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Incidence of genetic disorders of haemoglobins in the hospital population of Bahrain

 
 

Date   :  05-03-2007

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Incidence of genetic disorders of haemoglobins in the hospital population of Bahrain

 

Dr Kishore V Nadkarni*

Dr Shaikha S Al-Arrayed**

Dr Jayant P Bapat***

 

ABSTRACT

 

In a retrospective study, blood samples of 56198 Bahraini nationals received at the Pathology Department In Salmaniya Medical Centre over the six-year Period 1982-1987 were analysed ,Of the total , 5503 Were neonatal samples and the rest non-neonatal longest The latter, 68.82% showed abnormal haemo-globin.56.56% Showed sickle cell trait,10.44% showed sickle cell disease and 1.82% showed other forms of abnormal haemoglobins including rarer ones. Amongst the neonatal samples, abnormal haemoglobin were detected in 44.35%:24.2% were α-thalassaemia cases, 18.10% were sickle cell traits, and 2.1% were sickle cell disease. The highly variable concentration of the abnormal haemoglobin in both groups was also studied and analysed. Such high incidence of abnormal haemoglobin gene necessitates a prospective detailed study of the problem in general population followed by genetic counseling.

 

 

Studies of incidence and distribution of genetic disorders of haemoglobins in different countries in the Middle East have been reported in last few decades. The important and prevalent disorders in this part of the world are sickle cell trait and sickle cell anaemia .followed by β and α-thalassaemias . Sickle cell haemoglobin has been the commonest of all the abnormal haemoglobins with molecular abnormality caused by the replacement of glutamic acid in the 6th N-terminal of β-chains with valine.12 The homozygous abnormality of this disease, sickle cell disease, was first reported by Herrick and the first case of  sickle cell anaemia in the Middle East was reported in Egypt by Abbasy.4 According to Lehman, 5 sickling gene was first originated in the Arabian peninsula.Cases and incidence studies of sickle cell anaemia and sickle cell trait have been reported in the Middle East by several workers.4.11 Thalassaemia is also prevalent in the Middle East β-thalassaemia described by Cooley and Lee in 1923 was reported in Mediterranean immigrants in the United States. 12 It has homozygous genetic anomaly of the reduction or total absence of production of β-gloin chains. This is well-recognised in Saudi Arabia. 13.14 Similarly α-thalassaemia. A disorder of defective production of α-globin chains has also multiple phenotypes and is prevalent in several parts of the Middle East.11.15.19 Considering the magnitude of The problem in Bahrain. The amoint of published data in this field here, is indeed very minimal and the only study is that of Mohammad et al 20 on 10372cord-biood sampes . The purpose of this study is determine the  incidence of haemoglobinopathies and thalassaemia in hospital population to highlight the seriousness of this problem in Bahrain so that a detailed prospective study can be carried out.

 

 

 

 

METHODS

 

 

During the period from January 1982 to December 1987 samples of 56198 Bahraini patients were screened for abnormahaemglobins.These included cases referred from other wards at Salmaniya Medical centre ,out-pa-tient clinics, health centres and private hospitals. Expatriates were excluded from our study and a great deal of care was empioyed to avoid duplication of data . blood was collected in bottles containing ethylenediamine tetra-acetic acid disdium salt (Na2 EDTA Salt) which was used a anticoagulant .The method of Itano and Pauling as modified by Sergeant was used for sickling test prior to haemoglobin electrophoresis .21.22 Special hematological tests including Hb elecrophoresis on cellulose acetate paper and when necessary on agar gel ,foetal haemoglobin estimation and quantification of abnormal haemoglobin by densitometry were carried out 23.27 The values were anaiysed and tabulated but no sex analysis was carried out as haemoglobinopa and thalassaemias are not sex-linked disorders.

 

 

 

 

 

 

RESULTS

 

 

Of the total 56198 sampies, there were 50695non-neonatal and 5503 neonatal. Samples of patients one up to one year of age were grouped as neonatal and those above one year as non-neonatal. Such separation was necessary because the natural occurrence of higher amount of haemoglobin F and lowerrate of production of β-chains up to one year of age, make β-chain-containing adult haemoglobin and haemoglobin S less prevalent in neonates. Haemoglobin F is in negligible and undetectable quantity above the age of one year in normal cases. Amongst the non-neonatal cases, those manifesting abnormal haemoglobin pattems formed a striking majority of 34893 cases or 68.82%whereas, amongst the neonatal cases, they were 2441 cases or 44.35%(Table 1).

 

 

 

 

 

 

 

 

 

 

 

                                                 TABLE 1

Incidence of abnormal haemoglobin

Group

No.of

Cases

studied

No.of

With cases

Abnorniul Hb

%

Non-neonatal

50695

34893

68.82

Neonatal

 

 

5503

2441

44.35

Total

56198

37334

66.43

 

 

Table 2

Incidence of haemoglobin amongst

Non-neonatal cases

Hb patterns

No.of cases

%

Hb A/A (Normal pattern)

Hb S/F (sickle cell trait)

Hb S/F(sickle cell disease)

Hb S/S (sickle cell disease)

HbA/F/A2(β-thal.major)

Hb A/A2(β-thal.minor)

Α-thal.(multiple patterns)

Rarer forms

 

15802

 

28675

 

4437

 

857

 

82

 

446

235

 

161

31.18

 

56.56

 

8,75

 

 

 

 

 

 

0.40

 

0.32

Total

50695

100.00

 

In the non-neonatal samples. The sickle cell abnormalities constituted the largest group with 28675 cases (56.56%)having sickle cell trait and 5294 cases (10.44%) having sickle cell disease (Table 2).In the latter, the ratio of Hb S/F : Hb S/S was found to be 5.17:1 (4437:857).The incidence of thalassaemia gene was found to be comparatively much lower comprising1.5% of the total :β-thalassaemia major constituted 0.16% β-thalassaemia minor 0.88%and α-thalassaemia 0.46%. Other haemoglopathies formed only 0.32%of the total.

 

 

Amongst the 5503 neonatal samples.the normal Hb A/F pattern was see in 3062 cases (55.6%). Sickle cell trait was found to be not an uncommon abnormal- ity in the neonates, comprising 18.1%of the total which was a much lower rate of incidence than in the non-neonatal samples.Sickle cell disease too was found with much lower incidence rate (2.1%).Samples with Hb Barts formed the majority,24.2%with or without double heterozygous combination with sickle cell gene (Table 3).

 

 

Table 3

Incidence of haemoglobin amongst neonatal cases

Hb patterns

No. of cases

%

Hb A/f(normal pattern)

Hb A/S/F(sickle cell trait)

Hb S/F(sickle cell disease)

Hb A/F/ Barts(α-thalassaemia)

Hb S/F/ Barts(sickle cell disease with α-thalassaemia)

Hb A/S/F Barts(sickle cell trait with α-thalassaemia)

 

3062

995

114

863

 

85

 

 

384

55.6

18.1

2.1

15.7

 

1.5

 

 

7.0

Total

5503

100.0

 

 

         α-thalassaemia pattems with Hb Hand /or Barts in non-neonatal cases showed varying pattems.The commonest was Hb A/H.Combinations with sickle cell gene were much less common(Table4).

 

 

 

Other rare haemoglobins constituted 0.32% of the total: these included Hb D and Hb O in homozygous and double heterozygous forms of which Hb A/D was found to be the commonest with 0.16% incidence (Table5).

                                        

                                              

 

                                             Table 4

Distribution of α-thalassaemia haemoglobin patterns in non- neonates(N=50695)

                                              

Hb patterns

No.of cases

%

Hb A/H

Hb A/S/H

Hb A/S/Barts

Hb A/H/Barts

170

16

21

28

0.334

0.034

0,044

0,054

Total

235

0.46

 

Table5

 

Incidence of rarer forms of haemogloinopathies in non-neonates

                                    (N=50695)

Hb patterns

No.of cases

%

Hb A/D

Hb A/O

Hb S/O

Hb A/F/O

Hb D/D

Hb O/O

Hb S/D/F

80

34

30

3

8

4

2

0.160

0.070

0.060

0.006

0.016

0.008

0.004

 

Total

161

0.32

 

On quantitative estimation of abnormal haemoglobins. Surprisingly striking ranges were seen in different patterns.     Hb F varied between 2 to 40% in sickle cell disease with Hb S/F. The range beween 4.1 to 20% included the majority of cases (76,28%) (Table6).

 

Table 6

Distribution of Hb F in sickle disease samples of Hb S/F

Percent range of Hb levels

No.of cases

%

2.0 to4.0

4.1 to10,0

10.1 to20.0

20.1 to40.0

857

1990

1354

183

19.55

45.39

30.89

4.17

Total

4384*

100.00

 

*Out of 4437 cases. Data of 53 cases were unavailable

In β-thalassaemia major Hb F level showed a very wid range .from 10 to 77.3% (Table7). In β-thalassaemia minor HbA2 varied between 3.7 to 13.5% (Table8).Values of HbA2 of 3.6%and below were taken as normal.

 

 

 

 

 

 

Table 7

Distribution patterns of Hb F levels in

β-thalassaemia major

Percent range of Hb A2 levels

No.of cases

%

10.0 to30.0

30.1 to50.0

50.1 to77.3

12

23

47

14.7

28.0

57.3

Total

82

100.0

 

 

 

 

 

 

Table 8

Distribution pattern of Hb A2 levels in

β-thalassaemia minor

Percent range of

HbA2levels

 

No.of cases

%

3.7 to 5.0

5.1 to7.0

7.1 to10.0

10.1to 13.5

 

32

206

187

21

7.17

46.19

41.93

4.71

Total

446

100.0

 

Hb Barts was the commonest abnormal haemoglobin seen in 1332 cases of which 1071 were available for quantitative densitometric analysis. Hb Barts in α-thalassaemia varied over a wide range, from 1 to 40%(Table 9).

 

Table9

Distribution pattern of Hb Barts level in neonatal α-thalassaemia

 

Percent range of Hb Barts

No.of cases

%

1to5

5.1to10

10.1to15

15.1to20

20,1to25

25.1to40

301

603

110

28

12

17

28.10

56.30

10.27

2,62

1.12

1.9

Total

1071

100.00

 

 

 

Non-neonatal cases of α-thalassaemia also showed similar ranges of Hb H,from 1to38%(Table 10).

                                               

 

Table 10

Distribution pattern of Hb levels in non-neonatal cases of α-thalassaemia

%

No.of cases

Percent range of Hb H levels

25.44

55.08

19.48

30

65

23

1.0to10.0

10.1to20.0

20.1to38.0

100.00

118*

Total

 

*Out of 135 cases data of 17 were unavailable

 

DISCUSSION

 

Haemoglobinopathies and thalassaemias are both genetic abnormalities of the haemoglobin molecule; the former being the structural abnormality in the polypeptide sequence of the globin chain, and the latter being the absence or reduction of  any one or more of the globing chains. The study confirms the high frequency of both these abnormalities in Bahrain. The most common genetic abnormality encountered is sickle cell gene having an overall incidence of 63.25% in our sample (53.48% sickle cell trait and 9.77% sickle cell disease).This incidence is remarkably high when compared to reports from Saudi Arabia in which the total sickle cell gene in different regions varies between 4.3 and 30.2%.12In those regions the sickle cell trait varies between 1.6 and 23.9%,the sickle cell disease between 1.0 and 1.7%, and those with heterozygous combination with thalassaemia between 1.0to20.5%.The high incidence in our study is possibly due the fact that a good number of cases were referred from the health centers for. Hb electrophoresis after getting positive results from sick ling test. Another report from Saudi Arabia records an incidence of 14.3% for sickle cell trait in 648 children one to four years old.28A study of cord-blood samples in Bahrain, has revealed the incidence of sickle cell gene to be as high as 13.5% which included trait disease and double heterozygous forms.20It is comforting to note that in our series Hb S/F cases were 5.17 times more than the Hb S/S series. The favourable protective role played by Hb F in sickle cell disease is well-recognised by several workers 10.120.39The first report of a mild form of sickle cell disease associated with an unusually high level of Hb F of 15to25%came from Kuwait .30In our series, Hb F varied between 2to40%with severity of the disease being inversely proportional to the quantity of HbF In Qateef region of Saudi Arabia association of Hb F at steady high level in sickle cell disease has been the rule rather than exception.31High levels of Hb Fin sickle cell disease has also been observed in Iran and in India.32.33Heterozygous combination of sickle cell disease with α-thalassaemia as has been reported in other parts of the Middle East, also modifies the course of the disease; however, such cases are very few in our series.12.14.34The incidence of β-thalassaemia was found to be much lower (1.04%)than that of the sick ling deformity. Of these the majority of the cases were β-thalassaemia major (0.16%).A milder variant of β-thalassaemia of apparently homozygous form appears to be common in the Middle East.34.35HbFin our series of β-thalassaemia major varied from 10.0to 77.3%in comparison with other studies which showed a range of 2.6to70%.36Hb A2levels were generally lower than 3.9% in all of them and have not been statistically analysed .

Α-thalassaemia showed still lower incidence (0.46%) amongst the non-neonatal cases when grouped with neonatal samples having Hb Barts the overall incidence could be expressed as 2.74%.The haemoglobin patterns vary widely in α-thalassaemia depending on the phenotype. Co-existence  of α-thalassaemia with sickle cell gene, which has been found in number of cases amongst the neonates, contributes positively to the course of the disease. The ranges of Hb Barts and Hb H concentration varied widely .α-thalassaemia was found to be the major abnormality in neonates appearing either singly or in combination with the sickle cell gene. The presence of Hb Barts was found to be a useful marker for α-thalassaemia. In our study, 24.2% of neonates showed the presence of Barts was in conformity with cord-blood study in which incidence of Hb Barts was 24.3%, 20 while in new born Saudi babies the incidence was found to be as high as 65%.31 Yet the detectable incidence of α-thalassaemia is reduced remarkably in later life probably because majority of the cases are heterozygous α-thalassaemia 2,which get masked by low undetectable levels of Hb H . Only α-thalassaemia 1 continues to manifest itself with 2 gene deletions and higher levels of Hb H. The rarest of the haemoglobinopathies were those of Hb D and Hb O which occurred in trait, homozygous or double heterozygous forms. These findings caution us about the remarkably high prevalence of abnormal haemoglobin gene which could exist in the general population as exhibited in the hospital population of this large sample study. The treatment of these cases is an enormous task placing strain on the national resources. Many cases of hereditary haemolytic anaemias may remain undetected if the abnormal haemoglobin concentration is very low for which the recourse is DNA and/or globin chain analysis . To assess the real magnitude of the situation, a prospective study of the problem in general population appears to be highly mandatory. This should be coupled with institutionalized genetic counseling which will be an effective measure in the prevention of the high prevalence of this gene.

 

CONCLUSION

 

The prevalence of abnormal haemoglobin gene is remarkably   high in Bahrain as found in this largesample hospital-based study. The incidence of its different varieties are discussed and  compared with that in other studies in the region . A detailed  prospective study of general population to assess the magnitude of the problem, and an effective genetic counseling programme to check its high prevalence are both recommended.       

 

 

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19.McNeel JR.Family studies of alpha-thalassaemia haemoglobin H disease in eastern Saudia Arabia. J Med Assoc Thai 1971;54:153-8.

 

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21.Itano HA,Pauling L.A rapid diagnostic test for sickle cell anaemia. Blood 1949;4:66-8.

 

22.Serjeant BE,Serjeant GR. Awhole blood solubility and centrifugationtest for sicklecell haemoglobin-Aclinical triat. Am J Clin Pathol 1972;58:11-3.

 

23.Schmidt RM. Laboratory diagnosis of haemoglobinopathies. JAMA1973;224:1276-80.

 

24.Singer K,Chemoff F,SingerL. Studies in abnormal haemoglobins. I-their demonstration in sickle cell anaemia and other haemolytic disorder by means of alkali denturation. Blood 195;6:413-8.

 

 

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26.International Committee for standardization in haematology. Simple electorophoretic system for presemptive identification of abnormal haemoglobins. Blood 1978;52:1065-71.

 

 

27.International Committee for standardization in Haematology. Recommendations for selected methods for quantitative estimation of Hb A2and Hb A2 reference preparation Br Haematol 1978;38:573-8.

 

 

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