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


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


Definitions of anaemia in pregnancy:

1st trimester               <110g/l

After 1st trimester     <105g/l

Postpartum                <100g/l


Indications for testing ferritin prior to treatment

Anaemic women when:

  • Known haemoglobinopathy

  • Prior to IV Iron

Non-anaemic women when:

  • Previous anaemia

  • Multiparous (>3)

  • Consecutive pregnancies <1 year apart

  • Vegetarians

  • Teenagers

  • Recent bleeding

  • High risk of bleeding or Jehovah’s witness


Indications to treat:

Oral iron trial if Hb <110 at booking or <105 at 28 weeks

  • Only check ferritin first if known Hbpathy (then proceed if <30)

  • Re-check after 4 weeks, Hb should rise by >20g/l

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

Offer low dose 65mg/day if non-anaemic risk group from list above


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.



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



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


  • 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



  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


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