Changes in the Cytokine Profiles of Patients with Chronic Hepatitis B during Antiviral Therapy

Objective To investigate the changes in the cytokine profiles of chronic hepatitis B(CHB)patients undergoing antiviral treatment.Methods Hepatitis B e antigen(HBeAg)-positive patients were treated with Pegylated interferon(PEGIFN)and entecavir(ETV).Clinical biochemistry and cytokines were detected at baseline and every 3 months.Results In all,200 patients completed 48 weeks of treatment,100 in the PEG-IFN group and 100 in the ETV group.During 3–6 months of treatment,compared with baseline,the PEG-IFN group showed a significant decrease in interferon-gamma(IFN-γ),interleukin-17 A(IL-17 A),interleukin-6(IL-6),interleukin-10(IL-10),and transforming growth factor beta(TGF-β)(P<0.001)and a significant increase in interferon-alpha 2(IFN-α2)(P<0.001).In the ETV group,IL-10 and TGF-β1 decreased significantly(P<0.001).After 3 months,the levels of IFN-α2,IL-17 A,and tumor necrosis factor-alpha(TNF-α)in the PEGIFN group were significantly higher than those in the ETV group(P<0.01).The levels of IL-6 and TGF-β3 were significantly lower than those in the ETV group(P<0.01).After 6 months,the levels of IFN-α2,IFN-γ,and TNF-αin the PEG-IFN group were significantly higher than those in the ETV group(P<0.01),while the levels of IL-6 and TGF-β3 were significantly lower than those in the ETV group(P<0.01).Compared with ETV,PEG-IFN had higher HBeAg and HBsAg disappearance rates.Conclusion During antiviral therapy,a change in the cytokine profile occurred;in the aspect of immune control and functional cure,PEG-IFN was significantly better than ETV.

Serum cytokine levels in chronic hepatitis B patients receiving peginterferon alpha-2a therapy

BACKGROUND: The relationship between cytokines and responses to peginterferon α-2a treatment in chronic hepatitis B patients has not yet been fully elucidated. We analyzed the serum levels of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor, interferon-γ, tumor necrosis factor-α, monocyte chemotactic protein-1 (MCP1) and epidermal growth factor during the treatment with peginterferon α-2a. METHODS: Ninety-three serum samples from 20 chronic hepatitis B patients were collected before, during and after 48 weeks of peginterferon therapy and were assayed for 12 cytokines. The patients were categorized as either virologic responders (VRs) or non-responders (NRs) according to their HBV DNA levels taken at 6th month during treatment. The Evidence Investigator (Randox, Antrim, UK), a protein chip analyzer, was used to quantify cytokines. RESULTS: Among the 12 cytokines, the levels of MCP1 were increased and the levels of IL-4 were decreased during the treatment in VRs. However these cytokines were not significantly changed in NRs in the treatment phases. Area under the receiver operating characteristic curve (AUROC) value of HBV DNA measured before the treatment was 0.81 in predicting VRs, and that of the baseline MCP1 was 0.76. IL-6 levels at 3rd and 6th months during the treatment also showed AUROC values 0.85 and 0.78 respectively in predicting sustained VRs. CONCLUSION: Serum cytokine levels reflect the pathological differences of individual treatment phases and could also be useful in monitoring responses to peginterferon treatment in chronic hepatitis B patients.

Cytokine Profiles and Virological Marker Monitoring during 48 Weeks Peginterferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B

Objective This study aimed to investigate whether cytokine profiles and virological markers might add value in monitoring the effects of peginterferon(PEG-IFN)therapy for hepatitis B e-antigen(HBeAg)positive chronic hepatitis B(CHB).Methods HBeAg positive patients with CHB were treated with PEG-IFN for 48 weeks.Clinical biochemical,and HBV serological indexes,as well as cytokines,were detected at baseline and every12 weeks.Results A total of 116 patients with CHB were enrolled in this study;100 patients completed the 48-week treatment and follow-up,of whom 38 achieved serum HBeAg disappearance,25 achieved HBeAg seroconversion,37 showed HBsAg decreases≥1 log10 IU/mL,9 showed HBsAg disappearance,and 8became HBsAb positive.The cytokine levels at baseline and during treatment were similar between the HBeAg disappearance group and non-disappearance group.The disappearance of HBeAg was independently associated with HBeAg levels at weeks 12 and 24,and with the HBeAg decline at week 24(P<0.05).The HBsAg response was independently associated with HBsAg,the HBsAg decline,HBeAg,the HBeAg decline at week 12,and HBsAg at week 24(P<0.05).Conclusion There was no significant correlation between the response to interferon(IFN)and cytokines during PEG-IFN treatment.The changes in virological markers predicted the response to IFN after 48 weeks.

Cytokines predict virological response in chronic hepatitis B patients receiving peginterferon alfa-2a therapy

BACKGROUND Chronic hepatitis B virus infection remains a major global public health problem.Peginterferon-alpha-2a(PEG-IFN)has direct antiviral and immunoregulatory effects,and it has become one of the first choice drugs for the treatment of chronic hepatitis B(CHB).Cytokines play an important role in immunity,and they directly inhibit viral replication and indirectly determine the predominant pattern of the host immune response.AIM To determine the correlation between cytokine/chemokine expression levels and response to PEG-IFN treatment in patients with CHB.METHODS Forty-six kinds of cytokines were analyzed before PEG-IFN therapy and at 24 wk during therapy in 26 CHB patients.RESULTS The monokine induced by INF-γ(CXCL9)and serum interferon-inducible protein 10(IP-10)levels at baseline were higher in virological responders than in nonvirological responders(NRs)and decreased during treatment,whereas the NRs did not exhibit significant changes.The macrophage inflammatory protein 1d(MIP-1d)levels at baseline and during treatment were significantly higher in the virological responders than in the NRs,while thymus and activation-regulated chemokine(TARC)levels at baseline and during treatment were significantly lower in the virological responders than in the NRs.The CXCL9,IP-10,MIP-1d,and TARC baseline levels exhibited the expected effects for interferon treatment.The area under the receiver operating characteristic curve values of CXCL9,IP-10,MIP-1d,and TARC for predicting virological responses were 0.787,0.799,0.787,and 0.77(P=0.01,0.013,0.01,and 0.021),respectively.CONCLUSION We found that cytokine levels before and during treatment may represent potential biomarkers to select CHB patients who can respond to PEG-IFN.Therefore,cytokines can be used as an indicator of antiviral drug selection before CHB treatment.

Relationship between cytokine gene polymorphisms and chronic hepatitis B virus infection

Hepatitis B virus (HBV) infection is still a public health problem worldwide, being endemic in some parts of the world. It can lead to serious liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular cancer. The differences in host immune response can be one of the reasons for the various clinical presentations of HBV infection. Polymorphisms of genes encoding the proinflammatory and antiinflammatory cytokines, which are responsible for regulation of the immune response, can affect the clinical presentation of the infection. Particularly, the polymorphisms of the genes encoding cytokines such as interleukin (IL)-1, IL-6, IL-8, IL-10, IL-18, IL-28B, interferon-&#x003b3;, tumor necrosis factor-&#x003b1;, tumor growth factor-&#x003b2;1, and regulatory molecules like vitamin D receptor and chemokine receptor 5 can be responsible for different clinical presentations of HBV infections. The genomic information about cytokines and other mediators can be important for determining high-risk people for developing chronic hepatitis or hepatocellular cancer and may be used to plan treatment and preventive approaches for these people. In this review, the current knowledge in the literature on the association between cytokine/regulatory molecule gene polymorphisms and clinical course of chronic HBV infection is summarized, and the clinical implementations and future prospects regarding this knowledge are discussed.

He Jie Tang in the treatment of chronic hepatitis B patients

AIM： To explore the effect of He .lie Tang （decoction for medication） on serum levels of T lymphocyte subsets, NK cell activity and cytokines in chronic hepatitis B patients. METHODS： Eighty-five patients with chronic hepatitis B were divided randomly into two groups. Fifty patients in group I were treated with He .lie Tang （HIT） and 35 patients in group II were treated with combined medication. The levels of T-lymphocyte subsets （CD^3＋, CD^4＋, CD^8＋）, NK cell activity, cytokines （TNF-α, IL-8, sIL-2R） were observed before and after the treatment. Another 20 normal persons served as group 3. RESULTS： The level of CD^4＋ cells and NK cell activity were lower, whereas the level of CD^8＋ cells in patients was higher than that in normal persons （t = 2.685, 3.172, and 2.754 respectively; P〈0.01）. The levels of TNF-α, IL-8, and sIL-2R in chronic hepatitis B patients were higher than those in normal persons （t = 3.526, 3.170, and 2.876 respectively; P〈0.01）. After 6 months of treatment, ALT, AST, and TB levels in the two groups were obviously decreased （t = 3.421, 3.106, and 2.857 respectively; P〈0.01）. The level of CD^4＋ cells and NK cell activity were increased whereas the level of CD^8＋ cells decreased （t = 2.179, 2.423, and 2.677 respectively; P〈0.05） in group I. The levels of TNF-α, IL-8, and sIL- 2R in group I were decreased significantly after the treatment （t = 2.611, 2.275, and 2.480 respectively; P〈0.05） but had no significant difference in groupII after the treatment （t = 1.906, 1.833, and 2.029 respectively; P〉0.05）. The total effective rate had no significant difference between the two groups （X^2 = 2.882, P〉0.05） but the markedly effective rate was significantly different between the two groups （X^2 = 5.340, P〈0.05）. CONCLUSION： HIT is effective in treating chronic hepatitis B. HIT seems to exert its effect by improving the cellular immune function and decreasing inflammatory cytokines in chronic hepatitis B patients. The function of HIT in protecting liver function in the process of eliminating virus needs to be further studied.

Expression of SOCS-1 in the liver tissues of chronic hepatitis B and its clinical significance

AIM： To study the expression of suppressor of cytokine signaling-1 （SOCS-1） in the liver tissues of chronic hepatitis 13 （CHB） and the clinical significance of this expression. METHODS： The expression of SOCS-1 in liver tissues of 45 cases of CHB was investigated by immunohistochemical staining, and its correlations with inflammation grades and fibrosis stage were analyzed by SPSS statistics software. RESULTS： The result showed SOCS-1 expressing could be observed in the liver tissue of CriB. The expression of SOCS-1 was mainly distributed near the portal area in the liver tissue of mild inflammation CriB group, and was diffusely distributed in the liver tissue of moderate and severe inflammation groups. SOCS-1 positive stains mainly appear in the hepatocytes, only a few of liver interstitial cells were involved. Inside the hepatocyte, SOCS-1 positive stains are mainly distributed in the plasma. Some of the staining was observed on the membrane. The inclusion bodies in the plasma of hepatocytes were observed occasionally. There were both obvious correlations between the expression of SOCS-1 and the inflammatory grade, and that between the expression of SOCS-1 and the fibrosis stage, CONCLUSION： The distribution of SOCS-1 in the liver tissue of CriB is variable. This expression was correlated with the inflammation grade and fibrosis stage.

The Pathogenesis of Acute on Chronic Hepatitis B liver Failure

Acute-on-chronic liver failure is a characteristic clinical liver syndrome, which should be differentiated from acute liver failure, acute decompensated liver cirrhosis and chronic liver failure. The pathogenesis of ACLF is not fully understood yet. Viral factors and immune injury have been reported to be the two major pathogenesis. This paper reviewed the researches on the pathogenesis of acute on chronic hepatitis B liver failure in recent years, to provide theoretical basis for prompt and accurate diagnosis and treatment of this syndrome. This would benefit for the prognosis and raise the survival rate of patients.

Pegylated interferon α-2b up-regulates specific CD8+ T cells in patients with chronic hepatitis B

AIM:To investigate the effect of pegylated interferon (IFN) α-2b on specific CD8+ T lymphocytes in patients with chronic hepatitis B (CHB). METHODS:Twenty-one patients with CHB were treated with pegylated IFN α-2b. Periphery blood mononuclear cells were isolated from fresh heparinized blood by Ficoll-Hypaque density gradient centrifugation (density:1.077 g/L,Pharmingen) at weeks 0,4,8,12,and 24,respectively. Frequency of circulating hepatitis B virus (HBV) epitope-specific CD8 T cells was detected by flow cytometry. Cytokines were detected by cytometric bead assay. RESULTS:The frequency of circulating HBV core or env-specific CD8 T cells was higher (P < 0.05),the number of HBV core specific CD8 T cells was greater at week 24 (P < 0.05),the level of Th1-type cytokines [interleukin (IL)-12,tumor necrosis factor-α,and IFN-γ] was higher,while that of Th2-type cytokines (IL-4,IL-6,and IL-10) was lower in responders than in nonresponders (P < 0.05) after pegylated IFN α-2b treatment. The IL-6 level was correlated with HBV DNA (r = 0.597,P = 0.04),while the inducible protein-10 (IP-10) level was correlated with serum alanine aminotransferase (ALT) (r = 0.545,P = 0.005). The IP-10 level at week 8 after pegylated IFN α-2b treatment could predict the normalization of ALT in CHB patients (positive predict value = 56%,negative predict value = 92%). CONCLUSION:Pegylated IFN α-2b can enhance the immune response of CHB patients by increasing the frequency of HBV specific CD8+ T cells and regulating the Th1/Th2 cytokines.

Change of Cytokines in Chronic Hepatitis B Patients and HBeAg are Positively Correlated with HBV RNA, Based on Real-world Study

Background and Aims:The natural course of chronic hepatitis B virus(HBV)infection is widely studied;however,follow-up studies of the same patients are scanty.Here,we studied the dynamic changes of serum HBV RNA and cytokines in hepatitis B virus e antigen(HBeAg)-positive patients treated with entecavir(ETV)to explore the relationship between the HBV serum viral nucleic acids and host immunity.Methods:Thirty-three chronic hepatitis B patients who are HBeAg-positive,with high virus load(HBV DNA>20,000 IU/mL),and received standard nucleos(t)ide analogue(NA)antiviral therapy(ETV)for more than 48 weeks were included.The serum levels of HBV nucleic acids and selected cytokines were measured at 0,12,24,and 48 weeks respectively.Results:Serum HBV RNA could still be detected while serum HBV DNA had fallen below the detection limit in patients treated with ETV.There was a strong positive correlation between HBV RNA and HBeAg,with a concomitant decrease in the secretion of cytokines from type 1 helper T(Th1)/type 2 helper T(Th2)/interleukin(IL)-17 producing T(Th17)cells.IL-4 and IL-10 were the main cytokines negatively associated with serum HBV RNA.Conclusions:HBeAg can be used to reflect the load of HBV RNA indirectly,because serum HBV RNA has not been widely used in clinical practice.Meanwhile,serum IL-4 and IL-10 might be explored in combination with HBV RNA in guiding future clinical antiviral therapy.

Prognoses of patients with acute-on-chronic hepatitis B liver failure are closely associated with altered SOCS1 mRNA expression and cytokine production following glucocorticoid treatment

Suppressor of cytokine signaling （SOCS） 1 plays a crucial role in the immune response and might contribute to the prognoses of liver failure treated with glucocorticoid. We recruited 47 acute-on-chronic hepatitis B liver failure （ACHBLF） patients receiving glucocorticoid treatment and 30 healthy controls to determine the potential effects of glucocorticoid on the transcriptional level of SOCS1 in peripheral blood mononuclear cells. On the third and twenty-eighth days of glucocorticoid treatment, SOCS1 expression was negatively correlated with model for end-stage liver disease （MELD） score. Interleukin-6 （IL-6） and tumor-necrosis factor-a （＇I＇NF-a） levels were statistically lower, while the SOCS1 transcription level was higher in survivors than non-survivors both in pre- and post-treatment ACHBLF patients. The methylation rate of the SOCS1 promoter in ACHBLF patients was higher than in healthy control patients as determined by methylation-specific polymerase chain reaction. The mRNA level of SOCS1 in methylated promoters was significantly lower than from patients with unmethylated SOCS1 promoters, interferon （IFN）-y-responsive and STATl-dependent gene expression was higher in survivors and was dramatically decreased with rising expression of SOCS1 after glucocorticoid treatment. Mortality rates were significantly higher in methylated patients than for those without methylation at the end of a 90-day follow-up. Furthermore, we found that five in six surviving patients displayed demethylated SOCS1 on the twenty-eighth day after treatment, while that number was 3 in 10 in the non-survivors. These findings suggested that ACHBLF patients without SOCS1 methylation may have a favorable response to corticosteroid treatment.

DNA Methylation and Transcription of HLA-F and Serum Cytokines Relate to Chinese Medicine Syndrome Classification in Patients with Chronic Hepatitis B

Objective:To explore the molecular bases of Chinese medicine(CM) syndrome classification in chronic hepatitis B(CHB) patients in terms of DNA methylation,transcription and cytokines.Methods:Genome-wide DNA methylation and 48 serum cytokines were detected in CHB patients(DNA methylation:15 cases;serum cytokines:62 cases) with different CM syndromes,including dampness and heat of Gan(Liver) and gallbladder(CHB1,DNA methylation:5 cases,serum cytokines:15 cases),Gan stagnation and Pi(Spleen) deficiency(CHB2,DNA methylation:5 cases,serum cytokines:15 cases),Gan and Shen(Kidney) yin deficiency(CHB3,DNA methylation:5 cases,serum cytokines:16 cases),CHB with hidden symptoms(HS,serum cytokines:16 cases) and healthy controls(DNA methylation:6 cases).DNA methylation of a critical gene was further validated and its mRNA expression was detected on enlarged samples.Genome-wide DNA methylation was detected using Human Methylation 450 K Assay and further verified using pyrosequencing.Cytokines and mRNA expression of gene were evaluated using multiplex biometric enzyme-linked immunosorbent assay(ELISA)-based immunoassay and reverse transcription-quantitative polymerase chain reaction(RT-qPCR),respectively.Results:Totally 28,667 loci,covering 18,403 genes were differently methylated among CHB1,CHB2 and CHB3(P<0.05 and|△β value|> 0.17).Further validation showed that compared with HS,the hg19 CHR6:29691140 and its closely surrounded 2 CpG loci were demethylated and its mRNA expressions were significantly up-regulated in CHB1(P<0.05).However,they remained unaltered in CHB2(P>0.05).Levels of Interleukin(IL)-12 were higher in CHB3 and HS than that in CHB1 and CHB2 groups(P<0.05).Levels of macrophage inflammatory protein(MIP)-1αand MIP-1β were higher in CHB3 than other groups and leukemia inhibrtory factor level was higher in CHB1 and HS than CHB2 and CHB3 groups(P<0.05).IL-12,MIP-1α and MIP-1β concentrations were positively correlated with human leukocyte antigen F(HLA-F)mRNA expression(R;=0.238,P<0.05;R;=0.224,P<0.05;R;=0.447,P<0.01;respectively).Furthermore,combination of HLA-F mRNA and differential cytokines greatly improved the differentiating accuracy among CHB1,CHB2 and HS.Conclusions:Demethylation of CpG loci in 5’ UTR of HLA-F may up-regulate its mRNA expression and HLA-F expression was associated with IL-12,MIP-1α and MIP-1β levels,indicating that HLA-F and the differential cytokines might jointly involve in the classification of CM syndromes in CHB.(Registration No.ChiCTR-RCS-13004001)

The therapeutic effect of Lamivudine on HBV-DNA in PBMC and its inducement effect against cytokine

The purpose of this investigation was to study the therapeutic effect of Lamivudine on HBVDNA in peripheral blood mononudear cells （PBMC） and serum, and the level of cytokines in serum of the patients with chronic hepatitis B. The patients were divided into two groups （A = 47, B = 34）, and treated by Lamivudine, routine medicine, respectively. The levels of HBV-DNA in PBMC and serum and eytokines were all detected before and after treatment. After the treatment of Lamivndine for 36 weeks, the total conversion negative rates of HBV-DNA in PBMC and serum of the patients treated with Lamivudine were 55.32% （26/47） and 61.70% （29/47）, respectively. The total negative conversion rates of HBV-DNA in PBMC and serum of the patients treated by routine medicine were 26.47 % （9/34） and 32.35% （11/34）, respectively. There was significant difference between Lamivudine group and routine medicine group （ P 〈 0.01 ）. The negative conversion rates of HBeAg in serum of the patients were 46.81% （22/47） and 68.09% （32/47） at the end of 24 weeks and 36 weeks, and were higher than those of routine medicine group （ P 〈 0.05 and P 〈 0.01 ）. The levels of alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, ALT/AST in serum of the patients after being treated by Lamivudine, routine medicine were down-regulated to （30.1 ± 9.6） U/ml, （32.3 ±10.7） U/ml, 0.9 ±0.1 and （48.4±10.7） U/ml, （44.7 ±11.0） U/ml, 1.1 ±0.2. After the analysis of variance, the high significant difference was obvious between the two groups （ P 〈 0.01）. It was due to the high levels of IL-6, IL-8 and TNF-α in chronic hepatitis B which could be down-regulated to （250.5 ±33.3） pg/ml, （153.4 ±22.2） pg/ml, （232.6 ±21.2） pg/ml by Lamivudine, which was more obvious than that of routine medicine （ P 〈 0.01）. Lamivudine has high therapeutic effect on the treatment of HBVDNA in PBMC and serum and has better therapeutic effect than that of routine therapy. Lamivudine may also have higher down-regtdated inflananatory infdtration and secretion in local site caused by chemotactic cytokines and produce promotional effect on the recovery of liver function.

Ratios of T-helper 2 Cells to T-helper 1 Cells and Cytokine Levels in Patients with Hepatitis B

Background：Hepatitis B is an immune response-mediated disease.The aim of this study was to explore the differences of ratios of T-helper （Th） 2 cells to Thl cells and cytokine levels in acute hepatitis B （AHB） patients and chronic hepatitis B virus （HBV）-infected patients in immune-tolerance and immune-active phases.Methods：Thirty chronic HBV-infected patients in the immune-tolerant phase （IT group） and 50 chronic hepatitis B patients in the immuneactive （clearance） phase （IC group）,32 AHB patients （AHB group）,and 13 healthy individuals （HI group） were enrolled in the study.Th cell proportions in peripheral blood,cytokine levels in plasma,and serum levels of HBV DNA,hepatitis B surface antigen,and hepatitis B e antigen were detected.Results：The Th1 cell percentage and Th2/Th1 ratio in the HBV infection group （including IT,IC,and AHB groups） were significantly different from those in HI group （24.10% ± 8.66% and 1.72 ± 0.61 vs.15.16% ± 4.34% and 2.40 ± 0.74,respectively;all P 〈 0.001）.However,there were no differences in the Th1 cell percentages and Th2/Th1 ratios among the IT,IC,and AHB groups.In HBV infection group,the median levels of Flt3 ligand （Flt3L）,interferon （IFN）-γ,and interleukin （IL）-17A were significantly lower than those in HI group （29.26 pg/ml,33.72 pg/ml,and 12.27 pg/ml vs.108.54 pg/ml,66.48 pg/ml,and 35.96 pg/ml,respectively;all P 〈 0.05）.IFN-α2,IL-10,and transforming growth factor （TGF）-β2 median levels in hepatitis group （including patients in AHB and IC groups） were significantly higher than those in IT group （40.14 pg/ml,13.58 pg/ml,and 557.41 pg/ml vs.16.74 pg/ml,6.80 pg/ml,and 419.01 pg/ml,respectively;all P 〈 0.05）,while patients in hepatitis group had significant lower Flt3L level than IT patients （30.77 vs.59.96 pg/ml,P =0.021）.Compared with IC group,patients in AHB group had significant higher median level s of IL-1 0,TGF-β 1,and TGF-β2 （22.77 pg/ml,10,447.00 pg/ml,and 782.28 pg/ml vs.8.66 pg/ml,3755.50 pg/ml,and 482.87 pg/ml,respectively;all P 〈 0.05）.Conclusions：Compared with chronic HBV-infected patients in immune-tolerance phase,chronic HBV-infected patients in immune-active phase and AHB patients had similar Th2/Th 1 ratios,significantly higher levels of IFN-α2,IL-10,and TGF-β.AHB patients had significantly higher IL-10 and TGF-β levels than chronic HBV-infected patients in immune-active phase.

SOCS1在慢性HBV相关性肝病患者血清中的表达水平及临床意义

目的研究细胞因子信号传导抑制因子1(suppressor of cytokine signaling 1,SOCS1)在乙型肝炎病毒(hepatitis B virus,HBV)相关肝病中的表达水平及其临床意义。方法选取慢性乙型肝炎(chronic hepatitis B,CHB)、肝硬化及HBV相关性慢加急性肝衰竭(HBV associated chronic acute liver failure,HBV-ACLF)患者及健康对照各25例,采用RT-PCR方法检测外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中SOCS1 mRNA表达水平,用ELISA法检测慢性肝病患者及健康对照血浆中SOCS1、白细胞介素6(IL-6)水平。分析各组患者SOCS1相对表达量、SOCS1 mRNA表达水平及其他实验室检查指标如HBV-DNA、丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、凝血酶原活动度(prothrombin activity,PTA)、总胆红素(total bilirubin,TBil)之间的差异,并分析SOCS1 mRNA表达水平与上述实验室指标之间的关联性。结果SOCS1 mRNA表达水平及血清SOCS1在HBV-ACLF组最高,其次为肝硬化组,在健康对照组最低,各组间差异均有统计学意义(F=109.65,P<0.001);SOCS1 mRNA相对表达量与TBil(r=0.89,P<0.001)、ALT(r=0.89,P<0.001)、AST(r=0.84,P<0.001)、IL-6(r=0.93,P<0.001)呈正相关,与PTA(r=-0.89,P<0.001)呈负相关,与HBV DNA无显著相关性(P=0.28)。结论SOCS1在HBV相关慢性肝病患者中的表达水平可反映疾病的严重程度,并与评价肝病严重程度相关指标呈显著相关性。

细胞因子和病毒标志物对聚乙二醇干扰素治疗HBeAg阳性慢性乙型肝炎的意义

目的探究细胞因子和病毒标志物在监测聚乙二醇干扰素治疗HBeAg阳性慢性乙型肝炎(CHB)中的意义。方法选取2020年1月至2022年5月武威市中医医院收治的HBeAg阳性CHB患者117例。比较PEG-IFN治疗前、治疗24周和48周时的临床生化指标、HBV血清学指标以及细胞因子。结果117例患者中,血清HBeAg应答46例,未应答71例。应答组中HBsAg转阴23例,未应答组中HBsAg转阴17例。应答组和未应答组病毒学标志物和细胞因子水平相近,在24周时未应答组AST、ALT、TNF-α、TGF-β分别为(43.1±12.9)U/L、(56.58±8.2)U/L、(20.4±2.9)pg/mL、(3279±960.8)pg/mL,下降幅度均小于应答组的(33.4±7.4)U/L、(41.6±8.3)U/L、(15.4±2.8)pg/mL、(2610.8±705.6)pg/mL(均P<0.05)。治疗48周时未应答组AST、ALT、TNF-α、TGF-β、IL-10分别为(35.2±7.7)U/L、(33.2±9.5)U/L、(16.6±3.7)pg/mL、(3180.6±1040.9)pg/mL、(4.4±2.7)pg/mL,下降幅度均小于应答组的(27.2±6.9)U/L、(29.1±8.1)U/L、(13.8±2.5)pg/mL、(1975.0±474.0)pg/mL、(3.0±0.9)pg/mL(均P<0.05),而应答组IFN-γ为(530.9±146.5)pg/mL,高于未应答组(467.8±147.8)pg/mL(P<0.05)。结论TNF-α、TGF-β在治疗前后均与血清HBeAg具有相关性,有成为预测PEG-IFN治疗HBeAg阳性CHB疗效指标的潜在可能性,IFN在早期治疗不具有相关性,治疗48周后呈中度正相关,提示IFN可能是预测晚期疗效的指标。

HBV-DNA载量不同对CHB患者肝功能、免疫功能、细胞因子表达的影响

目的分析不同乙型肝炎病毒脱氧核糖核酸(HBV-DNA)载量对慢性乙型肝炎(chronic hepatitis B,CHB)患者肝功能、免疫功能、细胞因子表达的影响。方法随机抽取2021年3月至2022年3月在某院就诊的CHB患者200例,按照测量患者血清中HBV-DNA载量的不同进行分组,阴性组38例、低拷贝组58例、中拷贝组59例、高拷贝组45例,肝功能指标(ALT、AST、GGT)检测使用的仪器为全自动生化分析仪,T淋巴细胞亚群(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))检测使用的仪器为流式细胞仪及相关抗体,细胞因子(IL-2、IL-6、TNF-α)检测使用ELISA法,分析HBV-DNA载量和ALT、AST、GGT、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+)、IL-2、IL-6、TNF-α的相关性。结果ALT、AST、GGT、IL-2、IL-6、TNF-α阴性组最低,高拷贝组最高;CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+)阴性组最高,高拷贝组最低,且各组间对比均有统计学意义(P<0.05)。阴性组、低拷贝组、中拷贝组、高拷贝组肝功能指标(ALT、AST、GGT)水平呈递增趋势,CHB患者HBV-DNA载量和肝功能指标水平呈正相关(r=0.813、0.860、0.848,P<0.001);阴性组、低拷贝组、中拷贝组、高拷贝组细胞因子(IL-2、IL-6、TNF-α)水平呈递增趋势,CHB患者HBV-DNA载量和细胞因子水平呈正相关(r=0.831、0.842、0.761,P<0.001);阴性组、低拷贝组、中拷贝组、高拷贝组免疫功能指标(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))水平呈递减趋势,CHB患者HBV-DNA载量和免疫功能指标水平呈负相关(r=-0.903、-0.914、-0.879,P<0.001)。结论随着HBV-DNA载量的增高,肝功能指标、细胞因子指标水平逐渐提升,而免疫功能指标逐渐降低,HBV-DNA载量不同直接影响CHB患者损伤肝功能、免疫功能、炎症反应的严重程度。

复方栀子根颗粒联合替诺福韦酯对慢性乙型肝炎患者血清细胞因子水平的影响

目的:观察复方栀子根颗粒联合替诺福韦酯(TDF)治疗慢性乙型肝炎(CHB)患者的临床疗效及对细胞因子的影响。方法:纳入CHB初治患者80例,采用临床随机对照研究,除去脱落及剔除病例,共纳入分析75例(治疗组35例、对照组40例)。对照组患者给予口服TDF,治疗组患者在对照组基础上加用复方栀子根颗粒,两组患者均在治疗4周、24周时比较肝功能(ALT、AST、GGT)变化,在治疗24周比较病毒学指标(HBV DNA、HBsAg、HBeAg)、细胞因子(IL-6、IL-10、IL-17、IL-23)水平及临床疗效判定。结果:两组患者治疗24周后肝功能、病毒学指标、细胞因子水平均较治疗前显著降低(P<0.05)。组间比较,治疗4周后治疗组转氨酶下降水平更低,差异有统计学意义(Z=-2.90,P=0.004;Z=-3.26,P=0.001;Z=-2.24,P=0.025);治疗组24周时IL-6、IL-23水平较对照组低,差异有统计学意义(Z=-2.14,P=0.033;Z=-2.10,P=0.036);治疗组总有效率97.14%(34/35),对照组95.00%(38/40),治疗组总有效率高于对照组(χ2=9.49,P=0.019);治疗组较对照组不良反应更少,差异有统计学意义(χ2=6.19,P=0.044)。结论:复方栀子根颗粒联合TDF治疗早期能更快降低转氨酶水平,降低促炎细胞因子水平及提高临床综合疗效优于单用TDF,并减轻临床不良反应。

补肾清透方对慢性乙肝HBeAg阳性患者血清IL-2、IL-4、IL-10、TNF-α及IFN-γ的影响

目的观察补肾清透方治疗慢性乙型肝炎(CHB)乙型肝炎e抗原(HBeAg)阳性患者外周血中白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-10(IL-10)、肿瘤坏死因子α(TNF-α)和干扰素-γ(IFN-γ)的变化。方法 60例CHB HBeAg阳性患者被随机分成治疗组和对照组,每组30例,CHB治疗组接受补肾清透方治疗,疗程48周,CHB对照组不接受药物治疗。分别在开始和第48周时两组患者抽血检测HBV DNA、IL-2、IL-4、IL-10、TNF-α和IFN-γ。结果 CHB治疗组治疗后与治疗前比较,IL-2、TNF-α、IFN-γ明显升高,HBV DNA、IL-4、IL-10明显下降(P<0.01);CHB对照组治疗前、后各项指标比较,差异无统计学意义(P>0.05)。结论补肾清透方能抑制CHB HBeAg阳性患者HBV DNA复制,可提高机体的细胞免疫功能。

恩替卡韦联合苦参素改善HBeAg阳性慢性乙型肝炎患者Th1/Th2失平衡临床研究

目的:探讨恩替卡韦联合苦参素对HBe Ag阳性慢性乙型肝炎(chronic hepatitis B,CHB)患者Th1/Th2失平衡的影响。方法:将216例HBe Ag阳性CHB患者随机分为治疗组和对照组。治疗组112例给予恩替卡韦联合苦参素治疗,对照组104例给予恩替卡韦治疗,疗程48周。治疗48周后,应用ELISA检测患者外周血Th1型细胞因子(IFN-γ、IL-2)和Th2型细胞因子(IL-4、IL-10)的表达水平,应用实时定量PCR检测患者外周血Th1细胞特征性转录因子(T-bet)和Th2细胞特征性转录因子(GATA3)mRNA的表达水平。结果:治疗48周后,治疗组IFN-γ、IL-2的表达水平较对照组明显升高[(68.32±9.67)pg/m L vs(35.24±7.49)pg/m L,(216.81±31.55)pg/m L vs(115.63±29.13)pg/m L;t1=27.96,t2=24.43;P1、P2均<0.01];而治疗组IL-4、IL-10的表达水平较对照组明显降低[(18.79±5.83)pg/m L vs(22.58±5.32)pg/m L,(133.75±29.21)pg/m L vs(143.17±32.96)pg/m L;t3=4.98,t4=2.23;P3<0.01,P4<0.05]。治疗组IFN-γ与IL-4比值IFN-γ/IL-4较对照组明显增大(3.59±0.76 vs 1.61±0.53,t=22.05,P<0.01)。治疗48周后,治疗组T-bet mRNA的表达水平较对照组明显升高(1.52±0.41 vs 0.83±0.29,t=14.18,P<0.01);而治疗组GATA3 mRNA的表达水平较对照组明显降低(0.96±0.24 vs 1.05±0.37,t=2.14,P<0.05)。治疗组T-bet mRNA与GATA3 mRNA比值T-bet/GATA3较对照组明显增大(1.60±0.39 vs 0.81±0.32,t=16.20,P<0.01)。结论:恩替卡韦联合苦参素可以促进HBe Ag阳性CHB患者Th1型细胞因子的分泌,抑制Th2型细胞因子的分泌,促使HBe Ag阳性CHB患者外周血Th细胞向Th1细胞分化,使其Th1/Th2失平衡得到改善。