A case with insulinoma experiencing syndrome of inappropriate secretion of ADH/Insulinoma ve eslik eden uygunsuz ADH sendromu olan olgu.
Spontaneous fasting hypoglycemia in an otherwise healthy adult is most commonly due to insulinoma, an insulin-secreting tumor of the islets of Langerhans in pancreas (1,2). The most common clinical symptoms are due to the effect of hypoglycemia on the central nervous system (neuroglycemic symptoms), and include confusion, headache, disorientation, visual difficulties, irrational behaviour, or even coma. Also, most patients have symptoms due to excess catecholamine release secondary to the hypoglycemia, including sweating, tremor, and palpitations. Characteristically these attacks are associated with fasting (3). Insulinomas secrete additional hormones such as gastrin, adrenocorticotropic hormone, glucagon, human chorionic gonadotropin and somatostatin. The biochemical diagnosis is established during prolonged fasting (up to 72 hours) in 95% of the patients. The ratio of insulin ([micro]lu/ml) to plasma glucose (mg/dl) is diagnostic. In patients with insulinoma, the ratio rises during fasting (>0.25). Insulinoma resection is currently the therapy of choice (4).
SIADH is a relatively rare syndrome that has been associated with neurosurgery, hemorrhagic stroke, brain tumors, central nervous system infections, and respiratory infection (5). SIADH is also reported to be associated with the use of some drugs, e.g., neuroleptics such as oxcarbazepine, thiazides, etc. (6). Hypoglycemia stimulates AVID secretion through a mechanism that does not involve osmotic or hemodynamic alterations but rather involves the creation of intracellular glycopenia (7,8). Despite the known effect of hypoglycemia on AVID secretion, no case of SIADH or hyponatremia has been reported in an individual with insulinoma in the literature. The following is a case report of a patient with insulinoma and coexisting SIADH.
A 35-year-old woman was hospitalized for investigation of the etiology of her hypoglycemia. She had a medical history of epidural hematoma operation and hypertension one year before the hospitalization. At the second month of the cranial operation, she began to complain of weakness, dizziness, blurred vision, mild agitation. Especially in the mornings, she experienced slurred speech and a seizure. She was diagnosed as epilepsy and was given oxcarbazepine 300 mg per day. Her symptoms gradually increased up to twice a week. At the ninth month of the therapy she was admitted to the Emergency Department of Ankara University, School of Medicine, with a tonic-clonic convulsion. The plasma glucose concentration of the patient was found to be 34 mg/dl. So she was transferred to the Department of Endocrinology and Metabolic Diseases for advanced evaluation. Physical examination revealed a body mass index of 30.5 kg/m2. Her blood pressure was 120/80 mmHg; pulse was 84 beets per minute; temperature was 36.9[degrees]C; respiratory rate was 16 per minute. She had an operation scar on the temporoparietal side of the cranium. Abdominal and neurological examinations were normal. Laboratory investigations were as follows: Haemotocrit was 30.2%, haemoglobin was 9.8 g/dl, and white blood cell count was 5930 per mm'. Her sodium level was 123 mEq/L (normal range 136-145 mEq/L), potassium level was 4.6 mEq/L (normal range 3.5-5.1 mEq/L), blood urea nitrogen was 4 mg/dl (normal range 6-20 mg/dl). Because hyponatremia was noticeable, we tried to find out its etiology. Serum osmolarity was found to be as low as 242 mosm/kg (normal range 275-295 mosm/I). Twentyfour hour urine was collected and the urine sodium excretion was found to be 126 mEq/L (normal range 40-220 mEq/L), and the urine osmolarity was 701 mosm/kg (normal range 50-1200 mosm/kg), while urine creatinine was 990 mg/day. Her adrenocorticotropin (ACTH) level was 52.4 pg/ml (normal range 5-50 pg/ml), plasma cortisol level was 18.51 (6.2-19.4) in the early morning. This made the diagnosis of possible adrenocortical deficiency unlikely. Thyroid function tests were all within normal ranges.
For the diagnosis of epilepsy, electroencephalography (EEG) and cranial imaging were performed. No interictal activity was recorded during normal and sleeping EEG. Bitemporoparietal bone defect secondary to operation was seen in cranial computed tomography. In order to find the reason for hyponatremia, we did some more biochemical tests. Repeated serum sodium level was 118 mEq/L. Due to hyponatremic effect of oxcarbazepine, it was stopped and changed with valproic acid. We administered hypertonic (3%) saline infusion; the control serum sodium level was 123 mEq/L. Fluid restriction was started, which improved the hyponatremia, but the sodium levels did not normalize.
For the diagnostic evaluation of hypoglycemia, a prolonged fasting test was done. During prolonged fasting test, a typical hypoglycemic attack developed in the third hour, so the test was immediately terminated. Along with concomitant blood glucose level of 32 mg/dl, serum insulin level was 26.5 [micro]IU/ml, C-peptid was 6.8 ng/ml, and the insulin/glucose ratio was 0.82, confirming the diagnosis of insulinoma. For the localization of the tumor, endoscopic ultrasound was performed and a 18x19 mm lesion in the pancreatic neck was detected. The patient underwent surgery. Tumor was found and enucleated. Pathology confirmed the diagnosis of insulinoma. After the operation, hyperglycemia developed and persisted for a week, but there was no need for insulin application; plasma glucose levels never exceeded 250 mg/dl. In the follow up period she became euglycemic. Serum sodium levels were all found to be within normal ranges postoperatively (138 mEq/L, just after the operation), although fluid restriction was stopped and she was again given oxcarbazepine for epilepsy.
Surgical removal of the tumor led to full remission of the preoperative symptoms and signs associated with hypoglycemia and hyponatremia in this patient.
Insulinoma is the most common cause of tumor-induced hypoglycemia (1,2). The tumor may secrete insulin in short bursts, causing episodic hypoglycemia (4). Hypoglycemia causes adrenalin release, so adrenergic symptoms occur. Central nervous system dysfunction, known as neuroglycopenic symptoms, was temporally seen during prolonged fasting (4). SIADH is the most common neuroendocrine complication following traumatic brain injury, and its prevalence is as high as 33% (9). Oxcarbazepine, an aketo-analogue of carbamazepine, was approved for the treatment of seizures of partial onset (10). Hyponatremia after the use of oxcarbazepine is usually benign and asymptomatic as long as the acute water intoxication is effectively treated (11).Pendleburg and colleagues showed that the mean plasma sodium level fell from 137.5 mEq/L to 128.5 mEq/L in patients taking oxcarbazepine (12). In the literature oxcarbazepine-induced hyponatremia is not attributed to inappropriate secretion of AVID. Possible mechanisms include a direct effect of oxcarbazepine on the renal collecting tubules or an enhancement of their responsiveness to circulating AVID (13). Conversely in the literature, a case of inappropriate secretion of AVID after exposure to oxcarbazepine was reported (14). As the patient remained hyponatremic after the discontinuation of oxcarbazepine, and hyponatremia did not relapse after the oxcarbazepine administration following the surgical treatment of insulinoma, it can not be the cause of hyponatremia in our patient. It is important to recognize a paraneoplastic hormonal syndrome depending on the secretion of AVP by the tumor. By far, the most common umor associated with SIADH is small cell lung carcinoma (15). In the non-tumoral causes of SIADH, like head trauma, pneumonia, and chlorpropamide therapy, the plasma and urinary AVID concentrations are generally within normal ranges (16). As our patient was normonatremic after the epidural hematoma operation, it was hard to say that epidural hematoma was the underlying cause. Surgical removal of the tumor led to full remission of hyponatremia, so the secretion of AVID by the tumor might be suspected. We can not fully exclude the possibility of ectopic AVID secretion from the tumor, because we had not made immunohistochemical analysis for AVID postoperatively. However as the serum AVID level was in normal limits (2,5 pg/mL; normal range: 0-8 pg/mL), this was unlikely, in our opinion. Hypoglycemia stimulates AVID secretion through a mechanism that does not involve osmotic or hemodynamic alterations but rather involves the creation of intracellular glycopenia (17,18). AVID secretion has been dissociated from peripheral mechanisms of control and is under the control of central nervous system pathways whose functions are sensitive to changes in glucose metabolism (19). Seckl et al. investigated the AVID response to insulin-induced hypoglycemia in children. 14 children without diabetes insipidus or hypothalamo-pituitary dysfunction were enrolled into the study. The results suggested that insulin-induced hypoglycemia does not reliably stimulate AVID secretion in children (20). Kamoi et al. suggested that the mild hypoglycemia observed in two patients diagnosed adrenal insufficiency might be a primary stimulus for AVID secretion (21).
In the literature, there is no reported case diagnosed as insulinoma associated with SIADH. From this point of view, this is the first case with insulinoma presenting with persisting hyponatremia and improving after the insulinoma resection. In our opinion, the reason beyond this pathological condition was the hypoglycemia induced hyponatremia. Whether hypoglycemia causes hyponatremia through a mechanism via AVID stimulation directly from the central nervous system or some other peripheral mechanisms are involved in this situation is the matter of debate.
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(18.) Baylis PH, Heath DA. Plasma arginine-vasopressin response to insulin-induced hypoglycemia. Lancet. 1977; 310: 428-30.
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(20.) Seckl JR, Dunger DB, Huen K, Lightman L. The plasma arginine vasopressin response to insulin-induced hypoglycemia in children with short stature is related to age and the onset of puberty. Clin Endocrinol (Oxf).1987; 26: 347-53.
(21.) Kamoi K, Tamura T, Tanaka K, Ishibashi M, Yamaji T. Hyponatremia and osmoregulation of thirst and vasopressin secretion in patients with adrenal insufficiency. Clin Endocrinol Metab. 1993; 77:1584-8.
Ozgur Demir, Muyesser Sayki Arslan, Rifat Emral
Ankara University, School of Medicine, Endocrinology and Metabolic Diseases, Ankara, Turkey
Address for Correspondence: C.egor Demir, MD, Ankara University, School of Medicine, Endocrinology and Metabolic Diseases, Ankara, Turkey Phone: +90 312 508 21 00 Fax: +90 312 309 45 05 E-mail: firstname.lastname@example.org Recevied: 09.05.2009 Accepted: 22.08.2009
Turkish Journal of Endocrinology and Metabolism, published by Galenos Publishing. All rights reserved.
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|Author:||Demir, Ozgur; Arslan, Sayki; Emral, Rifat|
|Publication:||Turkish Journal of Endocrinology and Metabolism|
|Article Type:||Case study|
|Date:||Jun 1, 2009|
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