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Liu Y, Zheng Y, Lin X, Cao Z, Lu J, Ma L, Ren S, Zheng S, Hu Z, Xu B, Chen X. Analysis of clinical characteristics of thyroid disorders in patients with chronic hepatitis B treated with pegylated-interferon alpha. BMC Endocr Disord 2023; 23:115. [PMID: 37217910 DOI: 10.1186/s12902-023-01371-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 05/12/2023] [Indexed: 05/24/2023] Open
Abstract
BACKGROUND Thyroid disorders (TD) is a common complication of pegylated-interferon alpha (Peg-IFNα) therapy. Few studies have investigated the relationship between TD and the efficacy of interferon therapy for chronic hepatitis B (CHB). Therefore, we analyzed the clinical characteristics of TD in patients with CHB treated with Peg-IFNα, and evaluated the correlation between TD and Peg-IFNα treatment efficacy. METHODS In this retrospective study, the clinical data of 146 patients with CHB receiving Peg-IFNα therapy were collected and analyzed. RESULTS During the course of Peg-IFNα therapy, positive conversion of thyroid autoantibodies and TD occurred in 7.3% (85/1158) and 8.8% (105/1187) patients, respectively, and was diagnosed more often in women. The most common thyroid disorder was hyperthyroidism (53.3%), followed by subclinical hypothyroidism (34.3%). We found that thyroid function returned to normal in 78.7% of patients with CHB, and thyroid antibody levels returned to the negative range in approximately 50% of patients after interferon treatment cessation. Only 25% of patients with clinical TD required treatment. Compared with patients with hypothyroidism/subclinical hypothyroidism, patients with hyperthyroidism/subclinical hyperthyroidism showed greater reduction and seroclearance of hepatitis B surface antigen (HBsAg) levels. CONCLUSIONS TD are not an absolute contraindication for interferon therapy; however, patients should be monitored closely during interferon therapy. In pursuit of functional cure, a balance between efficacy and safety must be achieved.
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Affiliation(s)
- Yisi Liu
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Yanhong Zheng
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Xiao Lin
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Zhenhuan Cao
- Third Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Junfeng Lu
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Lina Ma
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Shan Ren
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Sujun Zheng
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Zhongjie Hu
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China
| | - Bin Xu
- Second Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xinyue Chen
- First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, No.8, Xi Tou Tiao, Youanmen Wai, Beijing, 100069, Fengtai District, China.
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Saruga T, Imaizumi T, Kawaguchi S, Seya K, Matsumiya T, Sasaki E, Sasaki N, Uesato R, Ishibashi Y. Role of MDA5 in regulating CXCL10 expression induced by TLR3 signaling in human rheumatoid fibroblast-like synoviocytes. Mol Biol Rep 2021; 48:425-433. [PMID: 33387195 PMCID: PMC7884359 DOI: 10.1007/s11033-020-06069-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/04/2020] [Indexed: 12/29/2022]
Abstract
C-X-C motif chemokine 10 (CXCL10) is an inflammatory chemokine and a key molecule in the pathogenesis of rheumatoid arthritis (RA). Melanoma differentiation-associated gene 5 (MDA5) is an RNA helicase that plays a role in innate immune and inflammatory reactions. The details of the regulatory mechanisms of CXCL10 production and the precise role of MDA5 in RA synovitis have not been fully elucidated. The aim of this study was to examine the role of MDA5 in regulating CXCL10 expression in cultured human rheumatoid fibroblast-like synoviocytes (RFLS). RFLS was stimulated with Toll-like receptor 3 (TLR3) ligand polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA mimetic. Expression of interferon beta (IFN-β), MDA5, and CXCL10 was measured by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay. A neutralizing antibody of IFN-β and siRNA-mediated MDA5 knockdown were used to determine the role of these molecules in regulating CXCL10 expression downstream of TLR3 signaling in RFLS. Poly I:C induced IFN-β, MDA5, and CXCL10 expression in a concentration- and time-dependent manner. IFN-β neutralizing antibody suppressed the expression of MDA5 and CXCL10, and knockdown of MDA5 decreased a part of CXCL10 expression (p < 0.001). The TLR3/IFN-β/CXCL10 axis may play a crucial role in the inflammatory responses in RA synovium, and MDA5 may be partially involved in this axis.
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Affiliation(s)
- Tatsuro Saruga
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan.
| | - Tadaatsu Imaizumi
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Shogo Kawaguchi
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Kazuhiko Seya
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Tomoh Matsumiya
- Department of Vascular Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Eiji Sasaki
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Norihiro Sasaki
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Ryoko Uesato
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
| | - Yasuyuki Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan
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Ferrari SM, Fallahi P, Ruffilli I, Elia G, Ragusa F, Paparo SR, Patrizio A, Mazzi V, Colaci M, Giuggioli D, Ferri C, Antonelli A. Immunomodulation of CXCL10 Secretion by Hepatitis C Virus: Could CXCL10 Be a Prognostic Marker of Chronic Hepatitis C? J Immunol Res 2019; 2019:5878960. [PMID: 31485460 PMCID: PMC6702819 DOI: 10.1155/2019/5878960] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/19/2019] [Accepted: 04/30/2019] [Indexed: 12/17/2022] Open
Abstract
Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and "chronic hepatitis C virus (HCV) infection" (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.
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Affiliation(s)
| | - Poupak Fallahi
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Ilaria Ruffilli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giusy Elia
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesca Ragusa
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Armando Patrizio
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Valeria Mazzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Michele Colaci
- Internal Medicine Unit, Cannizzaro Hospital, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Dilia Giuggioli
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Clodoveo Ferri
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Hwang Y, Kim W, Kwon SY, Yu HM, Kim JH, Choe WH. Incidence of and risk factors for thyroid dysfunction during peginterferon α and ribavirin treatment in patients with chronic hepatitis C. Korean J Intern Med 2015; 30:792-800. [PMID: 26552454 PMCID: PMC4642008 DOI: 10.3904/kjim.2015.30.6.792] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 07/22/2014] [Accepted: 09/18/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS Thyroid dysfunction (TD) is more likely to occur in patients with chronic hepatitis C (CHC) and is particularly associated with interferon (IFN) treatment. The purpose of this study was to investigate the incidence, outcomes, and risk factors for TD during pegylated interferon (PEG-IFN) and ribavirin (RBV) combined therapy in patients with CHC. METHODS A total of 242 euthyroid patients with CHC treated with PEG-IFN/RBV were included. Thyroid function and autoantibodies were measured at baseline, and virologic response and thyroid function were assessed every 3 months during therapy. RESULTS TD developed in 67 patients (27.7%) during the PEG-IFN/RBV treatment. The types of TD were subclinical hypothyroidism (50.7%), hypothyroidism (14.9%), thyroiditis (11.9%), subclinical hyperthyroidism (10.4%), and hyperthyroidism (10.4%). Most of the patients with TD recovered spontaneously; however, seven patients (10.4%) needed thyroid treatment. The sustained virological response rate was higher in patients with TD than those without (65.7% vs. 49.1%, p = 0.02). Baseline thyroid stimulating hormone (TSH) concentrations (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.96 to 8.77; p < 0.001), presence of the thyroid peroxidase antibody (OR, 8.81; 95% CI, 1.74 to 44.6; p = 0.009), and PEG-IFNα-2b (OR, 3.01; 95% CI, 1.43 to 6.39; p = 0.004) were independent risk factors for the development of TD. CONCLUSIONS TD developed in 27.7% of patients with CHC during PEG-IFN/RBV treatment, and 10.4% of these patients needed thyroid treatment. TD is associated with a favorable virologic response to PEG-IFN/RBV. Assessment of TSH and thyroid autoantibodies at baseline and close monitoring of thyroid function during PEG-IFN/RBV therapy are necessary for early detection and management of IFN-induced TD.
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Affiliation(s)
- Yong Hwang
- Department of Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea
| | - So Young Kwon
- Department of Medicine, Konkuk University School of Medicine, Seoul, Korea
- Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea
- Correspondence to So Young Kwon, M.D. Department of Internal Medicine, Konkuk University Medical Center, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea Tel: +82-2-2030-5027 Fax: +82-2-2030-5029 E-mail:
| | - Hyung Min Yu
- Department of Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Jeong Han Kim
- Department of Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Won Hyeok Choe
- Department of Medicine, Konkuk University School of Medicine, Seoul, Korea
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Zhang RW, Shao CP, Huo N, Li MR, Xi HL, Yu M, Xu XY. Thyroid dysfunction in Chinese hepatitis C patients: Prevalence and correlation with TPOAb and CXCL10. World J Gastroenterol 2015; 21:9765-9773. [PMID: 26361424 PMCID: PMC4562961 DOI: 10.3748/wjg.v21.i33.9765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 06/02/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship among pretreatment serum CXC chemokine ligand 10 (CXCL10), thyroid peroxidase antibody (TPOAb) levels and thyroid dysfunction (TD) in Chinese hepatitis C patients.
METHODS: One hundred and thirty-nine treatment-naive genotype 1 chronic hepatitis C patients with no history of TD or treatment with thyroid hormones were enrolled in this study. Patients underwent peginterferon alfa-2a/ribavirin (PegIFNα-2a/RBV) treatment for 48 wk, followed by detection of clinical factors at each follow-up point. Hepatitis C virus (HCV) antibodies were analyzed using microsomal chemiluminescence, and serum HCV RNA was measured by real-time PCR assay at 0, 4, 12, 24 and 48 wk after the initiation of therapy and 24 wk after the end of therapy. To assess thyroid function, serum thyroid stimulating hormone (TSH), free thyroxine (FT4), free triodothyronine (FT3) and TPOAb/thyroglobulin antibody (TGAb) levels were determined using chemiluminescent immunoassays every 3 mo. Serum CXCL10 levels were determined at baseline.
RESULTS: The prevalence of TD was 18.0%. Twenty-one (84.0%) out of twenty-five patients exhibited normal thyroid function at week 24 after therapy. The rate of sustained virological response to PegIFNα-2a/RBV in our study was 59.0% (82/139), independent of thyroid function. Pretreatment serum CXCL10 levels were significantly increased in patients with euthyroid status compared with patients with TD (495.2 ± 244.2 pg/mL vs 310.0 ± 163.4 pg/mL, P = 0.012). Patients with TD were more frequently TPOAb-positive than non-TD (NTD) patients (24.2% vs 12.3%, P = 0.047) at baseline. Three of the one hundred and fifteen patients without TPOAb at baseline developed TD at the end of treatment (37.5% vs 2.6%, P = 0.000). Female patients exhibited an increased risk for developing TD compared with male patients (P = 0.014).
CONCLUSION: Lower pretreatment serum CXCL10 levels are associated with TD, and TD prevalence increases in female patients and patients who are positive for TPOAb at baseline.
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Shao C, Huo N, Zhao L, Gao Y, Fan X, Zheng Y, Wang L, Lu H, Xu X, Guo X. The presence of thyroid peroxidase antibody of IgG2 subclass is a risk factor for thyroid dysfunction in chronic hepatitis C patients. Eur J Endocrinol 2013; 168:717-22. [PMID: 23419250 DOI: 10.1530/eje-12-0775] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To investigate the prevalence of thyroid dysfunction (TD) and IgG subclasses of thyroid autoantibodies (TAs) and to determine the predictive factors of TD in chronic hepatitis C (CHC) patients. DESIGN Three hundred and twelve untreated hepatitis C virus-infected patients without a history of TD or treatment with thyroid hormones were enrolled in a cross-sectional study. Clinical and biological factors were statistically analyzed to determine the correlation between TD and this patient population. RESULTS The incidence of TD WAS 12.5% in CHC patients. Clinical hypothyroidism (5.8%) and subclinical hypothyroidism (3.8%) were more frequent than clinical hyperthyroidism (1.6%) and subclinical hyperthyroidism (1.3%). The percentage of TA-positive patients was significantly higher in people 60 years than in those 60 years (31.9 VS 18.6%; P=0.042). Positive thyroid peroxidase antibody (TPOAb) was more frequent, and alanine aminotransferase (ALT) levels were lower in patients who displayed TD (TPOAb: 62.1 vs 10.8%, P=0.000; ALT: 43.5 vs 51 IU/l, P=0.046). The positive percentage of TPOAb IgG2 subclass in the TD group was significantly higher than that of patients without TD (66.7 vs 16.7%, P=0.005). Multiple logistic regression analysis indicated that only TPOAb IgG2 subclass positivity was an independent risk factor for TD in CHC patients (odds ratio=8; 95% CI: 1.225-52.246; P=0.030). CONCLUSIONS TPOAb IgG2 subclass positivity is a risk factor for TD in CHC patients before antiviral treatment. IgG2 subclass of TPOAb might play an important role in the presence of TD in CHC patients.
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Affiliation(s)
- Cuiping Shao
- Departments of Infectious Diseases, Peking University First Hospital, Xicheng District, Beijing, People's Republic of China
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Danilovic DLS, Mendes-Correa MC, Chammas MC, Zambrini H, Barros RK, Marui S. Thyroid disturbance related to chronic hepatitis C infection: role of CXCL10. Endocr J 2013; 60:583-90. [PMID: 23291435 DOI: 10.1507/endocrj.ej12-0321] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Association between autoimmune thyroid diseases (AITD) and hepatitis C is controversial, but may occur or worsen during alpha-interferon treatment. The mechanism responsible for autoimmune diseases in infected patients has not been fully elucidated. This study aims to evaluate the frequency of AITD in chronic hepatitis C and the association of chemokine (CXC motif) ligand 10 (CXCL10) and AITD. One hundred and three patients with chronic hepatitis C and 96 controls were prospectively selected to clinical, hormonal, thyroid autoimmunity and ultrasound exams, besides thyroxine-binding globulin (TBG) and CXCL10 measurements and hepatic biopsies. The frequency of AITD among infected subjects was similar to controls. TT3 and TT4 distributions were right shifted, as was TBG, which correlated to both of them. Thyroid heterogeneity and hypoechogenicity were associated with AITD. Increased vascularization was more prevalent in chronic hepatitis C.CXCL10 was higher in infected patients (p=0.007) but was not related to thyroid dysfunction. Increase in CXCL10 levels were consistent with hepatic necroinflammatory activity (p=0.011). In summary, no association was found between chronic hepatitis C and AITD. Infected subjects had higher TT3 and TT4 which were correlated to TBG. Increased CXCL10 was not associated to thyroid dysfunction in HCV-infected population.
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Affiliation(s)
- Debora Lucia Seguro Danilovic
- Unidade de Tireóide, Laboratório de Endocrinologia Celular e Molecular, LIM 25, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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Tran HA, Jones TL, Gibson R, Reeves GEM. Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study. BMC Endocr Disord 2011; 11:10. [PMID: 21605462 PMCID: PMC3123561 DOI: 10.1186/1472-6823-11-10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2010] [Accepted: 05/24/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not. METHODS We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls. RESULTS The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR. CONCLUSIONS Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined. TRIAL REGISTRATION The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB12610000830099.
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Affiliation(s)
- Huy A Tran
- Hunter Area Pathology Service and University of Newcastle, Locked Bag Number 1, Hunter Mail Region Centre, Newcastle, New South Wales 2310, Australia
| | - Tracey L Jones
- Hepatitis C Service, Gastroenterology Department, John Hunter Hospital and University of Newcastle, Locked Bag Number 1, Hunter Mail Region Centre, Newcastle, New South Wales 2310, Australia
| | - Robert Gibson
- Hepatitis C Service, Gastroenterology Department, John Hunter Hospital and University of Newcastle, Locked Bag Number 1, Hunter Mail Region Centre, Newcastle, New South Wales 2310, Australia
| | - Glenn EM Reeves
- Hunter Area Pathology Service and University of Newcastle, Locked Bag Number 1, Hunter Mail Region Centre, Newcastle, New South Wales 2310, Australia
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Akeno N, Smith EP, Stefan M, Huber AK, Zhang W, Keddache M, Tomer Y. IFN-α mediates the development of autoimmunity both by direct tissue toxicity and through immune cell recruitment mechanisms. THE JOURNAL OF IMMUNOLOGY 2011; 186:4693-706. [PMID: 21402899 DOI: 10.4049/jimmunol.1002631] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
IFN-α is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-α is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-α treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-α under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-α involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.
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Affiliation(s)
- Nagako Akeno
- Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
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Deng Y, Meyer SA, Guan X, Escalon BL, Ai J, Wilbanks MS, Welti R, Garcia-Reyero N, Perkins EJ. Analysis of common and specific mechanisms of liver function affected by nitrotoluene compounds. PLoS One 2011; 6:e14662. [PMID: 21346803 PMCID: PMC3035612 DOI: 10.1371/journal.pone.0014662] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Accepted: 12/06/2010] [Indexed: 12/20/2022] Open
Abstract
Background Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. Methodology/Principal Findings Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. Conclusions/Significance A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds.
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Affiliation(s)
- Youping Deng
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States of America.
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Abstract
Interferon-alpha (IFNalpha) is used for the treatment of various disorders, most notable chronic hepatitis C virus (HCV) infection. One of the commonest side effects of IFNalpha therapy is thyroiditis, with up to 40% of HCV patients on IFNalpha developing clinical or subclinical disease. In some cases interferon induced thyroiditis (IIT) may result in severe symptomatology necessitating discontinuation of therapy. IIT can manifest as clinical autoimmune thyroiditis, presenting with symptoms of classical Hashimoto's thyroiditis or Graves' disease, or as non-autoimmune thyroiditis. Non-autoimmune thyroiditis can manifest as destructive thyroiditis, with early thyrotoxicosis and later hypothyroidism, or as non-autoimmune hypothyroidism. While the epidemiology and clinical presentation of IIT have been well characterized the mechanisms causing IIT are still poorly understood. It is likely that the hepatitis C virus (HCV) itself plays a role in the disease, as the association between HCV infection and thyroiditis is well established. It is believed that IFNalpha induces thyroiditis by both immune stimulatory effects and by direct effects on the thyroid. Early detection and therapy of this condition are important in order to avoid complications of thyroid disease such as cardiac arrhythmias.
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Affiliation(s)
- Yaron Tomer
- Department of Medicine, Division of Endocrinology, Mount Sinai School of Medicine, Box 1118, One Gustave L. Levy Place, New York, NY 10029, USA.
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Abellán Galiana P, Pérez-Lázaro A, Aguilera Sancho-Tello V, Merino Torres JF, Berenguer Haym M, Piñón Sellés F. [Pegylated-interferon alpha plus ribavirin-induced subacute thyroiditis in chronic hepatitis C]. ACTA ACUST UNITED AC 2009; 56:136-9. [PMID: 19627727 DOI: 10.1016/s1575-0922(09)70844-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2008] [Accepted: 01/26/2009] [Indexed: 11/29/2022]
Abstract
Chronic hepatitis C virus infection may be associated with extrahepatic manifestations. Thyroid disease related to chronic hepatitis C virus infection has been associated with interferon-alpha treatment. We present the case of a 40-year-old woman with chronic hepatitis C virus infection, who developed subacute thyroiditis during treatment with pegylated interferon-alpha plus ribavirin.
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Affiliation(s)
- Pablo Abellán Galiana
- Servicio de Endocrinología y Nutrición, Hospital Universitario La Fe, Valencia, España.
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Tran HA, Malcolm Reeves GE, Gibson R, Attia JR. Development of thyroid diseases in the treatment of chronic hepatitis C with alpha-interferon may be a good prognosticator in achieving a sustained virological response: a meta-analysis. J Gastroenterol Hepatol 2009; 24:1163-8. [PMID: 19682190 DOI: 10.1111/j.1440-1746.2009.05874.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Thyroid dysfunction is the most common endocrinopathy associated with hepatitis C and its interferon-based treatment. When undergoing treatment, interferon and ribavirin synergize to potently stimulate the immune system in order to eradicate the virus. One of the innocent bystanders in this accentuated response is the thyroid. The present study investigated whether thyroid dysfunction while undergoing combination treatment for hepatitis C is a favorable prognostic maker for a sustained virological response. METHODS We carried out a prospective clinical audit in 201 patients treated with combination ribavirin and alpha-interferon and determined the prevalence of sustained virological response in patients in association with thyroid disease. A meta-analysis was also carried out pooling 741 patients from four previous studies on this topic. RESULTS There was positive and significant association between thyroid disease and viral clearance. This was not supported by the meta-analysis, however, and some plausible explanations are proffered for this inconsistency. CONCLUSION Despite lacking supportive evidence from the meta-analysis, it is important that this information is confirmed (or refuted) in future studies.
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Affiliation(s)
- Huy Anh Tran
- Hunter Area Pathology Service, John Hunter Hospital, University of Newcastle, New South Wales, Australia.
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