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Chang ML, Cheng JS, Chen WT, Shen YJ, Kuo CJ, Chien RN. Mixed cryoglobulinemia decelerates hepatocellular carcinoma development in hepatitis C patients with SVR by downregulating regulatory B cells: a 12-year prospective cohort study. Oncoimmunology 2025; 14:2470128. [PMID: 40008547 PMCID: PMC11866965 DOI: 10.1080/2162402x.2025.2470128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025] Open
Abstract
How mixed cryoglobulinemia (MC) affects cancer risk in chronic hepatitis C patients with sustained virologic response (SVR) remains unclear. In a 12-year prospective study, post-SVR MC was assessed every 3‒6 months. Among the 891 SVR patients, 265 (29.7%) had baseline (24 weeks after completing anti-HCV therapy) MC, and the 12-year cancer cumulative incidence was 19.7%. Among the 73 patients who developed cancer, 37 (50.7%) had hepatocellular carcinoma (HCC), with the following associated baseline variables: for cancer, male sex, age and alanine aminotransferase (ALT) levels; for HCC, male sex, age, and cirrhosis; and for non-HCC cancer, rheumatoid factor levels. Among patients with post-SVR HCC, the mean time to HCC was longer in those with than in those without baseline MC (1545.4 ± 276.5 vs. 856.9 ± 115.2 days, p = 0.014). Patients with baseline MC had decreased circulating interleukin-10 (IL-10)-positive B cell (CD19+IL-10+cells/CD19+cells) (31.24 ± 16.14 vs. 40.08 ± 15.42%, p = 0.031), regulatory B cell (Breg) (CD19+CD24hi CD27+cells/CD19+cells) (10.45 ± 7.10 vs. 15.76 ± 9.14%, p = 0.035), IL-10-positive Breg (CD19+CD24hiCD27+IL-10+cells/CD19+cells) (5.06 ± 4.68 vs. 8.83 ± 5.46%, p = 0.015) and HCC-infiltrating Breg (18.6 ± 10 vs. 33.51 ± 6.8%, p = 0.022) ratios but comparable circulating and HCC-infiltrating regulatory T cell ratios relative to patients without baseline MC. In conclusion, old male SVR patients with elevated ALT levels or cirrhosis require intensive monitoring for cancer development, especially HCC. Tailored HCC follow-up is needed for SVR patients according to their baseline MC, which might downregulate Bregs to decelerate HCC development for almost 2 years.
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MESH Headings
- Humans
- Male
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/epidemiology
- Cryoglobulinemia/immunology
- Cryoglobulinemia/complications
- Female
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Liver Neoplasms/etiology
- Liver Neoplasms/pathology
- Liver Neoplasms/epidemiology
- Middle Aged
- Prospective Studies
- B-Lymphocytes, Regulatory/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Hepatitis C, Chronic/immunology
- Sustained Virologic Response
- Aged
- Interleukin-10
- Antiviral Agents/therapeutic use
- Adult
- Hepacivirus
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Affiliation(s)
- Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jur-Shan Cheng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Yi-Jyun Shen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Elthes BZ, Vitalis Z, Papp M, Tornai T, Tornai D, Tornai I. Long Term Follow-Up of Patients with Cryoglobulinemia After Successful Treatment of Chronic C Virus Hepatitis. Dig Dis Sci 2025:10.1007/s10620-025-09033-8. [PMID: 40210820 DOI: 10.1007/s10620-025-09033-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 03/30/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND Mixed cryoglobulinemia is one of the most important extrahepatic manifestations of chronic hepatitis C infection. AIMS AND METHODS We screened 111 HCV-infected patients and identified 40 with cryoglobulinemia, who later achieved sustained virologic response (SVR). We prospectively followed them regarding laboratory findings and clinical symptoms for a median [IQR] of 5 [3-10] years. RESULTS Prior to antiviral treatment, the median serum cryoglobulin level was 297 (IQR: 61-1144) mg/L. In 25 patients type II, while in 15 type III cryoglobulinemia were found with significant difference in cryoglobulin levels (669 [297-2713] vs. 57 [33-123], respectively) (p < 0.001). Only 23 patients had clinical symptoms at the diagnosis, of whom 21 had cryoglobulinemic vasculitis and 2 non-Hodgkin's lymphoma (NHL), and 17 patients were asymptomatic. Cryoglobulin levels were monitored yearly after SVR. Median times to cryoglobulin disappearance were significantly different between type II and type III disease forms (36 vs. 12 months, pLog-Rank: 0.002). Improvement or complete cessation of complaints were parallel to the cryoglobulin disappearance. Vasculitis, in most cases (n = 16) and one NHL were cured spontaneously during follow-up observation. However, some patients required specific treatment, such as immunosuppression [n = 5] for vasculitis and combined chemotherapy [n = 1] for aggressive NHL. Relapses of cryoglobulinemia and related symptoms were detected in 2 patients. Importantly, polyneuropathy did not show improvement by any means. CONCLUSIONS Our results support that the monitoring of cryoglobulins is important even after SVR, especially in case of type II forms. Long-term complications such as severe vasculitis or NHL may still occur.
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Affiliation(s)
- Bianka Zsuzsa Elthes
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
- Faculty of Dentistry, Doctoral School of Dental Sciences, University of Debrecen, Debrecen, Hungary.
| | - Zsuzsanna Vitalis
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamas Tornai
- Institute for Pancreatic Disorders, Semmelweis University, Budapest, Hungary
- Department of Gastroenterology, Gent University Hospital, Ghent, Belgium
| | - David Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Istvan Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Faculty of Dentistry, Doctoral School of Dental Sciences, University of Debrecen, Debrecen, Hungary
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Wu JW, Chen WT, Huang CG, Chen YC, Hsu CW, Chien RN, Chang ML. Rheumatoid factor levels indicate cryoglobulinemia severity in hepatitis B e antigen-negative hepatitis B virus carriers: a 7-year prospective cohort study. Hepatol Int 2025; 19:118-130. [PMID: 39699792 DOI: 10.1007/s12072-024-10761-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/23/2024] [Indexed: 12/20/2024]
Abstract
BACKGROUND The phenotype of cryoglobulinemia in hepatitis B virus (HBV) carriers remains elusive. METHODS A 7-year prospective cohort of 648 hepatitis B e antigen (HBeAg)-negative Taiwanese HBV carriers [males: 344 (53%)] was conducted. RESULTS Among 648, 189 (29.2%) had cryoglobulinemia, and 26 (4.0%) had cryoglobulinemic syndrome (CS). More females; higher levels of rheumatoid factor (RF), immunoglobulin M (IgM) and fibrosis-4 indices; higher proportions of proteinuria, hematuria and hepatocellular carcinoma; and lower levels of quantitative HBsAg, C3, C4 and eGFR were noted in patients with than in those without cryoglobulinemia. The associations were RF levels with cryoglobulinemia (cutoff > 12.55 IU/mL), and RF levels and baseline autoimmune diseases with CS. CS patients, symptomless cryoglobulinemia patients and patients without cryoglobulinemia had the highest, moderate, and lowest RF levels, respectively. A greater percentage of mixed cryoglobulins [IgG (2 +), IgM (2 +) and IgA (1 +)] was noted in cryoglobulinemia patients with than in those without CS (11.5% vs. 0.81%, p = 0.002). Among the 7 CS patients treated with nucleos(t)ide analogues (Nucs), cryoglobulinemia disappeared in 3 and symptoms improved in 5 during therapy. The CS prevalence was highest (6%) in patients with a baseline age of 31-40 years. Among the 26 CS patients, 23 (88.5%), 20 (76.9%), and 16 (61.5%) had peripheral neuropathy, articular and skin involvement, respectively. The cumulative incidences of major outcomes and mortality did not differ between patients with and without cryoglobulinemia. CONCLUSIONS The prevalence rates of cryoglobulinemia and CS in HBeAg-negative HBV carriers were 29.2% and 4.0%, respectively. RF levels correlate with cryoglobulinemia severity. Mixed cryoglobulins of IgG (2 +), IgM (2 +) and IgA (1 +) are likely linked to CS, which might be alleviated by Nucs in some patients. The impact of cryoglobulinemia on long-term outcomes might be negligible.
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Affiliation(s)
- Jen-Wei Wu
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Guei Huang
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan
- Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan
| | - Yung-Chang Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chao-Wei Hsu
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan.
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Tsai YN, Lo JC, Tseng CH, Hsieh SC, Chiu WC, Tai CM, Chang CY, Lee FJ, Nguyen MH, Lin JT, Hsu YC. Changes in Serum Rheumatoid Factor Following Eradication of Hepatitis C Virus Infection With Interferon or Direct Antiviral Therapy. J Viral Hepat 2025; 32:1-8. [PMID: 39660778 DOI: 10.1111/jvh.14047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 11/09/2024] [Accepted: 11/30/2024] [Indexed: 12/12/2024]
Abstract
Hepatitis C virus (HCV) infection is associated with a myriad of extrahepatic manifestations (EHM), as well as the production of autoantibodies, including rheumatoid factor (RF). This study aims to elucidate whether serum levels of RF change before and after HCV eradication, and whether these changes differ according to the type of therapy used. This is a retrospective cohort study of adults with chronic HCV infection treated with interferon-free or interferon-based regimens. All patients had HCV viremia at baseline and documented sustained virological response (SVR) 12 or 24 weeks after completing treatment. We measured the serum levels of RF at baseline and at SVR-12 or -24 to analyse the changes after eradication. This study enrolled 297 patients (median age, 59 years; female, 48.5%; cirrhosis, 16.8%). Among them, 78 (26.3%) were RF-positive by qualitative serology at baseline. This number decreased to 49 (16.5%) at SVR-12 or -24 (p < 0.001). Quantitatively, the median RF also decreased from 1.6 IU/mL (interquartile range [IQR], undetectable-15.8) to undetectable (IQR, undetectable-6.6 IU/mL) (p < 0.001). Significant reductions were observed in both groups. The proportion with RF seropositivity decreased from 24.3% to 15.4% (p = 0.001) in patients treated with interferon-free agents (n = 214) and from 31.3% to 19.3% (p = 0.006) in patients treated with interferon-based regimens (n = 83), without significant difference between two groups (p = 0.40). Serum RF decreased after HCV eradication, regardless of treatment regimen. Our findings suggest that HCV eradication may attenuate HCV-related autoimmunity.
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Affiliation(s)
- Ying-Nan Tsai
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Jamie Chieh Lo
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Song-Chou Hsieh
- Division of Allergy, Immunology, and Rheumatology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Chin Chiu
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chi-Ming Tai
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chi-Yang Chang
- Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
| | - Fu-Jen Lee
- Division of Gastroenterology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
- Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California, USA
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Yao-Chun Hsu
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
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Chang ML, Le PH, Chen WT, Chen TD, Su CW, Chen CJ, Lin CY, Wu CH, Kuo CJ, Sung KF, Chien RN. Distinct characteristics of various autoimmune liver diseases: A 22-year hospital-based study in Taiwan. J Gastroenterol Hepatol 2024; 39:2835-2844. [PMID: 39307997 DOI: 10.1111/jgh.16736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/13/2024] [Accepted: 08/27/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND AND AIM The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC-AIH overlap syndrome (OS), have rarely been investigated and compared in Asia. METHODS At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC-AIH OS patients (85.7% treated with UDCA and IST) were enrolled. RESULTS Compared with AIH patients, PBC patients were older at baseline and had greater female-to-male sex ratios, alkaline phosphatase (ALP) and γ-glutamyl transferase (γ-GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22-year all-cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC-AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases. CONCLUSIONS Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.
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Affiliation(s)
- Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Tai-Di Chen
- Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chung-Wei Su
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Jen Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Yu Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chi-Huan Wu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kei-Feng Sung
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, New Taipei City, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Dashjamts G, Ganzorig AE, Tsedendorj Y, Dondov G, Nergui O, Badamjav T, Huang CF, Liang PC, Lonjid T, Batsaikhan B, Dai CY. Post-Treatment Occurrence of Serum Cryoglobulinemia in Chronic Hepatitis C Patients. Diagnostics (Basel) 2024; 14:1188. [PMID: 38893714 PMCID: PMC11171999 DOI: 10.3390/diagnostics14111188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/21/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Persistent cryoglobulinemia after the completion of antiviral treatment is an important consideration of clinical management in chronic hepatitis C patients. We aimed to investigate the occurrence of serum cryoglobulinemia in chronic hepatitis C patients without cryoglobulinemia at the initiation of antiviral treatment. METHODS In total, 776 patients without cryoglobulinemia were assessed for serum cryoglobulinemia after the completion of anti-HCV treatment. Serum cryoglobulinemia precipitation was assessed upon both the initiation and the completion of the treatment and analyzed for the clinical laboratory factors associated with chronic hepatitis C. RESULTS One hundred eighteen (118) patients were checked for serum cryo-precipitation after the completion of the treatment, and eight patients (4.6%) were positive for serum cryoglobulinemia. The patients who tested positive for cryoglobulinemia included a higher proportion of liver cirrhosis patients (4/50%, p = 0.033) and other organ cancer patients (5/62.5%, p = 0.006) than patients who showed no signs of cryoglobulinemia after treatment. In a multivariate analysis, liver cirrhosis (odds ratio [OR]-17.86, 95% confidence interval [95% CI]-1.79-177.35, p = 0.014) and other organ cancer (OR-25.17 95% CI-2.59-244.23, p = 0.005) were independently and significantly associated with positive cryoglobulinemia 3 months after antiviral treatment. CONCLUSIONS Three months after the antiviral DAA therapy had concluded, eight patients tested positive for cryoglobulinemia, representing a 6.7% prevalence. Liver cirrhosis and other organ cancer were independently and significantly associated with positive cryoglobulinemia after antiviral treatment. Further investigation into the causes of positive cryoglobulinemia after DAA antiviral therapy is warranted.
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Affiliation(s)
- Gantogtokh Dashjamts
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
| | - Amin-Erdene Ganzorig
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
| | - Yumchinsuren Tsedendorj
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
| | - Ganchimeg Dondov
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
| | - Otgongerel Nergui
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
| | - Tegshjargal Badamjav
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
- Department of Biological Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010031, China
| | - Chung-Feng Huang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.H.); (P.-C.L.)
- Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Po-Cheng Liang
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.H.); (P.-C.L.)
- Department of Occupational and Environmental Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Tulgaa Lonjid
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
| | - Batbold Batsaikhan
- Department of Internal Medicine, Institute of Medical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia; (G.D.); (A.-E.G.); (Y.T.); (G.D.); (O.N.); (T.B.); (T.L.)
- Department of Health Research, Graduate School, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
| | - Chia-Yen Dai
- Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan; (C.-F.H.); (P.-C.L.)
- Ph.D. Program in Environmental and Occupational Medicine, Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- College of Professional Studies, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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Méndez-Sánchez N, Coronel-Castillo CE, Ramírez-Mejía MM. Chronic Hepatitis C Virus Infection, Extrahepatic Disease and the Impact of New Direct-Acting Antivirals. Pathogens 2024; 13:339. [PMID: 38668294 PMCID: PMC11053783 DOI: 10.3390/pathogens13040339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 04/12/2024] [Accepted: 04/14/2024] [Indexed: 04/29/2024] Open
Abstract
Chronic hepatitis C virus infection is an important cause of liver cirrhosis, hepatocellular carcinoma and death. Furthermore, it is estimated that about 40-70% of patients develop non-hepatic alterations in the course of chronic infection. Such manifestations can be immune-related conditions, lymphoproliferative disorders and metabolic alterations with serious adverse events in the short and long term. The introduction of new Direct-Acting Antivirals has shown promising results, with current evidence indicating an improvement and remission of these conditions after a sustained virological response.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Unit Liver Research, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | | | - Mariana Michelle Ramírez-Mejía
- Unit Liver Research, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico;
- Plan of Combined Studies in Medicine (PECEM MD/PhD), Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
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Chang ML, Cheng JS, Le PH, Chen WT, Ku HP, Chien RN. Evolutionary relationship between antimitochondrial antibody positivity and primary biliary cholangitis in Taiwan: a 16-year hospital cohort study. Therap Adv Gastroenterol 2024; 17:17562848241241227. [PMID: 38560427 PMCID: PMC10981211 DOI: 10.1177/17562848241241227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 03/06/2024] [Indexed: 04/04/2024] Open
Abstract
Background How antimitochondrial antibody (AMA)-positive patients evolve to have primary biliary cholangitis (PBC) in viral hepatitis-endemic areas is unknown. Objectives We aimed to investigate this evolution in Taiwan. Design/methods A 16-year medical center-based cohort study of 2,095,628 subjects was conducted in Taiwan, an Asian country endemic to viral hepatitis. AMA-positive subjects were those with positive AMA with alkaline phosphatase (ALP) ⩽1.5 times the upper limit of normal (ULN), and PBC was defined as positive AMA with ALP >1.5 × ULN. Results AMA-positive subjects had a lower average age- and sex-adjusted prevalence than PBC patients (4.68/105 versus 11.61/105, p = 0.0002), but their incidence was comparable (0.99/105 versus 1.12/105, p = 0.36). The former group had a borderline significantly lower mean age (56.59 years versus 58.10 years, p = 0.06) and a lower female-to-male ratio (2.85:1 versus 5.44:1, p < 0.0001). Both AMA-positive subjects (prevalence change: 20.0%, p < 0.01; incidence change: -9.2%, p < 0.01) and PBC patients (prevalence change: 14.6%, p < 0.01; incidence change: -4.7%, p < 0.01) prevalence rate increased but the incidence rate decreased. Among the 423 AMA-positive subjects, 77 (18.2%) developed PBC, for a mean duration of 1.757 years. Compared with AMA-positive subjects, PBC patients had similar concurrent chronic hepatitis B (CHB) rates (2.7% versus 4.3%, p = 0.197) but lower chronic hepatitis C (CHC) rates (3.69% versus 15.60%, p < 0.01). Conclusion PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No. 5, Fu Hsing Street, Kuei Shan, Taoyuan 333423, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jur-Shan Cheng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Puo-Hsien Le
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hsin-Ping Ku
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Chang ML, Cheng JS, Chen WT, Hsu CW, Chen KH, Chen YC, Chien RN. Long-term renal function alterations in hepatitis C patients with SVRs: Impacts of therapies and mixed cryoglobulinemia. J Infect Public Health 2024; 17:486-494. [PMID: 38280352 DOI: 10.1016/j.jiph.2024.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 01/29/2024] Open
Abstract
BACKGROUND / AIMS Effects of anti-hepatitis C virus (HCV) therapeutic regimens and mixed cryoglobulinemia on long-term renal function of HCV-infected patients with viral clearance have not been determined. METHODS/MATERIALS A prospective 10-year cohort study of 1212 HCV-infected patients (interferon-based therapy, n = 615; direct-acting antiviral (DAA) therapy, n = 434) was conducted. RESULTS At baseline, age, body mass index (BMI), hemoglobin (Hb) and uric acid (UA) levels, and fibrosis-4 score were associated with estimated glomerular filtration rates (eGFRs) in HCV-infected patients. At 24 weeks posttherapy, age, BMI, and Hb and UA levels were associated with eGFRs in patients with a sustained virological response (SVR) (n = 930). Compared with those at baseline, the eGFRs were lower in SVR patients at 24 weeks posttherapy, regardless of the therapeutic regimen. The eGFRs reverted to baseline levels in interferon-treated SVR patients up to 10 years posttherapy but remained decreased in DAA-treated SVR patients up to 4 years posttherapy. Longitudinally, repeated measures analyses with generalized estimating equations showed that the interactions between DAA-based therapy and mixed cryoglobulinemia (OR: 3.291) and Hb levels (1.778) were positively, while DAA-based therapy (0.442), age (0.956), UA levels (0.698), homeostasis model assessment-insulin resistance index (0.961) and complement 4 levels (0.9395) were negatively associated with the eGFR. Among DAA-treated SVR patients, the baseline eGFR (OR: 1.014; 95%CI OR: 1.004-1.023) and high-sensitivity C-reactive protein (HR: 1.082; 95%CI HR: 1.018-1.15) were associated with eGFR reduction at 24 weeks and 4 years posttherapy, respectively. CONCLUSIONS Hepatic fibrosis was an HCV-related factor for renal function. Longitudinally, DAA therapy was negatively, while the interaction between DAA therapy and mixed cryoglobulinemia was positively associated with renal function in SVR patients; deteriorated renal function was recovered in interferon-treated SVR patients. Particularly in DAA-treated SVR patients, baseline renal function and systemic inflammation were associated with short- and long-term reductions in renal function, respectively.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Jur-Shan Cheng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Wei Hsu
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kuan-Hsing Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Yung-Chang Chen
- Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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10
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Assem NM, Mohammed AI, Barry HMA, El Sayed IET, Elmadbouh I. Serum cystatin C is an early renal dysfunction biomarker in patients with hepatitis C virus. EGYPTIAN LIVER JOURNAL 2022; 12:67. [DOI: 10.1186/s43066-022-00231-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 11/15/2022] [Indexed: 11/25/2022] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) may induce extrahepatic manifestations as acute or chronic renal dysfunction. The aim was to evaluate the diagnostic role of some biomarkers as cystatin C, cryoglobulins, rheumatoid factor (RF), and complement C3 for extrahepatic renal affection in newly diagnosed patients with HCV infection.
Methods
Blood and urine were collected from randomized individuals screened for new HCV infection (n=400). The studied populations were divided into 3 groups: control group I: thirty healthy individuals not suffering from either liver or kidney diseases, group IIa: thirty HCV patients who have positive HCV antibody test but showed negative PCR test, and group IIb: thirty HCV patients who showed positive results for both HCV antibody and PCR tests.
Results
In HCV group IIb, levels of serum total bilirubin, AST and ALT, and urine albumin/creatinine ratio were increased whereas serum albumin and creatinine clearance were decreased versus other groups. However, the levels of blood urea nitrogen and serum creatinine were still within the normal range in all groups. In HCV group IIb, cystatin C, cryoglobulins, and RF levels were increased; meanwhile, serum creatinine/cystatin C ratio and complement 3 levels were decreased compared to the other groups. HCV-infected patients significantly had higher serum cystatin C (>1.24 mg/L, P<0.001) and lower creatinine/cystatin C ratio (<70.1μMol/mg, P=0.002), and cystatin C was significantly correlated with liver and kidney parameters.
Conclusion
High serum cystatin C and low creatinine/cystatin C ratio may be early indicators of mild renal dysfunction with normal serum levels of creatinine in HCV-infected individuals.
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11
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Chang ML, Cheng JS, Chuang YH, Pao LH, Wu TS, Chen SC, Chang MY, Chien RN. Evolution of Cryoglobulinemia in Direct-Acting Antiviral-Treated Asian Hepatitis C Patients With Sustained Virological Responses: A 4-Year Prospective Cohort Study. Front Immunol 2022; 13:823160. [PMID: 35371039 PMCID: PMC8964347 DOI: 10.3389/fimmu.2022.823160] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background How cryoglobulinemia evolves after sustained virological response (SVR) following direct-acting antiviral (DAA) treatment in Asian hepatitis C virus (HCV)-infected patients remains elusive. Methods A prospective cohort study was conducted in 422 Taiwanese patients (358 completed DAA therapy and 353 experienced SVRs). Serum cryoglobulins were surveyed at baseline and every 3-6 months posttherapy. Results Of 422, 227 (53.8%) had cryoglobulinemia, 8 (1.89%) had cryoglobulinemic vasculitis. Of 227, 54 (23.8%), 57 (25.1%) and 116 (51.1%) had 1, 2 and 3 cryoglobulins, respectively; those with 3 cryoglobulins had the highest alanine aminotransferase, immunoglobulin G (IgG) and fibrosis-4 index. During a 4-year follow-up, among SVR patients, cryoglobulinemia rates decreased from 56.4% to 15.4%, single cryoglobulin rates increased (21.6% to 63.9%) and 3 cryoglobulin rates decreased (55.7% to 11.1%). Compared with baseline values, among SVR patients with baseline cryoglobulinemia, complement component 4 levels increased, and IgG and IgM levels decreased until 48 weeks posttherapy for those without posttherapy cryoglobulinemia. All 8 cryoglobulinemic vasculitis patients exhibited SVRs; 5 (62.5%) achieved complete clinical response 12 weeks posttherapy, of whom, 2 (40%) experienced clinical relapse 24~48 weeks posttherapy. Baseline IgM levels were associated with posttherapy cryoglobulinemia in SVR patients (cut-off values at 12, 24, 48 weeks and 4 years posttherapy: 130, 105, 118 and 168 mg/dL, respectively). Conclusions Among DAA-treated SVR patients, in 4 years, cryoglobulinemia rates decreased from 56.4% to 15.4%, multiple cryoglobulin rates decreased, cryoglobulinemia signals reversed, 62.5% of cryoglobulinemic vasculitis patients achieved complete clinical response (40% had relapse), and baseline IgM levels indicated posttherapy cryoglobulinemia.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jur-Shan Cheng
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ya-Hui Chuang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Dermatology, Chang Gung Memorial Hospital, Taipei and Linkou, Taiwan
| | - Li-Heng Pao
- Graduate Institute of Health-Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Ting-Shu Wu
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Department of Dermatology, Chang Gung Memorial Hospital, Taipei, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University, Taipei, Taiwan
| | - Ming-Yu Chang
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Chang ML, Lin YS, Chang MY, Hsu CL, Chien RN, Fann CSJ. Accelerated cardiovascular risk after viral clearance in hepatitis C patients with the NAMPT-rs61330082 TT genotype: An 8-year prospective cohort study. Virulence 2021; 12:270-280. [PMID: 33446046 PMCID: PMC7834047 DOI: 10.1080/21505594.2020.1870080] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/19/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Involvement of extracellular nicotinamide phosphoribosyltransferase (eNAMPT, i.e., visfatin or pre-B-cell colony-enhancing factor), a cancer metabokine, in chronically hepatitis C virus (HCV)-infected (CHC) patients with sustained virological responses (SVRs) remains elusive. This 8-year prospective cohort study evaluated eNAMPT profiles of 842 consecutive CHC patients, including 519 who had completed an anti-HCV therapy course and pre-therapy and 24-week post-therapy surveys. For 842 patients, pre-therapy associations were HCV RNA, homeostatic model assessment for insulin resistance (HOMA-IR) index, and body mass index with eNAMPT levels, and NAMPT-rs61330082 T allele with total cholesterol levels. NAMPT-rs10953502, NAMPT-rs2058539, and NAMPT-rs61330082 were in a linkage disequilibrium block, which was associated with total cholesterol levels. Compared to pre-therapy levels, at 24 weeks post-therapy, decreased eNAMPT and increased lipid levels were observed in SVR patients (n = 427). Among SVR patients, higher cumulative incidences of cardiovascular events occurred in those with a NAMPT-rs61330082 TT genotype than those with non-TT genotypes (28.2% vs. 8.4%, p < 0.001). NAMPT-rs61330082 TT genotype was independently associated with incident cardiovascular events (95% CI hazard ratio (HR): 1.88-10.37; HR: 4.415); no eNAMPT profiles were associated with incident malignancies. Of CHC patients, hepatic vascular endothelial cells and baseline peripheral leukocytes expressed higher eNAMPT levels than controls, and peripheral eNAMPT-positive leukocyte proportions decreased after SVR. During HCV infection, eNAMPT involvement in glucose metabolism was modulated by HCV RNA linked to lipid metabolism and NAMPT-associated SNPs. Hepatic endothelial cells and peripheral leukocytes potentially secrete eNAMPT. Caution is required for incident cardiovascular events in SVR patients with NAMPT-rs61330082 TT genotype.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Sheng Lin
- Healthcare Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Cardiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ming-Yu Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
- Division of Pediatric Neurologic Medicine, Chang Gung Children’s Hospital, Taoyuan, Taiwan
| | - Chia-Lin Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Rong-Nan Chien
- Liver Research Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cathy SJ Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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13
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Chang ML, Chen WT, Hu JH, Chen SC, Gu PW, Chien RN. Altering retinol binding protein 4 levels in hepatitis C: Inflammation and steatosis matter. Virulence 2021; 11:1501-1511. [PMID: 33135589 PMCID: PMC7605351 DOI: 10.1080/21505594.2020.1838742] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Both hepatitis C virus (HCV) infection and retinol-binding protein 4 (RBP4) might contribute to insulin resistance (IR), how RBP4 links to IR in HCV infection remain elusive. A joint study of a prospective cohort of 842 chronically HCV-infected (CHC) patients (with 842 controls) and a line of HCV core transgenic mice was conducted. Of 842 patients, 771 had completed anti-HCV therapy and 667 had sustained virological responses (SVRs). Compared with controls, CHC patients had lower RBP4 levels. At baseline, age (95% CI β: -0.87~-0.317), BMI (0.516~2.036), triglycerides (0.03~0.127), neutrophil-to-lymphocyte ratio (NLR) (1.561~7.327), and estimated glomerular filtration rate (eGFR) (-0.342~-0.149) levels were associated with RBP4 levels in CHC patients. At 24-week post-therapy, male sex (0.652~8.129), BMI (0.199~1.254), triglycerides (0.039~0.088), uric acid (0.599~3.067), eGFR (-0.247 ~-0.14) levels, and fibrosis-4 (-3.602~-0.039) scores were associated with RBP4 levels in SVR patients; compared with baseline, except genotype 3 HCV-infected patients, SVR patients had increased RBP4 levels, which were comparable with controls, while no HOMA-IR index alteration was noted after SVR. The HCV core transgenic mice exhibited nonobese hepatic steatosis, had higher hepatic RBP4 expression, higher serum levels of RBP4 and triglycerides, but comparable HOMA-IR levels than non-transgenic littermates. In conclusion, steatosis, sex, age, uric acid, NLR, and FIB-4 levels were associated with HCV-related RBP4 levels; BMI, triglycerides, and eGFR levels were associated with non-HCV-related RBP4 levels. Reversal of low RBP4 levels after SVR was evident in non-genotype 3 HCV-infected patients. Steatosis and inflammation linked with metabolic alteration other than IR, determined RBP4 levels in HCV-infected patients.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan
| | - Jing-Hong Hu
- Department of Internal Medicine, Chang Gung Memorial Hospital , Yunlin, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University , Taipei, Taiwan
| | - Po-Wen Gu
- Department of Medical Laboratory, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Division of Biotechnology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University , Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital , Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University , Taoyuan, Taiwan
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14
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Chang ML, Hu JH, Chen WT, Lin MS, Kuo CJ, Chen SC, Chien RN. Interactive Impacts from Hepatitis C Virus Infection and Mixed Cryoglobulinemia on Complement Levels. Dig Dis Sci 2021; 66:2407-2416. [PMID: 32737636 DOI: 10.1007/s10620-020-06507-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 07/19/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIM How hepatitis C virus (HCV) infection and mixed cryoglobulinemia interactively affect complement levels remains elusive, and we aimed to elucidate it. METHODS A prospective cohort study of 678 consecutive chronic HCV-infected (CHC) patients was conducted. Of 678, 438 had completed a course of anti-HCV therapy and 362 had achieved a sustained virological response (SVR). The baseline and 24-week post-therapy variables including complement levels and mixed cryoglobulinemia status were surveyed. RESULTS At baseline, lower complement component 3 (C3) and component 4 (C4) levels were noted in patients with than those without mixed cryoglobulinemia. The differences between pre-therapy (in 678 CHC patients) and 24-week post-therapy (in 362 SVR patients) factors associated with C3 levels were interferon λ3 (IFNL3) genotype, triglycerides, cirrhosis, and estimated glomerular filtration rate; the different associations with C4 levels were cirrhosis, sex and high sensitivity C-reactive protein. Compared with baseline, SVR patients without pre- and post-therapy mixed cryoglobulinemia had increased C3 levels, and SVR patients with pre-therapy mixed cryoglobulinemia had increased C4 levels. Lower C3 levels were noted in SVR patients with than those without post-therapy mixed cryoglobulinemia. CONCLUSIONS HCV might affect C3 levels through IFNL3 genotype, triglycerides, cirrhosis, and renal function; and affect C4 with a link to sex, inflammation, and cirrhosis. That C3 levels decreased in CHC patients without mixed cryoglobulinemia or in SVR patients with post-therapy mixed cryoglobulinemia, and C4 levels decreased in CHC patients with mixed cryoglobulinemia, suggested that mixed cryoglobulinemia and HCV infection antagonistically and synergistically decrease C3 and C4 levels, respectively.
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Affiliation(s)
- Ming-Ling Chang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan. .,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. .,Liver Research Center, Chang Gung Memorial Hospital, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan.
| | - Jing-Hong Hu
- Department of Internal Medicine, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Wei-Ting Chen
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Shyan Lin
- Department of Cardiology, Heart Failure Center, Chang Gung Memorial Hospital, Yunlin, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University, Taipei, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, No 5, Fu Hsing Street, Kuei Shan, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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15
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Chu YY, Cheng JS, Wu TS, Chen CW, Chang MY, Ku HP, Chien RN, Chang ML. Association between Hepatitis C Virus Infection and Esophageal Cancer: An Asian Nationwide Population-Based Cohort Study. J Clin Med 2021; 10:jcm10112395. [PMID: 34071668 PMCID: PMC8198559 DOI: 10.3390/jcm10112395] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Hepatitis C virus (HCV) infection causes many extrahepatic cancers, and whether HCV infection is associated with esophageal cancer development remains inconclusive. Methods: A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database (TNHIRD) was conducted. Results: From 2003 to 2012, of 11,895,993 patients, three 1:1:1 propensity score-matched cohorts, including HCV-treated (interferon-based therapy ≧6 months, n = 9047), HCV-untreated (n = 9047), and HCV-uninfected cohorts (n = 9047), were enrolled. The HCV-untreated cohort had the highest 9-year cumulative incidence of esophageal cancer among the three cohorts (0.174%; 95% confidence interval (CI): 0.068–0.395) (p = 0.0292). However, no difference in cumulative incidences was identified between the HCV-treated (0.019%; 0.002–0.109%) and HCV-uninfected cohorts (0.035%; 0.007–0.133%) (p = 0.5964). The multivariate analysis showed that HCV positivity (hazard ratio (HR): 5.1, 95% CI HR: 1.39–18.51) and male sex (HR: 8.897; 95% CI HR: 1.194–66.323) were independently associated with the development of esophageal cancer. Of the three cohorts, the HCV-untreated cohort had the highest cumulative incidence of overall mortality at 9 years (21.459%, 95% CI: 18.599–24.460) (p < 0.0001), and the HCV-treated (12.422%, 95% CI: 8.653–16.905%) and HCV-uninfected cohorts (5.545%, 95% CI: 4.225–7.108%) yielded indifferent cumulative mortality incidences (p = 0.1234). Conclusions: Although HCV positivity and male sex were independent factors associated with esophageal cancer development, whether HCV infection is the true culprit or a bystander for developing esophageal cancer remains to be further investigated. Interferon-based anti-HCV therapy might attenuate esophageal risk and decrease overall mortality in HCV-infected patients.
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Affiliation(s)
- Yin-Yi Chu
- Division of Gastroenterology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (Y.-Y.C.); (C.-W.C.)
- Department of Gastroenterology and Hepatology, New Taipei Municipal Tu Cheng Hospital, New Taipei City 236, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan; (T.-S.W.); (M.-Y.C.); (R.-N.C.)
| | - Jur-Shan Cheng
- Clinical Informatics and Medical Statistics Research Center, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
- Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Ting-Shu Wu
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan; (T.-S.W.); (M.-Y.C.); (R.-N.C.)
- Division of Infectious Diseases, Department of Internal Medicine, Linkou 333423, Taiwan
| | - Chun-Wei Chen
- Division of Gastroenterology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan; (Y.-Y.C.); (C.-W.C.)
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan; (T.-S.W.); (M.-Y.C.); (R.-N.C.)
| | - Ming-Yu Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan; (T.-S.W.); (M.-Y.C.); (R.-N.C.)
- Division of Pediatric Neurologic Medicine, Chang Gung Children’s Hospital, Taoyuan 333423, Taiwan
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Hsin-Ping Ku
- Department of Gastroenterology and Hepatology, New Taipei Municipal Tu Cheng Hospital, New Taipei City 236, Taiwan;
| | - Rong-Nan Chien
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan; (T.-S.W.); (M.-Y.C.); (R.-N.C.)
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
| | - Ming-Ling Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan; (T.-S.W.); (M.-Y.C.); (R.-N.C.)
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
- Correspondence: ; Tel.: +886-3-3281200 (ext. 8102); Fax: +886-3-3272236
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Maslennikov R, Ivashkin V, Efremova I, Shirokova E. Immune disorders and rheumatologic manifestations of viral hepatitis. World J Gastroenterol 2021; 27:2073-2089. [PMID: 34025065 PMCID: PMC8117740 DOI: 10.3748/wjg.v27.i18.2073] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/28/2021] [Accepted: 04/22/2021] [Indexed: 02/06/2023] Open
Abstract
Infection with hepatotropic viruses is not limited to the liver and can lead to the development of various immunological disorders (the formation of cryoglobulins, rheumatoid factor, antinuclear antibodies, autoantibodies specific for autoimmune hepatitis and primary biliary cholangitis, and others), which can manifest as glomerulonephritis, arthritis, uveitis, vasculitis (cryoglobulinemic vasculitis, polyarteritis nodosa, Henoch-Schonlein purpura, isolated cutaneous necrotizing vasculitis), and other rheumatologic disorders, and be a trigger for the subsequent development of autoimmune hepatitis and primary biliary cholangitis. A further study of the association between autoimmune liver diseases and hepatotropic virus infection would be useful to assess the results of treatment of these associated diseases with antiviral drugs. The relationship of these immune disorders and their manifestations with hepatotropic viruses is best studied for chronic hepatitis B and C. Only isolated cases of these associations are described for hepatitis A. These links are least studied, and are often controversial for hepatitis E, possibly due to their relatively rare diagnoses. Patients with uveitis, glomerulonephritis, arthritis, vasculitis, autoimmune liver diseases should be tested for biomarkers of viral hepatitis, and if present, these patients should be treated with antiviral drugs.
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Affiliation(s)
- Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
- The Interregional Public Organization “Scientific Community for the Promotion of the Clinical Study of the Human Microbiome”, Moscow 119435, Russia
- Department of Internal Medicine 1, Сonsultative and Diagnostic Center 2 of the Moscow City Health Department, Moscow 107564, Russia
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
| | - Elena Shirokova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Moscow 119435, Russia
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Chang ML, Chang SW, Chen SC, Chien RN, Hsu CL, Chang MY, Fann CSJ. Genetic Association of Hepatitis C-Related Mixed Cryoglobulinemia: A 10-Year Prospective Study of Asians Treated with Antivirals. Viruses 2021; 13:464. [PMID: 33799903 PMCID: PMC7998980 DOI: 10.3390/v13030464] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 12/16/2022] Open
Abstract
Genetic profiles of hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) in Asians remain elusive. A 10-year prospective cohort study was conducted with 1043 consecutive HCV Ab-positive Taiwanese surveyed with 13 single nucleotide polymorphisms (SNPs). Of 1043, 589 (56.5%) had baseline MC, 934 (89.5%) had positive HCV RNA, 796 completed anti-HCV therapy, and 715 had sustained virological responses (SVRs). SNP associations were surveyed withgenotypic, allelic, trend, permutation and multivariate analyses. At baseline, higher male sex and MC rates were noted in HCV RNA-positive than RNA-negative patients; higher female sex and positive HCV RNA rates but lower HCV RNA levels were noted in patients with than those without MC. Baseline associations were: HLA II-rs9461776 A allele, IFNL3-rs12979860 T allele, SERPINE1-rs6976053 C allele and MC with HCV RNA positivity; IFNL3-rs12979860 C allele, ARNTL-rs6486122 T allele and HCV RNA positivity with baseline MC. In SVR patients, RETN-rs1423096 C allele and SERPINE1-rs6976053 T allele were associated with 24-week and 10-year post-therapy MC, respectively. Conclusions: HCV RNA, IFNL3-rs12979860 and ARNTL-rs6486122 were associated with baseline MC; RETN-rs1423096 and SERPINE1-rs6976053 were associated with short- and long-term post-therapy MC in SVR patients, respectively. Links with HCV RNA and immune-associated SNPs suggest MC an immune reaction to expel HCV.
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Affiliation(s)
- Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
| | - Su-Wei Chang
- Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyua 333423, Taiwan;
- Division of Allergy, Asthma, and Rheumatology, Department of Paediatrics, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan
| | - Shiang-Chi Chen
- Department of Nursing, Taipei Medical University, Taipei 11031, Taiwan;
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333423, Taiwan;
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
| | - Chia-Lin Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan;
| | - Ming-Yu Chang
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 333423, Taiwan;
- Division of Pediatric Neurologic Medicine, Chang Gung Children’s Hospital, Taoyuan 333423, Taiwan
- Division of Pediatrics, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Cathy S. J. Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115024, Taiwan;
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Impact of Interferon-Based Therapy on Hepatitis C-Associated Rheumatic Diseases: A Nationwide Population-Based Cohort Study. J Clin Med 2021; 10:jcm10040817. [PMID: 33671397 PMCID: PMC7922671 DOI: 10.3390/jcm10040817] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/06/2021] [Accepted: 02/12/2021] [Indexed: 12/29/2022] Open
Abstract
Whether hepatitis C virus (HCV) infection-associated risk of rheumatic diseases is reversed by anti-HCV therapy remain elusive. A nationwide population-based cohort study of the Taiwan National Health Insurance Research Database was conducted. Of 19,298,735 subjects, 3 cohorts (1:4:4, propensity score-matched), including HCV-treated (6919 HCV-infected subjects with interferon and ribavirin therapy ≥ 6 months), HCV-untreated (n = 27,676) and HCV-uninfected (n = 27,676) cohorts, were enrolled and followed (2003–2015). The HCV-uninfected cohort had the lowest cumulative incidence of rheumatic diseases (95% confidence interval (CI): 8.416–10.734%), while HCV-treated (12.417–17.704%) and HCV-untreated (13.585–16.479%) cohorts showed no difference in the cumulative incidences. Multivariate analyses showed that HCV infection (95% CI hazard ratio (HR): 1.54–1.765), female sex (1.57–1.789), age ≥ 49 years (1.091–1.257), Charlson comorbidity index ≥ 1 (1.075–1.245), liver cirrhosis (0.655–0.916), chronic obstruction pulmonary disease (1.130–1.360), end-stage renal disease (0.553–0.98), diabetes mellitus (0.834–0.991) and dyslipidemia (1.102–1.304) were associated with incident rheumatic diseases. Among the 3 cohorts, the untreated cohort had the highest cumulative incidence of overall mortality, while the treated and un-infected cohorts had indifferent mortalities. Conclusions: HCV infection, baseline demographics and comorbidities were associated with rheumatic diseases. Although HCV-associated risk of rheumatic diseases might not be reversed by interferon-based therapy, which reduced the overall mortality in HCV-infected patients.
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Evolution of ferritin levels in hepatitis C patients treated with antivirals. Sci Rep 2020; 10:19744. [PMID: 33184464 PMCID: PMC7661708 DOI: 10.1038/s41598-020-76871-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/02/2020] [Indexed: 12/11/2022] Open
Abstract
The evolution of ferritin levels in hepatitis C virus (HCV)-infected patients with sustained virological responses (SVRs) following various therapy regimens remains elusive. An 8-year prospective cohort study of 1194 HCV-infected patients [interferon-based therapy (n = 620), direct-acting antiviral agent (DAA) therapy (n = 355)] was conducted. At baseline, sex, alanine aminotransferase (ALT), triglycerides, homeostatic model assessment of insulin resistance (HOMA-IR), estimated glomerular filtration rate (eGFR), hemoglobin, iron/total iron-binding capacity (Fe/TIBC) and IFNL3-rs12979860 genotypes were associated with ferritin levels. At 24 weeks posttherapy, ALT, triglycerides, total cholesterol, eGFR, Fe/TIBC and the therapy regimen were associated with ferritin levels in SVR patients. Among interferon-treated patients, ferritin levels increased at 24 weeks posttherapy, regardless of SVR, and 24-week posttherapy ferritin levels were higher in non-SVR patients (n = 111) than in SVR patients (n = 509); ferritin levels began decreasing at 3 years posttherapy and were lower than pretherapy levels since 4 years posttherapy in SVR patients. Among DAA-treated SVR patients (n = 350), ferritin levels decreased and remained stable since 24 weeks posttherapy. ALT, triglycerides, eGFR, and Fe/TIBC were HCV-unrelated factors associated with ferritin levels; sex, HOMA-IR, total cholesterol, hemoglobin and IFNL3-rs12979860 genotype were HCV-related factors associated with ferritin levels. In interferon-treated SVR patients, the increased trend of posttherapy ferritin levels was not reversed until 4 years posttherapy. In DAA-treated SVR patients, ferritin levels decreased since 24 weeks posttherapy.
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Metabolic Signature of Hepatic Fibrosis: From Individual Pathways to Systems Biology. Cells 2019; 8:cells8111423. [PMID: 31726658 PMCID: PMC6912636 DOI: 10.3390/cells8111423] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 11/08/2019] [Accepted: 11/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer’s ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans.
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