Publications by authors named "Dan Nakano"

22 Publications

  • Page 1 of 1

Effects of Mediterranean Diet in Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Randomized Controlled Trials.

Semin Liver Dis 2021 Aug 19;41(3):225-234. Epub 2021 Jun 19.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

We conducted a meta-analysis to investigate the effects of the Mediterranean Diet (Med-Diet) on hepatic steatosis and insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). Six randomized controlled trials were selected for the meta-analysis (sample size: 250 participants). In the meta-analysis, there was no significant difference in body mass index and waist circumference between the Med-Diet and control groups. Med-Diet significantly reduced fatty liver index (FLI) compared with the control diet (standard mean difference [SMD]: -1.06; 95% CI: -1.95 to -0.17;  = 0.02). Med-Diet significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) compared with the control diet (SMD: -0.34; 95% CI: -0.65 to -0.03;  = 0.03). Similarly, a meta-regression analysis using age showed that Med-Diet significantly reduced FLI and HOMA-IR (95% CI: -0.956 to -0.237,  = 0.001 and 95% CI: -0.713 to -0.003,  = 0.048, respectively). This meta-analysis demonstrated that Med-Diet improved hepatic steatosis and insulin resistance in patients with NAFLD. Thus, Med-Diet is a beneficial pharmaconutritional therapy in patients with NAFLD.
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http://dx.doi.org/10.1055/s-0041-1723751DOI Listing
August 2021

MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach.

Hepatol Res 2021 Jun 15. Epub 2021 Jun 15.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups.

Methods: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE.

Results: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235).

Conclusions: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.
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http://dx.doi.org/10.1111/hepr.13685DOI Listing
June 2021

Non-Obese MAFLD Is Associated with Colorectal Adenoma in Health Check Examinees: A Multicenter Retrospective Study.

Int J Mol Sci 2021 May 22;22(11). Epub 2021 May 22.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.

Colorectal adenoma is linked to metabolic dysfunction. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a precise definition and three subtypes, including non-obese MAFLD. We aimed to investigate the impact of MAFLD on the prevalence of colorectal adenoma by comparing it to non-alcoholic fatty liver disease (NAFLD) in health check-up examinees. This is a multicenter retrospective study. We enrolled 124 consecutive health check-up examinees who underwent colonoscopy. NAFLD and MAFLD were present in 58 and 63 examinees, respectively. Colorectal adenoma was diagnosed by biopsy. The impact of the MAFLD definition on the prevalence of colorectal adenoma was investigated by logistic regression, decision-tree, and random forest analyses. In logistic regression analysis, MAFLD was identified as the only independent factor associated with the presence of colorectal adenoma (OR 3.191; 95% CI 1.494-7.070; = 0.003). MAFLD was also identified as the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (29 variable importance value). Among the three subtypes of MAFLD, non-obese MAFLD was the sole independent factor associated with the presence of colorectal adenoma (OR 3.351; 95% CI 1.589-7.262; ≤ 0.001). Non-obese MAFLD was also the most important classifier for the presence of colorectal adenoma in decision-tree and random forest analyses (31 variable importance value). MAFLD, particularly non-obese MAFLD, is the most important factor associated with the presence of colorectal adenoma rather than NAFLD. Colonoscopy examination should be considered in patients with MAFLD, especially those who are non-obese.
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http://dx.doi.org/10.3390/ijms22115462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196881PMC
May 2021

Effects of a low-intensity resistance exercise program on serum miR-630, miR-5703, and Fractalkine/CX3CL1 expressions in subjects with No exercise habits: A preliminary study.

Hepatol Res 2021 Jul 2;51(7):823-833. Epub 2021 Jun 2.

Department of Orthopedics, School of Medicine, Kurume University, Kurume, Japan.

Aims: Exercise is effective for the prevention of liver cancer. Exercise exerts biological effects through the regulation of microRNAs (miRNAs) and cytokines/myokines. We aimed to investigate the effects of low-intensity resistance exercise on serum miRNA and cytokine/myokine expressions in subjects with no exercise habits.

Methods: We enrolled seven male subjects with no exercise habits in this prospective before-after study. All subjects performed a low-intensity resistance exercise program (three metabolic equivalents, approximately 20 min/session). Serum miRNA expressions were evaluated using microarrays. We performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of differentially expressed miRNAs before and after exercise. Serum cytokine/myokine expressions were evaluated using a multiplex panel.

Results: All subjects completed the exercise program with no adverse events. In the microarray analysis, seven miRNAs showed a significant change between before and after exercise. Of these, microRNA (miR)-630 and miR-5703 showed a >1.5-fold increase (miR-630: 40.7 vs. 69.3 signal intensity, p = 0.0133; miR-5703: 30.7 vs. 55.9 signal intensity, p = 0.0051). KEGG pathway enrichment analysis showed that miR-630- and miR-5703-related genes were enriched in 37 and 5 pathways, including transforming growth factor-beta and Wnt signaling pathways, respectively. In the multiplex analysis, 12 cytokines/myokines showed significant alteration after exercise compared to before exercise. Of these, fractalkine/CX3CL1 showed the most significant up-regulation by exercise (94.5 vs. 109.1 pg/ml, p = 0.0017).

Conclusions: A low-intensity resistance exercise program was associated with upregulation of serum miR-630, miR-5703, and fractalkine/CX3CL1 expressions in subjects with no exercise habits. Thus, even low-intensity exercise may alter miRNA and cytokine/myokine expressions in humans.
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http://dx.doi.org/10.1111/hepr.13670DOI Listing
July 2021

Effects of In-Hospital Exercise on Frailty in Patients with Hepatocellular Carcinoma.

Cancers (Basel) 2021 Jan 7;13(2). Epub 2021 Jan 7.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

Frailty including physical inactivity is associated with the survival of patients with hepatocellular carcinoma (HCC). We aimed to investigate the effects of in-hospital exercise on frailty in patients with HCC. This was a multi-center observational study. Patients with HCC were classified into exercise ( = 114) and non-exercise ( = 67) groups. The exercise group was treated with a mixture of aerobic and resistance exercises (20-40 min/day, median four days). Frailty was assessed using the liver frailty index (LFI). Factors for changes in LFI were examined by multivariate and decision-tree analyses. The factors were also examined after propensity score matching. During hospitalization, LFI was significantly improved in the exercise group compared to the non-exercise group (ΔLFI -0.17 vs. -0.02, = 0.0119). In multivariate analysis, exercise (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.240-4.570, = 0.0091) and females (OR 2.09; 95%CI, 1.062-4.109; = 0.0328) were identified as independent factors for the improvement of LFI. In the decision-tree analysis, exercise was identified as an initial classifier associated with the improvement of LFI. Similar findings were also seen in the propensity score matching analyses. We demonstrated that in-hospital exercise improved frailty in patients with HCC. Thus, in-hospital exercise may be beneficial for improving physical function in patients with HCC.
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http://dx.doi.org/10.3390/cancers13020194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826707PMC
January 2021

Effects of In-Hospital Physical Therapy on Activities of Daily Living in Patients with Hepatocellular Carcinoma.

Int J Environ Res Public Health 2020 12 6;17(23). Epub 2020 Dec 6.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

Activities of daily living (ADL) are frequently impaired in patients with hepatocellular carcinoma (HCC). In this retrospective study, we aimed to investigate the effects of physical therapy on ADLs in patients with HCC during hospitalization for cancer treatment. Nineteen patients with HCC were enrolled. During hospitalization, patients performed a combination of resistance training, stretching, and aerobic exercise (20-60 min/day). ADLs were assessed using the functional independence measure (FIM). Changes in FIM were evaluated by before-after analysis. No significant difference was seen in Child-Pugh class before and after physical therapy. The bilateral knee extension strength and chair stand test were significantly increased after physical therapy compared with before physical therapy ( = 0.001 and = 0.008, respectively). The total FIM score was significantly increased after physical therapy compared with that before physical therapy ( = 0.0156). Among the 18 indexes of FIM, the stairs index was significantly improved after physical therapy compared with that before physical therapy (5.9 vs. 6.4 points, = 0.0241). We demonstrated that physical therapy improved muscle strength without worsening liver function. Furthermore, physical therapy improved FIM, especially in the stairs index, in patients with HCC. Thus, physical therapy may be beneficial in patients with HCC during cancer treatment.
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http://dx.doi.org/10.3390/ijerph17239098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730642PMC
December 2020

MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.

Liver Int 2020 12;40(12):3018-3030

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Background & Aims: Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of the MAFLD definition vs the existing NAFLD criteria to identify patients with significant fibrosis and to characterize the impact of mild alcohol intake.

Methods: We enrolled 765 Japanese patients with fatty liver (median age 54 years). MAFLD and NAFLD were diagnosed in 79.6% and 70.7% of patients respectively. Significant fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥6.6 kPa using shear wave elastography. Mild alcohol intake was defined as <20 g/day. Factors associated with significant fibrosis were analysed by logistic regression and decision-tree analyses.

Results: Liver stiffness was higher in MAFLD compared to NAFLD (7.7 vs 6.8 kPa, P = .0010). In logistic regression, MAFLD (OR 4.401; 95% CI 2.144-10.629; P < .0001), alcohol intake (OR 1.761; 95% CI 1.081-2.853; P = .0234), and NAFLD (OR 1.721; 95%CI 1.009-2.951; P = .0463) were independently associated with significant fibrosis. By decision-tree analysis, MAFLD, but not NAFLD or alcohol consumption was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher for MAFLD than NAFLD (93.9% vs 73.0%). In patients with MAFLD, even mild alcohol intake was associated with an increase in the prevalence of significant fibrosis (25.0% vs 15.5%; P = .0181).

Conclusions: The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non-invasive tests. Moreover, in patients with MAFLD, even mild alcohol consumption is associated with worsening of hepatic fibrosis measures.
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http://dx.doi.org/10.1111/liv.14675DOI Listing
December 2020

Hybrid Training System Improves Insulin Resistance in Patients with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Pilot Study.

Tohoku J Exp Med 2020 09;252(1):23-32

Division of Rehabilitation, Kurume University Hospital.

Insulin resistance is associated with the progression of nonalcoholic fatty liver disease (NAFLD). Insulin resistance is regulated by various cytokines, including interleukin-6 (IL-6), a proinflammatory myokine, and selenoprotein P (SeP), a liver-derived secretory hepatokine. High levels of IL-6 and/or SeP have been shown to contribute to insulin resistance, and exercise is a first-line therapy for NAFLD. We have developed a hybrid training system (HTS): a neuromuscular electrical stimulation device to enhance exercise results. We aimed to investigate the effects of HTS on insulin resistance as well as serum IL-6 and SeP in patients with NAFLD. This is a randomized, single-blind (assessor), controlled trial. Subjects with NAFLD walked on a treadmill with or without HTS (9 subjects each) for 30 minutes three times a week for six weeks (HTS vs. control group; median age 45 vs. 45; male/female 5/4 vs. 6/3). We examined subjects before the first session and at the end of the final session. Serum SeP levels were measured by ELISA which measures the fragment of SeP. In the HTS group, HOMA-IR values were significantly reduced compared to the control group (Δ-0.71 vs. Δ0.05; P < 0.05). IL-6 and SeP levels in serum were also significantly reduced compared to that of the control group (IL-6; Δ-0.6 vs. Δ0.29 pg/mL; P < 0.05, SeP; Δ-1288.5 vs. Δ-435.4 ng/mL; P < 0.05, respectively). In conclusion, we propose that HTS improves insulin resistance by reducing serum IL-6 and SeP levels in patients with NAFLD.
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http://dx.doi.org/10.1620/tjem.252.23DOI Listing
September 2020

Patient-reported outcomes in patients with non-alcoholic fatty liver disease: A narrative review of Chronic Liver Disease Questionnaire-non-alcoholic fatty liver disease/non-alcoholic steatohepatitis.

J Gastroenterol Hepatol 2021 Mar 16;36(3):629-636. Epub 2020 Jul 16.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and one of the leading causes of hepatocellular carcinoma and liver transplantation. Moreover, patients with NAFLD frequently complain of non-specific symptoms including fatigue, abdominal discomfort, as well as anxiety, and NAFLD is reported to affect patient-reported outcomes (PROs). Thus, for clarifying the total burden of NAFLD, it is crucial to assess all associated outcomes, including not only clinical and economic outcomes but also PROs. PROs are thought to reflect what is happening in one's daily life and is an important way patients and health-care professionals communicate. There are various instruments for the assessment of PROs. Recently, a NAFLD/non-alcoholic steatohepatitis (NASH)-specific instrument called "Chronic Liver Disease Questionnaire (CLDQ)-NAFLD/NASH" has been developed. CLDQ-NAFLD/NASH comprises six domains: (i) abdominal symptoms, (ii) activity/energy, (iii) emotional health, (iv) fatigue, (v) systemic symptoms, and (vi) worry. CLDQ-NAFLD/NASH has demonstrated excellent internal consistency, face validity, content validity, and test-retest reliability. It has been sufficiently validated in two international phase 3 clinical trials. In this review, we summarize features of various instruments for assessing PROs by focusing on CLDQ-NAFLD/NASH. We also examine the validity of CLDQ-NAFLD/NASH in Japanese patients and alterations in CLDQ-NAFLD/NASH score in Japanese patients with significant hepatic fibrosis. Moreover, we discuss the utility of CLDQ-NAFLD/NASH in phase 3 clinical trials and in a real-world clinical setting.
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http://dx.doi.org/10.1111/jgh.15172DOI Listing
March 2021

Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: Multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT).

PLoS One 2020 28;15(4):e0232283. Epub 2020 Apr 28.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Metabolic reprograming is crucial in the proliferation of hepatocellular carcinoma (HCC). Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, affects various metabolisms. We investigated the effects of CANA on proliferation and metabolic reprograming of HCC cell lines using multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT).

Methods: The cells were counted 72 hours after treatment with CANA (10 μM; n = 5) or dimethyl sulfoxide (control [CON]; n = 5) in Hep3B and Huh7 cells. In Hep3B cells, metabolomics and iMPAQT were used to evaluate the levels of metabolites and metabolic enzymes in the CANA and CON groups (each n = 5) 48 hours after treatment.

Results: Seventy-two hours after treatment, the number of cells in the CANA group was significantly decreased compared to that in the CON group in Hep3B and Huh7 cells. On multi-omics analysis, there was a significant difference in the levels of 85 metabolites and 68 metabolic enzymes between the CANA and CON groups. For instance, CANA significantly downregulated ATP synthase F1 subunit alpha, a mitochondrial electron transport system protein (CON 297.28±20.63 vs. CANA 251.83±22.83 fmol/10 μg protein; P = 0.0183). CANA also significantly upregulated 3-hydroxybutyrate, a beta-oxidation metabolite (CON 530±14 vs. CANA 854±68 arbitrary units; P<0.001). Moreover, CANA significantly downregulated nucleoside diphosphate kinase 1 (CON 110.30±11.37 vs. CANA 89.14±8.39 fmol/10 μg protein; P = 0.0172).

Conclusions: We found that CANA suppressed the proliferation of HCC cells through alterations in mitochondrial oxidative phosphorylation metabolism, fatty acid metabolism, and purine and pyrimidine metabolism. Thus, CANA may suppress the proliferation of HCC by regulating metabolic reprograming.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232283PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188283PMC
July 2020

Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability toward Adverse Events.

Cancers (Basel) 2020 Apr 19;12(4). Epub 2020 Apr 19.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. : The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival ( < 0.001 and < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. : Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.
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http://dx.doi.org/10.3390/cancers12041010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226076PMC
April 2020

Impact of Decorin on the Physical Function and Prognosis of Patients with Hepatocellular Carcinoma.

J Clin Med 2020 Mar 28;9(4). Epub 2020 Mar 28.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.

The outcome of patients with hepatocellular carcinoma (HCC) is still poor. Decorin is a small leucine-rich proteoglycan, which exerts antiproliferative and antiangiogenic properties in vitro. We aimed to investigate the associations of decorin with physical function and prognosis in patients with HCC. We enrolled 65 patients with HCC treated with transcatheter arterial chemoembolization (median age, 75 years; female/male, 25/40). Serum decorin levels were measured using enzyme-linked immunosorbent assays; patients were classified into the High or Low decorin groups by median levels. Associations of decorin with physical function and prognosis were evaluated by multivariate correlation and Cox regression analyses, respectively. Age and skeletal muscle indices were not significantly different between the High and Low decorin groups. In the High decorin group, the 6-min walking distance was significantly longer than the Low decorin group and was significantly correlated with serum decorin levels ( = 0.2927, = 0.0353). In multivariate analysis, the High decorin group was independently associated with overall survival (hazard ratio 2.808, 95% confidence interval 1.016-8.018, = 0.0498). In the High decorin group, overall survival rate was significantly higher than in the Low decorin group (median 732 days vs. 463 days, = 0.010). In conclusion, decorin may be associated with physical function and prognosis in patients with HCC.
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http://dx.doi.org/10.3390/jcm9040936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230715PMC
March 2020

Impact of cancer rehabilitation on the prognosis of patients with hepatocellular carcinoma.

Oncol Lett 2020 Mar 24;19(3):2355-2367. Epub 2020 Jan 24.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan.

Sarcopenia is a prognostic factor for patients with hepatocellular carcinoma (HCC). Cancer rehabilitation (CR) improves patients' physical function and muscle mass. We investigated the effects of CR on the prognosis of patients with HCC. The present study was a prospective observational study, which analyzed 152 patients with HCC who underwent transcatheter arterial chemoembolization (TACE) between 2013 and 2016. Patients were classified into the CR (n=85) and control (n=67) groups. The effects of CR on muscle mass were evaluated by changes in the skeletal muscle index (SMI) before and after TACE. Independent factors associated with survival were evaluated by Cox regression analysis. Kaplan-Meier analysis was used to compare the survival rate between the CR and control groups. The difference in survival rate between the two groups was also examined after propensity score matching. SMI was significantly increased in the CR group compared with the control group. In Cox regression analysis, independent factors associated with survival were CR and Child-Pugh class A (estimate 1.760, 95% CI 0.914-3.226, P=0.001; estimate 1.602, 95% CI 0.426-2.998, P=0.0129). The survival rate was significantly higher in the CR group than in the control group (median 552 vs. 424 days; P=0.0359). The survival rate was also significantly higher in the CR group than that in the control group after propensity score matching (median 529 vs. 369 days; P=0.0332). CR was associated with prolonged survival in patients with HCC who underwent TACE. Patients with cancer are recommended to maintain physical activity even during cancer treatment.
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http://dx.doi.org/10.3892/ol.2020.11345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039060PMC
March 2020

Effects of a DPP4 Inhibitor on Progression of NASH-related HCC and the p62/ Keap1/Nrf2-Pentose Phosphate Pathway in a Mouse Model.

Liver Cancer 2019 Oct 4;8(5):359-372. Epub 2018 Sep 4.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Background And Aims: Diabetes mellitus is a risk factor for hepatocellular carcinoma (HCC) in patients with nonalcoholic steatohepatitis (NASH). Dipeptidyl peptidase-4 inhibitor (DPP4i), an antidiabetic agent, is reported to affect cell proliferation. We aimed to investigate the effects of DPP4i on the progression of NASH-related HCC and its metabolic pathway in a mouse model.

Methods: A mouse model of NASH-related HCC was used in this study. Eight-week-old mice were administered either DPP4i (sitagliptin 30 mg/kg/day; DPP4i group; = 8) or distilled water (control group; = 8) for 10 weeks. Then, HCC progression was evaluated by computed tomography. Changes in metabolites of HCC tissue were analyzed by metabolomic analysis. The localization and expression of p62, Keap1, Nrf2, and MCM7 were evaluated by immunostaining and immunoblotting, respectively.

Results: The number and volume of HCC were significantly lower in the DPP4i group than in the control group (1.8 ± 1.2 vs. 4.5 ± 1.7/liver, < 0.01; 11.2 ± 20.8 vs. 37.5 ± 72.5 mm3/tumor, < 0.05). Metabolome analysis revealed that DPP4i significantly increased 6-phosphogluconic acid and ribose 5-phosphate levels and decreased the AMP-to-adenine and GMP-to-guanine ratios (AMP-to-adenine ratio 0.7 ± 0.2 vs. 2.0 ± 1.2, < 0.01; GMP-to-guanine ratio 0.6 ± 0.3 vs. 1.5 ± 0.7, < 0.01). Immunostaining showed that p62 was localized in the cytoplasm of HCC in the DPP4i group, while p62 was localized in the nucleus of HCC in the control group. Keap1, Nrf2, and MCM7 expression decreased significantly in the DPP4i group compared to that in the control group.

Conclusions: We demonstrated that DDP4i prevented the progression of NASH-related HCC in a mouse model. Furthermore, metabolome analysis revealed that DDP4i downregulated the pentose phosphate pathway with suppression of the p62/Keap1/Nrf2 pathway. Thus, DDP4i may prevent tumor progression through inhibition of metabolic reprogramming in NASH-related HCC.
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http://dx.doi.org/10.1159/000491763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873068PMC
October 2019

Clinical utility of the Liver Frailty Index for predicting muscle atrophy in chronic liver disease patients with hepatocellular carcinoma.

Hepatol Res 2020 Mar 29;50(3):330-341. Epub 2019 Dec 29.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Aim: Muscle atrophy is a prognostic factor for patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). The Liver Frailty Index (LFI) is a simple physical function test; however, an association between LFI and muscle mass remains unclear. We aimed to investigate the utility of LFI for predicting muscle atrophy in CLD patients with HCC.

Methods: We enrolled 138 CLD patients with HCC (aged 77 years, female/male 34.8%/65.2%). Muscle mass was assessed by skeletal muscle index, and patients were classified into the muscle atrophy group (n = 109) or the non-muscle atrophy group (n = 29). Physical frailty was assessed by LFI. The optimal cut-off value of LFI for predicting muscle atrophy was identified by receiver operating characteristic analysis.

Results: In the muscle atrophy group, the prevalence of pre-frail/frail was significantly higher than the non-muscle atrophy group (87.2% vs. 58.6%, P = 0.0005). In the logistic regression analysis, being female and pre-frail/frail were identified as independent factors associated with muscle atrophy (pre-frail/frail; OR 3.601, 95% CI 1.381-9.400, P = 0.0088). In patients with normal grip strength, 71.1% of patients were pre-frail/frail, in which 82.8% of patients showed muscle atrophy. Receiver operating characteristic statistics provided an area under the curve of 0.74, and an LFI cut-off value of 2.94 for predicting muscle atrophy (sensitivity 88.06%, specificity 52.17%, accuracy 77.91%).

Conclusions: We showed that pre-frail/frail was an independent factor for muscle atrophy in CLD patients with HCC. Furthermore, LFI predicted muscle atrophy with high sensitivity, even in patients with normal grip strength. Thus, LFI might be a useful screening tool for muscle atrophy in CLD patients with HCC.
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http://dx.doi.org/10.1111/hepr.13453DOI Listing
March 2020

Profiles of advanced hepatic fibrosis evaluated by FIB-4 index and shear wave elastography in health checkup examinees.

Hepatol Res 2020 Feb 20;50(2):199-213. Epub 2019 Nov 20.

Department of Orthopedics, Kurume University School of Medicine, Kurume, Japan.

Aim: Advanced hepatic fibrosis is seen in individuals with potential hepatocellular carcinoma and cardiovascular disease. Hepatic fibrosis can be assessed using a combination of the FIB-4 index and imaging modalities, including shear wave elastography. We aimed to investigate the prevalence of advanced fibrosis in the general population and the profiles associated with advanced fibrosis using a data-mining analysis.

Methods: We enrolled 1155 health checkup examinees (median age 53 years, 685 women, 470 male). Advanced fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥8.07 kPa using shear wave elastography. Participants were classified as normal-mild fibrosis (n = 1035) or advanced fibrosis (n = 120). Factors associated with advanced fibrosis were analyzed by logistic regression and decision-tree analyses.

Results: Advanced fibrosis was observed in 10.4% of participants (120/1155). In the logistic regression analysis, independent factors for advanced fibrosis were age (≥75 years; OR 2.12, 95% CI 1.021-4.415; P = 0.0419) and the presence of metabolic syndrome (OR 2.51, 95% CI 1.416-4.462; P = 0.0017). The decision-tree analysis showed two profiles associated with advanced fibrosis: profile 1 - individuals aged ≥65 years with metabolic syndrome and mild-to-moderate alcohol consumption (prevalence of advanced fibrosis 73.3%); and profile 2 - individuals without metabolic syndrome, aged ≥75 years, with no exercise habit (prevalence of advanced fibrosis 56.3%).

Conclusions: Advanced fibrosis was observed in 10.4% of health checkup examinees. Furthermore, we showed that aging, metabolic syndrome with mild-to-moderate alcohol consumption, and physical inactivity were associated with advanced fibrosis. Thus, prevention of metabolic syndrome and alcohol withdrawal, as well as exercise habits, might inhibit the progression of hepatic fibrosis.
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http://dx.doi.org/10.1111/hepr.13436DOI Listing
February 2020

Slow walking speed overlapped with low handgrip strength in chronic liver disease patients with hepatocellular carcinoma.

Hepatol Res 2019 Dec 4;49(12):1427-1440. Epub 2019 Aug 4.

Division of Rehabilitation, Kurume University Hospital, Kurume, Japan.

Aim: Walking speed and grip strength are parameters of muscle function; however, evaluating walking speed is not always available in clinical practice. We aimed to investigate the impact of walking speed on the evaluation of muscle dysfunction in chronic liver disease (CLD) patients with hepatocellular carcinoma (HCC).

Methods: We enrolled 107 consecutive CLD patients with HCC in this study (age 76 years [range 60-92 years]; female/male 39/68; body mass index 22.9 [range 20.0-25.3]; chronic hepatitis/liver cirrhosis 25/82). Muscle dysfunction was evaluated using the Asian Working Group for Sarcopenia criteria (grip strength or walking speed) and the Japan Society of Hepatology criteria (grip strength). A correlation between walking speed and skeletal muscle index was evaluated. Independent factors for slow walking speed were evaluated using a logistic regression analysis.

Results: There was no significant correlation between walking speed and skeletal muscle index (r = 0.14, P = 0.16). For both the Asian Working Group for Sarcopenia and Japan Society of Hepatology criteria, 33.6% of all patients were classified as having muscle dysfunction. All patients with slow walking speed (4.7% of all patients) also showed low handgrip strength. The logistic regression analysis identified grip strength as an independent factor for slow walking speed (OR 0.65; 95% CI 0.432-0.838; P = 0.008).

Conclusions: No difference was seen in the prevalence of muscle dysfunction between the Asian Working Group for Sarcopenia and Japan Society of Hepatology criteria in CLD patients with HCC. Furthermore, all patients with slow walking speed also showed low handgrip strength. Thus, for the evaluation of muscle dysfunction, grip strength might be a suitable proxy for walking speed in CLD patients with HCC.
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http://dx.doi.org/10.1111/hepr.13405DOI Listing
December 2019

Effects of in-hospital exercise on sarcopenia in hepatoma patients who underwent transcatheter arterial chemoembolization.

J Gastroenterol Hepatol 2019 Mar 16;34(3):580-588. Epub 2018 Dec 16.

Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Japan.

Background And Aim: Sarcopenia is a prognostic factor in hepatocellular carcinoma (HCC) patients. HCC patients who underwent transcatheter arterial chemoembolization (TACE) are at a risk of muscle atrophy. We aimed to investigate the effects of in-hospital exercise on muscle mass and factors associated with muscle hypertrophy in HCC patients who underwent TACE.

Methods: We enrolled 209 HCC patients who underwent TACE. Patients were classified into either an exercise (n = 102) or control (n = 107) group. In the exercise group, patients were treated with in-hospital exercise (median 2.5 metabolic equivalents/20-40 min/day). The effects of exercise on muscle mass were evaluated by changes in skeletal muscle index (ΔSMI) between before and after TACE. Factors associated with an increase in SMI were analyzed by logistic regression and decision-tree analyses.

Results: There was no significant difference in serum albumin and bilirubin levels between the two groups. ΔSMI was significantly higher in the exercise group than in the control group (0.28 cm /m vs -1.11 cm /m , P = 0.0029). In the logistic regression analysis, exercise was an independent factor for an increase in SMI (hazard ratio 2.13; 95% confidence interval 1.215-3.846; P = 0.0085). Moreover, the decision-tree analysis showed that exercise was the initial divergence variable for an increase in SMI (the ratio of increased SMI: 53% in the exercise group vs 36% in the control group).

Conclusions: In-hospital exercises increased muscle mass in HCC patients who underwent TACE. In addition, exercise was an independent factor for muscle hypertrophy. Thus, in-hospital exercise may prevent sarcopenia in HCC patients who underwent TACE.
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http://dx.doi.org/10.1111/jgh.14538DOI Listing
March 2019

Spontaneous regression of hepatocellular carcinoma with reduction in angiogenesis-related cytokines after treatment with sodium-glucose cotransporter 2 inhibitor in a cirrhotic patient with diabetes mellitus.

Hepatol Res 2019 Apr 1;49(4):479-486. Epub 2018 Oct 1.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.

Spontaneous regression of hepatocellular carcinoma (HCC) is a rare event, and the pathogenesis remains unclear. Here, we present a case of spontaneous regression of HCC after treatment with sodium-glucose cotransporter 2 inhibitor (SGLT2i) in a cirrhotic patient with diabetes mellitus (DM). A 68-year-old man regularly visited our hospital for follow-up of HCC after treatment with transcatheter arterial chemoembolization, and management of liver cirrhosis and type 2 DM. Contrast-enhanced computed tomography scan showed a hypervascular tumor in the liver and elevated serum α-fetoprotein levels, indicating the recurrence of HCC. Simultaneously, the hemoglobin A1c value increased to 8.0%; therefore, he was treated with SGLT2i (canagliflozin 100 mg/day). Ten weeks after the initiation of SGLT2i treatment, he was admitted to our hospital for treatment of recurrent HCC. However, the hypervascular tumor had disappeared, and the elevated serum α-fetoprotein level had decreased to normal limits, indicating spontaneous regression of HCC. In addition, an angiogenesis array analysis revealed downregulated protein expression of matrix metalloproteinase-8, angiopoietin-1/2, platelet-derived growth factor-AA, and prolactin at 10 weeks after SGLT2i treatment. In this report, we first describe a case of spontaneous regression of HCC with reduction in angiogenesis-related cytokines after SGLT2i treatment.
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http://dx.doi.org/10.1111/hepr.13247DOI Listing
April 2019

Effects of isomaltulose on insulin resistance and metabolites in patients with non‑alcoholic fatty liver disease: A metabolomic analysis.

Mol Med Rep 2018 Aug 26;18(2):2033-2042. Epub 2018 Jun 26.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830‑0011, Japan.

Insulin resistance is associated with a poor prognosis in non‑alcoholic fatty liver disease (NAFLD) patients. Isomaltulose, a naturally‑occurring disaccharide, is reported to improve glucose and lipid metabolisms in obese patients. The present study aimed to investigate the effects of isomaltulose on insulin resistance and various metabolites in NAFLD patients. Five male patients with NAFLD consumed 20 g isomaltulose or sucrose (control). Changes in insulin resistance and metabolites were evaluated by alterations of serum C‑peptide immunoreactivity (CPR) and metabolomic analysis from baseline to 15 min after the administration, respectively. There was no significant difference in changes of blood glucose level; however, the CPR level was significantly decreased in the Isomaltulose group compared to the control group (0.94±0.89 vs. ‑0.12±0.31, P=0.0216). In a metabolomic analysis, a significant alteration was seen in 52 metabolites between the control and Isomaltulose groups. In particular, the taurodeoxycholic acid level significantly increased approximately 12.5‑fold, and the arachidonic acid level significantly decreased approximately 0.01‑fold. Together, it present study demonstrated that isomaltulose improved insulin resistance in NAFLD patients. It was also revealed that isomaltulose affects taurodeoxycholic acid and arachidonic acid. Thus, isomaltulose may have a beneficial effect on insulin resistance through alterations of bile acid and fatty acid metabolisms in NAFLD patients.
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http://dx.doi.org/10.3892/mmr.2018.9223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072173PMC
August 2018

[Treatment for sarcopenia in patients with chronic liver disease].

Nihon Shokakibyo Gakkai Zasshi 2018;115(5):439-448

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine.

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http://dx.doi.org/10.11405/nisshoshi.115.439DOI Listing
June 2019
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