[Show abstract][Hide abstract] ABSTRACT: The American Association for the Study of Liver Diseases guidelines recommend the use of all available markers for improving the accuracy of the diagnosis of small hepatocellular carcinoma (HCC). To determine whether clathrin heavy chain (CHC), a novel HCC marker, is effective in combination with glypican 3 (GPC3), heat shock protein 70, and glutamine synthetase, we compared the performances of a three-marker panel (without CHC) and a four-marker panel (with CHC) in a series of small HCCs (≤2 cm) and nonsmall HCCs by core biopsy with a 20- to 21-gauge needle. The series included 39 nonsmall HCCs and 47 small HCCs (86 in all); the latter showed a well-differentiated histology [small grade 1 (G1)] in 30 cases (63.8%). The panel specificity was analyzed with the adjacent/extranodular cirrhotic liver (n = 30) and low-grade (n = 15) and high-grade dysplastic nodules (n = 16) as a control group. Absolute specificity (100%) for HCC was obtained only when at least two of the markers were positive (which two markers were positive did not matter). The addition of CHC to the panel increased the diagnostic accuracy for small HCCs (from 76.9% to 84.3%), and there was an important gain in sensitivity (from 46.8% to 63.8%). The four-marker panel had lower rates of accuracy (67.4%) and sensitivity (50%) for small G1 HCCs versus nonsmall G1 HCCs (93.9% and 88.2%, respectively). In seven cases (including six small G1 HCCs), there was no staining with any of the markers. Cirrhotic control livers were stained for CHC in four cases (13.3%) and for GPC3 in one case (3.3%). CONCLUSION: The addition of CHC to the panel supports the diagnosis of small HCCs in challenging nodules on thin core biopsy samples. Small G1 HCCs include a group of earlier tumors characterized by a more silent phenotype and the progressive acquisition of the markers under study. The search for additional markers for early HCC diagnosis is warranted.
[Show abstract][Hide abstract] ABSTRACT: The identification of prognostic factors associated with mortality is crucial in any clinical setting.
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.
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 < or = 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.
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 < or = 10 at study entry had a prolonged life expectancy.
The American Journal of Gastroenterology 04/2009; 104(5):1147-58. · 7.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated 1336 hepatitis B surface antigen-positive subjects consecutively observed in 79 Italian hospitals over a 6-month period. The proportion of hepatitis B e antigen-negative cases was 86.4%, that of patients coinfected with hepatitis D virus was 9.7%, and the rate of patients coinfected with hepatitis C virus was 16.8%. Multiple logistic regression analysis showed that age >49 years, alcohol abuse, and anti-hepatitis D virus and anti-hepatitis C virus positivity were independent predictors of progression to liver cirrhosis. (copyright) 2007 by the Infectious Diseases Society of America. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Information on the impact of therapeutic strategies of hepatocellular carcinoma is still incomplete due to the lack of surveys involving primary-care centres.
The Gruppo Epatologico Lombardo (GEL) carried out a study on 361 incident hepatocellular carcinoma observed from January to December 1998 in 22 hospitals in Lombardy. The clinical, pathological and therapeutic data were collected from all patients; 5-year survival and factors related to outcome were analysed.
Two hundred and ninety-seven patients were male (M/F: 4.6/1, mean age 66); 61% were HCV-pos, 15% HBV-pos, 17% alcoholic. Cirrhosis was present in 333 (92%) and was classified as Child-A in 197 (59%), Child-B in 85 (26%) and Child-C in 51 (15%) cases. Hepatocellular carcinoma was multifocal/diffuse (more than three nodules) in 91 (25%), less than three nodules in 86 (24%) and monofocal in 184 (51%) (</=3cm in 146). As to the therapy: 145 hepatocellular carcinomas (40%) were untreated, 78 (22%) underwent percutaneous ethanol injection/radiofrequency ablation, 75 (20%) transarterial chemoembolization, 32 (9%) liver resection and 3 (0.8%) ortothopic liver transplantation (OLT). Survivals at 1, 3 and 5 years were 75%, 27% and 13%, respectively. Child-Pugh score, small size of the tumour and treatment, regardless of the type, were independent predictors of better prognosis.
This prospective, region-wide, cohort study showed that the characteristics of hepatocellular carcinoma in Lombardy (1998) do not differ from those reported in previous Italian surveys. Although most hepatocellular carcinomas were discovered at a relatively early stage, a large part remained untreated and the overall prognosis was poor. Efforts are warranted to implement screening-surveillance programmes and the impact of therapeutic strategies.
Digestive and Liver Disease 11/2007; 39(11):1011-7. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, that include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN) and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" cathegory requiring an accurate distinction from well-differentiated and early hepatocellular carcinoma. Nodules in cirrhosis are usually detected by non-invasive imaging techniques, being the latter unable to discriminate malignant from non-malignant forms, particularly in the 1-2 cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with US detectable nodules. The histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (cell atypia, cell crowding, trabecular thickness, microacini etc) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34) or tumor markers (HSP70 and Glipican 3 among others). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. The best diagnostic approach thus requires the integration of clinical, morphological and immunocytochemical information with imaging data (US pattern, perfusional pattern, helical CT/MR pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the cathegory of "borderline" nodules, that are mostly labelled as early, well differentiated HCC by eastern pathologists and as HGDN by western pathologists. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between eastern and western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for a proper clinical management and optimal therapy.
Annali italiani di chirurgia 09/2007; 79(2):81-9. · 0.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We assessed the prevalence of gallbladder disease (i.e. gallstones plus cholecystectomy) among patients with liver disease and its association with the severity and aetiology of hepatic injury. Subjects, referred to 79 Italian hospitals, were enrolled in a 6-month period. The independent effect of the severity and aetiology of liver disease on gallstone disease prevalence was assessed by multiple logistic regression analysis. Overall, 4867 subjects tested anti-hepatitis C virus (HCV) positive alone, 839 were hepatitis B virus surface antigen (HBsAg) alone, and 652 had an excessive alcohol intake. The prevalence of gallstone disease was 23.3% in anti-HCV-positive patients, 12.4% in HBsAg positive and 24.2% in subjects reporting excessive alcohol intake, respectively. Gallstone disease prevalence increased by age in each aetiological category. The proportion of patients with gallstone disease who had a cholecystectomy was the highest in HCV+ subjects. After adjusting for the confounding effect of age and
Journal of Viral Hepatitis 01/2007; 14(9):618-623. · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the efficacy of triple therapy (peginte-rferon or high dose standard interferon, plus ribavirin and amantadine) in nonresponders to prior combination therapy.
A total of 196 patients were enrolled in a multicenter, open, randomized study. Patients were given 180 mug/wk of peginterferon-alpha-2a (40 kDa) plus ribavirin (800-1000 mg/d) and amantadine (200 mg/d) for 48 wk (group A) or interferon-alpha-2a (6 MU/d for 4 wk, 3 MU/d for 20 wk, and 3 MU tiw for 24 wk) plus ribavirin (800-1000 mg/d) and amantadine (200 mg/d) for 48 wk (group B).
Overall sustained virologic response (SVR) was 26.6% (32.1% and 19.5% in group A and B, P = 0.057). Baseline ALT > 120 UI/L (OR 2.4; 95% CI: 1.11 to 5.20; P = 0.026) and HCV RNA negativity after 12 wk (OR 8.7; 95% CI: 3.87 to 19.74; P < 0.0001) were independently associated with SVR. Therapy discontinuation occurred less frequently in patients treated with peginterferon than standard interferon (P = 0.036).
More than 25% of nonresponders to combination therapy can eradicate HCV infection when retreated with triple therapy, especially if they have a high baseline ALT and are treated with pegylated interferon.
World Journal of Gastroenterology 10/2006; 12(33):5293-300. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The treatment of patients with hepatitis C virus (HCV) genotype 1 infection remains disappointing.
In 1999, we started a multicentre study comparing two regimens of recombinant interferon (IFN) alpha-2b plus ribavirin. Group A (90 patients) received ribavirin plus IFN alpha-2b 5 MU/day for 1 month (induction therapy) followed by IFN alpha-2b 5 MU thrice weekly for 5 months. Group B (85 patients) received ribavirin plus IFN alpha-2b 5 MU thrice weekly for 6 months. Responders in both arms received IFN alpha-2b 3 MU thrice weekly for a further 6 months. A follow-up evaluation was performed at 18 months.
One hundred and seventy-five consecutive treatment-naive patients with HCV genotype 1 infection were enrolled in the study. A sustained virological response (SVR) was obtained in 51 (29%) patients: 28 in group A (31%) and 23 in group B (27%). HCV-RNA clearance was greater at 3 months among patients who received induction therapy (57 vs 39%; p < 0.02). Age, sex, and initial viral load did not influence the achievement of a SVR. HCV clearance at the end of the study was lower in cirrhotic patients (3/26 vs 48/149; p < 0.05). The only SVR in patients with cirrhosis occurred in those from group A (p < 0.05). Both regimens were well tolerated.
This study confirms the low rate of SVR in treatment-naive patients with HCV genotype 1 infection treated with IFN alpha-2b plus ribavirin. A 4-week induction regimen was slightly superior to standard IFN alpha-2b plus ribavirin. Although the number of patients with cirrhosis was low, induction therapy seemed to be more effective in cirrhotics. Given its safety and tolerability, the induction regimen evaluated here may be a therapeutic option in treatment-naive patients with HCV genotype 1 infection.
Internal and Emergency Medicine 01/2006; 1(2):113-8. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 2001, 6 999 anti-HCV positive subjects referred to 79 Italian hospital in a 6 months enrolment period were evaluated. Of them, 5 632 (80.5%) tested anti-HCV positive alone, 1 163 (16.6%) reported also an excessive alcohol intake, and 204 (2.9%) were also HBsAg positive. Normal biochemistry was observed in 7.8% of cases, chronic hepatitis in 67.9% of cases, liver cirrhosis in 18.9% of cases, and hepatocellular carcinoma in 3.6% cases. HCV positive subjects with excessive alcohol intake were statistically significantly younger, of male sex, and having more severe liver disease than those without excessive alcohol intake. Adjusting for the confounding effect of age and sex by multiple logistic regression analysis, HCV positive chronic hepatitis cases drinking more than four alcoholic drinks daily were 2.2-fold (CI 95% = 1.3-4.0) more likely to progress to liver cirrhosis than teetotallers. These findings indicate that nearly a quarter of HCV positive subjects referred to hospitals in Italy have a sever
Journal of Viral Hepatitis 01/2006; 13(5):351-354. · 3.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Knowledge of the current epidemiology of chronic liver disease in Italy is mostly obsolete and fragmentary for the lack of up-to-date consistent data. In 2001, a 6-month prevalence study was undertaken in 79 hospitals to assess the characteristics of chronic liver disease in Italy. Both prevalent and incident cases were enrolled. A total of 9,997 patients were recruited, of whom 939 (9.4%) had normal liver biochemistry, 6,210 (62.1%) had chronic hepatitis, 1,940 (19.4%) had liver cirrhosis, and 341 (3.4%) had hepatocellular carcinoma (HCC). In 567 patients (5.7%) the diagnosis was not established. Hepatitis C virus (HCV) was found in 69.9% of the patients and was the only etiological factor in 56.3% of all the patients. Hepatitis B surface antigen (HBsAg) was present in the serum of 13.4% of the cases (in 10% it was the only etiological factor). A history of alcohol abuse was found in 23% of the cases (9.4% without viral infection). The prevalence of HCV-related cases was significantly lower in inciden
Journal of Medical Virology 01/2005; 75(4):522-527. · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: No recent national-level data on the aetiology of chronic hepatitis are available in Italy. Aim: To evaluate the current aetiology of chronic hepatitis in Italy. Patients: A total of 6210 chronic hepatitis patients (both prevalence and incident cases) consecutively admitted to 79 hospitals located throughout Italy were enrolled over a 6-month period in 2001. The hospitals were randomly selected through systematic cluster sampling. Results: The main agent associated with chronic hepatitis was hepatitis C virus, which was found in 76.5% of the patients (in 62.6% it was the only aetiologic factor). Hepatitis B surface antigen was present in the serum of 12.2% of the cases (in 9.2% it was the only aetiologic factor). Hepatitis B e antigen and hepatitis Delta were detected in 16.6% and 7.0%, respectively, of hepatitis B surface antigen-positive patients. A history of alcohol abuse was found in 19.2% of the cases (5.5% without viral infection). Autoimmune hepatitis and inborn metabolic disorders
Digestive and Liver Disease 01/2004; 36(12):829-833. · 3.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The natural outcome of ultrasound-detected macronodules in cirrhosis is still poorly understood. In this study we assessed the incidence and predictors of malignant transformation in a prospective study of 90 consecutive ultrasound-detected macronodules in cirrhosis.
Macronodules classification was based on recently proposed histological criteria. Extranodular large (LCC) and small cell changes were also evaluated. The follow-up included ultrasound and serum alfa-fetoprotein determination every 3 months. Independent predictors of hepatocellular carcinoma were evaluated by Cox proportional hazards regression analysis.
During a mean follow-up of 33 months, 28 (31%) nodules transformed into hepatocellular carcinoma. The incidence of hepatocellular carcinoma per 100 person-years of follow-up was 11.3%, with a malignant transformation rate of 3.5, 15.5, 31 and 48.5% at 1, 2, 3, and 5 years respectively. High-grade dysplastic nodules (HGDN) (hazard risk=2.4; CI 95%=1.1-5.0) and LCC (hazard risk=3.1; CI 95%=1.2-7.8) were independent predictors of malignant transformation. Eight additional hepatocellular carcinomas developed outside the original lesions raising the overall malignant transformation rate to 40% while 15 macronodules (17%) became undetectable at ultrasound (US).
Macronodules characterize a cirrhotic subpopulation with high risk of hepatocellular carcinoma. HGDN and LCC are strong predictors of malignant transformation; subjects with simultaneous presence of both these two conditions are at highest risk of cancer development. The management of cirrhotics with macronodules should be based on morphologic features detected on liver microsamples.
Journal of Hepatology 09/2003; 39(2):208-14. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The best treatment for chronic hepatitis C patients who do not respond to interferon is still unknown. Reported rates of response to treatment vary as the result of heterogeneous definitions of non-responders and small study size.
One hundred nineteen hepatitis C virus (HCV) RNA-positive non-responders to high-dose interferon monotherapy received alpha-interferon, 5 MU tiw plus oral ribavirin, 1000-1200 mg/day for 48 weeks (Group A, n=74) or alpha-interferon, 5 MU daily for 4 weeks, followed by 5 MU tiw plus oral ribavirin, 1000-1200 mg/day for 44 weeks (Group B, n=45) according to the Institution where they were followed. Persistently normal alanine aminotransferase and negative HCV RNA up to 72 weeks from treatment onset defined a sustained response.
Eighteen patients discontinued treatment (13 developed anemia, two mucositis, one granulocytopenia; two were dropouts), none for serious adverse events. There were 24 (20%) sustained responders, with similar final response rates in Groups A and B. Sustained response was more frequent in patients aged </=40 years (36% vs. 13%; P=0.006) and in those with non-1 genotype (44% vs. 14%; P=0.002). Among genotype 1 patients, the younger ones showed higher response rates (32% vs. 7%; P=0.005). Compared with patients harboring non-1 genotypes, the odds ratio of being a non-responder was 1.68 (confidence interval (CI): 0.53-5.37; P=0.381) in younger genotype 1 patients and 9.53 (CI: 2.84-32; P<0.001) in older genotype 1 patients.
Chronic hepatitis C patients who are non-responders to interferon monotherapy and infected by non-1 genotypes should undergo re-treatment with combination therapy. Treatment should be extended to younger genotype 1 patients who are more susceptible to liver disease worsening because of longer life expectancy and have a higher probability of being long lasting responders than their older counterparts.
Journal of Hepatology 04/2003; 38(4):499-505. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with cirrhosis are at significant risk for hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the relationship between the percentage of hepatocytes showing nucleolar hypertrophy and the development of HCC in cirrhosis of different causes. A total of 111 cirrhotic patients were studied, with a mean follow-up period of 83.3 months. Histologic sections from liver biopsy specimens were silver stained for selective visualization of the nucleolus; the nucleolar area was measured by image cytometry. Nucleoli with a size of 7 microm(2) or greater were considered to be hypertrophic. The nucleolar index was obtained by calculating the percentage of hepatocytes disclosing a nucleolar area of 7 microm(2) or greater. During the observation time, HCC was diagnosed in 39 of 111 patients. The incidence rate of HCC was greater in patients with nucleolar indexes of 2.5 or greater than in patients with nucleolar indexes of less than 2.5 (16.49%/y vs. 3.41%/y, respectively; P <.0001). The capacity of the nucleolar index to predict HCC development was separately tested in groups of patients divided by etiology, and it was found to be particularly relevant in hepatitis B virus (HBV)-related cirrhosis (P =.0006). Among patients with hepatitis C virus (HCV) infection, high nucleolar-index values were associated with a greater risk for HCC development, but the difference in the incidence rate of HCC between groups with a nucleolar index of 2.5 or greater and less than 2.5 was not statistically significant (P =.0944). In conclusion, our results have shown that high percentages of hepatocytes showing nucleolar hypertrophy significantly predict HCC development in patients with HBV infection, whereas their predictive value in HCV-related cirrhosis seems to be lower.
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that iron depletion improves the response to interferon in patients with chronic hepatitis C. We aimed to evaluate whether iron reduction by phlebotomy before interferon improves the rate of virological sustained response in previously untreated noncirrhotic patients.
One hundred fourteen hepatitis C virus (HCV) RNA positive patients with hepatic iron concentrations of > or =700 microg/g dry wt (men) and > or =500 microg/g dry wt (women), stratified according to HCV genotype and gamma-glutamyltransferase values, were randomly allocated to interferon alone (6 MU three times a week) (group A) or to phlebotomy until iron depletion followed by interferon (6 MU three times a week) (group B). After 4 months dosage was reduced to 3 MU three times a week for another 8 months.
Virological sustained response was observed in 25 patients (22%), nine (15.8%, 95% CI = 7.5-27.9) of group A and 16 (28.1%, 95% CI = 17.0-41.6) of group B. At univariate analysis the variables associated with the response were HCV genotypes 2-3, normal gamma-glutamyltransferase, higher levels of baseline ALT, normal ALT values, and negativity for HCV-RNA at the 3rd month of therapy. At multivariate analysis, genotype and ALT levels at enrollment maintained their association with the response. A trend toward a better response to interferon was observed in patients who received phlebotomy (odds ratio = 2.32, 95% CI = 0.96-6.24, p = 0.082). Patients with hepatic iron concentration of < or = 1100 microg/g dry wt had a trend toward a higher rate of virological sustained response (p = 0.059) when submitted to treatment B.
Iron removal by phlebotomy is able to improve the rate of response to interferon, especially in patients with lower hepatic iron deposits; it could be useful as adjuvant therapy to new therapeutic modalities.
The American Journal of Gastroenterology 05/2002; 97(5):1204-10. · 7.55 Impact Factor