Patients with Chronic Hepatitis C May be More Sensitive to Iron Hepatotoxicity than Patients with HFE-Hemochromatosis

Abstract

Aim In chronic hepatitis C, iron might play an important role as a hepatotoxic co-factor. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy. To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFEhemochromatosis. Methods Fourteen Japanese patients with chronic hepatitis C and eight Italian patients with HFEhemochromatosis underwent repeated venesection with a serum ferritin endpoint of 20 and 50 ng/mL, respectively. Serum iron indices and liver function tests were measured in pre-and post treatment blood samples from each patient. Body iron stores were calculated using the removed blood volume. Results In both patients with hepatitis and hemochromatosis, serum ferritin, aminotransferase and hepcidin 25 were reduced after venesection. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients (11.1 ± 9.2 ng/mL), but not so in hepatitis patients (30.7 ± 14.5 ng/mL). Inversely, the estimated body iron stores of hemochromatosis patients were 5,960 ± 2,750 mg, while those of hepatitis patients were 730 ± 560 mg. Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients. Conclusion Even though the threshold of iron hepatotoxicity and benefit of its removal differ between patients with chronic hepatitis C and those with HFE-hemochromatosis, venesection is a valid choice of treatment to reduce liver disease activity in both diseases.

Clinicopathological study of Japanese patients with genetic iron overload syndromes

“…This process is thought to contribute to hepatocellular necrosis and/or apoptosis in the liver with the subsequent activation of hepatic stellate cells and development of hepatic fibrosis and cirrhosis 26 . Similar to the hepatitis virus, iron may induce fibrosis via hepatocellular necrosis 27 . The patient with the HAMP genotype examined in this study first presented with hepatitis at 26 years of age 19 .…”

Phase II clinical trial of phlebotomy for non‐alcoholic fatty liver disease

“…As most subjects had normal HIC at baseline, we feel it is unlikely that the improvement in liver histology is solely due to reduction in liver iron. It is quite possible that iron reduction has anti‐inflammatory effects independent from decreasing tissue iron . Iron is a known potent catalyst of oxidative stress and may play a role in inducing fibrogenesis …”

Impact of iatrogenic iron overload on the course of hepatitis C in the dialysis population: A plea for caution

“…In fact phlebotomy was an accepted therapy for hepatitis C infection in the United States and Japan before the advent of directacting antiviral agents. [16][17][18] In a systematic review, Fanchini et al reported that patients treated with phlebotomy followed by interferon therapy (in 7 studies with 373 patients) had an odds ratio of 2.32 (95% CI: 0.96-6.24) for achieving a sustained virologic response as compared to patients receiving interferon alone 19 ; of note, in that metaanalysis CIs crossed 1, thus weakening the demonstration. Similarly, in a second meta-analysis of 6 randomized controlled trials including 367 patients, Desai and co-workers compared interferon therapy alone to interferon plus concomitant phlebotomy.…”

“…In addition, phlebotomy improves histologic lesions and potentiates the salutary effects of interferon. In fact phlebotomy was an accepted therapy for hepatitis C infection in the United States and Japan before the advent of direct‐acting antiviral agents . In a systematic review, Fanchini et al reported that patients treated with phlebotomy followed by interferon therapy (in 7 studies with 373 patients) had an odds ratio of 2.32 (95% CI: 0.96–6.24) for achieving a sustained virologic response as compared to patients receiving interferon alone; of note, in that meta‐analysis CIs crossed 1, thus weakening the demonstration.…”