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Hepatitis B surface antigen ( HBsAg) reduction during nucleoside/nucleotide analogue ( NA) therapy is slow and an alternative strategy for patients receiving ongoing NA to facilitate HBsAg reduction is required. We investigated whether switching to pegylated interferon ( PEG- IFN) after long-term NA administration enhances HBsAg reduction. Forty-nine patients who switched from long-term NA to 48 weeks of PEG- IFN alfa-2a were studied. The mean duration of previous NA was 48 months (sequential group). A total of 147 patients who continued NA and matched for baseline characteristics were analysed for comparison ( NA continuation group). The treatment response was defined as HBsAg reduction ≥1.0 log IU/mL at the end of PEG- IFN. HBsAg reduction at week 48 was 0.81±1.1 log IU/mL in the sequential group, which was significantly higher than that in the NA continuation group (0.11±0.3 log IU/mL, P < .001). The treatment response was achieved in 29% and 2% of the sequential group and NA continuation group ( P < .001), and the odds ratio of sequential therapy for the treatment response was 19 compared with the NA continuation ( P < .001). In patients tested positive for hepatitis B e antigen ( HBeAg), HBeAg seroconversion was higher in the sequential group (44% vs 8%, P < .001). In HBeAg-negative patients, only patients in the sequential group achieved HBsAg loss. No patient needed to resume NA administration because of HBV DNA increase accompanied by alanine aminotransferase flares. In summary, sequential therapy with PEG- IFN after long-term NA enhances the reduction of HBsAg and may represent a treatment option to promote HBsAg loss. [ABSTRACT FROM AUTHOR]

High rates of sustained virologic response ( SVR) has been achieved in Japanese patients with chronic hepatitis C virus ( HCV) genotype ( GT)1 and GT2 infection treated with ledipasvir/sofosbuvir ( LDV/ SOF) ±ribavirin ( RBV) and SOF+ RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants ( RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A ( GT1 only) and NS5B ( GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/ mL). In patients with HCV GT1 infection, 22.3% ( GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/ SOF and LDV/ SOF+ RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection ( GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/ SOF and SOF+ RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/ SOF for 12 weeks. [ABSTRACT FROM AUTHOR]

Background The relationship among natural allergen exposure, induction of blocking antibody and the occurrence of atopic allergy-particularly in the presence of IgE production-is debatable. Objective To clarify the relationship between the dose of cutaneous exposure to dust mite allergen and susceptibility to the IgE-mediated allergic response in relation to IgG production. Methods NC/Nga mice were epicutaneously exposed to various doses of Dermatophagoides pteronyssinus allergen to induce atopic dermatitis-like skin lesions. We then evaluated the skin lesions, induction of mite-specific immune responses, and susceptibility to anaphylaxis. Results Dose-dependent exacerbation of atopic dermatitis-like skin lesions and increases in mite-specific IgG and IgE production were observed. However, mice exposed to relatively low doses of mite allergen showed hypersusceptibility to mite allergen-specific anaphylaxis. We also showed that adoptive transfer of total IgG from Dp-sensitized mice rescued mice from the hypersusceptibility seen in those exposed to low doses of mite allergen. Conclusions and Clinical Relevance High-dose cutaneous exposure to dust mites induced effective blocking IgG production, even if accompanied by IgE production. Our data might support the concept that an increase in IgG titre, not a decrease in IgE titre, is a marker of clinical improvement in allergen-specific immunotherapy. [ABSTRACT FROM AUTHOR]

Significant associations of HLA-DP alleles with chronic hepatitis B ( CHB) infection are evident in Asian and Arabian populations, including Japanese, Han Chinese, Korean, and Saudi Arabian populations. Here, significant associations between CHB infection and five DPB1 alleles (two susceptibility alleles, DPB1*05:01 and *09:01, and three protective alleles, DPB1*02:01, *04:01, and *04:02) were confirmed in a population comprising of 2582 Japanese individuals. Furthermore, odds ratios for CHB were higher for those with both DPB1 susceptibility alleles than for those with only one susceptibility allele; therefore, effects of susceptibility alleles were additive for risk of CHB infection. Similarly, protective alleles showed an additive effect on protection from CHB infection. Moreover, heterozygotes of any protective allele showed stronger association with CHB than did homozygotes, suggesting that heterozygotes may bind a greater variety of hepatitis B-derived peptides, and thus present these peptides more efficiently to T-cell receptors than homozygotes. Notably, compound heterozygote of the protective allele (any one of DPB1*02:01, *04:01, and *04:02) and the susceptible allele DPB1*05:01 was significantly associated with protection against CHB infection, which indicates that one protective HLA-DPB1 molecule can provide dominant protection. Identification of the HLA-DPB1 genotypes associated with susceptibility to and protection from CHB infection is essential for future analysis of the mechanisms responsible for immune recognition of hepatitis B virus antigens by HLA-DPB1 molecules. [ABSTRACT FROM AUTHOR]

Inosine triphosphatase ( ITPA) genetic variants are strongly associated with ribavirin ( RBV)-induced anaemia during pegylated interferon ( PEG- IFN) plus RBV therapy. However, the treatment efficacy of ITPA genetic variants has not been fully explored. We enrolled 309 individuals infected with hepatitis C virus genotype 1, who were treated with PEG- IFN plus RBV for 48 weeks. The ITPA SNP: rs1127354 and IL28B SNP: rs8099917 were genotyped. We examined the risk factors for severe anaemia up to week 12 after the start of treatment and treatment efficacy. The incidence of severe anaemia, ≥3 g/dL reduction or <10 g/dL of haemoglobin ( Hb) up to week 12, was more frequent in patients with CC at rs1127354 [65% (145/224), 33% (73/224)] than in those with CA/ AA [25% (21/85), 6% (8/85)] ( P < 0.0001). ITPA genotype, pretreatment Hb level and age were independent predictive factors for severe anaemia: Hb < 10 g/dL. In IL28B favourable type, the sustained virologic response rate was higher in ≥60-year-old patients with CA/ AA than in those with CC [71% (22/31) vs 40% (26/65), P = 0.005], although there was no significant difference in treatment efficacy according to ITPA genetic variants in the <60-year-old patients. The proportion of patients administered ≥80% of the dosage of RBV was significantly higher in the patients with CA/ AA than in those with CC ( P = 0.025), resulting in a lower relapse rate. In conclusion, ITPA genetic variants were associated with severe RBV-induced anaemia and could influence the efficacy of PEG- IFN plus RBV treatment among elderly patients with IL28B favourable type. [ABSTRACT FROM AUTHOR]

. Hepatitis C virus (HCV) subtype 1b, which infects approximately 70% of Japanese carriers, is likely to be more eradicable by a telaprevir regimen than subtype 1a because of the higher genetic barrier of Val36 and Arg155 substitutions. The aims of this exploratory study were to evaluate the virological response and safety of 24-week oral administration of telaprevir alone in chronic HCV subtype 1b infection. Fifteen treatment-naïve patients were treated with telaprevir 750 mg every 8 h for 24 weeks. All patients were Japanese whose median age was 58.0 years (range: 45-68), and six patients (40%) were men. Median baseline HCV RNA level was 6.80 log10 IU/mL (range: 3.55-7.10). The HCV RNA levels decreased to undetectable in five patients (33%) within 8 weeks. Three patients (20%) with negative HCV RNA by Week 4 achieved end of treatment response. One patient (7%) who achieved sustained virological response had a low baseline viraemia of 3.55 log10 IU/mL. Most of the adverse events including anaemia and skin disorders were mild to moderate. Developed variants were T54A and A156V/T/F/Y with or without secondary substitutions rather than V36M ± R155K. Telaprevir alone for 24 weeks in Japanese patients with HCV subtype 1b resulted in an sustained viral response rate of 7% (1/15) and was well tolerated for 24 weeks. These results will support the implementation of further studies on oral combination of telaprevir with other direct-acting antiviral agents in patients infected with HCV subtype 1b. [ABSTRACT FROM AUTHOR]

. The FIB-4 index is a simple formula to predict liver fibrosis based on the standard biochemical values (AST, ALT and platelet count) and age. We here investigated the utility of the index for noninvasive prediction of progression in liver fibrosis. The time-course alteration in the liver fibrosis stage between paired liver biopsies and the FIB-4 index was examined in 314 patients with chronic hepatitis C. The average interval between liver biopsies was 4.9 years. The cases that showed a time-course improvement in the fibrosis stage exhibited a decrease in the FIB-4 index, and those that showed deterioration in the fibrosis stage exhibited an increase in the FIB-4 index with a significant correlation ( P < 0.001). Increase in the ΔFIB-4 index per year was an independent predictive factor for the progression in liver fibrosis with an odds ratio of 3.90 ( P = 0.03). The area under the receiver operating characteristic curve of the ΔFIB-4 index/year for the prediction of advancement to cirrhosis was 0.910. Using a cut-off value of the ΔFIB-4 index/year <0.4 or ≥0.4, the cumulative incidence of fibrosis progression to cirrhosis at 5 and 10 years was 34% and 59%, respectively in patients with the ΔFIB-4 index/year ≥0.4, whereas it was 0% and 3% in those with the ΔFIB-4 index/year <0.4 ( P < 0.001). In conclusion, measurement of the time-course changes in the FIB-4 index is useful for the noninvasive and real-time estimation of the progression in liver fibrosis. [ABSTRACT FROM AUTHOR]

This study investigated the molecular and pharmacokinetic mechanisms of the enhanced antiviral efficacy associated with pegylated interferon (PEG-IFN) alpha-2b and ribavirin. The study involved comparing the expression of serial double-stranded RNA-activated protein kinase (PKR) before and during treatment in 26 PEG-IFN alpha-2b and 26 conventional IFN alpha-2b recipients matched for age, body weight and dose of ribavirin. The pharmacokinetics of PEG-IFN alpha-2b and ribavirin was analysed in 15 of the 26 PEG-IFN recipients. There was a rapid increase in PKR expression in both treatment groups, although expression from day 2 onwards was maintained at a significantly higher level in the PEG-IFN recipients ( P < 0.05). Cmax of PEG-IFN occurred 12–48 h after the initial administration, with t1/2 and Cmin being 49 h and 190 pg/mL, respectively. In contrast to ribavirin, accumulation of PEG-IFN was minimal. There was no association between serum PEG-IFN and ribavirin levels and virological response. Although baseline expression of PKR before treatment was marginally higher in nonresponders (NRs), from day 2 onwards, sequential PKR expression in response to PEG-IFN was higher in sustained viral responders compared with the NRs ( P < 0.05). Significant correlations were found between kinetics of PKR expression and viral decline rates in each phase of hepatitis C virus dynamics (first phase, r = 0.67, P = 0.0006; second phase, r = 0.67, P = 0.001). In conclusion, improvement in pharmacokinetics following pegylation led to higher intracellular PKR expression, which was associated with enhanced virological efficacy of PEG-IFN-based combination therapy. The concentrations of both ribavirin and PEG-IFN alpha-2b were not associated with viral response and PKR expression. [ABSTRACT FROM AUTHOR]

There were few natural killer (NK) cells in the liver in very young mice at the age of 1–2 weeks. This was because the cell yield from the liver of young mice was low. The percentage of NK cells in the liver of young mice, however, was almost comparable with that in the liver of adult mice. Lymphocytes were isolated from the liver and spleen of C57BL/6 (B6) mice, and NK cytotoxicity and phenotype were herein examined in this study. NK cytotoxicity was extremely high in the liver of very young mice. This phenomenon was seen in the liver of various normal mouse strains. In contrast, the appearance of high cytotoxicity was not seen in NK cells of the spleen, irrespective of mouse strains. The quality of NK cells in the liver of young mice was different from that in adult mice. NK cells in the liver of young mice were mainly CD69+Mac-1– Fas ligand+, whereas those in the liver of adult mice were CD69–Mac-1+ Fas ligand–. These results revealed that the quality of hepatic NK cells changes in the process of ageing. Namely, liver NK cells in very young mice temporarily show the highest NK cytotoxicity and a unique activated phenotype. Physiological meaning of the present phenomenon was discussed. [ABSTRACT FROM AUTHOR]

In hepatitis C virus (HCV) genotype 2b infection, viral eradication (sustained viral response; sVR) is obtained in about 40% by interferon monotherapy, whereas a considerable proportion of non-sVR patients exhibit sustained biochemical response (sBR) showing normal biochemical values despite persistent viraemia. However, the mechanism of sBR has not yet been established. In this study, we analysed serial changes in full-length sequences of HCV genotype 2b before and after interferon (IFN) therapy in five patients with sBR and five with no response (NR; persistent viraemia and abnormal biochemical values after IFN therapy). The overall substitution rate of amino acids in the full-length HCV genome was higher in the sBR group than in the NR group [2.22 ± 0.48 (10−3 changes/site/year)vs1.04 ± 0.30:P = 0.002]. When the genetic changes were analysed for individual HCV proteins, the sBR group had significantly higher substitution rates of amino acid in NS4A [8.82 ± 2.80 (10−3 changes/site/year)vs0:P = 0.001]. These amino acid changes in sBR were mainly located in the binding motifs of HLA class I molecules including those frequently found in the Japanese population. These results demonstrated that the greater amino acid changes of HCV arising during interferon therapy are associated with the establishment of sBR. Although functional significance of these changes awaits further investigation, the finding that amino acid changes in NS4A in sBR patients are mainly located in the HLA class I binding motifs illustrated the potential roles of the escape mutations of HCV genome from CTLs in the decreasing activities of hepatitis in sBR. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms ( SNPs) in the interleukin 28 B gene ( IL28B) are good pretreatment predictors of anti-hepatitis C virus ( HCV) therapy with interferon. SNPs of the inosine triphosphatase ( ITPA) gene are associated with reduced haemoglobin levels during treatment with ribavirin. The i-densy™ (Arkray, Inc.), which is based on the quenching probe ( QP) method, automatically detects target genes in blood samples by fluorescence quenching within 100 min. Using a QP and primer set, a gene amplification response is generated that can quickly and easily detect a specific gene's arrangement by fluorometry. The present study was conducted to compare the utility of i-densy ( QP method) with that of conventional direct sequencing ( DS) for detecting SNPs in the IL28B and ITPA genes in chronic hepatitis C patients. Between June 2011 and January 2012, 73 consecutive patients underwent genotyping of IL28B, and 54 patients underwent genotyping of ITPA. All of the patients were seropositive for HCV- RNA. The IL28B and ITPA genotypes were tested for bi-allelic polymorphisms in rs8099917 ( T/ T, T/ G and G/ G; minor allele, G) and rs1127354 ( C/ C, C/ A and A/ A; minor allele, A), respectively. The results obtained with the QP method were identical to those obtained with the conventional DS method. The frequency of the IL28B genotypes TT, GT and GG were 74%, 24.7% and 1.4%, respectively, and those of the ITPA genotypes CC, AC and AA were 68.5%, 29.6% and 1.9%, respectively. These results indicate that the i-densy using the QP method can automatically, quickly and easily identify genotypes of IL28B and ITPA. [ABSTRACT FROM AUTHOR]

Background and Aims: The impact of hepatitis C virus (HCV) eradication via direct-acting antiviral (DAA) therapy on overall mortality, particularly non-liver-related mortality, is understudied., Methods: We recruited 4180 patients with chronic HCV infection who achieved sustained virological response (SVR) (HCV eradication) through DAA therapy (n = 2501, SVR group) or who did not receive antiviral therapy (n = 1679, non-SVR group); 1236 from each group were chosen using propensity score matching. Causes of death and all-cause mortality, including non-liver-related diseases, were investigated., Results: Of the 4180 patients, 592 died during the follow-up period. In the SVR group, the mortality rates from liver-related and non-liver-related diseases were 16.5% and 83.5%, respectively. Compared to the non-SVR group, mortality rates from liver-related and non-liver-related diseases were 50.1% and 49.9%, respectively (p < .001). In non-cirrhotic patients, multivariable analysis revealed that SVR was an independent factor associated with both liver-related (hazard ratio [HR], .251; 95% confidence interval [CI], .092-.686) and non-liver-related (HR, .641; 95% CI, .415-.990) mortalities. In cirrhotic patients, multivariable analysis revealed that SVR remained an independent factor significantly associated with liver-related mortality (HR, .151; 95% CI, .081-.279). In propensity score-matched patients, the eradication of HCV (SVR group) decreased both liver-related (p < .001) and non-liver-related mortality (p = .008) rates compared to persistent HCV infection (non-SVR group)., Conclusions: The elimination of HCV via DAA therapy reduced not only liver-related mortality but also non-liver-related mortality in patients with chronic HCV., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) requires at least one of five cardiometabolic criteria. It is unclear whether these criteria can be used as predictors and treatment targets for complications including liver-related events and major adverse cardiovascular events (MACE)., Aims: To investigate the relationship between cardiometabolic criteria and complications., Methods: We conducted a nationwide, population-based study of 979,352 patients with MASLD. We investigated relationships between a number of criteria at baseline and liver-related events or MACE risks. In a separate longitudinal analysis, we included patients with five criteria at baseline and investigated the relationship between improving the criteria and the incidence of complications after 1 year., Results: The cumulative incidence of MACE, but not liver-related events, increased with increasing baseline cardiometabolic criteria. In the longitudinal study, multivariable analysis using patients with five criteria (no improvement) as the reference, adjusted hazard ratios (95% confidence interval) of MACE in patients with 4, 3, 2, and 0-1 criteria (1 to 4-5 criteria improvement) were 0.55 (0.52-0.58, p < 0.001), 0.20 (0.17-0.22, p < 0.001), 0.13 (0.11-0.16, p < 0.001), and 0.06 (0.02-0.3, p < 0.001), respectively. The risk of MACE decreased as the cardiometabolic criteria improved. There was no significant association between improvement of the criteria and liver-related events., Conclusions: Cardiometabolic criteria can be used as predictors and treatment targets for cardiovascular event risk in MASLD. Developing predictors and therapeutic targets for liver-related events is a future challenge., (© 2024 John Wiley & Sons Ltd.)

Background: A multi-society consensus group proposed a new nomenclature for steatotic liver disease (SLD) including metabolic-dysfunction associated steatotic liver disease (MASLD), MASLD and increased alcohol intake (MetALD) and alcohol-associated liver disease (ALD). However, the risk of liver-related events, major adverse cardiovascular events (MACE) and all-cause mortality among various sub-groups is unknown., Aims: To evaluate the risk of liver-related events, MACE and death among patients with SLD., Methods: We conducted a nationwide, population-based study and enrolled 761,400 patients diagnosed with MASLD, MetALD or ALD. The primary endpoint was the occurrence of liver-related events, MACE and death in patients with MASLD, MetALD and ALD., Results: The cumulative incidence of liver-related events and death were highest in ALD, followed by MetALD and MASLD (p < 0.001 for both liver-related events and death), while the incidence of MACE was highest in MASLD, followed by MetALD and ALD (p < 0.001). Using MASLD as the reference and adjusting for age, sex, smoking, diabetes mellitus, dyslipidaemia and hypertension, the adjusted hazard ratios (95% confidence intervals) for liver-related events, MACE and death in MetALD were 1.42 (1.1-1.8), 0.68 (0.63-0.73) and 1.13 (0.98-1.3), respectively. In ALD, they were 3.42 (2.6-4.6), 0.58 (0.49-0.67) and 1.60 (1.3-2.0), respectively, for liver-related events, MACE and death., Conclusions: The new consensus nomenclature can be used to stratify the risk of complications and prognosis. The nomenclature is beneficial for risk stratification and identifying new mechanisms for disease-specific therapeutic implications., (© 2024 John Wiley & Sons Ltd.)

Background & Aims: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis., Methods: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured., Results: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years., Conclusion: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years., (© 2024 John Wiley & Sons Ltd.)

Background: Progression to cirrhosis in non-alcoholic steatohepatitis (NASH) is associated with a decrease in liver fat. However, the prognostic significance of liver fat content in NASH-related significant fibrosis and cirrhosis is unclear., Aim: To investigate the risk of decompensation, hepatocellular carcinoma (HCC) and mortality stratified by liver fat content in NASH-related significant fibrosis and cirrhosis., Methods: In this meta-analysis of individual participant data, 456 patients with both magnetic resonance elastography (MRE) and MRI-derived protein density fat fraction (MRI-PDFF) were enrolled, and 296 patients with longitudinal follow-up were analysed. MRE combined with fibrosis-4 (MEFIB-index), and MRI-PDFF were used to measure liver fibrosis and fat, respectively. MEFIB-negative, MEFIB-positive+ MRI-PDFF ≥5% and MEFIB-positive+ MRI-PDFF <5% were defined as no significant liver fibrosis, NASH with significant fibrosis and higher liver fat content, and NASH with significant fibrosis and low liver fat content groups, respectively. The primary outcome was hepatic decompensation, HCC and death., Results: The rates of decompensation, HCC and mortality were highest in the NASH with significant fibrosis and low liver fat group (33%, 17% and 17%, respectively), followed by the NASH with significant fibrosis and higher liver fat group (18%, 13% and 13% respectively), and lowest in the no significant fibrosis (MEFIB-negative) group (0%, 1% and 2% respectively). In multivariable-adjusted analysis, low liver fat content was strongly associated (HR = 42.2 [95% CI: 7.5-235.5, p < 0.0001]) with HCC, decompensation and death. Sensitivity analyses for patients with cirrhosis (MRE ≥5 kPa) determined consistent findings., Conclusions: Low liver fat content in patients with burnt-out NASH-related significant fibrosis and cirrhosis is associated with an increase in hepatic decompensation, HCC and mortality., (© 2023 John Wiley & Sons Ltd.)

Background: There are limited data regarding the longitudinal association between MEFIB-Index (MRE combined with FIB-4) versus MAST-Score (MRI-aspartate aminotransferase) and hepatic decompensation., Aim: To examine the longitudinal association between MEFIB-Index versus MAST-Score in predicting hepatic decompensation in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: This was a longitudinal, retrospective analysis of subjects from United States, Japan, and Turkey who underwent a baseline MRE and MRI-PDFF and were followed for hepatic decompensation. Cox-proportional hazard analyses were used to assess the association between MEFIB-Index versus MAST-Score with a composite primary outcome (hepatic decompensation) defined as ascites, hepatic encephalopathy, and varices needing treatment., Results: This meta-analysis of individual participants (IPDMA) included 454 patients (58% women) with a mean (±SD) age of 56.0 (±13.5) years. The MEFIB-Index (MRE ≥3.3 kPa + FIB 4 ≥1.6) and MAST-Score (>0.242) were positive for 34% and 9% of the sample, respectively. At baseline, 23 patients met criteria for hepatic decompensation. Among 297 patients with available longitudinal data with a median (IQR) of 4.2 (5.0) years of follow-up, 25 incident cases met criteria for hepatic decompensation. A positive MEFIB-Index [HR = 49.22 (95% CI: 6.23-388.64, p < 0.001)] and a positive MAST-Score [HR = 3.86 (95% CI: 1.46-10.17, p < 0.001)] were statistically significant predictors of the incident hepatic decompensation. MEFIB-Index (c-statistic: 0.89, standard error (SE) = 0.02) was statistically superior to the MAST-Score (c-statistic: 0.81, SE = 0.03) (p < 0.0001) in predicting hepatic decompensation., Conclusion: A combination of MRI-based biomarker and blood tests, MEFIB-Index and MAST-Score can predict the risk of hepatic decompensation in patients with MASLD., (© 2023 John Wiley & Sons Ltd.)

Background: Magnetic resonance elastography (MRE) has the highest diagnostic accuracy for liver fibrosis; however, the association between MRE-associated liver stiffness and the development of hepatic and extrahepatic complications as well as mortality remains unclear., Aim: In this study, we investigated the longitudinal association between MRE-associated liver stiffness and complications and mortality., Methods: This retrospective study included 2373 consecutive patients with chronic liver disease. All patients received standard of care and the development of complications was assessed every 1-6 months., Results: Newly diagnosed hepatocellular carcinoma (HCC), decompensation, major adverse cardiovascular events (MACE), extrahepatic cancer and death were observed in 99, 117, 73, 77 and 170 patients respectively. In multivariable analysis, the adjusted hazard ratios (aHR) (95% confidence interval [CI]) for HCC, decompensation, MACE, extrahepatic cancer and mortality were 1.28 (1.2-1.4), 1.34 (1.3-1.4), 0.96 (0.9-1.1), 1.00 (0.9-1.1) and 1.17 (1.1-1.2), respectively, with each 1-kPa increase in liver stiffness. Similarly, the aHR (95% CI) for HCC, decompensation, MACE, extrahepatic cancer and mortality were 4.20 (2.2-8.2), 67.5 (9.2-492), 0.83 (0.4-1.7), 0.90 (0.5-1.7) and 2.90 (1.6-5.4), respectively, in patients with cirrhosis (>4.7 kPa) compared to those with minimal fibrosis (<3 kPa)., Conclusions: Increased MRE-associated liver stiffness was associated with increased risk for HCC, decompensation and mortality in a dose-dependent fashion but not with MACE or extrahepatic cancer, implicating a significant role for MRE in liver-related events and mortality; however, further studies are warranted to explore its role in MACE and extrahepatic cancer., (© 2021 John Wiley & Sons Ltd.)

Background and Aims: Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated., Methods: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child-Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence-free survivals were compared in original and a propensity score weighted pseudo-population with 732 patients., Results: The median follow-up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo-population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36-0.86) and RFA (HR, 0.75; 95% CI, 0.57-1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence-free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non-SR. No treatment-related death occurred., Conclusions: For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: There have been no established predictive factors of responders to sorafenib in patients with unresectable hepatocellular carcinoma (HCC). This study aimed to investigate the factors predicting a good response to sorafenib in Japanese patients with HCC., Methods: A total of 465 patients with unresectable HCC in the Japanese Red Cross Liver Study Group were treated with sorafenib between January 2008 and August 2013, and 316 patients with sufficient clinical data were analysed. To determine the factors predicting a good response, the relationships between radiological response and the following clinicopathological factors were analysed: age, gender, performance status, liver function, tumour status and decrease in serum alpha-foetoprotein (AFP) level after 1 month., Results: This study included 259 males and 57 females with a median age of 70 years (range, 37-90 years), of which 191 (60.4%) were classified as Barcelona Clinic Liver Cancer stage C, and 271 (85.8%) had Child-Pugh class A liver function. The median overall survival time was 307 days and progression-free survival time was 109 days. According to the modified Response Evaluation Criteria In Solid Tumours, four patients achieved a complete response, 51 achieved a partial response, 136 had stable disease and 125 had progressive disease. Multivariate analysis identified female gender (P = 0.003) and decreased serum AFP level after 1 month (P = 0.042) as independent predictors of a complete or partial response., Conclusion: Our results suggest female gender and a decrease in serum AFP level are independent predictors of good response to sorafenib., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: To clarify the biological behaviour of small hypovascular hepatocellular carcinoma (HCC) because of insufficient evidence even though frequently encountered., Methods: The study covered naïve 4,474 patients who met solitary HCC ≤ 3 cm (mean, 2.1 cm), histopathologically proven and Child Pugh A or B. Macroscopic vascular invasion and distant metastasis were excluded. The hypovascularity of tumour was defined as hypo- or iso-enhancement in arterial phase of multiple dynamic imaging techniques., Results: Of them, 802 (18%) were hypovascular. The ratio of hypovascular HCC decreased as tumour size increased (P < 0.001) and most of them developed to hypervascular type when they grew over 1.5 cm. Hypovascular group showed a significantly higher ratio of well differentiated grade (P < 0.001) and marginally less incidence of microvascular invasion and metastases compared with hypervascular group. The histologic dedifferentiation (less differentiation) developed step-by-step as tumour size increased in hyper- and even hypovascular group. The des-γ-carboxy prothrombin (DCP) value ≥ 300 mAU/ml was closely correlated with increase of tumour size in both groups. Logistic regression analysis revealed five variables were independent predictors for hypovascular HCC; tumour size ≤ 1.5 cm, alpha-fetoprotein < 200 ng/ml, DCP < 40 mAU/ml, well differentiated grade, and positivity for hepatitis C virus antibody., Conclusions: Hypovascular HCC was biologically less aggressive and developed with stepwise dedifferentiation and transformation to hypervascular appearance along with tumour growth. These results will help in leading correct diagnosis of small hypovascular tumour and assessing optimal treatment for hypovascular HCC ≤ 3 cm., (© 2013 John Wiley & Sons A/S.)

Aims: The aim of this study was to clarify the pharmacokinetics of ribavirin and interferon-alpha (IFN-alpha) 2b when administered in combination for 24 weeks and effects of pharmacokinetics of both on treatment outcome in chronic hepatitis C with genotype 1b and high viral load., Methods: In this multicentre open study, 27 patients received 2-week daily induction therapy followed by 22-week, three-times-a-week maintenance therapy of intramuscular IFN-alpha 2b at a dose of 6 million units and oral ribavirin at 400 mg twice daily for 24 weeks, and followed up for 24 weeks post-treatment. Single- and multiple-dose pharmacokinetic studies were assessed by serial measurements of serum concentrations of both compounds at weeks 1 and 24., Results: Five patients attained sustained virological response. Serum ribavirin concentrations asymptoted after 4-8 weeks of treatment in all patients. The steady-state concentration correlated significantly with serum ribavirin clearance after multiple dosing (r = -0.875; 95% CI -0.932, -0.721; P < 0.001). Serum concentrations at weeks 4 and 8, Cmax and AUC(0,12 h) after multiple dosing and AUC(0,28 weeks) of ribavirin were significantly higher in sustained virological responders than in virological responders or nonresponders (P < 0.05, each). Increased Cmax and accumulation index of AUC(0,12 h) (median 10.5; 95% CI 6.4, 12.4), and prolonged washout half-life after multiple dosing reflected accumulation and slow clearance of ribavirin from the tissue compartments., Conclusions: Continuous exposure and accumulation of ribavirin may be necessary for sustained virological response to combination therapy in chronic hepatitis C with genotype 1b and high viral load.

Background: It is still unknown how jaw bone remodeling occurs at actual invasion sites of oral squamous cell carcinomas. Since there is no other human carcinomas which make a direct invasion of the bone, gingival carcinomas are valuable examples., Methods: Twelve surgical specimens of gingival squamous cell carcinoma were examined histopathologically and immunohistochemically for remodeling of bone and its surrounding tissue., Results: Three types of bone interfaces with carcinomatous invasion were distinguished. These included areas with bone resorption, smooth bone surface and new bone formation. In the bone-resorption area, numerous osteoclasts were located along the bone surface, which was surrounded by myxoid stroma. The myxoid stroma was characterized by immunopositivity for heparan sulfate proteoglycan (HSPG), abundant vascularity and macrophagic infiltration. In the bone-formation area, rows of osteoblasts were aligned on the bone surface. The stroma around osteoblasts was also HSPG-immunopositive, poor in vascularity but rich in activated fibroblasts. In the smooth-bone area, the stroma showed an organizing phase of granulation tissue with slender fibroblasts and mature collagen fibers but with less vascularity and inflammatory infiltrates., Conclusion: The results indicate that the stromal architecture, especially in terms of its inflammatory cellular, vascular and matrix compositions, is strictly regulated in the timing and site of jaw bone remodeling which is causes by carcinomatous invasion.

To assess the interaction of alcohol, hepatitis C virus (HCV), and hepatitis B virus (HBV) infection in hepatocarcinogenesis, we prospectively observed 449 patients with liver cirrhosis (LC) who presented to our outpatient clinics in 1 month; 164 patients with habitual drinking [alcoholic liver-liver cirrhosis (AL-LC)] who had taken > 72 g alcohol/day (HCV-positive 81 cases: HCV + AL; HCV-negative 83 cases: AL); 176 patients with HCV infection, but without alcohol intake: 34 patients with HBV infection: 6 patients with HCV and HBV coinfection; and 82 patients with liver diseases from other etiologies, such as primary biliary cirrhosis. In the HCV group, the cumulative occurrence rate of hepatocellular carcinoma (HCC) was 9%, 18%, and 23% in the first, second, and third years, respectively. In the HCV + AL group, that was 13%, 17%, and 28%, respectively. There was no difference in the HCC occurrence rate between the two groups. In the AL group, the cumulative HCC occurrence rate was only 1% during the observation period of 3 years. The occurrence rate was significantly lower in the AL group, compared with the HCV and the HCV + AL groups. In the HBV group, the cumulative occurrence rate of HCC during the observation period of 3 years was 17%, which was similar to that of the HBV + AL group, 14%. We also examined some other variables that might be related to the development of HCC. The cumulative occurrence rate of HCC in male patients was 31%, whereas that was 18% in female patients. In the HCV group, there was a significant increase of HCC occurrence rate in male patients. In contrast, no difference was observed in the HCC occurrence rate between male and female patients in the HBV group. The present study suggests that alcohol alone may not be an independent risk factor for HCC, nor does it accelerate HCC development in LC patients with HCV and HBV infection during the prospective observation of 3 years.

The clinical significance of serum antibodies against alcohol-altered rabbit hepatocytes was evaluated in 91 patients with alcoholic liver disease. Patients were divided into two groups according to the presence or absence of those antibodies at the time of first admission, and their clinical, biochemical, and histological findings were compared. In 38 seropositive patients, the total amount of ethanol consumption as well as serum activity of glutamate-oxaloacetate transaminase, serum levels of total bilirubin, gamma-globulin, IgG, and IgA were all significantly higher than in 53 seronegative patients. In addition, the extent of fibrosis, alcoholic hyalin, cholestasis, and lymphocytic and polymorpholeukocytic infiltrations in the liver were all significantly greater in the seropositive patients. Histological changes were compared in the 16 patients who continued to drink alcohol and who received repeated liver biopsies. Seven out of eight patients who were seropositive at the time of the first liver biopsy showed histological deterioration, whereas one of the eight seronegative patients showed a slight progression. These results suggest that the presence of serum antibodies against alcohol-altered liver cell membrane delineates a group of alcoholic patients with severe, advanced liver disease characterized by a tendency to progress with continued alcohol ingestion.