Mild Chronic Hepatitis Research Articles

Peginterferon-α and ribavirin have been recommended for the treatment of mild chronic hepatitis C,

Peginterferon-α and ribavirin have been recommended for the treatment of mild chronic hepatitis C,

Evaluation of Cardiac Function by Tissue Doppler Imaging in Children With Chronic Hepatitis

Pathoanatomic changes in cirrhosis result in impaired ventricular filling and diastolic dysfunction and were named as cirrhotic cardiomyopathy. However, cardiac functions have not been studied in patients with chronic hepatitis. We hypothesized that such patients might have subclinical ventricular dysfunction, detectable by tissue Doppler echocardiography and related to the severity of hepatic inflammation and fibrosis. We studied 63 clinically stable patients, 27 patients with mild chronic hepatitis (group 1), 22 patients with moderate chronic hepatitis (group 2) and 14 patients with severe chronic hepatitis (group 3) according to the scoring system of Knodell, and 36 age-matched healthy subjects. Patients with severe chronic hepatitis had impaired right ventricular diastolic function. The early diastolic velocity of the tricuspid valve annulus was lower in patients from group 3 than in healthy subjects (P < 0.001). Patients in group 3 had a greater isovolumic relaxation time (P < 0.001), indicating right ventricular diastolic dysfunction. Comparing group 3 with the healthy subjects, the ratio of peak early myocardial tissue velocity and peak late (or atrial) myocardial tissue velocity was significantly decreased (P < 0.001), at 1.4 (0.7) and 1.9 (0.7), respectively. There was also a slightly lower peak early myocardial tissue velocity and peak late (or atrial) myocardial tissue velocity ratio and a slightly longer isovolumic relaxation time in patients from group 2 than in healthy subjects (P < 0.05). We detected subclinical dysfunction of the right ventricle in children with chronic hepatitis in whom hepatic inflammation and fibrosis is prominent. Tissue Doppler echocardiography provides a quantifiable indicator useful for detection and monitoring of disease progression.

Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation

To determine whether combined therapy with interferon-alpha and ribavirin was more effective and cost-effective than no treatment for patients with mild chronic hepatitis C. A multicentre, randomised, controlled, non-blinded trial assessed the efficacy of combination therapy. A Markov model used these efficacy data combined with data on transition probabilities, costs and health-related quality of life (HRQoL) to assess the lifetime cost-effectiveness of the intervention. A multicentre NHS setting. Treatment-naive, adult patients with histologically mild chronic hepatitis C (Ishak necroinflammatory scores <4 and fibrosis scores <3 on liver biopsy). Patients were randomised to receive interferon-alpha and ribavirin for 48 weeks or no treatment (control). The primary outcome measure was the proportion of patients having a sustained virological response (SVR), measured at 6 months after cessation of therapy. Secondary outcome measures were: the ability of early phase kinetics to predict the eventual outcome of treating mild disease; HRQoL measured using the Short Form 36 and EuroQol (5 Dimensions) questionnaires, and the cost per quality-adjusted life-year (QALY) of interferon-alpha and ribavirin for mild disease compared with no treatment. In the treatment group, 32 out of 98 patients (33%) achieved an SVR. Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18% versus 49%, p = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved an SVR. HRQoL fell during treatment and rose with treatment cessation. For patients having an SVR there were modest improvements in HRQoL at 6 months post-treatment. The mean cost per QALY gained was 4535 pounds sterling for 40-year-old patients with genotype non-1 and 25,188 pounds sterling for patients with genotype 1. For patients with genotype 1 aged 65, providing interferon-alpha and ribavirin for mild disease led to fewer QALYs gained, and a mean cost per QALY of 53,017 pounds sterling. The model using efficacy estimates from the literature, showed that the cost per QALY gained from providing pegylated interferon alpha-2b and ribavirin at a mild stage rather than a moderate stage was 7821 pounds sterling for patients with genotype non-1 and 28,409 pounds sterling for patients with genotype 1. Based on the evidence collected in this study, interferon-alpha and ribavirin treatment for mild chronic hepatitis C patients is in general cost-effective at the 30,000 pounds sterling per QALY threshold previously used by policy-makers in the NHS. For patients with chronic hepatitis C aged 65 or over with genotype 1, antiviral treatment at a mild stage does not appear cost-effective. Further research is required on the cost-effectiveness of pegylated interferon and ribavirin, in particular the intervention's long-term impact on HRQoL and health service costs requires further evaluation. Further research is also needed to develop predictive tests, based on pharmacogenomics, that can identify those cases most likely to respond to antiviral therapy. Liver biopsy before treatment no longer appears justified apart from for older patients (aged 65 or over) with genotype 1. However, further research should monitor the impact this strategy would have on costs and outcomes.

Longitudinal Long-term Follow-up Study of Children with Vertically Acquired Hepatitis C Virus Infection

Seventeen children with vertically acquired hepatitis C virus (HCV) infection were followed from birth for a mean of 104 months. Alanine aminotransferase (ALT) levels were increased significantly at 3 and 6 months of age but were stable thereafter. HCV polymerase chain reaction was positive at 3 months in 16 patients and at 12 months in one patient. Viral load remained stable during follow-up at a mean value of 5.4 +/- 0.4 log10. Mild chronic hepatitis was the most common histopathological feature on liver biopsy, occurring in six of the seven children biopsied at a mean age of 4.0 +/- 2.4 years. Genotype did not seem to be related to the type of liver involvement. The results of this study suggest that vertically acquired HCV infection has a benign course in children, despite the presence of viraemia and persistent alterations in ALT levels.

Bone marrow transplantation in patients with thalassemia

In this study we report the long-term results of bone marrow transplantation (BMT) in 113 patients (M 56, F 57) with thalassemia major (TM) who were given 117 transplants from HLA identical sibling donor between May 1983 and September 2005. The median age was 9.09 years (0.11-28.11). The median number of transfusions given before BMT was 136 (2-900). The pretransplant liver biopsy performed in 78 patients showed: chronic persistent hepatitis in 35, mild chronic active hepatitis (CAH) in 10, moderate CAH in 23, severe CAH in 10. All patients received the same preparative therapy consisting of busulphan (BU) (13-14 mg/kg) and cyclophosphamide (200 mg/kg), preceded by an hypertransfusion regimen for 2-3 weeks. For graft-versus-host disease (GvHD) prophylaxis, 38 patients were given cyclosporine (CSA) alone and 75 received CSA and short course methotrexate. The median number of transplanted nucleated cells was 4.8 × 108/kg (2.3-10.1). Marrow engraftment was evident in 111 patients. The median time to achieve 0.5 × 109/L neutrophils and 50 × 109/L platelets was 19 (11-37) and 24 (10-55) days respectively. Four patients had an autologous reconstitution and are currently alive under transfusion therapy. The probability of graft rejection was 6.6%. The actuarial probability of developing acute GvHD grade II-IV and cumulative chronic GvHD was 21% and 17% (7% limited, 10% extensive) respectively. Transplant related mortality was 8.8%. Ten patients died for BMT related causes: pneumonia in 4, heart failure in 3, encephalopathy in 2, aGvHD in 1. Two late deaths occurred, one for septic shock 54 months post-BMT and one for parotitis carcinoma 138 months after BMT. As of October 2005, 101 patients are alive and 97 of them are cured after a median follow-up of 158 months (1-269). The 10-year actuarial probability of survival and disease-free survival (DFS) was 91% and 87% respectively. In multivariate analysis, no adverse risk factor affecting survival and DFS was identified among recipient-donor age and sex, number of pre-BMT transfusions, level of ferritin, type of CAH, grade of liver fibrosis, serum GPT level, HBV and HCV serology, dose of BU, type of GvHD prophylaxis, marrow cell dose. This study confirms the feasibility of curing the majority of patients with TM by BMT. In this study we report the long-term results of bone marrow transplantation (BMT) in 113 patients (M 56, F 57) with thalassemia major (TM) who were given 117 transplants from HLA identical sibling donor between May 1983 and September 2005. The median age was 9.09 years (0.11-28.11). The median number of transfusions given before BMT was 136 (2-900). The pretransplant liver biopsy performed in 78 patients showed: chronic persistent hepatitis in 35, mild chronic active hepatitis (CAH) in 10, moderate CAH in 23, severe CAH in 10. All patients received the same preparative therapy consisting of busulphan (BU) (13-14 mg/kg) and cyclophosphamide (200 mg/kg), preceded by an hypertransfusion regimen for 2-3 weeks. For graft-versus-host disease (GvHD) prophylaxis, 38 patients were given cyclosporine (CSA) alone and 75 received CSA and short course methotrexate. The median number of transplanted nucleated cells was 4.8 × 108/kg (2.3-10.1). Marrow engraftment was evident in 111 patients. The median time to achieve 0.5 × 109/L neutrophils and 50 × 109/L platelets was 19 (11-37) and 24 (10-55) days respectively. Four patients had an autologous reconstitution and are currently alive under transfusion therapy. The probability of graft rejection was 6.6%. The actuarial probability of developing acute GvHD grade II-IV and cumulative chronic GvHD was 21% and 17% (7% limited, 10% extensive) respectively. Transplant related mortality was 8.8%. Ten patients died for BMT related causes: pneumonia in 4, heart failure in 3, encephalopathy in 2, aGvHD in 1. Two late deaths occurred, one for septic shock 54 months post-BMT and one for parotitis carcinoma 138 months after BMT. As of October 2005, 101 patients are alive and 97 of them are cured after a median follow-up of 158 months (1-269). The 10-year actuarial probability of survival and disease-free survival (DFS) was 91% and 87% respectively. In multivariate analysis, no adverse risk factor affecting survival and DFS was identified among recipient-donor age and sex, number of pre-BMT transfusions, level of ferritin, type of CAH, grade of liver fibrosis, serum GPT level, HBV and HCV serology, dose of BU, type of GvHD prophylaxis, marrow cell dose. This study confirms the feasibility of curing the majority of patients with TM by BMT.

Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active hepatitis

The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy. Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transaminases was reported spontaneously and the other patients were treated in a clinical study. Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3 +/- 19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes. Liver function tests should be regularly followed on pegvisomant treatment. Biliary complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.

Fibrosis progression in initially mild chronic hepatitis C

The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 +/- 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 +/- 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow-up parameters. Sixty-four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (DeltaF/year) was associated with age (P < 0.0001), baseline and follow-up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years and advanced fibrosis/cirrhosis develops in one-third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C.

Candidates for therapy: HBV

Hepatitis B may cause liver damage ranging from mild chronic hepatitis to severe active hepatitis, cirrhosis and hepatocellular carcinoma. HIV and HBV co-infection is more likely to lead to lower rates of HBeAg seroconversion, and higher HBV DNA concentrations. Immune restitution may lead to more severe hepatitis. The timing of acquisition of HBV versus HIV will have a bearing on considerations of treatment. Patients may have acquired HIV super-infection of chronic hepatitis B, HBV super-infection of HIV; alternatively, reactivation of hepatitis B may occur in a HIV positive patient, or the patient may be co-infected at diagnosis. The patient may be naïve or experienced or have resistant (HBV) at the time of superinfection. The risk of death is higher in patients with co-infection compared to those with HBV alone. The goals of therapy for hepatitis B are to prevent progression of the disease. If HBV replication can be suppressed, the accompanying reduction in histological activity lessens the risk of progression. Patients may request treatment to reduce infectivity, and this is relevant in co-infected patients. HBV has little effect on HIV or the effect of treatment on HIV; however, HIV, and HIV treatment profoundly affects the natural history of HBV. Therefore, it is usually important to target treatment of HBV to alter the outcome and take into account the impact of HBV treatment on HIV. Special concepts of treatment are applicable in HIV and HBV co-infected patients.

Quality of life and cost-effectiveness of anti-HCV therapy in HIV-infected patients

Quality of life studies in chronic hepatitis C using specific questionnaires have been performed in mono-infected patients; however, these studies have just begun in HIV-HCV co-infected patients. The questionnaires used in mono-infected patients are not well adapted for co-infected patients and need to be redesigned. Typically, co-infected patients have multiple symptoms that may be attributable to HIV, to HCV, to a combination of both diseases or even to side effects related to drug therapy. These patients usually need substitutive therapy to manage side effects related to HCV therapy, particularly anaemia, leukopenia and depression. There are no cost-effectiveness studies published on the current HCV standard therapy with pegylated interferon and ribavirin. However, there is some research on the old standard interferon and ribavirin, which shows that HCV therapy is cost-effective. Cost-effectiveness studies in co-infected patients will have to take into account variables that do not affect mono-infected patients, such as the different levels of CD4, the increase in the fibrosis progression rate and the use of other expensive drugs for the management of side effects. Currently, the literature does not provide adequate information on the effect of HCV infection on the quality of life of HIV-HCV co-infected patients or the most cost-effective HCV therapy.

Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany—a 25-year multicenter study

The natural course of the hepatitis C virus genotype 1b (HCV-1b) infection is still unclear but important for therapeutic decisions. There are few unbiased long-term follow-up studies with known dates of infection. Between August 1978 and March 1979, 14 HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany. We reexamined 1980 women, representing 70% of the total cohort of 15 centers. After application of the contaminated anti-D, 93% of the recipients developed an acute hepatitis C. After 25 years, 86% of the 1833 affected women still tested positive for hepatitis C virus antibodies and 46% for HCV RNA. Only nine (0.5%) had overt liver cirrhosis, 30 women (1.5%) developed pre-cirrhotic stages and one HCC was diagnosed. Ten (0.5%) died of HCV related complications, half of these related to additional comorbidity. In the last 5 years, a continuous, but low increase of fibrotic scores was observed. Young women without comorbidity may clear HCV (1b) infection in more than half of the cases, or develop mild chronic hepatitis C. We confirmed the low risk of progression to cirrhosis in this cohort within 25 years.

Histopathological features of liver and its relation to serum transaminase levels in 91 cases of anti-HBe-positive chronic hepatitis B

For assessing the histopathological features and its relation to alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in anti-HBe-positive chronic hepatitis B in Babol, north of Iran, liver biopsy samples of 91 anti-HBe-positive chronic hepatitis B virus (HBV) infection with raised ALT were scored according to histological hepatitis activity index (HAI) from March 2000 to July 2003. Seventy-seven males and 14 females with a mean age of 32.24 (+/-11.92) years were studied. Mean ALT and AST levels were 112.5 (+/-98.9) and 69.57 (+/-60.6) IU/l, respectively. Minimal, mild, moderate and severe chronic hepatitis were seen in 35 (38.5%), 49 (53.8%), seven (7.7%) and 0 cases, respectively. There was not any significant difference between HAI and ALT levels of < 60, between 60-79 and > or = 80 IU/l (p = 0.299), but with regard to AST levels, this difference was significant (p = 0.005). This study showed that more than 90% of our cases are in the early stages of the liver disease. Although both serum ALT and AST levels are associated with the activity of hepatitis in HBV carriers, the AST is a better laboratory screening test for finding the severity of liver injury than ALT.

Plasma hydroxy-metronidazole/ metronidazole ratio in hepatitis C virus-induced liver disease

It has been suggested that the measurement of metronidazole clearance is a sensitive method for evaluating liver function. The aim of this study was to evaluate the usefulness of plasma hydroxy-metronidazole/metronidazole ratios as indicators of dynamic liver function to detect changes resulting from the various forms of chronic hepatitis C virus (HCV) infection. A total of 139 individuals were studied: 14 healthy volunteers, 22 healthy, asymptomatic, consecutive anti-HCV-positive HCV-RNA negative subjects, 81 patients with chronic hepatitis C (49 with moderate/severe chronic hepatitis and 34 with mild hepatitis), and 20 patients with cirrhosis of the liver. HCV status was determined by the polymerase chain reaction. Plasma concentrations of metronidazole and its hydroxy-metabolite were measured by reverse-phase high-performance liquid chromatography with ultraviolet detection in a blood sample collected 10 min after the end of a metronidazole infusion. Anti-HCV-positive HCV-RNA-negative individuals demonstrated a significantly reduced capacity to metabolize intravenously infused metronidazole compared to healthy individuals (0.0478 +/- 0.0044 vs 0.0742 +/- 0.0232). Liver cirrhosis patients also had a reduced plasma hydroxy-metronidazole/metronidazole ratio when compared to the other groups of anti-HCV-positive individuals (0.0300 +/- 0.0032 vs 0.0438 +/- 0.0027 (moderate/severe chronic hepatitis) vs 0.0455 +/- 0.0026 (mild chronic hepatitis) and vs 0.0478 +/- 0.0044 (anti-HCV-positive, HCV-RNA-negative individuals)). These results suggest an impairment of the metronidazole metabolizing system induced by HCV infection that lasts after viral clearance. In those patients with chronic hepatitis C, this impairment is paralleled by progression of the disease to liver cirrhosis.

Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients

We evaluated the effect of insulin resistance and viral factors on sustained virological response in patients with chronic hepatitis C treated with peginterferon plus ribavirin. Patients (n=159; 94 men; age, 41.7 +/- 11.1 years) with chronic hepatitis C (genotype 1, n=113; non-1 genotype, n=46) received treatment with interferon plus ribavirin. Serum levels of leptin and insulin were measured, and the insulin resistance index (HOMA-IR: homeostasis model of assessment) and body mass index were calculated. A sustained virological response was associated with lower age, insulin resistance index, body mass index, and gamma-glutamyltranspeptidase and serum leptin levels. There was no association with viral load, sex, type of interferon, or cholesterol levels. A sustained virological response was achieved in 43.4% (46/113) of genotype 1 and 89% (32/36) of genotype 2 and 3 (P=.0001) patients. Necroinflammatory activity and steatosis were not associated with the sustained virological response rate. Multivariate regression analysis indicated that the independent variables related to sustained virological response were genotype (odds ratio, 3.57; 95% confidence interval, 1.49-8.3; P=.001), insulin resistance index (odds ratio, 1.82; 95% confidence interval, 1.08-3.06; P=.012), and fibrosis (odds ratio, 1.36; 95% confidence interval, 1.01-1.84; P=.029). A sustained virological response in patients with genotype 1 and insulin resistance (HOMA-IR > 2) occurred in 23 of 70 (32.8%; 95% confidence interval, 21.9%-43.9%) patients, vs. 26 of 43 (60.5%; 95% confidence interval, 45.9%-75.1%) genotype 1 patients without insulin resistance (P=.007; odds ratio, 3.12, 95% confidence interval, 1.42-6.89). Insulin resistance, fibrosis, and genotype are independent predictors of the response to antiviral therapy in chronic hepatitis C patients treated with peginterferon plus ribavirin.

Relationship between core promoter mutation, clinical features and virus replication in HBV carriers

To elucidate the relationship between HBV core promoter mutation and clinical features as well as its effects on serum e system and viral replication. Semi-nested mutation specific PCR (msPCR) was employed for detecting core promoter mutation at nt 1 762-1 764 in 97 patients with HBV infection. The msPCR method was demonstrated to be specific and reliable for the mutation detection by sequencing the PCR products. The detection ratio of the mutation in patients with acute hepatitis, mild, moderate and severe chronic hepatitis and liver cirrhosis was 2/5, 7/43, 10/31, 1/3 and 7/15, respectively. The detection rate of the mutation in liver cirrhosis was significantly higher than that in light chronic hepatitis (P < 0.025). In 92 patients with chronic HBV infection, HBeAg positive rate in wild (25/92), mutant (42/92) and mixed (25/92) strain infection was 80.0%, 56.0% and 64.3%, HBV DNA level was (4.4 +/- 8.5) x 10(8), (1.1 +/- 1.6) x 10(9) and (1.4 +/- 1.8) x 10(9) copies/ml, the rate of abnormal ALT was 44.0%, 52.0% and 42.6%; ALT level was (58.6 +/- 79.0), (57.1 +/- 75.2) and (62.6 +/- 90.3) IU/L, respectively (P > 0.05). The msPCR method for detecting core promoter mutation at nt 1 762-1 764 is specific and reliable. Core promoter mutation is associated with the severity of liver disease, but neither related to the status of e system in serum nor to the virus replication.

Fibrinogen-like protein 2 fibroleukin expression and its correlation with disease progression in murine hepatitis virus type 3-induced fulminant hepatitis and in patients with severe viral hepatitis B

To evaluate the expression of fibrinogen-like protein 2 (fgl2) and its correlation with disease progression in both mice and patients with severe viral hepatitis. Balb/cJ or A/J mice were infected intraperitoneally (ip) with 100 PFU of murine hepatitis virus type 3 (MHV-3), liver and serum were harvested at 24, 48, and 72 h post infection for further use. Liver tissues were obtained from 23 patients with severe acute chronic (AOC) hepatitis B and 13 patients with mild chronic hepatitis B. Fourteen patients with mild chronic hepatitis B with cirrhosis and 4 liver donors served as normal controls. In addition, peripheral blood mononuclear cells (PBMC) were isolated from 30 patients (unpaired) with severe AOC hepatitis B and 10 healthy volunteers as controls. Procoagulant activity representing functional prothrombinase activity in PBMC and white blood cells was also assayed. A polyclonal antibody against fgl2 was used to detect the expression of both mouse and human fgl2 protein in liver samples as well as in PBMC by immunohistochemistry staining in a separate set of studies. Alanine aminotransferase (ALT) and total bilirubin (TBil) in serum were measured to assess the severity of liver injury. Histological changes were found in liver sections 12-24 h post MHV-3 infection in Balb/cJ mice. In association with changes in liver histology, marked elevations in serum ALT and TBil were observed. Mouse fgl2 (mfgl2) protein was detected in the endothelium of intrahepatic veins and hepatic sinusoids within the liver 24 h after MHV-3 infection. Liver tissues from the patients with severe AOC hepatitis B had classical pathological features of acute necroinflammation. Human fgl2 (hfgl2) was detected in 21 of 23 patients (91.30%) with severe AOC hepatitis B, while only 1 of 13 patients (7.69%) with mild chronic hepatitis B and cirrhosis had hfgl2 mRNA or protein expression. Twenty-eight of thirty patients (93.33%) with severe AOC hepatitis B and 1 of 10 with mild chronic hepatitis B had detectable hfgl2 expression in PBMC. No hfgl2 expression was found either in the liver tissue or in the PBMC from normal donors. There was a positive correlation between hfgl2 expression and the severity of the liver disease as indicated by the levels of TBil. PCA significantly increased in PBMC in patients with severe AOC hepatitis B. The molecular and cellular results reported here in both mice and patients with severe viral hepatitis suggest that virus-induced hfgl2 prothrombinase/fibroleukin expression and the coagulation activity associated with the encoded fgl2 protein play a pivotal role in initiating severe hepatitis. The measurement of hfgl2/fibroleukin expression in PBMC may serve as a useful marker to monitor the severity of AOC hepatitis B and a target for therapeutic intervention.

Mild chronic hepatitis C with steatosis

Mild chronic hepatitis C with steatosis

Long-Term Results of Bone Marrow Transplantation for Thalassemia Major in Pescara.

In this study we report the long-term results of bone marrow transplantation (BMT) in 111 patients (M 56, F 55) with thalassemia major (TM) who were given 115 transplants in Pescara between May 1983 and February 2004. The median age was 10.06 years (0.11–28.11). The median number of transfusions given before BMT was 139 (2–900). The median level of ferritin at time of BMT was 1328 (258–6640). Twenty-three patients showed evidence of HBV infection and 59 of HCV infection. A pretransplant liver biopsy was performed in 78 patients. On the basis of Knodell classification, results of liver biopsy were: mild siderosis with normal histology in 1 patient, chronic persistent hepatitis in 34, mild chronic active hepatitis (CAH) in 10, moderate CAH in 23, severe CAH in 10. Results of liver fibrosis were: no fibrosis in 4 patients, mild fibrosis in 39, moderate in 25 and severe in 10. All patients showed normal ejection fraction evaluated by echocardiogram (median 62%, range 56% to 70%). One hundred and seven patients received their marrow from HLA identical siblings, 3 from HLA identical parent and 1 from HLA identical uncle. All patients received the same preparative therapy consisting of Busulphan (BU) (13–14 mg/Kg) and Cyclophosphamide (CY) (200 mg/Kg), preceded by an hypertransfusion regimen for 2–3 weeks. For graft-versus-host disease (GvHD) prophylaxis, 37 patients were given Cyclosporine (CSA) alone and 74 received CSA in association with short course Methotrexate. The median number of transplanted nucleated cells was 4.7 x 108/Kg (2.3–10.1). Marrow engraftment was evident in 109 patients. The median time to achieve 0.5x109/L neutrophils and 50x109/L platelets was 19 (11–37) and 24 (10–55) days respectively. Four patients showed graft rejection and were given a second BMT from the same donor. The actuarial probability of developing acute GvHD grade II-IV and cumulative chronic GvHD was 21% and 17% (7% limited, 10% extensive) respectively.Transplant related mortality was 9%. Ten patients died for BMT related causes: pneumonia in 4, heart failure in 3 patients, encephalopathy in 2, aGvHD in 1. The median day of death was day 41 (12–212). Two late deaths occurred. One patient died of septic shock 54 months post-BMT. One patient died for parotitis carcinoma 138 months after BMT. As of July 2004, 99 patients are alive. Ninety five are cured after a median follow-up of 160 months (5–254). Four patients had an autologous reconstitution and are currently alive under transfusion therapy. To-date, 4 patients are receiving immunosuppressive therapy for active chronic GvHD. The 10-year actuarial probability of survival and disease-free survival (DFS) was 90% and 86% respectively. In multivariate analysis, no adverse risk factor affecting survival and DFS was identified among recipient-donor age and sex, number of pre-BMT transfusions, level of ferritin, type of CAH, grade of liver fibrosis, serum GPT level, HBV and HCV serology, dose of BU, type of GvHD prophylaxis, marrow cell dose. Three studies were activated in the post-transplant course in order to normalize the serum ferritin with phlebotomy (28 patients), to treat HCV related CAH (9 patients) and to ameliorate the growth velocity with recombinant human growth hormone (7 patients).

Replication and gene expression of mutant hepatitis B virus in a transgenic mouse containing the complete viral genome with mutantsgene

To establish the transgenic mouse line harbouring complete hepatitis B virus (HBV) genome with mutant s gene (adr subtype). Transgenic mice were generated by microinjecting HBV genome into fertilized eggs. Integration, expression, replication of HBV gene and histological changes in transgenic mice were estimated by genomic DNA PCR, serum DNA PCR, Southern blot, ELISA, HE staining, immunohistochemistry and transmission electron microscopy. Transgenic mice with HBsAg positive in serum were bred and analyzed. A total of 288 eggs survived from microinjections were transplanted into the oviducts of 13 pseudopregnant mice and 49 pups were produced. Twenty-six mice were identified to have the integrated HBV gene. Serum HBsAg and HBeAg were detected in 2 of 43 mice. HBsAg and HBcAg in cytoplasm or nuclei of hepatocytes were detected in 10 mice. Founders with HBsAg in serum were named lineages G145R-15 and G145R-18. Of the 16 F1 offsprings generated by G145R-15 founder, 12 were positive for HBV genome with PCR, 10 were positive for HBsAg and HBcAg with immunohistochemistry and 7 were positive for HBsAg and HBeAg with ELISA. Only 1 of 8 F1 offsprings generated by G145R-18 founder was survived and it was detected positive for HBV genome, HBsAg, HBcAg and HBeAg. Both of the two lineages had some pathological characteristics of mild chronic hepatitis B in the liver, such as swelling of hepatocytes and focal hepatocellular necrosis and parenchymal lymphomononuclear cell infiltrate. Transgenic mice harbouring HBV with mutant s gene can be generated. The HBV genes are integrated in the transgenic mice genome and can be expressed, replicated, packaged and excreted. HBV DNA can be stably transmitted in the transgenic mice.

Neurocognitive changes in chronic liver disease

Clinical presentation, changes in liver function test results, and liver morphology were examined in 41 consecutive patients with vitamin A hepatotoxicity. The cause of liver disease was suspected at initial interview in only 13 instances, whereas histological evidence of fat-storing cell hyperplasia with fluorescent vacuoles led to the diagnosis in the remaining cases. Cirrhosis was found in 17, mild chronic hepatitis in 10, noncirrhotic portal hypertension in 5, and “increased storage” alone in 9 cases. During a mean follow-up period of 4.6 years, 6 patients died of causes related to the liver disease. A precise appraisal of drug consumption was obtained in 29 cases. Among them the total cumulative intake was the highest in patients with cirrhosis (423 ± 103 × 106 IU) and significantly lower in those with noncirrhotic liver disease (88.5 ± 41;P < 0.02). The smallest continuous daily consumption leading to cirrhosis was 25,000 IU during 6 years, whereas higher daily doses (≥100,000 IU) taken during 2½ years resulted in similar histological lesions. It was concluded that at least in some western countries chronic vitamin A consumption might represent an appreciable cause of chronic liver disease, the recognition of which mainly relies on expert liver biopsy interpretation. The data also indicate that prolonged and continuous consumption of doses in the low “therapeutic” range can result in life-threatening liver damage.

Quality of life and cognitive function in hepatitis C at different stages of liver disease

Background/Aims: Hepatitis C has been associated with a decrease in quality of life and with neurological abnormalities. The aim of our study was to investigate the relationship between quality of life and cognitive function. Methods: Quality of life, clinical variables and neuropsychological function were evaluated in 120 patients with hepatitis C (mild chronic hepatitis, compensated cirrhosis and decompensated cirrhosis) and in healthy controls ( n=40, in each group). Results: Patients with chronic hepatitis or compensated cirrhosis showed a decrease in quality of life, in spite of unimpaired neuropsychological tests. Patients with decompensated cirrhosis exhibited a further decrease in quality of life and neuropsychological abnormalities. The decrease in quality of life was associated with the severity of liver failure, neuropsychological abnormalities and treatment with beta-blockers or diuretics. However, in the multivariable analysis, only treatment with beta-blockers or diuretics (which was limited to decompensated cirrhosis) was independently associated with quality of life. Conclusions: Hepatitis C causes a decrease in quality of life even in the absence of major cognitive impairment. The mechanisms that worsen quality of life are unknown. However, in cirrhotic outpatients with prior decompensations, treatment with beta-blockers or diuretics appears to have an important effect on quality of life.