Non-islet Cell Tumor Hypoglycemia Research Articles

7187 Non-islet Cell Tumor Hypoglycemia in a Patient With Metastatic Renal Cell Carcinoma

Abstract Disclosure: G.W. Bao: None. A.Y. Yin: None. We report a rare case of non-islet cell tumor hypoglycemia (NICTH) in a patient with metastatic renal cell carcinoma. NICTH is a paraneoplastic syndrome due to increased production of an incompletely processed form of insulin-like growth factor 2 (“big IGF-2”). It requires a high-level of suspicion for diagnosis and is challenging to manage. Our patient is a 69 year old gentleman with a history of deceased donor renal transplant in 1994 and 2008. He was diagnosed with renal cell carcinoma (RCC) metastatic to bone, lymph nodes, and lungs, which was initially treated with cabozantinib, later switched to lenvatinib and everolimus due to disease progression. On admission, he presented with anasarca and weakness. He had recurrent fasting hypoglycemia associated with confusion and lethargy. The lowest serum glucose was 28 mg/dL. He was also diagnosed with primary hypothyroidism (TSH 25.1 uIU/mL and free T4 0.31 ng/dL), suspected to be due to tyrosine kinase inhibitor therapy. Levothyroxine was initiated. Cosyntropin stimulation resulted in a post-stimulation cortisol of 7 ug/dL, although this was felt not to be reliably diagnostic of adrenal insufficiency in the setting of profound hypoalbuminemia. IGF-1 and IGF-2 were 16 ng/mL and 388 ng/mL, respectively; IGF-2: IGF-1 ratio was 24.3. He was treated with intravenous dextrose and prednisone 30mg daily with stabilization of glucoses for a few days. On hospital day 19, he acutely decompensated and passed away shortly after being transitioned to comfort-focused care. Non-diabetic hypoglycemia is relatively uncommon, and may be seen in patients with liver disease, sepsis, adrenal insufficiency, and malignancy. We report a case of NICTH in a patient with metastatic RCC, which is a particularly rare cause of hypoglycemia. NICTH is due to tumor production of “big IGF-2”, a precursor of IGF-2, which mimics the effects of insulin and causes fasting hypoglycemia. NICTH is more commonly associated with mesenchymal and epithelial tumors such as fibromas, fibrosarcomas, and hepatocellular carcinomas. NICTH due to RCC appears to be a much more rare entity, with as few as four cases reported in the literature. Laboratory findings of NICTH include low insulin, pro-insulin, C-peptide, and β-hydroxybutyrate during hypoglycemia. An IGF-2: IGF-1 ratio >10 is considered virtually diagnostic. Surgical excision is curative, although often delayed or not feasible, and patients frequently require intravenous dextrose. High-dose steroids (ie, prednisone 30-60mg daily) can be used, which promotes “big IGF-2” clearance. NICTH is likely under-recognized in patients with advanced malignancies. This diagnosis should be considered in those with refractory hypoglycemia, although management is challenging if tumor control cannot be achieved. Presentation: 6/1/2024

6712 Intractable Hypoglycemia: A Clue to Tumor Diagnosis

Abstract Disclosure: N. Kharkongor Chengappa: None. E.I. Krug: None. Background: Non-Islet Cell Tumor Hypoglycemia (NICTH) known as Doege-Potter syndrome, is a rare paraneoplastic syndrome of hypo-insulinemic hypoglycemia caused by excessive production of partially processed IGF-II from a solitary fibrous tumor (SFT).We present a case of a patient admitted with intractable hypoglycemia leading to the diagnosis and treatment of a large pelvic SFT. Clinical Case: A 59-year-old male with type 2 Diabetes Mellitus on metformin mono therapy, was admitted after he collapsed at work and was found to have blood glucose (BG) of 22 mg/dl. He was previously in his usual state of health except for an increase in his shoe size over the past year. Physical examination revealed coarse thick skin, large coarse bullous nose, enlarged fingers and a non-tender, firm abdomen with no obvious organomegaly. Laboratory results including CBC, CMP and thyroid function were normal. ACTH stimulation test revealed normal adrenal function. Hypoglycemic drug screen and insulin antibodies were negative. During a hypoglycemic event (BG of 45mg/dl) he had C-peptide level < 0.1ng/ml, beta-hydroxybutyrate levels of <0.05 and insulin level <0.4uIU/ml, indicating non-insulin mediated hypoglycemia. IGF-I and IGF-II levels were ordered. Due to a concern for paraneoplastic etiology of hypoglycemia. CT scan revealed a 20 cm solid mass, filling most of the pelvis and extending into the lower abdomen. Further investigations revealed normal PSA, CEA, CA19-9 and undetectable hCG and AFP levels. MRI confirmed a presence of 23 cm pelvic mass with few areas of central necrosis, extending into the lower abdomen. CT-guided biopsy revealed spindle cell neoplasm consistent with SFT. The patient underwent pelvic mass resection. Postoperatively, hypoglycemia resolved with BG readings of 138mg/dl to 178mg/dl. Surgical pathology results confirmed malignant SFT with positive STAT 6 and CD34 markers. IGF-II level obtained prior to surgery was markedly elevated at 2029 ng/ml (38-267 ng/mL). Conclusion: NICTH was described in 1930 by KW Doege and RP Potter. Less than 5% of patients with SFTs develop NICTH. Diagnosis requires manifestation of Whipple's triad, low insulin, pro-insulin and C-peptide levels, elevated IGF-II levels, or an IGF-I/IGF-II ratio>2, and the identification of the tumor. Positive immunohistochemical stain of the tumor for STAT6 confirms the diagnosis. Management involves resection of the tumor when feasible or debulking. For higher-risk tumors, radiation therapy may be considered. In inoperable cases, glucocorticoids, recombinant hGH and glucagon are recommended for palliation of hypoglycemia. Octreotide and Diazoxide are ineffective in NICTH.

9182 Metastatic Extra-Gastrointestinal Stromal Tumor Presenting As Hypoglycemia

Abstract Disclosure: O. faour: None. D. John: None. S.K. Suryanarayanan: None. A.A. Rizvi: None. Introduction: Non islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome seen in association with solid abdominal tumors of mesenchymal and epithelial origin. We report a case of metastatic extra-gastrointestinal stromal tumor (E-GIST) presenting with severe hypoglycemia as its initial manifestation. CASE DESCRIPTION: A 46-year-old patient was found to have a blood glucose of <45 mg/dl during a routine clinic visit with her primary care physician. Although she was asymptomatic, she was sent to the emergency room (ER) for further evaluation. She had a history of prediabetes managed by lifestyle modification. She has been experiencing multiple episodes of hypoglycemia previously which fulfilled the Whipple’s triad in the preceding months. These hypoglycemic episodes included loss of unconsciousness, falls in the shower with head injury, and several hospital visits. Serum glucose in the ER was 14 mg/dl and hypoglycemia persisted despite continuous dextrose solution. Physical examination was notable for a distended, non-tender abdomen and cervical lymphadenopathy. CT scan showed a 15 cm mass in the liver, multiple large masses in the mesentery, and a 11 cm lesion in the left pelvis. There were enlarged lymph nodes in the abdomen, chest, and neck. Serum chemistries drawn when the patient was hypoglycemic revealed potassium level of 2.7 mg/dl (3.5-5.5) an insulin level of <1.0 mIU/L (5-25), C-peptide <0.1 ng/mL (0.5-2), cortisol 13.8 mcg/dL (5-25), and insulin-like growth factor-2 (IGF-2) was 270 ng/mL (38-267). The IGF-2/IGF-1 molar ratio was 3.4 (normal <3:1). The sulfonylurea drug screen came back negative. Upper and lower endoscopies were unrevealing. Biopsy of the liver lesion showed cytology and immunohistochemical findings consistent with a epithelioid metastatic extra-gastrointestinal stromal tumor. A provisional diagnosis of NICTH was made. The patient responded well to intravenous glucose, oral carbohydrate intake and high-dose corticosteroids. She was subsequently started on therapy with the tyrosine kinase inhibitor (TKI) imatinib. Discussion: Paraneoplastic hypoglycemia is often seen in association with metastatic epithelial and mesenchymal tumors. IGF-2 and incompletely processed pro-IGF-2 activates autocrine, paracrine, and endocrine pathways that lead to tumor growth, fasting hypoglycemia, rarely of acromegalic features. Treatment with octreotide, diazoxide, and glucagon is generally ineffective, while glucocorticoid use and surgical intervention are helpful in ameliorating the hypoglycemia. Tumor-directed therapy with TKIs, primarily imatinib, appears promising in achieving remission. Our case is a clinical reminder that hypoglycemia secondary to NICTH can be the predominant presenting feature in patients with underlying E-GIST. Presentation: 6/3/2024

Clinical characteristics of gastrointestinal stromal tumors with hypoglycemia.

The development of tyrosine-kinase inhibitors has improved survival rates for patients with gastrointestinal stromal tumors (GISTs). Despite the progress, not all the patients can universally receive the benefit from treatment due to the individual underlying conditions in a real-world setting. The present study focused on the well-known but understudied condition of GIST with hypoglycemia. Hypoglycemia in GIST is characterized by hypoglycemic symptoms such as dizziness, sweating and confusion. It is caused by several factors such as multiple liver metastases, drug adverse effects, postoperative complications and paraneoplastic syndrome [non-islet cell tumor hypoglycemia (NICTH)]. Comprehensive analysis of this condition has been hindered due to its rarity, and has been mostly limited to case reports. In the present study, a single-institution retrospective analysis of GIST with hypoglycemia was conducted to investigate its prevalence and prognosis, and the cause of this condition. The present study identified that the prevalence of hypoglycemic episodes of GIST was 4.1% in all patients with GIST, and recurrent hypoglycemic cases had a poor prognosis. The present study identified 1 case with recurrent hypoglycemia due to NICTH. Since NICTH is a rare hypoglycemic cause and requires further evaluation, an autopsy and genetic sequencing were performed using the available clinical materials. Through this histological and genetic investigation, the histological diversity of NICTH-GIST was revealed and insulin-like growth factor II (IGF-II) amplification was identified. Furthermore, a chronological analysis was performed using multiple resected archived samples from the same case, and revealed that diffuse IGF-II expression may have occurred in the early phase of tumor development. The present study catalogued the characteristics of GIST with hypoglycemia with a focus on NICTH-GIST.

Non-islet cell tumor hypoglycemia that required immediate surgery after a long-term asymptomatic state: recommendation for early intervention.

An 82-year-old woman with a 60-year history of a lung tumor presented with hypoglycemia. Non-islet cell tumor hypoglycemia (NICTH) was suspected; however, her hypoglycemia stabilized with supplemental food. She was discharged, based on her wishes, and planned to undergo surgery later. After discharge, the hypoglycemia worsened rapidly and required immediate resection. Postoperatively, the hypoglycemia resolved. Western immunoblot analysis confirmed the presence of big insulin-like growth factor 2, confirming NICTH. This patient experienced the rapid progression of symptoms after an unprecedentedly long-term asymptomatic state. Therefore, when NICTH is suspected, early intervention is recommended regardless of the presence of asymptomatic state. In patients with NICTH, the onset of hypoglycemia is usually within a year of tumor detection, and few reports regarding long-term asymptomatic NICTH have been documented. NICTH can cause rapidly progressive symptoms after a long-term asymptomatic state, as in this case, and an asymptomatic state does not preclude the necessity for intervention, especially when patients are at risk for malnutrition. Tumor resection is the only curative treatment for patients with NICTH, but there is no consensus regarding the timing of surgery. However, considering the possibility of rapid symptom progression, patients should be examined and treated in a timely manner.

Non-islet cell tumour hypoglycaemia in adrenocortical carcinoma responding to combined growth hormone and corticosteroid therapy

Non-islet cell tumour hypoglycaemia in adrenocortical carcinoma responding to combined growth hormone and corticosteroid therapy

A Case of Non-Islet Cell Tumor Hypoglycemia Due to Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis

A Case of Non-Islet Cell Tumor Hypoglycemia Due to Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis

Addressing recurrent hypoglycaemia through thoracic surgical intervention: understanding Doege-Potter syndrome, a rarity in syndromes

Doege-Potter syndrome (DPS), a rare paraneoplastic phenomenon characterised by non-islet cell tumour hypoglycaemia (NICTH), presents clinicians with intricate diagnostic and therapeutic challenges. This comprehensive review consolidates current understanding, clinical presentations, diagnostic modalities, therapeutic interventions, and emerging trends in managing DPS. The pathophysiology of DPS revolves around dysregulated insulin-like growth factors (IGF), particularly IGF-2, produced by mesenchymal tumours, notably solitary fibrous tumours (SFT). Clinical manifestations encompass recurrent hypoglycaemic episodes, often distinct from typical hypoglycaemia, with implications for insulin and counterregulatory hormone levels. Diagnosis necessitates a multidisciplinary approach integrating biochemical assays, imaging studies, and histopathological confirmation of the underlying neoplasm. Surgical resection remains the cornerstone of treatment, complemented by adjunctive therapies to manage persistent hypoglycaemia. Prognosis is influenced by successful tumour resection and long-term surveillance for recurrence. A patient-centred approach, incorporating supportive services and multidisciplinary care, is essential for optimal outcomes in individuals affected by DPS.

Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy.

The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging in the last few decades, based on molecular and cellular findings, supports a broader role for IGF-II in cancer biology beyond its involvement in the paraneoplastic syndrome. In particular, a few key findings are constantly observed during tumorigenesis, (a) a relative and absolute increase in fetal insulin receptor isoform (IRA) content, with (b) an increase in IGF-II high-molecular weight cancer-variants (big-IGF-II), and (c) a stage-progressive increase in the IGF-II autocrine signal in the cancer cell, mostly during the transition from benign to malignant growth. An increasing and still under-exploited combinatorial pattern of the IGF-II signal in cancer is shaping up in the literature with respect to its transducing receptorial system and effector intracellular network. Interestingly, while surgical and clinical reports have traditionally restricted IGF-II secretion to a small number of solid malignancies displaying paraneoplastic hypoglycemia, a retrospective literature analysis, along with publicly available expression data from patient-derived cancer cell lines conveyed in the present perspective, clearly suggests that IGF-II expression in cancer is a much more common event, especially in overt malignancy. These findings strengthen the view that (1) IGF-II expression/secretion in solid tumor-derived cancer cell lines and tissues is a broader and more common event compared to the reported IGF-II association to paraneoplastic hypoglycemia, and (2) IGF-II associates to the commonly observed autocrine loops in cancer cells while IGF-I cancer-promoting effects may be linked to its paracrine effects in the tumor microenvironment. Based on these evidence-centered considerations, making the autocrine IGF-II loop a hallmark for malignant cancer growth, we here propose the functional name of IGF-II secreting tumors (IGF-IIsT) to overcome the view that IGF-II secretion and pro-tumorigenic actions affect only a clinical sub-group of rare tumors with associated hypoglycemic symptoms. The proposed scenario provides an updated logical frame towards biologically sound therapeutic strategies and personalized therapeutic interventions for currently unaccounted IGF-II-producing cancers.

Management of Symptomatic Refractory Hypoglycemia at the End of Life in a Nondiabetic Patient With Metastatic Urothelial Carcinoma.

Patients with advanced cancer can develop symptomatic hypoglycemia at the end of life which can be associated with significant distress. We report the case of a man with metastatic urothelial carcinoma who developed acute-onset, recurrent, and symptomatic hypoglycemia concerning for non-islet cell tumor hypoglycemia (NICTH). Hypoglycemic episodes were physically and emotionally distressing and refractory to glucose tablets and a low concentration of dextrose infusion. Based on symptom burden and goals of care, treatment was escalated to a concentrated dextrose infusion requiring a central venous line, oral corticosteroids, and subcutaneous somatotropin. He was transferred to the inpatient palliative service, and on this treatment regimen, did not have additional distressing hypoglycemia. For patients with metastatic cancer and symptomatic hypoglycemia, applying a palliative-based framework with discussion of prognosis, values, and goals will lead to goal-concordant care at the end of life that can include aggressive maintenance of euglycemia to relieve suffering.

THU560 Serum miRNA-483 As A Diagnostic And Therapeutic Marker Of IGF-II-producing Non-islet Cell Tumor Hypoglycemia (NICTH)

Abstract Disclosure: M. Okazaki-Hada: None. M. Nagao: Grant Recipient; Self; The Foundation for Growth Science. A. Asai: None. I. Fukuda: None. L. Eliasson: None. M. Iwabu: None. Objective: Non-islet cell tumor hypoglycemia (NICTH) is known as the second major cause of spontaneous hypoglycemia next to insulinoma. Abnormal higher molecular weight forms of insulin-like growth factor II (IGF-II), so-called “big IGF-II”, are frequently detected in the sera of patients with NICTH. Thus, the disease is referred to as IGF-II-producing NICTH. We have previously reported a significant elevation of serum microRNA (miRNA)-483-5p and -3p levels in patients with IGF-II-producing NICTH. The miRNA-483 family are encoded in an intron of IGF2 gene and thus suggested to be co-expressed with IGF-II. The aim of this study was to validate the usefulness of miRNA-483 family as a diagnostic and therapeutic marker of IGF-II producing NICTH, then to examine if the IGF-II-producing tumor tissues could be the source of these circulating miRNAs Design: Serum samples from patients who had been suspected to have IGF-II-producing NICTH (n = 134) were tested. The presence of big IGF-II was confirmed by Western blotting, and miRNA-483-5p and -3p levels were evaluated by quantitative PCR. IGF-II level was also analyzed by ELISA. In addition, IGF-II, miRNA-483-5p and -3p levels were compared before and after tumor removal in serum samples from surgically treated patients with IGF-II-producing NICTH (n=21). Expression levels of miRNA-483-5p and -3p were also analyzed in the big IGF-II-expressing tumor tissues and the surrounding surgical margins (n=9). Results: Big IGF-II was detected in the sera of 91 out of 134 patients. IGF-II, miRNA-483-5p and -3p levels were significantly higher in sera with big IGF-II than in those without. The area under the receiver operating characteristic curve of miRNA-483-5p (0.85) for IGF-II-producing NICTH were higher than those of miRNA-483-3p (0.75) and IGF-II (0.75). After tumor removal, serum miRNA-483-5p level decreased (P=0.0025), but serum miRNA-483-3p and IGF-II levels did not change significantly. The expression levels of miRNA-483-5p and -3p in the tumor tissues were significantly higher than those in the surgical margins (18 and 51 times for miRNA-483-5p and -3p, respectively). Conclusion: The present study confirms that miRNA-483-5p and -3p are elevated in sera of patients with IGF-II-producing NICTH and shows that miRNA-483-5p is significantly reduced after the surgical removal of big IGF-II-producing tumors. These results highlight the usefulness of the miRNA-483 family as a diagnostic and therapeutic marker for IGF-II-producing NICTH, and strongly suggest that the tumors produce miR-483-5p and -3p in parallel with the production of big IGF-II. Presentation: Thursday, June 15, 2023

FRI667 Profound And Persistent Hypoglycemia With Hepatocellular Carcinoma- A Non-islet Cell Tumor

Abstract Disclosure: A. Muneeb: None. M. Shahid: None. M. Raza: None. H. Zahoor: None. S. Sultan: None. Introduction: Tumor related hypoglycemia is rare and can be caused by islet cell tumors or non-islet cell tumors (NICT). Proposed mechanisms for non-islet cell tumor hypoglycemia (NICTH) include: increased big-IGF production (precursor of IGF2 which acts similar to insulin); increased insulin production; infiltration of liver/adrenals; and autoantibodies to insulin receptors. Clinical Case: A 78-year-old female with pertinent medical history of recently diagnosed locally advanced hepatocellular carcinoma (HCC) was found unresponsive at home. On arrival of EMS, the blood glucose (BG) level was in 30s. Dextrose water was administered that resulted in improvement of her mentation. She was alert and awake when brought to the hospital but was persistently hypoglycemic despite frequent feeding. She was started on dextrose infusion and was admitted for workup of persistent hypoglycemia. She denied history of diabetes, insulin or sulfonylurea use. She reported an admission to another facility for hypoglycemia 4 days ago where adrenal insufficiency was ruled out with normal morning cortisol levels. During this hospitalization, CBC and CMP were unremarkable except low BG. A CT scan of the abdomen/pelvis was consistent with locally advanced HCC. Fasting protocol was started and BG monitoring was performed every 30 minutes. When BG fell below 55 mg/dL; C-peptide, insulin and proinsulin levels were drawn which came back severely suppressed at 0.13 ng/mL, <1 mU/L, and 2.7 pmol/L respectively. IGF2 was low-normal at 339 ng/mL. Given aforementioned workup and exclusion of other causes including medications, insulinoma and adrenal insufficiency, hypoglycemia was attributed to big-IGF mediated NICTH. Dextrose infusion was re-initiated but the patient continued to have BG in 30s, which was verified by both finger-stick and serum chemistry. Dexamethasone was initiated and dextrose infusion was continued. Oncology deemed her a poor surgical candidate. She declined other therapies for HCC. BG stabilized after institution of steroids, dextrose infusion was weaned successfully, and patient was discharged. Conclusion: A high index of suspicion should be held for NICTH in patients with profound hypoglycemia refractory to dextrose infusions in the setting of NICT. The diagnosis of NICTH can be made with suppressed insulin and C-peptide, elevated big-IGF, and normal-reduced IGF2 levels. Management of NICTH related to HCC is tumor resection. However, local anti-tumor therapies can be considered in non-surgical candidates. Since NICTH can be refractory to dextrose infusion, steroids with or without GH are an effective option. In refractory cases, continuous glucagon infusion and parenteral nutrition can be considered. Further research is needed to help develop better treatment options. We hope to contribute to the current literature regarding NICTH and bring awareness to the medical community. Presentation: Friday, June 16, 2023

SAT174 Doege-Potter Syndrome In A Patient With Solitary Fibrous Tumor Of The Lung

Abstract Disclosure: N. Mon: None. S.S. Krishnasamy: None. Doege-Potter Syndrome is a non-islet cell tumor hypoglycemia (NICTH) due to a solitary fibrous tumor (SFT) with overexpression of Insulin-like growth factor 2 (IGF2). We report a case of refractory hypoglycemia in a patient with SFT of the lung. Case presentation: A 67-year-old homeless male with hypertension, chronic smoker presented with altered mental status after his blood glucose was found 34mg/dl by EMS. His confusion improved after D50W. He could not recall the event but he reported that he missed his dinner prior to the event. He denied taking any antidiabetic medications. He was diagnosed with left lung solitary fibrous tumor without metastases a week ago after he presented to ER with dyspnea, cough and wheezing. CT chest reported a 21x15.6x18.7 cm lesion with mass effect on the left hemidiaphragm, mediastinum shift to the right and occluded left lower lobe bronchi. Core needle biopsy of the mass revealed SFT with necrosis. He was discharged with Medrol dosepak 4mg daily for presumptive treatment of COPD exacerbation and a plan for elective surgery. While in the ER his BG improved to 136mg/dl after D50W. Few hours later BG dropped to 42mg/dl and D10W infusion was started. Physical exam was unremarkable except bilateral pedal edema. Work up showed BG 42mg/dl, Insulin 3.3 (2.6-24.9 uIU/mL), C peptide 0.39 (1.1-4.4ng/mL), Proinsulin 4.7 (<18.8pmol/L), beta-hydroxybutyrate <0.05 (0.02-0.27mmol/l), 8AM cortisol 10.7 (7.0-25.0 ug/dl), albumin 3.2mg/dl, HbA1c 5.8%, IGF1 53ng/mL (34-245ng/mL), IGF2 203ng/mL (267-616ng/mL) with a IGF2:IGF1 ratio of 3.8. In our patient, the IGF2:IGF1 ratio was not >10 since his IGF 2 was suppressed by the recent steroid use. The rest of the clinical and biochemical features strongly suggested NICTH. His preoperative evaluation showed new onset HFrEF with volume overload. He underwent staged percutaneous coronary interventions with stents placement. He was given hydrocortisone 50mg q6H then to q8H during hospitalization and discharged home with hydrocortisone 40mg TID. He underwent radical resection of lung tumor after optimization of his cardiac condition. He was on stress dose of steroid during surgery. Since he was on high dose steroid for > 3months, hydrocortisone dose was tapered slowly after the surgery. Final biopsy reported solitary fibrous tumor extending to parenchymal staple line. Tumor cells are positive for CD34 and STAT6, and negative for desmin, SMA, and SOX10. He recovered uneventfully and was discharged home with prednisone 5mg daily and follow up in endocrine clinic. Conclusion: NICTH is a rare paraneoplastic syndrome characterized by low levels of insulin, C-peptide, proinsulin, and beta-hydroxybutyrate. A ratio of IGF-2/IGF-1 more than 10 confirms NICTH; however, normal ratio cannot exclude the diagnosis and factors such as low IGFBP 3 or steroid therapy for other conditions need to be considered. Surgery is the mainstay of treatment. Presentation: Saturday, June 17, 2023

FRI663 A Rare Case Of Igf-2 Induced Hypoglycemia Associated With Metastatic Colon Cancer

Abstract Disclosure: A. Alshaakh Mohd Mari: None. A. Varshney: None. A. Sidhu: None. M. Matos: None. M. Kinaan: None. Introduction: The diagnosis of hypoglycemia in patients without diabetes is uncommon and nonislet cell tumor hypoglycemia (NICTH) represent a minority of these cases. The most common mechanism is related to IGF-2 production from tumor cells. Case description: A 66-year-old man with a history of stage IV colon cancer presented to the hospital due to breathlessness while receiving chemotherapy (Bevacizumab plus FOLFOX4). He had partial colectomy and chemotherapy 3 years earlier but was recently found to have metastatic disease to the liver. A CT abdomen during hospitalization showed a 15 cm hepatic mass occupying the entire right hepatic lobe. Endocrinology was consulted due to persistent postprandial and fasting hypoglycemia despite dextrose infusion. He had no history of diabetes and denied taking any diabetes medications. Plasma blood glucose (BG) was noted to be 74 mg/dl (74-106) while on dextrose. An 8AM cortisol was checked to exclude adrenal insufficiency and was 8.08 mcg/dL (4.30-22.40). A 72 hour fast was done but discontinued at 8 hours when plasma BG dropped to 48 and patient became symptomatic. At the time C-peptide and Insulin levels were low <0.05 ng/mL (0.48-5.05) and <1.0 mU/L (3.0-25) respectively, with normal Beta-hydroxybutyrate (BHB) 1.1 mg/dL (0.2-2.8). At the end of the fast 1 mg of glucagon was administered and his BG increased to 112 mg/dl in 2 hrs. IGF-1 levels were undetectable <15 ng/mL and IGF-2 levels were found to be 175 ng/mL. The IGF2:IG1 ratio was at 11 confirming IGF-2 mediated NICTH. Dexamethasone 10 mg daily was started, and BG were maintained > 70mg/dl without dextrose infusion. Discussion: In approximately 50% of NICTH, the tumor is identified prior to the onset of hypoglycemia, but up to 50% of these patients may be asymptomatic despite hypoglycemia. Our patient had a known hepatic lesion and was minimally symptomatic despite very low BG. The mechanism for NICTH can include insulin secretion from the tumor, replacement of hepatic tissue and increased glucose utilization by the tumor, or most commonly, IGF-2 secretion. In the case of IGF-2 mediated hypoglycemia insulin, proinsulin, C-peptide, and β-hydroxybutyrate levels are low. An elevated IGF-2:IGF-1 ratio (>10) confirms the diagnosis. The primary treatment is through surgical removal or debulking of the tumor. Neoadjuvant therapies such as radiation and chemotherapy may reduce occurrences of hypoglycemia, but only temporarily. Glucocorticoids may be used when the underlying malignancy cannot be treated. Presentation: Friday, June 16, 2023

SAT141 A Case Of Non-islet Cell Tumor Hypoglycemia Which Was Ameliorated By Pazopanib Treatment

Abstract Disclosure: N. Yamamoto: None. M. Yamamoto: None. N. Kiyota: None. Y. Inaba: None. K. Kanie: None. S. Urai: None. M. Suzuki: None. Y. Sasaki: None. Y. Oi: None. Y. Tsujimoto: None. Y. Motomura: None. Y. Ohmachi: None. H. Bando: None. G. Iguchi: None. M. Nagao: None. I. Fukuda: None. H. Fukuoka: None. W. Ogawa: None. Introduction: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by insulin-like growth factor II (IGF-II) hypersecretion from the tumors. It is characterized by incompletely processed big IGF-II with potent insulin-like activity. We present a case of NICTH complicated with solitary fibrous tumor (SFT) which was ameliorated with the administration of pazopanib, a multi-targeted tyrosine kinase inhibitor. Clinical Case: A 57-year-old man went into a coma and was hospitalized. His plasma glucose levels were 26 mg/dL, and he regained consciousness after glucose administration, leading to a diagnosis of hypoglycemic coma. Moreover, a contrast-enhanced CT scan showed multiple tumors in his liver and right kidney. He was referred to our hospital for further management. After 5 hours of fasting, he had a cold sweat, and his plasma glucose levels dropped to 32 mg/dL with suppressed serum insulin levels of 0.2 U/mL. Serum 3-hydroxybutyrate levels were as low as 21 μmol/L, and plasma glucose levels increased to 83 mg/dL after glucagon administration, suggesting an agent mimicking insulin. Percutaneous liver biopsy was performed, and the tumors were diagnosed with SFT. Immunoblotting for his serum showed big IGF-II, leading to a diagnosis of NICTH, and hypoglycemia due to hypersecretion of IGF-II. Due to multiple metastases, surgery was not indicated and pazopanib was administered. Hypoglycemia during the night was prevented by glucose infusion through the central venous port, and he was discharged. Three months later, when he was re-hospitalized for thrombophlebitis of the right jugular vein, hypoglycemia did not occur even after 10 hours of fasting and CT scan showed the necrotic change of the tumor. Two weeks later of pazopanib discontinuation due to the thrombogenic adverse effect, hypoglycemia recurred accompanied by the tumor enlargement. When the anticoagulation therapy regressed the thrombosis and pazopanib was re-administered, hypoglycemia improved reproducibly and remained stable for more than 2 years although the tumor showed gradual progression. Conclusion: This is the first case in which pazopanib was effective in suppressing NICTH associated with SFT. Presentation: Saturday, June 17, 2023

Recurrent Non-islet Cell Tumor Hypoglycemia Secondary to Hepatocellular Carcinoma: Case Report and Literature Review.

Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome caused by tumors other than insulinoma that is primarily due to excessive production of insulin-like growth factor-II (IGF-II). The prevalence of NICTH is likely underestimated because of a lack of clinical recognition. A 41-year-old male with massive malignant liver tumors presented with recurrent severe hypoglycemia, weight loss, and liver cirrhosis. NICTH related to IGF-II produced by hepatocellular carcinoma was diagnosed based on clinical symptoms, biochemical tests, and elevated IGF-II/IGF-I ratio. Initial treatment with intravenous glucose and parenteral nutrition showed limited efficacy. Glucocorticoids and recombinant human growth hormone led to progressive improvement in blood glucose levels. Due to extensive tumor burden and liver failure, surgical resection was not feasible, and the patient ultimately succumbed to refractory hypoglycemia and passed away in two weeks. Early recognition and diagnosis of NICTH are crucial in patients with recurrent hypoglycemia and large tumors. Surgical resection is the preferred treatment option, but supportive care and pharmacological interventions, such as glucocorticoids and growth hormone, can help manage refractory hypoglycemia. Further research is needed to explore novel treatment options, including anti-IGF-I and -IGF-II neutralizing antibodies.

SAT150 "Sawtooth" Hypoglycemia: Rare Case Of IGF-2 Mediated Hypoglycemia With Elevated Proinsulin Level And "Sawtooth" Pattern On CGMS

Abstract Disclosure: P. Goparaju: None. M. Zena: None. Background: IGF-2 mediated hypoglycemia is usually associated with low Insulin, C-peptide and Proinsulin levels. We present an extremely rare case of IGF-2 mediated hypoglycemia with elevated Proinsulin level and an unusual “saw tooth” pattern on Continuous glucose monitoring system(CGMS). Clinical Case: 53-year-old male with history of metastatic Liposarcoma was admitted to the hospital with severe hypoglycemia. Whipple’s triad was positive on presentation, patient had symptoms of altered sensorium, blood glucose of 24 mg/dl, and symptoms improved upon correction of hypoglycemia. The patient was admitted to the ICU and IV dextrose was initiated.As Liposarcomas are known to be associated with Non-islet cell tumor hypoglycemia (NICTH), treatment with Prednisone was started. Prior to this, initial hypoglycemia workup was sent when blood sample was drawn during a hypoglycemia episode. Patient has no personal or family history of Diabetes. Adrenal insufficiency was ruled out with morning cortisol of 17.8 ug/dl. Serum glucose was low at 40mg/dl, Insulin<1(0-17 pmol/L), C-peptide level low at 0.4 (0.8-3.9 ng/ml), IGF-1 level was low at 68 (74-225 ng/ml), normal IGF-2 at 626 (333-967 ng/ml) and increased IGF-2/IGF-1 ratio of 9.2(Normally around 3:1). All the lab work above is consistent with IGF-2 mediated hypoglycemia with low Insulin, C-peptide and IGF-1 levels and increased IGF-2/IGF-1 ratio. Interestingly, he has an elevated Proinsulin level of 36.9 (0.0-10.0 pmol/L) which is very unusual.Prednisone was started at 20mg daily to which there was reasonable response, dose was eventually increased to 60mg daily before he was safely sent home. He was discharged on a CGMS and the data was downloaded 2 weeks later. He had an interesting “Saw tooth” pattern of glycemia on the daily glucose graphs. As the patient had access to live data, he was trying to correct the falling blood glucose which briefly improved the readings but was quickly followed by another drop and this sequence carried on leading to a unique blood glucose pattern on the CGMS. Conclusion: Proinsulin level is usually suppressed in IGF-2 mediated hypoglycemia. Our case is unusually associated with high Proinsulin level. One hypothesis is the possible structural similarities leading to lab assay interactions between Proinsulin and “Pro-IGF-2”, which is thought to be one of the main molecules responsible for hypoglycemia in this condition. More studies in future will be helpful to study this possible association. Our case also had a remarkable “Saw tooth” pattern on CGMS glucose graphs which is very rarely seen in clinical practice.

THU618 Adrenal Cell Carcinoma Presenting With Post-menopausal Bleeding And IGF-2 Induced Hypoglycaemia

Abstract Disclosure: E.M. Lonergan: None. L.J. Tan: None. E. Ali: None. C.M. Joyce: None. N. Conlon: None. A. O'Sullivan: None. D.J. O'Halloran: None. Background: Non-islet cell tumour hypoglycaemia (NICTH) as a result of IGF-2 secretion is rare with a few case reports associated with adrenal tumours. Clinical Case: We present the case of a 59-year-old female initially presenting to gynaecology services with post-menopausal bleeding due to endometrial hyperplasia. Serum testosterone, oestradiol and adrenal androgens were found to be elevated and LH and FSH suppressed. A subsequent CT adrenals demonstrated a 12.8 x 13.2 x 10.6cm left adrenal mass and she failed a 1mg overnight dexamethasone suppression test. In the interim, while undergoing evaluation, the patient presented to A+E Department with point-of-care confirmed hypoglycaemia with a capillary blood glucose of 1.6mmol/L and neuroglycopaenic symptoms. There was no history of diabetes mellitus, prolonged fasting, access to sulphonylureas or insulin. During a supervised fast, symptomatic hypoglycaemia occurred within 5 hours at 2.0mmol/L fulfilling Whipple’s triad. Results of samples taken during hypoglycaemia revealed an elevated IGF-2 : IGF-1 ratio of 60.7 (normal <10) with a low paired C-peptide, insulin and pro-insulin, consistent with a suspected IGF-2-secreting tumour. Hypoglycaemia was successfully managed with low glycaemic index foods and clinical nutrition input. Radical surgical excision was undertaken including left adrenalectomy, nephrectomy, partial pancreatectomy and splenectomy. Post-operative pathology revealed an adrenocortical carcinoma (ACC) measuring 16.4cm in maximum dimension; Ki67 12%; Weiss score 5; lymph nodes negative. Tissue has been stained for IGF-2-IR. Post-operative IGF-2 : IGF-1 ratio normalised to 3.4. The patient is under active follow up with 3-monthly surveillance CT-TAP and has declined Mitotane therapy at present. Conclusion: This is a rare case of ACC secreting multiple hormones, resulting in post-menopausal bleeding and IGF-2 mediated hypoglycaemia. Presentation: Thursday, June 15, 2023

THU373 Refractory Hypoglycemia In A Patient With Metastatic Cholangiocarcinoma: Abstract

Abstract Disclosure: M.G. Fernandez: None. D.J. Selen: None. Background: Nonislet cell tumor hypoglycemia is an uncommon but severe complication of cancer. It results from tumoral overproduction of insulin-like growth factor 2 (IGF-2), which inhibits hepatic glycogenolysis and the release of glucagon and growth hormone (GH). These three mechanisms can result in severe and refractory hypoglycemia. Clinical Case: We present a case of a 57-year-old female newly diagnosed with metastatic cholangiocarcinoma who was admitted to the hospital after an episode of syncope at home in the setting of hypoglycemia with a serum blood glucose of 17 mg/dL (N >60 mg/dL). During the hospital admission, evaluation of hypoglycemia included a normal TSH of 1.170 (reference range [RR] 0.3-5.5 mIU/ml), fasting morning cortisol of 23.3 (RR >14-15 μg/dL), and a negative sulfonylurea screen. In addition, the patient had an undetectable level of Insulin <3.0 (RR 3-25 mU/L), Beta-hydroxybutyrate <0.10 (RR 0.02-0.27 mMol/L), C-peptide <0.1 (RR 0.5-3.3 ng/ml), and Pro-insulin <1.6 (RR 3-20 pmol/L). CT of the abdomen revealed disease progression with innumerable bilateral enhanced hypoattenuating masses in the liver. Management for refractory hypoglycemia required nutrition optimization, nausea control, close glucose monitoring, IV dextrose infusion, and intermittent intravenous glucagon for episodes of severe hypoglycemia (<40 mg/dL). During the hospitalization, the patient received the first cycle of chemotherapy with gemcitabine, cisplatin, and dexamethasone. On day 10 of admission, the IGF-2 resulted at 120 ng/ml (RR 180-580ng/ml) and IGF-1<10 (RR 50-317 ng/ml) with an IGF-2/IGF-1 ratio greater than 100 (cut off>10), diagnostic of a large nonislet cell tumor as the most likely cause of her severe hypoglycemia. Artificial nutrition did not align with this patient’s goals of care, so she was discharged from the hospital with a FreeStyle Libre 2 for continuous glucose monitoring. However, two weeks later, she returned to the emergency department with hypoglycemia (<40 mg/dL), ultimately choosing to pursue hospice. Conclusion: Patients with large liver tumor burden can experience hypoglycemia due to low glycogen content in the liver. In addition, these patients can have decreased oral intake and weight loss, which confounds the clinical scenario and can delay diagnostic workup. Patients with refractory hypoglycemia and nonislet cell tumors require further evaluation for IGF-2 production, and alternative temporary nutritional options should be discussed with the patient immediately. Therapeutic options depend on the ability to treat underlying cancer. Palliative chemotherapy, surgery, or radiation can be considered to control the tumor and improve hypoglycemia for quality of life when the cancer is otherwise untreatable. Presentation: Thursday, June 15, 2023

Non-islet cell tumor causing hypoglycemia: A paraneoplastic complication of hepatocellular carcinoma

Introduction: Hypoglycemia is a common complication in patients with diabetes who are using either insulin or oral hypoglycemic agents. In non-diabetic patient hypoglycemia is more rare and paraneoplastic syndrome should be considered if other causes have been excluded. Hepatocellular cancer is an example of a non-islet cell tumor that can cause hypoglycemia. Case Report: Here we present a case of a 71-year-old male with history of metastatic hepatocellular cancer, treated hepatitis C infection, and human immunodeficiency virus (HIV). The patient was on active treatment with nivolumab. During admission he developed multiple episodes of hypoglycemia. The tests revealed decreased C-peptide and insulin levels suggesting non-islet cell etiology. The patient was initially treated with glucagon, and then started on steroids thereafter his episodes of hypoglycemia resolved. He continued to have stable disease while on immunotherapy, as well as no further hypoglycemia events while remaining on long term steroids. Conclusion: This case illustrates an important example of non-islet cell tumor hypoglycemia in a patient with hepatocellular carcinoma (HCC) where immunotherapy is emerging as a promising treatment option and the use of steroids can interfere with treatment. In situations where tumor resection, debulking, or ablation cannot be done, treatment of choice is glucagon for acute episodes and steroids can be considered for long-term management.