haemoglopenopathy
normal haemoglobin
the normal haemoglobin molecule is comprised of two alpha and two non-alpha globin chains (1p. 1005). alpha globin chains are produced from two genes present on each chromosome 16 these are active throughout embryonic. fetal, infant and adult life. severe disorders of alpha globin chains may therefore cause intrauterine death. the non¬alpha chains are produced by genes present in single copy on each chromosome 11. production varies with age fetal
i haemoglobin (hbf-oc2yz) has two gamma chains but after the first trimester small amounts of haemoglobin a (hba-a2 (32) with two beta chains are produced. at birth about 80% of haemoglobin is hbf and 20% hba. thereafter gamma chain production is suppressed, such that by 6 months of age hba is the predominant haemoglobin with less than 1% hbf. disorders affecting the beta chain do not present until after 6 months of age. a constant small amount of haemoglobin az (hba2-(x282, usually < 2%) is made from birth.
abnormal haemoglobins
the haemoglobinopathies can be classified into qualitative or quantitative abnormalities.
qualitative abnormalities
in qualitative abnormalities (called the abnormal haemo¬slobins ). there is an alteration in the amino acid structure of the polypeptide chains of the globin fraction of haemo¬slobin. the best-known example is haemoglobin s, found in sickle-cell anaemia. these abnormalities usually result from amino acid substitutions which change the function of the qlobin chain at critical sites. for example, mutations around the haem-binding pocket cause the haem ring to fall out of the structure and produce an unstable haemoglobin. these substitutions often change the charge of the globin chains, producing different electrophoretic mobility, and this forms the basis for the diagnostic use of electrophoresis to identify haemoglobinopathies. several hundred such variants are known_ they were originally designated by letters of the alphabet. e.,1. s. c, d or e, but are now described by names usualln taken from the town or district in which they were first de~cribed.
quantitative abnormalities
in quantitative abnormalities (the thalassaemias), the amino acid sequence is normal but polypeptide chain production is impaired or absent for a variety of reasons. in these conditions the ratio of alpha to non-alpha chain production is disturbed. in alpha-thalassaemia excess beta chains are present, whilst in beta-thalassaemia excess alpha chains are present. the excess chains precipitate, causing red cell membrane damage and reduced red cell survival.
sickle cell anemia
sickle-cell disease results from a single glutamic acid to valine substitution at position 6 of the beta globin polypeptide chain. it is inherited as an autosomal recessive trait. homozygotes only produce abnormal beta chains that make haemoglobin s (hbs. termed ss), and this results in the clinical syndrome of sickle-cell disease. heterozygotes produce a mixture of normal and abnormal beta chains that make normal hba and hbs (termed as), and this results in the clinically asymptomatic sickle trait. the inheritance of sickle-cell disease is shown in figure 24.23.
epidemiology
individuals with sickle-cell trait are relatively resistant to the lethal effects of falciparum malaria in early childhood. the high incidence of this deletingrious gene in equatori
sickle-cell trait.
africa can be explained by the selective survival advantage it confers in areas where fo/ciparum malaria is endemic. patients with sickle-cell anaemia do not have correspond¬ingly greater resistance to falciparum malaria. the geo¬graphical distribution of sickle-cell anaemia and the other common haemoslobinopathies is shown in figure 24.24. the greatest prevalence of haemoelobinopathies occurs in tropical africa, where the heterozygote frequency is over 20%. in black american populations. sickle-cell trait has a frequency of 8%.
pathogenesis
when haemoglobin s is deoxygenated, the molecules of haemoglobin polymerise to form pseudocrystalline structures known as `tactoids . these distort the red cell membrane and produce characteristic sickle-shaped cells. the polymerisation is reversible when reoxygenation occurs. the distortion of the red cell membrane, however, may become permanent and the red cell `irreversibly sickled . the greater the concentration of sickle-cell haemoglobin in the individual cell. the more easily tactoids are formed, but this process may be enhanced or retarded by the presence of other haemoqlobins. thus haemoglobin c participates in the polymerisation more readily than haemoglobin a, whereas haemoslobin f strongly inhibits polymerisation.
clinical features
sickling is precipitated by hypoxia, acidosis, dehydration and infection. irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. this results in a number of acute syndromes termed `crises and chronic organ damage as shown in figure 24.25:
• vaso-occlusive crisis. plugging of small vessels in the bone produces acute severe bone pain. this affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora. humeri, ribs, pelvis and vertebrae in adults. patients usually have a systemic response with tachycardia, sweating and a fever. this is the most common crisis.
• sickle chest syndrome. this may follow on from a vaso-occlusive crisis and is the most common cause of death in adult sickle disease. bone marrow infarction results in fat emboli to the lungs which cause sickling and infarction, leading to ventilatory failure if not treated.
• sequestration crisis. thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. in children the spleen is the most common site. massive splenic enlargement may result in severe anaemia and circulatory collapse with death. recurrent sickling in the spleen in childhood results in infarction and adults may have no functional spleen. in adults the liver may undergo sequestration with severe pain due to capsular stretching.
• aplastic crisis. infection of adult sicklers with human erythrovirus 19 results in a severe but self-limiting red cell aplasia. this produces a very low haemoglobin which may cause heart failure. unlike in all other sickle crises, the reticulocyte count is low.
investigations
patients with sickle-cell disease have a compensated anaemia, usually around 60-80 g/1. the blood film shows sickle cells, target cells and features of hyposplenism. a reticulocytosis is present. the presence of hbs can be demonstrated by exposing red cells to a reducing agent such
thalassaemia sickle-cell anaemia hbc
hbd hbe
.
anaemias
ocular background retinopathy proliferative retinopathy vitreous bleeds
blood film
cns
cerebrovascular accident subarachnoid bleed
fits
cardiac
sickle myocardium cardiomegaly transfusional iron overload
fig. 24.25 clinical manifestations of sickle-cell disease.
as sodium dithionite hba gives a clear solution, whereas hbs polymerises to produce a turbid solution. this forms the basis of emergency screening tests before surgery in appropriate ethnic groups but cannot distinguish between sickle trait and disease. the definitive diagnosis requires haemoglobin electrophoresis to demonstrate no hba, 2-20% hbf and the predominance of hbs. both parents of the affected individual will have sickle trait.
management
all patients with sickle disease should receive prophylaxis with daily folic acid, and penicillin v to protect against pneumococcal infection which may be lethal in the presence of hyposplenism. these patients should be vaccinated against pneumococcus and, where available, haemophilus influenzae b and hepatitis b.
vaso-occlusive crises are managed by aggressive rehydration, oxygen therapy, adequate analgesia (which often requires opiates) and antibiotics. transfusion should be with fully genotyped blood wherever possible. simple top-up transfusion may be used in a sequestration or aplastic crisis. a regular transfusion programme to suppress hbs production and maintain the hbs level below 30% may be
indicated in recurrent severe complications such as cerebrovascular accidents in children or chest syndromes in adults. exchange transfusion, where a patient is simultaneously venesected and transfused to replace hbs with hba, may be used in life-threatening crises or to prepare patients for surgery.
a high hbf level inhibits polymerisation of hbs and reduces sickling. patients with sickle-cell disease and high hbf levels have a mild clinical course with few crises. some agents are able to induce increased synthesis of hbf and this has been used to reduce the frequency of severe crises. the oral cytotoxic agent hydroxycarbamide has been shown to have clinical benefit with acceptable side-effects in children and adults who have recurrent severe crises. relatively few allogeneic transplants from hla-matched siblings have been performed but this procedure appears to be potentially curative.
prognosis
in africa few children with sickle-cell anaemia survive to adult life without medical attention. even with standard medical care approximately 15% die by the age of 20 years and 50% by the age of 40 years.
1037
renal
enuresis haematuria papillary necrosis chronic renal failure
electrophoresis gel
blood disorders
la g as normal sickle-cell trait
fig. 24.23 possible genotype of offspring of parents with
sickle-cell trait.
africa can be explained by the selective survival advantage it confers in areas where .falciparum malaria is endemic. patients with sickle-cell anaemia do not have correspond¬ingly° greater resistance to falciparum malaria. the geo¬graphical distribution of sickle-cell anaemia and the other common haemoglobinopathies is shown in figure 24.24. the greatest prevalence of haemoglobinopathies occurs in tropical africa, where the heterozygote frequency is over 20%. in black american populations, sickle-cell trait has a frequency of 8%.
pathogenesis
when haemoglobin s is deoxygenated, the molecules of haemoglobin polymerise to form pseudocrystalline structures known as `tactoids . these distort the red cell membrane and produce characteristic sickle-shaped cells. the polymerisation is reversible when reoxygenation occurs. the distortion of the red cell membrane, however, may become permanent and the red cell `irreversibly sickled . the greater the concentration of sickle-cell haemoglobin in the individual cell, the more easily tactoids are formed, but this process may be enhanced or retarded by the presence of other haemoglobins. thus haemoglobin c participates in the polymerisation more readily than haemoglobin a, whereas haemoglobin f strongly inhibits polymerisation.
ss sickle-cell disease
clinical features
sickling is precipitated by hypoxia, acidosis, dehydration and infection. irreversibly sickled cells have a shortened sun-ival and plug vessels in the microcirculation. this results in a number of acute svndromes termed `crises and chronic organ damage as shown in figure 24.25:
0 1%aso-occlusive crisis. p1uqsine of small vessels in the bone produces acute severe bone pain. this affects areas of active marrow: the hands and feet in children (so-called dactylitis) or the femora, humeri. ribs, pelvis and vertebrae in adults. patients usuallv have a systemic response with tachycardia, sweating and a fever. this is the most common crisis.
i
* sickle chest syndrome. this may follow on from a vaso-occlusive crisis and is the most common cause of death in adult sickle disease. bone marrow infarction results in fat emboli to the lungs which cause sickling and infarction, leading to ventilatory failure if not treated.
0 sequestration crisis. thrombosis of the venous outflow from an organ causes loss of function and acute painful enlargement. in children the spleen is the most common site. massive splenic enlargement may result in severe anaemia and circulatory collapse with death. recurrent sickling in the spleen in childhood results in infarction and adults may have no functional spleen. in adults the liver may undergo sequestration with severe pain due to capsular stretching.
aplastic crisis. infection of adult sicklers with human erythrovirus 19 results in a severe but self-limiting red cell aplasia. this produces a very low haemoglobin which may cause heart failure. unlike in all other sickle crises, the reticulocyte count is low.
investigations
patients with sickle-cell disease have a compensated anaemia, usually around 60-80 g/l. the blood film shows sickle cells, target cells and features of hyposplenism. a reticulocytosis is present. the presence of hbs can be demonstrated by exposing red cells to a reducing agent such
thalassaemia sickle-cell anaemia hbc
hbd hbe
blood disorders
other abnormal haemoglobins
another beta chain haemoglobinopathy, haemoglobin c (hbc) disease, is clinically silent but associated with microcytosis and target cells on the blood film. compound heterozygotes inheriting one hbs gene and one hbc gene from their parents have haemoglobin sc disease. which behaves like a mild form of ~sickle-cell disease. it is associated with a reduced frequency of crises but is not uncommonly associated with complications in pregnancy and retinal vein thrombosis.
* thalassaemia
thalassaemia is an inherited impairment of haemoglobin production, in which there is partial or complete failure to synthesise a specific type of globin chain. in alpha¬thalassaemia, the alpha genes are deletingd loss of one gene (a /a) or both genes (a /a ) from each chromosome 16 may occur, in association with the production of some or no alpha globin chains. in beta-thalassaemia defective production usually results from disabling point mutations causing no ((3°) or reduced ((3-) beta chain production.
beta -thalassaemia
failure to synthesise beta chains (beta-thalassaemia) is the most common type of thalassaemia and is seen in highest frequency in the mediterranean area. heterozygotes have thalassaemia minor, a condition in which there is usually mild anaemia and little or no clinical disability. homozygotes (thalassaemia major) either are unable to synthesise haemoglobin a or at best produce very little and, after the first 4 months of life, develop a profound hypochromic anaemia. the diagnostic features are listed in box 24.33.
beta-thalassaemia minor is often detected only when iron therapy for a mild microcytic anaemia fails. the diagnostic features are also summarised in box 24.33. symptoms are absent or mild. intermediate grades of severity occur.
zer
24.34 treatment of beta-thalassaemia major
problem management
erythropoietic failure allogeneic bone marrow transplantation
from human leucocyte antigen
, (hla)-compatible sibling
! transfusion to maintain hb > 100 g/i
folic acid 5 mg daily
iron overload iron therapy forbidden
desferrioxamine therapy
splenamegaly causing splenectomy
mechanical problems,
excessive transfusion
needs
24.34. cure is now a possibility for selected children, with allogeneic bone marrow transplantation.
prevention
it is possible to identify a fetus with homozygous beta¬thalassaemia by obtaining chorionic villous material for dna analysis sufficiently early in pregnancy to allow termination. this examination is only appropriate if both parents are known to be carriers (beta-thalassaemia minor) and will accept a termination.
alpha-thalassaemia
the reduction or absence of alpha-chain synthesis is common in southeast asia. there are two alpha gene loci on chromosome 16 and therefore four alpha genes. if one is deletingd there is no clinical effect. if two are deletingd there may be a mild hypochromic anaemia. if three are deletingd the patient has haemoglobin h disease and if all four are deletingd the baby is stillborn (hydropingings fetalis). haemoglobin h is a beta-chain tetramer formed from the excess of chains. it is functionally useless. treatment of haemoglobin h disease is similar to that of beta-thalassaemia of intermediate severity. the combinations are shown in box 24.35.
1038
management
the treatment of beta-thalassaemia major is given in box
24.33 diagnostic features of beta-thalassaemia
major
~ profound hypochromic anaemia
~ evidence of severe red cell dysplasia
~ erythroblastosis
~ absence or gross reduction of the amount of haemoglobin a
~ raised levels of haemoglobin f
~ evidence that both parents have thalassaemia minor
minor
v mild anaemia
~ microcytic hypochromic erythrocytes (not iron-deficient)
~ some target cells
~ punctate basophilia
~ raised resistance of erythrocytes to osmotic lysis
~ raised haemoglobin az fraction
~ evidence that one parent has thalassaemia minor
24.35 alpha-thalassaemia
cause
0 failure of production of haemoglobin alpha chains due to gene
deletion
age and sex incidence
e both sexes from birth onward
genetics
e two alpha-chain genes from each parent
presentation
• hydropingings fetalis if all genes deletingd
• haemoglobin h if three genes deletingd
• mild hypochromic microcytic anaemia if two genes deletingd
treatment
• hydropingings fetalis: none available
• haemoglobin h: no specific therapy required avoid iron therapy
folic acid if necessary