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1.
Arch Toxicol ; 94(1): 245-256, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630224

RESUMO

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction. To date, identifying individuals at risk for IDILI remains challenging. This is a prospective study, where a nested case-control (1:5) design was adopted. For six patients who had abnormalities in liver function test after Polygonum multiflorum Thunb. (PM) ingestion (susceptible group), 30 patients with normal liver function were matched (tolerant group). Based on liquid chromatography-mass spectrometry, metabolomics analysis was done on serum samples prior to PM ingestion, to screen the differential metabolites and characterize metabolomic profiles of patient serum in the two groups. Multivariate analysis showed that there were remarkable separations between susceptible and tolerant groups. A total of 25 major differential metabolites were screened out, involving glycerophospholipid metabolism, sphingolipid metabolism, fatty acid metabolism, histidine metabolism and aromatic amino acid metabolism. Wherein, the area under the curve of the receiver operating characteristic curves of metabolites PE 22:6, crotonoyl-CoA, 2E-tetradecenoyl-CoA, phenyllactic acid, indole-5,6-quinone, phosphoribosyl-ATP were all greater than 0.9. The overall serum metabolic profile comprising of 25 metabolites could clearly distinguish susceptible and tolerant groups. This proof-of-concept study used metabolomics to characterize the metabolic profile of IDILI risk individuals before drug ingestion for the first time. The metabolome characteristics in patient serum before PM ingestion may predict the risk of liver injury after PM ingestion.

2.
J Cell Mol Med ; 23(3): 2032-2041, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30585398

RESUMO

Alcoholic liver disease (ALD) is a progressive liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Granulocytic myeloid-derived suppressor cell (gMDSC) populations have been observed to expand in various liver diseases and to inhibit innate and adaptive immunity in patients with liver disease. However, the characteristics of gMDSCs in patients with ALD have not been studied. We studied 24 healthy controls (HCs) and 107 patients with ALD and found an accumulation of gMDSCs in the peripheral blood of patients with alcoholic liver cirrhosis (ALC). Furthermore, ALC patients with a poor prognosis displayed a significant increase in peripheral gMDSCs and showed an increased capacity for arginase I production compared to HCs. In contrast, plasma arginase I levels in ALC patients were negatively correlated with total bilirubin and international normalized ratio, two key parameters of liver damage. Importantly, gMDSCs accumulated in the livers of ALC patients, and the frequency of liver gMDSCs significantly correlated with that of peripheral gMDSCs. In addition, gMDSC enrichment in vitro significantly inhibited the function of natural killer (NK) cells, perhaps preventing the NK-induced apoptosis of hepatic stellate cells. In summary, increased peripheral and intrahepatic gMDSC populations are present in patients with ALC and may contribute to enhancing the severity of liver cirrhosis.

3.
Medicine (Baltimore) ; 96(7): e6163, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28207552

RESUMO

Alcohol consumption in China has substantially increased over the last 3 decades and the number of patients with alcoholic liver disease (ALD) is rising at an alarming rate. However, accurate and representative data on time trends in its hospitalization rates are not available. The aim of this study is to assess the current status and burden of ALD in China by analyzing the data from a large tertiary referral hospital, Beijing 302 Hospital.Data were retrospectively recorded from patients diagnosed as ALD in Beijing 302 Hospital from 2002 to 2013. The disease spectrum and biochemical parameters of each patient were collected.The patients with ALD accounted for 3.93% (7422) of all patients (188,902) with liver diseases between 2002 and 2013. The number of patients hospitalized with ALD increased from 110 in 2002 to 1672 in 2013. The ratio of patients hospitalized with ALD to all patients hospitalized with liver diseases was rising almost continuously and increased from 1.68% in 2002 to 4.59% in 2013. Most patients with ALD were male. Age distribution of ALD hospitalization showed that the highest rate was in 40- to 49-year-old group in subjects. Notably, the annual proportion of severe alcoholic hepatitis (SAH) increased 2.43 times from 2002 to 2013. We found the highest levels of mean corpuscular volume, the aspartate aminotransferase/alanine aminotransferase ratio, total bilirubin, international normalized ratio, and alkaline phosphatase in SAH patients, while serum levels of hemoglobin, albumin, and cholinesterase were significantly decreased in SAH group. Among these ALD, the SAH patient population has the worst prognosis. Alcoholic cirrhosis (ALC) is the most common ALD, and annual admissions for ALC increased significantly during the analyzed period.The number of hospitalized patients with ALD and the annual hospitalization rate of ALD were increasing continuously in Beijing 302 Hospital from 2002 to 2013. More attention should be paid to develop population-based effective strategy to control ALD.


Assuntos
Hepatopatias Alcoólicas/epidemiologia , Hepatopatias Alcoólicas/fisiopatologia , Centros de Atenção Terciária/estatística & dados numéricos , Adulto , Distribuição por Idade , Alcoolismo/complicações , China , Feminino , Hepatite Alcoólica/epidemiologia , Hepatite Alcoólica/fisiopatologia , Humanos , Cirrose Hepática Alcoólica/epidemiologia , Cirrose Hepática Alcoólica/fisiopatologia , Hepatopatias Alcoólicas/etiologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Distribuição por Sexo
4.
J Ethnopharmacol ; 194: 299-306, 2016 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-27620661

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum L. is a famous traditional Chinese medicine that has always been perceived to be safe. Recently, the increasing case reports on hepatotoxicity induced by Raw P. multiflorum (RP) have attracted particular attention. However, the diagnosis and identification of RP-induced hepatotoxicity are still very difficult for its unknown mechanism and the lack of specific biomarkers. AIM OF THE STUDY: To further explore the toxicity and metabolic mechanisms involved in the hepatotoxicity induced by RP. MATERIALS AND METHODS: The hepatotoxicity induced by RP and its processed products (PP) (dosed at 20g/kg for 4 weeks) on rats were investigated using conventional approaches including the biochemical analysis and histopathological observations. Further, a urinary metabolomic approach was developed to study the metabolic disturbances caused by RP and PP, followed by the pattern recognition approach and pathways analysis. RESULTS: RP showed obvious hepatotoxity whereas PP did not. 16 potential biomarkers (pyridoxamine, 4-pyridoxic acid, citrate et al.) differentially expressed in RP group were identified compared with the control and PP-treated groups. The pathways analysis showed that vitamin B6 metabolism, tryptophan metabolism and citrate cycle might be the major enriched pathways involved in the hepatotoxicity of the herb. CONCLUSION: 16 differentially expressed metabolites were identified to be involved in the RP-induced hepatotoxicity. Vitamin B6 metabolism might be mostly related to the hepatotoxicity induced by RP. This finding may provide a potential therapeutic target or option to treat hepatotoxicity induced by RP.


Assuntos
Fígado/efeitos dos fármacos , Medicina Tradicional Chinesa/efeitos adversos , Metabolômica , Polygonum/química , Urinálise , Animais , Biomarcadores/metabolismo , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Fígado/lesões , Ratos , Espectrometria de Massas por Ionização por Electrospray
5.
J Gastroenterol Hepatol ; 31(8): 1476-82, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26896664

RESUMO

BACKGROUND AND AIM: Chinese herbal medicine (CHM), as well as Western medicine (WM), is an important cause of drug-induced liver injury (DILI). However, the differences between CHM and WM as agents implicated in liver injury have rarely been reported. METHODS: Overall, 1985 (2.05%) DILI cases were retrospectively collected from the 96 857 patients hospitalized because of liver dysfunction in the 302 Military Hospital between January 2009 and January 2014. RESULTS: In all the enrolled patients with DILI, CHM was implicated in 563 cases (28.4%), while 870 cases (43.8%) were caused by WM and the remaining patients (27.8%) by the combination of WM and CHM. Polygonum multiflorum was the major implicated CHM. Compared with WM, the cases caused by CHM showed more female (51 vs 71%, P < 0.001) and positive rechallenge (6.1 vs 8.9%, P = 0.046), a much greater proportion of hepatocellular injury (62.2 vs 88.5%, P < 0.001), and a higher mortality (2.8 vs 4.8%, P = 0.042); however, no differences in the rates of chronic DILI and ALF were found (12.9 vs 12.4%, P = 0.807; 7.6 vs 7.6%, P = 0.971). Based on Roussel Uclaf Causality Assessment Method, 75.6% of cases caused by CHM were classified as probable and only 16.6% as highly probable, significantly different from WM (38.4 and 60.3%, all P < 0.001). CONCLUSIONS: The causal relationship between CHM and liver injury is much complex, and the clinical characteristics of DILI caused by CHM differ from those caused by WM.


Assuntos
Doenças Biliares/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Medicamentos de Ervas Chinesas/efeitos adversos , Medicina Tradicional Chinesa/efeitos adversos , Pancreatopatias/induzido quimicamente , Adulto , Doenças Biliares/diagnóstico , Doenças Biliares/mortalidade , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/mortalidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatopatias/diagnóstico , Pancreatopatias/mortalidade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
6.
Expert Rev Gastroenterol Hepatol ; 10(3): 371-382, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26577047

RESUMO

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a model autoimmune disease with chronic cholestasis characterized by the hallmark of anti-mitochondrial antibodies and treated with ursodeoxycholic acid (UDCA). However, approximately 20-40% of patients incompletely respond to UDCA and have an increased risk of disease progression. Although there have been significant advances in the immunobiology of PBC, these have yet to be translated into newer therapeutic modalities. Current approaches to controlling the immune response include broad immunosuppression with corticosteroids as well as targeted therapies directed against T and B cells. In contrast, ameliorating cholestasis is the focus of other therapies in development, including obeticholic acid. In this article the authors will discuss ongoing clinical trials and, in particular, the rationale for choosing agents that may effectively target the aberrant immune response.


Assuntos
Sistema Biliar/efeitos dos fármacos , Colagogos e Coleréticos/uso terapêutico , Imunossupressores/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Animais , Ácidos e Sais Biliares/metabolismo , Sistema Biliar/imunologia , Sistema Biliar/metabolismo , Produtos Biológicos/uso terapêutico , Colagogos e Coleréticos/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/metabolismo , Transplante de Células-Tronco , Resultado do Tratamento
7.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 35(12): 1442-7, 2015 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-26882605

RESUMO

OBJECTIVE: To analyze hepatotoxicity of Polygonum multiflorum and clinical character- istics of drug-induced liver injury (DILI) caused by Polygonum multiflorum and its preparations. METHODS: A retrospective study was performed in 158 patients treated at 302 Military Hospital between January 2009 and January 2014. All of them had used Polygonum multiflorum and its preparations before the onset of DILI, and their clinical characteristics and prognoses were analyzed. RESULTS: Of the 158 DILI patients who used Polygonum multiflorum or its preparations, 92 (58.2%) combined with Western medicine or Chinese herbal preparations without Polygonum multiflorum; 66 patients (41.8%) used Polygonum mult florum and its preparations alone. In 66 DILI patients induced by Polygonum multiflorum or its preparations alone, 51 cases (77.3%) were induced by Polygonum multiflorum compounds and 22.7% by single Po- lygonum multiflorum; 4 cases (6.1%) were caused by crude Polygonum multiflorum and 62 (93.9%) by processed Polygonum multiflorum and its preparations. Clinical injury patterns were hepatocellular 92.4% (61 cases), cholestatic 1.5% (1 case), and mixed 6.1% (4 cases). Pathological examination was per- formed by liver biopsy in 32 cases (48.15%), manifested as hepatocellular degeneration and necrosis, fibroplasia, Kupffer cells with pigment granule, and a large number of eosinophil infiltration, were ob- served. Four patients were developed into liver failure, 4 into cirrhosis, and 1 died. CONCLUSION: Polygo- num multiflorum and its preparations could induce DILI, but clinical diagnosis of Polygonum multiflorum induced hepatotoxicity should be cautious.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Fallopia multiflora , Preparações de Plantas/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Colestase , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Cirrose Hepática , Falência Hepática , Polygonum , Estudos Retrospectivos
8.
J Proteome Res ; 13(8): 3792-3801, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24940827

RESUMO

Autoimmune hepatitis (AIH) is often confused with other liver diseases because of their shared nonspecific symptoms and serological and histological overlap. This study compared the plasma metabolomic profiles of patients with AIH, primary biliary cirrhosis (PBC), PBC/AIH overlap syndrome (OS), and drug-induced liver injury (DILI) with those of healthy subjects to identify potential biomarkers of AIH. Metabolomic profiling and biomarker screening were performed using proton nuclear magnetic resonance spectroscopy (1H NMR) coupled with a partial least-squares discriminant analysis. Compared with the levels in healthy volunteers and other liver disease patients, AIH patients exhibited relatively high levels of plasma pyruvate, lactate, acetate, acetoacetate, and glucose. Such metabolites are typically related to energy metabolism alterations and may be a sign of metabolic conversion to the aerobic glycolysis phenotype of excessive immune activation. Increased aromatic amino acids and decreased branched-chain amino acids were found in the plasma of AIH patients. The whole NMR profiles were stepwise-reduced, and nine metabolomic biomarkers having the greatest significance in the discriminant analysis were obtained. The diagnostic utility of the selected metabolites was assessed, and these biomarkers achieved good sensitivity, specificity, and accuracy (all above 93%) in distinguishing AIH from PBC, DILI, and OS. This report is the first to present the metabolic phenotype of AIH and the potential utility of 1H NMR metabolomics in the diagnosis of AIH.

9.
Zhongguo Zhong Yao Za Zhi ; 39(1): 5-9, 2014 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-24754159

RESUMO

Recently traditional Chinese medicine (TCM)-induced liver injury has been an unresolved critical issue which impacts TCM clinical safety. The premise and key step to reduce or avoid drug-induced liver injury (DILI) is to identify the drug source of liver injury in early stage. Then the timely withdrawal of drug and treatment can be done. However, the current diagnosis of DILI is primarily governed by exclusive method relying on administering history supplied by patients and experience judgment from doctors, which lacks objective and reliable diagnostic indices. It is obvious that diagnosis of TCM-induced liver injury is especially difficult due to the complicated composition of TCM medication, as well the frequent combination of Chinese and Western drugs in clinic. In this paper, we proposed construction of research pattern and method for objective identification of TCM-related DILI based on translational toxicology, which utilizes clinical specimen to find specific biomarkers and characteristic blood-entering constituents, as well the clinical biochemistry and liver biopsy. With integration of diagnosis marker database, bibliographic database, medical record database and clinical specimen database, an integrative diagnosis database for TCM-related DILI can be established, which would make a transformation of clinical identification pattern for TCM-induced liver injury from subjective and exclusive to objective and index-supporting mode. This would be helpful to improve rational uses of TCM and promote sustainable development of TCM industry.


Assuntos
Biomarcadores Farmacológicos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Medicina Tradicional Chinesa/efeitos adversos , Animais , Biópsia/métodos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Diagnóstico Precoce , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Ratos
10.
Mol Cells ; 37(1): 66-73, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24552712

RESUMO

Myeloid-derived suppressor cells (MDSCs) play an important role in impairing the function of T cells. We characterized MDSCs in two chronic hepatitis C (CHC) cohorts: a cross-sectional group that included 61 treatment-naive patients with CHC, 14 rapid virologic response (RVR) cases and 22 early virologic response (EVR) cases; and a longitudinal group of 13 cases of RVR and 10 cases of EVR after pegylated-interferon-α/ribavirin treatment for genotype 1b HCV infection. Liver samples from 32 CHC patients and six healthy controls were subjected to immunohistochemical analysis. MDSCs frequency in treatment-naive CHC was significantly higher than in RVR, EVR, or healthy subjects and was positively correlated with HCV RNA. Patients infected with HCV genotype 2a had a significantly higher frequency of MDSCs than those infected with genotype 1b. Decreased T cell receptor (TCR) ζ expression on CD8(+) T cells was significantly associated with an increased frequency of MDSCs in treatment-naive CHC patients and was restored by L-arginine treatment in vitro. Increased numbers of liver arginase-1(+) cells were closely associated with the histological activity index in CHC. The TCR ζ chain was significantly downregulated on hepatic CD8(+) T cells in CHC. During antiviral follow up, MDSCs frequency in peripheral blood mononuclear cells was directly correlated with the HCV RNA load in the plasma and inversely correlated with TCR ζ chain expression in CD8(+) T cells in both RVR and EVR cases. Notably, the RVR group had a higher frequency of MDSCs at baseline than the EVR group. Collectively, this study provides evidence that MDSCs might be associated with HCV persistence and downregulation of CD8 ζ chain expression.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Células Mieloides/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto , Idoso , Antivirais/uso terapêutico , Arginase/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Estudos de Casos e Controles , Feminino , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Células Mieloides/virologia , RNA Viral/sangue , Carga Viral , Adulto Jovem
11.
Cell Mol Immunol ; 9(5): 417-22, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22231552

RESUMO

Acute-on-chronic liver failure (ACLF) is a severe life-threatening complication. Liver transplantation is the only available therapeutic option; however, several limitations have restricted its use in patients. The use of corticosteroids as an optional therapy for ACLF has received a great deal of interest. The rationale behind its use is the possible role of the immune system in initiating and perpetuating hepatic damage. In order to assess the relationship between myeloid dendritic cells (mDCs) and the efficacy of methylprednisolone (MP) treatment for hepatitis B virus (HBV)-associated ACLF patients, we recruited 30 HBV-associated ACLF patients who had received MP treatment at 10-day intervals; 26 patients received conservative medical (CM) management as a control. The functionality of DC subsets was lower in these ACLF patients compared with healthy subjects. In addition, compared with survivors, dead/transplanted patients had lower functional mDC in both groups. Furthermore, a decreased numbers of mDC at baseline was associated with high mortality of ACLF patients. Importantly, MP treatment resulted in a significant decrease in 28-day mortality, and all MP patients exhibited an initial rapid decrease in circulating mDC numbers within 10 days of MP treatment. Subsequently, MP survivors displayed a continuous increase in mDC numbers accompanied by a decrease in total bilirubin levels by more than 30%. However, MP dead/transplanted patients lacked these sequential responses compared with survivors. This evidence suggests strongly that the higher mDC numbers at baseline and the recovery of mDC number at the end of treatment may represent a prognostic marker for favorable response to corticosteroid treatment in ACLF patients.


Assuntos
Células Dendríticas/metabolismo , Doença Hepática Terminal/tratamento farmacológico , Doença Hepática Terminal/mortalidade , Glucocorticoides/uso terapêutico , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/mortalidade , Metilprednisolona/uso terapêutico , Células Mieloides/metabolismo , Adulto , Estudos de Casos e Controles , Células Dendríticas/patologia , Doença Hepática Terminal/etiologia , Feminino , Hepatite B Crônica/complicações , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Células Mieloides/patologia
12.
PLoS One ; 6(3): e17484, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21390263

RESUMO

BACKGROUND: Extensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages. METHODOLOGY/PRINCIPAL FINDINGS: The frequencies, phenotypes, and functions of peripheral blood and intrahepatic monocyte/macrophage subsets were analyzed in 110 HBeAg positive CHB patients, including 32 immune tolerant (IT) carriers and 78 immune activated (IA) patients. Liver biopsies from 20 IA patients undergoing diagnosis were collected for immunohistochemical analysis. IA patients displayed significant increases in peripheral blood monocytes and intrahepatic macrophages as well as CD16(+) subsets, which were closely associated with serum alanine aminotransferase (ALT) levels and the liver histological activity index (HAI) scores. In addition, the increased CD16(+) monocytes/macrophages expressed higher levels of the activation marker HLA-DR compared with CD16(-) monocytes/macrophages. Furthermore, peripheral blood CD16(+) monocytes preferentially released inflammatory cytokines and hold higher potency in inducing the expansion of Th17 cells. Of note, hepatic neutrophils also positively correlated with HAI scores. CONCLUSIONS: These distinct properties of monocyte/macrophage subpopulations participate in fostering the inflammatory microenvironment and liver damage in CHB patients and further represent a collaborative scenario among different cell types contributing to the pathogenesis of HBV-induced liver disease.


Assuntos
Hepatite B Crônica/imunologia , Inflamação/imunologia , Cirrose Hepática/imunologia , Fígado/patologia , Monócitos/imunologia , Receptores de IgG/metabolismo , Índice de Gravidade de Doença , Adolescente , Adulto , Proliferação de Células , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/complicações , Humanos , Inflamação/complicações , Fígado/imunologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Células Th17/citologia , Células Th17/imunologia , Adulto Jovem
13.
Hepatology ; 51(1): 81-91, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19842207

RESUMO

UNLABELLED: Interleukin-17 (IL-17)-producing CD4(+) T cells (Th17)-mediated immune response has been demonstrated to play a critical role in inflammation-associated disease; however, its role in chronic hepatitis B virus (HBV) infection remains unknown. Here we characterized peripheral and intrahepatic Th17 cells and analyzed their association with liver injury in a cohort of HBV-infected patients including 66 with chronic hepatitis B (CHB), 23 with HBV-associated acute-on-chronic liver failure (ACLF), and 30 healthy subjects as controls. The frequency of circulating Th17 cells increased with disease progression from CHB (mean, 4.34%) to ACLF (mean, 5.62%) patients versus healthy controls (mean, 2.42%). Th17 cells were also found to be largely accumulated in the livers of CHB patients. The increases in circulating and intrahepatic Th17 cells positively correlated with plasma viral load, serum alanine aminotransferase levels, and histological activity index. In vitro, IL-17 can promote the activation of myeloid dendritic cells and monocytes and enhance the capacity to produce proinflammatory cytokines IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-23 in both CHB patients and healthy subjects. In addition, the concentration of serum Th17-associated cytokines was also increased in CHB and ACLF patients. CONCLUSION: Th17 cells are highly enriched in both peripheral blood and liver of CHB patients, and exhibit a potential to exacerbate liver damage during chronic HBV infection.


Assuntos
Linfócitos T CD4-Positivos/patologia , Hepatite B Crônica/patologia , Interleucina-17/biossíntese , Adolescente , Adulto , Células Dendríticas/imunologia , Feminino , Hepatite B Crônica/imunologia , Humanos , Fígado/citologia , Fígado/imunologia , Masculino , Pessoa de Meia-Idade
14.
J Hepatol ; 49(3): 396-406, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18644645

RESUMO

BACKGROUND/AIMS: Functionally impaired dendritic cells (DCs) play important roles in suppressing host immune responses and facilitating viral persistence in chronic hepatitis B virus (HBV) infection. However, little is known regarding the status of intrahepatic DCs in HBV infection. METHODS: Based on availability, 11 recipient liver samples were obtained from acute-on-chronic hepatitis B liver failure (ACHBLF) patients who had undergone liver transplantation. The frequencies, phenotypes, and functions of intrahepatic DC subsets were analyzed. RESULTS: Both plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) extensively infiltrated the liver of the ACHBLF patients and expressed mature phenotypes therein. In particular, activated hepatic pDCs produced interferon (IFN)-alpha, which subsequently induced interleukin (IL)-12 and IL-10 production via toll-like receptor-9 ligation in liver-infiltrating lymphocytes cultured in vitro. However, blockade of IFN-alpha production significantly reduced the cytokine production of the LILs. Further, a significantly low frequency of peripheral pDCs and highly reduced IFN-alpha production were observed in a large cohort of the ACHBLF patients, particularly in the non-survivors. Moreover, a persistently upregulated expression of hepatic IFN-alpha-associated genes was observed in the ACHBLF patients during disease progression. CONCLUSIONS: Activated pDCs accumulated in large numbers in the liver of the ACHBLF patients and regulated local immune responses in chronic HBV infection.


Assuntos
Células Dendríticas/patologia , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Falência Hepática Aguda/patologia , Falência Hepática Aguda/virologia , Fígado/patologia , Adulto , Idoso , Estudos de Casos e Controles , Contagem de Células , Células Dendríticas/metabolismo , Progressão da Doença , Feminino , Humanos , Interferon-alfa/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Lectinas Tipo C/metabolismo , Fígado/metabolismo , Fígado/cirurgia , Transplante de Fígado , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Receptores Imunológicos/metabolismo
15.
Gastroenterology ; 134(7): 1938-49, 1949.e1-3, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18455515

RESUMO

BACKGROUND & AIMS: Recent studies have shown that programmed death 1 (PD-1) expression can impair virus-specific CD8 T-cell responses during chronic viral infection, including hepatitis B virus (HBV). This study aimed to characterize the PD-1 expression during acute hepatitis B (AHB) and further address whether and how the PD-1-mediated pathway balances antiviral immunity versus immunopathology, possibly contributing to disease progression. METHODS: Peripheral and intrahepatic PD-1 expression was investigated longitudinally in 23 human HLA-A2-positive patients with acute hepatitis B. Four patients with HBV-related acute liver failure, 13 patients with chronic hepatitis B, and 9 healthy individuals were enrolled as controls. Flow cytometric, immunohistochemical, and immunofunctional assays were performed to analyze the impact of PD-1 expression. RESULTS: PD-1 expression was significantly up-regulated on HBV-specific CD8 T cells in the early phase of acute HBV infection, and successful viral clearance correlated with a subsequent decrease in PD-1 expression. Blocking the PD-1-mediated pathway in vitro enhanced HBV-specific CD8 T-cell proliferation and inflammatory cytokine production, while reducing interleukin-10 production and apoptosis, confirming the essential role of PD-1 in tempering the T-cell response during the acute phase of infection. In contrast, delayed PD-1 expression on HBV-specific CD8 T cells was associated with acute liver failure. CONCLUSIONS: PD-1 up-regulation may efficiently mitigate pathogenic CD8 T-cell responses and liver damage, correlating with disease progression of acute HBV infection. This study therefore shows how this negative signaling pathway functions in such early HBV infection, which will be important for better clinical management, prognosis, and new HBV treatments.


Assuntos
Antígenos CD/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Linfócitos T CD8-Positivos/virologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/imunologia , Hepatite B/imunologia , Falência Hepática/virologia , Fígado/virologia , Doença Aguda , Adulto , Antígenos CD/sangue , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/sangue , Antígeno B7-H1 , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Proliferação de Células , Citocinas/metabolismo , Progressão da Doença , Feminino , Citometria de Fluxo , Antígeno HLA-A2/metabolismo , Hepatite B/complicações , Hepatite B/patologia , Hepatite B/terapia , Hepatite B Crônica/complicações , Hepatite B Crônica/patologia , Hepatite B Crônica/terapia , Humanos , Imuno-Histoquímica , Fígado/imunologia , Fígado/patologia , Falência Hepática/imunologia , Falência Hepática/patologia , Estudos Longitudinais , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1 , Transdução de Sinais/imunologia , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima , Carga Viral
16.
Zhonghua Yi Xue Za Zhi ; 87(34): 2416-9, 2007 Sep 11.
Artigo em Chinês | MEDLINE | ID: mdl-18036321

RESUMO

OBJECTIVE: To investigate the frequencies of immunologically competent cells (ICCs) in the liver-infiltrating lymphocytes (LILs) and peripheral blood and their possible role in pathogenesis in patients with chronic severe hepatitis B (CSHB). METHODS: LILs were isolated from the liver tissue samples from 11 CSHB patients and 5 normal controls (NCs) by the method of combined grinding with semi-frosted microscopic slides and sedimentation of hepatic cells. The frequency of isolated ICCs, including CD3(+), CD4(+), and CD8(+) T-cells, NK cells, NKT cells, and B cells was examined and compared with that of the circulating ICCs in the CSHB patients. Comparison was conducted between the CSHB patients and the controls. RESULTS: (1) In the CSHB patients, the frequencies of CD4(+) T cells and B cells in LILs were 17% +/- 6% and 3.0% +/- 1.0% respectively, both significantly lower than those in the circulating blood (32% +/- 8% and 21.4% +/- 12.2% respectively, both P < 0.01); however, the frequencies of CD8(+) T cells, NK cells, and NKT cells in LILs were 38% +/- 13%, 34% +/- 18%, and 10% +/- 4% respectively, all significantly lower than those in the circulating blood (26% +/- 6%, 15% +/- 9%, and 6% +/- 4%, all P < 0.05). (2) The frequencies of infiltrating CD3(+) T cells and CD4(+) T cells of the CSHB patients were both significantly higher than those of the NCs (P = 0.042 and P = 0.001); and the frequency of infiltrating CD8(+) T cells of the CSHB patients was higher than that of the NCs, and the and the frequencies of infiltrating NK cells and NKT cells in LILs were lower than those of the NCs, however, not significantly. (3) Compared with the liver tissues from the NCs, the liver tissues from the CSHB patients exhibited a significantly higher ratio of liver-infiltrating CD4(+) T cells to peripheral blood CD4(+) T-cell subsets (P = 0.001), and significantly lower ratios of liver-infiltrating NKT cells and B cells to the peripheral blood NKT-cells and B cells (P = 0.029 and P = 0.001 respectively). CONCLUSION: The abundant infiltrating immune active cells, especially the CD4(+) T cells, CD8(+) T cells, and NK cells, may be the causal factors that drive the progressive development of CSHB.


Assuntos
Hepatite B Crônica/imunologia , Fígado/imunologia , Linfócitos/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos B/patologia , Relação CD4-CD8 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Hepatite B Crônica/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Fígado/patologia , Transplante de Fígado , Contagem de Linfócitos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/patologia
18.
Artigo em Chinês | MEDLINE | ID: mdl-16261212

RESUMO

OBJECTIVE: To investigate the relation of the viral markers in serum and those expressed by hepatocytes to pathological lesions of hepatic tissue in patients with chronic hepatitis B. METHODS: The relation of viral markers including HBsAg, HBsAb, HBeAg, HBeAb, HBcAb and HBV DNA in serum of 647 patients with chronic hepatitis B and HBsAg, HBcAg expressed by hepatocytes in 418 of these patients to pathological lesions of hepatic tissue was determined. RESULTS: Viral markers in serum and those expressed by hepatocytes in patients with chronic hepatitis B were closely correlated with pathological lesions of hepatic tissue. CONCLUSION: The degree of inflammation and fibrosis in hepatic tissue is milder in serum HBsAg, HBeAb, HBcAb positive and HBV DNA negative patients but more serious in those with negative hepatocytic expression of HBsAg and HBcAg. HBV DNA is not significantly associated with pathological lesions of hepatic tissue.


Assuntos
Vírus da Hepatite B/fisiologia , Hepatite B Crônica/sangue , Hepatite B Crônica/patologia , Fígado/patologia , Adolescente , Adulto , Criança , Pré-Escolar , DNA Viral/sangue , DNA Viral/genética , Feminino , Antígenos do Núcleo do Vírus da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/virologia , Interações Hospedeiro-Patógeno , Humanos , Lactente , Recém-Nascido , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Artigo em Chinês | MEDLINE | ID: mdl-12870029

RESUMO

BACKGROUND: To investigate the correlation of clinical features with pathology in chronic viral hepatitis (CH). METHODS: Analyses of single factor and multiple factors of serum biochemical indices, imaging examination results, symptoms and signs with degree of pathological lesion of hepatic tissue in 973 cases of CH were conducted. Meanwhile, the hepatic functional index (AAPEA index) was used to investigate the role of serum biochemical indices in diagnosis of CH. RESULTS: In these patients with CH,the severity of hepatic lesion was closely correlated to symptoms and signs, biochemical indices such as PTA, ALT, TBIL, ALB, A/G, gamma-globulin (gamma-G) by electrophoresis, AST and cholinesterase (CHE) as well as splenic thickness. AST was superior to ALT in reflecting degree of hepatic inflammatory activity. The total mistaken judgment rate of multiple factor analysis was 28.1%. The correlation coefficient of AAPEA index to degrees of hepatic inflammatory activity, fibrosis and pathological grading was 0.559, 0.545 and 0.529, respectively (P<0.000 1) CONCLUSIONS: The biochemical indices such as PTA, ALT, TBIL, ALB, A/G, gammaG, AST, CHE and the determination of splenic thickness by ultrasonography B could reflect hepatic pathological changes to certain extent. AST was superior to ALT in reflecting degree of hepatic inflammatory activity. Incorrect judgment rate was high in determination of moderate and severe CH by multiple factor analysis. Conformity rate between AAPEA index and pathological diagnosis was better than any of them alone in diagnosing CH.


Assuntos
Hepatite B Crônica/patologia , Hepatite C Crônica/patologia , Fígado/patologia , Adolescente , Adulto , Idoso , Biópsia por Agulha Fina , Criança , Pré-Escolar , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/diagnóstico , Hepatite C Crônica/sangue , Hepatite C Crônica/diagnóstico , Humanos , Lactente , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Baço/diagnóstico por imagem , Ultrassonografia
20.
Artigo em Chinês | MEDLINE | ID: mdl-15340576

RESUMO

BACKGROUND: To investigate the prognostic significance and role of coagulation factor V (CFV) levels in clinical diagnostic criteria for severe hepatitis. METHODS: The CFV level and prothrombin activity (PTA) were tested by turbidimetry for 129 times in 58 patients with severe hepatitis. Comparative studies and clinical significance of CFV and PTA were analyzed by SPSS and SDAS softwares. RESULTS: 1. The levels of CFV and PTA were 15.3%+/-9.7% and 23.5%+/-10.0%, respectively, at the onset of severe hepatitis. 2. The mortality of severe hepatitis gradually increased with the gradual decrease of CFV or PTA during the most severe stage of the illness (P=0.000). 3. The levels of CFV and PTA decreased continually and rapidly in patients who died but gradually increased in survivors. The decrease or increase of PTA preceded that of CFV on the exacerbation or convalescent stage. 4. Hepatic encephalopathy occurred in 14 cases (24.14%). In 10 cases, it occurred in the terminal stage of the illness, far later than the time of the decrease of CFV. 5. The level of CFV was closely related to PTA (the correlation coefficient was 0.812), the level of CFV was almost consistent with that of PTA. CONCLUSION: 1. The level of CFV is an important prognostic indicator in severe hepatitis and is more specific than PTA. 2. Simultaneous determination of CFV and PTA may be helpful in earlier and more accurate diagnosis of severe hepatitis. 3. Possible use of CFV as one of the criteria for liver transplantation in patients with severe hepatitis should be studied.


Assuntos
Técnicas e Procedimentos Diagnósticos , Fator V/análise , Hepatite/diagnóstico , Nefelometria e Turbidimetria/métodos , Adulto , Idoso , Fator V/metabolismo , Feminino , Hepatite/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Protrombina/análise , Protrombina/metabolismo , Adulto Jovem
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