In the name of GOD

1. In the name of GOD

2. Problem lists : • Neurogenic symptoms • Neuroglycopenicsymptoms • Positive fasting test

4. Hypoglycemia in persons without diabetes • Hypoglycemic disorders are rare in persons without diabetes. • Review the history, physical findings, and all available laboratory data seeking clues to specific disorders,drugs,critical illnesses, hormone deficiencies, nonislet cell tumors.

7. Factitious Hypoglycemia • Such patients have generally been healthy women younger than 50 years of age who have an underlying psychological disorder. • Causes : insulin injection , sulfonylureas or a meglitinide. • Because the main differential is insulinoma, most patients with this condition should undergo a 72-hour fast.

8. When the cause of the hypoglycemic disorder is not evident, i.e. in a seemingly well individual, measure plasma glucose, insulin, C-peptide, proinsulin, and β –hydroxyl butyrate concentrations and screen for oral hypoglycemic agents, during an episode of spontaneous hypoglycemia, and observe the plasma glucose response to iv injection of 1.0 mg glucagon.

9. When a spontaneous hypoglycemic episode cannot be observed, formally recreate the circumstances in which symptomatic hypoglycemia is likely to occur, i.e. during a fast of up to 72 h or after a mixed meal.

10. Our case :

12. Non–Islet Cell Tumors (NICTH) • NICTH is a rare paraneoplastic syndrome encountered in the setting of a wide variety of benign and malignant tumors. • NICTH occurs more commonly in patients with mesenchymal tumors, fibromas, carcinoid, myelomas, lymphomas, hepatocellular, and colorectal carcinomas. • Tumors of mesenchymal origin that generally are large and slow growing, but often malignant. • About one third are retroperitoneal, one third are intraabdominal, and one third are intrathoracic. • In Asia, hepatomas are the most common non–islet cell tumors associated with hypoglycemia.

13. Non–Islet Cell Tumors (NICTH) • Patients with NICTH may appear ill due to the underlying tumor. In such patients, common symptoms are weight loss and abdominal pain. • Clinical features of IGF2 producing nonisletcell Tumor hypoglycemia. Growth Horm IGF Res 2006; 16:211.

14. Nonislet cell tumor hypoglycemia (NICTH) • Pathophysiology : • The tumors typically secrete excessive amounts of pro-IGF-II, which results in stimulation of the insulin receptors and increased glucose utilization.

15. Nonislet cell tumor hypoglycemia (NICTH) • Pathophysiology : • The total level of IGF-II may be normal, but the ratio of pro-IGF-II to IGF-II may be elevated. Because of suppressed GH secretion and the resulting low IGF-I levels, IGF-II to IGF-I ratios are elevated. • Endogenous insulin secretion is suppressed appropriately in NICTH.

16. Nonislet cell tumor hypoglycemia (NICTH) • Pathophysiology : • Increased secretion of “big” IGF II which acts on insulin receptor, • Tumor invasion of liver, and adrenal glands blocking counter regulatory mechanisms to hypoglycemia, • Tumor producing insulin, • Increased glucose utilization by the tumor and antibodies against insulin or insulin receptor.

18. Nonislet cell tumor hypoglycemia (NICTH) • Diagnosis : • In most cases, diagnosis is not difficult, and patients generally are middle-aged to elderly; the tumor is usually large, and its presence is known before the onset of hypoglycemia or can be readily noted on physical examination and by ultrasonographic, computed tomographic, and nuclear magnetic resonance (NMR) studies.

19. Nonislet cell tumor hypoglycemia (NICTH) • Diagnosis : • Biochemically, the hypoglycemia is associated with appropriately suppressed plasma insulin and C-peptide levels and increased IGF-2 levels, as well as an increased IGF-2/ IGF-1 ratio, because of suppression of growth hormone secretion and hence suppressed IGF-1 release by IGF-2.

20. Nonislet cell tumor hypoglycemia (NICTH) • In some cases, hypoglycemia results mainly from increased glucose utilization by the tumor, and debulking by surgery or by radiation treatment can alleviate or ameliorate the hypoglycemia.

21. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH.

22. The first clinical manifestation in 31 of the patients (48%) was symptoms of hypoglycemic attack that included confusion, incoordination, difficulty in waking in the morning and sweating and coma. • However, in the remaining 34 patients (52%) the tumor was detected prior to the first hypoglycemic attack, with the most frequent presenting symptoms being loss of body weight, an abdominal massand pain. The mean duration until the first hypoglycemic attack from diagnosis of the tumor in these patients was 8.5 ± 1.9 months.

29. Adrenal insufficiency

30. Adrenal insufficiency • Adrenocortical failure is not commonly found as a cause of hypoglycemia in adults in the absence of other clinical clues. • A seemingly low plasma cortisol concentration measured during spontaneous hypoglycemia is not sufficient evidence of adrenocortical insufficiency.

31. Adrenal insufficiency • In a patient with chronic insulinoma , induced recurrent hypoglycemia, counter regulatory hormone responses to hypoglycemia were elicited at a lower glycemic threshold, and the absolute increase in counter regulatory hormone (cortisol, epinephrine, and norepinephrine) levels was less than that observed in the same patient after insulinoma resection.

32. Adrenal insufficiency • Mechanisms : • Recurrent severe hypoglycemia and hypoglycemia-induced hypercortisolemic insults to the HPA axis results in downregulation of counterregulatory hormone responses, including glucocorticoid levels.

33. Adrenal insufficiency • In such patients, insulin tolerance testing may not be test of choice, due to an anticipated attenuation in physiologic response to acute insulin-induced hypoglycemia. • Therefore, cosyntropin stimulation testing may be considered the preferred dynamic test.

34. Adrenal insufficiency • The choice between 1 μg and 250 μgcosyntropin stimulation remains challenging, given the operator variability that can occur with 1 μg dilution of cosyntropin. From a physiological perspective, it would appear that 1 μgcosyntropin stimulation test may be considered preferable, when the clinical suspicion supports a diagnosis of central adrenal insufficiency.