Beta Thalassemia

Background

Beta thalassemia is characterized by quantitative defects in the beta globin chain, one of the backbone proteins of the hemoglobin molecule. These defects lead to decreases in hemoglobin production with resulting anemia. There are hundreds of mutations within the beta globin gene, but approximately 20 different alleles comprise 80% of the mutations found world wide. Beta thalassemias are caused by mutations on chromosome 11. There are three general categories of beta thalassemia: beta thalassemia trait, beta thalassemia intermedia and beta thalassemia major.

OUTLINE

Disease Associations

Pathogenesis

Prognosis and Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

COAGULOPATHY

Haemostatic disorders in nonsplenectomized and splenectomized thalassaemic children.

Shebl SS, el-Sharkawy HM, el-Fadaly NH.

Department of Paediatrics, Faculty of Medicine, University of Tanta, Tanta, Egypt
East Mediterr Health J 1999 Nov;5(6):1171-7 Abstract quote
A group of 40 thalassaemic patients (20 splenectomized and 20 nonsplenectomized) from the Haematology Unit of Tanta University Hospital (age range: 3-14 years) were studied to identify the mechanisms by which haemorrhagic and thrombotic complications occur in thalassaemic patients. The patients' levels of protein C, antithrombin III and in vitro platelet aggregation in response to collagen were compared with those of 20 controls.

The study suggests that thrombocytosis, increased platelet aggregation and decreased natural coagulation inhibitors (protein C and antithrombin III) in splenectomized thalassaemic children may be significant in thrombotic complications in such patients. Defective platelet aggregation and prothrombin activity in nonsplenectomized children may also give rise to haemorrhagic tendencies.

OSTEOPOROSIS

Bone density in the Asian thalassaemic population: a cross-sectional review.

Bielinski BK, Darbyshire P, Mathers L, Boivin CM, Shaw NJ.

Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK..

Acta Paediatr 2001 Nov;90(11):1262-6 Abstract quote
As survival improves in beta-thalassaemia, osteoporosis is emerging as a significant problem. This study examines bone mineral density (BMD) of thalassaemic patients of Asian origin (age range 9.5-24 y) to evaluate the extent of problems in this group and identify potential risk factors.

Eleven patients were scanned using dual-energy X-ray absorptiometry. BMD z-scores and the bone mineral apparent density (BMAD) z-scores were calculated, to correct for short stature. All but three patients had lumbar spine BMD and BMAD z-scores below the mean. Three patients had BMAD z-scores more than 2.5 standard deviations below the mean. A negative correlation between age and BMAD was seen, as was an association between endocrine disorders and decreased bone density.

CONCLUSION: The data confirm significant reductions in BMD in the Asian thalassaemic population, even after correcting for body size. Further research is needed to identify risk factors and means of prevention.

Osteoporosis and beta-thalassemia major: role of the IGF-I/IGFBP-III axis.

Lasco A, Morabito N, Gaudio A, Crisafulli A, Meo A, Denuzzo G, Frisina N.

Department of Internal Medicine, University of Messina, Italy.
J Endocrinol Invest 2002 Apr;25(4):338-44 Abstract quote
Patients with beta-thalassaemia major are susceptible to osteopenia due to several factors which interfere with bone remodeling.

It is known that bone metabolism and skeletal consolidation result from a complex sequence of hormonal changes, where the concerted actions of GH, IGF-I and sex hormones and their receptors, are responsible for the timing and attainment of skeletal consolidation. IGF-I and the corresponding binding protein (IGFBP-III), markers of bone metabolism and lumbar and femoral neck BMD were measured in 28 adult patients, undergoing hormonal replacement and chelation therapy and a hypertransfusion program, with beta-thalassaemia major (12 males with mean age 22.5+/-3.1 and 16 females with mean age 27.5+/-8.2), and in 28 healthy volunteers matched for age, anthropometric features and sex to the patients. BMD values, both at lumbar and femoral neck level were significantly lower (p<0.001 and p<0.05) by 18.7 and 4.2% respectively, in patients than in the controls. Markers of bone resorption [pyridinoline (Pyr) 78.1+/-15.7 vs 47.5+/-11.2 pmol/pmol urinary creatinine, p<0.001 and deoxypyridinoline (D-Pyr) 21.9+/-3.5 vs 14.5+/-5.4 pmol/ micromol urinary creatinine, p<0.001] were higher in patients than in controls, whereas the marker of bone formation was slightly lower [osteocalcin (BGP) 3.8+/-0.6 vs 4.6+/-1.7 pmol/ml, p<0.05]. Plasma levels of IGF-I (21.07+/-5.12 vs 35.25+/-8.33 nmol/ml, p<0.001) and IGF binding protein III (IGFBP-III) (1.9+/-0.4 vs 2.5+/-0.1 mg/ml, p<0.001) were lower in patients than in controls and positively correlated with BMD L2-L4 (r=0.57, p<0.05 and r=0.47, p<0.05 respectively), BMD neck (r=0.40, p<0.05 and r=0.34, p<0.05 respectively) and BGP (r=0.52, p<0.05 and r=0.34, p<0.05 respectively).

Our beta-thalassaemic patients, in spite of normalizing hemoglobin levels, adequate hormone replacement and chelation therapies, showed osteopenia and an unbalanced bone turnover with an increased resorptive phase and a decreased formation phase probably correlated to low levels of IGF-I and IGFBP-III observed in our study.

PATHOGENESIS CHARACTERIZATION

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

TREATMENT

BONE MARROW TRANSPLANTATION

Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation.

Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G.

Unita Operativa di Ematologia e Centro Trapianto di Midollo Osseo di Muraglia, Azienda Ospedale di Pesaro, Italy.
Blood 2002 Jul 1;100(1):17-21 Abstract quote
To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy.

Two hundred eleven patients (mean age, 8.7 +/- 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors.

None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years.

Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.

DEFERIPRONE

Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial.

Maggio A, D'Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, Di Gregorio F, Garozzo G, Malizia R, Magnano C, Mangiagli A, Quarta G, Rizzo M, D'Ascola DG, Rizzo A, Midiri M.

Divisione di Ematologia II e Unita di Ricerca Piera Cutino, Azienda Ospedaliera V. Cervello, Palermo, Italy.
Blood Cells Mol Dis 2002 Mar-Apr;28(2):196-208 Abstract quote
Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major.

To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups.

Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.

Commonly Used Terms

Red Blood Cells

Internet Links

Northern California Comprehensive Thalassemia Center

Last Updated 7/8/2002

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DISEASE ASSOCIATIONS	CHARACTERIZATION
COAGULOPATHY
Haemostatic disorders in nonsplenectomized and splenectomized thalassaemic children. Shebl SS, el-Sharkawy HM, el-Fadaly NH. Department of Paediatrics, Faculty of Medicine, University of Tanta, Tanta, Egypt	East Mediterr Health J 1999 Nov;5(6):1171-7 Abstract quote A group of 40 thalassaemic patients (20 splenectomized and 20 nonsplenectomized) from the Haematology Unit of Tanta University Hospital (age range: 3-14 years) were studied to identify the mechanisms by which haemorrhagic and thrombotic complications occur in thalassaemic patients. The patients' levels of protein C, antithrombin III and in vitro platelet aggregation in response to collagen were compared with those of 20 controls. The study suggests that thrombocytosis, increased platelet aggregation and decreased natural coagulation inhibitors (protein C and antithrombin III) in splenectomized thalassaemic children may be significant in thrombotic complications in such patients. Defective platelet aggregation and prothrombin activity in nonsplenectomized children may also give rise to haemorrhagic tendencies.
OSTEOPOROSIS
Bone density in the Asian thalassaemic population: a cross-sectional review. Bielinski BK, Darbyshire P, Mathers L, Boivin CM, Shaw NJ. Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK..	Acta Paediatr 2001 Nov;90(11):1262-6 Abstract quote As survival improves in beta-thalassaemia, osteoporosis is emerging as a significant problem. This study examines bone mineral density (BMD) of thalassaemic patients of Asian origin (age range 9.5-24 y) to evaluate the extent of problems in this group and identify potential risk factors. Eleven patients were scanned using dual-energy X-ray absorptiometry. BMD z-scores and the bone mineral apparent density (BMAD) z-scores were calculated, to correct for short stature. All but three patients had lumbar spine BMD and BMAD z-scores below the mean. Three patients had BMAD z-scores more than 2.5 standard deviations below the mean. A negative correlation between age and BMAD was seen, as was an association between endocrine disorders and decreased bone density. CONCLUSION: The data confirm significant reductions in BMD in the Asian thalassaemic population, even after correcting for body size. Further research is needed to identify risk factors and means of prevention.
Osteoporosis and beta-thalassemia major: role of the IGF-I/IGFBP-III axis. Lasco A, Morabito N, Gaudio A, Crisafulli A, Meo A, Denuzzo G, Frisina N. Department of Internal Medicine, University of Messina, Italy.	J Endocrinol Invest 2002 Apr;25(4):338-44 Abstract quote Patients with beta-thalassaemia major are susceptible to osteopenia due to several factors which interfere with bone remodeling. It is known that bone metabolism and skeletal consolidation result from a complex sequence of hormonal changes, where the concerted actions of GH, IGF-I and sex hormones and their receptors, are responsible for the timing and attainment of skeletal consolidation. IGF-I and the corresponding binding protein (IGFBP-III), markers of bone metabolism and lumbar and femoral neck BMD were measured in 28 adult patients, undergoing hormonal replacement and chelation therapy and a hypertransfusion program, with beta-thalassaemia major (12 males with mean age 22.5+/-3.1 and 16 females with mean age 27.5+/-8.2), and in 28 healthy volunteers matched for age, anthropometric features and sex to the patients. BMD values, both at lumbar and femoral neck level were significantly lower (p<0.001 and p<0.05) by 18.7 and 4.2% respectively, in patients than in the controls. Markers of bone resorption [pyridinoline (Pyr) 78.1+/-15.7 vs 47.5+/-11.2 pmol/pmol urinary creatinine, p<0.001 and deoxypyridinoline (D-Pyr) 21.9+/-3.5 vs 14.5+/-5.4 pmol/ micromol urinary creatinine, p<0.001] were higher in patients than in controls, whereas the marker of bone formation was slightly lower [osteocalcin (BGP) 3.8+/-0.6 vs 4.6+/-1.7 pmol/ml, p<0.05]. Plasma levels of IGF-I (21.07+/-5.12 vs 35.25+/-8.33 nmol/ml, p<0.001) and IGF binding protein III (IGFBP-III) (1.9+/-0.4 vs 2.5+/-0.1 mg/ml, p<0.001) were lower in patients than in controls and positively correlated with BMD L2-L4 (r=0.57, p<0.05 and r=0.47, p<0.05 respectively), BMD neck (r=0.40, p<0.05 and r=0.34, p<0.05 respectively) and BGP (r=0.52, p<0.05 and r=0.34, p<0.05 respectively). Our beta-thalassaemic patients, in spite of normalizing hemoglobin levels, adequate hormone replacement and chelation therapies, showed osteopenia and an unbalanced bone turnover with an increased resorptive phase and a decreased formation phase probably correlated to low levels of IGF-I and IGFBP-III observed in our study.

Disease Associations
Pathogenesis
Prognosis and Treatment
Commonly Used Terms
Internet Links

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
TREATMENT
BONE MARROW TRANSPLANTATION
Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G. Unita Operativa di Ematologia e Centro Trapianto di Midollo Osseo di Muraglia, Azienda Ospedale di Pesaro, Italy.	Blood 2002 Jul 1;100(1):17-21 Abstract quote To identify the role of iron overload in the natural history of liver fibrosis, we reviewed serial hepatic biopsy specimens taken annually from patients cured of thalassemia major by bone marrow transplantation. The patients underwent transplantation between 1983 and 1989 and did not receive any chelation or antiviral therapy. Two hundred eleven patients (mean age, 8.7 +/- 4 years) were evaluated for a median follow-up of 64 months (interquartile range, 43-98 months) by a median number of 5 (interquartile range, 3-6) biopsy samples per patient. Hepatic iron concentration was stratified by tertiles (lower, 0.5-5.6 mg/g; medium, 5.7-12.7 mg/g; upper, 12.8-40.6 mg/g dry weight). Forty-six (22%) patients showed signs of liver fibrosis progression; the median time to progression was 51 months (interquartile range, 36-83 months). In a multivariate Cox proportional hazard model, the risk for fibrosis progression correlated to medium hepatic iron content (hazard rate, 1.9; 95% confidence interval [CI], 0.74-5.0), high hepatic iron content (hazard rate, 8.7; 95% CI, 3.6-21.0) and hepatitis C virus (HCV) infection (hazard rate, 3.1; 95% CI, 1.5-6.5). A striking increase in the risk for progression was found in the presence of both risk factors. None of the HCV-negative patients with hepatic iron content lower than 16 mg/g dry weight showed fibrosis progression, whereas all the HCV-positive patients with hepatic iron concentration greater than 22 mg/g dry weight had fibrosis progression in a minimum follow-up of 4 years. Thus, iron overload and HCV infection are independent risk factors for liver fibrosis progression, and their concomitant presence results in a striking increase in risk.
DEFERIPRONE
Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Maggio A, D'Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, Di Gregorio F, Garozzo G, Malizia R, Magnano C, Mangiagli A, Quarta G, Rizzo M, D'Ascola DG, Rizzo A, Midiri M. Divisione di Ematologia II e Unita di Ricerca Piera Cutino, Azienda Ospedaliera V. Cervello, Palermo, Italy.	Blood Cells Mol Dis 2002 Mar-Apr;28(2):196-208 Abstract quote Deferiprone has been suggested as an effective oral chelation therapy for thalassemia major. To assess its clinical efficacy, we compared deferiprone with deferoxamine in a large multicenter randomized clinical trial. One-hundred forty-four consecutive patients with thalassemia major and serum ferritin between 1500 and 3000 ng/ml were randomly assigned to deferiprone (75 mg/kg/day) (n = 71) or deferoxamine (50 mg/kg/day) (n = 73) for 1 year. The main measure of efficacy was the reduction of serum ferritin. Liver and heart iron contents were assessed by magnetic resonance. Liver iron content and fibrosis stage variations were assessed on liver biopsy by the Ishak score in all patients willing to undergo liver biopsy before and after treatment. The mean serum ferritin reduction was 222 +/- 783 ng/ml in the deferiprone and 232 +/- 619 ng/ml in the deferoxamine group (P = 0.81). No difference in the reduction of liver and heart iron content was found by magnetic resonance between the two groups. Thirty-six patients accepted to undergo repeat liver biopsy: 21 in the deferiprone and 15 in the deferoxamine group. Their mean reduction of liver iron content was 1022 +/- 3511 microg/g of dry liver and 350 +/- 524, respectively (P = 0.4). No difference in variation of the Ishak fibrosis stage was observed between the two groups. Treatment was discontinued because of reversible side effects in 5 patients in the deferiprone group (3 hypertransamin/asemia and 2 leukocytopenia) and in none in the deferoxamine group. These findings suggest that deferiprone may be as effective as deferoxamine in the treatment of thalassemia major with few mild and reversible side effects.