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1.
J Gastroenterol ; 57(2): 120-132, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35059853

RESUMO

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 × 104/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).


Assuntos
Carcinoma Hepatocelular , Hepatite C Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/patologia , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Resposta Viral Sustentada
2.
Microbiol Immunol ; 66(4): 179-192, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35084739

RESUMO

Antibodies against hepatitis B virus S protein can protect against hepatitis B virus (HBV) infection. Therefore, hepatitis B immunoglobulin (HBIG), which contains HBsAb, is used clinically as a therapy for HBV infection. In this study, a series of monoclonal antibodies that recognize multiple HBV genotypes was obtained. All the antibodies recognized conformational epitopes of S protein, but not linear epitopes. Several antibodies neutralized HBV infection and exhibited strong affinities and neutralizing activities. Antigenic epitope analysis demonstrated that they recognized residue Ile152 of S protein, which is localized outside the "a" determinant. Ile152 is highly conserved, and a mutation in this residue resulted in reduced expression of large hepatitis B surface proteins (L protein), suggesting that the amino acid at this position is involved in the expression of L protein. In addition, the antibodies neutralized the infection of hepatitis D virus possessing a Gly145 mutation to Arg in S protein, which is a well-known escape mutation against HBIG treatment. Using mouse monoclonal antibodies, a humanized antibody possessing affinities and neutralizing activities similar to those of the original mouse antibody was successfully established. The antibodies generated in this study may have the potential for use in alternative antibody therapies for HBV infection.


Assuntos
Vírus da Hepatite B , Hepatite B , Animais , Anticorpos Monoclonais , Anticorpos Neutralizantes , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B/genética , Camundongos
3.
Hepatology ; 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34855990

RESUMO

BACKGROUND AND AIMS: Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and HCC. However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood. APPROACH AND RESULTS: Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine-1-phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver. CONCLUSIONS: In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.

4.
Glob Health Med ; 3(5): 249-252, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34782865

RESUMO

In Japan, the estimated number of chronic HBV infections was 1.1-1.2 million and that of chronic HCV was 0.9-1.3 million in 2015. The mortality of hepatocellular carcinoma (HCC) had been increasing and hit a peak at around 2002, which subsequently started to decrease. Japan has a national action plan for addressing viral hepatitis called, "Basic Act on Hepatitis Measures", established in 2009. "Basic Guidelines for Promotion of Control Measures for Hepatitis" was issued in 2011 and was updated in 2016, comprising 9 principles in order to promote measures to prevent hepatitis B and C. According to these guidelines, national and local government share screening costs for testing HBV and HCV for those residents who are over 40 years old. Thus, out-of-pocket expenses from examinees are free of charge or reduced to a minimum. In addition, for patients with chronic hepatitis B or C being treated: drug prices of nucleotide analogues, interferon treatment or direct antiviral agents, and examination expenses should be covered by a special program for viral hepatitis. From December 2018, the special coverage program of medical expenses, shared by central and local government, has started for patients with HBV- or HCV-induced liver cancer and decompensated cirrhosis. However, in the cascade-of-care of viral hepatitis in Japan, significant gaps still remain in the diagnosis, treatment and transition to patients in need. Several advantages have prevailed in Japanese health care systems for patients with viral liver disease compared to those in other countries in the Western Pacific Region. Therefore, Japan should take a lead in helping the implementation of a practical hepatitis action plan for each country in need.

5.
Glob Health Med ; 3(5): 301-307, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34782873

RESUMO

Chronic viral hepatitis is one of the most widespread infectious diseases in Japan. In the 2009 financial year, the Japanese government enacted the Basic Act on Hepatitis Measures, followed by the Basic Guidelines for Promotion of Control Measures for Hepatitis 2 years later. The guidelines emphasize the importance of provision and dissemination of accurate information on viral hepatitis and public awareness-raising. A subsidy program on hepatitis was therefore launched by the Ministry of Health, Labour and Welfare in 2011, called "Shitte kan-en" (in English, "Let's learn about hepatitis"), and involves popular Japanese actors and singers. The project started awareness-raising activities in the 2013 financial year, as the "National Campaign Project for Hepatitis Measures". It aims to communicate concise and accurate information about hepatitis and the necessity of testing for viral hepatitis. It also encourages citizens to take a positive approach to early detection and treatment. To date, the main initiatives of the project are as follows: i) celebrity visits to prefectural governors to draw attention to the condition, ii) educational events in cooperation with hepatologists in regional core hospitals, iii) support for partner companies' hepatitis awareness activities in workplaces, and iv) support for the activities of program promoters. Targeting approaches to particular groups is likely to be key to success for general awareness-raising. Evaluation of the effectiveness of this multifaceted approach is warranted to reduce the undiagnosed population and improve the link between testing and care for viral hepatitis in Japan.

6.
Glob Health Med ; 3(5): 308-313, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34782874

RESUMO

Viral hepatitis is one of the major infectious diseases in Japan and causes liver cirrhosis and liver cancer. Therefore, screening for hepatitis viruses was started in 2002, based on the geriatric health care program. The screening plan has now been transferred to the Health Promotion Project and it is estimated that more than half of the population has been tested for hepatitis viruses. The Basic Act on Hepatitis Measures was enacted in 2009 and the Basic Guidelines for Promotion of Control Measures for hepatitis was issued in 2011. It reported that there were about 770,000 positive people who were unaware that they were infected, and about 0.5 to 1.2 million positive people who knew they were infected but did not continue to receive medical examinations. Ten years have passed since that report and it is estimated that the number of hepatitis virus-positive individuals who need medical examination/treatment is decreasing. Therefore, in order to eradicate viral hepatitis, it is essential to identify areas and age groups in which hepatitis virus testing is inadequate, to encourage people to undergo testing and to promptly send positive patients to hepatologists for continued medical care. This review describes the current status and challenges of hepatitis virus testing measures in Japan, led by the Ministry of Health, Labour and Welfare, and the promotion of visits to medical institutions by positive patients.

7.
Glob Health Med ; 3(5): 335-342, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34782877

RESUMO

Viral hepatitis poses a major public health problem in Japan. Chronic viral hepatitis is a progressive liver disease that eventually develops into liver cirrhosis and liver cancer. Since nucleic acid analog therapy for hepatitis B and interferon-free therapy for hepatitis C have made it possible to control the disease status or eliminate the viruses, it is very important that more people receive hepatitis virus tests to confirm the presence of infection at an early stage, and that patients with hepatitis detected by the tests receive appropriate medical care. Currently, the government of Japan is implementing comprehensive measures for hepatitis control based on five key strategies. Moreover, the goal listed in the Basic Guidelines on Hepatitis Measures is to reduce the frequency of progression of hepatitis to cirrhosis or liver cancer through a scheme consisting of testing people for hepatitis, getting those who test positive to visit a medical institution and receive treatment, and providing appropriate and high-quality hepatitis care through specialized medical institutions and regional core centers for the management of liver disease. To achieve the goal, various subsidy programs including an expense subsidy system for hepatitis treatment have been implemented in Japan. It is important for healthcare professionals to have sufficient knowledge of public support for efficient hepatitis C virus (HCV)-related liver disease detection and care.

8.
Viruses ; 13(10)2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34696531

RESUMO

Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.


Assuntos
Disbiose/virologia , Fezes/virologia , Hepatite A/complicações , Adulto , Disbiose/microbiologia , Microbioma Gastrointestinal/fisiologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/patogenicidade , Hepatite A/fisiopatologia , Hepatite A/virologia , Vírus da Hepatite A/patogenicidade , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Carga Viral , Eliminação de Partículas Virais
9.
Hepatol Commun ; 5(8): 1437-1447, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34430787

RESUMO

Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium-binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.

10.
Vaccine ; 39(36): 5224-5230, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34340855

RESUMO

The World Health Organization recommends the implementation of universal hepatitis B (HB) vaccination, and global coverage for this vaccine reached 84% in 2015. In Japan, the policy aimed at preventing mother-to-child transmission of HB virus (HBV) initially commenced as a specific vaccination program for infants born to mothers who were positive for HB surface antigen. In 2016, universal HB vaccination was implemented in this country to cover unvaccinated individuals at risk of horizontal HBV transmission. Although HB vaccination has been shown to be highly efficacious and safe, the issues of vaccine non-responders and of the loss of antibodies directed against HB surface antigen (anti-HBs) in HB vaccine recipients remain. To gain better insight into these problems, we previously performed an immunological analysis on adult vaccine recipients after they received an initial HB vaccination. We found that the course of successful HB vaccination is composed of the following distinct phases: 1) acquisition of anti-HBs antibody, 2) attainment of high anti-HBs antibody titers, and 3) maintenance of acquired anti-HBs antibody levels. In this review, we describe the significance of HB vaccination and suggest a potential means of improving the impact of HB vaccination based on our immunological analysis.


Assuntos
Vacinas contra Hepatite B , Hepatite B , Adulto , Feminino , Hepatite B/prevenção & controle , Anticorpos Anti-Hepatite B , Antígenos de Superfície da Hepatite B , Humanos , Imunização Secundária , Lactente , Transmissão Vertical de Doenças Infecciosas
11.
Cells ; 10(6)2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34198593

RESUMO

Overall response rates of systemic therapies against advanced hepatocellular carcinoma (HCC) remain unsatisfactory. Thus, searching for new immunotherapy targets is indispensable. NK cells are crucial effectors and regulators in the tumor microenvironment and a determinant of responsiveness to checkpoint inhibitors. We revealed the landscape of NK cell phenotypes in HCC patients to find potential immunotherapy targets. Using single cell mass cytometry, we analyzed 32 surface markers on CD56dim and CD56bright NK cells, which included Sialic acid-binding immunoglobulin-type lectins (Siglecs). We compared peripheral NK cells between HCC patients and healthy volunteers. We also compared NK cells, in terms of their localizations, on an individual patient bases between peripheral and intrahepatic NK cells from cancerous and noncancerous liver tissues. In the HCC patient periphery, CD160+CD56dim NK cells that expressed Siglec-7, NKp46, and NKp30 were reduced, while CD49a+CD56dim NK cells that expressed Siglec-10 were increased. CD160 and CD49a on CD56dim NK cells were significantly correlated to other NK-related markers in HCC patients, which suggested that CD160 and CD49a were signature molecules. CD49a+ CX3CR1+ Siglec-10+ NK cells had accumulated in HCC tissues. Considering further functional analyses, CD160, CD49a, CX3CR1, and Siglec-10 on CD56dim NK cells may be targets for immunotherapies of HCC patients.


Assuntos
Antígenos CD/metabolismo , Carcinoma Hepatocelular , Células Matadoras Naturais , Neoplasias Hepáticas , Fígado , Proteínas de Neoplasias/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Citofotometria , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino
12.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34035171

RESUMO

Immunoevasins are viral proteins that prevent antigen presentation on major histocompatibility complex (MHC) class I, thus evading host immune recognition. Hepatitis C virus (HCV) evades immune surveillance to induce chronic infection; however, how HCV-infected hepatocytes affect immune cells and evade immune recognition remains unclear. Herein, we demonstrate that HCV core protein functions as an immunoevasin. Its expression interfered with the maturation of MHC class I molecules catalyzed by the signal peptide peptidase (SPP) and induced their degradation via HMG-CoA reductase degradation 1 homolog, thereby impairing antigen presentation to CD8+ T cells. The expression of MHC class I in the livers of HCV core transgenic mice and chronic hepatitis C patients was impaired but was restored in patients achieving sustained virological response. Finally, we show that the human cytomegalovirus US2 protein, possessing a transmembrane region structurally similar to the HCV core protein, targets SPP to impair MHC class I molecule expression. Thus, SPP represents a potential target for the impairment of MHC class I molecules by DNA and RNA viruses.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Hepacivirus/fisiologia , Evasão da Resposta Imune/fisiologia , Animais , Apresentação do Antígeno/imunologia , Linhagem Celular , Regulação para Baixo , Hepacivirus/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos , Proteínas do Core Viral/fisiologia
13.
Hepatol Res ; 51(7): 823-833, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34014020

RESUMO

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.

14.
Hepatol Res ; 51(7): 803-812, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33998102

RESUMO

AIM: In patients with liver cirrhosis, high levels of serum myostatin are associated with poor prognosis. We aimed to clarify the influence of myostatin on the prognosis of patients with non-alcoholic fatty liver disease-hepatocellular carcinoma (NAFLD-HCC) without cirrhosis and on the progression of liver fibrosis. METHODS: Serum myostatin levels were evaluated in 234 patients who underwent primary surgical resection for single HCC. To clarify the impact of myostatin on liver fibrosis, we established human primary liver fibroblasts from resected livers, and cultured them in the presence of myostatin. RESULTS: The median age was 67.4 years, the median L3 skeletal muscle mass index was 44.4 cm2 /m2 , and the median body mass index was 23.4 kg/m2 . Eighty-two (35.0%) patients had sarcopenia (L3 skeletal muscle mass index: men <42, women <38 cm2 /m2 ). The etiologies of liver disease were hepatitis B virus (n = 61), hepatitis C virus (n = 86), and non-B non-C hepatitis (n = 87) including NAFLD (n = 74). High preoperative serum myostatin and vascular invasion were independent predictors of poor overall survival (OS). High serum myostatin was associated with poor OS in patients with no sarcopenia (n = 152). In patients without advanced liver fibrosis (Fibrosis stage, 0-2; n = 58), high levels of serum myostatin were also associated with poor OS, regardless of sarcopenia. Serum myostatin levels were increased with the progression of liver fibrosis. Liver fibroblasts were activated and produced collagen following stimulation with myostatin. CONCLUSIONS: In patients with NAFLD-HCC without advanced liver fibrosis, high levels of serum myostatin were associated with poor OS. Myostatin activated primary fibroblasts and stimulated collagen production.

15.
J Gastroenterol ; 56(5): 470-478, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33791882

RESUMO

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.


Assuntos
Hepatite C/etiologia , Cirrose Hepática/etiologia , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Estudos de Coortes , Feminino , Hepatite C/classificação , Humanos , Cirrose Hepática/classificação , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo
16.
Front Immunol ; 12: 603133, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33692781

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after in vitro stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56+ NK cell and CD56dim NK cell populations compared with HVs, and the CD56dim cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7+CD56dim NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56dim NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7-CD57+PD-1+CD56dim NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.


Assuntos
Antígenos de Diferenciação Mielomonocítica/imunologia , Antígenos CD57/imunologia , Células Matadoras Naturais/imunologia , Lectinas/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Feminino , Citometria de Fluxo , Humanos , Interferon gama/imunologia , Células Matadoras Naturais/patologia , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Glicoproteínas de Membrana Associadas ao Lisossomo/imunologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia
17.
BMC Gastroenterol ; 21(1): 55, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557759

RESUMO

BACKGROUND: Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model. METHODS: Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male). RESULTS: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs. CONCLUSIONS: ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.


Assuntos
Angiopoietina-2 , Hepatite C Crônica , Angiopoietina-2/uso terapêutico , Animais , Antivirais/uso terapêutico , Tetracloreto de Carbono , Hepatite C Crônica/complicações , Hepatite C Crônica/patologia , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica
18.
Immunol Med ; 44(3): 175-186, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33444517

RESUMO

Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) are becoming major liver diseases worldwide. Liver fibrosis and cirrhosis are among the most significant risk factors of hepatocellular carcinoma (HCC) and associated with the long-term prognosis of NAFLD patients. To stratify the risk of HCC in NAFLD patients clinically, the discovery of non-invasive fibrosis markers is needed urgently. Liver macrophages play critical roles in the regulation of inflammation and fibrosis by interacting with hepatic stellate cells (HSCs) and other immune cells. Thus, it is rational to explore feasible biomarkers for liver fibrosis by focusing on macrophage-related factors. We examined serum factors comprehensively in multiple cohorts of NAFLD/NASH patients to determine whether they were correlated with the biopsy-proven fibrosis stage. We found that the serum levels of interleukin (IL)-34, YKL-40 and soluble Siglec-7 (sSiglec7) were closely associated with liver fibrosis and served as diagnostic biomarkers in patients with NAFLD/NASH. In the NAFLD liver, IL-34 was produced by activated fibroblasts, and YKL-40 and sSiglec-7 were secreted from macrophages. The sensitivity and specificity of these markers to detect advanced liver fibrosis varied, supporting the notion that the combination of these markers with other modalities is an option for clinical application.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Biomarcadores , Fibrose , Humanos , Macrófagos
19.
Gene ; 766: 145145, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32941953

RESUMO

COVID-19, a novel coronavirus-related illness, has spread worldwide. Patients with apparently mild/moderate symptoms can suddenly develop severe pneumonia. Therefore, almost all COVID-19 patients require hospitalization, which can reduce limited medical resources in addition to overwhelming medical facilities. To identify predictive markers for the development of severe pneumonia, a comprehensive analysis of serum chemokines and cytokines was conducted using serial serum samples from COVID-19 patients. The expression profiles were analyzed along the time axis. Serum samples of common diseases were enrolled from a BioBank to confirm the usefulness of predictive markers. Five factors, IFN-λ3, IL-6, IP-10, CXCL9, and CCL17, were identified as predicting the onset of severe/critical symptoms. The factors were classified into two categories. Category A included IFN-λ3, IL-6, IP-10, and CXCL9, and their values surged and decreased rapidly before the onset of severe pneumonia. Category B included CCL17, which provided complete separation between the mild/moderate and the severe/critical groups at an early phase of SARS-CoV-2 infection. The five markers provided a high predictive value (area under the receiver operating characteristic curve (AUROC): 0.9-1.0, p < 0.001). Low expression of CCL17 was specifically observed in pre-severe COVID-19 patients compared with other common diseases, and the predictive ability of CCL17 was confirmed in validation samples of COVID-19. The factors identified could be promising prognostic markers to distinguish between mild/moderate and severe/critical patients, enabling triage at an early phase of infection, thus avoiding overwhelming medical facilities.


Assuntos
Biomarcadores/sangue , Quimiocina CCL17/sangue , Infecções por Coronavirus/sangue , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/sangue , Pneumonia Viral/fisiopatologia , Betacoronavirus/fisiologia , COVID-19 , Citocinas/sangue , Hospitalização , Humanos , Pandemias , SARS-CoV-2 , Índice de Gravidade de Doença
20.
J Gastroenterol ; 56(1): 67-77, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33001338

RESUMO

BACKGROUND: Real-world data on the efficacy and safety of sofosbuvir plus velpatasvir (SOF/VEL) treatment for patients with hepatitis C virus (HCV)-related decompensated cirrhosis are limited in Japan. METHODS: A total of 190 patients with compensated (108) or decompensated (82) cirrhosis who initiated direct-acting antiviral (DAA) treatment between February 2019 and August 2019 were enrolled. Sustained virologic response (SVR) was defined as undetectable serum HCV-RNA at 12 weeks after the end of treatment (EOT). RESULTS: The SVR12 rates were 92.6% in patients with compensated cirrhosis and 90.2% in patients with decompensated cirrhosis (p = 0.564), and the treatment completion rates were 98.1% and 96.3%, respectively (p = 0.372). In patients with decompensated cirrhosis, 3 patients discontinued treatment and 2 patients died because of liver-related events. In patients with decompensated cirrhosis with SVR12, 50% of patients with Child-Pugh class B at baseline showed improvement to class A at SVR12, and 27% and 9% of patients with Child-Pugh class C at baseline showed improvement to class B and class A at SVR12, respectively. Patients who achieved SVR12 showed elevated serum albumin levels at the EOT, which were further elevated at SVR12, but no elevated serum albumin levels after the EOT were observed in patients with baseline serum albumin levels less than 2.8 g/dl. CONCLUSIONS: Real-world efficacy of SOF/VEL treatment for patients with decompensated cirrhosis was similar to Japanese phase 3 study, although treatment discontinuation and death related to liver disease occurred. In patients with poor hepatic reserve, whether it improves continuously after viral clearance requires further evaluation.


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Cirrose Hepática/virologia , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Combinação de Medicamentos , Feminino , Seguimentos , Hepatite C Crônica/complicações , Hepatite C Crônica/mortalidade , Humanos , Japão , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Resposta Viral Sustentada , Resultado do Tratamento
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