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Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance.

Background: Autoimmune hepatitis requires long‐term therapy, and systemic cor‐ ticosteroids are the backbone of therapeutic management. Prolonged use of corti‐ costeroids may lead to adverse events but data from long‐term studies are mainly derived from studies in rheumatic diseases. Aim: To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long‐term maintenance treatment of patients with autoimmune hepatitis. Methods: We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a gen‐ eralised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagno‐ sis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects. Results: A total of 6634 years, with a median of 13 (range 1‐40) per patient were recorded. The median age at diagnosis was 44 years (range 2‐88). Adverse events were documented in 120 (25%) patients. Low‐dose predniso(lo)ne (0.1‐5.0 mg/d) in‐ creased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years. Conclusions: Even low doses of corticosteroids frequently lead to substantial ad‐ verse events refuting the assumption that adverse events are prevented by adminis‐ tering low doses.

Background: Evidence for the efficacy of TIPSS in ectopic variceal bleeding (EctVB) is largely based on relatively small series. Aim: To define the efficacy of TIPSS in EctVB. Methods: Retrospective analysis of consecutive patients with chronic liver disease who presented with EctVB and received TIPSS in three tertiary centres in 1992-2016. Results: The study included 53 patients (70% male, median age 61 years, median model for end-stage liver disease (MELD) score 11). The ectopic varices were located around the insertion of stomas (40%), duodenum (23%), rectum (17%) and at other sites (20%). Three-quarters of the patients had previously received unsuccessful medical, endoscopic or surgical therapy. The median follow-up was 14.0 months. Following TIPSS, bleeding recurred in 12 patients: 6 of 12 (50%) with duodenal varices, 2 of 9 (22%) with rectal varices and one each with stomal (1/21), intraperitoneal (1/3), hepaticojejunostomy (1/2) and ascending colon varices (1/2). The risk factors for re-bleeding were MELD score at TIPSS placement (HR: 1.081 per point; 95% confidence interval (CI): 1.012-1.153; P = 0.034), varices located at site other than an enterostomy (HR: 9.770; 95%CI

Background: Knowledge about bacterascites is limited and management guidelines are based on small patient series. The purpose of this study was to add further insight into the clinical characteristics, microbiological findings, and prognosis of patients diagnosed with bacterascites. Methods: Retrospective analysis of patients with advanced chronic liver disease diagnosed with bacterascites and SBP between January 2003 and August 2016. Results: In this study, 123 patients were included with 142 episodes of bacterascites. The median MELD score was 20 and clinical symptoms of infection were present in 78%. Empiric antibiotic treatment was initiated in 68

Background: Few studies with diverging results and a small sample size have compared autoimmune hepatitis (AIH) in the elderly to younger patients. Aim: To unbiasedly investigate the role of age in behaviour and treatment outcome of AIH. Methods: All patients with probable or definite AIH type 1 in four tertiary academic centres were included in this retrospective - and since 2006 prospective - cohort study. Influence of age on presentation, remission and outcome of AIH were investigated. Results: 359 patients were included. Presence of cirrhosis at AIH diagnosis around 30% was independent of age. ALAT was higher at age 30-60 years on AIH diagnosis, and above age 60 there were less acute onset, less jaundice and more concurrent autoimmune disease. Remission was reached in 80.2%, incomplete remission in 18.7%, only 1.1% (all aged 50-65) was treatment-refractory. Age was not an independent predictor of remission, while cirrhosis was. Above age 45 there was more diabetes, above age 60 more loss of remission. Rate of progression to cirrhosis was 10% in the 10 years after diagnosis and unrelated to age at AIH diagnosis. With onset below age 30, there was more development of decompensated cirrhosis over time. With higher age at AIH diagnosis there was a lower survival free of liver-related death or liver transplantation. Conclusions: AIH presents at all ages. Age influences features at diagnosis, but not response to treatment, while survival without liver-related death or liver transplantation decreases with higher age at diagnosis.

Background: Recent investigations suggest an increasing prevalence of Gram-positive and antibiotic-resistant bacteria causing spontaneous bacterial peritonitis (SBP), probably related to changes in antibiotic prescription patterns, in particular more widespread and long-term use of antibiotic prophylaxis with quinolones. Objective: The primary objective of this study was to assess potential changes in the microbiology of SBP in two patient cohorts studied at a 10-year interval. Further aims were to study prognostic factors and outcome of SBP. Methods: A retrospective double-cohort study, including all ascitic cultures from patients with cirrhosis obtained 2003–2005 and 2013–2014, was conducted. Results: In total 312 patients were included, 125 patients in the first and 187 patients in the second cohort. SBP was diagnosed in 132 of 840 analyzed ascitic fluid samples; 62 samples were culture positive. An increase of Gram-positive bacterial isolates was noted from 26% to 46% between cohorts (p = 0.122). The prevalence of multidrug-antibiotic–resistant pathogens increased from 25% to 32% (p = 0.350). Survival after SBP among the two cohorts was comparable. Conclusion: This single-center study in the Netherlands found a modest but nonsignificant increase in the proportion of patients with SBP caused by Gram-positive bacteria and multidrug-antibiotic–resistant bacteria over a 10-year period. Our findings differ from reported data in other countries and suggest empiric antibiotic prophylaxis and treatment of SBP should be based on national and regional microbiological findings and resistance patterns.

Changes over time in the presenting features and clinical course of patients with primary biliary cholangitis are poorly described. We sought to describe temporal trends in patient and disease characteristics over a 44-year period across a large international primary biliary cholangitis cohort of 4,805 patients diagnosed between 1970 and 2014, from 17 centers across Europe and North America. Patients were divided into five cohorts according to their year of diagnosis: 1970-1979 (n = 143), 1980-1989 (n = 858), 1990-1999 (n = 1,754), 2000-2009 (n = 1,815), and ≥2010 (n = 235). Age at diagnosis, disease stage, response to ursodeoxycholic acid, and clinical outcomes were compared. Mean age at diagnosis increased incrementally by 2-3 years per decade from 46.9 ± 10.1 years in the 1970s to 57.0 ± 12.1 years from 2010 onward (P < 0.001). The female to male ratio (9:1) and antimitochondrial antibody positivity (90%) were not significantly variable. The proportion of patients presenting with mild biochemical disease (according to Rotterdam staging) increased from 41.3% in the 1970s to 72.2% in the 1990s (P < 0.001) and remained relatively stable thereafter. Patients with a mild histological stage at diagnosis increased from 60.4% (1970-1989) to 76.5% (1990-2014) (P < 0.001). Correspondingly, response to ursodeoxycholic acid according to Paris-I criteria increased; 51.7% in the 1970s and 70.5% in the 1990s (P < 0.001). Recent decades were also characterized by lower decompensation rates (18.5% in the 1970s to 5.8% in the 2000s, P < 0.001) and higher 10-year transplant-free survival (48.4%, 68.7%, 79.7%, and 80.1% for each respective cohort; P < 0.001). Conclusion: In recent decades, a pattern of primary biliary cholangitis presentation consistent with an older age at diagnosis alongside reduced disease severity has been noted; the observed trends may be explained by an increase in routine testing of liver function and/or a changing environmental trigger.

Background: Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus. Methods: A multicenter investigator-initiated, double-blind, randomized placebo-controlled trial to evaluate the effect of bezafibrate on cholestatic pruritus in 84 adult patients with primary biliary cholangitis or primary/secondary sclerosing cholangitis. Primary outcome is the proportion of patients with a reduction of itch intensity of 50% or more (measured on a Visual Analog Scale) after 21 days of treatment with bezafibrate 400 mg qid or placebo. Secondary outcomes include the effect of bezafibrate on a five-dimensional itch score, liver disease-specific quality of life, serum liver tests and autotaxin activity. Safety will be evaluated through serum parameters for kidney function and rhabdomyolysis as well as precise recording of (serious) adverse events. We provide a schematic overview of the study protocol and describe the methods used to recruit and randomize patients, collect and handle data and perform statistical analyses. Discussion: Given its favorable safety profile and anticholestatic properties, bezafibrate may become the new first-line treatment option for treating cholestatic pruritus. Trial registration: Netherlands Trial Register, ID: NCT02701166. Registered on 2 March 2016; Netherlands Trial Register, ID: NTR5436. Registered on 3 August 2015.

Objective To evaluate the long-term outcome of autoimmune pancreatitis. Methods Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosed malignancies, and mortality. In addition, pancreatic function and quality of life were assessed prospectively. Results 107 patients were included (87% men, 90% with type 1), with a median follow-up of 74 (interquartile range, 49-108) months. One third was operated for suspected pancreatic cancer (32%). Most patients were (successfully) treated with steroids (83%), but relapses were common (52%), for which no risk factors could be identified. Pancreatic carcinoma was not observed. Prospective data were obtained from 64%, as 17% had died, 7% were lost to follow-up, and 13% refused to participate. After a median of 75 (interquartile range, 50-106) months, 46% still used active treatment. Exocrine and endocrine insufficiencies were highly prevalent (82% and 57%, respectively). Quality of life and survival were not impaired, as compared with a reference population. Conclusions Despite an excellent initial treatment response, relapses are common, even in type 2, and almost half of the patients require maintenance therapy. Pancreatic insufficiency is highly prevalent, which calls for active screening. Pancreatic cancer was not observed, and quality of life and survival are not impaired.

OBJECTIVE: The objective of this study was to compare efficacy of high versus low doses of prednisone for induction of remission in autoimmune pancreatitis (AIP). METHODS: This is a retrospective, multicenter study including patients diagnosed with AIP between May 1992 and August 2011. Clinical, laboratory and imaging findings were assessed before treatment and at 1, 3, and 6 months after starting treatment. RESULTS: A total of 65 patients (57 males; median age, 63 years) were treated with an initial low dose (10-20 mg/d, n = 14), a medium dose (30 mg/d, n = 15), or a high dose (40-60 mg/d, n = 36) of prednisone. There were no significant differences in baseline characteristics between the treatment groups including age, presenting symptoms and laboratory results. During a follow-up period of 6 months, in nearly all patients, symptoms (jaundice, weight loss) resolved completely. After 6 months, treatment response with respect to symptomatic, radiological, and laboratory improvement was comparable for the different dosage groups. CONCLUSIONS: Response to therapy was comparable for AIP patients treated with doses of prednisone in the range of 10 to 60 mg/d. A prospective trial should be conducted to confirm efficacy of lower-dose prednisone treatment.

OBJECTIVE: The objective of this study was to compare efficacy of high versus low doses of prednisone for induction of remission in autoimmune pancreatitis (AIP). METHODS: This is a retrospective, multicenter study including patients diagnosed with AIP between May 1992 and August 2011. Clinical, laboratory and imaging findings were assessed before treatment and at 1, 3, and 6 months after starting treatment. RESULTS: A total of 65 patients (57 males; median age, 63 years) were treated with an initial low dose (10-20 mg/d, n = 14), a medium dose (30 mg/d, n = 15), or a high dose (40-60 mg/d, n = 36) of prednisone. There were no significant differences in baseline characteristics between the treatment groups including age, presenting symptoms and laboratory results. During a follow-up period of 6 months, in nearly all patients, symptoms (jaundice, weight loss) resolved completely. After 6 months, treatment response with respect to symptomatic, radiological, and laboratory improvement was comparable for the different dosage groups. CONCLUSIONS: Response to therapy was comparable for AIP patients treated with doses of prednisone in the range of 10 to 60 mg/d. A prospective trial should be conducted to confirm efficacy of lower-dose prednisone treatment.

OBJECTIVE To evaluate the occurrence and histopathologic characteristics of immunoglobulin G4 (IgG4)- related prostatic involvement in patients diagnosed with autoimmune pancreatitis. METHODS Nine cases of IgG4-related prostatitis were identified among 117 men in the autoimmune pancreatitis and IgG4-associated cholangitis patient databases in 2 tertiary hospitals. Clinical information was retrieved, and available prostatic tissue samples and 18 prostatitis control samples were evaluated for characteristic IgG4-related disease (IgG4-RD) features: maximum number of IgG4-positive cells per high-power field; dense lymphoplasmacytic infiltrate; fibrosis, arranged at least focally in a storiform pattern; phlebitis with or without obliteration of the lumen; and increased number of eosinophils. RESULTS The aspecific sign of urine retention was commonly present in IgG4-RD patients with prostatic involvement. In these patients with IgG4-related prostatitis, the median number of IgG4-positive cells in prostatic tissue was 150 (interquartile range, 20-150) per high-power field compared with a median of 3 (interquartile range, 1-11) in control patients (P ¼ .008). Dense lymphoplasmacytic infiltrate was observed in most (86% in cases and 72% in control patients) tissue samples independent of the underlying cause of prostatitis. Fibrosis in at least a focally storiform pattern was seen rarely in both groups, and (obliterative) phlebitis was absent in all patients. Furthermore, eosinophil numbers were more often elevated in patients with IgG4-RD compared with controls (P <.001). In 2 cases, amelioration of the prostatitis symptoms on corticosteroid treatment was documented. CONCLUSION Prostatic involvement might not be rare in patients with pancreatic or biliary IgG4-RD. Clinicians should consider this disease entity in patients with IgG4-RD and prostatic symptoms

OBJECTIVE: Several diagnostic scoring systems for autoimmune pancreatitis (AIP) have been proposed including the Asian, HISORt (Histology, Imaging, Serology, Other organ involvement and Response to therapy), and International Consensus Diagnostic Criteria (ICDC), which have been compared by a few studies. We evaluated the diagnostic performance of these criteria in patients diagnosed with AIP between May 1992 and August 2011. METHODS: Scoring systems were applied retrospectively using data obtained in the initial evaluation period, before pancreatic resection was performed. RESULTS: One hundred fourteen cases with AIP were included. Eighty-two percent met the diagnostic criteria for AIP according to either the Asian, HISORt, or ICDC criteria. Only 33% met the Asian criteria, probably mainly related to a low rate of diagnostic pancreatography. In 18%, all scoring systems failed to confirm the diagnosis, even though these patients were considered to have a firm diagnosis of AIP. CONCLUSIONS: In this cohort of AIP patients, the 3 major diagnostic scoring systems for AIP proved to be complementary rather than overlapping. Our data indicate that one-fifth of our AIP patients do not meet any of these scoring systems. The ICDC, Asian, and HISORt criteria should be considered as useful clinical tools but not as criterion standard for the diagnosis. Copyright

Background: Autoimmune pancreatitis (AIP) is often difficult to distinguish from pancreatic carcinoma or other pancreatobiliary diseases. High serum levels of carbohydrate antigen 19-9 (Ca 19-9) are indicative of malignancies, whereas high levels of immunoglobulin (Ig)G4 (>1.4 g/l) are characteristic of AIP. We investigated whether serum levels of these proteins can differentiate between these diseases. Methods: We measured levels of Ca 19-9 and IgG4 in serum samples from 33 patients with AIP, 53 with pancreatic carcinoma, and

We report four patients with pneumothorax as a complication of ERCP with sphincterotomy. With conservative treatment all patients recovered. Previously, 16 comparable cases have been reported in the literature. The main risk factor for this rare complication seems (pre-cut) sphincterotomy. Pneumothorax is usually right-sided or bilateral and accompanied by pneumomediastinum, pneumoretroperitoneum and subcutaneous emphysema. The prognosis seems favourable with a non-surgical approach including intravenous antibiotics, fasting and when indicated chest tube drainage.

Background: Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided. Methods: All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked. Results: A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients. Conclusions: The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy.

Background: A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirem

BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fatigue is a major clinical problem. Abnormal amino acid (AA) patterns have been implicated in the development of fatigue in several non-hepatological conditions but for PBC and PSC no data are available. This study aimed to identify abnormalities in AA patterns and to define their relation with fatigue. METHODS: Plasma concentrations of tyrosine, tryptophan, phenylalanine, valine, leucine and isoleucine were determined in plasma of patients with PBC (n = 45), PSC (n = 27), chronic hepatitis C (n = 22) and healthy controls (n = 73). Fatigue and quality of life were quantified using the Fisk fatigue severity scale, a visual analogue scale and the SF-36. RESULTS: Valine, isoleucine, leucine were significantly decreased in PBC and PSC. Tyrosine and phenylalanine were increased (p < 0.0002) and tryptophan decreased (p < 0.0001) in PBC. In PBC, but not in PSC, a significant inverse relation between tyrosine concentrations and fatigue and quality of life was found. Patients without fatigue and with good quality of life had increased tyrosine concentrations compared to fatigued patients. Multivariate analysis indicated that this relation was independent from disease activity or severity or presence of cirrhosis. CONCLUSION: In patients with PBC and PSC, marked abnormalities in plasma AA patterns occur. Normal tyrosine concentrations, compared to increased concentrations, may be associated with fatigue and diminished quality of life.

BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) significant therapeutic effects of glucocorticoids have not been documented. The most important clinical problem in patients with these diseases is fatigue, which is occasionally invalidating. Abnormalities in the hypothalamo-pituitary-adrenal axis have been suggested as a cause of fatigue. Most effects of glucocorticoids are mediated by the glucocorticoid receptor (hGR alpha). Recently a causative role for a splicing variant of the glucocorticoid receptor (hGR beta) has been proposed in glucocorticoid resistance in asthma and ulcerative colitis, whereas another splicing variant (hGR P) might be associated with glucocorticoid-resistant haematological malignancies. The aims of the present pilot study were to assess abnormalities in glucocorticoid receptor expression and to relate these abnormalities to the development of fatigue and to disease activity and severity in autoimmune cholestatic liver disease. METHODS: Five fatigued and five nonfatigued patients with PBC or PSC were included, and the results were compared with healthy controls. RESULTS: The expression of hGR P was not different from controls, but hGR beta mRNA was significantly increased (p=0.02) and hGR alpha mRNA decreased (p=0.015). There were no significant differences between fatigued and nonfatigued patients. A significant negative correlation between the serum activity of alkaline phosphatase and hGR alpha and hGR P mRNA was found. CONCLUSION: Although there was no relation with fatigue, abnormalities in hGR expression appear to occur in patients with these diseases, and may play a role in its pathophysiology and the poor response to glucocorticoid treatment.

BACKGROUND: We studied whether the theoretical advantages of a spring-loaded liver biopsy needle exist in clinical practice and if so if they are dependent upon the experience of the physician performing the biopsy. METHODS: In a stratified randomised study we enrolled 215 consecutive patients to compare the safety and efficacy of a new automatic biopsy gun (Acecut) with that of a standard Tru-Cut needle. RESULTS: A total of 464 biopsies were performed. The endpoints of the study were number of needle passes needed per patient, tissue yield of each needle pass and post-biopsy complications. The performance of the automatic needle was superior and more consistent with respect to tissue yield compared with the Tru-Cut needle (median yield 100% and 80%, respectively; p < 0.001). The difference was most marked for inexperienced physicians. There was no difference between the two needles in the number of passes needed. More post-biopsy pain and post-biopsy use of analgesics were observed in the automatic needle group (p = 0.04). CONCLUSION: The automatic Tru-Cut needle offers an advantage, particularly for physicians with no or limited experience in liver biopsies. However more post-biopsy pain and post-biopsy use of analgesics were observed in the automatic needle group.

BACKGROUND: Fatigue is a major clinical problem in many patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). An effective treatment has not been defined. Recently, a large proportion of patients with these diseases was found to have symptoms of depression. Because fatigue is a frequent symptom of depression and there is some evidence that treatment with an antidepressant improves fatigue in patients with fibromyalgia, we hypothesised that the antidepressant fluvoxamine might improve fatigue related to PBC and PSC. METHODS: Fatigued patients were randomised to receive fluvoxamine (75 mg BID) or placebo for a six-week period. Fatigue and quality of life were quantified using a visual analogue scale, the Fisk Fatigue Severity Scale, the Multidimensional Fatigue Inventory and the SF-36. RESULTS: Seventeen and 16 patients were allocated to fluvoxamine and placebo, respectively. There was no statistically significant beneficial effect of fluvoxamine on fatigue or quality of life. The median VAS scores in the fluvoxamine and placebo groups were 7.40 and 7.45 at day 0, 6.9 and 7.15 at day 14, 7.45 and 7.65 at day 42 and 7.8 and 8.0 four weeks after treatment discontinuation. CONCLUSION: We found no evidence for a beneficial effect of fluvoxamine on fatigue in these patients with cholestatic liver disease and severe chronic fatigue.

BACKGROUND: Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. METHODS: 166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs. RESULTS: During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk. CONCLUSION: In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver ci

It is widely known that long-term use of anthranoid-containing laxatives is the cause of melanosis coli. We describe a case of melanosis coli, which occurred in a 39-year-old liver transplant patient who took an over-the-counter product containing aloe, rheum and frangula. The typical brownish pigmentation of the colonic mucosa developed in a period of ten months. The anthranoid medication was stopped and follow-up colonoscopy one year later showed normal looking mucosa once more. However, in contrast to previous examinations, a sessile polypoid lesion was found in the transverse colon. Histology showed tubulovillous adenoma with extensive low-grade dysplasia. Since there have been preliminary reports suggesting a possible role of anthranoid-containing laxatives in the development of colorectal adenomas and cancer, their use should be discouraged.

BACKGROUND: Although bacterial cholangitis is frequently mentioned as a cause of secondary sclerosing cholangitis, it appears to be extremely rare, with only one documented case ever reported. CASE PRESENTATION: A 48-year-old woman presented with an episode of acute biliary pancreatitis that was complicated by pancreatic abcess formation. After 3 months she had an episode of severe pyogenic (E. Coli) cholangitis that recurred over the subsequent 7 months on a further two occasions. Initially, cholangiography suggested the presence of extra-biliary intrahepatic abcesses while repeated investigations demonstrated development of multiple segmental biliary duct strictures. After maintenance antibiotic treatment was started, no episodes of cholangitis occurred over a 14-month period. CONCLUSIONS: Sclerosing cholangitis can rapidly develop after an episode of bacterial cholangitis. Extra-biliary involvement of the hepatic parenchyma with abcess formation may be a risk factor for developing this rare but particularly severe complication.

Our work focussed on one of the most frequent and serious complications of portal hypertension i.e. variceal bleeding. In particular, studies were initiated aimed at developing a more effective therapeutic strategy for the primary and secondary prevention of variceal bleeding. Aspects of primary prevention of variceal bleeding are discussed in Chapters 2, 3 and 4. Primary prevention implies the need to identify patients at risk. Chapter 2 discusses the feasibility of a simple radiological method to detect oesphageal varices and addresses the reliability of this approach in comparison with the more usual endoscopic diagnostic method. The majority of patients with oesphageal varices will remain free of bleeding. On the other hand, in a proportion of patients variceal haemorrhage will be a fatal event. Therefore, identification of risk factors for variceal bleeding is of paramount importance, in particular with respect to selecting patients for prophylactic therapy. In chapter 3 we report a study assessing the reliability of the NIEC risk score system and report on attempts to further improve its prognostic reliability. Chapter 4 reports the results of a multicentre randomized controlled trial assessing sclerotherapy as prophylaxis for first variceal bleeding. Variceal bleeding is a medical emergency associated with significant morbidity and mortality. In patients with active bleeding one of the medical priorities and challenges is to arrest bleeding. The results of a study on the use of thrombin as an endoscopic haemostatic agent are reported in chapter 5. A number of treatments have been proposed for the secondary prevention of variceal bleeding. Relative new therapeutic options are TIPS and endoscopic band ligation. In chapter 6 we report the results of a randomized controlled clinical trial comparing these treatment modalities, and discuss our results in the context of the cumulative results of comparable studies.

Background: Although bacterial cholangitis is frequently mentioned as a cause of secondary sclerosing cholangitis, it appears to be extremely rare, with only one documented case ever reported. Case presentation: A 48-year-old woman presented with an episode of acute biliary pancreatitis that was complicated by pancreatic abcess formation. After 3 months she had an episode of severe pyogenic (E. Coli) cholangitis that recurred over the subsequent 7 months on a further two occasions. Initially, cholangiography suggested the presence of extra-biliary intrahepatic abcesses while repeated investigations demonstrated development of multiple segmental biliary duct strictures. After maintenance antibiotic treatment was started, no episodes of cholangitis occurred over a 14-month period. Conclusions: Sclerosing cholangitis can rapidly develop after an episode of bacterial cholangitis. Extra-biliary involvement of the hepatic parenchyma with abcess formation may be a risk factor for developing this rare but particularly severe complication.

The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant f

The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant f