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1.
J Med Virol ; 95(9): e29103, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37721366

RESUMEN

Hepatitis C virus (HCV) infection remains a challenge to human public health despite the development of highly effective direct-acting antivirals (DAAs). Sofosbuvir (SOF), a key component in most DAA-based anti-HCV cocktail regimens, is a potent viral RNA polymerase (NS5B) inhibitor with a high barrier to drug resistance. The serine-to-threonine mutation at NS5B 282 (S282T) confers the SOF resistance, but severely impairs viral replication in most HCV genotypes (GTs) and cannot be stably maintained after the termination of the SOF-based therapies. In this study, we first developed a new HCV GT-6a subgenomic replicon PR58D6. Next, we selected SOF-resistant PR58D6 variants by culturing the replicon cells in the presence of SOF. Interestingly, unlike many other HCV replicons which require additional mutations to compensate for the S282T-inducing fitness loss, S282T alone in PR58D6 is genetically stable and confers the SOF resistance without significantly impairing viral replication. Furthermore, we showed that amino acid residue at NS5B 74 (R74) and 556 (D556) which are conserved in GT 6a HCV contribute to efficient replication of PR58D6 containing S282T. Finally, we showed that the G556D mutation in NS5B could rescue the replication deficiency of the S282T in JFH1, a GT-2a replicon. In conclusion, we showed that a novel GT-6a HCV replicon may easily render SOF resistance, which may call for attention to potential drug resistance during DAA therapies of HCV GT-6a patients.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Humanos , Sofosbuvir/farmacología , ARN Subgenómico , Hepacivirus/genética , Antivirales/farmacología , Hepatitis C/tratamiento farmacológico , Genotipo
2.
J Hepatol ; 75(1): 163-176, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33610678

RESUMEN

BACKGROUND & AIMS: Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown. METHODS: Il20 knockout (Il20-/-) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively. RESULTS: Il20-/- mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20-/- mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis. CONCLUSIONS: IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection. LAY SUMMARY: Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Infecciones Bacterianas , Hepatitis Alcohólica , Hepatitis , Interleucina-1beta/metabolismo , Interleucinas/metabolismo , Animales , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/metabolismo , Descubrimiento de Drogas , Regulación de la Expresión Génica/efectos de los fármacos , Hepatitis/tratamiento farmacológico , Hepatitis/inmunología , Hepatitis/metabolismo , Hepatitis Alcohólica/inmunología , Hepatitis Alcohólica/metabolismo , Humanos , Hígado/metabolismo , Ratones , Ratones Noqueados , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Proteolisis , Regulación hacia Arriba
3.
Hepatology ; 72(2): 412-429, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-31705800

RESUMEN

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C-X-C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high-fat diet (HFD)-fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD-fed mice and to test the therapeutic potential of IL-22 in this new NASH model. APPROACH AND RESULTS: Overexpression of Cxcl1 in the liver alone promotes steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal-regulating kinase 1 and p38 mitogen-activated protein kinase) activation. Myeloid cell-specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1-induced NASH and stress kinase activation in HFD-fed mice. Treatment with interleukin (IL)-22, a cytokine with multiple targets, ameliorated CXCL1/HFD-induced NASH or methionine-choline deficient diet-induced NASH in mice. Mechanistically, IL-22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL-22 treatment attenuated the inflammatory functions of hepatocyte-derived, mitochondrial DNA-enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. CONCLUSIONS: Hepatic overexpression of CXCL1 is sufficient to drive steatosis-to-NASH progression in HFD-fed mice through neutrophil-derived reactive oxygen species and activation of stress kinases, which can be reversed by IL-22 treatment via the induction of metallothionein.


Asunto(s)
Quimiocina CXCL1/biosíntesis , Interleucinas/uso terapéutico , Hígado/metabolismo , Infiltración Neutrófila , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos , Interleucina-22
4.
Ren Fail ; 43(1): 1329-1337, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34541999

RESUMEN

BACKGROUND: This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. METHODS: In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. RESULTS: In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14-1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. CONCLUSION: The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.


Asunto(s)
Lesión Renal Aguda/etiología , COVID-19/complicaciones , Hipofosfatemia/complicaciones , Neumonía Viral/complicaciones , Lesión Renal Aguda/epidemiología , COVID-19/epidemiología , China/epidemiología , Femenino , Hospitalización , Humanos , Hipofosfatemia/epidemiología , Incidencia , Unidades de Cuidados Intensivos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Neumonía Viral/epidemiología , Neumonía Viral/virología , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2
5.
J Hepatol ; 72(4): 736-745, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31786256

RESUMEN

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by liver failure on pre-existing chronic liver disease. It is often associated with bacterial infection and high short-term mortality. Experimental models that fully reproduce ACLF are lacking, so too are effective pharmacological therapies for this condition. METHODS: To mimic ACLF conditions, we developed a severe liver injury model by combining chronic injury (chronic carbon tetrachloride [CCl4] injection), acute hepatic insult (injection of a double dose of CCl4), and bacterial infection (intraperitoneal injection of bacteria). Serum and liver samples from patients with ACLF or acute drug-induced liver injury (DILI) were used. Liver injury and regeneration were assessed to ascertain the potential benefits of interleukin-22 (IL-22Fc) administration. RESULTS: This severe liver injury model recapitulated some of the key features of clinical ACLF, including acute-on-chronic liver injury, bacterial infection, multi-organ injury, and high mortality. Liver regeneration in this model was severely impaired because of a shift from the activation of the pro-regenerative IL-6/STAT3 pathway to the anti-regenerative IFN-γ/STAT1 pathway. The impaired IL-6/STAT3 activation was due to the inability of Kupffer cells to produce IL-6; whereas the enhanced STAT1 activation was due to a strong innate immune response and subsequent production of IFN-γ. Compared to patients with DILI, patients with ACLF had higher levels of IFN-γ but lower liver regeneration. IL-22Fc treatment improved survival in ACLF mice by reversing the STAT1/STAT3 pathway imbalance and enhancing expression of many antibacterial genes in a manner involving the anti-apoptotic protein BCL2. CONCLUSIONS: Acute-on-chronic liver injury or bacterial infection is associated with impaired liver regeneration due to a shift from a pro-regenerative to an anti-regenerative pathway. IL-22Fc therapy reverses this shift and attenuates bacterial infection, thus IL-22Fc may have therapeutic potential for ACLF treatment. LAY SUMMARY: A mouse model combining chronic liver injury, acute hepatic insult, and bacterial infection recapitulates some of the key features of acute-on-chronic liver failure (ACLF) in patients. Both fibrosis and bacterial infection contribute to the impaired regenerative capacity of the liver in patients with ACLF. Herein, we show that IL-22Fc therapy improves ACLF by reprogramming impaired regenerative pathways and attenuating bacterial infection. Thus, it may have therapeutic potential for patients with ACLF.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Interleucinas/administración & dosificación , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae , Regeneración Hepática/efectos de los fármacos , Enfermedad Aguda , Insuficiencia Hepática Crónica Agudizada/inducido químicamente , Insuficiencia Hepática Crónica Agudizada/microbiología , Adulto , Animales , Tetracloruro de Carbono/administración & dosificación , Tetracloruro de Carbono/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Modelos Animales de Enfermedad , Femenino , Hepatocitos/metabolismo , Humanos , Infecciones por Klebsiella/microbiología , Macrófagos del Hígado/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Resultado del Tratamiento , Interleucina-22
6.
Am J Gastroenterol ; 115(12): 2026-2035, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32858565

RESUMEN

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined by the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium and the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) as an acute deterioration of cirrhosis with multiple organ failures and high short-term mortality. However, their diagnostic criteria differ. We aimed to compare these 2 criteria in the prediction of prognosis in hospitalized cirrhosis. METHODS: This was a prospective study of nonelectively hospitalized patients with cirrhosis (N = 468) from a single tertiary hospital between 2016 and 2018. Baseline characteristics, incidence, and types of organ failure and survival data at 7, 28, and 90 days were collected. Prognostic utilities of the 2 criteria were compared. RESULTS: One hundred thirty-seven of 468 patients (29.3%) had EASL-CLIF ACLF, and 35 of 468 (7.4%) had NACSELD ACLF. The 28-day transplant-free survival of ACLF was 58.4% using EASL-CLIF and 37.1% using the NACSELD criteria. In predicting 28-day mortality, the NACSELD criteria demonstrated significantly higher overall accuracy (92.0% vs 85.3%, P < 0.01), specificity (99.7% vs 84.0%, P < 0.001), and positive predictive value (97.1% vs 50.4%, P < 0.001) but lower sensitivity (49.3% vs 92.5%, P < 0.001) and negative predictive value (91.6% vs 98.5%, P < 0.001) than those of EASL-CLIF. The results were similar in predicting 7-day outcome. However, the overall accuracy became similar between NACSELD and EASL-CLIF ACLF criteria in predicting 90-day mortality (86.3% vs 88.7%, P = 0.27) because of the decrease of sensitivity and negative predictive value of NACSELD ACLF criteria. The prognostic performance of these 2 ACLF criteria was similar when applied to patients with or without hepatitis B virus infection as an etiology of cirrhosis. DISCUSSION: There are both caveats and utilities of NACSELD and EASL-CLIF ACLF criteria in prognosis prediction in patients with cirrhosis. NACSED criteria is highly accurate in predicting morality, whereas the EASL-CLIF criteria is more sensitive to identify patients who would benefit from liver transplantation.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada/diagnóstico , Cirrosis Hepática/diagnóstico , Insuficiencia Hepática Crónica Agudizada/clasificación , Femenino , Humanos , Pacientes Internos , Cirrosis Hepática/clasificación , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos
7.
J Viral Hepat ; 26(7): 835-845, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30974482

RESUMEN

Extensive hepatocyte death leads to hepatic inflammation and contributes to systemic inflammation in decompensated cirrhosis. We aimed to investigate the prognostic value of serum cell death markers in patients with hepatitis B virus (HBV)-related acute decompensation (AD) of cirrhosis with and without acute-on-chronic liver failure (ACLF). We studied two cohorts-cohort 1: 201 outpatients with stable chronic hepatitis B (49 cirrhosis); cohort 2: 232 inpatients with HBV-related cirrhosis admitted for AD. Cell death was determined with serum keratin-18 (K18) for total death and serum caspase-cleaved-K18 (cK18) for apoptosis. Survival analyses were performed using competing risk method. We found that serum K18 and cK18 were significantly (P < 0.001) higher in patients from cohort 2 than those from cohort 1. Among cohort 2, ACLF patients had significantly (P < 0.001) increased K18 and cK18 comparing to those without ACLF. Increased K18 and cK18 were mainly attributed to HBV flare and were associated with liver and coagulation failure. HBV-AD patients without ACLF who admitted with upper tertile of K18 or cK18 were at higher risk of developing ACLF during follow-up. Baseline serum K18 or cK18 was significantly associated with transplant-free 90-day survival independent of leucocytes, HBV DNA, bacterial infection, encephalopathy and severity scores. The combination of cell death biomarkers significantly improved the prognostic value of the currently established prognostic scores. The reduction of cell death level after standard treatment was associated with increased short-term survival. In conclusion, measurements of serum K18 or cK18 in HBV decompensated cirrhosis are a promising tool for predicting ACLF and risk stratification of short-term outcome.


Asunto(s)
Biomarcadores , Hepatitis B Crónica/sangre , Queratina-18/sangre , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Adulto , Muerte Celular , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/virología , Humanos , Cirrosis Hepática/etiología , Cirrosis Hepática/mortalidad , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Carga Viral
8.
Hepatology ; 68(4): 1604-1620, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29633303

RESUMEN

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), a key antibacterial protein, is highly elevated in patients with end-stage liver disease that is often associated with bacterial infection. LCN2 is expressed at high levels in both hepatocytes and neutrophils; however, how hepatocyte-derived and neutrophil-derived LCN2 cooperate to combat bacterial infection remains unclear. Here, by studying hepatocyte-specific and myeloid-specific Lcn2 knockout mice in two models of systemic and local Klebsiella pneumoniae infections, we demonstrated that hepatocytes played a critical role in controlling systemic infection by secreting LCN2 protein into the circulation following intraperitoneal injection of bacteria, whereas neutrophils were more important in combating local lung infection by carrying LCN2 in their specific granules to the local infection site following intratracheal intubation of bacteria. Both hepatocyte-derived and myeloid cell-derived LCN2 were required against bacterial infection in the peritoneal cavity and liver necrotic areas following intraperitoneal injection of Klebsiella pneumoniae. LCN2/NGAL protein was detected in neutrophil extracellular traps (NETs) in activated neutrophils from mice and humans. Disruption of the Lcn2 gene in neutrophils abolished LCN2 on NETs, whereas deletion of this gene in hepatocytes did not affect LCN2 protein on NETs. Genetic deletion of the Lcn2 gene globally or specifically in neutrophils did not affect NET formation but reduced the bactericidal effect of NETs in vitro. Finally, NGAL-positive NETs were detected in the liver from patients with various types of liver diseases. CONCLUSION: Both hepatocytes and neutrophils combat bacterial infection through the production of LCN2; extracellular LCN2 secreted by hepatocytes limits systemic bacterial infection, whereas neutrophils carry LCN2 protein to the local site and against local bacterial infection through NETs. (Hepatology 2018).


Asunto(s)
Trampas Extracelulares/metabolismo , Infecciones por Klebsiella/metabolismo , Klebsiella pneumoniae/patogenicidad , Lipocalina 2/genética , Proteínas de Fase Aguda/metabolismo , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Hepatocitos/metabolismo , Humanos , Infecciones por Klebsiella/patología , Lipocalina 2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/metabolismo , Distribución Aleatoria
9.
Hepatology ; 68(4): 1519-1533, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29631342

RESUMEN

Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)-induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time-dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin-2, kidney injury molecule 1 (KIM-1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase-2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase-2 knockout mice were partially protected from BDL-induced renal injury and had less impairment in microvascular function. In human-cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase-2 and markers of tubular cell injury. CONCLUSION: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase-2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (Hepatology 2018; 00:000-000).


Asunto(s)
Lesión Renal Aguda/metabolismo , Arginina/metabolismo , Síndrome Hepatorrenal/patología , Túbulos Renales/patología , Óxido Nítrico Sintasa/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores/metabolismo , Biopsia con Aguja , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Síndrome Hepatorrenal/mortalidad , Síndrome Hepatorrenal/fisiopatología , Humanos , Inmunohistoquímica , Túbulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Distribución Aleatoria , Medición de Riesgo , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Tasa de Supervivencia
10.
Liver Int ; 39(10): 1943-1953, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31206235

RESUMEN

BACKGROUND: Hepatitis B virus (HBV) flare can occur in HBV patients either naïve or have interruption to treatment. Bacterial infection (BI) is a common complication of cirrhosis with potential severe outcomes. We aimed to assess the impact of HBV flare on the outcome of patients with HBV-related decompensated cirrhosis and BI. METHODS: This was a retrospective study from 2 tertiary academic hospitals in Shanghai, China of HBV patients admitted with or developed BI during admission. The characteristics of BI, prevalence of HBV flare, its impact on organ failure, acute-on-chronic liver failure (ACLF) and 90-day survival were evaluated. RESULTS: A total of 360 hospitalized patients (median age: 50 years, male: 79%, BI: at admission: 58.6%; during admission: 41.4%) were included. All patients including those with HBV flare (21%) received antiviral therapy after admission. Patients with HBV flare and BI had significantly higher percentage of liver (93.3% vs 48.8%), coagulation (64.0% vs 39.6%), cerebral (40.0% vs 21.8%) (all P < 0.01), and kidney failure (38.7% vs 26.3%, P < 0.05) compared to BI alone, associated with a higher risk of developing ACLF with a subdistribution hazard ratio (sHR) of 2.23 (95% confidence interval [CI]: 1.68-2.96). Multivariate analysis showed that ACLF development was the strongest risk factor for 90-day mortality (sHR, 95%CI: 7.36, 4.12-13.16). CONCLUSIONS: In HBV-related decompensated cirrhosis patients admitted with BI, HBV flare increased the risk of additional organ failures and ACLF, raising the risk of 90-day mortality by seven-fold. Optimization of HBV treatment in these patients should minimize the risk of HBV flare with improved outcomes.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada/mortalidad , Infecciones Bacterianas/epidemiología , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/complicaciones , Cirrosis Hepática/epidemiología , Insuficiencia Hepática Crónica Agudizada/microbiología , Insuficiencia Hepática Crónica Agudizada/terapia , Adulto , Antivirales/uso terapéutico , China , ADN Viral/sangre , Femenino , Virus de la Hepatitis B/aislamiento & purificación , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica , Insuficiencia Renal/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Carga Viral
12.
J Med Virol ; 89(11): 1973-1980, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28671305

RESUMEN

The diversity of HCV genotypes is ever-evolving and requires continuous surveillance. The aim of this study was to investigate the dynamics of HCV genotypes, and their associated demographic and clinical patterns in China. By searching computerized hospital information system, a total of 1155 HCV-positive patients eligible for analysis were retrospectively identified from 12 380 consecutive in-patients in the Department of Infectious Diseases, Ruijin Hospital in China between 2009 and 2014. The percentages of HCV genotype 1, 2, 3, or 6 were 61.3%, 12.8%, 18.5%, or 7.4%, respectively. The number of patients hospitalized for HCV infection increased gradually over the study period, particularly those infected by genotype 3 HCV. Patients of genotype 1, 2, 3, or 6 were significantly different. Genotype 1 or two patients were much older, with higher proportion of blood transfusion history. In contrast, genotype 3 or six patients were younger, predominantly male, with more exposure to intravenous drug use. The cirrhosis incidence was higher in genotype 1 or two patients, followed by genotype 3 and six patients. Strikingly, genotype 3 cirrhotic patients were younger, and their estimated infection durations were also shorter, suggestive of a faster disease progression in genotype 3 patients. Multivariate analysis demonstrated that presence of HBcAb was an independent predictor of cirrhosis (OR 2.19, 95%CI 1.27-3.42; P = 0.004). The leading increase and the younger trend of cirrhosis incidence in genotype 3 patients argue for a higher priority to manage the infection in this highly at-risk population.


Asunto(s)
Hepacivirus/genética , Hepatitis C Crónica/epidemiología , Hepatitis C/epidemiología , Cirrosis Hepática/epidemiología , Adulto , Factores de Edad , Anciano , China/epidemiología , Progresión de la Enfermedad , Femenino , Genotipo , Hepacivirus/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis C/sangre , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Hospitalización , Humanos , Incidencia , Cirrosis Hepática/sangre , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Abuso de Sustancias por Vía Intravenosa/complicaciones , Adulto Joven
13.
Liver Int ; 37(11): 1612-1621, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28772348

RESUMEN

BACKGROUND & AIMS: Serum Golgi protein 73 (GP73) is a potential biomarker for fibrosis assessment. We aimed to develop an algorithm based on GP73 and liver stiffness (LS) for further improvement of accuracy for significant fibrosis in patients with antiviral-naïve chronic hepatitis B virus (HBV) infection. METHODS: Diagnostic accuracy evaluation of GP73 and development of GP73-LS algorithm was performed in training cohort (n = 267) with an independent cohort (n = 133) for validation. RESULTS: A stepwise increasing pattern of serum GP73 was observed across fibrosis stages in patients with antiviral-naïve chronic HBV infection. Serum GP73 significantly correlated (rho = 0.48, P < .001) with fibrosis stage and was an independent predictor for the presence of significant fibrosis (OR, 95%CI: 1.02, 1.01-1.03, per increase in 1 ng/mL, P < .001). Both LS (AUROC, 95%CI: 0.82, 0.77-0.87, accuracy: 74.7%) and GP73 (AUROC, 95%CI: 0.76, 0.71-0.82, accuracy: 71.5%) well-predicted significant fibrosis and outperformed APRI (AUROC, 95%CI: 0.69, 0.63-0.76, accuracy: 66%) and FIB-4 (AUROC, 95%CI: 0.66, 0.60-0.73, accuracy: 63.6%). Using GP73-LS algorithm, GP73 < 63 in agreement with LS < 8.5 provided accuracy of 81.7% to excluded significant fibrosis. GP73 ≥ 63 in agreement with LS ≥ 8.5 provided accuracy of 93.3% to confirm significant fibrosis. Almost 64% or 68% of patients in the training or validation cohort could be accurately classified. CONCLUSIONS: Serum GP73 is a robust biomarker for significant fibrosis diagnosis. GP73-LS algorithm provided better diagnostic accuracy than currently available approaches. More than 60% antiviral naïve CHB patients could use this algorithm without resorting to liver biopsy.


Asunto(s)
Hepatitis B Crónica/complicaciones , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Hígado/fisiopatología , Proteínas de la Membrana/sangre , Adulto , Algoritmos , Biomarcadores/sangre , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad
14.
J Gastroenterol Hepatol ; 32(3): 677-686, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27548078

RESUMEN

BACKGROUND AND AIM: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is an acute deterioration of liver function on chronic liver disease with immune disorder. Th22 cells and IL-22 were correlated with inflammatory and autoimmune diseases. However, Th22 cells and IL-22 in the pathogenesis of HBV-ACLF remains to be elucidated. It was investigated the correlation between Th22 and prognosis in HBV-ACLF. METHODS: Seventy-one HBV-ACLF and 65 chronic hepatitis B patients were recruited. The peripheral frequencies of Th22, Th17 and Th1, or IL-22 and IL-17 were determined, using flow cytometry or ELISA, respectively. It was further analyzed the correlation between Th22 mediated circulating IL-22 and survival rate of HBV-ACLF patients. RESULTS: It was upregulated that the peripheral frequencies of Th22/Th17 cells as well as plasma IL-22 and IL-17 in HBV-ACLF patients, but the frequency of Th1 cells was decreased, compared with health controls. Elevated Th22 cells and IL-22 were correlated with HBV-ACLF disease severity. Elevated plasma IL-22 level (>29.5 pg/ml) was correlated with poor survival rate of HBV-ACLF patients at baseline, using Kaplan-Meier analysis. CONCLUSIONS: Persistently elevated circulating Th22 reversely correlates with prognosis in HBV-ACLF. Th22 cells/IL-22 might be served as biomarkers for evaluating the prognosis of HBV-ACLF.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada/etiología , Hepatitis B Crónica/complicaciones , Interleucinas/sangre , Linfocitos T Colaboradores-Inductores , Insuficiencia Hepática Crónica Agudizada/mortalidad , Adulto , Biomarcadores/sangre , Femenino , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/mortalidad , Humanos , Interleucinas/inmunología , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Linfocitos T Colaboradores-Inductores/inmunología , Adulto Joven , Interleucina-22
15.
Hepatobiliary Pancreat Dis Int ; 16(2): 181-188, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28381383

RESUMEN

BACKGROUND: The IL-33/ST2 axis is involved in the pathogenesis of many diseases such as autoimmune diseases, cancer, and heart failure. However, studies of the IL-33/ST2 pathway in HBV-related acute-on-chronic liver failure (HBV-ACLF) are lacking. The present study aimed to determine the prognostic role of serum IL-33/soluble ST2 (sST2) in HBV-ACLF. METHODS: Serum levels of IL-33 and sST2 in healthy controls (HC, n=18), chronic hepatitis B (CHB, n=27) and HBV-ACLF (n=51) patients at the 1st and 4th week after enrollment were detected using ELISA, and clinical data were collected. The follow-up of HBV-ACLF patients lasted for 6 months at least. RESULTS: There was no significant difference of serum IL-33 level among HC, CHB and HBV-ACLF patients at week 1. However, serum sST2 level differed significantly among the three groups: highest in the HBV-ACLF group, moderate in the CHB group and lowest in the HC group. There was a reverse correlation between serum sST2 level and the survival of HBV-ACLF patients. The level of serum sST2 in HBV-ACLF survivors was significantly declined from week 1 to week 4 following the treatment, whereas that in HBV-ACLF non-survivors remained at a high level during the same period. Furthermore, serum sST2 level was significantly correlated with laboratory parameters and the most updated prognostic scores (CLIF-C OF score, CLIF-C ACLF score and ACLF grades). The receiver operating characteristics curves demonstrated that serum sST2 level was a good diagnostic marker for predicting the 6-month mortality in HBV-ACLF patients, comparable to the most updated prognostic scores. Serum sST2 cut-off points for predicting prognosis in HBV-ACLF patients were 76 ng/mL at week 1 or 53 ng/mL at week 4, respectively. HBV-ACLF patients with serum sST2 level above the cut-off point often had a worse prognosis than those below the cut-off point. CONCLUSION: Serum sST2 may act as a promising biomarker to assess severity and predict prognosis of patients with HBV-ACLF and help for the early identification and optimal treatment of HBV-ACLF patients at high risk of mortality.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada/sangre , Hepatitis B/complicaciones , Proteína 1 Similar al Receptor de Interleucina-1/sangre , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/mortalidad , Insuficiencia Hepática Crónica Agudizada/virología , Adulto , Área Bajo la Curva , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Hepatitis B/diagnóstico , Hepatitis B/mortalidad , Humanos , Interleucina-33/sangre , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Adulto Joven
17.
J Hepatol ; 63(1): 148-55, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25681556

RESUMEN

BACKGROUND & AIMS: Th22 cells regulate host immunity against pathogenic invasion, including protecting host against chronic hepatitis B; however, the relationship between drug induced liver injury (DILI) and Th22/Th17 cells is still unclear. We investigated the role of Th22 cells in DILI development. METHODS: The frequencies of peripheral Th22/Th17/Th1 cells and intrahepatic IL-22/IL-17 production from DILI, non-DILI liver diseases, and healthy controls were examined. Plasma IL-22/IL-17 and the related cytokines were determined in DILI patients at week 0 (defined as the occurrence of liver injury within 7days), 4 and 24. Multivariable stepwise logistic regression was applied to explore the associations between various factors and recovery of DILI. RESULTS: The frequencies of Th22/Th17 cells were significantly higher in DILI onset patients than HC. Significant increase of Th22 cells and the related cytokines levels was observed in DILI with hepatocellular injury type. There was a positive correlation between intrahepatic IL-22 level and liver regeneration. Plasma IL-22 level was higher in DILI patients with improved liver function than unimproved function. Multivariable analysis showed that the odds ratio (OR) of plasma IL-22 at 4weeks was 1.054 [95% confidence interval (CI), 1.012, 1.124]. CONCLUSIONS: Increased peripheral and intrahepatic IL-22-secreting cells are detected in DILI. Th22 and its related cytokines might be hepato-protective, which might provide new perspective for understanding the immunopathogenesis of DILI. Plasma IL-22 might be a reliable indicator to evaluate the prognosis of DILI and provide a novel therapeutic target for DILI treatment.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Interleucinas/metabolismo , Hígado/metabolismo , Células Th17/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Estudios de Seguimiento , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Células Th17/metabolismo , Interleucina-22
18.
J Virol ; 88(3): 1484-91, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24227861

RESUMEN

Hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases. Progress in the HCV field was greatly enhanced by constructing infectious cDNA clone of JFH-1. Since then, JFH-1-based intra- and intergenotypic recombinants have been developed, and this permitted the study of vaccines and antiviral inhibitors for all genotypes. Recently, highly efficient HCV culture systems have been established by using consensus sequence-based clones. We developed a novel strategy to construct infectious HCV cDNA clone by combining functional screening of sequences directly from a genotype 2a clinical isolate (PR63) and cell culture adaptation. Using JFH-1 cDNA as the starting backbone, we sequentially replaced the JFH-1 fragments with a sequence from the pools of PR63 sequences. Through engineering adaptive mutations that improve HCV infectivity, we finally established a full-length cell culture-derived infectious clone of PR63, named PR63cc, that could efficiently produce virus particles in Huh7-derived cells, with peak titers of 1.6 × 10(5) focus-forming units/ml. The PR63cc could be neutralized by an anti-E2 antibody and inhibited by antiviral agents but appeared more resistant to an NS5A inhibitor than JFH-1. In summary, we developed a new approach to construct an infectious HCV cDNA clone that can produce viruses efficiently in cell culture. This approach could be applied to other viral isolates, with potential implications for individualized treatments of HCV patients.


Asunto(s)
Técnicas de Cultivo de Célula/métodos , Ingeniería Genética/métodos , Hepacivirus/fisiología , Hepatitis C/virología , Replicación Viral , Línea Celular Tumoral , ADN Complementario/genética , ADN Complementario/metabolismo , Hepacivirus/clasificación , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Humanos , Datos de Secuencia Molecular , Mutación , Filogenia , ARN Viral/genética , ARN Viral/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismo , Cultivo de Virus
20.
Cell Biosci ; 14(1): 90, 2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38971765

RESUMEN

Metabolic disorders are currently threatening public health worldwide. Discovering new targets and developing promising drugs will reduce the global metabolic-related disease burden. Metabolic disorders primarily consist of lipid and glucose metabolic disorders. Specifically, metabolic dysfunction-associated steatosis liver disease (MASLD) and alcohol-associated liver disease (ALD) are two representative lipid metabolism disorders, while diabetes mellitus is a typical glucose metabolism disorder. In this review, we aimed to summarize the new drug candidates with promising efficacy identified in clinical trials for these diseases. These drug candidates may provide alternatives for patients with metabolic disorders and advance the progress of drug discovery for the large disease burden.

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