Haemochromatosis

Question 1

What is haemochromatosis?

Answer 1

Autosomal recessive disease in which increased intestinal absorption of iron causes accumulation of iron in tissues (hemosiderosis), which may lead to organ damage (particularly liver, joints, pancreas, pituitary and heart). 

Question 2

What causes haemochromatosis?

Answer 2

1. Primary Haemochromatosis → hereditary, most common form. Autosomal recessive inheritance. Mutations on the HFE gene.
   - the most common genotype being homozygosity for HFE C282Y on chromosome 6. This mutation in the HFE gene disrupts the control of iron absorption, leading to excessive iron accumulation in the body.
2. Secondary Haemochromatosis → caused by iron overload. Commonly transfusion related.

Question 3

Summarise the epidemiology of haemochromatosis

Answer 3

• RARE
• More frequent in middle aged men than women – tends to present later in women (menstrual blood loss protective)
• Hereditary haemochromatosis is one of the most common genetic disorders in people of Northern European descent, particularly in populations of Celtic origin.

Question 4

What are the presenting symptoms and signs of haemochromatosis?

Answer 4

1. Often ASYMPTOMATIC until the late stages of the disease
2. Symptoms usually start between 40-60 yrs
   - Bronze skin
   - Type 2 diabetes mellitus
   - Fatigue
   - Joint pain
   - Sequalae of chronic liver disease/cirrhosis
   - Adrenal insufficiency
   - Testicular Atrophy

Question 5

What 2 models explain the pathogenesis of Hereditary hemochromatosis? Explain the 2

Answer 5

1. Liver model: HFE deficiency causes decreased expression of the hepatic hormone hepcidin which causes increased duodenal iron absorption through a lack of the inhibitory effect of hepcidin on ferroportin (the protein which exports iron from enterocytes into circulation).
2. Crypt cell model: The HFE protein interacts with the transferrin receptor 1 in duodenal crypt cells. Mutations in HFE may impair uptake of transferrin-bound iron into crypt cells, resulting in upregulation of the iron transporter DMT1 in the crypt cells as they migrate up the villus and mature into enterocytes = increased iron absorption.

Question 6

What are some of the risk factors for haemochromatosis?

Answer 6

• Middle age
• Male
• White
• Family history
• Supplemental iron

Question 7

How is haemochromatosis managed?

Answer 7

1. Dietary Changes → diet low in iron, avoidance of undercooked seafood – bacteria thrive on raised iron, in particular listeria monocytogenes. Also avoid fruit juices, in particular those containing large amounts of vitamin C, as they increase the rate of absorption of iron
2. Therapeutic Phlebotomy (Regular Venesection) (1st line) → 1/2 sessions per week aiming for target ferritin and transferrin levels
   - Monitor via ferritin levels and transferrin saturation
3. Drug-Induced Iron Chelation (2nd line if Venesection can’t be performed) → Deferoxamine (lowers iron levels)

Question 8

What investigations are used to diagnose/ monitor haemochromatosis?

Answer 8

1. High Serum Iron
2. Serum Transferrin Saturation (iron carrier protein) → >45%. First test to become abnormal. Most useful marker. (Transferrin = Low)
3. Raised Serum Ferritin (protein complex responsible for iron storage, also raised in inflammation, but not always raised in the early stages)
4. Low TIBC (Total iron-binding capacity → determines capacity of blood to bind to iron)
5. Genetic Tests → if first degree relative with haemochromatosis & confirmed iron overload. Would show mutation of HFE gene.
6. MRI imaging of the brain and heart to identify evidence of iron deposition
7. Liver biopsy to confirm increased iron stores, with Perl’s stain quantifying the level of iron loading

Question 9

What complications may arise following haemochromatosis?

Answer 9

1. Reversible complications:
   - Dilated cardiomyopathy, bronze skin
2. Irreversible complications:
   - Cirrhosis (once hepatocellular architecture is changed – there is no reversibility), diabetes mellitus, hypogondaotrophic hypogonadism (pituitary dysfunction) and arthropathy