Luigi Pagliaro

Clinical Management of Hepatocellular Carcinoma. Conclusions of the Barcelona-2000 EASL Conference

Hepatocellular carcinoma (HCC) is a neoplasm the incidence of which is increasing worldwide, but striking geographical differences are observed for both risk factors and occurrence [1]. HCC represents more than 5% of all cancers and the estimated annual number of cases exceeds 500 000. It mostly affects patients with liver cirrhosis and currently represents their most common cause of death. Its clinical relevance and the existence of several diagnostic and therapeutic controversies explain the huge interest raised by this neoplasm. This prompted the European Association for the Study of the Liver (EASL) to organize a Monothematic Conference on Clinical Management of Hepatocellular Carcinoma, which was held in Barcelona in September 2000. During the meeting, a panel of international experts (Appendix A) met to prepare the present document that gives up-dated guidelines for the current clinical practice, and an overview of those aspects that should be the target of future clinical research.

Survival and prognostic indicators in compensated and decompensated cirrhosis

Six-year survival of cirrhosis was assessed in a series of 1155 consecutive patients (751 men, 404 women). Among the men, 33% were alcoholics and 18% were HBsAg positive; corresponding figures for the women were 15% and 6%, respectively. Features of decompensation at first presentation were observed in 63% of the patients. Six-year survival was 54% in compensated and 21% in decompensated patients. No significant differences in survival were found between alcoholics and nonalcoholics. Leading causes of death were liver failure (49%), hepatocellular carcinoma (22%), and bleeding (13%). The prognostic role of 21 variables was evaluated separately in compensated and decompensated patients by the Coxs regression model. The following variables were found to be significant predictors of death risk in compensated patients: male sex, HBsAg positivity, age, prothrombin time prolongation, and esophageal varices. In decompensated disease the significant indicators of death risk were: hepatocellular carcinoma, encephalopathy, hemorrhage, SGOT, esophageal varices, gamma globulins, prothrombin time prolongation, continued abuse of alcohol, HBsAg positivity, gamma glutamyl transpeptidase, and cholinesterase. A simple prognostic index based upon the relative risk coefficient of the significant variables is suggested.

Smoking habits and recurrence in Crohn's disease

BACKGROUND/AIMS Smoking may be a risk factor for surgical recurrence of Crohns disease. However, other variables associated with recurrence could be confounding factors for smoking. The aim of this study was to evaluate the role of smoking as an independent predictor of clinical, surgical, and endoscopic recurrence. METHODS In a series of 182 patients who underwent surgery for Crohns disease, a multivariate analysis was performed that included all of the significant variables associated with recurrence: sex, age at diagnosis, time between onset of symptoms and surgery, site of disease, indication for surgery, extent of disease, extraintestinal manifestation, and smoking habit. RESULTS Independent predictors of clinical recurrence by the Cox proportional hazard model were smoking (hazard ratio, 1.46; 95% confidence interval [CI], 1.1-1.8), extraintestinal manifestations (hazard ratio, 1.61; 95% CI, 1.0-2.5), and extent of disease (hazard ratio, 1.57; 95% CI, 1.0-2.4). Smoking was the only significant predictor of surgical recurrence (hazard ratio, 2.0; 95% CI, 1.2-2.3). For endoscopic recurrence, logistic regression showed that smoking (odds ratio, 2.2; 95% CI, 1.2-3.8) and extent of disease (odds ratio, 2.6; 95% CI, 1.0-6.7) were predictive factors of recurrence. CONCLUSIONS Smoking is an independent risk factor for clinical, surgical, and endoscopic recurrence in Crohns disease.

Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices : an analysis of data and prognostic factors in 589 patients from four randomized clinical trials

BACKGROUND The value of beta-adrenergic-antagonist drug therapy for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices is uncertain, both positive and negative study results having been reported. METHODS In this study, we analyzed data on individual patients from four randomized, controlled trials to assess the efficacy of this treatment. Of the 589 patients studied, 286 received a beta-adrenergic-antagonist drug (propranolol in 203 and nadolol in 83) and 303 received placebo. RESULTS After two years, the mean (+/- SE) percentage of patients who had had no upper gastrointestinal bleeding was 78 +/- 3 percent in the beta-adrenergic-antagonist treatment group and 65 +/- 3 percent in the control group (P = 0.002). The percentage of patients without fatal bleeding was 90 +/- 2 percent in the treatment group and 82 +/- 3 percent in the control group (P = 0.01). The percentage of patients surviving after two years was 71 +/- 3 percent in the treatment group and 68 +/- 3 percent in the control group (P = 0.34). After age and severity of cirrhosis were taken into account, the survival rate was better in the treatment group (P = 0.09). The percentage of surviving patients who had had no bleeding after two years was 62 +/- 3 percent in the treatment group and 53 +/- 3 percent in the control group (P = 0.04). Both propranolol and nadolol prevented a first episode of bleeding. Severe cirrhosis and especially the presence of ascites were associated with bleeding (P less than 0.001) and death (P less than 0.001) in both groups. The efficacy of beta-adrenergic-antagonist therapy in the prevention of bleeding (P less than 0.001) and of fatal bleeding (P = 0.004) and in the prevention of bleeding or death (P = 0.005) was the same after adjustment for cause and severity of cirrhosis, ascites, and size of varices. CONCLUSIONS Propranolol and nadolol are effective in preventing first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity.

Hepatocellular carcinoma : a worldwide problem and the major risk factors

Male sex, age, cirrhosis, and HBsAg are the major risk factors for hepatocellular carcinoma (HCC). The geographic distribution of HCC is highly uneven, such that three distinct incidence areas are recognized. To clarify the reason(s) for this geographic variability of HCC, the risk factors in earch incidence area were assessed. In parallel with the geographic distribution of HCC, HBsAg prevalence was highest in both HCC patients and in general population in Africa and Asia, where mothers of HCC patients are frequently HBsAg-positive, suggesting that hepatitis B virus hyperendemicity and perinatal infection account for the high HCC incidence in these areas. Cirrhosis, which is found on autopsy in 80% of the cases of HCC patients worldwide, is the most prevalent risk factor for HCC in areas where hepatitis B virus infection is less common. However, HBsAg carriage adds to the HCC risk carried by cirrhosis and explains the higher incidence of HCC in cirrhotics from Africa and Asia as well as elsewhere. Available data suggest that chronic HCV infection is a risk factor for cirrhosis and HCC. HBV vaccination should decrease HCC incidence rates worldwide; however, HCC prevention in regions where HBsAg carriage is infrequent may also require prevention of the other causes of cirrhosis in order for HCC rates to decline.

Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis : a case-control study

OBJECTIVE To determine whether chronic hepatitis C virus (HCV) infection is an independent risk factor for hepatocellular carcinoma and whether it increases the cirrhosis-related risk for hepatocellular carcinoma. DESIGN Two pair-matched case-control studies. SETTING A referral-based hospital. PATIENTS In study I, 212 patients with hepatocellular carcinoma (197 of whom had known underlying cirrhosis) were compared with controls who had chronic nonhepatic diseases. In study II, the 197 patients with hepatocellular carcinoma and cirrhosis were compared with 197 pair-matched controls who had cirrhosis but not hepatocellular carcinoma. MEASUREMENTS Levels of antibody to HCV (anti-HCV), hepatitis B surface antigen (HBsAg), and antibody to hepatitis B core antigen (anti-HBc) were assayed, and alcohol abuse was assessed by history. MAIN RESULTS In study I, 151 patients (71%) with hepatocellular carcinoma were anti-HCV positive compared with 11 controls (5%) with chronic nonhepatic diseases (odds ratio, 42; 95% CI, 22 to 95). Multivariate analysis showed that anti-HCV was an independent risk factor for hepatocellular carcinoma (odds ratio, 69; CI, 15 to 308). The analysis also showed that HBsAg (odds ratio, 8.7; CI, 1.5 to 50) and anti-HBc (odds ratio, 4.2 (CI, 1.7 to 11) were risk factors for hepatocellular carcinoma. No statistically significant interaction was found between anti-HCV and the markers of HBV infection. In study II, 146 patients (74%) with hepatocellular carcinoma and cirrhosis were anti-HCV positive compared with 122 patients (62%) with cirrhosis alone (odds ratio, 1.8; CI, 1.1 to 2.8). Multivariate analysis confirmed that anti-HCV (odds ratio, 2.0; CI, 1.3 to 32) and HBsAg (odds ratio, 2.0; CI, 1.0 to 4.2) were independent risk factors for hepatocellular carcinoma. CONCLUSIONS Hepatitis C virus infection is a risk factor for hepatocellular carcinoma, apparently by inducing cirrhosis and, to a lesser extent, by enhancing the risk in patients with cirrhosis. Hepatitis C virus infection acts independently of HBV infection (another risk factor) and of alcohol abuse, age, or gender.

Interferon for non-A, non-B chronic hepatitis: A meta-analysis of randomised clinical trials

We reviewed randomised clinical trials evaluating the effect of lymphoblastoid or recombinant alpha-interferon in non-A, non-B chronic hepatitis. The outcomes assessed were the rates of serum alanine aminotransferase normalization and relapse during and after stopping interferon. Data were pooled by meta-analysis and a 50% overall rate difference, favouring treated patients, was found. Results showed homogeneity in direction of treatment effect both after short-term (2-6 months, greater than or equal to 2 mega-units thrice weekly) and long-term (9-18 months, variable dose) interferon course. Moreover, results did not change when type of publication (abstracts vs. full reports) and treatment duration or schedule were accounted for. About 50% of patients originally responding to treatment relapsed within 6 months of either dose reduction or stopping interferon, thus suggesting that only in about one out of four patients is benefit from treatment sustained up to 1 year. We conclude that larger trials are needed to identify an optimal schedule of treatment and to evaluate predictors of interferon effectiveness in patients with non-A, non-B chronic hepatitis.

Prevention of First Bleeding in Cirrhosis: A Meta-Analysis of Randomized Trials of Nonsurgical Treatment

OBJECTIVE To assess the effectiveness of beta-blockers and endoscopic sclerotherapy in the prevention of first bleeding and reduction of mortality in patients with cirrhosis and esophagogastric varices. DATA SOURCES Pertinent studies were selected using MEDLINE (1980 to 1990), reference lists from published articles or reviews, and congress abstract lists. STUDY SELECTION Randomized trials comparing beta-blockers or sclerotherapy with a nonactive treatment. Nine randomized clinical trials of beta-blockers and 19 trials of sclerotherapy were reviewed. Seven trials of beta-blockers and 15 of sclerotherapy were published as full papers. DATA EXTRACTION Crude rates of bleeding and death in treated and control groups were extracted from each trial by three independent observers according to the intention-to-treat principle. The quality of published papers was systematically assessed and scored. DATA SYNTHESIS The Mantel-Haenszel-Peto method was used for statistical evaluation of heterogeneity and for pooling of the results. No substantial heterogeneity was found, and the incidence of bleeding in trials of beta-blockers was significantly reduced (pooled odds ratio, 0.54; 95% CI, 0.39 to 0.74), particularly in patients with large or medium-sized varices or in those with varices and a hepatic vein pressure gradient above 12 mm Hg; however, only a trend toward reduced mortality was obtained. Sclerotherapy trials were highly heterogeneous in the direction of the treatment effects on both bleeding (pooled odds ratio, 0.6; CI, 0.49 to 0.74) and mortality (pooled odds ratio, 0.76; CI, 0.61 to 0.94). The quality of the trials and the rate of bleeding in the untreated groups were the major sources of heterogeneity. The favorable results of sclerotherapy were obtained in trials with high bleeding rates among controls; several of these trials had a low quality score. CONCLUSIONS Beta-blockers may be recommended for prevention of first bleeding in cirrhotic patients with varices who have a high risk for bleeding. The effectiveness of sclerotherapy remains undetermined. Further trials in high-risk patients may prove useful if improved criteria to predict bleeding risk become available.

Natural history of congestive gastropathy in cirrhosis

In a prospective study of the natural history of congestive gastropathy, 212 consecutive cirrhotic patients (75 treated with sclerotherapy) were included. Mean follow-up was 46 months. Mild gastropathy (mosaiclike pattern) was found in 110 patients and severe gastropathy (granular mucosa with cherry spots) was found in 20. Prevalence of Helicobacter pylori, formerly Campylobacter pylori, was 50% in patients without, 43% in those with mild, and 28% in those with severe gastropathy. Congestive gastropathy was significantly more frequent in patients treated with sclerotherapy (83% vs. 50%, P less than 10(-5)). Sixty-month actuarial proportions of patients free of anemia (in the absence of hematemesis or melena), were 17% with severe, 62% with mild, and 93% without gastropathy (P less than 10(-8]. Corresponding figures for overt bleeding were 25%, 73%, and 87% (P less than 10(-7], whereas those for survival were 46%, 72%, and 85% (P = 0.0005), respectively. A multivariate regression analysis supported the following conclusions: (a) sclerotherapy and the presence of large esophageal varices significantly increase the risk of congestive gastropathy, which (b) is a significant risk indicator of both chronic and overt bleeding but does not independently affect survival.

Prevalence of Cytomegalovirus Infection in Severe Refractory Ulcerative and Crohn's Colitis

Abstract OBJECTIVES Cytomegalovirus infection has been reported as a cause of refractory inflammatory bowel disease, but no data are available on its prevalence in severe colitis. The aim of this study was to evaluate the prevalence and outcome of cytomegalovirus infection in a consecutive series of patients with severe steroid refractory colitis admitted to our department from 1997 to 1999. METHODS: Among 62 patients with severe colitis, 55 with ulcerative colitis and seven with Crohn’s disease, 19 (30%) were resistant to intravenous steroids and bowel rest. In all of them, rectal biopsies were examined for cytomegalovirus (the flexible proctoscopy being performed without air insufflation and limited to the first 10 cm). Buffy coat preparation on leukocytes was also performed to detect systemic infection. If cytomegalovirus was not detected, cyclosporine was started. RESULTS: In seven (five with ulcerative colitis and two with Crohn’s disease) out of 19 (36%) patients with refractory disease, cytomegalovirus was diagnosed in the rectal specimens as well as by buffy coat preparation. Five patients went into remission after antiviral treatment (three with ganciclovir and two with foscarnet). One patient did not respond and was operated on. In one patient, cytomegalovirus was found in the surgical specimen. CONCLUSIONS: Cytomegalovirus infection is a frequent cause of severe refractory colitis. Rectal biopsy should always be performed in severe steroid-resistant colitis.