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haemoglobinopathies Flashcards

1
Q

describe the structure of Hb

A
  • Made up of 4 globin subunits, each with a haem prosthetic group
  • Different subunits have slightly differing amino acid sequences
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2
Q

how does the amino acid sequence affect the globin subunits?

A

Differences in the AA sequence affect how they fold and fit together

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3
Q

what is the structure of adult haemoglobin?

A

2 alpha globin subunits and 2 beta subunits (a2b2)

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4
Q

how many genes are there for the alpha subunit and what chromosome are they found on?

A

2 genes on chromosome 16

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5
Q

what genes are there for the beta subunit and what chromosome are they found on?

A

5 genes for the beta subunit on chromosome 11 – epsilon, gamma A, gamma G, delta and beta

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6
Q

which can bind O2 more efficiently; HbA or HbF?

A

HbF

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7
Q

when and where is Hb Gower-1 formed?

A

First form of HbF produced in the embryonic yolk sac (up to about 6 weeks)

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8
Q

what is the structure of Hb Gower-1?

A

zeta 2 epsilon 2

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9
Q

what is the function of Hb Gower 1?

A

allows for angiogenesis in the fetus

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10
Q

what does the difference in affinity for O2 between HbA and HbF allow for?

A

allows the transfer of O2 from the mother to the fetus as the blood passes through the placenta

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11
Q

how is O2 stored in fetal muscle?

A

In the fetus, the myoglobin of the fetus has a higher affinity for O2 so O2 molecules pass from HbF to be stored in fetal muscle

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12
Q

what form of Hb replaces Hb Gower 1 and when, how and where does this happen?

A

After 6 weeks gestation, the zeta gene is switched off and HbF made of 2 alpha and 2 gamma subunits is made in the liver and spleen and replaces Hb Gower 1

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13
Q

which has a higher affinity for oxygen; HbF or Hb Gower 1?

A

Hb Gower 1

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14
Q

when does HbA replace HbF?

A

3-6 months after birth

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15
Q

define thalassaemia

A

a genetic defect resulting in inadequate quantities of one or other of the subunits that make up Hb

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16
Q

define alpha thalassaemia

A

results when one or more of the alpha genes on chromosome 16 is deleted or faulty

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17
Q

define beta thalassaemia

A

results when there’s a point mutation on chromosome 11

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18
Q

what can cause a genetic defect?

A
  • A mutation in the noncoding introns of the gene
  • The partial or total deletion of a globin gene
  • A mutation in the promoter leading to decreased expression
  • A mutation at the termination site leading to production of unstable mRNA
  • A nonsense mutation
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19
Q

when does alpha thalassaemia manifest?

A

immediately at birth

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20
Q

what does the severity of alpha thalassaemia depend on?

A

depends on the number of gene alleles defective or missing

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21
Q

what cause alpha thalassaemia minima?

A
  • 1 alpha gene is defective
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22
Q

how does alpha thalassaemia present?

A

minimal effect on Hb synthesis
• 3 alpha globin genes are enough to permit normal Hb production
• No clinical symptoms - Silent carriers
• May have a slightly reduced mean corpuscular volume and mean corpuscular Hb

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23
Q

what is alpha thalassaemia minor?

A

2 alpha genes are defective or missing

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24
Q

how does alpha thalassaemia minor present?

A

• 2 alpha genes permit nearly normal production of RBCs but there’s a mild microcytic hypochromic anaemia

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25
Q

what can alpha thalassaemia minor be confused with?

A

Can be mistaken for iron deficiency anaemia – treated inappropriately with iron

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26
Q

what is HbH disease?

A

3 alpha genes are defective or missing
• 2 unstable Hbs are present in the blood – Hb Barts and HbH
o Have a higher affinity for oxygen than normal Hb  poor release of oxygen in tissues

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27
Q

which form of HbH is more severe?

A

• HbH caused by deletion of 3 genes is less severe than cases in which 2 genes are deleted and the 3rd gene has a point mutation

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28
Q

what’s the most common form of non-deletional HbH?

A

HbH Constant Spring (HCS)

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29
Q

how do 4 defective/missing alpha genes present?

A
  • Fetus can’t live outside the uterus and may not survive gestation
  • Born as stillborn with hydrops fetalis
  • Those born alive die shortly after birth – edematous with little circulating Hb and the Hb that is present is all tetrameric y chains (Hb Barts)
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30
Q

what causes beta thalassaemia?

A

Caused by mutations in the haemoglobin B gene on chromosome 11

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31
Q

how is beta thalassaemia inherited?

A

autosomal recessive

32
Q

what are the 2 main genotypes of beta thalassaemia?

A

heterozygous (thalassemia trait, beta thalassemia minor) and homozygous (beta thalassemia major)

33
Q

what is beta thalassaemia intermedia?

A

occurs when both of the beta globin genes are mutated, but still able to make some beta chains

34
Q

when does beta thalassaemia manifest?

A

Disease manifests when the switch from gamma to beta chain synthesis occurs several months after birth

35
Q

why are there increased levels of HbF and HbA2 in beta thalassaemia?

A

May be a compensatory increase in g and d chain synthesis resulting in increased levels of Hb F and A2

36
Q

why is there underproduction of HbA in beta thalassaemia?

A

In BT major the body makes less beta globins – underproduction of HbA microcytic anaemia

37
Q

why does hypochromic microcytic anaemia occur in beta thalassaemia?

A
  • Loss of beta globins means excess alpha globins are produced in developing RBCs in the bone marrow
  • Alpha tetramers are unstable and precipitate on the RBC membrane
  • Causes intra-medullary destruction of developing RBCs, erythroid hyperplasia and ineffective erythropoiesis
38
Q 
what are the levels of;
- Hb
- MCV
- MCH
- HbA
- HbA2
- HbF
in heterozygous beta thalassaemia?
A 
Hb = low
MCV = v low
MCH = v low
HbA = normal
HbA2 = high
HbF = normal
39
Q 
what are the levels of;
- Hb
- MCV
- MCH
- HbA
- HbA2
- HbF
in homozygous beta thalassaemia?
A 
Hb = v low
MCV = v low
MCH = v low
HbA = v low or absent
HbA2 = high
HbF = v high
40
Q

what are the effects of untreated beta thalassaemia major?

A
  • Hypochromic, Microcytic Anaemia.
  • Bone marrow expansion, splenomegaly
  • Bone deformity, extramedullary erythropoietic masses
  • Failure to thrive from about 6 months of age
  • Heart failure and death by age 3-4
41
Q

what are treatments of thalassaemia?

A

• Regular blood transfusions (but can cause iron overload)
• Iron chelation therapy
• Splenectomy (not usually necessary now)
• Allogeneic bone marrow transplant (for young children if sibling donor available)
- • In some patients, supplementation of iron or folic acid may be useful

42
Q

what are alternative treatments of thalassaemia?

A

HbF modulating agents

43
Q

what is the future for thalassaemia?

A

gene therapy

44
Q

how are people with mild forms of alpha thalassaemia treated?

A

may not require specific treatment except as needed for management of low Hb levels

45
Q

what is the difference between iron deficiency anaemia and thalassaemia?

A

In thalassaemia, although RBCs are microcytic, serum iron and ferritin are normal

46
Q

why is iron overload bad?

A

• RBCs are broken down in the spleen
• Haem group is separated from the globin units
• Iron removed from haem and attached to ferritin which binds the iron securely
• With excess haemolysis some free Fe may be released from haem and enter blood
• If hydrogen peroxide is present, the Fenton reaction can occur – produces hydroxyl radicals – oxidise and damage all biological tissues
o FR is responsible for cirrhosis, diabetes, glandular dysfunction (especially growth hormone deficiency) and other effects of chronic iron overload

47
Q

what does the fenton reaction cause?

A

o FR is responsible for cirrhosis, diabetes, glandular dysfunction (especially growth hormone deficiency) and other effects of chronic iron overload

48
Q

name iron chelation therapies

A
  • desferoxamine
  • deferiprone, ferriprox
  • deferasirox, exjade
49
Q

what is desferoxamine?

A
  • 8-12 hr s.c. infusion 5-7 days per week

* Chelation enhanced with ascorbate

50
Q

what are the adverse effects of desferoxamine?

A

•Toxicity with higher doses eg diarrhoea, vomiting, fever, hearing loss, and eye problems

51
Q

what is deferiprone?

A

oral iron chelator

52
Q

what are the adverse effects of deferiprone? when shouldnt it be used?

A

Agranulocytosis/neutropenia may occur: Not to be used in pregnancy

53
Q

what is deferasirox?

A

once daily oral iron chelator

54
Q

what are the adverse effects of deferasirox?

A

can cause GI bleeding and kidney or liver failure

55
Q

what is sickle cell disease?

A

Mutant form of one of the beta Hb subunits causes the RBCs to become sickle-shaped

56
Q

what are the signs of sickle cell disease?

A
  • Haemolytic anaemia: haemoglobin levels in the range of 6–8 g/dL
  • Microvascular occlusion: rigid sickle cells adhere to endothelium, interact with white cells and vessel wall, cause nitric oxide depletion
  • Large vessel damage
57
Q

what mutation causes sickle haemoglobin?

A

valine substitution at codon 6 of the beta globin chain

• Abnormal beta chain is produced  abnormal Hb called HbS

58
Q

how does sickle cell disease lead to anaemia?

A
  • In deoxygenated blood, HbS may precipitate/crystallise, distorting RBCs into a sickle shape – fragile and easily destroyed  anaemia
  • Sickled RBCs have decreased survival time  anaemia
59
Q

how does sickle Hb lead to ischaemia?

A

•SRBCs can occlude capillaries  ischaemia and infarction of organs downstream of the blockage

60
Q

what are diagnostic tests for confirming sickle cell disease?

A
  1. Complete blood count & blood film
  2. Sickle solubility test (A mixture of HbS in a reducing solution gives a turbid appearance, whereas normal Hb gives a clear solution)
  3. Hb electrophoresis
  4. Hb HPLC (high performance liquid chromatography)
61
Q

what are the major clinical consequences of sickle cell disease

A
  • Anaemia
  • Increased susceptibility to infection (particularly encapsulated bacteria)
  • Vaso-occlusive crises (commonest is painful crisis)
  • Chronic tissue damage (eg stroke, avascular necrosis of hip, retinopathy)
62
Q

how should sickle cell disease be managed?

A
  • Infection prophylaxis
  • Analgesics for painful crises
  • Education, life style, avoidance of precipitants
  • Transfusions for specific acute and chronic complications
  • Hydroxyurea (Increases HbF, reduces painful crises)
  • Bone marrow transplantation (few have been done in UK)
63
Q

why is carrier screening good?

A

allows identification of couples at risk of producing affected offspring – can then get counselling about the genetic risk, consequences of having an affected child and the options for avoiding an affected pregnancy

results interpretation isnt usually problematic

64
Q

how is carrier screening done?

A

easily done with a simple blood analysis (FBC and haemoglobinopathy screen)

65
Q

when is carrier screening done?

A

early in pregnancy

or before pregnancy

66
Q

what time is a high risk time for sickle cell complications?

A

6 months - 2 years

67
Q

how is sickle cell diagnosed?

A

Cord blood or heel-prick sample can be used

68
Q

why is early diagnosis of sickle cell important?

A

Enables treatment with antibiotic prophylaxis, parental education, and early intervention for complications

69
Q

what is haemoglobin C?

A

mutation where there’s an abnormal beta subunit –> reduced plasticity and flexibility of the RBC –> excess haemolysis

70
Q

what is haemoglobin E?

A

abnormal Hb with a single point mutation in the beta chain

71
Q

when does HbE occur?

A

• HbE occurs when the offspring inherits HbE gene from parents

72
Q

how do babies homozygous for HbE present and why?

A
  • Babies homozygous for HbE allele don’t present with symptoms bc of HbF
  • After 3-6 months, HbF disappears and HbE increases  mild B-thalassaemia
73
Q

what is the inheritance pattern of G-6-P dehydrogenase deficiency?

A

X-linked recessive

74
Q

when does jaundice occur in someone with G6P dehydrogenase?

A

Resultant jaundice in response to a number of triggers e.g. certain foods e.g. fava beans or oxidative drugs

75
Q

what are carriers of the G6P deficiency gene protected against?

A

malaria

76
Q

when is a diagnosis of G6P deficiency suspected?

A

Diagnosis is suspected when patients from certain ethnic groups develop anemia, jaundice and symptoms of hemolysis after exposure to triggers such oxidative drugs

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