Thalassaemia (Haemoglobinopathies) Flashcards
What is haemoglobin?
iron-containing oxygen transport metalloprotein within RBC
reduction in haemoglobin = reduced oxygen carrying capacity
What is the structure of haemobglobin?
globular protein–> quaternary structure
4 x polypeptide subunits = 2 x alpha chains + 2 x beta chains
What is the normal body Hb?
HbA (>90%) [a2-b2]
&
HbA2 (<5%) [a2-d2]
What is the difference between HbF and HbA?
HbF = in utero = ALPHA and GAMMA HbA = in adults = ALPHA and BETA
What is a haemoglobinopathy?
a disease caused by an abnormality in globin chain structure
What are examples of haemoglobinopathies?
single gene disorders e.g. sickle cell diseases
or CDA - congenital dyserythropoietic anaemia (–>dc in # of RBC)
What is thalassaemias?
ABSENT or REDUCED PRODUCTION of a/b globin chains which form the normal adult HbA (a2b2)
What can cause thalassaemias?
mutations in regulatory genes producing a2b2
may overlap with haemoglobinopathies (abnormalities in globin chain STRUCTURE) e.g. HbS/b-thalassaemia
How do you investigate haemoglobinopathies?
FBC (microcytic hypochromic anaemia),
blood film,
Hb electrophoresis [measures different types hemoglobin, also called]
How do you screen for haemobloginopathies?
guthries test (new borns heel prick)
What is the difference between haemoglobinopathies and thalassaemias?
haemoglobinopathies = abnormalities in a/b globin chain STRUCTURE while thalassaemia = ABSENT or REDUCED production of a/b globin chains (but structure is ~normal)
What is the pathophysiology of thalassaemia?
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
what are the types of thalassaemia?
alpha and beta
What is alpha thalassaemia?
-mainly caused by gene deletions
-humans have 4x α-globin genes encoding the alpha –>
# of these deleted determine severity
What is beta thalassaemia?
usually point mutations in B-globin gene on chr11
- asian children
What are the 3 types of alpha thalassaemia?
Alpha thalassemia major/Hb Barts hydrops fetalis (⍺0 homozygous)
HBH disease
Alpha thalassaemia trait (minor) (⍺+ heterozygous)
What are the 4 types of beta thalassaemia?
Beta thalassaemia major/Cooley’s anaemia (β0 homozygotes)
Beta thalassemia intermedia
Beta thalassemia trait (minor) (β+ heterozygotes)
δβ thalassemia (aka delta-beta)
What is Alpha thalassemia major/Hb Barts hydrops fetalis (⍺0 homozygous) ?
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
what is HbH disease?
-3/4 alpha globin genes deleted
Anemia & splenomegaly
Some are transfusion dependent
What is Alpha thalassemia trait (minor) (⍺+ heterozygous)?
- some alpha chain production
- 1 or 2/4 alpha globin genes deleted
Normally asymptomatic
May have mild anemia/ haemolytic disease
Treatment usually not required
What is Beta thalassaemia major/Cooley’s anaemia (β0 homozygotes)?
-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
What is the Rx of Beta thalassaemia major/Cooley’s anaemia (β0 homozygotes)?
Rx med and surg.
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
What is beta thalassemia intermedia?
- large amount of HbF produced
- Moderate anaemia
- Blood transfusions may be needed
What is Beta thalassemia trait (minor) (β+ heterozygotes)?
-one normal and one affected β-globin chain
Normally asymptomatic (carrier state)
Or mild anemia which may worsen in pregnancy
What is δβ thalassemia?
-depletion of delta chain gene (part of HbA2, 2% adult haemoglobin)
Mild to moderate disease
What other issues can you get from thalassaemia?
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)
How do you investigate thalassaemia?
FBC, MCV, Blood film, iron, HbA2, HbF, Hb electrophoresis, MRI can monitor myocardia siderosis from iron overload
What is the treatment for thalassaemias?
- 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
