Iron Levels in Hepatocytes and Portal Tract Cells Predict Progression and Outcomes of Patients With Advanced Chronic Hepatitis C

Abstract

Background & Aims Iron might influence severity and progression of non-hemochromatotic liver diseases. We assessed the relationships between iron, variants in HFE, and progression and outcomes using data from the HALT-C Trial. We determined whether therapy with pegylated interferon (PegIFN) affects iron variables. Methods Participants were randomly assigned to groups given long-term therapy with PegIFN (n=400) or no therapy (n=413) for 3.5 y and followed for up to 8.7 y (median 6.0 y). Associations between patient characteristics and iron variables, at baseline and over time, were made using Kaplan-Meier analyses, Cox regression models, and repeated measures analysis of covariance. Iron was detected by Prussian blue staining. Results Patients with poor outcomes (increase in Child-Turcotte-Pugh score to ≥ 7, development of ascites, encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, hepatocellular carcinoma, death) had significantly higher baseline scores for stainable iron in hepatocytes and cells in portal tracts than those without outcomes. Staining for iron in portal triads correlated with lobular and total Ishak inflammatory and fibrosis scores (P<0.0001). High baseline levels of iron in triads increased the risk for poor outcome (hazard ratio=1.35, P=0.02). Iron staining decreased in hepatocytes but increased in portal stromal cells over time (P<0.0001). Serum levels of iron and total iron binding capacity decreased significantly over time (P <0.0001), as did serum ferritin (P=0.0003). Long-term therapy with PegIFN did not affect levels of iron staining. Common variants in HFE did not correlate with outcomes, including development of hepatocellular carcinoma. Conclusions Degree of stainable iron in hepatocytes and portal tract cells predicts progression and clinical and histological outcomes of patients with advanced chronic hepatitis C. Long-term therapy with low-dose PegIFN did not improve outcomes or iron variables.

Chronic hepatitis C and liver fibrosis

“…This is largely attributed to misregulation of the iron regulatory hormone hepcidin [68,69] , which is transcriptionally inhibited by HCVinduced oxidative stress [70] . Even though iron antagonizes HCV replication by inactivating the viral polymerase NS5B [71,72] , hepatic iron accumulation [73] , elevated serum ferritin [74] or reduced serum hepcidin levels [75] are associated with progression of liver disease. The hemochromatosis protein HFE, an atypical major histocompatibility complex class Ⅰ molecule, may also contribute to liver fibrogenesis as an upstream regulator of hepcidin and/or as possible immunological factor [76,77] .…”

Single nucleotide polymorphisms and risk of hepatocellular carcinoma in cirrhosis

“…A recent prospective study enabled a link to be made between hepatic iron overload, HFE variations and development of HCC in alcoholic cirrhosis [39] while neither of these two factors affected the risk of liver cancer in HCV-infected cirrhotic patients. This finding has been partially confirmed in HCV-infected patients included in the HALT-C trial [76], in whom HFE gene mutations did not correlate with the development of HCC. In addition to the impact of the underlying liver disease, iron overload also depends on a complex set of polygenic and epidemiological factors that are still poorly understood.…”

Safety Issues in Iron Treatment in CKD

“…There is irrefutable evidence that an increased iron burden can intensify and iron depletion by phlebotomy can ameliorate hepatitis and modify the response to interferon therapy. 63,[74][75] In addition, the stainable iron level in hepatocytes and portal tract cells is a predictor of progression and clinical outcomes in advanced chronic hepatitis C. 76 Therefore, caution should be exercised in the use of IV iron in patients with liver disease.…”