Our study, encompassing a sample size of 1,682 patients, represents the most extensive population analyzed to date in examining the factors and their correlation with pre-treatment ferritin levels in patients with HCV. To ensure the robustness of our study and minimize confounding variables, we diligently excluded patients with decompensated cirrhosis, a history of HCC, ESKD, HIV coinfection, organ transplantation, heightened alcohol consumption, and iron deficiency anemia that enhanced the reliability and validity.
We demonstrated that individuals aged > 50 years and those with ALT levels exceeding > 2 folds ULN were more likely to exhibit hyperferritinemia, consistent with previous researches.9,23,24. Conversely, sex and eGFR at a cut-off of 60 mL/min/1.73m2 were not found to be correlated with hyperferritinemia. The apparent discrepancy in the influence of eGFR on ferritin dynamics compared to earlier reports may be attributed to our exclusion of participants with ESKD and the inclusion of a limited number of participants with an eGFR below 60 mL/min/1.73m2, who were susceptible to hyperferritinemia.25
Patients with HCV are at risk of developing insulin resistance, which can lead to MS.26–28 The prevalence of NAFLD among individuals with HCV is estimated to be as high as 55%, with a range spanning from 40–86%, influenced by the distribution of MS and HCV genotypes.29 According to the diagnostic criteria of MASLD, an updated nomenclature aimed at encompassing a broader spectrum of etiologies for steatotic liver disease, our population exhibits a prevalence rate of MASLD of 38.6%.20 Within MASLD alone, there is a notable correlation between hyperferritinemia and the severity of liver fibrosis.30,31 While no studies have specifically examined the prevalence rate of hyperferritinemia in individuals with concurrent HCV and MASLD, it can be inferred that this population likely exhibits greater rates compared to HCV or MASLD alone. The prevalence rate of hyperferritinemia among our patients reached 53%, significantly higher than the reported prevalence rates of approximately 30% in subjects with MASLD alone.32
Chronic HCV infection induces hepatocyte injury, accompanied by the accumulation of extracellular matrix (ECM) proteins, ultimately resulting in accelerating hepatic fibrotic. The process of fibrotic change is dynamic, with later stages indicating increased severity.33,34 While the stage of hepatic fibrosis and hyperferritinemia indicate the severity of hepatocyte damage, previous studies have provided limited evidence linking the severity of hepatic fibrosis to hyperferritinemia. Our study is the first to demonstrate a positive correlation between hyperferritinemia and the severity of hepatic fibrosis, utilizing two noninvasive indices, the FIB-4 scores and LSMs, as assessment tools. Univariate analysis revealed either higher FIB-4 scores (> 3.25) or LSMs (≥ 9.5 kPa) were associated with hyperferritinemia in both the entire population and those with MASLD. Due to the high collinearity between the FIB-4 score and LSM, and a relatively smaller sample size compared to the entire population, LSM was excluded as an independent risk factor in the multivariate model for association with hyperferritinemia among participants with MASLD. We also demonstrated that within the context of MASLD, T2D or obesity did not increase the risk of hyperferritinemia. This implies that the presence of MS, regardless of the potential contributing factors, may lead to systemic inflammation, thus resulting in hyperferritinemia.20,35,36
Current evidence indicates that neither the HCV vial load nor genotype correlates with ALT levels or histological presentation, including necroinflammation or fibrosis. This is evident from our observations, showing no correlation between either ALT level or FIB-4 score with HCV viral load.37 However, to date, no studies have investigated the correlation of hyperferritinemia with HCV viral load or genotype. This study is the first to demonstrate a lack of significant correlation between HCV viral load/genotype and hyperferritinemia.
With regard to HBV infection, prior studies hypothesized that active HBV replication may result in elevated serum levels of iron and ferritin.38 However, our participants with HBV coinfection, characterized by an almost negligible median log10 HBV viral load of 0 and more than half of them without detectable HBV DNA, demonstrated that neither HBsAg nor the viral load were associated with hyperferritinemia. Additionally, the median log10 HBV viral load did not show a significant association with ALT levels or FIB-4 scores. While our observation fails to confirm the proposed hypothesis, the lack of association of hyperferritinemia with HBV DNA due to the suppression of HBV load from active HCV replication may not be extrapolated to individuals with HBV alone, where the HBV viral load tends to be higher than that in HBV/HCV-coinfected subjects.39,40
Although the risk of hyperferritinemia is consistently increased among individuals with chronic HCV infection, it remains unclear if there is a dosing effect of viral load on serum ferritin levels. In contrast to the low HBV load in our coinfected participants, most of whom had active HCV replication, as evidenced by a high median viral load. However, the HCV load did not exhibit a significant association with serum ferritin levels, ALT levels, or FIB-4 scores. Based on the similar trends observed in the association of HBV or HCV load with serum ferritin levels, we deduce that rather than direct virological effects, the serum level of ferritin is augmented indirectly through immune responses to HBV or HCV.
Despite enrolling a sizable number of participants and meticulously excluding potential confounders to mitigate the imprecise risk estimates, several limitations are present in the current study. Firstly, this study was conducted exclusively in East Asians, and external validation should be conducted to confirm our findings in other ethnic populations. Secondly, we did not conduct HFE C282Y and H63D testing to exclude participants with HFE hemochromatosis. However, the presence of C282Y homozygotes and C282Y/H63D heterozygote in Asians is rare, rendering the genetic testing unnecessary.5 Thirdly, we did not analyze the serum iron and transferrin saturation because only a minority of subjects with chronic viral hepatitis exhibit these derangements.2
In conclusion, our study reveals that hyperferritinemia in patients with chronic HCV infection is primarily influenced by host factors such as age, severity of hepatic fibrosis, MASLD, and ALT levels, rather than viral factors. While viral factors may not directly predispose to hyperferritinemia, vigilant management of HBV and HCV using effective antiviral therapies remains essential to indirectly mitigate hyperferritinemia by reducing viral-induced hepatic necroinflammation and fibrosis.