Hereditary Haemochromatosis

Question 1

What is hereditary haemochromatosis?

Answer 1

Inherited disorder of iron metabolism in which increaed intestinal iron absorption leads to iron deposition in joints, the liver, heart, pancreas, pituitary, adrenals, and skin

Question 2

Who does haemochromatosis most commonly affect?

Answer 2

Middle aged men

Question 3

What gene is responsible for haemochromatosis?

Answer 3

HFE - commonest mutations are C282Y and H63D

Question 4

What is the mechanism of damage in hereditary haemochromatosis?

Answer 4

HFE gene protein interacts with the transferrin receptor 1 -> Iron is taken up by the mucosal cells inappropriately, exceeding the binding capacity of transferrin.

Hepcidin, a protein synthesized in the liver, is central to the control of iron absorption; it is increased in iron deficiency states and decreased with iron overload. The mutations described above disrupt hepcidin expression, thereby internalizing ferroportin leading to uninhibited iron overload.

Hepatic expression of the hepcidin gene is decreased in HFE haemochromatosis, facilitating liver iron overload. Excess iron is then taken up by the liver and other tissues gradually over a long period. It seems likely that it is the iron itself that precipitates fibrosis.

Question 5

What are clinical features of hereditary haemochromatosis?

Answer 5

Initially

• Tiredness
• Arthalgia
• Decreased libido

Later

• Slate-grey/bronze skin pigmentation
• Signs of chronic liver disease
• Endocrinopathies
• Hepatomegaly
• Cirrhosis
• Dilated cardiomyopathy

Question 6

What endocrinopathies can occur with hereditary haemochromatosis?

Answer 6

• Diabetes mellitus - bronze diabetes
• Hypogonadism

Question 7

Why can diabetes occur in hereditary haemochromatosis?

Answer 7

Build up of iron in the pancreas -> bronze diabetes

Question 8

Why does arthralgia/arthopathy occur in hereditary haemochromatosis?

Answer 8

Calcium pyrophosphate deposition in the joints - leading to chondrocalcinosis

Question 9

Why does bronze pigmentation occur in hereditary haemochromatosis?

Answer 9

Melanin deposition

Question 10

What is the classic traid of features seen in hereditary haemochromatosis?

Answer 10

• Skin pigmentation
• Diabetes mellitus
• Hepatomegaly

Question 11

What complications can occur from hereditary haemochromatosis?

Answer 11

Hepatocellular Carcinoma - if cirrhotic, 30% chance

Question 12

What investigations would you consider doing in someone with suspected haemochromatosis?

Answer 12

• Bloods - LFTs, Iron studies, glucose, HFE genetic analysis, testosterone, FSH, LH
• MRI liver
• Liver biopsy
• Consider echocardiogram/ECG

Question 13

What tests are included in iron studies?

Answer 13

• Ferritin
• Serum Iron
• Transferrin/Total iron binding capacity (TIBC)
• Transferrin saturations

Question 14

What can cause ferritin to rise?

Answer 14

Acute phase protein

• Liver disease
• Malignancy
• Inflammation

Question 15

What does TIBC show?

Answer 15

Reflects the availibility of iron binding sites on transferrin

Question 16

How is TIBC affected in Iron overload?

Answer 16

Decreased TIBC - the amount of transferrin that is available for iron to bind to is decreased

Question 17

What might iron studies show in someone with haemochromatosis?

Answer 17

• Elevated serum iron
• Decreased TIBC
• Transferrin saturation > 45%
• Elevated serum ferritin

Question 18

Why might you consider doing serum testosterone, FSH and LH in someone with suspected haemochromatosis?

Answer 18

May be low in those with hypogonadism

Question 19

Why might you do an echo/ECg in someone with suspected haemochromatosis?

Answer 19

Look for features of cardiomyopathy

Question 20

What might you find on liver biopsy in someone with haemochromatosis?

Answer 20

Iron loading and cirrhosis

Question 21

How would you manage someone with hereditary haemochromatosis?

Answer 21

• Venesection - until ferritin < 50 ug/L
• Low iron diet + food/drink which decreases iron absorption
• Ensure vitamin preparations do not contain iron
• Family screening

Question 22

What can cause secondary haemochromatosis?

Answer 22

Repeated transfusion

Question 23

What is the mode of inheritence of heredittary haemochromatosis?

Answer 23

Autosomal recessive inheritence

Question 24

What does serum total iron represent?

Answer 24

Measures the total amount of iron in the liquid portion of the blood, nearly all of which is bound to transferrin.

Question 25

What does measurement of serum ferritin represent?

Answer 25

Measures the level of ferritin, a protein made by almost all cells in response to increased iron to sequester it and prevent it causing toxic damage. The ferritin level reflects the total body iron.

It will be low when there is iron deficiency and high when there is an excess of iron in the body.

Question 26

What does a measurement of transferrin saturation represent?

Answer 26

Saturation = iron concentration/TIBC

Produces an estimate of how many of transferrin iron-binding sites are occupied; this is called the transferrin saturation. Under normal conditions, transferrin is typically one-third saturated with iron. This means that about two-thirds of its capacity is held in reserve