Critical role of triglycerides for adiponectin levels in hepatitis C: a joint study of human and HCV core transgenic mice.

BACKGROUND: Both hepatitis C virus (HCV) infection and adiponectin are critically involved in metabolism. The reversal and associations of altering adiponectin levels after sustained virological responses (SVRs) following direct-acting antivirals (DAA) in HCV-infected patients remained elusive. METHODS: A joint study was conducted in a prospective cohort of 427 HCV-infected patients and a line of HCV core transgenic mice. RESULTS: Of 427, 358 had completed a course of DAA therapy and 353 had SVRs. At baseline, male sex (95% CI ß: - 1.44 to - 0.417), estimated glomerular filtration rate (eGFR) (- 0.025 to - 0.008), triglycerides (- 0.015 to - 0.005), and fibrosis-4 levels (0.08-0.297) were associated with adiponectin levels; BMI (0.029-0.327) and triglycerides levels (0.01-0.03) were associated with homeostatic model assessment for insulin resistance (HOMA-IR) in HCV-infected patients. At 24-week post-therapy, in SVR patients, male sex (- 1.89 to - 0.5) and eGFR (- 0.02 to - 0.001) levels were associated with adiponectin levels, levels of BMI (0.094-0.335) and alanine transaminase (0.018-0.078) were associated with HOMA-IR; compared with baseline levels, adiponectin levels decreased (6.53 ± 2.77 vs. 5.45 ± 2.56 µg/mL, p < 0.001). In 12-month-old HCV core transgenic mice with hepatic steatosis, triglyceride levels (0.021-0.111) were associated with adiponectin levels, and hepatic adipopnectin expression was comparable with that of control mice. CONCLUSIONS: Triglycerides and hepatic fibrosis are associated with HCV-specific alteration of adiponectin levels, and adiponectin may affect insulin sensitivity through triglycerides during HCV infection. In DAA-treated patients, after SVR, adiponectin levels decreased and the linking function of triglycerides between adiponectin and insulin sensitivity vanished. Moreover, HCV core with hepatic steatosis might affect extrahepatic adiponectin expression through triglycerides.

Interactive Impacts from Hepatitis C Virus Infection and Mixed Cryoglobulinemia on Complement Levels.

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.

Anti-Mitochondrial Antibody Titers Decrease Over Time in Primary Biliary Cholangitis Patients With Ursodeoxycholic Acid Therapeutic Response: A Cohort Study Followed Up to 28 Years.

Background: How anti-mitochondrial antibody (AMA) and liver biochemistry levels change in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic acid (UDCA) remains unclear. Methods: A 28-year cohort of 157 PBC patients was conducted. Patients with alkaline phosphatase (Alk-p) levels >1.67 × upper limit of normal after 1 year of UDCA treatment were considered nonresponders. Results: At baseline, of 157 (mean age: 54.41 years), 136 (86.6%) were female, 51 (32.5%) had cirrhosis, and 128 (81.5%) had detectable AMAs (immunoglobulin G). UDCA nonresponders (n=61) were younger and had higher Alk-p and total bilirubin levels and cirrhosis rates than UDCA responders (n=84). Alk-p levels and cirrhosis were negatively associated with UDCA response. Regardless of cirrhosis and UDCA response, most PBC patients had decreased Alk-p and γ-glutamyltransferase levels at last follow-up (up to 28.73 years) compared with baseline levels. Patients with baseline cirrhosis (2.78 ± 2.56 vs. 6.84 ± 9.00 mg/dL, p=0.024) and UDCA nonresponders (2.54 ± 2.19 vs. 4.51 ± 6.99 mg/dL, p=0.006) had increased total bilirubin levels while patients without cirrhosis (AST: 91.5 ± 84.5 vs. 58.9 ± 43.7 U/L, p<0.001; ALT: 107.3 ± 122.5 vs. 50.7 ± 36.8 U/L, p<0.001) and UDCA responders (AST: 83.8 ± 101.3 vs. 45.58 ± 38.42 U/L, p=0.014; ALT: 95.10 ± 144.6 vs. 39.12 ± 30.65 U/L, p=0.009) had decreased aminotransferase levels. Only UDCA responders had decreased AMA titers from 1 year after UDCA treatment (p=0.028) until the last follow-up (p<0.001). Conclusions: UDCA responders exhibited decreased AMA titers 1 year after treatment. Regardless of UDCA response, PBC patients showed improved cholestatic features, but only UDCA responders and patients without baseline cirrhosis exhibited attenuated hepatobiliary damage following UDCA treatment.

Evolution of Cryoglobulinemia in Direct-Acting Antiviral-Treated Asian Hepatitis C Patients With Sustained Virological Responses: A 4-Year Prospective Cohort Study.

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.

Fetal Macrophages Exposed to Salmonella Antigens Elicit Protective Immunity Against Overwhelming Salmonella Challenge in A Murine Model.

Despite the evidence for fetal immunization following maternal infection, it remained a mystery how the fetal immune system was primed by vertically-transmitted pathogens or microbial antigens, especially before its full maturation. We previously demonstrated the capacity of fetal macrophages for endocytosing oncoprotein and allergens to bridge towards adaptive immunity in postnatal life. To investigate the immunological consequences of fetal contact with microbial antigens and the role of fetal macrophages in the defense against infection before T-cell development, we exposed gestational day 14 murine fetuses and their macrophages to flagellin and heat-killed Salmonella Typhimurium. Recipients with in utero exposure to Salmonella antigens or adoptive transfer of microbial antigen-loaded fetal macrophages were examined for immune responses to Salmonella antigens and resistance to virulent Salmonella challenge. Fetal exposure to microbial antigens or adoptive transfer of microbial antigen-loaded fetal macrophages could confer antigen-specific adaptive immunity. However, protective immunity against lethal Salmonella challenge was only granted to those receiving heat-killed Salmonella antigens, presenting as heightened recall responses of serum anti-lipopolysaccharide immunoglobulins and interferon-gamma. In immunized recipients surviving Salmonella challenge, their serum transfer to succeeding recipients provided immediate protection from lethal Salmonella challenge in preference to lymphocyte transfer, indicating a more active role of humoral immunity in the prevention of Salmonella invasiveness. Our study sheds insight on the role of fetal macrophages in immunogenicity to transplacental pathogens regardless of fetal lymphocyte maturity, paving the way for fetal macrophage therapies to enhance vaccine responsiveness or increase resistance to pathogenic microorganisms in perinatal life.

Genetic Association of Hepatitis C-Related Mixed Cryoglobulinemia: A 10-Year Prospective Study of Asians Treated with Antivirals.

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.

Altering retinol binding protein 4 levels in hepatitis C: Inflammation and steatosis matter.

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 ß: -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.

Evolution of ferritin levels in hepatitis C patients treated with antivirals.

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.