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Acute cholestatic liver injury induced by Enoxacin
139
LETTERS TO THE EDITOR
change of-20.6% at the end o f l F N therapy. The reason for this dichotomy is obscure and further experiments regarding the effects of IFN are necessary. As shown in Fig. 1, 6 months after finishing IFN therapy, only patients in the CR group showed significant decline in JCC units (-50.5 ± 38.7%, mean 4S.D.). In contrast, JCC units rebounded to pretreatment levels in the TR or NR groups. JCC units at 6 months correlated well with the effect of IFN therapy during the 12-month observation period. All patients were positive for HCV RNA measured by the reverse transcription-nested polymerase chain reaction (RT-nested PCR) with primers from the 5'noncoding region of the HCV genome. HCV RNA disappeared in 12 patients by the end of IFN therapy (CR: 7/7, TR: 4/10, NR: 1/4) (4). HCV RNA of six patients in the CR group was undetectable at 6 and 12 months after IFN. In the TR and NR groups, all patients had recurrence. Table 1 shows that the mean decrease in anti-JCC units at 6 months after the therapy of the six patients in whom HCV RNA disappeared was higher than that in nine patients who were persistent by positive for HCV RNA. Decreasing JCC units corresponded well to the disappearance of HCV RNA. Therefore, JCC titers
were thought to be increased by the recurrence of viral replication in the TR and NR groups. Analysis of HCV RNA by PCR is technically difficult, while determination of JCC units is relatively simple. Accordingly, we believe the titration of JCC units 6 months after completing IFN therapy is a useful marker of therapeutic effect. Yuko Taura a, Shigetoshi Fujiyama a, Shin-ichi Kawano a, Shinjiro Sato a, Masafumi Goto a, Hideto Chikazawa a, Junji Shibata a, Kyosuke Mizuno b and Tatsuo Sato a aThe Third Department of Internal Medicine, Kumamoto University School of Medicine and bThe Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan
References 1 2 3 4
Choo QL, Kuo G, Welner A J, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne nonA, non-B viral hepatitis gemome. Science 1989; 244: 359-62. Okamoto H, Okada S, Sugiyama Y, et al. The 5 '-terminal sequence ofthe hepatitis C virus genome. Jpn J Exp Med 1990; 60: 167-77. Kawano S, Fujiyama S, Sato S, et al. Clinical evaluation of three anti-HCV ELISAs in patients with various liver disease. Dig Dis Sci 1992; 37: 1268-74. Hagiwara H, Hayasi H, Mita H, et al. Detection of hepatitis C virus RNA in serum of patients with chronic hepatitis C treated with interferon-g. Hepatology 1992; 15: 37-41.
HEPAT 01326
Acute cholestatic liver injury induced by Enoxacin Enoxacin (1-ethyl-6-fluoro- 1,4-dihydro-4-oxo-7-(piperazin-l-yl)-l,8 naphthyridine-3-carboxylic acid) is a broad spectrum antibiotic belonging to the group of quinolones. It is used in bacterial infections especially of the respiratory and urinary tracts (1). Although mild elevations in liver enzymes have been reported in patients taking quinolones (2), clinically overt hepatitis induced by enoxacin has never been described. We would like to present a case of a patient with acute liver damage caused by this drug. A 27-year-old woman was admitted to our hospital on January 1991 complaining of jaundice, itching, dark urine and pale stools that started 7 days before. She had never had fever or abdominal pain. There was no history of chronic liver disease or allergies. Recent alcohol abuse, blood transfusions or surgery were excluded. Nine days before the admission the patient had a flu-like syndrome and took enoxacin 400 mg t.d. orally. After the second dose the patient started to itch.
On examination she looked well and showed scratch marks, an enlarged liver with no palpable spleen. No other signs of chronic liver disease were seen. Biochemical investigations showed: total bilirubin 119 mmol/1 (conjugated 68); albumin 3.8 g/l; AST 140 (up to 25 IU/I); ALT 201 (up to 29 IU/I); alkaline phosphatase 430 (.up to 207 IU/1); GGT 28 (up to 38 IU/I); LDH 400 (up to 320 IU/1); prothrombin time normal; gammaglobulin 0.9 g/l. Renal function tests and full blood count were normal. HBsAG, IgM anti-HBcAG, IgM antiHAV, anti-HCV, IgM anticytomegalovirus, autoantibodies (ANA, AMA, SMA) were all negative. Liver ultrasonography confirmed the hepatomegaly with normal biliary tract: the gallbladder was normal with no gallstones. A retrograde endoscopic cholangiopancreatography showed a normal biliary tree. One month after the onset of the symptoms, bilirubin reached 374 mmol/1 while aminotransferase decreased to 1.5 the upper limit of the normal range. The patient was
140
LETTERS TO THE EDITOR
Bil. T. #moPI
AST I.U. ENOX.
400
160
140
//i
la3
\\
I00
i li
I
after 10 weeks (Fig. 1) and were repeatedly confirmed to be normal after six months of follow-up. The clinical course of the illness is suggestive of a cholestatic liver injury caused by enoxacin according to the criteria currently in use (3). To our knowledge this is the first report of acute enoxacin liver injury. Lucio Amitrano a, Tullio Gigliotti a, Maria Anna Guardascione b and Antonio Ascione b
~
$
t
9
rl
13
Weeks Fig. 1. Changes in ALT
( -- ) and bilirubin (- - -) after administration
of enoxacin.
aDivisione di Gastroenterologia and bServizio di Fisiopatologia Epatica, Ospedale A. Cardarelli, Napoli, Italia
References 1
treated conservatively because the possibility of druginduced liver damage was raised. The jaundice regressed progressively. All liver function tests were within the normal range
2 3
Maple P, Brumfitt W, Hamilton-Miller JM. A review of the antimicrobial activity of the fuoroquinolones. J Chemother 1990; 2: 280-94. Halkin H. Adverse effects of the fluoroquinolones. Rev Infect Dis 1988; 10 (suppl 1): $258-61. Criteria of drug-induced liver disorders. Report of an International Consensus Meeting. J Hepatol 1990; !1: 272-6.
LETTERS TO THE EDITOR
change of-20.6% at the end o f l F N therapy. The reason for this dichotomy is obscure and further experiments regarding the effects of IFN are necessary. As shown in Fig. 1, 6 months after finishing IFN therapy, only patients in the CR group showed significant decline in JCC units (-50.5 ± 38.7%, mean 4S.D.). In contrast, JCC units rebounded to pretreatment levels in the TR or NR groups. JCC units at 6 months correlated well with the effect of IFN therapy during the 12-month observation period. All patients were positive for HCV RNA measured by the reverse transcription-nested polymerase chain reaction (RT-nested PCR) with primers from the 5'noncoding region of the HCV genome. HCV RNA disappeared in 12 patients by the end of IFN therapy (CR: 7/7, TR: 4/10, NR: 1/4) (4). HCV RNA of six patients in the CR group was undetectable at 6 and 12 months after IFN. In the TR and NR groups, all patients had recurrence. Table 1 shows that the mean decrease in anti-JCC units at 6 months after the therapy of the six patients in whom HCV RNA disappeared was higher than that in nine patients who were persistent by positive for HCV RNA. Decreasing JCC units corresponded well to the disappearance of HCV RNA. Therefore, JCC titers
were thought to be increased by the recurrence of viral replication in the TR and NR groups. Analysis of HCV RNA by PCR is technically difficult, while determination of JCC units is relatively simple. Accordingly, we believe the titration of JCC units 6 months after completing IFN therapy is a useful marker of therapeutic effect. Yuko Taura a, Shigetoshi Fujiyama a, Shin-ichi Kawano a, Shinjiro Sato a, Masafumi Goto a, Hideto Chikazawa a, Junji Shibata a, Kyosuke Mizuno b and Tatsuo Sato a aThe Third Department of Internal Medicine, Kumamoto University School of Medicine and bThe Chemo-Sero-Therapeutic Research Institute, Kumamoto, Japan
References 1 2 3 4
Choo QL, Kuo G, Welner A J, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne nonA, non-B viral hepatitis gemome. Science 1989; 244: 359-62. Okamoto H, Okada S, Sugiyama Y, et al. The 5 '-terminal sequence ofthe hepatitis C virus genome. Jpn J Exp Med 1990; 60: 167-77. Kawano S, Fujiyama S, Sato S, et al. Clinical evaluation of three anti-HCV ELISAs in patients with various liver disease. Dig Dis Sci 1992; 37: 1268-74. Hagiwara H, Hayasi H, Mita H, et al. Detection of hepatitis C virus RNA in serum of patients with chronic hepatitis C treated with interferon-g. Hepatology 1992; 15: 37-41.
HEPAT 01326
Acute cholestatic liver injury induced by Enoxacin Enoxacin (1-ethyl-6-fluoro- 1,4-dihydro-4-oxo-7-(piperazin-l-yl)-l,8 naphthyridine-3-carboxylic acid) is a broad spectrum antibiotic belonging to the group of quinolones. It is used in bacterial infections especially of the respiratory and urinary tracts (1). Although mild elevations in liver enzymes have been reported in patients taking quinolones (2), clinically overt hepatitis induced by enoxacin has never been described. We would like to present a case of a patient with acute liver damage caused by this drug. A 27-year-old woman was admitted to our hospital on January 1991 complaining of jaundice, itching, dark urine and pale stools that started 7 days before. She had never had fever or abdominal pain. There was no history of chronic liver disease or allergies. Recent alcohol abuse, blood transfusions or surgery were excluded. Nine days before the admission the patient had a flu-like syndrome and took enoxacin 400 mg t.d. orally. After the second dose the patient started to itch.
On examination she looked well and showed scratch marks, an enlarged liver with no palpable spleen. No other signs of chronic liver disease were seen. Biochemical investigations showed: total bilirubin 119 mmol/1 (conjugated 68); albumin 3.8 g/l; AST 140 (up to 25 IU/I); ALT 201 (up to 29 IU/I); alkaline phosphatase 430 (.up to 207 IU/1); GGT 28 (up to 38 IU/I); LDH 400 (up to 320 IU/1); prothrombin time normal; gammaglobulin 0.9 g/l. Renal function tests and full blood count were normal. HBsAG, IgM anti-HBcAG, IgM antiHAV, anti-HCV, IgM anticytomegalovirus, autoantibodies (ANA, AMA, SMA) were all negative. Liver ultrasonography confirmed the hepatomegaly with normal biliary tract: the gallbladder was normal with no gallstones. A retrograde endoscopic cholangiopancreatography showed a normal biliary tree. One month after the onset of the symptoms, bilirubin reached 374 mmol/1 while aminotransferase decreased to 1.5 the upper limit of the normal range. The patient was
140
LETTERS TO THE EDITOR
Bil. T. #moPI
AST I.U. ENOX.
400
160
140
//i
la3
\\
I00
i li
I
after 10 weeks (Fig. 1) and were repeatedly confirmed to be normal after six months of follow-up. The clinical course of the illness is suggestive of a cholestatic liver injury caused by enoxacin according to the criteria currently in use (3). To our knowledge this is the first report of acute enoxacin liver injury. Lucio Amitrano a, Tullio Gigliotti a, Maria Anna Guardascione b and Antonio Ascione b
~
$
t
9
rl
13
Weeks Fig. 1. Changes in ALT
( -- ) and bilirubin (- - -) after administration
of enoxacin.
aDivisione di Gastroenterologia and bServizio di Fisiopatologia Epatica, Ospedale A. Cardarelli, Napoli, Italia
References 1
treated conservatively because the possibility of druginduced liver damage was raised. The jaundice regressed progressively. All liver function tests were within the normal range
2 3
Maple P, Brumfitt W, Hamilton-Miller JM. A review of the antimicrobial activity of the fuoroquinolones. J Chemother 1990; 2: 280-94. Halkin H. Adverse effects of the fluoroquinolones. Rev Infect Dis 1988; 10 (suppl 1): $258-61. Criteria of drug-induced liver disorders. Report of an International Consensus Meeting. J Hepatol 1990; !1: 272-6.