8. Haemoglobinopathies: thalassaemias

Question 1

thalassaemia

Answer 1

reduction in synthesis of alpha or beta chains
caused by a variety of mutations affecting the genes foreither the alpha or beta globin genes
Alpha globin genes - 4 copies (chromosome 16)
Beta globin genes - 2 copies (chromosome 11)

All copies are used to the same extent - i.e. if one copy of beta globin gene deleted, 50% of the normal level of protein produced

~5% of world’s population has a globin variant, but only 1.7% has a thalassaemia

Question 2

thalassaemia classified according to

Answer 2

globin gene affected eg alpha or e=beta
rate of synthesis eg alpha+ (reduced synthesis) or alpha^0 (no synthesis)
genotype is heterozygous a^+

Question 3

distribution of thalassaemia

Answer 3

Distribution of thalassemia and sickle cell anaemia overlap since carriers (heterozygotes) of these mutant genes provided protection against malaria
Prevalent in areas of the world where malaria is endemic
Alpha thalassaemia – Far East
Beta thalassaemia - Mediterranean

Question 4

α thalassaemia classification

Answer 4

4 alpha globin genes inherited, two from each parent
normal genotype αα/αα
α+ heterozygote α-/αα
α+ homozygote α-/α-
α^0 heterozygote αα/–
α^0 homozygote –/–
α^0α+ double heterozygote (haemoglobin H disease) –/α-, only one functioning alpha globin gene

Question 5

genetics of α thalassaemia

Answer 5

a gene may be deleted or (les frequently) dysfunctional
four genes (2 from each parent) are needed to make alpha globin chains
One alpha gene deleted: silent carrier, heterozygous α+ thalassaemia no signs of illness
2 deleted alpha genes: alpha thalassaemia trait
α+ homozygotes (α-/α-) or α0 heterozygotes (–/αα). Not enough alpha globin protein synthesised
3 deleted alpha genes: haemoglobin H disease.Compound Heterozygote for α+ and α0 thalassemia (α-/–).Moderate to severe anaemia and hepatosplenomegaly due to increased rbc breakdown
Microcytosis, hypochromasia, fragmented red cells, poikilocytosis, polychromasia (blood film blue tinge as increased production of reticulocytes)

Question 6

alpha thalassaemia - four alpha genes deleted ?

Answer 6

Haemoglobin Barts Hydrops Fetalis
Absence of alpha globin synthesis
No functionally normal haemoglobins synthesised after 10 weeks gestation
Haemoglobin Barts (γ4) (gamma) and Haemoglobin H (β 4) are synthesised(accumulation of chains that aren’t balanced)
higher affinity for O2 so don’t release it so detrimental to foetus
mismatched Hb as excess of one type of Hb so not balanced and get accumulation of abnormal Hb (4 betas produced instead)
Microcytosis, hypochromasia, fragmented red cells, poikilocytosis, numerous nucleated red cells
Almost always fatal

Question 7

problem of alpha thalassaemia

Answer 7

Impaired synthesis of alpha globin chains results in accumulation of the other globin chains
Unpaired globin chains are unstable and form insoluble aggregates within the cell
Severely damages developing erythroblasts
not soluble so when become unstable and unpaired theyre insoluble and form aggregates within the cell and damage surrounding cells so rbc destroyed prematurely

Question 8

blood film of alpha thalassaemia

Answer 8

Blood film – hypochromic, microcytic cells with target cells and poikilocytosis
Fine, deeply stained deposit caused by aggregates of β globin chains (precipitates)

Question 9

classification of beta thalassaemia

Answer 9

2 beta globin genes inherited, one from each parent
+ reduced synthesis, 0 no production of b globin
Normal β/β
β+ heterozygote β+/β
β+ homozygote β+/β+
β0 heterozygote β0/β
β0 homozygote β0/β0

Question 10

beta thalassaemia

Answer 10

Decreased synthesis of the beta chains results in β Thalassaemia
Abnormal gene for beta polypeptide synthesis inherited from both parents
Absence of beta chain expression (β0)
Reduced amounts of beta chain synthesised (β+)

Question 11

causes o beta thalssaemia

Answer 11

Most β thalassemias result from point mutations in β globin gene or close to β globin gene
tend to be mutated rather than deleted
Mutations are mainly point mutations
Mutations are spread throughout the gene and also in the promoter and enhancer sequences

Question 12

severity of beta thalassaemia

Answer 12

minor: heterozygous, asymptomatic
intermedia: globin chain production moderately impaired, mild anaemia, might need transfusions
major: homozygous, significant imbalance of a and b globin chains, severe anaemia, lifelong trnasfusions.
the more severe the disease the more genes affected

Question 13

genetics of beta thalassaemia

Answer 13

one gene affected: thalassaemia trait

two genes affected: moderate or severe anaemia

Question 14

pathogenesis

Answer 14

see diagram
Normal erythroblast in a normal individual
B thalassaemia, reduced beta globin synthesis, increased alpha globin excess. Imbalance in rbc . Leads to alpha globin forming insoluble alphaglobin aggregates in rbc during development of the rbc, abnormal erythroblast.
Production of Hb is in mitochondria, production of rbc in the bone marrow. most abnormal erythroblasts can die within the bone marrow as not fully functional (ineffective erthyropoiesis) but some will remain .a few will leave the bone marrow and go into circulation, not normal but will carry some o2 round body and broken down prematurely in spleen. Not 120 days , causes haemolytic anaemia which can be detected by tissues as reduced amount of o2 delivered to tissues detected, will increase production of erythropoietin which will aim to increase ur rbc production. Puts bone marrow into overdrive so they continue to produce rbc which are not fully functioning , marrow expansion . Haemotopoeisis can occur in skull eg mandibular process. Can see enlarged mandible and skulls
Theerythroblasts that die , iron broken down goes into circulation with the other iron that is present
Can lead to secondary iron overload due to increased breakdown . Iron still present within the body
Often treated with blood transfusion increases more iron into circulation can again be at risk of iron overload but transfusion is necessary to reduce the hypoxic and anoxyic conditions within tissue that then stimulate the production of erythrothpoitin that stimulates the production of abnormal rbc (we want to reduce this)

Question 15

β Thalassemia Major - Clinical

Answer 15

Severe anaemia (3-6 months after birth)
Hepatosplenomegaly (Spleen and liver become enlarged)
Bones expand (caused by erythroid hyperplasia)
Secondary Iron overload - 1L of transfused blood contains 500 mg iron
Iron chelation can help to treat iron overload
Infections - bone marrow overproducing rbc may affect other cells and reduced wbc produced
enlarged maxilla and prominent frontal and parietal bones

Question 16

β Thalassemia Intermedia

Answer 16

Cases where thalassaemia is moderately severe
Haemoglobin 7-10 g/dL
Patients don’t need regular transfusions

Caused by…

Homozygous beta thalassaemia where HbF is synthesised in greater amounts than normal
Mild defects in beta chain synthesis
Dominant beta thalassaemia - Beta thalassaemia trait which is unusually severe

Clinical

Bone abnormalities
Enlarged spleen or liver
Extramedullary erythropoiesis
Iron overload
(less severe than major)

Question 17

β Thalassemia Minor (Trait)

Answer 17

If the abnormal gene for the condition is inherited from one parent the affected person is described as a carrier or as having the Thalassaemia trait

Mild anaemia that is asymptomatic (haemoglobin 10-12g/dL)

Hypochromic, microcytic blood

High red cell count >5.5 x 1012L to overcompensate

Question 18

β Thalassemia Major - Diagnosis

Answer 18

Severe hypochromic, microcytic anaemia
Raised reticulocyte (immature rbc) percentage

Electrophoresis to detect haemoglobin levels of HbA and HbF (increased)

DNA analysis to detect genetic mutations

Iron Overload tests
Serum ferritin most common
Liver biopsy

Question 19

thalassaemia treatment

Answer 19

Blood Transfusions

• Moderate to severe thalassaemias - blood transfusions of red blood cells are main treatment
• Haemoglobin levels should be kept above 10g/dL
• This requires 2-3 units of blood every 4-6 weeks
• Repeated transfusions may be required as red blood cells only live 120 days

Iron Chelation Therapy

• Regular blood transfusions can cause an increase in iron
• Iron chelation therapy removes any extra iron (binds iron so it is secreted)
• Most common drug is deferoxamine

Deferiprone

• Active orally given thee times a day
• Iron is excreted in urine

Deferasirox
-New iron chelator
Given once a day

Folic Acid

• If diet is poor then folic acid is prescribed (5mg per day)
• Splenectomy
• Immunisation – hepatitis B
• Bone marrow transplants