Risk factors for relapse of autoimmune hepatitis in Japan: A nationwide survey.

AIM: Some autoimmune hepatitis (AIH) patients experience relapse during their clinical course, and some risk factors for relapse have been identified previously using a relatively small sample size. The aim of the present study was to identify the risk factors for relapse in recently diagnosed AIH patients using a nationwide survey in Japan. METHODS: The nationwide survey performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017 was re-evaluated. A total of 614 patients who received corticosteroids were enrolled in the present study. Associations between relapse and patients' characteristics at diagnosis were evaluated using logistic regression analysis. RESULTS: Relapse was identified in 143 (23.3%) patients after remission. At the time of diagnosis of the disease, there were significant differences in the γ-glutamyl transpeptidase (γ-GTP) level, prevalence of liver cirrhosis, and degree of liver fibrosis. Multivariable logistic regression analysis showed that γ-GTP elevation and liver cirrhosis were significantly associated with relapse. CONCLUSION: The γ-GTP level at diagnosis could help identify AIH patients at higher risk of relapse.

Differences in autoimmune hepatitis based on inflammation localization.

Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

Bezafibrate Improves GLOBE and UK-PBC Scores and Long-Term Outcomes in Patients With Primary Biliary Cholangitis.

In Japan, bezafibrate (BF) is a second-line agent for primary biliary cholangitis (PBC) that is refractory to ursodeoxycholic acid (UDCA) treatment. From a retrospective cohort (n = 873) from the Japan PBC Study Group, we enrolled 118 patients who had received UDCA monotherapy for at least 1 year followed by combination therapy with UDCA+BF for at least 1 year. GLOBE and UK-PBC scores after UDCA monotherapy (i.e., immediately before UDCA+BF combination therapy) were compared with those after 1 year of UDCA+BF combination therapy. The real outcomes of enrolled patients estimated by Kaplan-Meier analysis were compared with the predicted outcomes calculated using GLOBE and UK-PBC scores. In addition, the hazard ratio of BF treatment was calculated using propensity score analysis. The mean GLOBE score before the combination therapy was 0.504 ± 0.080, which improved significantly to 0.115 ± 0.085 (P < 0.0001) after 1 year of combination therapy. The real liver transplant-free survival of enrolled patients was significantly better than that predicted by GLOBE score before introducing BF. Combination therapy did not significantly improve the real rates of liver transplantation or liver-related death compared with those predicted by UK-PBC risk score before introducing BF, but the predicted risk was significantly reduced by the addition of BF (P < 0.0001). Cox regression analysis with inverse probability of treatment weighting showed that the addition of BF significantly reduced the hazard of liver transplant or liver-related death in patients who, after 1 year of UDCA monotherapy, had normal serum bilirubin (adjusted hazard ratio 0.09, 95% confidence interval 0.01-0.60, P = 0.013). Conclusion: Addition of BF to UDCA monotherapy improves not only GLOBE and UK-PBC scores but also the long-term prognosis of PBC patients, especially those with early-stage PBC.

IFN-λ3 as a host immune response in acute hepatitis E virus infection.

BACKGROUND AND AIM: Hepatitis E virus (HEV) is mainly transmitted orally, either waterborne or zoonotic foodborne. Intestinal viruses such as rotavirus are known to induce type III interferon (IFN) in the gastrointestinal (GI) tract where type III IFN dominantly functions in comparison with type I IFN. Therefore, the aim of this study is to investigate the significance of type III IFN (IFN-λ3) in acute hepatitis E. METHODS: IFN-λ3 and HEV RNA levels in the sera of patients with acute HEV infection and in the supernatant of HEV-inoculated cells were measured, using an in-house high-sensitivity method and reverse transcription-polymerase chain reaction, respectively. RESULTS: High serum IFN-λ3 levels were found in the early phase of acute HEV infection, which normalized after resolution. Interestingly, serum IFN-λ3 levels correlated well with serum HEV RNA titers in the same sera, both of which showed the peak before the robust increase of transaminases. In vitro experiments demonstrated that HEV replicated well in the cells with little IFN-λ3 induction (Caco-2, A549) and recombinant IFN-λ3 inhibited HEV replication in a dose-dependent manner. In contrast, in HT-29 cells, a colon cancer cell line, HEV poorly replicated and induced IFN-λ3 in a titer-dependent manner. CONCLUSIONS: These clinical and experimental observations suggest that HEV induced IFN-λ3 as a host innate immune response, which may play a protective role against HEV.

A validation study of the Ursodeoxycholic Acid Response Score in Japanese patients with primary biliary cholangitis.

BACKGROUND/PURPOSE: Although ursodeoxycholic acid (UDCA) is a first-line treatment for primary biliary cholangitis (PBC), 20%-30% of patients with PBC exhibit an incomplete response to UDCA. Recently, the UDCA Response Score was proposed for predicting response to UDCA using pretreatment parameters in patients with PBC. We aimed to validate the UDCA Response Score in Japanese patients with PBC. METHODS: Registry data of Japanese patients (n = 873) were collected. Patients with data on all clinical parameters required for calculating the UDCA Response Score were selected. The endpoint was UDCA response, defined as alkaline phosphatase <1.67 times the upper limit of the normal value after 12 months of UDCA treatment. RESULTS: All parameters were available in 804 patients (male/female = 120/684, age 58.9 [interquartile range 51.1-66.9] years). Bezafibrate was commenced within 12 months of UDCA in 78 patients (9.7%) because of the lack of an early response. We found that the endpoint was not reached in these 78 patients, and the area under the receiver operating characteristic curve (AUROC) of the score was 0.74 (95% confidence interval [CI] 0.70-0.79). The AUROC was 0.77 (95% CI 0.70-0.83) in patients undergoing UDCA monotherapy (n = 726). Finally, the AUROC of the modified UDCA Response Score using only data from the treatment start date was 0.80 (95% CI 0.70-0.90) in patients receiving a combination therapy of UDCA and bezafibrate (n = 160). CONCLUSION: The validity of the UDCA Response Score was acceptable in Japanese patients; this score will be informative in patients treated with a combination therapy of UDCA and bezafibrate.

A case of extrahepatic growth-type hepatocellular carcinoma presenting with bleeding from colonic metastasis.

A 60-year-old woman visited our hospital due to hematochezia. Colonoscopy revealed a 50-mm-diameter submucosal tumor with ulceration of the left side of the transverse colon, and magnetic resonance imaging (MRI) demonstrated the presence of small hepatic nodules. Submucosal tumor of the colon with liver metastasis was therefore diagnosed. To prevent tumor bleeding, we performed partial transverse colectomy. The histopathological diagnosis was moderately differentiated hepatocellular carcinoma presenting as a submucosal tumor with a high frequency of vascular invasion. Computed tomography (CT) angiography revealed a 40-mm-diameter confluent multinodular-type hepatocellular carcinoma with outward spread from segment II and multiple intrahepatic metastases. Our final diagnosis was hepatocellular carcinoma with hematogenous colon metastasis.

Rare case of transfusion-transmitted hepatitis E from the blood of a donor infected with the hepatitis E virus genotype 3 indigenous to Japan: Viral dynamics from onset to recovery.

AIM: The transfusion transmission of hepatitis E can occur even in non-endemic areas in the world as autochthonous hepatitis E has been increasingly reported in developed countries where the hepatitis E virus (HEV) is not prevalent. We investigated the post-transfusion transmission of hepatitis E in a patient by molecularly confirming its presence, and characterized the viral kinetics of HEV in this case. METHODS: A Japanese man underwent re-thoracotomy for hemostasis followed by platelet transfusion. After the transfusion, the blood donor was found to be HEV positive. The donated blood was re-examined and was found to contain HEV. Throughout the prospective follow up of the patient, we analyzed the viral kinetics, chronological anti-HEV antibody level changes and disease progression during the entire course of HEV infection from transfusion until the end of viremia. RESULTS: Sequence analysis of the strains isolated from both the donor and the patient who contracted acute hepatitis E showed an identical match for 326 nucleotides in open reading frame 1. Two strains belonged to HEV genotype 3 indigenous to Japan. CONCLUSION: To the best of our knowledge, this is the first detailed report on the entire natural course of hepatitis E from viral transmission, then clearance, to replication preceding liver injury caused by HEV genotype 3, which is responsible for autochthonous infection in developed countries. The findings provide valuable insights into the mechanism of the transfusion transmission of HEV and subsequent viral dynamics.

Factors associated with the effect of interferon-α sequential therapy in order to discontinue nucleoside/nucleotide analog treatment in patients with chronic hepatitis B.

AIM: The factors associated with the outcome of sequential therapy with interferon-α (IFN-α) in order to halt nucleoside/nucleotide analog (NUC) maintenance treatment for chronic hepatitis B were analyzed. METHODS: A total of 50 patients with chronic hepatitis B who underwent IFN-α sequential therapy for cessation of NUC were enrolled retrospectively. The subjects received NUC plus IFN-α for 4 weeks followed by IFN-α alone for 20 weeks. Natural IFN-α of 6-MU doses was administrated three times a week. A successful response to NUC/IFN-α sequential therapy was defined as serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL, serum alanine aminotransferase (ALT) below 30 IU/L, and hepatitis B e-antigen negativity at 24 months after completing the treatment. RESULTS: Multivariate analysis revealed that hepatitis B surface antigen (HBsAg) of 3.0 log U/mL or more (P < 0.002) and hepatitis B core-related antigen (hepatitis B core-related antigen [HBcrAg]) of 4.5 log U/mL or more (P < 0.003) at the start of IFN-α administration were significant factors associated with a 24-month non-response. Maximal levels of ALT and HBV DNA during the follow-up period after completing IFN-α therapy were significantly related (P < 0.001), and receiver operating characteristic analysis showed that both maximal ALT (P < 0.001) and HBV DNA (P < 0.001) were significantly related to the final 24-month response. CONCLUSION: The combinational use of HBsAg and HBcrAg levels may be useful to predict the 24-month outcome of NUC/IFN-α sequential therapy. Maximal levels of ALT and HBV DNA during post-treatment follow-up may also help monitor responses to IFN-α sequential therapy.

Efficacy and long-term outcomes of radiofrequency ablation in the elderly with hepatocellular carcinoma.

AIM: The use of radiofrequency ablation (RFA) in elderly patients is increasing in those with hepatocellular carcinoma (HCC). This study compares the elderly (≥75 years old) to non-elderly patients (<75 years old) in the outcomes of the efficacy and safety of RFA. METHODS: Three hundred and thirty-five patients, 103 elderly and 232 non-elderly, with naive HCC who were treated with RFA from 1999 to 2012 were enrolled. Patient characteristics, complications, length of hospital stay, overall survival (OS), median survival time (MST), recurrence-free survival (RFS) and factors related to OS were analyzed. RESULTS: Median age was 79 years (range, 75-88) in the elderly group and 65 years (38-74) in the non-elderly group. The proportion of women (45.6% and 28.0%), hepatitis C virus infection (63.1% and 50.4%) and comorbidities (78.6% and 44.0%) in the elderly group compared to the non-elderly group, respectively, was significantly higher. No difference existed in the complications and length of hospital stay. The 5-year OS rates and MST were 67.3% and 90.5 months in the elderly group and 60.9% and 86.4 months in the non-elderly group, respectively (P = 0.486). The median RFS time was 20 months in the elderly group and 18.7 months in the non-elderly group (P = 0.429). In multivariate analysis, the Child-Pugh grade and tumor-node-metastasis stage were significantly associated with OS (P < 0.001, =0.003); age was not (P = 0.355). CONCLUSION: RFA in elderly patients is as effective and safe as in non-elderly patients for the treatment of HCC.

Autoimmune Hepatitis with Metabolic Dysfunction-associated Fatty Liver Disease.

Objective Metabolic-associated fatty liver disease (MAFLD) has only recently been proposed; therefore, the characteristics of patients with autoimmune hepatitis (AIH) and MAFLD remain unclear. This study evaluated the effect of MAFLD on AIH patients with AIH. Methods We reevaluated the Japanese Nationwide Survey of AIH in 2018, which involved a survey of patients diagnosed with AIH between 2014 and 2017. We categorized patients with AIH according to the presence or absence of MAFLD and compared the clinical characteristics between the two groups. Results A total of 427 patients (77 men and 350 women) were included in this study. The overall prevalence of MAFLD was 10.5%. Compared to AIH patients without MAFLD, AIH patients with MAFLD had the following characteristics at the time of the AIH diagnosis: (1) a higher body mass index, (2) a higher prevalence of hypertension, (3) mild elevation of hepatobiliary enzymes and total bilirubin, and (4) histologically progressive fibrosis. However, the levels of hepatobiliary enzymes and total bilirubin after treatment were significantly higher in AIH patients with MAFLD than in those without MAFLD. Conclusions AIH patients with MAFLD had characteristics different from those of AIH patients without MAFLD. These findings could help increase our understanding of patients with AIH with MAFLD.

Reactivation of hepatitis B virus in patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma.

Despite increasing reports of hepatitis B virus (HBV) reactivation in hematological malignancies, its incidence, and risk factors are still obscure. The aim of this study was to clarify the frequency and risk factors of HBV reactivation in hepatitis B surface antigen (HBsAg) undetectable patients with malignant lymphoma or multiple myeloma, during or after chemotherapy. A total of 109 patients with undetectable HBsAg undergoing chemotherapy for malignant lymphoma or multiple myeloma were enrolled in this study. Anti-hepatitis B surface (anti-HBs) and anti-hepatitis B core (anti-HBc) were checked before treatment, and HBV DNA in sera was quantified monthly during and after chemotherapy. Out of 109 patients, 42 (38.5%) had anti-HBs and 59 (54.1%) had anti-HBc. Among the 59 anti-HBc positive patients, four patients (4/59, 6.8%) showed HBV reactivation during 20.5 median follow-up months. In all four patients with HBV reactivation, peripheral lymphocyte counts before chemotherapy were lower than those without HBV reactivation (P=0.033). HBV reactivation occurred during and after chemotherapy containing rituximab for non-Hodgkin lymphoma. Four patients, who had HBV reactivation, did not develop de novo hepatitis due to HBV reactivation and were able to undergo chemotherapy against malignant lymphoma as scheduled. Monitoring of HBV DNA in sera is useful for the early diagnosis of HBV reactivation, and preemptive therapy is an useful alternative to prevent hepatitis due to HBV reactivation. Patients must be monitored periodically for HBV-DNA levels during and after chemotherapy.

Feasibility of the virtual needle tracking system for percutaneous radiofrequency ablation of hepatocellular carcinoma.

AIM: To evaluate the feasibility of the real-time virtual needle tracking system for percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: An electromagnetic field created by an ultrasound (US) machine detected the tracking bracket mounted onto the RFA needle. When the needle tip was confirmed to be in the accurate plane extracorporeally, the needle was inserted into the liver using the virtual navigation US system, and RFA was performed. Eight patients with eight liver lesions underwent percutaneous RFA under ultrasound for HCC from October to November 2012 using the real-time electromagnetic virtual needle tracking system (VirtuTRAX). RESULTS: The average size of the tumors was 11.5 mm with one lesion in S4, two in S5, two in S7 and three in S8. Sufficient margins were obtained in a single session in all cases. Using only B-mode, the needle tip was obscured due to the condition of the surrounding liver or subcutaneous fat tissue, but it was identifiable with the use of the virtual needle tracking device in all cases. In one case where the lesion was large, the needle was placed twice deliberately, but the second puncture was made difficult by the ablation artifact of the first puncture. With the tracking device, however, it was possible to perform the second puncture accurately. CONCLUSION: The virtual tracking system is useful in cases where the needle tip is obscured due to surrounding liver conditions or when multiple punctures are necessary due to the ablation artifact's obscuring the needle tip. Freehand puncturing may be possible in the future using this technique with further improvements in the system.

Feasibility of fused imaging for the evaluation of radiofrequency ablative margin for hepatocellular carcinoma.

AIM: To evaluate the feasibility of fusion of conventional imaging modalities to facilitate assessment of ablative margin of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: Two hundred and thirty-nine liver lesions in 109 patients underwent percutaneous RFA under ultrasound for HCC from January 2008 to December 2010. Within these patients, 13 lesions in 12 patients who developed local tumor progression in the follow-up period of at least 8 months were retrospectively reviewed. Imaging obtained before and after RFA was used for creating fused images on a workstation. Ablative margins were assessed using only axial images, and with fused images. RESULTS: The ablative margin was assessed as sufficient in all 13 lesions using side-by-side axial images; however, all lesions were assessed as insufficient with fused imaging evaluation. The reason for the discrepancy of the assessment results were differences in the respiratory dislocation of the liver in the pre- and post-RFA images in eight lesions (61.5%), and rotational displacement of the liver and the torso in five (38.5%). The site of local tumor recurrence relative to the HCC lesion was craniocaudal in 12 lesions, dorsoventral in seven and lateral in seven. In all lesions, the site of local tumor recurrence was congruent with the area of the thinnest ablative margin. CONCLUSION: Assessment of ablative margin with fused imaging revealed insufficiency of ablation previously evaluated as sufficient with conventional axial imaging. Fused imaging evaluation has proved to be an accurate and useful tool for the assessment of RFA margins.

No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations.

BACKGROUND: A recent genome-wide association study (GWAS) using chronic HBV (hepatitis B virus) carriers with and without hepatocellular carcinoma (HCC) in five independent Chinese populations found that one SNP (rs17401966) in KIF1B was associated with susceptibility to HCC. In the present study, a total of 580 HBV-derived HCC cases and 1351 individuals with chronic hepatitis B (CHB) or asymptomatic carrier (ASC) were used for replication studies in order to evaluate the reported association with HBV-derived HCC in other East Asian populations. RESULTS: We did not detect any associations between rs17401966 and HCC in the Japanese cohorts (replication 1: OR = 1.09, 95 % CI = 0.82-1.43; replication 2: OR = 0.79, 95 % CI = 0.54-1.15), in the Korean cohort (replication 3: OR = 0.95, 95 % CI = 0.66-1.36), or in the Hong Kong Chinese cohort (replication 4: OR = 1.17, 95 % CI = 0.79-1.75). Meta-analysis using these cohorts also did not show any associations with P = 0.97. CONCLUSIONS: None of the replication cohorts showed associations between rs17401966 and HBV-derived HCC. This may be due to differences in the genetic diversity among the Japanese, Korean and Chinese populations. Other reasons could be the high complexity of multivariate interactions between the genomic information and the phenotype that is manifesting. A much wider range of investigations is needed in order to elucidate the differences in HCC susceptibility among these Asian populations.

Potential of PALBI-T score as a prognostic model for hepatocellular carcinoma in alcoholic liver disease.

BACKGROUND AND AIM: With the control of viral hepatitis, alcoholic hepatocellular carcinoma (HCC) is becoming increasingly important in Japan. In alcoholic cirrhosis, the impact of portal hypertension is significant. Thus, it may be difficult to predict prognosis accurately with the reported prognostic scores. Here we propose the platelet-albumin-bilirubin tumor nodes metastasis (TNM) score (PALBI-T score) as a prognostic model for HCC in alcoholic liver disease, and investigate its usefulness. The PALBI-T score is an integrated score based on the TNM stage and PALBI grade including platelets, reflecting portal hypertension. METHODS: This study included 163 patients with alcoholic HCC treated at our Center from 1997 to 2018. We compared the prognostic prediction abilities of the Japan Integrated Staging (JIS) score, ALBI-T score, and PALBI-T score. The PALBI-T score was calculated similarly to the JIS and ALBI-T scores. Areas under the receiver operating characteristic curve (AUC) were calculated for predicting overall survival (OS). RESULTS: In predicting the 1-year survival, the JIS score had a larger AUC (AUC = 0.925) than the ALBI-T score (AUC = 0.895) and PALBI-T score (AUC = 0.891). On the other hand, there was no significant difference in predicting OS among the integrated scores. The PALBI-T score (AUC = 0.740) had the largest AUC, and the JIS score (AUC = 0.729) and ALBI-T score (AUC = 0.717) were not significantly different from the PALBI grade (AUC = 0.634). The PALBI grade reflected the degree of portal hypertension. CONCLUSION: In patients with alcoholic HCC, the Japan Integrated Staging score is useful for predicting short-term prognosis. The PALBI-T score, which reflects portal hypertension, appears to be a more valid prognostic score for predicting long-term prognosis.

Serum miR-192-5p levels predict the efficacy of pegylated interferon therapy for chronic hepatitis B.

We examined the association between serum miRNA (-192-5p, -122-3p, -320a and -6126-5p) levels and the efficacy of pegylated interferon (Peg-IFN) monotherapy for chronic hepatitis B (CHB) patients. We enrolled 61 CHB patients treated with Peg-IFNα-2a weekly for 48 weeks, of whom 12 had a virological response (VR) and 49 did not VR (non-VR). A VR was defined as HBV DNA < 2,000 IU/ml, hepatitis B e antigen (HBeAg)-negative, and nucleos(t)ide analogue free at 48 weeks after the end of treatment. The non-VR group showed a significantly higher HBeAg-positivity rate, ALT, HBV DNA, and serum miR-192-5p levels at baseline (P = 0.024, P = 0.020, P = 0.007, P = 0.021, respectively). Serum miR-192-5p levels at 24-weeks after the start of treatment were also significantly higher in the non-VR than the VR group (P = 0.011). Multivariate logistic regression analysis for predicting VR showed that miR-192-5p level at baseline was an independent factor (Odds 4.5, P = 0.041). Serum miR-192-5p levels were significantly correlated with the levels of HBV DNA, hepatitis B core-related antigen, and hepatitis B surface antigen (r = 0.484, 0.384 and 0.759, respectively). The serum miR-192-5p level was useful as a biomarker for the therapeutic efficacy of Peg-IFN in CHB treatment.

[Sarcomatoid carcinoma of the liver: a case report and review of the literature].

A 66-year-old woman presented to our outpatient clinic with abdominal discomfort in April, 2008. Ultrasound revealed a hypo-echoic 10cm mass in the right hepatic lobe but no indication of chronic liver disease, with similar results in her history, on physical exam, and imaging. Serum testing did not identify any systemic disease. The mass was suspected to be intrahepatic cholangiocarcinoma and right hepatic lobectomy was performed. Histologic examination of the specimen revealed numerous spindle cells, and immunostaining confirmed a definitive diagnosis of sarcomatoid carcinoma of the liver. On subsequent review of the case, an abdominal CT performed 2.5 years earlier for unrelated symptoms had shown a 1cm faint low density area in the same location as the mass. The doubling time of this tumor was about 95 days.