Inherited Haemoglobin disorders Flashcards
What is haemoglobin
Tetrameric complex of globin chains
Each globin chain is associated with a heme group
Each heme group contains a single atom of iron
Heme groups carry oxygen
Adults:
Main haemoglobin in HbA
HbA=alpha2beta2
What are the globin gene clusters
2 genes encode the alpha globin chain on Ch16
1 genes encodes the beta globin chain on Ch11
What chains are in regal haemoglobin
HbF
Alpha2gamma2
Chains in adult Hb
HbA Alpha2 beta 2 95% HbA2 Alpha2delta2 3.5% HbF Alpha2 gamma2 0.5-1%
How are haemoglobin disorders classified
Qualitatively
- changes to the globin chain amino acid sequence, resulting in variant haemoglobin e.g. Sickle cell disease
Quantitative
- Complete or partial reduction of a globin chain i.e. Thalassaemia
Sickle cell anaemia at risk population
African/Caribbean heritage
Middle eastern e.g. Yemeni
South Asian e.g. Indian
Consider family origins not skin colour
Evolutionary advantage for carrier state - confers some protection against falciparum malaria
Genetic basis of sickle cell disease
A genetic polymorphism results in substitution of the amino acid valine for glutamic acid at position 6 of the beta globin chain
Autosomal recessive inheritance
- HbSS, homozygotes - sickle cell disease
Both beta globin chains are abnormal - instead of making HbA (alpha alpha beta beta) they make a variant chain haemoglobin HbS (alpha alpha SS)
- HbAS heterozygotes - sickle cell trait
Only one of the beta globin genes is abnormal
They make both HbA and HbS
Other sickling syndromes
SC
S/beta thalassaemia
Spectrum of disorders, variable genotype, phenotype, haemoglobin, clinical presentations
What is the sickle cell trait genetic state
Carrier state
Do you get any protection from falciparum malaria in sickle cell trait
Partial
Symptoms of sickle cell trait
Usually asymptomatic with normal life expectancy
Can be associated with renal disease, splenic infarction, increased risk of thromboembolism, pregnancy complications, sickling under extreme physiological stress
Genetics to future children
Risk of the disease - HbSS -consider genetic counselling
What is the pathophysiology of SCD
HbS (alphalphaSS) has a propensity to polymerise when in the deoxyhaemoglobin state
Alters the structure of the red blood cells - appear like sickles on the blood film
Reduced deformability of the red blood cells resulting in venoocclusion
Reduced life span of red cells because of haemolysis
As SCD is a form of haemolytic anaemia what effects can this cause
Shortened life span of red cells - increased bilirubin - pigment gallstones Compensatory increase in red cell production - reticulocytosis - potential for folate deficiency
Acute presentation of SCD
Painful vasocclusive crises Infections - septicaemia, meningitis, UTI, osteomyelitis - hyposplenism (functional asplenia/splenic atrophy) Acute chest syndrome Stroke Acute splenic sequestration Acute hepatocyte sequestration Aplastic crisis- parvovirus B19 infection Priapism Growth delay Any other illness
How to manage a painful crisis
Analgesia-
-prompt
- tailored to the patient
- e.g. Paracetamol, ibuprofen, opiates morphine, diamorojine
Early review of efficacy
Fluids- oral preferred, careful fluid balance
Oxygen - monitor sats on air as well as on O2
LMWH- increased risk of thromboembolic events
Outpatient model - hospitalisation not required for uncomplicated crisis
Drug depends how is rare - only a concern in a minority of patients
What are the complications of an acute crisis
Sepsis
- frequent precipitate of admission
- frequent cause of morbidity and mortality
- may not see all classical signs
Renal
- leading cause of morbidity and mortality
- close fluid balance, monitor renal function
VTE
Acute sickle chest syndrome
What is acute sickle chest syndrome
A form of acute lung injury distinct from pneumonia
Leading cause of death
High risk - inpatients in crisis, pregnancy, post partum
Tachypnoea, cough
Chest pain, rib pain
Hypoxia
Fever
Clinical or radiological evidence of consolidation, pulmonary infiltrates
Risk of recurrence
Treatment of acute chest syndrome
Emergency
Recognise early - significant morbidity
Urgent cross match - extended phenotyping
Urgent outreach/Critical care review
Respiratory support - O2, CPAP, ventilation
General support - fluids, physio
Transfusion - top up /exchange
SCD as a chronic illness - what happens in end organ damage ?
Renal - concentration defect, CKD Lungs- chronic sickle lung Strokes - infarct or haemorrhage Cardiac - cardiomegaly, right heart failure, pulmonary hypertension Eyes - retinopathy Hepatobiliary - gallstones Leg ulcers - int/ext malleoli Avascular necrosis at femoral heads Erectile dysfunction secondary to priapism
General principles of SCD management-acute
Early recognition and prompt expert management
General principles of SCD management- chronic
Education
PSychological support
Primary / secondary prevention
Screening
- children - transcranial dopplers to assess risk of stroke
- adults - echocardiography to pulmonary hypertension
Management of established complications
What specific interventions are included in patient SCD management
Folic acid Analgesia Infection - penicillin prophylaxis - vaccination - pneumococcal, HIb, meningococcal, flu - early recognition of symptoms - self referral, direct access - empowerment to ask for expertise Blood transfusion - top up exchange - exchange transfusion - regular transfusion programmes e.g. To prevent stroke in children with high risk Dopplers Hydroxycarbamide - patients with severe recurrent painful crises or episodes of acute chest syndrome
Risks of blood transfusions
Alloimmunisation Haemolytic transfusion reactions Transfusion associated infections Iron overload with chronic transfusion Hyperviscosity
When considering transfusion
- seek expert advice
- consider the patients steady state Hb
Genetic basis of alpha thalassaemia
Reduction of a globin chain production - lack of HbA Relative excess of beta and gamma chains , from abnormal haemoglobins Beta 4 = Hb H Gamma 4 = Hb Barts
Autosomal recessive inheritance, various genetic defects
Pathophysiology
- ineffective haemopoiesis and haemolysis due to unstable red cells cause anaemia
What is the regional variation in carrier type
Alpha 0- aa/ -- High risk haplotype SE Asia East Med Alpha + a/-a Low risk haplotyoe Africa India
What happens as the globin chains reduce
aa/aa - normal
- a/– heterozygous + low MCV /MCH
- a/-a homozygous + low MCV/MCH
- -/aa heterozygous 0 low MCV/MCH
- -/-a heamoglobin H disease Thal intermedia
- -/– Hb Barts Hydrops
Genetic basis of beta thalassaemia
Reduction of beta globin chain production
Beta 0 mutations - total loss of beta chain production from the gene
Beta + mutations - partial reduction of beta chain production from the gene
B/B normal
B/B0 beta thal trait
B0/B0 homozygous B0 thalassaemia - beta thalassaemia major
B0/B+ compound heterozygote = beta thalassaemia intermedia
Pathophysiology of beta thalassaemia
Absent or severely reduced beta chain production
Relative access of alpha chains
Excess alpha chains are unstable and precipitate in red cell precursors, interfering with red cell maturation
Ineffective erythropoiesis and haemolysis lead to anaemia
Presentation of beta thalassaemia major
Healthy at birth
Progressive anaemia as HbF reduces
Failure to thrive
Cardiac failure
Extramedullary haemopoiesis - liver, spleen
Bony overgrowth - e.g. Skull, dental abnormalities
Ideally detected as part of antenatal screening programme and monitored/ followed up for complications
Requirement for blood transfusion in beta thalassaemia
Starts around 6-9 months continues 2-4 weekly for life ( unless they have a bone marrow transplant )
Reverses progressive anaemia
What is iron overload
Major toxicity of chronic blood transfusion
Contributes or growth failure
Multiple endocrine dysfunctions
Cardiac and hepatic toxicity
Endocrine dysfunction in beta thalassaemia major
Associated with high levels of iron overload
Anterior pituitary iron deposition affect hypothalamus-pituitary axis
- hypogonadism - delayed puberty, subfertility
- hypoparathyroidism - calcium metabolism
- hypothyroidism
Pancreatic damage
Diabetes Mellitus , increased with FH of type 2 DM
What is the management of diabetes
Screw with glucose tolerance test
- earlier with family history
Intervention
- lifestyle advice, chelation
Manage with help of diabetic care specialists
- fructosamine monitoring (HbA1c unreliable)
- long term complications
What happens to the bones in beta thalassaemia
Osteoporosis
Short stature
Bony overgrowth
Calcium profile, vit D, PTH assessment and replacement if low
Bone deformity - monitoring every 2 years from childhood
Lifestyle intervention - smoking, alcohol, diet, exercise
Sex hormone replacement
How is cardiac disease associated with beta thalassaemia
Associated with chronic severe iron overload
Before iron chelation therapy it was universal
Still remains a major chase of death
- severe cardiac failure, dysrhythmia
Preventable with iron chelation
Assess cardiac iron using MRI T2*
How is liver disease associated with beta thalassaemia
Associated with chronic severe iron overload
Cirrhosis
Other liver diseases can increase the risk of progression
- transfusion acquired hep B and C
Risk of HCC
What drug is used in iron chelation and how is it administered
Desferrioxamine
3-5 night a week of over night subcutaneous infusions
Start around 2 yo
Concordance issues
Are there another ways to administer iron chelation
Oral forms
Deferasirox - once daily solution
Renal and liver toxicity require monitoring
Deferiprone
Thrice daily schedule
Risk of neutropenia so FBC monitoring
Very effective in removing cardiac iron
Acute presentation of thalassaemia - infections
Infections - splenectomy - penicillin prophylaxis, immunisations Biliary tract sepsis Unusual infections seen - yersinia Query neutropenia if on deferiprone Line related sepsis Travel history - malaria
Acute presentation of thalassaemia - cardiac
History of poor compliance , low T2* (<10mins)
Dysthymia
Cardiac failure
Cardiology care - inotropes, ACE inhibitors, diuretics, intensive chelation- IV DFO, deferiprone
Psychological support
Acute presentation of thalassaemia - endocrine
Diabetic
Hypoadrenal crisis
Hypocalcaemia
What is the only curative option for beta thalassaemia
Bone marrow transplant Risk of mortality/morbidity -death -graft - GvHD - infertility Ideally done as an infant before developing comorbidity
What are the screening programmes for beta thalassaemia
Antenatal and neonatal only
Antenatal screening to identify ‘at risk’ pregnancy
Aim to screen in the first trimester- early offers most choices
Screening strategy determined by local prevalence
- bham universal screening
- less prevalent areas selective screening based on family origin
Neonatal screening
Aim to identify infants with SCD to allow early intervention I.e. Education, penicillin, vaccination
Additionally it identifies carriers of other structural variants and beta thalassaemia major
Investigations to do in beta thalassaemia
FBC Hb MCV MCH RBC -blood film Ferritin Iron deficiency is differential for microcytic anaemia apparent in thalassaemia
What is part of the haemoglobinopathy screen
Sickle solubility test
Screen for HbS pos if HbSA train or HbSS SCD
HPLC/Hb electrophoresis
Separate and quantify proportions of normal haemoglobins
Identify variant haemoglobins
HbA2 is raised in beta thalassaemia
What are the result of the blood investigation in those with the sickle cell trait
FBC normal
Film usually normal
Solubility test positive
HPLC HbA and HbS
What are the result of the blood investigation in those with the sickle cell disease
Hb variable 60-110 g/L MCV normocytic MCH normochromic Film sickle cells target cells Solubility test positive HPLC HbS
What are the result of the blood investigation in those with the alpha mad beta thalassaemia trait
Hb low normal or reduced
MCV microcytic e.g. 65fl
MCH hypochromic e.g. 20p.g.
RBC raised > 5 x 10^12 /L
Film microcytic hypochromic, anisopoikilocyosis , target cells, tear drops, basiphikic stippling, fragements, uncleared reds
HbA2 raised in beta thalsasseamia normal in alpha thal
Ferritin normal unless coexisting iron deficiency
