haemoglobinopathies

Question 1

structure of Hb

Answer 1

tetramet made up of 2 alpha globin like chains + 2 beta globin like chains

1 haem group attached to each globin chain

Question 2

major forms of haemoglobin

Answer 2

HbA - 2 alpha + 2 beta

HbA2 - 2 alpha + 2 delta

HbF - 2 alpha + 2 gamma chains

(in adults, HbA is major form present)

Question 3

genetic control of globin chain production

Answer 3

alpha like genes - chromosome 16

beta like genes - on chromosome 11

(expression of globin genes changes during embryonic life + childhood)

Question 4

relevance of Hb production chances in early life

Answer 4

adult levels reached bt 6-12 months of age so beta chain problems wont manifest until then

Question 5

haemoglobinopathies

Answer 5

hereditary conditions affecting globin chain sysnthesis
- autosomal recessive disorders

• commonest monogenic disorders
• increasingly frequent in UK due to changing population demographics

Question 6

2 main groups of haemoglobinopathies

Answer 6

thalassaemia -> decreased rate of globin synthesis

structural haemoglobin variants -> normal production of abnormal globin chain - variant haemoglobin eg HbS

Question 7

thalassaemias

Answer 7

reduced globin chain synthesis resulting in impaired haemoglobin production
- alpha thalassaemia -> alpha chains affected
- beta thalassaemia - beta chains affected

both = autosomal recessive
overall effects = varying degrees of anaemia

Question 8

pathophysio of thalassaemias

Answer 8

RBCs are more fragile + break down more easily
spleen acts as sieve to filter

in thalassaemia, the spleen collects all the destroyed RBCs + swells -> resulting in splenomegaly

the bone marrow expands to produce extra RBCs to compensate for chronic anaemia
- this causes susceptibility to fractures + prominent features (forehead + malar eminences)

Question 9

thalassaemia presentation

Answer 9

microcytic anaemia
fatigue, pallor
jaundice, gallstones
splenomegaly
poor growth + development
pronounced forehead + malar eminences

Question 10

diagnosis of thalassaemias

Answer 10

FBC - microcytic anaemia

haemoglobin electrophoresis - diagnose globin abnormalities

DNA testing

Question 11

consequences of thalassaemias

Answer 11

inadequate Hb production -> microcytic hypochromic anaemia

if severe -
- unbalanced accumulation of globin chains which are toxic to the cell
- ineffective erythropoiesis
- haemolysis

Question 12

general management of thalassaemias

Answer 12

Regular blood transfusions
monitor serum ferritin for iron overload
- limit transfusions + iron chelation (e.g. desferrioxamine)

Question 13

alpha thalassamia

Answer 13

mutations affecting alpha globin synthesis
normal = aa/aa chromosome 16
AT = -a/aa or –/aa

-> results in reduced or absent alpha chain synthesis from that chromosome
—–> alpha chain present in HbA, HbA2 + HbF therefor all are affected

has to be detected through gene analysis

Question 14

which chromosome is affected in alpha thalassaemia

Answer 14

chromosome 16

Question 15

types of alpha thalassamia

Answer 15

trait - 1 or 2 alpha globulins affected

HbH disease - 3 affected

hydrops fetalis, Bart’s hydrops - 4

Question 16

alpha thalassaemia trait

Answer 16

1 or 2 alpha genes missing
- asymptomatic carrier trait
- microcytic hypochromic
- BUT ferritin + Hb normal

Question 17

HbH disease

Answer 17

only 1 alpha gene left (–/-a)
- moderate to severe anaemia
- anaemia with v low MCV + MCH
- excess beta chains from tetramets (B4) called HbH

jaundice, splenomegaly
may need transfusion
common in SE asia

Question 18

Hb Barts hydrops fetalis

Answer 18

no function alpha genes (–/–), incompatible with life
- none inherited from either parent
- minimal or no a chain production -> HbF + HbA cant be made

risk if both parents from SE Asia where alpha thalassaemia trait prevalent
- antenatal screening to avoid risk

Fx = cardiac failure, growth retardation, almost all die in utero

Question 19

beta thalassaemias

Answer 19

disorder of beta chain synthesis, usually caused by point mutations
- only B chains + hence only HbA affected

Question 20

beta thalassaemia trait

Answer 20

asymptomatic, no/mild anaemia
disporportionate low MCV

raised HbA2 via HPLC = diagnostic

Question 21

B thalassaemia intermedia

Answer 21

moderate severity requiring occasional transfuson
- similar phenotype to HbH disease

Question 22

beta thalassaemia major

Answer 22

severe, lifelong transfusion dependency
presents age 6-24months -> AS HbF FALLS

pallor, failure to thrive
extramedullary haematopoiesis causing
- hepatosplenomegaly, skeletal changes, organ damage

Question 23

complications of extramedullary haematopoiesis

Answer 23

(like in beta thalassaemia major)

expanding marrow
can lead to cord compression

Question 24

haemolysis analysis in beta thalassamia major

Answer 24

mainly HbF + HbA2
no HbA

Question 25

which chromosome is affected in beta thalassaemia major

Answer 25

chromosome 11

Question 26

management of beta thalassaemia major

Answer 26

regular transfusion programme to maintain Hb at 95-105g/L
- suppresses ineffective erythropoiesis
- inhibits over absorption of iron

bone marrow transplant may be an option if carried out before complications develop

(Mx = repeated transfusion
this leads to iron overload → organ failure
iron chelation therapy is therefore important (e.g. desferrioxamine)

Question 27

key complication + cause of mortality in bata thalassaemia major? investigation + management?

Answer 27

iron overload -> organ failure
iron chelation therapy important -> desferrioxamine
–> binds to iron which is then excreted

occurs in thalassaemia as a result of faulty creation of red blood cells, recurrent transfusions + increased absorption of iron in response to anaemia

Ix = monitor serum ferritin levels

Question 28

iron overload presentation

Answer 28

(similar to haemochromatosis)

fatigue
liver cirrhosis
infertility + impotence
heart failure, arrythmias
arthritis
diabetes
osteoporosis + joint pain