Non-islet cell tumor hypoglycemia

Non-islet cell tumor hypoglycemia (NICTH) is a rare clinical syndrome characterized by recurrent episodes of hypoglycemia in patients with large, non-islet cell tumors. It is most commonly associated with mesenchymal tumors such as sarcomas, but can also occur with other types of tumors like hepatocellular carcinoma, adrenal carcinoma, and large gastrointestinal tumors. NICTH results from the tumor's excessive production of insulin-like growth factor 2 (IGF-2), which leads to increased glucose uptake and utilization by tissues, thereby lowering blood glucose levels.

Etiology and Pathophysiology

NICTH is primarily caused by the ectopic production of a high molecular weight form of IGF-2, known as "big IGF-2". Big IGF-2 is less bound to IGF-binding proteins in the plasma, leading to an increased free IGF-2 level, which in turn has insulin-like effects on muscle and fat tissues, enhancing glucose uptake and inhibiting gluconeogenesis in the liver. This process results in hypoglycemia. Unlike insulinoma, where insulin is directly produced by the tumor, NICTH involves a paraneoplastic syndrome where the tumor secretes substances that indirectly cause hypoglycemia.

Clinical Presentation

Patients with NICTH typically present with symptoms of hypoglycemia, which can include sweating, tremors, confusion, seizures, and even loss of consciousness. These symptoms are more pronounced during periods of fasting or exertion. Diagnosis is often challenging due to the nonspecific nature of these symptoms and requires a high index of suspicion, especially in patients with large or metastatic tumors.

Diagnosis

The diagnosis of NICTH involves demonstrating hypoglycemia in the presence of inappropriately low levels of insulin and C-peptide during a hypoglycemic episode. Laboratory tests also show elevated levels of IGF-2 and a high ratio of IGF-2 to IGF-1. Imaging studies and tumor biopsies can help identify the underlying tumor.

Treatment

The primary treatment for NICTH is the surgical removal of the tumor, which can resolve the hypoglycemic episodes. However, in cases where surgery is not feasible, management of hypoglycemia involves frequent meals and the administration of glucocorticoids, which can help inhibit the effects of IGF-2. In some cases, recombinant growth hormone may be used to decrease the levels of free IGF-2.

Prognosis

The prognosis of NICTH largely depends on the type and stage of the underlying tumor. Complete resection of the tumor can potentially cure the hypoglycemia. However, in patients with inoperable or metastatic tumors, the management of hypoglycemia can be challenging, and the prognosis is generally poor.