Haemochromatosis (CH)

Question 1

Define haemochromatosis.

Answer 1

Autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation + increased iron release from macrophages

Question 2

Which groups does haemochromatosis happen more commonly in? (2)

Answer 2

• M>F
• > 40 years of age

Question 3

What is primary vs secondary haemochromatosis?

Answer 3

• primary haemochromatosis: hereditary, most common form
  
  • autosomal recessive inheritance
  • mutations in HFE gene on chromosome 6
• secondary haemochromatosis: caused by iron overload
  
  • commonly transfusion-related

Question 4

What are the four types of haemochromatosis?

Answer 4

• type 1: hereditary haemochromatosis - most common, autosomal recessive, HFE mutation - arthropathy, skin pigmentation, liver damage, DM, endocrine dysfunction, cardiomyopathy, hypogonadism
• type 2: juvenile - autosomal recessive disorder due to mutation of haemojuvelin gene or hepcidin gene, early onset (<30), hypogonadism and cardiomyopathy prevalent
• type 3: transferrin receptor 2 haemochromatosis - autosomal recessive disorder due to mutation in transferrin receptor 2 gene (7q22), same features as type 1
• type 4: ferroportin disease - autosomal dominant disorder due to mutation of SLC4oA1 gene –> type 4A (loss of function for ferroportin excretion, characterised by iron deposition in spleen) and type 4B (non-classical disease, gain of function, associated with fatigue and joint pain)

Question 5

What is the phenotypic hallmark of haemochromatosis?

Answer 5

Elevated transferrin saturation - diagnosis confirmed by genetic testing

Question 6

What is Wilson’s disease (haemochromatosis)?

Answer 6

Autosomal recessive disorder, which leads to excess copper deposition in tissues, hence low serum copper

Question 7

What combination of two diseases points towards Wilson’s disease (haemochromatosis)?

Answer 7

• liver disease - hepatitis, cirrhosis
• neurological disease - basal ganglia degeneration, asterixis, chorea, dementia

Question 8

What sign would you see in the eyes of a patient with Wilson’s disease (haemochromatosis)?

Answer 8

Kayser-Fleischer rings –> green-brown rings in the periphery of the iris

Question 9

What are the blood findings of Wilson’s disease (haemochromatosis)? (2)

Answer 9

• low copper
• low caeruloplasmin

Question 10

How do we treat Wilson’s disease (haemochromatosis)?

Answer 10

Penicillamine

Question 11

What is the triad of features in haemochromatosis?

Answer 11

Fatigue, arthralgia (often of the hands) and erectile dysfunction (loss of libido due to hypogonadism)

Question 12

What are the clinical features of haemochromatosis? (5)

Answer 12

• fatigue, weakness, lethargy
• arthralgia (often of the hands)
• erectile dysfunction (loss of libido due to hypogonadism) + loss of libido
• diabetes mellitus - polyuria, polydipsia, nocturia
• liver issues - cirrhosis, hepatomegaly

Question 13

What might you see on examination of haemochromatosis? (5)

Answer 13

• hepatomegaly
• skin pigmentation (bronzing to grey/brown with slate-grey patches)
• congestive heart failure
• arrhythmias
• porphyria cutanea tarda - skin disease and liver dysfunction (mildly elevated LFTs) - fragile skin, blisters, bullae

Question 14

What are some risk factors for haemochromatosis? (5)

Answer 14

• male sex
• middle age
• white ancestry
• Fx
• supplemental iron / high dietary iron intake

Question 15

What are the first-line investigations for haemochromatosis? (5)

Answer 15

Iron studies:

• serum transferrin saturation (raised)
• serum transferrin (low)
• serum ferritin (raised)
• serum iron (raised)
• total iron binding capacity (low) - capacity of blood to bind to iron

Question 16

What is the most useful marker of haemochromatosis?

Answer 16

Serum transferrin saturation:

• > 50% in men
• > 45% in women
• low transferrin

Question 17

What is transferrin and what does it mean if it is high or low (haemochromatosis)?

Answer 17

Iron carrier protein:

• high in IDA
• low in iron overload

Question 18

What is transferrin saturation and what does it mean if it is high or low (haemochromatosis)?

Answer 18

Percentage of transferrin (iron carrier) bound to iron:

• high suggests iron overload
• low suggests IDA

Question 19

What is serum ferritin like in haemochromatosis?

Answer 19

Raised:

• > 674picomols/L (>300ng/L) in men
• > 449picomols/L (>200ng/L) in women

Question 20

How can we confirm diagnosis of haemochromatosis?

Answer 20

Genetic testing - if there is a first-degree relative with haemochromatosis and confirmed iron overload, it will show mutation of HFE gene

Question 21

What finding increases likelihood of severe clinical complications in haemochromatosis?

Answer 21

Serum ferritin >1000ug/L

Question 22

What are some differential diagnoses for haemochromatosis? (6)

Answer 22

• iron overload from chronic transfusion
• hepatitis B or C
• NAFLD
• dysmetabolic hyperferritinaemia
• excessive iron supplementation
• hereditary aceruloplasminaemia

Question 23

What is required for diagnosis of haemochromatosis?

Answer 23

282Y homozygosity required

Question 24

What are the stages of haemochromatosis? (5)

Answer 24

• stage 0: normal serum transferrin and ferritin + no clinical Sx
• stage 1: increased transferrin saturation (>45%), normal ferritin + no clinical Sx
• stage 2: increased transferrin saturation + increased serum ferritin (>300ng/L men, >200ng/L women) + no clinical Sx
• stage 3: increased transferrin saturation + increased serum ferritin + clinical Sx affecting QoL attributed to this disease (e.g. asthenia, impotence, arthropathy)
• stage 4: increased transferrin saturation + increased serum ferritin + clinical Sx manifesting organ damage predisposing to early death (e.g. cirrhosis with risk of HCC, insulin-dependent DM, cardiomyopathy)

Question 25

What dietary changes are needed in haemochromatosis management?

Answer 25

Diet low in iron

Avoid iron/vitamin C supplements + alcohol

Question 26

What is the first-line management for haemochromatosis?

Answer 26

Therapeutic phlebotomy (regular venesection) - monitor via ferritin levels and transferrin saturation

Question 27

What is the second-line treatment for haemochromatosis?

Answer 27

If therapeutic phlebotomy cannot be performed (venesection not possible) –> drug-induced iron chelation (deferoxamine) to lower iron levels

Question 28

How do we manage stage 0 haemochromatosis?

Answer 28

• observation
• 3-yearly follow up
• avoid iron/vitamin C supplements
• avoid alcohol
• hep A and B vaccination

Question 29

How do we manage stage 1 haemochromatosis (raised transferrin saturation)?

Answer 29

1-yearly follow up

Question 30

How do we manage stages 2-4 haemochromatosis (high ferritin +/- clinical symptoms)?

Answer 30

1. therapeutic phlebotomy or erythrocytapheresis
   
   • 7ml/kg of body weight per session but <550ml
   • monitor ferritin and transferrin saturations
   • check Hb and MCV for anaemia
2. iron chelation therapy (deferasirox/desferrioxamine/deferiprone/deferoxamine) - if phlebotomy CI, severe heart disease, problems with venous access

Question 31

What are some complications of haemochromatosis? (8)

Answer 31

• hepatocellular carcinoma (may need US screening)
• liver cirrhosis
• DM
• chronic CHF - dilated RCM
• AF
• hypogonadism
• bone loss
• infections