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Background and aimsThe risk factors in the progression of nonalcoholic fatty liver disease (NAFLD) have not been fully clarified. Porphyromonas gingivalis (P.g) has been considered to be a confounding risk factor for systemic diseases. We aimed to evaluate the effect of P.g infection on risk of progression to NASH.Methods(1) Serum IgG antibody titers against P.g fimbriae (fimA) in 200 biopsy-proven NAFLD patients were measured by ELISA and compared with histological findings. (2) C57BL/6J mice were fed a control diet (CD) or high-fat diet (HFD) with or without P.g-odontogenic infection and analyzed histologically. Mouse livers were analyzed using CE–TOFMS and LC–TOFMS.Results(1) A significant correlation between fibrosis progression and antibody titers against P.g possessing fimA type 4 was identified (P = 0.0081). Multivariate analysis identified older age and type 4 P.g-positivity as risk factors for advanced fibrosis. (2) Fibrosis and steatosis were more severe in HFD P.g(+) mice compared with HFD P.g(−) mice. In metabolome analysis, fatty acid metabolism was significantly disrupted with HFD in P.g-infected mouse livers. Monounsaturated/saturated fatty acid ratios were significantly higher in the HFD P.g(+) group than in the HFD P.g(−) group (P < 0.05). Moreover, expression levels of SCD1 and ELOVL6 were significantly reduced.ConclusionsThese results suggest that P.g infection is an important risk factor for pathological progression in NAFLD. Increase in the monounsaturated/saturated fatty acid ratio may be an important change that facilitates progression of NAFLD.

BackgroundThe FIB4 index is clinically useful, but because its formula includes age, the appropriate cutoff point may differ by age group. Here, new FIB4 index cutoff points were validated using cohort data from 14 hepatology centers in Japan.MethodsThe FIB4 index was determined in biopsy-confirmed NAFLD patients (n = 1050) who were divided into four groups: ≤ 49, 50–59, 60–69, and ≥ 70 years. ROC analysis predicted advanced fibrosis in each age group; low and high cutoff points were defined by a sensitivity and specificity of 90%. The new and conventional cutoffs were compared for detecting advanced fibrosis.ResultsThe modified low and high cutoff points were 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 3.24 in 60–69 years, and 1.95 and 4.56 in ≥ 70 years. In ≥ 60 years, the false-negative rate was increased using the modified high cutoff point, and the high cutoff point was better with the conventional cutoff point. The new proposed low and high cutoff points are 1.05 and 1.21 in ≤ 49 years, 1.24 and 1.96 in 50–59 years, 1.88 and 2.67 in 60–69 years, and 1.95 and 2.67 in ≥ 70 years; these cutoff points improved the accuracy of advanced fibrosis diagnosis.ConclusionsFIB4 index cutoff points for predicting advanced fibrosis in NAFLD increased with age. Cutoff points modified by age improved the diagnostic accuracy of estimations of advanced liver fibrosis using the FIB4 index.

Background We investigated the effects of dental infection with Porphyromonas gingivalis ( P.g. ), an important periodontal pathogen, on NASH progression, by feeding mice a high fat diet (HFD)and examining P.g. infection in the liver of NASH patients. Methods C57BL/6J mice were fed either chow-diet (CD) or HFD for 12 weeks, and then half of the mice in each group were infected with P.g. from the pulp chamber (HFD- P.g. (−), HFD- P.g. (+), CD- P.g. (−) and CD- P.g. (+)). Histological and immunohistochemical examinations, measurement of serum lipopolysaccharide (LPS) levels and ELISA for cytokines in the liver were performed. We then studied the effects of LPS from P.g. ( P.g. -LPS) on palmitate-induced steatotic hepatocytes in vitro, and performed immunohistochemical detection of P.g. in liver biopsy specimens of NASH patients. Results Serum levels of LPS are upregulated in P.g. (+) groups. Steatosis of the liver developed in HFD groups, and foci of Mac2-positive macrophages were prominent in HFD- P.g. (+). P.g. was detected in Kupffer cells and hepatocytes. Interestingly, areas of fibrosis with proliferation of hepatic stellate cells and collagen formation were only observed in HFD- P.g. (+). In steatotic hepatocytes, expression of TLR2, one of the P.g. -LPS receptors, was upregulated. P.g. -LPS further increased mRNA levels of palmitate-induced inflammasome and proinflammatory cytokines in steatotic hepatocytes. We demonstrated for the first time that P.g. existed in the liver of NASH patients with advanced fibrosis. Conclusions Dental infection of P.g. may play an important role in NASH progression through upregulation of the P.g. -LPS-TLR2 pathway and activation of inflammasomes. Therefore, preventing and/or eliminating P.g. infection by dental therapy may have a beneficial impact on management of NASH.

Purpose Previous reports suggest that contrast-enhanced ultrasonography (CEUS) is useful for predicting the efficacy of sorafenib and lenvatinib treatment. However, there are no reports on the utility of CEUS for predicting the efficacy of atezolizumab plus bevacizumab combination therapy (Atezo + Bev). This study aimed to identify CEUS parameters for predicting the efficacy of Atezo + Bev. Methods A total of 30 patients with hepatocellular carcinoma (HCC) treated with Atezo + Bev who underwent CEUS before and 5 weeks after treatment initiation were included. Results Post area under the curve (post AUC) was identified as a predictive factor for early progressive disease (PD). The optimal cut-off value of post AUC for predicting progression-free survival (PFS) was 61.3. Conclusion The results of this study suggest that CEUS at 5 weeks after initiation of Atezo + Bev may predict PFS in HCC patients. Changes to the treatment plan may need to be considered in patients with post AUC > 61.3.

Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAF mean ) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAF mean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

Background The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD. Methods In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated. Results The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7 % (hypertriglyceridemia, 45.3 %; increased low-density lipoprotein cholesterol, 37.5 %; decreased high density lipoprotein cholesterol, 19.5 %) of patients. Hypertension was present in 30.2 %, and diabetes mellitus (DM) in 47.3 %. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage. Conclusions DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

BackgroundThis study investigated time-course changes in skeletal muscle volume per year with tolvaptan in patients with refractory ascites that was unresponsive to loop diuretics and aldosterone antagonists.MethodsThis retrospective study included 42 patients who received tolvaptan for refractory ascites and/or hepatic edema and underwent computed tomography (CT) before and ≥ 3 months after initiating tolvaptan. The time-course changes in skeletal muscle index per year [ΔSMI (%)] was calculated as follows: ΔSMI (%) = (SMI at final CT scan − SMI at initial CT scan)/SMI at initial CT scan × 100/years between CT scans.ResultsEligible patients were 23 men and 19 women of median age of 71 years (range 21–94 years). The median follow-up period was 22.7 (range 3.5–54.6) months. ΔSMI (%) was significantly higher in the responders group than in the nonresponder group. Multivariate analysis showed the response to tolvaptan was an independent and significant factor associated with an increase in muscle mass [odds ratio (OR) 20.364; 95% CI 2.327–178.97; P = 0.006]. Overall survival with tolvaptan was significantly higher in the responder group than in the nonresponder group. Multivariate analysis showed that the response to tolvaptan treatment was a significant contributor to good prognosis (OR 3.884; 95% CI 1.264–11.931; P = 0.018). A significant negative correlation was observed between the dosage of furosemide and ΔSMI (%) (P = 0.014).ConclusionsTreatment of refractory ascites with tolvaptan may attenuate the progression of sarcopenia and improve the prognosis in patients with decompensated cirrhosis.

BackgroundCombination therapy with glecaprevir (GLE) and pibrentasvir (PIB) has high efficacy for pan-genotypic hepatitis C virus (HCV)-infected patients. However, the efficacy of the therapy for failures to prior direct-acting antiviral (DAA) regimens in real-world practice is not well known.MethodsThirty patients infected with HCV genotype 1b, 2a, 2b, or 3a who failed to respond during prior DAA therapies were treated with GLE/PIB for 12 weeks. HCV NS3 and NS5A drug resistance-associated variants (RAVs) were determined by direct sequencing.ResultsTwenty-eight out of 30 patients (93.3%) achieved SVR12 by GLE/PIB treatment. SVR12 rates were similar between patients with and without advanced liver fibrosis (94.7% and 91.0%, respectively). All 9 patients with genotype 2a, 2b, or 3a HCV infection achieved SVR12. However, two genotype 1b HCV-infected patients who failed previous daclatasvir plus asunaprevir treatment experienced HCV relapse after the end of GLE/PIB treatment. Direct sequence analysis showed the presence of NS3-D168E plus NS5A-L31I/P58S/Y93H RAVs in one patient and NS5A-L31F/P32del RAVs in another patient before GLE/PIB treatment. In the former patient, NS3-D168E plus NS5A-L31I/P58S/Y93H RAVs persisted, and additional NS5A-L28M/V75A variants emerged after HCV relapse.ConclusionsGLE/PIB treatment for HCV-infected patients who did not respond to prior DAA treatments was highly effective regardless of liver fibrosis stage. However, some genotype 1b HCV-infected patients, especially those with NS5A-P32del, may have low susceptibility to the treatment.

Background Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma. Methods Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample ( n  = 51) and tumor tissue ( n , baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood. Results Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies. Conclusions Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma. Plain language summary Two types of therapy for liver cancer are immunotherapy and anti-angiogenic therapy. Immunotherapy helps the patient’s immune system to attack the tumor. Anti-angiogenic therapy blocks the formation of new blood vessels (angiogenesis) in the tumor, and this type of therapy might also impact the immune system. We analyzed changes in the immune characteristics of human liver cancer samples induced by lenvatinib, an anti-angiogenic therapy. Patient outcomes on lenvatinib did not depend on the immune features of the tumor before treatment. However, immune characteristics of the tumors did change after treatment, and this may mean these tumors become easier to treat with immunotherapies. These findings help us to understand the effects of lenvatinib in liver cancer and whether, for example, it might be useful to combine this drug with immunotherapy. all Yamauchi et al. investigate the effects of treatment with the kinase inhibitor lenvatinib on immune parameters via multi-omics analysis of liver cancer and peripheral blood samples. Immune signatures associated with T-cell functions and interferon response are enriched during early treatment, while immunoinhibitory signatures are downregulated.

Purpose Transient elastography (TE) and the controlled attenuation parameter (CAP) have been used for diagnosis of liver fibrosis and steatosis. Obesity is a limiting factor to the accuracy of elastography; however, an XL probe was validated for use in obese patients. Two-dimensional shear wave elastography (2D-SWE) and attenuation imaging (ATI) have also been developed. It is unknown if obesity affects 2D-SWE/ATI values for evaluation of liver fibrosis and steatosis. We assessed the reliability of the measurement rate and the diagnostic performance of TE/CAP versus SWE/ATI. Methods The patients ( n  = 85) underwent TE/CAP, 2D-SWE/ATI, and liver biopsy on the same day. They were diagnosed with chronic hepatitis based on liver biopsy. The patients were divided into three groups by skin–liver capsule distance (SCD). Results The reliability of the measurement rate for the M probe was lower than that for the XL probe in the group with SCD over 22.5 mm. The rate achieved with 2D-SWE was high in all groups regardless of the SCD. In the assessment of the diagnostic performance, there was no difference between the area under the receiver-operating curve (AUROC) of TE compared to 2D-SWE to stratify the fibrosis stage. There was no difference in the AUROC for the stratification of the steatosis grades between CAP and ATI. The diagnostic accuracy of TE for F ≥ 3 fibrosis evaluated with the M probe and 2D-SWE was lower than that of TE evaluated with the XL probe in the group with SCD over 22.5 mm. Conclusion The ability of 2D-SWE to stratify fibrosis stage and steatosis grade was as good as FibroScan. However, 2D-SWE had a high reliability in the measurement rate regardless of the SCD with one probe. And the XL probe showed high diagnostic accuracy for severe fibrosis in the group with SCD over 22.5 mm.