“iron - avoiding deficiency” bronwyn williams haematologist – hssa / rch
TRANSCRIPT
“Iron - Avoiding deficiency”
Bronwyn Williams
Haematologist – HSSA / RCH
Iron -
Points for Discussion
Iron metabolism and its regulationPrevalence and causes of iron deficiencyDiagnostic workup /differential diagnosisTreatment 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.
Stoltzfus RJ. J Nutr. 2001;131(2 Suppl 2):697S-700S.
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
Brush border Basolateral
Fe(II)Fe(II)Fe(II) Fe(II)
Fe(II)
Fe(III)
Tf
Fe(III)
Fe(III)
Fe(III)
Fe(III)Fe(III)
DMT1
Fe reductase
Ferroportin
HCP1
Labile ironpool
Fe(III)
Endocytic vesicle
Fe(II)
HephaestinFe(II)
Fe(II)Fe(II)
Fe(II)Fe(II)
Fe(II)Fe(II)
Fe(II)
Fe(III)Fe(III)Fe(III)
ferritin
Tf
Haem
Tf = transferrin; TfR = transferrin receptor.
Cellular control of iron transport in duodenal enterocyte
TfR
Brush border Basolateral
Fe(II)Fe(II)Fe(II) Fe(II)
Fe(II)
Fe(III)
Tf
Fe(III)
Fe(III)
Fe(III)
Fe(III)Fe(III)
DMT1
Fe reductase
Ferroportin
HCP1
Labile ironpool
Fe(III)
Endocytic vesicle
Fe(II)
HephaestinFe(II)
Fe(II)Fe(II)
Fe(II)Fe(II)
Fe(II)Fe(II)
Fe(II)
Fe(III)Fe(III)Fe(III)
ferritin
Tf
Haem
Hepcidin
Tf = transferrin; TfR = transferrin receptor.
Cellular control of iron transport in duodenal enterocyte
TfR
Ajioka RS, Prchal J. The Hematologist. 2008;5:(5)1.
Stimulatory and inhibitory
signals to hepcidin
Hepcidin
LGDF15
TMPRSS6HIF1-α
ErythropoiesisLow Fe storesHypoxia
Iron overloadInflammation
HSMADsSTAT-3
Inherited IDAMutation
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 (%)
• 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.
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
Causes of iron deficiency
Increased physiological requirements:growth, menses
pregnancyEPO
Blood lossmenorrhagia
GIT lossparasites
other
Limited supply: dietary
malabsorptionplacental
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?
• Hypochromia
• Microcytosis
• Anisocytosis
• High RDW
• Typically low to normal RCC
Hoffbrand AV, et al., editors. Essential haematology.5th ed. Malden, MA; Oxford: Blackwell, 2006.
The Blood in IDA
Differential diagnosis:• Iron deficiency• Thalassaemia• Sideroblastic anaemias - rare• Lead poisoning - rare
Stages of iron deficiency
Modified after Brugnara C. Clin Chem. 2002;48:981-2.
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.
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
Proceed to treatment
Detailed medical-/+ gynaecological history
-/+Occult blood
GI workup
Infants+ “ supply” cause
AdolescentsMost others
Initial workup:Hb, MCV, Tf saturation, serum
ferritin +/- sTfR
Category:
Negative Positive
Its iron deficiency! - BUT why is it present?
GI = gastrointestinal.
GIT causes of IDA
• Coeliac disease IgA level and endomysial and TTG antibodies
• 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 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.
Logan RP, Walker MM. BMJ. 2001;323:920-2.
Prevalence of H. pylori infectionP
reva
len
ce (
%)
0
20
40
60
80
100
Age (years)0 10 20 30 40 50 60 70 80
Developing countries
Developed countries
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 = 0.17mg/5gm10% absorption ~ 0.015mg/5gm
~1.5mg/90gm
• Iron = 6.5mg/5gm(spinach 0.9mg / cup fresh)
if 5% absorption ~ 0.33mg / 5gm
• + Vitamin C ( and B12)• Few studies (rats /
humans) - improves iron status /non toxic - ? dose
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