Hereditary Haemochromatosis

Hereditary haemochromatosis (HH) is a genetic condition, inherited in an autosomal recessive manner, which leads to increased intestinal iron absorption and iron deposition in various tissues.

Epidemiology

Hereditary haemochromatosis mostly affects populations with Northern European ancestry - France, Ireland and Denmark have high prevalence of the condition.^[i] Male patients tend to present between 40 and 60, and women around 10 years later as menstruation leads to iron loss, and subsequent protection.^[ii]

Causes

HH is caused by a mutation in the HFE gene – the two most common mutations are the C282Y and H63D mutations.

Secondary causes of haemochromatosis include frequent blood transfusions which can lead to iron overload e.g. treating thalassaemia.

Pathophysiology

HFE is a gene coding for the HFE protein which is important in regulating iron absorption. It firstly works by decreasing iron absorption by cells by blocking transferrin receptors which are necessary for absorbing circulating iron.

Secondly, HFE protein causes reduced expression of hepcidin, a hormone which inhibits iron absorption.^[iii]

Thus, due to mutated HFE, you get unregulated iron absorption from the gut, leading to iron overload. As there is no physiological mechanism for iron excretion, iron begins to accumulate in various tissues.

Free iron is toxic to cells – the main reason for this toxicity is due to the Fenton reaction which is where free iron is oxidised and reduced by hydrogen peroxide, which produces damaging free radicals.^[iv]

Clinical Features

Initially, patients may be asymptomatic or be fatigued – at this stage, they may be diagnosed incidentally due to routine checking of serum iron levels. As time progresses, iron begins to accumulate in tissues causing problems.

• Liver: Iron accumulation in the liver tissue leads to hepatomegaly, abdominal pain, cirrhosis and potentially even hepatocellular carcinoma.
• Skin: Accumulation in the skin leads to hyperpigmentation.
• Joints: Arthropathy and arthralgia due to iron depositing within joints.
• Endocrine tissue:
  • Patients can also acquire diabetes (type 1 or 2), due to damage of the pancreatic tissue by iron deposits.
  • Hypothyroidism due to thyroid deposits
  • Infertility, erectile dysfunction, amenorrhoea from gonadal deposits
• Heart: Cardiomyopathy due to accumulation here
• Other:
  • Fatigue
  • Hair loss

Investigations

Bloods

• Transferrin and Ferritin
  • Transferrin saturation: Iron carrier which transports iron in the circulation
  • Ferritin: Protein used to store iron within cells. It is also an acute phase protein i.e. like CRP and will rise in inflammatory states such as an infection.
  • High transferrin saturation and high ferritin should trigger suspicion of iron overload.
• FBC, U&E, LFT, Clotting: Baseline

Special Tests

• HFE genotyping is used to confirm the diagnosis by identifying the presence of the HFE mutations.
• A liver biopsy can also be done with Perl’s stain – this allows visualisation of iron accumulation.^[v] 

Management

As per UK guidelines, fit patients who have iron loading should undergo weekly venesection (venepuncture) until the ferritin levels are between 20-30 µ/l and the transferrin saturation is <50% - the patient’s full blood count should also be simultaneously monitored to ensure haemoglobin levels are adequate.

Venesection lowers iron levels by removing haemoglobin (and thus iron) from the body, and also by stimulating erythropoesis which stimulates mobilisation of iron stores.

For patients unable to tolerate venesection, iron chelating drugs such as desferrioxamine can be used.^[vii]

This is not a curative process so once the iron levels are brought down, patients will need venesection to maintain normal blood iron levels though this is usually done on an ‘as-needed’ basis.

References

^[i] PC Adams. Epidemiology and diagnostic testing for hemochromatosis and iron overload. [internet]. 2019. [cited 11^th August 2019]. Available from: https://onlinelibrary.wiley.com/doi/pdf/10.1111/ijlh.12347

^[ii] NIH. Hereditary hemochromatosis. [internet]. 2019. [cited August 11^th 2019]. Available from: https://ghr.nlm.nih.gov/condition/hereditary-hemochromatosis#

^[iii] NORD. Classic Hereditary Hemochromatosis. [internet]. 2016. [cited 11^th August 2019]. Available from: https://rarediseases.org/rare-diseases/classic-hereditary-hemochromatosis/

^[iv] Kohgo Y, Ikuta K, Ohtake T, Torimoto Y and Kato J. Body iron metabolism and pathophysiology of iron overload. [internet]. 2008. [cited 11^th August 2019]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516548/#CR35

^[v] The Newcastle upon Tyne Hospitals. Hereditary Haemochromatosis. [internet]. 2019. [cited 11^th August 2019]. Available from: http://www.newcastle-hospitals.org.uk/services/ng_npcg_common_hh.aspx

^[vi] Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). [internet]. 2018. [cited 11^th August 2019]. Available from: https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.15164

^[vii] Oxford Handbook