Publications by authors named "Yuya Seko"

101 Publications

The serum levels of IgM-free apoptosis inhibitor of macrophage /CD5L as a predictive and early diagnostic marker for NASH-associated hepatocellular carcinoma.

Hepatol Res 2022 Aug 8. Epub 2022 Aug 8.

The Institute for AIM Medicine, 8-1 Kawatacho Shinjuku-ku, TWINS, Tokyo, 162-8666, Japan.

Background: The apoptosis inhibitor of macrophage (AIM) is usually associated with the IgM pentamer in the blood and dissociated from IgM in various diseases, including hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH). We aimed to elucidate whether IgM-free AIM (fAIM) is useful for detecting latent HCC in NASH.

Methods: This research consisted of 2 cohort studies. The levels of serum fAIM, alpha-fetoprotein (AFP), and des-gamma carboxy prothrombin (DCP) of 18 NASH patients who developed HCC were measured during the follow-up period before HCC diagnosis (median: 4.7 years). In total, 199 patients with nonalcoholic fatty liver disease (NAFLD) were included in the HCC survey. The serum fAIM levels were analyzed using enzyme-linked immunosorbent assays.

Results: In the cohort of 18 patients with HCC, 12 had high fAIM at the time of the initial blood sample, 3 had normal fAIM levels throughout the follow-up period, and 3 had fAIM elevated from normal to positive. The positive ratio of fAIM prior to HCC diagnosis remained significantly higher than that of AFP and DCP, and the fAIM ratio gradually increased. In a survey of 199 non-HCC NAFLD patients, a Cox regression analysis using the independent variables, such as AFP, fAIM, age, albumin, bilirubin, and fibrosis stage, revealed that fAIM and AFP were significantly associated with the incidence of HCC.

Conclusions: During the development of NASH-HCC, AIM activation in blood appears to start even before HCC is diagnostically detectable. Thus, the serum IgM-free AIM levels could be a new, sensitive biomarker for latent NASH-HCC. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/hepr.13826DOI Listing
August 2022

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

Hepatol Res 2022 Aug 3. Epub 2022 Aug 3.

Division of Interventional Radiology, Shizuoka Cancer Center, Sunto-Gun, Japan.

Aim: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation.

Methods: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019).

Results: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111).

Conclusion: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.
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http://dx.doi.org/10.1111/hepr.13818DOI Listing
August 2022

Medical checkup data analysis method based on LiNGAM and its application to nonalcoholic fatty liver disease.

Artif Intell Med 2022 06 22;128:102310. Epub 2022 Apr 22.

Shiga University of Medical Science, Japan.

Although medical checkup data would be useful for identifying unknown factors of disease progression, a causal relationship between checkup items should be taken into account for precise analysis. Missing values in medical checkup data must be appropriately imputed because checkup items vary from person to person, and items that have not been tested include missing values. In addition, the patients with target diseases or disorders are small in comparison with the total number of persons recorded in the data, which means medical checkup data is an imbalanced data analysis. We propose a new method for analyzing the causal relationship in medical checkup data to discover disease progression factors based on a linear non-Gaussian acyclic model (LiNGAM), a machine learning technique for causal inference. In the proposed method, specific regression coefficients calculated through LiNGAM were compared to estimate the causal strength of the checkup items on disease progression, which is referred to as LiNGAM-beta. We also propose an analysis framework consisting of LiNGAM-beta, collaborative filtering (CF), and a sampling approach for causal inference of medical checkup data. CF and the sampling approach are useful for missing value imputation and balancing of the data distribution. We applied the proposed analysis framework to medical checkup data for identifying factors of Nonalcoholic fatty liver disease (NAFLD) development. The checkup items related to metabolic syndrome and age showed high causal effects on NAFLD severity. The level of blood urea nitrogen (BUN) would have a negative effect on NAFLD severity. Snoring frequency, which is associated with obstructive sleep apnea, affected NAFLD severity, particularly in the male group. Sleep duration also affected NAFLD severity in persons over fifty years old. These analysis results are consistent with previous reports about the causes of NAFLD; for example, NAFLD and metabolic syndrome are mutual and bi-directionally related, and BUN has a negative effect on NAFLD progression. Thus, our analysis result is plausible. The proposed analysis framework including LiNGAM-beta can be applied to various medical checkup data and will contribute to discovering unknown disease factors.
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http://dx.doi.org/10.1016/j.artmed.2022.102310DOI Listing
June 2022

Potential Therapeutic Targets and Promising Agents for Combating NAFLD.

Biomedicines 2022 Apr 14;10(4). Epub 2022 Apr 14.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is a growing cause of liver cirrhosis and liver cancer worldwide because of the global increases in obesity, dyslipidemia, hypertension, and type 2 diabetes mellitus. Contrary to the advancements in therapies for viral hepatitis, effective treatments remain unestablished for patients with NAFLD. NAFLD, including NASH, is characterized by steatosis, inflammation, hepatic necrosis, and fibrosis. Despite our understanding of its pathophysiology, there are currently no effective treatments for NAFLD. In this review, we provide an update on the known pathophysiological mechanisms involved in the development of NAFLD and the role of hepatic stellate cells, and summarize the potential therapeutic agents, including natural products, for NAFLD.
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http://dx.doi.org/10.3390/biomedicines10040901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9032837PMC
April 2022

Loss of KAP3 decreases intercellular adhesion and impairs intracellular transport of laminin in signet ring cell carcinoma of the stomach.

Sci Rep 2022 03 23;12(1):5050. Epub 2022 Mar 23.

School of Health Sciences, Bukkyo University, Nakagyo, Kyoto, 604-8418, Japan.

Signet-ring cell carcinoma (SRCC) is a unique subtype of gastric cancer that is impaired for cell-cell adhesion. The pathogenesis of SRCC remains unclear. Here, we show that expression of kinesin-associated protein 3 (KAP3), a cargo adaptor subunit of the kinesin superfamily protein 3 (KIF3), a motor protein, is specifically decreased in SRCC of the stomach. CRISPR/Cas9-mediated gene knockout experiments indicated that loss of KAP3 impairs the formation of circumferential actomyosin cables by inactivating RhoA, leading to the weakening of cell-cell adhesion. Furthermore, in KAP3 knockout cells, post-Golgi transport of laminin, a key component of the basement membrane, was inhibited, resulting in impaired basement membrane formation. Together, these findings uncover a potential role for KAP3 in the pathogenesis of SRCC of the stomach.
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http://dx.doi.org/10.1038/s41598-022-08904-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8943207PMC
March 2022

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2022 Jan 6;11(1):48-60. Epub 2021 Dec 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet.

Approach And Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, = 267; period 2: 2013-2016, = 352; period 3: 2017-2019, = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC.

Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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http://dx.doi.org/10.1159/000519868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820147PMC
January 2022

Re-administration of nivolumab after immune checkpoint inhibitor-induced cholangitis: the first reported case.

Clin J Gastroenterol 2022 Apr 24;15(2):467-474. Epub 2022 Feb 24.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan.

Immune checkpoint inhibitors (ICIs) cause various immune-related adverse events (irAEs). We encountered a patient in whom nivolumab was re-administered effectively and safely treat laryngeal cancer after nivolumab-induced cholangitis. A 60-year-old man with metastatic laryngeal squamous cell carcinoma received 3rd-line treatment with nivolumab. After the 8th cycle of chemotherapy, laboratory tests revealed grade 3 elevations of gamma-glutamyl transpeptidase and alkaline phosphatase. Computed tomography and endoscopic retrograde cholangiopancreatography showed diffuse hypertrophy, dilation of bile ducts, and intrahepatic bile ducts with irregular walls and mild stenosis. The histologic findings of a liver biopsy revealed portal inflammation and cholangitis, mainly composed of T cell infiltration. We diagnosed nivolumab-induced cholangitis and administered 30 mg of prednisolone (0.5 mg/kg) and ursodeoxycholic acid (600 mg) per day. Although we initiated 4th-line cytotoxic anticancer drug after the cholangitis improved, the laryngeal cancer progressed rapidly. Based on the improvement in hematologic parameters, radiologic imaging, and pathologic findings, we cautiously restarted nivolumab. During the 30 months after re-administration of nivolumab, the cholangitis did not recur and the disease was well-controlled.
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http://dx.doi.org/10.1007/s12328-022-01590-zDOI Listing
April 2022

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

J Gastroenterol 2022 02 15;57(2):90-98. Epub 2022 Jan 15.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Background: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs).

Methods: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared.

Results: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008).

Conclusions: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.
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http://dx.doi.org/10.1007/s00535-021-01837-5DOI Listing
February 2022

Honokiol Acts as a Potent Anti-Fibrotic Agent in the Liver through Inhibition of TGF-β1/SMAD Signaling and Autophagy in Hepatic Stellate Cells.

Int J Mol Sci 2021 Dec 12;22(24). Epub 2021 Dec 12.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.

Chronic liver injury may result in hepatic fibrosis, which can progress to cirrhosis and eventually liver failure. There are no drugs that are specifically approved for treating hepatic fibrosis. The natural product honokiol (HNK), a bioactive compound extracted from , represents a potential tool in the management of hepatic fibrosis. Though HNK has been reported to exhibit suppressive effects in a rat fibrosis model, the mechanisms accounting for this suppression remain unclear. In the present study, the anti-fibrotic effects of HNK on the liver were evaluated in vivo and in vitro. In vivo studies utilized a murine liver fibrosis model, in which fibrosis is induced by treatment with carbon tetrachloride (CCl). For in vitro studies, LX-2 human hepatic stellate cells (HSCs) were treated with HNK, and expression of markers of fibrosis, cell viability, the transforming growth factor-β (TGF-β1)/SMAD signaling pathway, and autophagy were analyzed. HNK was well tolerated and significantly attenuated CCl-induced liver fibrosis in vivo. Moreover, HNK decreased HSC activation and collagen expression by downregulating the TGF-β1/SMAD signaling pathway and autophagy. These results suggest that HNK is a new potential candidate for the treatment of hepatic fibrosis through suppressing both TGF-β1/SMAD signaling and autophagy in HSCs.
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http://dx.doi.org/10.3390/ijms222413354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8705910PMC
December 2021

Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.

Front Oncol 2021 2;11:758549. Epub 2021 Nov 2.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.
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http://dx.doi.org/10.3389/fonc.2021.758549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593418PMC
November 2021

Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice.

Lab Invest 2022 03 3;102(3):281-289. Epub 2021 Nov 3.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor β-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.
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http://dx.doi.org/10.1038/s41374-021-00680-9DOI Listing
March 2022

Clinical practice advice on lifestyle modification in the management of nonalcoholic fatty liver disease in Japan: an expert review.

J Gastroenterol 2021 12 31;56(12):1045-1061. Epub 2021 Oct 31.

Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, 1-2 Kawazonocho, Suita, Osaka, 564-0013, Japan.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide, including in Japan. The Japanese Society of Gastroenterology (JSGE) and the Japanese Society of Hepatology (JSH) have established the Japanese NAFLD/NASH guidelines in 2014 and revised these guidelines in 2020. As described in these guidelines, weight reduction by diet and/or exercise therapy is important for the treatment of NAFLD patients. The I148M single nucleotide polymorphism (rs738409 C > G) of PNPLA3 (patatin-like phospholipase domain-containing 3 protein) is widely known to be associated with the occurrence and progression of NAFLD. In the Japanese, the ratio of PNPLA3 gene polymorphisms found is approximately 20%, which is higher than that found in Westerners. In addition, the ratio of lean NAFLD patients is also higher in Japan than in Western countries. Therefore, the method for lifestyle guidance for the NAFLD patients in Japan would be different from that for the people in Western countries. The problems in the treatment of NAFLD patients include alcohol consumption and sarcopenia. Therefore, guidelines that can help clinicians treat Japanese patients with NAFLD are needed. In this expert review, we summarize evidence-based interventions for lifestyle modification (diet, exercise, alcohol, and sarcopenia) for the treatment of patients with NAFLD, especially from Japan and Asian countries.
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http://dx.doi.org/10.1007/s00535-021-01833-9DOI Listing
December 2021

Role of vitamin E in the treatment of non-alcoholic steatohepatitis.

Free Radic Biol Med 2021 12 29;177:391-403. Epub 2021 Oct 29.

Hepatology Center, Saiseikai Suita Hospital, Osaka, Japan. Electronic address:

Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD), can progress to cirrhosis, hepatocellular carcinoma (HCC), and hepatic failure/liver transplantation. Indeed, NASH will soon be the leading cause of HCC and liver transplantation. Lifestyle intervention represents the cornerstone of NASH treatment, but it is difficult to sustain. However, no pharmacotherapies for NASH have been approved. Oxidative stress has been implicated as one of the key factors in the pathogenesis of NASH. Systematic reviews with meta-analyses have confirmed that vitamin E reduces transaminase activities and may resolve NASH histopathology without improving hepatic fibrosis. However, vitamin E is not recommended for the treatment of NASH in diabetes, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. Nevertheless, vitamin E supplementation may improve clinical outcomes in patients with NASH and bridging fibrosis or cirrhosis. Further studies are warranted to confirm such effects of vitamin E and that it would reduce overall mortality/morbidity without increasing the incidence of cardiovascular events. Future clinical trials of the use of vitamin E in combination with other anti-fibrotic agents may demonstrate an additive or synergistic therapeutic effect. Vitamin E is the first-line pharmacotherapy for NASH, according to the consensus of global academic societies.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.10.017DOI Listing
December 2021

[Clinics in fatty liver;present situation and future prospects].

Nihon Shokakibyo Gakkai Zasshi 2021;118(9):797-804

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.

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http://dx.doi.org/10.11405/nisshoshi.118.797DOI Listing
September 2021

Tyrosine Kinase Inhibitors Stimulate HLA Class I Expression by Augmenting the IFNγ/STAT1 Signaling in Hepatocellular Carcinoma Cells.

Front Oncol 2021 11;11:707473. Epub 2021 Aug 11.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Combination treatment with tyrosine kinase inhibitors (TKIs) and immunotherapies has shown efficacy in the treatment of multiple cancers, but the immunomodulatory effect of TKIs on the tumor cell phenotype remains unknown in hepatocellular carcinoma (HCC). Given that human lymphocyte antigen class I (HLA-I) is essential for tumor antigen presentation and subsequent antitumor immunity, we examined the effects of regorafenib, as well as other TKIs (sorafenib, lenvatinib and cabozantinib) on HLA-I expression in HCC cell lines. Regorafenib increased cell surface HLA-I and β2-microglobulin protein expression in the presence of interferon γ (IFNγ). The expressions of various genes associated with the HLA-I antigen processing pathway and its transcriptional regulators were also upregulated by regorafenib. Furthermore, we found that regorafenib had an activating effect on signal transducers and activators of transcription 1 (STAT1), and that regorafenib-induced HLA-I expression was dependent on the augmented IFNγ/STAT1 signaling pathway. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also activated IFNγ/STAT1 signaling and increased HLA-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not. Given that regorafenib directly inhibits Raf/MEK/ERK signaling, the downregulation of the MEK/ERK pathway appears to be one of the mechanisms by which regorafenib promotes STAT1 activation. Sorafenib, lenvatinib, and cabozantinib also showed the same effects as regorafenib, while regorafenib had most potent effects on HLA-I expression, possibly dependent on its stronger inhibitory activity against the MEK/ERK pathway. These results support the clinical combination of TKIs with immunotherapy for the treatment of HCC.
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http://dx.doi.org/10.3389/fonc.2021.707473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385668PMC
August 2021

The Effect of Genetic Polymorphism in Response to Body Weight Reduction in Japanese Patients with Nonalcoholic Fatty Liver Disease.

Genes (Basel) 2021 04 22;12(5). Epub 2021 Apr 22.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Background: weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of rs738409 and rs6834314 variants in response to diet therapy in Japanese patients with NAFLD.

Methods: we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to and genotypes.

Results: the bodyweight (BW) reduction rate was greater in patients with the genotype CC than CG and GG ( = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in CG/GG (r = 0.279/0.381), but not in CC ( = 0.187). Change in LSM was correlated with change in BW only in patients with AG/GG (r = 0.425), but not the AA genotype ( = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of AG/GG (B = 3.043, = 0.032), but not AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) ( = 0.038).

Conclusions: in Japanese patients with NAFLD, rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.
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http://dx.doi.org/10.3390/genes12050628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145113PMC
April 2021

Type IV Collagen 7S Is the Most Accurate Test For Identifying Advanced Fibrosis in NAFLD With Type 2 Diabetes.

Hepatol Commun 2021 04 16;5(4):559-572. Epub 2020 Nov 16.

Department of Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Kyoto Japan.

This study aimed to examine whether the diagnostic accuracy of four noninvasive tests (NITs) for detecting advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is maintained or is inferior to with or without the presence of type 2 diabetes. Overall, 874 patients with biopsy-proven NAFLD were enrolled. After propensity-score matching by age, sex, and the prevalence of dyslipidemia, 311 patients were enrolled in each group of with or without diabetes. To evaluate the effect of diabetes, we compared the diagnostic accuracy of the fibrosis-4 (FIB-4) index, the NAFLD fibrosis score (NFS), the aspartate aminotransferase to platelet ratio index (APRI), and type IV collagen 7S (COL4-7S) in patients with NAFLD with and without diabetes. The areas under the receiver operating characteristic curve (AUROC) for identifying advanced fibrosis in patients without diabetes were 0.879 for the FIB-4 index, 0.851 for the NFS, 0.862 for the APRI, and 0.883 for COL4-7S. The AUROCs in patients with diabetes were 0.790 for the FIB-4 index, 0.784 for the NFS, 0.771 for the APRI, and 0.872 for COL4-7S. The AUROC of COL4-7S was significantly larger than that of the other NITs in patients with NAFLD with diabetes than in those without diabetes. The optimal high and low cutoff points of COL4-7S were 5.9 ng/mL and 4.8 ng/mL, respectively. At the low cutoff point, the accuracy of COL4-7S was better than that of the other NITs, especially in patients with diabetes. COL4-7S measurement might be the best NIT for identifying advanced fibrosis in NAFLD, especially in NAFLD with diabetes.
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http://dx.doi.org/10.1002/hep4.1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034577PMC
April 2021

Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study's clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glucocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased expression. EGFR degradation or inactivation represents a novel approach for NASH-HCC treatment and prevention, and the GR-MIG6 axis is a newly defined target that can be activated by HNK and related compounds.
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http://dx.doi.org/10.3390/cancers13071515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037653PMC
March 2021

SOX2 enhances cell survival and induces resistance to apoptosis under serum starvation conditions through the AKT/GSK-3β signaling pathway in esophageal squamous cell carcinoma.

Oncol Lett 2021 Apr 9;21(4):269. Epub 2021 Feb 9.

School of Health Sciences, Bukkyo University, Nakagyo, Kyoto 604-8418, Japan.

The human gene was recently identified as a novel major oncogene, recurrently amplified and overexpressed in esophageal squamous cell carcinoma (ESCC). However, the role and molecular mechanism of SOX2 in the carcinogenesis of ESCC remain to be elucidated. The present study investigated the effect of SOX2 on ESCC cell survival and resistance to apoptosis under serum starvation conditions. An adenoviral vector-mediated expression system and RNA interference were used to study the effect of SOX2. The present results revealed that SOX2 promoted ESCC cell survival and enhanced resistance to apoptosis under serum starvation conditions, but not in culture conditions with serum. Mechanistically, SOX2 increased the expression levels of phosphorylated AKT and glycogen synthase kinase-3β (GSK-3β), a downstream factor of AKT, under serum starvation conditions, leading to the promotion of ESCC cell survival. Additionally, SOX2 activated AKT through the PTEN/PI3K/phosphoinositide-dependent protein kinase 1 and mammalian target of rapamycin complex 2 signaling pathways. Therefore, SOX2 may facilitate the survival of ESCC cells under poor nutrient conditions by activating the AKT/GSK-3β signaling pathway.
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http://dx.doi.org/10.3892/ol.2021.12530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885160PMC
April 2021

The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040.

Hepatol Int 2021 Apr 12;15(2):366-379. Epub 2021 Feb 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, 780 Welch Road, CJ250K, Palo Alto, CA, 94304, USA.

Background: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD.

Methods: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients.

Results: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD.

Conclusion: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.
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http://dx.doi.org/10.1007/s12072-021-10143-4DOI Listing
April 2021

PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat.

Sci Rep 2020 11 11;10(1):19578. Epub 2020 Nov 11.

Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyou-ku, Kyoto, 602-8566, Japan.

We explored the beneficial effects of GW7647, a peroxisome proliferator activated receptor α (PPARα) agonist, and metformin, an anti-diabetic drug on an advanced nonalcoholic steatohepatitis (NASH) model in rodents and investigated the possible mechanisms involved. Mice were fed control chow or a choline-deficient L-amino acid-defined diet containing 45% fat (HF-CDAA). The mice fed HF-CDAA diets for 16 weeks were divided into four groups: the no treatment (HF-CDAA), HF-CDAA containing 1000 mg/kg metformin, HF-CDAA containing 10 mg/kg GW7647, and HF-CDAA with both metformin and GW7647 groups. Metformin alone slightly deteriorated the aspartate and alanine aminotransferase (AST/ALT) values, whereas co-treatment with GW7647 and metformin greatly suppressed liver injury and fibrosis via activation of the AMP-activated protein kinase (AMPK) pathway. Further study revealed that co-treatment decreased the expression of inflammatory-, fibrogenesis-, and endoplasmic reticulum (ER) stress-related genes and increased the oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH) ratio, suggesting the superiority of co-treatment due to restoration of mitochondrial function. The additive benefits of a PPARα agonist and metformin in a HF-CDAA diet-induced advanced NASH model was firstly demonstrated, possibly through restoration of mitochondrial function and AMPK activation, which finally resulted in suppression of hepatic inflammation, ER stress, then, fibrosis.
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http://dx.doi.org/10.1038/s41598-020-75805-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658250PMC
November 2020

The Appropriate Opportunity for Evaluating Liver Fibrosis by Using the FIB-4 Index in Patients with Nonalcoholic Fatty Liver Disease in Japan.

Diagnostics (Basel) 2020 Oct 19;10(10). Epub 2020 Oct 19.

Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566, Japan.

In patients with nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the predictive factor for liver-related events and prognosis. This retrospective study aimed to evaluate longitudinal changes in the FIB-4 index and to determine a strategy for diagnosing and following patients with NAFLD using this index. We analyzed the FIB-4 index at baseline and after 1 and 5 years in 272 consecutive patients with biopsy-proven NAFLD. Of these, 52 patients underwent serial biopsies. The change in the FIB-4 index was correlated with changes in the fibrosis stage among these patients ( = 0.048). The median FIB-4 index was 1.64 at baseline, 1.45 at 1 year, and 1.74 at 5 years. The negative predictive value for advanced fibrosis at a low cutoff point was 90.4/90.1 at baseline/1 year. Its specificity at a high cutoff point increased from 65.0% at baseline to 82.3% at 1 year. Multivariate analysis identified the FIB-4 index at 1 year as a predictive factor for a FIB-4 index > 2.67 at 5 years. A FIB-4 index < 1.30 was acceptable for excluding advanced fibrosis at baseline. In contrast, to evaluate and predict advanced liver fibrosis with the FIB-4 index at a high cutoff point, we should use the index at 1 year after appropriate therapy.
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http://dx.doi.org/10.3390/diagnostics10100842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603133PMC
October 2020

Effect of pemafibrate on fatty acid levels and liver enzymes in non-alcoholic fatty liver disease patients with dyslipidemia: A single-arm, pilot study.

Hepatol Res 2020 Dec 1;50(12):1328-1336. Epub 2020 Oct 1.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Aim: Dyslipidemia (DL) is commonly associated with non-alcoholic fatty liver disease (NAFLD). Pemafibrate, a selective peroxisome proliferator activated receptor α modulator (SPPARMα), has been shown to improve liver function among patients with DL. The aim of this single-arm prospective study is to evaluate the efficacy of pemafibrate in NAFLD patients with DL.

Methods: Twenty NAFLD patients with DL who received pemafibrate (0.1 mg) twice a day for 12 weeks were prospectively enrolled in this study. The primary end-point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12.

Results: Serum ALT levels decreased from 75.1 IU/L at baseline to 43.6 IU/L at week 12 (P = 0.001). Significant improvements in triglyceride, high-density lipoprotein cholesterol, total fatty acid, saturated fatty acid (SFA), and unsaturated fatty acid were also noted. The serum level of remnant-like protein cholesterol, SFA, and polyunsaturated / saturated fatty acid ratio (PUFA / SFA ratio) at baseline were correlated with change in ALT level (r = -0.53, r = -0.57, and r = 0.46, respectively). Change in PUFA and change in PUFA / SFA ratio were negatively correlated with change in ALT level (r = -0.49 and r = -0.53). No hepatic or renal adverse events were reported.

Conclusions: Selective peroxisome proliferator activated receptor α could be a promising novel agent for treatment of NAFLD patients with DL by regulating fatty acid composition. A further long-term large-scale trial is warranted to confirm the efficacy of SPPARMα on NAFLD with DL.
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http://dx.doi.org/10.1111/hepr.13571DOI Listing
December 2020

Surveillance of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Diagnostics (Basel) 2020 Aug 10;10(8). Epub 2020 Aug 10.

Japan Strategic Medical Administration Research Center (J-SMARC), Nagoya, Aichi 460-0011, Japan.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is sufficient epidemiological cohort data to recommend the surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommends that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) consider HCC surveillance. NITs include the fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US), which is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US, or if an US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, the lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and the protein induced by the absence of vitamin K or antagonist-II (PIVKA-II), can help identify a high risk of HCC in NAFLD patients. Innovative parameters, including a Mac-2 binding protein glycated isomer, type IV collagen 7S, free apoptosis inhibitor of the macrophage, and a combination of single nucleoside polymorphisms, are expected to be established. Considering the large size of the NAFLD population, optimal screening tests must meet several criteria, including high sensitivity, cost effectiveness, and availability.
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http://dx.doi.org/10.3390/diagnostics10080579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459689PMC
August 2020

The Association between the Platelet Count and Liver Volume in Compensated Cirrhosis Patients after the Eradication of Hepatitis C virus by Direct-acting Antivirals.

Intern Med 2020 1;59(15):1811-1817. Epub 2020 Aug 1.

Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Japan.

Objective Although most patients who obtain a sustained virological response (SVR) show an improved liver function, some show decreased platelet counts after the eradication of hepatitis C virus (HCV). The aim of this retrospective study was to clarify the association of the liver and spleen volumes with the platelet count after SVR achieved by direct-acting antiviral (DAA) treatment. Methods This study enrolled 36 consecutive patients treated by DAAs who obtained an SVR between September 2014 and December 2018. The liver and spleen volumes were derived from computed tomography scans obtained at pretreatment, SVR, and 48 weeks after SVR. No patient developed hepatocellular carcinoma during this study. Results Compared with pretreatment, the median aspartate aminotransferase, alanine aminotransferase, albumin serum levels, and platelet counts were significantly improved at SVR and 48 weeks after SVR. The liver/spleen volumes per body weight had decreased significantly from 22.5/4.2 mL/kg at baseline to 21.1/3.6 mL/kg at 48 weeks after SVR. The change in the liver volume was associated with the change in the platelet count, and the change in the spleen volume was negatively associated with the change in the serum albumin level. A multivariate analysis identified the change in the liver volume (≥95%, odds ratio 76.9, p=0.005) as the factor associated with improvement in the platelet count at 48 weeks after SVR. The patients with an increased liver volume at 48 weeks after SVR showed an increased platelet count. Conclusion Both the liver and spleen volume decreased significantly after the eradication of HCV. The patients with a re-increased liver volume showed a rapid increase in the platelet count.
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http://dx.doi.org/10.2169/internalmedicine.4442-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474995PMC
October 2020

Intrahepatic Tumor Burden as a Novel Factor Influencing the Introduction of Second-line Chemotherapy for Hepatocellular Carcinoma.

Anticancer Res 2020 Jul;40(7):3953-3960

Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background/aim: To examine the factors influencing the introduction of the second-line chemotherapy and discuss the selection of first-line agent for hepatocellular carcinoma (HCC).

Patients And Methods: We retrospectively studied 154 patients with HCC who received sorafenib therapy.

Results: A total of 109 (70.8%) patients, maintained Child-Pugh grade A and Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 upon sorafenib discontinuation. Multivariate analysis revealed that the up-to-seven criteria status in the hepatic lesion [p=0.019; odds ratio=OR, 2.685], albumin-bilirubin (ALBI) grade (p=0.002; OR=3.589), and macroscopic vascular invasion (MVI) (p=0.008; OR=2.972) were significant factors at sorafenib initiation that influenced the maintenance of Child-Pugh grade A and ECOG-PS ≤1 upon therapy discontinuation.

Conclusion: Not only ALBI grade and MVI, but also up-to-seven criteria status in the hepatic lesion influence the introduction of second-line therapy, and could affect the selection of the first-line therapy.
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http://dx.doi.org/10.21873/anticanres.14387DOI Listing
July 2020

Attenuated effect of PNPLA3 on hepatic fibrosis by HSD17B13 in Japanese patients with non-alcoholic fatty liver disease.

Liver Int 2020 07 12;40(7):1686-1692. Epub 2020 May 12.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Background & Aims: PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD.

Methods: We analysed the associations of these genetic variants with liver histology in 290 Japanese patients with biopsy-proven NAFLD diagnosed during 2002-2019. During follow-up, 14 patients (4.8%) developed hepatocellular carcinoma.

Results: Prevalences of the PNPLA3 rs738409 genotypes were 0.17 for CC, 0.41 for CG, 0.42 for GG, and those for HSD17B13 rs6834314 were 0.54 for AA, 0.39 for AG and 0.07 for GG. There was no significant interaction between the PNPLA3 and HSD17B13 genotypes. Prevalences of advanced fibrosis according to PNPLA3/HSD17B13 genotypes were 0.16 for CC,CG/AG,GG, 0.20 for CC,CG/AA, 0.30 for GG/AG,GG and 0.37 for GG/AA. Multivariate analysis identified PNPLA3 GG as a predictor of advanced fibrosis (stage 3/4) in carriers of HSD17B13 AA (odds ratio 2.4, P = .041), but not HSD17B13 AG/GG (P = .776). The HSD17B13 genotype G was significantly associated with lower prevalences of severe inflammation and ballooning and tended to be associated with a higher prevalence of advanced steatosis.

Conclusions: In Japanese patients with NAFLD, carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis.
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http://dx.doi.org/10.1111/liv.14495DOI Listing
July 2020

Diagnostic accuracy of FibroScan-AST score to identify non-alcoholic steatohepatitis with significant activity and fibrosis in Japanese patients with non-alcoholic fatty liver disease: Comparison between M and XL probes.

Hepatol Res 2020 Jul 13;50(7):831-839. Epub 2020 May 13.

Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Aim: Recently, FibroScan-AST (FAST) score was reported to be effective for identifying non-alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non-alcoholic fatty liver disease (NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut-off values and diagnostic accuracy between the FibroScan M and XL probes.

Methods: Eighty-two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.

Results: No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut-off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut-off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut-off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe.

Conclusions: There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.
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http://dx.doi.org/10.1111/hepr.13508DOI Listing
July 2020

Early Tumor Shrinkage as a Predictive Factor for Outcomes in Hepatocellular Carcinoma Patients Treated with Lenvatinib: A Multicenter Analysis.

Cancers (Basel) 2020 Mar 23;12(3). Epub 2020 Mar 23.

Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

We investigated the association between early tumor shrinkage (ETS) and treatment outcome in patients with hepatocellular carcinoma treated with lenvatinib (LEN). A retrospective analysis was performed in 104 patients. ETS was defined as tumor shrinkage at the first evaluation in the sum of target lesions' longest diameters from baseline according to the Response Evaluation Criteria in Solid Tumors (RECIST). The median overall survival (OS) was not reached, whereas the median progression-free survival (PFS) was 5.0 months. The receiver operating characteristic curve analysis in differentiating long-term responders (PFS ≥ 5.0 months) from short-term responders (PFS < 5.0 months) revealed an ETS cut-off value of 10%. ETS ≥ 10% was significantly correlated with better PFS and OS compared with ETS < 10%. Additionally, ETS ≥ 10% showed a better discrimination ability on prognosis compared with modified RECIST-based objective response at the first evaluation. Multivariate analysis confirmed ETS ≥ 10% as an independent predictor of better OS, as well as a Child-Pugh score of 5 and macrovascular invasion. In conclusion, ETS ≥ 10% was strongly associated with outcome in patients treated with LEN. This biomarker could allow earlier assessment of the treatment response and guide treatment decision-making for HCC.
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http://dx.doi.org/10.3390/cancers12030754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140019PMC
March 2020
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