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Hiroki Oikawa,
Chihaya Maesawa, Kanta Oikawa, Akiko Yashima-Abo, Koji Kotani,
Tomoyuki Masuda, Department of Pathology, Iwate Medical
University School of Medicine, Morioka, Japan
Ryo Sato, Kazuyuki Suzuki, Department of Internal Medicine I,
Iwate Medical University School of Medicine, Morioka, Japan
Hiroyuki Yamada, Seizo Oriso, Department of Internal
Medicine, Iwate Prefectural Ninohe Hospital, Ninohe, Japan
Sadahide Ono, Department of Pathology, Iwate Prefectural
Central Hospital, Morioka, Japan
Supported by Grants-in-Aid No. 16590289, 16790211 and
16790212, and �Open Research Center� Project for Private
Universities: Matching fund Subsidy (2004-2008), from Ministry of
Education, Culture, Sports, Science and Technology, Japan
Correspondence to: Dr. Chihaya Maesawa, Department of
Pathology, Iwate Medical University School of Medicine, Uchimaru
19-1, Morioka 020-8505, Japan.
chihaya@iwate-med.ac.jp
Telephone: +81-19-651-5111
Fax: +81-19-629-9340
Received: 2005-01-18
Accepted: 2005-04-09
Abstract
The anti-arrhythmic agent amiodarone (AD) is associated with
numerous adverse effects, but serious liver disease is rare. The
improved safety of administration of daily low doses of AD has
already been established and this regimen is used for long-term
medication. Nevertheless, asymptomatic continuous liver injury by AD
may increase the risk of step-wise progression of non-alcoholic
fatty liver disease. We present an autopsy case of AD-induced liver
cirrhosis in a patient who had been treated with a low dose of AD
(200 mg/d) daily for 84 mo. The patient was a 85-year-old male with
a history of ischemic heart disease. Seven years after initiation of
treatment with AD, he was admitted with cardiac congestion. The
total dose of AD was 528 g. Mild elevation of serum aminotransferase
and hepatomegaly were present. Liver biopsy specimens revealed
cirrhosis, and under electron microscopy numerous lysosomes with
electron-dense, whorled, lamellar inclusions characteristic of a
secondary phospholipidosis were observed. Initially, withdrawal of
AD led to a slight improvement of serum aminotransferase
levels, but unfortunately his general condition deteriorated and he
died from complications of pneumonia and renal failure. Long-term
administration of daily low doses of AD carries the risk of
progression to irreversible liver injury. Therefore, periodic
examination of liver function and/or liver biopsy is required for
the management of patients receiving long-term treatment with AD.
� 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Amiodarone; Liver cirrhosis; NASH; NAFLD; Liver
biopsy
Oikawa H, Maesawa C, Sato R, Oikawa K, Yamada H, Oriso S, Ono S,
Yashima-Abo A, Kotani K, Suzuki K, Masuda T. Liver cirrhosis induced
by long-term administration of a daily low dose of amiodarone: A
case report. World J Gastroenterol
2005; 11(34): 5394-5397
http://www.wjgnet.com/1007-9327/11/5394.asp
INTRODUCTION
Amiodarone (AD) is a cationic, amphophilic, iodinated benzofuran
derivative primarily used for the treatment of refractory
ventricular tachyarrythmias[1].
Although AD has been used since 1962, it causes various side effects
affecting the lung, thyroid gland, cornea, peripheral nerves, and
liver[1-3]. In
early clinical trials, higher maintenance doses of AD (300-800 mg/d)
caused serious side effects in the first year of therapy, and these
patients required drug withdrawal[1-6].
In the last two decades, several investigators have shown that daily
lower doses of AD (<200 mg/d) are better tolerated but still
possess appreciable efficacy in serious cardiac arrhythmias[4-6].
The hepatotoxicity associated with AD is
manifested as an asymptomatic and transient elevation of serum
aminotransferase[2,3,6-8].
Fortunately, the vast majority of these events are reversible after
discontinuation of the medication[2,3,6].
The safer schedule of administration of low doses daily may
contribute to reducing the incidence of serious hepatic adverse
effects. The histologic appearance of AD-induced liver disease
shares several features with that of alcoholic hepatitis.
Asymptomatic continuous liver injury by AD may increase the risk of
step-wise progression of non-alcoholic fatty liver disease (NAFLD)[7-19].
This implies that severe morphological alterations of the liver may
coexist with very mild symptoms in patients receiving long-term
treatment with daily low doses of AD. We present herein an autopsy
case of AD-induced liver cirrhosis in a patient treated with a low
dose of AD daily for 84 mo. We discuss the risk of progression to
irreversible liver injury during administration of AD and the value
of liver biopsy for patients receiving long-term treatment with a
low dose of AD daily.
CASE REPORT
A 85-year-old male with a history of ischemic heart disease was
being treated with AD for continuing symptomatic ventricular
arrhythmias. He was admitted with cardiac congestion in December
2001, 7 years after administration of AD had begun. There was no
history of alcohol abuse, obesity or diabetes mellitus. Serological
screening and PCR examination for hepatitis viruses were all
negative. There were no signs of autoimmune hepatitis. His initial
dose of AD was 400 mg daily for 17 d, which was then reduced to a
maintenance dose of 200 mg daily. The patient had received
continuous medication with AD for 84 mo. On physical examination,
corneal opacities were found. No skin discoloration or neuronal
symptoms were seen.
Serum total bilirubin was 1.2 mg/dL, aspartate
amino-transferase 81 IU/L, alanine aminotransferase 35 IU/L,
alkaline phosphatase 452 IU/L, gamma-glutamyl transpeptidase 210 IU/L,
lactate dehydrogenase 848 IU/L, and prothrombin time activity 59%.
Up to that time, no elevation of serum aminotransferase or signs
suggesting liver dysfunction had been observed.
The chest radiograph revealed cardiac enlargement
and bilateral pleural effusion without findings of interstitial
fibrosis. Abdominal ultrasonography showed enlargement of the left
lobe of the liver relative to atrophy of the right lobe, and an
irregular liver surface. In addition, ascites and mild splenomegaly
were seen. An unenhanced computed tomography (CT) scan of the upper
abdomen showed an abnormally high density of liver tissue [111.8
Hounsfield units (HU); normal range 30-70 HU] (Figure 1). A
percutaneous liver biopsy examination revealed micronodular
cirrhosis accompanied by findings of alcoholic liver disease (Figure
2). Fibrous septa containing proliferating bile ductules and
neutrophil polymorphs connected adjacent portal areas (Figure 2).
Scattered foci of hepatocellular necrosis with neutrophilic
infiltration were observed (Figure 2). Electron microscopic
observations showed that hepatocytes contained numerous lysosomes
with electron-dense, whorled, lamellar inclusions (LI),
characteristic of a secondary phospholipidosis (Figure 3). The
findings of the CT scan and the liver biopsy indicated that
AD-induced liver cirrhosis was responsible for the hepatotoxicity
and his poor general condition. Administration of AD was
discontinued. The total dose of AD administered over the 84 mo was
528 g.
Initially, withdrawal of AD led to a slight
improvement in the serum aminotransferase level and the ascites. The
CT density of the liver decreased to 97.2 HU in February 2002,
whereas no significant improvement was observed in the size of the
liver. Unfortunately, his general condition deteriorated as a result
of complications of pneumonia and renal failure. He died in April
2002.
Autopsy was performed on April 22nd,
2002. Micros-copically, features affected by AD were observed in the
follicular epithelial cells of the thyroid gland and in the liver.
Notably, there were no histological findings suggesting AD-induced
pulmonary toxicity, which is more common and often more serious than
hepatotoxicity, whereas both his lungs revealed congestion with
pneumonic foci.
We compared the light-microscopic and
electron-microscopic findings for the biopsy (December 2001) and
autopsy (April 2002) materials (Table 1). Light microscopy of the
autopsy materials also revealed micronodular cirrhosis. The biopsy
material showed both microvesicular and macrovesicular steatosis,
but the autopsy material showed only microvesicular steatosis. The
number of hepatocytes with Mallory bodies was similar to that of the
biopsy specimen. We counted the number of lysosomes with LI relative
to the total number of lysosomes in the liver. The incidence was
relatively lower in the autopsy specimen compared with the biopsy
specimen (Table 1). Unfortunately, we could not assess the tissue
concentration of AD.
Table 1 Comparison
of CT density and light and electron microscopic findings between
biopsy and autopsy specimens of the liver
| |
Biopsy |
Autopsy |
| CT
density (HU) |
111.8 |
97.2 |
| Light
microscopic findings |
|
|
| Nodular
formation |
Micronodular |
Micronodular |
| Fibrosis |
Dense |
Dense |
| Steatosis |
Macro/microvesicular |
Microvesicular |
| Infiltration
of inflammatory cells |
Moderate |
Moderate |
| Electron
microscopic findings |
|
|
| Number
of lysosomes with |
992/2
726 (36.4%) |
862/2
578 (33.4%) |
| lamellar
inclusion/total |
|
|
| number
of lysosomes (%)1 |
|
|
1Counts
were performed of 10 fields (�18 000) of five blocks for each
material.
Figure
1 An unenhanced
computed tomography (CT) scan of the upper abdomen. The liver has a
greatly increased density (111.8 HU).
Figure 2 Microscopic
features of the liver biopsy specimen. A:
Micronodular cirrhosis has become established (silver impregnation,
scale bar = 200 �m); B:
Low power view of the liver biopsy specimen (hematoxylin and eosin
stain, scale bar = 200 �m). Fatty
degeneration and marked fibrosis with inflammatory cell infiltration
were observed; C:
High power view of the liver biopsy specimen (hematoxylin and eosin
stain, scale bar = 20 �m). Foci of hepatocellular necrosis and
dense fibrosis with neutrophilic infiltration were observed.
Hepatocytes showed both the microvesicular and macrovesicular
types of steatosis.
Figure
3 Transmission
electron micrograph of the biopsy specimen with lamellated
inclusions in the cytoplasm of the hepatocyte (original
magnification �20 000).
DISCUSSION
The true incidence of AD-induced liver cirrhosis is obscure, since
liver biopsy has not been performed routinely in AD-treated
patients. Almost all cases of AD-induced liver cirrhosis have been
reported in patients receiving higher maintenance doses[15,16],
and only five cases arising from administration of daily low doses
have been described in the literature (Table 2)[12-14,18,19].
Some investigators have speculated that the total cumulative dose
might be more important in estimating the risk of irreversible liver
injury[10,15,16].
The cumulative doses of the patients previously reported ranged from
165 to 213 g, with a duration of treatment of 12-48 mo. The present
patient had been treated with 200 mg of AD daily for 84 mo, with a
total cumulative dose of 528 g.
Even though this dosage is greater than that in previous
reports, hepatic abnormalities were not detected during the course
of treatment. As asymptomatic progression of liver disease might
occur more frequently in patients receiving long-term treatment with
AD, periodic examination of liver function and/or biopsy should be
performed to detect liver injury. Gilinsky et al.[9]
described that drug withdrawal was insufficient to restore
liver function, if irreversible liver damage had already occurred.
Early histological examination for hepatic abnormalities is helpful
to warn off irreversible liver changes.
Table 2 Summary of
published cases of cirrhosis after long-term administration of daily
low doses of AD
| No |
Reference |
Age
(yr) |
Duration
(mo) |
Cumulative
dose (g) |
Outcome |
| 1 |
Present
case |
85 |
84 |
528 |
Dead |
| 2 |
12 |
76 |
48 |
Not
described |
Dead |
| 3 |
13 |
68 |
13.5 |
165 |
Dead |
| 4 |
14 |
77 |
12 |
202 |
Dead |
| 5 |
18 |
79 |
33 |
200 |
Dead |
| 6 |
19 |
83 |
35 |
213 |
Non-fatal |
We suggest that genetic background might also be important in
determining the risk of progression of NAFLD in patients receiving
long-term treatment with AD. It is well known that steatosis and
non-alcoholic steatohepatitis (NASH) can be induced by drugs such as
tamoxifen, some anti-retroviral agents and AD[20-22].
These drugs inhibit the mitochondrial b-oxidation
of fatty acids (causing steatosis) and respiration[20,23].
Inhibition of respiration decreases ATP and also increases the
mitochondrial formation of reactive oxygen species (ROS). In
hepatocytes, ROS and lipid peroxidation products further impair the
respiratory chain, either directly or indirectly through oxidative
damage to the mitochondrial genome. Mitochondrial dysfunction can
also lead to apoptosis or necrosis, depending on the energy status
of the cell. ROS and lipid peroxidation products also activate
stellate cells, thus resulting in fibrosis. Finally, ROS and lipid
peroxidation increase the generation of several cytokines (TNF-a,
TGF-b,
and Fas ligand) that play various roles in the pathogenesis of
drug-induced NASH[20,23].
Some investigators have postulated that in
insulin resistance the combination of elevated plasma concentrations
of glucose and fatty acids promotes hepatic fatty acid synthesis and
impairs oxidation, leading to hepatic steatosis[20,24,25].
Several polymorphisms in genes related to insulin resistance appear
to be associated with the severity of steatosis[25-29].
We examined a few polymorphisms in the TNF-a,
HFE, CYP2E1, and IL-10 genes, but the
susceptibility alleles were not present in the patient (data not
shown). However, we are now undertaking a genome-wide single
nucleotide polymorphism study in patients with drug-induced NASH[20].
Further, several experimental and clinical studies suggest that a
number of drugs could be useful for the prevention and/or treatment
of NASH. These genetic and clinical approaches may help increase the
safety of the long-term administration of AD.
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