Rotterdam score predicts early mortality in Budd-Chiari syndrome, and surgical shunting prolongs transplant-free survival.

BACKGROUND: Budd-Chiari syndrome carries significant mortality, but factors predicting this outcome are uncertain. AIM: To determine factors associated with 3-month mortality and compare outcomes after surgical shunting or liver transplantation. METHODS: From 1985 to 2008, 51 patients with Budd-Chiari syndrome were identified. RESULTS: By logistic regression analysis, features associated with higher risk of 3-month mortality were Rotterdam class III, Clichy >6.6, model for end-stage liver disease (MELD) >20 and Child-Pugh C. Rotterdam class III had the best performance to discriminate 3-month mortality with sensitivity of 0.89 and specificity of 0.63, whereas Clichy >6.60 had sensitivity of 0.78 and specificity of 0.69; MELD >20 had sensitivity of 0.78 and specificity of 0.75 and Child-Pugh C had sensitivity of 0.67 and specificity of 0.72. Eighteen patients underwent surgical shunts and 14 received liver transplantation with no significant differences in survival (median survival 10 +/- 3 vs. 8 +/- 2 years; log-rank, P = 0.9). CONCLUSIONS: Rotterdam score is the best discrimination index for 3-month mortality in Budd-Chiari syndrome and should be used preferentially to determine treatment urgency. Surgical shunts constitute an important therapeutic modality that may help save liver grafts and prolong transplantation-free survival in a selected group of patients with Budd-Chiari syndrome.

Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have relapsed or not responded to a first course of pegylated interferon-based therapy.

BACKGROUND: Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported. AIM: To assess the effectiveness of the retreatment of patients who have previously failed an initial course of pegIFN-based therapy with pegIFNalpha-2a and ribavirin. METHODS: A post-hoc analysis of a multicentre open-label study was performed. Patients received pegIFNalpha-2a and ribavirin at a dose of 800 mg/day and later 1000 mg/day to 1200 mg/day for 24 to 48 weeks at the discretion of the investigator. Outcomes at week 12 (early virological response [EVR]) and week 24 (sustained virological response [SVR]) were analyzed. RESULTS: Eighty-seven patients who had relapsed after previous pegIFN-based therapy (n=28; 78% genotype 1) or were nonresponders (n=59; 71% genotype 1) were analyzed. Of the relapsers, 86% achieved an EVR and 68% achieved an SVR. In relapsers to pegIFN monotherapy (n=15) or pegIFN plus ribavirin (n=13), 60% and 77% achieved an SVR, respectively. Fibrosis and genotype did not affect the likelihood of SVR in relapsers although this may be the result of the relatively small number of patients. In previous nonresponders, an EVR was achieved in 53% but an SVR occurred in only 17%. In nonresponders to pegIFN monotherapy (n=9) and pegIFN plus ribavirin (n=50), 33% and 14% achieved an SVR, respectively. Genotype did not affect SVR in nonresponders. Only 10% with a METAVIR score of F3 or F4 on liver biopsy achieved an SVR. CONCLUSIONS: Relapse after previous pegIFN-based therapy is associated with a strong probability of treatment success whereas retreatment of those with previous nonresponse does not.

Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alpha-2a plus ribavirin.

BACKGROUND: The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice. AIM: To examine the impact of exposure to peginterferon alpha-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-naive patients with HCV genotype 1 infection enrolled in a large expanded access programme. METHODS: Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (>or=75 kg) and peginterferon alpha-2a 180 microg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated. RESULTS: Mean ribavirin exposure in week 0-12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P < 0.001; SVR, 45% vs. 54%, respectively, P = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received (P < 0.001 for both). CONCLUSIONS: Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.

Exploring differences in response to treatment with peginterferon alpha 2a (40kD) and ribavirin in chronic hepatitis C between genotypes 2 and 3.

Chronic hepatitis C virus (HCV) infections with genotype 2 or 3 are associated with favourable sustained virologic response (SVR) rates. However, genotype 3 may respond less well. We reassessed all treatment-naive patients with genotype 2 and 3 participating in a large expanded-access, non-randomized, open-label trial, evaluating 180microg pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly and 800 mg/day ribavirin for 24-48 weeks. Factors measured prior to initiation of antiviral therapy were considered in the multiple logistic regression model for predicting SVR. In total, 180 patients were analysed of which 72 (40%) were infected by genotype 2 and 108 (60%) genotype 3. The baseline characteristics between patients infected by genotype 2 or 3 were no different including the distribution of hepatic fibrosis stages by METAVIR score. Overall SVR was lower in those patients infected with genotype 3. The significant multivariate predictors of lack of SVR were hepatic fibrosis (P = 0.014) and genotype 3 (P = 0.030). The negative impact of cirrhosis (METAVIR score F4) on treatment response was more evident among subjects with genotype 3 than those with genotype 2 (P = 0.027). There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy. This finding should be confirmed in a larger population.

Reverse transcriptase activity in patients with primary biliary cirrhosis and other autoimmune liver disorders.

BACKGROUND: Patients with biliary disease make retroviral antibodies and the Human Betaretrovirus has been characterized in patients with primary biliary cirrhosis. AIM: To screen patients with autoimmune liver disease for evidence of retroviral infection. METHODS: Real-time reverse transcriptase polymerase chain reaction was used to detect Human Betaretrovirus, and a reverse transcriptase assay to measure reverse transcriptase activity in plasma. RESULTS: Using reverse transcriptase polymerase chain reaction, 24% of primary biliary cirrhosis samples were positive for Human Betaretrovirus when compared to 13% with autoimmune hepatitis, 5% of other liver diseases and 3% of the non-liver disease control subjects. Reverse transcriptase activity was found in 73% of patients with autoimmune hepatitis, 42% with primary biliary cirrhosis, 22% of liver patients without viral or autoimmune disease and 7% of subjects without liver disease. In patients with autoimmune liver disease, detection of reverse transcriptase activity was related to higher ALT levels, whereas others stabilized on immunosuppressive therapy either preliver or postliver transplantation were less likely to be reverse transcriptase-positive. CONCLUSIONS: Most patients with autoimmune hepatitis have detectable reverse transcriptase activity. Investigations will be required to assess whether this represents the expression of endogenous retroviruses and retrotransposable elements in inflamed tissue, or signifies the presence of exogenous retroviral infection.

Systematic review: renal and other clinically relevant outcomes in hepatorenal syndrome trials.

BACKGROUND: Although reversal of pretransplant renal dysfunction in hepatorenal syndrome reduces post-transplant complications, the overall impact on morbidity and mortality requires clarification. AIM: To review trials of pharmacologic interventions in hepatorenal syndrome, with specific assessment of trial quality and study endpoints, including patient survival and renal outcome measures. METHODS: Literature search and selection was carried out by a single reviewer. Data extraction and quality analysis were carried out by two independent reviewers. RESULTS: Of 848 identified articles, 36 were eligible for inclusion. Twenty-one were full-text. Only 19% were randomized-controlled trials. About 50% of studies included only Type 1 hepatorenal syndrome patients. Serum creatinine, urine output and urine sodium were the most common renal outcome measures. Only 42% defined a primary renal endpoint. About 88% of articles reported mortality rates. CONCLUSIONS: Existing literature of pharmacologic agents for use in hepatorenal syndrome is limited by poor study design, including non-randomization, heterogeneous study populations, lack of power, and limited use of clinically relevant outcomes. There is insufficient information in most trials to judge the impact of pharmacologic therapy on mortality or rates of transplantation. The validity of renal outcome measures as surrogate markers of more clinically relevant endpoints has not been established.

Induction versus noninduction antiviral therapy for chronic hepatitis C virus in patients with congenital coagulation disorders: a Canadian multicentre trial.

BACKGROUND: Patients with congenital coagulation disorders and chronic hepatitis C virus (HCV) infection have multiple risk factors (ie, infection predominantly with genotype-1 HCV, long duration of the disease, HIV coinfection and male sex) for poor response to antiviral therapy. The present study compared induction therapy with interferon-alpha (IFN-alpha)-2b with standard IFN-alpha2b therapy. Pegylated IFN was not available at the time that the study was initiated. PATIENTS AND METHODS: A randomized study was performed comparing the efficacy of traditional IFN-alpha2b therapy (group A -- three million units, three times weekly for 24 to 48 weeks) and daily ribavirin (1.0 g to 1.2 g according to weight for 24 to 48 weeks), with induction IFN-alpha2b therapy (group B -- three million units, daily for eight weeks followed by the same dose administered three times a week for a further 16 to 40 weeks) and daily ribavirin (same dose as above) in IFN-naive patients with congenital coagulation disorders and chronic HCV infection. RESULTS: Between 2000 and 2003, 54 HIV-negative patients were recruited and randomly assigned to group A or B (n=27 each). Both groups were comparable in terms of age, sex, ethnicity, body mass index, baseline HCV RNA titre, viral genotype, liver fibrosis stage and type of coagulation disorder. Induction therapy did not significantly alter sustained virological response rates (group A 50%, group B 50%; P=1.0). Multiple logistic regression analysis indicated that induction therapy did not benefit individuals with difficult-to-treat infection (ie, those infected with genotypes 1 and 4, or those with high baseline viral loads). CONCLUSIONS: There was no benefit with induction antiviral therapy for HCV infection in individuals with congenital coagulation disorders.

Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed previous interferon therapy.

BACKGROUND: The management of patients with chronic hepatitis C who have relapsed or failed to respond to interferon based therapies is an important issue facing hepatologists. AIMS: We evaluated the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in this population by conducting a multicentre open label study. PATIENTS: Data from adults with detectable serum hepatitis C virus (HCV) RNA who had not responded or had relapsed after previous conventional interferon or conventional interferon/ribavirin combination therapy were analysed. METHODS: Patients were retreated with peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 800 mg/day for 24 or 48 weeks at the investigators' discretion. The study was conceived before the optimal dose of ribavirin (1000/1200 mg/day) for patients with genotype 1 was known. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA (<50 IU/ml) after 24 weeks of follow up. The analysis was conducted by intention to treat. RESULTS: A total of 312 patients (212 non-responders, 100 relapsers) were included. Of these, 28 patients were treated for 24 weeks and 284 for 48 weeks. Baseline characteristics between non-responders and relapsers were similar although more non-responders had genotype 1 infection (87% v 69%). Overall SVR rates were 23% (48/212) for non-responders and 41% (41/100) for relapsers. When data were analysed by genotype, SVR rates were 24% (61/253) in genotype 1 and 47% (28/59) in genotype 2/3. CONCLUSIONS: These results in a large patient cohort demonstrate that it is possible to cure a proportion of previous non-responders and relapsers by retreating with peginterferon alfa-2a (40KD) plus ribavirin.

Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice.

BACKGROUND: Pegylated interferon alfa-2a (40 KD) plus ribavirin therapy induces sustained virological response rates up to 63% in randomized-controlled trials. AIM: To conduct a prospective open-label programme to examine the efficacy and safety of this therapy in routine clinical practice. METHODS: Treatment-naive patients with chronic hepatitis C received, at the discretion of the investigator, pegylated interferon alfa-2a 180 microg/week + ribavirin 800 mg/day for 24 or 48 weeks. In total, 508 patients were enrolled [334 non-cirrhotic; 174 cirrhotic (defined as stage F3 and F4)]. RESULTS: In genotype 1 patients treated for 48 weeks, sustained virological response rates were 41% in non-cirrhotics and 34% in cirrhotics. Sustained virological response rates in genotype 2 or 3 non-cirrhotics were 79% (24 weeks) and 72% (48 weeks). Corresponding values for cirrhotic genotype 2/3 were 66% and 44%. The negative predictive value of an early virological response at week 12 was 94%. Predictive factors for sustained virological response on multivariate analysis were genotype (2/3 vs. 1), low viral load and degree of fibrosis. Rates of serious adverse events (

A multicentre study of the usefulness of liver biopsy in hepatitis C.

The role of liver biopsy in the assessment of chronic hepatitis C is generally accepted yet there is no prospective data available to quantify its contribution. A previous single centre pilot study suggested that the clinician could predict the amount of fibrosis and to a lesser extent, inflammation with moderate accuracy. The 2002 National Institute of Health Hepatitis C Consensus Conference recommended further study of the role of liver biopsy. Our objective was to compare a prediction of biopsy findings by expert clinicians using usually available clinical and laboratory data to actual biopsy results in order to determine whether biopsy is required routinely. This was a prospective observational study conducted at seven university centres in which the accuracy of clinician's predictions of the degree of inflammation and fibrosis were compared with the actual liver biopsy using an adaptation of a standard histological scoring system. We studied 81 adults with previously untreated chronic hepatitis C, raised serum transaminases and positive HCV-RNA in serum. Clinicians predicted the inflammatory grade in 44 of 80 cases (55%) and the fibrosis stage in 46 of 81 cases (57%). Nine of 17 cirrhotic cases were predicted (sensitivity 53%, specificity 56%). No unexpected additional diagnoses were made on the biopsies. Thus despite knowledge of the clinical and laboratory investigations of patients with hepatitis C, clinicians are unable to accurately predict the hepatic inflammatory grade and fibrotic stage. Liver biopsy is an essential investigation to accurately evaluate the grade and stage of liver disease patients with hepatitis C.

Effect of HCV viral dynamics on treatment design: lessons learned from HIV.

Viral load measurements provide an indication of viral replication, and thereby serve as a valuable tool to guide the initiation of therapy and subsequent changes. Plasma human immunodeficiency viral load strongly predicts the rate of decrease in CD4+ lymphocyte count, and progression to AIDS and death. Furthermore, the efficacy of antiretroviral therapy can be assessed by monitoring changes in plasma human immunodeficiency viral load. Similarly, viral load provides valuable information about the natural history of the hepatitis C virus infection. Hepatitis C viral load can be used to predict the likelihood of response to standard interferon-alpha treatment and other interferon-alpha regimens and to monitor treatment efficacy. Increased understanding of the natural history of the hepatitis C virus infection and the nature of resistance to interferon-alpha therapy suggests that effective treatment regimens must maintain serum levels of interferon-alpha. Ideally, interferon-alpha serum levels should provide constant pressure on the virus and should prevent viral rebound, thereby avoiding continued viral replication and minimizing the potential for emergence of resistant quasi-species. Current regimens designed to address these points include early aggressive intervention, combination drug regimens, prolonged maintenance, and novel interferons. By enabling the design and rapid assessment of new treatment regimens, viral load measurement will revolutionize the clinical management of the hepatitis C virus infection, as it has the HIV.

A case of Histoplasma capsulatum causing granulomatous liver disease and Addisonian crisis.

A 56-year-old man with persistently elevated liver enzyme levels, fatigue, lethargy and a 9.0 kg weight loss over six months underwent a percutaneous liver biopsy that demonstrated multiple granulomas. Screening serologies were positive for histoplasmosis, and he was started on itraconazole treatment. He returned to hospital the same night with coffee-ground emesis and in Addisonian crisis requiring parenteral steroids and intensive care unit support. An abdominal computed tomography scan revealed bilaterally enlarged, nonenhancing adrenal glands suggestive of infarcts, presumed secondary to histoplasmosis. Treatment was initiated with amphotericin B, and Histoplasma capsulatum was cultured from his urine and cerebrospinal fluid. A serum immunodiffusion test was also positive for both H and M bands, indicating active infection with Histoplasmosis species. His serum and urine samples were also weakly positive for the antigen. Despite complications of renal failure, pneumonia and congestive heart failure, he recovered with medical therapy and was discharged home to complete a prolonged course of itraconazole therapy. While hepatic granulomas often reflect an occult disease process, the cause may remain undiscovered in 30% to 50% of patients despite exhaustive investigations. H capsulatum is an uncommon cause of granulomatous liver disease, and with its protean clinical presentation, a high index of suspicion is needed to make the diagnosis and avoid the potentially high fatality rate associated with disseminated infection.

Predicting the liver histology in chronic hepatitis C: how good is the clinician?

OBJECTIVE: Liver biopsy is believed to be necessary before antiviral treatment in hepatitis C. Studies have found symptoms and biochemistry poorly predictive of grade and stage. In practice, a combination of factors is used to anticipate histology. The aim of this study is to evaluate the ability of global clinical assessment to predict histology in hepatitis C. METHODS: Fifty-four consecutive patients referred to a university center for consideration of antiviral therapy were enrolled. Clinical and laboratory data were recorded as was a prediction of the inflammatory grade (0-3) and fibrotic stage (0-3), with fibrotic stage 3 referring to cirrhosis. Liver biopsies were read by a blinded pathologist. The predictive value of the clinical assessment and individual parameters was assessed. RESULTS: All predictions were < or = 1 point off the actual grade and stage. Thirty-six (66.7%) patients' grades and 41 (75.9%) patients' stages were exactly predicted. All four cirrhotic patients (sensitivity 100%, specificity 94%) and one case of hemochromatosis were correctly predicted. Spider nevi, organomegaly, white blood cell count < or = 4 x 10(9)/L, ALT > 120 U/L, bilirubin > 20 micromol/L, albumin < or = 35 g/L, and ferritin > 200 microg/L predicted grade > or =2. Stage > or =2 was associated with age > 40 yr, previous decompensation, spider nevi, organomegaly, white blood cell count < or = 4 x 10(9)/L, albumin < or = 35 g/L, platelets < or = 150 x 10(9)/L, and international normalized ratio > 1.2. Grade correlated with stage (Spearman coefficient = 0.54, p < 0.001). By multivariate analysis, ferritin plus spider nevi or hypoalbuminemia was independently predictive of inflammation. Spider nevi and thrombocytopenia, with either splenomegaly or hypoalbuminemia, were useful three-variable models for predicting fibrosis. The corresponding scoring systems produced useful likelihood ratios. CONCLUSIONS: Global clinical assessment mirroring clinical practice in a tertiary liver transplant center is moderately accurate in predicting grade and stage in hepatitis C. Liver biopsy is the current gold standard; however, the amount of new information gleaned is less than was perceived. The need for routine biopsy before antiviral treatment in hepatitis C should be reevaluated in a multicenter study.

Bioartificial liver support.

Bioartificial liver support has been increasingly the focus of both basic and clinical research in an attempt to replicate the multiplicity of normal liver function. The concept is attractive because, if it is effective, patients with acute liver failure may be supported until native liver regeneration occurs or, by optimizing their condition, until liver transplantation is possible. Current bioartificial liver support systems utilize primary porcine hepatocytes or transformed human hepatocytes, which are housed within a bioreactor, through which the patient's blood or plasma is pumped in an extracorporeal circuit. The optimal source for the hepatocytes is an area of debate; however, a genetically engineered cell line may provide optimal function. Novel three-dimensional matrices that anchor the hepatocytes are being designed to mimic architectural features of the normal liver. Large multicentre, randomized, controlled trials are ongoing following several pilot studies. Serious side effects such as hemodynamic instability and immune reactions have been infrequent. Much controversy, however, surrounds the issue of possible transmission of pig endogenous retrovirus to humans, and current trials are being carefully monitored. Bioartificial liver support is a promising technology, and the results of current and planned studies are awaited with great interest.

Genotypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance.

BACKGROUND/AIMS: Hepatitis B mutant strains of virus emerging during treatment with the nucleoside analog lamivudine are being increasingly recognized. In the majority of lamivudine-resistant isolates the mutations have been reported to occur within the YMDD motif of the viral polymerase, either as a single mutation M552I or as M552V concomitant with L528M. We analyzed the time course and genetic succession pattern during the emergence of lamivudine resistance. METHODS: Seven patients with breakthrough viremia in the setting of chronic hepatitis (n=5) or recurrent HBV after liver transplantation (n=2) were investigated. Pre- and post-breakthrough serum samples were evaluated by single- or second-round PCR amplification and sequencing analysis. RESULTS: Genotypic succession of the virus populations was observed to occur from M552I to M552I/L528M (n=2) and from L528M to M552V/L528M (n=1). The double mutations M552I/L528M (n=4) or M552V/L528M (n=2) were found in six out of seven patients, and represented the stable virus populations throughout the follow-up period. Breakthrough viremia was not associated with the single L528M mutation. The mean duration of uninterrupted treatment with lamivudine until breakthrough was 422 days (range 182-642) and was longer in the setting of chronic hepatitis B than in recurrent hepatitis B after liver transplantation. HBV DNA levels after breakthrough were lower than pretreatment levels in the majority of patients with chronic hepatitis but higher after liver transplantation. CONCLUSION: Our observations show that the virus populations conferring resistance to lamivudine can evolve from single to double mutations at amino acid 552 and 528 of the HBV polymerase, and that M552I/ L528M or M552V/L528M seem to be the predominant mutations arising during long-term antiviral therapy with lamivudine.

Graft-versus-host disease after liver transplantation complicated by systemic aspergillosis with pancarditis.

Graft-versus-host disease after liver transplantation complicated by systemic aspergillosis with pancarditis. Can J Gastroenterol 2000;14(7):637-640. Acute graft-versus-host disease (GVHD) is a common complication after bone marrow transplantation, with characteristic rash and diarrhea being the most common features. After liver transplantation, however, this phenomenon is very rare. Most transplant patients are on a variety of medications, including immunosuppressants; therefore, the differential diagnosis of skin rash or diarrhea is broad. A 37-year-old man who underwent liver transplantation for primary biliary cirrhosis, and developed a rash and watery diarrhea, is presented. Skin and colonic biopsies confirmed acute GVHD. A pulse of intravenous steroids was given. The skin rash improved, but he developed pancytopenia. His course was complicated by central line infection, jugular and subclavian vein thrombosis, pseudomembranous colitis, recurrent bacteremia, cholestasis on total parenteral nutrition and cytomegalovirus infection. After the onset of pleuritic chest pain and clinical sepsis, spiral computed tomography scan of his chest and abdomen revealed septic infarcts in multiple organs. Despite empirical treatment with amphotericin B, he died of multiorgan dysfunction syndrome within 72 h. Autopsy revealed systemic aspergillosis with pancarditis, endocardial vegetations, and septic pulmonary, splenic, hepatic and renal infarcts. The pathogenesis and experience with this rare, but often fatal, complication of liver transplantation are reviewed. In contrast to GVHD after bone marrow transplantation, pancytopenia is common and liver dysfunction is rare. One should have a high level of suspicion in the liver transplant recipient presenting with rash and/or diarrhea.

Prospective study of biliary strictures to determine the predictors of malignancy.

BACKGROUND: There have been few prospective studies regarding the investigation of biliary strictures, principally because of rapid technological change. The present study was designed to determine the sensitivity of various imaging studies for the detection of biliary strictures. Serum biochemistry and imaging studies were evaluated for their role in distinguishing benign from malignant strictures. METHODS: Thirty-one patients with suspected noncalculus biliary obstruction were enrolled consecutively in the study. A complete biochemical profile, ultrasound, Disida scan and cholangiogram (endoscopic retrograde cholangiopancreatography [ERCP] or percutaneous cholangiogram) were obtained at study entry. Stricture etiology was determined based on cytology, biopsy and/or clinical follow-up at one year. RESULTS: Twenty-nine of 31 patients had biliary strictures, of which 15 were malignant. The mean age of the malignant cohort was 73.9 years versus 53.9 years in the benign cohort (P<0.001). Statistically significant differences between the malignant and benign groups, respectively, were as follows: alanine transaminase 235.2 versus 66.9 U/L (P=0.004), aspartate transaminase 189.8 versus 84.5 U/L (P=0.011), alkaline phosphatase 840.2 versus 361.1 U/L (P=0.002), bilirubin 317.8 versus 22.1 micromol/L (P<0. 001) and bile acids 242.5 versus 73.2 micromol/L (P=0.001). Threshold analysis using receiver operative characteristic (ROC) curves demonstrated that a bilirubin level of 75 micromol/L was most predictive of malignant strictures. Intrahepatic duct dilation was present in 93% of malignant strictures versus 36% of benign strictures (P=0.002). Common hepatic duct dilation was less discriminatory (malignant 13.5 versus benign 9.6 mm; P=0.11). Ultrasound was highly sensitive (93%) in the detection of the primary tumour in the bile duct or pancreas, or in the visualization of nodal or liver metastases. In benign disease, ultrasound failed to detect evidence of intrahepatic or extrahepatic biliary dilation in most cases. Disida scans were not able to distinguish between malignant or benign strictures and could not accurately localize the level of obstruction. The sensitivity of Disida scan for the diagnosis of obstruction was 50%. Cholangiographic characterization of strictures revealed an equal distribution of smooth (eight of 13) and irregular (five of 13) strictures in the malignant group. Ten of 13 benign strictures were characterized as smooth. Malignant strictures were significantly longer than benign ones - 30.3 versus 9.2 mm (P=0.001). Threshold analysis using ROC curves showed that strictures greater than or equal to 14 mm were predictive of malignancy (sensitivity 78%, specificity 75%, log odds ratio 11.23). CONCLUSIONS: A serum bilirubin level of 75 micromol/L or higher, or a stricture length of greater than 14 mm was highly predictive of malignancy in patients with a biliary stricture. Ultrasound was useful in predicting malignant strictures by detecting either intrahepatic duct dilation or by visualizing the tumour (primary or metastases). Strictures with a 'benign' cholangiographic appearance are frequently malignant. Disida scan did not add additional information. ERCP is necessary to diagnose benign strictures, which tend to be less extensive at presentation.

Ogilvie's syndrome associated with acute cytomegaloviral infection after liver transplantation.

Ogilvie's syndrome, or acute colonic pseudo-obstruction, is a rare complication following liver transplantation. We describe two cases in which the onset of Ogilvie's syndrome is strongly temporally associated with acute cytomegaloviral (CMV) infection in immunosuppressed liver transplant recipients. The pseudo-obstruction resolved rapidly in both cases following treatment with intravenous ganciclovir. Acute CMV infection therefore appeared to be causally linked to pathogenesis of Ogilvie's syndrome in these two cases. This association has not been described previously to our knowledge, and should be considered in any transplant patient presenting with Ogilvie's syndrome.

Chronic viral hepatitis C: management update.

The management of chronic viral hepatitis C is evolving rapidly. Monotherapy with interferon, the accepted standard of treatment until recently, achieves only a modest sustained virological response rate of 15%. Combination treatment with alpha-2b interferon and ribavirin has been shown to increase sustained response rates to 40% in patients who have never been treated with interferon and to 50% in those who have relapsed following monotherapy with interferon. However, side effects, which have led to the discontinuation of combination treatment in a significant proportion of patients, must be carefully monitored. Treatment with interferon alpha-2b and ribavirin has now been approved in Canada, but the selection and monitoring of patients suitable for combination treatment requires special expertise. Although improvements in current therapeutic options may be possible with more frequent, higher doses or long-acting forms of interferon together with ribavirin, low sustained response rates (i.e., below 30%) for patients with hepatitis C virus genotype 1 emphasize the need for novel antiviral medications that will target the functional sites of the HCV genome.