Federico Tremolada

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.

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C

BACKGROUND/AIMS The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Virus replication and liver disease in chronic hepatitis B virus infection.

Recent studies on the natural history of chronic hepatitis B virus infection have provided evidence for a close temporal relationship between the phase of active virus replication and development of liver lesions. To assess the role that virus replication plays in this phase in determining the severity of the liver disease, we studied serum levels of virus-specific DNA-polymerase activity and hepatitis Be antigen/antibody status in 48 chronic carriers of the hepatitis B surface antigen found positive for the hepatitis B core antigen in the liver. There was a remarkably evident inverse correlation between virus replication activity and liver disease activity, patients with minimal histological changes having the highest DNA-polymerase levels (mean±sd: 3879±2557 cpm) and those with severe chronic active hepatitis the lowest enzyme levels (419±246 cpm), while cases of chronic persistent hepatitis and of mild chronic active hepatitis had intermediate levels. Serum hepatitis Be antigen was detected in 31/32 patients with milder liver lesions and in 11/16 with severe liver lesions; the remaining five cases were anti-HBe-positive despite the presence of the core antigen in the liver. Serum levels of virus replication markers closely correlated with the distribution pattern of the core antigen in the liver. These findings indicate that in chronic hepatitis B the severity of liver disease is not directly related to levels of virus replication, thus suggesting a predominant role of host immune mechanisms.

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype‐specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy‐proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan–Meier 5‐year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non‐1b, respectively (P=0.8); the corresponding figures for decompensation were 18% and 7% (P=0.0009) and for event‐free survival were 79% and 89% (P=0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47–2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2–7.4) and decreased event‐free survival by a factor of 1.7 (0.9–3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.

Comparative histology of acute hepatitis B and non-A, non-B in Leuven and Padova

A histological study was performed on liver biopsies from patients with acute hepatitis A (n=13), B (n=35) and non-A, non-B (nAnB) (n=35) in search for microscopical features characteristic for each type of hepatitis. Biopsies from two centres (Padova, Italy and Leuven, Belgium) were studied in order to determine whether the histological pattern in acute hepatitis A, B and nAnB may differ from one centre to another. The histology of cases of hepatitis A and B from Italy and Belgium did not differ. Less liver cell plemorphism was found in hepatitis A than in B. Clear differences were observed between acute hepatitis nAnB occurring in Padova when compared with cases from Leuven. The Padova-biopsies obtained from patients with transfusion-induced viral hepatitis were mainly characterized by a high degree of lympho-histiocytic intrasinusoidal infiltration whereas the Leuven-biopsies, mostly taken in patients with sporadic hepatitis, were characterized by the presence of numerous acidophilic bodies and Mallory body-like cytoplasmic alterations. Morphologically, the latter cases appear to be closely related to hepatitis B.

Receptors for polymerized human serum albumin on hepatitis B virus particles detected by radioimmunoassay: changes in receptor activity in serum during acute and chronic infection.

Receptor sites that bind polymerized human serum albumin on hepatitis B virus (HBV) particles were evaluated in purified virus particle preparations and in HBsAg positive sera, by using solid phase radioimmunoassay. The receptor, found in previous reports to be species-specific, was inhibited neither by native human serum albumin, nor by anti-human immunoglobulins or anti-C1q sera, indicating that these host components are not involved in the reaction. Differential receptor expression on various HBsAg particles was evaluated by relating levels of HBsAg to those of polyalbumin binding activity. This ratio was lower in HBsAg particles purified from hepatitis Be antigen (HBeAg) positive serum (mean ratio: 3.5) than in those obtained from anti-HBe positive serum (mean ratio: 20.1), suggesting that HBeAg/anti-HBe status influences the expression of the receptor on virus particles. Accordingly, during acute hepatitis type B receptor activity was high in sera obtained at the onset, but rapidly decreased afterwards, particularly at the time of anti-HBe seroconversion. A similar behavior of the receptor was observed in cases of chronic HBV infection, where mean receptor counts by radioimmunoassay were 3825±4422 (mean cpm ±SD) in HBeAg positive cases and 868±1196 cpm in anti-HBe positive cases (P<0.01). Seven HBsAg chronic carriers, all initially HBeAg positive, were followed up over a period of 1 to 4 yr and in all of them a progressive decrease in receptor activity was noted, independently of HBeAg persistence. These results indicate that the expression of the receptor for polymerized human albumin on HBV particles is an early event in the natural course of acute and chronic HBV infection, being followed by a progressive reduction in receptor activity, that parallels the reduction in virus replication, often independently of HBsAg serum levels.

Blood-transmitted and clotting-factor-transmitted non-A, non-B hepatitis: clinical differences and evolution

In a prospective study of post-transfusion hepatitis (PTH) in open-heart surgery patients, non-A, non-B hepatitis was diagnosed by exclusion criteria in 100 patients (14.1%). The frequency of hepatitis was significantly higher (56.9%; p less than 0.001) in patients receiving blood units and clotting-factor concentrates of commercial origin, which were administered for the occurrence of bleeding complications during surgery, as compared to patients treated with blood units alone (10.3%). When clinical features of hepatitis at presentation were compared in the two groups of patients, a shorter incubation period (p less than 0.05) and a higher prevalence of jaundice (p less than 0.01) were found in patients receiving blood and clotting-factors. Persistence of abnormal alanine aminotransferase (ALT) levels after 12 months from onset were found in more than 70% of patients in both groups. Late biochemical remission, however, was observed in 21% of patients receiving blood units alone, but in none of those who received clotting factors. All these latter patients had histologic features of active liver disease during the chronic phase of the illness, as compared to only 46% of patients receiving blood units alone (p = 0.02). Our results show significant differences in the clinical course of non-A, non-B hepatitis transmitted by blood as compared to clotting factors, supporting the hypothesis of different etiological non-A, non-B agents.

Hepatitis C Viremia and Serologic Profile in Post-Transfusion Non-A, Non-B Hepatitis

Serial serum samples from 19 patients with post-transfusion hepatitis C, followed for an average of 8 years, were tested for HCV antibody by individual synthetic peptide-based ELISA (core, NS3/4, El, E2/NS1 and NS5) and four-antigen RIB A, and for HCV-RNA by PCR amplification with nested primers from 5′ noncoding region and type-specific primers from core and NS5 regions. Ten patients progressed from acute to chronic hepatitis and 9 recovered. An expanded antibody pattern seems to correlate with a higher frequency of HCV-RNA-positive patients. The disappearance with time of HCV antibody was observed only in patients who cleared HCV. The persistence of HCV-RNA in 5 of 9 recovered patients suggests the existence of a ‘healthy’ carrier state of HCV. Most patients with chronic hepatitis had type I or II HCV infection, whereas most asymptomatic HCV carriers were infected with type IV HCV.

Hepatitis C virus infection and replication in patients with hepatocellular carcinoma

To evaluate the risk of hepatocellular carcinoma (HCC) development in cirrhosis of viral etiology, 239 consecutive patients with cirrhosis were followed prospectively. At entry, 20.9% of patients were hepatitis B surface antigen (HBsAg)- positive, 68.9% were anti-hepatitis C virus (HCV)-positive, and 6.7% were both HBsAg- and anti-HCV positive. Twenty-six (10.8%) patients developed HCC during follow-up. HCC appeared in 18.7% of HBsAg-positive patients, in 11.7% of anti-HCV-positive patients, and in 33.3% of patients positive for both HBsAg and anti-HCV. By univariate analysis, age above 59 years (P = 0.025), duration of cirrhosis (P = 0.014), and positivity for both HBsAg and anti-HCV (P = 0.004) were related to HCC development. By multivariate analysis, age (P = 0.038) and positivity for both HBsAg and anti-HCV (P = 0.004) were independently related to HCC incidence. Serum HCV-RNA was investigated by polymerase chain reaction (PCR) in 7 anti-HCV positive patients developing HCC and was positive in 42.8% before and 85.7% after tumor development. Concurrent HBV and HCV infection is a significant risk factor for HCC development in our cirrhotic patients. Enhancement of HCV replication seems to occur in anti-HCV positive cirrhotic patients when they develop HCC.

Hepatitis C Virus Antibody Response in Acute and Chronic Non-A, Non-B Hepatitis

Patients with post-transfusion, community-acquired or hemodialysis-acquired non-A, non-B hepatitis (NANBH) were tested for antibody to hepatitis C virus (HCV) during acute-phase and resolving or chronicized illness. HCV appears to be involved in most cases of post-transfusion and hemodialysis-acquired NANBH, but only in 40% of community-acquired NANBH. Second generation HCV antibody assays are more specific and sensitive, favoring early detection of HCV seroconversion and identification of HCV-antibody-positive individuals years after exposure to the virus.