Surgery in Congenital Hyperinsulinismless. Winfried Barthlen

Transcription

1 Surgery in Congenital Hyperinsulinismless may be more Winfried Barthlen

2 congenital hyperinsulinism - very rare (1:40.000) - uncontrolled insulin secretion - life threatening hypoglycemia symptoms - unconsciousness, apathia, fits, - severe neurological damage

3 Genetics ABCC8 KCNJ11 GCK GLUD1 HADH HNF1A HNF4A UCP2 SLC16A1 45% 10% Saint-Martin 2011, Senniappan / Prof. Barthlen

4 CHI forms segmental mosaic focal normal islets pathological islets diffuse

5 Focal CHI: -paternal mutation in ABCC8 or KCNJ11 -maternal loss of heterozygosity (LOH) only in the focal lesion Saint-Martin et al. Sem Pediatr Surg 20,1:18-22, / Prof. Barthlen

6 Josip,6 months 18 F- DOPA- PET/CT 6 / Prof. Barthlen

7 frozen sections during surgery normal pathological Josip: n = 29 7 / Prof. Barthlen

8 Josip, 6 Monate 8 / Prof. Barthlen

9 Ashton from Malaysia, 17 months old paternal heterozygous mutation KCNJ11 18 F- DOPA PET/CT 9 / Prof. Barthlen

10 Ashton 10 / Prof. Barthlen choledochal duct - gastroduodenal,hepatic, lienal artery

11 Ashton venous confluens 11 / Prof. Barthlen

12 personal series focal CHI n = 42 Charité Berlin Greifswald today focal focal lesion visible and palpable 1 0 cured 19 (86%) 19(95%) 2nd surgery 3rd surgery laparoscopy 3 9 Roux-en-Y 4 6 complications 1 pseudocyst 1 pulmonary embolism (factor V Leiden mutation) 1 adhesion ileus, 1 NEC 12 / Prof. Barthlen

13 Asyraf from Malaysia, 6 months three surgeries August / Prof. Barthlen

14 CHI forms segmental mosaic focal normal islets pathological islets diffuse

15 persisting hypoglycemia (< 50 mg/dl or < 2.8 mmol/l) Laboratory simultaneous blood taking for blood glucose, insulin, ß-hydroxybutyrat, fatty acids Differential diagnoses - transient hypoglycemia of the newborn - diabetes mellitus of the mother - hypopituitarism, cortisol deficiency - etc. Long term therapy (for years) Long term therapy (for years) Diagnosis: congenital hyperinsulinism hypoglycemia and normal or elevated insulin levels, low ß-hydroxybutyrate, free fatty acids, glucose demand >8mg/kg/min; glucagon testing: rise in blood glucose > 30 mg/dl, + + Diazoxide 5-15 mg/kg/day - Octreotide 15-50mg/kg/day - Glucagon 1-2 mg/day - Genetics ABCC8, KCNJ11, GK, GLUD1, HADH, SLC16A1, HNF4A, UCP2 non-focal lap. pancreatic biopsy lap. restrictive pancreatic resection - unresponsive? 18 F-DOPA-PET/CT focal CHI selective surgical resection of the focal lesion 15 / Prof. Barthlen Arnoux 2011

16 sub- or near-total resection 95-98% is still recommended and widely performed! 98% 95% 16 / Prof. Barthlen

17 subtotal pancreatectomy: long term results: diabetes 19% postop 42% at 8 yrs 91% at 14 yrs hyperglycemia n= Hopital Necker Paris insulin therapy Beltrand, de Lonlay et al Diabetes Care / Prof. Barthlen

18 segmental mosaic

19 Jolina, 15 months medically unresponsive laparoscopic biopsies: segmental mosaic CHI 19 / Prof. Barthlen

20 20 / Laparoscopic pancreatic tail resection Prof. Barthlen

21 Lota from Croatia, 9 months 21 / Prof. Barthlen

22 restrictive surgery in segmental mosaic CHI pat age at diagnosis (months) mutation medication before surgery JB 6 none diazoxide 7mg/kg/d LH 5 none diazoxide 7.5mg/kg/d FS 3 none diazoxide 22mg/kg/d and octreotide 15mg/kg/d HB 3 ABCC8 compund heterozygous octreotide 17 mg/kg/d and glucagon 11 mg/kg/h response to medication unsatisfactory age at surgery (months) medication after surgery time follow-up (september 2013) 15 none 31 insufficient 15 diazoxide 7.1 mg/kg/d insufficient 18 diazoxide 8.8 mg/kg/d insufficient 10 lanreotide 60mg/month complications n=0 22 / Prof. Barthlen

23 Results segmental mosaic CHI 23 / Prof. Barthlen

24 CHI forms segmental mosaic focal normal islets pathological islets diffuse

25 Yildirim, 21 Monate Homozygous KCNJ11 Octreotide 111mg/kg/d (15-50mg/kg/d) Laparoscopic biopsies: diffuse chi 25 / Prof. Barthlen

26 Restrictive surgery in diffuse CHI pat age at diagnosis (months) mutation medication before surgery BY neonatal KCNJ11 homozygous octreotide 111 mg/kg/d DI neonatal ABCC8 octreotide heterozygous 90 mg/kg/d dominant AN neonatal none diazoxide 7.9 mg/kg/d EC neonatal none diazoxide 5 mg/kg/d CN neonatal none diazoxide 6.6 mg/kg/d RP neonatal ABCC8 diazoxide compund 8.5 mg/kg/d heterozygous SB neonatal ABCC8 heterozygous dominant AK neonatal ABCC8 compound heterozygous Elizabeth P neonatal ABCC8 heterozygous Elias P neonatal ABCC8 heterozygous diazoxide 5mg/kg/d octreotide 20 mg/kg/d + iv glucose 7.6 mg/kg/min octreotide 8 mg/kg/d octreotide 8 mg/kg/d response to age at medication time medication surgery (months) after surgery follow-up (september 2013) insufficient 21 none 29 unsatisfactory 14 lanreotide 60mg/month unsatisfactory 360 none 23 (30 years) insufficient 20 none 22 insufficient 28 lanreotide 60mg/month insufficient 7 lanreotide 60mg/month unsatisfactory 132 (11 years) insufficient 2 subtotal resection none 15 unsatisfactory 5 octreotide 8 5 mg/kg/d unsatisfactory 5 none 8 8/1 complication n=1 (hematoma) 26 / Prof. Barthlen

27 Results diffuse CHI 27 / Prof. Barthlen

28 Dizygotic twins from Argentina same mutation: ABCC8 p.g716c (c.2146g>t) same surgery: laparoscopic pancreatic tail resection Elizabeth still on octreotide HE 10x Elias nothing HE 10x diffuse diffuse 28 / Prof. Barthlen

29 1 µv Glucose 10mM Pharmacology Tübingen, Germany pancreas slice of child Eloise from Guatemala 30 s 200 µm Fraction of plateau phase (FOPP) = percentage of time with spike activity = 48% 29 / Prof. Barthlen

30 5 µv isolated islet of Eloise diazoxide 150 µm K ATP channel modulators tolbutamide 400 µm Glucose 10mM electrode with islet without 3 min 30 / Prof. Barthlen

31 Surgery in Congenital Hyperinsulinismless is more! cure in focal CHI: 95% weaning of medication in non-focal CHI : 43% reducing the risk of diabetes 31 / Prof. Barthlen

32 Greifswald Magdeburg Berlin 32 / Prof. Barthlen

33 referral area for CHI surgery n=34 since 2010 from abroad 44% 33 / Prof. Barthlen

34 Greetings from Germany! 34 / Prof. Barthlen

35 35 / Prof. Barthlen