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 (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
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:
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)
Consecutive pregnancies <1 year apart
Vegetarian / Vegan diet
High risk of bleeding or Jehovah’s witness
Indications for testing ferritin prior to starting treatment in non-anaemic women:
High risk of bleeding
Declining blood products, e.g. Jehovah’s witness
Difficulty in providing compatible blood products
Management of Iron Deficiency in Pregnancy
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
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
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.
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
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