Version May 2024
INTRODUCTION — 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 without diabetes mellitus: Clinical manifestations, causes, and diagnosis" and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology".)
PATHOPHYSIOLOGY — 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 [2,6]. The tumors are usually large in size, weighing on average 2 to 4 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 pro-IGF-2 [6-11], or rarely, IGF-1 [12]. In one series of 28 patients with NICTH, for example, 25 had elevated serum pro-IGF-2 concentrations; the concentration of normal IGF-2 was reduced [10]. Pro-IGF-2 also suppresses glucagon and growth hormone release [6]. The net result is continued glucose utilization by skeletal muscle and inhibition of glucose release, glycogenolysis, and gluconeogenesis in the liver [6]. (See "Physiology of insulin-like growth factor 1".)
Nonislet tumors can secrete insulin, although it is uncommon [13-15]. In one report of NICTH associated with a cervical cancer, in situ hybridization confirmed the presence of proinsulin mRNA in the tumor, providing evidence for tumoral insulin production [16].
Another potential mechanism includes extensive replacement of hepatic tissue by tumor with or without glucocorticoid deficiency due to extensive replacement of the adrenal glands by tumor or hemorrhage [17].
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 [18]. Thus, severe hypoglycemia was mediated by mechanisms other than excess insulin and likely due to extensive tumor burden in the liver.
CLINICAL MANIFESTATIONS — Patients with nonislet cell tumor hypoglycemia (NICTH) may appear ill due to the underlying tumor, particularly when the mechanism of hypoglycemia is extensive tumor burden in the liver. In such patients, common symptoms are weight loss and abdominal pain [6].
In one series of patients with insulin-like growth factor 2 (IGF-2)-producing tumors, however, hypoglycemia was the initial presentation of the tumor in 48 percent (31 of 65 cases), whereas the tumor was present before the onset of hypoglycemia in 52 percent (34 cases) [19]. Symptoms of hypoglycemia more often occur in the fasting state and may include confusion, lethargy, diaphoresis, or progressive somnolence, with some patients presenting with coma as the initial manifestation of hypoglycemia [2]. Hypokalemia may be present in patients with IGF-2 secreting tumors, likely secondary to the insulin–like activity of pro-IGF-2 [19].
DIAGNOSTIC APPROACH — The diagnosis of nonislet cell tumor hypoglycemia (NICTH) is based upon clinical and biochemical findings (table 2).
Clinical findings
●Patient with known tumor burden – Regardless of the mechanism of NICTH, the identification of this disorder is not usually difficult. When a patient with known tumor burden is found to be hypoglycemic, the cause is typically apparent from the history and physical examination. In these cases, a search for other causes of hypoglycemia is generally unwarranted, especially if the tumor type is known to be associated with hypoglycemia (table 1).
The causes of hypoglycemia in patients with known tumors include extensive tumor infiltration, resulting in destruction of the liver or adrenal glands; tumoral production of incompletely processed insulin-like growth factor 2 (pro-IGF-2); or rarely, production of insulin. Dynamic testing can be performed to establish the diagnosis of adrenal insufficiency in patients in whom hypoadrenalism is suspected due to adrenal gland destruction. (See "Diagnosis of adrenal insufficiency in adults", section on 'ACTH stimulation tests'.)
●Well-appearing patient – A healthy-appearing person with episodes of hypoglycemia is less likely to have NICTH, although in some cases, hypoglycemia was the initial event that led to the diagnosis of a tumor [19,20]. In such cases, a detailed evaluation to determine the cause of hypoglycemia is necessary. The diagnostic approach to hypoglycemia is reviewed in more detail separately. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Initial assessment to determine the etiology'.)
The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in relationship to meals), existence of underlying illnesses or conditions, medications taken by the individual and by family members, and social history. Clinical evidence for adrenal insufficiency or nonislet cell tumor should be considered. In a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination (table 3 and algorithm 1).
Biochemical findings — The initial laboratory evaluation includes measurement of glucose, insulin, proinsulin, C-peptide, beta-hydroxybutyrate, and sulfonylurea/meglitinide screening during an episode of hypoglycemia. In contrast to the biochemical findings in individuals with hyperinsulinemic hypoglycemia, patients with NICTH have low serum insulin and C-peptide concentrations during hypoglycemia (table 2) [21,22]. However, the beta-hydroxybutyrate concentration is also low, consistent with insulin-like activity (algorithm 2).
In patients with low serum insulin, C-peptide, and beta-hydroxybutyrate, the plasma glucose response to glucagon administration can be used to confirm the action of an insulin-like factor. The plasma glucose response to glucagon administration is >25 mg/dL unless there has been extensive tumoral replacement of hepatic tissue, resulting in low hepatic glycogen stores [22,23]. The tumor burden should be apparent on dedicated imaging studies.
Additional testing to confirm the diagnosis
●Patients with known malignancy – If clinical and biochemical findings are compelling for NICTH, additional assessment is usually not necessary. If the diagnosis remains in question, measurement of serum IGF-1, IGF-2, and pro-IGF-2 (if available) may be helpful. In patients with NICTH mediated by pro-IGF-2, serum pro-IGF-2 and the IGF-2/IGF-1 ratio may be elevated. Nonetheless, hypoglycemia may be due to non-IGF-mediated mechanisms, and, therefore, normal IGF concentrations do not exclude the diagnosis. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)
●Patients without known malignancy – The finding of hypoglycemia with low levels of serum insulin, C-peptide, and beta-hydroxybutyrate (confirmed by repeat testing) in a healthy-appearing person should prompt evaluation for a tumor with cross-sectional imaging of the chest, abdomen, and pelvis [2]. If a tumor is found, evaluation should proceed as with any newly localized tumor. If the diagnosis of NICTH remains in question, serum IGF-1, IGF-2, and pro-IGF-2 (if available) levels should be measured.
DIFFERENTIAL DIAGNOSIS — There are few other disorders that cause hypoglycemia with low levels of serum insulin, C-peptide, and beta-hydroxybutyrate. In patients with nonislet cell tumor hypoglycemia (NICTH), the plasma glucose response to glucagon administration is typically >25 mg/dL. If the glucose response to glucagon is <25 mg/dL, possibilities include extensive tumoral replacement of hepatic tissue, resulting in low hepatic glycogen stores, or an alternative mechanism. Hypoglycemia associated with some medications, such as opiates or alcohol, can produce similar biochemical findings. Although rare in adults, hypoglycemia arising during primary and secondary adrenal insufficiency also can present with similar biochemical findings.
Insulin autoimmune hypoglycemia occurs in patients who have antibodies directed to endogenous insulin. It has been described in patients with multiple myeloma and Hodgkin lymphoma [24,25]. Symptoms can occur postprandially, fasting, or in both states. Serum insulin and C-peptide levels are usually elevated, however, not low. Insulin antibodies (and their affinity for insulin) can be measured to distinguish insulin autoimmune hypoglycemia from other causes of hypoglycemia. Insulin antibodies do not need to be drawn during hypoglycemia. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'C-peptide level ≥0.2 mmol/L'.)
TREATMENT — There are three components to therapy in patients with nonislet cell tumor hypoglycemia (NICTH):
●Immediate correction of hypoglycemia
●Treatment directed at the underlying malignancy
●Prevention of recurrent hypoglycemia if the tumor cannot be controlled
Acute management — The acute management of hypoglycemia is similar to the management of hypoglycemia during the treatment of diabetes. In brief, treatment of severe hypoglycemia, when the patient is unconscious or unable to ingest carbohydrate, requires a subcutaneous or intramuscular injection of glucagon (0.5 to 1.0 mg). Patients brought to the hospital can be treated more quickly by giving 25 g of 50 percent glucose (dextrose) intravenously. This topic is reviewed in detail elsewhere. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)
Treatment of the tumor — The mainstay of therapy for NICTH is treatment of the underlying malignancy. When a tumor is producing insulin-like growth factors (IGFs) or insulin, complete removal of the tumor results in cure of hypoglycemia [2,6]. If surgery is delayed, ongoing management of hypoglycemia includes increasing caloric intake (sometimes via enteral or parenteral feedings) and intravenous glucose or dextrose, if needed.
If the tumor is not resectable, palliative tumor debulking is usually performed. Depending upon the tumor type, chemotherapy, radiation, cryoablation, radiofrequency ablation, or selective embolization of tumor feeding blood vessels may be used to control the tumor and improve hypoglycemia [26].
Medical therapy — In situations where the underlying malignancy cannot be treated, medical therapy is required to prevent recurrent hypoglycemia. Selection of glucose-raising drugs must be done in concert with knowledge of the potential interaction with chemotherapy. Thus, NICTH is often a disorder treated by the oncologist. The presence of hypoglycemia in such patients is generally associated with a poor prognosis. In case series and reports, hypoglycemia was controlled with glucocorticoids (eg, prednisone 40 mg daily), glucagon, or recombinant human growth hormone (rhGH) [2,3,23,27]. Somatostatin analogues and diazoxide have not been effective [2,28,29].
●Initial medical therapy – Glucocorticoids (eg, 30 to 60 mg prednisone or equivalent daily) are a reasonable initial therapy. Glucocorticoids decrease the amount of pro-IGF-2 by increasing its clearance [2]. They also impair insulin action. In one review, glucocorticoids were used in 25 percent of the individual cases reviewed [2]. In some cases, hypoglycemia was refractory to high-dose glucocorticoids, particularly in patients with widespread disease.
●Refractory hypoglycemia – If hypoglycemia persists, patients with IGF-mediated hypoglycemia (and, therefore, a preserved glycemic response to glucagon) may respond to intravenous glucagon infusion (0.06 to 0.30 mg/hour). (See 'Biochemical findings' above.)
We prefer not to use growth hormone therapy, unless for palliation in end-stage cancer patients with NICTH. Although rhGH hormone at supraphysiologic doses of 3 to 12 mg daily has been successful in many cases [28,30-35], including one pediatric case [36], it also increases IGF-1 and has the potential to increase tumor growth.
Growth hormone has been shown to increase IGF-binding protein and acid labile subunit, which bind IGF-2 and prevent interaction with the insulin receptor, thereby reducing hypoglycemia [2,27,30]. In one case report, the addition of growth hormone allowed a reduced dose of glucocorticoids, limiting long-term side effects [30].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Low blood sugar in people with diabetes (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathophysiology – Severe hypoglycemia has been observed in a small percentage of patients with nonislet cell tumors, usually of mesenchymal or epithelial cell types (table 1). (See 'Pathophysiology' above.)
The most common cause of this type of hypoglycemia is tumoral overproduction of an insulin-like factor such as incompletely processed insulin-like growth factor 2 (pro-IGF-2). Other potential mechanisms include extensive replacement of hepatic tissue by tumor; extensive replacement of the adrenal glands by tumor or hemorrhage (with glucocorticoid deficiency); or rarely, tumoral production of insulin. (See 'Pathophysiology' above.)
●Clinical presentation – Patients with nonislet cell tumors typically appear ill due to the underlying tumor, particularly when the mechanism of hypoglycemia is extensive tumor burden in the liver. However, hypoglycemia may be the initial presentation in patients with IGF-2-producing tumors. Symptoms of hypoglycemia more often occur in the fasting state and may include confusion, lethargy, diaphoresis, or progressive somnolence. (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of nonislet cell tumor hypoglycemia (NICTH) is based on clinical and biochemical findings.
•Clinical findings – When a patient with known tumor burden is found to be hypoglycemic, the cause is typically apparent from the history and physical examination. In these cases, a search for other causes of hypoglycemia is generally unwarranted, especially if the tumor type is known to be associated with hypoglycemia (table 1). (See 'Clinical findings' above.)
Although a healthy-appearing person with episodes of hypoglycemia is less likely to have NICTH, a detailed evaluation to determine the cause of hypoglycemia is necessary (algorithm 1). In a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination (table 3). (See 'Diagnostic approach' above.)
•Biochemical findings – The initial laboratory evaluation includes measurement of glucose, insulin, proinsulin, C-peptide, beta-hydroxybutyrate, and sulfonylurea/meglitinide screening during an episode of hypoglycemia. In contrast to the biochemical findings in individuals with hyperinsulinemic hypoglycemia, patients with IGF-induced hypoglycemia have low serum insulin, C-peptide, and beta-hydroxybutyrate concentrations during hypoglycemia (algorithm 2 and table 2). (See 'Biochemical findings' above and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)
•Additional testing – Measurement of IGF-1, IGF-2, and pro-IGF-2 may provide additional supportive data but is not always essential in patients with known malignancy and large tumor burden. (See 'Additional testing to confirm the diagnosis' above and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)
●Treatment
•Initial treatment – The treatment involves immediate correction of hypoglycemia, treatment directed at the underlying malignancy (typically surgery), and prevention of recurrent hypoglycemia if the tumor cannot be controlled. For medical therapy if the underlying malignancy cannot be treated, we suggest glucocorticoids as initial therapy (Grade 2C). A typical regimen is prednisone 30 to 60 mg (or equivalent) daily. (See 'Treatment' above and "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)
•Persistent hypoglycemia – If hypoglycemia persists, patients with a glycemic response to glucagon (eg, NICTH due to pro-IGF-2) can be treated with a long-term intravenous glucagon infusion (0.06 to 0.30 mg/hour). We prefer not to use growth hormone therapy, unless for palliation in end-stage cancer patients with NICTH. (See 'Treatment' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F John Service, MD, PhD, now deceased, who contributed to an earlier version of this topic.
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