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


BACKGROUND
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.


BACKGROUND
Trial identifier: NCT01631708; Registry: ClinicalTrials.gov.
Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Sim Yee
SY
Ong
Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
Lara
L
Dolling
Iron Metabolism Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Jeannette L
JL
Dixon
Department of Gastroenterology, Eastern Health, Box Hill, Victoria, Australia Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Amanda J
AJ
Nicoll
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Lyle C
LC
Gurrin
Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
Michelle
M
Wolthuizen
Transfusion Research Unit, Department of Epidemiology and Preventive Medicine, Monash University, Prahran, Victoria, Australia.
Erica M
EM
Wood
Iron Metabolism Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Greg J
GJ
Anderson
Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Grant A
GA
Ramm
Gastro and Food Allergy, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Allergy and Immunology, Royal Children's Hospital, Parkville, Victoria, Australia.
Katrina J
KJ
Allen
Department of Gastroenterology, Fiona Stanley and Fremantle Hospitals, Murdoch, Western Australia, Australia.
John K
JK
Olynyk
School of Medicine, University of Queensland, Herston, Queensland, Australia.
Darrell
D
Crawford
Department of Gastroenterology, Fiona Stanley and Fremantle Hospitals, Murdoch, Western Australia, Australia.
Jennifer
J
Kava
Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Louise E
LE
Ramm
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.
Paul
P
Gow
Bone Marrow Transplant and Haematology, Royal Brisbane Hospital, Herston, Queensland, Australia.
Simon
S
Durrant
RBWH Centre for the Advancement of Clinical Research, Royal Brisbane & Women's Hospital, Herston, Queensland, Australia.
Lawrie W
LW
Powell
Bruce Lefroy Centre, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia.
Martin B
MB
Delatycki
D000293:Adolescent; D000328:Adult; D000368:Aged; D001781:Blood Component Removal; D017707:Erythrocyte Transfusion; D005293:Ferritins / Q000097:blood*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D019190:Iron Overload / Q000628:therapy*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D005293:Ferritins
erythrocytapheresis; ferritin; haemochromatosis; phlebotomy; venesection