Iron overload (IOL) (BSH 2021)

 

introduction

Simplified testing for 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

Conditions associated iron overload

Haemoglobinopathies - thalassaemias, sicke cell disease

Hereditary haemochromatoses

Rare anaemias - e.g. congenital sideroblastic anaemia (CSA), congenital dyserythropoietic anaemia (CDA)

Red cell membranopathies

Chronic haem malignancies - e.g. MDS

Iron overload in haemoglobinopathies

15,000 patients in UK with haemoglobinopathies or rare anaemias that are at risk of iron overload

TDT = Transfusion-dependent thalassaemia

NTDT = Non-transfusion-dependent thalassaemia

NTRIA = Non-transfused rare inherited anaemia

NTDT and NTRIA are still at risk of iron overload from chronic increase in GI iron absorption and ad hoc transfusions.

Average iron accumulation from transfusion in TDT = 0.4mg/kg/day

Est. iron accumulation from GI absorption in NTDT = 0.01mg/kg/day

 

Complications of Iron Overload

Excess iron first accumulates in macrophages (liver, spleen and BM) and then —> into liver hepatocytes.

As liver iron accumulates the transferrin saturation rises, and once >70% then non-transferrin-bound plasma iron (NTBI) starts to form.

It is NTBI that results in iron deposition in endocrine organs and the heart.

Cardiac

  • Arrhythmias - AF, VT, heart block

  • Acute heart failure - MRI T2* predicts the risk of this, allowing opportunity to intervene

  • Chronic heart failure - LV function expected to recover with chelation.

Liver

  • Cirrhosis - results from NTBI causing cell necrosis —> fibrosis.

  • Hepatocellular carcinoma

Endocrine

  • Diabetes

  • Hypoadrenalism

  • Hypothyroidism, hypoparathyroidism, hypogonadotropic hypogonadism

  • Endocrinopathies are potentially reversible with chelation

Other

  • Vasculopathies

  • Other malignancies

  • Adipose tissue remodelling

Testing/monitoring for iron overload

Tests include:

  • Serum ferritin, glucose, thyroid function, cortisol, gonadal function, Vitamin D, LFTs, Hep B/C

  • Growth charts / pubertal status / oral glucose tolerance test

  • ECG (?arrhythmias)

  • Echo (?LV function)

  • MRI Cardiac T2*

    • A value of <20ms ass. w/ increased cardiac iron. <10ms inc. risk of cardiac failure

  • Liver ultrasound (?cirrhosis)

  • Liver R2 (Ferriscan), R2* or T2*

    • >7mg/g dry weight liver iron concentration ass. w/ risk of fibrosis.

  • Bone density scan

Testing schedules vary by condition, but e.g.

  • Calculate transfusional iron loading at annual review

  • Ferritin every 1-3 months

  • Baseline MRI heart and liver, followed by interval surveillance

Iron Chelation

 

1 unit RBC = 200-250mg iron

Long-term ferritin control is prognostic. Ferritin <2500 ass. with lower risk of cardiac disease and death

Formula for calculating rate of iron loading is in the guideline.

 

Aims:

  1. Prevent harmful effects of free iron

  2. Prevent or reverse organ damage

  3. Maximise quality of life

  4. Prolong survival

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

 

When to start?

After first 10-12 units RBC or >100ml/kg/yr of red cells

Or when ferritin >1000 ng/ml (Small print: >800 for NTDT, >500 for NTRIA)

Or MRI Liver demonstrates >5mg/gram of dry weight iron loading

Deferasirox (Exjade, Jadenu) DFX

Exjade - film coated tablet, OD

7-21mg/kg/day

1st line for adults and children >6 years old

Better tolerated but slower change in free iron levels

Side effects

  • GI disturbance / ulcers

  • Rash

  • Transaminitis (monthly LFT)

  • Renal impairment (monthly U&E and urinalysis)

  • Hearing impairment (annual audiometry)

  • Visual impairment (annual ophthalmology)

Desferrioxamine (Desferal) 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)

1st line for children <6 years old. Alternative option at any age.

Side effects

  • Hearing / Visual impairment (annual screening mandated)

  • Yersinia infection (mimic appendicitis)

  • Arthralgia / Myalgia

  • Transaminitis (monthly LFT)

  • Renal impairment (monthly U&E and urinalysis)

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

Alternative option for adults and children >6 years old

Insufficient evidence to recommend for children

Superior improvement in cardiac function than desferrioxamine

Side Effects

  • GI disturbance

  • Small joint arthritis

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

  • Transaminitis (monthly LFT)

  • Renal impairment (monthly U&E and urinalysis)

 

Treatment intensification / combination

Complex, specialist decision making

Details available in the BSH guideline