Amiodarone-induced liver injury with bright liver sign: A case report

Abstract

BACKGROUND

Amiodarone is an antiarrhythmic drug with well-recognized hepatotoxicity; however, its radiologic appearance mimicking hepatic iron deposition has been rarely reported. We describe a case in which the initial imaging findings were misinterpreted as hemochromatosis, whereas the final diagnosis was amiodarone-induced liver injury (AILI).

CASE SUMMARY

An 85-year-old woman received oral amiodarone hydrochloride for 5 months for the treatment of atrial fibrillation and subsequently developed recurrent nausea, vomiting, and progressive elevation of liver enzymes. Given the well-documented medication history and a Roussel Uclaf Causality Assessment Method score of 8, AILI secondary to intrahepatic drug deposition was clinically suspected. Non-contrast chest computed tomography (CT) demonstrated diffusely increased hepatic attenuation, and hemochromatosis was initially diagnosed on imaging. However, abdominal magnetic resonance imaging (MRI) revealed mildly decreased hepatic signal intensity on T2-weighted imaging without other characteristic features of iron overload, and iron studies were within normal limits. AILI was subsequently diagnosed. Following discontinuation of amiodarone, the patient’s gastrointestinal symptoms resolved, and liver enzyme levels gradually returned to baseline.

CONCLUSION

Amiodarone deposition within the liver can result in hepatic injury accompanied by diffuse hepatic hyperattenuation on CT, mimicking other conditions associated with increased liver attenuation. MRI plays a crucial role in differential diagnosis. By combining this case with a review of the relevant literature, we summarize the characteristic imaging features of AILI to facilitate its diagnosis and management.

Key Words: Amiodarone; Hepatic iodine deposition; Drug-induced liver injury; Computed tomography; Magnetic resonance imaging; Hemochromatosis; Case report

Core Tip: We report a case of amiodarone-induced hepatic iodine deposition and review the relevant literature to highlight the key distinguishing features between amiodarone-induced liver injury (AILI) and hemochromatosis. Although diffuse hepatic hyperattenuation on computed tomography can be easily misdiagnosed as hemochromatosis, a normal T2-weighted imaging (T2WI) signal on magnetic resonance imaging, in contrast to the diffuse hypointensity across all sequences typically observed in hemochromatosis, may aid in differential diagnosis. However, mildly decreased hepatic signal intensity on T2WI does not definitively exclude AILI. Normal serum iron parameters further support an accurate differential diagnosis.

INTRODUCTION

Amiodarone is a Class III antiarrhythmic agent widely used in clinical practice, primarily for the treatment of arrhythmias such as atrial fibrillation and ventricular tachycardia. Amiodarone and its major metabolite, desethylamiodarone, are highly lipophilic, possess a large volume of distribution, and are predominantly metabolized in the liver. With a half-life ranging from 25 days to 100 days, these compounds tend to accumulate in lipid-rich tissues, including the liver, lungs, and cornea, leading to toxic effects. Available data indicate that the incidence of adverse events is approximately 15% during the first year of treatment and may reach 50% in patients receiving long-term therapy[1]. These adverse effects include corneal deposits, thyroid dysfunction, interstitial pneumonitis, and multiorgan injury, including liver damage and even cirrhosis[2-5].

Amiodarone-induced liver injury (AILI) encompasses a broad spectrum of clinical manifestations. Most patients present with asymptomatic elevations in liver enzyme levels, whereas a small proportion may progress to liver cirrhosis and fatal hepatic failure, posing a substantial threat to survival. Evidence suggests that liver cirrhosis may develop after a mean cumulative amiodarone dose of 280 g, and the 5-month mortality rate may reach 60% following the diagnosis of amiodarone-associated cirrhosis[6]. Notably, each amiodarone molecule contains two iodine atoms, accounting for 37.3% of its molecular weight. Prolonged amiodarone administration can result in substantial intrahepatic iodine accumulation, which radiologically manifests as diffuse hepatic hyperattenuation on computed tomography (CT). Such imaging findings are readily misinterpreted as hemochromatosis, a disorder characterized by excessive hepatic iron deposition. At present, studies investigating the imaging characteristics of hepatic amiodarone deposition and its differentiation from hemochromatosis remain limited worldwide. This lack of clinical awareness frequently contributes to misdiagnosis and delayed diagnosis in routine practice.

This report describes a patient with atrial fibrillation who developed abnormal liver function and imaging findings highly suggestive of hemochromatosis following amiodarone therapy and was ultimately diagnosed with AILI. Through analysis of the patient's clinical and imaging characteristics, together with the key considerations for differential diagnosis, this report aims to increase awareness of this condition among clinicians and radiologists and to emphasize the critical role of imaging in its diagnosis and management.

CASE PRESENTATION

Chief complaints

An 85-year-old woman was admitted on June 2, 2025, with a 6-month history of intermittent nausea and vomiting that had recurred one week before admission.

History of present illness

Six months before admission, the patient developed acute atrial fibrillation with a rapid ventricular response and was treated with oral amiodarone hydrochloride at a dose of 0.2 g three times daily. She was successfully converted to sinus rhythm and continued taking oral amiodarone hydrochloride at the same dosage. Four months later, laboratory tests revealed elevated alanine aminotransferase (ALT) levels of 146 U/L (reference range: 7-40 U/L), aspartate aminotransferase (AST) levels of 79 U/L (reference range: 13-35 U/L), and gamma-glutamyl transferase (GGT) levels of 309 U/L (reference range: 7-45 U/L), accompanied by fatigue and shortness of breath. Drug-induced liver injury was strongly suspected. The amiodarone hydrochloride dosage was reduced to 0.1 g once daily, other potentially hepatotoxic medications, including statins, were discontinued, and hepatoprotective therapy was initiated. Follow-up laboratory tests performed one week later demonstrated improvement in liver enzyme levels, with ALT, AST, and GGT values of 79 U/L, 39 U/L, and 214 U/L, respectively. One week before admission, the patient developed recurrent nausea and vomiting. Liver enzyme levels increased again, with ALT, AST, and GGT values of 310 U/L, 182 U/L, and 214 U/L, respectively (Figure 1A).

Figure 1 Changes in liver and thyroid function before and after amiodarone administration. A: Amiodarone dosing timeline; B: Dynamic changes in liver function tests during amiodarone therapy. The line graph illustrates serial trends in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels throughout the clinical course. Liver enzyme levels increased substantially during prolonged amiodarone therapy and gradually declined following amiodarone discontinuation and initiation of hepatoprotective treatment; C: Dynamic changes in thyroid function tests during amiodarone therapy. The line graph illustrates serial trends in serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) levels during amiodarone treatment. During therapy, FT4 levels progressively increased, whereas FT3 levels decreased. TSH was not appropriately suppressed despite elevated FT4 levels. These thyroid function abnormalities persisted after discontinuation of amiodarone. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transferase; FT3: Free triiodothyronine; FT4: Free thyroxine; TSH: Thyroid stimulating hormone; QD: Daily.

History of past illness

The patient had a 20-year history of hypertension and was receiving oral sacubitril/valsartan 100 mg once daily. She also had a 23-year history of type 2 diabetes mellitus and was treated with oral linagliptin 5 mg daily (QD) and miglitol 50 mg QD. In addition, she had a history of coronary atherosclerotic heart disease and lacunar cerebral infarction for more than 10 years. Twenty-five years previously, she had undergone partial right pneumonectomy because of bronchiectasis. She had no history of liver disease, including viral hepatitis, alcoholic liver disease, or nonalcoholic fatty liver disease.

Personal and family history

The patient had no history of alcohol consumption or tobacco use. She had no known drug or food allergies and no history of exposure to harmful toxins or chemicals. Her family history was unremarkable for hereditary liver disorders, including hemochromatosis and Wilson disease.

Physical examination

The patient’s temperature was 36.4 °C, blood pressure was 148/57 mmHg, heart rate was 76 beats/minute, height was 143 cm, weight was 42 kg, and body mass index was 20.5 kg/m². The patient was alert but lethargic and exhibited no abnormal skin pigmentation. The thyroid gland was palpable and normal in texture. A few moist rales were audible in the left lower lung field, and diminished breath sounds were noted in the right lower lung field. Cardiac auscultation revealed an irregularly irregular rhythm with a heart rate of 85 beats/minute, and no pathological murmurs were detected. A linear surgical scar approximately 30 cm in length extended from the right anterior chest wall to the right scapular region. The abdomen was soft and flat without tenderness. The liver and spleen were not palpable. No edema was observed in either lower extremity.

Laboratory examinations

Laboratory investigations on admission revealed marked hepatocellular liver enzyme elevation, with an ALT level of 310 U/L and an AST level of 182 U/L (Figure 1B). Thyroid function tests were abnormal, showing a free triiodothyronine (FT3) level of 2.39 pmol/L, a free thyroxine (FT4) level of 24.67 pmol/L, and a thyroid-stimulating hormone (TSH) level of 0.767 mIU/L (Figure 1C). Ferritin and transferrin saturation levels were within the normal ranges.

Imaging examinations

Non-contrast chest CT performed on admission revealed diffusely increased hepatic attenuation, measuring approximately 120 Hounsfield units (HU), representing a marked increase from 52 HU on a previous CT examination obtained five months earlier, before initiation of amiodarone therapy. Abdominal magnetic resonance imaging (MRI) demonstrated isointense hepatic signal intensity on T1-weighted imaging (T1WI) and mildly decreased signal intensity on T2-weighted imaging (T2WI). No appreciable signal drop was observed on in-phase or out-of-phase sequences, and no abnormal enhancement was identified on any contrast-enhanced phase (Figure 2).

Figure 2 Serial liver imaging before and after amiodarone therapy. A and B: Chest computed tomography (CT) performed before initiation of amiodarone therapy (January 16, 2025) demonstrates homogeneous hepatic attenuation [approximately 52 Hounsfield units (HU)], comparable to that of the spleen; C and D: Chest CT obtained after amiodarone therapy (June 3, 2025) reveals a marked increase in hepatic attenuation (approximately 120 HU), substantially exceeding splenic attenuation. The liver is normal in size and contour, with smooth margins and no focal lesions; E-I: Abdominal magnetic resonance imaging performed after amiodarone therapy (June 5, 2025) demonstrates isointense hepatic parenchymal signal on T1-weighted imaging and mildly hypointense signal on T2-weighted imaging. No appreciable signal loss is observed on in-phase or out-of-phase sequences.

FINAL DIAGNOSIS

Given the patient’s history of amiodarone use, the Roussel Uclaf Causality Assessment Method (RUCAM) scale was applied to evaluate the causal relationship between drug exposure and liver injury[7]. Laboratory tests showed an ALT level of 310 U/L [upper limit of normal (ULN): 40 U/L] and an alkaline phosphatase (ALP) level of 173 U/L (ULN: 135 U/L). The calculated R value was 6.05 [R = (ALT/ULN)/(ALP/ULN)], which exceeded 5 and indicated a hepatocellular pattern of liver injury. The detailed scoring items were as follows: (1) Time interval between drug administration and symptom onset: > 90 days (1 point); (2) Clinical course: Liver enzyme levels decreased by at least 50% within 30 days after drug withdrawal (2 points); (3) Risk factors: No smoking history or pregnancy (0 points); age ≥ 55 years (1 point); (4) Concomitant medications: The temporal relationship between concomitant medications and the onset of liver injury was inconsistent (0 points); (5) Exclusion of alternative causes of hepatotoxicity: Acute hepatitis A, B, and C; biliary obstruction; alcohol-related liver injury; recent hypotension; shock; hepatic ischemia; autoimmune hepatitis; and sepsis were excluded, covering six etiologies in Group I and two categories in Group II (2 points); (6) Previous evidence of hepatotoxicity: Hepatotoxic adverse reactions were clearly documented in the official prescribing information for amiodarone injection (2 points); and (7) Rechallenge: No re-administration of amiodarone was performed (0 points).

The total RUCAM score was 8, indicating a highly probable causal relationship. In summary, long-term amiodarone administration resulted in progressive drug accumulation and deposition within the liver, causing gradual hepatocellular injury and ultimately leading to AILI.

TREATMENT

Amiodarone hydrochloride tablets were discontinued on June 4, 2025. As the patient’s atrial fibrillation remained well controlled, oral rivaroxaban 10 mg once daily was initiated for anticoagulation, and ursodeoxycholic acid was prescribed as hepatoprotective therapy.

OUTCOME AND FOLLOW-UP

Three weeks after discontinuation of amiodarone, follow-up liver function tests demonstrated substantial improvement, with ALT, AST, and GGT levels of 39 U/L, 33 U/L, and 102 U/L, respectively (Figure 1B). The patient's nausea and vomiting were also markedly relieved. During outpatient follow-up after discharge, liver function remained within the normal range, although intermittent episodes of asymptomatic paroxysmal atrial fibrillation continued to occur.

DISCUSSION

Clinical reports of AILI remain relatively limited, and its clinical manifestations vary considerably in severity. Approximately 24% of patients receiving amiodarone develop asymptomatic elevations in serum aminotransferase levels, whereas fewer than 1% develop clinically significant drug-induced liver injury, ranging from symptomatic hepatitis and micronodular cirrhosis to liver failure requiring liver transplantation[5]. The present patient exhibited nonspecific gastrointestinal symptoms, including recurrent nausea and vomiting with an insidious onset, highlighting the importance of early recognition. A comprehensive understanding of the underlying pathogenesis may facilitate clinical diagnosis.

The precise mechanisms of AILI have not yet been fully elucidated. Acute liver injury occurs predominantly during intravenous administration. Amiodarone contains a benzofuran ring structure and may directly injure hepatocytes by disrupting mitochondrial oxidative phosphorylation and electron transport[8]. In addition, amiodarone has been shown to exert direct hepatotoxic effects through inhibition of phospholipase A[9]. Both amiodarone and its principal metabolite, desethylamiodarone, can induce hepatic mitochondrial stress and activate Kupffer cells to release proinflammatory cytokines, thereby promoting hepatocellular injury[10]. Furthermore, polysorbate 80, the solubilizing agent used in intravenous amiodarone formulations, possesses intrinsic hepatotoxic properties[11].

In the setting of long-term oral therapy, the pathogenesis is primarily attributable to progressive intrahepatic iodine accumulation. Amiodarone carries an exceptionally high iodine load, approximately 75 mg per 200 mg dose, and hepatic concentrations may reach levels up to 500-fold higher than those in serum. Following drug discontinuation, iodine is gradually released from hepatocytes, resulting in a “tissue reservoir” effect[12,13]. Progressive accumulation of iodine within hepatocytes gradually disrupts cellular metabolism and ultimately leads to hepatocellular injury. In patients receiving intravenous amiodarone, liver enzyme levels typically increase within hours to days, and most cases are reversible following withdrawal of the offending agent. Nevertheless, cases of acute liver failure and even fatal outcomes have been reported[14,15]. During chronic therapy, recovery of liver function may be prolonged because of the long elimination half-life of amiodarone and its metabolites, together with sustained release from the intrahepatic tissue reservoir. Moreover, amiodarone is associated with multiorgan toxicity, and the thyroid gland represents another important target organ[4,16].

During amiodarone therapy, the patient developed thyroid function abnormalities characterized by elevated FT4, decreased FT3, and an inappropriately normal TSH level that was not suppressed (Figure 1C). This pattern is consistent with amiodarone-induced inhibition of type 1 5′-deiodinase, which impairs the peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and results in euthyroid hyperthyroxinemia, a pharmacological effect of amiodarone that currently does not require specific treatment. These thyroid function abnormalities persisted after discontinuation of amiodarone, consistent with its prolonged elimination half-life. Serial monitoring of thyroid function at 1-month to 3-month intervals is recommended following drug withdrawal.

Furthermore, studies have demonstrated that patients receiving a daily amiodarone dose of ≥ 400 mg for more than 2 months, or those receiving low-dose therapy for more than 2 consecutive years, constitute a high-risk population for AILI[17]. The present patient weighed only 42 kg and had multiple comorbidities. She received amiodarone at a dose of 600 mg/day for nearly 2 months, substantially exceeding the conventional 1-week to 2-week loading phase. This inappropriate dosing regimen resulted in high-risk drug exposure. The gradual recovery of liver function following drug discontinuation further supports the close association between the hepatic injury observed in this case and dose-dependent amiodarone toxicity. This case also highlights the importance of timely dose adjustment during amiodarone therapy.

Beyond medication history and clinical manifestations, imaging evaluation of hepatic amiodarone deposition is equally important. Among reported cases, diffusely increased hepatic attenuation represents the most characteristic imaging finding, with CT attenuation values reaching up to 164 HU. Most published studies have focused on this CT hyperattenuation. Tsuda et al[15] described two patients with amiodarone-induced hepatotoxicity, both of whom demonstrated diffuse hepatic hyperattenuation on CT. In one patient, follow-up CT performed 9 months after drug discontinuation showed marked normalization of hepatic attenuation. Kishimoto et al[18] reported a case in which serial CT examinations demonstrated progressive increases in hepatic attenuation from 60 HU to 102 HU over a 6-year period, and the patient subsequently died of hepatic encephalopathy. Murata et al[19] emphasized that the CT “bright liver” sign serves as an important diagnostic clue for hepatic amiodarone accumulation.

MRI is primarily used to exclude hepatic iron overload. According to the limited MRI data available from previously reported AILI cases, most patients demonstrate unremarkable signal intensity on T2WI. Yan et al[6] reported a case with CT attenuation values ranging from 125 HU to 164 HU, which initially raised suspicion of iron overload; however, normal T2WI findings helped exclude hemochromatosis. In the present case, CT demonstrated diffuse hepatic hyperattenuation, resulting in a strong suspicion of hemochromatosis. Notably, the patient also exhibited mildly decreased hepatic signal intensity on T2WI, closely resembling the “black liver” sign associated with iron overload and substantially complicating the differential diagnosis.

Unlike iron, iodine does not contain unpaired electrons and therefore does not produce a superparamagnetic effect. The observed reduction in T2WI signal intensity is more likely attributable to amiodarone-induced intralysosomal phospholipidosis, which alters the hepatic microarchitecture, rather than to the intrinsic magnetic properties of iodine itself. However, the exact underlying mechanism remains to be fully elucidated.

The imaging findings in this case were ultimately attributed to intrahepatic amiodarone deposition. Notably, the initial imaging manifestations were highly suggestive of hemochromatosis. Given the finding of diffuse hepatic hyperattenuation on CT, further differentiation using additional imaging modalities and laboratory investigations was essential. Hemochromatosis results from hereditary or secondary disorders of iron metabolism, leading to excessive iron deposition in parenchymal organs, including the liver, pancreas, and spleen, with subsequent structural and functional impairment[20]. On CT, hepatic iron overload typically manifests as diffuse hepatic hyperattenuation. A hepatic attenuation value exceeding 75 HU has high diagnostic specificity, whereas values greater than 100 HU may occur in severe cases[21]. MRI provides superior sensitivity and specificity. Owing to the superparamagnetic properties of iron, hepatic parenchymal signal intensity decreases across all MRI sequences, particularly on T2WI, resulting in the characteristic “black liver” sign[22,23]. In the present case, the combination of diffuse hepatic hyperattenuation on CT and hypointensity on T2WI initially led to a diagnosis of hemochromatosis. However, normal serum iron indices ultimately excluded this condition.

Wilson disease is pathologically characterized by excessive copper deposition within the liver. It may also present with increased hepatic attenuation on CT and reduced signal intensity on T2WI, accompanied by the characteristic “honeycomb” appearance. The disease is commonly associated with extrapyramidal neurological manifestations, corneal Kayser-Fleischer rings, and markedly decreased serum ceruloplasmin levels[24-26]. Glycogen storage disease may likewise manifest as increased hepatic attenuation on CT and decreased signal intensity on MRI due to intrahepatic glycogen accumulation[27,28]. When accompanied by hepatic steatosis, hyperintensity on T1WI may also be observed. This disorder predominantly affects infants and young children and is typically associated with hepatomegaly, fasting hypoglycemia, and growth retardation.

This differential diagnostic process also highlights the limitations of conventional single-energy CT. CT attenuation values reflect the overall X-ray attenuation effect, and diffuse hepatic hyperattenuation may result from the deposition of a variety of substances, including iodine, iron, copper, glycogen, and amyloid. These materials cannot be reliably distinguished on the basis of CT attenuation values alone. Dual-energy CT (DECT) exploits differences in material attenuation at different tube voltages and enables quantitative assessment of hepatic iodine concentration through material decomposition algorithms. Previous studies have demonstrated its feasibility for monitoring hepatic iodine burden in patients receiving amiodarone[29]. Therefore, when available, DECT may serve as a useful noninvasive supplementary tool for quantitative evaluation.

This case report has several limitations. First, as a single-case report, it reflects the characteristics of an individual patient, thereby limiting the generalizability of the findings. Second, the patient and her family declined liver biopsy and genetic testing for hemochromatosis. Consequently, the diagnosis was established on the basis of imaging findings, laboratory results, medication history, and the RUCAM score, without pathological confirmation. Furthermore, because of patient-related factors and practical clinical constraints, DECT was not performed to quantitatively assess hepatic iodine concentration. As a result, objective quantitative data regarding iodine deposition were unavailable, and additional radiologic confirmation of the extent of hepatic amiodarone accumulation could not be obtained.

In summary, prolonged amiodarone administration can result in intrahepatic iodine deposition, producing CT findings that closely resemble those of hemochromatosis and thereby creating a significant diagnostic challenge. MRI is an effective modality for differential diagnosis; however, mildly decreased hepatic signal intensity on T2WI does not exclude the diagnosis of AILI. A comprehensive evaluation integrating medication history and laboratory findings is essential for establishing an accurate diagnosis. Given the potential for amiodarone-induced multiorgan toxicity, clinicians should reduce the dosage to standard maintenance levels after completion of the loading phase. Serial monitoring of hepatic and thyroid function is essential for the early detection of adverse effects and the prevention of potentially life-threatening complications.

CONCLUSION

AILI is not uncommon in clinical practice. In the absence of a detailed medication history and appropriate laboratory investigations, diffuse hepatic hyperattenuation on CT may be misdiagnosed as hemochromatosis. A normal T2WI signal on MRI, in contrast to the diffuse hypointensity typically observed in hemochromatosis, may facilitate differential diagnosis; however, mildly decreased signal intensity on T2WI does not definitively exclude AILI. This case highlights the importance of regular follow-up during long-term amiodarone therapy and timely dose reduction after completion of the loading phase.

ACKNOWLEDGEMENTS

We are grateful to the endocrinology and radiology staff for their valuable support in image acquisition and patient coordination throughout this study.