Abstract

Iron deficiency (ID) affects billions of people worldwide and remains the leading cause of anemia with significant negative impacts on health. Our approach to ID and iron deficiency anemia (IDA) involves three steps (I3): (1) identification of ID/IDA, (2) investigation of and management of the underlying etiology of ID, and (3) iron repletion. Iron repletion options include oral and intravenous (IV) iron formulations. Oral iron remains a therapeutic option for the treatment of ID in stable patients, but there are many populations for whom IV iron is more effective. Therefore, IV iron should be considered when there are no contraindications, when poor response to oral iron is anticipated, when rapid hematologic responses are desired, and/or when there is availability of and accessibility to the product. Judicious use of red cell blood transfusion is recommended and should be considered only for severe, symptomatic IDA with hemodynamic instability. Identification and management of ID and IDA is a central pillar in patient blood management.

References

References
1.
World Health Organization
.
The Global Prevalence of anaemia in 2011
.
2015
. https://apps.who.int/iris/bitstream/handle/10665/177094/9789241564960_eng.pdf.
2.
McLean
E
,
Cogswell
M
,
Egli
I
,
Wojdyla
D
,
de Benoist
B
.
Worldwide prevalence of anaemia, WHO Vitamin and Mineral Nutrition Information System, 1993-2005
.
Public Health Nutr
.
2009
;
12
(
4
):
444
-
454
.
3.
Kassebaum
NJ
;
GBD 2013 Anemia Collaborators
.
The global burden of anemia
.
Hematol Oncol Clin North Am
.
2016
;
30
(
2
):
247
-
308
.
4.
Kyu
HH
,
Abate
D
,
Abate
KH
, et al
;
GBD 2017 DALYs and HALE Collaborators
.
Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017
.
Lancet
.
2018
;
392
(
10159
):
1859
-
1922
.
5.
Hentze
MW
,
Muckenthaler
MU
,
Galy
B
,
Camaschella
C
.
Two to tango: regulation of mammalian iron metabolism
.
Cell
.
2010
;
142
(
1
):
24
-
38
.
6.
Wang
CY
,
Babitt
JL
.
Liver iron sensing and body iron homeostasis
.
Blood
.
2019
;
133
(
1
):
18
-
29
.
7.
Mastrogiannaki
M
,
Matak
P
,
Peyssonnaux
C
.
The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions
.
Blood
.
2013
;
122
(
6
):
885
-
892
.
8.
Thomas
DW
,
Hinchliffe
RF
,
Briggs
C
,
Macdougall
IC
,
Littlewood
T
,
Cavill
I
;
British Committee for Standards in Haematology
.
Guideline for the laboratory diagnosis of functional iron deficiency
.
Br J Haematol
.
2013
;
161
(
5
):
639
-
648
.
9.
Weiss
G
,
Ganz
T
,
Goodnough
LT
.
Anemia of inflammation
.
Blood
.
2019
;
133
(
1
):
40
-
50
.
10.
Lopez
A
,
Cacoub
P
,
Macdougall
IC
,
Peyrin-Biroulet
L
.
Iron deficiency anaemia
.
Lancet
.
2016
;
387
(
10021
):
907
-
916
.
11.
Sawada
T
,
Konomi
A
,
Yokoi
K
.
Iron deficiency without anemia is associated with anger and fatigue in young Japanese women
.
Biol Trace Elem Res
.
2014
;
159
(
1-3
):
22
-
31
.
12.
Blanton
CA
,
Green
MW
,
Kretsch
MJ
.
Body iron is associated with cognitive executive planning function in college women
.
Br J Nutr
.
2013
;
109
(
5
):
906
-
913
.
13.
Mirza
FG
,
Abdul-Kadir
R
,
Breymann
C
,
Fraser
IS
,
Taher
A
.
Impact and management of iron deficiency and iron deficiency anemia in women’s health
.
Expert Rev Hematol
.
2018
;
11
(
9
):
727
-
736
.
14.
Breymann
C
,
Auerbach
M
.
Iron deficiency in gynecology and obstetrics: clinical implications and management
.
Hematol Am Soc Hematol Educ Progr
2017
;
2017
:
152
-
159
.
15.
Guyatt
GH
,
Patterson
C
,
Ali
M
, et al
.
Diagnosis of iron-deficiency anemia in the elderly
.
Am J Med
.
1990
;
88
(
3
):
205
-
209
.
16.
Goodnough
LT
,
Nemeth
E
,
Ganz
T
.
Detection, evaluation, and management of iron-restricted erythropoiesis
.
Blood
.
2010
;
116
(
23
):
4754
-
4761
.
17.
Guyatt
GH
,
Oxman
AD
,
Ali
M
,
Willan
A
,
McIlroy
W
,
Patterson
C
.
Laboratory diagnosis of iron deficiency anemia: an overview
.
J Gen Intern Med
.
1992
;
7
(
2
):
145
-
153
.
18.
Weiss
G
,
Goodnough
LT
.
Anemia of chronic disease
.
N Engl J Med
.
2005
;
352
(
10
):
1011
-
1023
.
19.
von Haehling
S
,
Ebner
N
,
Evertz
R
,
Ponikowski
P
,
Anker
SD
.
Iron deficiency in heart failure: An overview
.
JACC Heart Fail
.
2019
;
7
(
1
):
36
-
46
.
20.
Muñoz
M
,
Acheson
AG
,
Auerbach
M
, et al
.
International consensus statement on the peri-operative management of anaemia and iron deficiency
.
Anaesthesia
.
2017
;
72
(
2
):
233
-
247
.
21.
Drüeke
TB
,
Parfrey
PS
.
Summary of the KDIGO guideline on anemia and comment: reading between the (guide)line(s)
.
Kidney Int
.
2012
;
82
(
9
):
952
-
960
.
22.
Macdougall
IC
,
White
C
,
Anker
SD
, et al
;
PIVOTAL Investigators and Committees
.
Intravenous iron in patients undergoing maintenance hemodialysis
.
N Engl J Med
.
2019
;
380
(
5
):
447
-
458
.
23.
Archer
NM
,
Brugnara
C
.
Diagnosis of iron-deficient states
.
Crit Rev Clin Lab Sci
.
2015
;
52
(
5
):
256
-
272
.
24.
Ginzburg
YZ
.
New diagnostic tools for delineating iron status
.
Hematology Am Soc Hematol Educ Program
.
2019
;
2019
:
327
-
336
.
25.
Camaschella
C
.
Iron deficiency: new insights into diagnosis and treatment
.
Hematology Am Soc Hematol Educ Program
.
2015
;
2015
:
8
-
13
.
26.
Lasa
JS
,
Olivera
P
,
Soifer
L
,
Moore
R
.
Iron-deficiency anemia as a subclinical celiac disease presentation in an Argentinian population [in English, Spanish]
.
Rev Gastroenterol Mex
.
2017
;
82
(
3
):
270
-
273
.
27.
Dinaux
AM
,
Leijssen
LGJ
,
Bordeianou
LG
,
Kunitake
H
,
Berger
DL
.
Rectal cancer in patients under 50 years of age
.
J Gastrointest Surg
.
2017
;
21
(
11
):
1898
-
1905
.
28.
Goldman
M
,
Uzicanin
S
,
Scalia
V
,
O’Brien
SF
.
Iron deficiency in Canadian blood donors
.
Transfusion
.
2014
;
54
(
3 Pt 2
):
775
-
779
.
29.
Callum
JL
,
Waters
JH
,
Shaz
BH
,
Sloan
SR
,
Murphy
MF
.
The AABB recommendations for the Choosing Wisely campaign of the American Board of Internal Medicine
.
Transfusion
.
2014
;
54
(
9
):
2344
-
2352
.
30.
Onuoha
OC
,
Arkoosh
VA
,
Fleisher
LA
.
Choosing wisely in anesthesiology: the gap between evidence and practice
.
JAMA Intern Med
.
2014
;
174
(
8
):
1391
-
1395
.
31.
Hibbs
SP
,
Nielsen
ND
,
Brunskill
S
, et al
.
The impact of electronic decision support on transfusion practice: a systematic review
.
Transfus Med Rev
.
2015
;
29
(
1
):
14
-
23
.
32.
Choosing Wisely Canada
:
Transfusion medicine
. https://choosingwiselycanada.org/transfusion-medicine/.
33.
American Society of Hematology
.
Ten Things Physicians and Patients Should Question
.
2014
. https://www.choosingwisely.org/wp-content/uploads/2015/02/ASH-Choosing-Wisely-List.pdf.
34.
Lynch
SR
,
Cook
JD
.
Interaction of vitamin C and iron
.
Ann N Y Acad Sci
.
1980
;
355
:
32
-
44
.
35.
Tolkien
Z
,
Stecher
L
,
Mander
AP
,
Pereira
DIA
,
Powell
JJ
.
Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis
.
PLoS One
.
2015
;
10
(
2
):
e0117383
.
36.
Powers
JM
,
Buchanan
GR
,
Adix
L
,
Zhang
S
,
Gao
A
,
McCavit
TL
.
Effect of low-dose ferrous sulfate vs iron polysaccharide complex on hemoglobin concentration in young children with nutritional iron-deficiency anemia: A randomized clinical trial
.
JAMA
.
2017
;
317
(
22
):
2297
-
2304
.
37.
Moretti
D
,
Goede
JS
,
Zeder
C
, et al
.
Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women
.
Blood
.
2015
;
126
(
17
):
1981
-
1989
.
38.
Stoffel
NU
,
Cercamondi
CI
,
Brittenham
G
, et al
.
Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials
.
Lancet Haematol
.
2017
;
4
(
11
):
e524
-
e533
.
39.
Avni
T
,
Bieber
A
,
Grossman
A
,
Green
H
,
Leibovici
L
,
Gafter-Gvili
A
.
The safety of intravenous iron preparations: systematic review and meta-analysis
.
Mayo Clin Proc
.
2015
;
90
(
1
):
12
-
23
.
40.
Auerbach
M
,
Deloughery
T
.
Single-dose intravenous iron for iron deficiency: a new paradigm
.
Hematology Am Soc Hematol Educ Program
.
2016
;
2016
:
57
-
66
.
41.
Litton
E
,
Xiao
J
,
Ho
KM
.
Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials
.
BMJ
.
2013
;
347
:
f4822
.
42.
Ganzoni
AM
.
[Intravenous iron-dextran: therapeutic and experimental possibilities (in German)]
.
Schweiz Med Wochenschr
.
1970
;
100
(
7
):
301
-
303
.
43.
Koch
TA
,
Myers
J
,
Goodnough
LT
.
Intravenous iron therapy in patients with iron deficiency anemia: dosing considerations
.
Anemia
.
2015
;
2015
:
1
-
10
.
44.
Adkinson
NF
,
Strauss
WE
,
Macdougall
IC
, et al
.
Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: A randomized trial
.
Am J Hematol
.
2018
;
93
(
5
):
683
-
690
.
45.
Kulnigg
S
,
Stoinov
S
,
Simanenkov
V
, et al
.
A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial
.
Am J Gastroenterol
.
2008
;
103
(
5
):
1182
-
1192
.
46.
Avni
T
,
Bieber
A
,
Steinmetz
T
,
Leibovici
L
,
Gafter-Gvili
A
.
Treatment of anemia in inflammatory bowel disease—systematic review and meta-analysis
.
PLoS One
.
2013
;
8
(
12
):
e75540
.
47.
Derman
R
,
Roman
E
,
Modiano
MR
,
Achebe
MM
,
Thomsen
LL
,
Auerbach
M
.
A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia
.
Am J Hematol
.
2017
;
92
(
3
):
286
-
291
.
48.
World Health Organization
.
Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity
.
2011
.
49.
Kiss
JE
,
Brambilla
D
,
Glynn
SA
, et al
;
National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology and Donor Evaluation Study–III (REDS-III)
.
Oral iron supplementation after blood donation: a randomized clinical trial
.
JAMA
.
2015
;
313
(
6
):
575
-
583
.
50.
Cancelo-Hidalgo
MJ
,
Castelo-Branco
C
,
Palacios
S
, et al
.
Tolerability of different oral iron supplements: a systematic review
.
Curr Med Res Opin
.
2013
;
29
(
4
):
291
-
303
.
51.
Gereklioglu
C
,
Asma
S
,
Korur
A
,
Erdogan
F
,
Kut
A
.
Medication adherence to oral iron therapy in patients with iron deficiency anemia
.
Pak J Med Sci
.
2016
;
32
(
3
):
604
-
607
.
52.
Avni
T
,
Bieber
A
,
Steinmetz
T
,
Leibovici
L
,
Gafter-Gvili
A
.
Treatment of anemia in inflammatory bowel disease--systematic review and meta-analysis
.
PLoS One
.
2013
;
8
(
12
):
e75540
.
53.
Stein
RE
,
Plantz
K
,
Maxwell
EC
,
Mamula
P
,
Baldassano
RN
.
Intravenous iron sucrose for treatment of iron deficiency anemia in pediatric inflammatory bowel disease
.
J Pediatr Gastroenterol Nutr
.
2018
;
66
(
2
):
e51
-
e55
.
54.
Ratcliffe
LE
,
Thomas
W
,
Glen
J
, et al
.
Diagnosis and management of iron deficiency in CKD: A summary of the NICE guideline recommendations and their rationale
.
Am J Kidney Dis
.
2016
;
67
(
4
):
548
-
558
.
55.
Macdougall
IC
,
Bock
A
,
Carrera
F
, et al
;
FIND-CKD Study Investigators
.
The FIND-CKD study–a randomized controlled trial of intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: background and rationale
.
Nephrol Dial Transplant
.
2014
;
29
(
4
):
843
-
850
.
56.
Albaramki
J
,
Hodson
EM
,
Craig
JC
,
Webster
AC
.
Parenteral versus oral iron therapy for adults and children with chronic kidney disease
.
Cochrane Database Syst Rev
.
2012
;
1
:
CD007857
.
57.
Gafter-Gvili
A
,
Rozen-Zvi
B
,
Vidal
L
, et al
.
Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia - systematic review and meta-analysis of randomised controlled trials
.
Acta Oncol
.
2013
;
52
(
1
):
18
-
29
.
58.
Auerbach
M
,
Muñoz
M
,
Macdougall
IC
.
Intravenous iron: out of sight, out of mind
.
Lancet Haematol
.
2018
;
5
(
1
):
e10
-
e12
.
59.
Muñoz
M
,
Gómez-Ramírez
S
,
Besser
M
, et al
.
Current misconceptions in diagnosis and management of iron deficiency
.
Blood Transfus
.
2017
;
15
(
5
):
422
-
437
.
60.
Lim
W
,
Afif
W
,
Knowles
S
, et al
.
Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults
.
Vox Sang
.
2019
;
114
(
4
):
363
-
373
.
61.
Wolf
M
,
Chertow
GM
,
Macdougall
IC
,
Kaper
R
,
Krop
J
,
Strauss
W
.
Randomized trial of intravenous iron-induced hypophosphatemia
.
JCI Insight
.
2018
;
3
(
23
):
1
-
12
.
62.
Bager
P
,
Hvas
CL
,
Dahlerup
JF
.
Drug-specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions
.
Br J Clin Pharmacol
.
2017
;
83
(
5
):
1118
-
1125
.
63.
Schaefer
B
,
Würtinger
P
,
Finkenstedt
A
, et al
.
Choice of high-dose intravenous iron preparation determines hypophosphatemia risk
.
PLoS One
.
2016
;
11
(
12
):
e0167146
.
64.
Murphy
MF
.
The Choosing Wisely campaign to reduce harmful medical overuse: its close association with patient blood management initiatives
.
Transfus Med
.
2015
;
25
(
5
):
287
-
292
.
65.
Murphy
MF
,
Goodnough
LT
.
The scientific basis for patient blood management
.
Transfus Clin Biol
.
2015
;
22
(
3
):
90
-
96
.
66.
Zeller
MP
,
Kaufman
RM
.
Safeguarding the patient’s own blood supply
.
JAMA
.
2019
;
321
(
10
):
943
-
945
.
67.
Mueller
MM
,
Van Remoortel
H
,
Meybohm
P
, et al
;
ICC PBM Frankfurt 2018 Group
.
Patient blood management: Recommendations from the 2018 Frankfurt Consensus Conference
.
JAMA
.
2019
;
321
(
10
):
983
-
997
.
68.
Muñoz
M
,
Gómez-Ramírez
S
,
Cuenca
J
, et al
.
Very-short-term perioperative intravenous iron administration and postoperative outcome in major orthopedic surgery: a pooled analysis of observational data from 2547 patients
.
Transfusion
.
2014
;
54
(
2
):
289
-
299
.
69.
Johansson
PI
,
Rasmussen
AS
,
Thomsen
LL
.
Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial)
.
Vox Sang
.
2015
;
109
(
3
):
257
-
266
.
70.
Lin
Y
.
Preoperative anemia screening clinics
.
Hematology Am Soc Hematol Educ Program
.
2019
;
2019
:
570
-
576
.
71.
McDonagh
M
,
Cantor
A
,
Bougatsos
C
,
Dana
T
,
Blazina
I.
Routine iron supplementation and screening for iron deficiency anemia in pregnant women: A systematic review to update the U.S. Preventive Services Task Force Recommendation
.
Rockville, MD
:
Agency for Healthcare Research and Quality (US)
;
March, 2015
;
Report No. 13-05187-EF-2
.
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