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.
(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
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
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.
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
Indications for testing ferritin prior to treatment
Anaemic women when:
Prior to IV Iron
Non-anaemic women when:
Consecutive pregnancies <1 year apart
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
BM aspirate for Pearl’s stain
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
Type 1 Genetic Haemochromatosis
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)
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)
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
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
FTL gene mutation
Ferritin 400 - 6000 without tissue iron overload.
1 unit RBC = 200-250mg iron
Context (2016 NHS England policy document):
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
Prevent harmful effects of free iron
Prevent or reverse organ damage
Maximise quality of life
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)
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
2nd line license – as monotherapy if Desferol contraindicated or inadequate
Superior improvement in cardiac function than desferrioxamine
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
GI disturbance / ulcers