Thalassaemia (Haemoglobinopathies)

Question 1

What is haemoglobin?

Answer 1

iron-containing oxygen transport metalloprotein within RBC

reduction in haemoglobin = reduced oxygen carrying capacity

Question 2

What is the structure of haemobglobin?

Answer 2

globular protein–> quaternary structure

4 x polypeptide subunits = 2 x alpha chains + 2 x beta chains

Question 3

What is the normal body Hb?

Answer 3

HbA (>90%) [a2-b2]
&
HbA2 (<5%) [a2-d2]

Question 4

What is the difference between HbF and HbA?

Answer 4

HbF = in utero = ALPHA and GAMMA
HbA = in adults = ALPHA and BETA

Question 5

What is a haemoglobinopathy?

Answer 5

a disease caused by an abnormality in globin chain structure

Question 6

What are examples of haemoglobinopathies?

Answer 6

single gene disorders e.g. sickle cell diseases

or CDA - congenital dyserythropoietic anaemia (–>dc in # of RBC)

Question 7

What is thalassaemias?

Answer 7

ABSENT or REDUCED PRODUCTION of a/b globin chains which form the normal adult HbA (a2b2)

Question 8

What can cause thalassaemias?

Answer 8

mutations in regulatory genes producing a2b2

may overlap with haemoglobinopathies (abnormalities in globin chain STRUCTURE) e.g. HbS/b-thalassaemia

Question 9

How do you investigate haemoglobinopathies?

Answer 9

FBC (microcytic hypochromic anaemia),
blood film,
Hb electrophoresis [measures different types hemoglobin, also called]

Question 10

How do you screen for haemobloginopathies?

Answer 10

guthries test (new borns heel prick)

Question 11

What is the difference between haemoglobinopathies and thalassaemias?

Answer 11

haemoglobinopathies = abnormalities in a/b globin chain STRUCTURE while thalassaemia = ABSENT or REDUCED production of a/b globin chains (but structure is ~normal)

Question 12

What is the pathophysiology of thalassaemia?

Answer 12

excess production of other globin chains

• -> unmatched globins precipitate within the erythrocyte membrane, damaging it
• -> cell death within bone marrow (ineffective erythroiesis)
• -> premature removal of circulating cells by the spleen (haemolysis)
• -> microcytic anaemia & haemolysis while still in the marrow

Question 13

what are the types of thalassaemia?

Answer 13

alpha and beta

Question 14

What is alpha thalassaemia?

Answer 14

-mainly caused by gene deletions
-humans have 4x α-globin genes encoding the alpha –>
# of these deleted determine severity

Question 15

What is beta thalassaemia?

Answer 15

usually point mutations in B-globin gene on chr11

- asian children

Question 16

What are the 3 types of alpha thalassaemia?

Answer 16

Alpha thalassemia major/Hb Barts hydrops fetalis (⍺0 homozygous)
HBH disease
Alpha thalassaemia trait (minor) (⍺+ heterozygous)

Question 17

What are the 4 types of beta thalassaemia?

Answer 17

Beta thalassaemia major/Cooley’s anaemia (β0 homozygotes)
Beta thalassemia intermedia
Beta thalassemia trait (minor) (β+ heterozygotes)
δβ thalassemia (aka delta-beta)

Question 18

What is Alpha thalassemia major/Hb Barts hydrops fetalis (⍺0 homozygous) ?

Answer 18

NO ALPHA CHAIN PRODUCTION
-4/4 alpha globin genes deleted
Incompatible with life - death in utero or neonatal
Foetal anaemia results in formation of hydrops (swollen baby)
Hb is called Hb Barts - 4x gamma chains
Only survive if intrauterine transfusions until delivery & monthly transfusions afterwards

Question 19

what is HbH disease?

Answer 19

-3/4 alpha globin genes deleted

Anemia & splenomegaly

Some are transfusion dependent

Question 20

What is Alpha thalassemia trait (minor) (⍺+ heterozygous)?

Answer 20

• some alpha chain production
• 1 or 2/4 alpha globin genes deleted

Normally asymptomatic
May have mild anemia/ haemolytic disease
Treatment usually not required

Question 21

What is Beta thalassaemia major/Cooley’s anaemia (β0 homozygotes)?

Answer 21

-NO BETA CHAIN PRODUCTION
–> Severe hemolytic disease by 6months of age (pallor)
–> Failure to thrive in children
Extramedullary haemopoiesis (RBCs made outside the marrow) occurs in response
–> skull bossing, maxillary overgrowth
–> hepatosplenomegaly
–> osteopenia

Question 22

What is the Rx of Beta thalassaemia major/Cooley’s anaemia (β0 homozygotes)?

Rx med and surg.

Answer 22

Rx: monthly blood transfusions (aim Hb >10g/dl)

Chelation therapy:
–>SC desferrioxamine promotes urinary iron excretion
= preventing haemosiderosis (accumulation of iron causing cardiac failure, liver cirrhosis, diabetes, infertility, growth failure, skin pigmentation)

Surgery:
Bone marrow transplant is curative
90% survive into their 40s

Question 23

What is beta thalassemia intermedia?

Answer 23

• large amount of HbF produced
• Moderate anaemia
• Blood transfusions may be needed

Question 24

What is Beta thalassemia trait (minor) (β+ heterozygotes)?

Answer 24

-one normal and one affected β-globin chain
Normally asymptomatic (carrier state)
Or mild anemia which may worsen in pregnancy

Question 25

What is δβ thalassemia?

Answer 25

-depletion of delta chain gene (part of HbA2, 2% adult haemoglobin) Mild to moderate disease

Question 26

What other issues can you get from thalassaemia?

Answer 26

Bone: Extramedullary haemopoiesis – spine, spleen, liver, facial bones Osteoporosis ``` Endocrine: Hypothalamic – pituitary axis problems Diabetes Hypothyrodism Hypoparathyroidism Hypogonadism ``` Iron overload – liver and heart (no/reduced globin chains to hold it)

Question 27

How do you investigate thalassaemia?

Answer 27

``` FBC, MCV, Blood film, iron, HbA2, HbF, Hb electrophoresis, MRI can monitor myocardia siderosis from iron overload ```

Question 28

What is the treatment for thalassaemias?

Answer 28

- Promote fitness, healthy diet, folate supplements help (increase hb concen) - Regular (~2-4weekly) life-long transfusions to keep Hb >90g/L -- Iron-chelators to prevent iron overload --Large doses of ascorbic acid also increase urinary excretion of iron --Hormone replacements for endocrine failure caused by iron overload Splenectomy if hypersplenism (from getting rid of defunt RBC?) persists with increasing transfusion requirements Histocompatible marrow transplant can offer the chance of a cure