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A 74-year-old man with a history of transfusion at 35 years old in Egypt was referred to our hospital. He was infected with hepatitis C virus (HCV) genotype 4 (GT4), which is a rare HCV GT in Japan, and was also diagnosed with hepatic compensated cirrhosis. We safely treated the patient for 12 weeks with the combination of glecaprevir and pibrentasvir, and a sustained virologic response (SVR) was achieved. This is the first report of HCV GT4 infection in a treatment-naïve Japanese patient with cirrhosis in whom SVR was achieved with the combination treatment of glecaprevir and pibrentasvir.

Cytokines are secreted soluble glycoproteins that regulate cellular growth, proliferation, and differentiation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate cytokine signaling and form a classical negative feedback loop in the signaling pathways. There are eight members of the SOCS family. The SOCS proteins are all comprised of a loosely conserved N-terminal domain, a central Src homology 2 (SH2) domain, and a highly conserved SOCS box at the C-terminus. The role of SOCS proteins has been implicated in the regulation of cytokines and growth factors in liver diseases. The SOCS1 and SOCS3 proteins are involved in immune response and inhibit protective interferon signaling in viral hepatitis. A decreased expression of SOCS3 is associated with advanced stage and poor prognosis of patients with hepatocellular carcinoma (HCC). DNA methylations of SOCS1 and SOCS3 are found in HCC. Precise regulation of liver regeneration is influenced by stimulatory and inhibitory factors after partial hepatectomy (PH), in particular, SOCS2 and SOCS3 are induced at an early time point after PH. Evidence supporting the important role of SOCS signaling during liver regeneration also supports a role of SOCS signaling in HCC. Immuno-oncology drugs are now the first-line therapy for advanced HCC. The SOCS can be potential targets for HCC in terms of cell proliferation, cell differentiation, and immune response. In this literature review, we summarize recent findings of the SOCS family proteins related to HCC and liver diseases.

Recently, the use of immune checkpoint inhibitors (ICIs) with or without chemotherapeutic agents has been increasing in the treatment for advanced cancer. Here, we report the occurrence of liver failure after the use of pembrolizumab in an 82‐year‐old woman with metastatic liver disease derived from right advanced renal pelvis, ureteral cancer, and bladder cancer. She was successfully treated with 0.6 mg/kg daily prednisolone. In patients treated with ICIs, ICI‐induced hepatitis is occasionally observed. Even if patients are older, it appears important to diagnose and treat ICI‐induced hepatitis earlier by multidisciplinary therapies including steroid treatment. This is a first report of pembrolizumab‐induced liver failure in elder patient with age over 80 years. Even if patients are older, it appears important to diagnose and treat ICI‐induced hepatitis earlier by multidisciplinary therapies including steroid treatment., We experienced the occurrence of liver failure after the use of pembrolizumab in an 82‐year‐old woman with metastatic liver disease. Immune checkpoint inhibitor‐induced hepatitis is occasionally observed. It seems important to diagnose and treat older patients with immune checkpoint inhibitor‐induced hepatitis earlier by multidisciplinary therapies.

Background & aim: Higher elevation of alanine aminotransferase (ALT) occasionally leads to severe outcomes in hepatitis B virus (HBV)-infected patients. Our aim is to investigate the HBV sequence mutations associated with higher ALT elevation. Materials & methods: We analyzed full-length HBV sequences from patients with or without higher ALT elevation. Results: Nucleotide mutations in precore and core regions, which are associated with severe hepatitis B, were found in two HBV-infected patients with higher ALT elevation. Amino acid mutations within the pre-S1, pre-S2 and S regions were also found in a patient with HBV virologic breakthrough during the use of nucleoside analogs. Conclusion: It may be useful for HBV-infected patients with higher ALT elevation to analyze full-length HBV genome.

Hepatis virus C (HCV) infection causes liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The objective of our study was to examine the effects of the HCV nonstructural protein (NS) 3/4A inhibitor glecaprevir/NS5A inhibitor pibrentasvir on real-world HCV patients in the northern part of Tokyo, Japan. Although 106 patients were consecutively included, a total of 102 HCV-infected patients with chronic hepatitis or compensated cirrhosis, who received 8- or 12-week combination treatment with glecaprevir/pibrentasvir and were followed up to week 12 after the end of treatment were analyzed retrospectively. Only three patients discontinued treatment due to adverse events; however, they achieved a sustained virologic response at 12 weeks (SVR12). Finally, SVR rates were 99.0% (101/102). Only one patient without liver cirrhosis was a treatment relapser who received hepatic resection for HCC approximately two years after commencement of the 8-week combination treatment with glecaprevir/pibrentasvir. After the exclusion of patients with HCV genotype 1b and P32 deletion in the HCV NS5A region, a 12-week combination of glecaprevir/pibrentasvir led to SVR12 in all nine direct-acting antiviral-experienced patients. Glecaprevir/pibrentasvir had a high efficacy and an acceptable safety profile for real-world HCV patients in a single hospital in Japan.

Background Hepatocellular carcinoma (HCC) occasionally presents with simultaneous or metachronous primary malignancies of other organs. Despite the limited scope of cytocidal anticancer drugs or molecular targeted agents, immune checkpoint inhibitors (ICIs) can still be used for various malignancies. Here, we present cases of double cancers including HCC treated with ICIs. Case report Case 1: A 70-year-old man with lung cancer and 80-mm HCC underwent nivolumab therapy. The sizes of both cancers remained constant for nine months. Case 2: A 58-year-old man with pharyngeal cancer and HCC. Nivolumab was administered, but was withdrawn after one session because of progressive disease. Case 3: A 71-year-old man with a 5 cm HCC invading the inferior vena cava, and early esophageal cancer. HCC showed a significant volume reduction and esophageal cancer demonstrated slight improvement by atezolizumab and bevacizumab therapy. Conclusion A combination therapy including ICI is a promising treatment option for HCC with concurrent malignancies.

Background: Direct-acting antiviral agents (DAAs) have improved sustained virologic response (SVR) rates in patients with chronic hepatitis C virus (HCV) infection. Our aim was to elucidate the occurrence of hepatocellular carcinoma (HCC) and to compare the outcomes of patients aged 75 years or older (older group) with those of patients younger than 75 years (younger group) after SVR. Methods: Among 441 patients treated with interferon-free DAA combinations, a total of 409 SVR patients were analyzed. We compared the two age groups in terms of HCC incidence and mortality rates. Results: Older and younger groups consisted of 68 and 341 patients, respectively. Occurrence of HCC after SVR did not differ between the two groups of patients with a history of HCC. Occurrence of HCC after SVR was observed more in younger patients without a history of HCC (p &lt, 0.01). Although older patients without a history of HCC had a higher mortality rate (p &lt, 0.01), their causes of death were not associated with liver diseases. Among younger patients without a history of HCC, none died. Conclusions: After SVR, liver disease may not be a prognostic factor in older HCV patients without a history of HCC.

Hepatitis B virus (HBV) genotypes affect the pathogenesis of disease progression during the course of HBV infection. In Japan, HBV genotype H is one of the rare HBV genotypes. We recovered HBV genotype H from a blood sample from a Japanese HIV-infected patient with acute exacerbation of chronic HBV infection. Due to the development of drugs for treating HBV and HIV, HBV genotype H and HIV coinfection has been well controlled by nucleos(t)ide analogs and highly active antiretroviral therapy, respectively, from 2002 to 2019. Further study is needed with regard to HBV genotype H and its pathogenesis.

BACKGROUND We examined treatment the efficacy and data on long-term outcomes in real-world Japanese patients infected with hepatitis C virus (HCV) genotype 2 treated with 12-week sofosbuvir/ribavirin combination therapy. PATIENTS AND METHODS In a total of 86 patients who were treated with sofosbuvir/ribavirin, sustained virological response (SVR) rates and long-term-outcomes were retrospectively analyzed. RESULTS The adherence to this combination therapy was 98.8%. The rates of SVR at week 24 (SVR24) achieved with this treatment according to the 'intention-to-treat' and 'per-protocol' analyses were 89.5% and 96.2%, respectively. Two patients who experienced relapse did not have any previously reported resistance-associated substitutions in the HCV non-structural protein 5B (NS5B) polymerase region. We did not observe any patients who experienced late relapse but did observe that 50% and 1.3% of patients with and without a previous history of hepatocellular carcinoma (HCC), respectively, developed HCC after achieving SVR24 (with a mean follow-up period of 2.7±0.8 years). CONCLUSION Patients with SVR should be carefully followed-up to screen for the occurrence of HCC, although it is infrequent.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing worldwide. Several effective drugs for these diseases are now in development and under clinical trials. It is important to reveal the mechanism of the development of NAFLD and NASH. We investigated the role of arrestin domain-containing protein 3 (ARRDC3), which is linked to obesity in men and regulates body mass, adiposity and energy expenditure, in the progression of NAFLD and NASH. We performed knockdown of endogenous ARRDC3 in human hepatocytes and examined the inflammasome-associated gene expression by real-time PCR-based array. We also examined the effect of conditioned medium from endogenous ARRDC3-knockdown-hepatocytes on the apoptosis of hepatic stellate cells. We observed that free acids enhanced the expression of ARRDC3 in hepatocytes. Knockdown of ARRDC3 could lead to the inhibition of inflammasome-associated gene expression in hepatocytes. We also observed that conditioned medium from endogenous ARRDC3-knockdown-hepatocytes enhances the apoptosis of hepatic stellate cells. ARRDC3 has a role in the progression of NAFLD and NASH and is one of the targets for the development of the effective treatment of NAFLD and NASH.

Recently, we experienced an outbreak of acute hepatitis A virus (HAV) infection between 2018 and 2020. Herein, we describe this male-dominant HAV infection outbreak observed among non-human immunodeficiency virus (HIV)-infected persons in the northern part of Tokyo, Japan. Clinical information was collected from patient interviews and from medical record descriptions. In the present study, 21 patients were retrospectively analyzed. A total of 90.4 and 33.3% of patients were males, and men who have sex with men (MSM), respectively. The total bilirubin levels and platelet counts tended to be lower in the MSM group than in the non-MSM group. C-reactive protein (CRP) levels tended to be higher in acute liver failure (ALF) patients than in non-ALF patients. Prolonged cholestasis was observed in one patient (4.8%). We also found that 18 HAV isolates belonged to HAV subgenotype IA/subgroup 13 (S13), which clustered with the HAV isolate (KX151459) that was derived from an outbreak of HAV infection among MSM in Taiwan in 2015. Our results suggest that the application of antivirals against HAV, as well as HAV vaccines, would be useful for the treatment and prevention of severe HAV infection.

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.

The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.

A 70-year-old woman with hepatitis C cirrhosis underwent balloon-occluded retrograde transvenous obliteration for hepatic encephalopathy due to spleno-renal shunt. Because the shunt was thick, long, and winding, we used a coaxial and double interruption system, which enables the effective occlusion of the drainage route, and shape-memory coils, which are more physically stable than conventional metallic coils because they form three-dimensional loops. The patient was successfully treated with the combined usage of these devices, resulting in a normal serum ammonia level. Thereafter, the patient was treated with direct-acting antivirals, and a sustained virological response was achieved.

Objective: Hepatitis C virus (HCV) infection has long been treated with interferon therapy (IFN). Currently, more than 90% of IFN-treated patients show a sustained virological response (SVR) when also treated with ribavirin and/or a protease inhibitor. Histological inflammation and fibrosis improve in IFN-treated patients, which indicates HCV clearance. IFN also reduces the incidence of hepatocellular carcinoma (HCC). However, a small proportion of patients with SVR develop HCC. To investigate the causes of hepatic carcinogenesis after SVR, we compared the liver histological findings before IFN to those after the development of HCC. Patients and methods: In total, 602 patients infected with type C chronic hepatitis or with liver cirrhosis who received IFN therapy during the period from 1992 through 2015 were included in this study. We assessed 14 of the 287 patients who achieved an SVR. Results: HCC was diagnosed by computed tomography, angiography or liver biopsy. The longest time from the SVR until HCC detection was 16.5 years, and the mean was 7.2±4.6 years. Nine of the 14 patients underwent surgery and one radiofrequency ablation. The histological findings of 10 patients were available for comparison. The comparison of the histological findings before treatment with those after the HCC diagnosis revealed an amelioration of liver fibrosis and other inflammatory changes. All ten patients showed improvements in fibrosis and steatosis. However, we observed that mild inflammatory change persisted from 1.8 years to 16.5 years after the confirmation of SVR in all cases. Conclusion: We suspect that persistent histological inflammation is one of the factors contributing to hepatocarcinogenesis (i.e., HCC development) even after successful treatment.

Background: The involvement of serum ornithine carbamoyltransferase (OCT) in the progression of chronic hepatitis and liver cirrhosis is unclear. Methods: A total 256 patients with chronic hepatitis C and 5 healthy controls were examined. Serum OCT concentrations were measured by enzyme-linked immunosorbent assay. Serum OCT concentrations were compared with serum cytokine and chemokine levels, and with disease severity and development of hepatocellular carcinoma (HCC). Results: The median OCT concentrations were 21.8 ng/ml for healthy controls, 36.7 ng/ml for F0 stage disease, 48.7 ng/ml for F1 stage, 77.9 ng/ml for F2 stage, 104.8 ng/ml for F3 stage, and 121.4 ng/ml for F4 stage. OCT concentrations were correlated with aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet counts, indocyanine green retention rate at 15 min, prothrombin times, the molar ratio of branched chain amino acids to tyrosine, and tyrosine. Furthermore, there were significant correlations among OCT concentrations and IP10 and IL18 levels. There were weak correlations between serum OCT concentrations and liver histology. The cumulative incidence of HCC in the high-OCT concentration group (≥75.3 ng/ml) was higher than that in the low-OCT concentration group. Conclusion: The measurement of serum OCT concentration may provide a useful marker of disease severity, and thus could be a useful marker for a high risk of HCC occurrence.

Objective: This study aimed to assess the relationship between steatosis and long-term outcomes of patients with chronic hepatitis C (CH) and liver cirrhosis (LC). Patients and methods: The study population included 282 subjects with CH or LC who underwent liver biopsy at our institute. All patients achieved a sustained virological response (SVR) to interferon (IFN). Clinical characteristics, including age, gender and body mass index (BMI), were compared. The liver biopsy specimens of all patients were examined and scores were assigned to indicate the severity of each of the following features: inflammatory cell infiltration in the periportal, parenchymal and portal areas; F (fibrosis) stage; portal sclerotic change; perivenular fibrosis; pericellular fibrosis; bile duct damage; hepatic steatosis. Results: Of the 282 patients, 112 (39.7%) were free of steatosis. The other 170 patients (60.3%) had steatosis. The blood biochemical parameters of the patients with hepatic steatosis were significantly poorer than those of patients free of steatosis. Inflammatory cell infiltration and F stage were both significantly more severe in patients with than in those without steatosis. The incidences of hepatocellular carcinoma differed significantly between the two groups. However, the incidences of hepatocellular carcinoma did not differ significantly between the groups with BMI above and below 25. Conclusion: We consider hepatic steatosis to potentially affect the blood biochemical parameters and clinical profiles of Japanese patients with CH due to hepatitis virus type C. Patients with this form of CH showed favorable clinical responses to IFN. Furthermore, fibrosis and steatosis appear to affect the long-term outcomes of these patients. However, BMI alone cannot be used to predict HCC development.

We experienced two patients with serious arrhythmias associated with the administration of ledipasvir (LDV) and sofosbuvir (SOF). Neither patient took amiodarone, an agent for which concomitant use is prohibited. One patient was 82 years old and hypertensive; the other was 72 years old and had no cardiovascular risk factors such as hypertension or diabetes mellitus. The arrhythmias were both serious ventricular tachycardia (VT) that converted spontaneously to sinus rhythm, without treatment, and both patients had good outcomes. These cases suggest that LDV/SOF may be associated with an increased risk of heart-related events.

We examined treatment the efficacy and data on long-term outcomes in real-world Japanese patients infected with hepatitis C virus (HCV) genotype 2 treated with 12-week sofosbuvir/ribavirin combination therapy.In a total of 86 patients who were treated with sofosbuvir/ribavirin, sustained virological response (SVR) rates and long-term-outcomes were retrospectively analyzed.The adherence to this combination therapy was 98.8%. The rates of SVR at week 24 (SVR24) achieved with this treatment according to the 'intention-to-treat' and 'per-protocol' analyses were 89.5% and 96.2%, respectively. Two patients who experienced relapse did not have any previously reported resistance-associated substitutions in the HCV non-structural protein 5B (NS5B) polymerase region. We did not observe any patients who experienced late relapse but did observe that 50% and 1.3% of patients with and without a previous history of hepatocellular carcinoma (HCC), respectively, developed HCC after achieving SVR24 (with a mean follow-up period of 2.7±0.8 years).Patients with SVR should be carefully followed-up to screen for the occurrence of HCC, although it is infrequent.

Genotype 2 hepatitis C virus (HCV) accounts for up to 30% of chronic HCV infections in Japan. The standard of care for patients with genotype 2 HCV - peginterferon and ribavirin for 24 weeks - is poorly tolerated, especially among older patients and those with advanced liver disease. We conducted a phase 3, open-label study to assess the efficacy and safety of an all-oral combination of the NS5B polymerase inhibitor sofosbuvir and ribavirin in patients with chronic genotype 2 HCV infection in Japan. We enrolled 90 treatment-naïve and 63 previously treated patients at 20 sites in Japan. All patients received sofosbuvir 400 mg plus ribavirin (weight-based dosing) for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after therapy (SVR12). Of the 153 patients enrolled and treated, 60% had HCV genotype 2a, 11% had cirrhosis, and 22% were over the aged 65 or older. Overall, 148 patients (97%) achieved SVR12. Of the 90 treatment-naïve patients, 88 (98%) achieved SVR12, and of the 63 previously treated patients, 60 (95%) achieved SVR12. The rate of SVR12 was 94% in patients with cirrhosis and in those aged 65 and older. No patients discontinued study treatment due to adverse events. The most common adverse events were nasopharyngitis, anaemia and headache. Twelve weeks of sofosbuvir and ribavirin resulted in high rates of SVR12 in treatment-naïve and previously treated patients with chronic genotype 2 HCV infection. The treatment was safe and well tolerated by patients, including the elderly and those with cirrhosis.

This report describes a case of liver failure secondary to pancreatoduodenectomy and rapid recovery following treatment. A 68-year-old woman with cancer on the ampulla of Vater underwent surgery for pancreatoduodenectomy. The patient developed liver failure 3 months postsurgically. She was hospitalized after presenting with jaundice, hypoalbuminemia and decreased serum zinc. Computed tomography (CT) of the abdomen showed a reduction in CT attenuation values postoperatively. We suspected fatty liver due to impaired absorption caused by pancreatoduodenectomy. We initiated treatment with branched-chain amino acids and a zinc formulation orally. Trace elements were administered intravenously. Two months after treatment, there was a noticeable improvement in CT findings. The patient’s jaundice and hypoalbuminemia prompted a liver biopsy, which led to a diagnosis of non-alcoholic steatohepatitis.

It has been reported that levels of soluble intercellular adhesion molecule-1 (ICAM-1) in the blood are elevated in hepatocellular carcinoma patients. In the present study, serial observations of the localization of ICAM-1 in the liver were made by light and electron microscopy in rats with carcinogen-induced cancer. Male Fisher rats were given diethylnitrosamine (DEN) orally in their drinking water. Rats were sacrificed at 6, 8, 12, or 14 weeks after the start of DEN administration and the liver tissue was collected. ICAM-1 expression in liver was assessed using indirect immunoperoxidase staining with anti-rat ICAM-1 antibody. Although ICAM-1 expression by endothelial cells in livers of DEN-treated rats was lower than in the control group at 8 weeks, it was higher in the membrane and cytoplasm of hepatocytes. The expression of ICAM-1 in mesenchymal cells was decreased, paralleling development of cellular atypia, whereas in hepatocyte membranes and cytoplasm it was increased in these atypia. ICAM-1 was localized to the cytoplasm of cancer cells, but to the membrane of hepatocytes in the treated livers at 14 weeks. Furthermore, the levels of ICAM-1 in mesenchymal cells tended to be lower in the cancerous area than in the atypical hyperplastic nodule, and were reduced as the density of cell atypia increased, in comparison to cells in areas without cancerous nodules. We concluded that ICAM-1 may be influenced the development of cancer induced in the rat liver by a chemical carcinogen.

We treated patients with C-viral chronic hepatitis (CH) and liver cirrhosis (LC) with polaprezinc and determined prospectively the effect on long-term outcome. 62 patients were enrolled. Of these, 32 were administered 1.0 g polaprezinc and the remainder were not administered polaprezinc. We measured the serum zinc concentrations using conventional atomic absorption spectrometry and conducted a prospective study to determine the long-term outcome of the polaprezinc therapy. Changes of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in the polaprezinc administration group were significantly lower than those of the untreated group. The decrease in platelet count was clearly less than that of the untreated group. The factors that inhibited increases in serum zinc concentrations following administration of polaprezinc included low serum zinc concentration states. Furthermore, the reductions of AST and ALT levels in the low zinc group were significantly greater than those of the high zinc group. When the patients who were administered polaprezinc were divided into two groups whose zinc concentrations increased (zinc responders) or remained stable or decreased (zinc non-responders), the zinc responders had a clearly lower cumulative incidence of HCC than the zinc non-responders. We conclude zinc supplementation improved the long-term outcome in C-viral CH and LC patients.

We examined prospectively the influence of occult hepatitis B virus (HBV) infection on the histopathological features and clinical outcome of HCV RNA-positive chronic hepatitis (CH-C) and detected hepatitis B core (HBc) particles in hepatocytes. The subjects were 468 patients with CH-C or liver cirrhosis (LC) who were negative for serum hepatitis B surface antigen (HBsAg) by enzyme-linked immunosorbent assay. HBV DNA was detected in serum by nested PCR. HBsAg and HBc antigen (HBcAg) in liver were investigated using immunohistochemical techniques and light (LM) and electron microscopy (EM). Serum HBV DNA was detected in 43.6% of the patients studied. There were no significant differences between HBV DNA-positive and DNA-negative patients in terms of their clinical profiles. For HBV DNA-positive patients, the degree of inflammatory cell infiltration and irregular regeneration of hepatocytes was significantly greater than for HBV DNA-negative patients. The cumulative probability of development of hepatocellular carcinoma (HCC) was significantly higher for HBV DNA-positive patients than for HBV DNA-negative patients. HBV DNA positivity was a risk factor for the occurrence of HCC according to multivariate analysis. HBsAg and HBcAg were detected in 8.5 and 72.3%, respectively, of the livers of serum HBV DNA-positive individuals. Core particles were detected in the nuclei of the hepatocytes by IEM. The histopathological features and long-term outcome of CH-C or LC could be affected by occult HBV infection.

Summary Background Compared with other countries, patients with chronic hepatitis C infection in Japan tend to be older, have more advanced liver disease, and are more likely to have been previously treated for hepatitis C. We aimed to assess the efficacy and safety of an all-oral, fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection. Methods In this randomised, open-label study, we enrolled patients from 19 clinical Japanese centres. Patients were randomly assigned (1:1) to receive either ledipasvir (90 mg) and sofosbuvir (400 mg) or ledipasvir, sofosbuvir, and ribavirin (dosed according to the Japanese Copegus product label—ie, patients ≤60 kg received 600 mg daily, patients >60 kg to ≤80 kg received 800 mg daily, and patients >80 kg received 1000 mg daily) orally once daily for 12 weeks. After completion or early discontinuation of treatment, patients were followed up off-treatment for 24 weeks. Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log 10 IU/mL, creatinine clearance of at least 1·0 mL/s, and a platelet count of at least 50 × 10 9 per L. An interactive web response system was used to manage patient randomisation and treatment assignment. Randomisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category (relapser or breakthrough, non-responder, or interferon-intolerant) for previously treated patients. Within each strata, patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12) assessed in all patients who were randomly assigned and received at least one dose of study drug; safety outcomes were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01975675. Findings Between Oct 15, 2013 and Dec 13, 2013, 341 patients were randomly assigned to treatment groups and received at least one dose of study treatment. SVR12 was achieved in all 171 (100%) patients (83 of 83 treatment naive and 88 of 88 treatment experienced) receiving ledipasvir-sofosbuvir (95% CI 98–100) and 167 (98%) of 170 patients (80 of 83 treatment naive and 87 of 87 treatment experienced) receiving ledipasvir-sofosbuvir plus ribavirin (95% CI 95–100). Of the 76 patients with baseline NS5A resistant variants, 75 (99%) achieved SVR12. Two (1·2%) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events. The most common adverse events were nasopharyngitis (50 [29·2%] of 171), headache (12 [7·0%] of 171), and malaise (nine [5·3%] of 171) in patients receiving ledipasvir-sofosbuvir; and nasopharyngitis (40 [23·5%] of 170), anaemia (23 [13·5%] of 170), and headache in those receiving ledipasvir-sofosbuvir and ribavirin (15 [8·8%] of 170). Interpretation Although existing regimens for the treatment of hepatitis C virus are effective for many patients, medical needs remain unmet, particularly in Japan where the population with hepatitis C virus genotype 1 is generally older and treatment-experienced, with advanced liver disease. The efficacy, tolerability, and absence of drug–drug interactions of ledipasvir-sofosbuvir suggest that it could be an important option for treatment of genotype 1 hepatitis C virus in Japanese patients. Funding Gilead Sciences.

Treating latent tuberculosis infection is a strategy for eliminating tuberculosis, and isoniazid is recommended as preventive therapy. However, concerns have been raised regarding the application of isoniazid due to its toxicity, particularly hepatotoxicity; however, biochemical monitoring is not routinely performed during treatment. We herein present a case of fatal isoniazid-induced acute liver failure. The patient's liver function was not periodically examined and isoniazid therapy was continued for 10 days despite the onset of symptoms associated with hepatitis. The patient died four months after hospitalization. It is essential to consider the potential toxicities of isoniazid and establish strategies to prevent acute liver failure.

OBJECTIVE To determine the impact of phlebotomy on the laboratory values and the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. METHODS Study patients with chronic hepatitis C were treated with glycyrrhizin injection and oral ursodeoxycholic acid and either with (n=52) or without (n=50) phlebotomy during the period of 2005-2012. Six phlebotomized patients had previously received interferon therapy and were subsequently excluded from the data analysis. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase, lactate dehydrogenase, ferritin, iron and albumin, as well as the hemoglobin concentration, platelet count and prothrombin time, were determined. We compared the long-term outcomes based on the incidence of HCC and laboratory values, including the baseline serum ferritin levels, in patients treated with versus without phlebotomy. RESULTS In the phlebotomy group, the mean AST and ALT levels decreased significantly at each one-year interval over five years (p

Hepatitis B virus (HBV) DNA has been detected in the sera of hepatitis patients who are negative for hepatitis B surface antigen (HBsAg) by polymerase chain reaction (PCR). The purpose of the present study was to clarify the clinical characteristics of patients with chronic hepatitis C who are negative for serum HBsAg and positive for HBV DNA. The subjects included 49 patients with chronic hepatitis C who were negative for serum HBsAg and 119 blood donors who served as healthy controls. Serum samples were tested for the presence of HBV DNA by the nested PCR method. Serum HBV DNA was detected in 18 (37.7%) of the 49 chronic hepatitis C patients and in none (0%) of the 119 blood donors. Among the hepatitis C patients, HBV DNA was detected in 20.7% of those who were negative for all HBV-associated markers and in 57.1% of those who were positive for one or more HBV-associated marker. The HBV DNA-positive rate among those in each F stage did not significantly differ. The liver function parameters of the HBV DNA-positive and the HBV DNA-negative chronic hepatitis C patients did not significantly differ. These results suggest that hepatitis C virus is frequently coinfected with serum HBsAg-negative HBV, and that the incidence of HBV infection in blood donors is low. However, it is considered that HBsAg-negative HBV infection does not modify the blood biochemical features of chronic hepatitis C.

We administered zinc supplementation therapy over three years to patients with chronic hepatitis C and reported and that the aspartate aminotransferase (AST) and alanine aminotaransferase (ALT) levels decreased, and platelet counts increased, significantly in the group with increased serum zinc concentrations. We are continuing this treatment to clarify the long-term consequences and report here the changes in serum zinc concentrations over seven years and compare the cumulative incidence of hepatocellular carcinoma (HCC). We administered polaprezinc to 32 patients, randomly selected for zinc therapy (treatment group), while another 30 formed the control group. We measured the serum zinc and albumin concentrations and conducted a prospective study to determine long-term outcomes. The changes and rates of change of serum zinc concentrations after seven years were 76.7 ± 18.2 µg/dl and +0.302 ± 0.30% in the treatment group and 56.7 ± 12.4 µg/dl and +0.033 ± 0.21% in the control group and had increased significantly (p = 0.0002, p = 0.0036). Progression of liver disease seemed to vary, depending on serum albumin concentrations. In the group with baseline serum albumin concentrations of 4.0 g/dl or more, the change and rate of change of serum zinc concentrations increased significantly, and the cumulative incidence of HCC tended to decrease, in the treated group. According to multivariate analysis, the factors that contribute to a reduction in the incidence of HCC are zinc therapy (risk ratio: 0.113, 95% CI: 0.015-0.870, p = 0.0362), and platelet counts (0.766, 0.594-0.989, 0.0409). Zinc supplementation therapy seems to improve liver pathology and reduce the incidence of HCC.

A 58-year-old man presented with the chief complaint of abdominal bloating and was incidentally found to have a liver tumor. As diagnostic imaging studies could not rule out malignancy, the patient underwent partial resection of segment 3 of the liver. The lesion pathologically showed eosinophilic proliferation, in addition to immunohistochemical positivity for human melanoma black 45 and Melan-A, thereby leading to the diagnosis of a hepatic perivascular epithelioid cell tumor (PEComa). A PEComa arising from the liver is relatively rare. Moreover, the name ‘PEComa’ has not yet been widely recognized, and the same disease entity has been called epithelioid angiomyolipoma (EAML), further diminishing the recognition of PEComa. In addition, PEComa imaging findings mimic those of malignant liver tumors, and clinically, this tumor tends to enlarge. Therefore, a PEComa is difficult to diagnose. We conducted a systematic review of PEComa and EAML cases and discuss the results, including findings useful for differentiating perivascular epithelioid cell tumors from malignant liver tumors.

The efficacy of a combination therapy of interferon (IFN) alpha-2b plus ribavirin (RBV) in chronic hepatitis C, and the factors contributing to efficacy, were investigated. One hundred eighty-six cases were enrolled in this study and treated with a combination of IFN alpha-2b plus RBV. IFN alpha-2b was administered at 6-10 mega-units daily for 2-4 weeks and three times per week for 20-22 weeks, in combination with oral intake of RBV at 600 or 800 mg for 24 weeks. Rates of sustained virological response (SVR) were 34.9% in serogroup 1 (SG1) and 82.5% in SG2. SVR rates in cases with both drugs discontinued, reduced, and unchanged were 4.2%, 40%, and 42.7% in SG1 and 42.9%, 76.9%, and 91.9%, in SG2. In terms of the total RBV dose per kilogram body weight, SVR rates were 14.3% and 46.2% with1600 mg, 36.2% and 91.7% with 1600-2000 mg, and 62.1% and 95% withor =2000 mg in SG1 and SG2, respectively. Total doses of RBV per body weight and negative HCV RNA at 8 weeks were the significant factors contributing to SVR in SG1 cases. These results indicate that it was critical to tailor the doses of RBV and IFN to the individual. To improve the rate of SVR, it is necessary to make efforts, where possible, not to discontinue drug use or reduce the drug dose.

We evaluated zinc concentrations in patients with hepatitis C virus (HCV)-positive chronic liver disease and correlated them with the clinical profiles of the patients. A total of 100 patients with chronic hepatitis (CH), 29 with liver cirrhosis (LC), and 6 who were asymptomatic HCV carriers (ASC) were examined. All of the patients were positive for serum HCV RNA. One hundred eighteen HCV antibody-positive hepatocellear carcinoma (HCC) patients and 11 healthy subjects also were included in this study. Serum zinc concentrations were evaluated using conventional atomic absorption spectrometry. The median concentration of zinc in patients with CH was statistically lower than that in healthy control subjects. The median zinc concentrations of the LC and HCC groups were significantly lower than that of the CH group. A significant correlation was observed between the zinc concentrations and the platelet counts and albumin concentrations. The zinc concentrations did not correlate with tumor size and number and decreased with the development of Child-Pugh stage. The cumulative survival rate after therapy for HCC nodules in the low zinc concentration group was significantly lower than in the high group. We conclude that the serum concentration of zinc influences the clinical profiles in patients with C-viral chronic liver disease.

Objective: We measured the concentrations of serum intercellular adhesion molecule 1 (sICAM-1) in patients with C-viral chronic liver diseases and started prospective studies immediately thereafter, in order to determine whether the concentration of sICAM-1 is useful for predicting the occurrence of hepatocellular carcinoma (HCC) following C-viral chronic hepatitis (CH) and liver cirrhosis (LC). Methods: We studied 74 patients with CH, 18 with LC, and 28 patients with HCC who visited our institute from 1993 through 1996. All were positive for hepatitis C virus RNA in the blood. The concentrations of sICAM-1 were measured using enzyme-linked immunosorbent assay kits. The expression of ICAM-1 in the liver was detected by indirect immunoperoxidase staining. Results: The concentrations of sICAM-1 were significantly higher in patients with LC and HCC than in patients with CH. The sICAM-1 concentrations were high in patients whose platelet counts were low. ICAM-1 in the liver was localized to the endoplasmic reticulum or the membrane of cancer cells. The cumulative rate of occurrence of HCC from CH or LC was significantly higher in the high-sICAM-1 group (>400 ng/ml) than in the low-sICAM-1 group. Multivariate analysis revealed that elevation of the sICAM-1 concentration is a significant risk factor for the occurrence of HCC. Conclusion: Evaluation of the sICAM-1 concentration is useful for prediction of the occurrence of HCC in patients with C-viral CH or LC.

AIM: To evaluate the histopathological findings of type C liver disease to determine risk factors for development of hepatocellular carcinoma (HCC). METHODS: We studied 232 patients, who underwent liver biopsy for type C chronic liver disease between 1992 and 2009, with sustained virological response (SVR) after interferon therapy. The patients were divided into two groups according to the F stage 0 + 1 + 2 group (n = 182) and F3 + 4 group (n = 50). We prospectively observed and compared the incidence of HCC of the patients with SVR in the F0 + 1 + 2 and F3 + 4 groups. Then, the background factors and liver histopathological findings, including the degree of fibrosis, F stage, inflammation, necrosis, bile duct obstruction, fat deposition, and degree of irregular regeneration (IR) of hepatocytes, were correlated with the risk of developing HCC. RESULTS: HCC developed in three of 182 (1.6%) patients in the F0 + 1 + 2 group, and four of 50 (8.0%) in the F3 + 4 group. The cumulative incidence of HCC in the former group was found to be significantly lower than in the F3 + 4 group (log rank test P = 0.0224). The presence of atypical hepatocytes among IR of hepatocytes in the F3 + 4 group resulted in a higher cumulative incidence of HCC, and was significantly correlated with risk of HCC development (RR = 20.748, 95%CI: 1.335-322.5, P = 0.0303). CONCLUSION: Atypical hepatocytes among the histopathological findings of type C liver disease may be an important risk factor for HCC development along with progression of liver fibrosis.