Non-islet Cell Tumor-induced Hypoglycemia Research Articles

SAT159 A Unique Case Of IGF-2 Induced Hypoglycemia As First Manifestation Of Hepatocellular Carcinoma

Abstract Disclosure: I. Ali: None. M. Alnaher: None. A. Arida: None. Introduction: Hypoglycemia is one of the manifestations of non-islet cell tumor-induced hypoglycemia (NICTH). In hepatocellular carcinoma (HCC), it has been reported in 4-27% of patients, and it is associated with poor prognosis. Case: Patient is a 70-years-old Female with past medical history of prediabetes and untreated Hepatitis C infection who presented with sever weakness and was found to have blood glucose of 37. She was started on Dextrose 10% with improvement of her symptoms. During hospital course she had recurrent episodes of symptomatic hypoglycemia. Patient denied any family history of diabetes with no access to diabetes medication. Blood work showed elevated AST, ALT with low albumin, low prealbumin and AM cortisol 13, Sulfonylureas screen is Negative. Result of 72 hours hypoglycemia protocol while blood glucose level was 48 mg/dl as follow: Proinsulin, Intact 1.6 mmol/L (Ref: less than 8.0), insulin like growth factor -1 (IGF-1): 10 ng/ml (26-226), IGF-2: 69 ng/ml (180-580) so IGF-2/IGF-1 ratio of 6.9Insulin: 0.2 uIU/ml (1.9-23), C-Peptide 0.1 ng/ml (0.5-3.3) and Beta hydroxybutyrate: 0.1 mmol/L. CT abdomen: 7.0 x 7.2 x 10.5 cm right hepatic lobe mass with extension to right portal vein that is most consistent with hepatocellular carcinoma with background liver cirrhosis with portal hypertension without ascites. Right hepatic artery tumor biopsy showed moderately differentiated HCC. Patient was started on steroid therapy then octreotide. Multidisciplinary meeting discussed in details treatment options and prognosis including treatment of her cancer with surgery vs chemoradiation therapy, but patient and her family opted for DNR/DNI, and patient passed away during that admission. Discussion: Even though HCC-related hypoglycemia is a known phenomenon, knowledge about prevention and treatment is lacking. The suggested mechanism of hypoglycemia in NICTH include increased consumption of glucose by tumor in malnourished patients with low glycogen deposits and defective gluconeogenesis or may be caused by IGF-2 overproduction that crosses capillary membranes and stimulates insulin receptor. Hypoglycemia work up reveals low levels of insulin, pro-insulin, C-peptide, and β-hydroxybutyrate. Levels of GH and IGF-1 will also be low due to the suppressive effect of IGF-2. Total IGF-2 may be elevated or normal but the ratio of IGF-2/IGF-1 is usually elevated 3:1. Management of an IGF-2 producing tumor with surgical resection, radiation, and/or chemotherapy can potentially resolve hypoglycemia. Medical therapy with glucocorticoids has been utilized by promoting hepatic gluconeogenesis and lipolysis and reducing peripheral glucose uptake. Glucocorticoids also help to decrease the levels of IGF-2 either by decreased tumor production or increased clearance. Case reports have documented the use of glucagon, growth hormone, and octreotide, however, effects are limited. Presentation: Saturday, June 17, 2023

PSAT277 Glucocorticoid Therapy for Management of Hypoglycemia in the context of Non-Islet Cell Tumor-Induced Hypoglycemia

Abstract Background Non-islet cell tumor-induced hypoglycemia (NICTH) is a rare paraneoplastic syndrome which can cause recurrent hypoglycemia. There is no clear standard of care for management of hypoglycemia. Often, these patients have high morbidity and therefore surgical tumor resection is not always possible. Clinical case: This is the case of a 69 year-old male presenting with altered mental status in the context of hypoglycemia without clear etiology with an initial serum glucose level of 32 mg/dL (normal range 60-100 mg/dL) which quickly corrected after administration of intravenous glucose. He was found to have a large bowel obstruction with CT abdomen revealing an underlying neoplasm. Biopsy of suspected lesion on colonoscopy revealed colorectal adenocarcinoma. Repeated episodes of hypoglycemia complicated by seizures required inpatient management. Workup included serum insulin level which resulted in suppressed level (<1. 0 uU/mL, normal range 1.9-23. 0 uU/mL), low c-peptide level (0.1 ng/mL, normal range 1.1-4.4 ng/mL), low beta hydroxybutyrate level (0. 07 mmol/L, normal level <0.3 mmol/L), cortisol level of 43.7 mcg/dL, undetectable insulin like growth factor-1 (IGF-1) level (<10 ng/mL, normal range 59-230 ng/mL) and low insulin like growth factor-2 (IGF-2) level (66 ng/mL, normal range 333 - 967 ng/mL). IGF2: IGF1 ratio was 66 (ratio >10 is indicative for diagnosis of non-islet cell tumor hypoglycemia). Due to extremely poor oral intake and recurrent episodes of hypoglycemia despite continuous dextrose infusion, the patient was started on 20 mg prednisone daily. Eventually, 40 mg of intravenous methylprednisolone in addition to dextrose infusion was needed as maintenance therapy effectively preventing hypoglycemia. Given his poor functional status, the surgical and oncology team decided he was no longer a surgical or chemotherapy candidate. Eventually, palliative medicine was consulted and the patient was transitioned to comfort care with a plan for outpatient hospice. Conclusion NICTH should be suspected in any patient with hypoglycemia without clear etiology, especially if there are suggestions to NICTH such as known malignancy or newly diagnosed mass. Once NICTH is identified and a primary tumor is found, complete tumor resection represents ideal management, however, not always attainable. In such cases, dextrose infusion might be insufficient to prevent hypoglycemia and is not always the preferred option given the required long-term venous access. In these circumstances, early high dose glucocorticoids are safe and appear to successfully prevent hypoglycemic events. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Hypoglycaemic crisis induced by non-islet cell tumours in two dogs

Two dogs were admitted for the diagnosis and treatment of neoplasia (a hepatic and a mammary tumour, respectively), lethargy, quadriparesis and abnormal mentation with hypoglycaemia. The blood analyses showed severe hypoglycaemia (1.32 and 1.60 mmol/l, respectively). Although prompt treatment, including intravenous administration of dextrose, was initiated, the blood glucose concentrations were not restored to a normal range. After the diagnostic procedures, no aetiology other than the hepatic tumour identified by the abdominal radiography and ultrasonography, and a mammary tumour that might have caused the hypoglycaemia, were identified. Because there was a high suspicion of non-islet cell tumour-induced hypoglycaemia as a paraneoplastic syndrome, the dogs underwent a hepatic lobectomy and total mastectomy with an ovariohysterectomy, respectively. Within 12 hours after surgery, the blood glucose concentrations of both cases had normalised, even without the administration of dextrose. The histopathological examinations identified a hepatocellular adenoma and a mammary carcinoma, respectively. The endocrine analysis of the serum at admission revealed low serum insulin concentrations (< 1.44 pmol/l) and high serum concentrations of insulin-like growth factor 2 in both dogs. Therefore, the diagnosis in both dogs was confirmed to be non-islet cell tumour-induced hypoglycaemia. Both dogs remained alive without the recurrence of hypoglycaemia 24 months later. Previously, the administration of intravenous dextrose has been considered as the initial treatment in dogs with hypoglycaemia; however, this can temporarily ameliorate the clinical signs related to the non-islet cell tumour-induced hypoglycaemia and help the anaesthesia for the surgical tumour resection as an emergency. Therefore, the definitive treatment of non-islet cell tumour-induced hypoglycaemia might be rapid surgical intervention, which can be associated with good prognosis in dogs with severe non-islet cell tumour-induced hypoglycaemia.

SUN-328 Non-Islet Cell Tumor-Induced Hypoglycemia in a Patient with IGF-2 Producing Spindle Cell Neoplasm

Background: Non-islet cell tumor-induced hypoglycemia is a rare paraneoplastic syndrome with approximately 300 reported cases in the literature. Classically these tumors secrete insulin-like growth factor-2 (IGF-2) to induce hypoglycemia, but the etiology and regulation of the hormone secretion remains poorly understood. We present a case of non-islet cell hypoglycemia from a spindle cell neoplasm of the lung, which appeared to show inconsistent secretion of IGF-2. Clinical case: A 72-year-old, non-diabetic male presented with episodes of altered mental status due to hypoglycemia with unintentional weight loss. Blood glucose was 35 mg/dL upon admission. CT chest showed an 18 cm tumor in the left hemithorax. The patient continued to have hypoglycemia throughout his hospital stay. At a time when the serum glucose was 48 mg/dL, a biochemical work up for hypoglycemia showed C-peptide 0.21 ng/mL (0.78-5.19 ng/mL), proinsulin 1.6 pmol/L (0-10 pmol/L), insulin 0.1 U/mL (1.9-23 U/mL), β-hydroxybutyrate 0.1 mmol/L (0-0.4 mmol/L), and a negative sulfonylurea screen. Given the large lung tumor, IGF hormones were measured: IGF-1 59 ng/mL (36-215 ng/mL), IGF-2 670 ng/mL (333-967 ng/mL). While both were within normal ranges, the IGF-2/IGF-1 ratio was 11.35. Biopsy of the lung mass showed benign spindle cell neoplasm, consistent with solitary fibrous tumor. The patient was diagnosed with paraneoplastic non-insulin mediated hypoglycemia and was transferred to our hospital for resection of the lung mass. During the first 96 hours after transfer, the patient had no hypoglycemic episodes and repeat laboratory values showed IGF-1 of 72 ng/mL, IGF-2 of 162 ng/mL, IGF-2/IGF-1 ratio of 2.25 with a glucose of 119 mg/dL, indicating the secretion of IGF-2 may have been intermittent. However, he later developed recurrent hypoglycemia and underwent resection of the tumor. Pathology showed a malignant solitary fibrous tumor. Blood sugars improved within 2 days after tumor resection and patient did not have further hypoglycemia. Discussion: Literature review shows that tumors causing non-islet cell hypoglycemia are large with one-third located in the chest and two-thirds in the retroperitoneum. They can secrete “big” IGF-2, which can activate insulin receptors to inhibit glucose output from the liver and increase uptake in muscle and adipose tissue leading to hypoglycemia. Interestingly, the IGF-2 level is not always outside the normal range, but a ratio of IGF-2/IGF-1 greater than 10 can be another marker of paraneoplastic hypoglycemia. We believe our case is unique in that during a 48-hour period of intense observation, the patient had no hypoglycemia and the IGF-2 levels and IGF-2/IGF-1 ratio decreased to the normal range. Thus, in patients with suspected tumor-mediated hypoglycemia, the IGF levels may need to be drawn during a hypoglycemic event, much like the workup for insulinoma.

Refractory spontaneous hypoglycaemia: a diagnostic conundrum

SummaryA frail 79-year-old lady with dementia presented with a 2-year history of frequent falls. Recurrent hypoglycaemic episodes were diagnosed and treated with continuous glucose infusion in multiple hospital admissions. Hypoadrenalism and hypothyroidism were ruled out. Whilst hypoglycaemic (blood glucose 1.6 mmol/L), both plasma C-peptide and proinsulin concentrations, were inappropriately elevated at 4210 pmol/L (174–960) and >200 pmol/L (0–7) respectively with plasma insulin suppressed at 12 pmol/L (0–180). Whilst reported cases of proinsulinoma are typically pancreatic in origin, radiological investigations of the pancreas in this patient did not identify abnormalities. Unexpectedly contrast CT identified a heterogeneously enhancing mass (6.6 cm) at the lower pole of the left kidney consistent with renal cell carcinoma. Non-islet cell tumour-induced hypoglycaemia has been associated with renal malignancy; however, a serum IGF2:IGF1 ratio measured at <10 effectively excludes this diagnosis. Concomitantly on the CT, extensive peripherally enhancing heterogeneous mass lesions in the liver were identified, the largest measuring 12 cm. A palliative approach was taken due to multiple comorbidities. On post-mortem, the kidney lesion was confirmed as clear cell renal carcinoma, whilst the liver lesions were identified as proinsulin-secreting neuroendocrine tumours. In conclusion, the diagnosis of proinsulinoma can be missed if plasma proinsulin concentration is not measured at the time of hypoglycaemia. In this case, the plasma insulin:C-peptide ratio was too high to be accounted for by the faster relative clearance of insulin and was due to proinsulin cross-reactivity in the C-peptide assay. In addition, the concomitant malignancy proved to be a challenging red herring.Learning points:Even in non-diabetics, hypoglycaemia needs to be excluded in a setting of frequent falls. Insulin- or proinsulin-secreting tumours are potentially curable causes.Whilst investigating spontaneous hypoglycaemia, if plasma insulin concentration is appropriate for the hypoglycaemia, it is prudent to check proinsulin concentrations during the hypoglycaemic episode.Proinsulin cross-reacts variably with C-peptide and insulin assays; the effect is method dependent. In this case, the discrepancy between the insulin and C-peptide concentrations was too great to be accounted for by the faster relative clearance of insulin, raising the suspicion of assay interference. The C-peptide assay in question (Diasorin liaison) has been shown to be 100% cross reactive with proinsulin based on spiking studies with a proinsulin reference preparation.Whilst reported cases of proinsulinoma and 99% of insulinomas are of pancreatic origin, conventional imaging studies (CT, MRI or ultrasound) fail to detect neuroendocrine tumours <1 cm in 50% of cases.The concomitant renal mass identified radiologically proved to be a red herring. In view of the rarity of proinsulinoma, no conclusive association with renal cell carcinoma can be established.

Electroencephalographic alterations in a mare with presumed intermittent neuroglycopenia caused by severe hypoglycaemia‐associated with nonislet cell tumour

SummaryThe focus of this report was to document the electroencephalogram (EEG) findings associated with nonislet cell tumour‐induced hypoglycaemia (NICTH) in a racing Thoroughbred mare subsequently diagnosed with renal carcinoma and carcinomatosis. We evaluated cortical cerebral activity and confirmed paroxysmal activity consistent with subclinical seizures by performing an EEG prior to onset of clinical signs of seizures. We showed that the electrical activity pattern progressed in a similar fashion as in humans with severe, progressive hypoglycaemia and presumed neuroglycopenia. The glycaemic threshold for abnormalities detected in EEG showed that abnormal electrical cortical activity appeared when blood glucose dropped to 44 mg/dL (2.4 mmol/L) and paroxysmal activity spread, becoming generalised when blood glucose dropped to 23 mg/dL (1.3 mmol/L). NICTH is an uncommon paraneoplastic phenomenon in several species. In horses, NICTH has been reported most frequently in primary renal tumours, followed by primary hepatic tumours. This report highlights the importance of investigating the possibility of hypoglycaemia in cases of horses that present altered state of consciousness with or without intermittent seizures. This case report also highlights that the diagnostic work‐up for horses presenting with episodic hypoglycaemia should comprise investigation of possible neoplasia, as paraneoplastic hypoglycaemia should be included in the list of differentials of horses with hypoglycaemia.

Non-Islet Cell Tumor Hypoglycemia

SESSION TITLE: Non-Small Cell Lung Cancer SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Non-islet cell tumor hypoglycemia (NICTH) is a serious but rare complication seen with certain malignancies. Tumor over production of insulin-like growth factors (IGF) causes the increased utilization of glucose resulting in symptomatic hypoglycemia. CASE PRESENTATION: A 74 year old non-diabetic male with a medical history significant for sarcomatoid carcinoma of the right lung presented with altered mental status and global weakness. He had been diagnosed with sarcomatoid lung cancer 8 years ago and had undergone a lobectomy with radiation therapy, but had been lost of follow up. He denied any illicit drug use, including herbal or over the counter medications. On presentation, the patient was disoriented and unable to follow simple commands. Pulmonary auscultation revealed distant breath sounds, and a 1.5 by 1.5 cm lesion with central necrosis was present on his left buccal area. Laboratory investigations were significant for blood glucose of 28 mg/dL, confirming hypoglycemia, potassium of 2.8mEq/L, and a negative urine toxicology screen. A CT head was negative for acute events. CT chest, abdomen and pelvis showed progression of his sarcomatoid lung cancer. Administration of dextrose immediately resolved his symptoms. An extensive work-up during subsequent hypoglycemic events measured an IGF-1 of 51 ng/mL, IGF-II of 290 ng/mL, growth hormone of 0.6 ng/mL, C-Peptide of 0.16 ng/mL (low) and insulin levels at <1 uIU/mL. Big IGF-2 was not available at our facility. Based on these results a diagnosis of NICTH was made. DISCUSSION: A history and physical examination in a patient with an active tumor remains key in making the diagnosis. The mechanism of hypoglycemia in NICTH remains unclear but is thought to be related to tumor secretion of IGF, specifically big IGF-2, which suppresses glucagon and growth hormone, resulting in hypoglycemia. Some suggest the secretion of insulin by the tumor results in hypoglycemia. In addition to hypoglycemia, hypokalemia may be present due to the insulin like activity of IGF. In patients with NITCH, low serum insulin and C-peptide levels are seen during hypoglycemic episodes. Measurement of IGF-1, IGF-2, and big IGF-2 may be supportive as well, but should not deter diagnosis. Glucagon and dextrose intravenously can be used to help resolve the hypoglycemic events. Steroids have also been shown to help by increasing clearance of IGF-2. Treatment of the underlying malignancy provides a definite solution. CONCLUSIONS: Our patient deferred treatment for his advanced cancer. He was started on prednisone 60 mg once a day, with resolution of his symptoms upon discharge, and he remained asymptomatic at follow-up appointments, 2 and 4 weeks later. He was offered palliative care services, but declined as well. Reference #1: de Groot JW, Rikhof B, van Doorn J, et al. Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases. Endocr Relat Cancer. 2007;14(4):979-993. DISCLOSURE: The following authors have nothing to disclose: Oteni Hamilton, Timothy Legare, Sarah Dhannoon, Sayed Ali No Product/Research Disclosure Information

Non-islet cell tumour-induced hypoglycaemia secondary to haemangiopericytoma: A case report

Non-islet cell tumour-induced hypoglycaemia secondary to haemangiopericytoma: A case report

Life-threatening hypoglycemia resulting from a nonislet cell tumor.

Nonislet cell tumor-induced hypoglycemia (NICTH), also known as Doege-Potter syndrome, is a rare paraneoplastic syndrome seen in association with various nonpancreatic tumors, benign and malignant, and comprising mesenchymal, vascular, or epithelial cell types. We report a case of recurrent life-threatening hypoglycemia from a large pelvic solitary fibrous tumor.

Paraneoplastic hypoglycemia in a patient with a malignant solitary fibrous tumor.

SummaryHypoglycemia is a common medical emergency. It is the most frequent complication induced by anti-diabetic treatment. However, it can be observed in other conditions unrelated to diabetes such as insulinoma, autoimmune disorders, and neoplasia. Herein, we report the case of a rare cause of severe and recurrent hypoglycemia in a 77-year-old woman with a malignant solitary fibrous tumor (MSFT). A 77-year-old woman was admitted to the emergency department for loss of consciousness induced by severe hypoglycemia. Her standard laboratory findings were unremarkable. HbA1c, albumin, renal, liver, thyroid, and adrenal function tests were normal. Cerebral CT scan was also normal. At the time of confirmed hypoglycemia, the serum level of insulin and C-peptide was low. On the basis of the past medical history and the absence of other comment etiologies, a paraneoplastic cause was suspected. Thus, the diagnosis of a non-islet cell tumor-induced hypoglycemia (NICTH) was established by the presence of incompletely processed precursors of IGF2 (big IGF2) in plasma electrophoresis. However, the IGF1 level was low. Therapy with corticosteroids improved hypoglycemia and clinical symptoms. NICTH is a rare cause of hypoglycemia. It should be considered in patients with mesenchymal or malignant epithelial tumors suffering from recurrent episodes of hypoglycemia. The diagnosis will be established in the case of low serum insulin concentrations and elevated levels of big IGF2. Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels.Learning points NICTH is a very rare condition that should be considered in patients known to have mesenchymal or malignant epithelial tumors and suffering from recurrent episodes of hypoglycemia.The diagnosis of an NICTH is established on the basis of the hypoinsulinemic hypoglycemia, the MSFT history, and the presence of paraneoplastic secretion of IGF1 or an immature form of IGF2.Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels in NICTH.

Non-islet cell tumor-induced hypoglycemia: a report of five cases and brief review of the literature

SummaryWe describe the clinical presentation, diagnostic and management issues in five cases of non-islet cell tumor hypoglycemia (NICTH), diagnosed at a tertiary care institute over a period of 15 years. The clinical, laboratory, and histopathological findings of these patients along with diagnostic utility of IGF2:IGF1 ratio are discussed. The mean age of presentation was 52 years, with a male predominance (3:2). Three patients presented with recurrent episodes of fasting hypoglycemia and it was detected in other two patients during hospitalization. Two patients had acromegaloid features that regressed following treatment. One patient had hypokalemia. Low levels of insulin, C-peptide, GH, and IGF1 were invariably found in all. The IGF2 level was elevated in only one patient; however, IGF2:IGF1 ratio was more than 10 in four of the five patients. The mean tumor size was 16.4 cm and mean weight was 3.6 kg. Four patients had mesenchymal tumors and one had epithelial tumor. NICTH is a rare cause of hypoglycemia. Hypoinsulinemic hypoglycemia with low IGF1 and IGF2:IGF1 ratio more than 10 is suggestive of this entity.Learning points NICTH should be considered in patients presenting with tumor of mesenchymal origin and hypoglycemia.Hypoinsulinemic hypoglycemia with low IGF1 is a strong biochemical evidence of NICTH.IGF2:IGF1 ratio of more than 10 is a complementary investigation in the absence of an assay facility for IGF2.

Non–Islet Cell Tumor-Induced Hypoglycemia Associated with Macronodular Pulmonary Metastases from Poorly Differentiated Thyroid Carcinoma

Non-islet cell tumor-induced hypoglycemia (NICTH), a major cause of fasting hypoglycemia, is caused by the overproduction of incompletely processed, high molecular-weight insulin-like growth factor-II (IGF-II), termed "big" IGF-II. To the best of our knowledge, only two cases of thyroid carcinoma associated with NICTH have been documented. We report the case of a 72-year-old woman who was brought to the emergency department with impaired consciousness. The patient had a history of pulmonary metastases from poorly differentiated thyroid carcinoma (PDTC), spanning 12 years since initial treatment. Laboratory tests showed decreased plasma glucose levels even though immunoreactive insulin, IGF-I, and growth hormone (GH) were undetectable. Computed tomography (CT) scan revealed macronodular pulmonary metastases the estimated volume of which was 456 mL. Both the biochemical data and imaging results suggested NICTH. The results of Western blot analysis performed on a fractionated serum sample showed an increased expression of big IGF-II, an important indicator in the diagnosis of NICTH. Because the massive pulmonary metastases were considered inoperable, immunohistochemical analysis of stored formalin-fixed, paraffin-embedded tissues was performed. The analysis revealed that the tumor cells were positive for both IGF-II and thyroglobulin. A whole-body CT excluded extrapulmonary metastatic lesions. A retrospective review revealed a gradual decrease in glycohemoglobin levels accompanied by an increase in the estimated volume of pulmonary metastases. These findings suggested that NICTH had been caused by pulmonary metastases from PDTC. We describe here the third reported case of NICTH associated with thyroid carcinoma. This is also the first case reporting big IGF-II in the serum of a patient with thyroid carcinoma.

Double jeopardy: hypoglycaemia and advanced hepatocellular carcinoma

Nonislet cell tumour-induced hypoglycaemia is an uncommon, but serious complication of malignancy. The aetiopathogenesis is largely as a result of tumoral overproduction of incompletely processed insulin-like growth factor-II. We describe the case of a 30-year-old black male patient who presented with recurrent hypoglycaemic episodes in the absence of diabetes or any medications known to cause hypoglycaemia. Extensive investigations revealed that the hypoglycaemia was the result of an advanced hepatocellular carcinoma.

Hypoglycemia in a Patient With a Big “Big”-IGF-II-Producing Tumor

Non-islet cell tumor-induced hypoglycemia is a rare cause of hypoglycemia (1). Mesenchymal and epithelial tumors account for most cases (2, 3). A 60-year-old man with a palpable abdominal mass (computed tomography scan, 12 16 16-cm lesion, retroperitoneal) presented with neuroglycopenia responding to iv glucose. A fasting test confirmed symptomatic hypoglycemia (plasma glucose, 2.3 mmol/L within 4 h). Plasma levels of insulin (0.2 mU/L) and C-peptide ( 10 pmol/L) were suppressed, excluding endogenous hyperinsulinemia. Plasma IGF-I was also suppressed ( 2.6 nmol/L). Plasma total IGF-II was normal (460 ng/mL; 0.57 SD score) but pro-IGF-IIE (68–88) (“big”-IGF-II) was markedly raised (98 ng/ml; 8.97 SD score) (4). In agreement with the hypothesis that aberrant processing of IGF-II disrupts the ternary complex of IGF-II, IGF-binding protein 3, and acid labile subunit, we show here that pro-IGF-IIE (68– 88) was mainly present within binary complexes and as plasma free “big”-IGF-II (Figure 1). This would increase its accessibility to insulin and IGF-I receptors, ultimately leading to hypoglycemia and suppression of the pituitary GH-IGF-I axis (2, 3). Our patient fully recovered after surgery (histology, Figure 2), and successfully passed a 72-hour fasting test (glucose, 4.6 mmol/L). All laboratory parameters, including pro-IGF-IIE (68–88), had normalized. The distribution of “big”-IGF-II in the postoperative plasma became comparable to control plasma (Figure 1). The patient is still asymptomatic 1 year after surgery, with 10-year recurrence-free survival expected to be 50% (5). “Big”-IGF-II-producing tumors should be considered in tumor patients presenting with hypoglycemia. This case demonstrates that the ensuing changes in “big”-IGF-II distribution toward free pro-IGF-IIE (68–88) coincide with IGF-I suppression and are fully reversible.

Non-islet cell tumour induced-hypoglycaemia as a cause of delirium

Non-islet cell tumour induced hypoglycaemia (NICTH) is a rare but potentially reversible cause of recurrent low blood glucose.

Severe hypoglycemia with “Big”-IGF-2 oversecretion by a giant phyllode tumor of the breast: A rare case of non-islet cell tumor-induced hypoglycemia (NICTH)

ObjectiveWe report an exceptional case of non-islet cell tumor-induced hypoglycemia (NICTH) secondary to “Big”-IGF-2 oversecretion due to a giant phyllode tumor of the breast. Clinical presentationA 49-year-old woman was admitted in emergency for brutal neurologic defect revealing severe hypoglycemia. Several similar episodes were observed throughout hospitalization, requiring continue perfusion of hypertonic glucose solution. Beside these metabolic disorders, we observed a giant and hard tumor of the left breast (about 30cm in diameter). InterpretationSupplementary blood analysis revealed serum levels of C-peptide and insulin suppressed during hypoglycemia, excluding the possibility of either endogenous or exogenous hyperinsulinism. Low plasma levels of GH and IGF-1 were found, suggesting a negative feedback loop on somatotroph axis function. Therefore, the hypothesis of an insulinomimetic compound released by tumor cells was evoked because of abnormal presence of high-weight and immature form of IGF-2 (called “Big”-IGF-2) in the serum identified by western immunoblot analysis. A left mastectomy was performed and completely restored glucose homeostasis and confirmed the paraneoplastic origin of hypoglycemia because of markedly elevated expression of IGF-2 mRNA (qPCR) within the tumor cells. Finally, the anatomopathology analysis diagnosed a mesenchymatous tumor, namely a high-grade phyllode sarcoma of the breast. ConclusionAlthough NICTH due to “Big”-IGF-2 overproduction is a rare phenomenon, mainly observed in case of mesenchymatous tumor, it should be considered in presence of severe hypoglycemia with voluminous tumor and without hyperinsulinism.

Gastrointestinal stromal tumor of the pelvic soft tissue presenting with symptomatic hypoglycemia: A case report and brief review of current literature of non-islet cell tumor-induced hypoglycemia

► Presentation of a rare case of pelvic gastrointestinal stromal tumor. ► Non-islet cell induced hypoglycemia causing severe hypoglycemia. ► The pathogenesis of non-islet cell induced hypoglycemia due to over-production of precursors of insulin-like growth factor-II. ► Complete resolution of hypoglycemia following resection of the tumor.

Recurrent Solitary Fibrous Tumor of the Pleura with Malignant Transformation and Non-islet Cell Tumor-induced Hypoglycemia due to Paraneoplastic Overexpression and Secretion of High-molecular-weight Insulin-like Growth Factor II

A 41-year-old man was diagnosed with a solitary fibrous tumor (SFT) of the pleura in the posterior mediastinum. Despite two surgeries for excision, the SFT recurred and progressed with direct invasion of the chest wall and bone metastases. He was hospitalized because of cerebral infarction and presented with recurrent severe hypoglycemia fourteen years later. High-molecular-weight (HMW) insulin-like growth factor II (IGF-II) was identified in the serum and tumor using Western blotting and immunohistochemistry. These findings suggested that the cause of the recurrent severe hypoglycemia was SFT production of HMW IGF-II, a mediator of non-islet cell tumor-induced hypoglycemia (NICTH).

Treatment of Hemangiopericytoma-Associated Hypoglycemia with Glucocorticoid Therapy

Non-islet cell tumor-induced hypoglycemia (NICTH) is associated with mesenchymal tumor types, including hemangiopericytoma, fibrosarcoma, mesothelioma, and neurofibroma, as well as carcinoma of the liver, adrenal glands, and kidneys. Non- islet cell tumors induce hypoglycemia by overproducing an abnormal form of insulin-like growth factor II (IGF m. Complete removal of the tumor or reduction of the tumor mass is a successful therapeutic strategy in cases of NICTH. However, if the tumor re-grows, curative resection is nearly impossible, and hypoglycemia occurs repeatedly. Glucocorticoids are effective in terms of long-term relief from hypoglycemia through promotion of gluconeogenesis in the liver, tumor suppression, production of 'big'-IGF-II, and correction of the attendant biochemical abnormalities involving the growth hormone (GH)-IGF axis. We found that administration of corticosteroid therapy to a patient suffering from NICTH resulted in improvement of hypoglycemia associated symptoms.

Hypoglycaemia in a 63-Year-Old Female with a Large, Recurrent, Metastatic Gastrointestinal Stromal Tumour (GIST)

Non-islet cell tumour-induced hypoglycaemia (NICTH) is rare, with few cases reported in patients with gastrointestinal stromal tumour (GIST). A 63-year-old Chinese female with known metastatic GIST presents with persistent hypoglycaemia. Investigations revealed a likely diagnosis of NICTH, and she underwent debulking surgery. There was complete resolution of her hypoglycaemia post-operatively NICTH should be considered in patients with GIST and hypoglycaemia. Surgical debulking is recommended as part of the management of NICTH.