Necroinflammatory Changes Research Articles

Rapidly progressive recurrent hepatitis C virus infection starting 9 days after liver transplantation

Early histological recurrence of hepatitis C after liver transplantation (LT) has a negative impact on patient and graft survival. We report a case of histological recurrence of HCV occurring in the second week after LT. A 75-year-old woman with chronic HCV and hepatocellular carcinoma underwent LT with an organ from a 75-year-old HCV-negative deceased donor. After an uneventful early postoperative period, an increase in the transaminases was observed, and on postoperative day 9 day, the alanine aminotransferase (ALT) was 673 IU/mL and aspartate aminotransferase (AST) 300 IU/mL, with normal alkaline phosphatase and bilirubin. Analysis of liver biopsy samples showed diffuse necroinflammatory changes with acidophilic bodies and concomitant mild acute cellular rejection. Subsequently there was a further increase in the transaminases, and on postoperative day 13, the AST rose to 445 IU/mL and ALT to 992 IU/mL. Repeat biopsy was performed, and analysis of the samples revealed lymphocytic portal inflammation with lymphoid aggregates and mild interface hepatitis, parenchymal necrosis, activation of sinusoidal lining cells, and mild steatosis. The biopsy sample was characteristic for HCV recurrence. The HCV RNA level was 84,000,000 copies/mL, and markers for other viral causes were not present. The patient became jaundiced and her course progressively worsened. She died on day 87 after transplantation. To our knowledge, this is the earliest reported case of histological recurrence of HCV after LT. It illustrates the importance of older donor and recipient age in the same patient as cofactors for early HCV recurrence and poor outcome.

Natural history of unexplained chronic hepatitis after liver transplantation

Unexplained chronic hepatitis (CH) in the adult liver allograft recipient is not uncommon, but its natural history and clinical significance is unknown. A retrospective study was undertaken of adult liver allograft recipients to determine the frequency and natural history of unexplained CH. We evaluated only those patients who had undergone >or=2 liver biopsies after 6 months and were grafted for indications where recurrent disease could be confidently excluded (alcoholic liver disease [ALD] in those who remained abstinent and fulminant hepatic failure [FHF] from drug reactions). Of 288 patients who were transplanted for ALD or FHF, 30 fulfilled the above criteria. CH was first diagnosed at a median of 15.25 months after transplantation. A total of 24 patients showed mild necroinflammatory changes, and 12 had mild or moderate fibrosis. Liver tests did not reflect the presence or degree of inflammation or fibrosis. After a median of 4 years, necroinflammatory scores were increased in 5; new or progressive fibrosis was noted in 13%; 3 had developed cirrhosis; and 5 developed clinical evidence of portal hypertension. Progressive fibrosis was associated with a high titer of anti-nuclear antibodies (>1:1600) and a portal tract plasma cell infiltrate. There was a trend for correlation between necroinflammatory activity and fibrosis stage, but this did not reach statistical significance (P = 0.06). Serum alkaline phosphatase (P = 0.012) and female gender of the donor (P = 0.033) were associated with progressive fibrosis. Unexplained CH is not uncommon in the liver allograft and may progress to established cirrhosis in a subgroup of patients transplanted for ALD or FHF. Standard liver tests do not reflect the extent of these changes, so protocol liver biopsies may be required to detect these changes. We recommend careful history and follow-up in these patients.

Metformin Prevents Alcohol-Induced Liver Injury in the Mouse: Critical Role of Plasminogen Activator Inhibitor-1

The biguanide drug metformin has recently been found to improve steatosis and liver damage in animal models and in humans with nonalcoholic steatohepatitis. The aim of the present study was to determine whether metformin also prevents steatosis and liver damage in mouse models of acute and chronic alcohol exposure. Acute ethanol exposure caused a >20-fold increase in hepatic lipids, peaking 12 hours after administration. Metformin treatment significantly blunted the ethanol effect by >60%. Although metformin is a known inducer of AMP kinase (AMPK) activity, the hepatoprotective property of metformin did not correlate with activation of AMPK or of AMPK-dependent pathways. Instead, the protective effects of metformin correlated with complete prevention of the upregulation of plasminogen activator inhibitor (PAI)-1 caused by ethanol. Indeed, a similar protective effect against acute alcohol-induced lipid accumulation was observed in PAI-1-/- mice. Hepatic fat accumulation caused by chronic enteral ethanol feeding was also prevented by metformin or by knocking out PAI-1. Under these conditions, necroinflammatory changes caused by ethanol were also significantly attenuated. Taken together, these findings suggest a novel mechanism of action for metformin and identify a new role of PAI-1 in hepatic injury caused by ethanol.

Tyrosinemia type I—Diagnostic issues and prenatal diagnosis

A fifteen-month-old boy, born to consanguineously married couple, presented with asymptomatic hepatomegaly. Investigations revealed mildly deranged liver functions, necroinflammatory changes and cirrhosis on liver biopsy, a markedly raised alpha feto protein and tyrosine levels in plasma and a generalized aminoaciduria. His diagnosis of hereditary tyrosinemia was established on findings of raised serum and urine succinylacetone and a deficient activity of fumaryl acetoacetate hydroxylase enzyme. Prenatal diagnosis of hereditary tyrosinemia was performed in a subsequent pregnancy in this family from India.

Nonalcoholic Steatohepatitis and the Metabolic Syndrome

Relatively recently, the liver has been recognized as a major target of injury in patients with insulin resistance or the metabolic syndrome. Insulin resistance is associated with fat accumulation in the liver, a condition called nonalcoholic fatty liver disease (NAFLD). Excess fat in the liver is not a benign condition. Some patients with NAFLD develop necroinflammatory changes in the liver called nonalcoholic steatohepatitis (NASH) and a fraction of those will develop cirrhosis. About 20% all adults have NAFLD and 2% to 3% of adults have NASH. Approximately 20% of patients with NASH are at risk for developing cirrhosis and subsequently dying from end-stage liver disease. The diagnosis of NASH requires a high index of suspicion, especially in obese patients over the age of 45 years who have diabetes, because these are the patients at greatest risk for developing cirrhosis. Treatment focuses on addressing the underlying insulin resistance with increased exercise and weight reduction.

Interobserver variation in the histopathological assessment of nonalcoholic steatohepatitis

Pathological assessment is considered as the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). However, there is no agreement of histological features required for the diagnosis of NASH. In the present study, eight experienced hepatopathologists read liver biopsy specimen slides of 21 cases of NASH and suspected NASH independently and were asked to assess histopathological features and render a diagnosis. Interobserver variation among pathologists was evaluated by kappa statistics. Significant, good agreement was present in evaluation of the extent of steatosis and grade of fibrosis. Agreement was moderate concerning the localization of steatosis, localization of fibrosis, and glycogen nuclei. Only slight or poor agreement was seen in evaluation of type of steatosis, ballooning, intralobular necroinflammatory change, portal inflammation, and degree of neutrophilic infiltration. Thus the agreement varied for histological variables. Significant, moderate agreement was seen in the diagnosis of NASH but agreement was poor in the diagnosis of suggestive NASH. The agreement for the diagnosis of NASH was not high as for the individual histological findings that were thought to be the basis of the diagnosis. In conclusion, some histological features in NASH might prove useful for the development of a standardized and reliable pathological diagnosis and scoring system.

Expression of hepatocyte growth factor and its receptor c-met, correlates with severity of pathological injury in experimental alcoholic liver disease

Expression of hepatocyte growth factor (HGF) and its receptor, c-met is up-regulated in various forms of liver injury. This study evaluated the relationship between HGF and c-met expression and pathological changes in experimental alcoholic liver disease. Rats (5 per group) were fed ethanol and a diet containing saturated fat corn oil or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in controls. In a second set of experiments, Kupffer cells, endothelial cells and hepatocytes were isolated from rats in each group. Pathological evaluation and analysis of HGF and c-met expression were performed in liver and the different cell types. Increased expression of HGF and c-met expression was detected in the liver of rats showing necroinflammatory changes. The Kupffer and endothelial cells were primarily responsible for the increase in HGF, c-met expression was seen only in hepatocytes. Thus, up-regulation of HGF and c-met occurred in the presence of the necrosis and inflammation suggesting that HGF may be acting to protect against liver injury or accelerate the regenerative process.

Specific ssDNA concentration in liver tissue as an index of apoptosis in hepatitis C virus-infected patients

To evaluate the activity of apoptosis in liver tissue and explore its possible association with hepatic necroinflammation and fibrosis as well as serum hepatitis C virus (HCV) load. The studied population included 50 chronic hepatitis C patients (20 women and 30 men, aged 18-66 years). HCV-RNA quantification was performed by two-step real-time quantitative RT-PCR method using the TaqMan technology (reagents of Applera Corporation firm, USA). The morphology of liver tissue was assessed descriptively and scored (necroinflammatory activity and fibrosis). The early apoptosis activity in liver tissue was examined by ssDNA apoptosis ELISA kit, (Chemicon, Germany). The correlation between apoptosis and fibrosis in liver tissue was observed. High intensification of apoptosis was proportional to the increase of fibrosis (ssDNA: 16.65 x 10(-5) microug/g; 12.71 x 10(-5) microg/g), however, this difference was not statistically significant (P>0.05). Activity of apoptosis in the liver tissue, expressed by ssDNA concentration did not depend on hepatic necroinflammatory changes, HCV-RNA viral load, ALT, and AST activity as well as prothrombin time and INR index. Fibrosis in the tissue is closely associated with early apoptosis in HCV-infected patients.

Acute pancreatitis

Acute pancreatitis is characterized by the occurrence of necroinflammatory changes in the pancreas. Three types of necrosis may be distinguished: (1) interstitial tissue necrosis, which subsequently may also involve acinar and ductal cells, (2) ductal necrosis, and (3) acinar necrosis. The first type of necrosis is autodigestive in nature and is typical of the most common forms of acute pancreatitis, which are associated with alcohol, bile duct disease, metabolic conditions, and other rare factors. Clinically, these types of pancreatitis may be either mild or severe (Atlanta classification). The mild form is also known as edematous pancreatitis, because there is edematous swelling of the pancreas combined with tiny foci of interstitial (fat) necrosis. Severe or necrotizing pancreatitis shows large areas of often hemorrhagic necrosis of the pancreatic and particularly the peripancreatic tissue. The ductal type of necrosis is rare and may be seen in pancreatitis associated with prolonged circulatory failure. The acinar type of necrosis is caused by infectious agents. Complications of acute pancreatitis, such as pseudocyst, bleeding, and infection, determine the course of the disease.

P0311 SEROLOGICAL AND HISTOPATHOLOGICAL FEATURES OF CHILDREN WITH AUTOIMMUNE HEPATITIS - OVERLAP SYNDROME

Introduction: Autoimmune hepatitis in children is chronic progressive disease, which can coexist with hepatotropic viral infection and primary sclerosing cholangitis. The specifity of circulating autoantibodies can be used to distinguish between type I (ANA< SMA) and type II (LKM). Aim of the study was to compare the antibody profile and histopathogical changes in autoimmune hepatitis, coexisting other diseases. Methods: 100 children with autoimmune hepatitis type I and 21 children with autoimmune hepatitis type II have been scored (IAHP Report 1999) according to the histologic criteria (interface hepatitis, bridging necrosis, biliary lesions, granuloma formations, Pearl’s stain for iron), serum biochemistry (ALT level, alkaline phosphatase), gamma globulin concentration including IgG, serum autoantibodies (ANA, AMA, LKM, AMA, pANCA), viral markers (antibodies against HCV, antiHbs, Hbe, Hbc, PCR for HCV). Results: At the time of diagnosis histology of the liver was characterised by necroinflammatory changes accompanied by fibrosis and/or cirrhosis. Viral infection occurred in 8 children (2 children were infected by HCV, 6 children by HBV), 6 children demonstrated features of primary sclerosing cholangitis, including 3 children with ulcerous colitis. Necroinflammatory changes in autoimmune and viral hepatitis were severe (according to Batts&Ludwig 1995); in HBV: predominantly lobular changes, lymph follicle formations; in HCV: steatosis and Fe accumulation in the hepatocytes and Kupffer cells. Histological features of biliary changes and mild cholestasis were seen in all cases of primary sclerosing cholangitis; granuloma formation in the portal tracts in 2 cases. All children were treated with Azathioprine and Prednisolone (without Interferone in 8 cases of viral hepatitis). IN PSC: mitovhondrial pattern in ANA HEP-2 = coarse granular in the cytoplasm; cytokeratin pattern = dots in the nucleus and fibrous cytokeratin structure of the cytoplasm. IN AIH type II 10 children were anti-HCV positive, but only 3 of them were RNA positive. Conclusion: Variable autoantibody level with false positivity for anti HCV occurs in autoimmune hepatitis (7 children with PCR negative for HCV) and overlapping syndrome (2 0children with PCR positive for HCV). Histopathological changes in overlap syndrome are not diagnostic, but suggestive for the aetiology. Overlap syndrome in children responded poorly to classical treatment of autoimmune hepatitis.

Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation.

Alcoholic liver disease is associated with a state of hepatic fatty acid overload. We examined the effect of ethanol and different types of dietary fat on the expression of mRNA for liver fatty acid binding protein (L-FABP), peroxisome proliferator-activated receptor-alpha (PPARalpha), and peroxisomal fatty acyl CoA oxidase (FACO). Four groups of rats (n = 5) were fed intragastrically, a liquid diet with or without ethanol (10-16 g/kg/day) for 4 weeks. Pair-fed controls received isocaloric amounts of dextrose. The source of fat was either corn oil or fish oil. Ethanolfed rats developed fatty liver, necrosis, and inflammation; the changes were more severe in the fish oil-ethanol (FE) rats. PPARalpha mRNA levels were not different between groups, although there was a trend toward increased levels in ethanol-fed rats. We calculated L-FABP/PPARalpha and FACO/PPARalpha ratios as a measure of FACO and L-FABP up-regulation relative to PPARalpha expression. Both FACO/PPARalpha and L-FABP/PPARalpha ratios were significantly decreased in FE rats. However, only L-FABP/PPARalpha was decreased in corn oil plus ethanol rats. Also, the level of L-FABP/mRNA correlated inversely with the degree of fatty liver in ethanol-fed rats. Since expression of PPARalpha response genes was impaired in ethanol-fed rats, we determined whether activation of PPARalpha would normalize the PPARalpha response and prevent the pathological changes in ethanol-fed rats. Treatment with clofibrate, a PPARalpha-activating ligand, led to a marked decrease in fatty liver and complete abrogation of necroinflammatory changes in FE rats. Also, nuclear factor kappaB activation and up-regulation of tumor necrosis factor-alpha and cyclooxygenase-2 was also abolished in clofibrate-treated rats. We conclude that adaptive gene regulation of FACO and L-FABP by PPARalpha is impaired in ethanol-fed rats and that treatment with clofibrate, a PPARalpha ligand, prevents alcohol-induced pathological liver injury, possibly by reversing the above changes.

Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice.

In alcoholic steatohepatitis, hepatic microvascular changes have pathogenic significance for hepatocellular function, perisinusoidal fibrosis, and portal hypertension. It is unclear whether similar changes occur in other forms of steatohepatitis. We therefore examined whether hepatic microvascular dysfunction occurs in fibrosing steatohepatitis induced by feeding mice a high-fat methionine- and choline-deficient (MCD) diet. Using in vivo microscopic--as well as histological and electron microscopic--methods, together with measurements of alanine aminotransferase (ALT), lipid content, and oxidative stress, hepatic microvascular structure and function were studied in relation to inflammatory and fibrotic changes during evolution of steatohepatitis. At 3 weeks of MCD diet intake, serum ALT was elevated and hepatic steatosis was pronounced. By 5 weeks, necroinflammatory change was noteworthy, and by 8 weeks perisinusoidal fibrosis was established. Compared with mice receiving the high-fat diet supplemented with methionine and choline (controls), levels of hepatic lipid and lipoperoxides were elevated at 3 weeks and beyond. The numbers of perfused sinusoids were significantly reduced at each time point. Enlarged, fat-laden hepatocytes together with perivascular fibrosis narrowed sinusoidal lumens, making vessels tortuous and impairing sinusoidal perfusion. At 3 and 5 weeks, MCD diet caused significant increases in phagocytic activity of macrophages in centrilobular regions. By 8 weeks, macrophage activity was less striking, but the number of leukocytes adherent to the sinusoidal lining had increased 5-fold compared with controls. In conclusion, these results are consistent with a dysfunctional hepatic microvasculature. Thus, microvascular changes may contribute to progressive liver injury in metabolic and toxic forms of steatohepatitis.

Treatment of Hepatitis C Virus in the Liver Transplant Recipient.

Significant necroinflammatory and/or fibrotic histologic changes should prompt consideration of antiviral therapy in liver transplant recipients with chronic hepatitis C. Depending on the patient, consideration of lower-dose pegylated interferon initially, with an increase to standard doses over the course of 1 month, may improve patient compliance and tolerance. The use of growth factors to prevent anemia and leukopenia is encouraged. Liver transplant recipients should be treated for at least 1 year, until data are available on optimal duration of therapy in non-genotype 1 patients in this patient subpopulation.

Combined antiviral options for the treatment of chronic hepatitis C

In the absence of antiviral treatment, chronic hepatitis C virus (HCV) infection is a liver disease characterized by the development of necroinflammatory changes and progressive liver fibrosis, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma (HCC). The approval of ribavirin in combination therapy regimens with interferon (IFN) dramatically improved therapy. Another advance was the introduction of pegylated IFNs, which allow a once-weekly subcutaneous administration and show more favorable pharmacokinetics and greater efficacy. Two forms are available: pegylated IFN alpha-2b (12 kDa) (1.5 μg/kg) and pegylated IFN alpha-2a (40 kDa) (fixed dosage of 180 μg). Ribavirin is administered orally, at doses ≥10.6 mg/kg, resulting in higher sustained virological responses (SVR) than IFN monotherapy. The highest SVR rates are attained with pegylated IFNs in combination with ribavirin. Factors associated with treatment outcome include HCV genotype, viral load, body weight, age, cirrhosis or bridging fibrosis, coinfection with HIV or hepatitis B virus, and treatment adherence and tolerance. Currently, the main therapeutic challenges ahead are: (a) the dosage optimization of pegylated IFNs and ribavirin according to the patients’ characteristics; and (b) to evaluate the efficacy and safety of this combination therapy for difficult-to-treat patients, such as nonresponders, cirrhotics, transplant recipients, renal disease patients or those coinfected with HIV.

Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis

Background/Aims : We explored the involvement of cell types, cytokines and lipid peroxidation in a rat dietary model of fibrosing steatohepatitis. Methods : Male rats were fed a high fat diet deficient in methionine and choline (MCD) for up to 17 weeks. Whole liver, hepatocytes and non-parenchymal cells were analysed for reduced glutathione (GSH) levels, products of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), liver injury, and fibrosis. Results : MCD diet-fed rats developed hepatic steatosis at week 2 and focal necroinflammatory change by week 5, while pericellular fibrosis evolved and progressed between weeks 12 and 17. Collagen α 1(1) gene expression was upregulated by week 5 and increased fivefold by week 17. Stellate cells were the unique source of collagen gene expression. TIMP-1 and -2 were increased at week 12. Livers of MCD diet-fed rats exhibited lowered levels of GSH and elevated TBARS. Hepatocytes were the source of lipid peroxidation, and mRNA levels for TGFβ1 were increased only in this cell type. Conclusions : The MCD model of ‘fibrosing steatohepatitis’ replicates the histologic features of human steatohepatitis, and the sequence of steatosis, inflammatory cell injury and fibrogenesis. The temporal sequence is consistent with a concept for involvement of oxidative injury in inflammatory recruitment and pathogenesis of hepatic fibrogenesis.

Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin

To assess the efficacy and safety of maintenance therapy with ribavirin alone in chronic hepatitis C, 108 patients were treated with the combination of interferon alfa and ribavirin for 24 weeks; those who failed to have a virologic response were offered enrollment in a randomized, double-blind, controlled trial of ribavirin (1,000-1,200 mg daily) versus placebo for the subsequent 48 weeks. Patients were monitored at regular intervals with symptom questionnaires, serum aminotransferase levels, hepatitis C virus (HCV) RNA levels, and complete blood counts and underwent liver biopsy at the completion of therapy. Among 108 patients, 50 were still HCV RNA positive after 24 weeks of treatment, of whom 34 agreed to be randomized to continue either ribavirin monotherapy or placebo. Among 17 patients who received placebo, there was no overall improvement in symptoms, serum alanine aminotransferase (ALT) levels, HCV RNA levels, or hepatic histology. Among the 17 patients who received ribavirin, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels, and hepatic fibrosis scores were not changed significantly from baseline. Responses to ribavirin seemed to be categorical, such that 8 patients (47%) had definite improvement in liver histology. Patients with improved histology had improvements in serum ALT levels both on combination therapy and after switching to ribavirin monotherapy. In conclusion, continuation of ribavirin monotherapy may maintain serum biochemical improvements that occur during interferon-ribavirin combination therapy in some patients and that these improvements are often associated with decreases in necroinflammatory changes in the liver. Whether these improvements will ultimately result in prevention of progression of hepatitis C requires further study. (H epatology 2003;38:66-74.)

Continued Lamivudine Therapy in Patients with Chronic Hepatitis B

From September 1995 through April 2002, 286 patients with chronic hepatitis B were started on lamivudine at the Toranomon Hospital in Tokyo, Japan, and most of them continued with it. At present, 16 patients received lamivudine for 5 years, 7 of whom for 7 years or longer. YMDD mutants increased gradually and developed in 69% of them during the 7 years on lamivudine. Biochemical and virological responses were achieved in 9 of the 16 patients (56%) at 5 years, and in 4 of the 7 patients (57%) at 7 years. Histological assessments were performed at 3 years in the 16 patients and further at 4 and 7 years in the 7 patients. Necroinflammatory changes improved remarkably with a decrease in the total histological activity score from 11.3 ± 3.0 to 4.1 ± 1.7 (p < 0.0001) at 3 years in the 16 patients. Histological improvements continued in 4 of the 7 patients (57%) at 7 years on lamivudine, while the pathology was unchanged in 2 patients (29%) and aggravated in the remaining 1 patient (14%). Severe acute exacerbation of hepatitis developed in 1 patient, who received additional interferon-α therapy to cope with it. Based on my experience, the continuation of lamivudine in patients with chronic hepatitis B benefits approximately two thirds of them with persistent virological and biochemical responses accompanied by histological improvements. Breakthrough hepatitis induced by YMDD mutants along the way in a small number of patients needs to be diagnosed promptly by regular monitoring for transaminases and, if it develops, it can be treated with interferon or other antiviral agents.

Clinical trial results of peginterferons in combination with ribavirin.

Of the large number of patients chronically infected with hepatitis C virus (HCV), only about one third have progressive liver disease, and will eventually develop cirrhosis and hepatocellular carcinoma. These are the patients for whom effective antiviral treatment is most needed. Therapy is currently recommended for patients with chronic hepatitis C who have abnormal alanine aminotransferase (ALT) levels, detectable hepatitis C virus ribonucleic acid (HCV RNA) in the blood, and significant necroinflammatory changes and/or fibrosis on liver biopsy. The current gold standard in terms of treatment efficacy is the combination of peginterferon (PEG-IFN) and ribavirin. The overall sustained virological response rate (SVR) with these regimens is 54 to 61% following 48 weeks of therapy. Patients with genotype 1 infection have a 42 to 51% likelihood of response to 48 weeks of therapy. Those with genotypes 2 or 3 infection will respond to 24 weeks of therapy in 78 to 82% of cases. These SVR rates are 5 to 10 percentage points higher in all patient groups than in those obtained with standard doses of interferon (IFN) and ribavirin. Retreatment of nonresponders to standard IFN monotherapy using PEG-IFN and ribavirin has achieved SVR rates of 34 to 40%. Retreatment of patients who relapsed after IFN monotherapy has resulted in an SVR rate of about 60%. A SVR after retreatment of relapsers and nonresponders with PEG-IFN and ribavirin is more likely in patients previously treated with IFN monotherapy, those with HCV genotypes 2 or 3, patients with low viral load (<2 million copies/mL), and individuals who had a significant decrease in HCV RNA levels during the initial treatment. The potential benefits of long-term anti-HCV suppressive therapy in nonresponders are currently under investigation.

Histopathological study of chronic hepatitis B and C: a comparison of two scoring systems

Background/Aims: Several histological scoring systems are used to evaluate chronic viral hepatitis. This study was undertaken to determine the correlation between the Ishak system (modified histological activity index, HAI) and the METAVIR system, in Indian patients with chronic viral hepatitis.Methods: Liver biopsies from 127 patients with chronic viral hepatitis B or C were examined, and scored using the Ishak and METAVIR systems, and weighted kappa analysis of correlation was done. Correlation of necroinflammatory activity with serum transaminase levels was analyzed, and prevalence of specific histological features compared in hepatitis B virus (HBV) and HCV biopsies.Results: HBV infection accounted for 64.6% of cases, and HCV for 35.4%; 91.3% of patients had minimal or mild hepatitis. The necroinflammatory scores of the Ishak and METAVIR systems correlated moderately well (weighted kappa 0.627), while there was excellent correlation with regard to fibrosis (weighted kappa 0.998). Similar concordance was found when HBV and HCV cases were analyzed separately. HAI showed poor correlation with serum transaminases (weighted kappa 0.21). Micronodular cirrhosis, lymphoid aggregates, bile duct damage, bile ductular proliferation and steatosis were significantly more common in HCV biopsies compared to HBV.Conclusions: Concordance between Ishak and METAVIR scoring systems is good for necroinflammatory change, and excellent for fibrotic change.

Hepatitis C in childhood

The approach of a pediatric hepatologist in managing children with hepatitis C virus (HCV) differs from adult practice, because the pediatric hepatologist is dealing with the beginning of a chronic illness in which long-term outcomes will not occur for 20 or 40 years, and it is not possible to predict in the early stages of the infection which patients have a more sinister prognosis. The prevalence of chronic HCV in children is low, but varies between different countries in the Asia-Pacific region. In most countries, screening of blood products for HCV has virtually eliminated the risk of post-transfusion HCV, so that in Australia children aged less than 11 years will not have acquired HCV from blood transfusion or extracorporeal membrane oxygenation. The risk of perinatal transmission of this virus is only about 6%, but this remains virtually the only source of HCV transmission for children in most countries. While available data are limited, mild histological changes are present in the majority of children with hepatitis C, and cirrhosis is rare. Unfortunately, long-term natural history studies of the course of HCV infection in children have not been reported. Individual decisions on antiviral treatment are more difficult in childhood, not because the treatment is any less effective or because of the severity of side-effects (which tend to be less severe than for adults), but because the long-term outcome of infection is unclear. At present, treatment should be confined to those with significant hepatic fibrosis and continued moderate to severe necroinflammatory change. Measures to prevent HCV infection in childhood center on whether, as recently suggested, elective cesarean section may reduce the risk of transmission. Despite the presence of HCV-RNA in some breast milk samples, there is no evidence that breast-feeding confers any risk of HCV infection.