Hypoglycemia can arise from a multitude of tumors, including both islet and non-islet cell tumors. Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome that occurs most commonly in patients with mesenchymal tumors (such as gastrointestinal stromal tumors, hemangiopericytomas, and solitary fibrous tumors), hepatocellular carcinomas, and sarcomas (1). In NICTH, hypoglycemia occurs secondary to the tumor production of insulin-like growth factor two (IGF-II). IGF-II is a protein that regulates growth during normal fetal development but may be dysregulated in tumorigenesis (2).

IGF-II has metabolic actions on the liver, adipose tissue, and skeletal muscle. In the liver, IGF-II suppresses glucose output and increases glycogen synthesis (3). In peripheral tissues, it increases glucose uptake. Normally, IGF-II is sequestered and inactivated by binding to specific binding proteins, such as IGF-BP3. Growth hormone (GH) promotes hepatic synthesis of IGF-BP3. Elevated IGF-II levels inhibit endogenous insulin and GH secretion, resulting in decreased GH levels and increased circulating free IGF-II. Additionally, IGF-II also suppresses counter-regulatory glucagon release, which amplifies the vulnerability and the significance of hypoglycemia (4). In NICTH, tumor production of IGF-II promotes hypoglycemia. This occurs through a variety of mechanisms, including increased peripheral glucose uptake, reduced lipolysis, reduced hepatic gluconeogenesis, reduced glycogenolysis, and suppressed anterior pituitary growth hormone secretion (5).

We present a case of NICTH in a patient with recurrent hypoglycemia during an inpatient stay, who was diagnosed with primary rectal adenocarcinoma with distant metastasis. This case highlights the diagnostic process, the challenges in management, and reviews other cases in the literature.

A 51-year-old male with a medical history of pre-diabetes, gastroesophageal reflux disease, and tobacco use disorder, presented to the emergency department with worsening fatigue, an unintentional 50-pound weight loss over the past three months, and increasing shortness of breath. Over the past few months, the patient had been evaluated in the outpatient setting by his primary care physician for microcytic anemia and unintentional weight loss. He was advised to undergo an outpatient colonoscopy and a computed tomography (CT) scan of the abdomen and pelvis; however, these had not yet been scheduled or completed. The patient’s family history was notable for renal cell carcinoma in his brother and unspecified lung cancer in his father. In the Emergency Department, the patient was tachycardic (heart rate of 125) but maintaining normal oxygen saturation on room air without hypoxia. His blood pressure was 132/90 mmHg.

Initial laboratory results revealed hypoglycemia (with a glucose of 59 mg/dl), elevated transaminases, microcytic anemia, leukocytosis, and lactic acidosis. A thorough set of inpatient laboratory findings are displayed in Table I.

The patient underwent a CT of the abdomen and pelvis with intravenous contrast, which revealed rectal wall thickening with nonspecific perirectal lymph node enlargement, a 3.2×3.6 cm pancreatic/peripancreatic mass with mild dilation of the pancreatic duct, and innumerable liver lesions concerning for metastatic disease. Figure 1 displays a view of the CT imaging. CT pulmonary angiography revealed multiple bilateral fairly well-circumscribed pulmonary nodules, including a 1.1 cm nodule in the left lower lobe, raising concern for metastatic disease. With tachycardia, leukocytosis, and lactic acidosis, the patient met sepsis criteria and was treated by the admitting Internal Medicine team with intravenous fluids and broad-spectrum antibiotics with piperacillin-tazobactam whilst searching for a source of infection.

Gastroenterology was consulted and recommended evaluation for malignancy with colonoscopy, esophago-gastroduodenoscopy (EGD), and upper endoscopic ultrasound (EUS) with fine-needle aspiration for biopsy. EGD revealed a normal esophagus, gastroesophageal junction, stomach, and duodenum. Upper EUS revealed calcifications in the head of the pancreas, a 2.0 cm × 1.3 cm pancreatic septated cyst, a 3.3 mm dilated main pancreatic duct, and a 2.7 cm × 3.0 cm lesion in the left lobe of the liver. Fine needle biopsy was performed of the liver lesion. Colonoscopy revealed a partially obstructing rectal mass 1-2 cm from the anal verge, which was biopsied. Figure 2 displays different images of the rectal mass during colonoscopy.

Biopsy of the rectal mass revealed moderately differentiated primary rectal adenocarcinoma, with positive immunostaining for CK20 and negative for CK7. Liver biopsy revealed adenocarcinoma morphologically consistent with a rectal primary. Gastric biopsy showed benign mucosa.

During his hospital stay, the patient developed recurrent hypoglycemia. Initially, this was treated with as-needed oral dextrose (15 g) and intravenous dextrose (50% solution of 25 g). Given the presence of malignancy, NICTH was suspected, and laboratory evaluation was performed. Results revealed low insulin (<0.4 μlU/ml), low pro-insulin (2.4 pmol/l), low C-peptide (0.2 ng/ml), low growth hormone (0.1 ng/ml), and low IGF-I (20 ng/ml). IGF-II was low-normal (346 ng/ml) and the IGF-II:IGF-I ratio was elevated at 17.3, supporting the diagnosis.

Due to the refractory hypoglycemia, the patient was initiated on a continuous infusion of dextrose 5% in sodium chloride. With continued hypoglycemia, the patient was transitioned to dextrose 10% in sodium chloride. Recurrent symptomatic hypoglycemia persisted, with glucose levels in the 20-40 mg/dl range. The patient was started on dexamethasone 4 mg every 8 h, which was later increased to every 4 h. Intramuscular glucagon was trialed without success. The patient was subsequently transferred to the Intensive Care Unit (ICU). Upon consultation with Endocrinology, Nephrology, and Inpatient Pharmacy, the patient was initiated on a combination of dextrose 25% in sterile water, dextrose 10% in continuous sodium bicarbonate, continued on dexamethasone, and initiated on enteral nutrition through a nasogastric tube. With this comprehensive regimen, the patient’s hypoglycemia resolved, and the steroid regimen was subsequently tapered.

Medical Oncology was consulted for management recommendations regarding metastatic rectal adenocarcinoma. Due to the extent of metastasis and the patient’s poor clinical status, he was not a candidate for tumor resection and chemotherapy was deemed inappropriate. Per the patient and family’s wishes, chemotherapy with oxaliplatin 200 mg, leucovorin 800 mg, and fluorouracil 900 mg was initiated. As the patient was preparing to receive the first cycle, his clinical status worsened, marked by increasing lethargy and tachypnea. After a goals-of-care discussion, the patient and family opted for comfort care measures. The patient passed away shortly thereafter.

Suspicion for NICTH should arise in patients with an unexplained hypoglycemia, particularly when a known benign or malignant tumor is present. The Endocrine Society guidelines recommend investigation in patients with Whipple’s Triad (6). Whipple’s Triad consists of symptomatic hypoglycemia, a serum glucose of <50 mg/dl, and relief of symptoms after glucose ingestion. Symptoms of hypoglycemia may present as sweating, palpitations, tremors, and anxiety, along with neuroglycopenic symptoms such as disorientation, exhaustion, seizures, and loss of consciousness.

When NICTH is suspected, it is important to rule out other potential causes of hypoglycemia. These include medication-induced hypoglycemia, critical illness, hormonal deficiencies (such as adrenal insufficiency), and endogenous hyperinsulinism (such as insulinoma). Laboratory evaluation for NICTH should include measurement of insulin, pro-insulin, C-peptide, beta-hydroxybutyrate, and an oral hypoglycemic agent screen (1). If these tests reveal low insulin, pro-insulin, C-peptide, and beta-hydroxybutyrate levels, insulin mimicry should be considered. At this time, IGF-I and IGF-II levels should be measured (7). A pattern of low serum glucose, insulin, pro-insulin, C-peptide, beta-hydroxybutyrate, low growth hormone, IGF-I (suppressed below 100 ng/ml) and normal-to-high IGF-II levels are suggestive of NICTH. Notably, IGF-II measurement in isolation has limited diagnostic utility, as IGF-II levels may be normal in over half of cases (8). An elevated IGF-II:IGF-I ratio (especially >10) is a useful diagnostic indicator. Imaging tests, such as CT and magnetic resonance imaging (MRI) are crucial for identifying a primary tumor. Positron emission tomography (PET) scans may assist in detecting tumors if traditional imaging is unclear.

Treatment options for hypoglycemia include oral glucose, intravenous dextrose, intramuscular glucagon, and dextrose-containing fluids. In NICTH, the mainstay of treatment is surgical resection of the underlying tumor. In many cases, such as in our scenario, surgical resection may not be feasible due to the patient’s underlying critical condition and widespread metastatic disease.

When surgery is not an option, management of hypoglycemia becomes more complex and varies. Partial excision and localized treatments, such as radiotherapy, may effectively reduce tumor burden and alleviate hypoglycemia (1). Local antitumor therapy with chemotherapy, cryoablation, and radiofrequency ablations, among others, have led to resolution of NICTH in prior cases. A multimodal approach, including increased nutritional intake, may be necessary to prevent recurrent hypoglycemia. For patients unable to increase carbohydrate intake, parenteral nutrition may be utilized (9). However, parenteral nutrition carries its own risks, including risk of bloodstream infection and electrolyte imbalances. Glucocorticoids have been used extensively in NICTH management (10). A variety of agents, including hydrocortisone, prednisone, and dexamethasone, have been utilized. Glucocorticoids increase glucose production in the liver, reduce the body’s sensitivity to insulin, and hinder glucose uptake by peripheral cells. In NICTH, glucocorticoids also reduce levels of IGF-II and increase levels of IGF-1 (11). Another option that has been utilized is recombinant human growth hormone (rhGH) at supraphysiological doses of 3-12 mg daily. This may provide relief from hypoglycemia due to suppression of peripheral glucose uptake and an increase in IGF-I levels (12). However, rhGH should be used with caution due to its potential to stimulate tumor growth (13).

Therapies that have been trialed in the past without significant success include diazoxide and octreotide. Diazoxide is a nondiuretic benzothiadiazine derivative that has been used to treat hypoglycemia in patients with insulinoma, due to its reduction in insulin secretion by beta-cells (1). However, no known successful uses have been documented in NICTH (14-16). Octreotide, a somatostatin analog, has been used in the past due to its suppression of insulin secretion from the pancreas. Despite this, it has been used ineffectively in multiple cases of NICTH (14,17). Recently, alpelisib has been utilized with good response in isolated cases for treatment of intractable NICTH (18). Alpelisib is a phosphatidylinositol 3 (PI3) kinase inhibitor utilized to treat metastatic breast cancer. PI3 kinase inhibitors inhibit proIGF-II stimulation of insulin-IGF-I signaling, thereby reducing glucose transport to muscle cells (18).

In our case, a multimodal approach was used to manage NICTH. The patient was placed on parenteral nutrition, scheduled intravenous dexamethasone therapy, escalated to continuous dextrose 25% infusion therapy via a central venous catheter, and trialed on injectable glucagon. This regimen effectively resolved the patient’s hypoglycemia, although it was only a temporary measure and not sustainable in the long term. Unfortunately, due to the patient’s condition, he was unable to undergo surgical resection or receive chemotherapy for definitive treatment of his rectal adenocarcinoma and NICTH.

Table II summarizes many of the other reported cases of NICTH in the literature, including the patient’s age and sex at presentation, the primary tumor, and the subsequent management. Patient cases span across two sexes and across a wide variety of ages (ranging from ages 3-87 years old). Multiple cases were found in the literature secondary to a GIST, solitary fibrous tumor, hepatocellular carcinoma, and phyllodes tumor. No cases were found secondary to rectal adenocarcinoma; however, two cases were found secondary to colon cancer (35,37). Interestingly, a majority of cases displayed low-to-normal levels of IGF-II, but all cases with retrievable IGF-II levels demonstrated elevated IGF-II:IGF-I ratios. Management approaches varied widely, including tumor resection, continuous dextrose infusions, glucocorticoids, rhGH, and glucagon administration.

NICTH is a challenging paraneoplastic syndrome characterized by hypoglycemia resulting from ectopic IGF-II secretion. This case highlights the importance of considering NICTH in the differential diagnosis for patients with tumors presenting with unexplained or recurrent hypoglycemia and emphasizes the complexities in its management. While surgical tumor resection is the definitive treatment for NICTH, it is not always feasible in patients with widespread metastatic disease. In such instances, alternative therapies must be utilized. In this case, a combination of continuous concentrated dextrose infusions, dexamethasone, parenteral nutrition, and glucagon, were employed to manage recurrent hypoglycemia. However, without a definitive treatment for the patient’s underlying malignancy, the patient’s prognosis remained poor. Notably, few (if any) prior cases of NICTH in the literature have been documented secondary to primary rectal adenocarcinoma. This case contributes to the growing body of literature surrounding the complexities of managing NICTH in advanced cancer. Ongoing research, including the exploration of PI3 kinase inhibitors, may provide new therapeutic options and improve outcomes for patients with NICTH.

The Authors have no conflicts of interest to disclose in relation to this study.

Saad Rashid, Heena Parkash, Zeeshan Muzammil, and Nadia Hrynewycz reviewed the literature and drafted the manuscript. Sultan Ahmed and Mohammed Zaman were responsible for editing the manuscript. Saad Rashid was responsible for submission of this publication. All Authors have read and approved the final version of the manuscript.

The Authors declare that there are no acknowledgments to disclose.

The Authors received no funding for this report.