Amiodarone-induced syndrome of inappropriate antidiuresis with hepatic transaminitis

Abstract

A 72-year-old woman with hypertrophic cardiomyopathy was admitted to the hospital after an appropriate implantable cardioverter-defibrillator shock for ventricular fibrillation. She was discharged after the addition of amiodarone. Eight months after discharge, she was admitted to the hospital with a sign of somnolence. She had low levels of serum sodium and plasma osmolality, as well as hepatic transaminitis. She underwent a computed tomography scan, which detected high liver density. Amiodarone-induced syndrome of inappropriate antidiuresis with hepatic transaminitis was diagnosed, and amiodarone was discontinued. After discharge, her hepatic transaminitis improved, and there was no recurrence of hyponatremia with a sign of somnolence. Amiodarone is an important drug used to treat ventricular arrhythmias. However, it has a variety of adverse effects. Syndrome of inappropriate antidiuresis is a rare complication of amiodarone. If hyponatremia occurs after starting amiodarone, this complication should be considered.

Learning objective

Amiodarone is an important drug used to treat ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation. However, amiodarone has a variety of adverse effects. Syndrome of inappropriate antidiuresis is a rare complication of amiodarone. If hyponatremia occurs after starting amiodarone, this complication should be considered.

Introduction

Amiodarone, an important drug used to treat ventricular arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF), has a variety of adverse effects, including pulmonary dysfunction and thyroid toxicity [1]. Therefore, patients taking amiodarone should be carefully monitored. Syndrome of inappropriate antidiuresis (SIAD) and hepatic transaminitis are rare complications of amiodarone. We herein report our experience with a patient who developed both SIAD and hepatic transaminitis induced by amiodarone and review the associated literature.

Case report

A 72-year-old woman was admitted to the hospital after an appropriate implantable cardioverter-defibrillator (ICD) shock for VF. She had a past medical history of hypertrophic cardiomyopathy, paroxysmal atrial fibrillation, hypertension, and dyslipidemia. Twelve years previously, she had undergone an ICD implantation due to the induction of VF during an electrophysiological study. The results of her physical examination were as follows: height 150.0 cm, weight 41.6 kg, body mass index 18.5 kg/m². Her oral medications were bisoprolol (2.5 mg/day), edoxaban (30 mg/day), pravastatin (10 mg/day), and eperisone (150 mg/day). She was discharged after the addition of amiodarone (200 mg/day). The laboratory data on admission are shown in Table 1A.

Table 1.

Laboratory data.

Laboratory data	Value (A)	Value (B)	Value (C)	Reference
White blood cells (×103/μL)	7.4	10.6	6.0	3.3–8.6
Red blood cells (×104/μL)	372	381	349	386–492
Hemoglobin (g/dL)	11.9	12.7	10.6	11.6–14.8
Platelet count (×104/μL)	28.8	32.0	27.2	15.8–34.8
AST (U/L)	26	76	25	13–30
ALT (U/L)	19	80	16	7–23
Total bilirubin (mg/dL)	0.6	1.1	0.6	0.4–1.5
γ-GTP (U/L)	21	53	38	9–32
LDH (U/L)	176	198	170	124–222
CHE (U/L)	269	266	264	201–421
Urea (mg/dL)	16	15	19	8–20
Creatinine (mg/dL)	0.68	0.56	0.75	0.46–0.79
Serum sodium (mmol/L)	131	114	132	138–145
Serum potassium (mmol/L)	5.2	4.5	4.8	3.6–4.8
Serum chloride (mmol/L)	95	77	96	101–108
S-OSM (mOsm/kg)	–	237	279	275–290
U-OSM (mOsm/kg)	–	550	503	50–1300
Urinary sodium (mmol/L)	–	67	140	–
Plasma renin activity (ng/mL/h)	–	0.2	–	0.2–2.3
ACTH (pg/mL)	–	64.0	–	7.2–63.3
ADH (pg/mL)	–	23.3	–	≤2.8
Cortisol (μg/dL)	–	31.8	–	7.07–19.6
Free T3 (pg/mL)	2.76	2.10	3.08	2.30–4.00
Free T4 (ng/dL)	1.47	2.36	1.83	0.90–1.70
TSH (μIU/mL)	1.510	2.960	3.050	0.500–5.000

Value (A) Admission due to appropriate implantable cardioverter-defibrillator shock for ventricular fibrillation. Value (B) Admission due to hyponatremia. Eight months after amiodarone treatment. Value (C) Three months after discontinuing amiodarone.

ACTH, adrenocorticotropin; ADH, antidiuretic hormone; ALT, alanine transaminase; AST, aspartate transaminase; CHE, cholinesterase; γ-GTP, gamma-glutamyl transpeptidase; LDH, lactate dehydrogenase; S-OSM, serum osmolality; TSH, thyroid-stimulating hormone; U-OSM, urine osmolality.

Eight months after the addition of amiodarone, she was admitted to the hospital with a sign of somnolence. Her weight was 39.7 kg, and she had no bilateral lower leg edema. She had a serum sodium level of 114 mmol/L, a serum chloride level of 77 mmol/L, a serum osmolality of 237 mOsm/kg, a urine osmolality of 550 mOsm/kg, a urinary sodium level of 67 mmol/L, and a plasma renin activity level of 0.2 ng/mL/h, which were suggestive of SIAD. She had neither severe hypothyroidism nor severe hypocortisolism (Table 1B). In addition, she did not take any diuretics, including thiazides. She also had elevated levels of serum aspartate transaminase (AST; 76 U/L) and alanine transaminase (ALT; 80 U/L) levels (Table 1B). The patient underwent a computed tomography (CT) scan, which showed no significant tumor lesions in the adrenal glands or central nervous system but high liver density (Fig. 1A), suggestive of amiodarone liver [2], [3]. Based on previously reported criteria [4], amiodarone-induced SIAD with hepatic transaminitis was diagnosed. Her hyponatremia was treated with saline and hypertonic saline (3 % sodium chloride).

Fig. 1.

Computed tomography. (A) Eight months after amiodarone treatment. (B) Three months after amiodarone discontinuation.

Amiodarone was discontinued at discharge, and bisoprolol was gradually increased to 5 mg/day for the treatment of VT/VF on an outpatient basis. After discharge, her hepatic transaminitis improved, and there was no recurrence of hyponatremia with a sign of somnolence (Table 1C). Three months after discharge, her CT showed that the CT density of the liver had decreased (Fig. 1B). Laboratory data and treatments are shown in Fig. 2.

Fig. 2.

Laboratory data and treatments in this patient.

ALT, alanine transaminase; AST, aspartate transaminase.

Discussion

Amiodarone is a class III antiarrhythmic drug used to treat ventricular arrhythmias such as VT and VF [1], [5]. However, amiodarone has a variety of adverse effects, including pulmonary dysfunction and thyroid toxicity [1], [5]. Since its first description in 1999 [6], SIAD has been reported as an extremely rare complication of amiodarone. Amiodarone-induced SIAD has been reported with both oral and intravenous treatment and with both acute and chronic onsets [7]. Aslam et al. reported that amiodarone-induced SIAD was a dose-dependent complication [8]. Therefore, it is possible that we should have reduced the dose of amiodarone to 100 mg/day during the treatment of our present case. There is no consensus on the mechanism of amiodarone-induced SIAD due to a lack of evidence, and further studies are needed to reveal this mechanism.

Interestingly, this patient had not only SIAD but also hepatic transaminitis caused by amiodarone. Hepatotoxicity due to amiodarone is another complication [1], [5]. In the present case, laboratory data and CT imaging were suggestive of hepatotoxicity caused by amiodarone [2], [3]. To the best of our knowledge, this is the first case of the development of both SIAD and hepatic transaminitis due to amiodarone treatment. In our patient, amiodarone treatment was discontinued. A previous report described a case of rechallenging amiodarone treatment after the development of amiodarone-induced SIAD [7]. On the other hand, another previous report suggested that amiodarone should be discontinued in cases of doubled AST/ALT levels [5]. In our case, we increased bisoprolol to 5 mg/day to prevent VT/VF recurrence after discontinuing amiodarone. If VT/VF occurs in our case in the future, a rechallenge of amiodarone would be difficult due to hepatotoxicity. Therefore, control with catheter ablation or other antiarrhythmic drugs should be considered. Patients who receive amiodarone treatment must be carefully followed up with liver function monitoring.

Conclusion

Amiodarone-induced SIAD and hepatotoxicity are important complications of amiodarone. Patients taking amiodarone must be carefully monitored.

Consent statement

Written informed consent was obtained from the patient.

Conflicts of interest

The authors declare that there are no conflicts of interest.