Drug-Induced Steatohepatitis Leading to Cirrhosis: Long-Term Toxicity of Amiodarone Use

Raja, Kaiser; Thung, Swan N.; Fiel, M. Isabel; Chang, Charissa

doi:10.1055/s-0029-1240011

Cited by 52 publications

(36 citation statements)

References 17 publications

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“…Although, life style choices of a high carbohydrate or a high fat diet and excessive alcohol consumption are specific causes of hepatic steatosis and NAFLD, nutritional factors (e.g., malnutrition and rapid weight loss) [15], drug exposure (e.g., glucocorticoids, methotrexate, Amiodarone, Tamoxifen, HIV protease inhibitors, etc.) [12, 16], specific diseases (e.g., inflammatory bowel disease, primary biliary cirrhosis, Cushing's syndrome, Hematochromatosis, etc. ), and genetic factors [17] are also relevant causes of fatty liver diseases [16, 18–22].…”

Section: Causes Of Hepatic Steatosis In Nafldmentioning

confidence: 99%

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PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid ω‐Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

et al. 2009

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Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis), due to a decrease in mitochondria β-oxidation with an increase in both peroxisomal β-oxidation, and microsomal ω-oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs). How steatosis increases PPARα activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid β-oxidation and ω-oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA), monounsaturated (MUFA), or saturated (SFA) may be determined by the interplay of PPARs and HNF4α with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the ω-oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPARα. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid ω-hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA) CYP4A and long-chain fatty acid (LCFA) CYP4F ω-hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to steatohepatitis.

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Section: Causes Of Hepatic Steatosis In Nafldmentioning

confidence: 99%

“…[12, 16], specific diseases (e.g., inflammatory bowel disease, primary biliary cirrhosis, Cushing's syndrome, Hematochromatosis, etc. ), and genetic factors [17] are also relevant causes of fatty liver diseases [16, 18–22]. …”

Section: Causes Of Hepatic Steatosis In Nafldmentioning

confidence: 99%

PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid ω‐Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

et al. 2009

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“…Drug induced liver disease or toxic hepatitis can cause both cholestatic or hepatocellular hepatic abnormalities [43,44], but these have been ruled out by the detailed frequent questioning of the three patients. Another issue regarding toxic hepatitis is that most injures are of acute forms, and only few medications (like miodarone and methotrexate) have been reported to cause liver fibrosis and cirrhosis [45,46]. Familial forms of intra-hepatic inherited cholestatic syndromes were unlikely in the first and the second patient, because of the age of presentation, and because both of them had negative family history of liver disease [3].…”

Section: Discussionmentioning

confidence: 99%

Autoimmune liver disease - are there spectra that we do not know?

Fallatah

Akbar

2011

Comp Hepatol

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Autoimmune liver diseases (AILDs) are common leading causes for liver cirrhosis and terminal stage of liver disease. They have variable prevalence among patients with liver disease and have two major clinical and biochemical presentations. Autoimmune hepatitis (AIH) is the typical example of hepatocellular AILD, but it can also be presented under a cholestatic pattern. AIH has a scoring diagnostic system and respond in most cases to the treatment with prednisolone and azathioprine. Primary biliary cirrhosis (PBC) is the second most common AILD, with a cholestatic presentation and characterized by positive antimitochondrial antibody (AMA). It has an excellent response and long term outcome with the administration of ursodeoxycholic acid (UDCA). Another AILD that is thought to be a variant of PBC is the autoimmune cholangitis, being a disease that has biochemical and histological features similar to PBC; but the AMA is negative. Primary sclerosing cholangitis (PSC) is a rare entity of AILD that has a cholestatic presentation and respond poorly to the treatment, with the ultimate progression to advance liver cirrhosis in most patients. Other forms of AILD include the overlap syndromes (OS), which are diseases with mixed immunological and histological patterns of two AILD; the most commonly recognized one is AIH-PBC overlap (AIH-PSC overlap is less common). The treatment of OS involves the trial of UDCA and different immunosuppressants. Here we present three case reports of unusual forms of chronic liver diseases that most likely represent AILD. The first two patients had a cholestatic picture, whereas the third one had a hepatocellular picture at presentation. We discussed their biochemical, immunological and histological features as well as their response to treatment and their outcomes. Then, we compared them with other forms of AILD.

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“…Hepatotoxicity is a relatively uncommon side effect of amiodarone 37. Although asymptomatic elevation of aminotransferases is reported in up to 25% of patients, symptomatic hepatic dysfunction occurs in less than 1% of patients on chronic amiodarone therapy 38.…”

Section: Amiodarone: Properties and Side Effect Profilementioning

confidence: 99%

Managing atrial fibrillation in the elderly: critical appraisal of dronedarone

Trigo¹,

Fischer²

2011

CIA

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Atrial fibrillation is the most commonly seen arrhythmia in the geriatric population and is associated with increased cardiovascular morbidity and mortality. Treatment of the elderly with atrial fibrillation remains challenging for physicians, because this unique subpopulation is characterized by multiple comorbidities requiring chronic use of numerous medications, which can potentially lead to severe drug interactions. Furthermore, age-related changes in the cardiovascular system as well as other physiological changes result in altered drug pharmacokinetics. Dronedarone is a new drug recently approved for the treatment of arrhythmias, such as atrial fibrillation and/or atrial flutter. Dronedarone is a benzofuran amiodarone analog which lacks the iodine moiety and contains a methane sulfonyl group that decreases its lipophilicity. These differences in chemical structure are responsible for making dronedarone less toxic than amiodarone which, in turn, results in fewer side effects. Adverse events for dronedarone include gastrointestinal side effects and rash. No dosage adjustments are required for patients with renal impairment. However, the use of dronedarone is contraindicated in the presence of severe hepatic dysfunction.

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Drug-Induced Steatohepatitis Leading to Cirrhosis: Long-Term Toxicity of Amiodarone Use

Cited by 52 publications

References 17 publications

PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid ω‐Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid ω‐Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

Autoimmune liver disease - are there spectra that we do not know?

Managing atrial fibrillation in the elderly: critical appraisal of dronedarone

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