Haemochromatosis

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Haemochromatosis

• Ed Morris
• Haematologist
• Townsville Cancer Centre, The Townsville Hospital
• The Mater Hospitals, Townsville

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Spectrum of iron disorders

• Anaemia of chronic disease
• Insufficient iron made available for haemopoiesis

• Haemochromatosis
• Iron deposition liver, endocrine organs, heart
  skin

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PO iron
Hepatocyte (Fe storage reservoir)
Duodenal enterocyte
Transferrin receptor

• Balance maintained by regulation of absorption
  distribution
• No physiological excretion method

Fe Ferroportin Transferrin
Transport of Fe to bone marrow for Hb production
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PO iron
Hepatocyte (Fe storage reservoir)
Duodenal enterocyte
Transferrin receptor
RBC
Macrophage
Fe Ferroportin Transferrin
Transport of Fe to bone marrow for Hb production
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Hepcidin

• Produced by hepatocytes
• Highly evolutionarily conserved
• Insects
• Fish
• Mice
• Pigs
• Humans
• Identified due to anti-microbial activity

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Fe uptake
Fe release into plasma

• Fe exporting cell
• Duodenal enterocyte
• Macrophage
• Hepatocyte

Fe Ferroportin
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Fe retained
Fe uptake

• Fe exporting cell
• Duodenal enterocyte
• Macrophage
• Hepatocyte

Fe Ferroportin Hepcidin
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Hepcidin

• Increased production
• Inflammation (IL-6 driven)
• Decreased production
• Anaemia
• Hypoxia
• Haemochromatosis

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PO iron
Hepatocyte (Fe storage reservoir)
Duodenal enterocyte
RBC
Macrophage
Fe Ferroportin Transferrin
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Increased hepcidin
PO iron
Hepatocyte (Fe storage reservoir)
Duodenal enterocyte
RBC
Macrophage
Hepcidin
Fe Ferroportin Transferrin
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• Decreased hepcidin

PO iron
Hepatocyte (Fe storage reservoir)
Duodenal enterocyte
RBC
Macrophage
Hepcidin
Fe Ferroportin Transferrin
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Hepcidin iron disorder pathogenesis
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Iron studies
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Iron studies

• Serum iron
• Very variable - diurnal variation
• Not very useful for assessing iron stores

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Iron studies

• Transferrin
• Iron transport molecule
• Deposits iron in any cell expressing transferrin
  receptors

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Iron studies

• Transferrin Saturation
• Suggests the amount of iron being actively
  transported

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Iron studies

• Ferritin
• Reasonable reflection of body stores
• Acute phase protein. Synthesized in the liver

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74 yr old male
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74 yr old male

• Consistent with iron deficiency

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41 yr old male
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41 yr old male

• Consistent with iron overload

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67 yr old female
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67 yr old female

• Consistent with chronic inflammation

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Haemochromatosis

• Deposition of excessive amounts of iron in
  parenchymal cells
• Tissue damage impaired organ function.
• Liver cirrhosis
• Diabetes mellitus
• Arthritis
• Cardiomyopathy
• Hypogonadotropic hypogonadism

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Classification of Haemochromatosis
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Classification of Haemochromatosis
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Classification of Haemochromatosis
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Hereditary Haemochromatosis

• Prevalence
• HFE mutations among most common inherited disease
  alleles
• Prevalence varies between ethnic groups
• Most common in populations of northern European
  extraction
• Approximately 1 in 10 heterozygous carriers
• 0.30.5 homozygotes

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HFE

• Encoded chromosome 6
• Genotypes associated with inherited HFE
  haemochromatosis
• C282Y/C282Y
• C282Y/H63D
• C282Y/S65C
• ? H63D/H63D

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• Healthy subjects participating in Melbourne
  Collaborative Cohort Study
• 40-69 years old
• 12 yrs of FU

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Non-C282Y homozygotes

• Evidence of iron overload

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Hereditary Haemochromatosis

• Expression of the disease highly variable and
  modified by several factors
• Alcohol
• Liver disease
• Blood loss menstruation, pregnancy and blood
  donation

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Haemochromatosis clinical approach

• Frequently present with non-specific symptoms
• Unexplained arthropathies
• Impotence
• Hyperpigmentation
• Liver dysfunction
• Diabetes
• Cardiomyopathy

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lt45
Clinical suspicion
Reassure Retest later?
Transferrin saturation
gt45
HFE Genotype
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lt45
Clinical suspicion
Reassure Retest later?
Transferrin saturation
gt45
HFE Genotype
FHx
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lt45
Clinical suspicion
Reassure Retest later?
Transferrin saturation
gt45
Normal or other genotype
Consider secondary causes Consider non-HFE
haemochromatosis
HFE Genotype
FHx
C282Y/C282Y C282Y/H63D
Ferritin, LFTs, GHPS
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lt45
Clinical suspicion
Reassure Retest later?
Transferrin saturation
gt45
Normal or other genotype
Consider secondary causes Consider non-HFE
haemochromatosis
HFE Genotype
FHx
C282Y/C282Y C282Y/H63D
Ferritin lt300 LFTs N
Observe Retest 6-12 months
Ferritin, LFTs, GHPS
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lt45
Clinical suspicion
Reassure Retest later?
Transferrin saturation
gt45
Normal or other genotype
Consider secondary causes Consider non-HFE
haemochromatosis
HFE Genotype
FHx
C282Y/C282Y C282Y/H63D
Ferritin lt300 LFTs N
Observe Retest 6-12 months
Ferritin, LFTs, GHPS
Abnormal LFT
Ferritin gt300 LFTs N
No iron overload
Iron overload
Ix as appropriate
Liver biopsy
Phlebotomy
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MRI

• Magnetic ferritin and hemosiderin interact with
  hydrogen nuclei in tissue water
• Shorten relaxation times with changes in the MR
  signal intensity

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MRI

• Liver
• Slow (approx 20 mins)
• Relatively simple
• Good correlation with iron levels and cirrhosis

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MRI

• Heart
• Rapid (single breath hold)
• T2 imaging highly sensitive for
  moderate-to-severe iron deposition
• Normal gt 50 msec
• T2 lt20 msec
• LV systolic function declines progressively
• ? LV end-systolic volume
• ?LV mass.

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Management

• Venesection
• If Ferritin gt1000 - need to remove up to 25g Fe
• 500mls blood contains 250mg Fe

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Management

• Venesection
• Induction Phase
• Usually weekly
• 7ml/kg (max 550mls)
• Ensure Hbgt110
• Check ferritin
• Every 4 weeks until lt300
• Every 2 weeks until lt50

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Management

• Venesection
• Maintenance
• Aim to keep ferritin lt50
• Usually required 1-4 monthly
• Check ferritin every 2nd venesection

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Management

• Diet
• Realistically little role
• Avoid large quantities Vitamin C
• Increased Fe absorption
• Increases Fe release from storage sites
• Rare reports of inducing lethal cardiac failure

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Management

• Future perspectives
• Chelation
• Can remove approx 25mg Fe per day (500mls blood
  250mg)
• Desferoxamine (Desferal)
• 8-12 hour S/C infusions 5 days/week
• Optic effects

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Management

• Future perspectives
• Deferiprone (Ferriprox)
• Idiosyncratic agranulocytosis
• Deferasirox (Exjade)
• GI upset
• Renal impairment
• VERY expensive

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Management

• Future perspectives
• Hepcidin assay
• Evolutionary conservation
• Only available in research laboratories
• ?? Hepcidin replacement therapy

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Any questions?
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Any questions?