THE THALASSAEMIAS

The thalassaemias affect people throughout the world. Normally there is balanced (1 : 1) production of α and β chains. The defective synthesis of globin chains in thalassaemia leads to ‘imbalanced’ globin chain production,

leading to precipitation of globin chains within the red cell precursors and resulting in ineffective erythropoiesis. Precipitation

of globin chains in mature red cells leads to haemolysis

.

b-ThalassaemiaIn homozygous β-thalassaemia, either no normal β chains areproduced (β0), or β-chain production is very reduced (β+).There is an excess of α chains, which precipitate in erythroblastsand red cells causing ineffective erythropoiesis andhaemolysis. The excess α chains combine with whatever β,δ and γ chains are produced, resulting in increased quantitiesof Hb A2 and Hb F and, at best, small amounts of Hb A. Inheterozygous β-thalassaemia there is usually symptomlessmicrocytosis with or without mild anaemia. Table 8.11 showsthe findings in the homozygote and heterozygote for thecommon types of β-thalassaemia

Molecular geneticsThe molecular errors accounting for over 200 genetic defectsleading to β-thalassaemia have been characterized. Unlike inα-thalassaemia, the defects are mainly point mutations ratherthan gene deletions. The mutations result in defects in transcription,

RNA splicing and modification, translation viaframe shifts and nonsense codons producing highly unstableβ-globin which cannot be utilized

Clinical syndromesClinically, β-thalassaemia can be divided into the following:

■thalassaemia minor (or trait), the symptomlessheterozygous carrier state

■thalassaemia intermedia, with moderate anaemia, rarelyrequiring transfusions

■thalassaemia major, with severe anaemia requiringregular transfusions.

Thalassaemia minor (trait)This common carrier state (heterozygous β-thalassaemia) isasymptomatic. Anaemia is mild or absent. The red cells arehypochromic and microcytic with a low MCV and MCH, andit may be confused with iron deficiency. However, the twoare easily distinguished, as in thalassaemia trait the serumferritin and the iron stores are normal .The RDWis usually normal .Hb electrophoresis usuallyshows a raised Hb A2 and often a raised Hb F. Ironshould not be given to these patients unless they haveproven coincidental iron deficiency.

Thalassaemia intermediaThalassaemia intermedia includes patients who are symptomaticwith moderate anaemia (Hb 7–10 g/dL) and who donot require regular transfusions.

Thalassaemia intermedia may be due to a combination ofhomozygous mild β+- and α-thalassaemia, where there isreduced α-chain precipitation and less ineffective erythrop

esis and haemolysis. The inheritance of hereditary persistenceof Hb F with homozygous β-thalassaemia also resultsin a milder clinical picture than unmodified β-thalassaemiamajor because the excess α chains are partially removed bythe increased production of γ chains.Patients may have splenomegaly and bone deformities.Recurrent leg ulcers, gallstones and infections are also seen.

It should be noted that these patients may be iron overloadeddespite a lack of regular blood transfusions. This is causedby excessive iron absorption which results from the underlyingDyserythropoiesis.

Thalassaemia major (Cooley’s anaemia)

Most children affected by homozygous β-thalassaemiapresent during the first year of life with:

■failure to thrive and recurrent bacterial infections ■severe anaemia from 3 to 6 months when the switch

from γ- to β-chain production should normally occur ■extramedullary haemopoiesis that soon leads to

hepatosplenomegaly and bone expansion, giving rise tothe classical thalassaemic facies

Skull X-rays in these children show the characteristic ‘hairon end’ appearance of bony trabeculation as a result ofexpansion of the bone marrow into cortical bone).The expansion of the bone marrow is also shown in an X-rayof the handThe classic features of untreated thalassaemia major aregenerally only observed in patients from countries withoutgood blood transfusion support.

ManagementThe aims of treatment are to suppress ineffective erythropoiesis,

prevent bony deformities and allow normal activity anddevelopment.

■Long-term folic acid supplements are required. ■Regular transfusions should be given to keep the Hb

above 10 g/dL. Blood transfusions may be requiredevery 4–6 weeks.

If transfusion requirements increase, splenectomy mayhelp, although this is usually delayed until after the ageof 6 years because of the risk of infection. Prophylaxisagainst infection is required for patients undergoingsplenectomy

Iron overload caused by repeated transfusions(transfusion haemosiderosis) may lead to damage to theendocrine glands, liver, pancreas and the myocardiumby the time patients reach adolescence. Magneticresonance imaging (myocardial T2- relaxation time) isuseful for monitoring iron overload in thalassaemia, boththe heart and the liver can be monitored. The standardiron-chelating agent remains desferrioxamine, althoughit has to be administered parenterally. Desferrioxamineis given as an overnight subcutaneous infusion on 5–7nights each week. Ascorbic acid 200 mg daily is given,as it increases the urinary excretion of iron in responseto desferrioxamine

Often young children have a veryhigh standard of chelation as it is organized by theirparents. However, when the children become adults andtake on this role themselves they often rebel andchelation with desferrioxamine may becomeproblematic. Preliminary results on a new once-dailyoral iron chelator, deferasirox, indicate that it is safe,similar in effectiveness to desferrioxamine and welltolerated. Deferiprone, an oral iron chelator, is also nowavailable.

Intensive treatment with desferrioxamine has beenreported to reverse damage to the heart in patients withsevere iron overload, but excessive doses ofdesferrioxamine may cause cataracts, retinal damageand nerve deafness. Infection with Yersiniaenterocolitica occurs in iron-loaded patients treated withdesferrioxamine. Iron overload should be periodicallyassessed by measuring the serum ferritin and byassessment of hepatic iron stores by MRI.

Bone marrow transplantation has been used in youngpatients with HLA-matched siblings. It has beensuccessful in patients in good clinical condition with a3-year mortality of less than 5%, but there is a highmortality

(> 50%) in patients in poor condition with ironoverload and liver dysfunction.■ Prenatal diagnosis and gene therapy. ■ Patients’ partners should be tested. If both partnershave β-thalassaemia trait, there is a 1 in 4 chance ofsuch pregnancy resulting in a child having β-thalassaemia major. Therefore, couples in this situationmust be offered prenatal diagnosis.

Alpha thalassaemiaMolecular geneticsIn contrast to β-thalassaemia, α-thalassaemia is often causedby gene deletions, although mutations of the alpha globingenes may also occur. The gene for α globin chains is duplicatedon both chromosomes 16, i.e. a normal person has atotal of four alpha globin genes. Deletion of one α-chain gene

)α (+or both α-chain genes (α0) on each chromosome 16 mayoccur The former is the most common of theseabnormalities.

Four-gene deletion (deletion of both genes on bothchromosomes); there is no α-chain synthesis and onlyHb Barts (γ4) is present. Hb Barts cannot carry oxygenand is incompatible with life).Infants are either stillborn at 28–40 weeks or die veryshortly after birth. They are pale, oedematous and haveenormous livers and spleens – a condition calledhydrops fetalis.

Three-gene deletion; there is moderate anaemia (Hb

7–10 g/dL) and splenomegaly (Hb H disease). Thepatients are not usually transfusion-dependent. Hb A,

Hb Barts and Hb H (β4) are present. Hb A2 is normal orreduced.

Two-gene deletion (α-thalassaemia trait); there is

microcytosis with or without mild anaemia. Hb H bodies

may be seen on staining a blood film with brilliant cresyl

blue.

One-gene deletion; the blood picture is usually normal.Globin chain synthesis studies for the detection of a

reducedratio of α to β chains may be necessary for the definitivediagnosis of α-thalassaemia trait.Less commonly, α-thalassaemia may result from geneticdefects other than deletions, for example mutations in thestop codon producing an α chain with many extra aminoacids (Hb Constant Spring

SICKLE SYNDROMESSickle cell haemoglobin (Hb S) results from a single-basemutation of adenine to thymine which produces a substitutionof valine for glutamic acid at the sixth codon of the β-globin chain (α2β26glu→val). In the homozygous state (sickle cellanaemia) both genes are abnormal (Hb SS), whereas in theheterozygous state (sickle cell trait, Hb AS) only one chromosomecarries the gene. As the synthesis of Hb F is normal,the disease usually does not manifest itself until the Hb Fdecreases to adult levels at about 6 months of age.The sickle gene is commonest in Africans (up to 25%gene frequency in some populations) but is also found inIndia, the Middle East and Southern Europe

PathogenesisDeoxygenated Hb S molecules are insoluble and polymerize.The flexibility of the cells is decreased and they become rigidand take up their characteristic sickle appearanceThis process is initially reversible but, with repeated sickling,the cells eventually lose their membrane flexibility and becomeirreversibly sickled. This is due to dehydration, partly causedby potassium leaving the red cells via calcium activatedpotassium channels called the Gados channel. These irreversiblysickled cells are dehydrated and dense and will notreturn to normal when oxygenated. Sickling can produce:■ a shortened red cell survival■ impaired passage of cells through the microcirculation,leading to obstruction of small vessels and tissueinfarction.

Sickling is precipitated by infection, dehydration, cold, acidosisor hypoxia. In many cases the cause is unknown, butadhesion proteins on activated endothelial cells (VCAM-1)may play a causal role, particularly in vaso-occlusion whenrigid cells are trapped, facilitating polymerization. Hb Sreleases its oxygen to the tissues more easily than doesnormal Hb, and patients therefore feel well despite beinganaemic (except of course during crises or complications).Depending on the type of haemoglobin chain combinations,

three clinical syndromes occur

homozygous Hb SS have the most severe disease

■ combined heterozygosity (Hb SC) for Hb S and C who suffer intermediate symptoms

■ heterozygous Hb AS (sickle cell trait) have no symptoms

Clinical featuresVaso-occlusive crisesThe earliest presentation in the first few years of life is acutepain in the hands and feet (dactylitis) owing to vasoocclusion of the

small vessels. Severe pain in other bones,e.g. femur, humerus, vertebrae, ribs, pelvis, occurs in olderchildren/adults. These attacks vary in frequency from dailyto perhaps only once a year. Fever often accompanies thepain

Anaemia

Chronic haemolysis produces a stable haemoglobin level,

usually in the 6–8 g/dL range but an acute fall in the haemoglobin

level can occur owing to:

■ splenic sequestration

■ bone marrow aplasia

■ further haemolysis.

Splenic sequestrationVaso-occlusion produces an acute painful enlargement ofthe spleen. There is splenic pooling of red cells and hypovolaemia,leading in some to circulatory collapse and death.The condition occurs in childhood before multiple infarctionshave occurred. The latter eventually leads to a fibrotic nonfunctioningspleen. Liver sequestration can also occur.

Bone marrow aplasiaThis most commonly occurs following infection with erythrovirusB19, which invades proliferating erythroid progenitors.There is a rapid fall in haemoglobin with no reticulocytes inthe peripheral blood, because of the failure of erythropoiesisin the marrow.Haemolysis due to drugs, acute infection or associatedG6PD deficiency also occurs. Anaemia can also result fromfolate deficiency.

Long-term problemsIn adults, nearly every organ is involved eventually, aspatients survive longer with better treatment.Growth and development. Young children are short butregain their height by adulthood. However, they remain belowthe normal weight. There is often delayed sexual maturationwhich may require hormone therapy.Bones are a common site for vaso-occlusive episodes,leading to chronic infarcts. Avascular necrosis of hips, shoulders,compression of vertebrae and shortening of bones inthe hands and feet occur. These episodes are the commoncause for the painful crisis. Osteomyelitis is commoner insickle cell disease and is caused by Staphylococcus aureus,Staph. pneumoniae and salmonella .Occasionallyhip joint replacement may be required.

Infections are common in tissues susceptible to vasoocclusion,e.g. bones, lungs, kidneys.Respiratory. The acute chest syndrome occurs in up to

30% ,and pulmonary hypertension and chronic lung diseaseare the commonest cause of death in adults with sickle celldisease. The acute chest syndrome is caused by infection,fat embolism from necrotic bone marrow or pulmonaryinfarction due to sequestration of sickle cells. It comprisesshortness of breath, chest pain, hypoxia, and new chest Xraychanges due to consolidation. The presentation may begradual or very rapid, leading to death in a few hours. Initialmanagement is with pain relief, inspired oxygen, antibioticsand exchange transfusion to reduce the amount of Hb S to

>20% ;occasionally ventilation may be necessary. Infectionscan be due to chlamydia and mycoplasma, as well as Streptococcuspneumoniae.

Leg ulcers occur spontaneously (vaso-occlusive episodes)or following trauma and are usually over the medialor lateral malleoli. They often become infected and are quiteresistant to treatment, sometimes blood transfusion mayfacilitate ulcer healing.Cardiac problems occur, with cardiomegaly, arrhythmiasand iron overload cardiomyopathy. Myocardial infarctionsoccur due to thrombotic episodes which are not secondaryto atheroma.

Neurological complications occur in 25% of patients,with transient ischaemic attacks, fits, cerebral infarction,

cerebral haemorrhage and coma. Strokes occur in about11% of patients under 20 years of age. The most common

finding is obstruction of a distal intracranial internal carotidartery or a proximal middle cerebral artery. 10% of childrenwithout neurological signs or symptoms have abnormalblood-flow velocity indicative of clinically significant arterialstenosis; such patients have very high risk of stroke. It hasnow been demonstrated that if children with stenotic cranialartery lesions, as demonstrated on transcranial Dopplerultrasonography, are maintained on a regular programme oftransfusion that is designed to suppress erythropoiesis sothat no more than 30% of the circulating red cells are theirown, about 90% of strokes in such children could beprevented.

Cholelithiasis. Pigment stones occur as a result ofchronic haemolysis.Liver. Chronic hepatomegaly and liver dysfunction arecaused by trapping of sickle cells.Renal. Chronic tubulo-interstitial nephritis occursPriapism. An unwanted painful erection occurs fromvaso-occlusion and can be recurrent. This may result inimpotence. Treatment is with an α-adrenergic blocking drug,analgesia and hydration.Eye. Background retinopathy, proliferative retinopathy,vitreous haemorrhages and retinal detachments all occur.Regular yearly eye checks are required.Pregnancy. Impaired placental blood flow causes spontaneousabortion, intrauterine growth retardation, preeclampsiaand fetal death. Painful episodes, infections andsevere anaemia occur in the mother. Prophylactic transfusiondoes not improve fetal outcome. Oral contraceptives withlow-dose oestrogens are safe

Investigations ■Blood count. The level of Hb is in the range 6–8 g/dL

with a high reticulocyte count (10–20%). ■Blood films can show features of hyposplenism and

sickling. ■Sickle solubility test. A mixture of Hb S in a reducing

solution such as sodium dithionite gives a turbidappearance because of precipitation of Hb S, whereasnormal Hb gives a clear solution. A number ofcommercial kits such as Sickledex are available forrapid screening for the presence of Hb S, for examplebefore surgery in appropriate ethnic groups and in theA&E department.

■Hb electrophoresis is always needed toconfirm the diagnosis. There is no Hb A, 80–95% Hb SSand 2–20% Hb F.

■The parents of the affected child will show features ofsickle cell trait.

ManagementPrecipitating factors should be avoided or treatedquickly. The complications requiring inpatient managementAcute painful attacks require supportive therapy withintravenous fluids, and adequate analgesia. Oxygen and antibioticsare only given if specifically indicated. Crises can beextremely painful and require strong, usually narcotic, analgesia.

Morphine is the drug of choice. Milder pain can sometimesbe relieved by codeine, paracetamol and NSAIDs

Prophylaxis is with penicillin 500 mg daily and vaccinationwith polyvalent pneumococcal and Haemophilus influenzaetype B vaccine .Folic acid is given to all patientswith haemolysis.