POSTGRAD. MED. J., '(1965), 41, 624

HAEMOGLOBINOPATHIES IN IMMIGRANTFAMILIES

M. J. BEARD, M.R.C.P. (Edin.), M.C. Path. A. GORDON SIGNY, M.B., S.C. Path.Senior Registrar, Department of Haematology. Consultant Haematologist.

Group Laboratory,St. Stephen's Hospital, London, S.W.10.

MANY of the haemoglobinopathies occur almostexclusively in the negro races and howeverthese patients present clinically, the presence ofan abnormal haemoglobin can usually bequickly confirmed or excluded. When theseconditions occur in other racial groups such asIndians, Asians and in the Mediterraneancountries, then their presence may not be sus-pected so quickly and thus lead to confusionand unnecessary treatment.A knowledge of the geographical distribution

of the haemoglobinopathies is a useful guideto the probable abnormality which may existin the individual patient. The main facts arewell known but a few points are worthre-emphasizing.Haemoglobin S shows a main incidence in

people of African stock but it does alsooccur in some areas of Southern India.Thalassaemia was originally thought to beconcentrated in the Mediterranean but is nowknown to extend in a broad belt eastwardsand to have a high incidence in many Asiancountries. Thalassaemia is rare in many partsof Africa, fl-thalassaemia having been estimatedat 1 in 2,000 in Nigeria (Watson Williams, 1965).The wide distribution of these harmful genes

has led to investigations into possible balancingfavourable effects. It is now generally acceptedthat the sickle cell trait protects the beareragainst the lethal effects of P. falciparummalaria, and there is some evidence that thepresence of haemoglobin C trait may act in asimilar way.

It has been our experience that many of thepatients we see have, surprisingly, not beendiagnosed before their arrival in this country,but this will obviously become less commonas medical care becomes more widely available.The clinical difficulties are numerous and oneof the most important is the difficulty ofassessing anaemia in the darker skinned races.As the case reports show, many conditions maybe simulated and crises accompanied byabdominal or bone pain may be particularlyworrying if the underlying haemoglobinopathy

has not been previously diagnosed.The particular association of salmonella

osteomyelitis with sickle cell anaemia has beenwell documented (Van Oye, 1960).

Structure and Inheritance of HaemoglobinHaemoglobin is a chromoprotein with a

probable molecular weight of 64,458. Thethree dimensional structure of its 4 polypeptidechains and its 4 haem groups has been exten-sively studied. Each a chain has been foundto contain 141 amino-acid residues and each f8chain 146. These chains are folded and coiledin a complex arrangement to each other withcross-binding hydrogen bonds to increasestability. The haem moiety is thought to benear the surface of the molecule with its ironforming a bond with the amino-acid histidineof its corresponding polypeptide chain. Theexact mechanism whereby this complexstructure enables haemoglobin to undertake itsoxygen-carrying functions remains unknown.

In addition to haemoglobin A, two otherhaemoglobins occur in normal adults, foetalhaemoglobin with 2 a chains and 2 y chainsand haemoglobin A2 with 2 y chains and 2 8chains. Both y and 8 chains show close simi-larities to , chains in their amino acidsequences. Foetal haemoglobin is resistant toalkali and in the adult less than 2% is present,the exact amount recorded depending upon thetechnique used. Haemoglobin A2 shows a meanvalue of 2.5% when the most accurate tech-niques are employed. There is evidence that thelevel of foetal haemoglobin in the adult isunder independent control and the familialcondition of hereditary persistence of high foetalhaemoglobin supports this. In this condition,there is no anaemia and no change in red cellmorphology, but a considerable increase in the%/O of foetal haemoglobin.Most abnormal haemoglobins are charac-

terised by the substitution of just one amino-acid in either the a or the p chain. Mostcommonly the substitution occurs in the p

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BEARD and SIGNY: Haemoglobinopathies

chain whereas a chain substitution is less com-mon. The effects of this amino-acid replacementseems to depend mainly on the nature of thenew amino-acid and its position in the poly-peptide chain. Thus the replacement of just2 out of 574 amino-acids may lead on the onehand to severe disease with a high mortalityand on the other to no detectable clinicalabnormality. The overall changes in theelectrical charge of the molecule that occur asa result of its altered amino-acid content areparticularly important.

The common abnormal haemoglobins S, C, Eand D are all inherited as Mendeliandominants. The severity of illness associatedwith the homozygous state varies but hetero-zygote are nearly always symptom free. How-ever, in thalassaemia a heterozygote mayshow a mild or moderate anaemia andsome studies have suggested that the sicklecell trait may not be so benign as it is usuallyassumed to be. In the sickle trait, haematuria,splenic infarction and abscess, hip joint changesand osteomyelitis have all been recorded. Theunderlying defects and mode of inheritance ofthalassaemia are extremely complex and anexplanation 'based on multiple genetic defects,which are usually inherited together but maybe transmitted independently, seems best ableto explain the varied clinical picture. Inthalassaemia, no abnormal haemoglobin hasbeen identified and the anaemia is thought to re-sult from a partial or complete suppression ofone of the pairs of polypeptide chains ofhaemoglobin A. The , chain is more commonlyinvolved than the a chain and when demon-strated the cases are referred to as either a or,B thalassaemia.The production of a and /8 chains is under

independent genetic control and each individualinherits genes controlling the nature of thesechains from both parents. The inheritance ofan a chain defect from one parent with a /8chain defect from the other, could then leadto the presence of up to four haemoglobins inthe one individual. Cases illustrating this havebeen recorded (Raper, Gammack, Huenns andShooter, 1960; Hall-Craggs, Marsen, Raper,Lehmann and Beale, 1964) and they provideexcellent support for the present genetic theoryof haemoglobin production. It is also interestingto note that the polypeptide chains always occurin identical pairs and mixed mole-cules such as aAaA//3AflS do not occur. It hasthus been postulated that biosynthesis of thesechains occurs in pairs or that identical chains

are paired before they contact unlike chains(Itano and Robinson, 1959).

Effects on the BloodIn the homozygous state the effects of an

amino-acid substitution in the polypeptidechains vary greatly. Almost always somemorphological change is seen in the red cells,target cells being seen in many instances.The altered physical properties of haemoglobinS provide a basis for the clinical picture indiseases associated with this abnormal haemo-globin. Oxyhaemoglobin A and S have thesame solubility but whereas the solubility ofhaemoglobin A falls by half on deoxygenation,the solubility of haemoglobin S falls by 50times. Thus when deoxygenated, and also whenthe pH falls, haemoglobin S forms a semisolidgel within the red cell producing the characteris-tic sickle or holly-leaf deformity. The easewith which this gel is formed is related to theconcentration of haemoglobin S in the cell.The concentration of S is 80-100% in sicklecell anaemia, 50-60% in haemoglobin S-Cdisease and 20-40% in sickle trait and this formsthe basis for their differing clinical severity.Deoxygenation or fall in pH causes sicklingwhich results in increased blood viscosity.Vascular stasis leads to the estagblishment of avicious circle ending in thrombosis andinfarction.Most of the abnormal haemoglobins in the

homozygote produce a haemolytic state ofvariable severity but substitution in the histidylamino-acid linking haem to the polypeptidechain, may affect the oxygen carrying abilityof the molecule and this forms one type ofinherited methaemoglobinaemia. In thalas-saemia variable suppression of haemoglobin Aoccurs and deformed, hypochromic red cellsare produced, the anaemia being a combinationof defective production and shortened red celllife.

Screening TestsExamination of the blood film will almost

always reveal some abnormalities but cannotbe relied upon to exclude a haemoglobinopathy.Target cells are common and are seen ingreatest numbers in haemoglobin C disease.Sickle cells may be seen on the stained filmand if they are, this nearly always indicateseither sickle cell anaemia, or the S-C;S-thalassaemia combinations. The hypochro-masia of thalassaemia is easily confused withiron deficiency but in iron deficiency theMCHC is more markedly reduced whereas in

October, 1965 625

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626 POSTGRADUATE MEDICAL JOURNAL October, 1965

RED CELL OSMOTIC FRAGILITY

00 ___-_ C-ca5.!-6O Homozygous\\Thalassaemka-case I.

N20 A-2

02 0NACL304 5-6PER 070CEN 09NACL - PER CENT

FIG. 1.-Fragility curves.

thalassaemia target cells, punctate basophilia,nucleated red cells, and polychromasia may alsobe seen. An increased resistance to hypotonicsaline (i.e. shift to left in fragility curve) (Fig. 1)is frequently found, but again is of little useas a screening procedure. Except perhaps inthalassaemia, haemoglobin S can be detectedby the in vitro sickling test.

Electrophoresis forms the basis for detectionof abnormal haemoglobins in the hospitallaboratory. Many technical variations have beenemployed, but the use of cellulose acetate asa quick screening method together with starch-gel electrophoresis for more critical studies is auseful combination. (Fig. 2). Starch-gel electro-phoresis is probably the best method ofseparating haemoglobin A2, and this is ofgreat importance in the diagnosis of thalas-saemia carriers. Using a starch gel the amountof haemoglobin A2 in normals is about 2.5%,whereas in over 90% of thalassaemia carriers,values of about 5% are found. It is importantto remember that haemoglobin electrophoresismay have to be carried out using differentbuffers and at differing pH before some of theabnormal haemoglobins can be detected.

Alkali resistant haemoglobin may also beestimated by a number of techniques. Singer'stechnique (Singer, Chemoff and Singer, 1951)is most commonly used but is unreliable indetecting values below 2%. The fact that onlyabout 50%/ of thalassaemia carriers will showa raised foetal haemoglobin emphasises thegreater value of haemoglobin A2 estimation inthis context.More recently extremely interesting results

have been obtained from techniques which candemonstrate the distribution of some normaland abnormal haemoglobins in the red cellpopulation. An example of this is the techniqueof Betke and Kleihauer (1958) for foetal

haemoglobin. This has demonstrated that inhereditary persistence of high foetal haemo-globin, haemoglobin F is evenly distributed inall red cells, whereas in sickle cell anaemia,foetal haemoglobin is present in only a minorityof the red cells and in amounts which varyfrom cell to cell. The application of this inthe precise diagnosis of sickle cell anaemia isdiscussed by Apthorp, Measday and Lehmann(1963).

Screening tests have been applied to largehospital populations and are being used inclinical anaemias with surprising results. Thusthe identification of thalassaemia in a familyof pure Scottish ancestry (Buchanan, Kinlock,Hutchinson, Pinkerton and Cassidy, 1963) andin the South of England (Roberts, 1963)demonstrate the value of these techniques. It isstrongly recommended that regular screeningtests for abnormal haemoglobin should 'be usedin the increased coloured population of thecountry-particularly as part of the routinetesting of pregnant women.

CASE I

I I I

Died aged Propositus Sibling2k aged 12 aged 10

Case no. 1. Thalassaemia MajorThe child was first seen at the age of three yearswhen he was found to be grossly anaemic.Family History: His parents are Cypriots. Theyhad lost one daughter at the age of 21 with

thalassaemia major and recurrent severe haemolyticcrises. The second child, a 'boy, is the patient heredescribed and they also have a third child, a boy,who only has the trait and is in perfectly good health.The father and the third child have no haemoglobinF, but raised A2, and the mother has both haemo-globin F (4.5%) and A2 raised. (See chart).On examination the spleen was 5 cm. ibelow thecostal margin. His haemoglobin was 3.6 g./100 ml.,MCHC 30%, the blood film was hypochromic withmoderate numbers of target cells. Reticulocytes 4%.Haemoglobin F level 70%. No abnormal haemo-globins present, and the haemoglobin A2 content wasnot increased. iBlood from his father showed a fewtarget cells 'but a normal fragility and no hypo-chromasia. Haemoglobin F was not detected, butthe haemoglobin A2 raised. Blood from his motherwas hypochromic with an abnormal red cell fragility.Haemoglobin F 4.5%, haemoglobin A2 raised.

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October, 1965 BEARD and SIGNY: Haemoglobinopathies 627

.:; l.' ,:·' ···: i.:

88 !0 98............... -i::B.B :l8:,lilgijiii%Ziiii ... l'

FIG. 2.-Abnormal haemoglobins. Starch gel electrophoresis.

This child is now 12 years old and has required160 pints of blood during the past 9 years withincreasing frequency, in an attempt to maintainhaemoglobin level at 7 g./100 ml., and transfusionhas to be instituted when it falls to below 4 g./100 ml.He leads a moderately normal life between, but isvery resentful of the regular hospitalisation for bloodtransfusion. Iron chelating agents are being usedin an attempt to minimise the inevitable iron over-load. His illness has caused many difficulties andmuch distress for his family. In an attempt to reducehis transfusion requirements the advisability ofsplenectomy was now considered, his spleen being8 cm. below the costal margin. It was performed on29.7.65. Haemolysis was demonstrated by radioactivechromium studies. The red cell half life of a mixedpopulation of .red cells '(chromium 51) was 19 dayswith some excess accumulation of activity over thesplenic area rbefore the operation.Comment: The suffering of both patient and parents

that occurs in the clinically severe haemoglobino-pathies is shown in this case. The advisability ofsplenectomy should be considered in every case ofthalassaemia with a high transfusion requirement.The problem of iron overload should be tackled asearly as possible, the easiest way being to incorporatea chelating agent in the transfused blood.Case no. 2. Thalassaemia Trait

This lady was 73 when she was admitted forre-evaluation in 1964. She was of mixed Irish andPakistan extraction. She had had a hypochromicanaemia for 20 years which had not responded toiron therapy. For the past 7 years she had beentroubled by recurrent urinary tract infections.A diagnosis of thalassaemia trait was suggested by

the following findings:Haemoglobin 9.0 g./100 ml. MCHC 31%. Reti-

culocytes 2-3%. Red cells showed fairly markedhypochromasia with moderate punctate basophilia.The degree of hypochromasia was felt to be toomarked to be explained by chronic infection alone.Red cells showed an increased resistance to hypotonicsaline. Serum iron normal. Bone marrow showed anerythroid hyperplasia and an increase in stainableiron, but only a slight increase in sideroblasts andno ring sideroblasts were present. Haemoglobin F.was not detected but haemoglobin A2 level raisedto 5%.

Despite her recurrent urinary infections, her bloodurea remains normal. Her urinary infection is nowbeing treated with long term antibiotics. The familyhave so far resisted attempts to confirm the diagnosisbeyond all doubt.

Case no. 3. Thalassaemia CarrierThis Greek Cypriot lady was 32 when seen in

July 1964. She was six months pregnant and had hada small ante partum haemorrhage. She was anaemicwith a haemoglobin of 8.8 g./100 ml. Reticulocytes3%, MCHC 30%. The blood film showing moderatehypochromasia with fairly marked punctate basophilia.The haemoglobin remained unchanged and thereticulocytes slightly raised despite adequate oraland parenteral iron therapy followed by folic acid.The possibility of thalassaemia was then consideredand although the foetal haemoglobin was not raised,the haemoglobin A2 fraction was elevated. Sheeventually required caesarian section for placenta-praevia. Six weeks after delivery her haemoglobinwas 11.0 g./100 ml.Her past obstetric history showed pregnancies in

1955 and 1957 'both supervised at a London teachinghospital. On each occasion the haemoglobin wasrecorded as 60% and the blood film hypochromic;oral and parenteral iron were given but no recordof the response made.The diagnosis of thalassaemia carrier is beingestablished by family studies.Comment: The difficulty of diagnosing thalassaemia

carriers is well recognised. The much greater value ofhaemoglobin A2 estimation as opposed to haemoglobinF. estimation as a screening procedure is illustratedhere. The precipitation of anaemia by the pregnancyand the return of the haemoglobin to near normalvalues after delivery are also worth noting.In Case 2, the patient has taken large quantitiesof iron unnecessarily for about 20 years. It is likelyalso that the degree of anaemia has been made moresevere by the constant urinary tract infection.These two cases illustrate the variable haemoglobinlevel that may be found in the thalassaemia trait and

its fluctuation in association with conditions that mayput stress on the bone marrow.The near impossibility of adequate family studies

in an immigrant community makes full investigationof this aspect of haemoglobinopathies difficult in thiscountry. The difficulty of establishing the diagnosisof the thalassaemia trait makes family studies moreimportant than in some of the other more easilydiagnosed haemoglobinopathies.Case no. 4. Haemoglobin C Disease

This 26 years old West Indian lady attended theantenatal clinic in 1962 when she was 5 monthspregnant. She was symptom-free and said she hadbeen in good health all her life. She had had threeprevious pregnancies in Barbados and all had beenapparently normal.

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628 POSTGRADUATE MEDICAL JOURNAL October, 1965

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FIG. 3.-Homozygous C disease. Target cells withmicrospherocytes.

On examination her spleen was just palpable andafter delivery it was felt 3 cm. below the costalmargin.The haemoglobin varied between 8 and 10 g./100

ml. and the reticulocytes were 4%. The blood filmshowed many target cells and moderate numbers ofmicrospherocytes. (Fig. 3). Haemoglobin electro-phoresis showed haemoglobin C only, foetal haemo-globin not being detected. No family studies werepossible.Comment: This patient was homozygous for

haemoglobin C and shows how mild this particulardefect may be clinically.Case no. 5. Sickle Cell Anaemia

This lady was 31 when she presented in 1963.She came from Sierra Leone. She complained ofrecurrent ulceration of the left leg since 1956. Therewas a past history of typhoid in 1955 and in 1956she had a long illness with much pain in the left leg.The ulceration developed subsequent to this latterillness. Since 1956 she had been in good generalhealth.On examination she was jaundiced and anaemic.

The ulcer was about 3 cm. in diameter, surroundedby scar tissue and situated over the medial aspectof the left tibia just above the ankle joint. X-rayexamination of the left leg showed an old osteomye-litis of the fibula mainly of its middle third with crossunion between it and the tibia. (Fig. 4). There was thusno obvious direct connection between the skinulceration and the old osteomyelitis. A swab fromthe ulcer grew staphylococcus aureus sensitive topenicillin.The spleen was just palpable. A loud ejection

systolic murmur was heard over the entire precordium.Chest X-ray revealed marked cardiac enlargement.The haemoglobin was 9.0 g./100 ml. and the

reticulocytes 11%. The blood film showed fairnumbers of sickle cells and occasional target cells.(Fig. 5). Haemoglobin electrophoresis revealed onlyhaemoglobin S; alkali denaturation gave a foetalhaemoglobin of 3.9%.The ulcer healed with bed rest and she was dis-

charged symptom free. The cardiac enlargement andmurmur were thought to Ibe an example of the cardiaccomplications which may occur in sickle cell anaemia.She was seen again in 1964 when she was 4 months

pregnant. Her haemoglobin now gradually fell to7.5 g./100 ml. and the reticulocytes showed a tendency

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BEARD and SIGNY:

to rise averaging 25% in late pregnancy. Duringpregnancy she was easily tired and required severaladmissions to hospital for rest. She was digitalisedwhen 8 months pregnant as there had been evidenceof congestive cardiac failure. For the last 4 monthsof pregnancy she had been taking 20 mg. of folicacid daily. Delivery and subsequent progress ofmother and child were normal. Three months afterdelivery she returned to Africa. During and afterthe pregnancy the spleen could not now be felt.Comment: This case is interesting for the mild

clinical state despite the fairly severe haemolyticanaemia. The history suggests that this may havebeen an example of salmonellae osteomyelitis althoughS. typhi is only very rarely isolated from these cases.Salmonellae of the food poisoning type (i.e. typhi-murium) are usually involved and emphasize howdangerous a relatively benign enteritis may be forpatients with sickle cell disease. The complete absenceof any crises is also an unusual feature.The possible decrease in spleen size may be

observer error. However in America the spleen israrely reported as being palpable in sickle cellanaemia and this contrasts with the fairly frequentsplenomegaly reported in 50-80% of cases seen inAfrica. There is evidence that spleen size in thiscondition may be partly related to co-existing malarialinfection, or to repeated infarctions.Case no. 6. Sickle Cell Anaemia

This patient also came from Sierra Leone and firstpresented in 1951 at the age of 26. He complainedof intermittent yellowness of the eyes for 12 years.There was a past history of malaria as a child. Hishaemoglobin Iwas 7.4 g./100 ml., reticulocytes 19%,and many sickle cells were seen on the blood film.The bilirubin varied between 2.6 and 9.0 mg./100 ml.Haemoglobin electrophoresis established the diagnosisof homozygous sickle cell disease, the haemoglobin F.level not being increased.Over the next 6 years his clinical course was

extremely episodic, he remained anaemic and jaun-diced throughout ibut his degree of jaundice fluctuated.He had several crises. A typical one occurred in1957 when he was admitted to hospital with a 4-dayhistory of pain and swelling of the interphalangealjoints and the left ankle, together with fever andheadache. On examination he was jaundiced andanaemic. Temperature was 1030F. Slightly enlargedglands were present in axillae and groins. Thesesymptoms and signs gradually subsided over thefollowing two weeks. In other crises unexplainedabdominal pain was a prominent feature.

In 1953 priapism associated with thrombosis ofthe dorsal vein of the penis was troublesome. For aperid of about 3 weeks late in 1953 an ulcer 5 cm.in diameter appeared just above the right ankle, butthis cleared spontaneously. An X-ray in 1957 showedavascular necrosis of the left femoral head. Hereturned to Africa in December 1957. Family studieswere not possible.Comment: Many features of sickle cell disease are

shown by this patient. The recurrent crises with joint,bone, and abdominal pain, priapism, avascularnecrosis of the femoral head, and leg ulceration wereall seen at some stage.Case no. 7. Haemoglobin S-C DiseaseThe patient was a male aged 48 from the West

Indies. When he presented in December 1964, he hadhad pain in the right side of the chest with apersistent cough and shortness of breath for oneweek. He gave a past medical history of pneumoniain 1954 and June 1964, but apart from this he had

October, 1965 Haemoglobinopathies 629

been in good health all his life. Hb. 12.0 g.%,retics 5%. Electrophoresis shows S-C. haemoglobinpattern.No firm diagnosis was made, but he was thought

to have either pneumonia or pulmonary infarction andthe X-ray shadowing gradually returned to normal.Four days after admission he complained of pain inthe right calf and this was due to deep veinthrombosis.Apart from some residual pain in the right leg he

is now in good health.Comment: This patient has been in good health

almost all his life, with nothing to suggest a crisis atany time. It has been suggested that there may bean increased incidence of venous thrombosis andpulmonary embolism in haemoglobin S-C disease butthis remains unproven. It seems likely that in boththis case and in case 8, pulmonary infarction occurred.Case no. 8This lady from Barbados was 39 when she attended

the antenatal clinic in 1963. She was 11 weekspregnant and gave a past history of a normalpregnancy in 1947, but miscarriages at 22 and 24weeks in 1961 and 1962. In 1962 she had toxaemiaand a right lower lobe pneumonia which was resistantto antibiotics but after the spontaneous delivery of amacerated foetus she rapidly returned to normalhealth. During these admissions the haemoglobin was11 to 12 g./100 ml., the reticulocytes between 2 and11 %. Haemoglobin electrophoresis showed S. and C.haemoglobins, only foetal haemoglobin not beingdetected.The present pregnancy proceeded normally until

the onset of vaginal bleeding at 24 weeks and whenshe was admitted to hospital it was found she alsohad a left lower lobe pneumonia and a urinaryinfection. Again the chest infection proved resistantto antibiotics and after admission she had an episodeof haemoptysis. After several weeks she was deliveredof a macerated foetus with subsequent clinicalimprovement. To prevent further pregnancies, bilateralsalpingectomy was performed.Comment: This patient with S-C disease suffered

three successive miscarriages all at about six months,althought some years previously she had had a normalpregnancy. There were no demonstrable antibodiespresent in her blood. The usual resistance of thechest condition to antibiotics, together with thehaemoptysis and radiological appearances made pul-monary infarction the most likely diagnosis, althoughunlike Case 7 no evidence of peripheral venousthrombosis could be found. The association of S-Cdisease with an increased incidence of abortion is wellrecognised. (Curtis, 1959).PrognosisThe prognosis of these conditions varies

enormously. In many the exact prognosis isdifficult to assess. The general level of healthand nutrition and the amount of medical careavailable will vary from country to country,and these factors will significantly affect theprognosis. This may partly or wholly explainthe poorer prognosis for sickle cell anaemiain Africa when compared with the SouthernStates of America. There is good reason tohope that with the improvement in livingstandards and medical care the overall prognosiswill improve.

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Sickle cell anaemia, thalassaemia and thevarious combinations of S with other defects asin S-C disease and S-thalassaemia, make upnearly all the severely affected patients. It isimpossible to generalise concerning the prog-nosis in the thalassaemias. In homozygotesmany cases are severely affected even leadingto death in utero or hydrops foetalis. However,cases which are clinically mild also occur.Fessas (1963) discussed the very complicatedproblem of classification of thalassaemia and itsrelation to the prognosis in the individual case.

Sickle cell anaemia has a poor prognosis,many patients dying in the first decade and thisis reflected in statistics from Leopoldville, whereout of 1,879 sickle cell anaemias only 15 wereover 18 years of age (Vandepitte and Stijns,1963).Although the prognosis in haemoglobin S-C

disease is better than in sickle cell anaemia,crises may occur and pregnancy is thought tobe particularly hazardous. The maternalmortality in two large series was 21.6%(Eisenstein, Posner and Friedman, 1956) and10% (Fullerton, Hendrickse and Watson-Williams, 1963). Improvements in managementintroduced by Fullerton and others considerablylowered their mortality rate in the later part oftheir series.PreventionThe theoretical possibility of prevention of

sickle cell anaemia and other homozygous statesby controlling marriage between affected carriersis generally held to be impracticable. If themain benefit conferred by the sickle gene is adegree of protection against malaria, then withthe control of malaria in many parts of theworld, the incidence of the sickle gene willgradually fall. However, it may be important tothe individual to know whether he carries anyof these abnormalities as he may choose toavoid a marriage which might result in thebirth of severely affected children, but this isno more likely than the avoidance of an Rh.positive partner by a Rh. negative woman!

Modification of the disease in the neonateby marrow infusions from normal donors isan attractive possibility. The survival of onlya few cells capable of producing haemoglobinA might significantly influence the developmentof severe sickle cell anaemia or thalassaemiamajor. Many difficulties must be overcomebefore this becomes a reality. Relatively littleis known about the immunologic reactivity ofthe neonate and furthermore the precise diag-nosis of the homozygous state is often extremelydifficult at birth.

TreatmentThere is much that can be done to prolong

life and reduce suffering and often an undulypessimistic view is taken of therapy. The useof transfusions in correcting anaemia will varyfrom patient to patient, but many do not requireblood unless the haemoglobin falls below 6g./100 ml. Exchange transfusions have beenused in treating crises occurring in pregnancycomplicated by haemoglobin S-C disease. Folicacid therapy has been shown to increase thehaemoglobin levels in an appreciable numberof patients with sickle cell anaemia in Africa.It has also been used in the treatment of crisesin which depletion of folic acid may occur, andin the common megaloblastic anaemia ofpregnancy in haemoglobin S-C disease. In factshould pregnancy occur in any woman withmoderate or severe haemoglobinopathy, folicacid should be given prophylactically as earlyas possible in the pregnancy. There is evidencethat in Africa, physical immaturity in patientswith severe disease may be considerablyimproved by long term folic acid therapy. Thebeneficial effect of folic acid in Africa may bepartly related to the lower dietary intake offolic acid in many of the population.

Crises require symptomatic treatment, but inaddition antibiotics and folic acid should begiven. Heparin has been used in sickle cellanaemia and haemoglobin S-C disease and wasthought to be beneficial particularly in crisesassociated with bone pain. Although theduration of the pain was unchanged, the therapywas thought to have reduced the death rate(Fullerton and others, 1963). Apthorp andothers (1963) advocate the use of magnesiumsulphate and sodium bicarbonate in dosessufficient to keep the urine alkaline and con-sider that this reduces the frequency and severitvof crises in sickle cell anaemia. The unpredic-table nature and frequency of these crises,which may occur in most chronic haemolyticstates, makes it very difficult however to assessthe value of therapeutic agents. It has beenestablished that anaesthesia is dangerous insickle cell ,anaemia, but in the sickle cell traitits effects have still to be assessed. In anypatient with sickle cell anaemia, sickle cell traitor haemoglobin S combined with some otherabnormality, the use of tourniquets at any timemust be avoided.

Splenectomy may have to be considered inthalassaemia (see Case 1) and careful pre-operative assessment is essential (Smith,Erlandson, Stern and Schulman, 1960). Sub-stantial reduction in transfusion requirements

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have been recorded after splenectomy inproperly selected cases, but against this mustbe balanced the risks of the operation and thepossible subsequent death from overwhelmingsepsis. Several such cases have been recordedmostly some appreciable time after theoperation, but the exact risk is difficult toassess.

Chelating agents should prove valuable inpreventing the iron overload in those casesrequiring frequent transfusions. It is essentialto start this treatment early rather than waituntil a state of iron overload exists.

Finally it is important to stress the need tomaintain good general health and an adequatedietary intake. There is good evidence thatincreased amounts of folic acid are requiredparticularly by the more severely affectedpatients and the ease with which they maybecome folic acid deficient will obviously berelated to their dietary intake.

Glucose-6-Phosphate Dehydrogenase DeficiencyG 1 u c o s e - 6 - phosphate dehydrogenase

(G.6.P.D.) deficiency has been estimated toaffect roughly 100 million people. Its irregulargeographical distribution closely parallels boththe frequency of the sickle cell gene and thedistribution of falciparum malaria. Thedeficiency can be subdivided into two maingroups, the "negro" and the "non-negro". Thenegro type has an incidence of around 10% inthe American negro and probably about thesame level in the West Indian islands. In WestAfrica and the Congo the incidence averagesabout 20% although much lower frequenciesare seen in the South African Bantu and it isvirtually absent among Ethiopians. The non-negro group is widely distributed in manyMediterranean countries, particularly Greece,Italy, Sardinia and among certain Jewish groups.High incidences (up to 70%) have been foundin Jews from Kurdistan, Iraq and Persia, butlow incidences among European Jews (0.4%/0)and North African Jews. Further East G.6.P.D.deficiency has been recorded in India, Chinaand the East Indies and there is a high incidencein Thailand. A number of fundamentaldifferences exist between the negro and non-negro groups. Electrophoretic studies on theG.6.P.D. enzyme itself have shown differencesboth in enzyme-deficient and normal individualsfrom these two racial groups. Furthermore thedecrease in enzyme activity is much moremarked in the non-negro group and this cor-relates with the more severe clinical effects inthis group. The mode of inheritance is thowever

the same in the two groups, being X-linked,affected males and homozygous females show-ing similar decreases in enzyme activity withheterozygous females having a less markeddecrease.

Clinically a number of syndromes are as-sociated with G.6.P.D. deficiency and theseinclude drug-induced haemolysis, haemolysiscaused by various foods, neonatal jaundice,haemolysis occurring during infections and afew cases which have been classified as heredi-tary non-spherocytic haemolytic anaemia. Thecommoner drugs to cause haemolysis includechloroquine and primaquine, certain sulphona-mides such as sulphanilamide and sulphathi-azole, probenecid and water-soluble analoguesof vitamin K. A more complete list is given byMotulsky (1965) and detailed studies of theeffects of various drugs have been done by anumber of investigators including Tarlov,Bremmer, Carson and Alding (1962). The foodinvolved is invariably fava beans, but othervegetables may have some clinical significance.A knowledge of the geographical distributionand the precipitating factors of G.6.P.D. de-ficiency will enable the clinician to advise thepatient on how to avoid many of its harmfuleffects. It is of great importance to explainto the patient the nature of this defect and togive him a list of precipitating factors.

Case ReportMrs. C. A. was a Nigerian aged 28. Six daysbefore admission she developed pain in the rightside of the abdomen and some dysuria. The nextday she became febrile, had several rigors and herurine darkened in colour. Three days before admis-sion dysuria and abdominal pain persisted and she

was seen by her general practitioner who thoughtshe had a urinary infection and gave her furadantin.The day before admission she still had abdominalpain and remained pyrexial and had developed painin both shoulders.On admission her temperature was 99'F., she wasjaundiced, the liver was tender and the edge felt3 cm. below the costal margin. There was also ten-derness in the right iliac fossa. A clinical diagnosisof infective hepatitis was made.Investigations however, gave the following results:Hb. 8.8 g./100 ml., WBC 15,000 with a polymorphleucocytosis, the red cells showing slight poly-chromasia with a fair number of target cells.Bilirubin 5 mg./100 ml. with a strong positive directreaction. Thymol turbidity 2 units, zinc sulphateturbidity 3 units, alkaline phosphatase 150 units,SGPT 30 units. Plasma proteins normal. The urine

showed many pus cells and cultures grew E. coli.Blood urea 70 mg./100 ml.Two days after admission her haemoglobin had

fallen to 4.5 g. /100 ml. with 35,000 white cells in mm.mainly polymorphs and metamyelocytes. 3.5%reticulocytes and many nucleated red cells were pre-sent in the blood smear. Malarial parasites were not

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seen. Bone marrow examination revealed anerythroid hyperplasia with a normal iron content.By this time, the bilirubin and alkaline phosphatasehad fallen to just within the normal range. Red cellG.6.P.D. activity gave results within the normalrange.She was given four pints of packed cells and

courses of ampicillin and tetracycline. Two days afterthe transfusion the urea had fallen to 29 mg. /100 ml.Her haemoglobin gradually returned to normal, thereticulocytes reached a peak of 7% three days afterthe transfusion, and she rapidly became symptomfree. Subsequent tests showed that she carried thehemoglobin C trait. the red cell survival was normal.Cholecystogram normal. Repeat red cell G.6.P.D.estimation two months after the end of her illness,showed an enzyme level decreased to approximately50% of the lower range of normal.Comment

Mrs. C. A. is almost certainly heterozygous forG.6.P.D. deficiency, although no family studies weredone. The original normal G.6.P.D. estimated whichwas obtained in the middle of the haemolytic episodeemphasizes the need for repeated tests well after thehaemolysis has subsided in order to detect milderdegres of enzyme deficiency. A comibination ofurinary infection and treatment with a nitrofurantoinmust have precipitated the haemolysis but the picturewas complicated by a number of unusual features.The haemoglobin fell to a surprisingly low level. Theenlarged and tender liver with an obstructive picturein the liver function tests implied that liver dysfunc-tion was a least playing some part in the productionof her jaundice. The appearances of her blood filmswith evidence of haemolysis together with target cellssuggested initially that this was a crisis occuring inone of the homozygous haemoglobinopathies, butthis was disproved by haemoglobin electrophoresis.This patient also emphasizes the need to estimate theG.6.P.D. when the reticulocytes have fallen to nearernormal levels after the haemolytic episode.

Clinical FeaturesThe self-limiting haemolytic episode with

jaundice, anaemia, reticulocytosis and perhapshaemoglobinuria is fairly easy to recognise andonly certain aspects will be considered in greaterdetail. As already stated the cl;inical severityparallels the degree of enzyme deficiency andtherefore non-negro racial groups will be themore markedly affected. Perhaps as an exampleof this, neonatal jaundice has not yet beenshown to be related to G.6.P.D. deficiency innegro infants and neither has favism been de-finitely proved to occur in negroes, whereasin the non-negro groups they are importantmanifestations of G.6.P.D. deficiency. It isrecognised that favism is often more severe thanan episode of drug-induced haemolysis and itis commonly assumed that in favism some ad-ditional unidentified factor is involved.

In drug-induced haemolytic episodes, thedisease for which the drug was given may mergewith the haemolysis producing a complicatedclinical picture. In addition, certain infections,

both bacterial and viral, may themselves pro-duce haemolysis in enzyme-deficient subjects.The importance of the dose of the drug usedhas been emphasized in several studies. Innegro infants, Zinkham (1963) showed that2.5 mg. of Synkavit will not cause any detectablehaemolysis. Primaquine usually fails to produceany in G.6.P.D. deficient negroes in a dosageof less than 15 mg. per day, whereas 30 mg.daily will induce severe haemolysis. Nitro-furantoin in normal doses (400 mg./day) hasbeen shown to produce only slight effect, where-as double the normal dose will induce severehaemolysis. One must constantly bear in mindthe differences between the two G.6.P.D. de-ficient groups, the negro and the non-negro,as results of investigations on one group do notnecessarily apply to the other due to the differ-ing degree of enzyme deficiency.

Finally among Northern Europeans andJapanese a very rare G.6.P.D. deficiency mayoccur which results in a chronic haemolyticstate which was originally classified in theType I group of Hereditary Non-spherocyticHaemolytic Anaemias.

Laboratory TestsDirect estimation of G.6.P.D. activlty by ultra-

violet spectrophotometry has been widely usedbut more simple procedures to detect thisenzyme deficiency have been developed. Mostof these procedures will diagnose accuratelyaffected males and homozygous females, butwill not detect differing percentages in anygroup of heterozygous females. In routineclinical practice a method should be used whichwill detect the majority of female heterozygotes.The Heinz body induction test is too in-

accurate. The glutatbione stability test failsto detect adequate numbers of female hetero-zygotes. However, Heinz bodies will occurtransiently during the haemolytic episode andshould lbe 'looked for in the reticulocyte prepara-tions. The two tests which have -been mostwidely used are the brilliant Cresyl Blue testof Motulsky and Campbell-Kraut '(1961) andthe methaemoglobin reduction test of Brewer,Tarlov and Alving (1960). For routine hospitalpractice the methaemoglobin reduction test isprobably the method of choice if direct estima-tion of enzyme activity is not practicable.With this test one should be able to detectapproximately 80% of female heterozygotes.Normal subjects will show 0 to 5%10 methaemo-globin whereas enzyme deficient subjects willrange from 5 to 9.5%/o according to the severityof the deficiency.

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October, 1965 BEARD and SIGNY: Haemoglobinopathies 633

We would like to thank the Physicians andObstetricians at the Hospitals in the Group for theirco-operation and permission to publish these cases,and Miss Celia Nelson for technical assistance anddrawings.

REFERENCESAPHmORP, G. M., MEASDAY, B., LEHMANN, H. (1963):Pregnancy in Sickle Cell Anaemia, Lancet, i, 1346.

BETKE, K., KLEIHAUER, E. (1958): Fetaler undBleibender Blutfarbstoff in Erythrozyzyten undErythroblasten von menschlichen Feten undNeugeborenen, Blut, 4, 241.

BREWER, G. J., TARLOV, A. R., and ALVING, A. S.(1960): Methaemoglobin Reduction Test, Bull.Wld. Hlth. Org., 22, 633.

BUCHANAN, K. D., KINLOCK, J. D., HUTCHINSON, H.E.,PINKERTON, P. D., and CASSIDY, P. (1963):Thalassaemia in Scots., J. clin. Path., 16, 6, 596.

CURTIS, E. M. (1959): Pregnancy in Sickle CellAnaemia, Sickle Cell-H.U.C. Disease and VariantsThereof, Amer. J. Obstet. Gynec., 77, 1312.

EISENSTEIN, M I., POSNER, A. C., and FRIEDMAN, S.(1956): Sickle Cell Anaemia in Pregnancy, Amer.J. Obstet. Gynec., 72, 622.

FESSAS, P. H., (1965): Forms of Thalassaemia.Abnormal Haemoglobins in Africa. p.71 C.I.O.M.S.Symposium, Oxford: Blackwells.

FULLERTON, W. T., HENDRICKSE, J.P. de V., WATSON-WILLIAMS, E. J. (1965): Haemoglobin S-C Diseasein Pregnancy. Abnormal Haemoglobins in Africa,p.411, C.I.O.M.S. Symposium, Oxford: Blackwells.

HALL-CRAGGS, M., MARSEN, P. D., RAPER, A. B.,LENHANN, H., BEALE, D. (1964): HomozygousSickle Cell Anaemia arising from Two DifferentHaemoglobins S., Brit. med. J., ii, 87.

ITANO, H. A. and ROBINSON, E. (1959): Propertiesand Inheritance of Haemoglobin by AsymmetricRecombination, Nature (Lond.)., 184, 1468.

MOTULSKY, A. G. (1965): Theoretical and ClinicalProblems of Glucose-6P:hosphate-DehydrogenaseDeficiency. Abnormal Haemoglobins in Africa,

p.143., C.I.OjM.S. Symposium, Oxford: Blackwells.MOTULSKY, A. G., and CAMPBELL KRAUT, J. M.

(1961): Population Genetics of Glucose-6-phos-phate Dehydrogenase Deficiency of the Red Cell.Poceedings of the Conference on Genetic Poly-morphisms and Geographic Variations in Diseasep.159, New York and London:: Grune andStratton.

RAPER, A. B., GAMMACK, D. B., HUENNS, E. R., andSHOOTER, E. M. (1960): Four Haemoglobins in oneIndividual, Brit. med. J., ii, 1257.

ROBERTS, P. D., (1963): The Thalassaemia Trait inan English Family, J. clin. Path., 16, 6, 593.

SINGER, K., CHERNOFF, A. I., SINGER, L. (1951):Studies on Abnormal Haemoglobins, I and II,Blood, 6, 413.

SMITH, C. H., ERLANDSON, M. E., STERN, G.,SCHULMAN, I. (1960): The Role of Splenectomy inthe Management of Thalassaemia, Blood, 15, 197.

TARLOV, A. R., BREWER, G. J., CARSON, P. E., andALVING, A. S. (1962): Primaquine, Sensitivity-Glucose-6-phosphate Dehydrogenase Deficiency, anInborn Error of Metabolism of Medical and Bio-logical Significance, Arch. intern. med., 109, 209.

VADERPITE, J., and STIJNS, J. (1965): Haemoglobin-opathies in the Congo (Leopoldville) and theRwanda4Burundi. Abnormal Haemoglobins inAfrica, p.321, C.I.O.M.S. Symposium, Oxford:Blackwells.

VAN OYE, E. (1960): Sur L'Association entreOst6omyelite a Salmonella et L'H6mglobin-opathie chez l'enfant Africain, Bull. Soc. Path.,Exot., 53, 89.

WATSON-WILLIAMS, E. J. (1965): Hereditary Persis-tence of Foetal Haemoglobin and Thalassaemia inNigerians. Abnormal Haemoglobins in Africa,p.264, C.I.O.M.S. Symposium, Oxford: Blackwells.

ZINKHAM, W. H. (1963): Peripheral Blood and Bili-rubin, Values in Normal Full Term PrimaquineSensitive Negro Infants: Effect of Vitamin K.,Paediatrics, 31, 983.

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December, 1965 Book Reviews 787

while Cumins contributes an interesting account oflipid changes in experimental and human demyelina-tions and some views on the pathogenesis. Depres-sive states are discussed by Pratt and Curzon. Inthe lecture on Genetic Mental Disorders, Slaterconcentrates on Wilson's disease, Schizophrenia andHuntington's chorea, while Richter gives a detailedaccount of the biochemical aspects of phenylketonuria,a comprehensive list of geneticailly determined meta-bolic disorders, and an lintesresting discussin onon therelation of -genes to enzymes.The editors are 'to be congratulated on this well

produced book, which is a mine lof useful informationand should prove as popular as its predecessor.Depression

A Cambridge Postgraduate Medical Course.Edited by E. BERESFORD DAVIES, M.A., M.D.,D.P.M. Pp. 378. Cambridge: University Press.1964. 90s.

This is a tape recording of a symposium held atCambridge lin 1959. lt has been splendidly edited byDr. Beresford Davies, who is the senior consultantpsyohialtrist Ito the United Cambridge Hospitals ,soas to be eminently readable and never dull, despiteits length.One hundred and ninety participated in the sym-

posium and among them were many of the mostprominent British psychiatrists including the late Dr.W. Mayer Gross, the late Professor A. Kennedy,Sir Aubrey Lewis, Professor E. Stengel and Dr. W.Sarganit, as well as a few representatives from othercountries. The symposium was divided into foursections-clinical, psychological, neuropharmaoologicaland therapeuitic and eadh section comprised three orfour main 'papers followed by Ithe detailed proceedingsof Ithree 'to five discussion groups. Every aspect ofdepression is covered and there can be no doubt thatthe 'book will be of value to all psychiatric con-sultants and trainees. Sir Aubrey Lewis' generalreview of depressive condictions and Dr. Sargant'spaper on 'the Iphysical treatments of depression deserveespecial mention. One cannot help feeling, however,that had all the discussion group proceedings beenomitted and the book reduced to the main papers litwould 'have commanded a very wide circulation.As it is irts price is so high and its size lis so formid-able ithait is will not commend itself to generalphysicians or general practitioners. A furtherdifficulty is that publioa'tilon was not possible untilfive years after Ithe symposium took place and duringthat five years a host of new antidepressant drugshave become available.

Elastolysis and AgeingDAVID A. HALL. Pp. xiii+160 illustrated. Spring-

field, Illinois: Charles C. Thomas. 1964. Price$6.75.

This monograph in the American Lecture Series iswritten by the leader of the elastic tissue researchgroup at Leeds University.

In it Dr. Hall summarises what is known of thestructure and biochemistry of elastic tissue and itschanges with age.

Elastin, unlike collagen, has no characteristic X-raydiffraction patterns or electron microscopic appear-ances. It cannot therefore be studied by physicalmeans and chemical methods are essential. Theprincipal technique has been the study of elastolysis,the name given to the new breakdown of elastin bythe pancreatic enzymes, elastase and elastolipopro-teinase.

Dr. Hall first reviews the properties of elastin itself.He then discusses the enzymes causing elastolysis andthe substances which inhibit their action in vitro andin vivo. In a final chapter he discusses elastolysis inrelation to the process of ageing and atherosolerosis.The susceptability to elastolysis of elastic tissue inthe wall of the aorta is minimal in the young butincreases steadily with age. Dr. Hall postulates thatthis may be due to the loss with advancing years ofinhibiting substances which prevent elastolysis inyouth. Elastin is a lipoprotein and Dr. Hall suggeststhat separation of the lipid fraction may underlie theformation of the atheroscerostic plaque.

Dr. Hall gives nearly 300 references including 50 towork by himself or his colleagues but much of thebook deals with hypothesis and there is evidently aneed for much more research before this complexsubject can be crystallised for the general medicalreader. At present it is a field for specialists who willundoubtedly be stimulated by Dr. Hall's challengingmonograph.Relations of Development and Ageing

Edited by JAMES E. BIRREN, Ph.D. Pp. v+256illustrated. Springfield, Illinois: Charles C.Thomas. 1964. $9.50.

This book present the proceedings of a conferenceof the Gerontological Society of America held atMiami Beach, Florida, in 1964.The contributors are mostly psychologists and

sociologists, though there are a few interesting con-tributions in other fields particularly one on agechanges in bones by Garn, Rohanm and Nolan.Much of the psychology is very academic and will

prove heavy going for the medical reader, but it isinteresting to see the way in which research ingerontology is looking further and further back inan attempt to see the processes of ageing in rela-tion to the whole span of human life. The child isafter all father to the man.

ERRATUM:'Haemoglobinopathies in Immigrant Families' by M. J. Beard and A. Gordon Signy. Postgrad. med. J.(1965), 41, 624-633.Section headed Laboratory Tests, p. 632:

1. lines 6 and 7 should read "and will detect differing percentages . . ." instead of "but will notdetect . . .".

2. bottom line should read "will range from 5 to 95% according to the severity of the deficiency."instead of "5 to 9.5% .. .".