Acta Haematol 2014;132:340–347 DOI: 10.1159/000360235

Published online: September 10, 2014

Thalassemia Major and Sickle Cell Disease in Adolescents and Young Adults Joanne Yacobovich a, b Hannah Tamary a, b b

Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Key Words Adolescence · Care transition · Sickle cell anemia · Thalassemia major · Young adults

Abstract The increased longevity of patients with thalassemia and sickle cell disease (SCD) introduces new clinical challenges due to the accumulation of disease-related morbidity, psychosocial issues and health care adjustments. Patients with thalassemia major now live into adulthood without suffering heart failure but must confront delayed puberty, impaired fertility and progressive bone disease. The increased survival in SCD brings to the front previously unrecognized complications including pulmonary hypertension, silent cerebral infarcts and also reproductive dysfunction. Adolescents and young adults (AYAs) have age-related psychosocial needs in their transition from the pediatric health care environment to the adult system. In this review we present the uniquely age-related medical issues facing the AYA thalassemia and SCD cohort in their transition into adulthood. © 2014 S. Karger AG, Basel

© 2014 S. Karger AG, Basel 0001–5792/14/1324–0340$39.50/0 E-Mail [email protected] www.karger.com/aha

Introduction

Adolescents and young adults (AYAs) with thalassemia major (TM) and sickle cell disease (SCD) pose unique challenges in their medical treatment. Improved availability of medical services, growing knowledge of the pathogenesis of disease symptoms, novel pharmaceutics and advancing technology are all responsible for the longevity of patients with the hereditary hemoglobinopathies. In Italy 60% of the patients with TM in 2009 were above 30 years of age [1], while in Greece the probability of survival was 65% at the age of 50 years [2]. Similarly, in SCD the survival has greatly improved; in 1994 the median survival for males with sickle cell anemia was 42 years and for females 48 years [3], while one decade later the Dallas cohort reported 85.6% overall survival [4]. Children with thalassemia require regular blood transfusions and have to adhere to iron chelation protocols in order to minimize iron overload complications leading to cardiac and endocrine toxicity. As AYAs they often face problems of delayed puberty and infertility as well as osteopenic/osteoporotic bone disease. Similarly, sickle cell AYA patients continue to experience the complications that manifest in childhood such as vaso-occlusive crises, and additionally suffer the accumulating effects of lung Hannah Tamary, MD Head of Hematology Unit, Schneider Children’s Medical Center of Israel 14 Kaplan Street Petah Tikva 49202 (Israel) E-Mail htamary @ post.tau.ac.il

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a

Thalassemia Major

Regular red cell transfusion effectively prevented classical complications of thalassemia, including facial malformations and high-output heart failure. Unfortunately iron overload complications leading to cardiac, endocrine and hepatic dysfunction have become a major cause of morbidity and mortality. In recent years however, the development of oral, parenteral and combination iron chelation therapy and access to noninvasive measures of iron burden by various MRI techniques have improved the survival of thalassemia patients [5]. Therefore there is an increasing AYA population that faces age-related endocrine complications including delayed puberty and reduced fertility. In addition, the development of bone disease [6–10], a major problem affecting a large proportion of adult patients with β-TM, starts manifesting in AYAs. Delayed Puberty Hypogonadotropic hypogonadism (HH) is the commonest endocrinopathy in thalassemic patients affecting 70–80% of patients and causing sexual infantilism, poor growth, infertility and osteoporosis [11–13]. Since quality of life and not merely preservation of life is a major issue for thalassemia patients today, the morbidity related to sexual infantilism is significant. Clinical signs of HH appear early in the second decade of life with failure of initiation of puberty, failure of progression of puberty and primary or secondary amenorrhea [14]. High serum ferritin levels have been associated with delayed puberty implicating poor chelation in the clinical signs of HH [15, 16]. Since it is known that iron loading precedes clinical signs of toxic damage in the heart and pancreas [17, 18], it is logical to assume that the same is relevant for the pituitary. Wood et al. [19] found decreased pituitary volume in thalassemic patients using T2 MRI which was accentuated with iron accumulation. This study showed that pituitary iron loading occurs commonly in children below the age of 10 years and as young as 4 years [19]. A susceptibility to develop HH was associated with severity Hemoglobinopathies in AYAs

of the thalassemic genotype. Patients with severe defects have increased red cell requirements, thus greater iron loading, and may also have a greater vulnerability to free radical damage. Endocrine tissue, similarly to cardiac tissue, takes up circulating labile iron species not bound by transferring, thereby suffering its more toxic effects [14]. Iron accumulation in the gonadotrope cells is not the sole cause of HH in thalassemic patients. Adipose tissue also suffers from iron loading, and in turn leptin synthesis is impaired. Leptin is a hormone produced in fat cells and has a physiological role in sexual maturation and fertility, most probably as a permissive signal for the process of puberty. The decreased levels of leptin in thalassemia seem to correlate with transferring receptor levels, indicating a relationship with iron toxicity [14]. Pituitary function must be monitored from an early age to guide chelation therapy. It was shown that intensive combination therapy can reverse existing HH and prevent new-onset hypogonadism [20]. Once diagnosed early, the treatment of delayed puberty with gonadotropin-releasing hormone can induce sexual maturation in up to 80% of cases [14]. If irreversible damage has already occurred, sex steroid replacement therapy is indicated. The timely treatment of HH is critical as it can prevent sexual infantilism and stunted growth as well as improve reproductive potential and minimize bone disease. Fertility Fertility is a growing issue and point of concern for the thalassemic AYA. Young women with thalassemia have impaired fertility mainly due to HH. Iron loading of the pituitary begins as early as at the age of 4 years with marked volume loss in the second decade of life [19]. The effect of iron overload on the ovary is less clear. Recently, use of antimüllerian hormone as a biomarker for the assessment of ovarian reserve has shown that fertility is preserved in the majority of thalassemic women younger than 30–35 years [21]. Over 400 pregnancies have been reported, more than half of them in women with amenorrhea, requiring ovulation induction [22]. Despite these optimistic data, infertility still disrupts family planning for the patients stressing the importance of early stringent chelation, active assessment of reproductive capacity and specialized fertility counseling. Pregnancies in thalassemic women bear a high risk, for the mother and fetus. Underlying cardiac and glucose metabolism impairments are more pronounced, and blood requirements increase [23]. A close follow-up is necessary with the cooperation of maternal-fetal clinics and hematologists familiar with the complications of pregnancies in thalassemia. Acta Haematol 2014;132:340–347 DOI: 10.1159/000360235

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disease, neurocognitive impairment and also reproductive dysfunction. In addition to the medical aspects of being AYAs with a chronic disease, these patients are faced with the challenges of the transition to adult treatment facilities, becoming independent individuals, considering family planning and a productive future. In this review we will address the issues uniquely facing the AYA patients with β-TM and SCD.

Bone Disease Osteoporosis is another complication that becomes problematic in the AYA population [25]. The pathogenesis of bone disease is multifactorial being affected by delayed sexual maturation, endocrine dysfunction, extramedullary hematopoiesis, iron toxicity and chelator therapy [26]. Normally, bone mineral density rises throughout childhood until the age of 12 years and then accelerates during the onset of puberty paralleling the growth spurt. Thalassemic youth, often suffering from absent or delayed puberty due to HH, may fail to proceed with the proper bone mineralization and not achieve peak bone mass [27–30]. Thalassemic patients also continue later on to have an increased bone resorption secondary to hypogonadism [31]. Genotype differences including β0/β+ compound heterozygotes and additional α-thalassemia mutations mediate red cell consumption, iron loading and thereby the rate of endocrine complications. When patients were grouped according to thalassemia genotype, gonadal function was found to be the only factor associated with decreased bone mineral density [32, 33]. Additionally, polymorphisms known to affect bone mineral density can identify patients at greater risk for osteoporosis and fractures [34]. Growth hormone secretory dysfunction has been described in thalassemia as well as diminished levels of insulin-like growth factor-1 [35, 36]; these may also directly contribute to demineralization of the femoral head [37]. Additional factors that affect the tendency for osteoporosis include vitamin D deficiency and depletion of trace elements by poor nutrition combined with chelation therapy [38– 41]. The best way to treat osteoporosis in thalassemics is prevention. Regular transfusions, adequate diet and correction of nutritional deficiencies with supplementation 342

Acta Haematol 2014;132:340–347 DOI: 10.1159/000360235

are essential, especially during childhood and puberty. Induction of puberty and further hormone replacement therapy are important in the prevention of bone disease [42, 43]. If osteoporosis is diagnosed, the use of biphosphonates has shown short-term success in improving bone mass Z score [44]. Specifically, monthly infusions of pamidronate were shown to significantly improve bone volume in thalassemic men and women [45], while neridronate, a third-generation bisphosphonate, significantly reduced bone resorption, increased bone density and reduced back pain [46]. Implementation of hormone replacement, dietary supplementation and bisphosphonate therapy should lead to improved quality of life and better daily functioning.

Sickle Cell Disease

The clinical complications of SCD begin from early childhood and continue to accumulate through the AYA age group into later adulthood. With contemporary care the survival of these patients has also greatly increased. The major vaso-occlusive events such as pain crises, acute chest syndrome and stroke that contribute to significant morbidity from the pediatric age range have been extensively documented [47, 48], while pulmonary hypertension (PH), silent cerebral infarcts and fertility difficulties are increasingly related to a significant handicap in the AYA age group. Research into age-related trends has shown poorer outcome and increased mortality during the period of transition of patients from pediatric to adult care [3, 49, 50]. By recognizing the specific health needs of the AYA sickle cell anemia population, it will be possible to focus on improving their care and outcome. Pulmonary Disease Acute chest syndrome (ACS) is the leading cause of premature death and the second most common reason for admission among patients with SCD [3]. The major causes of ACS include pneumonia, bone marrow/fat embolism and in situ sickling/pulmonary infarct [51]. This complication is most common in children, however severer in adults [52]. In adults often ACS follows pain crises, supposedly secondary to hypoventilation due to splinting with chest wall pain or immobilization due to lower limb pain [53]. Additionally is has been recognized that secretory phospholipase A2 can induce inflammatory lung injury by converting bone marrow fat into free fatty acids and may predict the onset of ACS [54]. In a study of 14 adolescents, secretory phospholipase A2 was used as a Yacobovich/Tamary

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There is a paucity of literature on the effects of thalassemia on male fertility. One study found that in addition to the hormonal disturbances due to hypothalamic/pituitary axis failure, thalassemic males have a decreased sperm count, sperm motility and proportion of sperm with normal morphology. A comprehensive assessment is required to determine the source of male infertility in order to compile the appropriate fertility therapy [24]. Intensive combined chelation with deferiprone and deferoxamine was shown to prevent progression of subclinical endocrinopathies and even reverse hypothalamic dysfunction due to iron overload toxicity [20]. Recognizing this possibility should provide the incentive for the AYA thalassemic population to aggressively chelate with the goal of normalizing the iron status.

Neurological/Cognitive Complications Cerebral and/or neurocognitive insult due to multiple factors is of growing concern in the treatment of SCD as it limits the functioning potential of the developing child and young adult. Silent cerebral infarct (SCI) is the most common neurological injury in SCD and occurs in about one third of children before their 14th birthday [62]. The definition of SCI is challenging requiring investigation of the previous history of any neurological complaints (seizure, focal weakness, ataxia, dizziness), specific requirements upon MRI and strict guidelines to rule out mimickers of SCI [63]. The Silent Cerebral Infarct Trial included 814 children with SCI-like lesions who were examined by a pediatric neurologist to rule out the presence of focal deficits that were explained by the radiological findings. It was found that hemoglobin

Thalassemia major and sickle cell disease in adolescents and young adults.

The increased longevity of patients with thalassemia and sickle cell disease (SCD) introduces new clinical challenges due to the accumulation of disea...
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