Nonislet cell tumor hypoglycemia
- F John Service, MD, PhD
F John Service, MD, PhD
- Emeritus Professor of Medicine
- Mayo Clinic College of Medicine
- Adrian Vella, MD
Adrian Vella, MD
- Professor of Medicine
- Mayo Clinic
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 . 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  (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 . Big IGF-2 also suppresses glucagon and growth hormone release . The net result is continued glucose utilization by skeletal muscle and inhibition of glucose release, glycogenolysis, and gluconeogenesis in the liver .
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