Maria Guido

Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease

BACKGROUND/AIMS In chronic viral hepatitis, liver biopsy is performed for assessing disease activity and fibrosis. In this study, we evaluated the impact of the size of liver biopsy on the grading and staging. METHODS We selected 161 liver biopsies from patients with chronic types B and C hepatitis on the basis of their length (> or =3 cm) and width (1.4 mm). Ishak scoring system was used for grading and staging. The score was blindly repeated reducing the length of the specimen from > or =3 to 1.5 cm and to 1 cm long and width from 1.4 to 1 mm. RESULTS Reducing the length of the biopsy led to an increase of cases with mild grades: 49.7% in > or =3 cm, 60.2% in 1.5 cm and 86.6% in 1 cm long specimens (P<0.001). Similarly, cases staged as having mild fibrosis significantly increased in the shorter specimens: 59% in > or =3 cm, 68.3% in 1.5 cm and 80.1% in 1 cm long specimens (P<0.001). As for the width, both grade and stage were significantly underscored in the 1 mm samples, regardless of their length. CONCLUSIONS Liver biopsy size strongly influences the grading and staging of chronic viral hepatitis. The use of fine needles should be discouraged in this setting.

Pathologic diagnosis of early hepatocellular carcinoma : a report of the international consensus group for hepatocellular neoplasia

Advances in imaging techniques and establishment of surveillance protocols for high-risk populations have led to the detection of small hepatic nodules in patients with chronic liver diseases, particularly those with cirrhosis or chronic hepatitis caused by hepatitis B or C viruses. These nodules, comprising a broad range of diagnostic entities—some benign and some with malignant potential—are currently defined histologically, and their clinical management often depends on the ability to make a reliable histologic diagnosis. Evidence accumulated in the last two decades strongly favors the existence of a sequence of events in hepatic nodules that precedes the emergence of hepatocellular carcinoma (HCC),1-10 and these lesions are recognized as precursors of HCC. However, from the beginning of their recognition, there has been considerable confusion concerning nomenclature and diagnostic approaches to these hepatic nodules. To clarify these issues, an International Working Party (IWP) of the World Congresses of Gastroenterology proposed a consensus nomenclature and diagnostic criteria for hepatocellular nodular lesions in 1995.11 The IWP classified nodular lesions found in chronic liver disease into large regenerative nodule, lowgrade dysplastic nodule (L-DN), high-grade dysplastic nodule (H-DN), and HCC; this nomenclature has been widely adopted. In addition, the IWP introduced the concept of dysplastic focus as a cluster of hepatocytes with features of early neoplasia (in particular small cell change or iron-free foci in a siderotic background) measuring less than 0.1 cm, and defined small HCC as a tumor measuring less than 2 cm. More recent studies support the division of small HCC into two clinico-pathological groups that have been termed early HCC and progressed HCC. Early HCC has a vaguely nodular appearance and is well differentiated. Progressed HCC has a distinctly nodular pattern and is mostly moderately differentiated, often with evidence of microvascular invasion.12 Early HCC has a longer time to recurrence and a higher 5-year survival rate compared with progressed HCC.13 Small lesions with malignant potential have only subtle differences from the surrounding parenchyma, making them difficult to assess reproducibly. Differences in the application of diagnostic criteria between Western and Eastern pathologists has been a persistent difficulty in research and clinical management of these lesions.14 In order to obtain a refined and up-to-date international consensus on the histopathologic diagnosis of nodular lesions, such as dysplastic nodules and early HCC, the International Consensus Group for Hepatocellular Neoplasia (ICGHN) was convened in April 2002 in Kurume, Japan. The group has met several times up to July 2007 under the auspices of the Laennec Liver Pathology Society. The ICGHN is currently comprised of 34 pathologists and two clinicians from 13 countries. It includes most members of the original IWP who are still active and all the participants from the first ICGHN meeting. This consensus document summarizes the results of our meetings.

A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma.

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) recurs in approximately 70% of cases after resection. Vascular invasion by tumor cells can be classified as gross or microscopic (microvascular invasion [mVI]) and is a risk factor for recurrence. We examined a large cohort of patients with HCC who were treated by resection to identify features of mVI that correlated with recurrence and survival. METHODS We reviewed the records of all HCC resections performed at the Mount Sinai School of Medicine between January 1990 and March 2006 to identify those with mVI, established by histologic analysis. The numbers and sizes of vessels invaded, invasion of a vessel with a muscular wall, distance from the tumor, and satellite nodules were recorded. RESULTS Of the 384 patients who underwent resection for HCC, 131 (34.1%) met the entry criteria. The median follow-up period was 28.9 months. There were 68 recurrences and 54 deaths. In multivariate analysis, invasion of a vessel with a muscular wall predicted recurrence (hazard ratio, 1.8; P = .02), and invasion of a vessel with a muscular wall (hazard ratio, 2.2; P = .018) and invasion of a vessel that was more than 1 cm from the tumor (hazard ratio, 2.1; P = .015) predicted survival. A risk score that assigned points for the presence of each variable correlated with recurrence (P = .028) and survival (P < .0001). CONCLUSIONS A novel classification system that includes invasion of a vessel with a muscular wall and invasion of a vessel that is more than 1 cm from the tumor can accurately predict risk of recurrence and survival of patients with mVI after resection of HCC.

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

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 Course of Chronic Hepatitis C in Children: From Viral Clearance to End-Stage Liver Disease

BACKGROUND & AIMS The natural course of chronic hepatitis C (CHC) in children is not well understood. The aim of this study was to assess the long-term course of CHC in a large sample of otherwise healthy children. METHODS From 1990 to 2005, 504 consecutive antihepatitis C virus (HCV)-positive children were enrolled at 12 centers of a national observatory and were followed up retrospectively/prospectively. RESULTS Putative exposure was perinatal in 283 (56.2%) cases, parenteral in 158 (31.3%), and unknown in 63 (12.5%). At baseline, 477 (94.6%) cases were HCV RNA seropositive, 118 (24.7%) of which were treated with standard interferon alpha. Ten years after putative exposure, the outcome in 359 HCV RNA-positive, untreated patients was (1) undetectable viremia in 27 (7.5%) (by Cox regression analysis, spontaneous viral clearance was independently predicted by genotype 3 [hazard ratio 6.44; 95% confidence interval: 2.7-15.5]) and (2) persistent viremia in 332 (92%) cases. Six of these 332 cases (1.8%) progressed to decompensated cirrhosis (mean age, 9.6 years). This latter group included 5 Italian children perinatally infected with genotype 1a (4 of the mothers were drug users). Thirty-three (27.9%) treated patients achieved a sustained virologic response. CONCLUSIONS Over the course of a decade, few children with chronic HCV infection cleared viremia spontaneously, and those who did were more likely to have genotype 3. Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a. Children with such features should be considered for early treatment.

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

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.)

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

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.

Chronic hepatitis C virus infection in childhood: clinical patterns and evolution in 224 white children.

The characteristics and evolution of hepatitis C virus (HCV) infection were retrospectively investigated in a study of 224 HCV RNA-seropositive white children who were consecutively recruited at 7 European centers in 1980-1998. At presentation, all patients were positive for antibodies to hepatitis C virus, 87% were asymptomatic, and 48% had alanine aminotransferase (ALT) levels that were < or =2 times the upper limit of the range considered to be normal. Of 200 children followed for 1-17.5 years (mean follow-up +/- standard deviation [SD], 6.2+/-4.7 years), only 12 (6%) achieved sustained viremia clearance and normalization of the ALT level. In 92 revised liver biopsy specimen analyses, the mean fibrosis score (+/-SD) was 1.5+/-1.3 for children <15 years of age and 2.3+/-1.2 for children > or =15 years of age (range, 0-6 years; P<.01). Pediatric HCV infection is usually mild, but few patients, especially those who are perinatally infected, clear viremia in the medium-term follow-up. Conversely, the higher rates of fibrosis observed in older patients suggest the possibility of an insidious progression of HCV-associated liver disease.

Chronic Hepatitis C in Children: The Pathological and Clinical Spectrum

BACKGROUND & AIMS Apart from the high-risk groups, the pathology of chronic hepatitis C in children is not well known. The aim of this study was to investigate the morphology of chronic hepatitis C in children without any underlying systemic disease and to evaluate its relationship to clinicovirological factors. METHODS Liver biopsy specimens from 80 children positive for antibody to hepatitis C virus were evaluated using a semiquantitative scoring system. RESULTS Chronic hepatitis was mild in most cases but had high-grade activity in 17 children (21.2%). A significant association was found between the grade of focal necrosis and alanine transaminase levels (P < 0.003). Fibrosis was absent in 22 cases (27.5%), mild in 44 (55%), and moderate in 13 (16.2%). Only 1 patient had cirrhosis. A significant relationship was detected between fibrosis scores and (1) duration of disease (P < 0.03); (2) portal inflammation (P < 0. 002); and (3) interface hepatitis (P < 0.003). CONCLUSIONS In otherwise healthy children, chronic hepatitis C is a morphologically mild disease in most cases. Fibrosis increases with the duration of disease, suggesting that end-stage disease may develop in young adulthood. Alanine transaminase levels correlate with intralobular focal necrosis but not with other lesions. In this respect, liver biopsy retains its importance in the management of chronic hepatitis C in children.

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.