Metabolic and hepatic effects of bloodletting in dysmetabolic iron overload syndrome: A randomized controlled study in 274 patients.
Dysmetabolic iron overload syndrome (DIOS) is a common cause of hyperferritinemia, accounting for a mild increase of iron stores in insulin-resistant subjects. Iron removal could improve insulin sensitivity. We performed a prospective, randomized, controlled trial (NCT01015525) in nondiabetic DIOS patients with hepatic iron >50 μmol/g at magnetic resonance imaging to compare the metabolic and hepatic outcomes of 1-year maintenance of serum ferritin levels <50 μg/L by bloodletting associated with lifestyle and diet advice (LFDA) to those of LFDA only. Patients were randomly assigned (1:1) with stratification by center (n = 8) and hyperglycemia (>5.6 mmol/L). Sample size was calculated to provide 90% power and a difference in fasting glycemia of 0.25 mmol/L. Analysis was done in an intention-to-treat population. In 2010-2014, 146 patients were randomly assigned to receive venesections with LFDA and 128 to LFDA only. At the end of the study, comparison of iron-depleted patients and controls showed ferritin levels 71 ± 48 μg/L after removal of 4.9 ± 1.6 L of blood versus 733 ± 277 μg/L (P < 0.0001), glycemia 5.44 ± 0.7 versus 5.49 ± 0.7 mmol/L (P = 0.57), body weight +0.5 ± 4.3% versus -0.6 ± 3.3% (P = 0.03), homeostasis model of assessment of insulin resistance 3.39 versus 2.40 (P = 0.002), alanine aminotransaminase 33 ± 22 versus 37 ± 21 IU/L (P = 0.10), aspartate aminotransaminase 27 ± 13 versus 27 ± 10 IU/L (P = 0.81), gamma-glutamyl transferase 54 ± 138 versus 49 ± 35 IU/L (P = 0.72), Fatty Liver Index 58.9 ± 24.6 versus 61.2 ± 22.9 (P = 0.37), and Fibrosis-4 score 1.5 ± 0.6 versus 1.30 ± 0.6 (P = 0.51). Fatigue occurred in 25.3% of venesected patients versus 2.3% of controls (P < 0.0001). In the subgroup of patients who lost weight, glycemia, homeostasis model of assessment of insulin resistance, serum ferritin, lipid profile, and liver function tests improved irrespective of bloodletting.



In DIOS patients, iron depletion by bloodletting does not improve metabolic and hepatic features, is associated with weight gain, and is not as well tolerated as expected; sustained modification of diet and lifestyle habits remains the first therapeutic intervention in DIOS. (Hepatology 2017;65:465-474).
INSERM CIC 1414, CHU Rennes, Rennes, France.|INSERM U 991, CHU Rennes, Rennes, France.|Liver Unit, CHU Rennes, Rennes, France.
Fabrice
F
Lainé
Department of Internal Medicine, CHU Estaing, and Clermont University, Auvergne University, EA 4681, PEPRADE, Clermont-Ferrand, France.
Marc
M
Ruivard
Liver-Gastroenterology Department, CHU Limoges, INSERM U850, Limoges, France.
Véronique
V
Loustaud-Ratti
INSERM CIC 1414, CHU Rennes, Rennes, France.|Department of Endocrinology-Diabetology, CHU Rennes, France.|University of Rennes 1, Rennes, France.
Fabrice
F
Bonnet
Liver-Gastroenterology Department, University Hospital, and UPRES 3859, LUNAM University, Angers, France.
Paul
P
Calès
INSERM CIC 1414, CHU Rennes, Rennes, France.|INSERM U 991, CHU Rennes, Rennes, France.|Liver Unit, CHU Rennes, Rennes, France.|University of Rennes 1, Rennes, France.
Edouard
0000-0002-0784-0710
E
Bardou-Jacquet
INSERM CIC 1413 and CHU, IMAD, Nantes, France.
Sylvie
S
Sacher-Huvelin
Liver-Gastroenterology and Oncology Department, CHR Orléans, Orléans, France.
Xavier
X
Causse
CHR Saint-Malo, Saint-Malo, France.
Christine
C
Beusnel
INSERM CIC 1414, CHU Rennes, Rennes, France.|University of Rennes 1, Rennes, France.
Alain
A
Renault
INSERM CIC 1414, CHU Rennes, Rennes, France.|University of Rennes 1, Rennes, France.
Eric
E
Bellissant
INSERM CIC 1414, CHU Rennes, Rennes, France.|University of Rennes 1, Rennes, France.
Yves
Y
Deugnier
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001774:Blood Chemical Analysis; D016009:Chi-Square Distribution; D005260:Female; D005293:Ferritins / Q000097:blood*; D005500:Follow-Up Studies; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D019190:Iron Overload / Q000097:blood / Q000175:diagnosis* / Q000628:therapy*; D008019:Life Style; D008111:Liver Function Tests; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D018962:Phlebotomy / Q000379:methods*; D011446:Prospective Studies; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D015430:Weight Gain / Q000502:physiology
D005293:Ferritins