Hepatoblastoma Concerns and Growth Hormone Therapy in Small for Gestational Age Children
Yoshikazu Nishi, MD
Approximately 5% of children are born small for gestational age (SGA).1 Most of the SGA children present catch-up growth during their first year with completion of the growth recovery by two years of age.2 After the initial catch-up, most of the height gain is maintained up to adult height. However, children born SGA usually are shorter during childhood and attain adult heights that on average are approximately 1 SD lower than the mean.2 Approximately 10% of SGA infants do not experience spontaneous catch-up growth and remain short throughout childhood and adolescence and into adulthood.1,2 These short adults born SGA comprise up to 20% of the total population of short-statured adults.3
Growth hormone (GH) therapy for short children born SGA has been explored for nearly 40 years. Many international studies have shown that most of these children benefit from GH therapy by normalizing height during childhood, maintaining a normal growth velocity during the prepubertal years and through puberty, and attaining an improved adult height. In 2001 GH was approved, by the US Food and Drug Administration (FDA) and in 2003 by the European Agency for Evaluation of Medicinal Products (EMEA), for the treatment of short children born SGA who fail to manifest catch-up growth with a height <−2.0 SD by 2 years (FDA) or <−2.5 SD by 4 years (EMEA).2 In 2008, GH treatment was also approved in Japan for short SGA children who fail to manifest catch-up growth with a height <−2.5 SD by 3 years. The FDA, EMEA and Japan approved GH doses for SGA treatment (70/μg/kg/day, 35/μg/kg/day and 33−67/μg/kg/day, respectively) are high because of the presumed GH resistance contributing to the lack of catch-up growth in the SGA population and the results of heightened efficacy at high doses.2 These doses are up to three times greater than the standard replacement doses used to treat children with GH deficiency; furthermore, higher doses are used in children with marked growth retardation.
GH Therapy for Short SGA Children
The goal of GH therapy in short SGA children is to normalize adult height. To evaluate the impact of GH therapy on adult height in short SGA children, a meta-analysis of randomized controlled trials (RCTs) was performed by Maiorana and Cianfarani.4 A systematic review of controlled studies was made using as data source the Cochrane Central Register of Controlled Trials, Medline, and the bibliographic references from all retrieved articles describing RCTs up to November 2008. The adult height of the GH-treated group significantly exceeded controls by 0.9 SD. Mean height gain was 1.5 SDS in GH-treated versus 0.25 SD in untreated SGA subjects. No significant difference in adult height was observed between the two GH dose regimens (33 and 67 μg/kg/day). It was concluded that GH therapy seems to be an effective approach to partially reduce the adult height deficit in short SGA children.
The response to GH therapy is highly variable, and therefore additional studies are needed to identify the responders versus the non-responders. Maiorana and Cianfarani4 have reported that practitioners and policy makers need to address the clinical importance and value of the height gained, including the impact of the height gained on physical and psychosocial well-being, safety and adverse effects, cost of therapy, and patients' expectations.
Adverse Events in GH treated SGA Children
Simon et al5 reported that clinical trials and a large post-marketing survey have shown that GH treatment is well tolerated in SGA children. However, two particular issues need to be addressed pertaining to this population of SGA patients: the potential risk of malignancy due to high-dose GH treatment and the effects of GH on glucose metabolism. There is a large body of evidence that suggests that low birth weight (LBW) and very low birth weight (VLBW) are associated with a wide range of metabolic and physiological disorders in later life.2 It is currently unknown whether GH therapy − with higher doses used for SGA children throughout childhood and adolescence − may be associated with an amplification of risk for metabolic consequences such as glucose metabolism, insulin resistance, metabolic syndrome, coronary heart disease and stroke in adulthood.
GH is a known mitogenic agent and insulin-like growth factor (IGF)-I has antiapoptotic effects; therefore, researchers have expressed concern about the oncogenic potential of GH therapy.6 It is also known that serum IGF-I levels become high among those receiving the high-dose GH; a dose-dependent increase in the IGF-I level has been observed. High IGF-I levels over a prolonged period of time may increase the risk for malignancies; thus, it is currently recommended that IGF-I levels be monitored closely to maintain them within the normal range during GH treatment in SGA children.5
The consensus statement of international societies for the management of children born SGA have not reported that LBW has been shown to be associated with increased risk of cancer in general, with the possible exceptions of testicular, and to a lesser extent renal, cancer.2 In contrast, there is good evidence that high birth weight is associated with an increased risk of cancer, best documented for breast cancer.2 To date, no reports (including consensus statements of international societies for management of the child born SGA) have addressed the potential relationship of development of hepatoblastomas (HB) during or after GH therapy. A significantly higher rate of HB has been observed among LBW (<2500 g) and VLBW (<1500 g) children.7-10
Hepatoblastoma in Children with LBW
Hepatoblastoma is the most common liver cancer in children, occurring most frequently in premature infants, particularly those with LBW or VLBW, aged less than 5 years, especially less than 3 years.7-10 In SGA children treated with GH the occurrence of HB was mostly considered coincidental.11 Because data on VLBW and other childhood cancers are sparse, Spector et al7 examined the risk of malignancy with VLBW in a large data set. They combined case-control data sets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which included 17,672 children diagnosed as having cancer at 0 to 14 years of age and 57,966 randomly selected control subjects. They found that most childhood cancers were not associated with LBWs. However, a birth weight of 350−1499 g was associated with a considerably high risk of HB (odds ratio [OR]:17.18 and 95% confidence interval [CI]: 7.46-39.54), relative to a weighing ≥2500 g at birth.7
Reynolds et al8 also reported that using California's statewide registry (the California Cancer Registry), a striking elevated risk of HB was found in children from birth to 4 years of age who were born VLBW (OR: 50.57; 95% CI: 6.59-387.97). An analysis of Japanese cancer registry data from 1969-1994 also revealed an increasing trend in HB incidence among children of VLBW.9 The relative risk of HB among children with birth weights of <1000-2499 g compared with children with birth weight >2500 g is listed in the Table.9
Spector et al7 also reported that retinoblastoma and glioma (other than astrocytomas and ependymomas) were possibly associated with VLBW. Additionally, VLBW was associated with more than a twofold increased OR for gliomas (birth weight <1500 g, OR: 2.13 [95% CI: 0.71-6.39]; birth weight 1500-1999 g, OR: 3.58 [95% CI: 1.98-6.47]) and retinoblastomas (birth weight <1500 g, OR: 2.43 [95% CI: 1.00-5.89]). There was a significant OR of 1.42 (95% CI: 1.01-1.99) for intracranial embryonal cell tumors associated with birth weights of 2000-2499 g.7
Causes of Hepatoblastoma in LBW Children
The causes of HB development in LBW or VLBW children are not fully understood. Infants born with LBW or VLBW may undergo multiple medical interventions in the NICUs at a time in development when antioxidant capacity is decreased and xenobiotic metabolizing enzyme expression is variable; thus iatrogenic causes of HB, such as prolonged oxygen therapy and furosemide use, are plausible.7-10 The presence of erythropoietin receptors in HB has been also postulated to potentially contribute to this increased incidence of HB because many premature infants with LBW or VLBW receive erythropoietin during their time in the NICU.7-10
Latini et al12 also proposed that perinatal phthalate exposure may play a role in increasing the risk of HB among children with VLBW. Di(2-ethylhexyl)phthalate (DEHP) is the most commonly used plasticizer in polyvinylchloride (PVC) medical devices. In 2001, the Center for Devices and Radiological Health of the FDA reported that neonates in the NICU constitute a population at a particularly increased risk of toxicity because of multiple medical device-related DEHP exposure. In addition, it is well known that in animal models the liver is the most responsive target of the adverse effects of DEHP and that DEHP is a rodent hepatocarcinogen. As a consequence, prenatal and postnatal exposures to potential carcinogens may have synergistic and cumulative actions in producing adverse neonatal effects, especially for VLBW infants.
The GH-IGF-I axis may also be partially involved in HB development. Gray et al13 reported that the IGF-I axis plays an important role in many diverse cellular functions including promotion of cell growth and cell survival. The main producer of circulating IGF-I and IGF-II is the liver, and the ability of these peptides to mediate mitogenic, anti-apoptotic and differentiation signals is likely to be primarily via the IGF-I receptor. Using RNAase protein analysis (RPA), Gray et al13 examined the gene expression for IGF-1 and IGF-2, their receptors (IGF-IR and M6P/IGF-2R), and two IGF binding proteins ([IGFBP]; IGFBP-1 and IGFPB-2) in a series of HBs with corresponding normal liver from the same individuals. The results showed that the expression of many of the IGF-axis genes altered between tumor and normal, and indicated that the IGF-axis may be involved in HB development. Gray and colleagues concluded that the IGF-axis is affected in HB. While there are no definitive explanations on the role of IGF-axis, these alterations may play in the tumorigenesis process. One potential result of these alterations may be local concentrations of IGFs, in combination with reduced levels of IGFBPs, promote clonal expansion of the tumor cells. Further studies are indicated in order to determine the exact importance of the IGF-axis in HB.
Perinatal medicine has rapidly progressed and its sophisticated services have become standard; the survival of infants with LBW and VLBW has increased in recent decades. Treatment with GH for short children born SGA is also increasing - thereby escalating the risk of developing adverse events during and after GH therapy. Although HB occurs most frequently in infants or very young children before 3 years of age, and the usual start of GH therapy is after 2 years, the occurrence of HB has been mostly considered coincidental. However, an early start of GH therapy in short children born SGA has been encouraged14; this may increase the potential risks of developing complications - such as HB - for which these patients may be more susceptible than other types of patients being treated with GH.
The precise diagnosis of malignancies in GH-treated children born SGA has not always been reported; some papers may not classify the malignancies precisely, ie other tumors, and perhaps some patients who developed HB were not necessarily included in those reports. Therefore the prevalence of HB in GH-treated SGA patients is not really known.
Diagnosing HB before clinical signs and symptoms develop is important. HB is usually diagnosed as an asymptomatic abdominal mass. Therefore pediatric endocrinologists who follow short SGA children who are being treated with GH should monitor them carefully and repeatedly. Serum a-fetoprotein measurements and if possible, abdominal sonography, should be performed before and during GH therapy to assess for HB. Although the occurrence of malignancy is currently considered coincidental, the families of these children should be informed of the possible occurrence of HB. Furthermore, IGF-I levels should be monitored closely to maintain them within the normal range during GH treatment in SGA children.
The longest post-marketing GH surveillance study has been ongoing in the US for over 25 years - the Genentech National Cooperative Growth Study (NCGS). Recently, Bell et al reported more than 20 years of data covering approximately 55,000 patients treated with GH.15 This is a very valuable analysis of the experience gathered about the use of this drug; the data are reassuring regarding the safety and efficacy of GH.16 A review of the data by Roberto Lanes is summarized in this issue of GGH. However, the NCGS, as well as other similar studies performed by other companies (eg, KIGS, Pfizer International Growth Database), are not scientific-controlled studies. These post-marketing reporting groups rely on the voluntary reporting by physicians, thus the potential spectrum of potential adverse events may not be comprehensively assessed. The above paper by Yoshikazu Nishi clearly points out this potential weakness; it alerts us to the risk of hepatoblastomas in LBW children who may be treated with GH. The pediatric endocrine community has not hitherto considered this potential risk.
Fima Lifshitz, MD
References - (linked to )