Opis przypadku Case report
Amiodarone (2-n-butyl-3-[3,5
diiodo-4-diethylamino-ethoxybenzoyl]-benzofuran; B2-O-Et-N- belongs to the
class III anti-arrythmic drugs (16). It blocks potassium
channels, elongates refraction time of myocardium,
which results in an extended QT distance in ECG
re-cords. In addition, it blocks sodium and calcium
chan-nels. Amiodarone is a strongly lipophylic substance with
an extensive distribution volume, which is linked to
the need of the saturation of the patients body with
the drug and to its prolonged period of elimination (15,
16). The drug is metabolised by a hepatic p450
cyto-chrome system and excreted with feces (15). It is used
in a broad range of arrhythmias, in particular in atrial
fibrillation and ventricular rhythm disturbances in
humans and dogs (12, 15). It used to be applied
simul-taneously with other anti-arrhythmic drugs, e.g. with
beta-blockers (15). The drug exerts a number of side
effects, linked to its toxic action on the thyroid, lungs,
cornea, nerves and liver and it induces alterations
in blood smear (1, 3, 4, 8, 10, 14). The toxicity of
amiodarone reflects its toxic action on mitochondria,
including dissociation of oxidative phosphorylation
and respiratory chain electron transfer, restricted
â-oxi-dation of fatty acids, with the resulting excessive
cellular storage of phospholipid deposits (9, 16). The
cytotoxicity of amiodarone reflects its content of
iodine-containing 2-butyl-benzofluorate group and the
process of dealkylation of the molecule (14). The most
frequently encountered side effect of amiodarone
ad-ministration involves corneal inclusion bodies, present
in close to 90% of treated humans (15). Numerous
undesirable effects are linked to the thyroids.
Amio-darone therapy may induce either hypothyroidism
(encountered more frequently) or hyperthyroidism (5,
7, 15). Signs/symptoms of hyperthyroidism indicate
the need of the discontinuation of amiodarone
treat-ment. Much less frequently side effects from other
organs are noted. In dogs hematological alterations
were observed, including anemia, thrombocytopoenia
and neutropoenia. Moreover, a positive Coombs test
noted in dogs points to the immunological background
of the amiodarone-induced disturbances (3). Both in
humans and in dogs supravital liver injuries have been
detected, developing after a few months of
amio-darone treatment (2, 4, 15). In humans, a few cases
were described of various degrees of liver pathology
in the course of amiodarone treatment, ranging from
a transient increase in the activity of analine
amino-transferase (ALT) and aspartate aminotrasferase (AST),
through hepatitis up to liver cirrhosis (2, 6, 8-13). Until
now only benign hepatic disturbances were described
in dogs, which subsided after the cessation of
amio-darone treatment (4).
Injury to a canine liver induced by long-term oral
administration of amiodarone. A case report
AGNIESZKA NOSZCZYK-NOWAK, MARCIN NOWAK*, URSZULA PAS£AWSKA Department of Internal Diseases and Parasitology with Horses, Dogs and Cats Clinic, Faculty of Veterinary Medicine,
University of Environmental and Life Sciences, pl. Grunwaldzki 47, 50-366 Wroc³aw, Poland
*Department of Pathological Anatomy, Faculty of Veterinary Medicine, University of Environmental and Life Sciences, Norwida 31, Wroclaw 50-366, Poland
Noszczyk-Nowak A., Nowak M., Pas³awska U.
Injury to a canine liver induced by long-term oral administration of amiodarone. A case report
SummaryAmiodarone is an antiarrhythmic drug commonly used in veterinary and human medicine. In humans, a few cases have been described of various degrees of liver pathology in the course of amiodarone treatment. Until now only benign hepatic disturbances have been described in dogs. The authors observed signs of liver damage in a dog after 26 months of treatment with amiodarone: AST (U/l) = 189, ALT (U/l) = 860, proteins (g/l) = 41, albumin (g/l) = 20. After carrying out an autopsy and histopatological examination, inflammatory processes and pronounced degenerative lesions, including fatty degeneration, with a clear reconstruction of hepatic parenchyma and development of cirrhosis were noted. This is the first description of fatal damage of the liver in a dog with arrhythmias, which was treated with amiodarone for 2 years.
Case description
On 22 December 2003, owners of a 5-year-old small bull-dog reported to the cardiologic laboratory of the Chair of Inner and Parasitic Diseases with Department of Horse, Dog and Cat Diseases. The dog, 32 kg body weight, suffered from a severe orthopnoeic dispnoe. The signs developed suddenly and had already lasted for 3 hours. Clinical exa-mination disclosed mucosal cyanosis, elongated time of fil-ling the capillaries, accelerated cardiac action, dull cardiac sounds, palpated difficulty, accelerated pulse. Electrocar-diographic examination documented monomorphic ventri-cular tachycardia, ~300/min (VT). In order to interrupt the arrhythmia, 2% lignocain was administered i.v., at a dose of 2 mg/kg body weight. The maneuver was successful in interrupting tachycardia with a return of the sinus rhythm for around 10 min, but following an extrasystole (VPs) the
tachycardia returned. Amiodarone infusion was administe-red i.v., at a dose of 5 mg/kg body weight. This interrupted the ventricular tachycardia with the return of a normal sinus rhythm of 130/min. The amiodarone was continued per os, at divided doses of 8 mg/kg body weight, twice daily. Unfor-tunately, at the 25th day of the therapy a pro-arrhythmic
effect developed, in the form of the a multiform ventricular tachycardia of Torsa des Pointes type, which subsided spon-taneously. Nevertheless, the episode resulted in a disconti-nuation of amiodarone and in substituting it with a beta--blocker group drug, metoprolol prolongatum (a slow release drug) at the preliminary dose of 25 mg and a subsequent dose of 50 mg once daily (1.5 mg/kg body weight). Initially, a 24-hour ECG examination according to Holter disclosed numerous extrasystolic beats exceeding 10 000 beats/24 h, which was reduced to around 100 VPs after 3 months of metoprolol treatment. Echocardiographic examination demonstrated normal sizes of individual cardiac cavities and normal contractility of myocardium (tab. 1). Control resting ECG records demonstrated no disturban-ces in cardiac rhythm. ECG examination using Holters technique, performed every 6 months, documented individual VPs of up to 100/24 h. Unfortunately, after 24 months of the metoprolol treat-ment ECG examination using Holters technique demonstrated attacks of ven-tricular tachycardia, ~140/min. A deci-sion was made to re-introduce amioda-rone at 5 mg/kg body weight in divided doses.
Two months after re-introduction of amiodarone, ECG examination using Holters technique disclosed no attacks
) m m ( r e t e m a r a P Obtainmentvalue n o it a n i m a x e 1 2examinaiton 3examinaiton r e t e m a i d c il o t s y s -d n e r a l u c ir t n e v tf e L 3.1 3.2 4.9 r e t e m a i d c il o t s a i d -d n e r a l u c ir t n e v tf e L 4.4 4.4 5.9 r e t e m a i d c il o t s y s -d n e ll a w r a l u c ir t n e v tf e L 1.8 1.6 1.3 r e t e m a i d c il o t s a i d -d n e ll a w r a l u c ir t n e v tf e L 1.1 1.1 0.8 r e t e m a i d c il o t s y s -d n e m u t p e s r a l u c ir t n e v a rt n I 1.5 1.4 1.0 r e t e m a i d c il o t s a i d -d n e m u t p e s r a l u c ir t n e v a rt n I 1.0 1.1 1.0 n o it c a rf n o it c e j e r a l u c ir t n e v tf e L 57.21 55.11 33.61 n o it c a rf g n i n e tr o h S 29.81 28.41 16.21 a tr o A 2.0 1.9 2.1 m u ir t a tf e L 3.8 3.9 4.5
Tab. 1. The results of echocardiography examination
Tab. 2. The results of blood tests
s r e t e m a r a P epxraemilminianaitoryn 2atfmeor 6atfmero 1a2tfmero 2a4tfemro 2a5tfmero 2a6tfmero 2a6tfmero norm )l / U ( s e s a r e f s n a rt o n i m a e t a tr a p s A 80 213 91 88 169 199 317 189 <90 )l / U ( s e s a r e f s n a rt o n i m a e n i n a l A 90 976 98 70 1014 1252 1363 860 <100 )l / U ( e s a t a h p s o h p e n il a k l A 130 382 201 136 501 389 419 354 <200 )l /l o m m ( a e r U 4.2 4.4 4.9 4.7 3.36 3.49 3.72 5.1 3.3-8.9 )l /l o m u ( e n i n it a e r C 109 110 140 121 139 156 98 99 88-159 )l / U ( e s a l y m A 893 330 900 890 670 890 1120 540 388-1800 )l / U ( T G G 7 9 5 5 11 10 19 7 5-25 )l / g ( s n i e t o r P 74 70 72 68 78 50 51 41 48-78 )l / g ( n i m u b l A 30 23 29 28 25 23 22 20 25-35 )l / G ( C B W 14.1 14.5 13.1 12.1 12.1 13.4 14.1 6.9 6.0-15.0 )l / T ( C B R 7.32 7.33 6.91 6.81 7.22 7.10 6.90 6.42 5.5-8.9 )l /l o m m ( b H 11.6 11.0 10.4 11.1 10.9 11.9 10.8 9.4 7.4-11.8 )l /l ( t H 0.514 0.490 0.510 0.410 0.480 0.520 0.51 0.444 0.370-0.550 K+(mmo/l)l 4.0 3.7 4.2 4.5 4.3 4.5 4.5 4.1 3.5-5.1 a N +(mmo/l)l 110 114 114 114 115 110 111 114 142-158 )l /l o m m ( a C 2.2 2.45 2.3 2.6 2.4 2.3 2.2 2.28 2.0-3.0
of ventricular tachycardia. Echocardiography documented slight dilation of both cardiac ventricles; the contractility remained within normal range (tab. 1). The dog felt well and in subsequent control examinations no return was observed of arrhythmia attacks or deteriorated cardiac mechanical activity (tab. 1). A slight, transient increase was observed in amino-transferase activities (tab. 2). After two years of amiodarone treatment a sudden deterioration was noted in the health of the dog. Vomiting appeared, accom-panied by hepatomegaly and, then, by ascites. Activities of amino-transferases increased several-fold (AST 213 U/l, ALT 976 U/l). Echocardiographic examination documen-ted dilation of the left cardiac ventricle and its decreased contractility (tab. 1). Ultrasonographic examination of the abdominal cavity detected an enlarged liver and tumorous lesions on its surface, liver parenchyma demonstrated a non--homogenous echogenicity. The owners did not agree for a liver biopsy in the dog. Due to the poor general condition and an unfavorable prognosis the dog was subjected to euthanasia. Upon autopsy, yellowish discoloration of skin and mucosa was noted.
Opening of the abdomen determined the presence of around 4000 cm3 of fluid in peritoneal cavity, a small
amount of a transparent fluid was also detected in the pleural cavities. The heart was slightly enlarged in its trans-verse dimension and the endocardium showed yellowish discoloration. The liver was enlarged, it showed a solid con-sistency and numerous nodules of various sizes at its surface. In the histopathology, regions prevailed in which hepato-cyte cytoplasm contained fine lipid droplets (fine droplet fatty degeneration), which compressed the cell nucleus and dislocated it to the periphery (fig. 1).
In a proportion of hepatocytes the lipids were accumulated in the form of larger vacuoles (large droplet fatty degene-ration) and the cell nucleus underwent degradation. In some lobules such lesions were observed only in the lobule centre but in most cases they included the entire lobule. In several sites a typical swelling of hepatocyte was seen, resulting from the accumulation of lipids, water and pro-tein in the cytoplasm of the injured cell (fig. 2). A reaction of neutrophilic granulocytes was quite clear: the neutrophils massively infiltered the lobuli and accumulated around the degenerating hepatocytes (fig. 3). Moreover, an extensive accumulation of both neutrophils, lymphocytes and of ma-crophages was seen in portal spaces, wherefrom the inflam-matory cells penetrated the interior of the lobuli (fig. 4).
Fig. 1. Fine lipid droplets in hepatocyte cytoplasm Fig. 2. Swelling and rounding-off of hepatocytes
Fig. 3. Infiltrates of neutrophilic granulocytes around
The described above inflammation was accompanied by stimulated fibrosis of the perisinusoidal, perivenous and periportal type (fig. 5). In several sites bands of connective tissue surrounded groups of chaotically dispersed hepato-cytes, forming so called regeneration nodules of various sizes (figs. 6 and 7). Cholestasis and slight accumulation of haemosiderin was also observed in hepatocytes and Browicz-Kupfer cells (fig. 8). In the performed histopatho-logical examination of liver samples a massive inflamma-tory process was noted as well as pronounced degenerative lesions, including fatty degeneration, with a clear recon-struction of hepatic parenchyma and the development of cirrhosis.
Discussion
Various degrees hepatic disturbances are relatively
common following amiodarone administration. Both
in humans and in dogs the first noticeable sign of liver
injury following long-term amiodarone treatment
involves augmented activities of aminotransferases (4,
13). In humans, cases of acute hepatitis have also been
seen following intravenous administration of
amio-Fig. 5. Foci of pronounced fibrosis (staining according to
Van-Gieson) Fig. 6. Fibrosis and formation of regeneration nodules (sta-ining according to VanGieson)
Fig. 7. Fibrosis and formation of regeneration nodules (HE
staining) Fig. 8. Accumulation of haemosiderin in hepatocytes
darone (2, 8, 11). In dogs, increased activities of ALT
and AST have been reported, along with a disturbed
consciousness (lethargy) and anorexia. The signs
dis-appeared around 2 weeks after discontinuation of
amio-darone and a return to reference ALT and AST
activi-ties was seen 6-8 weeks after the discontinuation of
the treatment (4). In experimental dogs and rats
admi-nistered with high doses of amiodarone, storage of
lipids in hepatocytes has been noted, accompanied by
inflammatory infiltrates (9), but till now the
anti--arrhythmic therapy in the animals was never noted to
result in stable organ lesions. In humans, a few cases
of a pseudo-alcohol cirrhosis have been reported
following long-term therapy with low doses of
amio-darone (6, 9, 13). In all such cases liver cirrhosis
manifested a typical pattern of pseudo-alcoholic
cir-rhosis, resembling alcohol-induced cirrhosis. Such
a form of liver injury was always noted in patients
subjected to long-term therapy with amiodarone
(ex-ceeding 22 months of the treatment). A similar
situ-ation developed in the dog described above, in which
amiodarone treatment exceeded 24 months. Persons
who developed liver cirrhosis in the course of
amio-darone treatment never abused alcohol (anamnestic
data). In our dog, obviously, alcohol abuse could have
been excluded. Moreover, literature of the subject
contains no reports which would indicate that
beta--blocker (in this case metoprolol) therapy induces
liver cirrhosis. Therefore, the only cause of the
patho-logy seems to involve long-term amiodarone treatment.
Summing up, it should be noted that both in our case
and in many humans no potential exists for the
discon-tinuation of the drug, since this may provoke the
de-velopment of life risk linked to heart rhythm
distur-bances. On the other hand, prolonged therapy with
amiodarone in some patients leads to liver cirrhosis
which, in the absence of the potential to transplant the
organ, leads to death. A similar situation has
deve-loped in the described dog, which had to be subjected
to euthanasia due to progressive hepatic insufficiency
resulting from liver cirrhosis.
References
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Authors address: dr Agnieszka Noszczyk-Nowak, pl. Grunwaldzki 47, 50-366 Wroc³aw; e-mail: agnieszkann@poczta.onet.pl
