Introduction

The term haemochromatosis is usually used to describe a group of autosomal recessive disorders of iron metabolism. It is sometime called hereditary haemochromatosis and abbreviated to HHC.

The most common mutations are in the HFE gene. Types of mutation of this mutations of this gene include C282Y and H63D. C282Y is by far the most common mutation. Heterozygous mutations are very common in caucasians (up to 20%) and often not clinically significant. Even in homozygous mutations, only a minority of patients will develop iron overload.

The genetic defects result in excessive iron absorption from the diet.
The excess iron accumulates in tissues, causing a wide variety of signs and symptoms as a result of problems with iron metabolism and excretion. These include:

• Skin discolouration
• Liver disease – these are usually the most serious complications
  • Cirrhosis
  • Liver carcinoma
  • Hepatocellular carcinoma
• Diabetes (pancreatic involvement)
• Joint involvement (arthiritis)
• Pituitary – sexual dysfunction
• Heart failure, cardiomyopathy and arrhythmia
• Neurological signs
  • Impaired memory
  • Mood swings
  • Irritability
  • Depression

Genetics

• The most common form of the disease involves a mutation of the HFE gene on the short arm of chromosome 6. This is carried by approximately 0.4% of the population, however expression is highly variable
• Varied penetrance: homozygosity of defective HFE gene does not necessarily cause haemochromatosis
• Men affected more than women. When women are affected then tend to present approximately 10 years later in life
• Most prevalent in northern European populations
• General population level genetic screening is not recommended
  • HFE testing should be considered in patients with raised iron and deranged LFTs
  • Screening for haemochromatosis in patients with deranged LFTs is recommended by requesting iron studies
• Siblings of patients diagnosed with HFE-HHC should have their own genetic testing – they have a 25% chance of being affected

Genetic test results

• C282Y – homozygous
  • Most patients will accumulate iron but only a minority with become symptomatic
  • More often affects men
• C282Y + H63D
  • Most have normal iron levels
  • Some will accumulate iron but likely to remain asymptomatic
  • Severe iron overload can occur in the context of other liver disease (e.g. alcoholism or viral hepatitis)
• H63D – homozygous
  • Most have normal iron levels
  • A small percentage may develop iron overload in the context of other risk factors (as above)
• C282Y – heterozygous
  • Very common! Affects about 10% of caucasians
  • Most have normal iron levels, some will have elevated iron
  • Very rarely causes iron overload
• H36D – heterozygous
  • Even more common! Affects about 20% of caucasians
  • Very unlikely to cause iron overload
• No mutation found
  • May still have HHC – of unknown genetic cause
  • Diagnosis confirmed with liver biopsy on background of iron overload despite no obvious cause

Presentation

• Presents late in disease process
• Typically age 30-50, later (usually post-menopause) in women
• Usually begins with non-specific symptoms: lethargy, malaise, weakness, joint pains, erectile dysfunction
• Later symptoms include: skin discolouration (darker), cirrhosis, hepatocellular carcinoma, diabetes, heart failure
• Often diagnosed incidentally – when iron studies and / or LFTs are taken for another reason

Investigations

• ↑Ferritin
  • Normal serum ferritin effectively rules out HHC as a differential
  • Raised ferritin is non-specific and can be due to acute inflammation, and many other liver diseases
• ↑Iron – transferrin saturation often >70%
• Deranged LFTs (late sign)
• Genetic testing – for C282Y and H63D mutations of the HFE gene are recommended for all patients with increased ferritin and transferrin saturation
  • Indicated if iron overload is present:
    • Ferritin >1000 g/L
    • Ferritin >200 in women or >300 in men AND transferrin saturation >45%
    • In patients with elevated ferritin but transferrin saturation <45% consider other causes, including – alcohol, malignancy, diabetes, liver disease (including fatty liver)
• Liver biopsy may be considered – previously this was the diagnostic investigation of choice but has been superseded by genetic testing. May still be indicated in assessing fibrosis and cirrhosis.

Differentials

• Iron overload anaemias – e.g. Thalassaemia, sideroblastic anaemia
• Drugs
• Haemodialysis
• Chronic liver diseases
  • Hepatitis
  • Alcoholic liver disease
  • NAFLD
  • Cirrhosis
• Myelodysplastic syndrome
• Multiple blood transfusions

Management

• Venesection
  • Indicated if ferritin >200mcg/L in females and >300mcg/L in males
  • Iron unloading phase – 500mls blood removed once every 1-4 weeks (depending on any side effects from loss of blood volume)
    • Check Hb before each treatment
    • Ensure Hb remains above 120g/L
    • Give B12 and folate supplementation if Hb falls below this
    • Check ferritin after 4 treatments – maintain in range 20-50 mcg/L
  • Maintenance phase
    • Maintain ferritin in 50-100 mcg/L range
    • Typically this involves venesection 3-4x per year for men and 1-2x per year for menstruating women
    • Check ferritin every 6-12 months
• Specialist referral
  • If ferritin >1000mcg/L
  • Liver biopsy may be considered as these patients are high risk for liver damage
  • Will also be assess for cardiac damage and diabetes
  • Also refer – patients who meet HCC iron overload criteria, but gene testing is negative
• Lifestyle factors
  • Avoid alcohol
  • Avoid vitamin C supplements
  • Avoid iron supplements
• Minimising complicating factors
  • Consider vaccination against hepatitis A and B whilst iron overloaded to minimise risk of co-morbidities than can result in liver failure
• Liver transplant
  • May be required in decompensated liver disease
  • Survival rates after transplant appear to be lower than in patients who have liver transplant for another reason
    • 64% survival at one year
    • 34% survival at 5 years
• Monitoring
  • Patients who are homozygous C282Y with normal ferritin levels and transferrin saturation should have iron studies every 2-3 years
  • Check Hb and iron studies every 2-6 months in patients who have previous required venesection. Perform venesection as indicated
• Screening of relatives
  • Screen first degree relatives with iron studies and HFE gene testing
  • In children – start screening in late teens or early adult years
  • Advise about inheritance patterns

Flashcard

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Hereditary Haemochromatosis – Health Pathways
• Hereditary Haemochromatosis – patient.info
• Haemachromatosis – Gastroenterological Society of Australia

Read more about our sources

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