Low-dose iron replacement - PowerPoint Presentation

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Low-dose iron replacementThe new normal?

Dr.

Thomas Lofaro

FRCPath

Consultant Haematologist – East & North Hertfordshire NHS Trust

Honorary Consultant Haematologist – University College London Healthcare NHS Trust

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Iron deficiency

Classically microcytic

anaemia

Decreased iron intake

– poor diet, malnutritionDecreased iron absorption - coeliac allergy, certain foods/medications, chronic pancreatitis, crohn’s, sprue, achlorhydria & gastrectomy, parasitic infectionsIncreased iron loss – bleeding, pregnancy, surgery, parasitic infectionsAltered iron metabolism – anaemia of chronic disease, lead

Bain B et al.

Dacie

and Lewis Practical Haematology. 12

th

edition.

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Iron deficiency

Common

Fatigue, shortness of breath

Anaemia, greater surgical morbidity, more post op transfusionsThrombocytosis, microcytosisIn the elderly – decreased performance scores, greater frailty, decompensated cardiac conditionsGold standard Rx – oral ironAbsorption varies from 10-30% (with food-fasting), majority being unabsorbedGI side effects lead to poor compliance, failure of Rx, delays for hospital care, need for IV replacement

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Iron deficiency

Ferritin/apoferritin

Transferrin/

apotransferrin

HaemoglobinVitamin CHepcidinFerroportinErythroferroneHaemojuvelinHaemosiderinIron-regulatory proteinsIron-response elements

Bain B et al. Dacie and Lewis Practical Haematology. 12th edition.

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Iron metabolism

Roth MP et al. (2019). Regulators of Hepcidin Expression. Vitamins & Hormones.

Volume 110, 2019, Pages 101-129.

Pantopoulos

K. Inherited Disorders of Iron Overload. Front Nutr. doi: 10.3389/fnut.2018.00103

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Hepcidin

Produced in the liver

Negatively correlates with iron

bioavailabiltyReleased if iron is present/in surplus. Suppressed by iron def, hypoxiaAlso released in response to inflammationBinds ferroportin

which is the main iron transporterReduces iron levels in plasmaReduces absorption of iron from the intestine. Increases GI iron loss.Reduces iron release from the liver/macrophages. Reduces recycling of FeReduces iron availability for erythropoiesisMichels K et al. Hepcidin and host defense against infectious diseases. PLOS Pathogens 2015. DOI:10.1371/journal.ppat.1004998

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From the SPC for Ferrous Sulphate (reviewed on 20/4/22)

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Study – Lancet 2017 (n=60)

Used radiolabelled oral ferrous sulphate to measure absorption in a cohort of iron deficient women with comparable ferritins. Dietary restrictions & questionnaires to confirm compliance

2 randomisations

R1: 60mg eFe OD x14/7 or 60mg eFe alt day x27/7R2: 120mg eFe OD x3/7 or 60mg eFe BD x3/7all participants crossed over to the other regimen 14/7 days later within individual comparisons madeIron absorption measured for each patient

Stoffel N et al. lron 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 2017.

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Study – Lancet 2017 (n=60)

Results:

lower frequency led to greater proportions of iron absorbed (so less GI loss)

R1: 16%/131mg vs 21.8%/175mgR2: 11.8%/44.3mg vs 13.1%/49mgHepcidin levels increased by BD dosaging.

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Study – Blood 2015 (n=54)

Dose finding study using radiolabelled Fe, aimed at measuring hepcidin response to iron supplementation. Hepcidin and plasma Fe measured.

3

substudiesS1: randomised to a dose of 40-, 60-, 80-, 160-, 240mg eFe (FeSO4) on 1 day or 2 consecutive days (with cross over design)S2: 60mg eFe OD x2S3: 60mg eFe BD x3In all 3 studies, radiolabelled iron incorporation into red cells measured

at 14/7Moretti D et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015

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Results:At doses >60mg eFe daily, hepcidin levels increased, fractional iron absorption decreased, although absolute absorption still increased.

No superiority of BD

dosaging

Recommend lower dosages (40-80mg eFe), avoiding twice daily dosaging

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Moretti D et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015

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Study 3 – Cochrane Review 2015 (n=5490)

Meta-analysis to assess effects of oral iron supplementation on maternal and

fetal

outcomes21 trials with >5400 women comparing daily vs intermittent iron replacementIndividually, studies were regarded as having low quality of evidenceSome studies studied replacement with iron alone, others with iron and folic acid or other vitamins. For any iron preparation, there was no difference in outcomes between the two groups for fetal or maternal outcomes, with fewer side effects in women on intermittent replacement (average RR 0.56; 95% CI 0.37 to 0.84)Similar when statistics focussed on studies including iron replacement alone

Pena-Rosas JP et al. Intermittent oral iron supplementation during pregnancy Cochrane Database of Systematic Reviews 2015, Issue 10. DOI: 10.1002/14651858.CD009997.pub2

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Study 3 – Cochrane Review 2015 (n=5490)

Available data indicate that in comparison with women receiving daily supplements, women receiving iron intermittently:

had a similar risk of anaemia at term;

had similar haemoglobin (Hb) concentrations at term;had a similar risk of premature infants;had the same risk of delivering low birthweight infantshad fewer side effects;had a reduced risk of high Hb concentrations throughout pregnancy.Given all the above, intermittent supplementation with iron could be considered as a feasible strategy to prevent gestational anaemia.In order to improve the success of this intervention in public health, it is important to encourage continued monitoring of Hb concentrations during pregnancy and establish logistic procedures that facilitate and improve accessibility to supplements and foster compliance.

Pena-Rosas JP et al. Intermittent oral iron supplementation during pregnancy Cochrane Database of Systematic Reviews 2015, Issue 10. DOI: 10.1002/14651858.CD009997.pub2

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Guideline iron def in pregnancy – BJH 2019

Until further research determines the optimal dose of elemental oral iron, 40–80 mg every morning is suggested, checking Hb at 2–3 weeks to ensure an adequate response (2C).

take oral iron supplements correctly -on an empty stomach, with water or a source of vitamin C. Other

medications, multivitamins and antacids should not be taken at the same time (1B).Treatment for anaemia should be started promptly. Escalation to specialist medical care is required if anaemia is severe (Hb <70 g/l) and/or associated with significant symptoms or advanced gestation (>34 weeks) (2B), or if the Hb is failing to respond after 2–3 weeks of oral iron correctly taken.For nausea and epigastric discomfort, alternate day dosing or preparations with lower iron content should be tried. Slow release and enteric-coated forms should be avoided (1A).Repeat Hb testing is required 2–3 weeks after commencing treatment for established anaemia, to assess

compliance, correct administration and response to treatment (1B).Once the Hb is in the normal range, replacement should continue for 3 months and until at least 6 weeks postpartum to replenish iron stores (1D).If response to oral iron replacement is poor, compliance should be confirmed and concomitant causes that may be contributing to the anaemia considered, such as folate deficiency or malabsorption (1A).Pavord S et al. UK Guidelines on the management of iron deficiency in pregnancy. 2019. doi: 10.1111/bjh.16221

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Guideline Fe def in adults – Gut 2021

We recommend that the initial treatment of IDA should be with one tablet per day of ferrous sulphate, fumarate or gluconate. If not tolerated, a reduced dose of one tablet every other day, alternative oral preparations or parenteral iron should be considered (evidence quality—medium, consensus—92%, statement strength—strong).

We recommend that patients should be monitored in the first 4 weeks for an Hb response to oral iron, and treatment should be continued for a period of around 3 months after normalisation of the Hb level, to ensure adequate repletion of the marrow iron stores (evidence quality—medium, consensus—92%, statement strength—strong).

Snook J et al. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut 2021. doi:10.1136/gutjnl-2021-325210

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Iron deficiency

no single blood test can offer an accurate reflection of iron absorption/storage/utilisation

No test is free from confounders

In the absence of haemoglobinopathy, MCV/MCH/MCHC values below normal are suggestive BUT NOT DIAGNOSTIC of iron deficiencyNormal MCV/MCH/MCHC do not exclude iron deficiency as a cause of anaemia. Dual pathologyNovel conditions: Subclinical iron deficiency // Anaemia of chronic disease with reduced total body ironTestingFerritinIron studies – iron, transferrin, total iron binding capacity, unsaturated iron binding capacity, transferrin saturation

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Iron deficiency - Ferritin

Most of our iron is stored in a soluble form called

Ferritin

Levels less than 15 are diagnostic of iron deficiency<30 consistent with iron-depletedReliable if systemically wellUnreliable in the elderly, systemically unwell, renal impairment, multiple liver disease, inflammation, cancer – acute phase proteinFerritin is an acute phase reactant - higher levels may still be present with iron deficiency in context of chronic disease or inflammation, and clinical correlation or inclusion of iron studies are required in the appropriate situations

Wayne Thomas D et al. Guideline for the laboratory diagnosis of functional iron deficiency. BJH 2013. doi:10.1111/bjh.12311

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Iron deficiency - treatment

Oral iron

ferrous sulphate or similar,

Once daily or alternate day onlyOnce iron replete, continue for 3 monthsVitamin CIntravenous ironOral iron may be less effective in patients with renal impairment

, GI disease or comorbidityCONTRAINDICATED IN THE FIRST TRIMESTER OF PREGNANCY, caution during breast feedingInvestigate for a cause in males, postmenopausal females, nonmenstrual bleeding, FH of bowel Ca, combined haematinic def, prominent GI symptomsPrevention – diet, heavy periodsSMPC for Venofer available online; SMPC for Monofer available onlineGoddard AF et al, Guidelines for the management of iron deficiency anaemia. Gut. 2011. Oct;60(10):1309-1316

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Iron deficiency vs Thalassaemia trait

Haemoglobin - decreased

MCV - decreased

MCH – decreased, but also reduced in all other disorders of Hgb synthesisMCHC - decreasedRDW – increasedRCC – decreasedPlatelets - increasedBlood film – pencil cells, target cells, elliptocytes, hypochromic red cellsReticulocytes – decreased (but rise with iron replacement)Ferritin – decreasedTransferrin saturation – decreased, Transferrin - increasedHistory – assessments of FBC and ferritin over time, ethnicity

Haemoglobin –

mildly decreased

MCV – markedly decreasedMCH – markedly decreasedMCHC - normalRDW – decreased

RCC – increasedPlatelets - normalBlood film – more frequent target cells, red cell inclusions, less shape variation Reticulocytes –

normal/increased

Ferritin –

normal or elevated

Transferrin saturation –

normal or elevated

History

– typical ethnicity, long standing results with little change, family history

Haemoglobin electrophoresis

– exclusion of iron def

pretest

is required for correct interpretation

You may have both!

Bain B et al.

Dacie

and Lewis Practical Haematology. 12

th

edition.

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Anaemia of chronic disease

History

- Sustained inflammatory process, multiple comorbidities

Inflammatory markers may be raisedRenal impairment a common cause. Do EPO levelMore common in the elderlyParaprotein, BJPIron studies – iron variable, T sat often reduced, transferrin level/iron binding capacity also often reducedOver time patients can also develop an iron deficiency

Haemoglobin – decreased

MCV & MCH & MCHC – variable

RDW – variableRCC – decreasedPlatelets - increasedNeutrophils & Lymphs - increasedBlood film – reactive features: rouleaux, reactive lymphocytes

Ferritin – elevatedReticulocytes - variableIron studies – variable

Bain B et al.

Dacie

and Lewis Practical Haematology. 12

th

edition.

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When to use iron supplements with caution…

Patients with

no evidence of iron deficiency

(elevated ferritin, transferrin saturation >20-30%)Patients with confirmed or suspected red cell disorders Thalassemia intermedia/thalassaemia major, HbH disease, hereditary spherocytosisSickle cell disease on regular blood transfusionConsider medical history, family history, FBC findings, ethnicityPatients with haemochromatosisPatients with a diagnosis of Polycythaemia vera

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Case 1

A young 28

yr

old lady with a sustained thrombocytosis and a normal ferritin (35) for investigation of a marrow causePlatelet 480 approx. on multiple occasionsSome fatigue, put down to her jobFerritin borderline low – in keeping with an element of iron deficiencySent molecular testing for marrow causes. JAK2, MPL and CALR mutations negativeTrial of iron replacement. Platelets 370 post. Diagnosis – subclinical iron deficiency, due to heavy periods

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Case 2

18F, Admitted with community acquired pneumonia

Noted to be anaemic, Hgb 94, MCV 77. Medical team organised haematinics

B12 and folate were normal, ferritin was 70They called to ask for a bone marrow biopsy on account of normocytic anaemia, normal ferritinDiagnosis – iron deficiency anaemia probably due to menstrual losses, reactive/acute phase ferritin riseGiven iron supplements rather than bone marrow biopsy, advice to followup Hgb and iron studies/ferritin

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