Should HFE p.C282Y homozygotes with moderately elevated serum ferritin be treated? A randomised controlled trial comparing iron reduction with sham treatment (Mi-iron)

Abstract

IntroductionHFE p.C282Y homozygosity is the most common cause of hereditary haemochromatosis. There is currently insufficient evidence to assess whether non-specific symptoms or hepatic injury in homozygotes with moderately elevated iron defined as a serum ferritin (SF) of 300–1000 µg/L are related to iron overload. As such the evidence for intervention in this group is lacking. We present here methods for a study that aims to evaluate whether non-specific symptoms and hepatic fibrosis markers improve with short-term normalisation of SF in p.C282Y homozygotes with moderate elevation of SF.Methods and analysisMi-iron is a prospective, multicentre, randomised patient-blinded trial conducted in three centres in Victoria and Queensland, Australia. Participants who are HFE p.C282Y homozygotes with SF levels between 300 and 1000 μg/L are recruited and randomised to either the treatment group or to the sham treatment group. Those in the treatment group have normalisation of SF by 3-weekly erythrocytapheresis while those in the sham treatment group have 3-weekly plasmapheresis and thus do not have normalisation of SF. Patients are blinded to all procedures. All outcome measures are administered prior to and following the course of treatment/sham treatment. Patient reported outcome measures are the Modified Fatigue Impact Scale (MFIS-primary outcome), Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study 36-item short form V.2 (SF36v2) and Arthritis Impact Measurement Scale 2 short form (AIMS2-SF). Liver injury and hepatic fibrosis are assessed with transient elastography (TE), Fibrometer and Hepascore, while oxidative stress is assessed by measurement of urine and serum F2-isoprostanes.Ethics and disseminationThis study has been approved by the Human Research Ethics Committees of Austin Health, Royal Melbourne Hospital and Royal Brisbane and Women's Hospital. Study findings will be disseminated through peer-reviewed publications and conference presentations.Trial registrationTrial identifier: NCT01631708; Registry: ClinicalTrials.gov

RNAi‐mediated silencing of ferritin genes in the brown planthopper Nilaparvata lugens affects survival, growth and female fecundity

“…found that the injection of recombinant ferritin helped inhibit bacterial growth in the silkworm Bombyx mori by limiting the iron level in the hemolymph. Similar results have indicated that ferritin expression is upregulated in response to pathogen challenges in the swallowtail butterfly Papilio xuthus (Lepidoptera), 22 the beetle Tribolium castaneum (Coleoptera), 23 the bumblebee Bombus ignitus (Hymenoptera), 24 the horseshoe crab Limulus (Merostomata) 25 and the ark shell Scapharca broughtonii (Lamellibranchia) 26 . Taken together, these findings indicate that ferritin can function as an acute antibiotic protein by storing iron in host cells to inhibit pathogen growth.…”

Haemochromatosis: a clinical update for the practising physician

“…suggest the potential benefit of early treatment in patients with SF concentrations between the upper limit of normal and 1000 μg/L. Due to confounders and the lack of a randomised clinical trial, the potential benefit of treatment for patients with a mild to moderate iron burden awaits validation . The presence of clinical symptoms is not a prerequisite for diagnosis or treatment.…”

Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes

“…12–14 However, there is limited evidence on whether patients with only moderately elevated SF (300–1,000 μg/l) benefit from phlebotomy and whether the optimal target should be <300 μg/l (the upper limit of the clinically normal range) or <100 μg/l. The results of a randomized controlled trial comparing iron reduction by erythrocytapheresis with sham treatment by plasmapheresis, 23 which will be available later this year, will for the first time provide high-quality evidence to answer this question.…”