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Case Reports in Urology
Volume 2014, Article ID 136984, 6 pages
http://dx.doi.org/10.1155/2014/136984
Case Report

Amiodarone Induced Hyponatremia Masquerading as Syndrome of Inappropriate Antidiuretic Hormone Secretion by Anaplastic Carcinoma of Prostate

1Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Nehru Hospital, 4th Floor, F Block, Chandigarh 160012, India
2Department of Urology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
3Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
4Department of Laboratory Medicine and Surgical Pathology, St. Michael’s Hospital, Room 2-101V, 30 Bond Street, Toronto, ON, Canada M5B 1W8

Received 31 January 2014; Accepted 2 March 2014; Published 8 April 2014

Academic Editor: Ravishankar Jayadevappa

Copyright © 2014 Pinaki Dutta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hyponatremia. The usual causes are malignancies, central nervous system, pulmonary disorders, and drugs. Amiodarone is a broad spectrum antiarrhythmic agent widely used in the management of arrhythmias. The different side effects include thyroid dysfunction, visual disturbances, pulmonary infiltrates, ataxia, cardiac conduction abnormalities, drug interactions, corneal microdeposits, skin rashes, and gastrointestinal disturbances. SIADH is a rare but lethal side effect of amiodarone. We describe a 62-year-old male who was suffering from advanced prostatic malignancy, taking amiodarone for underlying heart disease. He developed SIADH which was initially thought to be paraneoplastic in etiology, but later histopathology refuted that. This case emphasizes the importance of detailed drug history and the role of immunohistochemistry in establishing the diagnosis and management of hyponatremia due to SIADH.

1. Introduction

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hyponatremia. This syndrome is caused by various malignancies, lung diseases, central nervous system disorders, and drugs. The commonest malignancy associated with SIADH is small cell carcinoma of the lung [1]. There are a few case reports of SIADH in patients with small cell and anaplastic carcinoma of prostate [2]. Amongst various drugs selective serotonin reuptake inhibitors, carbamazepine, thiazide diuretics, chlorpropamide, and alkylating agents are commonly associated with SIADH [36]. Amiodarone is extensively used in clinical practice for a wide variety of arrhythmias. The adverse effect profile is very broad; however, there are very few cases of hyponatremia due to SIADH reported with this drug [716]. We describe one such case in an elderly male which was initially thought to be due to ectopic secretion of vasopressin by an anaplastic carcinoma of prostate but later refuted by immunohistochemistry of the tumor and normalization of serum sodium level following omission of amiodarone.

2. Case Report

A 63-year-old male, known to be hypothyroid for the past three years, on treatment with 100 μg of L-thyroxine presented to his primary care physician with history of 3 episodes of syncopal attacks 8 months back. He was a smoker with history suggestive of chronic bronchitis. He was also hypertensive for the last 4 years. His blood pressure was stable on 100 mg of losartan per day. Electrocardiogram and 24-hour holter revealed runs of ill sustained ventricular tachycardia and he was started on 100 mg of amiodarone per day 8 months back. He had history of prostatism since 2008 and was on tamsulosin 0.4 mg once daily. He had some relief, but in 2010 there was recurrence of symptoms. His ultrasound revealed enlarged prostate of size 5.2 × 4.8 × 5.4 cm with a residual urine volume of 75 mL. The serum prostate specific antigen (PSA) was found to be elevated (152 ng/mL, normal <5). MRI of prostate reconfirmed the same and showed ill-defined low intensity signal in peripheral zone of prostate and adjacent portion of bilateral seminal vesicles suggestive of stage III disease (Figures 1(a) and 1(b)). Biopsy showed adenocarcinoma of the prostate (Gleason’s Grade 3 + 3). Bone scan was normal and he had normal serum electrolyte at that time. The patient was started on goserelin acetate (Zoladex 10.8 mg) once every three monthly as he refused orchidectomy. The PSA level decreased to 6 ng/mL in mid-2012. In May 2013, he was hospitalized elsewhere with acute urinary retention requiring catheterization followed by hematuria. His sonogram of the prostate showed the same findings and PSA was 23.16 ng/mL at this juncture. He was subjected to bilateral orchidectomy, cystoscopy, and transurethral prostate resection (Figure 2). Two months later he presented with generalized tiredness and disorientation. His hemoglobin was 8.8 gm/dL, urea 20 mg/dL, creatinine 0.8 mg/dL, sodium 124 mmol/L, potassium 3.9 mmol/L, uric acid 2.2 mg/dL, protein 5.4 g/dL, and serum albumin 3.6 g/dL. His liver function test was normal. He was started on fluid restriction, 10–15 gms of added salt per day, and tolvaptan 60 mg per day without much improvement in his symptoms. This time he was admitted to our hospital for further evaluation and treatment. On evaluation, his hemoglobin was 8.6 mg/dL, and he had normal renal function, sodium 109 mmol/L, serum cortisol 738 nmol/L (N: 350–540), T3 1.2 ng/mL (N: 0.8–2.0), T4 10.2 μg/dL (N: 4.8–12.7), TSH 4.64 mIU/mL (N: 0.27–4.2), plasma osmolality 242 mOsm/kg (N: 275–295), urine osmolality 504 mOsm/kg (N: 50–1200), and spot urine sodium 105 mmol/L (N > 20). Follow-up bone scan revealed increased osteoblastic activity in right fifth rib suggestive of metastatic process. Fluorodeoxyglucose-positron emission tomography (FDG PET) showed avid lesions in the prostate, pelvic bones, abdominal lymph nodes, left transverse abdominal muscles, and liver. Tolvaptan was continued and patient was advised liberal oral salt (15 gms/day) and to restrict his fluid intake. Hyponatremia persisted despite these measures. It was thought to be because of SIADH due to ectopically secreted vasopressin from prostatic malignancy, which was negated by immunohistochemistry. A literature review at this juncture made us suspect the possibility of amiodarone induced hyponatremia. Amiodarone was stopped and on the third day of the discontinuation of the drug, serum sodium improved to 122 mmol/L. Metoprolol was introduced replacing amiodarone; however, patient succumbed to refractory ventricular tachycardia in the next five days. Autopsy could not be performed.

fig1
Figure 1: MRI showed ill-defined low intensity signal in peripheral zone of prostate and adjacent portion of bilateral seminal vesicles.
136984.fig.002
Figure 2: Resected prostatectomy specimen showing large prostatic mass with variegated appearance with infiltration of capsule and bilateral seminal vesicles.

Light microscopy of the biopsy specimen at our institute showed nontumorous prostate containing glands, muscle, and connective tissue. Adjacent to it there was a cellular neoplasm. The tumor exhibited a diffuse pattern arranged predominantly in sheets, nests, and trabeculae and is composed of relatively small pleomorphic cells possessing a narrow rim of mildly acidophilic cytoplasm, elongated or rounded hyperchromatic nuclei, and inconspicuous nucleoli. Apoptotic nuclei and mitotic figures (6–8/10 hpf) are easily recognized. The tumor was seen infiltrating the muscle. Numerous bizarre tumor cells are also seen. In addition 2% of tumor cells showed back to back arrangement in glandular configuration. For immunohistochemistry, the streptavidin-biotin-peroxidase complex method was used. The tumor cells were positive for CD-56 and neuron specific enolase (Figures 3(a) and 3(b)) and conclusively negative for vasopressin and neurophysin (the carrier protein of vasopressin, Figures 3(c) and 3(d)). No immunopositivity was noted in the tumor cells for prostate specific antigen (PSA, Figure 3(e)). Immunostaining performed for Ki-67 using MIB-1 antibody showed abundant nuclear positivity indicating a rapid cell proliferation rate (Figure 4). Additionally, the tumor cells were negative for LCA, TTF-1, and chromogranin. These findings were suggestive of dedifferentiation of small cell carcinoma of patients towards an anaplastic carcinoma.

136984.fig.003
Figure 3: ((a) and (b)) Microphotograph from the prostate shows a tumor present in sheets with hyperchromatic nuclei and scanty cytoplasm consistent with morphology of small cell carcinoma H&E ×200. Insets show (a) tumor cells at high power which show moulding H&E ×400 and (b) strong positivity with neurone specific enolase IHC ×100. (c) Immunohistochemistry showing vasopressin negativity. (d) Immunohistochemistry for the carrier protein neurophysin is negative. (e) Immunohistochemistry for prostate specific antigen (PSA) is conspicuously negative suggestive of dedifferentiated tumor.
136984.fig.004
Figure 4: Immunohistochemistry showing strong positivity for Ki-67, a marker for proliferation.

3. Discussion

SIADH was first reported by Schwartz et al. in 1957 in patients with bronchogenic carcinoma and meningitis [1]. The essential criteria include normovolemic hyponatremia in a patient who is euthyroid and eucortisolic [5]. In 1971 four cases of chlorpropamide-induced hyponatremia were described by Weissman et al. [5]. Since then, a variety of drugs have been added to the list of drugs that cause SIADH.

The clinical symptoms of SIADH are nonspecific and are essentially those of hyponatremia. The magnitude and rate of development of hyponatremia determines the presence and severity of symptoms. In general, slowly progressive hyponatremia is associated with fewer symptoms. Patients with moderate chronic hyponatremia may have decreased reaction time, cognitive slowing, and ataxia resulting in frequent falls. Sudden significant decline in serum sodium may lead to altered sensorium and seizures. The symptoms pertaining to the etiology of SIADH may be present if the underlying cause is CNS or pulmonary disorders.

Amiodarone, a benzofuran derivative, was developed by a Belgian company (Labaz) in 1961 by Tondeur and Binon as an antianginal drug. Since then it has been used extensively as a broad spectrum antiarrhythmic agent [17]. The first case of amiodarone-induced hyponatremia was reported in 1996. To the best of our knowledge a total of 11 cases of amiodarone-induced SIADH have been published in English literature [716]. The summary of reported cases is shown in Table 1.

tab1
Table 1: Summary of cases of SIADH Induced by amiodarone, including the present case.

Amongst the 11 reported cases, the majority (9/11) were elderly men. Elderly subjects as such appear to be particularly at risk for drug-induced SIADH. In a study of 736 cases of selective serotonin reuptake inhibitor-induced SIADH, 75% of patients were over 65 years of age [46].

The time from the introduction of amiodarone to the development of SIADH varied from 3 days to 6 months in the reported cases. The hyponatremia usually occurred within the first 2 weeks in those who received loading doses of amiodarone. In contrast, it occurred at 2 weeks to 6 months in patients receiving maintenance doses. The level of serum sodium varied from 105 to 120 (mean = 115) mmol/L.

In 7 cases, the serum sodium level normalized within 7–14 days after discontinuation of amiodarone along with fluid restriction. In our case the serum sodium started improving within 3 days of stoppage of the drug. Amiodarone-induced SIADH seems to be more prevalent after a loading dose of the drug. However, because of the long half-life of amiodarone, the cumulative effect on the development of SIADH remains undefined. Amiodarone-induced SIADH is a rare adverse effect, which occurs predominantly in elderly patients, who typically have multiple comorbidities, especially cardiovascular disease.

The only definitive treatment of SIADH is the elimination of its underlying cause. In all but 3 cases, amiodarone was discontinued and fluid restriction was instituted. In the remaining cases, the dose was decreased. One patient required hemodialysis due to low serum sodium accompanied by development of altered mental status.

The mechanism of SIADH secondary to amiodarone and why it occurs in a limited number of cases exposed to the drug are unclear. It could possibly be due to the independent secretion of arginine vasopressin relative to plasma osmolality or inherited mutations of the aquaretic (i.e., water channel regulating) vasopressin receptor. Most medications cause SIADH either by sensitizing the kidneys to antidiuretic hormone, by stimulating the release of antidiuretic hormone, or by both. Of note Shavit and Sherer speculated that amiodarone might induce SIADH by its channel-modulating properties on either renal or neural tissues [13]. It is definitely not due to thyroid dysfunction as none of the reported cases were hypothyroid.

The severity of hyponatremia directly correlates with mortality in hospitalized patients [3, 18]. Therefore symptomatic treatment as well as removal of the cause, if possible, is required. In the index case, we continued tolvaptan, restricted fluid, and gave liberal salt. With these measures the hyponatremia improved as happened in previously reported cases [19].

In the index case initially the SIADH was suspected to be due to ectopic secretion of vasopressin by the advanced prostatic malignancy as there are instances of it in the literature [2]. However negativity of the histopathology specimen for vasopressin and neurophysin is against it. There is a remote possibility that vasopressin was released from and not stored in the tumor cells. This suggestion is unlikely because immune-positivity is practically always seen in tumors producing excessive amount of hormones ectopically. As our patient was euthyroid and eucortisolic without any underlying kidney disease, amiodarone treatment appeared to be the cause of SIADH. This study provides substantial evidence that amiodarone was responsible for SIADH. This was confirmed by improvement in patient’s hyponatremia within 3 days of discontinuation of the drug.

In conclusion, this is a case of SIADH due to an iatrogenic reason. Prostate cancer was erroneously thought to be the cause. Amiodarone induced SIADH can occur as early as 3 days after receiving a loading dose or as late as 6 months in patients on maintenance doses. Elderly males appear to be more predisposed. High index of suspicion is required to suspect this rare but life threatening adverse event when treating patients with amiodarone. The severity of hyponatremia directly correlates with increased mortality.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

The authors are thankful to Dr. Vladimir Iakovlev, M.D., FRCPC, FCAP Department of Laboratory Medicine and Surgical Pathology, St. Michael’s Hospital, Toronto, Canada, for interpreting the histopathology slides along with Professor Kalman Kovacs. The authors also express their gratitude to Ms. Shallu Singhmar for typing the paper and Mr. Brijlal, Department of Photography, for providing quality photographs.

References

  1. W. B. Schwartz, W. Bennett, S. Curelop, and F. C. Bartter, “A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone,” The American Journal of Medicine, vol. 23, no. 4, pp. 529–542, 1957. View at Google Scholar · View at Scopus
  2. S.-P. Chen, C.-H. Peng, and Y.-S. Yang, “Syndrome of inappropriate antidiuretic hormone secretion as an initial presentation of prostate cancer: a poor prognosis sign,” The Endocrinologist, vol. 19, no. 4, pp. 177–178, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. K. Belton and S. H. L. Thomas, “Drug-induced syndrome of inappropriate antidiuretic hormone secretion,” Postgraduate Medical Journal, vol. 75, no. 886, pp. 509–510, 1999. View at Google Scholar · View at Scopus
  4. B. A. Liu, N. Mittmann, S. R. Knowles, and N. H. Shear, “Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone associated with the use of selective serotonin reuptake inhibitors: a review of spontaneous reports,” Canadian Medical Association Journal, vol. 155, no. 5, pp. 519–527, 1996. View at Google Scholar · View at Scopus
  5. P. N. Weissman, L. Shenkman, and R. I. Gregerman, “Chlorpropamide hyponatremia: drug-induced inappropriate antidiuretic-hormone activity,” The New England Journal of Medicine, vol. 284, no. 2, pp. 65–71, 1971. View at Google Scholar · View at Scopus
  6. D. H. Ellison and T. Berl, “Clinical practice. The syndrome of inappropriate antidiuresis,” The New England Journal of Medicine, vol. 356, no. 20, pp. 2064–2072, 2007. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Odeh, E. Schiff, and A. Oliven, “Hyponatremia during therapy with amiodarone,” Archives of Internal Medicine, vol. 159, no. 21, pp. 2599–2600, 1999. View at Publisher · View at Google Scholar · View at Scopus
  8. A. I. M. Ruiz, A. C. Elipe, E. G. Vega, J. J. G. Martinez, E. V. Lopez, and C. G. Fernandez, “Pancreatitis and inappropiate ADH secretion syndrome associated with amiodarone,” Anales de Medicina Interna, vol. 13, no. 3, pp. 125–126, 1996 (Spanish). View at Google Scholar · View at Scopus
  9. G. P. Patel and J. B. Kasiar, “Syndrome of inappropriate antidiuretic hormone-induced hyponatremia associated with amiodarone,” Pharmacotherapy, vol. 22, no. 5, pp. 649–651, 2002. View at Google Scholar · View at Scopus
  10. M. K. Aslam, C. Gnaim, J. Kutnick, R. C. Kowal, and D. K. Mcguire, “Syndrome of inappropriate antidiuretic hormone secretion induced by amiodarone therapy,” Pacing and Clinical Electrophysiology, vol. 27, no. 6, pp. 831–832, 2004. View at Google Scholar · View at Scopus
  11. H. Ikegami, T. Shiga, T. Tsushima, T. Nirei, and H. Kasanuki, “Syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by amiodarone: a report on two cases,” Journal of Cardiovascular Pharmacology and Therapeutics, vol. 7, no. 1, pp. 25–28, 2002. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Paydas, F. Araz, and M. Balal, “SIADH induced by amiodarone in a patient with heart failure,” International Journal of Clinical Practice, vol. 62, no. 2, p. 337, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. E. Shavit and Y. Sherer, “Hyponatremia induced by amiodarone therapy,” Israel Medical Association Journal, vol. 9, no. 7, pp. 564–565, 2007. View at Google Scholar · View at Scopus
  14. S. Singla, A. L. Strobel, A. J. Deshmukh, and H. Paydak, “Amiodarone-related hyponatremia: rare but potentially lethal,” American Journal of Therapeutics, vol. 20, no. 5, pp. 564–565, 2013. View at Publisher · View at Google Scholar · View at Scopus
  15. F. Afshinnia, N. Sheth, and R. Perlman, “Syndrome of inappropriate antidiuretic hormone in association with amiodarone therapy: a case report and review of literature,” Renal Failure, vol. 33, no. 4, pp. 456–458, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. L. Pham, A. J. Shaer, and T. Marnejon, “Hyponatremia—a rare but serious complication of amiodarone: a case report and review of literature,” Case Reports in Nephrology and Urology, vol. 3, no. 1, pp. 46–50, 2013. View at Publisher · View at Google Scholar
  17. G. Deltour, F. Binon, R. Tondeur et al., “Studies in the benzofuran series—VI. Coronary-dilating activity of alkylated and aminoalkylated derivatives of 3-benzoylbenzofuran,” Archives Internationales de Pharmacodynamie et de Thérapie, vol. 139, pp. 247–254, 1962 (French). View at Google Scholar · View at Scopus
  18. G. Gill, B. Huda, A. Boyd et al., “Characteristics and mortality of severe hyponatraemia—a hospital-based study,” Clinical Endocrinology, vol. 65, no. 2, pp. 246–249, 2006. View at Publisher · View at Google Scholar · View at Scopus
  19. J. G. Verbalis, S. Adler, R. W. Schrier, T. Berl, Q. Zhao, and F. S. Czerwiec, “Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion,” European Journal of Endocrinology, vol. 164, no. 5, pp. 725–732, 2011. View at Publisher · View at Google Scholar · View at Scopus