Alfredo Alberti

Non-invasive evaluation of liver fibrosis using transient elastography

Transient elastography (TE, FibroScan) is a novel non-invasive method that has been proposed for the assessment of hepatic fibrosis in patients with chronic liver diseases, by measuring liver stiffness. TE is a rapid and user-friendly technique that can be easily performed at the bedside or in the outpatient clinic with immediate results and good reproducibility. Limitations include failure in around 5% of cases, mainly in obese patients. So far, TE has been mostly validated in chronic hepatitis C, with diagnostic performance equivalent to that of serum markers for the diagnosis of significant fibrosis. Combining TE with serum markers increases diagnostic accuracy and as a result, liver biopsy could be avoided for initial assessment in most patients with chronic hepatitis C. This strategy warrants further evaluation in other aetiological types of chronic liver diseases. TE appears to be an excellent tool for early detection of cirrhosis and may have prognostic value in this setting. As TE has excellent patient acceptance it could be useful for monitoring fibrosis progression and regression in the individual case, but more data are awaited for this application. Guidelines are needed for the use of TE in clinical practice.

Management of hepatitis C.

Hepatitis C is a major cause of liver-related morbidity and mortality worldwide and represents a major public health problem. Its epidemiology has been changing during the last decade and great progress has been made in the development of new diagnostic tests and treatment strategies thanks to the combined efforts of the academic and industry-sponsored research. However, there are still a number of issues that have not yet been completely solved, particularly in relation to the full understanding of the pathogenesis of liver disease and mechanisms leading to chronicity and to severe end stage. Therapy has improved in recent years and eradication of hepatitis C virus (HCV) by treatment is a reality in many chronically infected patients, but the issue of a substantial number of non-responders is still unsolved. This review addresses the main recent developments in the field of basic and clinical research on HCV, with particular reference to the clinical management of acute and chronic hepatitis C.

Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications

Background and aims: The natural history of initially compensated cirrhosis due to hepatitis B (HBV) or hepatitis C (HCV) virus is only partially defined. We have investigated morbidity and mortality rates and the hierarchy of complications in compensated viral cirrhosis over a long follow up period. Patients and Methods: A cohort of Italian patients with initially compensated cirrhosis of viral aetiology were followed up at six monthly intervals with laboratory tests to identify major complications (ascites, gastrointestinal bleeding, portal-systemic encephalopathy, hepatocellular carcinoma) and to assess the progression of Child’s stage and mortality rate due to liver related causes. Results: Between 1986 and 1996, 312 patients (43 HBV positive, 254 HCV positive, and 15 HBV and HCV coinfected) were included. During a median follow up of 93 (range 14–194) months, 102 (32.6%) patients developed at least one complication (HCV positive 31.1%; HBV positive 34.8%; HBV and HCV coinfected 53.3%). Overall, the most frequent complication was hepatocellular carcinoma which occurred in 65 (20.8%) cases, followed by ascites (61 cases, 19.5%), gastrointestinal bleeding (14 cases, 4.5%), and portal-systemic encephalopathy (six cases, 1.9%). Progression of Child’s stage was observed in 62 patients (19.8%). Death from liver disease occurred in 58 (18.6%) cases and in 70.7% this was due to hepatocellular carcinoma. Hepatocellular carcinoma was the first complication to develop in 59 cases and represented the most frequent first complication in both HCV and HBV/ HCV related cirrhosis. Conclusions: These results indicate significant morbidity and mortality during the first decade after diagnosis of compensated cirrhosis due to HBV and/or HCV, and identify hepatocellular carcinoma as the most frequent and life threatening complication, particularly in HCV positive cases.

Natural history and prognostic factors for chronic hepatitis type B.

One hundred and five hepatitis B surface antigen (HBsAg) positive patients presenting with chronic persistent hepatitis (n = 46) or chronic active hepatitis without cirrhosis (n = 59) were followed longitudinally for one to 16 years (mean 5.5 years) and underwent follow up biopsy. During a mean histological follow up of 3.7 years, active cirrhosis developed in 21 (20%) patients one to 13 years after entry to the study with a calculated annual incidence of 5.9%. The probability of evolution to cirrhosis was significantly higher in patients with chronic active hepatitis and bridging hepatic necrosis than in those with moderate chronic active hepatitis or chronic persistent hepatitis (p less than 0.0001). Cox multiple regression analysis showed that the following three variables independently implied poor prognosis: older age, presence of bridging hepatic necrosis, and persistence of hepatitis B virus DNA in serum (p less than 0.0001). These findings indicate that patients with severe chronic active hepatitis and persistent hepatitis B virus replication are at very high risk of rapid progression to cirrhosis.

Natural history of hepatitis C

Ten years after the discovery of the hepatitis C virus (HCV) and its association with NANB hepatitis as a major cause of chronic liver disease worldwide, our knowledge of the natural history of hepatitis C is still limited. The asymptomatic course of the disease in most patients, its slow and silent progression and heterogeneous outcome and the widespread use of interferon therapy during the past decade explain why many questions are still unsolved. The changing epidemiological pattern of HCV and the significant contribution of several cofactors to the severity of liver disease also complicate the development of a general model describing the natural history of hepatitis C. Available data indicate that HCV infection may resolve without any clinical signs of liver disease in individuals exposed to low dose inoculum and that these cases may develop T cell immunity even in the absence of anti-HCV seroconversion. Rates of complete biochemical and virological resolution of acute hepatitis C range between 10 and 50%, and are probably affected by the route of infection, size and type of inoculum and acute phase clinical features. Chronic HCV infection may develop with or without ALT abnormalities and with or without chronic inflammation and increasing fibrosis in the liver. Studies conducted in patients who acquired hepatitis C by blood transfusion 15-25 years ago indicate that 20-30% of them have now progressed to cirrhosis, including 5-10% with end stage liver disease and 4-8% who died of liver-related causes. Similar studies conducted in patients infected by other routes have shown a more benign course of hepatitis C, with little evidence of cirrhosis and no liver-related mortality during the first two decades. Outcomes after longer follow-up need to be assessed. In patients presenting with chronic hepatitis C, fibrosis progression is extremely variable over time and can be partially predicted by the age at infection, disease duration, liver histologic activity and stage of fibrosis and by the ALT profile. However, it is often difficult to predict clinical outcomes in individual cases. In patients who have developed cirrhosis, the 5-year risk of decompensation is between 15 and 20% and that of hepatocellular carcinoma around 10%. Several variables have been shown to influence the natural course of shown C, the most significant being age at infection, alcohol consumption and coinfection with HBV and HIV Studies are being performed to assess the role of host genetics. Viral factors, such as the HCV type and load, seem to have inconsistent or marginal effects.

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country‐specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.

HCV-associated liver cancer without cirrhosis

Chronic infection with hepatitis C virus (HCV) is regarded as a risk factor for hepatocellular cancer, mostly in patients with liver cirrhosis. We looked for HCV genomes in the livers of patients with hepatocellular cancer who did not have cirrhosis to see whether HCV was directly oncogenic. Cancerous and non-cancerous liver tissue, and serum samples from 19 patients negative for hepatitis B surface antigen were analysed by polymerase chain reaction for the presence of HCV genome, HCV replication, HCV genotyping, and HBV genome. 13 of 19 patients were HCV RNA-positive in cancerous and non-cancerous liver tissue; 8 of 17 tested were anti-HCV positive. Among the 13 HCV RNA-positive patients, 11 had genotype 1b and 2 had genotype 2a. 7 of 13 serum samples were HCV RNA positive. 7 of 19 patients were HBV DNA positive in cancerous and non-cancerous liver tissue, 5 of them anti-HBc positive. 4 patients were both HCV RNA and HBV DNA positive and 3 were both HCV RNA and HBV DNA negative. Our results provide evidence for the association of HCV, mostly genotype 1b, with hepatocellular cancer without the intermediate step of cirrhosis.

Long-term follow-up of non-A, non-B (type C) post-transfusion hepatitis.

Abstract One hundred and thirty-five patients who developed non-A, non-B post-transfusion hepatitis mostly after cardiac surgery, were followed for a mean (±S.D.) of 90±41 months (range: 13–180) to evaluate clinical and histological outcome. Thirty-one cases resolved within 12 months, while 104 (77%) progressed to chronicity. Twenty-one of 65 (32%) biopsied patients developed cirrhosis at the end of the follow-up, and one further progressed to hepatocellular carcinoma. One patient had a complete histological remission (1%). The remaining cases had chronic active (37%), chronic persistent (27%) or chronic lobular hepatitis (3%). About half of the cases with cirrhosis developed portal hypertension, and three of these died due to esophageal varices hemorrhage, one due to liver failure, and one due to hepatocellular carcinoma. Out of 26 patients with the initial histologic diagnosis of chronic hepatitis that were rebiopsied during follow-up, 13 (50%) progressed to cirrhosis. These patients were significantly older than patients who did not develop cirrhosis (mean age 57 and 45 years respectively; p During acute hepatitis anti-HCV was positive in all but one of the 114 patients tested. Percentages were similar for patients who recovered (95%) and those who developed chronic hepatitis (100%). However, during follow-up, 71% of the 1st generation and 21% of the 2nd generation ELISA test patients with acute resolved hepatitis became anti-HCV negative, while the same figures in chronic cases were only 8.5% ( p p =0.012). This suggests a correlation between anti-HCV antibody activity, hepatitis C virus replication, and the development of chronic liver disease.

Antibodies to the Surface of Halothane-Altered Rabbit Hepatocytes in Patients with Severe Halothane-Associated Hepatitis

Circulating antibodies reacting specifically with the cell membrane of hepatocytes isolated from halothane-anesthetized rabbits were detected in nine of 11 patients with fulminant hepatic failure after helothane-induced anesthesia. The immunoglobulin deposition, as revealed by immunofluorescence, showed a granular pattern on the hepatocyte surface membrane. Preincubation of halothane-pretreated, but not of control, hepatocytes with serum containing this antibody rendered them susceptible to cytotoxic effects of normal lymphocytes in vitro. Control studies using serum from subjects repeatedly exposed to halothane without the development of liver damage, and from patients with viral and toxic liver injury have confirmed the specificity of these findings to serve halothane-associated liver injury. These results provide further evidence of an immunologic component in this condition.

Effect of peginterferon alfa‐2a on liver histology in chronic hepatitis C: A meta‐analysis of individual patient data

Multicenter randomized trials have shown that once‐weekly pegylated interferon (peginterferon) alfa‐2a is more efficacious than conventional interferon alfa‐2a (IFN) in patients with chronic hepatitis C. We performed a meta‐analysis of 1,013 previously untreated patients (from 3 randomized trials) with pretreatment and post‐treatment liver biopsies to assess the differences between peginterferon alfa‐2a and IFN in terms of their effects on liver histology. Reported values were standardized mean differences (SMD) between patients receiving peginterferon alfa‐2a and those receiving IFN (post‐treatment value minus baseline value for each group). We used a random‐effects model to quantify the average effect of peginterferon alfa‐2a on liver histology. Peginterferon alfa‐2a significantly reduced fibrosis compared with IFN (SMD, −0.14; 95% CI: −0.27, −0.01; P = .04). A reduction in fibrosis was observed among sustained virologic responders (SMD, −0.59; 95% CI: −0.89, −0.30; P < .0001) and patients with recurrent disease (SMD, −0.34; 95% CI: −0.54, −0.14; P = .0007), whereas no significant reduction was observed among nonresponders (SMD, −0.13; 95% CI: −0.32, 0.05; P = .15). Logistic regression analysis indicated that patients with sustained virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI: 1.14, 2.29) for reduction in fibrosis compared with patients without SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m2) had an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal‐weight (BMI < 25 kg/m2) and overweight patients (BMI, 25–30 kg/m2). In conclusion, in patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa‐2a (relative to IFN) significantly reduced fibrosis. The beneficial effects of peginterferon on liver histology are closely related to virologic response. (HEPATOLOGY 2004;39:333–342.)