Luigi Roffi

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

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.

Time course of circulatory and humoral effects of rapid total paracentesis in cirrhotic patients with tense, refractory ascites

BACKGROUND/AIMS Tense ascites of cirrhosis can be treated with total paracentesis; however, the short-term effects of this procedure are poorly defined. METHODS The circulatory and humoral changes induced by total paracentesis (250 mL/min) were studied in 12 cirrhotics with tense, refractory ascites. Data were collected before, during, and after paracentesis and 24 hours later (after albumin infusion). Hormonal parameters were recorded again 48 hours and 6 days thereafter. RESULTS Paracentesis (10.7 +/- 4.4 L; 64 +/- 20 minutes) caused marked reduction of intra-abdominal, intrathoracic, right atrial, and pulmonary pressures. Heart rate did not change. Cardiac output and heart volumes increased. Systemic vascular resistances and mean arterial pressure slightly decreased. Baseline plasma renin and aldosterone levels were markedly increased; a reduction was already evident during paracentesis with the lowest values at the end of the procedure. All changes were maintained 24 hours later. Hormones regained baseline levels 6 days later. CONCLUSIONS Rapid total paracentesis is accompanied by marked cardiovascular and humoral changes. Some of these changes can be explained by mechanical factors that are directly or indirectly related to the relief of abdominal pressure. However, other changes (systemic vasodilatation, humoral deactivation) have a non-mechanical nature and may depend on reflexes originating from cardiac volume receptor stimulation. Most changes may beneficially (albeit transiently) influence the cardiovascular system of cirrhotic patients with tense ascites.

Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection : prevalence, etiology, and management

Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the treatment, in spite of a complete initial response (breakthrough). We studied 191 HCV Ab-positive patients with histologically proven chronic hepatitis. All of them were treated with r-IFN alpha 2 (3 MU three times a week). A complete response was seen in 54.4%. However, 12 of 104 responders experienced a breakthrough. At the time of breakthrough, neutralizing IFN antibodies were positive in 6 of 12 patients. Binding IFN antibodies were positive in all of these 12 patients. Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients.

HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients

BACKGROUND/AIMS Hepatitis C virus (HCV) easily undergoes genomic changes, thus accounting for the presence of different genotypes, with different geographic distributions and different outcomes of chronic hepatitis. Type 1b is frequently found in advanced diseases; however, since this genotype is the most prevalent in older patients, the association with advanced age and severity of the disease is confounding. The aim of this study was to assess changes in the prevalence of HCV genotypes by surveying a large population of chronic hepatitis C patients in Northern Italy, and to assess if the high prevalence of genotype 1b in older patients with advanced diseases simply reflects the duration of HCV infection, rather than intrinsic biological properties of HCV. METHODS We studied 1368 HCV-RNA positive patients, with histologically proven chronic hepatitis. Drug addiction, blood transfusions and sporadically acquired infections represented the risk factors. RESULTS Genotype 1b, the most prevalent isolate, and genotype 2a were associated with older age, cirrhosis, sporadically-acquired infections and blood transfusion, while types 1a, 3a, and 4 were associated with younger age, chronic persistent hepatitis and drug addiction. Patients with a history of transfusions were divided into four groups depending on the period of transfusion. The prevalence of genotype 1b decreased with time. Type 3a appeared only after 1979. CONCLUSION The severity of chronic hepatitis C could be related more to the duration of the infection rather than to the intrinsic pathogenicity of HCV genotypes.

Correlation of Interferon-Induced Expression of MxA mRNA in Peripheral Blood Mononuclear Cells with the Response of Patients with Chronic Active Hepatitis C to IFN-alpha Therapy

MxA, a protein with selective activity against certain viruses, is an accepted specific indicator of type I interferon (IFN) activity. We have developed an internally controlled quantitative-competitive PCR to measure the amounts of MxA mRNA expressed in peripheral blood mononuclear cells (PBMC). This assay is more sensitive, quantitative, and easily applied to serial clinical samples than previously described methods. We have applied this assay retrospectively to 27 patients with chronic active hepatitis C given IFN-alpha2. Most such patients gain no sustained benefit but nevertheless suffer from the side effects, expense, and inconvenience of the treatment. Fourteen of the 27 had been classified on clinical grounds as responders and 13 as nonresponders at the end of a 6 month treatment period. We measured MxA mRNA in PBMC obtained before and after 8 weeks of IFN-alpha2 treatment. All the patients expressed some level of mRNA before treatment began, and after 8 weeks of treatment, the level rose in 19. This increase was significant (p < 0.001) only in patients classified as responders. This strongly suggests that hepatitis C virus (HCV) patients who express increased amounts of MxA mRNA in their PBMC during IFN-alpha treatment are most likely to obtain long-term benefit. If this finding is confirmed in future prospective studies, it will provide an extremely important predictive marker for managing IFN-alpha therapy in patients with HCV.

Liver iron concentration in chronic viral hepatitis: a study of 98 patients.

Objective: To compare the liver iron concentration (LIC)of Italian patients with chronic hepatitis B and C with those of controls, to evaluate increased LIC frequency in patients and to investigate the influence of the haemochromatosis gene in the development of liver iron overload. Design and setting: Prospective controlled trial in two northern Italian hospitals. Patients: Ninety-eight patients (61 men and 37 women), 85 with chronic hepatitis C and 13 with chronic hepatitis B, and 38 control individuals (20 men and 18 women). Methods: Atomic absorption spectrophotometry was used to determine LIC; standard lymphocytotoxicity test was used for HLA typing in patients with increased LIC; and family studies were performed for patients with major iron overload. Results: Mean LIC was significantly higher in both patient groups than in the controls. Thirty-five patients (36%) had an increased LIC. Twenty-six of these patients had a minor iron overload, whereas nine (9.2%) had a major overload. HLA-A3 antigen was present in five out of the 26 and in four out of the nine patients, respectively. Family studies revealed two siblings HLA-identical to their own proband without evidence of iron overload and chronic hepatitis. Conclusion: Increased LIC is frequent in Italian patients with chronic hepatitis. The mechanism by which the hepatitis virus promotes liver iron accumulation is not known, but it can favour the development of major iron overload in some cases. HLA-A3 antigen prevalence and family studies suggest that in these cases a single haemochromatosis gene probably coexists with the viral infection. LIC should be determined as part of the screening evaluation in patients with suspected chronic hepatitis B or C. European Journal of Gastroenterology & Hepatology 1995, 7:1203–1208

Liver damage in Italian patients with hereditary hemochromatosis is highly influenced by hepatitis B and C virus infection.

We evaluated the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in 78 Italian patients with hereditary hemochromatosis as well as the relation between HCV antibody (anti-HCV) status, hepatitis B surface antigen (HBsAg) and liver histology. None of the patients had been transfused or ever consumed more than 60 g of alcohol per day. Eighteen showed histological signs of chronic hepatitis, active cirrhosis was present in 12, chronic active hepatitis in 4 and chronic persistent hepatitis in 2. Liver fibrosis or cirrhosis without inflammatory activity was observed in 31 subjects, whereas liver histology was normal except for iron overload in 18. The prevalence of HBsAg in the whole series was 5% and of anti-HCV was 20.5%. The prevalence of HBsAg and anti-HCV was significantly higher in the chronic hepatitis group than in the fibrosis/cirrhosis (p = 0.01) and the normal groups (p < 0.01). Fourteen of 18 hereditary hemochromatosis patients with chronic hepatitis were HBsAg (4) or anti-HCV (10) positive and all the latter subgroup had HCV-RNA in their serum as shown by the polymerase chain reaction. Although most of the patients with associated chronic hepatitis had cirrhosis, their serum ferritin levels and amount of mobilizable iron were significantly lower than those of the fibrosis/cirrhosis group (p < 0.01). This indicates that hepatitis viral infection acts synergistically with iron in accelerating the development of liver damage.

Survival of patients with HCV cirrhosis and sustained virologic response is similar to the general population

BACKGROUND & AIMS Life expectancy of patients with compensated hepatitis C virus (HCV) cirrhosis achieving sustained virologic response (SVR) is limited by liver events as compared to the general population. Thus, survival benefit of SVR remains to be measured. METHODS The study includes prospective surveillance data from three cohorts of Italian patients with compensated HCV cirrhosis who achieved SVR on an interferon-based (IFN) regimen, compared to simultaneously observed non-SVR, untreated and decompensated patients. Overall survival was calculated from the date of start of IFN to death. The number of deaths expected during the at-risk period was determined by applying age- and sex-specific mortality rates recorded in Italy for person-years adequate for the enrolment period. The standardized mortality ratio (SMR) determined the relative risk of death over that of the age and sex matched general population. RESULTS Overall, 28/181 patients followed-up for a median period of 9.6years (range 1-25years) died. The 10 and 20-year overall survival rates for the whole series were 90.9% (95% CI, 84.3-94.8) and 62.9% (95% CI, 45.9-75.9), respectively. The number of expected deaths in the corresponding age and sex matched general population was 28.1, corresponding to a SMR=1.00 (95% CI, 0.72-1.35), with an SMR for non-SVR patients of 3.85 (95% CI, 3.43-4.30), for untreated of 3.01 (95% CI, 2.64-3.42) and for decompensated of 6.70 (95% CI, 5.39-8.22). CONCLUSIONS Patients with compensated HCV cirrhosis achieving SVR by IFN obtain a main benefit levelling their survival curve to that of the general population. Wider applicability of IFN-free regimens will possibly make this achievement more generalizable.

Hepatocyte proliferation and risk of hepatocellular carcinoma in cirrhotic patients.

Abstract OBJECTIVES: High hepatocyte proliferation has been recently proposed as a risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess whether hepatocyte proliferation is an independent risk factor for HCC when considered together with clinical and demographic characteristics. METHODS: We retrospectively evaluated 97 consecutive patients with a histological diagnosis of cirrhosis and preserved liver function, enrolled in a surveillance program for early diagnosis of HCC. Hepatocyte proliferation was evaluated by flow-cytometric analysis in liver samples collected at the time of histological diagnosis of cirrhosis. All patients were followed with abdominal US and serum α-fetoprotein (AFP) assays every 6 months. RESULTS: During a mean follow-up of 53 months (range, 12–120 months), 12 patients developed HCC, giving an annual incidence of 2.8%. The mean S-phase fraction was 2.5% ± 1.6 in patients who developed HCC and 0.9% ± 0.6 in those who did not ( p p p p p p CONCLUSIONS: Patients with high S-phase fraction and/or above-normal serum AFP are at higher risk of developing HCC and should be offered a close surveillance program.