Several groups have evaluated the effects of iron reduction on chronic HCV infection [38
]. The majority of the studies performed phlebotomies of 400–500 ml of whole blood every 1 or 2 weeks until the development of an iron-deficient anemia. Hayashi and colleagues [39
] first reported that iron reduction performed by repeated venesection led to normalization of serum alanine aminotransferase (ALT) levels in 5 of the 10 patients. However, serum ALT levels significantly decreased in all patients (from 152 ± 49 to 55 ± 32 U/L, P
< 0.001). According to a report by Piperno and colleagues [41
], serum ALT levels significantly improved in 32 iron-depleted patients with chronic HCV infection. Similar results were subsequently reported by other groups with phlebotomy alone [42
]. However, no significant reduction in serum HCV RNA levels was observed [42
]. The long-term effect of phlebotomy on biochemical and histological parameters of chronic HCV infection was addressed by Yano and colleagues in 25 patients undergoing a 5-year maintenance phlebotomy program [47
]. Interestingly, the authors found that the mean serum ALT levels decreased significantly during the initial phlebotomy program (from 117 to 75 U/l, P
< 0.05) and this improvement persisted during the study period. Furthermore, phlebotomies were able to prevent the progression of liver histology because the severity of liver fibrosis (staging score) decreased from 2.3 to 1.7 (P
< 0.05) in the iron-reduction group, whereas the mean values increased from 1.7 at baseline to 2.0 at the end of follow-up in controls (P
= NS). Likewise, the severity of inflammation (grading score) remained unchanged in the study group (1.8 vs. 2.0, P
= NS) but progressed in the control group (2.0 vs. 2.9, P
< 0.005). Thus, the authors concluded that long-term maintenance of iron depletion is a safe and effective alternative to IFN treatment and could be particularly indicated for those patients who do not respond to antiviral therapy or cannot tolerate such drugs.
Recently, Alexander and colleagues [48
] found that iron depletion was associated with a biochemical response in 22% of patients who did not respond to IFN monotherapy and that, among patients with serum ALT normalization, there was a significant reduction of serum markers of liver fibrosis (procollagen III peptide). Kaito and colleagues [49
] found that iron-reduction therapy by phlebotomy significantly reduced lipid peroxidation and oxidative stress, which mediate the deleterious effect of iron overload on the liver.
Finally, other groups have demonstrated that the association of a low-iron diet to phlebotomy has an additional effect in removing iron-induced oxidative stress [50
]. Indeed, in a study conducted by Kato and colleagues [51
], 34 patients with chronic HCV infection unresponsive to IFN therapy were maintained in an iron-depleted state with phlebotomy and a low-iron diet for 6 years. This therapy was associated with a high rate of biochemical response (65%), improvement in liver histology, and reduction in hepatic levels of 8-OHdG, a marker of oxidant stress. In a recent cohort study, the same authors demonstrated that long-term phlebotomy with a low-iron diet therapy reduced the risk of progression of chronic HCV infection to hepatocellular carcinoma [52
Table summarizes the results of the most important studies on the effect of iron depletion by phlebotomy on chronic HCV infection.
Summary of the most important studies on the effect of iron depletion by phlebotomy on chronic hepatitis C virus infection