[ ] 169 NICTH Nadler WH Wolfer JA NICTH. (nonislet cell tumor. (hypoglycemia) (nonislet cell tumor hypoglycemia, NICTH)

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1 [] (nonislet cell tumor hypoglycemia, NICTH) (paraneoplastic syndrome) NICTH (macromolecules insulin-like growth factor-ii, big IGF-II)Big IGF-II (tumor burden) NICTH NICTH 2016; 26: DOI: / Nadler WH Wolfer JA [1] (nonislet cell tumor, NICT) (hypoglycemia) (nonislet cell tumor hypoglycemia, NICTH)NICTH NICTH

2 Taiwan J Fam Med Vol. 26 No.3 28B cm (T3bN0M1, radiology staging: stage IVb, BCLC staging: C) (Sorafenib) mg/dl Whipple s triad 5% (Dextrose 5% in Water, D5W) (YF No.5 injection; dextrose and electrolyte solution) mg/dl C-(C-peptide) (insulin) (C-0.23 ng/ml ng/ml< 1.2 μu/ml 0-22 μiu/ml) NICTH (2,200 kcal/day)250 kcal9g 4 6 (22 mg/dl) 10%(Dextrose 10% in Water, D10W) 1,500 ml/day50% (Dextrose 50% in Water, D50W)40 mlmegestrol acetate 480 mg/day 20 (Port-A) ,000 mld10wd50w (Dexamethasone 4mg Q12H) (Dexamethasone 4mg QD) NICTH 流行病學 [2] NICTH (mesenchymal origin)

3 (epithelial origin) 20% NICTH [3] (adrenocortical carcinoma) [3,7] NICTHBodnar [2] NICTH , % [4] 病理生理機轉 1988NICTH (insulinlike growth factor-ii, IGF-II) (macromolecules insulin-like growth factor-ii, big IGF-II) [5] IGF-II 11prepro-IGF- IIPrepro-IGF-IIN (signal peptide)bcade (domain) prepro-igf-ii pro-igf-ii big IGF-IIE21 E (glycosylation) EIGF-II 1 [3] big IGF-II IGF-II10-20% 1Prepro-IGF-IIIGF-II Prepro-IGF-IIpro-IGF-IIbig IGF-IIE 21E(glycosylation)E IGF-IIBCADNICTHIGF-II big IGF-IIIGF-IIbig IGF-II ; 26: 20-9

4 Taiwan J Fam Med Vol. 26 No.3 IGF-II (insulin-like growth factor, IGF) (proinsulin) IGF 70-80%IGF-IIIGF (IGF binding protein, IGFBP) 150-kDa 20-30%IGF-IIIGFBP 50-kDa1% IGF-II IGF-II [3] NICTH IGF-IIbig IGF-II70% IGF-II pro-igf-iiigf-ii big IGF-II big IGF-IIIGFBP IGF-II big IGF-II IGF big IGF-II [3,6,7] [8] 臨床徵狀 NICTH NICTH Fukuda NICTH 31(48%) [9] [9] [2] 診斷 NICTH big IGF-II [3,6] NICTH (insulinoma) (noninsulinoma pancreatogenous hypoglycemic syndrome, NIPHS) (insulin autoimmune syndrome, IAS) [7,10] C--

5 ; 26: 20-9 (-hydroxybutyrate)big IGF- II -hydroxybutyrate 1 NICTH IGF-II/IGF-INICTH IGF-IIIGF-I IGF-II/IGF-IIGF-II/IGF-I > 10 [6] NICTH 治療 NICTH

6 Taiwan J Fam Med Vol. 26 No mg [11] NICTH [3,6] (glucocorticoids, GCs) (recombinant human growth hormone, rhgh) 1. NICTH [12] GCsbig IGF-II big IGF-II GCs prednisolone30-60 mg GCs [6] 2. [6] mg/ hr [6,13] 3. GCs rhgh [6] rhgh (supraphysiological doses: 3-12 mg/day) NICTH [14] IGFBP pro-igf-ii GCs 1 (μu/ml) (pmol/l) C- (nmol/l) - (mmol/l) < 3 < 5 < 0.2 > NIPHS* IAS** >> 3 >> 5 >> NICTH*** < 3 < 5 < *NIPHS: noninsulinoma pancreatogenous hypoglycemic syndrome **IAS: insulin autoimmune syndrome ***NICTH: nonislet cell tumor hypoglycemia ; 26: 20-9

7 [6] NICTH 2 3 C- IGF-IIGF-IIbig IGF-II NICTH NICTH 1. Nadler WH, Wolfer JA: Hepatogenic hypoglycemia associated with primary liver cell carcinoma. Arch Intern Med 1929; 44: de Groot JW, Rikhof B, van Doorn J, et al: Non-islet cell tumour-induced hypoglycaemia: a review of the literature including two new cases. Endocr Relat Cancer 2007; 14: Dynkevich Y, Rother KI, Whitford I, et al: Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory and the historical archive. Endocr Rev 2013; 34: Luo JC, Hwang SJ, Wu JC, et al: Paraneoplastic syndromes in patients with hepatocellular carcinoma in Taiwan. Cancer 1999; 86: Daughaday WH, Emanuelle MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P: Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 1988; 319: Bodnar TW, Acevedo MJ, Pietropaolo M: Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab 2014; 99: Thomas J, Kumar SC: Nonislet cell tumor hypoglycemia. Case Rep Endocrinol 2013; 2013: Fukuda I, Hizuka N, Ishikawa Y, et al: Clinical features of insulin-like growth factor-ii producing non-islet-cell tumor hypoglycemia. Growth Horm IGF Res 2006; 16: Cryer PE, Axelrod L, Grossman AB, et al: Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin

8 Taiwan J Fam Med Vol. 26 No (GCs) 1. big IGF-II prednisone mg/day mg mg/ hr GCs mg/ day GCs J Clin Endocrinol Metab 2014; 99:

9 Endocrinol Metab 2009; 94: Seaquist ER, Anderson J, Childs B, et al: Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. J Clin Endocrinol Metab 2013; 98: Teale JD, Wark G: The effectiveness of different treatment options for non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf) 2004; 60: Hoff AO, Vassilopoulou-Sellin R: The role of glucagons administration in the diagnosis and treatment of patients with tumor hypoglycemia. Cancer 1998; 82: Bourcigaux N, Arnault-Ouary G, Christol R, et al: Treatment of hypoglycemia using combined glucocorticoid and recombinant human growth hormone in a patient with a metastatic non-islet cell tumor hypoglycemia. Clin Ther 2005; 27:

10 178 [Case Report] End-stage Hepatocellular Carcinoma with Refractory Hypoglycemia: A Case Report Hui-Ting Hsieh, Ching-Fen Hsu, Cheng-Yu Chen and Lin-Chen Ho Nonislet cell tumor hypoglycemia (NICTH) denotes the syndrome of hypoglycemia produced by any neoplasm other than an insulinoma. Hepatocellular carcinomas are one of the most common neoplasms which result in NICTH, a rare but life-threatening paraneoplastic syndrome in need of early diagnosis and treatment. The major cause of NICTH is tumoral overproduction of incompletely processed insulinlike growth factor II, termed "big" IGF-II, which can stimulate insulin receptors and exhibits insulin-like activities. Moreover, big IGF-II also suppresses glucagon and growth hormone release. The net result is continued glucose utilization and inhibition of glucose release, glycogenolysis, and gluconeogenesis in the liver. Other potential but less common causes of NICTH include the production of autoantibodies against insulin or the insulin receptor and extensive tumor burden resulting in destruction of the liver or adrenal glands. The mainstay of treatment for NICTH is surgical resection, which is curative for hypoglycemia if resection is complete. When the underlying malignancy cannot be treated, medical therapy is required to prevent recurrent hypoglycemia symptoms. Other than oral glucose and/or IV glucose- or dextrose-containing fluids, glucocorticoids, glucagon, or recombinant human growth hormone (rhgh) can be added to control intractable hypoglycemia. The case report presents a 28-yearold man of hepatocellular carcinoma with refractory hypoglycemia. Epidemiology, pathophysiology, clinical manifestation, diagnosis, and treatment of NICTH are also introduced after literature review. (Taiwan J Fam Med 2016; 26: ) DOI: / Key words: glucocorticosteroids, hepatocellular carcinoma, insulin-like growth factor-ii, non-islet cell tumor hypoglycemia Department of Family Medicine, Taipei Tzu Chi Hospital, New Taipei, Taiwan. Received: September 14, 2015; Revised: November 23, 2015; Accpted: December 9, 2015.