine and glycine conjugated, at all infusion doses. Ursodeoxycholic acid is quantitatively recovered at low doses and recovered less at high infusion rates. Cholic acid is almost entirely recovered at all infusion doses. Ursodeoxycholic acid conjugation pattern is dependent on the dose, and glucuronidation and sulfation operate at high doses. Cholic acid is taurine conjugated at low doses; at high doses, large amounts of unconjugated bile acids are observed. Methylursodeoxycholic acid presents a delayed secretion and hypercholeresis. Ursodeoxycholic acid presents similar results at high infusion rates, possibly by reaching a high intrahepatic concentration of free form. The octanol/water partition coefficients of ursodeoxycholic acid and 23-methylur-sodeoxycholic acid are similar and higher than that of cholic acid. A chole-hepatic shunting of 23-methylursodeoxycholic acid may explain both the low recovery in bile and hypercholeresis and is consistent with its hydrophobicity. The high water solubility and hydrophilicity of cholic acid, on the contrary, makes possible its high recovery in bile. The effect on biliary lipid secretion is unpredictable and affected by the dose and, in consequence, by the conjugation pattern of the bile acid. The detergency of the intrahepatic pool of the secreted bile acid and the physicochemical state of the native bile may be the driving force determinant for cholesterol and phospholipid biliary secretion.