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September lectures yr 3 (2018) > Inherited hemoglobin disorders > Flashcards

Inherited hemoglobin disorders Flashcards

1
Q

Why do we need to know about hemoglobinopathy?

A

most common single gene disorder - carrier rate of around 7%
growing impact as infant mortality reduces
most common genetic disorder in UK

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2
Q

What is hemoglobin made up of?

A

tetrameric complex of globin chains - each one of associated with a haem group containing a single atom of iron - carry oxygen
Adults = main haemboglobin = HbA
HbA = 2 alpha and 2 beta

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3
Q

What genes/chromosomes encode the alpha and beta chains?

A

2 genes encode the alpha globin chain - ch 16

1 gene encodes the beta globin chain - ch11 - abnormality is found on the beta globin chain in sickle cell disease

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4
Q

What is fetal hemoglobin and what are the other variations of adult hemoglobin?

A 
Fetal = HbF = 2 alpha and 2 gamma chains - they don;t have a problem until about 12 weeks after birth  
Adults = HbA - 95%, HbA2 (2 alpha and 2 delta chains - 2-3.5%), HbF (0.5-1%)
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5
Q

How can hemoglobin disorders be classified?

A

Qualitative
- changes in globin chain amino acid sequence = variant hemoglobin (shape of RBC is bad) e.g. sickle cell disease

Quantitative
- complete or partial reduction of a globin chain e.g. thalassemia - insufficient Beta chains produced

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6
Q

What is sickle cell trait advantageous against?

A

evolutionary advantage confers some protection against falciparum malaria - sickle cell is present in the areas where malaria is present

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7
Q

What populations are at risk of sickle cell trait and disease?

A

African/caribbean heritage
Middle eastern e.g. yemeni
South Asian e.g. indian

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8
Q

What is the genetic basis of sickle cell disease?

A

genetic polymorphism results in substitution of amino acid valine for glutamic acid at position 6 of the beta globin chain
Autosomal recessive inheritance

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9
Q

What is the difference genetically between sickle cell disease and sickle cell trait?

A

HbSS, homozygotes = SCD
- both beta globin chains are abnormal - instead of making HbA they make the variant hemoglobin HbS (alpha, alpha, S,S)

HbAS, heterozygotes - SCT (carrier)

  • only one of the beta chains is abnormal
  • they make both HbA and HbS
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10
Q

How can you screen for haemoglobinopathies?

A

FBC, iron status, sickle solubility test, Hb A2, and Hb electrophoresis

  • MCV and MCH are usually low in thalassaemia
  • HbA2 is usually raised in carriers of β thalassemia, as the β chains are replaced with δ chains
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11
Q

What are the clinical effects of sickle cell trait (HbAS)?

A

Protection against falciparum malaria
usually asymptomatic - normal life expectancy
can be associated with renal disease, splenic infarction, increased risk of thromboembolism, pregnancy complications, sickling under extreme physiological stress
Risk of bay with HbSS - consider genetic counseling

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12
Q

Can you still sickle in the carrier state?

A

yes but very rare - e.g. hypoxia, high altitude

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13
Q

What is the pathophysiology of SCD?

A

HbS has the propensity to polymerase when in the deoxyhaemoglobin state - collapse = stick together and interact with the vascular wall and this can cause ischemic pain
Altered structure appears like sickles on the blood film
Reduced deformability of rbcs = venoocclusion
Reduced life span of RBCs due to hemolysis

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14
Q

In SCD (form of congenital hemolytic anaemia) what are the key changes to the RBCs and what compensatory changes occur?

A

Shortened lifespan of RBCs

  • increased bilirubin, jaundice
  • pigmented gallstones

Compensatory increase in red blood cell production

  • reticulocytosis
  • potential for folate deficiency
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15
Q

How can SCD present acutely?

A

painful vasocclussive crisis
infections - septicemia, meningitis, UTI, osteomyelitis, can have hyposplenism and therefore at particular risk of pneumococcus, haemophilus and meningococcus (encapsulated bacterial infections more common)
- functional hyposplenism means infections are more likely and therefore given prophylaxis penicillin and pneumococcal immunization is important
acute chest syndrome
stroke

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16
Q

What is vasocclusive crisis?

A

occur anywhere - occlusion of small blood vessels by sickled blood cells - very painful
- precipitating factors include temperature, stress and infection

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17
Q

How are patients in sickle cell crisis treated?

A

Analgesia - morphine preferred to pethidine
Fluids - dilates out sickle cells to help reduce pain
Monitoring oxygen sats
LMWH as they are at increased risk of thromboembolic events

18
Q

What can sickle cell disease be complicated by?

A

renal dysfunction
hepatic sequestration
priapism
stroke and sepsis

19
Q

What complications can arise in children with SCD?

A

dactylics
Life-threatening acute splenic sequestration
aplastic crisis in parvovirus infection
and stroke.

20
Q

What is acute sickle chest syndrome?

A

form of acute lung injury distinct from pneumonia
leading cause of death
High risk factors: inpatient crisis, pregnancy and postpartum

21
Q

What are the symptoms/signs of acute sickle chest syndrome?

A 
tachypnoea, cough
chest pain, rib pain 
hypoxia 
fever 
clinical or radiological evidence of consolidation, pulmonary infiltrates 
risk of recurrence 
yellow sputum
22
Q

How is acute sickle chest syndrome treated?

A

give oxygen - CPAP, ventilation
physio
blood transfusion

medical emergency

23
Q

What is another major cause of death in SCD?

A

stroke - hemorrhagic or ischemic

  • hemorrhagic tend to occur in middle age
  • ischaemic tend to occur early or later ages
24
Q

What end organ damage is common in SCD?

A 
Renal failure 
chronic sickle lung 
retinopathy 
avascular necrosis 
leg ulcers 
right sided heart failure 
cardiomegaly
25
Q

What is used to reduce risk of acute crisis in SCD?

A

Hydrocarbamide - given to pats with severe recurrent crises or episodes of acute chest syndrome

26
Q

What are the risks of blood transfusions?

A 
alloimmunisation 
hemolytic transfusion reactions 
transfusion associated infection 
iron overload with chronic transfusion 
hyper viscosity - increases risk of stroke
27
Q

What is alpha thalassemia?

A

reduction in alpha globin chain production
- a relative excess of beta and gamma chains form abnormal hemoglobin
Autosomal recessive inheritance
Pathophysiology = ineffective haemopoeisis and hemolysis due to unstable red cells cause anaemia

Hb barts hydrops (no alpha chains) - still birth (gamma 4)

28
Q

What regions are thalassaemias most common?

A

in equatorial countries

29
Q

How can carriers of thalamssaemia be identified?

A

FBCs - low MCH/MCV (mean corpuscular hemoglobin/volume)

Beta thalassemia can be identified by HbA2

30
Q

When is alpha thalassemia compatible with life?

A

only compatible with life if there are some alpha chains present - it is therefore a quantitative reduction in alpha chains

31
Q

What is beta thalassemia and what are the different genetic variations ?

A

reduction in beta globin chain production
beta/beta = normal
beta/beta0 = beta-thalassemia trait
beta0/beta0 = homozygous beta0 thalassemia major - don’t make enough to survive so they have to have blood transfusions for life - iatrogenic problems are the key issues these patients have
beta0/beta+ (partial reduction of bet chain production) = beta-thalassemia intermedia

32
Q

What happens in beta-thalassemia major?

A

excess of alpha globin chains = precipitate in the normoblast red cell precursors and this leads to ineffective erythropoiesis and reduced RBC survival = anaemia

33
Q

How does beta-thalassemia major present?

A

healthy at birth
progressive anaemia as HbF reduces
failure to thrive
cardiac failure
extra medullary hemopoiesis - liver, spleen
bony overgrowth e.g. skull, dental abnormalities - bone marrow tries to grow to produce more RBCs
it is ideally detected as part of ante-natal screening and monitored/followed up for complications

34
Q

How is beta-thalassemia major treated?

A

starting from 6-9 months - blood transfusions every 2-4 weeks for life unless pt receives a bone marrow transplant

35
Q

What are some major risks with bone marrow transplants?

A

graft rejection and infertility

36
Q

What does iron overload cause?

A

major toxicity of chronic blood transfusion - check liver iron levels annually
iron can build up in any organ
contributes to growth failure
multiple endocrine dysfunctions - can lead to diabetes, thyroid dysfunction
cardiac and hepatic toxicity - sudden death

37
Q

What does iron overload do to the pituitary gland?

A

anterior pituitary iron deposits affects HPA

  • hypogonadism = delayed puberty, sub fertility
  • hypoparathyroidism = calcium metabolism
  • hypothyroidism
38
Q

What is iron chelation therapy?

A

desferrioxamine - subcutaneous infusions = started at around 2 years old - concordance issues

oral forms - deferasirox = once daily solution (renal and liver toxicity require monitoring. Deferiprone (thrice daily - risk of neutropenia so FBC monitoring, very effective in removing cardiac iron)

39
Q

What are the acute presentations of thalassemia?

A

infections

cardiac and endocrine

40
Q

Why do bone deformities occur in thalassemia and how are they treated?

A

low calcium and vitamin D levels

- treated with bisphosphonates, sex hormone replacement, and lifestyle changes

41
Q

Why is cardiac complications a key cause of death in beta-thalassemia ?

A

before iron chelation therapy it was a major cause of cardiac disease and it still is a major cause of death due to arrhythmias and CCF
MRI should be carried out to identify cardiac iron

42
Q

When are bone marrow transplantations usually done?

A

ideally done as an infant/child before develop co-morbidities e.g. age 2-3

September lectures yr 3 (2018) (56 decks)

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