Franco Noventa

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.

Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study

A multicenter longitudinal study was performed to assess the survival of hepatitis B surface antigen positive compensated cirrhosis, primarily in relation to hepatitis B virus replication and hepatitis delta virus infection, and to construct a prognostic index based on entry characteristics. This cohort study involved nine university medical centers in Europe. Three hundred and sixty-six Caucasian HBsAg positive patients with cirrhosis who had never had clinical manifestations of hepatic decompensation were enrolled and followed for a mean period of 72 months (6 to 202 months). Inclusion criteria were biopsy-proven cirrhosis, information on serum hepatitis B e antigen and antibody to hepatitis D virus at the time of diagnosis and absence of complications of cirrhosis. At entry 35% of the patients were HBeAg positive, 48% of the patients tested were HBV-DNA positive and 20% anti-HDV positive. Death occurred in 84 (23%) patients, mainly due to liver failure (45 cases) or hepatocellular carcinoma (23 cases). The cumulative probability of survival was 84% and 68% at 5 and 10 years, respectively. Coxs regression analysis identified six variables that independently correlated with survival: age, albumin, platelets, splenomegaly, bilirubin and HBeAg positivity at time of diagnosis. According to the contribution of each of these factors to the final model, a prognostic index was constructed that allows calculation of the estimated survival probability. No difference in survival of hepatitis D virus infected and uninfected patients was observed. Termination of hepatitis B virus replication and/or biochemical remission during follow up correlated with a highly significant better survival. These data show that in compensated cirrhosis B, hepatitis B virus replication, age and indirect indicators of poor hepatic reserve and established portal hypertension significantly worsen the clinical course of the disease, whereas hepatitis D virus infection does not influence the prognosis. The highly significant improvement in life expectancy following cessation of hepatitis B virus replication and biochemical remission favors antiviral therapy in those patients with a guarded prognosis, as estimated by a prognostic index.

A simple ultrasound approach for detection of recurrent proximal-vein thrombosis.

BackgroundThe objective of this study was to develop a simple ultrasound method for measuring thrombus regression in patients with proximal deep-vein thrombosis (DVT) and to test its utility for the detection of DVT recurrence.Methods and Resuls. The study comprised a cross-sectional survey and a prospective investigation (149 and 145 patients, respectively). In both phases, the normalization rate of a previously abnormal ultrasound test, applying the criterion of full compressibility of the common femoral and popliteal veins (C-US method), was assessed. In the prospective study, the vein diameter under maximum compression (thrombus thickness) was measured in the abnormal venous segments at scheduled times (1, 3, 6, and 12 months). In patients presenting with suspected DVT recurrence, the procedure was repeated and results were compared with those available from the previous examination. Noncompressibility of a previously normal(ized) venous segment and enlargement of thrombus thickness (.

Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis: A Randomized Controlled Trial

2 mm) were considered diagnostic of proximal DVT recurrence. The diagnostic accuracy of the C-US method alone, as well as of the combined ultrasound methods (C-US + thrombus thickness), was assessed against contrast phlebography. C-US test normalization occurred in only 301% of patients within 1 year. A significant reduction of the thrombus mass (P<.0001) was recorded throughout the entire study period. However, a major decrease in thrombus mass (>50%o) was recorded within the first 3 months. Of 29 patients who developed a suspected recurrent DVT, phlebography confirmed diagnosis in 11. The C-US method alone showed an excellent accuracy (100%) but was applicable in only 6 patients (21%). Both the sensitivity and the specificity for proximal DVT recurrence of the combined ultrasound methods were 100%o (95% confidence interval, 69% to 100% and 81% to 100%, respectively) and were applicable in all patients. ConclusionsThe serial ultrasound measurement of thrombus mass after an acute episode of DVT may allow the correct identification of patients who develop a recurrent proximal-vein thrombosis.

Chronic hepatitis B in children after e antigen seroclearance: Final report of a 29‐year longitudinal study

CONTEXT Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00353093.

SAFE biopsy: A validated method for large-scale staging of liver fibrosis in chronic hepatitis C†

Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long‐term prognosis remains unsettled. This report describes the results of a 29‐year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg‐positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 ± 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg‐negative hepatitis and the other 84 became inactive carriers. During a mean follow‐up of 14.5 ± 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg‐negative hepatitis at the last follow‐up. Of the 8 initially HBeAg‐negative children, 2 had HBeAg‐negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg‐negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow‐up, 15 of the 89 initially HBeAg‐positive patients and 2 of 8 initially HBeAg‐negative children had cleared hepatitis B surface antigen. In conclusion, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg‐negative hepatitis. Long‐term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse. (HEPATOLOGY 2006;43:556–562.)

Long term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood.

The staging of liver fibrosis is pivotal for defining the prognosis and indications for therapy in hepatitis C. Although liver biopsy remains the gold standard, several noninvasive methods are under evaluation for clinical use. The aim of this study was to validate the recently described sequential algorithm for fibrosis evaluation (SAFE) biopsy, which detects significant fibrosis (≥F2 by METAVIR) and cirrhosis (F4) by combining the AST‐to‐platelet ratio index and Fibrotest‐Fibrosure, thereby limiting liver biopsy to cases not adequately classifiable by noninvasive markers. Hepatitis C virus (HCV) patients (2035) were enrolled in nine locations in Europe and the United States. The diagnostic accuracy of SAFE biopsy versus histology, which is the gold standard, was investigated. The reduction in the need for liver biopsies achieved with SAFE biopsy was also assessed. SAFE biopsy identified significant fibrosis with 90.1% accuracy (area under the receiver operating characteristic curve = 0.89; 95% confidence interval, 0.87‐0.90) and reduced by 46.5% the number of liver biopsies needed. SAFE biopsy had 92.5% accuracy (area under the receiver operating characteristic curve = 0.92; 95% confidence interval, 0.89‐0.94) for the detection of cirrhosis, obviating 81.5% of liver biopsies. A third algorithm identified significant fibrosis and cirrhosis simultaneously with high accuracy and a 36% reduction in the need for liver biopsy. The patients age and body mass index influenced the performance of SAFE biopsy, which was improved with adjusted Fibrotest‐Fibrosure cutoffs. Two hundred two cases (9.9%) had discordant results for significant fibrosis with SAFE biopsy versus histology, whereas 153 cases (7.5%) were discordant for cirrhosis detection; 71 of the former cases and 56 of the latter cases had a Fibroscan measurement within 2 months of histological evaluation. Fibroscan confirmed SAFE biopsy findings in 83.1% and 75%, respectively. Conclusion: SAFE biopsy is a rational and validated method for staging liver fibrosis in hepatitis C with a marked reduction in the need for liver biopsy. It is an attractive tool for large‐scale screening of HCV carriers. (HEPATOLOGY 2009.)

Prognostic Usefulness of Hepatic Vein Catheterization in Patients With Cirrhosis and Esophageal Varices

Seventy-six children aged 1-13 years who were known to be positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months and who had biopsy-proven chronic hepatitis have been followed longitudinally for 1-12 years (mean, 5 years). Twenty-three of them are now young adults. Eight patients had acute type B hepatitis 12-24 months before entering the study, while 68 patients came to observation during a chronic phase. At the beginning of follow-up, all 76 children were positive in serum for hepatitis B virus DNA, and 44 (58%) had chronic active hepatitis, associated with cirrhosis in two cases. During follow-up, 23 (30%) patients remained hepatitis B e antigen-positive, most with unchanged biochemical and histological features. The other 53 (70%) cases seroconverted to hepatitis B e antibody and cleared hepatitis B virus DNA from serum, including 7 of 8 (87%) patients with acute hepatitis at presentation. After seroconversion, alanine aminotransferase levels normalized in all patients and remained normal in 49 patients (92.5%) throughout a mean observation period of 3 years. Five of these children, including 2 of 7 (29%) with previous acute hepatitis, eventually cleared hepatitis B surface antigen from their sera. Finally, 4 (7.5%) patients experienced a mild increase of alanine aminotransferase levels several months after seroconversion in the absence of hepatitis B virus replication or of delta virus superinfection. Clinical and virological parameters did not significantly differ between patients with or without acute onset; however, seroconversion occurred earlier, and the rate of hepatitis B surface antigen clearance was greater in the former than in the latter group. The present data indicate that approximately two thirds of children with hepatitis B e antigen- and hepatitis B virus DNA-positive chronic hepatitis clear hepatitis B virus DNA from their sera before reaching adulthood. After termination of viral replication, most patients achieve a sustained biochemical remission, suggesting the disappearance of disease activity. Reactivation of virus replication after hepatitis B e antibody seroconversion has never been observed in this series, although mild alanine aminotransferase level abnormalities could be detected in a minority of cases.

Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection

Clinical and anamnestic data, Pugh score, and size of esophageal varices were obtained in 129 cirrhotics. Hepatic vein catheterization was performed to measure hepatic venous pressure gradient (HVPG), indocyanine green (ICG) intrinsic hepatic clearance, and hepatic plasma flow. During a follow-up period of up to 60 months, 44 patients experienced gastrointestinal bleeding and 54 died. Applying Cox regression analysis, ICG intrinsic hepatic clearance, Pugh score, previous variceal bleeding, and HVPG were the only significant prognostic determinants of survival. In addition, Coxs regression analysis showed that HVPG, Pugh score, size of varices, and previous variceal bleeding all contained significant prognostic information regarding risk of gastrointestinal bleeding. The models were validated using a split-sample technique, and prognostic indexes for death and gastrointestinal bleeding were calculated. The prognostic index predicting death had significantly improved prognostic accuracy over a prognostic index calculated excluding the data obtained from hepatic vein catheterization (P less than 0.05). In conclusion, prognostic accuracy in cirrhosis with portal hypertension is significantly improved by information obtained from hepatic vein catheterization.

Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity

Context Many persons infected with hepatitis C virus (HCV) are asymptomatic. The extent of liver disease in these persons is unclear. Contribution The researchers tested 4820 apparently healthy persons in Italy for hepatitis C virus. Among the 116 (2.4%) who tested positive, 85 were viremic; only about half of these 85 patients had elevated alanine aminotransferase (ALT) levels. Liver biopsy showed substantial inflammation or fibrosis in 19% of persons with normal ALT levels and 61% of persons with abnormal ALT levels. Implications The substantial prevalence of abnormal liver histology among asymptomatic persons is a provocative but incomplete rationale for screening for HCV. The prevalence of infection and the effectiveness of treatment are also important considerations. The Editors Although new hepatitis C virus (HCV) infections have declined during the past decade in most developed countries (1), hepatitis C remains a major health problem because of the many persons infected before serologic testing became available (2, 3). Many persons with HCV infection are asymptomatic and unaware that they are infected. While it is clear that HCV contributes greatly to end-stage liver disease, the natural history of hepatitis C in asymptomatic individuals is poorly defined. Published studies indicate that the natural history of hepatitis C is heterogeneous. Several factors, including age at infection, alcohol use, and co-infection with hepatitis B virus or HIV, increase the risk for cirrhosis (4-8). Independent of these cofactors, prognosis is related to hepatic histopathology, particularly the type and amount of liver necroinflammation and fibrosis (9-11). Our understanding of the histology of hepatitis C in asymptomatic persons comes mainly from studies of blood donors (a selected population) (12-14). We report an investigation of the prevalence, histologic activity, and stage of HCV infection in 4820 otherwise apparently healthy adults living in northeastern Italy. Methods Patients We tested for serum anti-HCV in 4820 adults (2132 men and 2688 women; age range, 16 to 60 years) who were undergoing a screening program for cardiovascular risk factors. To be eligible for this program, persons had to be free of acute or chronic illness (based on history and clinical symptoms) at the time of evaluation. Telecom Italy proposed and promoted the screening program to employees and their relatives. Participation was voluntary. Participants lived in one of three regions (Veneto, Trentino-Alto-Adige, and Friuli-Venezia-Giulia) in northeastern Italy and included a wide range of socioeconomic strata (from employees in lower positions to senior managers and their relatives). All 4820 persons (1210 employees and 3610 relatives) gave written informed consent and underwent clinical evaluation and testing for anti-HCV by enzyme-linked immunosorbent assay (ELISA) (Ortho Diagnostic Systems, Raritan, New Jersey) at the initial visit. Within 1 month, we retested persons who were positive for anti-HCV by ELISA. Serum that was confirmed to be HCV positive was tested for HCV RNA by polymerase chain reaction (PCR) (Amplicor HCV Monitor test, Roche Diagnostics, Indianapolis, Indiana). We retested serum for HCV RNA after 1 and 3 months in confirmed anti-HCVpositive persons whose initial test results for HCV RNA had been negative. We monitored serum alanine aminotransferase (ALT) levels 1, 3, 6, and 12 months after anti-HCV detection. We proposed liver biopsy for all viremic persons. These biopsies were done 6 to 14 months after detection of anti-HCV; patients provided informed consent. Liver biopsy specimens were evaluated according to the METAVIR scoring system (15). We classified patients with METAVIR scores of F2 and higher or A2 and higher as having significant liver disease according to international guidelines (16). Statistical Analysis Prevalences of HCV infection and of liver disease were compared by using the Fisher exact test for 2 2 tables. The chi-square test for linear trend was used to compare prevalences in age subgroups. Role of the Funding Source The study protocol was developed by a Scientific Committee of the Italian National Research Council (CNR), approved by a National Ethical Committee, and directly funded by the Italian National Research Council. The Italian National Research Council had no role in the collection, analysis, and reporting of the study or in the decision to publish the manuscript. Results Prevalence of HCV Infection in the Screened Population Of the 4820 persons tested, 116 (2.4% [CI, 1.97% to 2.84%]) were repeatedly positive for anti-HCV by ELISA and 12 additional persons were initially positive but were negative on repeated testing. Samples confirmed to be anti-HCV positive were tested for HCV RNA; 75 of these were positive. The 41 persons who were initially positive for anti-HCV but negative for HCV RNA were tested for serum HCV RNA 1 and 3 months after anti-HCV detection; 10 were positive in both (n = 8) or one (n = 2) follow-up test. Thus, 85 of 116 anti-HCVpositive persons (73.3%), or 85 of 4820 screened individuals (1.76 % [CI, 1.39% to 2.14%]) were positive for HCV RNA. Among the 85 HCV RNApositive individuals, ALT levels were normal (<50 U/L) at all times (at 0, 1, 3, 6, and 12 months) in 39 persons (46%), elevated at all times in 37 persons (43.5%), and abnormal at least once in 9 patients (10.5%). The 10 persons with intermittent HCV RNA positivity had persistently normal ALT levels during follow-up. Liver Histology in HCV-Infected Persons Seventy-eight of the 85 persons who were positive for HCV RNA had liver biopsies; these 78 patients included 32 of 39 persons with persistently normal ALT levels and all 46 persons with elevated ALT levels. The Figure summarizes the histopathologic characteristics of the 78 HCV-positive persons according to the ALT profile during the observation period. Overall, 52% of patients with elevated ALT levels and 19% of patients with normal ALT levels had significant fibrosis (F2 to F4), whereas 24% of patients with elevated ALT levels and none with normal ALT levels had significant necroinflammatory activity (A2 to A3). Thus, on the basis of a fibrosis score of 2 or higher or an activity score of 2 or higher, moderate to severe chronic hepatitis was seen in 28 of 46 (61% [CI, 45.4% to 74.9%]) patients with elevated ALT levels and in 6 of 32 (19% [CI, 7.21% to 36.4%]) patients with normal ALT levels (P < 0.001). Both mean and peak ALT values during the 12-month follow-up period correlated with activity and fibrosis stage (Table). The percentage of patients with significant activity or fibrosis increased with increasing ALT levels (data not shown). Figure. Histologic activity and fibrosis stage of the 78 persons with normal or elevated alanine aminotransferase levels who were positive for hepatitis C virus. Table. Liver Histology during the 12-Month Follow-up Period in 78 Hepatitis C VirusPositive Persons Prevalence of HCV Infection and Liver Disease by Age Prevalence of HCV RNA positivity increased with age: 0.67% (CI, 0.23% to 1.57%) in persons age 16 to 30 years, 1.4% (CI, 0.93% to 2.08%) in persons age 31 to 45 years, and 2.4% (CI, 1.8% to 3.2%) in persons age 46 to 60 years (P = 0.003). The percentage of persons with persistently normal ALT levels was similar in the three age groups, but severity of liver disease increased with age. The prevalence of significant fibrosis (F2) was 20% in the persons age 16 to 30 years and 48% in the persons age 46 to 60 years. When only patients with abnormal ALT levels were considered, the corresponding figures were 33% in persons age 16 to 30 years, 50% in the persons age 31 to 45 years, and 79% in the persons age 46 to 60 years. HCV Genotypes Among the 85 persons positive for HCV RNA, 52 (61.2%) were infected with HCV genotype 1b, 5 (5.8%) with genotype 1a, 20 (23.5%) with genotype 2a/2c, and 8 (9.4%) with genotype 3. Four of 5 patients age 16 to 30 years were infected with genotype 3, and the fifth was infected with genotype 1a. Genotype in persons age 31 to 45 years and 46 to 60 years did not differ significantly. The HCV genotypes were not significantly associated with ALT levels or histologic features after adjustment for age (data not shown). Discussion It has been difficult to estimate precisely how many asymptomatic HCV-infected persons are at significant risk for progressive liver disease. This is a result of the limited available information on the actual burden of HCV in the general population and uncertainty about the natural course of HCV infection in asymptomatic individuals (16). Previous studies mainly considered blood donors screened for anti-HCV and rarely reported systematic data on liver histology. Our survey was conducted in a less highly selected population and might therefore better represent the burden of HCV in the general population. Limitations of our study include the uncertain generalizability to other geographic areas, the inclusion of only working adults and their relatives, and the lack of detailed information on risk factors in the screened population and of cofactors known to influence hepatitis C progression (use of alcohol or drugs; co-infection with hepatitis B virus or HIV) in the HCV-positive persons. Our data may underestimate the prevalence of HCV because of a healthy worker effect. Despite these limitations, our data indicate that progressive liver disease can be detected in a substantial proportion of apparently healthy, asymptomatic persons with HCV infection. Of note, almost 40% of individuals positive for HCV RNA, representing 0.70% of the general population cohort screened, had active inflammatory lesions or advanced fibrosis (as shown by liver biopsy results). These histologic features are considered the hallmark of progressive HCV infection and indications for antiviral therapies (16). Our findings would suggest that broader screening for HCV in the general population might be indi