Non-islet Cell Tumor Hypoglycemia Research Articles

Glucocorticoid Treatment for Hypoglycemia in a Patient with Non-islet Cell Tumor Hypoglycemia Confirmed on CGM

Glucocorticoid Treatment for Hypoglycemia in a Patient with Non-islet Cell Tumor Hypoglycemia Confirmed on CGM

Management of Non-Islet-Cell Tumor Hypoglycemia: A Clinical Review

Non-islet cell tumor hypoglycemia (NICTH) is a rare but serious paraneoplastic syndrome in which a tumor secretes high molecular weight IGF-II, causing hypoglycemia. Complete tumor resection is curative but is often delayed or unfeasible. There is no clear "standard of care" for managing these patients. PubMed searches were conducted for: "non-islet-cell tumor hypoglycemia," "NICTH," "Doege-Potter," "Doege-Potter syndrome," "high molecular weight IGF-II," and "big IGF-II." Relevant articles were reviewed in detail. We limited our review to English-language articles, focusing on 1988-2013 (corresponding with the elucidation of the pathophysiology of NICTH). The available literature exists as case reports or small case series, with a void of higher-order treatment studies. Thus, an evidence-based approach to data synthesis was difficult. Nevertheless, the available literature is presented objectively with an attempt to describe clinically useful trends and findings in the management of NICTH. Appropriate identification of NICTH and prompt and complete tumor resection represents ideal management. However, when prompt resection is not feasible, iv glucose or dextrose often does not suffice to prevent hypoglycemia. In such cases, we suggest consideration of local antitumor therapies for disease control and trial of glucocorticoids alone or in combination with GH. Continuous glucagon infusion can be successful if the patient has a positive response to a glucagon stimulation test, and parenteral nutrition may allow higher glucose delivery, but both are limited by the need for continuous iv infusion. Diazoxide and octreotide have no role 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.

IGF2 and cancer

Insulin-like growth factor 2 (IGF2) is a 7.5 kDa mitogenic peptide hormone expressed by liver and many other tissues. It is three times more abundant in serum than IGF1, but our understanding of its physiological and pathological roles has lagged behind that of IGF1. Expression of the IGF2 gene is strictly regulated. Over-expression occurs in many cancers and is associated with a poor prognosis. Elevated serum IGF2 is also associated with increased risk of developing various cancers including colorectal, breast, prostate and lung. There is established clinical utility for IGF2 measurement in the diagnosis of non-islet cell tumour hypoglycaemia, a condition characterised by a molar IGF2:IGF1 ratio >10. Recent advances in understanding of the pathophysiology of IGF2 in cancer have suggested much novel clinical utility for its measurement. Measurement of IGF2 in blood and genetic and epigenetic tests of the IGF2 gene may help assess cancer risk and prognosis. Further studies will determine whether these tests enter clinical practice. New therapeutic approaches are being developed to target IGF2 action. This review provides a clinical perspective on IGF2 and an update on recent research findings.

Severe refractory non-islet cell tumour hypoglycaemia due to metastatic colorectal carcinoma

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Doege-Potter syndrome presenting with hypoinsulinemic hypoglycemia in a patient with a malignant extrapleural solitary fibrous tumor: a case report

IntroductionDoege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II. We describe the diagnosis and management of Doege-Potter syndrome and the use of transarterial chemoembolization in a patient with a malignant extrapleural solitary fibrous tumor.Case presentationOur patient was a 64-year-old Caucasian woman who initially presented with urinary incontinence and was found to have a 14.5×9.0×9.0cm retroperitoneal solitary fibrous tumor compressing her bladder. Her tumor was surgically resected but recurred with multiple hepatic metastatic lesions. The hepatic metastases progressed despite systemic chemotherapy and treatment with doxorubicin transarterial chemoembolization. Her course was complicated by the development of recurrent fasting hypoglycemia, most likely secondary to Doege-Potter syndrome. Her hypoglycemia was managed with corticosteroid therapy and frequent scheduled nutrient intake overnight.ConclusionsThe rarity of hepatic solitary fibrous tumors and consequent lack of controlled trials make this report significant in that it describes the diagnostic approach to Doege-Potter syndrome, describes our experience with the use of doxorubicin transarterial chemoembolization, and presents management options for tumor-associated hypoglycemia in the case of extensive disease not amenable to surgical resection.

Nonislet Cell Tumor Hypoglycemia

Nonislet cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia. It is characterized by increased glucose utilization by tissues mediated by a tumor resulting in hypoglycemia. NICTH is usually seen in large mesenchymal tumors including tumors involving the GI tract. Here we will discuss a case, its pathophysiology, and recent advances in the management of NICTH. Our patient was diagnosed with poorly differentiated squamous cell carcinoma of esophagus. He continued to be hypoglycemic even after starting continuous tube feeds and D5W. General workup for hypoglycemia was negative and insulin-like growth factor II (IGF II) was in the normal range. Hypoglycemia secondary to “big” IGF II was considered, and patient was started on steroids. His hypoglycemia resolved within a day of treatment with steroids. Initially patient had hypoglycemia unawareness, which he regained after maintaining euglycemia for 48 hours.

A Novel Case of Functional Gastric Neuroendocrine Carcinoma Occurred after Endoscopic Submucosal Dissection

In Japan, endoscopic submucosal dissection (ESD) is becoming a standard treatment for intramucosal differentiated gastric cancer. Although ESD is associated with a high cure rate for patients with early gastric cancer, tumors may recur, albeit rarely. We performed ESD on an 80-year-old man with a small depressed type of gastric cancer of the posterior wall of the cardia, found to be locally invasive on histology. Thirty months later, local recurrence and multiple liver metastases were detected, accompanied by frequent severe hypoglycemia. Despite chemotherapy, the patient died 6 months after relapse. On autopsy, the recurrent gastric lesion and liver metastases were examined immunohistochemically. Several characteristic tumor cells were positive for chromogranin A, cluster of differentiation (CD) 56, Ki-67, and insulin-like growth factor (IGF)-II. Western blot analysis of the patient's serum obtained during a hypoglycemic attack showed the high molecular weight form of IGF-II or “big” IGF-II. The patient was diagnosed with non-islet cell tumor hypoglycemia (NICTH), with “big” IGF-II being produced by the gastric neuroendocrine carcinoma. This is the novel case of a functional gastric neuroendocrine carcinoma that occurred after ESD and induced a hypoglycemic attack associated with NICTH.

Gastric Neuroendocrine Carcinoma with Non-islet Cell Tumor Hypoglycemia Associated with Enhanced Production of Insulin-like Growth Factor II

A 75-year-old man was admitted to the hospital with a loss of consciousness. His blood glucose level was 24 mg/dL. Abdominal computed tomography revealed multiple metastatic lesions in the liver, while upper endoscopy disclosed advanced gastric cancer. The hypoglycemia was refractory despite the administration of glucose and steroid therapy. The patient died within one month of admission. An autopsy revealed neuroendocrine-type gastric cancer, which, on examination with immunohistochemistry, was found to be negative for insulin and insulin-like growth factor I and positive for insulin-like growth factor II (IGF-II). The patient was diagnosed as having gastric cancer with non-islet cell tumor hypoglycemia (NICTH) caused by IGF-II.

Remarkable body weight gain in a patient in the terminal phase of gastric carcinoma secondary to ‘big IGF-II’— producing tumor

Weight loss as a result of cachexia with malignancy is frequently encountered in clinical practice. However, previous reports have not demonstrated weight gain in terminal phase of malignancy. We report a 69-year-old male admitted with an exacerbation of interstitial pneumonia and multiple metastases of relapsed gastric adenocarcinoma complicated with refractory hypoglycemia. He had gained approximately 10 kg weight with an acromegaloid appearance in a one-month period before admission. The presence of big insulin-like growth fact II (Big IGF-II) in his blood and an immunohistochemical study on the tumor cells confirmed a diagnosis of non-islet cell tumor hypoglycemia. This report possibly illustrates an unreported differential diagnosis of weight gain in terminal phase of malignancy.

A case report of non-islet cell tumour hypoglycaemia associated with ovarian germ-cell tumour

Background: Non-islet cell tumour hypoglycaemia is a rare paraneoplastic condition in which tumours secrete a high-molecular-weight precursor of insulin-like growth factor-II causing hypoglycaemia and can be difficult to identify and treat. Case Presentation: This is the case of a 27-year-old patient from Africa with metastatic ovarian yolk sac tumour who presented with hypoglycaemia and was subsequently diagnosed with non-islet cell tumour hypoglycaemia. Case Management: Our patient required higher doses of glucocorticosteroids than reported in the literature in combination with recombinant growth hormone therapy in order to control her hypoglycaemia. Case Outcome: This is the first case of non-islet cell tumour hypoglycaemia described in association with a germ-cell tumour. Her management required collaboration between the endocrinology team, the palliative care team, the acute medicine team and physicians in Africa to enable her safe journey home. Conclusions: This case illustrates the need for awareness among general physicians of rare tumour manifestations and the need for multidisciplinary input for the optimal management of these patients.

Clinical Validation of ELISA Assays for Insulin-Like Growth Factor-II (IGF-II)

Background : Insulin-like growth factor-II (IGF-II) is known to be dysregulated in malnutrition and in non-islet cell tumour hypoglycaemia (NICTH). Its measurement may be used diagnostically in the latter condition but little information is available on its utility as a nutritional marker. The aims of this study were to clinically validate two ELISAs for measurement of IGF-II in these conditions and to provide further information relevant to their use in nutritional contexts. Methods : IGF-II concentrations were measured by extraction and non-extraction ELISA and RIA in 20 malnourished patients referred for nutrition support. IGF-II concentrations were also measured by both ELISAs in 10 subjects with clinical features of NICTH. Results : Baseline IGF-II measured by both ELISAs correlated with body weight in patients referred for parenteral nutrition (PN) (P Conclusions : IGF-II may have a place in monitoring of nutrition support and merits further study of its utility as a nutritional marker. Whilst the ELISAs investigated can sensitively detect IGF-II and are valid for the measurement of IGF-II in nutritional contexts they are unlikely to replace RIA for the purpose of investigating NICTH. doi:10.4021/jem82w

Clinical Validation of ELISA Assays for Insulin-Like Growth Factor-II (IGF-II)

Background : Insulin-like growth factor-II (IGF-II) is known to be dysregulated in malnutrition and in non-islet cell tumour hypoglycaemia (NICTH). Its measurement may be used diagnostically in the latter condition but little information is available on its utility as a nutritional marker. The aims of this study were to clinically validate two ELISAs for measurement of IGF-II in these conditions and to provide further information relevant to their use in nutritional contexts. Methods : IGF-II concentrations were measured by extraction and non-extraction ELISA and RIA in 20 malnourished patients referred for nutrition support. IGF-II concentrations were also measured by both ELISAs in 10 subjects with clinical features of NICTH. Results : Baseline IGF-II measured by both ELISAs correlated with body weight in patients referred for parenteral nutrition (PN) (P < 0.05). Following commencement of PN, IGF-II concentrations climbed from baseline reaching statistical significance at days 5 and 7 of PN (P < 0.05). In specimens from subjects considered to have NICTH, IGF-II results from both ELISAs were positively biased compared to those measured by RIA. In comparison to RIA, the non-extraction ELISA yielded two false positive results and the extraction ELISA one false positive and one false negative result. Conclusions : IGF-II may have a place in monitoring of nutrition support and merits further study of its utility as a nutritional marker. Whilst the ELISAs investigated can sensitively detect IGF-II and are valid for the measurement of IGF-II in nutritional contexts they are unlikely to replace RIA for the purpose of investigating NICTH. J Endocrinol Metab. 2012;2(2):72-81 doi: https://doi.org/10.4021/jem82w

IGF2-induced hypoglycemia unresponsive to everolimus

Large tumours, usually of mesodermal origin, can cause severe and often intractable hypoglycaemia in the presence of undetectable levels of insulin. This phenomenon, referred to as non-islet-cell tumour hypoglycaemia (NICTH), is now generally thought to be due to secretion by the tumour of insulin-like growth factor-2 (IGF-2). Various interactions of IGF-2 with different receptors have been described,1 but most of the biological actions of IGF-2 are thought to be mediated via the IGF-1 receptor (IGF-1R), the binding of which results in differentiation, malignant transformation and the regulation of cell–cell adhesion. Interaction with the IGF-2 receptor (IGF2-R) promotes endocytosis and degradation of extra-cellular IGF-2 and may play a role in the transport of lysosomal enzymes, but is unlikely to be pathologically important. However, IGF-2 has also been shown to have high affinity binding with the insulin receptor; binding to the A isoform predominantly leads to mitogenic effects, but it also has (low) affinity with the B isoform that is principally concerned with its metabolic effects, including hypoglycaemia. Usually, IGF-2 is extensively bound to its binding-protein BP-3, and thus very little has access to the extravascular space. In NICTH the secretory product is principally the precursor pro-IGF-2, which is unable to bind BP-3 and thus can access extra-vascular receptors such as the insulin receptor isoforms. Thus, it has been thought that the hypoglycaemia in this condition relates to IGF-2 occupation of the insulin receptor. Downstream signalling form the insulin receptor involves the mammalian target of rapamycin (mTOR) pathway, and several recent case reports have suggested that blockade of the mTOR pathway with everolimus can effectively treat the severe hypoglycaemia associated with …

Rezidivierende Hypoglykämien und ein großer intraabdominaler Tumor bei einer 61-jährigen Patientin

A 61-year-old woman was found unconscious by her husband. The emergency doctor detected hypoglycemia (blood glucose 1.7 mmol/l). This was the first such event, the patient had not been known to have diabetes mellitus. At admission the physical examination and the laboratory findings revealed no abnormalities. A fasting test was aborted shortly after the start because of the onset of neurological symptoms. An insulinoma was excluded by detecting suppressed levels of insulin and C-peptide. Computed tomography of the abdomen revealed a mesenteric tumour of 9 cm in diameter, which was identified immunhistologically as a grade 1 follicular lymphoma (FL). After exclusion of endocrinological causes the recurrent hypoglycaemia was diagnozed as part of a paraneoplastic syndrome associated with a non-islet cell tumour hypoglycaemia (NICTH) with a newly diagnosed FL. Specific medication with the CD20 antibody rituximab (375 mg/m2, once per week for a total of four cycles) was initiated. There were no further episodes of hypoglycaemia. After one year the patient remains free of any symptoms. After exclusion of any endocrinological reasons for hypoglycemia, differential diagnosis should include NICTH as paraneoplastic syndrome. In rare cases a hematological malignancy may be the underlying disease. The specific treatment of this disease likewise represents the causal treatment of NICTH.

Doege-Potter syndrome and ‘big-IGF2’: a rare cause of hypoglycaemia

The authors discuss non-islet cell tumour hypoglycaemia (NICTH), which is associated with increased insulin-like growth factors (IGFs) and Doege-Potter syndrome (DPS). They state that DPS was first reported in a patient with spindle cell tumor with spontaneous hypoglycaemia. Furthermore, the authors suggest that patients with spontaneous, fasting, and chronic hypoglycaemia with hypoinsulinaemia that show personality changes and lethargy should undergo diagnosis of NICTH.

Plasma Distribution and Signaling Activities of IGF-II Precursors

IGF-II is thought to function through activation of the IGF-I receptor (IGF-IR) and the A isoform of the IR, with the IGF-IR being relevant to tumorigenesis and the IR to both tumorigenesis and metabolic control. In the paraneoplastic syndrome of nonislet cell tumor hypoglycemia, tumor-derived IGF-II has been proposed to exert both proliferative and metabolic effects, exemplifying this dual mode of action. Increased levels of IGF-II precursors ("big" and pro-IGF-II) have been reported in the circulation of nonislet cell tumor patients and have been proposed to exert greater or different effects than mature IGF-II. However, most studies have not defined which version is being investigated, and the relative activation of the IR and IGF-IR by IGF-II precursors has not been delineated. In this study, we determined the distribution of IGF-II isoforms in normal human plasma and their ability to activate the alternative versions of the IR. The majority (71%) of total IGF-II in human plasma was the mature form, while "big" and pro-IGF-II comprised 16% and 13%, respectively, with more variation seen in the levels of mature IGF-II. In IGF-IR-deficient cells expressing similar levels of human IR-A or IR-B, mature and "big" IGF-II exhibited similar activation of IR signaling, while pro-IGF-II exhibited significantly less activation. Downstream activation of Akt by mature and "big" IGF-II was greater in IR-A cells, consistent with previous reports of the greater affinity of IR-A for IGF-II. Thus, both IGF-II precursor forms are present in human plasma but do not preferentially activate the IR.

Severe hypoglycemia associated with insulin-like growth factor II-producing liver metastasis from gastric carcinoma treated with overnight total parenteral nutrition via a central vein catheter reserve port.

Hypoglycemia caused by insulin-like growth factor II is difficult to control. A 77-year-old woman was diagnosed with gastric cancer and multiple liver metastases in September 2006 and underwent chemotherapy; however, at that time there were no symptoms of hypoglycemia. From January 2007 onwards, hypoglycemic comas and symptoms of hypoglycemia began to appear frequently. Her serum level of insulin was normal; thus, we suspected the presence of big insulin-like growth factor II was causing the hypoglycemia. This was proven by Western immunoblotting and we diagnosed non-islet cell tumor hypoglycemia associated with gastric cancer. Overnight nutrition provided via a central venous catheter port to prevent hypoglycemia allowed the patient to become ambulant and to remain free of hypoglycemic coma at follow-up until her death 7months later.

Large solitary fibrous tumor with overexpression of insulin-like growth factor-2

We present the case of a 66-year-old woman in whom a large solitary fibrous tumor (SFT) in the right thoracic cavity caused intermittent symptoms of hypoglycemia. A diagnosis was made of non-islet cell tumor hypoglycemia on the basis of the presence of hypoglycemia requiring continuous glucose infusion, elevated serum insulin-like growth factor-2 (IGF-2), and a large well-defined tumor in the right thoracic cavity. The patient underwent complete resection of the tumor. Histological examination revealed spindle tumor cells with a hemangiopericytoma-like vascular pattern. Mitotic figures and necrotic areas were rare, and cellular atypia and nuclear pleomorphism were mild. Under immunohistochemical examination, the tumor cells were positive for CD34. Overexpression of IGF-2 mRNA in the tumor was detected by reverse-transcription polymerase-chain reaction. The diagnosis of SFT with IGF-2 production was confirmed. Immediately after surgery, her serum glucose level was normalized (without the need for glucose infusion) and serum IGF-2 level was decreased. Two years after surgery, the patient remains alive and well, with no signs of recurrence or hypoglycemia.

A case of gastric cancer with non-islet cell tumor hypoglycemia detected by insulin-like growth factor II

A case of gastric cancer with non-islet cell tumor hypoglycemia detected by insulin-like growth factor II