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Nonislet cell tumor hypoglycemia

F John Service, MD, PhD
Adrian Vella, MD
Section Editor
Irl B Hirsch, MD
Deputy Editor
Jean E Mulder, MD


Hypoglycemia can be caused by several tumors, including islet and nonislet tumors. Nonislet cell tumor hypoglycemia (NICTH) is a rare but serious complication of malignancy [1,2]. The most common cause of this type of hypoglycemia is tumoral overproduction of incompletely processed insulin-like growth factor-2 (IGF-2), which results in stimulation of the insulin receptors and increased glucose utilization. Other potential but less common causes include the production of autoantibodies against insulin or the insulin receptor and extensive tumor burden resulting in destruction of the liver or adrenal glands. NICTH occurs more commonly in patients with mesenchymal tumors, fibromas, carcinoid, myelomas, lymphomas, hepatocellular, and colorectal carcinomas (table 1) [2-5].

The pathophysiology, clinical manifestations, and diagnostic evaluation of NICTH will be reviewed here. Islet cell tumors (insulinomas), other causes of hypoglycemia, and the diagnostic approach to hypoglycemic disorders in general are discussed elsewhere. (See "Insulinoma" and "Hypoglycemia in adults: Clinical manifestations, definition, and causes" and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach".)


In the first case report of a patient with metastatic hepatocellular carcinoma and severe hypoglycemia, extensive postmortem examination found no abnormality in the pancreas, extracts from the liver tumor contained no insulin, and the glycogen content was low in the liver (in contrast to the abundant hepatic glycogen in patients with hyperinsulinism) and absent in the tumor [6]. Thus, severe hypoglycemia was mediated by mechanisms other than excess insulin and likely due to extensive tumor burden in the liver.

Subsequently, severe hypoglycemia has been observed in a small percentage of patients with nonislet cell tumors, usually of mesenchymal (eg, fibrosarcoma), vascular (eg, hemangiopericytoma), or epithelial cell types (table 1) [1-5]. Among tumors of epithelial cell origin, hepatocellular carcinomas are most common [2,7]. The tumors are usually large in size, weighing on average two to four kilograms; they are located in the chest in approximately one-third and in the retroperitoneal region in two-thirds of cases.

No single pathogenetic mechanism explains all cases of nonislet cell tumor hypoglycemia (NICTH). However, the major cause of NICTH appears to be increased glucose utilization (particularly in skeletal muscle) and inhibition of glucose release from the liver due to tumoral secretion of incompletely processed insulin-like growth factor-2 (IGF-2), termed "big" IGF-2 [7-12], or rarely, IGF-1 [13] (see "Physiology of insulin-like growth factor-1"). In one series of 28 patients with NICTH, for example, 25 had elevated serum big IGF-2 concentrations; the concentration of normal IGF-2 was reduced [11]. Big IGF-2 also suppresses glucagon and growth hormone release [7]. The net result is continued glucose utilization by skeletal muscle and inhibition of glucose release, glycogenolysis, and gluconeogenesis in the liver [7].

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Literature review current through: Sep 2017. | This topic last updated: Jul 24, 2017.
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  1. Scott K. Non-islet cell tumor hypoglycemia. J Pain Symptom Manage 2009; 37:e1.
  2. Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab 2014; 99:713.
  3. Marks V, Teale JD. Tumours producing hypoglycaemia. Endocr Relat Cancer 1998; 5:111.
  4. Ma RC, Tong PC, Chan JC, et al. A 67-year-old woman with recurrent hypoglycemia: non-islet cell tumour hypoglycemia. CMAJ 2005; 173:359.
  5. Pink D, Schoeler D, Lindner T, et al. Severe hypoglycemia caused by paraneoplastic production of IGF-II in patients with advanced gastrointestinal stromal tumors: a report of two cases. J Clin Oncol 2005; 23:6809.
  6. Nadler WH, Wolfer JA. Hepatogenic hypoglycemic associated with primary liver cell carcinoma. Arch Intern Med 1929; 44:701.
  7. Dynkevich Y, Rother KI, Whitford I, et al. Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocr Rev 2013; 34:798.
  8. Eastman RC, Carson RE, Orloff DG, et al. Glucose utilization in a patient with hepatoma and hypoglycemia. Assessment by a positron emission tomography. J Clin Invest 1992; 89:1958.
  9. Gorden P, Hendricks CM, Kahn CR, et al. Hypoglycemia associated with non-islet-cell tumor and insulin-like growth factors. N Engl J Med 1981; 305:1452.
  10. Shapiro ET, Bell GI, Polonsky KS, et al. Tumor hypoglycemia: relationship to high molecular weight insulin-like growth factor-II. J Clin Invest 1990; 85:1672.
  11. Zapf J, Futo E, Peter M, Froesch ER. Can "big" insulin-like growth factor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? J Clin Invest 1992; 90:2574.
  12. Phillips LS, Robertson DG. Insulin-like growth factors and non-islet cell tumor hypoglycemia. Metabolism 1993; 42:1093.
  13. Nauck MA, Reinecke M, Perren A, et al. Hypoglycemia due to paraneoplastic secretion of insulin-like growth factor-I in a patient with metastasizing large-cell carcinoma of the lung. J Clin Endocrinol Metab 2007; 92:1600.
  14. Shetty MR, Boghossian HM, Duffell D, et al. Tumor-induced hypoglycemia: a result of ectopic insulin production. Cancer 1982; 49:1920.
  15. Shames JM, Dhurandhar NR, Blackard WG. Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med 1968; 44:632.
  16. Kiang DT, Bauer GE, Kennedy BJ. Immunoassayable insulin in carcinoma of the cervix associated with hypoglycemia. Cancer 1973; 31:801.
  17. Seckl MJ, Mulholland PJ, Bishop AE, et al. Hypoglycemia due to an insulin-secreting small-cell carcinoma of the cervix. N Engl J Med 1999; 341:733.
  18. Frankton S, Baithun S, Husain E, et al. Phaeochromocytoma crisis presenting with profound hypoglycaemia and subsequent hypertension. Hormones (Athens) 2009; 8:65.
  19. Fukuda I, Hizuka N, Ishikawa Y, et al. Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia. Growth Horm IGF Res 2006; 16:211.
  20. Soares-Welch CV, Zeldenrust SR, Conover CA, et al. Hodgkin's lymphoma manifesting with hypoglycemia. Endocr Pract 2003; 9:96.
  21. Dyer PH, Chowdhury TA, Milles J. Recurrent hypoglycaemia. Postgrad Med J 1998; 74:279.
  22. Pun KK, Young RT, Wang C, et al. The use of glucagon challenge tests in the diagnostic evaluation of hypoglycemia due to hepatoma and insulinoma. J Clin Endocrinol Metab 1988; 67:546.
  23. Hoff AO, Vassilopoulou-Sellin R. The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia. Cancer 1998; 82:1585.
  24. Redmon B, Pyzdrowski KL, Elson MK, et al. Hypoglycemia due to a monoclonal insulin-binding antibody in multiple myeloma. N Engl J Med 1992; 326:994.
  25. Walters EG, Tavaré JM, Denton RM, Walters G. Hypoglycaemia due to an insulin-receptor antibody in Hodgkin's disease. Lancet 1987; 1:241.
  26. de Boer J, Jager PL, Wiggers T, et al. The therapeutic challenge of a nonresectable solitary fibrous tumor in a hypoglycemic patient. Int J Clin Oncol 2006; 11:478.
  27. Teale JD, Marks V. Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH). Clin Endocrinol (Oxf) 1998; 49:491.
  28. Perros P, Simpson J, Innes JA, et al. Non-islet cell tumour-associated hypoglycaemia: 111In-octreotide imaging and efficacy of octreotide, growth hormone and glucocorticosteroids. Clin Endocrinol (Oxf) 1996; 44:727.
  29. Morbois-Trabut L, Maillot F, De Widerspach-Thor A, et al. "Big IGF-II"-induced hypoglycemia secondary to gastric adenocarcinoma. Diabetes Metab 2004; 30:276.
  30. Bourcigaux N, Arnault-Ouary G, Christol R, et al. Treatment of hypoglycemia using combined glucocorticoid and recombinant human growth hormone in a patient with a metastatic non-islet cell tumor hypoglycemia. Clin Ther 2005; 27:246.
  31. Powter L, Phillips S, Husbands E. A case report of non-islet cell tumour hypoglycaemia associated with ovarian germ-cell tumour. Palliat Med 2013; 27:281.
  32. Mukherjee S, Diver M, Weston PJ. Non islet cell tumor hypoglycaemia in a metastatic Leydig cell tumor. Acta Oncol 2005; 44:761.
  33. Silveira LF, Bouloux PM, MacColl GS, et al. Growth hormone therapy for non-islet cell tumor hypoglycemia. Am J Med 2002; 113:255.
  34. Teale JD, Blum WF, Marks V. Alleviation of non-islet cell tumour hypoglycaemia by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem 1992; 29 ( Pt 3):314.
  35. Drake WM, Miraki F, Siddiqi A, et al. Dose-related effects of growth hormone on IGF-I and IGF-binding protein-3 levels in non-islet cell tumour hypoglycaemia. Eur J Endocrinol 1998; 139:532.
  36. Agus MS, Katz LE, Satin-Smith M, et al. Non-islet-cell tumor associated with hypoglycemia in a child: successful long-term therapy with growth hormone. J Pediatr 1995; 127:403.