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BACKGROUND: The relationship between liver fibrosis and inflammation and Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with chronic liver disease (CLD) other than hepatitis C remains uncertain, owing to the limitations of qualitative methods. Here, we evaluated the influence of liver fibrosis and inflammation on quantitative M2BPGi (M2BPGi-Qt) in CLD, considering each etiology. METHODS: We recruited 1373 patients with CLD. To evaluate the influence of liver fibrosis and inflammation on M2BPGi-Qt levels, we assessed M2BPGi-Qt levels at each fibrosis and activity stage within different etiologies of CLD based on pathological findings. Subsequently, we evaluated if the accuracy of fibrosis staging based on M2BPGi-Qt could be improved by considering the influence of liver inflammation. RESULTS: In patients with viral hepatitis, non-alcoholic fatty liver disease, and primary biliary cholangitis, the median M2BPGi-Qt levels increased liver fibrosis progression. Median M2BPGi-Qt levels were not associated with the degree of fibrosis in patients with autoimmune hepatitis (AIH). Median M2BPGi-Qt levels increased with the progression of liver activity in all etiologies. A significant difference was found at each stage in AIH. Considering the liver inflammation, we established an algorithm, M2BPGi-Qt, to determine the alanine aminotransferase-to-platelet ratio (MAP-R) in liver cirrhosis (LC). The area under the receiver operating characteristic curve (AUC) of MAP-R was higher than that of the M2BPGi-Qt for detecting LC (AUC MAP-R = 0.759 and M2BPGi-Qt = 0.700, p < 0.001). CONCLUSIONS: The quantitative measurement system for M2BPGi depends on liver fibrosis and inflammation, regardless of etiology. Liver inflammation complicates the interpretation of M2BPGi-Qt results when assessing the fibrosis stage.

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AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

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Haptophytes synthesize unique ß-glucans containing more ß-1,6-linkages than ß-1,3 linkages, as a storage polysaccharide. To understand the mechanism of the synthesis, we investigated the roles of Kre6 (yeast 1,6-ß-transglycosylase) homologs, PhTGS, in the haptophyte Pleurochrysis haptonemofera. RNAi of PhTGS repressed ß-glucan accumulation and simultaneously induced lipid production, suggesting that PhTGS is involved in ß-glucan synthesis and that the knockdown leads to the alteration of the carbon metabolic flow. PhTGS was expressed more in light, where ß-glucan was actively produced by photosynthesis, than in the dark. The crude extract of E. coli expressing PhKre6 demonstrated its activity to incorporate 14C-UDP-glucose into ß-glucan of P. haptonemofera. These findings suggest that PhTGS functions in storage ß-glucan synthesis specifically in light, probably by producing the ß-1,6-branch.

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BACKGROUND: This study aimed to evaluate the quantitative measurement of Mac-2 binding protein glycosylation isomer (M2BPGi) levels using the new chemiluminescent enzyme immunoassay. METHODS: The data of a total of 347 patients with hepatitis C virus (HCV) infection and 150 health volunteers from 13 locations in Japan were evaluated. The quantitative system for measuring M2BPGi-Qt levels was based on a new chemiluminescent enzyme immunoassay. We evaluated the reproducibility and quantitation range in quantitative M2BPGi-Qt measurement. We also investigated the confidence ratio of M2BPGi-Qt levels measured by the new quantitative system to M2BPGi levels measured by the current semi-quantitative system for validating the clinical utility of the new method. RESULTS: The reproducibility of M2BPGi-Qt in HCV samples with negative, positive 1+, and positive 2+ was 0.77 ± 0.02 AU/mL, 2.25 ± 0.03 AU/mL, and 6.55 ± 0.21 AU/mL, respectively, and the corresponding coefficient of variation (CV)s were 2.1%, 1.3%, and 3.2%, respectively. The range of quantification assessment resulted that all CVs showed less than 5% in investigated range. Sample stability testing found that the mean percentage difference between the pre- and post-storage values of 6 samples ranged between 96.2 and 103.9%. The correlation coefficient between M2BPGi and M2BPGi-Qt in patients with HCV and the healthy volunteers was 0.986 and 0.991, respectively. M2BPGi-Qt could be quantitatively assessed in a patient with over 20 C.O.I. CONCLUSION: Compared with qualitative methods, the M2BPGi quantitative measurement system could provide a numerical value unaffected by interpretation bias, and measurements are more precise at high M2BPGi levels.

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Fatty liver is known to be associated with extra-hepatic diseases including atherosclerotic cardiovascular disease and extra-hepatic cancers, which affect the prognosis and quality of life of the patients. The inter-organ crosstalk is mediated by metabolic abnormalities such as insulin resistance and visceral adiposity. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a new definition for fatty liver. MAFLD is characterized by the inclusion criteria of metabolic abnormality. Therefore, MAFLD is expected to identify patients at high risk of extra-hepatic complications. In this review, we focus on the relationships between MAFLD and multi-organ diseases. We also describe the pathogenic mechanisms of the inter-organ crosstalk.

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AIMS: The real-world efficacy of sofosbuvir/velpatasvir treatment for patients with hepatitis C virus-related decompensated cirrhosis is unclear. We aimed to identify factors that improve liver functional reserve after treatment. METHODS: This was a multicenter retrospective study of 12-week sofosbuvir/velpatasvir treatment. A total of 48 patients with Child-Pugh (CP) class B or C were enrolled at 11 institutions. We evaluated changes in liver functional reserve at 24 weeks post-treatment. RESULTS: At baseline, 40 and eight patients were CP class B and C, respectively. The overall rate of sustained virologic response 12 weeks post-treatment was 95.8% (46/48). Serum albumin, alanine aminotransferase and α-fetoprotein levels, and the FIB-4 index were significantly improved post-treatment (P < 0.05). Among patients who achieved sustained virologic response 12 weeks post-treatment, those with CP class A increased from 0 to 24 patients (56%) at 24 weeks post-treatment. In multivariate analysis, body mass index (BMI) ≥25 was an independent factor that inhibited CP class improvement (P < 0.05). In decision tree analysis, after treatment, the initial divergent variable for CP class improvement was hepatic encephalopathy, followed by serum sodium level and BMI. CONCLUSION: Sofosbuvir/velpatasvir treatment improved the liver functional reserve in patients with hepatitis C virus-related decompensated cirrhosis at 24 weeks post-treatment. However, BMI ≥25 inhibited improvement in CP class. Additionally, decision tree analysis revealed that a combination of hepatic encephalopathy, serum sodium levels, and BMI were diversity profiles associated with no improvement in liver functional reserve after the treatment.

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Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is a rare autosomal recessive disorder that is characterized by intermittent episodes of jaundice and intense pruritus and caused by pathogenic variants of adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1). The presence of genetic heterogeneity in the variants of ATP8B1 is suggested. Herein, we describe a unique clinical course in a patient with BRIC1 and a novel heterozygous pathogenic variant of ATP8B1. A 20-year-old Japanese man experienced his first cholestasis attack secondary to elevated transaminase at 17 years of age. Laboratory examinations showed no evidence of liver injury caused by viral, autoimmune, or inborn or acquired metabolic etiologies. Since the patient also had elevated transaminase and hypoalbuminemia, he was treated with ursodeoxycholic acid and prednisolone. However, these treatments did not relieve his symptoms. Histopathological assessment revealed marked cholestasis in the hepatocytes, Kupffer cells, and bile canaliculi, as well as a well-preserved intralobular bile duct arrangement and strongly expressed bile salt export pump at the canalicular membrane. Targeted next-generation sequencing detected a novel heterozygous pathogenic variant of ATP8B1 (c.1429 + 2T > G). Taken together, the patient was highly suspected of having BRIC1. Ultimately, treatment with 450 mg/day of rifampicin rapidly relieved his symptoms and shortened the symptomatic period.

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Growth differentiation factor 15 (GDF15) has been reported to be associated with fibrosis and cancer in liver disease. Diagnosis of autoimmune hepatitis (AIH) is often difficult because of the lack of specific markers. We investigated whether GDF15 is useful for diagnosing AIH and determined its therapeutic effects. We enrolled 171 Japanese patients as follows: AIH (n = 45), hepatitis B (HB) (n = 17), hepatitis C (HC) (n = 15), primary biliary cholangitis (PBC) (n = 20), and 74 healthy controls. Serum GDF15 levels were measured, and immunohistological analyses of GDF15 were performed using liver tissue of AIH patients. (1) GDF15 levels (pg/ml) were higher in AIH (1994.3 ± 1258.0) and HC (1568.0 ± 822.3) than in HB (953.2 ± 871.4), PBC (643.9 ± 247.0), and controls (475.3 ± 145.3) (p < 0.0001), as well as in cirrhosis patients (n = 31) than in non-cirrhosis patients (n = 66) (1926.6 ± 1026.0 vs. 1249.1 ± 1124.1, p < 0.0001). In non-cirrhosis patients, GDF15 levels were higher in AIH (1914.0 ± 1327.2) than in HC (955.7 ± 502.7), HB (519.3 ± 197.5), and PBC (643.9 ± 247.0) (p < 0.0001). (2) GDF15 was positively correlated with M2BPGi (r = 0.7728), total bilirubin (r = 0.6231), and PT-INR (r = 0.6332). (3) GDF15 levels could be used to distinguish AIH from other liver diseases in non-cirrhosis patients, with an area under the curve of 0.9373 (sensitivity 93.6%, specificity 79.3%, cut-off value 931.3). (4) GDF15 in AIH decreased after treatment. (5) Immunohistological analyses in AIH liver tissues revealed that GDF15 was strongly expressed in inflammatory cells, hepatic cytoplasm, and sinusoidal endothelial cells, but decreased after treatment. GDF15 is a novel diagnostic marker for AIH and is also expected to be a therapeutic marker for AIH.Clinical Trials Registration: The study protocol was approved by the institutional review board of Kurume University (Approval No.: 19049).

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Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is a systemic inflammatory disorder characterized by the above-mentioned symptoms. Because of the similarity in phenotypes between TAFRO syndrome and decompensated liver cirrhosis, an accurate diagnosis is often difficult. We herein report a 62-year-old Japanese patient with TAFRO syndrome who was misdiagnosed with intractable ascites associated with liver cirrhosis. Improvement of symptoms after treatment with prednisolone was associated with interleukin-6 rather than C-reactive protein. The pathogenesis of TAFRO syndrome, which has similar clinical manifestations to liver cirrhosis, remains unclear, and our findings may help elucidate the concept of this condition.

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Advanced liver fibrosis is the most important risk factor for hepatocellular carcinoma (HCC) development after achieving sustained virological response (SVR) by direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C. Wisteria floribunda agglutinin-positive Mac-2-binding protein (M2BPGi), enhanced liver fibrosis (ELF) score, type IV collagen and fibrosis-4 (FIB-4) index have been reported as non-invasive biomarkers for liver fibrosis. In the present study, the possibility of using fibrosis biomarkers and other parameters to predict the development of HCC was evaluated. A total of 743 patients infected with hepatitis C virus who achieved SVR by using DAA were retrospectively enrolled. Of these, 122 patients whose blood samples were stored were selected. The aforementioned four fibrosis biomarkers were analyzed at baseline, at the end of treatment (EOT) and at post-treatment week 24 (PTW24). Tumor markers and laboratory tests were also analyzed. The baseline/EOT/PTW24 values for each fibrosis biomarker were as follows: ELF score: 11.5±1.2/10.8±1.1/10.4±1.0; type IV collagen: 213±85/190±67/174±55 ng/ml; M2BPGi: 4.8±3.5/2.7±2.0/2.2±1.8; and FIB-4 index: 5.31±3.82/4.36± 2.79/4.24±3.09. Of the 122 patients, 23 developed HCC. A high baseline ELF score (P=0.0264), PTW24 ELF score (P=0.0003), PTW24 α-fetoprotein level (P=0.0133), baseline FIB-4 index (P=0.0451) and low baseline prothrombin time (P=0.0455) were risk factors for HCC development based on univariate analyses. Based on the multivariate analysis, a high PTW24 ELF score was the only risk factor for HCC development (P=0.0035). The ELF score after DAA therapy was strongly associated with HCC development; therefore, it may be a useful marker for predicting HCC.

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Nucles(t)ide analogs (NAs) are effective for chronic hepatitis B (CHB). NAs suppress hepatic decompensation and hepatocarcinogenesis, leading to a dramatic improvement of the natural course of patients with CHB. However, renal dysfunction is becoming an important issue for the management of CHB. Renal dysfunction develops in patients with the long-term treatment of NAs including adefovir dipivoxil and tenofovir disoproxil fumarate. Recently, several studies have reported that the newly approved tenofovir alafenamide (TAF) has a safe profile for the kidney due to greater plasma stability. In this mini-review, we discuss the effectiveness of switching to TAF for NAs-related renal tubular dysfunction in patients with CHB.

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We report a case of primary sclerosing cholangitis (PSC) with autoimmune hemolytic anemia (AIHA). A 47-year-old woman was diagnosed with PSC. One year later, she was admitted to our hospital for jaundice and fatigue. Magnetic resonance cholangiopancreatography (MRCP) showed worsening of the biliary stricture, and rapidly progressive anemia developed simultaneously. Based on the various laboratory findings, she was diagnosed with AIHA. The administration of prednisolone improved not only the anemia but also the biliary stricture. This case is impactful, as there are few case reports of PSC with AIHA. In addition, we were able to observe the changes in imaging findings using MRCP over time.

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The aim of the present study was to evaluate the effects of switching to tenofovir alafenamide (TAF) in patients who had received a nucleos(t)ide analog (NA) for the treatment of chronic hepatitis B (CHB). The data from 33 Japanese patients with CHB who received TAF therapy after using NA [adefovir dipivoxil (ADV) and/or tenofovir disoproxil fumarate (TDF)] were retrospectively analyzed. Specifically, the biochemical and virological markers from the start of the TAF treatment to 6 months later were assessed. Comparative evaluation was performed by dividing patients into two groups: Long-term (n=19) and short-term administration groups (n=14), with a cutoff administration duration of 10 years. In all 33 patients, the levels of serum hepatitis B surface antigen (HBsAg; 1,126±1,724 to 1,001±1,591 IU/ml; P<0.0001), serum alkaline phosphatase (ALP) (320±126 to 283±124 U/l; P=0.028), serum bone specific alkaline phosphatase (19.7±9.0 to 17.7±8.0 µg/l; P=0.0006) and urine ß2-microglobulin-creatinine ratio (U-BMG/Cr; 5,224±17,471 to 3,547±14,652 µg/g·Cre; P=0.002) significantly decreased from baseline after 6 months. Serum HBsAg, serum ALP and U-BMG/Cr showed a significant reduction in both groups. In conclusion, switching from ADV or TDF to TAF resulted in a decrease in serum HBsAg and improvement in serum ALP and U-BMG/Cr after 6 months of treatment in patients regardless of history of treatment with NA.

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BACKGROUND & AIMS: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. METHODS: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. RESULTS: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens. CONCLUSIONS: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. LAY SUMMARY: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.

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AIM: Hepatitis B vaccination in infancy was carried out in Japan only when the mother was persistently infected from 1986 to 2016. The aim of the present study was to elucidate the results of vaccination for the prevention of hepatocellular carcinoma in young adults. METHODS: We studied the number of patients who had liver cancer and died from 1976 to 2017 using a national database. Furthermore, we carried out a nationwide survey focusing on patients with hepatitis B virus-related hepatocellular carcinoma who were diagnosed when aged <40 years from 2007 to 2016. RESULTS: The national database showed that the number of deaths of patients aged <40 years decreased from 337 in 1986 to 61 in 2016. Among the 122 patients with hepatocellular carcinoma (HCC) who were registered in the survey, just three patients were born after the start of the vaccination in 1986. Liver cirrhosis, defined by a high Fib-4 index (≥3.25), was found in just 12.5% of the patients at the time of the survey. HCC was incidentally diagnosed in 85 of the 122 (69%) patients. More than 60% of the patients (54/88) were dead at the time of the study, which may be attributed to the delay in diagnosis. CONCLUSIONS: Selective vaccination was effective for the prevention of hepatitis B virus-related HCC. In contrast, many young adults who missed the chance of hepatitis B vaccination and HCC surveillance developed HCC and died. Hepatitis B virus screening in young adults and careful follow up of infected patients are important to prevent HCC development.

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Although the incidence of hepatocellular carcinoma (HCC) occurring after hepatitis C virus (HCV) eradication has decreased, there are still reports of hepatocarcinogenesis. The present study investigated the histological changes of non-cancerous liver tissue obtained prior to interferon (IFN) therapy and after HCC development. A total of 669 HCV-infected Japanese patients who achieved sustained virological response (SVR) by IFN-based therapy were retrospectively enrolled. Of these, the present study investigated 18 patients who developed HCC after IFN-based SVR. Specimens from 9 of 18 patients were available for histological comparisons prior to IFN therapy and following HCC development. Of these 9 patients, the specimens of 5 individuals were compared via immunohistochemical staining [CD3, CD4, CD8, CD20, forkhead box P3 (FOXP3), transforming growth factor-ß1 and granzyme B]. The current study included 6 control patients with HCV-associated chronic liver disease who subsequently developed HCC (non-SVR-HCC group). Mann-Whitney and Wilcoxon tests were used to compare groups. Bonferroni correction was used for multiple comparisons. P<0.05 was used as a critical P-value, and following Bonferroni's correction, P<0.017 was considered to indicate a statistically significant difference. In the 9 patients examined, continuous inflammation and fibrosis were observed after HCC development. There was also a significant decrease in the positive rate of FOXP3 in all 5 patients at the time of HCC development compared with that prior to IFN therapy (P=0.0084). Additionally, there was a significant difference in the positive rate of FOXP3 between the 5 patients after HCC development and the control individuals (P=0.0022). In patients who developed HCC after IFN-based SVR, the frequency of FOXP3 decreased, but inflammation and fibrosis remained. The extent of the reduction of FOXP3 differed in patients who developed HCC in the presence of HCV. Inflammation and fibrosis remained for a long duration after SVR, which may be associated with hepatocarcinogenesis.