Iron avoiding deficiency bronwyn williams haematologist hssa rch
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“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.

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Iron avoiding deficiency bronwyn williams haematologist hssa rch

“Iron - Avoiding deficiency”

Bronwyn Williams

Haematologist – HSSA / RCH


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

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)

Fairbanks VF, Beutler E. Ironmetabolism. In: Beutler E, et al. editors. Williams Hematology, 6th ed. New York: McGraw-Hill; 2001. p.295-.304.

ROS = reactive oxygen species.


Functional implications of iron deficiency

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.


Iron avoiding deficiency bronwyn williams haematologist hssa rch

Cellular control of iron transport in duodenal enterocyte

Brush border

Basolateral

DMT1

Ferroportin

Fe(II)

Fe(II)

Fe(II)

Fe(II)

Fe(II)

Hephaestin

Fe reductase

Fe(II)

Fe(II)

Fe(II)

Labile iron

Fe(II)

Fe(II)

pool

Fe(III)

Fe(III)

Fe(II)

Fe(II)

Fe(II)

Tf

Fe(II)

Fe(III)

HCP1

Fe(III)

Haem

Endocytic

Fe(III)

Fe(III)

Tf

vesicle

Fe(III)

Fe(III)

Fe(III)

TfR

ferritin

Fe(III)

Tf = transferrin; TfR = transferrin receptor.


Iron avoiding deficiency bronwyn williams haematologist hssa rch

Cellular control of iron transport in duodenal enterocyte

Brush border

Basolateral

Hepcidin

DMT1

Ferroportin

Fe(II)

Fe(II)

Fe(II)

Fe(II)

Fe(II)

Hephaestin

Fe reductase

Fe(II)

Fe(II)

Fe(II)

Labile iron

Fe(II)

Fe(II)

pool

Fe(III)

Fe(III)

Fe(II)

Fe(II)

Fe(II)

Tf

Fe(II)

Fe(III)

HCP1

Fe(III)

Haem

Endocytic

Fe(III)

Fe(III)

Tf

vesicle

Fe(III)

Fe(III)

Fe(III)

TfR

ferritin

Fe(III)

Tf = transferrin; TfR = transferrin receptor.


Stimulatory and inhibitory signals to hepcidin

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

Inherited IDA

Andrews NC. Blood. 2008;112(2):219-30 .


Prevalence and causes of iron deficiency

Prevalence and causes of iron deficiency


Prevalence of iron deficiency anaemia

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.


Causes of iron deficiency

Causes of iron deficiency

Increased

physiological

requirements:

growth, menses

pregnancy

EPO

Limited supply:

dietary

malabsorption

placental

Blood loss

menorrhagia

GIT loss

parasites

other


Risk groups 0 18yrs

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 Diagnosis! – Is it iron deficiency?


The blood in ida

Hypochromia

Microcytosis

Anisocytosis

High RDW

Typically low to normal RCC

The Blood in IDA

  • 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

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

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

    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 or thal trait? - A common conundrum


    Iron deficiency vs thalassemia

    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

    Its iron deficiency! - BUT why is it present?

    Hb, MCV, Tf saturation, serum ferritin +/- sTfR

    Initial workup:

    Infants +

    “supply” cause

    Most others

    Category:

    Adolescents

    Detailed medical +/-

    gynaecological history +/-

    Occult blood

    Negative

    Positive

    Proceed to treatment

    GI workup

    GI = gastrointestinal.


    Git causes of ida

    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.

    .


    Prevalence of h pylori infection

    Prevalence of H. pylori infection

    100

    80

    60

    Developing countries

    Developed countries

    40

    20

    0

    10

    20

    30

    40

    50

    60

    70

    80

    0

    Prevalence (%)

    Age (years)

    Logan RP, Walker MM. BMJ. 2001;323:920-2.


    Treatment a spoon full of

    Treatment – a spoon full of #!*


    Options for treatment of ida

    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

    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/5gm

    10% 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

    Food for thought?


    More info http www bloodsafelearning org au

    More info - http://www.bloodsafelearning.org.au


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