ß-Thalassemia Major: Experience at King Fahad Hofuf Hospital, Al-Hassa, Saudi Arabia

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1 Case Reports Adewale Ayodele Laditan, FRCP; Mohamed Amin El-Agib, DCH; Saad Al-Naeem, ABDP; Michael Georgeos, CES; Sameera Khabour, DCH From the Departments of Pediatrics (Drs. Laditan, El-Agib, Al-Naeem, Khabour) and Laboratory Services (Mr. Georgeos), King Fahad Hofuf Hospital, Al-Hassa. Address reprint requests and correspondence to Dr. Laditan: Department of Pediatrics, King Fahad Hofuf Hospital, Al-Hassa, 31982, Saudi Arabia. Accepted for publication 1 April Received 23 October AA Laditan, MA El-Agib, S Al-Naeem, M Georgeos, S Khabour, ß-Thalassemia Major: Experience at King Fahad Hofuf Hospital, Al-Hassa, Saudi Arabia. 1996; 16(5): ß-thalassemia major is a rare disease that occurs mostly in the Mediterranean and Middle Eastern regions, as well as in countries where people from such areas have migrated. 1 Despite numerous review articles on its genetic/molecular aspects, clinical features, management and complications, 2-5 the problems of iron overload and its associated morbidity and mortality still remain a major concern. 5 Excessive iron accumulation from blood transfusions without adequate iron chelation often leads to growth retardation, cardiac complications, hepatic failure and endocrine disturbances. 6-8 At present, the only available method for preventing and treating iron overload is by subcutaneous infusion of an iron chelating agent, desferrioxamine (DF), from a small portable syringe driver pump over eight to 12 hours. 9 Prior to the establishment of a hereditary blood diseases center (HBDC) at King Fahad Hofuf Hospital (KFHH), Al-Hassa, Saudi Arabia, in July 1992, all thalassemics were managed with blood transfusions on an irregular basis. They were transfused with blood whenever they came in with pallor and also received 25 mg/kg body weight of DF intravenously before and after blood transfusion. However, since the inception of the center, the management and follow-up of the thalassemics had become regular, with blood transfusion given at three to four weekly intervals. At the same time, DF and pumps for its delivery, both at the center and at home, became available. Each patient was given a pump while DF was provided on a regular basis. The present report analyzes the clinical data, the management as well as the outcome of ß-thalassemia major patients who are attending the HBDC at King Fahad Hofuf Hospital, Al-Hassa, Saudi Arabia. Patients and Methods The hospital records of 42 ß-thalassemia major patients who have been managed and followed up in our HBDC from July 1992 until June 1995, were retrospectively reviewed. The clinical data as well as the specific diagnostic investigations, management and the postdiagnostic clinical status of the patients were recorded and analyzed. The diagnosis of ß-thalassemia major was based on the clinical history and laboratory investigations. A history of pallor, jaundice, hepatosplenomegaly, repeated blood transfusions and evidence of bone marrow expansion was obtained in the majority of the patients. Also contributory to the diagnosis was a blood smear that showed microcytic hypochromic anemia with target cells, basophilic stippling and large numbers of nucleated red cells. The hemoglobin electrophoretic results of F (95%-98%) and A 2 (2%-5%) on a cellulose acetate medium at an alkaline ph of 8.4 helped us to make a diagnosis of ß-thalassemia major, while an observation of ß-thalassemia minor in both parents was also of diagnostic value. The subjects were transfused at the center every three to four weeks with enough packed red cells to achieve a posttransfusion hemoglobin level of 10.0 to 12.0 g/dl. Patients who developed hypersplenism of a significant degree (a need for packed red cell transfusion of more than 200 ml/kg body weight per annum) underwent splenectomy. Although all the splenectomized patients were older than five years of age, 0.5 to 1.0 ml of pneumovax vaccine was given intramuscularly before splenectomy whenever available, while monthly intramuscular injection of benzathine penicillin was started thereafter. For those who did not tolerate the intramuscular injections, oral methoxyphenyl penicillin (ospen) in a dose of 125 to 250 mg twice daily was administered. We did not use erythromycin, since none of our patients showed allergy to penicillin. Subcutaneous infusions of DF at mg/kg body weight per night and for five nights per week were introduced at the same time that blood transfusion was started. Additionally, intravenous DF (40 mg/kg body weight) was given at the time of blood transfusion in the center.

2 Those who did not comply with subcutaneous infusion of DF at home were given up to 60 mg/kg of intravenous DF during blood transfusion. We did not give ascorbic acid routinely because most of our patients did not have DF infusion regularly. However, we advised parents to give fresh orange juice or juice to the patients regularly. We also advised taking tea with meals to reduce absorption of iron from the gastrointestinal tract. Although the most reliable method of determining body iron stores is by direct iron measurement in a liver biopsy, serum ferritin estimation, which is a less hazardous procedure, gives a good indication of body iron stores 14 and that was why it was measured at six-month intervals. The clinical status of the patients at follow-up was evaluated by their mean Hb level, which was calculated as the average of the pre- and post-transfusional Hb values during one year, the mean volume of packed red cells transfused per kg body weight per annum, and the mean serum ferritin levels, as well as their average body weight and height. For the purpose of analysis, the data obtained for body weight and height were compared with those of 50th percentiles obtained for normal Saudi children. 10 But their mean Hb level per annum, mean packed red cells transfused per annum and mean serum ferritin level were compared with the recommended data for well-controlled thalassemics. 11 The subjects were also divided into two groups. Group 1 comprised 17 subjects whose mean Hb level was less than 10 g/dl, while the remaining 25 in Group 2 had more than 10 g/dl. Furthermore, a separate analysis was done for 10 children younger than five years of age who were diagnosed just before the inception of the HBDC. The paired t-test was used to test the level of significance between the subject's mean values and the reference data. Student's t-test was used to compare the strength of significance between mean values. Results Age and Sex Distribution All 42 patients were Saudi citizens. Their ages ranged from 1.5 to 15 years with a mean age of 8.3±3.9 years. There were 26 (61.9%) males and 16 (38.1%) females with a male to female ratio of 1.6 to 1.0. Table 1 shows the age and sex distribution of the patients, with 50% in the age range of six to 12 years. The pattern of family distribution showed that 19 families had one child affected, seven had two children affected, and three families had three children affected. Clinical Features Although pallor was present in mild to moderate degree in the 42 patients, jaundice was either not present, or present in only a mild degree. The spleen was less than 5 cm enlarged in 24 (57.1%) subjects, but more than 5 cm in six (14.3%) others, while the remaining 12 (28.6%) had undergone splenectomy. Of the six patients with splenic size greater than 5 cm, only two had massive splenomegaly of 10 and 12 cm. Unlike the spleen, the liver showed a greater degree of enlargement, which was more pronounced in the splenectomized subjects. It was more than 5 cm below the right costal margin in 24 (57.1%) of the patients. Abnormal facial configuration as one of the features of bone marrow expansion was observed in 28 (66.7%) of our subjects; it was mild to moderate in 12 and severe in the remaining 16. Table 2 shows the clinical features of the patients. Although pubertal changes were not evaluated in the present study, it was observed that the six subjects who were aged 12 to 15 years were not only small for their age, but also showed delayed pubertal development. Management Attendance for blood transfusion became regular after establishing the HBDC. Unfortunately, eight of the 42 patients (19%) did not attend regularly for blood transfusion, while just 10 (23.8%) used DF and its pump at home. The rest either did not use the pumps at all or used them inconsistently. The older subjects started resenting regular blood transfusion and DF infusions. Some parents found it difficult to carry out subcutaneous infusion of DF in their children every night. Because of this, we were unable to undertake a hypertransfusion regime for our patients. Splenectomy was carried out in the 12 patients because of increasing transfusion requirement and hypersplenism, but following splenectomy, both the frequency and the volume of red cells transfused became reduced.

3 Table 1. Age and sex distribution of 42 patients with β-thalassemia major. Age (years) Sex Male Female Total (%) < (35.7) (50.0) (14.3) Total (100.0) Outcome Table 2. The clinical features of the 42 thalassemic patients. Clinical features Number of cases (%) Pallor Mild 21 (50.0) Moderate 19 (45.2) Severe 2 (4.8) Jaundice Nil 6 (14.3) Mild 36 (85.7) Enlarged spleen <5 cm 24 (57.1) >5 cm 6 (14.3) Splenectomy 12 (28.6) Enlarged liver <5 cm 18 (42.9) >5 cm 24 (57.1) Abnormal facial appearance Mild: 12 Moderate/severe: (66.7) There was a mortality of 4.8% in the present series since two of the 42 patients (one male and one female) died at the age of 13 and 14 years respectively. Both died of ß-thalassemia complications, the former from cardiac arrhythmia and failure and the latter from hepatic failure and acquired insulin-dependent diabetes mellitus (IDDM). Three other patients have also developed signs and symptoms of cardiac dysfunction, such as dilated cardiomyopathy with cardiac failure from iron overload. Table 3 shows the clinical performance of the 42 patients. With their mean age of 8.3 years, their data were compared with the expected reference values. 10,11 It can be seen from this table that our subjects deviated significantly from the reference standards. Their mean Hb level was statistically lower ( P <0.001), the mean volume of red cells transfused was also lower ( P <0.005), while their mean serum ferritin level was higher ( P <0.001). Similarly, their body weight (P <0.001) and height ( P <0.002) were significantly lower than the reference values. Our subjects were growth retarded, and were undertransfused with low Hb level, but still had high serum ferritin levels. Table 4 compares the clinical performance between group 1 and 2 subjects. The mean Hb level per annum was 9.2±0.4 g/dl in group 1, 10.4±0.4 g/dl in group 2, and the difference between them was statistically significant ( P <0.001). Although there were statistically significant differences in the physical growth between the two groups, most subjects in either group had not thrived, as their body weight and height were between the 3rd and 10th percentiles of the reference standards. There was no statistically significant difference between the two groups with regard to their serum ferritin levels and the average blood volume transfused per kg body weight per annum, thus indicating undertransfusion and hypertransferrinemia in the two groups. Data comparison between the 10 subjects who were under five years of age and the standard reference values showed that they were better off than the older subjects (Table 5). They had no accumulated iron (mean serum ferritin level of ng/ml)

4 compared with a level of ng/ml in the older subjects. The difference between the two serum ferritin levels was statistically significant ( P <0.001) and there was a similar statistical difference in their Hb levels ( P <0.02) even though the difference between the mean volume of red cells transfused per kg body weight per annum was not statistically significant ( P <0.5) Table 3. The clinical status of the 42 thalassemic patients at follow-up. Parameters assessed Data (±SD) Reference standard values P Age (years) 8.3± Body weight (kg) 20.8± <0.001 Height (cm) 114.1± <0.002 Mean Hb level/ annum (g/dl) 9.9± <0.001 Mean red cell volume transfused (ml/kg/annum) 184.4± <0.005 Mean serum ferritin level (ng/ml) ± <0.001 Table 4. Comparison of the clinical status at follow-up between group I and II subjects. Parameter Group I (n=17) Group II (n=25) assessed (Hb<10g/dL) (Hb>10g/dL) P Age (years) 10.5± ±3.8 <0.002 Weight (kg) 24.6± ±7.3 <0.01 Height (cm) 125.1± ±21.3 <0.005 Mean Hb level/ 9.2± ±0.4 <0.001 annum (g/dl) Mean red cell volume transfused (ml/kg/annum) 188.0± ±33.4 NS Mean serum ferritin level (ng/ml) ± ± NS Discussion ß-thalassemia major is a chronic disease whose exact frequency, incidence and prevalence in Al-Hassa is not known. However, the frequency rate of the ß-thalassemia gene is reported as 3.5% in the Eastern Province of Saudi Arabia to which Al-Hassa belongs. 12 The presence of pallor in all our patients, with almost nonicteric sclerae, must have been a reflection of ineffective erythropoiesis in the marrow rather than peripheral destruction of red cells. Furthermore, the more noticeable hepatomegaly, especially after splenectomy, was probably due to an increased extramedullary erythropoiesis in the liver. Extramedullary hematopoiesis in ß-thalassemia major is known to contribute to enlargement of the spleen and the liver, especially in early life, although later enlargement of the liver results from extensive cirrhosis. 13,14 Two-thirds of our patients had developed an abnormal facial configuration due to bone marrow expansion because of undertransfusion and inadequate iron chelation. This is not surprising, since only 10 (23.8%) of our subjects used DF regularly at home.

5 Table 5. Comparison of post-diagnostic clinical data between the subjects who were under 5 years of age and those older. <5 years of age (10) >5 years of age (32) Parameters assessed Data (+SD) Ref. values P Data (+SD) Ref. values P Age (years) 3.1± ± Body weight (kg) 11.5± < ± <0.001 Height (cm) 84.9± < ± <0.01 Mean Hb/annum (g/dl) 10.4± < ± <0.001 Mean red cell vol. (ml/kg) 173.9± < ± <0.02 Our management was not different from the standard treatment, which comprised blood transfusion, subcutaneous DF infusion and splenectomy whenever indicated. 4,15 Although it is best to treat ß-thalassemia major by regular and aggressive blood transfusion so as to promote normal physical growth, avoid skeletal deformity and control morbidity from hypoxia, 15 such an aggressive transfusion program is unfortunately often complicated by iron overload, especially if not accompanied by adequate iron chelation. 16 We could not undertake such a hypertransfusion regime because of noncompliance of our patients with DF infusion. But despite the fact that our patients were undertransfused, they still had high serum ferritin levels. Undertransfusion in thalassemia major is known to enhance gastrointestinal iron absorption, 17 and this could contribute to thalassemic iron overload. Features such as hepatomegaly, poor physical growth and very high serum ferritin levels lend support to the evidence of iron overload in our patients. The mean serum ferritin level of 4437 ng/ml in our series also indicated persistence of a high level of excess iron burden, which may have been responsible for growth retardation as well as cardiac and hepatic complications in our patients. One sad observation in the present series is that two of our patients died from complications of iron overload. A further disturbing problem is the fear that a few more may develop morbidity from the iron overload, especially now that 16 (38.1%) of them are in their second decade of life. Although our older subjects performed poorly with retarded physical growth, abnormal facial appearance and very high serum ferritin level due to their rejection of the standard method of treatment, the younger subjects who were diagnosed since the inception of the HBDC performed better. The current method of preventing iron overload is difficult and expensive, with almost total rejection by both the patients and their parents. This made the clinical course and prognosis of our patients vary widely. An early discovery of a more acceptable and preferably oral form of iron-chelating agent will be most rewarding. Acknowledgment The authors gratefully acknowledge the contributions of the nursing staff at the HBDC in the management of these patients. References 1. Whipple GM, Bradford WL. Mediterranean disease - thalassemia (erythroblastic anemia of Cooley); associated pigment abnormalities simulating hemochromatosis. J Pediatr 1932;9: Nienhuis AW, Benz EJ, Propper R, et al. Thalassemia major; molecular and clinical aspects. Ann Int Med 1979;91: Kulosik AE. Beta thalassemia: molecular pathogenesis and clinical variability. Eu J Pediatr 1992;151: Modell CB. Total management of ß-thalassemia major. Arch Dis Childh 1977;52: Economidou J. Problems related to the treatment of ß-thalassemia major. Paediatrician 1982;11: McIntosh N. Endocrinology in thalassemia major. Arch Dis Childh 1976;51: Johnstone FE, Hertzog KP, Malina RM. Longitudinal growth in thalassemia major. AJ Dis Child 1966; 112: Engle MA. Cardiac involvement in Cooley's anemia. Ann NY Acad Sci 1964;119: Propper RD, Cooper B, Ruffo RR, et al. Continuous administration of desferrioxamine in patients with iron overload. N Engl J Med 1977;297: Osman M, Magbool G, Kaul KK. Hegira adaptation of the NCHS weight and height charts. Ann Saudi Med 1993;13:170-1.

6 11. Cao A, Gabutti V, Masera G, et al. Management protocol for the treatment of thalassemia patients. New York: Cooley's Anemia Foundation, Munchi N, De-Silva V, White JM. The frequencies of Hb, S, α and ß-thalassemia in Saudi Arabia: preliminary national values. Saudi Med J 1989;10: Witzleben CL, Wyatt JP. The effect of long survival on the pathology of thalassemia major. J Pathol 1961;82: O'Brien RT, Pearson HA, Spencer RP. Transfusion-induced decrease in spleen size in thalassemia major: documentation by radioisotopic scan. J Pediatr 1972;81: Freedman MH. Management of ß-thalassemia major using transfusion and iron chelation with desferrioxamine. Transfus Med Rev 1988;2: Letsky E, Miller F, Worwood M, Flynn DM. Serum ferritin in children with thalassemia regularly transfused. J Clin Path 1974;27: De Alarcon PA, Donovan ME. Iron absorption in thalassemic syndromes and its inhibition by tea. N Engl J Med 1979;300:5-8.