Iron and thalassaemia

Question 1

How many binding sites for iron does transferrin have?

Answer 1

2

Question 2

% saturation of transferring measures what?

Answer 2

Measures iron supply.

Question 3

What is the major negative regulator of iron?

Answer 3

Hepcidin.

Question 4

What is the function of DMT-1

Answer 4

Transports iron into the duodenal enterocyte.

Question 5

What is the role of ferroportin?

Answer 5

Facilitates iron export from the enterocyte.

Question 6

What is the role of hepcidin?

Answer 6

To down regulate ferroportin in response to iron overload.

Question 7

Skins changes in low iron? (2)

Answer 7

1) Koiloncychia.

2) Angular stomatitis

Question 8

Anaemia of chronic disease e.g. iron malutilisation

Answer 8

Increased plasma hepcidin blocks ferroportin mediated release of iron.

Results in impaired iron supply to marrow erythroblastosis and eventually hypochromic red cells.

Question 9

Iron overload with what amount of iron?

Answer 9

Usually with >5g

Question 10

Clinical features of hereditary haemochromoatosis?

Answer 10

Weakness/fatigue 
Joint pains 
Impotence. 
Arthritis 
Cirrhosis 
Diabetes 
Cardiomyopathy

Question 11

Largest parenchymal store of iron?

Largest total iron store?

Answer 11

Liver = largest parenchymal store.

Haemoglobin = largest total store.

Question 12

The causative mutations for haemochromoatosis are what?

Answer 12

C282Y

H63D

Question 13

Management of haemochromoatosis?

Answer 13

Regular venesection is 1st line.

Question 14

Typical presentation of haemochromatosis?

Answer 14

Typical patient is middle aged man.

Early: asymptomatic then fatigue, arthralgia, weakness.

Late: Slate grey skin, liver failure, diabetes&raquo_space; bronzed diabetes

Question 15

What is defined as anaemia for an:

1) Adult male
2) Adult female non pregnant
3) Adult female pregnant

Answer 15

1) <130
2) <120
3) <110

Question 16

At what level of Hb do you transfuse people?

Answer 16

<70

Question 17

Treatment of hereditary haemochromoatosis?

Answer 17

Weekly phlebotomy (450-500ml)

Initial aim to exhaust iron stores (ferritin < 20ug/l)

Thereafter, keep ferritin below 50ug/l

Note: hereditary haemochromatosis may be asymptomatic until irreversible organ damage has occurred, this underlines the importance of family studies.

Question 18

Causes of secondary iron overload?

Answer 18

Iron loading anaemias; repeated red cell transfusions (in thalassaemia and myelodysplastic syndromes)

Each unit of blood contains around 200-250mg iron, patients with thalassaemia required transfusion every 2-3 weeks.

Increased iron absorption can also cause an iron loading anaemia (over active erythropoiesis)

Question 19

Treatment of secondary iron overload:

Answer 19

Venesection not usually an option in already anaemia patients

Therefore iron cheleasting agents are used:
- Desferrioxamine (SC or IV infusion)

New oral agents e.g. deferiprone are v expensive.

Question 20

What is a thalassaemia?

Answer 20

A genetic defect of globin chain synthesis.

Question 21

What is HbA composed of?

Answer 21

Alpha 2. Beta 2

Question 22

What is HbA2 made of?

Answer 22

Alpha 2, delta 2

Question 23

What is HbF composed of?

Answer 23

Alpha 2 Gamma 2

Question 24

Where are alpha like genes located?

How many per chromosome?

Answer 24

Alpha genes occur on chromosome 16, Two alpha genes per chromosome (4 per cell)

Question 25

What chromosome are beta genes found on? How many?

Answer 25

Beta genes are on chromosome 11, one beta per chromosome (2 per cell

Question 26

What are 2 main groups of haemoglobinopathies?

Answer 26

Thalassaemias (decreased rate of globin chain production) Structural haemoglobin variants e.g. HbS

Question 27

Thalassaemias result in which type of anaemia?

Answer 27

Result in a hypochromic, microcytic anaemia

Question 28

In alpha thalassaemia, which types of haemoglobin will be affected?

Answer 28

All types due to alpha chains being present in all forms.

Question 29

Unaffected individuals have 4 normal a genes (aa/aa) What does silent a thalassaemia trait look like?

Answer 29

Only one copy missing (-a/aa). = clinically asymptomatic

Question 30

Alpha thalassaemia trait? Genotype and symptoms

Answer 30

Either (aa/—) or (a-/a-) Clinically asymptomatic, Fbc will show a mild anaemia. Red cell inclusions (Heinz bodies) (HbH bodies) can sometimes be seen with special stains.

Question 31

What is HbH disease?

Answer 31

Severe form of alpha thalassaemia, only one working alpha gene. (-a/- - ) Anaemia with very low MCV and MCH. Due to globin chain imbalance, excess B tetramers form called HbH which cannot carry oxygen.

Question 32

How you diagnosis HbH disease (Alpha thalassaemia)

Answer 32

High performance liquid chromatography.

Question 33

Clinical features of HbH disease?

Answer 33

Splenomegaly due to extramedullary haemtopoesis. Jaundice due to haemolytic and ineffective erythroporsis.

Question 34

Inheritance of HbH disease?

Answer 34

Behaves in an autosomal recessive fashion.

Question 35

Management of alpha thalassaemia?

Answer 35

Folic acid supplementation. (Aids erythropoesis) Mild: intermittent transfusion Severe: Regular transfusions.

Question 36

What is Hb Barr’s Hydrops Fetalis:

Answer 36

Severest form of alpha thalassaemia. Occurs when patients have no alpha genes. Therefore, the only type of Hb that can be produced in Hb Barts. Results in hydrops fetalois and uterine death.

Question 37

What is Hb Barts?

Answer 37

Gamma 4

Question 38

Diagnosis of alpha thalassaemia?

Answer 38

HPLC or haemoglobin electrophoresis.

Question 39

Note: molecular testing is needed to confirm alpha thal trait and determine the mutation involved. PCR used to screen for common mutations guided by patient’s ethnic background.

Answer 39

...

Question 40

Beta thalassaemias are usually caused by what? How are they inherited?

Answer 40

Caused by point mutations. Inherited in an autosomal recessive fashion.

Question 41

B+ means what B(nought) means what?

Answer 41

B+ means reduced Beta nought means absent .

Question 42

What is diagnostic for Beta thalassaemia trait?

Answer 42

A raised HbA2

Question 43

When does beta thalassaemia major occur?

Answer 43

Occurs when the patient is homozygous for Beta nought.

Question 44

When does beta thalassaemia present?

Answer 44

Usually presents in the first year of life with failure to thrive, severe anaemia. Extramedullary haemotopoiesis (hepatoslpenogaly, frontal bossing, multiple organ damage)

Question 45

What does the Skull XR show in beta thal major?

Answer 45

Hair on end sign.

Question 46

Lab features of B thal major?

Answer 46

Moderate to severe anaemia (Hb 30-90) Reticulocytosis Film shows: anispoikilocytosis and target cells HPLC shows mainly HbF present, small amount of HbA and HbA2 often elevated.

Question 47

Management of B thal major?

Answer 47

Life long transfusion. Folate supplentation. THe main mortality is from iron overload from loads of transfusions.

Question 48

How is sickle cell anaemia inherited?

Answer 48

Autosomal recessive.

Question 49

What is the pathophysiology of Sickle Cell anaemia?

Answer 49

A point mutation in codon 6 of the Beta globin gene that substitutes glutamine to valine (denoted Beta(s) This alters the structure of Hb to HBS (alpha 2, Beta(s)2)

Question 50

What happens to HbS if it is exposed to low oxygen?

Answer 50

It polymerises, the distorts the red cell damaging the cell membrane.

Question 51

Sickle cell trait = one abnormal beta gene., features?

Answer 51

May sickle in severe hypoxia e.g. high altitude, under anaesthesia. Few clinical features as HbS levels too low to polymerise. Blood film normal or mild drop in MCV/MCH.

Question 52

What does MCH stand for?

Answer 52

Mean Corpuscular Haemoglobin. Normal value - normochromic. Low value = hypochromic.

Question 53

Treatment of painful crisis in sickle cell disease?

Answer 53

``` Opiate analgesia. Hydration Rest Oxygen Antibiotics if evidence of infection. Red cell exchange transfusion in severe crisis e.g. chest or neuro crisis. ```

Question 54

What can be used in sickle cell disease to reduce the severity of disease by inducing HbF production?

Answer 54

Hydroxycarbamide.