“Iron - Avoiding deficiency”
Bronwyn Williams
Haematologist – HSSA / RCH
Iron -
Points for Discussion
Iron metabolism and its regulation
Prevalence and causes of iron deficiency
Diagnostic workup /differential diagnosis
Treatment of IDA
Metabolic functions of iron – a transition metal
•
Haem iron compounds
– cytochrome a,b,c (oxidative energy)
– cytochrome P450 (drug metabolism)
– catalase, peroxidase (ROS protection)
– haemoglobin, myoglobin
•
Non-haem iron compounds
– NAD dehydrogenase (mitochondrial respiration)
– succinate dehydrogenase
– xanthine oxidase (nucleotide catabolism)
– ribonucleotide reductase (nucleotide synthesis)
ROS = reactive oxygen species.
Fairbanks VF, Beutler E. Ironmetabolism. In: Beutler E,
et al. editors. Williams Hematology, 6th ed.
New York: McGraw-Hill; 2001. p.295-.304.
Functional implications of iron deficiency
• Abnormal mental and motor development in infancy
• Impaired work capacity / fatigue
• Increased risk of premature delivery
• Increased maternal and infant mortality in severe anaemia
Stoltzfus RJ. J Nutr. 2001;131(2 Suppl 2):697S-700S.
Cellular control of iron transport in
duodenal enterocyte
Brush border
Fe(II)
Basolateral
DMT1
Fe reductase
Fe(II)
Fe(II)
Fe(II)
Fe(II)
Fe(III)
Ferroportin
Fe(II)
Hephaestin
Fe(II)
Labile iron
pool
Fe(II)
Fe(II)
Fe(II)
Fe(II)
Fe(III)
Fe(II)
Fe(II)
Tf
Fe(II)
Haem
HCP1
Fe(III)
Fe(III)
Fe(III)
ferritin
Tf = transferrin; TfR = transferrin receptor.
Fe(III)
Endocytic
vesicle
Fe(III)
Fe(III)
TfR
Fe(III)
Fe(III)
Cellular control of iron transport in
duodenal enterocyte
Brush border
Basolateral
Hepcidin
Fe(II)
DMT1
Fe reductase
Fe(II)
Fe(II)
Fe(II)
Fe(II)
Fe(III)
Ferroportin
Fe(II)
Hephaestin
Fe(II)
Labile iron
pool
Fe(II)
Fe(II)
Fe(II)
Fe(II)
Fe(III)
Fe(II)
Fe(II)
Tf
Fe(II)
Haem
HCP1
Fe(III)
Fe(III)
Fe(III)
ferritin
Tf = transferrin; TfR = transferrin receptor.
Fe(III)
Endocytic
vesicle
Fe(III)
Fe(III)
TfR
Fe(III)
Fe(III)
Stimulatory and inhibitory
signals to hepcidin
Hepcidin
Erythropoiesis
Low Fe stores
Hypoxia
Iron overload
Inflammation
L
GDF15
TMPRSS6
HIF1-α
H
SMADs
STAT-3
Ajioka RS, Prchal J. The Hematologist. 2008;5:(5)1.
Inherited IDA
Mutation
Mice
Microcytic anaemia (mk)
DMT1
Sex-linked anaemia (sla)
Hephaestin
Haemoglobin deficit (hbd)
Sec15 (endosome trafficking)
Rats
Belgrade rat (b)
DMT1
Zebrafish
Weissherbst (weh)
Ferroportin
Chardonnay (cdy)
DMT1
Frascati
Mitoferrin (mitochondrial iron transport)
Man
Iron deficiency anaemia and tissue siderosis
DMT1
Iron deficiency anaemia and tissue siderosis
Atransferrinemia
Iron refractory iron deficiency anaemia IRIDA
Transmembrane serine protease (matriptase-2)
Andrews NC. Blood. 2008;112(2):219-30 .
Prevalence and causes of iron deficiency
Prevalence of iron deficiency anaemia (%)
Region
Children
Children
Men
Women
Pregnant
Age (y)
0–4
5–12
15–59
15–49
15–49
Africa
56
49
20
44
63
North America
8
13
4
8
–
Latin America
26
26
13
17
30
East Asia
20
22
11
18
20
South Asia
56
50
32
58
68
Europe
14
5
2
12
14
Oceania
18
15
7
19
25
Developed regions
12
7
3
11
14
Developing regions
51
46
26
47
59
Cut-off values (g/dL)
11
12
13
12
11
• The population of Earth is estimated to be 6,993,000,000 ( US Census
Bureau) – hence IDA may affect over 2 billion people worldwide
DeMaeyer E, Adiels-Tegman M. World Health Stat Q. 1985;38:302-16.
Causes of iron deficiency
Limited supply:
dietary
malabsorption
placental
Increased
physiological
requirements:
growth, menses
pregnancy
EPO
Blood loss
menorrhagia
GIT loss
parasites
other
Risk groups: 0 – 18yrs
• Premature / sick infants
• Certain ethnic groups
– Aboriginals, immigrants
• Growth phases
– First 2 years
– Adolescence
• Excess loss
– menses
The Diagnosis! – Is it iron deficiency?
The Blood in IDA
•
Hypochromia
•
Microcytosis
•
Anisocytosis
•
High RDW
•
Typically low to normal RCC
Differential diagnosis:
• Iron deficiency
• Thalassaemia
• Sideroblastic anaemias - rare
• Lead poisoning - rare
Hoffbrand AV, et al., editors. Essential haematology.
5th ed. Malden, MA; Oxford: Blackwell, 2006.
Stages of iron deficiency
Depleted
iron
stores
Iron
deficiency
(normal Hb)
Iron
deficiency
anaemia
Serum ferritin
Transferrin sat
Erythrocyte ZPP
Haemoglobin
MCV
% Hypo
Serum TfR
CHr
CHr = haemoglobin content of reticulocytes; Hb = haemoglobin;
Hypo = hypochromic erythrocytes; ZPP = zinc protoporphyrin.
Modified after Brugnara C. Clin Chem. 2002;48:981-2.
Beware - iron studies
•
Serum iron is labile
– high if haemochromatosis, enteric iron load, sideroblastic, aplastic, ineffective
erythropoiesis
– low if deficiency, infection, fasting, vit C def.
•
Transferrin affected by disease states
– low in infection/inflammation, malignancy hypoproteinemic states, congenital
def
– high with OCP, pregnancy
 TIBC calculated from Transferrin
 Transferrin Saturation calculated from Se Fe and TIBC
•
Ferritin
– high in acute phase; liver disease/injury, iron loading
– low in deficiency, congenital (rare)
– Interpretable in acute phase if know CRP
– >100umol/L in CRF, chronic inflammation - Fe deficiency unlikely
Other indicators of iron status
•
Reticulocyte Hb ( CHr)
 Indirect measure of iron available for new red cell production (few days)
 Useful for diagnosis of deficiency and response to therapy (esp IV)
 BUT not routinely available on all analysers or validated for all populations
•
Zinc Protoporphyrin
 Old test and very sensitive to Fe deficiency
 Accumulates in Fe deficiency and lead poisoning
 Not readily available – referred test for many labs
•
Transferrin Receptor
 Maintains cellular iron homeostasis
 Increased production if iron deficient or if increased erythropoiesis
 Useful marker of deficiency in states where there is confounding effect of inflammation /
infection
 Not helpful to discriminate thalassemia trait as levels overlap with those of iron
deficiency
 Available most labs
Iron deficiency or thal trait? - A common conundrum
•
•
•
•
•
Case 1 – mohamid
Hb 93, MCV 61
RDW 20 ( 11 – 15)
CRP 24
Ferritin 32umol/l
• Iron deficient
• Tests depend on why
• ? diet ? bleeding ??
malabsorption
•
•
•
•
•
Case 2 – mahali
Hb 100, MCV 67
RDW 14.6 ( 11 – 15)
CRP 28
Ferritin 159umol/l
• Thal trait
• iron deficiency unlikely
• Additional testing with
haemoglobin studies
Iron deficiency vs thalassemia
• Both reasonably common and can coexist
• Assess for iron intake / malabsorption/ loss issues
• Consider age
 Iron issues peak in 0 – 4 and 10 – 16y
• Ethnicity and family history may be helpful
• ? RC indices
 RDW, RCC, morphology ( stippling / targets++), dimorphism
• Iron studies first line in most
 Be aware of limitations and effects of acute phase
 Interpretation with CRP helpful
• Thalassemia testing if iron replete ( ? Post trial of iron)
 Hb studies +/- family studies +/- alpha gene testing
Its iron deficiency! - BUT why is it present?
Initial workup:
Category:
Hb, MCV, Tf saturation, serum
ferritin +/- sTfR
Infants +
“supply” cause
Adolescents
Most others
Detailed medical +/gynaecological history
+/Negative Occult blood Positive
Proceed to treatment
GI = gastrointestinal.
GI workup
GIT causes of IDA
•
Coeliac disease

•
•
•
H. pylori infection

Occult bleeding, competition for iron, interferes with acid production ( iron conversion)

serology and urease breath test

Worth thinking about especially in certain ethnic groups ( see next slide)
Occult / overt bleeding

Eg GOR / oesphagitis; Meckels; telengiectasia / angiodysplasia; portal HT; Inflammatory bowel
disease

Human Hb, calprotectin, endoscopy
Iron transport defect

•
IgA level and endomysial and TTG antibodies
Iron absorption challenge; genetic testing**
Autoimmune atrophic gastritis

Rare in children, association with H Pylori infection

gastrin, parietal cell antibodies, anti-IF
TTG = tissue transglutaminase;
anti-IF = anti-intrinsic factor.
.
Prevalence of H. pylori infection
100
Prevalence (%)
80
60
40
20
Developing countries
Developed countries
0
0
10
20
30
40
50
60
70
80
Age (years)
Logan RP, Walker MM. BMJ. 2001;323:920-2.
Treatment – a spoon full of #!*
Options for treatment of IDA
• Oral medications: tablets
 ferrous sulphate, gluconate or citrate containing ~ 50 mg elemental
iron / tablet +/- vitamin C/ folate
• Oral medications: syrup
 ferrous sulphate – liquid 6mg elemental iron / ml
• Parenteral preparations - IV
 Venofer: iron saccharose 100 mg/5ml ampoule
– Maximum dose 1 ampoule
 Ferinject: iron carboxymaltose 100 mg/ 2ml or 500mg / 10ml vials (
dilute 100mg / 50ml N Saline)
– Various dosing protocols – Formula; <35kg -15mg/kg, >35kg – 500mg;
15mg/kg up to 1000mg maximum
– NOTE: Maximum weekly dose 1000mg
Muñoz M, et al. J Clin Pathol. 2011;64:287-96.
Principles of IDA treatment
• Response rate to parenteral and oral iron is similar
• Difference between formulations mainly cost not quality
– Choice based on age / acceptance by patient
– Mostly trial oral replacement would precede IV iron
– Compliance important to consider
• Administration issues
– Consider degree of symptoms / tolerance to decide dose/ frequency
and agent
– Duration of treatment should be very long
 At least 4 months for adequate repletion with standard oral dosing
• Response to iron is the ultimate test for IDA
Hershko C, Skikne B. Semin Hematol. 2009;46:339-50.
Food for thought?
• Iron = 0mg / 5gm
• Iron = 6.5mg/5gm
(spinach 0.9mg / cup fresh)
 if 5% absorption ~ 0.33mg
/ 5gm
• Iron = 0.17mg/5gm
10% absorption ~ 0.015mg/5gm
~1.5mg/90gm
• + Vitamin C ( and B12)
• Few studies (rats /
humans) - improves iron
status /non toxic - ? dose
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