DİYABETİK OLMAYAN HASTALARDA HİPOGLİSEMİ

Glukoz, beyin tarafından kullanılan ana maddedir ve bu nedenle, glikoz konsantrasyonlarını korumak için çok sayıda düzenleyici mekanizma mevcuttur. Temel düzenleyici mekanizmalar insülin salınımının kesilmesi, glukagon sekresyonu, kortizol ve büyüme hormonu salınımıdır. Bu düzenleyici mekanizmalar başarısız veya kusurlu olduğunda, hipoglisemi ortaya çıkar. Diyabet tedavisi alan hastalar hariç tutulursa, hipoglisemi nadir bir sendromdur ancak önemli morbitidilere neden olabilir. Spontan hipoglisemilerde tanı ve tedavide zorluklar yaşanmaktadır. Bu nedenle hastanın klinik, laboratuvar ve görüntülemelerinin incelendiği tam bir değerlendirme gerekir. Hipogliseminin semptomları spesifik değildir ve bu nedenle, hipoglisemi için bir değerlendirmeye başlamadan önce Whipple triadının varlığını belirleyerek hipoglisemiyi doğrulamak önemlidir. Whipple triadı hipoglisemi ile tutarlı semptomlar, plazma glikoz seviyesinin 55 mg / dl'den düşük olması ve semptomların plazma glikoz seviyesinin yükseltilmesi sonrasında düzelmesi bileşenlerinden oluşur. Hipoglisemi değerlendirmesi semptomların kendiliğinden ortaya çıktığı anda yapılmalıdır. Bu mümkün değilse, 72 saat uzamış açlık testi ile hipoglisemi ortaya çıkarılmaya çalışılır. Post prandiyal hipoglisemiden kuşkulanıldığında ise karışık yemek testi (mixed-meal test) de uygulanabilir. Endojen hiperinsülinemik hipogliseminin nedenleri arasında insülinoma, post-bariatrik hipoglisemi ve non-insülinoma pankreatik hipoglisemi sendromu bulunur. Endojen hiperinsülinemi tespit edilen hastalarda tanısal görüntüleme çalışmlaları da yapmak gerekir. Otoimmün hipoglisemi sendromu klinik ve biyokimyasal olarak insülinomaya benzer, ancak yüksek seviyelerde insülin antikorları ve plazma insülini ile ilişkilidir. Hipogliseminin diğer önemli nedenleri arasında; ilaçlar, adacık hücreli dışı tümörler, hormonal eksiklikler, kritik hastalıklar ve faktisiyöz hipoglisemi bulunur. Hipoglisemi ataklarının önlenmesi için etiyolojiyi belirleyecek tanısal çalışmalar yapılmalıdır. Hipogliseminin altında yatan nedeni bulmak bize mekanizmayı da gösterir ve uygun tedavinin seçilmesini sağlar. Bu derlemede diyabetik olmayan hastalarda hipogliseminin patogenezi ve yönetimine genel bir bakış sunuyoruz.

Anahtar Kelimeler:

Hipoglisemi, Hiperinsülinizm, İnsulinoma.

HYPOGLYCEMIA IN NON-DIABETIC PATIENTS

Glucose is the main substance used by the brain, and as such, multiple regulatory mechanisms exist to maintain glucose concentrations. The main regulatory mechanisms are cessation of insulin secretion the stimulation of glucagon, cortisol and growth hormone secretion. When these regulatory mechanisms fail or are defective, hypoglycemia occurs. Hypoglycemia is a rare syndrome but can cause significant morbidity, excluding patients on diabetes treatment. Spontaneous hypoglycemia has difficulties in diagnosis and treatment. Therefore, a complete evaluation of the patient's clinical, laboratory and imaging studies is required. The symptoms of hypoglycemia are nonspecific and therefore it is important to confirm hypoglycemia by identifying the presence of the Whipple triad before starting an evaluation for hypoglycemia. The Whipple triad consists of symptoms consistent with hypoglycemia, a plasma glucose level of less than 55 mg/dl, and a resolution of symptoms after raising the plasma glucose level. Evaluation of hypoglycemia should be made as soon as symptoms occur spontaneously. If this is not possible, hypoglycemia is tried to be revealed with a 72-hour prolonged fasting test. If post-prandial hypoglycemiais suspected, the mixed-meal test can also be applied. Causes of endogenous hyperinsulinemic hypoglycemia include insulinoma, post-bariatric hypoglycemia, and non-insulinoma pancreatic hypoglycemia syndrome. Diagnostic imaging studies should also be performed in patients with endogenous hyperinsulinemia. Autoimmune hypoglycemia syndrome is clinically andbiochemically similar to insulinoma, but is associated with high levels of insulin antibodies and plasma insulin. Other important causes of hypoglycemia include; drugs, non-islet cell tumors,hormonal deficiencies, critical illness, and factorial hypoglycemia. In order to prevent hypoglycemia attacks, diagnostic studies should be performed to determine the etiology. Findingthe underlying cause of hypoglycemia also shows us the mechanism and enables the selection of the appropriate treatment. In this review, we provide an overview of the pathogenesis and management of hypoglycemia in non-diabetic patients.

Keywords:

Hypoglycemia, Hyperinsulinism, Insulinoma,

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1. Guettier JM, Gorden P. Hypoglycemia. Endocrinology and metabolism clinics of North America. 2006;35(4):753-66.
2. Kittah NE, Vella A. MANAGEMENT OF ENDOCRINE DISEASE: Pathogenesis and management of hypoglycemia. European journal of endocrinology. 2017;177(1):37-47.
3. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2009;94(3):709-28.
4. Svensson A-M, McGuire DK, Abrahamsson P, Dellborg M. Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events. European Heart Journal. 2005;26(13):1255-61.
5. Pinto DS, Skolnick AH, Kirtane AJ, et al. U-Shaped Relationship of Blood Glucose With Adverse Outcomes Among Patients With ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology. 2005;46(1):178-80.
6. Martens P, Tits J. Approach to the patient with spontaneous hypoglycemia. European Journal of Internal Medicine. 2014;25(5):415-21.
7. Kosiborod M, Inzucchi SE, Goyal A, Krumholz HM, Masoudi FA, Xiao L, et al. Relationship Between Spontaneous and Iatrogenic Hypoglycemia and Mortality in Patients Hospitalized With Acute Myocardial Infarction. JAMA. 2009;301(15):1556-64.
8. Mitrakou A, Ryan C, Veneman T, et al. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. The American journal of Physiology. 1991;260 (1):67-74.
9. Cryer PE, White NH, Santiago JV. The relevance of glucose counterregulatory systems to patients with insulin-dependent diabetes mellitus. Endocrine reviews. 1986;7(2):131-9.
10. Cryer PE, Gerich JE. Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. The New England journal of medicine. 1985;313(4):232-41.
11.Cryer PE. Hypoglycemia, functional brain failure, and brain death. The Journal of Clinical Investigation. 2007;117(4):868-70.
12. Service FJ. Hypoglycemic disorders. The New England journal of medicine. 1995;332(17):1144-52.
13. DeRosa MA, Cryer PE. Hypoglycemia and the sympathoadrenal system: neurogenic symptoms are largely the result of sympathetic neural, rather than adrenomedullary, activation. American journal of physiology Endocrinology and metabolism. 2004;287(1): 32-41.
14. Towler DA, Havlin CE, Craft S, Cryer P. Mechanism of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuroglycopenic symptoms. Diabetes. 1993;42(12):1791-8.
15. Service FJ. Diagnostic approach to adults with hypoglycemic disorders. Endocrinology and metabolism clinics of North America. 1999;28(3):519-32.
16. Kar P, Price P, Sawers S, Bhattacharya S, Reznek RH, Grossman AB. Insulinomas May Present with Normoglycemia after Prolonged Fasting but Glucose-Stimulated Hypoglycemia. The Journal of Clinical Endocrinology & Metabolism. 2006;91(12):4733-6.
17. Hirshberg B, Livi A, Bartlett DL, Libutti SK, Alexander HR, Doppman JL, et al. Forty-eight-hour fast: the diagnostic test for insulinoma. The Journal of clinical endocrinology and metabolism. 2000;85(9):3222-6.
18. Hogan MJ, Service FJ, Sharbrough FW, Gerich JE. Oral glucose tolerance test compared with a mixed meal in the diagnosis of reactive hypoglycemia. A caveat on stimulation. Mayo Clinic proceedings. 1983;58(8):491-6.
19. Lev-Ran A, Anderson RW. The diagnosis of postprandial hypoglycemia. Diabetes. 1981;30(12):996-9.
20. Placzkowski KA, Vella A, Thompson GB, et al. Secular trends in the presentation and management of functioning insulinoma at the Mayo Clinic, 1987-2007. The Journal of Clinical Endocrinology and Metabolism. 2009;94(4):1069-73.
21. Noone TC, Hosey J, Firat Z, Semelka RC. Imaging and localization of islet-cell tumours of the pancreas on CT and MRI. Best Practice & Research Clinical Endocrinology & Metabolism. 2005;19(2):195-211.
22. Virgolini I, Traub-Weidinger T, Decristoforo C. Nuclear medicine in the detection and management of pancreatic islet-cell tumours. Best practice & research Clinical Endocrinology & Metabolism. 2005;19(2):213- 27.
23. Cuthbertson DJ, Banks M, Khoo B, Antwi K, Christ E, Campbell F, et al. Application of Ga(68) -DOTA-exendin-4 PET/CT to localize an occult insulinoma. Clinical endocrinology. 2016;84(5):789-91.
24. Kauhanen S, Seppänen M, Minn H, et al. Fluorine-18-l-Dihydroxyphenylalanine (18F-DOPA) Positron Emission Tomography as a Tool to Localize an Insulinoma or β-Cell Hyperplasia in Adult Patients. The Journal of Clinical Endocrinology & Metabolism. 2007;92(4):1237-44.
25. Marsk R, Jonas E, Rasmussen F, Näslund E. Nationwide cohort study of post-gastric bypass hypoglycaemia including 5,040 patients undergoing surgery for obesity in 1986–2006 in Sweden. Diabetologia. 2010;53(11):2307-11.
26. Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycemia After Gastric Bypass Surgery: Current Concepts and Controversies. The Journal of Clinical Endocrinology and Metabolism. 2018;103(8):2815-26.
27. Himpens J, Dapri G, Cadière GB. Laparoscopic Conversion of the Gastric Bypass into a Normal Anatomy. Obesity Surgery. 2006;16(7):908-12.
28. Davis DB, Khoraki J, Ziemelis M, et al. Gastric bypass hypoglycemia resolves with gastric feeding or reversal: Confirming a non-pancreatic etiology. Molecular Metabolism. 2018;9:15-27.
29. Lee CJ, Brown T, Magnuson TH, et al. Hormonal response to a mixed-meal challenge after reversal of gastric bypass for hypoglycemia. The Journal of Clinical Endocrinology and Metabolism. 2013;98(7):1208-12.
30. Service FJ, Natt N, Thompson GB, et al. Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes. The Journal of clinical Endocrinology and Metabolism. 1999;84(5):1582-9.
31. Won JGS, Tseng H-S, Yang A-H, et al. Clinical features and morphological characterization of 10 patients with noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS). 2006;65(5):566-78.
32. Goldman J, Baldwin D, Rubenstein AH, Klink DD, Blackard WG, Fisher LK, et al. Characterization of circulating insulin and proinsulin-binding antibodies in autoimmune hypoglycemia. The Journal of Clinical Investigation. 1979;63(5):1050-9.
33. Yu L, Herold K, Krause-Steinrauf H, et al. Rituximab selectively suppresses specific islet antibodies. Diabetes. 2011;60(10):2560-5.
34. Yale J-F, Paty B, Senior PA. Hypoglycemia. Canadian Journal of Diabetes. 2018;42:104-8.
35. Murad MH, Coto-Yglesias F, Wang AT, et al. Drug-Induced Hypoglycemia: A Systematic Review. The Journal of Clinical Endocrinology & Metabolism. 2009;94(3):741-5.
36. O'Keefe SD, Marks V. Lunchtıme Gın And Tonıc A Cause Of Reactıve Hypoglycæmıa. The Lancet. 1977;309(8025):1286-8.
37. Fukuda I, Hizuka N, Ishikawa Y, et al. Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia. Growth hormone & IGF research :official journal of the Growth Hormone Research Society and the International IGF Research Society. 2006;16(4):211-6.
38. Daughaday WH. Hypoglycemia in Patients with Non-Isiet Cell Tumors. Endocrinology and metabolism clinics of North America. 1989;18(1):91-101.
39. Daughaday WH, Kapadia M. Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors. 1989;86(17):6778-82.
40. Teale Jd, Marks V. Inapproprıately Elevated Plasma Insulın-Lıke Growth Factor Iı In Relatıon To Suppressed Insulın-Lıke Growth Factor I In The Dıagnosıs Of Non-Islet Cell Tumour Hypoglycaemıa. 1990;33(1):87-98.
41. Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. The Journal of Clinical Endocrinology and Metabolism. 2014;99(3):713-22.
42. Daughaday WH, Emanuele MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P. Synthesis and Secretion of Insulin-like Growth Factor II by a Leiomyosarcoma with Associated Hypoglycemia. 1988;319(22):1434-40.
43. Hermanides J, Bosman RJ, Vriesendorp TM, Dotsch R, Rosendaal FR, Zandstra DF, et al. Hypoglycemia is associated with Intensive Care Unit Mortality*. 2010;38(6):1430-4.
44. Teale JD, Wark G. The effectiveness of different treatment options for non-islet cell tumour hypoglycaemia. Clinical endocrinology. 2004;60(4):457-60.