Hepato-biliary: 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

(presents late in disease process)

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

Classic triad in hereditary haemochromatosis

Answer 6

Heptaomegaly

DM

Hyperpigementation

Question 7

What endocrinopathies can occur with hereditary haemochromatosis?

Answer 7

• Diabetes mellitus - bronze diabetes
• Hypogonadism
• Hypothyroidim
• Hypoparathyroidism

Question 8

Why can diabetes occur in hereditary haemochromatosis?

Answer 8

Build up of iron in the pancreas -> bronze diabetes

Question 9

Why does arthralgia/arthopathy occur in hereditary haemochromatosis?

Answer 9

Calcium pyrophosphate deposition in the joints - leading to chondrocalcinosis

Question 10

Why does bronze pigmentation occur in hereditary haemochromatosis?

Answer 10

Melanin deposition

Question 11

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

Answer 11

• Skin pigmentation
• Diabetes mellitus
• Hepatomegaly

Question 12

What complications can occur from hereditary haemochromatosis?

Answer 12

Hepatocellular Carcinoma - if cirrhotic, 30% chance

Question 13

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

Answer 13

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

Question 14

What tests are included in iron studies?

Answer 14

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

Question 15

What can cause ferritin to rise?

Answer 15

Acute phase protein

• Liver disease
• Malignancy
• Inflammation

Question 16

What does TIBC show?

Answer 16

Reflects the availibility of iron binding sites on transferrin

Question 17

How is TIBC affected in Iron overload?

Answer 17

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

Question 18

What might iron studies show in someone with haemochromatosis?

Answer 18

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

Question 19

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

Answer 19

May be low in those with hypogonadism

Question 20

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

Answer 20

Look for features of cardiomyopathy

Question 21

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

Answer 21

Iron loading and cirrhosis

Question 22

How would you manage someone with hereditary haemochromatosis?

Answer 22

• Venesection - until ferritin < 50 ug/L
  
  • Initially over a week
  • Ferritin levels maintained
  • Then ever 3-4 months
• Low iron diet + food/drink which decreases iron absorption
  
  • ​Can drink if no evidence of liver damage
• Ensure vitamin preparations do not contain iron
• Family screening

Ultimately liver transplant

Question 23

What can cause secondary haemochromatosis?

Answer 23

Repeated transfusion

Question 24

What is the mode of inheritence of heredittary haemochromatosis?

Answer 24

Autosomal recessive inheritence

Question 25

What does serum total iron represent?

Answer 25

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

Question 26

What does measurement of serum ferritin represent?

Answer 26

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 27

What does a measurement of transferrin saturation represent?

Answer 27

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