Haemochromotosis Flashcards
Where is iron acquired from
Food - essential mineral
HAEM - animal meat
NON-HAEM - legumes, leafy greens, fortified foods
What is ferritin? Is it soluble?
Water soluble Fe storage protein. low serum ferritin = release of transferrin from liver to bring levels back up
what is haemosiderin
Water-insoluble Fe storage complex
what is transferrin?
a carrier protein found in the blood
How is excess iron excreted?
haem via bile, faeces in the form of stercobilin, urine in the form of urobilin, menstruation, intestinal exfoliation, skin desquamation
why is iron recycling important in the body?
It is important because dietary iron is often 10 times less than what is required- you need 20mg daily but often only 1-2mg is absorbed
What happens in the body when iron concentration is increased?
- increased ferritin concentration
- HFE protein (human homeostatic iron regulator) up-regulates hepcidin in a signalling pathway. Hepcidin decreases dietary iron absorption
-Hepcidin downregulates ferroportin (a transmembrane protein) which transports iron in and out of cells
How is hereditary haemochromotosis transmitted?
It is an inherited condition
What is haemochromotosis
chronic excessive intestinal absorption of dietary iron which results in a pathological increase of iron stores in tissues and organs
What are the symptoms of HH?
Fatigue and malaise (discomfort), joint pain, abdominal pain, skin discoloration (bronze or grey), arrythmia, erectile dysfunction or decreased libido, amenorrhoea (lack of menstruation) and symptoms of endocrine impairment
Is HH dominant or recessive?
typically autosomal recessive but depends on the mutation
Which types of HH are autosomal recessive?
types 1-3
What type of HH is autosomal dominant
Type 4 (ferroportin disease)
Write a note on Type 1 HH
Caused by a cysteine to tyrosine substitution at amino acid 282 (C282Y) or ahistidine to aspartate substitution at amino acid 63 (H63D) on the HFE gene that codes the HFE protein. C282Y (the position on the HFE protein) is the most prevalent type
Write a note on HH Type 2
Also known as juvenile haemochromotosis. Is caused by mutations in the HJV gene that code for an iron regulatory protein hemojuvelin. Symptoms usually develop earlier in life
Write a note on HH Type 3
It is caused by mutations in the TfR2 gene that codes for transferrin receptor protein 2. This mediates cellular uptake of iron, and when it is inactive, it results in iron overload
Write a note on Type 4 HH
known as ferroportin disease and is quite rare. Caused by mutations in the SLC40A1 gene that codes for ferroportin. At least 39 mutations in the SLC40A1 gene have been identified in patients with ferroportin diease.
What is the pathogenesis of Type 1?
- Hepcidin deficiency and iron absorption not reduced in response to increased iron levels
- ferroportin is not downregulated and iron is still exported to blood
- increased ferritin
- transferrin saturation
What is the pathogenesis of Type 2 HH
- Haemojuvelin regulates hepcidin
- mutated HJV = dysregulated hepcidin = inability to reduce serum iron concentration
- hepcidin deficiency
what is type 3 HH pathogenesis
- Transferrin receptor protein 2 (TfR2) mediates cellular update of transferrin bound iron
- so the mutated TfR2 gene = deficiency in TfR2 protein and = inability to reduce serum iron concentrations
What is the pathogenesis for type 4 HH
- Ferroportin is a transmembrane protein that transports iron in and out of cells/tissues
- a Mutated SLC40A1 gene = excessive cellular iron
What are the complications of HH
-Splenic and liver iron overload + dysfunction. May develop fibrosis and cirrhosis- hepatocellular carcinoma
- diabetes (pancreatic iron deposition)
- arrhythmia and congestive heart failure (iron deposits in muscle fibres and conductivity system)
- hypogonadism/amenorrhoea- endocrine dysfucntion
-skin hyperpigmentation from haemosiderin and melanin deposition
- osteoporosis
- anaemia in type 4 HH
-Foodborne infection - raw bivalves
HH epidemiology
Really common in Northern Europe. Type 1 mostly confined to those of Northern Europe descent . Type 1-3 manifests in adulthood, but Juvenile HH can become apparent between ages 10-30. male to female ratio 3:1:8- women become symptomatic later in life (menstruation)
HH treatment- Phlebotomy
Phlebotomy- Induction: blood removed frequently until serum iron levels are normal (takes 12 months), or Maintenance: blood taken quarterly or biannually to manage iron levels. Life long therapy.
HH treatment- Chelation therapy
Chelation therapy used when phlebotomy is not possible. Chelating agent binds to iron and is excreted via faeces or urine. Iron chelation with desferrioxamine is used in Ireland. Side effects such as dizziness, sensory impairments, muscle cramps, thrombocytopenia, tachycardia
HH treatment - Therapeutic erythrocytapheresis
Involves the removal of erythrocytes rather than whole blood. Use of cell separator. Data shows this therapy = x4 reduction of phlebotomy sessions. However phlebotomy is cheaper and should be first line therapy
HH treatment- diet
avoid foods fortified with iron, alcohol, raw bivalves (oysters/clams)
What haemoglobin level would suggest haemochromotosis?
> 18 g/dL
What is used to diagnose haemochromatosis?
Biochemistry: Increased transferrin saturation & ferritin levels
Haematology: FBC - increased Hb, MCH, & MCHC
Histopathology: iron deposits in hepatocytes - Perl’s Prussian Blue stain haemosiderin granules blue
Molecular Biology: confirm diagnosis
What causes absolute malabsorption of iron?
Coeliac disease
What cause relative malabsorption of iron?
Pregnancy & puberty
How is Fe recycled?
Senescent RBCs broken down by macrophages in liver & spleen - releases haem which binds to transferrin - 80% to bone marrow for erythropoiesis
What is the other 20% of Fe used for?
Respiration & DNA synthesis
