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.
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 [
A 63-year-old male, known to be hypothyroid for the past three years, on treatment with 100
MRI showed ill-defined low intensity signal in peripheral zone of prostate and adjacent portion of bilateral seminal vesicles.
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
((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.
Immunohistochemistry showing strong positivity for Ki-67, a marker for proliferation.
SIADH was first reported by Schwartz et al. in 1957 in patients with bronchogenic carcinoma and meningitis [
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 [
Summary of cases of SIADH Induced by amiodarone, including the present case.
Serial number | Author and year | Age | Gender | Sodium level at diagnosis |
Amiodarone dose and duration | Time to develop hyponatremia | Management | Day on which serum sodium normalized |
---|---|---|---|---|---|---|---|---|
1 |
Ruiz et al. 1996 [ |
67 | F | 110 | Not mentioned | 4 Months | Discontinuation | Unknown |
2 |
Odeh et al. 1999 [ |
62 | F | 120 | 300 mg qd | 6 Months | Discontinuation | 5 Days |
3 |
Patel and Kasiar 2002 [ |
67 | M | 117 | 200 mg qd | 3 Months | Fluid restriction, Discontinuation of therapy | 3 Days |
4 |
Ikegami et al. 2002 [ |
63 | M | 119 | 800 mg qd | 7 Days | Amiodarone dose reduced to 100 mg qd, fluid restriction | 28 days |
5 |
Ikegami et al. 2002 [ |
87 | M | 121 | 200 mg qd for seven days then 100 mg qd | 15 Days | Fluid restriction only | 14 Days |
6 |
Aslam et al. 2004 [ |
72 | M | 117 | 2 g qd (loading dose) | 5 Days | Decrease dose to 200 mg qd | Normalized on 2nd day, Stable on 14th day |
7 |
Paydas et al. 2008 [ |
58 | M | 107 | Not mentioned | 5 Months | Cessation of treatment | 14 Days |
8 |
Shavit and sherer 2007 [ |
85 | M | 122 | Not mentioned | 30 Days | Cessation of treatment | A few days, stable at 3rd month |
9 |
Singla et al. 2013 [ |
66 | M | 120 | Loading followed by 400 mg four times a day | 3 Days | Discontinuation of amiodarone and hemodialysis | Not Mentioned |
10 |
Afshinnia et al. 2011 [ |
72 | M | 117 | 150 mg IV loading, 900 mg over 24 hours, 400 mg TDS | 7 days | 16 Days | |
11 |
Pham et al. 2013 [ |
84 | M | 105 | Loading followed by 400 mg 8 hourly ×3 days. Then 400 mg OD | 11 Days | Hypertonic saline, Fluid restriction, Demichlocycline, | 10 Days |
12 | Dutta et al. (Present Case) | 62 | M | 109 | 100 mg OD | 9 Months | Fluid restriction, stoppage of amiodarone | 3 Days |
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 [
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 [
The severity of hyponatremia directly correlates with mortality in hospitalized patients [
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 [
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.
The authors declare that there is no conflict of interests regarding the publication of this paper.
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.