Mild Chronic Active Hepatitis Research Articles

Autoimmune Hepatitis in Association With Sofosbuvir.

Sofosbuvir in combination with ribavirin was approved by the Food and Drug Administration as a treatment option for hepatitis C (HepC) in 2013. We describe a case of autoimmune hepatitis triggered in a patient on therapy with sofosbuvir and ribavirin. A 65-year-old woman with a medical history of diabetes mellitus, hypertension, and HepC (genotype 2) underwent pretreatment liver biopsy in May 2012, which demonstrated mild chronic active hepatitis with focal piece-meal necrosis and mild stage 1 periportal fibrosis with no increased iron deposition. No features of autoimmune hepatitis were seen on biopsy. The patient was administered 400 milligrams (mg) sofosbuvir and weight-based 1000 mg ribavirin for a planned duration of 12 weeks. Liver function tests (LFTs) initially improved on therapy; however, 3 weeks after the treatment initiation, the patient started complaining of weakness and fatigue. Repeat tests revealed elevated LFTs. Autoimmune titers were positive for antinuclear antibody, anti-smooth muscle antibody with elevated immunoglobulin (IgG), and serum gamma globulin levels. Repeat liver biopsy in June 2014 showed markedly distorted architecture secondary to formation of nodules completely enclosed by fibrous septa and areas of confluent necrosis with mild to moderate chronic inflammation consisting mainly of lymphocytes and plasma cells along with moderate to severe interface hepatitis. Ballooning degeneration of hepatocytes, with rosette formation possibly associated with regenerative activity was seen, consistent with superimposed autoimmune hepatitis. Based on laboratory and biopsy findings, diagnosis of drug-induced autoimmune hepatitis was made, and the treatment for HepC with sofosbuvir and ribavirin was discontinued. The patient was subsequently administered prednisolone with improvement in LFTs. We describe a patient with autoimmune hepatitis after initiation of sofosbuvir and ribavirin. To our knowledge, this complication has never been reported before in association with sofosbuvir. The most frequent adverse events noticed with this combination regimen have been headache, anemia, fatigue, and nausea.

Is management with lamivudine always the appropriate choice for HBV patients with onco-hematologic diseases?

Dear Editor, We read with interest the article by Yi-Fu H. et al. [1] about the effectiveness of Lamivudine (LAM) prophylaxis in preventing hepatitis B viral (HBV) reactivation in Rituximab containing regimens (so called immunochemotheraphy, ICT) for lymphoma and would like to make a contribution to this emerging topic. All patients diagnosed with Non-Hodgkin Lymphoma (NHL) from January 2005 to March 2008, at our Institution, were screened for HBV serology: HBsAg, anti-HBs, anti-HBc, HBeAg, anti-HBe. Patients were also tested for HCV antibodies (HIV-positive patients were not included): 18 out of 159 patients (11.3%) had serological signs of HBV exposure. 12 out of 159 (8.1%) patients were HCV-infected. Seven out of 18 HBV carriers were coinfected with HCV (38.8%). In 11 out of 18 patients (61%), HBsAg were negative [2], anti-HBc (nine patients), anti-HBs (one patient, no history of previous vaccination), anti-HBc/anti-HBe/anti-HBs (one patient) being the only positive markers of previous HBV exposure. Three patients were known to be affected by mild HBV chronic active hepatitis at the time of lymphoma diagnosis and were treated with LAM to contain the disease process before and after ICT. The remaining four inactive HBsAg carriers and the 11 HBsAg-negative/antiHBc-positive patients were started on LAM as a preemptive treatment to prevent possible disease reactivation [3]. Patients began treatment with LAM 100 mg/day po on average 3–4 weeks before embarking on chemotherapy, after signing informed consent. All 159 patients were given R-CHOP or R-CHOP-like regimens [4]. LAM treatment was extended to 18 months after that the new indications from the dedicated commission of the Italian Study of the Liver became widely available in 2007 [3]. During and after ICT discontinuation, patients were tested every 2 months for HBsAg, quantitative-HBV-DNA, ALT, and AST. Median follow-up time was 7 months (range 3–43). Five of the seven HBsAg-positive patients (71.4%) became HBV-DNA positive during follow-up at 25, 18, 18, 10, and 7 months after commencing LAM. In two patients, emergence of HBV-DNA positivity was associated with an increase of serum transaminases (up to five times the upper normal limit). In these five patients, AdefovirDipivoxyl, 10 mg/day po, was combined with LAM, resulting in a disappearance of HBV-DNA and regression of the biochemical signs of hepatitis. None of these patients had to discontinue ICT because of HBV reactivation. No liver-related deaths occurred. None of the HBcAbpositive, anti-HBs-positive/HBsAg-negative patients (potential silent carriers) developed HBV reactivation during the period of observation. No side effect related either to LAM or ADV was registered. Four out of seven of these patients are now undergoing new treatments because of lymphoma progression. The prevalence of HBV infection is high among patients diagnosed with NHL as compared to less than 2% of the Italian adult population [5]. Reactivation of HBV infection can present a serious threat to these patients and to the Ann Hematol (2009) 88:283–284 DOI 10.1007/s00277-008-0609-2

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.

Long-term evolution of liver histopathology in patients with chronic hepatitis C and sustained response

To evaluate the evolution of histological changes observed in patients with chronic hepatitis C (CHC) and sustained response (SR) compared to non-responders (NR) to antiviral treatment. A retrospective study was performed in a total of 176 patients with CHC. These were divided into two groups: 132 SR and 44 NR. All had undergone a basal liver biopsy prior to treatment onset. A second biopsy was performed in 143 patients, 104 SR and 39 NR. Inflammatory activity and the degree of liver fibrosis was measured by Metavir units (MU). The progression and regression index of fibrosis was calculated before and after treatment. The time elapsed between the two biopsies was 5.9 +/- 0.3 years for SR and 6.6 +/- 0.3 years for NR (NS). At baseline, 53% of SR patients had mild, chronic active hepatitis (CAH), while this was moderate in 43% of NR patients (p < 0.0001). The time elapsed between baseline and post-treatment liver biopsies was 5.9 +/- 0.3 years for SR subjects and 6.6 +/- 0.4 years for NR subjects (NS). After antiviral treatment 47% of SR subjects presented a normal liver or minimal changes, whilst mild CAH persisted in 34.4% and moderate CAH in 37.5% of NR subjects. Necro-inflammatory activity decreased by 50% in SR subjects and by 15% in NR subjects (p < 0.0001), and fibrosis decreased by 82% in SR subjects (p < 0.0001) and by 66% in NR subjects (p < 0.001). Fibrosis progression index was 0.14 MU/year in SR subjects and 0.21 MU/year in NR subjects (NS). Fibrosis regression index was -0.11 in SR subjects and -0.14 in NR subjects (NS). In our series of patients with CHC and SR, we observed histological normalization in approximately fifty per cent of cases during long-term follow-up. NR subjects also showed improvement, especially in the fibrosis score. Both groups showed a marked regression of liver fibrosis after treatment.

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

Abstract 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).

Outcome of 67 patients with hepatocellular cancer detected during screening of 1125 patients with chronic hepatitis.

We performed this prospective screening trial in chronic hepatitis virus-infected patients to determine the incidence of hepatocellular cancer (HCC) and the resectability and long-term survival rates of these HCC patients. Chronic hepatitis B or C virus infection is a major etiologic factor in human HCC. It is not clear if routine screening of chronic viral hepatitis patients improves the survival of patients who develop HCC. Screening for HCC was offered to patients chronically seropositive (>5 years) for hepatitis B or C infection. All patients underwent percutaneous core liver biopsy to assess the histologic severity of chronic liver injury. Patients were screened initially and every 3 months thereafter with serum alpha-fetoprotein and transabdominal ultrasound evaluations; HCC was confirmed by needle biopsy of liver tumors. Screening was performed on 1125 hepatitis-positive patients (804 with hepatitis C, 290 with hepatitis B, 31 with both). On liver biopsy, 800 patients had mild chronic active hepatitis and 325 had severe chronic active hepatitis, cirrhosis, or both. Initial screening detected HCC in 61 patients. HCC was detected in six more patients during follow-up; thus, the incidence of HCC was 5.9% (67/1125). However, 66 of the 67 HCC cases (98.5%) arose in the 325 patients with severe chronic active hepatitis or cirrhosis (66/325 [20.3%] vs. 1/800 [0.1%], p < 0.0001 [Wilcoxon signed rank]). Median follow-up of the 67 HCC patients was 24 months. Locally advanced or metastatic, unresectable HCC occurred in 43 patients (64.2%); 24 patients (35.8%), including the 6 patients detected during follow-up screening, underwent margin-negative resection. The median survival for the 24 resected patients was 26 months, compared to 6 months for the 43 patients with unresectable cancer (p < 0.0001, Wilcoxon signed rank). HCC was found to arise in 20.3% of patients with chronic hepatitis B or C infection and severe liver injury. Initial screening detected resectable lesions in less than half the HCC patients. Routine screening of chronic hepatitis B or C virus-infected patients with ultrasound and alpha-fetoprotein determination should be reserved for patients with severe chronic active hepatitis, cirrhosis, or both.

Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors.

Prolonged Q-T interval predicts severe arrhythmias and sudden death, and has been shown to occur in alcoholic liver disease and cirrhotic patients who are candidates for liver transplantation. This study first evaluated the prevalence of prolonged Q-T interval in a large population of unselected patients with cirrhosis, and assessed the relationship between abnormal Q-T, etiology, and severity of liver disease and mortality of patients. Possible causes of Q-T abnormality were also explored. Ninety-four patients with cirrhosis without overt heart disease and 37 control subjects with mild chronic active hepatitis were enrolled. Rate-corrected Q-T interval (Q-Tc) was assessed along with routine liver tests, Child-Pugh score, serum bile salts, electrolytes and creatinine, plasma renin activity, aldosterone, norepinephrine, atrial natriuretic factor and, gonadal hormones. Q-Tc was longer in patients with cirrhosis than in controls (440.3 +/- 3.2 vs. 393.6 +/- 3.7 ms; P < .001) and prolonged (> 440 ms) in 44 patients (46.8%) and 2 controls (5.4%; P < .001). Q-Tc length was not influenced by the etiology of cirrhosis and correlated with Child-Pugh score (r = .53; P < .001), liver tests such as prothrombin activity, and serum concentrations of albumin and bilirubin, plasma bile salts, and plasma norepinephrine. Multivariate analysis showed that only Child-Pugh score and plasma norepinephrine were independently correlated with Q-Tc duration. Over a median follow-up period of 19 months (range, 2-33 months), patients with Q-Tc longer than 440 ms had a significantly lower survival rate than those with normal Q-Tc. Q-T interval is frequently prolonged in patients with cirrhosis, regardless the etiology of the disease, worsens in parallel with the severity of the disease, and may have an important prognostic meaning. In addition to other undefined factors related to the severity of cirrhosis, sympathoadrenergic hyperactivity may play a pathogenetic role.

A comparison of four types of interferon alpha in the treatment of chronic hepatitis C

Several clinical trials and meta-analyses have shown that the efficacy of interferon (IFN)-alpha in the treatment of chronic hepatitis C is variable, depending on the type of IFN-alpha used. We randomly assigned 220 patients with hepatitis C to receive a 6-month treatment (3 megaunits three times per week) with lymphoblastoid IFN-alpha (group A), recombinant IFN alpha-2a (group B), leukocyte IFN-alpha (group C), or recombinant IFN alpha-2b (group D). The groups were homogeneous with reference to histologic severity of the disease (chronic persistent hepatitis, 21.4%; mild chronic active hepatitis, 28.2%; moderate chronic active hepatitis, 28.6%; and severe chronic active hepatitis, 21.8%). We used common laboratory techniques to detect and assess all serum variables. Liver biopsy was conducted according to Menghini's modified technique, and administration of IFN alpha was conducted according to a double-masked method. A total of 220 patients were enrolled in the study. Ninety-two patients dropped out because of side effects, comorbidity unrelated to the baseline disease, or voluntary termination and 128 patients (32 patients in each group) completed the treatment course and the follow-up period. At the 6-month end point, 14 of 32 patients were completed responders in group A, 13 of 32 in group B, 14 of 32 in group C, and 8 of 32 in group D. After completion of the follow-up period, 10 of 32 patients had a sustained response in group A, 9 of 32 in group B, 10 of 32 in group C, and 8 of 32 in group D. Treatment failure and relapse rates were higher in the patients treated with recombinant alpha IFNs than in patients treated with leukocyte or lymphoblastoid IFN alpha. We observed no relation between the relapse rate and baseline severity of the disease. Among the recombinant IFNs, a major rate of clinical response was observed in patients treated with recombinant IFN alpha-2a. Although leukocyte IFN-alpha and lymphoblastoid IFN-alpha treatments showed an overlapping efficacy in terms of complete or sustained response, the former achieved a lower rate of treatment failure or relapse.

An Intermediate Dose of Alpha-Recombinant Interferon-2a for Chronic Hepatitis C with Nonsevere Histological Pattern

In the light of recent research, which suggests an interferon (IFN) therapy schedule on the basis of single patient characteristics (e.g. histological pattern, viral genotype) and the cost/benefits of such therapy, we studied the efficacy and tolerability of an intermediate dose (4.5MU 3 times a week) of alpha-recombinant interferon-2a (α-r IFN-2a) in 28 patients with histologically proven chronic hepatitis C. 20 were hepatitis C virus (HCV)-RNA +ve, 5 were HCV-RNA −ve, and in 3 patients HCV-RNA status was not carried out. The viral genotypes were: 13 (65%) 1b, 2 (10%) 1a, 1 (5%) 1a + 1b, 3 (15%) 2a, 1 (5%) 3a; histological pattern: 21 (75%) mild chronic active hepatitis (CAH), 7 (25%) moderate CAH. 4.5MU of α-r IFN-2a were given 3 times a week for 6 months, followed by 3MU 3 times a week for 6 months. Six patients (21.4%) had a biochemical and virological sustained response (SR), 8 patients (28%) had ALT normalisation during therapy (transient complete response [TCR]) followed by relapse, 3 patients (10.7%) had a TCR with breakthrough (BT), 4 patients (14.3%) had a partial response (PR) and 7 patients (25%) were nonresponders (NR). We observed persistent HCV-RNA serum loss in all patients with SR, transient HCV-RNA serum loss in 8 patients with TCR, TCR with BT and PR; in 5 patients who were NR no HCV-RNA serum loss occurred. The prevalence of HCV genotype 1b and the duration of disease in SR and NR groups showed a significant difference. Moreover, we found a significant correlation between prevalence of HCV genotype 1b and type of response (r = 0.899, p < 0.05) between mean age in the different patient response groups and prevalence of HCV genotype 1b (r = 0.881, p < 0.05), and between disease duration and type of response (r = 0.874, p < 0.05). The schedule we used can be considered as well tolerated and efficacious at least in chronic hepatitis C with nonsevere histological pattern, with an HCV genotype other than 1b.

Hepatitis C virus infection in pregnancy

To evaluate the clinical aspects of hepatitis C virus (HCV) liver disease in anti-HCV+ve mothers, both during pregnancy and six months after delivery, and to assess the outcome of pregnancy. Obstetric department for high risk pregnancies of the University of Padova, Italy. Seventeen hundred consecutive pregnant women were studied. Each woman underwent the following: 1. serological screening for hepatitis surface antigen (HBsAg), antibodies to HCV (anti-HCV), antibodies to human immunodeficiency virus type 1 (HIV1) within the first trimester of pregnancy; and 2. clinico-biochemical assessment in order to ascertain previous or active liver disease and risk factors for viral infections. Twenty-nine (1.7%) of the 1700 women were found anti-HCV positive. Eight of them had an associated positivity for HIV infection. HCV-RNA was positive in 64.2% of anti-HCV positive women. Liver function tests (included transaminases) were within the normal range in 27 mothers (both during and six months after delivery). Only 2/29 women had a slight increase in AST/ALT; liver biopsy in these cases was compatible with mild chronic active chronic active hepatitis. In all women the outcome of pregnancy was favourable (12/29 anti-HCV positive mothers underwent caesarean delivery for causes independent from HCV infection). A substantial proportion of anti-HCV positive pregnant mothers, even if asymptomatic, have circulating HCV-RNA. The pregnancy does not induce a deterioration of liver disease, and vice versa, HCV infection does not increase the risk of obstetric complications.

Recombinant interferon-alfa therapy in children with chronic hepatitis C

The efficacy of recombinant interferon-alfa therapy in children with chronic hepatitis C has been evaluated in a randomized, controlled pilot study including 27 patients, aged 2 to 14 years, without underlying systemic diseases. On entry, all patients had abnormal alanine transaminase (ALT) levels, 22 were hepatitis C virus (HCV) RNA positive, 19 had mild chronic active hepatitis, and 8 had chronic persistent hepatitis on liver biopsy. Fourteen children received 5 MU/m2 of recombinant interferon-alfa2b thrice weekly for 4 months. If at this time ALT had been reduced to at least 50% the baseline level, treatment was continued up to 12 months. The other 13 children remained untreated. The whole follow-up period lasted 24 months. Interferon was stopped at 4 months in 4 children because of an ALT increase (2 cases), unchanged ALT and febrile convulsions (1 case), and slight ALT decrease (1 case). This latter patient, however, had normal ALT at 6 months and throughout further follow-up, and cleared HCV RNA, thus behaving as a sustained responder. All 10 children treated for 12 months had normal levels of ALT, and 9 were HCV RNA negative at the end of treatment. Of the 9 children who could be followed to 24 months, 4 relapsed soon after therapy withdrawal and 5 maintained a sustained biochemical and virologic response. Overall, 6 (43%) of 14 treated children had a sustained ALT normalization associated with HCV RNA clearance as compared with only 1 (7.5%) untreated child who had a sustained ALT normalization but did not clear HCV RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant interferon-alfa therapy in children with chronic hepatitis C

Recombinant interferon-alfa therapy in children with chronic hepatitis C

Mild or aggressive chronic active hepatitis (CAH) due to hepatitis C virus (HCV) are associated with different combinations of HCV genotypes: [formula omitted] Gastroenterology, Univ Modena ∗Spedali Civili, Brescia, Italy

Mild or aggressive chronic active hepatitis (CAH) due to hepatitis C virus (HCV) are associated with different combinations of HCV genotypes: [formula omitted] Gastroenterology, Univ Modena ∗Spedali Civili, Brescia, Italy

Recurrence of hepatitis C following orthotopic liver transplantation: a polymerase chain reaction and histological study

Hepatitis C virus was sought by nested polymerase chain reaction in the preoperative biopsy or the explanted liver of 100 consecutive adult patients undergoing orthotopic liver transplantation. In those found to be positive preoperatively, polymerase chain reaction was performed on subsequent biopsies. Of the 12 patients in whom HCV-RNA was identified in the liver by polymerase chain reaction preoperatively, viral recurrence was documented in ten of the 11 with posttransplant liver tissues available for study. In the one exception, hepatitis C virus was undetectable in the liver graft despite repeated co-amplification of albumin mRNA as an internal control, which may indicate viral clearance. In eight of the ten positive cases, HCV-RNA was also detectable in serum postoperatively, while HCV-RNA was undetectable in serum in both the cases in whom HCV-RNA was undetectable in tissue and in the patient who declined post-transplant biopsy. Two of the 12 patients infected with hepatitis C virus preoperatively have died during the follow-up period from causes unrelated to hepatitis C virus infection. While biochemical liver function in seven of those remaining has been excellent, histological evidence of at least mild chronic active hepatitis has been present in all ten cases for whom long-term biopsies are available. Three cases have progressed to severe, symptomatic chronic active hepatitis within 2 years of transplantation. Recurrent hepatitis C is associated with progressive liver disease and appreciable morbidity in a significant proportion of patients.

What should we clinicians do for healthy, asymptomatic, hbsag-positive carriers?

Objective: To assess the long-term outcome in hepatitis B surface antigen (HBsAg) carriers who have normal liver function tests, focusing on survival and the development of severe liver disease and hepatocellular carcinoma. Design: Cohort study with a mean follow-up of 130 months. Setting: Liver clinic of a referral center. Patients: Ninety-two HBsAg-positive blood donors with normal liver function tests. Measurements: Histologic evaluation of liver specimens at baseline; clinical, biochemical, and serologic follow-up; and repeat liver biopsy if clinically indicated or after 10 years of follow-up. Results: At baseline, 69 subjects had normal histologic findings or only minor abnormalities, 18 had chronic persistent hepatitis, and 5 had mild chronic active hepatitis. Serum enzyme levels remained normal in 58 of 68 patients who had regular follow-up. Three patients had biochemical changes consistent with hepatitis B virus (HBV) infection; in one of these patients, a later histologic evaluation showed progression to chronic active hepatitis. One patient developed alcoholic cirrhosis. Six other patients had mild or transient transaminase elevations, with no evidence of HBV replication, hepatitis D virus infection, hepatitis C virus (HCV) infection, or histologic deterioration. Liver histologic findings also remained unchanged in 21 patients who showed no biochemical changes during 10 years of follow-up and consented to have repeated liver biopsy. Ten patients showed loss of HBsAg; 2 of these patients acquired antibody to hepatitis B surface antigen (anti-HBs). All patients who did not have regular follow-up, except 1, were interviewed by telephone during 1990; All denied having liver disease. No patients developed hepatocellular carcinoma. Conclusions: Italian HBsAg carriers with initially normal liver function tests have an excellent prognosis: Delta superinfection is infrequent and the risk for developing hepatocellular carcinoma is low.

The natural history of asymptomatic hepatitis B surface antigen carriers.

To assess the long-term outcome in hepatitis B surface antigen (HBsAg) carriers who have normal liver function tests, focusing on survival and the development of severe liver disease and hepatocellular carcinoma. Cohort study with a mean follow-up of 130 months. Liver clinic of a referral center. Ninety-two HBsAg-positive blood donors with normal liver function tests. Histologic evaluation of liver specimens at baseline; clinical, biochemical, and serologic follow-up; and repeat liver biopsy if clinically indicated or after 10 years of follow-up. At baseline, 69 subjects had normal histologic findings or only minor abnormalities, 18 had chronic persistent hepatitis, and 5 had mild chronic active hepatitis. Serum enzyme levels remained normal in 58 of 68 patients who had regular follow-up. Three patients had biochemical changes consistent with hepatitis B virus (HBV) infection; in one of these patients, a later histologic evaluation showed progression to chronic active hepatitis. One patient developed alcoholic cirrhosis. Six other patients had mild or transient transaminase elevations, with no evidence of HBV replication, hepatitis D virus infection, hepatitis C virus (HCV) infection, or histologic deterioration. Liver histologic findings also remained unchanged in 21 patients who showed no biochemical changes during 10 years of follow-up and consented to have repeated liver biopsy. Ten patients showed loss of HBsAg; 2 of these patients acquired antibody to hepatitis B surface antigen (anti-HBs). All patients who did not have regular follow-up, except 1, were interviewed by telephone during 1990: All denied having liver disease. No patients developed hepatocellular carcinoma. Italian HBsAg carriers with initially normal liver function tests have an excellent prognosis: Delta superinfection is infrequent and the risk for developing hepatocellular carcinoma is low.

Non responders to interferon therapy among chronic hepatitis patients infected with hepatitis C virus.

We studied a series of 268 chronic hepatitis C patients (31 chronic persistent hepatitis CPH, 69 mild chronic active hepatitis CAH, 125 severe CAH, and 43 active cirrhosis) enrolled from 1988 to 1991 in different therapeutic protocols using lymphoblastoid or recombinant interferon (IFN) at a dosage of 3 mega units (M.U.), three times a week for 12 months. Of these patients 54.8% showed a complete response (normalization of aminotransferases), 14.2% a partial response (decrease in aminotransferases of over 50%), 27.6% no response, and 3.4% a substantial progressive increase in the liver enzymes during IFN (becoming worse). The prevalence of non responders was lower in CPH (9.7%) than in CAH patients (31.9% in the mild form and 20.8% in the severe), and significantly higher in patients with cirrhosis (53.5%). No correlation was observed between non response and the baseline aminotransferase level or the patient's sex. Patients under 35 had a better response to IFN when compared with patients 36-50 years. This is probably due to the higher prevalence of CPH patients with a good response to IFN in the youngest group. No effect was gained in non responders by increasing the dose or shifting from recombinant to lymphoblastoid IFN; three patients were then treated with steroids, but only one benefitted. For 5 of the 9 patients who became worse, steroids were started after discontinuation of IFN therapy, and they induced a favorable response only for the 3 who had developed autoantibodies during IFN treatment.

Clinical assessment and incidence of hepatitis C RNA in 50 consecutive RIBA-positive volunteer blood donors.

(i) To assess evidence of liver disease in 50 consecutive volunteer blood donors who were anti-hepatitis C virus (anti-HCV) antibody positive and who were referred to one hepatologist; (ii) to assay for viral RNA in serum in these patients. Royal Prince Alfred Hospital, a teaching hospital of the University of Sydney. Fifty people who were detected by the NSW Red Cross Blood Transfusion Service to be anti-HCV antibody positive and to have a positive result on recombinant immunoblot assay (RIBA) were assessed by one hepatologist for symptoms, signs and biochemical evidence of hepatic dysfunction. These patients were consecutive referrals from this source. Sixteen of these patients also consented to liver biopsy assessment. All patients had serum assayed for viral RNA by polymerase chain reaction with a combination of 3' and 5' primers. The 50 blood donors consisted of 28 men and 22 women, with a mean age of 34.5 years. Forty-six patients were asymptomatic. Only six had a past history of hepatitis while 14 had minor signs of chronic liver disease. In 28, injecting drug use was thought the most likely source of exposure to HCV. The minimal mean time since exposure to HCV in these patients was 8.8 +/- 5.2 years. Eight patients had received a blood transfusion at a mean time of 15.0 +/- 9.8 years from the time of consultation. The mean maximum level of alanine aminotransferase (ALT) in all 50 patients was 102.8 U/L. Five patients had persistently normal ALT levels; another 22 had at least one normal ALT level. Liver biopsies indicated chronic persistent hepatitis in 11 patients, mild chronic active hepatitis in three patients and more severe chronic active hepatitis in one. One patient had cirrhosis on biopsy. Forty-two patients had viral RNA detected in serum. Chronic infection with HCV in blood donors was invariably asymptomatic; 78% of patients had no signs of chronic liver disease and 68% had a maximum hepatic transaminase level of less than 100 U/L. Although severe liver disease was seen in two of 16 biopsies, the majority of these patients have mild liver disease despite a mean of about 10 years since exposure to the virus. Eighty-four per cent of patients had evidence of viral RNA in serum.

Course of hepatitis B and D virus infection in auxiliary liver grafts in hepatitis B-positive patients: A light-microscopic and immunohistochemical study

Four patients who received an auxiliary partial liver graft for decompensated liver cirrhosis due to hepatitis B (HBV), associated in two cases with hepatitis D virus (HDV) superinfection, were studied. The sequential appearance of hepatitis B and D antigens in the grafts was investigated in serial liver biopsies by immuno-histochemical methods and compared with the viral antigenic profiles of the host livers. The histological changes in the liver grafts were studied in relation to the viral expression patterns. One week after transplantation, expression of HBsAg was already apparent in two grafts. HBcAg was found in the graft of the only patient with HBcAg in the host liver. HDAg was expressed in the grafts of both patients with HDV superinfection; in one of these cases HDAg was present without HBsAg. At 3 months, viral antigen expression was maximal. Expression of HBsAg and HBcAg in the grafts of the two HDV-positive patients was, however, less extensive than in the two HBV-positive patients. All patients developed a mild lobular hepatitis, histologically demonstrated between the 47th and 107th posttransplantation day. In the two HBV-positive, HDV-negative patients, cirrhotic transformation of the graft occurred within 1 year. In the HDV-positive patients only a mild chronic active hepatitis with slight or moderate fibrosis was observed after 1 year. We conclude that recurrence of HBV and HDV infection in auxiliary liver grafts is demonstrable within 1-3 weeks. HBV infection in liver grafts may be a rapidly progressive disease. Coinfection with HDV does not aggravate the acute hepatitis and may even suppress the progression of chronic HBV.