Inherited hemoglobin disorders Flashcards
Why do we need to know about hemoglobinopathy?
most common single gene disorder - carrier rate of around 7%
growing impact as infant mortality reduces
most common genetic disorder in UK
What is hemoglobin made up of?
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
What genes/chromosomes encode the alpha and beta chains?
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
What is fetal hemoglobin and what are the other variations of adult hemoglobin?
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%)
How can hemoglobin disorders be classified?
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
What is sickle cell trait advantageous against?
evolutionary advantage confers some protection against falciparum malaria - sickle cell is present in the areas where malaria is present
What populations are at risk of sickle cell trait and disease?
African/caribbean heritage
Middle eastern e.g. yemeni
South Asian e.g. indian
What is the genetic basis of sickle cell disease?
genetic polymorphism results in substitution of amino acid valine for glutamic acid at position 6 of the beta globin chain
Autosomal recessive inheritance
What is the difference genetically between sickle cell disease and sickle cell trait?
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
How can you screen for haemoglobinopathies?
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
What are the clinical effects of sickle cell trait (HbAS)?
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
Can you still sickle in the carrier state?
yes but very rare - e.g. hypoxia, high altitude
What is the pathophysiology of SCD?
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
In SCD (form of congenital hemolytic anaemia) what are the key changes to the RBCs and what compensatory changes occur?
Shortened lifespan of RBCs
- increased bilirubin, jaundice
- pigmented gallstones
Compensatory increase in red blood cell production
- reticulocytosis
- potential for folate deficiency
How can SCD present acutely?
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
What is vasocclusive crisis?
occur anywhere - occlusion of small blood vessels by sickled blood cells - very painful
- precipitating factors include temperature, stress and infection
How are patients in sickle cell crisis treated?
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
What can sickle cell disease be complicated by?
renal dysfunction
hepatic sequestration
priapism
stroke and sepsis
What complications can arise in children with SCD?
dactylics
Life-threatening acute splenic sequestration
aplastic crisis in parvovirus infection
and stroke.
What is acute sickle chest syndrome?
form of acute lung injury distinct from pneumonia
leading cause of death
High risk factors: inpatient crisis, pregnancy and postpartum
What are the symptoms/signs of acute sickle chest syndrome?
tachypnoea, cough chest pain, rib pain hypoxia fever clinical or radiological evidence of consolidation, pulmonary infiltrates risk of recurrence yellow sputum
How is acute sickle chest syndrome treated?
give oxygen - CPAP, ventilation
physio
blood transfusion
medical emergency
What is another major cause of death in SCD?
stroke - hemorrhagic or ischemic
- hemorrhagic tend to occur in middle age
- ischaemic tend to occur early or later ages
What end organ damage is common in SCD?
Renal failure chronic sickle lung retinopathy avascular necrosis leg ulcers right sided heart failure cardiomegaly
What is used to reduce risk of acute crisis in SCD?
Hydrocarbamide - given to pats with severe recurrent crises or episodes of acute chest syndrome
What are the risks of blood transfusions?
alloimmunisation hemolytic transfusion reactions transfusion associated infection iron overload with chronic transfusion hyper viscosity - increases risk of stroke
What is alpha thalassemia?
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)
What regions are thalassaemias most common?
in equatorial countries
How can carriers of thalamssaemia be identified?
FBCs - low MCH/MCV (mean corpuscular hemoglobin/volume)
Beta thalassemia can be identified by HbA2
When is alpha thalassemia compatible with life?
only compatible with life if there are some alpha chains present - it is therefore a quantitative reduction in alpha chains
What is beta thalassemia and what are the different genetic variations ?
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
What happens in beta-thalassemia major?
excess of alpha globin chains = precipitate in the normoblast red cell precursors and this leads to ineffective erythropoiesis and reduced RBC survival = anaemia
How does beta-thalassemia major present?
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
How is beta-thalassemia major treated?
starting from 6-9 months - blood transfusions every 2-4 weeks for life unless pt receives a bone marrow transplant
What are some major risks with bone marrow transplants?
graft rejection and infertility
What does iron overload cause?
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
What does iron overload do to the pituitary gland?
anterior pituitary iron deposits affects HPA
- hypogonadism = delayed puberty, sub fertility
- hypoparathyroidism = calcium metabolism
- hypothyroidism
What is iron chelation therapy?
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)
What are the acute presentations of thalassemia?
infections
cardiac and endocrine
Why do bone deformities occur in thalassemia and how are they treated?
low calcium and vitamin D levels
- treated with bisphosphonates, sex hormone replacement, and lifestyle changes
Why is cardiac complications a key cause of death in beta-thalassemia ?
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
When are bone marrow transplantations usually done?
ideally done as an infant/child before develop co-morbidities e.g. age 2-3
