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The clinical outcome of cirrhotic patients with hepatocellular carcinoma (HCC) depends both on the residual liver function and tumor characteristics. However, the relative prognostic weight of these variables is not well defined. The aims of this study were to verify the value of known prognostic factors and to devise a prognostic index more sensitive than the commonly used Okuda stage. A retrospective analysis of the cases of HCC diagnosed at 16 Italian institutions from 1990 to 1992 was performed. Overall survival was the only end point used in the analysis. The Cox model, stratified by locoregional treatment, was used for multivariate analyses. The final model was derived from 10 randomly chosen training samples, and the prognostic validity of the Cancer of the Liver Italian Program (CLIP) score was assessed on the corresponding testing samples. Four hundred thirty-five cases of HCC were collected. As of January 1997, 313 patients (72%) were deceased. Overall median survival was 20 months. At multivariate analysis, independent predictive factors of survival were Child-Pugh stage, tumor morphology, alpha-fetoprotein (AFP), and portal vein thrombosis. A simple scoring system (CLIP score) was thus produced, assigning linear scores (0/1/2) to the covariates. Compared with Okuda stage, the CLIP score, structured as a six-category tool, has a greater discriminant ability, revealing a class of patients with an impressively more favorable prognosis and another class with a relatively shorter life expectancy. The CLIP score is a new prognostic system that accounts for both liver function and tumor characteristics. It is easy to calculate and appears to give more precise information than the Okuda stage.

Hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis C virus (HCV) are responsible for the majority of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) cases worldwide. 1-4 Multiple HBV and HDV infection has been extensively investigated in past years and found to be associated with a fulminant course of acute hepatitis, with the more severe forms of chronic liver disease, and with a rapid progression to liver cirrhosis. 5-8 An inhibitory effect exerted by HDV on HBV replication has also been shown. 9 The prevalence of patients with HCV and HBV coinfection has been described as high in geographic areas where a high endemic level of both infections is reported, such as Western Asia and the Mediterranean Basin. 10-14 The interaction between HCV and HBV has so far been poorly investigated. Little is known on the clinical presentation, the natural history, and the response to antiviral treatment of liver diseases associated with HBV and HCV coinfection. However, small pilot studies have prompted the hypothesis that HCV may have an inhibitory effect on HBV replication [15][16][17][18][19] and that multiple HBV and HCV infection may be associated with a more severe clinical presentation. 10,[20][21][22][23][24][25] The interaction between HDV and HCV in hepatitis B surface antigen (HBsAg) chronic carriers has not as yet been investigated.In this article we report the data from an Italian multicenter case-control study with incident cases, performed on a high number of patients with chronic hepatitis from a multiple hepatitis virus infection who were compared with patients with chronic hepatitis caused by a single virus. We investigated the interference between viruses, the clinical impact of a multiple virus infection compared with a single HBV or HCV infection, and tested the hypothesis that anti-HCV-positive/ anti-hepatitis B core antigen (HBc)-positive patients lacking both HBsAg and anti-hepatitis B surface antigen (HBs) might be a subgroup of patients with a multiple HBV and HCV infection. MATERIALS AND METHODSPatients. Seven liver units in different geographic areas of Italy, 1 in the north (Padua), 1 in the center (Rome), 2 in the south (Naples and Bari), 1 in Sardinia (Sassari), and 2 in Sicily (Palermo and Messina), participated in the study. These liver units had participated in numerous multicenter studies on chronic hepatitis in the past 2 decades and had been using similar criteria for the clinical approach and the histologic diagnosis. The investigation was planned as a cross-sectional case-control study with incident cases during a preliminary consensus meeting of the senior investigators from the participating centers.Chronic hepatitis was diagnosed on the basis of high serum transaminase values for at least 6 months.

Objective: The objective of this review was to define a core set of recommendations for the treatment of HCVassociated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. Methods: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. Results: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A lowantigencontent diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. Conclusion: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

No abstract

To evaluate whether HCV genotype and a "silent" HBV infection may be related to a more severe clinical presentation of liver disease, 205 anti-HCV/HCV-RNA positive, HBsAg/anti-HBs negative patients with chronic hepatitis (113 males and 92 females; median age 55 years, range 18-77), were studied on presentation at the Liver Unit from January 1993 to December 1997. Presence of serum anti-HBc, in the absence of HBsAg and anti-HBs, was considered a marker of "silent" HBV infection. Of the 205 patients, 134 had undergone percutaneous liver biopsy. Two main diagnosis groups were established: the mild liver disease group (76 patients), and the severe liver disease group (109 patients); 20 patients who had refused to undergo liver biopsy were not included in the clinical and virological evaluation because the diagnosis was uncertain. The prevalence of severe liver disease was similar in the genotype 1 and non-1 groups (61.3% of 98 patients with genotype 1 and 52.9% of 70 patients with a non-1 genotype). Instead, the 88 patients with "silent" HBV infection showed a higher percentage of severe liver disease than the 97 anti-HBc negative patients (72.7% vs. 46.4%, respectively: P < 0.0005). Of the 88 anti-HBc positive patients, the prevalence of those with severe liver disease was similar in the 32 cases with serum HBV-DNA as detected by PCR and in the 56 HBV-DNA negative (81.2% vs. 67.8%, P = 0.4). The relation between "silent" HBV infection and severe liver disease was observed both in genotype 1 and non-1 infected patients. Nevertheless, the anti-HBc negative patients infected by genotype 1 showed a severe liver disease more frequently than those infected by a non-1 genotype, with a difference that is significant to the statistical analysis (P < 0.05). The findings suggest that "silent" HBV infection in anti-HCV positive chronic hepatitis enhances the severity of the liver disease. Evidence was also found that in patients without "silent" HBV infection there is a correlation between the presence of HCV genotype 1 and the severity of liver disease.

Prognosis of patients with cirrhosis and hepatocellular carcinoma (HCC) depends on both residual liver function and tumor extension. The CLIP score includes Child-Pugh stage, tumor morphology and extension, serum alfa-fetoprotein (AFP) levels, and portal vein thrombosis. We externally validated the CLIP score and compared its discriminatory ability and predictive power with that of the Okuda staging system in 196 patients with cirrhosis and HCC prospectively enrolled in a randomized trial. No significant associations were found between the CLIP score and the age, sex, and pattern of viral infection. There was a strong correlation between the CLIP score and the Okuda stage. As of June 1999, 150 patients (76.5%) had died. Median survival time was 11 months, overall, and it was 36, 22, 9, 7, and 3 months for CLIP categories 0, 1, 2, 3, and 4 to 6, respectively. In multivariate analysis, the CLIP score had additional explanatory power above that of the Okuda stage. This was true for both patients treated with locoregional therapy or not. A quantitative estimation of 2-year survival predictive power showed that the CLIP score explained 37% of survival variability, compared with 21% explained by Okuda stage. In conclusion, the CLIP score, compared with the Okuda staging system, gives more accurate prognostic information, is statistically more efficient, and has a greater survival predictive power. It could be useful in treatment planning by improving baseline prognostic evaluation of patients with HCC, and could be used in prospective therapeutic trials as a stratification variable, reducing the variability of results owing to patient selection.

Liver histology seems to be more severe in chronic coinfection with HBV and HCV than in single infection, particularly when HCV replication is impaired.