Growth of children with β-thalassemia major
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《美国医学杂志》
Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, PR, China
Abstract
Hypertransfusion and regular chelation therapy have allowed improved survival in patients with thalassemia major (TM). Despite medical advances, growth failure and hypogonadism remain significant clinical problems in these patients in adolescence. Disproportionate truncal shortening which is common especially among adolescents with thalassemia, is due to platyspondyly resulting from a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements. Although growth hormone (GH) deficiency and GH neurosecretory dysfunction have been described in TM patients, most short TM patients have normal GH reserve. The low serum IGF-1 and IGFBP-3 concentrations in TM patients despite having normal GH reserve and serum GH binding protein levels suggest that a state of secondary GH insensitivity exists. The pubertal growth spurt may be impaired in TM patients going through spontaneous or induced puberty and may have a negative effect on final adult height. GH therapy in dosages ranging from 0.5-1.0 IU/kg/wk has resulted in a significant improvement in growth velocity in short TM children without any adverse effects on skeletal maturation, blood pressure, glucose tolerance and serum lipids. There is limited evidence that GH treatment can result in an improved final adult height in short TM children. Careful and regular clinical and biochemical monitoring should be preformed on these patients while they are treated with GH.
Keywords: Thalassaemia major; Truncal shortening; GH insensitivity
The thalassemias are a group of inherited hematological disorders characterised by early onset of anemia resulting from reduced synthesis of one or more globin chains which can be caused by many different globin gene mutations. β-thalassemia major is the most common genetic variant of transfusion-dependent thalassaemia seen in the Indian subcontinent, the Mediterranean basin, Southeast Asia and China. Recent advances in medical management of regular blood transfusion and chelation therapy have allowed most of these patients to have improved survival well into adult life and improved quality of life.[1],[2],[3],[4] Recently bone marrow transplantation (BMT) in early childhood has resulted in disease-free survival in patients with thalassaemia major and is now an important alternative to regular transfusion and chelation therapy.[5],[6] In children who received their BMT before 7 years of age, their mean final adult height is not significantly different from their mean target height. In contrast, short stature is present in a significant proportion of thalassemic children transplanted later in life.[7]
Growth in Medically Treated Patients with
β-Thalassemia Major
Before the introduction of hypertransfusion and chelation therapy in the routine management of patients with β-thalassemia major, chronic tissue hypoxia and iron toxicity from transfusion hemosiderosis have been implicated as major causes of growth retardation.[2],[8] Progressive accumulation of iron in the body in thalassemic patients results from repeated blood transfusion and increased absorption of dietary iron because of increased ineffective erythropoiesis. Without chelation, hemosiderosis can lead to tissue damage due to free radical formation, lipid peroxidation resulting in mitochondrial, lysosomal and sarcolemal damage and increased collagen deposition secondary to increased activity of the iron-dependent protocollagen proline hydroxylase enzyme activity.[8]
Modern medical therapy has allowed thalassemic children to grow normally in the first decade of life but growth retardation continues to be observed in a significant proportion of these adolescents.[2],[3],[9],[10],[11],[12],[13],[14],[15],[16] Borgna-Pignatti et al reported that among over 250 Italian adolescents, 29% of the females and 52% of the males were short.[9] In another recent report involving 476 Italian thalassemic patients, the mean standing height SDS was comparable to their mean target height SDS in the first decade of life.[14] Short stature was still common in patients in the 10 to 36 years age group and was present in 18% of the patients.[14] Kattamis et al reported that 21.7% of the males and 13% of the females were growth retarded among 405 Greek patients with thalassemia major with the highest incidence of growth failure being detected in the 15-20 years age group.[2] A more recent publication from Greece reported that 8% of prepubertal boys and none of the prepubertal girls (n=50%) were short.[15] Short final adult height was reported in 29% and 12% of male patients with and without endocrinopathy and in 29% and 15% of female patients with or without endocrinopathy among a cohort of 95 Greek adult thalassemic patients.[15] A surprising finding was reported from Italy that the growth rate of children receiving high transfusion and early chelation in early childhood was significantly slower than the childhood growth of patients treated with chelation in late childhood or early adolescence.[12] This may have been due to the effect of desferrioxamine toxicity which became recognised as problem in late 1980s.
In our own cross sectional study of 68 children with β-thalassemia major in Hong Kong, 75% of the girls and 62% of the boys over the age of 12 years were below the third percentile in height.[10] A high prevalence of growth and pubertal delay has been reported in thalassaemic patients from Turkey and India.[11],[17] Cross sectional studies on growth of thalassemic patients are problematic and must been interpreted in the light that patients had been treated with different transfusion regimes and different dosages and age of initiation of chelation therapy over time which would undoubtedly affect their growth and final adult height. Patients treated with hypertransfusion and early appropriate chelation therapy with meticulous dosage adjustment to avoid desferrioxamine toxicity should lead to a more optimistic growth outcome than depicted here.
In addition to short stature, an abnormal sitting height has been reported in studies on thalassemic patients from Australia[18] and Italy.[12],[14],[16] Among the short Italian patients with thalassemia, the majority (77%) of the patients had disproportionate short stature with short trunk but with less severe impairment of subischial leg length.[12] In our study of 71 Chinese children and adolescents with thalassemia, we found an upper to lower (U:L) segment ratio below the 10th percentile in 60% of the boys and 63% of the girls.[19] This abnormality of body proportion was due to platyspondyly as revealed by skeletal radiology and was present as early as 4 years of age in our patients but was more common in adolescence. The U:L segment ratio was not different among female patients with or without short stature but was significantly lower in the boys with short stature as compared to those with normal heights. We have no obvious explanation for the sex difference observed but this has not been reported in other studies.[12],[18] It would appear that short trunk frequently observed in patients with β-thalassemia is not necessarily the cause of the short stature. Platyspondyly has been observed in patients treated with transfusion but without chelation[12] and also in patients with low serum ferritin level while on hypertransfusion and regular chelation therapy since early childhood.[18] It is reasonable to suggest that platyspondyly in such patients can be the result of a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements.[19]
It is now recognised that short stature and skeletal dysplasia can be induced by injudicious use of desferrioxamine.[3],[16],[20],[21] Clinically, the patients with desferrioxamine-induced skeletal dysplasia have short trunk, genu valgum, metaphyseal widening of long bones, joint stiffness and a decreased growth velocity. Radiological changes include thickened growth plate with widening and cupping of the metaphyses of long bones, sclerosis of subchondral bone, osteoporosis and small radioluscent metaphyseal lesions. Desferrioxamine can inhibit DNA synthesis, fibroblast proliferation and collagen formation.[3],[16] The toxic effects of desferrioxamine can also be due to a deficiency of trace elements such as copper and zinc.[3],[16] In order to balance between the efficacy and toxicity of desferrioxamine, the toxicity index (mean daily dose of desferrioxamine in mg/kg serum ferritin in mg/L) should be monitored on a regular basis and should not exceed 0.025.[22]
The Growth Hormone-IGF-1 Axis in Patients with Thalassaemia Major
The studies on growth hormone (GH) secretion in patients have shown both normal[13],[23],[24] and reduced response[25],[26],[27],[28] to a variety of pharmacological stimuli. Normal or subnormal spontaneous growth hormone secretion has been reported in thalassemic patients.[25],[29],[30] The growth hormone response to growth hormone releasing hormone (GHRH) has been reported to be normal[23] or reduced.[31],[32],[33] In patients with delayed puberty, the GH response to GHRH was reported to be impaired, but the response improved with the onset of spontaneous or induced puberty with sex steroids or gonadotropin.[32] In thalassemic patients with impaired GH response to GHRH, the combination of GHRH with either pyridostigmine or arginine restored the GH response to stimulation to a level comparable to that observed in normal controls.[33] This finding suggests that the impaired GH secretion in some thalassemic patients may be due to an increase in the somatostatinergic tone on GH release. We have found an impaired GH response to insulin induced hypoglycemia in 12% of 41 short thalassemic children, all of whom were older than 9 years of age.[10] GH deficiency was reported to be present in 24% and 50% of short thalassemic patients from the United States[25] and Great Britain.[26] The prevalence of GH deficiency among 65 short Greek thalassemic patients was found to be 20%.[15] It is likely that as the patients survive longer, the prevalence of GH deficiency or neurosecretory dysfunction among these patients will increase with advancing age.
The serum IGF-1 and IGFBP-3 levels have been shown to be low in patients with transfusion dependent thalassemia major.[10],[23],[27],[28],[30],[34],[35] The low serum IGF-1 level in patients with thalassemia has previously been attributed to a decreased hepatic synthesis due to liver damage from transfusion hemosiderosis but this is unlikely to be the important causative factor. No evidence for a defect in growth hormone binding to liver membranes was found in patients with thalassemia major.[36] We have found that serum GH binding protein (GHBP) level was normal in short thalassemic patients without GH deficiency[34] and this finding has been confirmed in subsequent studies.[28] We also found no difference in the serum IGF-1 levels between Chinese thalassemic children (both prepubertal and pubertal) with or without growth failure suggesting that the growth failure in patients with thalassemia may not be specifically related to the GHRH-GH-IGF-1 axis.[10]
The IGF-1 generation test following GH administration was reported to be subnormal in thalassemic patients by some investigators.[27],[35] However normal IGF-1 generation tests have also been found in similar patients following GH administration.[28],[30] In thirteen non-GH deficient short thalassemic children, GH therapy resulted in significant improvement in the growth velocity as well as a dramatic rise in the serum IGF-1 and IGFBP-3 levels.[37] The present evidence (of normal GH reserve and serum GHBP levels with low serum IGF-1 and IGFBP-3 concentrations) suggests that a partial secondary GH insensitivity state exists in patients with transfusion-dependent thalassemia major and that supraphysiological doses of GH can overcome this resistance and lead to an improvement in the growth of such patients.
Hypogonadism and Growth in Adolescence
Hypogonadism is the most frequent endocrine complication in patients with thalassemia and is an important cause of growth retardation in adolescence. In a multicentre study from Italy involving 1861 patients, hypogonadism was present in 47% of girls older than 15 years of age and secondary amenorrhoea in 23%, menstrual irregularity in 14% and arrest of sexual maturation in 13%. Hypogonadism was present in half the male patients.[38] Similarly high prevalence of disordered puberty has been reported in other studies.[10],[18],[19],[25] Abnormal sexual maturation and hypogonadism were reported in 36% of the male and 67% of female patients from Australia.[18] Bronspiegal-Weintrob et al. reported that chelation therapy with desferrioxamine before puberty can help thalassemic children to attain normal sexual maturation. They observed that 90% of patients who received adequate chelation before 10 years of age had normal sexual development as compared to 38% in patients receiving chelation therapy after this age.[13] Favourable outcome in similar patients following medical therapy has also been reported from England.[26] However even in patients who have gone through spontaneous puberty, secondary amenorrhoea and hypogonadism will invariably develop with time.[38]
Hypogonadotropic hypogonadism is due to damage from iron deposition in the hypothalamus and pituitary gland but occasionally primary gonadal failure can also occur. The pituitary gonadotropes are particularly sensitive to oxidative damage induced by iron overload. Magnetic resonance imaging (MRI) of the anterior pituitary has shown that a decrease in signal intensity of spin-echo images of the pituitary is associated with increasing iron deposition in the anterior pituitary, and may be a useful investigative tool in the assessment of pituitary hemosiderosis. It has been shown that the gonadotropin response to gonadotropin releasing hormone stimulation is correlated with the grading of MRI-assessed iron deposition in the pituitary gland.[39] It has also been shown recently that patients with certain globin gene mutations (homozygous or double heterozygous mutation for 39 and IVSInt110) may be particularly susceptible to the development of hypogonadism due to iron overload.[16]
De Sanctis et al reported that the peak growth velocity during puberty was below the 10th percentile in 66% of males and 70% of females who had low pre-transfusion hemoglobin and were started on desferrioxamine late between 14 and 15 years of age.[12] 100% of the males and 46% of the females who were given high transfusion and started on chelation between 6 to 7 years of age had a peak growth velocity below the 10th precentile.[12] In a group of patients given transfusion and no chelation, an attenuated growth spurt was reported in all females with spontaneous or induced puberty and in 33% of boys during testosterone replacement.[40] In a study of 41 patients attending our centre who were over the age of 14 years, spontaneous puberty only occurred in 32% of the patients.[19] A significant pubertal growth spurt with spontaneous or induced puberty was observed in 46% of the patients. A retrospective analysis of the growth of 20 patients between 3 years of age and their final heights showed that the patients without a pubertal growth spurt had a significantly higher serum ferritin concentration and a shorter final height when compared to those patients who experienced a growth spurt during puberty.[19]
Thus, it can be concluded that short adult stature in transfusion-dependent thalassemia patients could be the result of a number of factors including chronic anaemia, hemosiderosis, endocrinopathy (disorder of the GH-IGF-1 axis, hypothyroidism and hypogonadism), skeletal dysplasia (hemosiderosis and desferrioxamine toxicity) and impaired pubertal growth.
Growth Promoting Treatment in Patients with Thalassemia Major
Over 130 children with thalassemia major and short stature have been treated with growth hormone for the past 20 years.[25],[27],[37],[41],[42],[43],[44],[45],[46],[47],[48] These children were either GH deficient or had normal growth hormone reserve and they were treated with GH in dosages varying from 0.5 IU/kg/week to 1.0 IU/kg/week. All the studies were open label studies with the exception of the study by Arcasoy et al.[44] which was a randomised controlled trial. All the studies have demonstrated that short term GH treatment for one year resulted in significant increase in the growth velocity without increase in rate of skeletal maturation table1. De Sanctis et al found no response in 4 out of 15 thalassaemic children with short stature and GH deficiency after one year of treatment with recombinant GH in a dose of 06-0.8 IU/kg/week and recommended the use of higher GH dosage for the treatment in such children.[48]
In our experience, a positive effect on growth was still present in children with thalassaemia major treated with GH for 3 to 4 years with improvement in the height SDS for both bone age and chronological age.[3],[49] In contrast, Cavallo et al. reported that the positive growth response to GH treatment in the first year did not persist during the second and third years of treatment.[50] A positive growth response to GH was demonstrated in the second year of treatment in the report by Wu et al.[47] The discrepant results in these studies may be due to a difference in GH dosage, the presence of other endocrinopathies like hypogonadism, hypothyroidism or the presence of skeletal dysplasia due to desferrioxamine toxicity.
Information on thalassaemic patients treated with GH until final height is still limited. Theodoridis et al. reported the final height in 13 patients treated for 1.66 to 9 years with growth hormone at a dose of 0.5 IU/kg/week. The final height SDS of -1.75 ±0.3 in boys (n=4) and -1.58±0.6 in girls (n=9) after GH treatment was significantly better than the pre-treatment height SDS for chronological age of -3.7±1.0 in boys and -2.8±0.5 in girls[15]. We have reported the final height data of 10 non-GH deficient thalassaemic patients treated with GH at a dose of 1.0 IU/kg/week from a mean age of 11.64±2.06 years for 2.5 to 7 years.[51] Treatment resulted in significant improvement in the final height SDS of -0.61±1.65 from a pretreatment height SDS for chronological age of -2.39±1.05. The final adult height SDS was better than the target height SDS of -1.02±0.71 based on the patients' parental heights.
Insulin dependent diabetes mellitus is a known complication in children with transfusion-dependent β-thalassemia and tends to occur in adolescence. The acute and chronic effects of GH on glucose homeostasis and insulin action are well established. One of our patients developed glycosuria while on GH treatment but no impairment of glucose tolerance was demonstrated after oral glucose challenge one week after stopping GH treatment. In eight prepubertal patients, there was no significant change in the fasting glucose, fasting insulin, serum fructosamine and insulin sensitivity indices derived from intravenous glucose tolerance test in our patients during the 3 years of GH therapy.[49],[51] GH therapy in these patients did not result in any worsening of the body disproportions.[3] We also addressed the concern of GH therapy on lipid metabolism in our thalassaemia patients. A significant increase in apolipoprotein(a) (Lpa) was demonstrated in 12 patients after 3 months of GH therapy but the elevated Lp(a) levels returned to pretreatment values within 12 months of treatment and remained at the basal level after 36 months of GH therapy.[52] Our patients all had low pretreatment total and high density lipoprotein-cholesterol (HDL-C) and there was a further significant fall in the total cholesterol concentration with GH treatment. Long-term GH therapy in thalassaemic patients did not promote an atherogenic lipid profile.[52] There was no significant change in the blood pressure, the blood count, renal and liver function tests, morning cortisol and thyroid function during GH therapy.[49],[51] However, meticulous monitoring of blood pressure, insulin sensitivity, biochemical and hormone parameters should be done on all patients regularly while they are on GH treatment.
The administration of long acting testosterone preparation of 1 mg/kg/month was given in 11 non-GH deficient boys with thalassaemia and delayed puberty aged 14.97±1.2 yrs for 1 to 3.6 years. Androgen replacement produced a significant improvement in height velocity from 2.39±0.9 cm/yr to 7.5±1.7 cm /yr.[15] This was similar to the results reported by investigators from Italy.[53] However we and others have previously shown that sex hormone replacement in thalassaemic patients do not necessarily lead to a significant growth spurt.[12],[19]
Conclusion
Despite advances in medical therapy, growth retardation and hypogonadism continue to be problems observed in transfusion-dependent patients with thalassemia major. Abnormal GH secretion may be seen in some of the patients but the majority of the short thalassemic patients do not have GH deficiency. The low serum IGF-1 and IGFBP-3 concentrations in short thalassemic patients with normal GH reserve and serum GHBP levels suggest a secondary GH insensitivity state. Supraphysiological doses of GH can overcome this partial GH insensitivity state in these patients resulting in improvement in the short-term growth as well as limited evidence on an improvement in the final adult height. GH therapy appears to be safe but careful regular monitoring for the development of side effects should be performed while the patients are on GH treatment.
Acknowledgement
The author would like to thank Ms J Cheng for her help in the preparation of the manuscript.
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30. Roth C, Pekrum A, Bartz M et al. Short stature and failure of pubertal development in thalassemia major: Evidence for hypothalamic neurosecretory dysfunction of growth hormone secretion and defective pituitary gonadotropin. Eur J Pediatr 1997; 156: 777-783.
31. Pintor C, Cella SG, Manso P et al. Impaired growth hormone (GH) response to GH-releasing hormone in thalassemia major. J Clin Endocrinol Metab 1986; 62: 263-267.
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44. Arcasoy A, Ocal G, Kemahli S et al. Recombinant human growth hormone treatment in children with thalassemia major. Pediatr Int 1999; 41: 655-661.
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Abstract
Hypertransfusion and regular chelation therapy have allowed improved survival in patients with thalassemia major (TM). Despite medical advances, growth failure and hypogonadism remain significant clinical problems in these patients in adolescence. Disproportionate truncal shortening which is common especially among adolescents with thalassemia, is due to platyspondyly resulting from a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements. Although growth hormone (GH) deficiency and GH neurosecretory dysfunction have been described in TM patients, most short TM patients have normal GH reserve. The low serum IGF-1 and IGFBP-3 concentrations in TM patients despite having normal GH reserve and serum GH binding protein levels suggest that a state of secondary GH insensitivity exists. The pubertal growth spurt may be impaired in TM patients going through spontaneous or induced puberty and may have a negative effect on final adult height. GH therapy in dosages ranging from 0.5-1.0 IU/kg/wk has resulted in a significant improvement in growth velocity in short TM children without any adverse effects on skeletal maturation, blood pressure, glucose tolerance and serum lipids. There is limited evidence that GH treatment can result in an improved final adult height in short TM children. Careful and regular clinical and biochemical monitoring should be preformed on these patients while they are treated with GH.
Keywords: Thalassaemia major; Truncal shortening; GH insensitivity
The thalassemias are a group of inherited hematological disorders characterised by early onset of anemia resulting from reduced synthesis of one or more globin chains which can be caused by many different globin gene mutations. β-thalassemia major is the most common genetic variant of transfusion-dependent thalassaemia seen in the Indian subcontinent, the Mediterranean basin, Southeast Asia and China. Recent advances in medical management of regular blood transfusion and chelation therapy have allowed most of these patients to have improved survival well into adult life and improved quality of life.[1],[2],[3],[4] Recently bone marrow transplantation (BMT) in early childhood has resulted in disease-free survival in patients with thalassaemia major and is now an important alternative to regular transfusion and chelation therapy.[5],[6] In children who received their BMT before 7 years of age, their mean final adult height is not significantly different from their mean target height. In contrast, short stature is present in a significant proportion of thalassemic children transplanted later in life.[7]
Growth in Medically Treated Patients with
β-Thalassemia Major
Before the introduction of hypertransfusion and chelation therapy in the routine management of patients with β-thalassemia major, chronic tissue hypoxia and iron toxicity from transfusion hemosiderosis have been implicated as major causes of growth retardation.[2],[8] Progressive accumulation of iron in the body in thalassemic patients results from repeated blood transfusion and increased absorption of dietary iron because of increased ineffective erythropoiesis. Without chelation, hemosiderosis can lead to tissue damage due to free radical formation, lipid peroxidation resulting in mitochondrial, lysosomal and sarcolemal damage and increased collagen deposition secondary to increased activity of the iron-dependent protocollagen proline hydroxylase enzyme activity.[8]
Modern medical therapy has allowed thalassemic children to grow normally in the first decade of life but growth retardation continues to be observed in a significant proportion of these adolescents.[2],[3],[9],[10],[11],[12],[13],[14],[15],[16] Borgna-Pignatti et al reported that among over 250 Italian adolescents, 29% of the females and 52% of the males were short.[9] In another recent report involving 476 Italian thalassemic patients, the mean standing height SDS was comparable to their mean target height SDS in the first decade of life.[14] Short stature was still common in patients in the 10 to 36 years age group and was present in 18% of the patients.[14] Kattamis et al reported that 21.7% of the males and 13% of the females were growth retarded among 405 Greek patients with thalassemia major with the highest incidence of growth failure being detected in the 15-20 years age group.[2] A more recent publication from Greece reported that 8% of prepubertal boys and none of the prepubertal girls (n=50%) were short.[15] Short final adult height was reported in 29% and 12% of male patients with and without endocrinopathy and in 29% and 15% of female patients with or without endocrinopathy among a cohort of 95 Greek adult thalassemic patients.[15] A surprising finding was reported from Italy that the growth rate of children receiving high transfusion and early chelation in early childhood was significantly slower than the childhood growth of patients treated with chelation in late childhood or early adolescence.[12] This may have been due to the effect of desferrioxamine toxicity which became recognised as problem in late 1980s.
In our own cross sectional study of 68 children with β-thalassemia major in Hong Kong, 75% of the girls and 62% of the boys over the age of 12 years were below the third percentile in height.[10] A high prevalence of growth and pubertal delay has been reported in thalassaemic patients from Turkey and India.[11],[17] Cross sectional studies on growth of thalassemic patients are problematic and must been interpreted in the light that patients had been treated with different transfusion regimes and different dosages and age of initiation of chelation therapy over time which would undoubtedly affect their growth and final adult height. Patients treated with hypertransfusion and early appropriate chelation therapy with meticulous dosage adjustment to avoid desferrioxamine toxicity should lead to a more optimistic growth outcome than depicted here.
In addition to short stature, an abnormal sitting height has been reported in studies on thalassemic patients from Australia[18] and Italy.[12],[14],[16] Among the short Italian patients with thalassemia, the majority (77%) of the patients had disproportionate short stature with short trunk but with less severe impairment of subischial leg length.[12] In our study of 71 Chinese children and adolescents with thalassemia, we found an upper to lower (U:L) segment ratio below the 10th percentile in 60% of the boys and 63% of the girls.[19] This abnormality of body proportion was due to platyspondyly as revealed by skeletal radiology and was present as early as 4 years of age in our patients but was more common in adolescence. The U:L segment ratio was not different among female patients with or without short stature but was significantly lower in the boys with short stature as compared to those with normal heights. We have no obvious explanation for the sex difference observed but this has not been reported in other studies.[12],[18] It would appear that short trunk frequently observed in patients with β-thalassemia is not necessarily the cause of the short stature. Platyspondyly has been observed in patients treated with transfusion but without chelation[12] and also in patients with low serum ferritin level while on hypertransfusion and regular chelation therapy since early childhood.[18] It is reasonable to suggest that platyspondyly in such patients can be the result of a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements.[19]
It is now recognised that short stature and skeletal dysplasia can be induced by injudicious use of desferrioxamine.[3],[16],[20],[21] Clinically, the patients with desferrioxamine-induced skeletal dysplasia have short trunk, genu valgum, metaphyseal widening of long bones, joint stiffness and a decreased growth velocity. Radiological changes include thickened growth plate with widening and cupping of the metaphyses of long bones, sclerosis of subchondral bone, osteoporosis and small radioluscent metaphyseal lesions. Desferrioxamine can inhibit DNA synthesis, fibroblast proliferation and collagen formation.[3],[16] The toxic effects of desferrioxamine can also be due to a deficiency of trace elements such as copper and zinc.[3],[16] In order to balance between the efficacy and toxicity of desferrioxamine, the toxicity index (mean daily dose of desferrioxamine in mg/kg serum ferritin in mg/L) should be monitored on a regular basis and should not exceed 0.025.[22]
The Growth Hormone-IGF-1 Axis in Patients with Thalassaemia Major
The studies on growth hormone (GH) secretion in patients have shown both normal[13],[23],[24] and reduced response[25],[26],[27],[28] to a variety of pharmacological stimuli. Normal or subnormal spontaneous growth hormone secretion has been reported in thalassemic patients.[25],[29],[30] The growth hormone response to growth hormone releasing hormone (GHRH) has been reported to be normal[23] or reduced.[31],[32],[33] In patients with delayed puberty, the GH response to GHRH was reported to be impaired, but the response improved with the onset of spontaneous or induced puberty with sex steroids or gonadotropin.[32] In thalassemic patients with impaired GH response to GHRH, the combination of GHRH with either pyridostigmine or arginine restored the GH response to stimulation to a level comparable to that observed in normal controls.[33] This finding suggests that the impaired GH secretion in some thalassemic patients may be due to an increase in the somatostatinergic tone on GH release. We have found an impaired GH response to insulin induced hypoglycemia in 12% of 41 short thalassemic children, all of whom were older than 9 years of age.[10] GH deficiency was reported to be present in 24% and 50% of short thalassemic patients from the United States[25] and Great Britain.[26] The prevalence of GH deficiency among 65 short Greek thalassemic patients was found to be 20%.[15] It is likely that as the patients survive longer, the prevalence of GH deficiency or neurosecretory dysfunction among these patients will increase with advancing age.
The serum IGF-1 and IGFBP-3 levels have been shown to be low in patients with transfusion dependent thalassemia major.[10],[23],[27],[28],[30],[34],[35] The low serum IGF-1 level in patients with thalassemia has previously been attributed to a decreased hepatic synthesis due to liver damage from transfusion hemosiderosis but this is unlikely to be the important causative factor. No evidence for a defect in growth hormone binding to liver membranes was found in patients with thalassemia major.[36] We have found that serum GH binding protein (GHBP) level was normal in short thalassemic patients without GH deficiency[34] and this finding has been confirmed in subsequent studies.[28] We also found no difference in the serum IGF-1 levels between Chinese thalassemic children (both prepubertal and pubertal) with or without growth failure suggesting that the growth failure in patients with thalassemia may not be specifically related to the GHRH-GH-IGF-1 axis.[10]
The IGF-1 generation test following GH administration was reported to be subnormal in thalassemic patients by some investigators.[27],[35] However normal IGF-1 generation tests have also been found in similar patients following GH administration.[28],[30] In thirteen non-GH deficient short thalassemic children, GH therapy resulted in significant improvement in the growth velocity as well as a dramatic rise in the serum IGF-1 and IGFBP-3 levels.[37] The present evidence (of normal GH reserve and serum GHBP levels with low serum IGF-1 and IGFBP-3 concentrations) suggests that a partial secondary GH insensitivity state exists in patients with transfusion-dependent thalassemia major and that supraphysiological doses of GH can overcome this resistance and lead to an improvement in the growth of such patients.
Hypogonadism and Growth in Adolescence
Hypogonadism is the most frequent endocrine complication in patients with thalassemia and is an important cause of growth retardation in adolescence. In a multicentre study from Italy involving 1861 patients, hypogonadism was present in 47% of girls older than 15 years of age and secondary amenorrhoea in 23%, menstrual irregularity in 14% and arrest of sexual maturation in 13%. Hypogonadism was present in half the male patients.[38] Similarly high prevalence of disordered puberty has been reported in other studies.[10],[18],[19],[25] Abnormal sexual maturation and hypogonadism were reported in 36% of the male and 67% of female patients from Australia.[18] Bronspiegal-Weintrob et al. reported that chelation therapy with desferrioxamine before puberty can help thalassemic children to attain normal sexual maturation. They observed that 90% of patients who received adequate chelation before 10 years of age had normal sexual development as compared to 38% in patients receiving chelation therapy after this age.[13] Favourable outcome in similar patients following medical therapy has also been reported from England.[26] However even in patients who have gone through spontaneous puberty, secondary amenorrhoea and hypogonadism will invariably develop with time.[38]
Hypogonadotropic hypogonadism is due to damage from iron deposition in the hypothalamus and pituitary gland but occasionally primary gonadal failure can also occur. The pituitary gonadotropes are particularly sensitive to oxidative damage induced by iron overload. Magnetic resonance imaging (MRI) of the anterior pituitary has shown that a decrease in signal intensity of spin-echo images of the pituitary is associated with increasing iron deposition in the anterior pituitary, and may be a useful investigative tool in the assessment of pituitary hemosiderosis. It has been shown that the gonadotropin response to gonadotropin releasing hormone stimulation is correlated with the grading of MRI-assessed iron deposition in the pituitary gland.[39] It has also been shown recently that patients with certain globin gene mutations (homozygous or double heterozygous mutation for 39 and IVSInt110) may be particularly susceptible to the development of hypogonadism due to iron overload.[16]
De Sanctis et al reported that the peak growth velocity during puberty was below the 10th percentile in 66% of males and 70% of females who had low pre-transfusion hemoglobin and were started on desferrioxamine late between 14 and 15 years of age.[12] 100% of the males and 46% of the females who were given high transfusion and started on chelation between 6 to 7 years of age had a peak growth velocity below the 10th precentile.[12] In a group of patients given transfusion and no chelation, an attenuated growth spurt was reported in all females with spontaneous or induced puberty and in 33% of boys during testosterone replacement.[40] In a study of 41 patients attending our centre who were over the age of 14 years, spontaneous puberty only occurred in 32% of the patients.[19] A significant pubertal growth spurt with spontaneous or induced puberty was observed in 46% of the patients. A retrospective analysis of the growth of 20 patients between 3 years of age and their final heights showed that the patients without a pubertal growth spurt had a significantly higher serum ferritin concentration and a shorter final height when compared to those patients who experienced a growth spurt during puberty.[19]
Thus, it can be concluded that short adult stature in transfusion-dependent thalassemia patients could be the result of a number of factors including chronic anaemia, hemosiderosis, endocrinopathy (disorder of the GH-IGF-1 axis, hypothyroidism and hypogonadism), skeletal dysplasia (hemosiderosis and desferrioxamine toxicity) and impaired pubertal growth.
Growth Promoting Treatment in Patients with Thalassemia Major
Over 130 children with thalassemia major and short stature have been treated with growth hormone for the past 20 years.[25],[27],[37],[41],[42],[43],[44],[45],[46],[47],[48] These children were either GH deficient or had normal growth hormone reserve and they were treated with GH in dosages varying from 0.5 IU/kg/week to 1.0 IU/kg/week. All the studies were open label studies with the exception of the study by Arcasoy et al.[44] which was a randomised controlled trial. All the studies have demonstrated that short term GH treatment for one year resulted in significant increase in the growth velocity without increase in rate of skeletal maturation table1. De Sanctis et al found no response in 4 out of 15 thalassaemic children with short stature and GH deficiency after one year of treatment with recombinant GH in a dose of 06-0.8 IU/kg/week and recommended the use of higher GH dosage for the treatment in such children.[48]
In our experience, a positive effect on growth was still present in children with thalassaemia major treated with GH for 3 to 4 years with improvement in the height SDS for both bone age and chronological age.[3],[49] In contrast, Cavallo et al. reported that the positive growth response to GH treatment in the first year did not persist during the second and third years of treatment.[50] A positive growth response to GH was demonstrated in the second year of treatment in the report by Wu et al.[47] The discrepant results in these studies may be due to a difference in GH dosage, the presence of other endocrinopathies like hypogonadism, hypothyroidism or the presence of skeletal dysplasia due to desferrioxamine toxicity.
Information on thalassaemic patients treated with GH until final height is still limited. Theodoridis et al. reported the final height in 13 patients treated for 1.66 to 9 years with growth hormone at a dose of 0.5 IU/kg/week. The final height SDS of -1.75 ±0.3 in boys (n=4) and -1.58±0.6 in girls (n=9) after GH treatment was significantly better than the pre-treatment height SDS for chronological age of -3.7±1.0 in boys and -2.8±0.5 in girls[15]. We have reported the final height data of 10 non-GH deficient thalassaemic patients treated with GH at a dose of 1.0 IU/kg/week from a mean age of 11.64±2.06 years for 2.5 to 7 years.[51] Treatment resulted in significant improvement in the final height SDS of -0.61±1.65 from a pretreatment height SDS for chronological age of -2.39±1.05. The final adult height SDS was better than the target height SDS of -1.02±0.71 based on the patients' parental heights.
Insulin dependent diabetes mellitus is a known complication in children with transfusion-dependent β-thalassemia and tends to occur in adolescence. The acute and chronic effects of GH on glucose homeostasis and insulin action are well established. One of our patients developed glycosuria while on GH treatment but no impairment of glucose tolerance was demonstrated after oral glucose challenge one week after stopping GH treatment. In eight prepubertal patients, there was no significant change in the fasting glucose, fasting insulin, serum fructosamine and insulin sensitivity indices derived from intravenous glucose tolerance test in our patients during the 3 years of GH therapy.[49],[51] GH therapy in these patients did not result in any worsening of the body disproportions.[3] We also addressed the concern of GH therapy on lipid metabolism in our thalassaemia patients. A significant increase in apolipoprotein(a) (Lpa) was demonstrated in 12 patients after 3 months of GH therapy but the elevated Lp(a) levels returned to pretreatment values within 12 months of treatment and remained at the basal level after 36 months of GH therapy.[52] Our patients all had low pretreatment total and high density lipoprotein-cholesterol (HDL-C) and there was a further significant fall in the total cholesterol concentration with GH treatment. Long-term GH therapy in thalassaemic patients did not promote an atherogenic lipid profile.[52] There was no significant change in the blood pressure, the blood count, renal and liver function tests, morning cortisol and thyroid function during GH therapy.[49],[51] However, meticulous monitoring of blood pressure, insulin sensitivity, biochemical and hormone parameters should be done on all patients regularly while they are on GH treatment.
The administration of long acting testosterone preparation of 1 mg/kg/month was given in 11 non-GH deficient boys with thalassaemia and delayed puberty aged 14.97±1.2 yrs for 1 to 3.6 years. Androgen replacement produced a significant improvement in height velocity from 2.39±0.9 cm/yr to 7.5±1.7 cm /yr.[15] This was similar to the results reported by investigators from Italy.[53] However we and others have previously shown that sex hormone replacement in thalassaemic patients do not necessarily lead to a significant growth spurt.[12],[19]
Conclusion
Despite advances in medical therapy, growth retardation and hypogonadism continue to be problems observed in transfusion-dependent patients with thalassemia major. Abnormal GH secretion may be seen in some of the patients but the majority of the short thalassemic patients do not have GH deficiency. The low serum IGF-1 and IGFBP-3 concentrations in short thalassemic patients with normal GH reserve and serum GHBP levels suggest a secondary GH insensitivity state. Supraphysiological doses of GH can overcome this partial GH insensitivity state in these patients resulting in improvement in the short-term growth as well as limited evidence on an improvement in the final adult height. GH therapy appears to be safe but careful regular monitoring for the development of side effects should be performed while the patients are on GH treatment.
Acknowledgement
The author would like to thank Ms J Cheng for her help in the preparation of the manuscript.
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