Percutaneous radiofrequency thermal ablation for hepatocellular carcinoma.

BACKGROUND: Radiofrequency thermal ablation is the first therapeutic option in percutaneous treatment of hepatocellular carcinoma but data on its long-term efficacy and safety are not conclusive. AIM: This study reports a prospective survey on radiofrequency thermal ablation in north-east Italy. METHODS: Data were collected on 401 patients with hepatocellular carcinoma (males 301, mean age: 68 years) treated by radiofrequency thermal ablation in 13 centres. Indication to treatment was: single nodule not eligible for surgery in 77% of patients, 2-3 nodes in 18% and multiple lesions in 5%. Mean size was 3 cm (1-8 cm). Treatment response was assessed at 1 month by spiral computerized tomography and then with ultrasound examination and new spiral computerized tomography. RESULTS: Complete response was obtained in 67% of patients and in 27% response was 75-99%. Complete response raised to 77% in lesions smaller than 3 cm. The morbidity rate was 34%; the mortality was 0.5%, seeding was observed in four patients. Ten patients presented an unexpected rapid disease progression. CONCLUSION: The above data show that by radiofrequency thermal ablation, complete response can be achieved only in about two-third of the cases, clearly less than expected, and that, beyond seeding, unexpected progression can be observed.

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.

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C. European Concerted Action on Viral Hepatitis (EUROHEP).

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.

Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.

BACKGROUND & AIMS: Few data are available concerning the long-term prognosis of chronic liver disease associated with hepatitis C virus infection. This study examined the morbidity and survival of patients with compensated cirrhosis type C. METHODS: A cohort of 384 European cirrhotic patients was enrolled at seven tertiary referral hospitals and followed up for a mean period of 5 years. Inclusion criteria were biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of hepatitis A and B viruses and of metabolic, toxic, or autoimmune liver diseases. RESULTS: Antibodies against hepatitis C virus were positive in 98% of 361 patients tested. The 5-year risk of hepatocellular carcinoma was 7% and that of decompensation was 18%. Death occurred in 51 patients (13%), with 70% dying of liver disease. Survival probability was 91% and 79% at 5 and 10 years, respectively. Two hundred five patients (53%) were treated with interferon alfa. After adjustment for clinical and serological differences at baseline between patients treated or not treated with interferon, the 5-year estimated survival probability was 96% and 95% for treated and untreated patients, respectively. CONCLUSIONS: In this cohort of patients, life expectancy is relatively long, in agreement with the morbidity data showing a slowly progressive disease.

Prevalence of anti-HCV among spouses and offspring of anti-HCV positive subjects: an Italian multicentre study.

The role of familial environment in the spreading of hepatitis C virus (HCV) infection is not well established. We studied 1670 family members for 578 anti-HCV+ subjects enrolled in 8 centres distributed throughout Italy. The prevalence of anti-HCV positivity was significantly higher in spouses than in offspring (15.6% and 2.1% respectively; p < 0.01), with no difference between northern and central-southern regions of Italy. Anti-HCV positivity was found almost exclusively in adults; among offspring, during the first two decades of life, the prevalence of anti-HCV positivity was significantly lower than in subjects over 20 years old (0.6% vs 3.1%, respectively).

Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study.

BACKGROUND: Patients with cirrhosis have a high risk of hepatocellular carcinoma (HCC) but it is unclear how the etiology of liver disease influences tumor development. The authors evaluated hepatitis B and C virus (HBV, HCV) infection in cirrhosis in relation to the risk of HCC. METHODS: Two hundred and ninety consecutive cirrhotic patients were followed prospectively with periodic ultrasound examination. At entry, patients were tested for markers of HBV and HCV to assess relation to tumor development during follow-up. RESULTS: Twenty and five-tenths percent of patients were hepatitis B surface antigen (HBsAg) positive and 68.9% were positive for HCV antibodies. Previous alcohol abuse was present in 26.2%. During follow-up (46.3 +/- 21.4 months), HCC developed in 32 patients (11.0%) (annual incidence approximately 3%) including 19.6% of HBsAg-positive patients, 12.2% of HCV antibody positive patients and 14.4% of patients with a history of alcohol abuse. The highest rate of HCC was in patients with dual HBsAg and anti-HCV positivity with or without previous alcohol abuse, whereas the lowest incidence (0%) was in cases without risk factors. By univariate analysis, age older than 59 years (P < 0.005), longer duration of cirrhosis (P < 0.005), serum alpha-fetoprotein levels higher than 20 ng/ml (P < 0.05), and dual HBsAg and HCV positivity (P < 0.02) appeared to be associated with HCC. By multivariate analysis, age (P < 0.01), positivity for HBsAg and HCV antibodies (P < 0.05), male sex (P < 0.05), and previous alcohol abuse (P < 0.08) were independently related to tumor appearance. CONCLUSIONS: These results, although confirming that male sex and previous alcohol abuse are risk factors for hepatocellular carcinoma in cirrhosis, indicate that concurrent hepatitis B and C virus infection determines the highest risk of developing hepatocellular carcinoma.

Treatment of chronic hepatitis C with recombinant human interferon-alpha 2a: results of a randomized controlled clinical trial.

Sixty consecutive patients with chronic hepatitis C were included in a randomized controlled trial of recombinant human interferon-alpha 2a vs. no treatment. Treated patients received tapering doses of interferon thrice weekly for 1 yr. Twenty treated cases (66.7%) normalized serum aminotransferase levels within the first 4 mo of treatment, but reactivation or breakthrough frequently occurred afterward (20% in both cases). Only one of the untreated patients showed spontaneous normalization of serum aminotransferase levels. Liver histology did not improve in patients without a biochemical response or with breakthrough during therapy, whereas it did not worsen in long-term responders and reactivating patients. Lack of response does not appear to be related to serum interferon antibodies, although their early appearance is more frequent in patients who showed reactivation later on. No biochemical parameter was found to be predictive for positive response to treatment. Antibody to c100 became negative in 62.5% of long-term responders, whereas no change was recorded in other treated patients or controls. Reactivation and breakthrough often occur during treatment, and further studies are needed to determine the most effective schedule (dose and time) of interferon treatment. Loss of c100 antibody during therapy may be a marker of long-term maintenance of response to interferon therapy.

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

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 < 0.01). 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 < 0.0001) and 1.4% (p = 0.012). This suggests a correlation between anti-HCV antibody activity, hepatitis C virus replication, and the development of chronic liver disease.

Serum alanine aminotransferase levels among volunteer blood donors: effect of sex, alcohol intake and obesity.

Serum alanine aminotransferase (ALT) activity and antibody to hepatitis B core antigen (anti-HBc) were proposed as surrogate markers of non-A, non-B (NANB) infection. In this study we analyzed 649 consecutive repeat blood donors to define the possible exclusion rate if both surrogate markers were implemented in our Blood Service, and to assess risk factors associated with elevated ALT levels. One hundred and seven blood donors (16.5%) had slightly elevated ALT levels (higher than the upper reference value, but less than twice this level), but only 15 (2.3%) had a level higher than mean log + 2.25 SD. Seventy-seven (11.8%) resulted anti-HBc positive. Blood donors with elevated ALT levels and those who were anti-HBc positive belonged to different populations, being only 6 (0.9%) positive for both surrogate markers. Only two known donors (0.3%) resulted anti-HCV positive, and each of them was implicated in one of the four post-transfusion hepatitis (PTH) cases observed in 200 recipients of blood from these 649 donors. Both were negative for anti-HBc but one had elevated ALT levels. Male sex, age, alcohol use and obesity resulted all independently and significantly associated with elevated ALT levels. For both alcohol use and body weight we observed a significant linear relationship with serum ALT levels. These findings suggest that in our Region the exclusion of blood donors with ALT levels above the reference value, or those anti-HBc positive, would exclude an unacceptably high rate of blood donors without proven evidence of post-transfusion hepatitis prevention.(ABSTRACT TRUNCATED AT 250 WORDS)

Space-occupying lesions of the liver detected by ultrasonography and their relation to hepatocellular carcinoma in cirrhosis.

Fifty-four patients with cirrhosis, found to have a space-occupying lesion in the liver by ultrasound (US), underwent US-assisted biopsy of the lesion and were then followed prospectively to define outcome and survival. Histologic examination revealed hepatocellular carcinoma in 26 patients, while five had liver cell dysplasia without hepatocellular carcinoma and 23 had no evidence of tumor or of dysplasia. All five patients with an initial diagnosis of dysplasia developed hepatocellular carcinoma during follow-up and their survival curve was similar to that of patients with liver cancer and significantly worse than that of patients without dysplasia or tumor. There were five false-negative cases of hepatocellular carcinoma among the patients with negative histology. Overall, US-assisted liver biopsy diagnosed malignancy with a sensitivity of 72%, which increased to 86% when dysplasia was considered a pre-neoplastic lesion.

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.

Antibody to hepatitis C virus in post-transfusion hepatitis.

OBJECTIVE: To evaluate the prevalence of antibodies to hepatitis C virus (anti-HCV), their relation to outcome, and the seroconversion rate in patients with post-transfusion non-A, non-B hepatitis. DESIGN: Retrospective analysis of prospectively collected serum specimens. SETTING: A referral-based university hospital. PATIENTS: Sixty-three consecutive patients who developed non-A, non-B post-transfusion hepatitis after open-heart surgery. All patients had follow-up with serial serum testing and clinical evaluation. The mean (+/- SD) duration of follow-up after hepatitis onset was 81 +/- 33 months (range, 13 to 132 months). Seventeen patients recovered after acute-phase illness, whereas 46 developed chronic disease which, in 30 cases, was confirmed histologically. MAIN RESULTS: Of 32 patients tested before transfusion, 1 (3.1%) had anti-HCV. Fifty-nine (93%) patients were anti-HCV positive during acute-phase hepatitis: Patients with "early" seroconversion (less than 15 days after hepatitis onset) did not differ from those with "late" seroconversion (greater than 60 days after onset) in epidemiologic, clinical, and biochemical features. The rate of anti-HCV positivity during acute-phase illness was not significantly different among patients who recovered (76%) compared with those who developed chronic disease (95%). At 6 to 12 months, patients whose disease resolved had lower antibody activity than those with progressive disease. Further, during long-term follow-up (1 to 9 years), 53% of patients whose disease resolved but only 6.9% of patients who had progressive disease became anti-HCV negative. CONCLUSIONS: Hepatitis C virus is the major cause of post-transfusion hepatitis in Italy. The time to anti-HCV seroconversion varies widely after hepatitis onset and is not significantly associated with acute-phase features or outcome of disease.

Serum antibodies to thymus epithelial cells in non-A, non-B and cryptogenic chronic liver disease.

Antibodies against thymus epithelial cells (anti-TEC) and the basal cell layer (BCLA) of squamous epithelia have been described in association with HDV-related chronic liver disease (CLD). Data are lacking on their presence during nAnB virus infection. Sera from 51 patients with nAnB post-transfusion hepatitis, including acute and chronic cases diagnosed during a prospective study on candidates for cardiac surgery, and 167 with various forms of CLD were tested for the presence of anti-TEC and BCLA using indirect immunofluorescence on human thymus and rat forestomach sections. Both antibodies mainly occurred in nAnB, HDV and cryptogenic CLD (anti-TEC: 51%, 47% and 42%; BCLA: 29%, 38% and 31%, respectively). The prevalence of anti-TEC in nAnB CLD turned out to be higher than that recorded in alcoholic, HBV-related, autoimmune, liver and kidney microsomal antibody positive CLD and primary biliary cirrhosis (p ranging from less than 0.03 to less than 0.0004). Two monoclonal antibodies (Mabs) to cytokeratins gave a pattern superimposable on that of spontaneous anti-TEC (both Mabs) and BCLA (only one). Antibodies against epithelial constituents, presumably targeting cytokeratin-associated antigens, occur not only in HDV CLD, as previously reported, but also in nAnB CLD, where they might represent a diagnostic aid, due to the unavailability of reliable serological markers of nAnB infection. The close similarity of anti-TEC and BCLA status between nAnB and cryptogenic CLD suggests a nAnB etiology of at least a proportion of chronic liver patients at present scored as cryptogenic.

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.

Acute phase proteins in chronic and malignant liver diseases.

Six acute phase proteins (haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin, alpha 2-macroglobulin, C reactive protein and transferrin) have been measured in the sera of chronic liver disease (CLD) patients with different aetiology (viral, autoimmune and alcoholic) and histology (steatosis, chronic persistent hepatitis, chronic active hepatitis, cirrhosis), and in patients with liver cancer. 1) The most striking changes concerned alpha 2-macroglobulin (increased) and haptoglobin (decreased) levels. 2) Transferrin was lower in alcoholic liver disease than in viral CLD, CRP was lower in autoimmune than in viral or alcoholic CLD, and alpha 1-acid glycoprotein was lower in viral and alcoholic CLD than in autoimmune CLD. Acute phase protein assay may prove useful in differential diagnosis, particularly when specific markers are not available (autoimmune, non A, non B, alcoholic liver diseases). 3) No significant differences related to aetiology (B, non A non B, D viruses) were observed in viral CLD. 4) Patients who progressed to CLD after acute viral hepatitis type B or non A non B did not show different APP levels from those who had recovered when tested 8-12 months after the acute phase. 5) The pattern of APP changes observed in primary liver cell carcinoma was different from both the cirrhotic pattern and the pattern presented by other tumours with or without liver metastasis.

Changes in serum hepatitis B virus (HBV) DNA positivity in chronic HBV infection: results of a long-term follow-up study of 138 patients.

In an assessment of the clinical relevance of serum hepatitis B virus (HBV) DNA testing in chronic HBV infection, changes in the presence of this marker were investigated by spot hybridization in 138 hepatitis B surface antigen (HBsAg)-positive patients with chronic liver disease who were followed up for one to eight years. Forty-one patients were treated with steroids, often with evidence of potentiation of viral replication, whereas 92 patients remained untreated and had no evidence of sigma agent infection during follow-up. Data analysis in these patients allowed us to determine the significance of testing for hepatitis B e antigen and for HBV DNA in the natural history of the infection. The findings indicate that sequential testing for serum HBV DNA may be of great importance in HBsAg chronic carriers with liver disease for adequate evaluation of HBV replication and for the contribution of HBV DNA to the clinical assessment of chronic hepatitis.

In-vitro cell-mediated cytotoxicity for autologous liver cells in chronic non-A, non-B hepatitis.

To investigate the possible mechanisms of liver cell injury in chronic non-A, non-B (NANB) hepatitis, peripheral blood lymphocytes (PBL) from 16 patients with chronic NANB hepatitis were incubated with autologous hepatocytes in a microcytotoxicity assay. Significant cytotoxicity was demonstrated in 11 patients. T-enriched lymphocytes exhibited significantly greater cytotoxicity than non-T enriched cells. No significant inhibition of cytotoxicity was observed following preincubation of the liver cells with either monoclonal or polyclonal anti-HBc, or monoclonal anti-HBs, or addition of either purified HBsAg or recombinant HBcAg to the culture, indicating that there was no detectable cross-reactivity in this system between hepatitis B virus (HBV) and NANB-associated antigen(s). Preincubation of the patients' hepatocytes with polyclonal IgG purified from a serum of a patient who recovered from an acute NANB hepatitis, did not significantly alter cytotoxicity. Liver cell surface-bound IgG was detected by immunofluorescence in only two of the patients, a finding consistent with existing evidence of poor antibody responses to both liver membrane and NANB-associated antigens. Control experiments using PBL from allogeneic normal donors exhibited normal cytotoxicity for the patients' hepatocytes supporting the hypothesis that antibody-dependent cell-mediated cytotoxicity (ADCC) is unlikely to play a significant role in this clinical setting.