Haemochromatosis

Question 1

What is the mode of inheritance of hereditary haemochromatosis?

Answer 1

Autosomal recessive
HFE gene on the short arm of chromosome 6
Most caucasian patients are homozygous for the cysteine to tyrosine substitution at position 282 (C282Y)
Small portion are homozygous for histidine-to-aspartate substitution at position 63 (H63D)
Minority are compound heterozygous

There are no HH genes in Singapore

Question 2

How is haemochromatosis diagnosed?

Answer 2

1. Iron study - iron overload
   - Tsats >60% in males and >50% in females (clinically >45% to suspect)
   - High ferritin level (caution as acute phase reactant)
2. LFT derangement
3. Liver biopsy - parenchymal iron deposition
4. Genetic testing for C282Y and H63D
   - First degree relatives should undergo genetic testing

Question 3

What is the treatment of haemochromatosis?

Answer 3

1. Venesection
   - Initially twice weekly until transferrin saturation below 50%, then maintenance every three months
2. Iron chelation therapy - desferrioxamine
3. Erythrocytapheresis (apheresis RBC harvest)
4. Dietary modification - avoid alcohol, raw seafood, iron supplement
5. Hepatocellular carcinoma surveillance
6. Liver transplant in decompensated cirrhosis
7. Genetic screening for 1st degree relatives

Untreated haemochromatosis - 60% 10-year survival
Mostly mortality from heart related disease

Question 4

What are the complications of haemochromatosis?

Answer 4

1. Diabetes mellitus
2. Hypogonadism, testicular atrophy
3. Restrictive or dilated cardiomyopathy and cardiac failure
4. Cardiac arrhythmias
5. Pseudo-gout and arthritis
6. Liver cirrhosis
7. Osteoporosis
8. Hypothyroidism
9. Pituitary gland dysfunction
10. Risk of siderophoric infections - Listeria, Yersinia, Vibrio

Question 5

What are the examination findings of haemochromatosis?

Answer 5

Classic presentation: bronze diabetes, liver cirrhosis

1. Skin pigmentation - bronze or slate grey appearance, especially on sun exposed areas (face, hands)
2. Koilonychia
3. Gynaecomastia, reduced body hair, impotence - hypogonadism due to iron deposit in pituitary gland
4. Hepatomegaly
5. Arthropathy (MCP, PIP) , use of walking aid - calcium pyrophosphate crystal deposition
6. Check blood glucose monitor, fundoscopy, glycosuria - diabetes mellitus
7. Check restricted or dilated cardiomyopathy - raised venous pressure, S3, S4

Question 6

What are the causes of iron overload?

Answer 6

1. Hereditary haemochromatosis
2. Frequent blood transfusion - refractory anaemia, haemoglobinopathy such as thalassaemia
3. Porphyria cutanea tarda

Question 7

What are the types of haemochromatosis?

Answer 7

1. Primary - hereditary haemochromatosis
   - Type 1: HFE
   - Type 2: Juvenile
   - Type 3: transferrin receptor mutation
   - Type 4: SLC401A ferroportin
2. Secondary
   - Iron loading anaemia
   - Iron overload
   - Chronic liver disease
   - Dysmetabolic iron overload syndrome
   - Congenital atransferrniaemia

Question 8

Describe the pathophysiology of haemochromatosis

Answer 8

1. Normal body iron content: 3-4g
   - Pathological: 20-40g (10x more)
2. In HH
   A. HFE protein dysfunction - inappropriate uptake of iron by mucosal cells, exceeding binding capacity of transferrin
   B. Reduced hepcidin expression leads to iron overload (hepcidin functions to inhibit iron transport)
   C. Reduced ferroportin degradation leads to increased iron absorption and iron export in blood (ferroportin transports iron from cells to blood)
3. Excessive iron uptake by organs -> iron toxicity -> fibrosis
   - Liver, heart, pancreas, skin, pituitary gland
4. Liver iron overload and toxicity
   - Occurs throughout acinar zones, biliary tract, epithelium, Kupffer cells, connective tissues
   - Oxidative damage -> fibrosis and cirrhosis