0021-972X/06/$15.00/0 Printed in U.S.A.
The Journal of Clinical Endocrinology & Metabolism 91(8):2839 –2842 Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2006-0455
CLINICAL CASE SEMINAR The Diagnosis of Ectopic Focal Hyperinsulinism of Infancy with [18F]-Dopa Positron Emission Tomography Khalid Hussain, Marko Seppa¨nen, Kirsti Na¨nto¨-Salonen, N. Scott Adzick, Charles A. Stanley, Paul Thornton, and Heikki Minn London Center for Pediatric Endocrinology and Metabolism (K.H.), Hospital for Children National Health Service Trust, London WC1N 3JH, United Kingdom; The Institute of Child Health (K.H.), London WC1N 1EH, United Kingdom; Turku PET Center (M.S.) and Departments of Pediatrics (K.N.-S.) and Oncology and Radiotherapy (H.M.), Turku University Hospital, FIN 20521 Turku, Finland; Divisions of Surgery (N.S.A.) and Endocrinology (C.S.), Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; and Division of Endocrinology and Diabetes (P.T.), Cook Children’s Medical Center, Fort Worth, Texas 76104 Background: Congenital hyperinsulinism (CHI) is a cause of severe hypoglycemia in the neonatal and infancy period. Histologically, there are two subtypes with diffuse and focal disease. The preoperative differentiation of these two forms is very important because the surgical management is radically different. The focal form of the disease can be cured if the focal lesion can be localized accurately and completely resected with surgery. Aim: We report the case of a child who underwent three pancreatectomies with a choledochoduodenostomy and a cholecystectomy but continued to have severe hyperinsulinemic hypoglycemia.
ONGENITAL HYPERINSULINISM (CHI) causes recurrent and persistent hypoglycemia in the newborn and infancy period (1). There is a high risk of neurological complications secondary to the hypoglycemia (2). Mutations in the genes (ABCC8 and KCNJ11) encoding one of the subunits (SUR1 or KIR6.2, respectively) for the ␤-cell ATP-sensitive potassium channel are the most common cause of severe medically unresponsive forms of CHI (3, 4). Histologically, two subtypes of CHI have been described, focal and diffuse (5). The focal form is found in about 40 –50% of children and appears to be localized to one region of the pancreas. The focal form is associated with a unique genetic etiology that consists of two distinct genetic events. The first is paternal inheritance of a recessive ABCC8 or KCNJ11 mutation. The second necessary event is the somatic loss of heterozygosity of an unknown amount of the distal portion of the short arm of chromosome 11, resulting in paternal uniparental disomy of this chromosomal segment. This is the region that contains the ABCC8 and KCNJ11 channel genes and several imprinted genes that are important for the con-
First Published Online May 9, 2006 Abbreviations: ASVS, Arterial calcium stimulation/venous sampling; CHI, congenital hyperinsulinism; MRI, magnetic resonance images; PET, positron emission tomography. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.
Methods/Results: Radiological investigations including imaging with 18fluoro-L-Dopa positron emission tomography scan showed a clear focus of increased 18F-fluoro-L-Dopa uptake in the vicinity of the former head of the pancreas. On the magnetic resonance imaging scan, this focal uptake appeared to localize adjacent or next to duodenum (in the wall or cavity of the duodenum). Conclusions: This unique case highlights the importance of correctly localizing and completely resecting the focal lesion in patients with CHI. 18Fluoro-L-Dopa positron emission tomography scan can identify ectopic focal lesions in patients with CHI. (J Clin Endocrinol Metab 91: 2839 –2842, 2006)
trol of cellular proliferation (6 – 8). Hence the affected ␤-cell precursor carries only the paternal allele of this region of chromosome 11, and therefore, only the mutant ABCC8 or KCNJ11 allele. Furthermore, growth-suppressing genes (such as p57 and H19) that are paternally imprinted are not expressed (because the maternal allele is missing), and growth-stimulating genes (such as IGF2) that are maternally imprinted are overexpressed (9). Identification of those children who have the focal form of the disease preoperatively is a critical part of the management of patients with CHI (10). The preoperative localization allows radically different treatment options and medical outcomes. Focal disease is curable with limited (partial) pancreatectomy with few long-term complications. The current methods for identifying those children with focal and diffuse forms of the disease include intrahepatic pancreatic portal venous sampling (11, 12), the arterial calcium stimulation/venous sampling (ASVS) (13, 14), and the acute insulin response testing to iv glucose, calcium, and tolbutamide (15, 16). Portal venous sampling is a highly challenging and technically difficult procedure, which requires meticulous preparation of the child, can be performed in only a few centers around the world, and is only about 70% accurate. The ASVS test is somewhat simpler, but has a similar accuracy (13). The preoperative acute insulin response tests do not distinguish focal vs. diffuse disease because some KATP channel mutations retain responsiveness to tolbutamide, but the ASVS test seems to be
J Clin Endocrinol Metab, August 2006, 91(8):2839 –2842
more sensitive in localizing focal lesions in infants (17). More recently, 18F-fluoro-l-Dopa positron emission tomography (PET) has been successfully used to localize the focal domain (18, 19). This has many advantages over the highly invasive pancreatic venous sampling and intraarterial calcium stimulation tests. We report the case of a child who continues to have severe hyperinsulinemic hypoglycemia due to CHI, despite having undergone three pancreatectomies, a choledochoduodenostomy, and a cholecystectomy. Imaging with 18F-fluoro-lDopa PET has shown remnant of ectopic pancreatic tissue in the wall or cavity of the duodenum. Case Report
This patient was born at 33 wk gestation with a birth weight of 2.6 kg to unrelated South Asian parents. There was no significant antenatal history and no maternal diabetes mellitus. He was noted to have symptomatic (jittery, irritable, and feeding poorly) hypoglycemia (blood glucose concentration of 40 mg/dl) 2 h after birth. His hypoglycemia was persistent and he required about 20 mg/kg䡠min of iv glucose to maintain his blood glucose concentration above 72 mg/dl. The etiology of the hypoglycemia was found to be due to hyperinsulinism (serum insulin 150 pmol/liter with a simultaneous blood glucose concentration of 38 mg/dl). He was commenced on diazoxide (5–20 mg/kg䡠d) and chlorothiazide (7–10 mg/kg䡠d) but showed no response. In view of the failure of medical therapy, the patient underwent a subtotal pancreatectomy (approximately 95%) without any localization procedures at his local hospital. However, within the first 24 h postoperatively, he continued to have severe unremitting hypoglycemia, and investigations confirmed that he still had persistent hyperinsulinism (serum insulin 130 pmol/liter with a simultaneous blood glucose level of 30 mg/dl). The histology of the resected pancreas (later reviewed by the tertiary referral center) showed normal pancreatic endocrine tissue with no histological evidence of diffuse congenital hyperinsulinism. He was subsequently referred for a second opinion to a tertiary referral center (Children’s Hospital of Philadelphia). At this time, PET scanning was not available and ASVS was not performed because the patient had had a 95% pancreatectomy. At surgery, frozen sections revealed a focal lesion in the remaining 5% of the pancreas, located at the junction of the duodenum and choledochol duct. The lesion was removed, and the histology showed confluence of normally structured islets separated by few exocrine acini maintaining a normal lobular pancreatic architecture. The endocrine cells were arranged in clusters of variable sizes separated by thin fibro-vascular strands of acinar tissue. The ␤-cell nuclei were enlarged and hyperchromatic. However, in the postoperative period, the patient again developed hypoglycemia (blood glucose 32 mg/dl with a simultaneous serum insulin of 146 pmol/liter) and failed medical treatment including diazoxide, continuous octreotide by sc pump, and nifedipine. After discussion with the family, a decision was made to carry out a third operation with the goal of inducing diabetes mellitus. A choledochoduodenostomy, a cholecystectomy, and an incidental
Hussain et al. • [18F]-Dopa PET in Hyperinsulinism of Infancy
appendectomy were performed, in addition to scraping off all visible pancreatic tissue around the duodenum and common bile duct, and left no visible pancreatic tissue behind. Despite this, the patient was again hypoglycemic with severe hyperinsulinism (blood glucose 40 mg/dl with a simultaneous serum insulin level of 138 pmol/liter) postoperatively. Histology revealed islets in the smooth muscle of the duodenum at the site of the resected choledochol duct. The patient was then managed with continuous gastrostomy feeds and continuous infusion of glucagon (5–10 g/kg䡠h) and octreotide (5–20 g/kg䡠d). Even on this combination, his blood glucose level was just above 72 mg/dl. The patient’s family then moved to London, and the patient’s care was transferred to Great Ormond Street Children’s Hospital National Health Service Trust. Investigations at Great Ormond Street Children’s Hospital confirmed persisting severe hyperinsulinism. His management at this stage consisted of continuous high calorie gastrostomy feeds with continuous sc infusion of glucagon (5 g/kg䡠h) and up to four injections of sc octreotide (15–20 g/kg䡠d). Because the patient had undergone over three procedures to remove his pancreas, it was postulated that there may be a focal lesion somewhere causing his persistent hyperinsulinism. A 18F-fluoro-l-Dopa PET was performed to localize the focal lesion. His genetic analysis confirmed that he was carrying only the paternal mutation in the ABCC8 gene inherited from his father (a single nucleotide deletion in exon 25, nucleotide 3084 del g). PET imaging
Treatment with glucagon and octreotide were stopped 24 h before the PET scan, and normoglycemia was maintained by adjusting glucose infusion via a central venous line, with the highest infusion rate of 12.7 mg/kg䡠min. Blood glucose levels were monitored frequently, especially during the fasting period necessary before anesthesia. This patient underwent a whole body PET scan from the level of eyes to thigh (total emission time, 5 min) with a GE Advance PET Scanner (General Electric Medical Systems, Milwaukee, WI) operated in two-dimensional mode. To correct for photon attenuation, a 2-min postemission transmission scan was performed with robotically operated 68Ge rods. 18F-Fluorol-Dopa was synthesized via electrophilic procedure with [18F]F2 as a source for radiolabeled fluorine (20). The iv injected dose of 18F-fluoro-l-Dopa was 60 MBq (body weight, 15.7 kg). Scanning began 62 min postinjection under pentobarbital-induced general anesthesia after 6 h fast. Plasma glucose level was monitored closely, with target concentration between 72 and 90 mg/dl during the scan. To obtain images for visual and quantitative analysis, the data were corrected for deadtime, decay, and photon attenuation and reconstructed in a 128 ⫻ 128 matrix. The final in-plane resolution in segmented attenuation correction and iterative reconstructed (SAC-OSEM) and Hann-filtered (4.6 mm) images was 5 mm (full-width half-maximum). Intraabdominal tissue uptake of axial PET slices was correlated by coreading with slicewise optimized reference magnetic resonance images (MRI) before and after gadolinium contrast performed 1 d before PET scanning. PET images were analyzed visually (axial, coronal, and sag-
Hussain et al. • [18F]-Dopa PET in Hyperinsulinism of Infancy
J Clin Endocrinol Metab, August 2006, 91(8):2839 –2842
FIG. 1. 18Fluoro-L-Dopa PET (A) and axial MRI (B) of the 3-yr, 4-month-old boy having ectopic hyperinsulinemic focus indicated with a white line on PET. The highest tracer uptake is seen bilaterally in the kidneys dorsal from the focus.
ittal views) and semiquantitatively by calculating maximum and mean standardized uptake value in the region of interest. Findings in the PET study
A clear focus of increased 18F-fluoro-l-DOPA uptake could be seen ventral and medial to the right renal pelvis in the vicinity of the region of former head of the pancreas with the maximum and mean standardized uptake value values of 5.7 and 3.9 g/ml (8 pixels), respectively (Fig. 1A). According to the MRI, this focal uptake appeared to localize adjacent or next to the duodenum (in the wall or cavity of the duodenum; Fig. 1B). The focus was suggestive of persistent hyperinsulinemic activity, although physiological bile activity associated with leakage from choledochoduodenostomy could not decisively be ruled out. However, there was no evidence of surgical complication, thus making the second interpretation unlikely. Apart from this pathological finding, physiologically increased tracer uptake was seen in the basal ganglia of brain, the bony growth plates, and the urinary collection system. The liver and brain cortex were also visualized, although less so than the previously named structures (Fig. 2).
protrusions of the region of the primitive gut epithelium. Signals within the developing gut endoderm specify the pancreatic region. Hence, during development, an ectopic remnant of the pancreas containing the focal lesion may have formed in the cavity or in the wall of the duodenum. In adults, ectopic pancreatic tissue is most frequently found in the stomach (25–35%), duodenum (30%), jejunum (15–20%), and ileum (5%) (23). Ectopic pancreatic tissue has been reported to cause hyperinsulinemic hypoglycemia in adults but not in children (24, 25). Because further surgery is potentially dangerous in this
Once the diagnosis of CHI has been established, then the identification of those patients with focal CHI is extremely important. Patients with focal disease may be “cured” by surgical resection if the focal lesion is completely removed. Focal lesions occur in about 50% of children with CHI although the incidence is higher in some centers (12, 21). This patient underwent an initial subtotal pancreatectomy without preoperative localization. As a result, when the focal lesion was identified, 95% of the pancreas was already removed and the patient missed the opportunity of cure without diabetes. The 18F-fluoro-l-Dopa PET scan in this patient shows an intense uptake of the 18F-fluorine isotope in the region of the duodenum (Figs. 1 and 2). Because whole pancreas was carefully removed in three operations, and there was histological evidence of islet tissue in the duodenal wall, we propose that the focal tracer activity represents ectopic pancreatic tissue either within the wall of the duodenum or inside the lining of the duodenum. The finding of pancreatic tissue within the duodenum would be consistent with the developmental biology of the pancreas. Pancreatic cell types originate from the endodermal cells lining the upper and duodenal region of the forgut (22). The development of the pancreas begins with the formation of the dorsal and ventral
FIG. 2. The focus is clearly detectable (white line) in the coronal PET views, showing also increased tracer uptake in growth plates, bladder, and lower abdominal region in the small intestine.
Hussain et al. • [18F]-Dopa PET in Hyperinsulinism of Infancy
J Clin Endocrinol Metab, August 2006, 91(8):2839 –2842
patient, he is now managed medically. His sc continuous glucagon infusion is now stopped, but at the age of 5 yr, he still requires eight bolus feeds of high-calorie milk during the day, continuous high-calorie milk gastrostomy feeds during the night, and four sc injections of octreotide. On this intensive regime, his blood glucose levels range between 50 –126 mg/dl. In terms of long-term outlook, it is possible that the focal lesion may undergo spontaneous apoptosis. There is early evidence that some focal lesions in patients with CHI have an increased rate of apoptosis (26), although the timing at which this occurs in different patients cannot be predicted. Preoperative localization of the focal lesion in the wall or cavity of the duodenum using 18F-fluoro-l-Dopa PET scanning would have changed the surgical approach to this patient’s management. This patient would then have required a duodenectomy and resection of the pancreatic head only with preservation of the body and tail of the pancreas. In summary, we report the use of PET scanning for the first time in the case of a child with severe CHI due to an active ectopic focal lesion either in the wall of the duodenum or in the cavity of the duodenum. Although repeated surgery was able to remove all remnants of the pancreas, it was not able to change the child’s hyperinsulinemia, strongly supporting existence of the focus being outside pancreatic bed and in line with findings on PET. This case illustrates the importance of accurate preoperative localization of the focal lesion, and it demonstrates that some cases of CHI can be due to ectopic focal lesions. 18F-Fluoro-l-Dopa PET scanning has potential to localize these ectopic focal lesions.
Acknowledgments Received February 28, 2006. Accepted May 2, 2006. Address all correspondence and requests for reprints to: Dr. K. Hussain, Unit of Biochemistry, Endocrinology and Metabolism, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: [email protected]
Research at the Institute of Child Health and Great Ormond Street Hospital for Children National Health Service (NHS) Trust benefits from R&D funding received from the NHS Executive.
References 1. Hussain K 2005 Congenital hyperinsulinism. Semin Fetal Neonatal Med 10: 369 –376 2. Menni F, de Lonlay P, Sevin C, Touati G, Peigne C, Barbier V, Nihoul-Fekete C, Saudubray JM, Robert JJ 2001 Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 107:476 – 479 3. Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, AguilarBryan L, Gagel RF, Bryan J 1995 Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 268: 426 – 429 4. Nestorowicz A, Wilson BA, Schoor KP, Inoue H, Glaser B, Landau H, Stanley CA, Thornton PS, Clement 4th JP, Bryan J, Aguilar-Bryan L, Permutt MA 1996 Mutations in the sulphonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet 5:1813–1822 5. Rahier J, Guiot Y, Sempoux C 2002 Persistent hyperinsulinaemic hypoglycaemia of infancy: a heterogeneous syndrome unrelated to nesidioblastosis. Arch Dis Child Fetal Neonatal Ed 82:F108 –F112 6. De Lonlay P, Fournet JC, Rahier J, Gross-Morand MS, Poggi-Travert F,
20. 21. 22. 23. 24. 25. 26.
Foussier V, Bonnefont JP, Brusset MC, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM, Junien C 1997 Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy. J Clin Invest 100:802– 807 Verkarre V, Fournet JC, Delonlay P 1998 Paternal mutation of the sulphonylurea receptor (SUR 1) gene and maternal loss of the 11p15 imprinted genes lead to persistent hyperinsulinism in focal adenomatous hyperplasia. J Clin Invest 102:1286 –1291 Ryan F, Devaney D, Joyce C, Nestorowicz A, Permutt MA, Glaser B, Barton DE, Thornton PS 1998 Hyperinsulinism: molecular aetiology of focal disease. Arch Dis Child 79:445– 447 Fournet JC, Mayaud C, de Lonlay P, Gross-Morand MS, Verkarre V, Castanet M, Devillers M, Rahier J, Brunelle F, Robert JJ, Nihoul-Fekete C, Saudubray JM, Junien C 2001 Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11. Am J Pathol 158:2177–2184 Aynsley-Green A, Hussain K, Hall J, Saudubray JM, Nihoul-Fe´ke´te´ C, De Lonlay-Debeney P, Brunelle F, Otonkoski T, Thornton P, Lindley KJ 2000 The practical management of hyperinsulinism in infancy. Arch Dis Child 82:F98 –F107 Brunelle F, Negre V, Barth MO, Fekete CN, Czernichow P, Saudubray JM, Kuntz F, Tach T, Lallemand D 1989 Pancreatic venous samplings in infants and children with primary hyperinsulinism. Pediatr Radiol 19:100 –103 de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, Sempoux C, Vici CD, Brunelle F, Touati G, Rahier J, Junien C, Nihoul-Fekete C, Robert JJ, Saudubray JM 1999 Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 340:1169 –1175 Stanley CA, Thornton PS, Ganguly A, MacMullen C, Underwood P, Bhatia P, Steinkrauss L, Wanner L, Kaye R, Ruchelli E, Suchi M, Adzick NS 2004 Preoperative evaluation of infants with focal or diffuse congenital hyperinsulinism by intravenous acute insulin response tests and selective pancreatic arterial calcium stimulation. J Clin Endocrinol Metab 89:288 –296 Abernethy LT, Davidson DC, Lamont GL, Shepherd RM, Dunne MJ 1998 Intra-arterial calcium stimulation test in the investigation of hyperinsulinaemic hypoglycaemia. Arch Dis Child 78:359 –363 Grimberg A, Ferry Jr RJ, Kelly A, Koo-McCoy S, Polonsky S, Glaser B, Permutt MA, Aguilar-Bryan L, Stafford D, Thornton PS, Baker L, Stanley CA 2001 Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 50:322–328 Huopio H, Jaaskelainen J, Komulainen J, Miettinen R, Karkkainen P, Laakso M, Tapanainen P, Voutilainen R, Otonkoski T 2002 Acute insulin response tests for the differential diagnosis of congenital hyperinsulinism. J Clin Endocrinol Metab 87:4502– 4507 Henwood MJ, Kelly A, Macmullen C, Bhatia P, Ganguly A, Thornton PS, Stanley CA 2005 Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphatesensitive potassium channel genes. J Clin Endocrinol Metab 90:789 –794 Otonkoski T, Nanto-Salonen K, Seppanen M, Veijola R, Huopio H, Hussain K, Tapanainen P, Eskola O, Parkkola R, Ekstrom K, Guiot Y, Rahier J, Laakso M, Rintala R, Nuutila P, Minn H 2006 Noninvasive diagnosis of focal hyperinsulinism of infancy with [18F]-DOPA positron emission tomography. Diabetes 55:13–18 Ribeiro MJ, De Lonlay P, Delzescaux T, Boddaert N, Jaubert F, Bourgeois S, Dolle F, Nihoul-Fekete C, Syrota A, Brunelle F 2005 Characterization of hyperinsulinism in infancy assessed with PET and 18F-fluoro-l-DOPA. J Nucl Med 46:560 –566 Bergman J, Haaparanta M, Lehikoinen P, Solin O 1994 Electrophilic synthesis of 6-[18F]fluoro-l-dopa, starting from aqueous [18F]-fluoride. J Label Comp Radiophram 35:476 – 477 Suchi M, Macmullen CM, Thornton PS, Adzick NS, Ganguly A, Ruchelli ED, Stanley CA 2006 Molecular and immunohistochemical analyses of the focal form of congenital hyperinsulinism. Mod Pathol 19:122–129 Edlund H 2001 Factors controlling pancreatic cell differentiation and function. Diabetologia 44:1071–1079 Cagirici U, Ozbaran M, Veral A, Posacioglu H 2001 Ectopic mediastinal pancreas. Eur J Cardiothoracic Surg 19:514 –517 Ashton MA 1995 Strumal carcinoid of the ovary associated with hyperinsulinaemic hypoglycaemia and cutaneous melanosis. Histopathology 27:463– 467 Morgello S, Schwartz E, Horwith M, King ME, Gordon P, Alonso DR 1988 Ectopic insulin production by a primary ovarian carcinoid. Cancer 61:800 – 805 Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B 2000 ␤-Cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49:1325–1333
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.