Risk of malignancies in autoimmune hepatitis type 1 patients with a long-term follow-up in Japan.

AIM: The risk of malignancies in autoimmune diseases is high and is regarded to be due to immunological abnormalities, the use of immunosuppressive agents, and/or chronic inflammation. The aim of this study was to investigate the incidence and risk of malignancies in patients with autoimmune hepatitis (AIH) type 1 in Japan. METHODS: Two hundred and fifty-six patients diagnosed with AIH were enrolled. A person-year calculation was carried out for AIH patients, and the numbers of expected events were clarified using data from "The Monitoring of Cancer Incidence in Japan Project" in order to examine the standard incident rate (SIR) of each type of malignancy. Biochemical data regarding carcinogenesis and its background factors were also examined. RESULTS: Twenty-seven patients (10.5%) developed malignancies; 11 (4.3%) with hepatobiliary cancer and 16 (6.3%) with extrahepatic malignancies. The overall SIR for malignancies in AIH was significantly high at 2.04 (95% confidence interval [CI], 1.34-2.96), and was high among female patients at 2.49 (95% CI, 1.60-3.71). The SIR for hepatobiliary cancer was 14.14 (95% CI, 7.05-25.30), and was markedly high for female patients at 21.83 (95% CI, 10.45-40.16). The SIR for oral/pharyngeal cancer was significantly high for female patients at 14.61 (95% CI, 1.64-52.77). The risk factors for hepatobiliary cancer at the diagnosis of AIH were low levels of alanine aminotransferase (P = 0.0226), low platelet counts (P < 0.0001), and cirrhosis (P = 0.0004). The risk factor for extrahepatic malignancy was relapse of AIH (P = 0.0485). CONCLUSION: The risk of malignancies was generally high among AIH patients. Those with the risk factors of malignancies should be carefully followed up.

First-line sorafenib sequential therapy and liver disease etiology for unresectable hepatocellular carcinoma using inverse probability weighting: A multicenter retrospective study.

BACKGROUND AND AIMS: Sequential therapy with molecular-targeted agents (MTAs) is considered effective for unresectable hepatocellular carcinoma (HCC) patients. This study purposed to evaluate the efficacy of sequential therapy with sorafenib (SORA) as a first-line therapy and to investigate the therapeutic impact of SORA in nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steato hepatitis (NASH)-related HCC. METHODS: We evaluated 504 HCC patients treated with SORA (Study-1). The times of administration for sorafenib from 2009 to 2015, 2016 to 2017, and 2018 and later were defined as the early-, mid-, and late-term periods, respectively. Among them, 180 HCC patients treated with SORA in addition to MTAs in the mid- and late-term periods were divided into groups based on disease etiology (NAFLD or NASH [n = 37] and viral or alcohol [n = 143]), and outcomes were compared after inverse probability weighting (IPW) (Study-2). RESULTS: Overall survival (OS) of HCC patients who received sequential MTA therapy after first-line SORA was significantly longer. The median survival times (MST) were 12.6 versus 17.6 versus 17.4 months in the early-term group, mid-term group, and the later-time group (early vs. mid, p = 0.014, early vs. later. p = 0.045), respectively. (Study-1). In Study-2, there was no significant differences in OS between the Virus/alcohol group and the NAFLD/NASH group in patients who received sequential therapy (MST was 23.4 and 27.0 months p = 0.173, respectively). The NAFLD or NASH, female sex, albumin-bilirubin (ALBI) grade 2b, and major Vp (Vp3/Vp4) were significant factors for OS treated with SORA. CONCLUSIONS: Sequential therapy with SORA as the first-line treatment improved the prognosis of unresectable HCC patients and was effective regardless of HCC etiology.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

Geological and hydrochemical prerequisites of unexpectedly high biodiversity in spring ecosystems at the landscape level.

This study explores the factors affecting the biodiversity of diatoms, vegetation with focus on bryophytes, and invertebrates with focus on water mites, in a series of 16 spring-habitats. The springs are located primarily from the mountainous part of the Emilia-Romagna Region (Northern Apennines, Italy), and two pool-springs from agricultural and industrial lowland locations. Overall, data indicate that biological diversity (Shannon-Wiener, α-diversity) within individual springs was relatively low, e.g.: Sdiatoms = 0-46, Swater-mites = 0-11. However, when examined at the regional scale, they hosted a very high total number of taxa (γ-diversity; Sdiatoms = 285, Swater-mites = 40), including several new or putatively-new species, and many Red-List taxa. This pattern suggested there is high species turnover among springs, as well as high distinctiveness of individual spring systems. A key goal was to assess the hydrogeological and hydrochemical conditions associated with this high regional-pool species richness, and to provide a guide to future conservation strategies. There was a striking variety of geological conditions (geodiversity, captured mainly with lithotype and aquifer structure) across the study region, which led to wide variation in the hydrosphere, especially in conductivity and pH. Agriculture and industrial activities (anthroposphere) in the lowlands resulted in nutrient enrichment and other forms of pollution. Across all 16 spring-systems, several hydrogeological conditions most strongly influenced the presence or absence of particular biota and were determinants of species importance: spring-head morphology, hydroperiod, discharge, current velocity, and elemental concentration. These findings have important practical consequences for conservation strategies. Our data show that it is imperative to protect entire regional groups of springs, including representatives of the different ecomorphological spring types, lithologies, and degrees of human influence. These findings suggest that springs, when studied from an ecohydrogeological perspective, are excellent systems in which to further investigate and understand geo-biodiversity relationships.

A randomized study of extended treatment with peginterferon alpha-2b plus ribavirin based on time to HCV RNA negative-status in patients with genotype 1b chronic hepatitis C.

OBJECTIVES: The treatment of patients with hepatitis C virus (HCV) genotype 1 with peginterferon plus ribavirin treatment for more than 48 weeks demonstrated high sustained virological response (SVR) rates. Although many studies extended the duration of therapy from 48 weeks to 72 weeks, the optimal duration has not yet been determined. METHODS: A total of 113 genotype 1b patients with high viral load were randomized at baseline to the standard (n=56) or extended (n=57) treatment group. The standard group patients received 48 weeks of peginterferon plus ribavirin treatment. In the extended group, the treatment was performed for 44 weeks after patients became negative for HCV RNA (total duration 48-68 weeks). RESULTS: The SVR rate of the standard and extended group was 36% (20 of 56) and 53% (30 of 57; P=0.07). However, the extended group patients who became negative for HCV RNA between weeks 16 and 24 had a significantly higher SVR rate (78%; 7 of 9) than that of standard group (9%, 1 of 11; P=0.005). The predictive factors for the SVR were the treatment regimen (the standard vs. extended treatment) and the time to HCV RNA negative-status. CONCLUSIONS: The extended treatment significantly increased the SVR rate in patients who were HCV RNA negative at 16-24 weeks.

Lamivudine treatment-related morphological changes of esophageal varices in patients with liver cirrhosis.

AIM: Many studies have reported the therapeutic effects of lamivudine on cirrhotic patients with hepatitis B; however, no study has investigated the morphological changes of esophageal varices after lamivudine treatment. METHOD: The morphological changes of esophageal varices in patients with cirrhosis were retrospectively compared between 12 patients treated with lamivudine and six historical untreated patients. RESULTS: In the treated group, the HBV DNA and hyaluronic acid (HA) levels in the serum were significantly lower than those in the untreated group (P = 0.013 and P = 0.009, respectively) at the end of follow-up, with a significant improvement in the Child-Pugh-Turcotte score (P = 0.022). In the treated group, the disappearance or reduction of esophageal varices was observed in six (50%) of the 12 patients. In three (25%) of the 12 patients, esophageal varices worsened. In the remaining three patients (25%), there were no changes in esophageal varices. In the untreated group, all patients showed the worsening of esophageal varices during the follow-up period, with a significant difference between this group and the treated group (P = 0.009). The serum HA level decreased in the nine treated patients without worsening of esophageal varices. However, in the three patients with worsening, the HA level significantly increased. CONCLUSION: Lamivudine treatment for patients with cirrhosis improves not only liver function but also esophageal varices.

Granulocytapheresis (GCAP) for severe alcoholic hepatitis-A preliminary report.

AIM: To evaluate the efficacy of granulocytapheresis therapy in alcoholic hepatitis. METHODS: We attempted to trap leukocytes in the peripheral circulation using the granulocytapheresis (GCAP) technique in patients with severe alcoholic hepatitis who showed a marked elevation of peripheral leukocytes. Corticosteroids were co-administered. RESULTS: The Maddrey's indices for these patients varied between 42 and 117 and MELD scores for alcoholic hepatitis (Mayo) ranged from 20 to 44. Survival rate was 50% (3/6), which is better than the results reported recently for similar patients in a national survey (29%). The effect of GCAP was reflected in decreases in interleukin-6 and interleukin-8 levels as well as in serum concentrations of soluble intercellular adhesion molecule. White blood cell counts were not affected. In the surviving patients, the Maddrey's indices and MELD scores for alcoholic hepatitis varied between 49 and 67, and 20 and 22, respectively, showing that GCAP is effective in patients with disease of moderate severity. Hemolytic anemia occurred in one patient after GCAP therapy. Other events such as pancreatitis, pneumonia, and cerebral hemorrhage were considered to be related to the alcoholic hepatitis itself. CONCLUSION: GCAP therapy deserves further evaluation as a new therapeutic modality for a moderately severe alcoholic hepatitis.

Timing of interferon therapy and sources of infection in patients with acute hepatitis C.

BACKGROUND/AIMS: Controversy over the selection of patients and optimum therapeutic method for acute hepatitis C has continued. The aims of this study were to investigate the source of infection, and to evaluate the timing of interferon (IFN) therapy in patients with acute hepatitis C in Japan. METHODS: The records of 102 patients from 12 facilities in Japan who developed acute hepatitis C after 1990 were investigated. In the patients treated with IFN, we performed multivariate analysis to investigate factors related to sustained virological response (SVR). RESULTS: Medical procedure was the most common source of infection, accounting for 32.4% in the 102 patients (33/102). Of 81 patients treated with IFN, 71 patients were followed after IFN therapy, and 57/71 (80.3%) had SVR. The SVR rate was significantly higher in patients treated with IFN within 24 weeks from onset of symptoms than the SVR rate in those treated after 25 weeks (P=0.0016). Multivariate analysis revealed that only the duration between onset of symptoms and initiation of IFN therapy (within 24 weeks) was related to SVR. CONCLUSIONS: Our multicenter cooperative survey revealed that medical procedure was the most frequent source of infection in acute hepatitis C. As concerns the therapy, interferon treatment should be initiated within 24 weeks after onset of symptoms.

A global review on ambient Limestone-Precipitating Springs (LPS): Hydrogeological setting, ecology, and conservation.

Springs are biodiversity hotspots and unique habitats that are threatened, especially by water overdraft. Here we review knowledge on ambient-temperature (non-geothermal) freshwater springs that achieve sufficient oversaturation for CaCO3 -by physical CO2 degassing and activity of photoautotrophs- to deposit limestone, locally resulting in scenic carbonate structures: Limestone-Precipitating Springs (LPS). The most characteristic organisms in these springs are those that contribute to carbonate precipitation, e.g.: the mosses Palustriella and Eucladium, the crenophilous desmid Oocardium stratum, and cyanobacteria (e.g., Rivularia). These organisms appear to be sensitive to phosphorus pollution. Invertebrate diversity is modest, and highest in pools with an aquatic-terrestrial interface. Internationally, comprehensive legislation for spring protection is still relatively scarce. Where available, it covers all spring types. The situation in Europe is peculiar: the only widespread spring type included in the EU Habitat Directive is LPS, mainly because of landscape aesthetics. To support LPS inventorying and management to meet conservation-legislation requirements we developed a general conceptual model to predict where LPS are more likely to occur. The model is based on the pre-requisites for LPS: an aquifer lithology that enables build-up of high bicarbonate and Ca(2+) to sustain CaCO3 oversaturation after spring emergence, combined with intense groundwater percolation especially along structural discontinuities (e.g., fault zones, joints, schistosity), and a proper hydrogeological structure of the discharging area. We validated this model by means of the LPS information system for the Emilia-Romagna Region (northern Italy). The main threats to LPS are water diversion, nutrient enrichment, and lack of awareness by non-specialized persons and administrators. We discuss an emblematic case study to provide management suggestions. The present review is devoted to LPS but the output of intense ecological research in Central Europe during the past decades has clearly shown that effective conservation legislation should be urgently extended to comprise all types of spring habitats.

An analysis of drug-induced liver injury, which showed histological findings similar to autoimmune hepatitis.

BACKGROUND: Drug-induced liver injury (DILI) sometimes resembles autoimmune hepatitis (AIH) in its hepatic histology. However, there is lacking data of a comparison of the characteristics between such DILI and DILI without histological findings like AIH. METHODS: We enrolled 62 patients with DILI who were diagnosed using the Roussel Uclaf Causality Assessment Method, and performed a liver biopsy. These patients were classified into two groups: DILI with histology like AIH (group A, n = 23) and DILI without such histology (group B, n = 39). Sixteen patients of group A could be further classified into two groups: patients with relapse of the liver injury (group C, n = 8) and without relapse (group D, n = 8), after the recovery of the DILI. We compared the clinical and histological findings between group A and B, and group C versus D. RESULTS: Group A was characterized by an older age (p = 0.043), higher immunoglobulin G level (p = 0.017), positive antinuclear antibody status (p = 0.044), and a higher frequency of complementary alternative medicines and Chinese herbal medicines as the causative drug (p = 0.008). There were no significant differences between group C and D regarding the clinical data and liver histological findings. CONCLUSIONS: The clinical characteristics of DILI, which showed histological findings similar to AIH, were revealed. In such patients, a liver biopsy is recommended in order to determine the appropriate treatment strategy. In DILI with histology like AIH patients, long-term follow-up is needed to perceive the relapse.

Evaluation of Resistance-Associated Substitutions in NS5A Using Direct Sequence and Cycleave Method and Treatment Outcome with Daclatasvir and Asunaprevir for Chronic Hepatitis C Genotype 1.

BACKGROUND: The aim of this study was to evaluate the efficacy of daclatasvir plus asunaprevir therapy in patients infected with hepatitis C virus and determine its relevance to resistant variants. METHODS: A total of 629 consecutive patients infected with hepatitis C virus genotype 1 were assessed. Daclatasvir (60 mg/day) plus asunaprevir (200 mg/day) was given for 24 weeks. The virological responses and resistance-associated substitutions of hepatitis C virus mutants were examined by the direct sequence and cycleave methods were evaluated. RESULTS: Overall, 89.4% (555/621) of patients exhibited a sustained virological response (SVR). The SVR rates in the patients with wild type, mixed, and mutant type Y93 by direct sequencing were 92.5% (520/562), 70.3% (26/37), and 42.9% (9/21), respectively. The SVR rates in the patients with 100%, 90%, 80%-30%, and 20%-0% Y93 wild by the cycleave method were 93.4% (456/488), 88.2%(30/34), 56.0%(14/25), and 36.8%(7/19), respectively. In contrast, the SVR rates for the wild type and mixed/mutant type L31 by direct sequencing were 90.2% (534/592) and 72.4% (21/29), respectively. In the multivariate analyses, the wild type Y93, no history of simeprevir therapy, the wild type L31, and low HCV RNA level were independent factors of SVR. CONCLUSION: NS5A resistance-associated substitutions, especially Y93H, were major factors predicting the SVR. Although direct sequencing can predict the SVR rate, the cycleave method is considered to be more useful for predicting the SVR when used in combination.

Clinical course of patients with chronic hepatitis B with viral breakthrough during long-term lamivudine treatment.

BACKGROUND: We evaluated the clinical course of patients with chronic hepatitis B who showed viral breakthrough during long-term lamivudine therapy. METHODS: We initially studied 141 patients treated with lamivudine for 1 year or more, and 49 patients who showed viral breakthrough were the subjects of this study. Their mean lamivudine administration period was 2.3 +/- 0.9 years. RESULTS: After viral breakthrough, breakthrough hepatitis occurred in 47 patients (95.9%), but did not occur in the other 2 (4.1%). Four of the 47 patients with breakthrough hepatitis were observed without further treatment, and the alanine transferase (ALT) level was normalized in 2 of them but fluctuated in the other 2. Breakthrough hepatitis was treated by injection of glycyrrhizin or ursodeoxycholic acid administration in 36 of the remaining 43 patients, and by antiviral drug administration in the other 7 (entecavir in 2 patients, adefovir in 2, and interferon in 3). The ALT level was normalized in 5 of the 36 patients treated with glycyrrhizin or ursodeoxycholic acid, but persistently fluctuated in the other 31. In those with normalized ALT after the occurrence of breakthrough hepatitis, the peak ALT level at that point was significantly lower (86 +/- 47 IU/l) than that in the patients without normalization (206 +/- 167 IU/l). CONCLUSIONS: These results showed that there were a few patients who did not develop breakthrough hepatitis after showing viral breakthrough, and some who showed normalization of the ALT level after the occurrence of breakthrough hepatitis, but in many patients, ALT continuously fluctuated.

Torsion of the gallbladder, localized in right subphrenic space in a patient with liver cirrhosis.

We report a case of torsion of the gallbladder displaced under the right subphrenic space in a patient with liver cirrhosis. An 82-year-old Japanese woman was admitted to our hospital for acute pain in the right upper quadrant. Clinical features suggested gallbladder torsion. She was under treatment for hepatitis C virus-related cirrhosis at our hospital. Abdominal CT showed the swollen fundus and body of the gallbladder under the right subphrenic space. Emergency laparoscopic cholecystectomy was performed. Intraoperative findings included a grossly necrotic gallbladder in the right subphrenic space with 360° clockwise torsion, together with liver cirrhosis and localized peritonitis. The clinical features and imaging findings in this rare case of misplaced gallbladder in right subphrenic space resembled those described in typical strangulated gallbladder. The displacement was probably related to right liver lobe atrophy associated with liver cirrhosis. Appropriate diagnosis and prompt surgical treatment are essential for a positive outcome.

A significant reduction in serum alanine aminotransferase levels after 3-month iron reduction therapy for chronic hepatitis C: a multicenter, prospective, randomized, controlled trial in Japan.

BACKGROUND: Increasing evidence indicates that iron cytotoxicity plays an important role in the pathogenesis of chronic hepatitis C (CHC). However, the biochemical effects of iron reduction therapy on CHC remain to be confirmed in a controlled study. This study aimed to test whether iron removal by repeated phlebotomy improves serum alanine aminotransferase (ALT) levels in patients with CHC. METHODS: Patients were randomly assigned to an iron reduction therapy or control group. The patients in the treatment group received 3-month iron reduction therapy by biweekly phlebotomy, while the patients in the control group were followed up for 3 months with regular blood tests alone. RESULTS: Thirty-three patients completed the 3-month treatment, while 29 patients received the complete follow-up. The serum ALT levels were reduced from 118 +/- 79 to 73 +/- 39 IU/L in the treatment group, but did not change in the control group (106 +/- 45 versus 107 +/- 48 IU/L). Posttreatment enzyme activity was decreased significantly from the baseline. Furthermore, it was significantly lower than the 3-month control level. Although 5 patients withdrew from the study, none was affected by any side effects of repeated phlebotomy that required them to discontinue the treatment. CONCLUSIONS: This short-term controlled trial demonstrated the biochemical efficacy and safety of iron reduction therapy for patients with CHC.

A pilot study of eicosapentaenoic acid therapy for ribavirin-related anemia in patients with chronic hepatitis C.

One of the major side effects of ribavirin/interferon alpha combination therapy for chronic hepatitis C is hemolytic anemia. One of the causes of hemolytic anemia is considered to be decreasing deformability of erythrocytes resulting from the accumulation of phosphorylated ribavirin in erythrocytes. The administration of eicosapentaenoic acid (EPA), which has a wide variety of pharmacological actions, increases the deformability of erythrocytes. We conducted an uncontrolled pilot study of EPA therapy for patients with ribavirin-related anemia. Six patients with chronic hepatitis C, who had developed anemia while receiving combination therapy, were treated with an oral ethyl ester of EPA (1800 mg/day) for two months. The hemoglobin level of all six patients increased following EPA therapy. The mean hemoglobin level significantly increased from 10.8 g/dl to 11.4 g/dl one month after therapy was initiated (P<0.05), and this level was obtained again one month later (11.5 g/dl). None of the patients developed an adverse reaction. These findings suggest that EPA has a beneficial effect in patients with ribavirin-related anemia. Further study is required to confirm our results.

Predictive factors for remission and death in 73 patients with autoimmune hepatitis in Japan.

The prognosis of patients with autoimmune hepatitis (AIH) has not been clearly defined. The aim of this study was to define the prognostic factors of AIH in a population with long-term follow-up in Japan. Seventy-three patients who were diagnosed as having type 1 AIH between January, 1972 - August, 1999 were enrolled in this study. Initial treatment included prednisolone (PSL) (n=62), other drug regimens (n=7), and none (n=4). We examined the relation between several factors obtained at diagnosis in relation to disease activity found at the final observation point (January, 2000 - April, 2000). Multivariate logistic regression and Cox regression were used for statistical analysis. During the observation period, 8 patients died of the following: hepatic failure (n=4), hepatocellular carcinoma (n=1), severe infection (n=1), and unknown causes (n=2). At the end point, the number of patients in complete remission was 13, those with a normal alanine aminotransferase (ALT) level requiring some treatment was 35, and those with an abnormal ALT level despite medication was 17. Factors related to remission were total bilirubin (TB) (Odds ratio, 0.87), and immunoglobulin G (IgG) (Odds ratio, 1.00). Factors related to death were the aspartate aminotransaminase (AST)/ALT ratio (Odds ratio, 11.67) and response to initial PSL regimen (Odds ratio, 0.03). The results of this study show an importance of achieving a good PSL response at onset, and that initial TB, the AST/ALT ratio, and IgG levels are useful for therapeutic strategy.

Short term and two-step interferon therapy for chronic hepatitis C patients with low HCV RNA levels.

Objective: Chronic hepatitis C patients with low HCV RNA levels were treated with short term therapy and for patients in whom the virus was not eliminated in this short therapy, we designed a two-step IFN therapy. Subjects: There were 31 patients with chronic hepatitis C whose HCV RNA level before IFN therapy was <1.0 Meq/ml or 100 kcopies/ml. The HCV serotypes were serotype 1 in nine patients, serotype 2 in 21 and mixed type in one. A 9--10 MU per day of natural IFN was administered daily for 2 weeks, then three times weekly for 8 weeks (the first therapy), then the therapy was ended. For patients in whom the virus was not eliminated, an additional IFN therapy was administered during the decreasing phase of HCV RNA (second therapy). The historical control group consisted of 57 patients who fulfilled the above criteria and underwent IFN therapy for 24 weeks. Complete responders were defined as patients in whom HCV RNA was not detected in their serum for at least 6 months after the end of treatment. Results: Nineteen (61%) of 31 patients who completed the first therapy showed complete response to the first therapy. Eight patients underwent the second therapy and the complete response rates were 0/4 and 2/4 (50%) in the serotype 1 and 2 groups, respectively. The overall complete response rate was 44% (4/9) in the serotype 1 group, 76% (16/21) in the serotype 2 group and 100% (1/1) in the mixed type. The complete response rate in the historical control group was 70% (40/57), showing no difference in efficacy. However, the IFN dosage was significantly lower in the patients than in the control group (P<0.001). Conclusions: In patients with low HCV RNA levels and serotype 2, short term therapy is sufficiently effective. Furthermore, 50% of the complete response was obtained by an additional second therapy. This therapy design showed high efficacy and was cost-effective in these patients.

Interferon-gamma brings additive anti-viral environment when combined with interferon-alpha in patients with chronic hepatitis C.

T-cell hyporesponsiveness may lead to chronicity of hepatitis C virus (HCV) infection. We evaluated whether interferon (IFN)-gamma injection can bring a Th1-dominant environment to patients with chronic hepatitis C. Seventeen patients with genotype 1b received natural IFN-alpha 5MU daily for the first 2 weeks and three times a week for the next 22 weeks followed by natural IFN-gamma 1 MU daily for 2 weeks. In 4 of 17 patients (23.5%), alanine aminotransferase (ALT) was normalized and 3 of these 4 patients (75.0%) cleared HCV RNA. beta2 microglobulin (BMG), neopterin and soluble (s) Fas increased with IFN-alpha and increased more with IFN-gamma. Serum interleukin (IL)-12, CD4 and CD8 remained unchanged with IFN-alpha but increased after IFN-alpha was replaced by IFN-gamma. IL-10 was not changed either with IFN-alpha or gamma. Productions of IL-2, IFN-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells did not change by IFN-alpha therapy, however, they were enhanced at the end of IFN-gamma therapy. Productions of IL-2 and 4 were unaffected. These results show that some immune parameters become Th1-dominant by additional IFN-gamma in patients with chronic hepatitis C. Combination of these two IFNs should be explored.

Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis.

Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.

Risk factors for hepatocellular carcinoma in Japanese patients with autoimmune hepatitis type 1.

BACKGROUND: Hepatocellular carcinoma (HCC) is occasionally seen even in patients with autoimmune hepatitis (AIH) without prior infection either with hepatitis C virus (HCV) or hepatitis B virus. The aim of this study was to identify the incidence of and risk factors for HCC with AIH in a large-scale population with a long-term follow-up in Japan. METHODS: One hundred and eighty patients diagnosed with AIH were enrolled (F/M = 159/21; mean age, 59.9 years; mean observation period, 80.2 months). Patients with positive HCV antibody/serum HCV RNA and/or positive HBs Ag were excluded. Initial treatment included immunosuppressant therapy (n = 147), other drugs (n = 28), and no drug (n = 5). Patients underwent abdominal ultrasonography at intervals of 3-6 months during observation. Patients' demographic factors, biochemical data, liver histology, medications, response to treatment, and complications were evaluated in relation to HCC. RESULTS: During the observation period, six patients (3.3%) developed HCC. Univariate analysis showed that risk factors for HCC were cirrhosis at diagnosis with AIH (p = 0.0002), absence of a treatment response (p = 0.033), abnormal alanine aminotransferase (ALT) at the final observation (p = 0.0002), and diabetes (p = 0.0015). Multivariate analysis showed that risk factors for HCC were cirrhosis at diagnosis of AIH (odds ratio 4.08) and abnormal ALT at final observation (odds ratio 3.66). CONCLUSION: This retrospective study showed that cirrhosis at diagnosis of AIH and abnormal ALT at final observation were independently associated with HCC development. It is important to pay attention to the presence of cirrhosis at diagnosis of AIH and to normalize ALT.