Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency

PLoS ONE

Oct 2013

DOI: 10.1371/journal.pone.0076516

Citations:46

Influential Citations:2

Observational Studies (Human)

Enhanced Details

Methods

Dietary/nosebleed questionnaire study: 50 hereditary hemorrhagic telangiectasia (HHT) patients; cross-sectional; assessed dietary iron intake with EPIC FFQ and nosebleed severity with Epistaxis Severity Score (ESS); 28 male (56%), 17 post-menopausal females (34%), 5 pre-menopausal females (10%); ages 20–80 (median 55). Iron-regulatory substudy: 21 HHT patients; 12 male, 9 female; ages 20–69; measured ferritin, hepcidin, transferrin saturation index (TfSI), hemoglobin, MCV, RDW, and other hematinic indices. Online nosebleed/dietary survey: large cohort; 913 started, 756 completed; 568 reported iron tablet use; data linked to nosebleed volumes/durations and dietary intake; analyses included regression modeling.

Intervention

Oral iron supplementation regimens; ferrous sulfate 325 mg tablets taken twice daily; some used 325 mg once daily or ferrous fumarate; duration not specified.

Results

HAIR (hemorrhage-adjusted iron requirement) sums the usual dietary iron allowance with additional iron needed to replace quantified non-menstrual hemorrhagic losses. In 50 HHT participants, 86% met RDA but only 20% met HAIR, indicating under-replacement of hemorrhagic iron losses. Higher HAIR predicted lower hemoglobin, lower mean corpuscular hemoglobin content, lower serum iron and higher RDW. Ferritin and ferritin2 explained ~60% of variance in hepcidin; the hepcidin:ferritin ratio was similar to controls. Iron supplement use increased the proportion meeting HAIR and attenuated HAIR–hematinic index associations; after adjusting for supplement use, HAIR remained inversely related to Hb and serum iron. Among 568 iron tablet users, about 26% reported side effects; persistent anemia was more common in HHT when iron tablets caused diarrhea or needed stopping. HAIR values may be a useful tool for prevention, assessment and management of iron deficiency in HHT, and under-replacement of nosebleed hemorrhagic iron losses appears to explain iron deficiency in this population. Findings support applying HAIR-derived dietary guidance to tailor iron intake for individuals with quantified hemorrhagic losses and potentially extendable to broader populations.

Limitations

Small, disease-specific samples; observational design with cross-sectional analyses; reliance on self-reported nosebleed volumes and dietary intake; analyses mainly observational with potential selection bias (online survey); lack of randomized control; generalizability to non-HHT populations is limited.

Abstract

Background Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient-specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). Methodology/Principal Findings The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin2 explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped. Conclusions/significance HAIR values, providing an indication of individuals’ iron requirements, may be a useful tool in prevention, assessment and management of iron deficiency. Iron deficiency in HHT can be explained by under-replacement of nosebleed hemorrhagic iron losses. show less