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

Abstract

Rationale Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome caused by tumors other than insulinoma that is primarily due to excessive production of insulin-like growth factor-II (IGF-II). The prevalence of NICTH is likely underestimated because of a lack of clinical recognition.

Patient Concerns A 41-year-old male with massive malignant liver tumors presented with recurrent severe hypoglycemia, weight loss, and liver cirrhosis.

Diagnosis NICTH related to IGF-II produced by hepatocellular carcinoma was diagnosed based on clinical symptoms, biochemical tests, and elevated IGF-II/IGF-I ratio.

Intervention Initial treatment with intravenous glucose and parenteral nutrition showed limited efficacy. Glucocorticoids and recombinant human growth hormone led to progressive improvement in blood glucose levels.

Outcome Due to extensive tumor burden and liver failure, surgical resection was not feasible, and the patient ultimately succumbed to refractory hypoglycemia and passed away in two weeks.

Lessons Early recognition and diagnosis of NICTH are crucial in patients with recurrent hypoglycemia and large tumors. Surgical resection is the preferred treatment option, but supportive care and pharmacological interventions, such as glucocorticoids and growth hormone, can help manage refractory hypoglycemia. Further research is needed to explore novel treatment options, including anti-IGF-I and -IGF-II neutralizing antibodies.

Zusammenfassung

Hintergrund Nicht-Inselzelltumor-Hypoglykämie (NICTH) ist ein paraneoplastisches Syndrom, das durch andere Tumoren als Insulinome verursacht wird. NICTH ist hauptsächlich auf eine übermäßige Produktion von insulinähnlichem Wachstumsfaktor II (IGF-II) zurückzuführen. Die Prävalenz von NICTH wird aufgrund mangelnder klinischer Anerkennung wahrscheinlich unterschätzt.

Anliegen des Patienten Ein 41-jähriger Mann mit massiven bösartigen Lebertumoren stellte sich mit rezidivierender schwerer Hypoglykämie, Gewichtsverlust und Leberzirrhose vor.

Diagnose NICTH im Zusammenhang mit IGF-II, das durch ein hepatozelluläres Karzinom hervorgerufen wird, wurde anhand klinischer Symptome, biochemischer Tests und eines erhöhten IGF-II/IGF-I-Verhältnisses diagnostiziert.

Medizinischer Eingriff Die anfängliche Behandlung mit intravenöser Glukose und parenteraler Ernährung zeigte eine begrenzte Wirksamkeit. Glukokortikoide und rekombinantes menschliches Wachstumshormon führten zu einer fortschreitenden Verbesserung des Blutzuckerspiegels

Ergebnisse Eine chirurgische Resektion war aufgrund der hohen Tumorlast und des Leberversagens nicht durchführbar. Der Patient erlag schließlich einer refraktären Hypoglykämie und verstarb innerhalb von zwei Wochen.

Blick nach vorne Die frühzeitige Erkennung und Diagnose von NICTH ist bei Patienten mit wiederkehrender Hypoglykämie und großen Tumoren von entscheidender Bedeutung. Die chirurgische Resektion ist die bevorzugte Behandlungsoption, aber unterstützende Maßnahmen und pharmakologische Interventionen wie Glukokortikoide und Wachstumshormone können bei der Behandlung einer refraktären Hypoglykämie helfen. Weitere Forschung ist erforderlich, um neue Behandlungsmöglichkeiten zu erkunden, einschließlich neutralisierender Anti-IGF-I- und IGF-II-Antikörper.

Schlüsselwörter

Fallbericht - hepatozelluläres Karzinom - Hypoglykämie von Nicht-Inselzelltumoren - insulinähnlicher Wachstumsfaktor - Leber - Metastasierung

Keywords

case report - hepatocellular carcinoma - non-islet-cell tumor hypoglycemia - insulin-like growth factor - liver - metastasis

Publication History

Received: 05 July 2023

Article published online:
05 October 2023

• References

• 1 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 (06) 798-826
• 2 Daughaday WH, Emanuele 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 (22) 1434-1440
• 3 Yu B, Douli R, Suarez JA. et al. 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 (08) 519-524
• 4 Rojbi I, Ben Elhaj W, Mchirgui N. et al. Non-islet-cell tumor hypoglycemia as first manifestation of an advanced hepatocellular carcinoma. Clin Case Rep 2021; 9 (10) e05012 DOI: 10.1002/ccr3.5012. (PMID: 34721868)
• 5 Izutsu T, Ito H, Fukuda I. et al. Early Improvement of Non-islet Cell Tumor Hypoglycemia by Chemotherapy Using Lenvatinib in a Case with Type 2 Diabetes and Hepatocellular Carcinoma Producing Big IGF-II. Intern Med Tokyo Jpn 2021; 60 (09) 1427-1432
• 6 Kim JH, Kim JO, Kim SY. et al. Two cases of large solitary fibrous tumors of the pleura associated with fasting hypoglycemia. Eur Radiol 2001; 11 (05) 819-824
• 7 Kishi K, Homma S, Tanimura S. et al. Hypoglycemia induced by secretion of high molecular weight insulin-like growth factor-II from a malignant solitary fibrous tumor of the pleura. Intern Med Tokyo Jpn 2001; 40 (04) 341-344
• 8 Chan G, Horton PJ, Thyssen S. et al. Malignant transformation of a solitary fibrous tumor of the liver and intractable hypoglycemia. J Hepatobiliary Pancreat Surg 2007; 14 (06) 595-599 DOI: 10.1007/s00534-007-1210-0. (PMID: 18040628)
• 9 Solsi A, Pho K, Shojaie S. et al. Doege-Potter Syndrome and Pierre-Marie-Bamberger Syndrome in a Patient With Pleural Solitary Fibrous Tumor: A Rare Case With Literature Review. Cureus 2020; 12 (05) e7919
• 10 Jannin A, Espiard S, Benomar K. et al. Non-islet-cell tumour hypoglycaemia (NICTH): About a series of 6 cases. Ann Endocrinol 2019; 80 (01) 21-25
• 11 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 Off J Growth Horm Res Soc Int IGF Res Soc 2006; 16 (04) 211-216 DOI: 10.1016/j.ghir.2006.05.003. (PMID: 16860583)
• 12 Nadler WH, Wolfer JA. Hepatogenic hypoglycemia associated with primary liver cell carcinoma. Arch Intern Med 1929; 44 (05) 700-710
• 13 Yeung RT. Hypoglycaemia in hepatocellular carcinoma: a review. Hong Kong Med J Xianggang Yi Xue Za Zhi 1997; 3 (03) 297-301 (PMID: 11847375)
• 14 Ishida S, Noda M, Kuzuya N. et al. Big insulin-like growth factor II-producing hepatocellular carcinoma associated with hypoglycemia. Intern Med Tokyo Jpn 1995; 34 (12) 1201-1206
• 15 de Groot JWB, 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 (04) 979-993 DOI: 10.1677/ERC-07-0161. (PMID: 18045950)
• 16 Uchida K, Kondo M, Takeda S. et al. Altered transcriptional regulation of the insulin-like growth factor 2 gene in human hepatocellular carcinoma. Mol Carcinog 1997; 18 (04) 193-198 (PMID: 9142213)
• 17 Wang Z, Ruan YB, Guan Y. et al. Expression of IGF-II in early experimental hepatocellular carcinomas and its significance in early diagnosis. World J Gastroenterol 2003; 9 (02) 267-270 DOI: 10.3748/wjg.v9.i2.267. (PMID: 12532445)
• 18 Mukherjee B, Ghosh S, Das T. et al. Characterization of insulin-like-growth factor II (IGF II) mRNA positive hepatic altered foci and IGF II expression in hepatocellular carcinoma during diethylnitrosamine-induced hepatocarcinogenesis in rats. J Carcinog 2005; 4: 12
• 19 Qiu LW, Yao DF, Zong L. et al. Abnormal expression of insulin-like growth factor-II and its dynamic quantitative analysis at different stages of hepatocellular carcinoma development. Hepatobiliary Pancreat Dis Int HBPD INT 2008; 7 (04) 406-411 (PMID: 18693177)
• 20 Breuhahn K, Vreden S, Haddad R. et al. Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression. Cancer Res 2004; 64 (17) 6058-6064 DOI: 10.1158/0008-5472.CAN-04-0292. (PMID: 15342387)
• 21 Tsai TF, Yauk YK, Chou CK. et al. Evidence of autocrine regulation in human hepatoma cell lines. Biochem Biophys Res Commun 1988; 153 (01) 39-45 DOI: 10.1016/s0006-291x(88)81186-0. (PMID: 2837209)
• 22 Bae MH, Lee MJ, Bae SK. et al. Insulin-like growth factor II (IGF-II) secreted from HepG2 human hepatocellular carcinoma cells shows angiogenic activity. Cancer Lett 1998; 128 (01) 41-46
• 23 Ji Y, Wang Z, Chen H. et al. Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 2018; 47 (01) 39-53
• 24 van Doorn J. Insulin-like growth factor-II and bioactive proteins containing a part of the E-domain of pro-insulin-like growth factor-II. BioFactors Oxf Engl 2020; 46 (04) 563-578 DOI: 10.1002/biof.1623. (PMID: 32026557)
• 25 Gowan LK, Hampton B, Hill DJ. et al. Purification and characterization of a unique high molecular weight form of insulin-like growth factor II. Endocrinology 1987; 121 (02) 449-458 DOI: 10.1210/endo-121-2-449. (PMID: 2439316)
• 26 O’Dell SD, Day INM. Molecules in focus Insulin-like growth factor II (IGF-II). Int J Biochem Cell Biol 1998; 30 (07) 767-771
• 27 Bond JJ, Meka S, Baxter RC. Binding characteristics of pro-insulin-like growth factor-II from cancer patients: binary and ternary complex formation with IGF binding proteins-1 to -6. J Endocrinol 2000; 165 (02) 253-260 DOI: 10.1677/joe.0.1650253. (PMID: 10810289)
• 28 Bodnar TW, Acevedo MJ, Pietropaolo M. Management of non-islet-cell tumor hypoglycemia: a clinical review. J Clin Endocrinol Metab 2014; 99 (03) 713-722 DOI: 10.1210/jc.2013-3382. (PMID: 24423303)
• 29 Tietge UJ, Schöfl C, Ocran KW. et al. Hepatoma with severe non-islet cell tumor hypoglycemia. Am J Gastroenterol 1998; 93 (06) 997-1000
• 30 Forde JJ, Ewelukwa O, Brar T. et al. Intractable Fasting Hypoglycemia as a Manifestation of Hepatocellular Carcinoma. Case Rep Hepatol 2017; 2017: 7465025 DOI: 10.1155/2017/7465025. (PMID: 28785493)
• 31 van den Berg S a. A, Krol CG. Pro-IGF2-induced hypoglycaemia associated with hepatocellular carcinoma. Endocrinol Diabetes Metab Case Rep 2017; 2017: 17-0004 DOI: 10.1530/EDM-17-0004. (PMID: 28567293)
• 32 North AS, Thakkar RG, James RA. et al. The palliative management of non-islet cell tumour hypoglycaemia with glucocorticoids and somatostatin analogues in an unresectable hepatocellular carcinoma. Ann R Coll Surg Engl 2022; 104 (06) e180-182
• 33 Okabayashi T, Shima Y, Sumiyoshi T. et al. Diagnosis and management of insulinoma. World J Gastroenterol 2013; 19 (06) 829-837 DOI: 10.3748/wjg.v19.i6.829. (PMID: 23430217)
• 34 de Herder WW. Insulinoma. Neuroendocrinology 2004; 80: 20-2 (PMID: 25905215)
• 35 Bränström R, Berglund E, Curman P. et al. Electrical short-circuit in β-cells from a patient with non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS): a case report. J Med Case Reports 2010; 4: 315
• 36 Cappellani D, Macchia E, Falorni A. et al. Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description. Diabetes Metab Syndr Obes Targets Ther 2020; 13: 963-978 DOI: 10.2147/DMSO.S219438. (PMID: 32308449)
• 37 Marks V, Teale JD. Tumours producing hypoglycaemia. Diabetes Metab Rev 1991; 7 (02) 79-91 DOI: 10.1002/dmr.5610070202. (PMID: 1665409)
• 38 Yamakawa-Yokota F, Ozaki N, Okajima A. et al. Retroperitoneal solitary fibrous tumor-induced hypoglycemia associated with high molecular weight insulin-like growth factor II. Clin Med Res 2010; 8: 159-162
• 39 Chang JC, Su KY, Chao SF. et al. Hypoglycemia in a patient with a huge malignant solitary fibrous tumor of the pleura. Pathol Int 2007; 57 (12) 791-793
• 40 Teale JD, Wark G. The effectiveness of different treatment options for non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf) 2004; 60 (04) 457-460 DOI: 10.1111/j.1365-2265.2004.01989.x. (PMID: 15049960)
• 41 Baxter RC, Holman SR, Corbould A. et al. Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia. J Clin Endocrinol Metab 1995; 80 (09) 2700-2708
• 42 Bourcigaux N, Arnault-Ouary G. 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 (02) 246-251
• 43 Setoyama T, Miyamoto S, Horimatsu T. et al. Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia. Cancer Biol Ther 2014; 15 (12) 1588-1592 DOI: 10.4161/15384047.2014.961878. (PMID: 25535894)