Case Presentation: A 60-year-old woman with type 2 DM, hypothyroidism, and Stage IVB cervical squamous cell carcinoma presented for progressive fatigue and anorexia. During her hospitalization, she had recurrent episodes of hypoglycemia with fingerstick glucose readings as low as 33 mg/dL in spite of discontinuing all diabetic medications several months prior due to excellent glycemic control. On exam, she appeared cachectic with significant bitemporal wasting. Preliminary laboratory evaluation was notable for thyroid stimulating hormone 24.5 uIU/mL (0.27–4.20), free T4 0.47 ng/dL (0.92–1.68), and morning cortisol 19.55 ug/dL (4.3–22.4). Mirtazapine for appetite stimulation and IV levothyroxine 50 mcg given concern for impaired absorption from anasarca were started, and the patient was encouraged to eat small frequent meals, including a bedtime snack. However, she continued to experience recurrent hypoglycemia. Additional hypoglycemia workup when serum glucose was 46 mg/dL revealed insulin < 0.4 uU/mL (2.6–24.9), c-peptide < 0.8 ng/mL (1.1–4.4), beta-hydroxybutyrate 0.1 mmol/L (0–0.4), insulin-like growth factor 1 (IGF-1) 33 ng/mL (60–207), and insulin-like growth factor 2 (IGF-2) 650 ng/mL (333–967). The patient was diagnosed with non-islet cell tumor hypoglycemia (NICTH) from excess secretion of IGF-2. While awaiting the results, she was started on empiric treatment for IGF-2-mediated hypoglycemia with prednisone 10 mg daily, which resulted in amelioration of her hypoglycemia.
Discussion: Hypoglycemia in patients with advanced malignancies is often multifactorial and can be refractory to treatment. In this case, multiple contributing factors were considered, including poor oral intake due to decreased appetite, cachexia with decreased glycogen stores, impaired renal gluconeogenesis secondary to acute kidney injury, uncontrolled hypothyroidism, and NICTH. Adrenal insufficiency and metastatic liver disease were ruled out.NICTH is an under-recognized yet treatable etiology of hypoglycemia in patients with end-stage malignancy. Although no formal diagnostic guidelines have been established, an IGF-2/IGF-1 ratio greater than 10:1 in the presence of a normal or elevated IGF-2 is considered diagnostic. [1] This ratio is generally 3:1 or less in healthy individuals. [2] Our patient had a normal IGF-2 level and low IGF-1, with IGF-2/IGF-1 ratio of 19.7.Tumors most commonly associated with IGF-2-mediated hypoglycemia are fibrous tumors and mesenchymal tumors followed by hepatocellular carcinoma. [3,4] However, NICTH has been reported with a wide variety of other tumors, including gastrointestinal stromal tumor, renal cell carcinoma, thyroid cancer, adrenal cortical carcinoma, and Burkitt’s lymphoma. [3,5] To our knowledge, our case is the first reported case of NICTH associated with cervical squamous cell carcinoma. Previous reports have identified serum IGF-2 levels as a potential marker for early diagnosis and therapeutic monitoring in cervical cancer, [6] suggesting that excessive IGF-2 secretion may occur in a subset of cervical cancers but remains under-recognized due to limited testing. First-line treatment is surgical removal for resectable cases. Medical therapy includes corticosteroids, octreotide and diazoxide.
Conclusions: Hypoglycemia in patients with advanced metastatic malignancy is often multifactorial and warrants a comprehensive evaluation that includes workup for IGF-2-mediated hypoglycemia as it may represent a treatable factor.
