Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C

Abstract

Background & aims: Iron may influence severity and progression of non-hemochromatotic liver diseases. Our aim was to assess the relationship of iron and HFE genetic variations to progression and outcomes in the HALT-C Trial and whether PegIFN therapy influenced iron variables.

Methods: Participants were randomized to receive long-term PegIFN [n = 400] or no therapy [n = 413] for 3.5 y, with follow-up for up to 8.7 y [median 6.0 y]. Associations of patient characteristics with iron variables at baseline and over time were carried out using Kaplan-Meier analyses, Cox regression models, and repeated measures analysis of covariance.

Results: Participants who developed clinical outcomes [CTP > 7, ascites, encephalopathy, variceal bleeding, SBP, HCC, death] had significantly higher baseline scores for stainable iron in hepatocytes and in portal tract cells than those without. There were significant direct correlations between stainable iron in portal triads and lobular and total Ishak inflammatory and fibrosis scores [P < 0.0001]. Iron in triads at baseline increased risk of outcomes (HR = 1.35, P = 0.02). Stainable iron in hepatocytes decreased, whereas that in portal stromal cells increased significantly [P < 0.0001] over time. Serum iron and TIBC fell significantly over time [P < 0.0001], as did serum ferritin [P = 0.0003]. Chronic PegIFN treatment did not affect stainable iron. HFE genetic variations did not correlate with outcomes, including development of hepatocellular carcinoma.

Conclusions: Stainable iron in hepatocytes and portal tract cells is a predictor of progression and clinical and histological outcomes in advanced chronic hepatitis C. Chronic low-dose PegIFN therapy did not improve outcomes, nor iron variables.

Trial registration: ClinicalTrials.gov NCT00006164.

Figure 1. Schematic of the HALT-C Trial and participants studied

**Each patient counted more than once.

Figure 2. Measures of iron status at baseline and development of clinical outcomes

A. Time to first clinical outcome by global hepatocytic iron score B. Time to first clinical outcome by percentage of portal triads that contained stainable iron. Clinical outcomes were defined as described previously. Stainable iron was assessed by a panel of hepatopathologists, as described in Materials and Methods, who had no knowledge of clinical features or outcomes.

Figure 3. Effect of time and treatment on hepatic stainable iron

Results are mean + SE. The global hepatocytic iron score fell significantly over time (P<0.0001). There was significant decrease in the percent of biopsies with stainable iron in hepatocytes (P=0.0005) and increases in the percent of biopsies with stainable iron in portal stromal cells (P<0.0001), with a strong trend to be greater in PegIFN group (P=0.06).

Figure 4. Effect of time and treatment on serum measures of iron status

Results are mean + SE. Serum iron and TIBC fell significantly, and progressively over time (p<0.0001) and significantly more in the PegIFN group (p=0.03 and p=0.0004). There were no significant changes in transferrin saturation. Serum ferritin also fell significantly over time (p=0.0003), but less so in the PegIFN group (p=0.048).