Haemochromatosis

Question 1

What is haemochromatosis?

Answer 1

Multisystem disorder of dysregulated dietary iron absorption and increased iron release from macrophages.

Question 2

What genetic pattern does haemochromatosis follow?

Answer 2

An autosomal-recessive disorder

Question 3

In haemochromatosis, in what organs can iron accumulate?

Answer 3

Iron accumulates in multiple organs including liver, heart, anterior pituitary, pancreas, joints, and other organs.

Question 4

Briefly describe the pathophysiology of haemochromatosis

Answer 4

HFE gene defect (homozygous) → defective binding of transferrin to its receptor → ↓ hepcidin synthesis by the liver → unregulated ferroportin activity in enterocytes → ↑ intestinal iron absorption → iron accumulation throughout the body → damage to the affected organs

Question 5

What risk factors are associated with haemochromatosis?

Answer 5

• Male gender
• Middle age
• Positive family history
• High dietary iron intake

Question 6

What are the signs of haemochromatosis?

Answer 6

• Hepatomegaly
• Skin pigmentation (bronzing of the skin)

Question 7

What are the symptoms of haemochromatosis?

Answer 7

• Fatigue
• Weakness
• Lethargy
• Arthalgias
• Symptoms of diabetes mellitus
• Impotence in males
• Loss of libido

Question 8

What investigations should be ordered for haemochromatosis?

Answer 8

• Serum transferrin saturation
• Serum ferritin
• HFE mutation analysis
• MRi liver
• Liver biopsy

Question 9

Why investigate transferrin saturation? And what may this show?

Answer 9

• First laboratory test to become abnormal
• >45%

Question 10

Why investigate serum ferritin? And what may this show?

Answer 10

• Raised in inflammation, alcoholism, chronic viral hepatitis, non-alcoholic fatty liver disease, and the dysmetabolic syndrome. If a patient has elevated serum ferritin level and one of the above confounding factors, liver biopsy should be considered; alternatively, estimation of visceral iron deposition can be done by hepatic MRI.
• Raised

Question 11

Why investigate HFE mutation analysis? And what may this show?

Answer 11

• Initial HFE mutation analysis should evaluate for C282Y and H63D polymorphisms
• C282Y mutation homozygosity (p.Cys282Tyr); less commonly compound heterozygosity (C282Y/H63D)

Question 12

Why investigate MRI of the liver? And what may this show?

Answer 12

• A non-invasive way to measure liver iron content with good sensitivity and specificity
• Liver to muscle signal intensity <0.88

Question 13

Why investigate liver biopsy? And what may this show?

Answer 13

• The most sensitive and specific test for measuring liver iron content, and has the added benefit of allowing the pathologist to assess for liver damage due to iron (i.e., fibrosis and cirrhosis)
• Iron content raised

Question 14

What lifestyle modifications should be made in haemochromatosis?

Answer 14

• All patients should avoid iron or iron-containing supplements
• Vitamin C or vitamin C-containing supplements should also be avoided, as vitamin C can lead to increased intestinal absorption of dietary iron
• Patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present)

Question 15

What if the main treatment for haemochromatosis?

Answer 15

Patients should be started on a phlebotomy regimen

Question 16

Briefly describe the phlebotomy regime for patients with haemochromatosis

Answer 16

This starts with weekly phlebotomy in an induction phase, and then transitions to a maintenance phase of intermittent phlebotomy with a goal to maintain the serum ferritin level ≤112 picomols/L (≤50 nanograms/mL).

Question 17

Why is phlebotomy used to treat haemochromatosis?

Answer 17

1. Removal of iron
2. By removing blood the patient’s bone marrow is stimulated to make new red cells using the iron they have in storage

Question 18

When is iron chelation therapy used in haemochromatosis?

Answer 18

Reserved for patients with a contraindication to phlebotomy (i.e., anaemia, severe heart disease, or severe problems with venous access).

Question 19

What are the complications of haemochromatosis?

Answer 19

• Cirrhosis
• Diabetes mellitus
• Chronic congestive heart failure
• Hepatocellular carcinoma (HCC)
• Hypogonadism
• Bone loss

Question 20

What differentials should be considered in haemochromatosis?

Answer 20

1. Iron overload from chronic transfusion
2. Hepatits B
3. Hepatitis C

Question 21

How does haemochromatosis and iron overload from chronic transfusion differ?

Answer 21

• Differentiating signs and symptoms: history of chronic transfusion and/or haematological disorder
• Differentiating investigations: patients with iron overload from chronic transfusion are likely to be anaemic at the time of diagnosis; therefore, an FBC is recommended

Question 22

How does haemochromatosis and hepatitis B differ?

Answer 22

• Differentiating signs and symptoms: history of or risk factors for hepatitis
• Differentiating investigations: positive hepatitis B serology (HBsAg-positive) without homozygous HFE mutations

Question 23

How does haemochromatosis and hepatitis C differ?

Answer 23

• Differentiating signs and symptoms: history of or risk factors for hepatitis
• Differentiatins investigations: positive hepatitis C serology (hepatitis C virus [HCV] antibody-positive) without homozygous HFE mutations