Sonia Rossi

Differential distribution of hepatitis C virus genotypes in patients with and without liver function abnormalities

Hepatitis C virus (HCV) infection persists for an indefinite length of time in a major proportion of patients, inducing chronic liver lesions that evolve to cirrhosis and hepatocellular carcinoma (HCC) in approximately 20% of cases. We studied HCV viremia and genotypes by reverse transcription–polymerase chain reaction (RT‐PCR) in 341 consecutive anti‐HCV–positive patients. Of these, 167 patients had persistently normal or near normal alanine aminotransferase (ALT) levels (fluctuations ≤5 IU above the upper limit of normal); the remaining 174 patients presented with elevated ALT and histological evidence of chronic liver disease. Seventy percent of patients with normal ALT values had circulating HCV RNA despite the absence of biochemical indicators of liver damage and mild histological forms of chronic hepatitis were detected in most patients who underwent liver biopsy. Isolated genotype III infection was significantly more prevalent in this patient group with respect to control patients with abnormal ALT values (70% vs. 39%; P < .001). Conversely, isolated genotype II was more frequently found in patients with elevated ALT values and evidence of chronic liver disease (45% vs. 23%; P < .01) and it was progressively more represented in advanced liver disease, such as cirrhosis and HCC. Virological features of HCV infection might be associated with different clinical manifestations, suggesting a potential prognostic significance on disease outcome. (HEPATOLOGY 1995;21:285–290.)

Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus–induced cirrhosis. A 12-year prospective follow-up study†

The incidence of de novo development of esophageal varices (EV) in patients with compensated liver cirrhosis has been determined by few studies in the short term and never in the long term. The aims of the present study were to determine the incidence and the risk factors associated with the development of EV and to assess whether antiviral treatment and achievement of sustained virologic response (SVR) may prevent de novo EV development in patients with HCV‐induced cirrhosis. We studied 218 patients with compensated EV‐free, HCV‐induced cirrhosis consecutively enrolled between 1989 and 1992 at three referral centers in Milan, Italy. Endoscopic surveillance was performed at 3‐year intervals according to international guidelines. SVR was defined as undetectable serum HCV‐RNA 24 weeks after treatment discontinuation. During a median follow‐up of 11.4 years, 149/218 (68%) patients received antiviral treatment and 34 (22.8%) achieved SVR. None of the SVR patients developed EV compared with 22 (31.8%) of the 69 untreated subjects (P < 0.0001) and 45 (39.1%) of the 115 non‐SVR patients (P < 0.0001). On multivariate analysis, HCV genotype 1b (hazard ratio [HR] 2.40; 95% confidence interval [CI] 1.17‐4.90) and baseline model for end‐stage liver disease (MELD) score (HR 1.20; 95% CI 1.07‐1.35 for 1 point increase) were independent predictors of EV. Conclusion: In the long term, the achievement of SVR prevents the development of EV in patients with compensated HCV‐induced cirrhosis. Therefore, in these patients, endoscopic surveillance can be safely delayed or avoided. Genotype 1b infection and MELD score identify the subset of patients at higher risk of EV development who need tailored endoscopic surveillance. Hepatology 2010

Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: A seventeen‐year prospective cohort study

Hepatocellular carcinoma (HCC) is the most frequent cause of death in patients with hepatitis C virus (HCV)–induced cirrhosis. Despite a number of studies in different populations worldwide suggesting an association between HCV genotype 1 and the risk of HCC, no consensus has emerged yet on this matter, which is still controversial. In an attempt to clarify this issue, a prospective study of 163 consecutive HCV‐positive patients with cirrhosis, who were enrolled between January 1989 and December 1990, was carried out. HCC occurrence was detected by ultrasound surveillance every 6 months. Independent predictors of HCC were assessed with a Cox regression analysis. After a median follow‐up of 10.7 years, 44 [4.26/100/year, confidence interval (CI) = 3.11–5.68/100/year] of 104 patients infected with genotype 1b developed HCC versus 10 (1.69/100/year, CI = 0.82–3.09/100/year) of 52 patients infected with genotype 2a/c (P = 0.0001). Multivariate analysis showed that HCV genotype 1b was independently associated with HCC development [hazard ratio (HR) = 3.02, 95% CI = 1.40–6.53]. Other predictors of HCC were esophageal varices (HR = 2.15, 95% CI = 1.03–4.47), male gender (HR = 2.12, 95% CI = 1.10–4.11), and age over 60 years (HR = 5.96, 95% CI = 1.23–28.8). Conclusion: HCV genotype 1b is associated with a statistically significant higher risk of developing HCC. Patients with cirrhosis that are infected with this genotype require more intensive surveillance for the early detection and aggressive management of neoplasia. (HEPATOLOGY 2007.)

Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial.

Abstract Objective To assess the incidence, cofactors, and excess risk of development of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis, attributable to tamoxifen in women. Design Prospective, randomised, double blind, placebo controlled trial. Setting and participants 5408 healthy women who had had hysterectomies, recruited into the Italian tamoxifen chemoprevention trial from 58 centres in Italy. Intervention Women were randomly assigned to receive tamoxifen (20 mg daily) or placebo for five years. Main outcome measure Development of non-alcoholic fatty liver disease in all women with normal baseline liver function who showed at least two elevations of alanine aminotransferase (≥ 1.5 times upper limit of normal) over a six month period. Results During follow up, 64 women met the predefined criteria: 12 tested positive for hepatitis C virus, and the remaining 52 were suspected of having developed non-alcoholic fatty liver disease (34 tamoxifen, 18 placebo)—hazard ratio = 2.0 (95% confidence interval 1.1 to 3.5; P = 0.04). In all 52 women ultrasonography confirmed the presence of fatty liver. Other factors associated with the development of non-alcoholic fatty liver disease included overweight (2.4, 1.2 to 4.8), obesity (3.6, 1.7 to 7.6), hypercholesterolaemia (3.4, 1.4 to 7.8), and arterial hypertension (2.0, 1.0 to 3.8). Twenty women had liver biopsies: 15 were diagnosed as having mild to moderate steatohepatitis (12 tamoxifen, 3 placebo), and five had fatty liver alone (1 tamoxifen, 4 placebo). No clinical, biochemical, ultrasonic, or histological signs suggestive of progression to cirrhosis were observed after a median follow up of 8.7 years. Conclusions Tamoxifen was associated with higher risk of development of non-alcoholic steatohepatitis only in overweight and obese women with features of metabolic syndrome, but the disease, in both the tamoxifen and the placebo group, after 10 years of follow up seems to be indolent.

Predicting Mortality Risk in Patients With Compensated HCV-Induced Cirrhosis: A Long-Term Prospective Study

OBJECTIVES:The identification of prognostic factors associated with mortality is crucial in any clinical setting.METHODS:We enrolled in a prospective study 352 patients with compensated hepatitis C virus (HCV)-induced cirrhosis, consecutively observed between 1989 and 1992. At entry, patients underwent upper endoscopy to detect esophageal varices, and were then surveilled by serial clinical and ultrasonographic examination. The model for end-stage liver disease (MELD) score was calculated with information collected at enrollment. Baseline predictors and intercurrent events associated with mortality were assessed using the Cox regression model.RESULTS:During a median follow-up of 14.4 years, 194 subjects received a single course of interferon monotherapy, 131 patients developed decompensation (ascites, bleeding, hepatic encephalopathy), 109 patients had hepatocellular carcinoma (HCC), 9 had liver transplant, and 158 died. Esophageal varices were associated with development of decompensation (hazard ratio (HR), 2.09; 95% confidence interval (CI), 1.33–3.30) and liver-related death (HR, 2.27; 95% CI, 1.41–3.66). A MELD score of 10 predicted overall mortality (HR, 2.15; 95% CI, 1.50–3.09). Overall survival of patients with MELD ≤10 was 80% at 10 years. HCC occurrence increased the risk of decompensation fivefold (HR, 5.52; 95% CI, 3.77–8.09). Hepatic and overall mortality hazard ratios were 8.62 (95% CI, 5.57–13.3) and 3.80 (95% CI, 2.67–5.42), respectively, for patients who developed HCC, and 16.9 (95% CI, 9.97–28.6) and 7.08 (95% CI, 4.88–10.2) for those who experienced decompensation.CONCLUSIONS:In patients with compensated HCV-induced cirrhosis, the presence of esophageal varices at baseline predicted decompensation and mortality. The development of HCC during follow-up strongly hastens the occurrence of decompensation, which is the main determinant of death. Patients with a MELD score ≤10 at study entry had a prolonged life expectancy.

Comparison of spontaneous ascites filtration and reinfusion with total paracentesis with intravenous albumin infusion in cirrhotic patients with tense ascites.

OBJECTIVE--To compare the effectiveness and safety of spontaneous ascites filtration and reinfusion and total paracentesis plus intravenous albumin infusion in cirrhotic patients with tense ascites. DESIGN--Randomised trial of the two treatments. SETTING--Teaching hospital and district general hospital in Milan. PATIENTS--45 consecutive cirrhotic patients with recurrent tense ascites and urinary sodium excretion rate less than 20 mmol/day. 35 fulfilled admission criteria and completed the study. 17 received spontaneous ascites filtration and 18 paracentesis plus albumin infusion. MAIN OUTCOME MEASURES--Body weight; urinary volume; serum and urinary electrolyte, serum fibrinogen, and plasma aldosterone concentrations; and plasma renin activity before the procedure and 24 hours and eight days afterwards. RESULTS--Both procedures were effective in all patients. Weight decreased in both groups and showed no substantial increase after eight days. In patients receiving ascites filtration, values decreased significantly (p less than 0.01) after 24 hours for platelet count (mean relative change 0.92; 99% confidence interval 0.86 to 0.98) and serum fibrinogen concentration (0.92; 0.88 to 0.98) but returned to pretreatment values after eight days; no laboratory and clinical signs of disseminated intravascular coagulation were noted. Three patients in this group had fever, which receded spontaneously. One patient in each group had dilutional hyponatraemia. CONCLUSIONS--Spontaneous ascites filtration and reinfusion is an effective treatment for tense ascites. Reinfusion of the patients concentrated proteins provides savings without compromising safety.

Interferon lambda-3 is not associated with clinical outcome in patients with HCV-induced compensated cirrhosis: a long-term cohort study.

BACKGROUND Interferon Lambda-3 (IFN-λ3) gene polymorphism is associated with spontaneous clearance of hepatitis C virus (HCV) and response to IFN-based therapy (IFN). However, very few data are available about its value in predicting sustained virologic response (SVR) in patients with cirrhosis, and whether IFN-λ3 genotype influences liver disease progression remains unclear. METHODS We determined IFN-λ3 genotype by PCR in a cohort of patients with compensated HCV-related cirrhosis, enrolled between 1989 and 1992. Person-years follow-up was calculated for each individual from the date of enrolment to the development of first episode of decompensation, HCC, liver transplant, death or end of follow-up. The follow-up of patients who achieved SVR was censored at the time of IFN initiation. Kaplan-Meier curves and Cox regression analyses were used to assess the association between IFN-λ3 genotype and clinical outcome. RESULTS IFN-λ3 was determined in 264 patients (52% males, mean age 57±8 years, 67% HCV genotype (G)1, while CC, CT and TT genotypes were 36%, 50% and 14%, respectively. During a median follow-up of 14.8 years, 149 (56%) patients received IFN. Overall, SVR was achieved in 31 (21%) patients, 40% among those with CC genotype (22% in G1 and 61% in G2, respectively) compared to 10% and 13% among patients with CT and TT genotypes (p<0.0001). Univariate and multivariate analyses found no association between IFN-λ3 (CC vs. non-CC genotype) and disease progression. CONCLUSION IFN-λ3 determination is fundamental for allocating cirrhotic patients to be treated with IFN, while it has no value in predicting the outcome of the disease.

P465 SVR IS ASSOCIATED WITH NO RISK REDUCTION OF HCC DEVELOPMENT IN PATIENTS WITH HCV-RELATED CIRRHOSIS. A PROSPECTIVE, UP-TO 23 YEARS, COHORT FOLLOW-UP STUDY

Methods: Sixty-five patients with cirrhosis tested for ETP with/without TM. Clinical, endoscopic variables, presence/absence of PVT by Doppler-US and/or TC examination were collected at basal evaluation and up to 4 years. The incidence of de novo PVT was the primary clinical end-point. We also considered transplantation freesurvival. ETP-ratio upper than the 95° percentile of 173 healthycontrols defined TM-resistance. Results: ETP-ratio was not different by comparing patients with (n =12) vs without PVT (n =53) at basal evaluation. Among no-PVT patients, 11 developed de novo PVT in the follow-up. The incidence of PVT was higher in those patients with TM-resistance (n =36) also after adjustment for Child-score (HR:7.68; 90%-CI: 1.32–44.54, p = 0.017). Seventeen patients experienced at least one PHT-related complication and 23 patients died or were transplanted. The mean survival time-free of transplantation was 2.7 vs 3.6 years by comparing, respectively, patients with vs without TM-resistance (p = 0.005, log-rank test). However, only Child-score independently predicted transplantation free-survival. Conclusions: The occurrence of PVT should be explained, in part, by the pro-coagulant imbalance described in patients with advanced liver disease. TM-resistance could be a potential modifiable factor to improve survival in patients with cirrhosis.

Sa1008 Interleukin-28b (IL-28B) Polymorphism Has No Impact on the Long-Term Outcome of Patients With HCV-Related Cirrhosis: A 15-Years Retrospective-Prospective Cohort Study

Background: Whether IL-28B polymorphism modulates the outcome of patients with HCVrelated cirrhosis remains unknown. Aim: to assess the effect of IL-28B polymorphism on the long-term course of patients with cirrhosis carrying HCV infection. Methods: IL-28B region (rs1297860) SNP was retrospectively determined by real-time PCR on DNA extracted from frozen blood EDTA or paraffin-embedded liver tissue. Differences in baseline demographical, virological, and clinical features of patients according to IL-28B genotype was assessed by the Student T, Fishers exact andMantel-Haenszel tests respectively for continuous categorical and ordinal variables. Results:IL-28B genotype determinationwas available for 213 (45%)of all consecutive HCV-infected patients with either compensated or decompensated cirrhosis (Child class C excluded) enrolled in a prospective long-term follow-up study (53% males, mean age 57±8,5 years, 63% genotype 1, 55% received antiviral therapy, 26% attained sustained virological response (SVR). Overall, the frequency of CC, CT and TT genotype was 34%, 53% and 13%, with no difference between compensated or decompensated patients, at entry. CC genotype was observed in 24% of patients infected with HCV genotype 1 compared to 51% of subjects infected with other genotypes (P<0.0001). SVR was achieved in 51% of patients with CC genotype compared to 13% and 6% in those with CT and TT genotype, respectively (p<0.0001). IL-28B and SVR remained independently associated after adjustment for HCV genotype (p=0.003). Among the 85 treated patients without previous decompensation who did not achieve SVR, no association was found between IL-28B and development of hepatic decompensation, hepatocellular carcinoma and death after a median follow-up of 15 years Conclusion: The present study shows that IL-28B genotype has no impact on the outcome of patients with HCV-related cirrhosis. These results also confirm that, irrespective of genotype, IL-28B CC polymorphism is associated with the likelihood to achieve SVR and with non-1 HCV genotype infection.