Case 71 – summary

Our patient had high ferritin which was detected on a routine blood test. Hyperferritinaemia is common and causes can usually be differentiated by history and clinical examination. Potential causes include:

  • Any inflammation including rheumatological conditions and renal failure
  • Infections
  • Liver disease
  • Chronic blood transfusion
  • Haemochromatosis
  • Myelodysplasia
  • Porphyria cutanea tarda
  • Hereditary hyperferritinaemia cataract syndrome
  • Inherited anaemias including sideroblastic anaemia, congenital dyserythropoietic anaemia and some inherited haemolytic syndromes
  • Thalassaemia (even without blood transfusion)
  • Haemophagocytic lymphohistiocytosis
  • Gaucher’s disease
  • Acaeruloplasminaemia (increased ferritin, normal T sats)
  • Hallervoden-Spatz syndrome (neurological/ataxia with brain iron accumulation)
  • Freidrich’s ataxia
  • Neuroferritinopathy


Usually the differential lies between liver disease, haemochromatosis and hyperferritinaemia due to inflammation. Here LFTs, transferrin saturations, abdominal ultrasound scanning, inflammatory markers and investigations into potential liver disease can help.


How common is genetic haemochromatosis?

Most cases of genetic haemochromatosis (90%) are due to a homozygous substitution for G to A  at nucleotide 845 of the HFE gene – cysteine to tyrosine amino acid substitution (i.e. C282Y). Also a mutation at nucleotide 187 leads to histidine to aspartic acid at amino acid 63 i.e. H63D (homozygotes HFE H63D do not accumulate significant iron but compound heterozygotes C282Y and H63D can). In UK genetic haemochomatosis is:

  • 90% homozygous HFE C282Y
  • 4% compound heterozygous HFE C282Y and HFE H63D
  • A smaller amount heterozygous HFE C282Y and HFE S65C (cysteine is substituted for serine at amino acid position 65)

The frequency of the C282Y mutation in the HFE gene is more common in Northern Europe. In UK 1 in 8 are carriers for HFE C282Y and 1 in 200-250 are homozygous. This map is taken from EASL Clinical Practice Guidelines for HFE Hemochromatosishaemochromatosis-map

It is the commonest genetic mutation in Caucasians but less than 10% of homozygotes ever develop clinically significant iron loading. For this reason population screening is not advised. The mutation is maintained due to a possible survival advantage of heterozygotes. The phenotype depends on:

  • Diet
  • Gender- females menstruate/pregnancy
  • Blood donors
  • Other genetic factors e.g. co-inheritance of haemolytic anaemias etc.

The mutation leads to reduced hepcidin leading to increased ferroportin and therefore increased iron absorption and increased iron storage. There is no easy way to excrete iron and when transferrin binding capacity is reached labile iron appears and taken up by cells leading to reactive oxygen species causing tissue damage.


Features and investigations

  • Clinical features:
    • OA (especially hands – (typically of the second and third metacarpophalangeal joints) – pyrophosphate deposition
    • Diabetes mellitus
    • Endocrine/gonadal failure/impotence/amenorrhoea
    • Fatigue
    • Hepatomegaly/liver failure/cirrhosis/HCC
    • Heart failure/arrhythmias
  • Transferrin saturation – better estimate of accumulation in liver compared with ferritin; also may increase transferrin saturations before ferritin (typically >45%)
  • Ferritin >200 (women); >300 (men) – check with CRP/ESR as may give a guide to elevation due to inflammation/infection
    • Ferritin of >1000 is more predictive of cirrhosis; especially if LFTs are deranged and/or platelets are low
  • With both transferrin and ferritin it is worth repeating this on a second sample
  • HFE genotyping – check for C282Y mutation and if heterozygous also check for H63D
    • HFE C282Y homozygosity alone is insufficient for a diagnosis – there must be evidence of iron loading as well – if iron studies normal repeat on an annual basis
    • Check if iron loading and no other cause or cause unclear
  • Liver biopsy – due to availability of genotyping the role of liver biopsy to assess for iron overload is generally not required.
    • Checks parenchymal (liver cell) stores and reticuloendothelial system (Kupffer cells)
    • Do if HFE mutation negative but suspicious of iron overload
    • Do to assess stage of cirrhosis (especially if deranged LFTs and ferritin>1000)
  • MRI T2* or USS for cirrhosis/HCC
  • AFP monitoring
  • Echo/ECG if cardiac problems
  • Endocrine screen – TFTs, glucose, LH, FSH, testosterone, calcium


Venesection is the mainstay of treatment, although it’s benefits have only been studies in retrospective case series. Start venesection when ferritin is elevated. Generally weekly venesection to aim for ferritin around 50 (some say less than 50); then move onto maintenance phase to keep ferritin 50-100. This generally consists of three to four venesections per year but can vary significantly. Iron deficiency should be avoided. Each unit of blood removes 200-250mg iron and generally 5-20g needs to be removed initially. Assuming there are no other contraindications patients with haemochromatosis can donate blood in the UK but their ferritin levels must still be monitored by a physician. Rarely patients may need a form of central access if venesection is difficult or iron chelation – if this is required then ferritin targets will change. Venesection reduces mortality from cardiac failure and liver failure/HCC. Patients may need fluids after venesection or during venesection to reduce risk of hypotension. Antihypertensives may need to be withheld on those days.


  • Improves DM, hypogonadism, ALT, arthralgia, fatigue, pigmentation
  • Does not improve cirrhosis, HCC, OA if already developed

It is often difficult to have full dietary restrictions that may interfere with patients psychological well being, however the below would seem sensible:

  • Avoid supplements or foods fortified with iron and vitamin C (the latter aids iron absorption)
  • Limit intake of foods high in vitamin C and iron to a minimum if possible
  • Keep alcohol to a minimum

A useful guide is given here from the Haemochromatosis Society.


Other forms of haemochromatosis are rare:

  • Type II haemochromatosis (juvenile) – Rare; autosomal recessive with iron overload in 20s/30s. Involve mutations in hepcidin HAMP and haemojuvelin HFE2 HJV. 
  • Type III haemochromatosis – Rare; autosomal recessive. Mutation in transferrin receptor 2 gene TFR2. Variable phenotype.
  • Type IV haemochromatosis – ferroportin disease. Autosomal dominant with high ferritin but normal transferrin saturations. Iron accumulation in reticuloendothelial system rather than parenchyma. Similar phenotype to alcoholic liver disease/metabolic syndrome/acaeruloplasminaemia. Loss of function in ferroportin means reduced export from cells; especially macrophages. Patients develop anaemia with venesection.


Family screening

Counselling patients is important – genetic diagnosis have implications for life insurance etc. All first degree relatives should be tested. Guidance recommends ferritin/transferrin saturations and HFE genotyping. If patients are found to have HFE C282Y homozygosity but no iron loading then yearly monitoring of iron studies is recommended.





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