Haemochromatosis

• Hereditary haemochromatosis is an autosomal recessive disorder that results in iron overload
• The disease is characterised by a state of iron overload that most commonly affects the liver, heart, joints, pancreas, and pituitary gland. Classically, it was termed ‘bronzed diabetes’ due to the typical skin pigmentation and development of diabetes mellitus from iron overload. The main manifestation of untreated HH is liver cirrhosis.
• HH is an autosomal recessive disorder most commonly due to an underlying genetic variant in the HFE gene. The HFE gene is located on chromosome 6. Two main variants:

  • C282Y
  • H63D
• The HFE gene, located on chromosome 6, encodes a transmembrane glycoprotein that interacts with other receptors to regulate iron within the body
• Iron is primarily absorbed from the upper gastrointestinal tract by a tightly regulated process. There is no regulatory pathway to excrete iron, but it may be lost through the desquamation of gastrointestinal cells, menstruation or blood loss. The latter is because blood is a major store of iron.

  Disruption to the regulatory pathway involved in iron absorption is seen in hereditary haemochromatosis.
• In HH, variants in the HFE gene enable increased levels of iron to accumulate within the body. This leads to increased stores of iron, which raises the level of measured serum ferritin (a marker of total body stores)
• Causes of raised ferritin:

  • Haemochromatosis
  • Infections (acute phase protein)
  • Chronic alcohol consumption
  • NAFLD
  • Hepatitis C
  • Cancer
• Transferrin saturation helps distinguish between high ferritin caused by iron overload (transferrin saturation is high) and other causes (transferrin saturation is normal).
• Usually presents after the age of 40 when the iron overload becomes symptomatic. It presents later in females due to menstruation acting to eliminate iron from the body regularly.
• Typical symptoms:

  • Chronic tiredness
  • Joint pain
  • Pigmentation
  • Testicular atrophy
  • Erectile dysfunction
  • Amenorrhoea (absence of periods)
  • Cognitive symptoms
  • Hepatomegaly
• Chronic iron deposition in the liver:

  • Fibrosis
  • Cirrhosis
• Heart:

  • Cardiomyopathy that results in HF
  • At risk of conduction defects
• Accumulation of iron in the pituitary gland:

  • Secondary hypogonadism: in men, low testosterone can lead to impotence and reduced sexual libido. In women, reduced sexual hormones may lead to amenorrhoea.
  • Secondary hypothyroidism: weakness, fatigue, cold intolerance, constipation, and weight gain amongst others.
• Pancreas:

  • Toxicity to beta cells that result in reduced insulin secretion and the development of T2DM
  • Polyuria
  • Polydipsia
  • Weight loss
• Joints:

  • Chronic arthropathy, particularly in the small joints of the hand
  • Most commonly affected joints are the second and third metacarpophalangeal joint
• Deposition of iron and melanin in the skin causes hyperpigmentation and gives the skin a bronzed colour
• Diagnosis:

  • Serum ferritin is the initial investigation
  • Transferrin saturation helps distinguish from other causes (high in HH)
  • Genetic testing for mutations in the HFE gene
  • Liver biopsy with Perl's stain can be used to establish the iron concentration in the liver (not usually needed if gene identified)
  • MRI
• • Transferrin saturation: the ratio of serum iron and total iron-binding capacity. Expressed as a percentage and will go up with excess iron as occurs in HH.
• Complications:

  • Secondary diabetes (iron affects the functioning of the pancreas)
  • Liver cirrhosis
  • Endocrine and sexual problems (hypogonadism, erectile dysfunction, amenorrhea and reduced fertility)
  • Cardiomyopathy (iron deposits in the heart)
  • Hepatocellular carcinoma
  • Hypothyroidism (iron deposits in the thyroid)
  • Chondrocalcinosis (calcium pyrophosphate deposits in joints) causes arthritis
• Management:

  • Venesection (regularly removing blood to remove excess iron – initially weekly)
  • Iron-chelation if unable to undergo venesection - deferasirox binds to iron to firm a stable complex than can be excreted by the kidneys
  • Monitoring serum ferritin
  • Monitoring and treating complications - cirrhosis and hepatocellular carcinoma