1. Insulinoma 2012 30 years experience with diagnosis and treatment Jan Škrha 3 rd Department of Internal Medicine, 1 st Faculty of Medicine, Charles University in Prague 27 th Symposium of the Federation of the International Danube-Symposia of Diabetes Mellitus, Budapest, 28-30th June, 2012

2. CAUSE OF HYPOGLYCEMIA 1.According to pathogenesis a) decreased glucose production - lack of contraregulatory hormones - liver or kidney disease, alcohol b) increased glucose utilisation - exogenously caused (DM treatment) - endogenously caused (insulinoma) 2. According to timing of the food ingestion a) fasting hypoglycemia (!!!) b) random hypoglycemia during the day - reactive (functional), postoperative

3. Hypoglycemia and activation of contraregulatory hormones GlucoseHormone 3,8-3,6 mmol/lglucagon 3,5-3,2 mmol/lcatecholamines 3,1-2,7 mmol/lgrowth hormone 2,8-2,6 mmol/lcortisol neurogenic symptoms neuroglycopenic symptoms

4. HYPOGLYCEMIC SYMPTOMS 1) neurogenic: sweatting, palpitations, tachycardia, (adrenergic) anxiety, tremor 2) neuroglycopenic: a) neurologic: confusion,headache, blurred vision, diplopy, dysarthria, decreased abbility to concentrate, impaired speech and consciousness, cramps, epilepsy b) psychiatric: unusual hesitation, temper changes (depression, euphory) impaired thinking

5. Characteristics of the patients (3 rd Departmrent of Internal Medicine: 1980 – 2012) Organic Functional hyperinsulinism hyperinsulinism (n = 125) (n = 30) Males / females 32 / 93 (~ 75 % women) 7 / 21 Age (yrs) 52 ± 17 27 ± 5 Duration of the disease (yrs) 3 (0,1 – 25) 1 (0,5 – 2) BMI (kg/m 2 ) 28,2 ± 5,3 (32 % normal) 24,3 ± 2,9 Blood pressure – systolic 134 ± 17 125 ± 15 (mm Hg) (55 % normal) diastolic 79 ± 10 78 ± 6

6. Fasting test Before After Positive: 100 % 91 % 98 %

7. Organic hyperinsulinism (3rd Department of Internal Medicine: 1980 – 2012) Imaginating method Finding by surgery Positive Negative Confirmed Removed from positive US 4 (8 %) 47 (92 %) 2 (50 %) 45 (88 %) EU 41 (84 %) 8 (16 %) 33 (83 %) 45 (94 %) CT 27 (30 %) 64 (70 %) 22 (85 %) 86 (95 %) AG 39 (43 %) 52 (57 %) 25 (64 %) 89 (94 %) Localised ~ 70 % of insulinomas before operation

11. Octreoscan

13. TREATMENT a)surgical - by laparotomy - by laparoscopy b)conservative - regimen (diet, activity) - pharmacological (diazoxide, octreotide)

14. Enucleation

15. Resection (hemipancreatectomy)

16. INSULINOMA – RESULTS OF TREATMENT (3 rd Department of Internal Medicine, 1980-2012) 125 insulinomas / microadenomatosis 115 operated 10 conservatively in 104 removed (90 %) in 11 undiscovered 3 removed 8 conservative (by reoperation) Surgical success: 93 % Agreement with preoperative examination : 64 of 81 (79 %)

17. Histology

18. Surgical and histological finding a)localization (n=115) Head: 30 % Body: 28 % Tail: 42 % b) histology Benign adenoma: 103 Malign carcinoma: 4 Uncertain biological activity: 5 Multiple microadenomatosis: 3

19. Algorithm of diagnosis in organic hyperinsulinism Clinical suspition Biochemical examination Diagnosis confirmedDiagnosis unconfirmed Topographic localisation CT Angiography Endosonography Localisation confirmedLocalisation unconfirmed Surgery Insulinoma removedInsulinoma unremoved Conservative treatment TREATMENT DIAGNOSIS

20. In differential diagnosis: HYPOGLYCEMIA FACTITIA

21. HYPOGLYCEMIA FACTITIA Characteristic signs: - suspicion on insulinoma - uncertainty from clinical picture - uncertainty from laboratory findings - frequent relationship of the patient to health care providers Attention: IATROGENIC HYPOGLYCEMIA

22. Insulinoma vs hypoglycemia factitia Laboratory variable InsulinomaHypoglycemia factitia caused by insulin Hypoglycemia factitia caused by sulphonylurea Plasma glucose↓↓↓ Plasma insulin↑ - ↑↑↑↑↑↑ Serum C-peptide↑ - ↑↑↓ - ↓↓↑ - ↑↑ Plasma proinsulin ↑ - ↑↑↔↔ Sulphonylurea (urine) negative positive

23. Conclusions for clinical practice to analyse symptoms (history !) to confirm hypoglycemia to elucidate cause of hypoglycemia (confirm diagnosis) to realize reliable treatment strategy removing hypoglycemia (related to diagnosis and clinical state of the patient) Hypoglycemia is deleterious for organism and is life threatening

24. Collaboration Surgery: Jan Šváb, Ladislav Krušina (†) Biochemistry: Jirina Hilgertová Marcela Jarolímková Pathologist: Jaroslava Dušková Metabolic ward staff: Eva Kotrlíková Gustav Šindelka (†) Imaging: Josef Hořejš, Radan Keil