The question concerns a male patient who has received treatment with Cordarone (amiodarone) since o

Fråga: The question concerns a male patient who has received treatment with Cordarone (amiodarone) since one year. Three months ago, signs of liver injury were noticed. (Serum transaminase levels were raised and albumine was lowered, but the values for prothrombine complex thrombocytes were normal.) The medication was withdrawn. The question is: could this type of liver damage be related to the Cordarone treatment and how soon after starting the medication can these side effects be expected? Is it possible to distinguish liver damage due to Cordarone from other causes, like abuse of alcohol?

Sammanfattning: Asymptomatic elevations of serum levels of hepatic enzymes are frequently observed during amiodarone therapy. The frequency noticed varies from 15-50 per cent and the latency period from several days to several months. Cases of steatosis, pseudoalcoholic hepatitis and micronodular cirrhosis due to amiodarone treatment have been reported. Especially the cumulative dose seems to be an important factor in the development of hepatic injury. It should be stressed that amiodarone is very slowly eliminated and accumulates extensively in the liver. Liver biopsy in combination with electron microscopy may, by showing the presence of hepatic phospholipidosis, help differentiate amiodarone hepatotoxicity from alcoholic liver disease or other causes of hepatic steatosis. In case of hepatomegaly or histological signs of liver injury, withdrawal or reduction of the therapy should be considered.

Svar: Amiodarone has proved very effective in the treatment of otherwise resistant cardiac tachyarrhythmias. Its use however, has been limited due to its side effects (1). The most frequent side effects are ocular (corneal microdeposits of phospholipids), dermal (photosensitivity) and neurologic (tremor, ataxia, neuropathy), whereas pulmonary fibrosis and clinical thyroid dysfunction are less common.

Amiodarone is metabolized by the liver and excreted in the bile. One metabolite, desethylamiodarone has been determined until now, of which the pharmacological activity is unknown (2). Characteristic of the drug is a very long terminal half-life (30-110 days) and a large volume of distribution: amiodarone accumulates extensively in the tissues, with preference in lipid-containing organs and the liver. Liver tissue levels of the drug and its metabolite may reach several gram/kg (3). Both amiodarone and desethylamiodarone can be measured in the plasma at least 3 months after withdrawal of the drug.

An asymptomatic elevation of liver enzymes, like serum aminotransferases or lactic dehydrogenase levels up to 4-fold the normal value, without changes in alkaline phosphatase or bilirubin, is frequently observed during amiodarone therapy. The reported frequency varies from 15-50 per cent (1), with a latency period from less than one week to several months. These elevations, without clinical hepatic dysfunction, seem to correlate with the plasma concentration of amiodarone and its metabolite (4) and diminish after dose reduction. A decline in these levels, despite continued amiodarone therapy has been noted as well (5).

However, several cases of amiodarone-induced micronodular cirrhosis and alterations similar to alcoholic hepatitis have been described especially in patients on high daily doses (400-600 mg). A 30-year old man (6) with no history of alcohol abuse, showed five-fold elevations of aminotransferase without clinical symptoms, while taking amiodarone 400 mg daily for five months. Liver biopsy tissue, at ten months after withdrawal of the drug still contained amiodarone and desethylamiodarone in high concentrations. This was accompanied by histologic abnormalities simulating active alcoholic hepatitis with fibrosis. Electron microscopy revealed hepatic phospholipodosis, the presence of phospholipid-laden lysosomal inclusions which are commonly seen with some basic drugs e.g. psychotropics. Also, a case has been described of a 68-year old patient (7) who, taking 600 mg daily of amiodarone for 19 months, developed a severe hepatitis progressing to a fatal micronodular cirrhosis.

Similar lesions have been observed after low doses of amiodarone, when taken during a long time, suggesting that rather than the daily dose, the cumulative dose of amiodarone could be a major factor in the development of hepatic injury (8). Daily dosage was 200 mg in 2 cases, 400 mg then 200 mg in one case and duration of therapy ranged between 36 and 60 months. Although symptoms were limited to hepatomegaly or elevations of serum aminotransferases, liver biopsy revealed alcohol-like lesions with fibrosis in 2 cases and cirrhosis in one case.

The mechanism of this alcohol-like liver injury is not known. To study the relationship between amiodarone-induced hepatic phospholipidosis and liver disease, liver biopsies from 13 patients were investigated (9). Amiodarone dosage varied from 200-400 mg daily and duration of therapy from 4 months to 15 years. Pseudoalcoholic liver lesions were found in 4 cases. In all patients, signs of hepatic phospholipidosis were found by electron microscopy, whether or not pseudoalcoholic liver lesions were present. Possibly, the presence of hepatic phospholipidosis could help differentiate amiodarone hepatotoxicity from alcoholic liver disease, or other causes of hepatic steatosis (10). On the other hand, amiodarone-induced hepatic phospholipidosis could also be only a morpholical marker of intrahepatic accumulation of the drug, independent of chronic liver disease.

So far, five cases have been reported to the Swedish Adverse Drug Reactions Committee of liver side effects possibly due to amiodarone: four cases of increased levels of liver enzymes and one case of liver steatosis.