5 4 1999 ; 332 337 1 : (IGF) (IGFBP), Abstract Hepatocellular Carcinoma with Severe Hypoglycemia : Involvement of Insulin-like Growth Factor I, II and Insulin-like Growth Factor Binding Proteins Seok Joo Kim, M.D., Bo Yeong Yun, M.D. and Ha Chin Choi, M.D. Department of Internal Medicine, Paik Hospital, College of Medicine, Inje University, Pusan We report a case of hepatocellular carcinoma presented with severe hypoglycemia. Computerized tomography and ultrasonography revealed a massive bilateral tumor with portal vein thrombosis. T he levels of IGF- II (113 ng/ml) and IGFBP- 3 (815 ng/ml) measured in the plasma, were lower than normal range. T here was strong immunoreactivity of IGF- I and IGF- II in immunohistochemical stain of tumor cells. (Korean J Hepatol 1999;5:332 337) Key Words : Hepatocellular carcinoma, Hypoglycemia, IGF, IGFBP :, 633-165 (islet cell tumor),1 (non- islet cell tumor).2-4 (paraneoplastic sydrome), 10-30%.5, 6,.7 (IGF),9-12 (IGFBPs).2, 13, 14
Seok Joo Kim, et al. Hepatocellular Carcinoma with Severe Hypoglycemia : Involvement of Insulin- like Growth Fa ctor I & II a nd Insulin- like Growth Factor Binding Proteins 333 IGF- I, IGF- II IGF- I, IGF- II IGFBP 1. 39.,, semicoma 42 mg/dl. 1 B, B. 68 kg, 162 cm 110/80 mmhg, 80 /, 20 /, 36.5.,,. 10 cm 4 cm.. 5,060/mm3, 9.8 g/dl, 209,000/ mm3, 7.5 g/dl, 4.2 g/dl, 1.1 mg/dl, AST 280 IU/L(10-33 IU/L), ALT 104 IU/L(4-40 IU/L). Alkaline phosphatase 1730 IU/L(< 120 IU/L), 21 (11-13 ). HBsAg (+), anti- HBs (- ), HBeAg (- ), anti- HBe (+), anti- HCV (- ), HCV- RNA (- ) HBV DNA 77 ng/ml. - fetoprotein 35,000 ng/ml(0-15 ng/ ml). immunoreactive insulin (IRI) 5.8 U/mL(0-30 U/mL), C- peptide 1.3 ng/ml(0.8-4.0 ng/mll). epinephrine 13.0 pg/ml(< 120 pg/ml), norepinephrine 83.0 pg/ml(< 400 pg/ml), Glucagon 38.3 pg/ml(40-130 pg/ml), Cortisol 15.0 g/dl(2-28 g/dl). IGF- I 83.4 ng/ml (178-344), IGF- II 113 ng/ml(288-736 ng/ml), IGFBP- 3 815 ng/ml(2,500-6,500 ng/ml). : IGF- I Immunoradiometric assay (IRMA) : IGF- I DSL- 5600 ACT IVE IGF- I Coated- T ube IRMA kit (Diagnostic Systems Laboratories, Corporate Headquarters, T exas, USA). 2-8 24-20 Figure 1. Ill- defined huge faint patch enhancement in left lobe on early phased CT scan. Figure 2. Well- defined wash- out patterned enhancement in left lobe on delay phased CT scan.
334 5 4 1999, hemolyzed lipemic specimen. IGF- II Immunoradiometric assay (IRMA) : IGF- II DSL- 9100 ACT IVE IGF- II Coated- tube IRMA kit (Diagnostic systmes Laboratories, Corporate Headquarters,T exas, USA). IGF- I. IGFBP- 3 Immunoradiometric assay (IRMA) : 3 Coated- T ube IRMA kit (Diagnostic Systems IGFBP- 3 DSL- 6600 ACTIVE IGFBP- Fig ure 3. T umor cells resemble hepatocytes. T here are prominent sinusoidal pattern, trabecular pattern of growth and nuclear atypicality(h&e, X 200). Laboratories, Corporate Headquarters, T exas, USA). 2-8 48-20 8, 100. (Figure 1, 2). Edmonson Grade II (Figure 3). mouse monoclonal IgG1 IGF- I, II (Figure 4, 5). : IGF 4 m 3- aminoprophyltriethoxy- saline (Sigma, USA). 100% 30%(v/v) 9:1 10 peroxidase T ris buffered saline (10 mm T ris, 150 mm NaCl, ph 7.2, T BS ) 3. 1% zinc sulfate (Sigma, USA) 10 mm Fig ure 4. Strong immunoreactivity of IGF- I in most tumor cells, disclosing cytoplasmic expression( 200). Fig ure 5. Strong immunoreactivity of IGF- II in most tumor cells, disclosing cytoplasmic expression( 200).
2. 1 : (IGF) (IGFBP) 335 Citrate (ph 6.0) microw ave 5 3. 0.5%(v/v) normal goat serum (Dako, USA) T BS 30.. IGF anti- Human IGF- I (1:100, mouse monoclonal, IgG1, upstate biotechnology, USA) anti- Human IGF- II (1:50, mouse monoclonal IgGl, upstate biotechnology, USA). ABC (Avidin- Biotin- Peroxidase complex) Mayer Hematoxyline. 24 13 mg/dl., growth hormone, octreotide adriamycin. 19 - fetoprotein 41,985 ng/ml, 2.8 g/dl, 19.3 mg/dl AST, ALT 533, 79 IU/L. epidural catheter opioid. 60,. 1), 2). 1), 2).5, 10 Insulin- like growth factors (IGFs, IGF- I and IGF- II) proinsulin relaxin 7.5 kda single- chain polypeptide. IGF- I IGF- II.8 Insulin, IGF- I, IGF- II, big IGF- II (pro- IGF- II).9-12 IGF- II IGF- II, IGF- II mrna IGF- II.15, 16 IGFs 75% IGF, IGFBP- 3 acid- labile - subunit ternary complex, 50 kda. IGF- II 150 kda ternary complex, 50 kda. IGF- II IGFBP- 3. IGF- II - subunit IGF- II IGFBP- 3 - subunit. IGFBP- 3 264 2 protease activity. IGFBP complex. IGF- II bioactivity.2, 14, 17 IGF IGFBP IGFBP IGF.18, 19 IGFBP IGF (bioavailability) IGF- II IGFBP. Phillip non- islet cell tumor 52 IGF
336 The Korean Journal of Hepatology : Vol. 5. No. 4. 1999 19, 22, 11 4 2 2.11 non- islet cell tumor IGF. 2.. (paraneoplastic syndrome) 13 mg/dl counter- regulatory hormone GH, cathecholamine, glucagon, cortisol. IGF- II IGFBP- 3.., IGF IGFBP- 3, IGF IGFBP.11, 20 IGF- I, IGF- II IGFBP- 3, IGF- I IGF- II. biosynthetic GH (2u subcutaneously once daily) somatostatin analogue octreotide (50 g subcutaneously) adriamycin,. 39 IGF- I, IGF- II IGFBP- 3. 1. Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332:1144-52. 2. Zapf J. Insulin like grow th factor binding proteins and tumor hypoglycemia. T rends Endocrinol Metab 1995;6:37-42. 3. Kahn CR. T he riddle of tumour hypoglycemia revisited. J Clin Endocrinol Metab 1980;9:335-60. 4. Unger RH. T he riddle of tumor hypoglycemia. Am J Med 1966;40:325-30. 5. McFadzean AJS, Yeung RT T. Further observations of hypoglycemia in hepatocellular carcinoma. Am J Med 1969;47:220-235. 6. Sherlock S. Diseases of the liver and biliary system, 8th ed. Oxford, Blackwell Sientific Publications. 1989;584. 7. Margolis S, Homcy C. Systemic manifestations of hepatoma. Medicine 1972;51:381-391. 8 Daughaday WH, Rotwein P. Insulin- like growth factors I and II: peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocrinol Rev 1989;10:68-91. 9. Wu JC, Daughaday WH, Lee SD, et al. Radioimmunoassay of serum IGF- I and IGF- II in patients with chronic liver diseases and hepatocellular carcinoma w ith or without hypoglycemia. J Lab Clin Med 1988;112:589-594. 10. Shapiro ET, Bell GI, Polonsky KS, et al. T umor hypoglycemia: relationship to high molecular w eight insulin- like growth factor II. J Clin Invest 1990;85:1672-1679. 11. Gorden P, Fendricks CM, Kahn R, et al. Hypoglycemia associated w ith non- islet cell tumor and insulin- like growth factors. N Engl J Med 1981;305:1452. 12. Nakanishi S, Inou J, Nomura M, et al.
Seok Joo Kim, et al. Hepatocellular Carcinoma with Severe Hypoglycemia : Involvement of Insulin- like Growth Fa ctor I & II a nd Insulin- like Growth Factor Binding Proteins 337 Increased insulin- like activity of the serum and tumor tissue in a patients with hypoglycemia associated with hepatocellular carcinoma. Acta Hepatologica Japonica 1986;27: 642. 13. Rosenfeld RG, Lamson G, Pham H, et al. Insulin- like growth factor binding proteins. Recent Progr Horm Res 1990;46:99. 14. Daughaday WH, Kapadia M. Significance of abnormal serum binding of insulin- like growth factor II in the development of hypoglycemia in patients with non- islet- cell tumors. Proc Natl Acad Sci USA 1989;86: 6778-6782. 15. Daughaday WH, Emanuelle MA, Brooks MH, et al. Synthesis and secretion of insulin- like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 1988;319:1434-1440. 16. Ron D, Powers AC, Pandian MR, et al. Increased insulin- like growth factor II production and consequent suppression of growth hormone secretion : a dual mechanism of tumor- induced hypoglycemia. J Clin Endocrinol Metab 1989;68:701-706. 17. Zapf J, Schmid CH, Guler HP, et al. Regulation of binding proteins for insulin- like growth factors (IGF) in humans : increased expression of IGF binding protein 2 during IGF I treatment of healthy adults and in patients with extrapancreatic tumor hypoglycemia. J Clin Invest 1990;86:952-961. 18. Ritvos O, Ranta T, Jalkanen J, et al. Insulinlike grwoth factor (IGF) binding protein from human decidua inhibits the binding and biological action of IGF- I in cultured choriocarcinoma cell. Endocrinology 1998;122:2150-2157. 19. Ross M, Francis GL, Szabo L, et al. Insulinlike growth factor (IGF)- binding proteins inhibit the biological activities of IGF- I and IGF- II but not des(1-3)- IGF- I Biochem J 1989;258:267-272. 20. Cambell PG, Novak JF. Insulin- like growth factor binding protein (IGFBP) inhibits IGF action a human osteosarcoma cells. J Cell Physiol 1991;149:293.