Impact of mixed cryoglobulinemia on patients with spontaneous hepatitis C virus clearance: A 13‐year prospective cohort study

Abstract

Background:The prevalence and associations of mixed cryoglobulinemia (MC) in patients with spontaneous clearance of hepatitis C virus (HCV) remain elusive. Materials and methods: A 13-year prospective cohort study of patients with spontaneous HCV clearance was conducted in a tertiary care centre. Baseline characteristics, incident cardiovascular and neurologic events and cancers were analysed. Results: Of 104 consecutive patients (mean age: 54.08 years old; females: 71 [68%]), 37 (34.6%) had MC and 6 (5.8%) had cirrhosis. MC (+) patients were more female (86% vs 58%, P = .002), had higher rate of cirrhosis (14% vs 1.5%, P = .012), higher levels of Immunoglobulin G (IgG; P = .001), IgM (P = .002) and fibrosis-4 (FIB-4) (P = .004), but lower levels of complement C4 (P = .034) than the MC (−) patients. Female gender (95% confidence interval [CI] of odds ratio: 1.402-26.715), levels of IgG (1.000-1.004), IgM (1.009-1.037) and FIB-4 (1.217-3.966) were independently associated with MC. Baseline rheumatoid factor (RF) levels were independently associated with incident cancer (95% CI hazard ratio [HR]: 1.001-1.030 [HR: 1.015], P = .039). With a cut-off value of 11.3 IU/mL, RF levels significantly predicted incident cancer (area under curve: 0.865, P = .002). No different cumulative incidences of cardiovascular and neurologic events, cancers or mortalities were identified between MC (+) and MC (−) patient. Conclusions: Approximately 1/3 of patients with spontaneous HCV clearance yielded MC, which harboured similar characteristics of MC in patients with chronic hepatitis C. Despite the negligible role of MC in the prognosis of patients with spontaneous HCV clearance, the connection between RF and incident cancer demands further investigation. K E Y W O R D S cancer, hepatitis C virus clearance, mixed cryoglobulinemia, rheumatoid factor 2 of 8 | LEE Et aL.

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

“…Type II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes, whereas in type III cryoglobulins, both IgM and IgG are polyclonal (28), and both type II and type III cryoglobulins are mixed cryoglobulins. Compared with patients without cryoglobulinemia, patients with 1 cryoglobulin had less severe hepatic inflammation but worse renal impairment; among those with cryoglobulinemia, patients with 3 cryoglobulins were most likely to have mixed cryoglobulinemia (3,10,26) and had the most severe hepatic fibrosis and impaired hepatic synthesis. In particular, no patients with 1 cryoglobulin harbored IgA cryoglobulin, which lessens the possibility of IgA nephropathy, since there is a close relationship between the presence of IgA in cryoglobulinemia immune complexes and its detection in glomeruli (29).…”

“…Among SVR patients with baseline cryoglobulinemia, at 12 weeks posttherapy, all signals for cryoglobulinemia had been reversed, as the levels of C3, C4, IgG, IgM and RF ( 3 , 10 ) all changed in those without 12-week posttherapy cryoglobulinemia, and the reversals persisted for all parameters except for C3 and RF until 48 weeks posttherapy for those without any posttherapy cryoglobulinemia. These findings were consistent with the notions that decreased C4 but not C3 was the unfailing stigma for mixed cryoglobulinemia in untreated CHC patients ( 31 ), and RF levels were correlated with the severity of mixed cryoglobulinemia in a dose-dependent manner ( 3 ).…”

“…This finding is consistent with the fact that mixed cryoglobulinemia was linked with a favorable interferon therapeutic response ( 25 ), and a lower cryoglobulinemia rate in patients with previous interferon treatment failure (46.5 vs. 64.5%) might reduce the average cryoglobulinemia rate in the current cohort. Compared with patients without cryoglobulinemia, patients with cryoglobulinemia had higher cirrhosis rates and FIB-4 indexes and lower TC levels and platelet counts, indicating that mixed cryoglobulinemia was associated with cirrhosis and poor cholesterol synthesis ( 3 , 10 ), while patients with cryoglobulinemia had higher levels of IgG and IgM and lower levels of C3, C4 and HCV RNA, reflecting the paramount phenotype of mixed cryoglobulinemia ( 3 , 10 , 26 ). Thus, the baseline comparisons strengthen the reliability of our data.…”

“…By contrast, in Asia, mixed cryoglobulinemia is an elusive condition. We previously showed that over 60% of Taiwanese patients with CHC had mixed cryoglobulinemia ( 3 ), and even among patients with spontaneous HCV clearance, approximately 1/3 had mixed cryoglobulinemia ( 10 ). Mixed cryoglobulinemia thus is not a minor issue for Asian individuals with HCV infection.…”

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

“…Subjects with human immunodeficiency virus infection, hepatitis B virus infection, hemochromatosis, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis or malignancy and recipients of solid organ transplants were excluded. Among the HCV Ab-positive subjects, CHC was defined as detectable HCV RNA by PCR for >24 weeks [3], spontaneous HCV clearance was defined as positive HCV Ab but undetectable HCV RNA without any anti-HCV therapy [24]. Mixed cryoglobulinemia was defined as positive serum mixed cryoglobulins.…”