Non-islet Cell Hypoglycemia: Case Series and Review of the Literature

Abstract

Non-islet cell hypoglycemia (NICH) is hypoglycemia due to the overproduction of insulin-like growth factor-2 (IGF-2) and its precursors which can activate the insulin receptor. Typically, large mesenchymal and epithelial tumors can cause NICH. Diagnosis is confirmed by finding an elevated IGF-2/IGF-1 ratio. The mainstay of treatment is surgical excision. Glucocorticoids may be used in cases where surgery is not possible. We present two cases of NICH with different outcomes. A 33-year-old male patient admitted with altered mental. He was found walking naked outside his house. Laboratory assessment revealed severe hypoglycemia. Further evaluation showed low levels of insulin, C-peptide, and beta-hydroxybutyrate along with an elevated IGF-2/IGF-1 ratio confirming the diagnosis of NICH. Computed tomography (CT) of the abdomen showed a massive tumor of the liver consistent with hepatocellular carcinoma. Since the patient refused surgery, he was started on prednisone however the hypoglycemia persisted. A 54-year-old female patient with a history of type 2 diabetes mellitus (DM) admitted with recent onset hypoglycemia. Despite stopping her insulin, she continued to have hypoglycemia necessitating the administration of high concentrations of intravenous dextrose. Further evaluation showed low levels of insulin, C-peptide, and beta-hydroxybutyrate along with an elevated IGF-2/IGF-1 ratio consistent with the diagnosis of NICH. CT abdomen showed a 24 cm tumor near the uterus. The pathology was consistent with a gastrointestinal stromal tumor (GIST). After surgical excision of the tumor, the hypoglycemia resolved.

Non-Islet Cell Tumor Hypoglycemia Caused by Recurrent Pelvic Solitary Fibrous Tumor

“…Spontaneous and recurrent hypoglycemia in the absence of hypoglycemic therapy is a medical challenge because it can have multiple etiologies, namely, postprandial hypoglycemia, insulinomas, insulin autoimmune syndrome, adrenal insufficiency, and critical illness (for example, renal or liver failure) [ 7 ]. Uncommonly, it can be a result of paraneoplastic syndrome secondary to extra-pancreatic tumors being this association termed as NICTH and first reported in 1929 by Nadler et al in a patient with hepatocellular carcinoma [ 8 - 9 ].…”

“…NICTH is associated with a variety of malignant and non-malignant tumors, usually of epithelial or mesenchymal origin [ 1 - 2 , 8 ], such as mesothelioma [ 8 ], hemangiopericytoma [ 8 ], adrenocortical carcinoma [ 8 ], pancreatic carcinoma [ 8 ], medullary thyroid carcinoma [ 8 ], lymphoma/leukemia [ 8 ], carcinoid syndrome [ 8 ], fibrosarcoma [ 7 , 8 , 10 ], gastrointestinal stromal tumor, renal cell carcinoma [ 7 , 10 ], prostate cancer, breast cancer, bladder cancer, and SFT [ 10 ]. Regarding SFT, NICTH is found in approximately 4% of cases [ 3 , 11 ] and was reported for the first time in literature, in 1930, by Doege and Potter [ 11 - 12 ].…”

“…Hypoglycemia can be the presenting form of this kind of tumor, or it can appear after its diagnosis [ 8 ]. Our patient had a previous history of benign ovarian tumor resected more than 10 years ago; she had presented a pelvic mass about one year before symptoms of hypoglycemia, which was compatible with disease relapse.…”

Non-islet cell tumor hypoglycemia as an initial presentation of hepatocellular carcinoma coupled with end-stage liver cirrhosis: A case report and review of literature

“…As to our patient, IGF-2 was inappropriately normal for the extremely low IGF-1 level. An IGF-2/IGF-1 ratio greater than 10 has been proposed to be enough to confirm the diagnosis of NICTH[ 16 , 20 , 21 ]. IGF-2 might be falsely normal in our patient because the sample was collected after the first dose of prednisolone was administered, which was able to inhibit the production of IGF-2[ 22 ].…”

Persistent hypoglycemia due to an IGF‐II‐secreting malignant pheochromocytoma: a case report and literature review

“…Nonislet cell tumor hypoglycemia (NICTH) constitutes an underdiagnosed cause of hypoglycemia due to its rarity, ambiguous laboratory picture, and atypical clinical presentation. It is caused by an excessive production of aberrant IGF‐II or pro‐IGF‐II in association with multiple tumors (especially epithelial and mesenchymal) 1 that potentially influences management strategy 2 . In contrast, by excessive production of catecholamines, pheochromocytomas frequently cause hyperglycemia due to a combination of a pro‐inflammatory state and a frank deterioration of early phasic release of insulin, which seems to be the predominant mechanism 3 .…”