Hepatic Cirrhosis Caused by Low-Dose Oral Amiodarone Therapy

doi:10.1097/00000441-200511000-00012

The American Journal of the Medical Sciences

Volume 330, Issue 5, November 2005, Pages 257-261

https://doi.org/10.1097/00000441-200511000-00012 Get rights and content

ABSTRACT:

A 63-year-old man presented with ascites after therapy with amiodarone, 200 mg orally once per day for 22.5 months. A liver biopsy showed grade 3 chronic hepatitis and micronodular cirrhosis. The presence of striking microvesicular steatosis on light microscopy and lysosomal inclusion bodies on electron microscopy suggested amiodarone hepatotoxicity. This is the first reported case of amiodarone-induced hepatic cirrhosis associated with chronic treatment with 200 mg orally once per day for less than 2 years.

Section snippets

Case Report

A 63-year-old white man was hospitalized at St. John’s Mercy Medical Center for abdominal distention of 1 week’s duration. He had a history of coronary artery disease that was treated with coronary artery bypass grafting at another hospital 23 months prior to this hospitalization. He also had long-standing diabetes mellitus and hypercholesterolemia, both of which were well controlled with medical therapy. He denied use of alcohol. Shortly after coronary artery bypass grafting, he developed

Discussion

Amiodarone, an iodinated benzofuran derivative, is lipophilic and thus accumulates in lipid-laden organs such as the liver. The half-life of amiodarone varies from 35 to 110 days.1., 2. Its major metabolite, N-desethylamiodarone, is pharmacologically active and has a longer elimination half-life than that of the parent compound.1., 2. Amiodarone and its metabolites accumulate in the lysosomes of hepatocytes, Kupffer cells, bile duct epithelium, and, to a lesser extent, in smooth muscle,

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Drug biokinetic and toxicity assessments in rat and human primary hepatocytes and HepaRG cells within the EU-funded Predict-IV project
2015, Toxicology in Vitro
Citation Excerpt :
AMI-induced liver pathologies commonly include lesions of non-alcoholic fatty liver disease (Babany et al., 1986; Lewis et al., 1990), which show signs of hepatitis, steatosis, Mallory bodies and fibrosis or even cirrhosis. In addition, AMI has been specifically associated with micro- and macro-vesicular steatosis (Lewis et al., 1990; Puli et al., 2005). Many drugs have been classified as steatogenic.
The overall aim of Predict-IV (EU-funded collaborative project #202222) was to develop improved testing strategies for drug safety in the late discovery phase. One major focus was the prediction of hepatotoxicity as liver remains one of the major organ leading to failure in drug development, drug withdrawal and has a poor predictivity from animal experiments. In this overview we describe the use and applicability of the three cell models employed, i.e., primary rat hepatocytes, primary human hepatocytes and the human HepaRG cell line, using four model compounds, chlorpromazine, ibuprofen, cyclosporine A and amiodarone. This overview described the data generated on mode of action of liver toxicity after long-term repeat-dosing. Moreover we have quantified parent compound and its distribution in various in vitro compartments, which allowed us to develop biokinetic models where we could derive real exposure concentrations in vitro. In conclusion, the complex data set enables quantitative measurements that proved the concept that we can define human relevant free and toxic exposure levels in vitro. Further compounds have to be analyzed in a broader concentration range to fully exploit these promising results for improved prediction of hepatotoxicity and hazard assessment for humans.
Amiodarone toxicity showing high liver density on CT scan with normal liver function and plasma amiodarone levels in a long-term amiodarone user
2014, International Journal of Cardiology
Hepatotoxicity of cardiovascular and antidiabetic drugs
2013, Drug-Induced Liver Disease
With the increasing prevalence of cardiovascular disease and associated disorders globally, there has been a proliferation of medications for antiplatelet therapy, dyslipidemia, glycemic control, and hypertension. Liver injury of varying degrees, from asymptomatic elevation in liver enzymes to liver transplantation or death, has been reported to result from members of many drug classes. Statins offer the best example of a class of agents that may cause asymptomatic liver enzyme abnormalities that are likely to be of no clinical consequence. On the other hand, first generation thiazolidinediones and some of the antihypertensive agents are more prominently associated with a capacity to induce severe liver disease. It behooves the clinician to have a framework of understanding from which to base the diagnosis and management of hepatotoxicity attributable to drugs used to treat these common diseases. Thus, the goal of this chapter is to review the pertinent literature on hepatotoxicity associated with medications used for cardiovascular diseases and diabetes, including clinical presentation, histology, mechanisms of injury, and disease outcomes.
Drug-induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver
2011, Journal of Hepatology
Citation Excerpt :
In the context of drug-induced steatohepatitis, fat accumulates usually as large vacuoles, although microvesicular steatosis can also be present in some hepatocytes. Inflammation and fibrosis can be of variable severity and occasionally cirrhosis occurs with drugs, such as amiodarone, perhexiline, and didanosine [116,149,190–192]. Importantly, drug-induced steatohepatitis shares many pathological and clinical features with alcoholic steatohepatitis and nonalcoholic steatohepatitis (NASH).
Numerous investigations have shown that mitochondrial dysfunction is a major mechanism of drug-induced liver injury, which involves the parent drug or a reactive metabolite generated through cytochromes P450. Depending of their nature and their severity, the mitochondrial alterations are able to induce mild to fulminant hepatic cytolysis and steatosis (lipid accumulation), which can have different clinical and pathological features. Microvesicular steatosis, a potentially severe liver lesion usually associated with liver failure and profound hypoglycemia, is due to a major inhibition of mitochondrial fatty acid oxidation (FAO). Macrovacuolar steatosis, a relatively benign liver lesion in the short term, can be induced not only by a moderate reduction of mitochondrial FAO but also by an increased hepatic de novo lipid synthesis and a decreased secretion of VLDL-associated triglycerides. Moreover, recent investigations suggest that some drugs could favor lipid deposition in the liver through primary alterations of white adipose tissue (WAT) homeostasis. If the treatment is not interrupted, steatosis can evolve toward steatohepatitis, which is characterized not only by lipid accumulation but also by necroinflammation and fibrosis. Although the mechanisms involved in this aggravation are not fully characterized, it appears that overproduction of reactive oxygen species by the damaged mitochondria could play a salient role. Numerous factors could favor drug-induced mitochondrial and metabolic toxicity, such as the structure of the parent molecule, genetic predispositions (in particular those involving mitochondrial enzymes), alcohol intoxication, hepatitis virus C infection, and obesity. In obese and diabetic patients, some drugs may induce acute liver injury more frequently while others may worsen the pre-existent steatosis (or steatohepatitis).
Strategies for the early detection of drug-induced hepatic steatosis in preclinical drug safety evaluation studies
2011, Toxicology
Citation Excerpt :
However, the distinction is not always clear-cut and can depend upon observation time, dose and other factors. For example, tamoxifen and ethanol can cause both steatosis in one patient, but mixed macro- and microvesicular steatosis in another (Puli et al., 2005; Raja et al., 2009). Independent of etiology, the hepatic microvesicular steatosis has a worse prognosis compared with macrovesicular steatosis.
Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the “two hit” theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R&D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.
The effect of β-naphthoflavone on the metabolism of amiodarone by hepatic and extra-hepatic microsomes
2010, Toxicology Letters
Amiodarone is a potent antiarrhythmic drug with several limiting side effects, some of which have been correlated with increased levels of its more toxic metabolite, desethylamiodarone. Elevated serum desethylamiodarone to amiodarone ratios are associated with a risk of amiodarone-induced pulmonary toxicity. Polycyclic aromatic hydrocarbons such as β-naphthoflavone are known to increase desethylamiodarone levels in rat in vivo. In this article we investigated if this increase was solely due to increased formation as a result of cytochrome P450 (CYP) 1A1 and 1A2 induction in different rat hepatic and extra-hepatic tissues. Additionally, the effect of amiodarone treatment on CYP1A1 and 1A2 gene expression and activity was investigated. In rats, β-naphthoflavone was found to increase desethylamiodarone forming activity in lung and kidney microsomes. Amiodarone increased β-naphthoflavone mediated induction of CYP1A1 gene expression in liver, lung and kidney. However, there was no significant change in CYP1A activity. As expected, the data indicated that the increase in desethylamiodarone levels in vivo was partly due to increased formation through CYP1A1 induction, although increased formation was only evident in some extra-hepatic tissues. Amiodarone treatment did not affect basal or induced CYP1A activity.

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Case ReportsHepatic Cirrhosis Caused by Low-Dose Oral Amiodarone Therapy

ABSTRACT:

Section snippets

Case Report

Discussion

J Pediatrics

Hum Pathol

J Hepatology

Amiodarone hepatotoxicity: prevalence and clinicopathologic correlations among 104 patients

Hepatology

Amiodarone hepatotoxicity simulating alcoholic liver disease

N Engl J Med

Granular cells as a marker of early amiodarone hepatotoxicity: a pathological and analytical study

J Clin Pathol

Amiodarone-induced hepatic phospholipidosis: correlation of morphological and biochemical findings in an animal model

Hepatology

Mechanisms of amiodarone toxicity: inhibition of phospholipase A

Circulation

The induction of pulmonary phospholipidosis and the inhibition of lysosomal phospholipases by amiodarone

Br J Exp Pathol

Neuropathy and fatal hepatitis in a patient receiving amiodarone

Br Med J

Case Reports
Hepatic Cirrhosis Caused by Low-Dose Oral Amiodarone Therapy