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Y3 > Inherited Haemoglobin disorders > Flashcards

Inherited Haemoglobin disorders Flashcards

1
Q

What is haemoglobin

A

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

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2
Q

What are the globin gene clusters

A

2 genes encode the alpha globin chain on Ch16

1 genes encodes the beta globin chain on Ch11

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3
Q

What chains are in regal haemoglobin

A

HbF

Alpha2gamma2

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4
Q

Chains in adult Hb

A 
HbA 
Alpha2 beta 2 95% 
HbA2
Alpha2delta2 3.5%
HbF 
Alpha2 gamma2 
0.5-1%
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5
Q

How are haemoglobin disorders classified

A

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

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6
Q

Sickle cell anaemia at risk population

A

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

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7
Q

Genetic basis of sickle cell disease

A

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

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8
Q

Other sickling syndromes

A

SC
S/beta thalassaemia
Spectrum of disorders, variable genotype, phenotype, haemoglobin, clinical presentations

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9
Q

What is the sickle cell trait genetic state

A

Carrier state

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10
Q

Do you get any protection from falciparum malaria in sickle cell trait

A

Partial

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11
Q

Symptoms of sickle cell trait

A

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

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12
Q

Genetics to future children

A

Risk of the disease - HbSS -consider genetic counselling

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13
Q

What is the pathophysiology of SCD

A

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

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14
Q

As SCD is a form of haemolytic anaemia what effects can this cause

A 
Shortened life span of red cells 
- increased bilirubin
- pigment gallstones
Compensatory increase in red cell production
- reticulocytosis
- potential for folate deficiency
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15
Q

Acute presentation of SCD

A 
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
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16
Q

How to manage a painful crisis

A

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

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17
Q

What are the complications of an acute crisis

A

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

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18
Q

What is acute sickle chest syndrome

A

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

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19
Q

Treatment of acute chest syndrome

A

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

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20
Q

SCD as a chronic illness - what happens in end organ damage ?

A 
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
21
Q

General principles of SCD management-acute

A

Early recognition and prompt expert management

22
Q

General principles of SCD management- chronic

A

Education
PSychological support
Primary / secondary prevention
Screening
- children - transcranial dopplers to assess risk of stroke
- adults - echocardiography to pulmonary hypertension
Management of established complications

23
Q

What specific interventions are included in patient SCD management

A 
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
24
Q

Risks of blood transfusions

A 
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
25
Q

Genetic basis of alpha thalassaemia

A 
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

26
Q

What is the regional variation in carrier type

A 
Alpha 0- aa/ --
High risk haplotype 
SE Asia 
East Med 
Alpha + a/-a 
Low risk haplotyoe 
Africa 
India
27
Q

What happens as the globin chains reduce

A

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
28
Q

Genetic basis of beta thalassaemia

A

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

29
Q

Pathophysiology of beta thalassaemia

A

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

30
Q

Presentation of beta thalassaemia major

A

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

31
Q

Requirement for blood transfusion in beta thalassaemia

A

Starts around 6-9 months continues 2-4 weekly for life ( unless they have a bone marrow transplant )
Reverses progressive anaemia

32
Q

What is iron overload

A

Major toxicity of chronic blood transfusion
Contributes or growth failure
Multiple endocrine dysfunctions
Cardiac and hepatic toxicity

33
Q

Endocrine dysfunction in beta thalassaemia major

A

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

34
Q

What is the management of diabetes

A

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

35
Q

What happens to the bones in beta thalassaemia

A

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

36
Q

How is cardiac disease associated with beta thalassaemia

A

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*

37
Q

How is liver disease associated with beta thalassaemia

A

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

38
Q

What drug is used in iron chelation and how is it administered

A

Desferrioxamine
3-5 night a week of over night subcutaneous infusions
Start around 2 yo
Concordance issues

39
Q

Are there another ways to administer iron chelation

A

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

40
Q

Acute presentation of thalassaemia - infections

A 
Infections
- splenectomy - penicillin prophylaxis, immunisations
Biliary tract sepsis 
Unusual infections seen - yersinia 
Query neutropenia if on deferiprone 
Line related sepsis 
Travel history - malaria
41
Q

Acute presentation of thalassaemia - cardiac

A

History of poor compliance , low T2* (<10mins)
Dysthymia
Cardiac failure
Cardiology care - inotropes, ACE inhibitors, diuretics, intensive chelation- IV DFO, deferiprone
Psychological support

42
Q

Acute presentation of thalassaemia - endocrine

A

Diabetic
Hypoadrenal crisis
Hypocalcaemia

43
Q

What is the only curative option for beta thalassaemia

A 
Bone marrow transplant
Risk of mortality/morbidity 
-death
-graft
- GvHD
- infertility 
Ideally done as an infant before developing comorbidity
44
Q

What are the screening programmes for beta thalassaemia

A

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

45
Q

Investigations to do in beta thalassaemia

A 
FBC 
Hb
MCV
MCH
RBC
-blood film
Ferritin
Iron deficiency is differential for microcytic anaemia apparent in thalassaemia
46
Q

What is part of the haemoglobinopathy screen

A

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

47
Q

What are the result of the blood investigation in those with the sickle cell trait

A

FBC normal
Film usually normal
Solubility test positive
HPLC HbA and HbS

48
Q

What are the result of the blood investigation in those with the sickle cell disease

A 
Hb variable 60-110 g/L
MCV normocytic
MCH normochromic 
Film sickle cells target cells
Solubility test positive
HPLC HbS
49
Q

What are the result of the blood investigation in those with the alpha mad beta thalassaemia trait

A

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

Y3 (22 decks)

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