Amiodaron Neuropathy: Further Arguments for Human Drug-Induced Neurolipidosis

Lemaire, J.F.; Autret, A.; Biziere, Kathleen; Romet-Lemone, J.L.; Gray, F

doi:10.1159/000115456

Cited by 34 publications

(8 citation statements)

References 5 publications

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“…observed in the liver (6)(7)(8)(9)(10) as well as in various other organs (11)(12)(13)(14)(15)(16) of patients receiving this therapy is the presence of intralysosomal myelin figures similar to those described in phospholipidosis. Since, in most published cases, this ultrastructural finding has been reported in association with PLL, it has been considered an argument supporting the responsibility of the drug in the occurrence of these lesions (8,10).…”

mentioning

confidence: 64%

Amiodarone-induced hepatic phospholipidosis: A morphological alteration independent of pseudoalcoholic liver disease

Guigui¹,

Perrot²,

Berry³

et al. 1988

Hepatology

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In order to study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies obtained from 13 patients treated with amiodarone for 4 months to 15 years were investigated by light and electron microscopy. Light microscopy showed pseudoalcoholic liver lesions that were probably related to amiodarone in four cases, various alterations (i.e. cirrhosis, three cases; steatosis and fibrosis, two cases; chronic venous congestion, one case; acute hepatitis, one case) that could be explained by another cause than amiodarone in seven cases and normal liver in two cases. In all cases, electron microscopy showed intralysosomal myelin figures suggestive of phospholipidosis. These myelin figures were associated with intralysosomal electron-dense deposits. In the four cases in which analysis by electron microprobe was performed, it demonstrated large amounts of iodine in the electron-dense deposit-containing lysosomes, indicating the accumulation of amiodarone. These results show that hepatic phospholipidosis is constantly observed in amiodarone-treated patients, whether or not pseudoalcoholic liver lesions are present. This phospholipidosis, which could be only a morphological marker of intrahepatic accumulation of the drug, should not therefore be considered grounds for attributing liver disease to the drug.

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mentioning

confidence: 64%

Amiodarone-induced hepatic phospholipidosis: A morphological alteration independent of pseudoalcoholic liver disease

Guigui¹,

Perrot²,

Berry³

et al. 1988

Hepatology

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“…Corneal microdeposits occur in the majority of treated adults, causing visual holes or blurred vision in as many as 10% of patients (17,(42)(43)(44). Peripheral neuropathy, muscle weakness and extrapyramidal symptoms also have been reported (11,45,46). Gastrointestinal complaints, including nausea, vomiting, constipation and anorexia are relatively common but rarely require stoppage of therapy (11,17).…”

Section: Discussionmentioning

confidence: 99%

Amiodarone hepatotoxicity: Prevalence and clinicopathologic correlations among 104 patients

et al. 1989

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The prevalence of apparent amiodarone-related hepatic injury in 104 patients followed prospectively is compared to that reported in the literature. Asymptomatic elevation of serum aminotransferase levels was detected in approximately one-fourth of the patients, a figure similar to the average of reported cases. The frequency of extrahepatic organ toxicity was increased in patients with elevated levels. Symptomatic "hepatitis" developed in 3% of this series and in less than 1% of cases in the literature. Evidence of hepatic phospholipidosis and the development of pseudoalcoholic liver injury is most likely due to the biochemical effects of the drug and to possible metabolic idiosyncrasy, respectively. Serial blood enzyme measurements, as recommended by the manufacturer, may offer some protection against the development of more serious liver injury. However, levels of amiodarone may persist in various tissues for weeks to months following withdrawal, and stopping the drug does not guarantee the prompt reversal of any organ toxicity. Accordingly, the risks posed and benefits offered by amiodarone should be carefully weighed prior to discontinuing the drug, as the risk of sudden cardiac death may outweigh the hazards of ongoing hepatic, pulmonary or other toxicity.

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“…17 Similar inclusions have been seen in peripheral nerve in patients with amiodarone-associated neuropathy. 31 Thus inclusions are seen in association with amiodarone-related adverse effects in some patients and probably in the corneal epithelium of most patients taking the drug. These findings, together with our data on tissue concentrations, again indicate that widespread 1072 tissue deposition of amiodarone and desethylamiodarone leads to ultrastructural changes in many sites.…”

Section: Methodsmentioning

confidence: 99%

Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy.

Adams¹,

Holt²,

Storey³

et al. 1985

Circulation

157

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The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. (89 and 470). and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive xray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages. blood neutrophils. and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with aniodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung. Circulation 72, No. 5, 1064-1075, 1985 AMIODARONE is recognized as an orally effective agent in the treatment of atrial and ventricular arrhythmias refractory to conventional therapy. It is a benzofuran derivative containing two iodine atoms per molecule. In man, only one major metabolite has been identified, desethylamiodarone.' During long-term therapy this compound reaches similar plasma concentrations to amiodarone, and both compounds show long terminal elimination half-lives reflecting a com-

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Amiodaron Neuropathy: Further Arguments for Human Drug-Induced Neurolipidosis

Cited by 34 publications

References 5 publications

Amiodarone-induced hepatic phospholipidosis: A morphological alteration independent of pseudoalcoholic liver disease

Amiodarone-induced hepatic phospholipidosis: A morphological alteration independent of pseudoalcoholic liver disease

Amiodarone hepatotoxicity: Prevalence and clinicopathologic correlations among 104 patients

Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy.

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