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

Introduction: HFE 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 analysis: Mi-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 dissemination: This 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 registration: Trial identifier: NCT01631708; Registry: ClinicalTrials.gov.

Keywords: erythrocytapheresis; ferritin; haemochromatosis; phlebotomy; venesection.

Figure 1

Flow chart of methodology for the Mi-iron Study. TS, transferrin saturation; SF, serum ferritin; MFIS, Modified Fatigue Impact Scale; SF36v2, Medical Outcomes Study 36-item short form V.2; HADS, Hospital Anxiety and Depression scale; AIMS2-SF, Arthritis Impact Measurement Scales 2 short form; TE, transient elastography.

Figure 2

A black opaque curtain prevents the participant from seeing the apheresis machine and therefore the individual cannot see if red blood cells or plasma is removed. (A) View from the patient's perspective, (B) View from the apheresis machine side of the curtain.

Figure 3

Equation to estimate postcollection haematocrit (Hct post) based on total blood volume (TBV) using Nadler's fomula. Adopted from the Haemonetics MCS Plus apheresis system manual. TBV, total blood volume; RBC, red blood cell; Hct, haematocrit.