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Two cases of persistent hyperinsulinemic hypoglycemia that showed spontaneous regression and maturation of the Langerhans islets
Two Cases of Persistent Hyperinsulinemic Hypoglycemia That Showed Spontaneous Regression and Maturation of the Langerhans Islets By Akio Kubota, Takeo Yonekura, Noriaki Usui, Takuya Kosumi, Katsuji Yamauchi, Mitsuo Yamasaki, Harumasa Oyanagi, Masahiro Nakayama, Shinobu Ida, and Tatsuro Nakajima Osaka, Japan
Near-total pancreatectomy has been recommended as the treatment for persistent hyperinsulinemic hypoglycemia (PHH) in infants. However, recently there has been a report described that one third of 95% pancreatectomy failed to prevent hypoglycemia and more than two thirds had diabetes ultimately. The authors experienced 2 cases of PHH, which raise a query about the extensive pancreatectomy. Case 1: A female patient who manifested PHH shortly after birth underwent less extensive pancreatectomy twice at age 2 months and 8 years. After each operation, her clinical symptoms regressed, and she became free from the disease eventually. Histologic findings showed nesidioblastosis in which the islets clearly matured. Case 2: A male infant with PHH had an absolute indication for pancreatectomy. However, after a meticulous control of the blood glucose level with parenteral nutrition followed by continuous enteral nu-
trition feeding combined with medication, he became free from the disease. The current cases show there exist cases of PHH in which the islets mature and symptoms regress spontaneously. Therefore, we conclude near-total pancreatectomy is not always the treatment of choice. As an alternate strategy, long-term controlled feeding and medication combined with or without less extensive pancreatectomy should be considered with the expectation of spontaneous regression. J Pediatr Surg 35:1661-1662. Copyright © 2000 by W.B. Saunders Company.
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alpha-fetoprotein and an intraabdominal cystic lesion led to exploratory laparotomy, which found a nodular lesion in the pancreatic body. Distal pancreatectomy was performed, and histologic findings showed diffuse nesidioblastosis with localized nesidioblastoma (Fig 1). After the surgery, her insulin level decreased significantly. However, hypoglycemic attacks occurred once or twice a year. At age of 7 years, octreotide was administered by continuous subcutaneous injection for 1 year, which proved efficacious and safe. It became clear that she was dependent on octreotide. Therefore, at the age of 8 years, 90% pancreatectomy was performed. Histologic findings showed formation of Langerhans islets and normal acini, which were still mixed with endocrine cells (Fig 2). Her postoperative course over the last 6 years has been uneventful, and her glucose and insulin levels have remained within the normal range.
EAR-TOTAL or 95% pancreatectomy has been recommended as the treatment for intractable persistent hyperinsulinemic hyperglycemia (PHH) or nesidioblastosis (NB) of the neonate.1-5 However, in 1997, Shilyansky et al6 reported that one third of 95% pancreatectomy failed to prevent hypoglycemia, and, ultimately, diabetes developed in more than two thirds, and they indicated that an alternative treatment strategy is needed for this disease. However, in 1989, Glaser et al7 showed the effectiveness and safety of long-term administration of the somatostatin analogue, octreotide, that directly inhibits insulin secretion from -cells, and they suggested that aggressive medical therapy, when effective, is preferable to partial pancreatectomy.8 We experienced 2 neonatal cases of PHH, which raised a query about near-total pancreatectomy as the treatment of choice. In one case of NB, histologic study showed maturation of the islet cells over an 8-years period of time. CASE REPORT
Case 1 A baby girl was born by cesarean section at 34 weeks of gestation with a birth weight of 4,254 g (⫹5.7 SD). She had Beckwith-Wiedemann syndrome, gigantism, omphalocele, and macroglossia, which had been diagnosed by antenatal ultrasonography. She manifested PHH shortly after birth. Blood glucose level was maintained solely with continuous intravenous nutrition for 20 days, then tube feeding was added. At the age of 2 months, an extremely high level of serum
INDEX WORDS: Nesidioblastosis, hyperinsulinemia, hypoglycemia, near-total pancreatectomy, persistent hypoglycemia.
Case 2 A boy manifested PHH shortly after birth, when blood glucose level was 40 mg/dL, and insulin level was 28 U/mL. A pancreatectomy was indicated because continuous glucose infusion at a dose of 22 mg/kg/ min or more was needed to maintain euglycemia for more than 2 months. However, after a meticulous control of the blood glucose level
From the Department of Surgery II, Kinki University, Department of Pathology, Osaka Medical Center for Maternal and Child Health, and the Department of Pediatrics, PL Hospital, Osaka, Japan. Presented at the 33rd Annual Meeting of the Pacific Association of Pediatric Surgeons, Las Vegas, Nevada, May 15-19, 2000. Address reprint requests to Akio Kubota, MD, Department of Surgery II, Kinki University School of Medicine, Osakasayama, Osaka 589-8511, Japan. Copyright © 2000 by W.B. Saunders Company 0022-3468/00/3511-0032$03.00/0 doi:10.1053/jpsu.2000.18346
Journal of Pediatric Surgery, Vol 35, No 11 (November), 2000: pp 1661-1662
1661
1662
KUBOTA ET AL
Fig 1. Photomicrogram of the resected pancreas, near the stump, from the first surgery at the age of 2 months. Tumorous proliferation of immature endocrine cells with deeply stained chromatin is noticed (these cells are positive by immunohistochemistry for insulin, glucagon, and somatostatin). Islets of Langerhans are not formed. (HE, original magnification ⴛ20.)
with continuous glucose infusion followed by nasogastric feeding, he resumed oral feeding, and blood glucose and insulin levels returned to normal. During the 2 years’ follow-up period, he has shown no residual symptoms or signs of PHH.
DISCUSSION
Although there is no standard extent of pancreatic resection for PHH, to reduce the risk of persistent hypoglycemia and the neurologic complications, extensive pancreatectomy increasingly has been advocated.1-5 However, only a few long-term outcome studies of extensive pancreatectomy have been performed. A strong possibility of the ultimate development of diabetes has been reported by Shilyansky et al and others.6,9 However, some other reports presented cases in which medical treatment could be discontinued, and pancreatectomy was avoided.8,10 These
Fig 2. Photomicrogram of the re-resected pancreas, near the distal end, or close to the specimen shown in Fig 1, from the surgery at the age of 8 years. Among the plenty of normal pancreatic acini, relatively matured endocrine cells are scattered. Small islets of Langerhans are formed partially. (HE, original magnification ⴛ20.)
long-term follow-up studies confirmed that there exist patients with PHH in which medication is indicated, either solely with continuous subcutaneous octreotide administration8 or oral diazoxide10 or combined with less extensive pancreatectomy. Furthermore, they supported the concept that PHH or NB is a disorder of the pancreas based on “islet cell dysmaturation syndrome,”5,11,12 which implies that the islets are able to mature, and the disease may regress spontaneously. The current cases support this concept, and the first case showed histologically the late maturation of islet cells. Where octreotide is available, long-term medication combined with or without less extensive pancreatectomy should be considered as treatment for PHH to avoid the strong possibility of ultimate development of diabetes in the expectation of spontaneous attenuation or regression.
REFERENCES 1. Kramer JL, Bell MJ, DeSchryver K, et al: Clinical and histological indications for extensive pancreatic resection in nesidioblastosis. Am J Surg 143:1169-119, 1982 2. Moazam F, Rodgers BM, Talbert JL, et al: Near-total pancreatectomy in persistent infantile hypoglycemia. Arch Surg 117:1151-1154, 1982 3. Martin LW, Ryckman FC, Sheldon CA: Experience with 95% pancreatectomy and splenic salvage for nesidioblastosis. Am Surg 200:355-360, 1984 4. Filler RM, Weinberg MJ, Cutz E, et al: Current status of pancreatectomy for persistent idiopathic neonatal hypoglycemia due to islet cell dysplasia. Prog Pediatr Surg 26:60-75, 1991 5. von Allmen D, Ziegler MM: Nesidioblastosis and insulinoma: Islet cell dysplasia, in Balistreri WF, Ohi R, Todani T, et al (eds): Hepatobiliary, Pancreatic and Splenic Disease in Children: Medical and Surgical Management. Amsterdam, Elsevier Science, pp 511-519, 1997 6. Shilyansky J, Fisher S, Cutz E, et al: Is 95% pancreatectomy the procedure of choice for treatment of persistent hyperinsulinemic hypoglycemia of the neonate? J Pediatr Surg 32:342-346, 1997
7. Glaser B, Landau H, Smilovici A, et al: Persistent hyperinsulinemic hypoglycemia of infancy: Long-term treatment with somatostatin analogue Sandostatin. Clin Endocrinol 31:71-80, 1989 8. Glaser B, Hirsch HJ, Landau H: Persistent hyperinsulinemic hypoglycemia of infancy: Long-term octreotide treatment without pancreatectomy. J Pediatr 123:644-650, 1993 9. Goossens A, Gepts W, Saudubray JM, et al: Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 13:766-775, 1989 10. Grant DB, Dunger DB, Burns EC: Long-term treatment with diazoxide in childhood hyperinsulinism. Acta Endocrinol 279S:340345, 1986 (suppl) 11. Bjerke HS, Kelly RB, Geffner ME, et al: Surgical management of islet cell dysmaturation syndrome in young children. Surg Gynecol Obstet 171:321-325, 1990 12. Geffner ME: Hypoglycemia, in Kaplan SA (ed): Clinical Pediatric Endocrinology. Philadelphia, PA, Saunders, 1990, pp 165-179
Near-total pancreatectomy has been recommended as the treatment for persistent hyperinsulinemic hypoglycemia (PHH) in infants. However, recently there has been a report described that one third of 95% pancreatectomy failed to prevent hypoglycemia and more than two thirds had diabetes ultimately. The authors experienced 2 cases of PHH, which raise a query about the extensive pancreatectomy. Case 1: A female patient who manifested PHH shortly after birth underwent less extensive pancreatectomy twice at age 2 months and 8 years. After each operation, her clinical symptoms regressed, and she became free from the disease eventually. Histologic findings showed nesidioblastosis in which the islets clearly matured. Case 2: A male infant with PHH had an absolute indication for pancreatectomy. However, after a meticulous control of the blood glucose level with parenteral nutrition followed by continuous enteral nu-
trition feeding combined with medication, he became free from the disease. The current cases show there exist cases of PHH in which the islets mature and symptoms regress spontaneously. Therefore, we conclude near-total pancreatectomy is not always the treatment of choice. As an alternate strategy, long-term controlled feeding and medication combined with or without less extensive pancreatectomy should be considered with the expectation of spontaneous regression. J Pediatr Surg 35:1661-1662. Copyright © 2000 by W.B. Saunders Company.
N
alpha-fetoprotein and an intraabdominal cystic lesion led to exploratory laparotomy, which found a nodular lesion in the pancreatic body. Distal pancreatectomy was performed, and histologic findings showed diffuse nesidioblastosis with localized nesidioblastoma (Fig 1). After the surgery, her insulin level decreased significantly. However, hypoglycemic attacks occurred once or twice a year. At age of 7 years, octreotide was administered by continuous subcutaneous injection for 1 year, which proved efficacious and safe. It became clear that she was dependent on octreotide. Therefore, at the age of 8 years, 90% pancreatectomy was performed. Histologic findings showed formation of Langerhans islets and normal acini, which were still mixed with endocrine cells (Fig 2). Her postoperative course over the last 6 years has been uneventful, and her glucose and insulin levels have remained within the normal range.
EAR-TOTAL or 95% pancreatectomy has been recommended as the treatment for intractable persistent hyperinsulinemic hyperglycemia (PHH) or nesidioblastosis (NB) of the neonate.1-5 However, in 1997, Shilyansky et al6 reported that one third of 95% pancreatectomy failed to prevent hypoglycemia, and, ultimately, diabetes developed in more than two thirds, and they indicated that an alternative treatment strategy is needed for this disease. However, in 1989, Glaser et al7 showed the effectiveness and safety of long-term administration of the somatostatin analogue, octreotide, that directly inhibits insulin secretion from -cells, and they suggested that aggressive medical therapy, when effective, is preferable to partial pancreatectomy.8 We experienced 2 neonatal cases of PHH, which raised a query about near-total pancreatectomy as the treatment of choice. In one case of NB, histologic study showed maturation of the islet cells over an 8-years period of time. CASE REPORT
Case 1 A baby girl was born by cesarean section at 34 weeks of gestation with a birth weight of 4,254 g (⫹5.7 SD). She had Beckwith-Wiedemann syndrome, gigantism, omphalocele, and macroglossia, which had been diagnosed by antenatal ultrasonography. She manifested PHH shortly after birth. Blood glucose level was maintained solely with continuous intravenous nutrition for 20 days, then tube feeding was added. At the age of 2 months, an extremely high level of serum
INDEX WORDS: Nesidioblastosis, hyperinsulinemia, hypoglycemia, near-total pancreatectomy, persistent hypoglycemia.
Case 2 A boy manifested PHH shortly after birth, when blood glucose level was 40 mg/dL, and insulin level was 28 U/mL. A pancreatectomy was indicated because continuous glucose infusion at a dose of 22 mg/kg/ min or more was needed to maintain euglycemia for more than 2 months. However, after a meticulous control of the blood glucose level
From the Department of Surgery II, Kinki University, Department of Pathology, Osaka Medical Center for Maternal and Child Health, and the Department of Pediatrics, PL Hospital, Osaka, Japan. Presented at the 33rd Annual Meeting of the Pacific Association of Pediatric Surgeons, Las Vegas, Nevada, May 15-19, 2000. Address reprint requests to Akio Kubota, MD, Department of Surgery II, Kinki University School of Medicine, Osakasayama, Osaka 589-8511, Japan. Copyright © 2000 by W.B. Saunders Company 0022-3468/00/3511-0032$03.00/0 doi:10.1053/jpsu.2000.18346
Journal of Pediatric Surgery, Vol 35, No 11 (November), 2000: pp 1661-1662
1661
1662
KUBOTA ET AL
Fig 1. Photomicrogram of the resected pancreas, near the stump, from the first surgery at the age of 2 months. Tumorous proliferation of immature endocrine cells with deeply stained chromatin is noticed (these cells are positive by immunohistochemistry for insulin, glucagon, and somatostatin). Islets of Langerhans are not formed. (HE, original magnification ⴛ20.)
with continuous glucose infusion followed by nasogastric feeding, he resumed oral feeding, and blood glucose and insulin levels returned to normal. During the 2 years’ follow-up period, he has shown no residual symptoms or signs of PHH.
DISCUSSION
Although there is no standard extent of pancreatic resection for PHH, to reduce the risk of persistent hypoglycemia and the neurologic complications, extensive pancreatectomy increasingly has been advocated.1-5 However, only a few long-term outcome studies of extensive pancreatectomy have been performed. A strong possibility of the ultimate development of diabetes has been reported by Shilyansky et al and others.6,9 However, some other reports presented cases in which medical treatment could be discontinued, and pancreatectomy was avoided.8,10 These
Fig 2. Photomicrogram of the re-resected pancreas, near the distal end, or close to the specimen shown in Fig 1, from the surgery at the age of 8 years. Among the plenty of normal pancreatic acini, relatively matured endocrine cells are scattered. Small islets of Langerhans are formed partially. (HE, original magnification ⴛ20.)
long-term follow-up studies confirmed that there exist patients with PHH in which medication is indicated, either solely with continuous subcutaneous octreotide administration8 or oral diazoxide10 or combined with less extensive pancreatectomy. Furthermore, they supported the concept that PHH or NB is a disorder of the pancreas based on “islet cell dysmaturation syndrome,”5,11,12 which implies that the islets are able to mature, and the disease may regress spontaneously. The current cases support this concept, and the first case showed histologically the late maturation of islet cells. Where octreotide is available, long-term medication combined with or without less extensive pancreatectomy should be considered as treatment for PHH to avoid the strong possibility of ultimate development of diabetes in the expectation of spontaneous attenuation or regression.
REFERENCES 1. Kramer JL, Bell MJ, DeSchryver K, et al: Clinical and histological indications for extensive pancreatic resection in nesidioblastosis. Am J Surg 143:1169-119, 1982 2. Moazam F, Rodgers BM, Talbert JL, et al: Near-total pancreatectomy in persistent infantile hypoglycemia. Arch Surg 117:1151-1154, 1982 3. Martin LW, Ryckman FC, Sheldon CA: Experience with 95% pancreatectomy and splenic salvage for nesidioblastosis. Am Surg 200:355-360, 1984 4. Filler RM, Weinberg MJ, Cutz E, et al: Current status of pancreatectomy for persistent idiopathic neonatal hypoglycemia due to islet cell dysplasia. Prog Pediatr Surg 26:60-75, 1991 5. von Allmen D, Ziegler MM: Nesidioblastosis and insulinoma: Islet cell dysplasia, in Balistreri WF, Ohi R, Todani T, et al (eds): Hepatobiliary, Pancreatic and Splenic Disease in Children: Medical and Surgical Management. Amsterdam, Elsevier Science, pp 511-519, 1997 6. Shilyansky J, Fisher S, Cutz E, et al: Is 95% pancreatectomy the procedure of choice for treatment of persistent hyperinsulinemic hypoglycemia of the neonate? J Pediatr Surg 32:342-346, 1997
7. Glaser B, Landau H, Smilovici A, et al: Persistent hyperinsulinemic hypoglycemia of infancy: Long-term treatment with somatostatin analogue Sandostatin. Clin Endocrinol 31:71-80, 1989 8. Glaser B, Hirsch HJ, Landau H: Persistent hyperinsulinemic hypoglycemia of infancy: Long-term octreotide treatment without pancreatectomy. J Pediatr 123:644-650, 1993 9. Goossens A, Gepts W, Saudubray JM, et al: Diffuse and focal nesidioblastosis. A clinicopathological study of 24 patients with persistent neonatal hyperinsulinemic hypoglycemia. Am J Surg Pathol 13:766-775, 1989 10. Grant DB, Dunger DB, Burns EC: Long-term treatment with diazoxide in childhood hyperinsulinism. Acta Endocrinol 279S:340345, 1986 (suppl) 11. Bjerke HS, Kelly RB, Geffner ME, et al: Surgical management of islet cell dysmaturation syndrome in young children. Surg Gynecol Obstet 171:321-325, 1990 12. Geffner ME: Hypoglycemia, in Kaplan SA (ed): Clinical Pediatric Endocrinology. Philadelphia, PA, Saunders, 1990, pp 165-179