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Non-islet-cell tumor associated with hypoglycemia in a child: Successful long-term therapy with growth hormone
Non-islet-cell tumor associated with hypoglycemia in a child: Successful Iong-term therapy with growth hormone Michael S. D. Agus, MD, Lorraine E. Levitt Katz, MD, Marta Satin-Smith, MD, Anna T. Meadows, MD, Ray L. Hintz, MD, and Pinchas Cohen, MD From the Departments of Pediatrics, Children's Hospital of Boston, Harvard UniversitySchool of Medicine, Boston, Massachusetts, Children's Flospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, and Stanford University Medical Center, Stanford, California
Hypoglycemia occurred in a 2-year-old girl with neuroblastoma. Initially, growth hormone secretion was suppressed, and she had Iow levels of insulin-like growth factor (IGF)-I and IGF binding protein-3, but elevated levels of large molecular weight IGF-II. We postulated that the pathogenesis of her hypoglycemia involved production of IGF-II by her neuroblastoma, leading to GH suppression and an abnormally elevated ratio of IGF to IGF binding protein. She was successfully treated with growth hormone; treatment was associated with normalization of the growth hormone-dependent growth factor levels and with euglycemia. (J PEDIATR 1995; 127:403-7)
Hypoglycemia has been associated with several non-isletcell neoplasms. The most common are large mesenchymal tumors in the abdomen and thorax, such as fibrosarcomas, mesotheliomas, and neurofibromas; others implicated include hepatomas, hepatocellular carcinomas, adrenal cortical cell tumors, and one congenital neuroblastoma. 1 In this condiüon, insulin and C-peptide levels are extremely low in the presence of insulin-like suppression of hepatic glucose production. Patients offen require continuous intravenous infusions of glucose and, in some cases, of glucagon. Complete remission is induced only by surgical resection of the tumor. The pathophysiology of NICT hypoglycemia, and therelore its treatment, has not yet been fully elucidated. Theories included an increased rate of metabolism by the tumor itself, or the elaboration by the tumor of a substance that affects the metabolic pathways of the host. Several studies have shown Supported in part by grant 1RO1 DK47591-01 and an American Diabetes Association Career Development Award (Dr. Cohen). Submitted for publication Feb. 15, 1995; accepted April 13, 1995. Reprint requests: Pinchas Cohen, MD, Assistant Professor of Pediatrics, D~vision of Endocrinology, Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$5.00 + 0 9/20/65519
that these tumors secrete a high molecular weight form of insulin-like growth factor II.2' 3 Hypoglycemia is thought to occur by direct action of IGF on the IGF and insulin receptors, and by increasing sensitivity to insulin. The initial insult is likely the suppression of growth hormone by IGF-II. " B i g " IGF-II has been demonstrated in several adult ALS CT GH IGF IGFBP NICT RIA .
Acid-labile subunit Computedtomography Growthhormone lnsulin-like growth factor Insulin-like growth factor binding protein Non-islet-celltumor Radioimmunoassay
patients with NICT hypoglycemia24 but has not been fully described in a child. Treatment of NICT hypoglycemia with exogenous GH has been attempted with varying degrees of success and failure, but in the long térm, treatment 5-7 has not been completely efficacious. W e describe correction of the biochemical abnormalities and of the clinical symptoms of NICT hypoglycemia with GH therapy. CASE REPORT
A 2N-year-old girl with familial stage III neuroblastoma was seen in the emergency department of the Children's Hospital of Phila403
404
Agus et al.
The Journal of Pediatrics September 1995
10-
5i_.. 0
2 . 7 5 mmol/L
~~
.cSupervised
fast
= 101 ~
0
0
2
4
6
8 10 12 Days in Hospital
14
16
Figtlre. Blood glucose, rate of dextrose infusion, and dose of growth hormone treatment per day during hospital course. Top panel:Labile blood glucose concentration with fewer values approaching 2.75 mmol/L (50 mg/dl) as GH treatment . is continued. Middle panel: High dextrose requirement for the first 10 days, and then an abrupt decrease on day 11 of hospitalizafion. Bottom panel: Total dally dose of GH. The patient was discharged to receive GH, 0.2 mg/kg per day intramuscularly in two divided doses. delphia with a blood glucose concentration of 0.6 mmol/L (11 mg/ dl) and seizures. She had been delivered vaginally at term without complications to a mother who, along with three of her four siblings, had neuroblastomas (all three of the mother's siblings died, at 26 days, 13 months, and 2fi years of age, respectively).8 The grandmother also had increased urinary catecholamine excretion and a mediastinal mass. Hirschspnmg disease (also familial) and neuroblastoma, in the form of right adrenal and right paraspinal masses, had been diagnosed in our patient at 3 weeks of age. Both were treated surgically. Follow-up abdominal computed tomography at 3 months of age showed regrowth of the abdominal tumor arising from the cefiac axes, and urinary homovanillic acid and vanillylmandelic acid values were elevated; results of bone marrow examination and bone scan were negative for metastatic disease. During the next 7 months, homovanillic and vanillylmandelic acid excretion continued to rise as the tumor extended across the diaphragm into her chest despite multiple courses of chemotherapy, including cyclophosphamide, cisplafin, doxorubicin, etoposide, and ifosfamide. Abdominal CT at 1 year of age suggested differentiation into benign ganglioneuroma,
with signs of calcifications and necrosis. The patient then received several 14-day courses of therapy with retinoic acid, as well as a treatment with metaiodobenzyl guanidine labeled with iodine 131. The tumor around the left kidney was partially resected to relieve ureteral compression at 21 months, with excellent results. The patient had no hypoglycemic symptoms until seen at the emergency department with seizures 1 day after having recovered from a viral gastroenteritis. She had maintained good oral intake during the previous 36 hours. On admission to the hospital, she required intravenous infusion of dextrose at 3.3 mmol/kg (6 mg/kg) per minute to maintain euglycemia (Figure). A stimulation test with adrenocorticotropic hormone produced an appropfiate cortisol response (1380 nmol/L [50 pg/dl). A supervised fast cansed a decrease in blood glucose values within 45 minutes and was terminated early because of symptomatic hypoglycemia. Blood values for insulin and C-peptide were suppressed in association with insulinomimetic suppression of ketogenesis, free fatty acids, and levels of IGF binding protein-1, and there was no appropfiate rise of GH with hypoglycemia (Table I). Cranial and abdominal CT revealed no increased tumor size or
The Journal of Pediatlqcs • Volume 127, Number 3
A g u s et aL
405
Table 1. Results of blood tests during a supervised fast before GH treatment
Time (min) 0 45 Normal fasting range
Glucose (mmol/l.)
Insulin (pmollL)
C-peptide (nmollL)
l~-OH-butyrate (mmol/L)
IGFBP- I (nmol/L)
Growth hormone (IJg/L)
5.1 1.7 2.8-6. I
79 180 <215
0.93 0.60 < 1.1
0.42 0.22 >2.0
3.2 2.0 >3.6
1.2 2.4 >10
l o b l e II. Levels of IGF and related molecules before and during GH therapy
Hospital day 4 12 Normal range for age
GH (mg/kg/ day)
IV dextrose (mg/kg/ min)
0 0.2 --
6 0 --
IGF-I (nmol/L) 11.1 38.7 1.5-27.5
Total IGF-II (ng/ml)
"Big" IGF-II (% total IGF-II)
IGF-IIE (ng/ml)
59.6 100.9 44.5-85.6
80% 50% <5%
10 1-4
evidence of metastatic disease. Resfing energy expenditure was approximately 110% of normal. Intramuscular administration of growth hormone was initiated at 0.05 mg/kg per day in divided doses, increased to 0.1 mg/kg per day 3 days later, and increased to 0.2 mg/kg per day after 2 more days. During that fime, the pafient's requirement for dextrose did not significantlychange. On the eighth day of GH treatment, the intravenous dextrose reqnirement dropped quickly within approximately 12 hours (Figure). The patient was maintalned on ovemight dextrose infusions for 2 more nights as a safety measure. During a subsequent 12-hour fast, her blood glucose concentration stayed at greater than 3.4 mmol/L (62 mg/dl). Throughout hospitalization the patient had episodes of sweafing, increased irritability, tachycardäa, and tachypnea, with concomitant blood glucose va/nes of 4.4 to 5.0 mmol/L (80 to 90 mg/dl). These were attributed to catecholamine secrefion. Surgery was not attempted because of the proxirnity of the tumor to the pafient's great vessels. She was discharged to receive GH, 0.2 mg/kg per day intramuscularly in two divided doses. After 12 months of followup, she continues to thrive on regular feedings without any episodes of hypoglycemia, and her linear growth has advanced from the 5th to the 50th percentile. Initially, attempts to reduce the GH dosage resulted in decreased blood sugar values. However, at the 6-month follow-up, the dosage of GH was reduced to 0.1 mg/kg per day without causing hypoglycemia. Repeated CT scans of the abdomen showed no change in the size of the tumor. The presence of "big" IGF-II in the patient's serum was demonstrated by column chromatography, which disclosed most of the IGF-II to be of 15 kD molecular weight, and by the presence of elevated IGF-IIE immtmoreactivity. As shown in Table II, serum IGF-I and total IGF-II levels increased after 8 days of GH therapy, and serum IGFBP-3 levels, initially in the GH-deficient range, rose threefold. Serum measurements of the acid-labile subunit, a component of the circulating 150 kD complex along with IGF and IGFBP, were initially low but doubled during GH therapy. The
8
ALS (% adult control)
IGFBP-3 (nmol/L)
Molar ratio (IGF-I + Il/ IGFBP-3)
69% 129% Not defined
25 105 35-75
2.8 1.3 0.8-1.2
increase in IGFBP-3 levels resulted in a normalizafion of the molar ratio of the IGFs to their major carrier protein. These changes were maintained after 6 months of GH therapy.
METHODS Analytic methods. Plasma IGF-I and IGF-II were measured after acid chromatography, by radioimmunoassay with specific antibodies. 4 IGF-1I chromatography was performed with a 120 cm G50 acid column (Pharmacia Inc., Piscataway, N.J.). IGF-II RIA was performed on the eluted fractions. High molecular weight IGF-II eluted 10 to 15 fractions away from small IGF-II.4 IGF-HE RIA was performed as previously described, with an antibody developed against a 16-amino acid segment of the IGF-I]E.4 Levels of IGFBP-1 were measured by specific RIA performed at Corning Nichols Institute, San Juan Capistrano, Calif. Levels of IGFBP-3 were measured by RIA performed at Endocrine Sciences, Calabasas Hills, Calif. The ALS was assayed by immunoblotting with the ECL kit (Amersham, Arlington, Ill.) and a specific antibody for ALS (Diagnostic Systems Laboratories, Houston, Tex.), and analyzed densitometrically.
DISCUSS1ON The pathophysiology of NICT hypoglycemia has been the subject of considerable debate and research. The postulate that the hypoglycemia is secondary to increased glucose consumption by the tumor has not been supported directly, and has not been shown to be true of most tumors. Eastman et al. 9 used positron emission tomography to demonstrate that, in a patient with hepatoma, glucose uptake was increased in skeletal muscle rather than in the tumor. Another study using hyperinsulinemic-euglycemic clamp studies
406
Agus et al.
demonstrated an increase in total body insulin sensitivity.1° In multiple studies, the GH/IGF axis has been demonstrated to play a major role in the induction of hypoglycemia. Tumors have been shown to produce an incompletely processed, high molecular weight, pro-IGF-II molecule24 that contains an extra peptide, the E-region, which is cleaved in normal hepatic processing to create mature serum IGF-II.4 This elevation of " b i g " IGF-II values is thought to suppress G H secretion, with a consequent reduction in IGF-I and in the major serum IGF binding protein, IGFBP-3.11 Normally, nearly all of the circulating IGF-I and IGF-II is bound to IGFBP-3 with ALS, forming a 150 kl) complex) 2 " B i g " IGF-II may, however, have a decreased tendency to form the ternary 150 kD complex. 3 With a relative deficit of IGFBP-3 and ALS, there is increased bioavailabifity of IGF-I and IGF-II, which are bound with other IGFBPs to form low molecular weight complexes. In this stare, IGFs have a shorter half-life in the circulation, enhanced, transendothelial passage, and relatively rapid delivery to target tissues, leading ultimately to insufin-like hypoglycemic effects. The Suppression of GH may also make a direct contribution to hypoglycemia, which is a well-recognized complication of GH deficiency. Because the decrease in GH level induced by the tumorproduced IGF-II is the central mechanism in ultimately producing the hypoglycemia, replacing GH might reverse this chain of events. Therapy with GH had been attempted previously with modest and transient success in one patient with metastatic neurofibrosarcoma. 5 Teale et al.6 achieved moderate success in three patients, but eventually all three required surgical resection before they could be maintained in a euglycemic stare without intravenous infusions of glucose. Wing et al.7 achieved only a transient decrease in exogenous glucose requirement. Our patient had long-term successful treatment of NICT hypoglycemia with exogenous GH. Because of the surgical risks, medical therapy was the only option for this patient. The dose of GH (0.2 mg/kg per day intramuscularly) and the duration of treatment (8 days) needed to achieve resolution of hypoglycemia had not previously been combined, and may represent requirements for successful treatment. Alternatively, peculiarities of this patient, her tumor, and other unknown factors may have contributed to her response to GH treatment. We do not know what caused the patient's long-standing tumor to begin producing " b i g " IGF-II. However, her chemotherapy included several 14-day courses of therapy with retinoic acid, a naturally occurring morphogen that inhibits neuroblastoma cell growth and induces differentiation into neufite cells. It has been suggested that retinoic acid induces IGF-1I expression in neuroblastoma cell lines) 3 Out patient received her last dose of retinoie acid 7 months before the
The Journal of Pediatrics September 1995
start of hypoglycemia, but this association deserves further investigation. The clinical relevance of this case may go beyond the advancement in out understanding of the GH/IGF axis. Studies on the use of IGFs in insulin-dependent diabetes mellitus suggest that these agents have a role in increasing insulin sensitivity and lowering of the blood sugar concentration. 14 Barzilal et al. 1° descfibed a patient with non-insulin-dependent diabetes mellitus, who had NICT hypoglycemia caused by a hepatoma, had gradually decreased insulin requirernents from 70 u nits per day to none, and still had hypoglycemia; euglycemic clamp studies demoustrated increased insulin sensitivity. These cases serve as a paradigm for the potential usefulness of IGF therapy in diabetic states. Suppression of GH secretion in diabetes may improve glycemic control and prevent long-term complications. Although hypoglycemia has rarely been associated with childhood tumors, this unusual case fits the model of other cases of NICT hypoglycemia in adults, and therefore supports the theory that tumor IGF-II production causes the derangements in the GH/IGF axis and the resultant hypoglycemia. The use of GH in adequate doses, given for a sufficiently long time, appears to counteract these hypoglycemic effects and should be considered for first-line therapy in futute patients, both as preoperative medical management and as sole therapy when surgery is contraindicated. REFERENCES
1. Shapiro M, Simcha A, Rosenmann E, $haffir E. Hypoglycemia associated with neonatal neuroblastoma and abnormal responses of serum glucose and ffee fatty a¢ids to epinephfine injection. Israel J Med Sci 1966;2:705-14. 2. Daughaday WH, Emanuelle MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P. Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 1988;319:1434-40. 3. Zapf J, Futo E, Peter M, Froesch ER. Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia. J Clin Inrest 1992;90:2574-84'. 4. Liu F, Baker BK, Powell DR, Hintz RL. Charactefization of proinsulin-like growth factor-II E-region immunoreacüvity in serum and other biological fluids. J Clin Endocfinol Metab 1993;76:1095-100. 5. Samaan NA, Pham FK, $ellin RV, et al. Successful treatment of hypoglycemiausing glucagon in a patient with an extrapancreatic tumor. Ann h~tem Med 1990;113:404-6. 6. Teale JD, Blum WF, Marks V. Alleviationof non-islet tel1 tumor hypoglycaemia by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem 1992;29:314-23. 7. Wing JR, Panz VR, Joffe BI, et al. Hypoglycemia in hepatocellular carcinoma: failure of short-term growth hormone administration to reduce enhanced glucose requirements. Metabolism 1991;40:508-12. 8. Chatten J, Voorhees ML. Familial neuroblastoma: report of a
The Journal of Pediatrics Volume 127, Number 3
Agus et al.
kindred with multiple disorders, including neuroblastomas in four siblings. N Engl J Med 1967;277:1230-6. 9. Eastman RC, Carson RE, Ofloff DG, et al. Glucose utilization in a patient with hepatoma and hypoglycemia: assessment by a positron emission tomography. J Cfin Invest 1992;89:195863. 10. Barzilai N, Cohen P, Bar-Illan R, McIntyre N, KarniefiE. Case report: increased insulin sensitivity in tumor hypoglycemia in a diabetic patient--glucose metabolism in tumor hypoglycemia. Am J Med Sci 1991;302:229-34. 11. Jorgensen JOL, Blum WF, Moller N, Ranke MB, Christiansen JS. Short-term changes in serum insulin-fike growth factors (IGF) and IGF binding protein 3 after different modes of intra-
407
venous growth hormone (GH) exposure in GH-deficient patients. J Clin Endocrinol Metab 1991;72:528-37. 12. Cohen P, Rosenfeld RG. Physiological and clinical relevance of the insulin-like growth factor binding proteins. Curr Opin Pediatr 1994;6:462-7. 13. Matsumoto K, Gaetano C, Daughaday WH, Thiele CJ. Retinoic acid regulates insulin-like growth factor II expression in a neuroblastoma cell line. Endocrinology 1992;130:3669-76. 14. Cheethan TD, Jones J, Taylor AM, Matthews DR, Dunger DB. The effects of recombinant insulin-likegrowth factor I administration on growth hormone levels and insulin requirementsin ad01escents with type 1 (insulin-dependent)diabetes mellitus. Diabetologia 1993;36:678-81.
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Hypoglycemia occurred in a 2-year-old girl with neuroblastoma. Initially, growth hormone secretion was suppressed, and she had Iow levels of insulin-like growth factor (IGF)-I and IGF binding protein-3, but elevated levels of large molecular weight IGF-II. We postulated that the pathogenesis of her hypoglycemia involved production of IGF-II by her neuroblastoma, leading to GH suppression and an abnormally elevated ratio of IGF to IGF binding protein. She was successfully treated with growth hormone; treatment was associated with normalization of the growth hormone-dependent growth factor levels and with euglycemia. (J PEDIATR 1995; 127:403-7)
Hypoglycemia has been associated with several non-isletcell neoplasms. The most common are large mesenchymal tumors in the abdomen and thorax, such as fibrosarcomas, mesotheliomas, and neurofibromas; others implicated include hepatomas, hepatocellular carcinomas, adrenal cortical cell tumors, and one congenital neuroblastoma. 1 In this condiüon, insulin and C-peptide levels are extremely low in the presence of insulin-like suppression of hepatic glucose production. Patients offen require continuous intravenous infusions of glucose and, in some cases, of glucagon. Complete remission is induced only by surgical resection of the tumor. The pathophysiology of NICT hypoglycemia, and therelore its treatment, has not yet been fully elucidated. Theories included an increased rate of metabolism by the tumor itself, or the elaboration by the tumor of a substance that affects the metabolic pathways of the host. Several studies have shown Supported in part by grant 1RO1 DK47591-01 and an American Diabetes Association Career Development Award (Dr. Cohen). Submitted for publication Feb. 15, 1995; accepted April 13, 1995. Reprint requests: Pinchas Cohen, MD, Assistant Professor of Pediatrics, D~vision of Endocrinology, Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$5.00 + 0 9/20/65519
that these tumors secrete a high molecular weight form of insulin-like growth factor II.2' 3 Hypoglycemia is thought to occur by direct action of IGF on the IGF and insulin receptors, and by increasing sensitivity to insulin. The initial insult is likely the suppression of growth hormone by IGF-II. " B i g " IGF-II has been demonstrated in several adult ALS CT GH IGF IGFBP NICT RIA .
Acid-labile subunit Computedtomography Growthhormone lnsulin-like growth factor Insulin-like growth factor binding protein Non-islet-celltumor Radioimmunoassay
patients with NICT hypoglycemia24 but has not been fully described in a child. Treatment of NICT hypoglycemia with exogenous GH has been attempted with varying degrees of success and failure, but in the long térm, treatment 5-7 has not been completely efficacious. W e describe correction of the biochemical abnormalities and of the clinical symptoms of NICT hypoglycemia with GH therapy. CASE REPORT
A 2N-year-old girl with familial stage III neuroblastoma was seen in the emergency department of the Children's Hospital of Phila403
404
Agus et al.
The Journal of Pediatrics September 1995
10-
5i_.. 0
2 . 7 5 mmol/L
~~
.cSupervised
fast
= 101 ~
0
0
2
4
6
8 10 12 Days in Hospital
14
16
Figtlre. Blood glucose, rate of dextrose infusion, and dose of growth hormone treatment per day during hospital course. Top panel:Labile blood glucose concentration with fewer values approaching 2.75 mmol/L (50 mg/dl) as GH treatment . is continued. Middle panel: High dextrose requirement for the first 10 days, and then an abrupt decrease on day 11 of hospitalizafion. Bottom panel: Total dally dose of GH. The patient was discharged to receive GH, 0.2 mg/kg per day intramuscularly in two divided doses. delphia with a blood glucose concentration of 0.6 mmol/L (11 mg/ dl) and seizures. She had been delivered vaginally at term without complications to a mother who, along with three of her four siblings, had neuroblastomas (all three of the mother's siblings died, at 26 days, 13 months, and 2fi years of age, respectively).8 The grandmother also had increased urinary catecholamine excretion and a mediastinal mass. Hirschspnmg disease (also familial) and neuroblastoma, in the form of right adrenal and right paraspinal masses, had been diagnosed in our patient at 3 weeks of age. Both were treated surgically. Follow-up abdominal computed tomography at 3 months of age showed regrowth of the abdominal tumor arising from the cefiac axes, and urinary homovanillic acid and vanillylmandelic acid values were elevated; results of bone marrow examination and bone scan were negative for metastatic disease. During the next 7 months, homovanillic and vanillylmandelic acid excretion continued to rise as the tumor extended across the diaphragm into her chest despite multiple courses of chemotherapy, including cyclophosphamide, cisplafin, doxorubicin, etoposide, and ifosfamide. Abdominal CT at 1 year of age suggested differentiation into benign ganglioneuroma,
with signs of calcifications and necrosis. The patient then received several 14-day courses of therapy with retinoic acid, as well as a treatment with metaiodobenzyl guanidine labeled with iodine 131. The tumor around the left kidney was partially resected to relieve ureteral compression at 21 months, with excellent results. The patient had no hypoglycemic symptoms until seen at the emergency department with seizures 1 day after having recovered from a viral gastroenteritis. She had maintained good oral intake during the previous 36 hours. On admission to the hospital, she required intravenous infusion of dextrose at 3.3 mmol/kg (6 mg/kg) per minute to maintain euglycemia (Figure). A stimulation test with adrenocorticotropic hormone produced an appropfiate cortisol response (1380 nmol/L [50 pg/dl). A supervised fast cansed a decrease in blood glucose values within 45 minutes and was terminated early because of symptomatic hypoglycemia. Blood values for insulin and C-peptide were suppressed in association with insulinomimetic suppression of ketogenesis, free fatty acids, and levels of IGF binding protein-1, and there was no appropfiate rise of GH with hypoglycemia (Table I). Cranial and abdominal CT revealed no increased tumor size or
The Journal of Pediatlqcs • Volume 127, Number 3
A g u s et aL
405
Table 1. Results of blood tests during a supervised fast before GH treatment
Time (min) 0 45 Normal fasting range
Glucose (mmol/l.)
Insulin (pmollL)
C-peptide (nmollL)
l~-OH-butyrate (mmol/L)
IGFBP- I (nmol/L)
Growth hormone (IJg/L)
5.1 1.7 2.8-6. I
79 180 <215
0.93 0.60 < 1.1
0.42 0.22 >2.0
3.2 2.0 >3.6
1.2 2.4 >10
l o b l e II. Levels of IGF and related molecules before and during GH therapy
Hospital day 4 12 Normal range for age
GH (mg/kg/ day)
IV dextrose (mg/kg/ min)
0 0.2 --
6 0 --
IGF-I (nmol/L) 11.1 38.7 1.5-27.5
Total IGF-II (ng/ml)
"Big" IGF-II (% total IGF-II)
IGF-IIE (ng/ml)
59.6 100.9 44.5-85.6
80% 50% <5%
10 1-4
evidence of metastatic disease. Resfing energy expenditure was approximately 110% of normal. Intramuscular administration of growth hormone was initiated at 0.05 mg/kg per day in divided doses, increased to 0.1 mg/kg per day 3 days later, and increased to 0.2 mg/kg per day after 2 more days. During that fime, the pafient's requirement for dextrose did not significantlychange. On the eighth day of GH treatment, the intravenous dextrose reqnirement dropped quickly within approximately 12 hours (Figure). The patient was maintalned on ovemight dextrose infusions for 2 more nights as a safety measure. During a subsequent 12-hour fast, her blood glucose concentration stayed at greater than 3.4 mmol/L (62 mg/dl). Throughout hospitalization the patient had episodes of sweafing, increased irritability, tachycardäa, and tachypnea, with concomitant blood glucose va/nes of 4.4 to 5.0 mmol/L (80 to 90 mg/dl). These were attributed to catecholamine secrefion. Surgery was not attempted because of the proxirnity of the tumor to the pafient's great vessels. She was discharged to receive GH, 0.2 mg/kg per day intramuscularly in two divided doses. After 12 months of followup, she continues to thrive on regular feedings without any episodes of hypoglycemia, and her linear growth has advanced from the 5th to the 50th percentile. Initially, attempts to reduce the GH dosage resulted in decreased blood sugar values. However, at the 6-month follow-up, the dosage of GH was reduced to 0.1 mg/kg per day without causing hypoglycemia. Repeated CT scans of the abdomen showed no change in the size of the tumor. The presence of "big" IGF-II in the patient's serum was demonstrated by column chromatography, which disclosed most of the IGF-II to be of 15 kD molecular weight, and by the presence of elevated IGF-IIE immtmoreactivity. As shown in Table II, serum IGF-I and total IGF-II levels increased after 8 days of GH therapy, and serum IGFBP-3 levels, initially in the GH-deficient range, rose threefold. Serum measurements of the acid-labile subunit, a component of the circulating 150 kD complex along with IGF and IGFBP, were initially low but doubled during GH therapy. The
8
ALS (% adult control)
IGFBP-3 (nmol/L)
Molar ratio (IGF-I + Il/ IGFBP-3)
69% 129% Not defined
25 105 35-75
2.8 1.3 0.8-1.2
increase in IGFBP-3 levels resulted in a normalizafion of the molar ratio of the IGFs to their major carrier protein. These changes were maintained after 6 months of GH therapy.
METHODS Analytic methods. Plasma IGF-I and IGF-II were measured after acid chromatography, by radioimmunoassay with specific antibodies. 4 IGF-1I chromatography was performed with a 120 cm G50 acid column (Pharmacia Inc., Piscataway, N.J.). IGF-II RIA was performed on the eluted fractions. High molecular weight IGF-II eluted 10 to 15 fractions away from small IGF-II.4 IGF-HE RIA was performed as previously described, with an antibody developed against a 16-amino acid segment of the IGF-I]E.4 Levels of IGFBP-1 were measured by specific RIA performed at Corning Nichols Institute, San Juan Capistrano, Calif. Levels of IGFBP-3 were measured by RIA performed at Endocrine Sciences, Calabasas Hills, Calif. The ALS was assayed by immunoblotting with the ECL kit (Amersham, Arlington, Ill.) and a specific antibody for ALS (Diagnostic Systems Laboratories, Houston, Tex.), and analyzed densitometrically.
DISCUSS1ON The pathophysiology of NICT hypoglycemia has been the subject of considerable debate and research. The postulate that the hypoglycemia is secondary to increased glucose consumption by the tumor has not been supported directly, and has not been shown to be true of most tumors. Eastman et al. 9 used positron emission tomography to demonstrate that, in a patient with hepatoma, glucose uptake was increased in skeletal muscle rather than in the tumor. Another study using hyperinsulinemic-euglycemic clamp studies
406
Agus et al.
demonstrated an increase in total body insulin sensitivity.1° In multiple studies, the GH/IGF axis has been demonstrated to play a major role in the induction of hypoglycemia. Tumors have been shown to produce an incompletely processed, high molecular weight, pro-IGF-II molecule24 that contains an extra peptide, the E-region, which is cleaved in normal hepatic processing to create mature serum IGF-II.4 This elevation of " b i g " IGF-II values is thought to suppress G H secretion, with a consequent reduction in IGF-I and in the major serum IGF binding protein, IGFBP-3.11 Normally, nearly all of the circulating IGF-I and IGF-II is bound to IGFBP-3 with ALS, forming a 150 kl) complex) 2 " B i g " IGF-II may, however, have a decreased tendency to form the ternary 150 kD complex. 3 With a relative deficit of IGFBP-3 and ALS, there is increased bioavailabifity of IGF-I and IGF-II, which are bound with other IGFBPs to form low molecular weight complexes. In this stare, IGFs have a shorter half-life in the circulation, enhanced, transendothelial passage, and relatively rapid delivery to target tissues, leading ultimately to insufin-like hypoglycemic effects. The Suppression of GH may also make a direct contribution to hypoglycemia, which is a well-recognized complication of GH deficiency. Because the decrease in GH level induced by the tumorproduced IGF-II is the central mechanism in ultimately producing the hypoglycemia, replacing GH might reverse this chain of events. Therapy with GH had been attempted previously with modest and transient success in one patient with metastatic neurofibrosarcoma. 5 Teale et al.6 achieved moderate success in three patients, but eventually all three required surgical resection before they could be maintained in a euglycemic stare without intravenous infusions of glucose. Wing et al.7 achieved only a transient decrease in exogenous glucose requirement. Our patient had long-term successful treatment of NICT hypoglycemia with exogenous GH. Because of the surgical risks, medical therapy was the only option for this patient. The dose of GH (0.2 mg/kg per day intramuscularly) and the duration of treatment (8 days) needed to achieve resolution of hypoglycemia had not previously been combined, and may represent requirements for successful treatment. Alternatively, peculiarities of this patient, her tumor, and other unknown factors may have contributed to her response to GH treatment. We do not know what caused the patient's long-standing tumor to begin producing " b i g " IGF-II. However, her chemotherapy included several 14-day courses of therapy with retinoic acid, a naturally occurring morphogen that inhibits neuroblastoma cell growth and induces differentiation into neufite cells. It has been suggested that retinoic acid induces IGF-1I expression in neuroblastoma cell lines) 3 Out patient received her last dose of retinoie acid 7 months before the
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start of hypoglycemia, but this association deserves further investigation. The clinical relevance of this case may go beyond the advancement in out understanding of the GH/IGF axis. Studies on the use of IGFs in insulin-dependent diabetes mellitus suggest that these agents have a role in increasing insulin sensitivity and lowering of the blood sugar concentration. 14 Barzilal et al. 1° descfibed a patient with non-insulin-dependent diabetes mellitus, who had NICT hypoglycemia caused by a hepatoma, had gradually decreased insulin requirernents from 70 u nits per day to none, and still had hypoglycemia; euglycemic clamp studies demoustrated increased insulin sensitivity. These cases serve as a paradigm for the potential usefulness of IGF therapy in diabetic states. Suppression of GH secretion in diabetes may improve glycemic control and prevent long-term complications. Although hypoglycemia has rarely been associated with childhood tumors, this unusual case fits the model of other cases of NICT hypoglycemia in adults, and therefore supports the theory that tumor IGF-II production causes the derangements in the GH/IGF axis and the resultant hypoglycemia. The use of GH in adequate doses, given for a sufficiently long time, appears to counteract these hypoglycemic effects and should be considered for first-line therapy in futute patients, both as preoperative medical management and as sole therapy when surgery is contraindicated. REFERENCES
1. Shapiro M, Simcha A, Rosenmann E, $haffir E. Hypoglycemia associated with neonatal neuroblastoma and abnormal responses of serum glucose and ffee fatty a¢ids to epinephfine injection. Israel J Med Sci 1966;2:705-14. 2. Daughaday WH, Emanuelle MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P. Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 1988;319:1434-40. 3. Zapf J, Futo E, Peter M, Froesch ER. Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia. J Clin Inrest 1992;90:2574-84'. 4. Liu F, Baker BK, Powell DR, Hintz RL. Charactefization of proinsulin-like growth factor-II E-region immunoreacüvity in serum and other biological fluids. J Clin Endocfinol Metab 1993;76:1095-100. 5. Samaan NA, Pham FK, $ellin RV, et al. Successful treatment of hypoglycemiausing glucagon in a patient with an extrapancreatic tumor. Ann h~tem Med 1990;113:404-6. 6. Teale JD, Blum WF, Marks V. Alleviationof non-islet tel1 tumor hypoglycaemia by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem 1992;29:314-23. 7. Wing JR, Panz VR, Joffe BI, et al. Hypoglycemia in hepatocellular carcinoma: failure of short-term growth hormone administration to reduce enhanced glucose requirements. Metabolism 1991;40:508-12. 8. Chatten J, Voorhees ML. Familial neuroblastoma: report of a
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kindred with multiple disorders, including neuroblastomas in four siblings. N Engl J Med 1967;277:1230-6. 9. Eastman RC, Carson RE, Ofloff DG, et al. Glucose utilization in a patient with hepatoma and hypoglycemia: assessment by a positron emission tomography. J Cfin Invest 1992;89:195863. 10. Barzilai N, Cohen P, Bar-Illan R, McIntyre N, KarniefiE. Case report: increased insulin sensitivity in tumor hypoglycemia in a diabetic patient--glucose metabolism in tumor hypoglycemia. Am J Med Sci 1991;302:229-34. 11. Jorgensen JOL, Blum WF, Moller N, Ranke MB, Christiansen JS. Short-term changes in serum insulin-fike growth factors (IGF) and IGF binding protein 3 after different modes of intra-
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venous growth hormone (GH) exposure in GH-deficient patients. J Clin Endocrinol Metab 1991;72:528-37. 12. Cohen P, Rosenfeld RG. Physiological and clinical relevance of the insulin-like growth factor binding proteins. Curr Opin Pediatr 1994;6:462-7. 13. Matsumoto K, Gaetano C, Daughaday WH, Thiele CJ. Retinoic acid regulates insulin-like growth factor II expression in a neuroblastoma cell line. Endocrinology 1992;130:3669-76. 14. Cheethan TD, Jones J, Taylor AM, Matthews DR, Dunger DB. The effects of recombinant insulin-likegrowth factor I administration on growth hormone levels and insulin requirementsin ad01escents with type 1 (insulin-dependent)diabetes mellitus. Diabetologia 1993;36:678-81.
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