Iron

iron metabolism

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Functional Iron Deficiency (Anaemia of Chronic Disease)

 

Insufficient iron incorporation into erythroid precursors, despite apparently adequate iron stores (Normal ferritin and BM iron stores).

 

ACD thought to be intended as a short-term effort to deprive pathogens of free iron, and to allow increase white cell production at the expense of red cells. Becomes a pathological process once occurring chronically.

 

Serum Ferritin

 

(N.B. There is now a 2018 BSH guideline exclusively for the Ix of raised ferritin (see here))

 

A surrogate measure of the intracellular stored ferritin, not of usable circulating iron.

Ferritin 1ug/l = 8mg of stored iron

 

A normal/raised ferritin is not equivalent to sufficient iron being made available to erythroblasts

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CKD Patients (NICE 2015)

 

Serum ferritin is not useful in CKD - elevated in 50% of patients on haemodialysis but not reflective of bioavailable iron. Therefore:

 

Hb <110g/l + Ferritin 200-800 --> Give IV iron for functional iron deficiency

Hb <110g/l + Ferritin <200 (HD) or <100 (no HD) --> Give IV iron for true iron deficiency

Ferritin >800 --> investigate for iron overload

 

Iron Supplements

 

Traditional recommended oral dose = 100-200mg elemental iron/day

Increasing evidence that this is inefficient, as the amount of iron absorbed from any one dose reduces the closer doses are to one another.

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Iron Deficiency in Pregnancy (BSH 2019)

 

Adult daily iron requirement = 1-2mg per day

Increases in 3rd trimester = 6mg per day

 

15% of dietary iron is absorbed, increases to 45% in 3rd trimester

 

UK – 24% of pregnant women anaemic, up to 46% by time of 28-week check. 14% of non-anaemic women had ferritin <30ug/l in first trimester.

Definitions of anaemia in pregnancy (under r/v by WHO as to validity & practicality, a/w outcome as of 2019):

1st trimester               <110g/l

After 1st trimester     <105g/l

Postpartum                <100g/l

FBC should be tested at booking and 28 weeks (NICE CG62)

  • Note physiological increase in MCV of approx. 6fl during pregnancy may mask microcytosis

 

Maternal effects of IDA in pregnancy:

  • Fatigue

  • Non-specific symptoms – pallor, weakness, poor concentration, hair loss, headache, palpitations, irritability, dizziness, dyspnea, restless legs, pica.

  • Poor quality of life, increased risk of post-natal depression

  • Increased risk of PPH (60% of women with Hb <85 had PPH in a UK prospective observational study)

 

Fetus/Neonate effects of IDA in pregnancy:

  • Increased risk of perinatal and neonatal mortality

  • Increased risk of low birth weight, pre-term birth

 

?Cut-off for low ferritin in pregnancy?

  • As ferritin rises along with other acute phase reactants in pregnancy, it may be appropriate to use a higher cut-off than other adults.

  • But, as of yet, no good research on pregnancy-specific cut-offs of serum ferritin

  • Current practice is to continue to use <30ug/l as per other adults

 

Indications for starting empirical oral iron supplementation:

1. If Hb <110 at booking or <105 at 28 weeks

  • Only check ferritin beforehand if known hbpathy or if planning IV iron

  • Re-check after 2-3 weeks, Hb should rise by >20g/l

  • Continue for 3 months and for at least 6 weeks postpartum

2. Non-anaemic women with a high risk of iron depletion (start with or without testing ferritin first)

  • Previous anaemia

  • Multiparous (>3)

  • Multiple pregnancy

  • Consecutive pregnancies <1 year apart

  • Vegetarian / Vegan diet

  • Teenagers

  • Recent bleeding

  • High risk of bleeding or Jehovah’s witness

 

Indications for testing ferritin prior to starting treatment in non-anaemic women:

  1. High risk of bleeding

  2. Declining blood products, e.g. Jehovah’s witness

  3. Difficulty in providing compatible blood products

 

Management of Iron Deficiency in Pregnancy

Dietary advice

  • RDA of iron in 2nd half of pregnancy = 27mg

  • Haem iron from meat, fish & poultry absorbed 2-3x more readily than non-haem iron

  • Vit C significantly increase iron absorption from non-haem foods

  • Tannins reduce iron absorption when consumed with, or shortly after, meals

  • Once iron-deficient in pregnancy, diet alone is not sufficient to ensure repletion

Oral Iron

  • Safe, cheap, effective

  • 40-80mg elemental iron once in the morning, or alternate days, on an empty stomach with a glass of water or orange juice.

  • Higher doses likely to result in increased side effects due to unabsorbed iron

  • Re-check Hb after 2-3 weeks

  • Once Hb is in normal range, continue for 3 months or until at least 6 weeks postpartum

IV Iron

  • Currently recommended for women from the 2nd trimester onwards with confirmed iron deficiency and intolerant / not responding to oral iron. Also consider for women presenting after 34 weeks with Hb <100g/l.

  • Adv: More likely to achieve target Hb, higher Hb at 4 weeks, and fewer side effects compared to oral iron

  • C/I: Prev anaphylaxis to IV iron, 1st trimester of pregnancy, active acute or chronic bacteraemia and decompensated liver disease.

  • Breast feeding: Transient increase in iron in milk, 3 days after treatment, compared to oral iron, but mean concentrations remained within normal range.

Delivery

  • IDA should not influence mode or timing of delivery

  • IDA with Hb <100g/l, deliver in an obstetrician-led unit

  • IDA is an indication for active management of 3rd stage of labour.

 

Further tests to assess FID/ACD

 

% Hypochromic red cells

>6% suggests FID in CKD patients who are on ESA’s

Reticulocyte MCH (CHr)

>32pg indicates adequate iron incorporation into reticulocytes

Red blood cell size factor (Rsf)

Relates MCV of RBC to that of reticulocytes. >87 fl suggests ACD rather than iron def

Zinc protoporphyrin (ZPP)

Trace byproduct or haem synthesis. Used to monitor response to therapy.

 

Further tests to assess iron stores

 

Soluble transferrin receptor (sTfR)

Increased in true iron deficiency. Expensive test, poor availability

Hepcidin Assay

BM aspirate for Pearl’s stain

 

Iron Overload

 

Simplified iron overload

Normal / Low Ferritin with Normal/low transferrin sats --> No iron overload

High Ferritin with Normal/low transferrin sats --> Inflammatory state (or rare causes)

Any level of Ferritin with High transferrin sats --> Test HFE Gene Mutation

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Type 1 Genetic Haemochromatosis

See separate notes on GH here

 

Rare Causes of Iron Overload

 

Type 2 Haemochromatosis (Juvenile Haemochromatosis)

HFE2 (syn. HJV) or HAMP gene mutations.

Causes severe iron overloading with cardiac failure and panhypopituitarism.

 

Type 3 Haemochromatosis (Transferrin receptor 2 deficiency)

TFR2 mutation.

European and Japanese ethnicities.

Clinical phenotype lies between Type 1 and Type 2 GH.

 

Type 4a Haemochromatosis (Ferroportin Disease)

Loss of function mutation in SLC40A1 (syn. FPN1) gene that encodes ferroportin

Reduced macrophage iron release --> RES iron overload.

Organ damage does not occur but patients develop iron deficiency anaemia with venesection.

 

Type 4b Haemochromatosis

Gain of function SCL40A1 mutation.

Similar phenotype to Type 1 GH.

 

Type 5 Haemochromatosis

FTH1 gene mutation.

Described in a single Japanese family.

 

Aceruloplasminaemia

CP gene mutation

Dystonia, ataxia, dementia (iron deposition in basal ganglia).

 

Hereditary Hyperferritinaemia Cataract Syndrome (HHCS)

Autosomal dominant

L-ferritin deposition in the ocular lens results in early-onset cataracts

There is no need to lower the SF level

 

African Iron Overload

Iron pots used for home brewing beer

 

Neonatal haemochromatosis

Related to acute liver injury, may have alloimmune element

 

Atransferrinaemia

TF gene mutation (Autosomal recessive)

Presents a birth with severe iron deficiency anaemia + paradoxical tissue iron overload

 

Benign Hyperferritinaemia

FTL gene mutation

Ferritin 400 - 6000 without tissue iron overload.

 

Gaucher Disease

See here

 

Iron Chelation

 

1 unit RBC = 200-250mg iron

 

Context (2016 NHS England policy document):

Sickle Cell

  • 12,500 SCD in UK, 80% living in London, 9% on long-term transfusion programme

  • 40% of the 9% are on chelation —> Approx 450 people

Thalassaemia

  • 1,500 thal pts in UK, 50% transfusion dependent

  • 60% on chelation (this more than the 50% on transfusion due to non-transfusion dependent Thal (NTDT) patients still prone to iron overload.

  • Both figures will increase in future with birth rate and increased survival

 

Aims:

  1. Prevent harmful effects of free iron

  2. Prevent or reverse organ damage

  3. Maximise quality of life

  4. Prolong survival

 

When to start?

After first 10-20 units RBC

Or when ferritin >1000 ng/ml

Or MRI Liver demonstrates >7mg/gram of dry weight iron loading

 

Desferrioxamine (Desferol) DFO

SC/IV injection or continuous infusion. Only works whilst infusing

20-60mg /kg / day

Ideally given as portable SC infusion for 8-12 hours daily (longer if tolerated)

Side effects

  • Hearing / Visual impairment (3 monthly screening mandated)

  • Yersinia infection (mimic appendicitis)

  • Arthralgia / Myalgia

SE are reducing by maintaining ratio of Mean Daily Dose (mg/kg) / ferritin below 0.025

 

Deferiprone (Ferriprox) DFP

Oral

75-100mg/kg/day TDS

2nd line license – as monotherapy if Desferol contraindicated or inadequate

Superior improvement in cardiac function than desferrioxamine

Side Effects

  • GI disturbance

  • Small joint arthritis

  • Agranulocytosis – weekly FBC for neutrophils. Re-challenge not recommended

 

Deferasirox (Exjade, Jadenu) DFX

Exjade - Oral dispersible tablet, OD, 10-40mg/kg/day

Jadenu – Coated tablet, 1/3 the dose of Exjade, usually better tolerated (fewer GI SE)

Better tolerated but slower change in free iron levels

Side effects

  • GI disturbance / ulcers

  • Rash

  • Transaminitis

  • Renal impairment