Hereditary Haemochromatosis Flashcards
Caoimhe
Haem sources of iron
animal meat
non haem sources of iron
lentils, beans, leafy veg and fortified cereals
What does an iron deficiency often result from
- Insufficient consumption
- Malabsorption (e.g: coeliac)
Where is iron absorbed
In the duodenum
What carrier protein is iron linked to in the blood
Transferrin
How does haem bind to transferrin
Old erythrocytes are broken down by macrophages in the liver and spleen and released haem binds to transferrin
Where is ferritin synthesised and stored
Ferritin is synthesised in the liver and stored in the liver, spleen, skeletal muscles and bone marrow
What is ferritin
A water soluble iron storage protein
What is Haemosiderin
Haemosiderin is a water insoluble iron storage complex
Where is haemosiderin found
Haemosiderin is found in macrophages
Ways that iron is excreted from the body
- Bile
- Faeces
- Urine
- Menstruation
- Intestinal exfoliation
- Skin desquamation
When is iron recycling critical
Iron recycling is critical when dietary iron is often 10x less than that recquired daily (20 mg)
What happens when iron concentration is increased
- Increased ferritin concentration
- HFE (human homeostatic iron regulator protein) upregulates hepcidin via signalling pathway, where hepcidin decreases iron levels by reducing dietary absorption
- Hepcidin downregulates ferroportin, where ferroportin is a transmembrane protein that transports Fe from inside the cell to outside the cell (intracellular to blood)
What is HH characterised by
Chronic excessive intestinal absorption of dietary iron and a pathological increase in iron stores within the body
Where does the excess iron accumulate
In tissues and organs such as the liver, pancreas, heart, joints, skin, gonads, thyroid, pituitary gland etc..
Symptoms of HH (8)
- Fatigue
- Joint pain
- Abdominal pain
- Skin discolouration (grey or bronze)
- Arrythmia
- Erectile dysfunction / decreased libido
- Symptoms of endocrine impairment
Which HH types are autosomal recessive (AR)
Types 1-3
What type of HH is autosomal dominant (AD) and what is this type known as
Type 4 is autosomal dominant. It is also called ferroportin disease
What causes Type 1 HH? (2)
- A cysteine to tyrosine substitution at amino acid 282 (C282Y)
- An aspartate to histidine substitution at amino acid 63 (H63D) on the HFE gene encoding the HFE protein
What is type 2 HH called
Juvenile Haemochromatosis (JH)
What is type 2 HH caused by
JH is caused by mutations in the HJV gene that encode an iron regulatory protein haemojuvelin
What is type 3 HH caused by
Mutations in the TfR2 gene that codes for the transferrin receptor protein TfR2
Note: Tfr2 mediates cellular uptake of transferrin bound iron and is involved in iron metabolism
What causes type 4 HH
Ferroportin disease is caused by mutations in the SLC40A1 gene that codes for ferroportin
Note: ferroportin is a transmembrane protein that transports iron from cell to blood
Type 1 HH pathogenesis
- Mutated HFE results in increased conc of iron (HFE normally functions to decrease iron concentrations by upregulating hepcidin. Hepcidin decreases iron conc by reducing dietary absorption)
- Hepcidin deficiency, iron absorption not reduced in response to high levels
- Ferroportin not downregulated (due to Hepcidin deficiency) and iron continues to be exported to blood
- Increased ferritin
- Transferrin saturation
