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CASE REPORT
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Hyponatremia Associated with Hepatocellular Carcinoma Seong Kwon Ma 1, Sung Sun Kim 2, Eun Hui Bae 1 and Soo Wan Kim 1
Abstract Hyponatremia is the most common electrolyte abnormality in clinical practice, and a differential diagnosis of the etiologic disorders is crucial because hyponatremia is associated with many different disease states including malignancies. Although only a few cases of hyponatremia with hepatocellular carcinoma (HCC) have been previously reported, the abnormal expression of arginine vasopressin (AVP) in tumor cells has not been demonstrated. We herein present a rare case of hyponatremia associated with the aberrant expression of AVP in tumor cells of HCC. This case suggests that an extensive diagnostic work-up is needed in patients with hyponatremia because hyponatremia may provide diagnostic clues for the presence of other underlying disorders. Key words: hyponatremia, hepatocellular carcinoma, arginine vasopressin (Intern Med 55: 961-963, 2016) (DOI: 10.2169/internalmedicine.55.5780)
Introduction
Case Report
Hyponatremia is the most common electrolyte abnormality encountered in clinical practice, and it is significantly associated with morbidity and mortality (1-3). Making a differential diagnosis of the etiologic disorders is crucial and difficult because hyponatremia is associated with many different disease states, including various malignancies (4). In patients with malignancy, hyponatremia may result from chemotherapy, excessive hydration, and volume depletion related to nausea and vomiting. The ectopic production of arginine vasopressin (AVP) by tumor cells has been suggested as the primary mechanism of hyponatremia in malignancies (5). Hyponatremia associated with hepatocellular carcinoma (HCC) is very rare, and to date only 5 cases have been documented (6-10). However, the ectopic production of AVP in tumor cells of HCC has not yet been demonstrated. We herein present a rare case of hyponatremia associated with the increased expression of AVP in tumor cells of HCC, which was successfully treated by ablation of the tumor mass.
A 75-year-old man presented with dizziness. On admission, his blood pressure was 130/70 mmHg; body temperature, 36.1℃; pulse rate, 58 beats/min; and respiration rate, 18 breath cycles/min. His mental status was alert, and he did not have any edema. The laboratory data were as follows: white blood cell count, 6,000/mm3; hemoglobin, 11.0 g/dL; platelet count, 189,000/mm3; blood urea nitrogen, 4.5 mg/dL; serum creatinine, 0.7 mg/dL; sodium, 118 mEq/L; potassium, 3.4 mEq/L; chloride, 79 mEq/L; uric acid, 3.0 mg/dL; glucose, 89 mg/dL; and serum osmolality, 234 mosmol/kg. The sodium concentration of random urine was 163 mEq/L, and the urine osmolality was 387 mosmol/kg. Contrast-enhanced chest computed tomography (CT) showed no abnormal findings. However, contrast-enhanced CT of the abdomen revealed a 1.6 cm-sized lesion in the S6 segment of the liver. This lesion was enhanced during the arterial phase, and the contrast media was washed out in the portal and delayed phase (Fig. 1). The serum level of αfetoprotein (AFP) was 1.78 IU/mL (reference range, 0-5.8 IU/mL). An ultrasonography (US)-guided percutaneous biopsy for the hepatic lesion was performed. Hematoxylin and eosin staining of the hepatic lesion showed thick trabecular
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Department of Internal Medicine, Chonnam National University Medical School, Korea and ２Department of Pathology, Chonnam National University Medical School, Korea Received for publication May 18, 2015; Accepted for publication July 12, 2015 Correspondence to Dr. Soo Wan Kim,
[email protected]
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DOI: 10.2169/internalmedicine.55.5780
Figure 1. Abdominal computed tomography showed a 1.6 cm-sized lesion in the S6 segment of the liver. This lesion was enhanced during the arterial phase (left panel) and the contrast media was washed out in the portal and delayed phase (right panel).
Figure 2. (a) Histopathological findings of the hepatic lesion are compatible with a well-differentiated hepatocellular carcinoma (HCC) (Hematoxylin and Eosin staining, original magnification 400×). (b) Immunohistochemistry shows the aberrant expression of arginine vasopressin (AVP) in the tumor cells from the present patient with hyponatremia (original magnification 400×). (c) AVP immunoreactivity is not observed in the tumor cells from another HCC patient without hyponatremia (original magnification 400×).
architectures and relatively clear cytoplasm, which were consistent with well-differentiated HCC (Fig. 2a). Immunohistochemistry for AVP revealed cytoplasmic granular staining in the tumor cells of this patient (Fig. 2b), and tumor cells from another HCC patient without hyponatremia did not show AVP immunoreactivity (Fig. 2c). The patient was initially treated with intravenous replacement of normal saline. However, his serum sodium level decreased from 118 mEq/L to 114 mEq/L. After subsequently switching to a 3% hypertonic saline infusion with water restriction, the serum sodium concentration reached 125 mEq/L. Then, the hypertonic saline infusion was discontinued and treatment with 15 mg per day of tolvaptan was initiated. US-guided radiofrequency ablation for HCC was performed following the definitive diagnosis of HCC by the pathological examination.
After US-guided radiofrequency ablation for HCC, the patient’s sodium levels were maintained within the normal range.
Discussion Hyponatremia is associated with in-hospital mortality and has been suggested to be a critical prognostic factor (2, 3). Furthermore, hyponatremia is clinically relevant because it is an initial manifestation of various diseases, such as pulmonary tuberculosis, Guillain-Barré syndrome, encephalitis, pituitary adenoma, and primary central nervous system (CNS) lymphoma (11-15). In the present case, the patient did not present with any symptoms or signs of HCC, and hyponatremia was the initial manifestation of HCC. Furthermore,
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the serum AFP level was within the normal range. Thus this case implies that an extensive diagnostic work-up is crucial because hyponatremia may be an initial manifestation of underlying disorders. The essential findings of the diagnostic criteria for the syndrome of inappropriate antidiuresis (SIAD) are increased urine sodium concentration and osmolality in patients with euvolemic hypoosmolar hyponatremia (16). Although AVP plays a crucial role in the pathogenesis of SIAD, the plasma AVP level is evaluated as supplemental criteria and it is seldom used in clinical practice because of low plasma concentration, the instability of plasma AVP, and the reliability of plasma AVP measurement (17-19). In patients with malignancy, a leading cause of hyponatremia is the ectopic production of AVP by malignant cells (5). We previously documented the increased expression of AVP in tumor cells of primary CNS lymphoma presenting hyponatremia (15). Only a few cases of hyponatremia with HCC have been reported, however, the previous reports did not document the aberrant AVP expression in tumor cells (6-10). In the present case, we did not measure the plasma AVP level of the patient. However, the tumor cells of this patient showed increased AVP expression. After ablation therapy, the patient’s serum sodium level normalized. These findings suggest that the ectopic AVP production by HCC may play a role in the development of hyponatremia. In conclusion, we herein presented a rare case of hyponatremia associated with the aberrant expression of AVP in tumor cells of HCC, which was confirmed by the histopathological examination. This case suggests that an extensive diagnostic work-up is needed in patients with hyponatremia because hyponatremia may provide diagnostic clues for the presence of other underlying disorders. The authors state that they have no Conflict of Interest (COI). Financial Support This study was financially supported by Chonnam National University (2013-2575), Chonnam National University Hospital Biomedical Research Institute (CRI14012-1), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF2014R1A1A2058250).
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