Hypoglycemia Associated with the Production of Insulin-like Growth Factor II in Adrenocortical Carcinoma
Takako EGUCHI, Atsushi TOKUYAMA, Yuri TANAKA, Yasunori TAKAHASHI, Gen KAWAHARA*, Motohiko AIBA ** , Yoji INISHI and Hisashi MINOWA
Abstract
A 78-year-old woman was hospitalized for congestive heart failure and repeated hypoglycemic attacks. The labo- ratory data showed a serum insulin level within the normal range and an increased level of serum insulin-like growth factor (IGF) II. Abdominal ultrasonogram and computed tomography scan revealed a huge mass lying above the left kidney. She was diagnosed as having an adrenocortical carcinoma. After the removal of the tumor, the plasma glu- cose level and the serum level of IGF-II were normalized. The tumor cells stained positively for IGF-II immunohis- tochemically. These findings suggested that the hypoglyce- mia was due to IGF-II produced by the adrenocortical car- cinoma.
(Internal Medicine 40: 759-763, 2001)
Key words: non-islet cell tumor hypoglycemia (NICTH), big insulin-like growth factor II, insulin-like growth factor II/insulin-like growth factor I ratio
Introduction
Non-islet cell tumor hypoglycemia (NICTH) is a syndrome defined by the presence of a solid tumor and fasting hypogly- cemia, which is caused by an insulin-independent pathway. Recently, it is believed that insulin-like growth factor (IGF) II produced by tumors is the primary hormonal mediator of NICTH, although other possible mechanisms have been pro- posed. Here we present a case of hypoglycemia associated with the production of IGF-II in adrenocortical carcinoma; this is relatively rare in NICTH.
Case Report
A 78-year-old woman, who had been followed for hyper-
tension and hypokalemia from 1994, was hospitalized on March 30, 1999 because of congestive heart failure by paroxysmal atrial fibrillation. Her family history included nothing note- worthy. Her past history included cholecystectomy in 1991 and cerebral apoplexy in 1998. Results of physical examination on admission showed: body temperature, 36.5℃; height, 139 cm; weight, 47 kg; blood pressure, 150/100 mmHg; and pulse, 100/ min and irregular. Examination of the heart, lungs and abdo- men revealed no abnormalities except for grade II/VI pansystolic heart murmur at apex. There was no skin texture, pigmentation, or male hair distribution. No superficial lymph nodes were swollen, but her lower limbs were mildly edema- tous. No abnormal neurological findings were revealed. The laboratory data on admission are shown in Table 1. The serum levels of C-reactive protein (CRP), lactate dehydrogenase (LDH), and y-glutamyl transpeptidase (y-GTP) were elevated. Her serum potassium level was low and plasma glucose (PG) level was within the normal range. The electrocardiogram showed atrial fibrillation with tachycardia and paroxysmal spo- radic ventricular contractions. The chest roentgenogram re- vealed an increased cardiothoracic ratio of 67%. The roent- genogram of the abdomen was normal.
After admission, paroxysmal atrial fibrillation was cured with verapamil and heart failure was improved. Hypokalemia was treated with the administration of 80 mEq potassium per day and the serum potassium level was maintained within the normal limit. CRP and LDH were lowered to within the nor- mal range.
On May 3, 1999, she had sudden onset of a fever of 40℃ and abdominal pain. At the same time, she had repeated hy- poglycemic attacks and fell into a coma. The level of serum potassium became lower and lower and CRP and LDH rose again (11.17 mg/dl and 1,570 IU/l, respectively). The labora- tory data at the time of hypoglycemic attack are shown in Table 2. The level of PG was low, whereas the serum insulin level measured by radio immunoassay (immunoreactive insulin, IRI) was within the normal range. Concentration of IGF-II in se- rum was elevated, and the serum levels of IGF-I and IGF bind-
From the Department of Cardiology and *Urology, Omori Red Cross Hospital, Tokyo and ** the Department of Pathology, Tokyo Women’s Medical College Daini Hospital, Tokyo
Received for publication October 27, 2000; Accepted for publication March 21, 2001
Reprint requests should be addressed to Dr. Takako Eguchi, the Department of Internal Medicine, Kanagawa Prefectural Ashigarakami Hospital, 866-1 Matsudasoryo, Matsuda-cho, Ashigarakami-gun, Kanagawa 258-0003
| WBC | 6,700/ul | AST | 20 IU/l |
| Neutrophil | 65.7% | ALT | 13 IU/l |
| Lymphocytes | 24.1% | LDH | 800 IU/l |
| Monocytes | 8.4% | LAP | 56 IU/l |
| Eosinophils | 1.0% | Y-GTP | 115 IU/l |
| Basophils | 0.8% | CPK | 52 IU/l |
| RBC | 450×104/ul | BUN | 6.2 mg/dl |
| Hb | 13.8 g/dl | Cr | 0.5 mg/dl |
| Ht | 40.7% | UA | 4.1 mg/dl |
| Plt | 31.5×104/ul | Na | 142 mEq/l |
| K | 2.7 mEq/l | ||
| CRP | 12.4 mg/dl | C1 | 101 mEq/l |
| TP | 6.4 g/dl | ||
| Alb | 3.6 g/dl | Arterial Blood Gas | |
| T-cho | 201 mg/dl | pH | 7.486 |
| TG | 68 mg/dl | PaCO2 | 42.4 mmHg |
| PG | 116 mg/dl | PaO2 | 60.9 mmHg |
| T-bil | 0.9 mg/dl | HCO3 | 32 mmol/l |
WBC: white blood cells, RBC: red blood cells, Hb: hemoglobin, Ht: hematocrit, Plt: platelets, CRP: C-reactive protein, TP: total protein, Alb: albumin, T-cho: total cholesterol, TG: triglyceride, PG: plasma glucose, T-bil: total bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactic dehydrogenase, LAP: leucine aminopeptidase, yGTP: y-glutamyl transpeptidase, CPK: creatine phosphokinase, BUN: blood urea nitrogen, Cr: creatinine, UA: uric acid, Na: sodium, K: potassium, CI: chloride.
ing protein-3 (IGFBP-3) were decreased. The serum levels of noradrenaline, dopamine, and cortisol were elevated. Urine 17- ketosteroid (17-KS) and 17-hydroxycorticosteroid (17-OHCS) levels, determined by total urine collection methods, were also elevated. Circadian rhythm of cortisol had disappeared (9.8 µg/ dl at 2 o’clock, 11.2 g/dl at 8 o’clock, 9.6 ug/dl at 14 o’clock, 11.5 µg/dl at 20 o’clock). Furthermore, urine 17-OHCS was not suppressed in the 2 mg and 8 mg dexamethasone suppres- sion test (before the administration; 66.2 mg/day, two days af- ter the administration of 2 mg dexamethasone; 91.3 mg/day, two days after the administration of 8 mg dexamethasone; 118.2 mg/day). Abdominal ultrasonogram, computed tomography (CT) scan and magnetic resonance imaging (MRI) demon- strated a well-defined huge mass, approximately 9×8x12 cm in diameter, lying above the left kidney which shifted the pan- creas towards the ventral direction. The border to the left kid- ney was clear comparatively. The mass was solid but partly cystic, and the findings of these examinations suggested the mass may have a necrotic lesion in the center. The scintigram of the bone and MIBG were normal, and the gallium scinti- gram demonstrated a hot spot in the left lumbar region. The renal scintigram showed a stain above the left kidney. The se- lective adrenal, renal, celiac and supramesenteric arterial angiograms revealed a hypervascular tumor, 10 cm in diam- eter, in the left lumbar region. The tumor was fed mainly by the ventral branch of the left renal artery.
| before the operation | after the operation | ||
|---|---|---|---|
| Insulin | uU/ml | 3.1 | 17 |
| Adrenaline | pg/ml | 77 | 12 |
| Noradrenaline | pg/ml | 1,097 | 287 |
| Dopamine | pg/ml | 28 | 23 |
| Cortisol | ug/ml | 19.3 | 7.7 |
| DHEA-S | ng/ml | 382 | 75 |
| Aldosteron | pg/ml | 68 | 53 |
| Renin | pg/ml/h | 1.5 | 0.2 |
| ACTH | pg/ml | 16 | 40 |
| GH | ng/ml | 3.01 | |
| TSH | μU/ml | 1.5 | |
| FT3 | pg/ml | 2.95 | |
| FT4 | ng/ml | 1.42 | |
| IGF-I | ng/ml | 16.7 | 110 |
| IGF-II | ng/ml | 889 | 379 |
| IGFBP-3 | µg/ml | 0.86 | 2.29 |
| U-17-KS | mg/day | 42.3 | 2.6 |
| U-17-OHCS | mg/day | 118 | 4.3 |
| U-VMA | mg/day | 1.6 | |
DHEA-S: dehydroepiandrosterone sulfate, ACTH: adrenocorticotro- pic hormone, GH: growth hormone, TSH: thyroid stimulating hor- mone, FT3: free 3, 3’, 5’-triiodothyronine, FT4: free thyroxine, IGF- I: insulin-like growth factor I, IGF-II: insulin-like growth factor II, IGFBP-3: insulin-like growth factor binding protein-3, U-17-KS: urin 17-ketosteroids, U-17-OHCS: 17-hydroxycorcicosteroids, U-VMA: urin vanillylmandelic acid.
Based on these clinical and laboratory findings, we made a provisional diagnosis of left adrenocortical carcinoma with Cushing’s syndrome. And also we supposed that hypoglyce- mic attacks and hypokalemia may be due to IGF-II produced by the tumor. Before the surgery, she had been treated with the administration of glucose (233 g per day by oral intake and 180 g per day by intravenous administration) for frequent hy- poglycemic attacks, and severe hypoglycemia was prevented. Hypokalemia had been cured with the administration of 90 mEq potassium per day, but it was difficult to maintain the serum potassium within the normal range.
In an exploratory surgery on June 28, 1999, the tumor was resected with the left kidney, because it was impossible to sepa- rate the tumor from the left kidney. The tumor was about 10 cm in diameter, and contained gel contents in the center (Fig. 1). On visible impression, normal adrenal gland was not found in the tumor. On microscopic findings, hematoxylin-eosin (HE) staining showed that the tumor contained little normal adrenal gland tissue and most of the tumor was composed of the com- pact cells arranged in a diffuse growth pattern (Fig. 2). The clear cells accounted for less than 25% in the tumor. And also it contained the cells with grade III nuclear atypia defined by Fuhrman et al (1) and small necrotic lesions. Based on the above findings, the pathological diagnosis of the adrenocortical car-
Hypoglycemia Associated with IGF-II
4
5
2
-
V
-1
1
30
83
20
1
2
5
4
5
10007 0557
1999-
cinoma was made according to the diagnostic criteria of ma- lignancy of adrenocortical tumors defined by Weiss (2). Also we immunohistochemically stained the formalin-fixed and par- affin embedded tumor tissue sections for insulin (using rabbit polyclonal antibody; DAKO) (Fig. 3) and IGF-II (using mouse
monoclonal antibody; Amano Pharmaceutical Co.) (Fig. 4) employing labeled streptavidin-biotin-peroxidase method (DAKO) with 3,3’-diaminobenzine as a chromogen and hema- toxylin for nuclear counterstaining. The tumor cells were nega- tive for insulin. However, they were positive for IGF-II, stain-
0
ing a brownish color in the Golgi area near the nucleus of some tumor cells. This staining pattern is typical for NICTH (3-5).
After the operation, her pyrexia and abdominal pain im- proved. Also the hypoglycemic attacks no longer occurred. The serum levels of IGF-II, IGF-I, IGFBP-3, catecholamine, po- tassium, CRP, LDH, and y-GTP were all normalized (Table 2).
Discussion
Since Nadler and Wolfer described a case of hepatic cell carcinoma associated with hypoglycemia in 1929 (6), other cases of NICTH have been reported and investigated. Among these NICTH cases, 45% were mesenchymoma; 23% hepatic cell carcinoma; 10% adrenocortical carcinoma; 8% carcinoma in digestive organs; and there were also lymphoma, leukemia, and pheochromocytoma (7). We presented the sixth case in Japan of adrenocortical carcinoma associated with hypoglyce- mia (8, 9).
The etiology of NICTH has been proposed to be multifacto- rial as follows: 1 excessive glucose utilization by the tumor, 2 inhibition of glycogenolysis and gluconeogenesis by pri- mary or metastatic tumor in the liver, 3 suppression of counter- regulatory hormones for insulin, 4 insulin-like activity (ILA) produced by the tumor, and 5 increased anabolic steroids pro- duced by the tumor. Here, the proposed etiology 1 was sup- ported by the result that glycogen content in the tumor tissue had been much lower than that in the normal tissue (8). As for the proposed etiology 2 (10-13), some NICTH cases did not have tumors in the liver, therefore this theory has not been con- clusive. Regarding the proposed etiology 3, the suppression of counter-regulatory hormones for insulin have not been proved actually in any studies. About the proposed etiology 5, some investigators speculated that the increased secretion of anabolic steroids by the tumor leads to the increment in consumption of
amino acids, following the decrement in gluconeogenesis (8, 14). However this theory also needs some investigation, be- cause Scholz et al reported a case of NICTH showing that the daily urinary excretion of 17-KS was not increased (14).
As for the proposed etiology 4, several investigators have tried to prove the elevation of ILA in NICTH patients, because they failed to detect an increased IRI. At first, the elevation of non-suppressible insulin-like activity (NSILA) in acid-ethanol was detected in the cases of NICTH (15), and then increased levels of IGF-II were proven in the serum (16-22) and the tu- mor extracts (23-25). Moreover, immunohistochemical stain- ing method using IGF-II antiserum allowed the detection of IGF-II localization in the tumor (23-25). In the present case, the serum level of IGF-II before the operation was elevated and the tumor tissue stained positively for IGF-II immunohistochemically. Moreover, the serum level of IGF-II was normalized after the removal of the tumor, and hypogly- cemic attacks no longer occurred after the operation. These findings suggest that the tumor may overproduce IGF-II and hypoglycemic attacks may be due to IGF-II.
Some investigators have reported that the molecular weight of tumor-derived IGF-II is higher than normal IGF-II, which is called “big IGF-II”. In the present case, we measured total IGF- II including normal and big IGF-II, and did not distinguish big IGF-II from the normal one. However the report by Hizuka et al (26) suggests that the big IGF-II level in the serum in the present case may be elevated, because they have reported that IGF-II/IGF-I ratios in the serum were higher than 20 in NICTH patients with elevated serum levels of big IGF-II, and the IGF- II/IGF-I ratio in our case was 53.
In the present case, the level of potassium in the serum was low before the operation and it was difficult to maintain a level within the normal range even when loading potassium intrave- nously. However, after the operation, it was possible to main- tain the serum potassium level within the normal range only by diet intake. Therefore, we suppose that the hypokalemia also may be due to IGF-II produced by the tumor, because in- sulin and IGF lead extracellular potassium into the cells.
In the hospital, the patient had a high fever and abdominal pain with hypoglycemic attacks and the progression of hy- pokalemia. Together with both CRP and LDH increment, these may be caused by the outflow of inflammatory substances and IGF-II from the necrotic lesion of the center of the tumor to the systemic blood flow. And sudden tumor enlargement is also suggested as another possibility.
In conclusion, we have reported a case of adrenocortical carcinoma with NICTH. In this disease, using an immunohis- tochemical method, we have proved IGF-II produced by the tumor, which is the first report in Japan. It will be necessary to further analyze the production of big IGF-II by Western blot- ting.
Acknowledgements: We thank Professors Tetsu Yamaguchi and Hironori Hirai, the Third Department of Internal Medicine, Toho University Ohashi Hospital, for their helpful critique.
Hypoglycemia Associated with IGF-II
Reference
1) Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morpho- logic parameters in renal cell carcinoma. Am J Surg Pathol 6: 655-663, 1982.
2) Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 8: 163-169, 1984.
3) Zapf J. Role of insulin-like growth factor II and IGF binding proteins in extrapancreatic tumor hypoglycemia. Horm Res 42: 20-26, 1994.
4) Wasada T, Hizuka N, Yamamoto M, et al. An insulin-like growth factor II producing histiocytoma associated with hypoglycemia. Metabolism 41: 310-316, 1992.
5) Aiba M, Hizuka N. Immunohistochemical studies of 15 cases with non- islet cell tumor hypoglycemia (NICTH). Clinical Endocrinology 46 (Suppl): 145-155, 1998 (in Japanese).
6) Nadler WH, Wolfer JA. Hepatogenic hypoglycemia associated with pri- mary liver cell carcinoma. Arch Inter Med 44: 700-710, 1929.
7) Kahn CR. The riddle of tumor hypoglycemia revisited. Clin Endocrinol Metab 9: 335-360, 1980.
8) Yoshikawa K, Wakasa H. Hypoglycemia by adrenocortical carcinoma with Cushing’s syndrome. Tohoku J exp Med 132: 49-60, 1980.
9) Kamio T, Shigematsu K, Kawai K, Tsuchiyama H. Immunoreactivity and receptor expression of insulinlike growth factor I and insulin in human adrenal tumors. An immunohistochemical study of 94 cases. Am J Pathol 138: 83-91, 1991.
10) Unger RH. The riddle of tumor hypoglycemia. Am J Med 40: 325-330, 1966.
11) Silverstein MN, Wakim KG, Bahn RC. Tryptophan metabolites in hy- poglycemia associated with neoplasia. Cancer 19: 2024-2028, 1966.
12) Silverstein MN. Tumor hypoglycemia. Cancer 23: 142-144, 1969.
13) Rustin MH, Bowcock SJ, Coomes EN. Adrenocortical carcinoma with tumor-induced hypoglycemia. J R Soc Med 76: 74-75, 1983.
14) Scholz DA, Horton ES, Lebovitz HE, Ferris DO. Spontaneous hypogly- cemia associated with an adrenocortical carcinoma. J Clin Endocrinol Metab 27: 991-996, 1967.
15) Megyesi K, Kahn CR, Roth J, Gorden P. Circulating NSILA-s in man:
Preliminary studies of stimuli in vivo and of binding to plasma compo- nents. J Clin Endocrinol Metab 41: 475-484, 1975.
16) Daughaday WH, Emanuele 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 319: 1434- 1440, 1988.
17) Zapf J, Futo E, Peter M, Froesch ER. Can “big” insulin-like growth fac- tor II in serum of tumor patients account for the development of extrapancreatic tumor hypoglycemia? J Clin Invest 90: 2574-2584, 1992.
18) Enjoh T, Hizuka N, Perdue JF, et al. Characterization of new monoclonal antibodies to human insulin-like growth factor-II and their application in western immunoblot analysis. J Clin Endicrinol Metab 77: 510-517, 1993.
19) Ilvesmaki V, Kahri AI, Miettinen PJ, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: High IGF-II expres- sion in functional adrenocortical carcinomas. J Clin Endocrinol Metab 77: 852-858, 1993.
20) Gicquel C, Bertagna X, Schneid H, et al. Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocrinol Metab 78: 1444-1453, 1994.
21) Liu J, Kahri AI, Heikkila P, Ilvesmaki V, Voutilainen R. H19 and insulin- like growth factor-II gene expression in adrenal tumors and cultured ad- renal cells. J Clin Endocrinol Metab 80: 492-496, 1995.
22) Ilvesmaki V, Liu J, Heikkila P, Kahri AI, Voutilainen R. Expression of insulin-like gorwth factor binding protein 1-6 genes in adrenocortical tumors and pheochromocytomas. Horm Metab Res 30: 619-623, 1998.
23) Schneid H, Seurin D, Noguiez P, Le Bouc Y. Abnormalities of insulin- like growth factor (IGF-I and IGF-II) genes in human tumor tissue. Growth Regul 2: 45-54, 1992.
24) Liu J, Kahri AI, Heikkila P, Blum WF, Voutilainen R. Glucocorticoids increase insulin-like growth factor-II mRNA accumulation in cultured human pheochromocytoma cells. J Endocrinol 142: 29-35, 1994.
25) Pavelic K, Cabrijan T, Hrascan R, et al. Molecular pathology of hemangiopericytomas accompanied by severe hypoglycemia: oncogenes, tumor-suppressor genes and the insulin-like growth factor family. J Can- cer Res Clin Oncol 124: 307-314, 1998.
26) Hizuka N, Fukuda I, Takano K, Okubo Y, Asakawa-Yasumoto K, Demura H. Serum insulin-like growth factor II in 44 patients with non-islet cell tumor hypoglycemia. Endocr J 45 Suppl: S61-S65, 1998.