Publications by authors named "Norifumi Kawada"

294 Publications

Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species.

Oncogenesis 2022 May 3;11(1):23. Epub 2022 May 3.

Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb-overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by HO challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.
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http://dx.doi.org/10.1038/s41389-022-00389-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065067PMC
May 2022

Distinct responsiveness to rifaximin in patients with hepatic encephalopathy depends on functional gut microbial species.

Hepatol Commun 2022 Apr 16. Epub 2022 Apr 16.

Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University (formerly, Osaka City University), Osaka, Japan.

Hepatic encephalopathy (HE) is the neuropsychiatric complication of liver cirrhosis (LC). The influence of gut microbiota on HE pathogenesis has been suggested but not precisely elucidated. Here, we investigate how the gut microbial profile changed in patients with HE to clarify the functional gut microbial species associated with HE. We focused on their responses to rifaximin (RFX), a nonabsorbable antibiotic used in HE therapy. Feces samples were collected from patients with decompensated LC (all HE), patients with compensated LC, and healthy controls, and fecal gut microbial profiles were compared using 16S ribosomal RNA gene amplicon and metagenomic sequencing. The linear discriminant analysis effect size was used to identify specific species. Urease-positive Streptococcus salivarius, which can produce ammonia, was identified as the most significantly abundant gut microbiota in the HE group, and its ability to elevate the levels of blood ammonia as well as brain glutamine was experimentally verified in mice. Urease-negative Ruminococcus gnavus was also identified as a significantly abundant species in patients with RFX-nonresponsive HE after RFX administration. Interestingly, R. gnavus enhanced urease activity of recombinant urease itself, implying that R. gnavus could amplify ammonia production of surrounding urease-positive microbiota. Furthermore, the sensitivity of S. salivarius and R. gnavus to RFX depended on conjugated secondary bile acid levels, suggesting a therapeutic potential of the combined use of secondary bile acid levels with RFX for enhancing the efficacy of RFX. This study identified specific gut bacterial species abundant in patients with HE and verified their functions linked to HE pathophysiology. Targeting these bacteria could be a potentially effective strategy to treat HE.
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http://dx.doi.org/10.1002/hep4.1954DOI Listing
April 2022

Capacity of extracellular globins to reduce liver fibrosis via scavenging reactive oxygen species and promoting MMP-1 secretion.

Redox Biol 2022 06 19;52:102286. Epub 2022 Mar 19.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan. Electronic address:

Background & Aims: Hepatic stellate cells (HSCs) are the primary cell type in liver fibrosis, a significant global health care burden. Cytoglobin (CYGB), a globin family member expressed in HSCs, inhibits HSC activation and reduces collagen production. We studied the antifibrotic properties of globin family members hemoglobin (HB), myoglobin (MB), and neuroglobin (NGB) in comparison with CYGB.

Approach & Results: We characterized the biological activities of globins in cultured human HSCs (HHSteCs) and their effects on carbon tetrachloride (CCl)-induced cirrhosis in mice. All globins demonstrated greater antioxidant capacity than glutathione in cell-free systems. Cellular fractionation revealed endocytosis of extracellular MB, NGB, and CYGB, but not HB; endocytosed globins localized to intracellular membranous, cytoplasmic, and cytoskeletal fractions. MB, NGB, and CYGB, but not HB, scavenged reactive oxygen species generated spontaneously or stimulated by HO or transforming growth factor β1 in HHSteCs and reduced collagen 1A1 production via suppressing COL1A1 promoter activity. Disulfide bond-mutant NGB displayed decreased heme and superoxide scavenging activity and reduced collagen inhibitory capacity. RNA sequencing of MB- and NGB-treated HHSteCs revealed downregulation of extracellular matrix-encoding and fibrosis-related genes and HSC deactivation markers. Upregulation of matrix metalloproteinase (MMP)-1 was observed following MB and NGB treatment, and MMP-1 knockdown partially reversed globin-mediated effects on secreted collagen. Importantly, administration of MB, NGB, and CYGB suppressed CCl-induced mouse liver fibrosis.

Conclusions: These findings revealed unexpected roles for MB and NGB in deactivating HSCs and inhibiting liver fibrosis development, suggesting that globin therapy may represent a new strategy for combating fibrotic liver disease.
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http://dx.doi.org/10.1016/j.redox.2022.102286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8956869PMC
June 2022

Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis.

J Gastroenterol 2022 02 20;57(2):120-132. Epub 2022 Jan 20.

Department of Gastroenterology, Toyokawa City Hospital, Toyokawa, Japan.

Background: Direct-acting antiviral (DAA) therapy enables a high rate of sustained virologic response (SVR) in patients with hepatitis C virus associated cirrhosis. However, the impact of DAA therapy on liver-related events in patients with cirrhosis is unclear.

Methods: A total of 350 patients with compensated and decompensated cirrhosis administered DAA therapy at 29 Japanese hospitals were enrolled (Child-Pugh class A [CP-A]: 195 patients, CP-B: 131 patients and CP-C: 24 patients).

Results: The SVR rates of patients with CP-A, CP-B and CP-C were 96.9%, 93.1% and 83.3%, respectively (p = 0.006). Seventy patients developed hepatocellular carcinoma (HCC), and male sex, previous HCC treatment, platelet counts < 10.0 × 10/µl, alpha-fetoprotein levels ≥ 5.0 ng/ml and CP-C were identified as significant factors in the multivariate analysis. The cumulative HCC occurrence/recurrence rates at 1 year were 6.6%/45.2%. The cumulative rate of decompensated cirrhotic events requiring hospital admission at 1 year was 9.1%. In the multivariate analysis, CP-B and CP-C were identified as significant factors. During the median observation period of 14.9 months, 13 patients died and one patient received liver transplant. The overall survival rates at 1 year were 98.4% in patients with CP-A, 96.4% in those with CP-B and 85.6% in those with CP-C (CP-A vs. CP-B: p = 0.759, CP-A vs. CP-C: p = 0.001 and CP-B vs. CP-C: p = 0.005).

Conclusions: HCC development and mortality in patients with CP-B were not different from those with CP-A. On the other hand, in patients with CP-C, the development of HCC and decompensated cirrhotic events requiring hospital admission, and death were frequent.

Trial Registration: University Hospital Medical Information Network (UMIN000036150).
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http://dx.doi.org/10.1007/s00535-021-01845-5DOI Listing
February 2022

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

Clin Gastroenterol Hepatol 2022 Jan 17. Epub 2022 Jan 17.

Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.

Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.

Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.

Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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http://dx.doi.org/10.1016/j.cgh.2022.01.002DOI Listing
January 2022

Soluble programmed cell death-1 predicts hepatocellular carcinoma development during nucleoside analogue treatment.

Sci Rep 2022 01 7;12(1):105. Epub 2022 Jan 7.

Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.

Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.
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http://dx.doi.org/10.1038/s41598-021-03706-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8741806PMC
January 2022

Lifestyle changes during the coronavirus disease 2019 pandemic impact metabolic dysfunction-associated fatty liver disease.

Liver Int 2022 May 18;42(5):995-1004. Epub 2022 Mar 18.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Background And Aims: The coronavirus disease 2019 (COVID-19) pandemic precipitated lifestyle changes. We aimed to clarify whether COVID-19-induced lifestyle changes affected the development of metabolic dysfunction-associated fatty liver disease (MAFLD).

Methods: This retrospective longitudinal study included 973 participants who underwent health check-ups between 2018 and 2020. We used data from the MedCity21 health examination registry. Participants' clinical characteristics and lifestyle habits were investigated. Independent lifestyle predictors of MAFLD development before the pandemic (2018-2019) and during the pandemic (2019-2020) were identified using logistic regression analysis.

Results: In 2018, 261 (27%) patients were diagnosed with MAFLD. Before the pandemic, 22 patients developed new MAFLD. During this time, routine late-night meals were identified as an independent lifestyle predictor of MAFLD development (hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.02-6.36, P = .046). In contrast, 44 patients developed new MAFLD during the pandemic. During this time, higher daily alcohol intake was identified as an independent lifestyle predictor of MAFLD development (HR 1.03, 95% CI 1.01-1.05, P = .008). In participants aged <60 years, daily alcohol intake and the proportion of participants who ate 2 times/day were significantly higher in patients who developed MAFLD during the pandemic than in those who did not. In participants aged ≥60 years, no lifestyle habits were associated with MAFLD development before or during the pandemic.

Conclusions: New MAFLD diagnoses increased during the COVID-19 pandemic. Changes in lifestyle factors, particularly in those aged <60 years, must be monitored and addressed as the pandemic continues.
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http://dx.doi.org/10.1111/liv.15158DOI Listing
May 2022

A mask-based infection control method for screening endoscopy may prevent SARS-CoV-2 transmission and relieve staff anxiety.

SAGE Open Med 2021 20;9:20503121211047060. Epub 2021 Sep 20.

Department of Gastroenterology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Objectives: Endoscopy confers high risk for acquiring coronavirus disease 2019. Although guidelines recommend that medical staff use personal protective equipment, no infection control equipment have been established for patients. This study aimed to clarify the usefulness of two face masks we had designed for transnasal and transoral endoscopy.

Methods: The efficacy of the masks was evaluated by simulating coughing in a mannequin with fluorescent dyes and mapping the droplet trajectory and number. The number of aerosols generated during endoscopy was clinically evaluated in the endoscopy room. Overall, 4356 screening endoscopies were performed with the patients wearing our masks at Medcity21, a health checkup facility, between June and December 2020; the effects of the masks on the patient's condition were evaluated retrospectively. An 11-item paper-based survey was performed by the endoscopy staff 6 months after the adoption of the mask-based infection control method.

Results: Use of both masks reduced the number of droplets released during the simulation. Clinically, the use of both masks did not affect the patients' conditions during endoscopy and prevented an increase in the aerosols in the endoscopy room. This mask-based infection control method was favorably received, and all staff indicated that understanding the efficacy of our mask-based infection control reduced their anxiety regarding infection. Until December 2020, none of our staff had contracted SARS-CoV-2.

Conclusion: Our mask-based infection control method is easy to adopt, inexpensive, and effective; understanding its effectiveness may help ease the fear of infection among endoscopy staff.
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http://dx.doi.org/10.1177/20503121211047060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8642037PMC
September 2021

Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study.

J Gastroenterol 2022 01 18;57(1):19-29. Epub 2021 Nov 18.

Teikyo Academic Research Center, Teikyo University, Tokyo, Japan.

Background: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case-control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case-control study to identify the environmental factors associated with the development of PBC in Japan.

Methods: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis.

Results: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01-2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07-1.92), ever smoking (OR, 1.70; 95% CI, 1.28-2.25), and hair dye use (OR, 1.57; 95% CI, 1.15-2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99-19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077-0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52-68.0) in the model for medical and familial factors.

Conclusions: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.
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http://dx.doi.org/10.1007/s00535-021-01836-6DOI Listing
January 2022

Direct-acting antivirals reduce the risk of tumour progression of hepatocellular carcinoma after curative treatment.

J Viral Hepat 2022 01 4;29(1):52-59. Epub 2021 Nov 4.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Hepatocellular carcinoma (HCC) has high recurrence rates. HCC sometimes progresses from early-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage 0/A) to advanced-stage HCC after repeated recurrences and treatments. HCC progression deteriorates quality of life and prognosis. However, the effect of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on HCC progression remains uninvestigated. We conducted a retrospective cohort study of patients with hepatitis C virus-related HCC with BCLC stage 0/A diagnosed for the first time and treated by curative resection or ablation. Using a time-varying method, we estimated the risk of tumour progression (defined as progression to BCLC stage B-D) and liver-related death and the characteristics of repeated recurrence. Overall, 165 patients were enrolled. Following curative HCC treatment, 72 patients received DAA therapy (DAA-treated group), whereas 93 did not (untreated group). Approximately 75% of the recurrences were at an early stage and expected to be disease-free by retreatment. We recorded 56 tumour progressions, of which 60.7% were observed after second recurrence. Multivariate adjusted time-varying Cox regression analysis showed that the DAA-induced SVR significantly reduced the risk of tumour progression (hazard ratio [HR] 0.28; p = .001) and liver-related death (HR 0.12; p < .001). The annual incidence of HCC treatment until tumour progression was 82.8% and 23.9% in the untreated and DAA-treated groups, respectively (HR 0.30; p < .001). DAA-induced SVR significantly reduced the risk for tumour progression and liver-related death and the frequency of HCC treatment following curative treatment for HCC at BCLC stage 0/A.
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http://dx.doi.org/10.1111/jvh.13627DOI Listing
January 2022

The Albumin-bilirubin Score Detects Changes in the Liver Function during Treatment for Budd-Chiari Syndrome: A Retrospective Observational Study.

Intern Med 2022 Apr 18;61(7):959-967. Epub 2021 Sep 18.

Department of Diagnostic and Interventional Radiology, Graduate School of Medicine, Osaka City University, Japan.

Objective Mapping the long-term prognosis of Budd-Chiari syndrome (BCS) is difficult, as the prognosis is associated with changes in the liver function. The present study evaluated the time course changes in the liver function in a treatment group with percutaneous old balloon angioplasty (POBA) and a non-treatment group using the albumin-bilirubin score (ALBI) and Child-Pugh score during long-term follow-up. Methods In this retrospective study, 13 consecutive patients diagnosed with BCS at our hospital between 2007 and 2020 were categorized into a treatment group (n=8), which received POBA, and a non-treatment group (n=5). Differences in the liver function in the ALBI and Child-Pugh scores between the initial visit and one- and three-year follow-up were calculated and statistically evaluated. We investigated the changes in the liver function during the long-term follow-up, including events such as re-stenosis and re-treatment. Results While the Child-Pugh scores in the treatment group did not differ significantly between the initial visit and 1- or 3-year follow-up, the ALBI scores in this group improved significantly between the initial visit and the 1- or 3-year follow-up visit (p=0.0078 and 0.0156, respectively). The liver function according to the ALBI score in the treatment group showed gradual improvement from the initial value but gradual worsening in the non-treatment group. The ALBI scores also revealed that the liver function varies according to re-stenosis and re-POBA in BCS patients. Conclusion Unlike the Child-Pugh score, the ALBI score was able to capture changes in the liver function of BCS patients during the long-term course of BCS.
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http://dx.doi.org/10.2169/internalmedicine.8020-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038474PMC
April 2022

A novel noninvasive formula for predicting cirrhosis in patients with chronic hepatitis C.

PLoS One 2021 10;16(9):e0257166. Epub 2021 Sep 10.

Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan.

Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = -6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, -0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10-81 and 1.88 × 10-48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257166PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432856PMC
November 2021

Postoperative direct-acting antiviral treatment after liver resection in patients with hepatitis C virus-related hepatocellular carcinoma.

Hepatol Res 2021 Nov 21;51(11):1102-1114. Epub 2021 Sep 21.

Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Aim: We investigated effects of direct-acting antiviral (DAA)-induced sustained virological response (SVR) after liver resection in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) for postoperative recurrence and survival.

Methods: Surgical outcomes in 18 patients with postoperative DAA-induced SVR (HCC-DAA group) were compared with those in 23 patients with preoperative DAA-induced SVR (DAA-HCC group) and those in 10 patients who did not receive DAA therapy (control group). Patients who received DAA therapy >1 year after surgery and those with recurrence <1 year after surgery were excluded.

Results: Serum concentrations of aminotransferases improved 1 year after surgery in both the HCC-DAA and DAA-HCC groups. The number of HCC-DAA patients with albumin-bilirubin (ALBI) grade 1 increased from 11 to 15. The disease-free survival rate did not differ between HCC-DAA group (3 years, 60%) and the other two groups (DAA-HCC group, 92% and control group, 60%). The 3-year overall survival rates were better in the DAA-HCC group (84%) and HCC-DAA group (100%) than in the control group (46%; all ps < 0.05 according to Holm's test). Multivariable analysis revealed that tumor stage was an independent risk factor for postoperative recurrence, and ALBI grade at 1 year after surgery was predictive of postoperative survival, but DAA-induced SVR was neither.

Conclusions: Although postoperative DAA-induced SVR itself may not suppress postoperative recurrence, improvement in liver function as a result of DAA administration after surgery may prolong postoperative survival.
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http://dx.doi.org/10.1111/hepr.13709DOI Listing
November 2021

Impact of alcohol abstinence on survival after hepatic resection for hepatocellular carcinoma in patients with alcohol-related liver disease.

Ann Med Surg (Lond) 2021 Aug 29;68:102644. Epub 2021 Jul 29.

Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.

Background: This study aimed to evaluate the prognostic impact of alcohol abstinence on survival after hepatic resection for hepatocellular carcinoma (HCC) in patients with alcohol-related liver disease (ALD).

Patients And Methods: In total, 92 patients with ALD-HCC who underwent initial and curative hepatic resection were identified, including 56 and 36 patients with and without alcohol abstinence, respectively.

Results: The 3-, 5-, and 7-year recurrence-free survival (RFS) were 46%, 43%, and 37% in the abstinence group, and 61%, 36%, and 36% in the non-abstinence group, respectively (p = 0.71). The 3-, 5-, and 7-year overall survival (OS) were 91%, 76%, and 66% in the abstinence group, and 87%, 57%, and 44% in the non-abstinence group, respectively (p = 0.023). Multivariate analysis revealed that non-abstinence was an independent prognostic factor for OS (P = 0.026). The incidence rate of liver-related death including HCC-specific death, liver failure, and renal failure in cirrhosis (hepatorenal syndrome) between the non-abstinence and abstinence groups were 41.7% vs. 19.6% (p = 0.032). Worsening of the Child-Pugh grade at intrahepatic recurrence was more frequently observed in the non-abstinence (33.3%) than that in the abstinence group (6.5%) (p = 0.039).

Conclusions: Alcohol abstinence might improve the long-term survival of patients with ALD-HCC undergoing hepatic resection.
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http://dx.doi.org/10.1016/j.amsu.2021.102644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346358PMC
August 2021

Validation of a two-step approach combining serum biomarkers and liver stiffness measurement to predict advanced fibrosis.

JGH Open 2021 Jul 10;5(7):801-808. Epub 2021 Jun 10.

Department of Hepatology Graduate School of Medicine, Osaka City University Osaka Japan.

Background And Aim: The Gut and Obesity in Asia Workgroup recently reported that a two-step approach using fibrosis scores followed by liver stiffness measurement (LSM) could accurately detect patients with non-alcoholic fatty liver disease (NAFLD) having advanced fibrosis in low-risk fibrosis populations. This study aimed to validate the utility of this approach using a Japanese health checkup registry.

Methods: This cross-sectional study included subjects who underwent a health checkup from 2014 to 2019. Using estimated fibrosis stage measured by LSM as a standard, we calculated the percentage of misclassification from assessments made based on fibrosis scores (NAFLD fibrosis score [NFS] or Fibrosis-4 score [FIB-4]) and LSM, alone or in combination.

Results: Of 630 subjects with NAFLD, 4 (0.8%) had advanced fibrosis. In the first-step evaluation, only 21.4-38.0% of subjects needed further testing. This approach was associated with a high specificity of approximately 100% and a negative predictive value of 99.7%. The percentage of misclassification based on NFS or FIB-4 values followed by LSM in all subjects and using LSM after NFS or FIB-4 determination only in subjects with indeterminate/high NFS or FIB-4 values (two-step approach) was 0% and 0.3% and 0.16% and 0.3%, respectively. In addition, very few false negatives occurred for both NFS and FIB-4.

Conclusion: The two-step approach helps to identify the subjects with NAFLD who have advanced fibrosis during a routine health checkup and is associated with only a few false negatives.
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http://dx.doi.org/10.1002/jgh3.12590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264241PMC
July 2021

The FibroScan-aspartate aminotransferase score can stratify the disease severity in a Japanese cohort with fatty liver diseases.

Sci Rep 2021 07 5;11(1):13844. Epub 2021 Jul 5.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

This study aimed to prove that the FibroScan-aspartate aminotransferase (FAST) scores can be used to stratify disease severity in a Japanese cohort with fatty liver diseases [metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease (NAFLD)]. All the participants (n = 2254) underwent liver stiffness measurements and controlled attenuation parameter assessments. We compared the clinical characteristics of the patients with MAFLD and NAFLD using the FAST scores and explored the independent determinants of FAST scores ≥ 0.35, which indicated possible progressive disease. Overall, MAFLD was diagnosed in 789 patients (35.0%), while NAFLD was diagnosed in 618 (27.4%). The proportion of patients that had a condition that suggested progressive liver disease was higher in those with MAFLD than in those with NAFLD [68 (8.6%) vs 48 (7.7%)]. The area under the receiver-operating characteristic curve of the FAST score for diagnosing advanced fibrosis was 0.969 in MAFLD and 0.965 in NAFLD. Multivariate analyses determined that diabetes mellitus, alanine aminotransferase (ALT) levels, fatty liver index, and Fibrosis-4 index independently predict FAST scores ≥ 0.35 in patients with MAFLD. ALT levels had the strongest correlation with the FAST scores (p = 0.7817). The FAST score could stratify the disease severity in the Japanese cohort with fatty liver diseases.
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http://dx.doi.org/10.1038/s41598-021-93435-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257719PMC
July 2021

Half-Moon-shaped Aortic Arch Thrombosis Induced by Lenvatinib.

Radiology 2021 08 15;300(2):289. Epub 2021 Jun 15.

From the Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.

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http://dx.doi.org/10.1148/radiol.2021204727DOI Listing
August 2021

Outcomes of Sequential Therapy With Tenofovir Alafenamide After Long-term Entecavir.

Am J Gastroenterol 2021 06;116(6):1264-1273

Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.

Introduction: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch.

Methods: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL).

Results: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR.

Discussion: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.
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http://dx.doi.org/10.14309/ajg.0000000000001157DOI Listing
June 2021

Eosinophilic esophagitis and asymptomatic esophageal eosinophilia display similar immunohistological profiles.

J Clin Biochem Nutr 2021 May 14;68(3):246-252. Epub 2020 Nov 14.

Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan.

Patients with asymptomatic esophageal eosinophilia (aEE) do not exhibit clinical symptoms because of esophageal dysfunction, although they have endoscopic and histological findings similar to those of eosinophilic esophagitis (EoE). The cause of the symptoms and the differences between aEE and EoE are unclear. The aim of this study is to determine whether aEE and EoE are same disease entities by comparing immune-related tissue biomarkers using immunohistological staining. Esophageal biopsy specimens from 61 patients, including 18 with aEE and 43 with EoE, were analyzed. Immunofluorescence staining was performed to quantify the immune-related tissue biomarkers such as major basic protein, eosinophil-derived neurotoxin, eotaxin-3, and immunoglobulin G4. Data are presented as median (interquartile range). There were no significant differences in clinical, endoscopic, or histological features, between patients with aEE and EoE, with the exception of body mass index. There were no significant differences in all immune-related tissue biomarkers between both groups. In conclusions, EoE and aEE displayed similar immunohistological profiles. Hence, they may be similar disease entities with some common pathogenic mechanisms. Our findings suggest that patients with aEE also have histopathological esophageal inflammation.
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http://dx.doi.org/10.3164/jcbn.20-49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129976PMC
May 2021

Sofosbuvir/Velpatasvir Plus Ribavirin Combination Therapy for Patients with Hepatitis C Virus Genotype 1a, 2a, or 3b after Glecaprevir/Pibrentasvir Therapy Failed.

Intern Med 2021 Nov 22;60(21):3441-3445. Epub 2021 May 22.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan.

Glecaprevir/pibrentasvir (GLE/PIB) is a pan-genotype anti-hepatitis C virus (HCV) therapy with high efficacy and safety. However, evidence supporting retreatment following failure of the GLE/PIB regimen is limited. We herein report 3 non-cirrhotic cases involving two men aged 51 and 58 years old and a woman aged 68 years old infected with HCV genotype 1a, 2a, and 3b respectively who failed anti-HCV therapies including GLE/PIB therapy. With combination therapy of sofosbuvir/velpatasvir plus ribavirin (SOF/VEL+RBV) for 24 weeks, all 3 patients had achieved a sustained viral response (SVR) at 24 weeks after completing treatment. SOF/VEL+RBV therapy was effective for retreatment of HCV after failure of GLE/PIB therapy.
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http://dx.doi.org/10.2169/internalmedicine.7028-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627798PMC
November 2021

Per-rectal portal scintigraphy as an alternative measure of hepatic venous pressure gradient in chronic liver disease: A preliminary report.

Clin Physiol Funct Imaging 2021 Jul 29;41(4):334-341. Epub 2021 Apr 29.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Aim: Hepatic venous pressure gradient (HVPG) measurement is a gold standard for the diagnosis of portal hypertension but can be invasive and difficult to conduct. Per-rectal portal scintigraphy (PRPS) can estimate portal haemodynamics noninvasively. However, no report to date has examined the association between HVPG and PRPS in patients with chronic liver disease, including cirrhosis.

Methods: This single-centre study included a total of 21 patients with chronic liver disease who underwent HVPG measurement and PRPS. For PRPS, the transit times from injection of the radiotracer to its inflow into the liver (TTL) and heart (TTH) were set and the time difference between TTL and TTH (TDLH) was calculated, while the shunt index (SI) was measured.

Results: Cirrhosis was observed in 18 cases (86%), and the median HVPG was 13 mmHg. HVPG (p = 0.028), TTL (p = 0.018), TDLH (p = 0.003) and SI (p = 0.033) were higher in patients with oesophageal varices (EV). Considering the diagnostic ability for EV, the area under the curve was 0.88 for TDLH and 0.80 for HVPG. TDLH was significantly correlated with the risk of EV rupture (p = 0.004).

Conclusion: Patients with chronic liver disease should undergo upper gastrointestinal endoscopy when the TDLH is high.
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http://dx.doi.org/10.1111/cpf.12703DOI Listing
July 2021

Applicability of APRI and FIB-4 as a transition indicator of liver fibrosis in patients with chronic viral hepatitis.

J Gastroenterol 2021 05 31;56(5):470-478. Epub 2021 Mar 31.

Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, Tokyo, 272-8516, Japan.

Background And Aims: The usefulness of APRI or FIB-4 is well established as a non-invasive liver fibrosis marker at a point of diagnosis in patients with chronic liver disease. However, their applicability for the monitoring of progression of liver fibrosis over time is yet to be determined. We aimed to clarify the feasibility of APRI and FIB-4 for the longitudinal evaluation of liver fibrosis in patients with chronic hepatitis B and C.

Methods: This is a multi-center retrospective and prospective cohort study, enrolling 1029 patients with HCV and 384 patients with HBV who were histologically diagnosed by liver biopsy. The observation period of retrospective and prospective study was 14 and 12 years, respectively. The APRI and FIB-4 were traced back in cases of histologically diagnosed cirrhosis, and those were prospectively analyzed after biopsy in cases diagnosed as F3 of METAVIR score, respectively.

Results: The averaged APRI and FIB-4 exhibited time-dependent increase in the retrospective study of hepatitis C patients (increase by 0.09/year in APRI and 0.29/year in FIB-4). In the prospective study of untreated hepatitis C patients, such increases were 0.14/year in APRI and 0.40/year in FIB-4, respectively. Neither the average of APRI nor FIB-4 showed a specific tendency with hepatitis B patients and treatment-experienced hepatitis C patients.

Conclusion: The APRI and FIB-4 may serve as a transition indicator of liver fibrosis in anti-viral treatment-naïve patients with chronic hepatitis C.
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http://dx.doi.org/10.1007/s00535-021-01782-3DOI Listing
May 2021

Successful Transcatheter Arterial Embolization for Hemothorax from a Spontaneous Rupture of Hepatocellular Carcinoma Metastasis to the Chest Wall in an Elderly Patient.

Intern Med 2021 Jul 22;60(14):2223-2228. Epub 2021 Feb 22.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan.

An 87-year-old man with hepatocellular carcinoma (HCC) presented with right-sided chest pain. Computed tomography revealed right bloody pleural effusion and an extravasation from an arterially enhanced mass in the right seventh posterior intercostal space. These findings indicated hemothorax from a rupture of HCC metastasis to the chest wall. Angiography of the intercostal arteries confirmed a hypervascular tumor, and transcatheter arterial embolization resulted in hemostasis. He was discharged with palliative care and remains alive after 9 months. Although hemothorax represents an unusual, life-threatening complication of HCC, our case suggests that transcatheter treatment can achieve hemostasis and a favorable survival even in elderly patients.
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http://dx.doi.org/10.2169/internalmedicine.6003-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355405PMC
July 2021

Hexa Histidine-Tagged Recombinant Human Cytoglobin Deactivates Hepatic Stellate Cells and Inhibits Liver Fibrosis by Scavenging Reactive Oxygen Species.

Hepatology 2021 06 22;73(6):2527-2545. Epub 2021 May 22.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan.

Background And Aims: Antifibrotic therapy remains an unmet medical need in human chronic liver disease. We report the antifibrotic properties of cytoglobin (CYGB), a respiratory protein expressed in hepatic stellate cells (HSCs), the main cell type involved in liver fibrosis.

Approach And Results: Cygb-deficient mice that had bile duct ligation-induced liver cholestasis or choline-deficient amino acid-defined diet-induced steatohepatitis significantly exacerbated liver damage, fibrosis, and reactive oxygen species (ROS) formation. All of these manifestations were attenuated in Cygb-overexpressing mice. We produced hexa histidine-tagged recombinant human CYGB (His-CYGB), traced its biodistribution, and assessed its function in HSCs or in mice with advanced liver cirrhosis using thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). In cultured HSCs, extracellular His-CYGB was endocytosed and accumulated in endosomes through a clathrin-mediated pathway. His-CYGB significantly impeded ROS formation spontaneously or in the presence of ROS inducers in HSCs, thus leading to the attenuation of collagen type 1 alpha 1 production and α-smooth muscle actin expression. Replacement the iron center of the heme group with cobalt nullified the effect of His-CYGB. In addition, His-CYGB induced interferon-β secretion by HSCs that partly contributed to its antifibrotic function. Momelotinib incompletely reversed the effect of His-CYGB. Intravenously injected His-CYGB markedly suppressed liver inflammation, fibrosis, and oxidative cell damage in mice administered TAA or DDC mice without adverse effects. RNA-sequencing analysis revealed the down-regulation of inflammation- and fibrosis-related genes and the up-regulation of antioxidant genes in both cell culture and liver tissues. The injected His-CYGB predominantly localized to HSCs but not to macrophages, suggesting specific targeting effects. His-CYGB exhibited no toxicity in chimeric mice with humanized livers.

Conclusions: His-CYGB could have antifibrotic clinical applications for human chronic liver diseases.
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http://dx.doi.org/10.1002/hep.31752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251927PMC
June 2021

Prevalence and risk factors of functional constipation in the Rome IV criteria during a medical check-up in Japan.

J Gastroenterol Hepatol 2021 Aug 15;36(8):2157-2164. Epub 2021 Feb 15.

Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Background And Aim: Functional constipation (FC) is one of the functional bowel disorders with symptoms of constipation in the Rome IV criteria. This study aimed to examine the epidemiology of FC in a large-scale survey of individuals undergoing a medical check-up in Japan.

Methods: A total of 13 729 subjects who underwent a medical check-up at MedCity21 between April 2018 and March 2019 were given a questionnaire that inquired about bowel habits. Among them, 10 658 subjects participated in this study, and FC was diagnosed based on the Rome IV criteria.

Results: The number of subjects who fulfilled diagnostic criteria of FC was 220, and the prevalence of FC was 2.1%. Compared with subjects with non-FC, those with FC were more complaining of abdominal bloating and distension, feeling stressed, getting annoyed, lack of motivation, fatigue upon waking, and feeling depressed. The risk of FC was significantly lower among subjects who drank alcohol more than 5 days a week, exercised for more than 30 min at least twice a week for more than 1 year, and were getting enough rest by sleeping, whereas it was significantly higher among women and subjects who were eating faster than other people.

Conclusions: The prevalence of FC in Japanese subjects during a medical check-up was relatively low compared with that in Western countries. Subjects with FC had troublesome symptoms, and it might be suggested that female sex, lack of regular exercise with moderate activity, insufficient rest by sleeping, and eating faster were a risk of FC.
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http://dx.doi.org/10.1111/jgh.15436DOI Listing
August 2021

Regression of portal hypertension: underlying mechanisms and therapeutic strategies.

Hepatol Int 2021 Feb 5;15(1):36-50. Epub 2021 Feb 5.

Hepatology, Department of Biomedical Research, University of Bern, Inselspital, Murtenstrasse 35, Maurice E. Müller-Haus, F821a, 3008, Bern, Switzerland.

Portal hypertension is the main non-neoplastic complication of chronic liver disease, being the cause of important life-threatening events including the development of ascites or variceal bleeding. The primary factor in the development of portal hypertension is a pathological increase in the intrahepatic vascular resistance, due to liver microcirculatory dysfunction, which is subsequently aggravated by extra-hepatic vascular disturbances including elevation of portal blood inflow. Evidence from pre-clinical models of cirrhosis has demonstrated that portal hypertension and chronic liver disease can be reversible if the injurious etiological agent is removed and can be further promoted using pharmacological therapy. These important observations have been partially demonstrated in clinical studies. This paper aims at providing an updated review of the currently available data regarding spontaneous and drug-promoted regression of portal hypertension, paying special attention to the clinical evidence. It also considers pathophysiological caveats that highlight the need for caution in establishing a new dogma that human chronic liver disease and portal hypertension is reversible.
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http://dx.doi.org/10.1007/s12072-021-10135-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886770PMC
February 2021

Combination of Entecavir or Tenofovir with Pegylated Interferon-α for Long-Term Reduction in Hepatitis B Surface Antigen Levels: Simultaneous, Sequential, or Add-on Combination Therapy.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.

Seroclearance of hepatitis B surface antigen (HBsAg) ("functional cure") is the optimal endpoint of antiviral therapy for chronic hepatitis B virus (HBV) infection. Currently available anti-HBV therapy includes nucleoside/nucleotide analogs (NAs) and peginterferon-α (Peg-IFNα). Combination of NAs and Peg-IFNα, each with different mechanisms of action, is an attractive approach for treating chronic HBV infection. In earlier studies, compared with monotherapy using IFNα, combination therapy showed greater on-treatment HBV DNA suppression but no difference in the sustained response. However, responses to the combination of non-pegylated IFNα with lamivudine or adefovir were not assessed based on HBsAg quantification but were defined by normal alanine aminotransferase levels, testing negative for hepatitis B e-antigen, and low HBV DNA load over a short term. Here, we reviewed previous reports regarding the effects of combination therapy of entecavir or tenofovir with Peg-IFNα, focusing on long-term reduction in HBsAg levels. Regimens of combination therapy were classified into "simultaneous" combination ("de novo" strategy); "sequential" combination, which involved starting with one therapy followed by the other ("switch-to" strategy); "add-on" combination, which involved adding Peg-IFNα to an ongoing NAs. Some studies have shown promising results, but there is no robust evidence that combination therapy is superior to monotherapy. Large studies are needed to assess the safety and efficacy of combination therapies to increase the rates of HBsAg seroclearance over the long term.
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http://dx.doi.org/10.3390/ijms22031456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867160PMC
February 2021

Precancerous Lesions and Liver Atrophy as Risk Factors for Hepatolithiasis-Related Death after Liver Resection for Hepatolithiasis.

Asian Pac J Cancer Prev 2020 Dec 1;21(12):3647-3654. Epub 2020 Dec 1.

Department of Hepato-Biliary-Pancreatic Surgery Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan.

Background: Cholangiocarcinoma and secondary biliary cirrhosis can develop after liver resection for hepatolithiasis and are causes of hepatolithiasis-related death. We determined potential risk factors for hepatolithiasis-related death and subsequent cholangiocarcinoma, including precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct, in patients undergoing liver resection for hepatolithiasis.

Methods: The study cohort included 62 patients who underwent liver resection for hepatolithiasis without concomitant cholangiocarcinoma and had surgical specimens available for pathological examination. Univariate and multivariate analyses were conducted to examine risk factors associated with subsequent cholangiocarcinoma after hepatolithiasis and hepatolithiasis-related death. In 28 patients with BilIN lesions, the specimens were immunohistochemically stained for γ-H2AX and S100P.

Results: In the study cohort, the causes of death were subsequent cholangiocarcinoma, biliary cirrhosis, and other diseases in 5, 3, and 7 patients, respectively. Liver atrophy, precancerous lesions, postoperative repeated cholangitis, and jaundice for ≥1 week during the follow-up period were risk factors for hepatolithiasis-related death. Multivariate analysis showed that liver atrophy and precancerous lesions were independent risk factors for hepatolithiasis-related death. Liver atrophy or precancerous lesions were also risk factors for subsequent cholangiocarcinoma by univariate analysis. The positive expression of γ-H2AX and S100P was observed in 18 and 14 of the 28 BilIN lesions, respectively.

Conclusions: Liver atrophy and precancerous lesions with malignant transformation were risk factors not only for subsequent cholangiocarcinoma but also hepatolithiasis-related death after liver resection for hepatolithiasis, indicating that long-term follow-up is necessary even after liver resection in patients harboring these risk factors.
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http://dx.doi.org/10.31557/APJCP.2020.21.12.3647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046297PMC
December 2020
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