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1
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Chillo AJ, Homsy S, Thida AM, Chiu E. Managing Non-islet Cell Tumor Hypoglycemia in Hepatocellular Carcinoma With Radiation Therapy. Cureus 2024; 16:e76372. [PMID: 39867043 PMCID: PMC11761841 DOI: 10.7759/cureus.76372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 12/24/2024] [Indexed: 01/28/2025] Open
Abstract
Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome associated with non-mesenchymal-derived and epithelial tumors. A 37-year-old male with stage IVB hepatocellular carcinoma (HCC) and pulmonary metastases presented with recurrent hypoglycemia despite glucose supplementation. Laboratory findings revealed low insulin growth factor 1 (IGF-1) (15 ng/mL), elevated insulin growth factor 2 (IGF-2) (395 ng/ml), and an IGF-2:IGF-1 ratio of 26:1, consistent with NICTH. After ruling out other causes of hypoglycemia, including endocrine deficiencies and medication-induced hypoglycemia, the patient was managed with steroids and intravenous (IV) glucose. Due to the metastatic nature of the cancer, he was treated with atezolizumab and bevacizumab. Palliative radiation therapy (RT) was initiated to improve glycemic control. Following RT, hypoglycemic episodes decreased, allowing discharge with oral steroids. NICTH management remains challenging due to limited therapeutic options and variable treatment responses. Surgical resection is the standard treatment for NICTH; however, conservative approaches include steroid use, glucose supplementation, and recombinant growth hormone (GH). In this case, radiation was chosen to target the tumor and alleviate hypoglycemia, resulting in improved glycemic stability post-treatment. NICTH associated with HCC is a rare and challenging complication with significant morbidity. Early use of RT alongside systemic treatment may offer a viable strategy for managing NICTH and improving patient outcomes.
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Affiliation(s)
- Anthony J Chillo
- Hematology and Oncology, State University of New York Downstate Health Sciences University, Brooklyn, USA
| | - Sylvester Homsy
- Hematology and Oncology, Stanford University School of Medicine, Stanford, USA
| | - Aye M Thida
- Hematology and Oncology, State University of New York Downstate Health Sciences University, Brooklyn, USA
| | - Edwin Chiu
- Medicine, State University of New York Downstate Health Sciences University, Brooklyn, USA
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2
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Nagasaka H, Suzuki T, Kondo T, Koizumi M, Terao H, Murohashi Y, Okubo Y, Yokose T, Kishida T. Retroperitoneal Doege-Potter syndrome with intraoperative blood glucose monitoring. IJU Case Rep 2024; 7:391-394. [PMID: 39224681 PMCID: PMC11366430 DOI: 10.1002/iju5.12765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 07/18/2024] [Indexed: 09/04/2024] Open
Abstract
Background Doege-Potter syndrome, characterized by solitary fibrous tumors and non-islet cell tumor hypoglycemia, is rare. Here, we report a case of Doege-Potter syndrome in which retroperitoneal tumor resection was performed with continuous intraoperative blood glucose monitoring. Case presentation A 37-year-old man presented with hypoglycemia-related symptoms, and a 10 × 12 × 9 cm tumor was found in his right kidney. Following tumor resection, insulin secretory abnormalities improved, and intraoperative blood glucose monitoring showed no hypoglycemic events. High levels of insulin-like growth factor-II confirmed the diagnosis of an insulin-like growth factor-II-producing tumor with non-islet cell tumor hypoglycemia. Postoperative serum insulin-like growth factor-II levels normalized, with no recurrence observed over 3 years. Conclusions This case highlights the rarity of primary retroperitoneal Doege-Potter syndrome, emphasizes the safety of intraoperative blood glucose levels during surgery, and suggests rapid recovery of insulin secretion postoperatively.
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Affiliation(s)
| | | | - Takuya Kondo
- Department of UrologyKanagawa Cancer CenterYokohamaJapan
| | | | - Hideyuki Terao
- Department of UrologyKanagawa Cancer CenterYokohamaJapan
| | - Yuko Murohashi
- Department of Diabetes EndocrinologyKanagawa Cancer CenterYokohamaJapan
| | - Yoichiro Okubo
- Department of PathologyKanagawa Cancer CenterYokohamaJapan
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3
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Schöler F, Storz MA, Khavaran A, Hümmler N, Russe MF, Wielenberg C, Laubner K, Seufert J. Effective management of recurrent Doege-Potter syndrome with somatostatin-analogues: A case report. Cancer Rep (Hoboken) 2024; 7:e1992. [PMID: 38441351 PMCID: PMC10913086 DOI: 10.1002/cnr2.1992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 12/10/2023] [Accepted: 01/15/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Doege-Potter syndrome is defined as paraneoplastic hypoinsulinemic hypoglycemia associated with a benign or malignant solitary fibrous tumor frequently located in pleural, but also extrapleural sites. Hypoglycemia can be attributed to paraneoplastic secretion of "Big-IGF-II," a precursor of Insulin-like growth factor-II. This prohormone aberrantly binds to and activates insulin receptors, with consecutive initiation of common insulin actions such as inhibition of gluconeogenesis, activation of glycolysis and stimulation of cellular glucose uptake culminating in recurrent tumor-induced hypoglycemic episodes. Complete tumor resection or debulking surgery is considered the most promising treatment for DPS. CASE Here, we report a rare case of a recurrent Doege-Poter Syndrome with atypical gelatinous tumor lesions of the lung, pleura and pericardial fat tissue in an 87-year-old woman. Although previously described as ineffective, we propose that adjuvant treatment with Octreotide in conjunction with intravenous glucose helped to maintain tolerable blood glucose levels before tumor resection. The somatostatin-analogue Lanreotide was successfully used after tumor debulking surgery (R2-resection) to maintain adequate blood glucose control. CONCLUSION We conclude that somatostatin-analogues bear the potential of being effective in conjunction with limited surgical approaches for the treatment of hypoglycemia in recurrent or non-totally resectable SFT entities underlying DPS.
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Affiliation(s)
- Felix Schöler
- Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Maximilian Andreas Storz
- Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
- Department of Internal Medicine II, Center for Complementary Medicine, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Ashkan Khavaran
- Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Nicolas Hümmler
- Department of Thoracic Surgery, Medical CenterUniversity Hospital of FreiburgFreiburgGermany
| | - Maximilian Frederik Russe
- Department of Radiology, Clinic for Diagnostic and Interventional Radiology, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | | | - Katharina Laubner
- Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Faculty of MedicineUniversity of FreiburgFreiburgGermany
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4
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Scalia P, Marino IR, Asero S, Pandini G, Grimberg A, El-Deiry WS, Williams SJ. Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy. Biomedicines 2023; 12:40. [PMID: 38255147 PMCID: PMC10813354 DOI: 10.3390/biomedicines12010040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 12/18/2023] [Accepted: 12/20/2023] [Indexed: 01/24/2024] Open
Abstract
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.
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Affiliation(s)
- Pierluigi Scalia
- The ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA 19102, USA; 93100 Caltanissetta, Italy
| | - Ignazio R. Marino
- Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Salvatore Asero
- The ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA 19102, USA; 93100 Caltanissetta, Italy
- ARNAS Garibaldi, UOC Chirurgia Oncologica, Nesima, 95122 Catania, Italy
| | - Giuseppe Pandini
- The ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA 19102, USA; 93100 Caltanissetta, Italy
| | - Adda Grimberg
- Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Wafik S. El-Deiry
- Legorreta Cancer Center, Brown University, Providence, RI 02903, USA
| | - Stephen J. Williams
- The ISOPROG-Somatolink EPFP Research Network, Philadelphia, PA 19102, USA; 93100 Caltanissetta, Italy
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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5
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Potalitsyn P, Mrázková L, Selicharová I, Tencerová M, Ferenčáková M, Chrudinová M, Turnovská T, Brzozowski AM, Marek A, Kaminský J, Jiráček J, Žáková L. Non-glycosylated IGF2 prohormones are more mitogenic than native IGF2. Commun Biol 2023; 6:863. [PMID: 37598269 PMCID: PMC10439913 DOI: 10.1038/s42003-023-05239-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 08/10/2023] [Indexed: 08/21/2023] Open
Abstract
Insulin-like Growth Factor-2 (IGF2) is important for the regulation of human embryonic growth and development, and for adults' physiology. Incorrect processing of the IGF2 precursor, pro-IGF2(156), leads to the formation of two IGF2 proforms, big-IGF2(87) and big-IGF2(104). Unprocessed and mainly non-glycosylated IGF2 proforms are found at abnormally high levels in certain diseases, but their mode of action is still unclear. Here, we found that pro-IGF2(156) has the lowest ability to form its inactivating complexes with IGF-Binding Proteins and has higher proliferative properties in cells than IGF2 and other IGF prohormones. We also showed that big-IGF2(104) has a seven-fold higher binding affinity for the IGF2 receptor than IGF2, and that pro-IGF2(87) binds and activates specific receptors and stimulates cell growth similarly to the mature IGF2. The properties of these pro-IGF2 forms, especially of pro-IGF2(156) and big-IGF2(104), indicate them as hormones that may be associated with human diseases related to the accumulation of IGF-2 proforms in the circulation.
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Affiliation(s)
- Pavlo Potalitsyn
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
- Department of Biochemistry, Faculty of Science, Charles University, 12800, Prague 2, Czech Republic
| | - Lucie Mrázková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, 12800, Prague 2, Czech Republic
| | - Irena Selicharová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Michaela Tencerová
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague 4, Czech Republic
| | - Michaela Ferenčáková
- Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague 4, Czech Republic
| | - Martina Chrudinová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Tereza Turnovská
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Andrzej Marek Brzozowski
- York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
| | - Aleš Marek
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Jakub Kaminský
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Jiří Jiráček
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic.
| | - Lenka Žáková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic.
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6
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Warda F, Richter A, Wehmeier K, Shahla L. Severe recurrent hypoglycaemia in a patient with aggressive melanoma. BMJ Case Rep 2021; 14:14/8/e243468. [PMID: 34353831 PMCID: PMC8344265 DOI: 10.1136/bcr-2021-243468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
We present a case of hypoglycemia in a young patient without diabetes mellitus who presented initially with enlarging neck mass and weight loss, and was found to have aggressive melanoma with metastasis to multiple organs and diffuse lymphadenopathy. He had presented to the emergency room two times with neuroglycopenic symptoms that required admission and intravenous dextrose continuously. Evaluation of hypoglycemia included C-peptide, insulin levels, insulin-like growth factor (IGF) -I and -II, and ß- hydroxybutyrate. Insulin levels were suppressed appropriately during hypoglycemia, however, IGF-II:IGF-I ratio was high, suggesting non-islet tumour induced hypoglycemia. The presence of IGF-II produced by large tumors results in a low hepatic glucose output and increased uptake by skeletal muscle, resulting in hypoglycemia especially in a patient with extremely low appetite such as our patient. Treating the culprit malignancy leads to resolution of hypoglycemia, but corticosteroids have been used to suppress IGF-II levels and alleviate symptoms.
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Affiliation(s)
- Firas Warda
- Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, Florida, USA
| | - Angela Richter
- Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, Florida, USA
| | - Kent Wehmeier
- Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, Florida, USA
| | - Leena Shahla
- Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, Florida, USA
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7
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Doege-Potter Syndrome: A Presumptive Case of Metastatic Hemangiopericytoma with Persistent Hypoglycemia in a 27-Year-Old Male. J ASEAN Fed Endocr Soc 2021; 36:90-94. [PMID: 34177094 PMCID: PMC8214353 DOI: 10.15605/jafes.036.01.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 02/28/2021] [Indexed: 11/17/2022] Open
Abstract
Doege-Potter syndrome (DPS) is a rare paraneoplastic condition characterized by hypoinsulinemic hypoglycemia from a solitary fibrous tumor. The underlying mechanism is the secretion of a prohormone form of insulin-like growth factor II (IGF-II) by the tumor, which causes decreased release of glucose into the circulation. We report the case of a 27-year-old Filipino male with presumptive DPS from a recurrent right temporo-zygomatic hemangiopericytoma (HPC). The complexity of DPS requires a multidisciplinary approach. Early screening for metastases from HPC may prevent the undesirable sequelae of the disease process.
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8
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Zolov SN, Imai H, Losiewicz MK, Singh RSJ, Fort PE, Gardner TW. Insulin-like growth factor-2 regulates basal retinal insulin receptor activity. J Biol Chem 2021; 296:100712. [PMID: 33915127 PMCID: PMC8138762 DOI: 10.1016/j.jbc.2021.100712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 04/15/2021] [Accepted: 04/23/2021] [Indexed: 11/14/2022] Open
Abstract
The retinal insulin receptor (IR) exhibits basal kinase activity equivalent to that of the liver of fed animals, but unlike the liver, does not fluctuate with feeding and fasting; it also declines rapidly after the onset of insulin-deficient diabetes. The ligand(s) that determine basal IR activity in the retina has not been identified. Using a highly sensitive insulin assay, we found that retinal insulin concentrations remain constant in fed versus fasted rats and in diabetic versus control rats; vitreous fluid insulin levels were undetectable. Neutralizing antibodies against insulin-like growth factor 2 (IGF-2), but not insulin-like growth factor 1 (IGF-1) or insulin, decreased IR kinase activity in normal rat retinas, and depletion of IGF-2 from serum specifically reduced IR phosphorylation in retinal cells. Immunoprecipitation studies demonstrated that IGF-2 induced greater phosphorylation of the retinal IR than the IGF-1 receptor. Retinal IGF-2 mRNA content was 10-fold higher in adults than pups and orders of magnitude higher than in liver. Diabetes reduced retinal IGF-2, but not IGF-1 or IR, mRNA levels, and reduced IGF-2 and IGF-1 content in vitreous fluid. Finally, intravitreal administration of IGF-2 (mature and pro-forms) increased retinal IR and Akt kinase activity in diabetic rats. Collectively, these data reveal that IGF-2 is the primary ligand that defines basal retinal IR activity and suggest that reduced ocular IGF-2 may contribute to reduced IR activity in response to diabetes. These findings may have importance for understanding the regulation of metabolic and prosurvival signaling in the retina.
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Affiliation(s)
- Sergey N Zolov
- Department of Ophthalmology & Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA; The Division of Pulmonary & Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
| | - Hisanori Imai
- Department of Ophthalmology, Kobe University Medical School, Kobe, Japan
| | - Mandy K Losiewicz
- Department of Ophthalmology & Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | | | - Patrice E Fort
- Department of Ophthalmology & Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Thomas W Gardner
- Department of Ophthalmology & Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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9
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Yu B, Douli R, Suarez JA, Gutierrez VP, Aldiabat M, Khan M. Non-islet cell tumor hypoglycemia as an initial presentation of hepatocellular carcinoma coupled with end-stage liver cirrhosis: A case report and review of literature. World J Hepatol 2020; 12:519-524. [PMID: 32952878 PMCID: PMC7475778 DOI: 10.4254/wjh.v12.i8.519] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/08/2020] [Accepted: 07/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-islet cell tumor hypoglycemia (NICTH) is a rare cause of persistent hypoglycemia seen in patients with hepatocellular carcinoma (HCC). It is likely to be underdiagnosed especially in the patients with poor hepatic function and malnutrition. Herein, we report a rare case of NICTH as the initial presentation of HCC in a patient with chronic hypoglycemia due to end-stage liver cirrhosis.
CASE SUMMARY A 62-year-old male with chronic fasting hypoglycemia secondary to end-stage hepatitis C-related cirrhosis, presented with altered mental status and dizziness. He was found to have severe hypoglycemia refractory to glucose supplements. Imaging studies and biopsy discovered well differentiated HCC without metastasis. Further evaluation showed low insulin, C-peptide and beta-hydroxybutyrate along with a high insulin-like growth factor-2/insulin-like growth factor ratio, consistent with the diagnosis of NICTH. As patient was not a candidate for surgical resection or chemotherapy, he was started on prednisolone with some improvements in the glucose homeostasis, but soon decompensated after a superimposed hospital acquired pneumonia.
CONCLUSION NICTH can occur as the sole initial presentation of HCC and is often difficult to correct without tumor removal. Clinicians should maintain high clinical suspicion for early recognition of paraneoplastic NICTH in patients at risk for HCC, even those with chronic fasting hypoglycemia in the setting of severe hepatic failure and malnutrition.
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Affiliation(s)
- Bo Yu
- Department of Medicine, Lincoln Medical Center, Bronx, NY 10451-5504, United States
| | - Rana Douli
- Department of Medicine, Lincoln Medical Center, Bronx, NY 10451-5504, United States
| | - Jose Amaya Suarez
- Department of Medicine, Lincoln Medical Center, Bronx, NY 10451-5504, United States
| | | | - Mohammad Aldiabat
- Department of Medicine, Lincoln Medical Center, Bronx, NY 10451-5504, United States
| | - Maria Khan
- Department of Medicine, Lincoln Medical Center, Bronx, NY 10451-5504, United States
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10
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The IGF-II-Insulin Receptor Isoform-A Autocrine Signal in Cancer: Actionable Perspectives. Cancers (Basel) 2020; 12:cancers12020366. [PMID: 32033443 PMCID: PMC7072655 DOI: 10.3390/cancers12020366] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/31/2020] [Accepted: 02/02/2020] [Indexed: 12/18/2022] Open
Abstract
Insulin receptor overexpression is a common event in human cancer. Its overexpression is associated with a relative increase in the expression of its isoform A (IRA), a shorter variant lacking 11 aa in the extracellular domain, conferring high affinity for the binding of IGF-II along with added intracellular signaling specificity for this ligand. Since IGF-II is secreted by the vast majority of malignant solid cancers, where it establishes autocrine stimuli, the co-expression of IGF-II and IRA in cancer provides specific advantages such as apoptosis escape, growth, and proliferation to those cancers bearing such a co-expression pattern. However, little is known about the exact role of this autocrine ligand–receptor system in sustaining cancer malignant features such as angiogenesis, invasion, and metastasis. The recent finding that the overexpression of angiogenic receptor kinase EphB4 along with VEGF-A is tightly dependent on the IGF-II/IRA autocrine system independently of IGFIR provided new perspectives for all malignant IGF2omas (those aggressive solid cancers secreting IGF-II). The present review provides an updated view of the IGF system in cancer, focusing on the biology of the autocrine IGF-II/IRA ligand–receptor axis and supporting its underscored role as a malignant-switch checkpoint target.
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11
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Guilmette J, Nosé V. Paraneoplastic syndromes and other systemic disorders associated with neuroendocrine neoplasms. Semin Diagn Pathol 2019; 36:229-239. [PMID: 30910348 DOI: 10.1053/j.semdp.2019.03.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Neuroendocrine paraneoplastic syndromes (PNS) consist of metabolic disorders that accompany benign and malignant neoplasms but remain unrelated to mass effects or invasion by the primary tumor or its metastases. The underlying pathogenesis responsible for PNS usual clinical presentation relies on aberrant production of protein hormones, proteins and other substances by the tumor. Prompt recognition of characteristic signs and symptoms combined with serological identification of key substances may result in early diagnosis of PNS and its underlying malignancy. For these reasons, healthcare professionals should familiarize themselves with tumor-induced hypercalcemia, syndrome of inappropriate antidiuretic hormone, carcinoid syndrome, virilisation syndrome, gynecomastia, acromegaly, Cushing syndrome, osteogenic osteomalacia, tumor-induced hypoglycemia, necrolytic migratory erythema, and watery diarrhea, hypokalemia and achlorydria syndrome. Medical awareness for PNS can improve patient outcomes through earlier administration of cancer therapy and treatment, better symptomatic relief and prolong overall survival.
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Affiliation(s)
- Julie Guilmette
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114-2696, United States; Department of Pathology, Charles-Lemoyne Hospital, Greenfield Park, Quebec, Canada
| | - Vânia Nosé
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114-2696, United States.
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12
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Hausken J, Haave EM, Haugaa H, Løberg EM, Kongsgaard UE. A patient with solid gynecologic cancer causing lactic acidosis, severe hypercalcemia, and hypoglycemia. Clin Case Rep 2019; 7:64-70. [PMID: 30656010 PMCID: PMC6332744 DOI: 10.1002/ccr3.1904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/23/2018] [Accepted: 10/20/2018] [Indexed: 12/02/2022] Open
Abstract
Though rare in cervical cancer patients, paraneoplastic syndrome usually presents with several endocrine and hormonal symptoms. Knowledge of the pathophysiology that underlies these abnormalities is beneficial to diagnosis and treatment. An interdisciplinary approach and test analysis prior to initiating specific treatment is recommended, though prognosis appears poor in advanced cases.
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Affiliation(s)
- John Hausken
- Department of Anesthesiology, Division of Emergencies and Critical CareOslo University HospitalOsloNorway
| | - Ellen M. Haave
- Department of endocrinologyOslo University HospitalOsloNorway
| | - Håkon Haugaa
- Department of Anesthesiology, Division of Emergencies and Critical CareOslo University HospitalOsloNorway
- Lovisenberg Diaconal University CollegeOsloNorway
| | - Else M. Løberg
- Department of PathologyOslo University HospitalOsloNorway
- Medical FacultyUniversity of OsloOsloNorway
| | - Ulf E. Kongsgaard
- Department of Anesthesiology, Division of Emergencies and Critical CareOslo University HospitalOsloNorway
- Medical FacultyUniversity of OsloOsloNorway
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13
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Wilson JM, Ginsberg J, Cutts K, Urban S. A Case of Non-Islet Cell Tumor Hypoglycemia (NICTH) Associated with Gastrointestinal Stromal Tumor (GIST). AMERICAN JOURNAL OF CASE REPORTS 2017; 18:984-988. [PMID: 28900071 PMCID: PMC5608149 DOI: 10.12659/ajcr.904753] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Patient: Male, 60 Final Diagnosis: Non-islet cell tumor hypoglycemia (NICTH) associated with gastrointestinal stromal tumor (GIST) Symptoms: Hypoglycemia Medication: — Clinical Procedure:— Specialty: Gastroenterology and Hepatology
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Affiliation(s)
- John M Wilson
- Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX, USA
| | - Jessica Ginsberg
- Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX, USA
| | - Karen Cutts
- Department of Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX, USA
| | - Steve Urban
- Department of Internal Medicine, Texas Tech University Health Sciences Center School of Medicine, Amarillo, TX, USA
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Pant V, Baral S, Sayami G, Sayami P. Doege-Potter Syndrome, cause of nonislet cell tumor hypoglycemia: the first case report from Nepal. Int Med Case Rep J 2017; 10:275-278. [PMID: 28860867 PMCID: PMC5566411 DOI: 10.2147/imcrj.s142260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Doege–Potter syndrome (DPS), a paraneoplastic syndrome, presents as a hypoinsulinemic hypoglycemia from the ectopic secretion of insulin-like growth factor II from a solitary fibrous tumor which may be intrapleural or extrapleural in origin. We report a case of severe hypoglycemia in a 70-year old female initially admitted for resection of left sided solitary fibrous tumor of pleura. Investigation revealed true hypoglycemia, and DPS was diagnosed. The tumor was completely resected, after which no further hypoglycemic episodes were seen in 2 years follow-up. This is the first case of solitary fibrous tumor of pleura with DPS reported from Nepal.
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Affiliation(s)
| | | | | | - Prakash Sayami
- Manmohan Cardiothoracic vascular and transplant Center, Institute of Medicine (IOM), Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal
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Kittah NE, Vella A. MANAGEMENT OF ENDOCRINE DISEASE: Pathogenesis and management of hypoglycemia. Eur J Endocrinol 2017; 177:R37-R47. [PMID: 28381450 DOI: 10.1530/eje-16-1062] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 03/15/2017] [Accepted: 04/05/2017] [Indexed: 01/03/2023]
Abstract
Glucose is the main substrate utilized by the brain and as such multiple regulatory mechanisms exist to maintain glucose concentrations. When these mechanisms fail or are defective, hypoglycemia ensues. Due to these robust mechanisms, hypoglycemia is uncommon and usually occurs in the setting of the treatment of diabetes using glucose-lowering agents such as sulfonylureas or insulin. The symptoms of hypoglycemia are non-specific and as such it is important to confirm hypoglycemia by establishing the presence of Whipple's triad before embarking on an evaluation for hypoglycemia. When possible, evaluation of hypoglycemia should be carried out at the time of spontaneous occurrence of symptoms. If this is not possible then one would want to create the circumstances under which symptoms occur. In cases where symptoms occur in the post absorptive state, a 72-h fast should be performed. Likewise, if symptoms occur after a meal then a mixed meal study may be the test of choice. The causes of endogenous hyperinsulinemic hypoglycemia include insulinoma, post-bariatric hypoglycemia and noninsulinoma pancreatogenous hypoglycemia syndrome. Autoimmune hypoglycemia syndrome is clinically and biochemically similar to insulinoma but associated with high levels of insulin antibodies and plasma insulin. Other important causes of hypoglycemia include medications, non-islet cell tumors, hormonal deficiencies, critical illness and factitious hypoglycemia. We provide an overview of the pathogenesis and management of hypoglycemia in these situations.
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Affiliation(s)
- Nana Esi Kittah
- Division of EndocrinologyDiabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
| | - Adrian Vella
- Division of EndocrinologyDiabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
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16
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Fang C, Fan CW, Yu YY, Wang C, Yang L, Li Y, Mo XM, Zhou ZG. Severe Hypoglycemia Caused by Recurrent Sarcomatoid Carcinoma in the Pelvic Cavity: A Case Report. Medicine (Baltimore) 2015; 94:e1577. [PMID: 26496258 PMCID: PMC4620829 DOI: 10.1097/md.0000000000001577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Nonislet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia in different tumor types of mesochymal or epithelial origin; however, NICTH is infrequently induced by sarcomatoid carcinoma (SC). Despite some sarcomatoid and epithelioid characteristics in few cases of malignancies from epithelium, NICTH induced by recurrent SC in pelvic cavity in this report is extremely rare.We report a case in which NICTH caused by recurrence and pulmonary metastases from SC in the pelvic cavity, and the computed tomography scan revealed multiple pelvic masses and multiple large masses in the pulmonary fields. During the treatment of intestinal obstruction, the patient presented paroxysmal loss of consciousness and sweating. Her glucose even reached 1.22 mmol/L while the serum glycosylated hemoglobin was normal and previous history of diabetes or use of oral hypoglycemic agents and insulin denied.The laboratory examination showed that the low level of insulin, C-peptide, and growth hormone levels in the course of hypoglycemic episodes suggesting to the diagnosis of hypoglycemia induced by nonislet cell tumor, and the decreased levels of insulin-like growth factor (IGF)-I and IGFBP3 and the high expression of big IGF-II in the serum further confirmed the diagnosis of NICTH. Because of the widely pelvic recurrence and pulmonary metastases were unresected, the patient was discharged from the hospital after 2 weeks treatment with dexamethasone and glucose and unfortunately died 1 week later.NICTH caused by SC in the pelvic cavity is extremely rare case in clinical. The aim of this report was to present the importance to examine big IGF-II expression in patient's serum in order to reach the diagnosis of NICTH in cases of intractable cancer-associated hypoglycemia.
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Affiliation(s)
- Chao Fang
- From the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, P.R. China (CF, CWF, YYY, CW, LY, ZGZ) and Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China (CF, CWF, YL, ZGZ); and Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China (XMM)
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Vagionas A, Tigas S, Oikonomou P, Pentheroudakis G, Malamou-Mitsi V, Pavlidis N. Relapsing Episodes of Loss of Consciousness in a Patient With Hepatocellular Carcinoma. World J Oncol 2014; 5:214-219. [PMID: 29147406 PMCID: PMC5649770 DOI: 10.14740/wjon790w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/20/2014] [Indexed: 02/06/2023] Open
Abstract
Hypoglycemia is common in people with diabetes treated with insulin or oral medications such as sulphonylureas or other secretagogues, and constitutes a relatively rare paraneoplastic syndrome in patients with a variety of mesenchymal or epithelial tumors. In this case report we present a 51-year-old patient with metastatic hepatocellular carcinoma and persistent, severe, symptomatic hypoglycemia and we discuss management options and review the relevant medical literature.
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Affiliation(s)
| | - Stelios Tigas
- Department of Endocrinology, University Hospital of Ioannina, Greece
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18
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Meng W, Zhu HH, Li H, Wang G, Wei D, Feng X. Solitary fibrous tumors of the pleura with Doege-Potter syndrome: a case report and three-decade review of the literature. BMC Res Notes 2014; 7:515. [PMID: 25113505 PMCID: PMC4267432 DOI: 10.1186/1756-0500-7-515] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Accepted: 07/18/2014] [Indexed: 02/08/2023] Open
Abstract
Background No case of solitary fibrous tumor of the pleura with Doege-Potter syndrome has
been reported in China. This study was to report a rare repeatedly recurrent case
of solitary fibrous tumor of the pleura with Doege-Potter syndrome diagnosed in
China and a three-decade literature review of solitary fibrous tumor of the pleura
with Doege-Potter syndrome worldwide. Case presentation A rare case of solitary fibrous tumor of the pleura with Doege-Potter syndrome
was diagnosed in 2005 with follow-up to 2011. All medical records were collected
and literature of solitary fibrous tumor of the pleura with Doege-Potter syndrome
from 1979 to 2011 was obtained through Medline. This typical case, diagnosed and
confirmed by histopathologic results, was a 72-year-old Chinese woman who had a
complaint of night sweat for a month. A localized mass 12 cm × 11 cm × 8 cm in
size was found associated with pleural effusion in her left low chest cavity, and
blood tests showed severe hypoglycemia. Removal of the mass solved the
hypoglycemia. The case was repeatedly recurrent in April, 2010 and March, 2011 and
had no signs of recurrence up to the end of 2011 after surgery. A review of 45
cases of solitary fibrous tumor of the pleura with Doege-Potter syndrome compared
and summarized clinical characteristics, treatments, and outcomes by benign and
malignant tumor nature. Conclusions Incidence of solitary fibrous tumor of the pleura with Doege-Potter syndrome
is similar between genders. There are no significant differences in clinical
characteristics between benign and malignant cases. Surgery is the first effective
treatment for solitary fibrous tumor of the pleura with Doege-Potter syndrome and
the completeness of the initial resection is the key to preventing recurrence.
Routine follow-up examinations are recommended for early detection of
recurrence.
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Affiliation(s)
| | - Hong-Hong Zhu
- Department of Public Health, College of Health and Human Service, Western Kentucky University, Bowling Green, KY 42101, USA.
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Iglesias P, Díez JJ. Management of endocrine disease: a clinical update on tumor-induced hypoglycemia. Eur J Endocrinol 2014; 170:R147-57. [PMID: 24459236 DOI: 10.1530/eje-13-1012] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Tumor-induced hypoglycemia (TIH) is a rare clinical entity that may occur in patients with diverse kinds of tumor lineages and that may be caused by different mechanisms. These pathogenic mechanisms include the eutopic insulin secretion by a pancreatic islet β-cell tumor, and also the ectopic tumor insulin secretion by non-islet-cell tumor, such as bronchial carcinoids and gastrointestinal stromal tumors. Insulinoma is, by far, the most common tumor associated with clinical and biochemical hypoglycemia. Insulinomas are usually single, small, sporadic, and intrapancreatic benign tumors. Only 5-10% of insulinomas are malignant. Insulinoma may be associated with the multiple endocrine neoplasia type 1 in 4-6% of patients. Medical therapy with diazoxide or somatostatin analogs has been used to control hypoglycemic symptoms in patients with insulinoma, but only surgical excision by enucleation or partial pancreatectomy is curative. Other mechanisms that may, more uncommonly, account for tumor-associated hypoglycemia without excess insulin secretion are the tumor secretion of peptides capable of causing glucose consumption by different mechanisms. These are the cases of tumors producing IGF2 precursors, IGF1, somatostatin, and glucagon-like peptide 1. Tumor autoimmune hypoglycemia occurs due to the production of insulin by tumor cells or insulin receptor autoantibodies. Lastly, massive tumor burden with glucose consumption, massive tumor liver infiltration, and pituitary or adrenal glands destruction by tumor are other mechanisms for TIH in cases of large and aggressive neoplasias.
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Affiliation(s)
- Pedro Iglesias
- Department of Endocrinology, Hospital Ramón y Cajal, Ctra. de Colmenar, Km 9.100, 28034 Madrid, Spain
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Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab 2014; 99:713-22. [PMID: 24423303 PMCID: PMC5393479 DOI: 10.1210/jc.2013-3382] [Citation(s) in RCA: 139] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
CONTEXT 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. EVIDENCE ACQUISITION 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). EVIDENCE SYNTHESIS 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. CONCLUSIONS 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.
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Affiliation(s)
- Timothy W Bodnar
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105
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21
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Richters L, Ortmann M, Faust M, Krämer S, Mallmann P, Harbeck N, Rhiem K. The oncological emergency case: paraneoplastic hypoglycemia in metastatic breast cancer - case report and brief review of the literature. ACTA ACUST UNITED AC 2014; 8:368-70. [PMID: 24415991 DOI: 10.1159/000355702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Paraneoplastic hypoglycemia is a rare syndrome amoung tumorous diseases. It is often associated with a paraneoplastic secretion of 'big' insulin-like growth factor-II. METHODS We describe this syndrome in a 60-year-old patient with advanced breast cancer 8 years after primary diagnosis. RESULTS AND CONCLUSION This non-islet cell tumor-induced hypoglycemia may be the only evidence for an otherwise clinically occult disease progression. Fast diagnosis and appropriate acute and causal treatment concepts should be part of oncological management.
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Affiliation(s)
- Lisa Richters
- Breast Center, Department of Obstetrics and Gynecology, University Hospital of Cologne, Germany
| | | | - Michael Faust
- Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, Germany
| | - Stefan Krämer
- Breast Center, Department of Obstetrics and Gynecology, University Hospital of Cologne, Germany
| | - Peter Mallmann
- Breast Center, Department of Obstetrics and Gynecology, University Hospital of Cologne, Germany
| | - Nadia Harbeck
- Breast Center, Department of Obstetrics and Gynecology, University Hospital of Cologne, Germany ; Breast Center, Department of Obstetrics and Gynecology, University Hospital of Munich, Germany
| | - Kerstin Rhiem
- Breast Center, Department of Obstetrics and Gynecology, University Hospital of Cologne, Germany
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22
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Dutta P, Aggarwal A, Gogate Y, Nahar U, Shah VN, Singla M, Khandelwal N, Bhansali A. Non-islet cell tumor-induced hypoglycemia: a report of five cases and brief review of the literature. Endocrinol Diabetes Metab Case Rep 2013; 2013:130046. [PMID: 24616774 PMCID: PMC3922193 DOI: 10.1530/edm-13-0046] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 10/22/2013] [Indexed: 12/26/2022] Open
Abstract
We 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.
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Affiliation(s)
- Pinaki Dutta
- Department of Endocrinology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - Anuradha Aggarwal
- Department of Endocrinology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - Yashpal Gogate
- Department of Endocrinology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - Uma Nahar
- Department of Histopathology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - Viral N Shah
- Department of Endocrinology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - Mandeep Singla
- Department of Endocrinology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - N Khandelwal
- Department of Radiodiagnosis Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
| | - Anil Bhansali
- Department of Endocrinology Post Graduate Institute of Medical Education and Research Chandigarh, 160012 India
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Ida T, Morohashi T, Ohara H, Goto T, Inamori M, Nakajima A, Maeda S, Tsukumo Y, Sakamoto A, Ishikawa Y. Gastric neuroendocrine carcinoma with non-islet cell tumor hypoglycemia associated with enhanced production of insulin-like growth factor II. Intern Med 2013; 52:757-60. [PMID: 23545670 DOI: 10.2169/internalmedicine.52.9372] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
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.
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Affiliation(s)
- Tomonori Ida
- Department of Gastroenterology, Omori Red Cross Hospital, Japan
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24
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Chan JKI, Cheuk W, Ho LC, Wen JM. Recurrent meningeal hemangiopericytoma with multiple metastasis and hypoglycemia: a case report. Case Rep Med 2012; 2012:628756. [PMID: 23024657 PMCID: PMC3457717 DOI: 10.1155/2012/628756] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Revised: 08/10/2012] [Accepted: 08/24/2012] [Indexed: 12/02/2022] Open
Abstract
Aims. We report on the unusual case of a 43-year-old man who developed recurrent meningeal hemangiopericytoma and presented with hypoglycemia 6 years after excision of the tumor. Methods and Results. We utilized computed tomography to assure multiple tumor metastasis and cranial recurrence of previous meningeal hemangiopericytoma and clinical laboratory tests and immunohistochemical staining to characterize this case. Magnetic resonance imaging and computed tomography showed the recurrent tumor at original torcular site was increased in size. Abnormal low levels of growth hormone, insulin, and insulin-like growth factor-I except insulin-like growth factor-II were detected in the serum. By immunohistochemistry, the neoplastic cells characteristically express diffusely CD99, bcl2, and variable CD34. After radio- and chemotherapy, serum glucose level of the patient returned to normal. Conclusions. Comparing other brain tumors, meningeal hemangiopericytoma has a higher recurrent and metastatic rate, but this tumor with hypoglycemia is very rare.
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Affiliation(s)
| | - Wah Cheuk
- Department of Pathology, Queen Elizabeth Hospital, Hong Kong
| | - Luen Cheong Ho
- Department of Pathology, Queen Elizabeth Hospital, Hong Kong
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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). ANNALES D'ENDOCRINOLOGIE 2012; 73:488-91. [PMID: 22867750 DOI: 10.1016/j.ando.2012.04.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Accepted: 04/25/2012] [Indexed: 11/22/2022]
Abstract
OBJECTIVE We 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 PRESENTATION A 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). INTERPRETATION Supplementary 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. CONCLUSION Although 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.
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Hypoglycaemia in a 63-year-old female with a large, recurrent, metastatic gastrointestinal stromal tumour (GIST). J Gastrointest Cancer 2012; 42:263-5. [PMID: 21057892 DOI: 10.1007/s12029-010-9227-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Non-islet cell tumour-induced hypoglycaemia (NICTH) is rare, with few cases reported in patients with gastrointestinal stromal tumour (GIST). CASE REPORT 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 DISCUSSION NICTH should be considered in patients with GIST and hypoglycaemia. Surgical debulking is recommended as part of the management of NICTH.
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Zumkeller W. The role of insulin-like growth factor system in soft tissue sarcomas: from physiopathology to targeted therapeutic approaches. Sarcoma 2011; 2:69-76. [PMID: 18521237 PMCID: PMC2395388 DOI: 10.1080/13577149878028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Purpose/Results. Although surgical, chemo- and radiotherapeutic treatment regimens in patients with soft tissue sarcomas have constantly been refined over the past two decades, the survival rate for these patients is rather low. Discussion. There is a great need to investigate the mechanisms for oncogenesis and to identify the factors involved in malignant transformation in sarcomas. Among these factors, IGFs are thought to play a pivotal role as progression factors in various types of sarcomas. The dysregulation of the IGF-II synthesis, e.g. by loss of imprinting which occurs in most
types of sarcomas, is a permissive effect through the suppression of cell death. In addition, cells that overexpress the type I IGF receptors are more susceptible to transformation by oncogenes. As TP53 suppresses the activity of IGF-II P3 and P4, as well as the type I IGF receptor promoter, mutations of TP53 in sarcomas may alternatively lead to the activation of these factors. Finally, the phenomenon of non-islet cell tumour hypoglycaemia that occurs in patients with sarcomas, and which is related to the secretion of IGF-II prohormones, is discussed. Future therapeutic strategies may be based upon the application of antibodies or antisense oligonucleotides directed against the type I IGF receptors, with the common goal of inducing apoptosis in sarcoma cells. Ultimately, these and other therapeutic approaches may lead to a better outcome in patients suffering from sarcoma.
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Affiliation(s)
- W Zumkeller
- Department of Hematology/Oncology Children's University Hospital Heidelberg Germany
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Tsai CY, Lai CH, Chang MH, Jong GP, Cheng YC, Tsai FJ, Tsai CH, Kuo WH, Hsieh DJY, Huang CY. IGF-II and MMP9 as surgical repair indicators of ventricular septal defects. Clin Chim Acta 2011; 412:761-765. [PMID: 21238444 DOI: 10.1016/j.cca.2011.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Revised: 01/04/2011] [Accepted: 01/04/2011] [Indexed: 11/20/2022]
Abstract
OBJECTIVE The insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and human growth hormone (h-GH) have been recognized as therapeutic targets for the heart disease therapy. The bioavailability and actions of insulin-like growth factors-II (IGF-II) and matrix metalloproteinase-9 (MMP9) are important for embryonic development and cardiomyocyte differentiation as well. However, the clinical manifestations following the change in the serum IGF-II and MMP9 in infants with isolated ventricular septal defect (VSD) undergoing surgical repair have not been clearly defined. STUDY DESIGN Serum samples were collected from 72 infants: Twenty normal infants (group I) and 51 consecutive infants with echocardiography established isolated VSD (aged from 3 months to 1 year) were investigated. Among the 51 infants with VSD, 28 with shunt fraction, Qp/Qs < or = 1.5 were free of congestive heart failure symptoms (group II); 23 with shunt fraction, Qp/Qs > or = 2.0 were in congestive heart failure (group IIIa); and 23 of these 23 infants had undergone VSD repair 6 months before their second study (group IIIb). All insulin-like growth factors-II (IGF-II) and human growth hormone (h-GH), insulin like growth factor binding protein-3 (IGFBP-3) and its specific serum protease-MMP9 concentration were analyzed using ELISA and zymography, respectively. RESULTS Serum IGF-II and MMP9 exhibited significant decreasing trends among the three groups and significantly lower concentrations of IGF-II, IGF-II/IGFBP-3 ratio and MMP9, were found only in the severe group whereas h-GH/IGF-II ratio became significantly higher in this group. Moreover, there were no significant differences in these parameters between the infants after surgical correction and the normal ones. CONCLUSIONS The improvement in IGF-II and MMP9 serum concentration was identified in infants with VSD after surgical repair. These findings also indicate a significant relationship between IGF-II, MMP9 and VSD which might be used as diagnosis and prognosis indicators for this defect. Slight reductions in IGF-II/IGFBP3 ratio and slight increase in the h-GH/IGF-II ratio indicate mild VSD. The reductions in the MMP9, IGF-II, and IGF-II/IGFBP3 ratio plus high increase in the h-GH/IGF-II ratio indicate severe VSD.
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Affiliation(s)
- Chen-Yen Tsai
- Department of Pediatrics, China Medical University Beigang Hospital, Yunlin, Taiwan
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Marks AG, Carroll JM, Purnell JQ, Roberts CT. Plasma distribution and signaling activities of IGF-II precursors. Endocrinology 2011; 152:922-30. [PMID: 21285309 PMCID: PMC3040053 DOI: 10.1210/en.2010-0784] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
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.
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Affiliation(s)
- Alicia G Marks
- Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239, USA
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Maruyama H, Tatsumi M, Kitayama H, Enomoto Y, Kuniyasu H, Uematsu K, Fukuda I, Kameya T, Konishi Y. A case of gastric cancer with non-islet cell tumor hypoglycemia detected by insulin-like growth factor II. Pathol Int 2010; 60:595-7. [PMID: 20618739 DOI: 10.1111/j.1440-1827.2010.02563.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Ishikura K, Takamura T, Takeshita Y, Nakagawa A, Imaizumi N, Misu H, Taji K, Kasahara K, Oshinoya Y, Suzuki S, Ooi A, Kaneko S. Cushing's syndrome and big IGF-II associated hypoglycaemia in a patient with adrenocortical carcinoma. BMJ Case Rep 2010; 2010:bcr07.2009.2100. [PMID: 22461853 DOI: 10.1136/bcr.07.2009.2100] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 41-year-old woman had a general health examination and was diagnosed with a non-functioning adrenocortical carcinoma (ACC). Despite surgery and chemotherapy with mitotane, the ACC progressed with metastases to the lymph nodes, liver and lung. Initially, she developed adrenal insufficiency and was treated with hydrocortisone. As the ACC progressed, it produced superabundant cortisol, resulting in clinically overt Cushing's syndrome. As the liver metastases grew, the patient developed hypoglycaemia with suppression of endogenous insulin secretion. She had to be given large quantities of glucose intravenously to remain normoglycaemic. The serum insulin-like growth factor (IGF)-II/IGF-I ratio had increased to 84. We identified big IGF-II, a primary hormonal mediator of non-islet cell tumour hypoglycaemia (NICTH), in the serum and tumour using western blotting. This is the first case of ACC that showed both Cushing's syndrome and NICTH associated with big IGF-II.
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Affiliation(s)
- Kazuhide Ishikura
- Kanazawa University Graduate School of Medical Science, Department of Disease Control and Homeostasis, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
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Losada López I, Nicolau Ramis JA, Gómez Gómez LA, Rodríguez Rodríguez I, Masmiquel Comas L. [Glucagon perfusion in paraneoplastic hypoglycemia]. ENDOCRINOLOGIA Y NUTRICION : ORGANO DE LA SOCIEDAD ESPANOLA DE ENDOCRINOLOGIA Y NUTRICION 2009; 56:143-146. [PMID: 19627729 DOI: 10.1016/s1575-0922(09)70846-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2008] [Accepted: 03/10/2009] [Indexed: 05/28/2023]
Abstract
Hypoglycemia is a common emergency, and is usually due to insulin therapy or oral hypoglycemic treatment in diabetic patients. In some cases, hypoglycemia can be a paraneoplastic sign. We report the case of a 61-year-old woman with a malignant peritoneal mesothelioma, who was admitted to hospital because of diminished consciousness. The final diagnosis was paraneoplastic hypoglycemia with a positive response to glucagon. The patient was finally discharged with glucagon perfusion.
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Affiliation(s)
- Inés Losada López
- Servicio de Medicina Interna, Servicio de Endocrinología. Hospital Son Llàtzer, Palma de Mallorca, Islas Baleares, España.
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Tani Y, Tateno T, Izumiyama H, Doi M, Yoshimoto T, Hirata Y. Defective expression of prohormone convertase 4 and enhanced expression of insulin-like growth factor II by pleural solitary fibrous tumor causing hypoglycemia. Endocr J 2008; 55:905-11. [PMID: 18552458 DOI: 10.1507/endocrj.k08e-062] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
A 75-year-old man was admitted to our hospital because of unconsciousness. His plasma glucose was very low, but his serum levels of insulin and IGF-I were also low. He was found to have a giant solitary pleural tumor, which was completely resected, after which his hypoglycemia ameliorated postoperatively. Histologically, the tumor was consistent with the pathological diagnosis of a solitary fibrous tumor derived from the pleura. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells. The presence of high molecular weight (HMW) form of IGF-II in the tumor tissue and patient's serum was confirmed by Western blot analysis. Steady-state mRNA levels of IGF-II and prohormone convertases (PC) 4, a potential protease responsible for IGF-II processing, as determined by RT-PCR were about 14-fold greater and 5-fold less in the tumor tissue than those in normal placental tissue, respectively. Therefore, it is suggested that biologically active, unprocessed HMW form of IGF-II generated from the impaired processing of IGF-II precursor by the defective PC4 expression in the tumor was responsible for the non-islet cell tumor hypoglycemia (NICTH) in the present case.
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Affiliation(s)
- Yuji Tani
- Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Japan
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Jacobs C. A Review of the Role of Insulin-like Growth Factor 2 in Malignancy and its Potential as a Modifier of Radiation Sensitivity. Clin Oncol (R Coll Radiol) 2008; 20:345-52. [DOI: 10.1016/j.clon.2008.02.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2007] [Revised: 01/31/2008] [Accepted: 02/04/2008] [Indexed: 11/28/2022]
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Li Y, Chang Q, Rubin BP, Fletcher C, Morgan TW, Mentzer SJ, Sugarbaker DJ, Fletcher JA, Xiao S. Insulin receptor activation in solitary fibrous tumours. J Pathol 2007; 211:550-554. [PMID: 17299733 DOI: 10.1002/path.2136] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Solitary fibrous tumours (SFTs) are known to overexpress insulin-like growth factor 2 (IGF-2). The down-stream oncogenic pathways of IGF-2, however, are not clear. Here we report uniform activation of the insulin receptor (IR) pathway in SFTs, which are mesenchymal tumours frequently associated with hypoglycaemia. Whereas the IR and its downstream signalling pathways were constitutively activated in SFTs, insulin-like growth factor 1 receptor (IGF-1R) was not expressed in these tumours. We also find that SFT cells secrete IGF-2 and proliferate in serum-free medium, consistent with an IGF-2/IR autocrine loop. The aetiological relevance of IGF-2 is supported by expression of IR-A, the IR isoform with high affinity for IGF-2, in all SFTs. Our studies suggest that IR activation plays an oncogenic role in SFTs.
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Affiliation(s)
- Y Li
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Q Chang
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - B P Rubin
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - Cdm Fletcher
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - T W Morgan
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - S J Mentzer
- Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - D J Sugarbaker
- Department of Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - J A Fletcher
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
| | - S Xiao
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
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Escobar GA, Robinson WA, Nydam TL, Heiple DC, Weiss GJ, Buckley L, Gonzalez R, McCarter MD. Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: a case report. BMC Cancer 2007; 7:13. [PMID: 17229322 PMCID: PMC1781460 DOI: 10.1186/1471-2407-7-13] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2006] [Accepted: 01/17/2007] [Indexed: 11/10/2022] Open
Abstract
Background Non-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it. Case presentation A thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm × 25 cm × 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, "big" insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT. Conclusion Optimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11–20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established.
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Affiliation(s)
- Guillermo A Escobar
- Department of Surgery, Division of GI, Tumor and Endocrine Surgery, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - William A Robinson
- Department of Medicine, Divisions of Medical Oncology and Endocrinology, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - Trevor L Nydam
- Department of Surgery, Division of GI, Tumor and Endocrine Surgery, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - Drew C Heiple
- Department of Medicine, Divisions of Medical Oncology and Endocrinology, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - Glen J Weiss
- Department of Medicine, Divisions of Medical Oncology and Endocrinology, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - Linda Buckley
- Department of Medicine, Divisions of Medical Oncology and Endocrinology, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - Rene Gonzalez
- Department of Medicine, Divisions of Medical Oncology and Endocrinology, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
| | - Martin D McCarter
- Department of Surgery, Division of GI, Tumor and Endocrine Surgery, University of Colorado Health Sciences Center. 4200 E. 9Ave, Denver, CO, 80262, USA
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Davda R, Seddon BM. Mechanisms and management of non-islet cell tumour hypoglycaemia in gastrointestinal stromal tumour: case report and a review of published studies. Clin Oncol (R Coll Radiol) 2007; 19:265-8. [PMID: 17433971 DOI: 10.1016/j.clon.2006.12.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2006] [Accepted: 12/11/2006] [Indexed: 10/23/2022]
Abstract
Tumour-related hypoglycaemia is a rare paraneoplastic phenomenon most frequently occurring with insulinomas, but also associated with non-islet cell tumours. It has been observed in a range of tumour types, but recently a small number of cases have been described in association with gastrointestinal stromal tumours. We describe a further case of a patient with gastrointestinal stromal tumour that was complicated by non-islet cell tumour hypoglycaemia, and discuss the mechanisms and management of non-islet cell tumour hypoglycaemia in the context of gastrointestinal stromal tumour.
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Affiliation(s)
- R Davda
- London Bone and Soft Tissue Tumour Service, Department of Oncology, University College Hospital, London, UK
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Abstract
Under physiologic conditions, glucose plays a critical role in providing energy to the central nervous system. A precipitous drop in the availability of this substrate results in dramatic symptoms that signal a medical emergency and warrant immediate therapy aimed at restoring plasma glucose to normal levels. A systemic approach to the differential diagnosis is useful in identifying the cause of hypoglycemia. Once established, a specific and/or definitive intervention that addresses that underlying problem can be implemented. In most cases, this systemic approach to diagnosis and therapy is rewarded with a good outcome for the patient.
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Affiliation(s)
- Jean-Marc Guettier
- National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892, USA.
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39
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Hirai A, Nakanishi R. Solitary fibrous tumor of the pleura with hypoglycemia associated with serum insulin-like growth factor II. J Thorac Cardiovasc Surg 2006; 132:713-4. [PMID: 16935145 DOI: 10.1016/j.jtcvs.2006.05.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2006] [Accepted: 05/12/2006] [Indexed: 11/18/2022]
Affiliation(s)
- Ayako Hirai
- Department of Thoracic Surgery, Shin-Kokura Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Kitakyusyu, Japan
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40
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Fukuda I, Hizuka N, Ishikawa Y, Yasumoto K, Murakami Y, Sata A, Morita J, Kurimoto M, Okubo Y, Takano K. Clinical features of insulin-like growth factor-II producing non-islet-cell tumor hypoglycemia. Growth Horm IGF Res 2006; 16:211-216. [PMID: 16860583 DOI: 10.1016/j.ghir.2006.05.003] [Citation(s) in RCA: 128] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Revised: 05/22/2006] [Accepted: 05/30/2006] [Indexed: 12/29/2022]
Abstract
In some patients with non-islet-cell tumor hypoglycemia (NICTH), a high molecular weight form of IGF-II (big IGF-II) derived from tumors is present in the circulation and might be associated with recurrent hypoglycemia. In this study, in order to survey the clinical characteristics of patients with IGF-II producing NICTH, we analyzed the medical records of 78 patients with NICTH (M/F 44/34, age 62+/-1.8, range; 9-86 years.) whose serum contained a large amount of big IGF-II. Hepatocellular carcinoma and gastric carcinoma were the most common causes of NICTH. The diameters of the tumors were more than 10 cm in 70% of the patients. Basal immunoreactive insulin (IRI) levels were less than 3 microU/dl in 79% of the patients. Hypoglycemic attack was the onset of disease in 31 of 65 cases (48%), but the tumor was revealed prior to the occurrence of hypoglycemia in 34 cases (52%). Twenty-five of 47 (53%) patients had decreased serum potassium levels. These data suggested that hypoinsulinemic hypoglycemia associated with the presence of a large tumor supports the diagnosis of IGF-II producing NICTH. Hypokalemia was associated with hypoglycemia in some patients. The BMI (21.4+/-0.6 kg/m2) and serum total protein levels (6.6+/-0.1g/dl) were preserved at the occurrence of first hypoglycemic attack suggesting that malnutrition might not be the main cause of hypoglycemia in most patients.
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Affiliation(s)
- Izumi Fukuda
- Department of Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical University, Tokyo, Japan
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Rikhof B, Van Den Berg G, Van Der Graaf WTA. Non-islet cell tumour hypoglycaemia in a patient with a gastrointestinal stromal tumour. Acta Oncol 2006; 44:764-6. [PMID: 16227170 DOI: 10.1080/02841860500267816] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Bart Rikhof
- Department of Internal Medicine, Division of Medical Oncology, University Medical Center Groningen, University of Groningen, The Netherlands.
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42
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Metabolic Emergencies in Oncology. Oncology 2006. [DOI: 10.1007/0-387-31056-8_72] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Qiu Q, Basak A, Mbikay M, Tsang BK, Gruslin A. Role of pro-IGF-II processing by proprotein convertase 4 in human placental development. Proc Natl Acad Sci U S A 2005; 102:11047-52. [PMID: 16040806 PMCID: PMC1182422 DOI: 10.1073/pnas.0502357102] [Citation(s) in RCA: 81] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Fetal growth restriction (intrauterine growth restriction, IUGR) is a leading cause of perinatal mortality. However, the causes of aberrant development of the placenta and, thus, of the fetus, are not currently known. Insulin-like growth factor II (IGF-II) has been shown to be an important regulator of fetoplacental growth. This growth factor must undergo posttranslational processing, and, thus, we hypothesized that aberrant processing of pro-IGF-II to IGF-II may be a cause of IUGR. Here, we have found that the proprotein convertase PC4 is expressed in the human placenta and that it cleaves pro-IGF-II to generate the intermediate processed form, IGF-II (1-102) and, subsequently, mature IGF-II (1-67), which are accounted for by the removal of terminal basic residues by carboxypeptidases. This processing confers the ability of IGF-II to activate invasive trophoblast cells through AKT phosphorylation, whereas inhibition of PC4 by a PC4-specific inhibitor blocks pro-IGF-II processing and reduces trophoblast cell migration, which can be partly restored by addition of mature IGF-II. Consistent with the hypothesis that IGF-II processing is implicated in IUGR, sera of patients carrying IUGR fetuses displayed elevated levels of pro-IGF-II. Thus, abnormal processing of IGF-II by PC4 may represent a previously uncharacterized mechanism involved in the pathophysiology of fetoplacental growth restriction, and elevated pro-IGF-II may be a useful clinical marker for risk of IUGR.
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Affiliation(s)
- Qing Qiu
- Hormones, Growth, and Development and Disease of Aging Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1Y 4E9
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Miraki-Moud F, Grossman AB, Besser M, Monson JP, Camacho-Hübner C. A rapid method for analyzing serum pro-insulin-like growth factor-II in patients with non-islet cell tumor hypoglycemia. J Clin Endocrinol Metab 2005; 90:3819-23. [PMID: 15840753 DOI: 10.1210/jc.2004-2090] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Non-islet cell tumor hypoglycemia (NICTH) results from the hypersecretion of pro-IGF-II by a large, usually mesenchymal tumor. Detection of pro-IGF-II in serum is a potential tumor marker in these patients. OBJECTIVE The aim of this study was to validate a rapid and reliable method for determining serum pro-IGF-II. PATIENTS Serum samples from 16 patients with NICTH were studied. MAIN OUTCOME MEASURE The main outcome measure was serum concentration of pro-IGF-II determined by immunoblot analysis of pro-IGF-II and mature IGF-II after 16.5% tricine-SDS-PAGE, which was compared with pro-IGF-II measured by standard RIA after size-exclusion acid chromatography. RESULTS The analyses of patients' sera by size-exclusion acid chromatography showed that 68 +/- 19% of IGF-II were present in the pro-IGF-II form, whereas only 18 +/- 4% corresponded to pro-IGF-II in controls. Scanning densitometry of immunoblots showed 67 +/- 16% in the bands corresponding to pro-IGF-II in patients' sera, compared with 27 +/- 9% in controls. The detection sensitivity of tricine-SDS-PAGE method was the same as for size-exclusion chromatography, but the tricine-SDS-PAGE method is quicker and requires smaller amounts of serum. CONCLUSION Tricine-SDS-PAGE followed by IGF-II immunoblot analysis provides a rapid, reproducible, and sensitive method for the separation of serum pro-IGF-II from mature IGF-II and is a useful laboratory evaluation of patients with a clinical diagnosis of NICTH.
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Affiliation(s)
- Farideh Miraki-Moud
- Department of Endocrinology, 51-53 Bartholomew Close, St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom
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Hanley MB, Napolitano LA, McCune JM. Growth hormone-induced stimulation of multilineage human hematopoiesis. Stem Cells 2005; 23:1170-9. [PMID: 15955828 DOI: 10.1634/stemcells.2004-0322] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Growth hormone (GH) has been shown to have significant positive effects on hemato-lymphopoiesis in rodent models and, more recently, to increase thymic mass and circulating naïve CD4+ T cells in humans infected with the human immunodeficiency virus, type 1. To determine whether the latter effects on human T lymphopoiesis might be due, at least in part, to effects on the bone marrow (BM), we examined the specific effects of GH and its proximal mediator, insulin-like growth factor I (IGF-I), on human multilineage hematopoiesis in fetal BM (FBM). Using in vitro analysis, we found that GH and IGF-I each stimulated the expansion of primitive multilineage CD34+CD38- hematopoietic progenitor cells and increased yields of several hematopoietic subpopulations, including CD34+CD38+CD10+ lymphoid progenitor cells. Additionally, GH and IGF-I had direct effects on FBM stromal elements, inducing the expansion of myeloid-like CD45+CD14+ FBM stromal cells and enhancing production of the hematopoietic cytokine interleukin-3 by fibroblast-like CD45-CD10+ FBM stromal cells. Surface expression of GH and type-I IGF receptors correlated with the observed biologic responses to these hormones. Whereas GH enhanced the proliferation of FBM progenitors and stroma, IGF-I exerted a predominantly antiapoptotic effect. Finally, both GH and IGF-I stimulated the generation of hematopoietic colony forming cells. These findings identify specific targets of GH and IGF-I within human FBM, and demonstrate direct and indirect effects that may contribute to GH-mediated enhancement of human hemato-lymphopoiesis.
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Affiliation(s)
- Mary B Hanley
- Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158-2261, USA
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Sato R, Tsujino M, Nishida K, Otani Y, Minami T, Shichiri M, Hizuka N, Aiba M, Hitara Y. High molecular weight form insulin-like growth factor II-producing mesenteric sarcoma causing hypoglycemia. Intern Med 2004; 43:967-71. [PMID: 15575249 DOI: 10.2169/internalmedicine.43.967] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
An 81-year-old woman presented with frequent episodes of hypoglycemia. Her serum level of insulin was normal, but her serum insulin-like growth factor (IGF)-II level was high. She was found to have a spindle cell sarcoma originated from the mesentery of the sigmoid colon, which was completely resected. Postoperatively, hypoglycemia ameliorated with concomitant reduction in serum IGF-II levels. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells, and the abundant expression of IGF-II mRNA was demonstrated by RT-PCR. The presence of high molecular weight (HMW) form IGF-II in patient's serum was confirmed by immunoblotting. This is the first report of a patient with HMW form IGF-II-producing mesenteric sarcoma causing hypoglycemia.
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Affiliation(s)
- Ryuji Sato
- Division of Internal Medicine and Surgery, Tokyo Metropolitan Fuchu Hospital, Tokyo
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Kato A, Bando E, Shinozaki S, Yonemura Y, Aiba M, Fukuda I, Hizuka N, Kameya T. Severe hypoglycemia and hypokalemia in association with liver metastases of gastric cancer. Intern Med 2004; 43:824-8. [PMID: 15497518 DOI: 10.2169/internalmedicine.43.824] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We report an 80-year-old man who presented with non-islet cell tumor hypoglycemia (NICTH) in association with hepatic recurrence of gastric cancer. His serum potassium was reduced from 3.9 to 3.1 mmol/l 5 weeks after gastrectomy, and he subsequently developed hypoglycemic coma. He was diagnosed as having NICTH because of the presence of serum big IGF-II and positive staining for IGF-II in gastric cancer cells obtained at surgery. A computed tomography showed multiple liver metastases. His hypoglycemia was refractory to steroid therapy. This case suggested that NICTH could develop in association with hepatic metastases of gastric cancer. Unexpected hypokalemia may be a manifestation of occult NICTH.
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Affiliation(s)
- Akihiko Kato
- Renal, Endocrine and Metabolism Division, Shizuoka Cancer Center Hospital, Nagaizumi-cho
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Ko AH, Bergsland EK, Lee GA. Tumor-associated hypoglycemia from metastatic colorectal adenocarcinoma: case report and review of the literature. Dig Dis Sci 2003; 48:192-6. [PMID: 12645810 DOI: 10.1023/a:1021836806316] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- Andrew H Ko
- Division of Hematology and Oncology, University of California, San Francisco, California 94115, USA
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Silha JV, Gui Y, Murphy LJ. Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice. Am J Physiol Endocrinol Metab 2002; 283:E937-45. [PMID: 12376320 DOI: 10.1152/ajpendo.00014.2002] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Glucose homeostasis was examined in male transgenic (Tg) mice that overexpressed the human insulin-like growth factor (IGF)-binding protein (IGFBP)-3 cDNA, driven by either the cytomegalovirus (CMV) or the phosphoglycerate kinase (PGK) promoter. The Tg mice of both lineages demonstrated increased serum levels of human (h) IGFBP-3 and total IGF-I compared with wild-type (Wt) mice. Fasting blood glucose levels were significantly elevated in 8-wk-old CMV-binding protein (CMVBP)-3- and PGK binding protein (PGKBP)-3-Tg mice compared with Wt mice: 6.35 +/- 0.22 and 5.22 +/- 0.39 vs. 3.99 +/- 0.26 mmol/l, respectively. Plasma insulin was significantly elevated only in CMVBP-3-Tg mice. The responses to a glucose challenge were significantly increased in both Tg strains: area under the glucose curve = 1,824 +/- 65 and 1,910 +/- 115 vs. 1,590 +/- 67 mmol. l(-1). min for CMVBP-3, PGKBP-3, and Wt mice, respectively. The hypoglycemic effects of insulin and IGF-I were significantly attenuated in Tg mice compared with Wt mice. There were no differences in adipose tissue resistin, retinoid X receptor-alpha, or peroxisome proliferator-activated receptor-gamma mRNA levels between Tg and Wt mice. Uptake of 2-deoxyglucose was reduced in muscle and adipose tissue from Tg mice compared with Wt mice. These data demonstrate that overexpression of hIGFBP-3 results in fasting hyperglycemia, impaired glucose tolerance, and insulin resistance.
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Affiliation(s)
- Josef V Silha
- Department of Physiology, University of Manitoba, Winnipeg R3E 0W3, Canada
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Hamidou M, Bani-Sadr F, Kenzi A, Sagan C, Grolleau JY. [Hypoglycemia associated with pleural fibromas. Study of insulin-like growth factors (IGF) and pathogenic considerations]. Rev Med Interne 2002; 23:447-53. [PMID: 12064216 DOI: 10.1016/s0248-8663(02)00592-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Pathogeny of hypoglycemia associated with non-islet-cell tumors is unclear. We discuss the mechanisms of this syndrome. CURRENT KNOWLEDGE AND KEY POINTS We report three cases of spontaneous hypoglycemia revealing pleural fibroma. Endocrine tests before surgery showed low serum growth hormone and insulin-like growth factor I (IGF-I), reduced serum IGF-II levels in two patient. Insulin-like growth factor binding protein-3 (IGFBP-3) was low and electrophoretic profile of IGF-II was the 'big IGF-II' type. We discuss the mechanisms of hypoglycemia associated with non-islet-cell tumor. Impaired formation of the ternary complexes and its consequences seem the main pathogenic factor. FUTURE PROSPECTS AND PROJECTS Analysis of IGF and IGFBP and in situ measurements of IGF mRNA could help in understanding this syndrome and allow therapeutic considerations in the management of hypoglycemia by corticosteroids and growth hormone.
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Affiliation(s)
- M Hamidou
- Service de médecine interne A, Hôtel-Dieu, CHU, 44035 Nantes, France.
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