“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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