Diagnostic Problems in Hepatology
Severe Ductopenia and Cholestasis from Levofloxacin Drug-Induced Liver Injury: A Case Report and Review Calley Levine, MD1
Anshu Trivedi, MD2
Swan N. Thung, MD2
1 Department of Medicine, Icahn School of Medicine at Mount Sinai,
New York, New York 2 The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
Ponni V. Perumalswami, MD1
Address for correspondence Calley Levine, MD, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 (e-mail: [email protected]).
Semin Liver Dis 2014;34:246–251.
Abstract
Keywords
► antibiotics ► drug-induced liver injury ► hepatotoxicity ► levofloxacin ► vanishing bile duct syndrome
A 67-year-old woman with hypertension, hypothyroidism, and glaucoma was referred for jaundice and elevated liver function tests. She was treated for streptococcal endophthalmitis with 2 weeks of intravenous (IV) levofloxacin followed by 2 months of oral levofloxacin. The patient had no prior history of liver disease and denied alcohol intake. Her physical exam was remarkable for jaundice and scleral icterus without any stigmata of liver disease. Viral hepatitis serologies and antibodies, including myeloperoxidase, proteinase 3, and antinuclear, antimitochondrial, antiliver kidney microsome, antismooth muscle antibodies, were all within normal limits. The liver biopsy revealed severe cholestasis, extensive bile duct loss, and fibrosis. The patient had no known exposure to any other systemic medications or inciting factors other than levofloxacin. Although there are a few reported cases of drug-induced liver disease (DILI) related to levofloxacin, this case is believed to be the first reported case of ductopenia or vanishing bile duct syndrome (VBDS) associated with levofloxacin. Although fluoroquinolones, such as levofloxacin, are generally considered safe antibiotics, health practitioners must be aware of their association with DILI, as the diagnosis of DILI is one of exclusion and requires a high index of suspicion.
Case History A 67-year-old woman with history of hypertension, hypothyroidism, and glaucoma presented to the liver faculty practice at the Mount Sinai Medical Center (MSMC) in New York City for further evaluation of jaundice and elevated liver function tests. Several months prior to presentation, she developed eye swelling and redness on a return flight from India to the United States. She was admitted to a local New York hospital, where she was diagnosed with streptococcal endophthalmitis, which ultimately resulted in loss of vision in her left eye. During her 2-week long hospitalization, she received IV
Issue Theme Drug-Induced Liver Injury; Guest Editors, Naga Chalasani, MD, and Paul H. Hayashi, MD, MPH
steroids and antibiotics, including intravitreous vancomycin and ceftazidime, as well as IV levofloxacin 500 mg daily. She was discharged home on levofloxacin 500 mg oral daily for 2 months, prednisone 60 mg oral twice daily, and moxifloxacin ophthalmic solution. She was scheduled to return 2 months later for follow-up with ophthalmology for a possible surgical intervention. Eight weeks postdischarge, the patient presented to her primary care physician (PCP) for routine preop testing and was found to be jaundiced on exam. Upon questioning, she admitted to voiding dark urine for the past week. Her blood tests revealed a total bilirubin (TB) 16.3 mg/dL, direct bilirubin (DB) 9.4 mg/dL, aspartate aminotransferase (AST) 273 IU/L, alanine aminotransferase
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1375964. ISSN 0272-8087.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
246
247
1.0
Levine et al.
Seminars in Liver Disease
Vol. 34
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; DB, direct bilirubin; INR, international normalized ratio; TB, total bilirubin.
1.0 1.0 1.0 1.0 1.0 1.0 1.1 1.1 1.0 1.0 0.9 INR
0.9
389
13.0 13.2
476 448
13.7 15.1
432 380
12.2 14.0
419 382
14.8 19.4
349 304
15.1 23.6
315 299
19.2 16.3
ALP (IU/L)
483
0.4
60
TB (mg/dL)
8.4 9.1 9.0 9.0 11.0 12.8 13.4 >9 13.8 21.6 9.4 – DB (mg/dL)
17.5
132
97 108
126 129
105 112
124 120
110 131
151 210
187 187
220 209
158 166
167 196
ALT (IU/L)
273
614
14
16
AST (IU/L)
239
60 55 50 45 40 34 29 25 21 16 13 0 Number of weeks since discontinuation of levofloxacin
65 60 55 50 44 39 35 31 26 23 10 Baseline from prior year Number of weeks since initiation of levofloxacin
Table 1 Summary of laboratory data
(ALT) 614 IU/L, alkaline phosphatase (ALP) 483 U/L, total protein 6.3 g/dL, albumin 3.8 g/dL, and international normalized ratio (INR) of 0.9. Her laboratory data from the prior year was within normal limits. She had no evidence of ascites or asterixis on exam. Following treatment with intraocular injections, the patient was admitted to a local New York hospital for evaluation of her abnormal liver tests. The ophthalmologic surgery was deferred. The workup included several diagnostic exams. An initial abdominalultrasound and computed tomography (CT) scan revealed no biliary ductal dilatation or stigmata of chronic or advanced liverdisease. A subsequent magnetic resonance cholangiopancreatography (MRCP) also excluded any ductal dilatation or mechanical obstruction. A transjugular liver biopsy revealed severe cholestasis, extensive bile duct loss, and portal fibrosis. These findings were consistent with druginduced liver injury (DILI). The patient was started on a course of steroids with minimal improvement in her laboratory values. She was soon discharged home with instructions to continue her steroid course and was provided an outpatient referral to MSMC. At her initial outpatient visit at MSMC, approximately 3 months after the elevated liver tests were discovered, she was asymptomatic except for jaundice and hair loss over the previous few months. She denied any nausea, vomiting, weight loss, fevers, chills, and abdominal pain. She had no known history of liver disease and her family history was only significant for cardiac disease. She had no signs or symptoms of liver failure, and no evidence of gastrointestinal bleeding, fluid overload, encephalopathy, coagulopathy, or renal dysfunction. She was on amlodipine and metoprolol for hypertension, levothyroxine for hypothyroidism, and prednisone since her most recent hospitalization. She denied taking any other medications, and a thorough history failed to reveal exposure to any other toxins. She denied taking any herbal or over-the-counter supplements, including teas, powders, and oils. She has a known allergic reaction to penicillin manifesting with a rash. She denied any alcohol, tobacco, or drug use. The patient was hemodynamically stable and afebrile. Her exam was significant for deeply icteric sclera. She had no signs of chronic liver disease: no palmar erythema, asterixis, ascites, or peripheral edema. There was no evidence for hepatosplenomegaly. Serologies for hepatitis A, B, C, and E viruses, myeloperoxidase, proteinase 3, antinuclear, antimitochondrial, antiliver kidney microsome, antismooth muscle antibodies were all negative. Immunoglobulin IgA, IgM, and IgG were low at 43 mg/dL, 411 mg/dL, and 28 mg/dL, respectively. The patient was started on ursodiol and tapered off the prednisone within a few weeks. She was also referred for evaluation at the MSMC liver transplant program in case she developed subfulminant liver failure. The patient never progressed to liver failure and was not listed for a liver transplant. She has been followed monthly in our liver practice; serial laboratories have shown slow, but steady improvement in her cholestasis and hyperbilirubinemia (see ►Table 1). Clinically, she continues to do well, with resolution of hair loss and placement of a prosthetic eye.
70
Levofloxacin-Induced Cholestasis and Ductopenia
No. 2/2014
Levofloxacin-Induced Cholestasis and Ductopenia
Levine et al.
Pathology Findings A liver needle biopsy was performed approximately 4 months afterexposure to levofloxacin. The specimen showed severe cholestasis, mainly canalicular, with canaliculi being dilated by inspissated thick bile, and intrahepatocytic bile pigment resulting in feathery degeneration of hepatocytes (►Fig. 1A). Few scattered lobular inflammatory infiltrates are present (►Fig. 1B). Portal areas are remarkable for extensive bile duct loss without significant inflammation and only minimal ductular reaction (►Figs. 2A and B). CK7 immunostain shows bile duct loss in 25 of 27 portal tracts and formation of metaplastic hepatocytes in periportal zones, the latter indicative of chronic cholestasis (►Fig. 3). Portal and periportal fibrosis are present. The conglomeration of these findings are consistent with cholestatic hepatitis with paucity of intrahepatic bile ducts (ductopenia), most likely drug induced. There is no evidence of sclerosing cholangitis.
Discussion Based on the laboratory values and histological results, this patient was diagnosed with DILI, consistent with a vanishing bile duct pattern along with predominant cholestatic injury.
Fig. 2 (A) Portal tract with an artery (arrow) and no accompanying bile duct (hematoxylin and eosin [H&E], 200 ). (B) Another portal tract with mild fibrosis and bile duct loss (H&E, 200 ).
Levofloxacin was determined to be the most likely culprit as she had not started any other new medications prior to the development of DILI. She completed a 10-week-long course of levofloxacin comprised of 2 weeks of intravenous therapy followed by 2 months of oral therapy immediately preceding the diagnosis of abnormal liver tests and jaundice, as
Fig. 1 (A) Liver biopsy specimen with hepatocellular cholestasis and dilated bile canaliculi (arrows) (hematoxylin and eosin [H&E], 200 ), and (B) lobular necroinflammation (long arrow) and apoptotic body (short arrow) formation (H&E, 400 ). Seminars in Liver Disease
Vol. 34
No. 2/2014
Fig. 3 CK7 immunostain confirms the absence of bile duct and shows minimal ductular reaction (dark brown) and cholestatic hepatocyte formation (light brown) (Immunostain, 200 ).
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
248
summarized in ►Table 1. She reported no prior history of liver injury prior to these preoperative laboratories. Since the cessation of levofloxacin, our patient’s liver tests remained elevated, but demonstrated improvement. Her AST and ALT have decreased slowly over time, with ALT decreasing over fivefold within a 9-month period. Similarly, her ALP and bilirubin levels have remained elevated, but with slow improvement. There have been multiple case reports and review articles in the literature describing the association of fluoroquinolones and hepatotoxicity. However, there are only a few reported cases describing prolonged cholestasis associated with levofloxacin. To our knowledge, this is the first reported case of levofloxacin induced vanishing bile duct syndrome (VBDS). “Liver injury” is defined as an increase in ALT or TB of over 2 times () the upper limit of normal (ULN), or a combined increase in AST, ALP, and TB provided one of them is over 2 ULN.1 A consensus reached at the Fogarty International Center Conference on Hepatotoxicity in 1978 characterized elevations in liver enzymes, AST, and ALT more than 3 ULN or ALP more than 1.5 ULN in combination with elevated bilirubin (> 3 the ULN) as a sign of serious liver injury any time after a new medication is initiated.2–4 Now known as “Hy’s law” or “Hy’s rule,” named after Dr. Hyman Zimmerman, DILI that is significant enough to lead to AST or ALT elevations in the presence of jaundice (bilirubin elevations) can be very ominous and can lead to death, especially if the implicated drug is not stopped. The associated fatality rate of DILI in the presence of clinical jaundice has been reported to be 10%.5,6 The annual incidence of DILI is reported to be one in 10,000 to 100,000.7 Over 1,100 drugs, including medications and supplements, have been reported to cause hepatotoxicity.8 Moreover, DILI is the most common reason for withdrawing drugs from the market and for “black box” warnings by the U. S. Food and Drug Administration (FDA).4,9 Obtaining a thorough and accurate history of drug allergies and prior medications is crucial to the diagnosis of DILI. In determining the inciting agent, there are several important factors to consider: the latency or time to onset of DILI, clinical features, prior cases of DILI with the implicated drug, risk factors, exclusion of other causes, liver biopsy results, and the course after cessation of the drug. A positive rechallenge (i.e., readministration of the drug) is considered the gold standard in determining a causal relationship, but is regarded as clinically dangerous.2 Scoring systems, including the Roussel Uclaf Causality Assessment Method (RUCAM) Scale, have been used to assess causality. However, a comparison in 2010 revealed considerable variability between the RUCAM Scale and structured expert opinion.10 Risk factors that have been associated with DILI include genetic susceptibility (especially related to P450 enzymes), female gender (although more recent studies have found no difference between genders), age over 55 years, history of prior drug reactions, drug dose, concomitant alcohol use, extremes of nutritional status (obesity and malnutrition), and pregnancy.9,11 The pattern of injury can be classified in many ways, but most commonly as either hepatocellular,
Levine et al.
cholestatic, or mixed. The pattern is determined by the ratio (R) of ALT/ALP. Hepatocellular damage is consistent with R > 5, cholestatic pattern with R < 2, and a mixed pattern if R > 2 but < 5.2 In an analysis of 461 DILI cases submitted to a Spanish Registry, hepatocellular pattern was the most prevalent (58%) and was associated with ALT values 30 ULN in 22% of cases. The cholestatic pattern was associated with jaundice in 81% of cases.11 The first step in treatment is to discontinue the offending agent. Cessation of the implicated agent (i.e., dechallenge) as soon as possible is critical to spontaneous recovery and generally followed by clinical improvement. The recovery time can vary and is often extended in the cholestatic type of DILI.2,9 After stopping a culprit drug, hepatocellular damage is considered “very suggestive” if ALT levels decrease by at least 50% of the excess above the ULN within 8 days and ALT levels return to normal within one month. A cholestatic or mixed pattern, however, is considered “suggestive” if the ALP or TB decreases by at least 50% of the excess above the ULN within 6 months.2 However, in a study performed in United Kingdom of 44 patients with DILI identified over an 18-year period, 39% of patients had persistent abnormalities in their liver blood tests and/or imaging (including abdominal ultrasounds and isotope scans) at 1 to 19 year (median 5-y) followup.12 Additionally, if a patient develops a chronic liver injury or acute liver failure secondary to DILI, improvement during dechallenge may be negligible.13 Drug-induced liver disease can be very severe, in some instances leading to prolonged jaundice, acute liver failure, and transplant or death. Druginduced liver disease can be very difficult to diagnose and causality is very difficult to determine. As a result, DILI is often is a diagnosis of exclusion.2,4,10 Drug-induced liver disease should always be on the differential diagnosis for a patient who presents with liver dysfunction, whether acute or chronic. Drug-induced liver disease accounts for 13% of acute liver injury cases in the United States, with antibiotics as the most common cause, especially antituberculosis therapies and amoxicillin-clavulanate.2,4,9,11,14 Fluoroquinolones are frequently used in both the inpatient and outpatient settings in the United States, becoming the most commonly prescribed antibiotic class among adults in 2002.15,16 They are generally well tolerated, have a safe side effect profile, are easily dosed, have broad antibiotic coverage, and are highly bioavailable when given orally.15 Fluoroquinolone-induced hepatotoxicity is uncommon, but when it occurs, is usually transient and associated with minimal liver symptoms and injury. However, rare cases have been reported in which patients with fluoroquinolone-induced DILI required liver transplant or suffered death secondary to acute liver failure.17 Of note, the FDA restricted the distribution of trovafloxacin, a third-generation fluoroquinolone, due to serious hepatotoxicity, resulting in transplant or death.18 Licata et al reviewed 35 cases of reported hepatotoxicity associated with fluoroquinolone use, with ciprofloxacin implicated in 45.7%, levofloxacin in 31.4%, moxifloxacin in 20.0%, and norfloxacin in 2.9% of cases. The time between Seminars in Liver Disease
Vol. 34
No. 2/2014
249
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Levofloxacin-Induced Cholestasis and Ductopenia
Levofloxacin-Induced Cholestasis and Ductopenia
Levine et al.
initiation of the fluoroquinolone and the discovery of hepatic injury ranged from 1 to 39 days (median 8 d). Fluoroquinolones were found to be associated with hepatocellular (51.4%), cholestatic (28.6%), and mixed (20.0%) patterns.17 Histologic findings often had immunoallergic features consistent with a hypersensitivity reaction, including fevers, rash, and eosinophilia.4,15 These features were not seen in our patient. The first reported case of severe hepatotoxicity associated with levofloxacin use was in 2001. A 74-year-old received IV levofloxacin for treatment of a lower respiratory tract infection. Within 2 days of drug initiation, she was found to have significant elevation of transaminases consistent with hepatocellular DILI, which resolved after discontinuation of levofloxacin.19 In 2001, the first reported case of fatal levofloxacin-associated acute liver failure was also reported. A 99-year-old man progressed to acute fatal liver failure after exposure to levofloxacin 500 mg daily for treatment of a urinary tract infection. His biopsy showed hepatocellular necrosis and a mixed cellular infiltrate, which included numerous eosinophils. At that time, it was believed that the rarity of levofloxacin-induced liver injury and presence of eosinophils on biopsy supported an immunoallergic reaction.20 Since 2001, several more cases of levofloxacin-related liver injury have been reported, predominantly consistent with the hepatocellular pattern of injury.17 There were no cases, however, of levofloxacin-induced liver injury leading to VBDS. Vanishing bile duct syndrome, also referred to as ductopenia, is defined by the histologic appearance on liver biopsy: the absence of interlobar bile ducts in 50% or more small portal tracts, with characteristic sparing of the larger extrahepatic biliary tree. It results from the destruction of intrahepatic bile ducts and their progressive disappearance from the liver parenchyma.21 Over 40 medications have been associated with causing VBDS, including chlorpromazine, ajmaline and arsenical derivatives, phenytoin, clindamycin, trimethoprim-sulfamethoxazole, and tetracyclines.21–23 More commonly, these medications cause varying degrees of drug-induced cholestasis. Drug-induced cholestasis can persist for several months following removal of the offending agent and rarely can progress to the development of VBDS. Liver tests and jaundice may gradually improve in some cases, even in the setting of persistent ductopenia.24 As in this case, the patient many continue to suffer from prolonged jaundice or chronic liver disease despite cessation of the drug.9 Liver failure may progress in some cases following cessation of the drug, eventually leading to secondary biliary cirrhosis, liver failure, transplantation, or death. Antibiotics, including amoxicillin/ clavulanic acid, ampicillin, clindamycin, erythromycin, and tetracyclines, have been reported to cause VBDS.24 Only a handful of case reports have linked fluoroquinolone usage with the development of VBDS. Robinson et al reported a case of VBDS after a short course of moxifloxacin.21 Additionally, Orman et al described a case of a 46-year-old woman who presented with a cholestatic pattern of elevated liver tests beginning 8 days after starting a course of moxifloxacin. This patient had 1.3 years of prolonged jaundice and eventuSeminars in Liver Disease
Vol. 34
No. 2/2014
ally developed hepatic failure, requiring a liver transplant. The biopsy of the explanted liver was consistent with VBDS.15 Another case reported ductopenia in a patient after 6 months of daily ciprofloxacin usage.25 To our knowledge, our patient’s case is the first reported case of VBDS following the use of levofloxacin. Fluoroquinolones make up a widely used and generally safe class of antibiotics. However, health care providers should be aware of the rare association of fluoroquinolones, such as levofloxacin, with severe hepatotoxicity. It is crucial for health care providers to obtain an accurate history of drug allergies and to only prescribe fluoroquinolones (or any other drugs and/or medications) when appropriate. Unfortunately, the pathophysiology of fluoroquinoloneinduced drug injury is not yet well understood. As hepatotoxicity associated with fluoroquinolone usage has a short latency and patients often manifest features consistent with an immunoallergic reaction, a hypersensitivity reaction may be a possible mechanistic explanation. Further research, including determination of genetic risk factors, is needed to establish which patients are most at risk of DILI and to predict which patients are likely to develop a reaction to a particular drug. Research, such as that being performed by the Drug Induced Liver Injury Network is vitally needed to develop specific and mechanism-based treatment options for patients with DILI. Current management consists of removing the offending agent and supportive care. Neither a course of steroids nor ursodiol or antioxidant therapy has been shown to be efficacious in the treatment of DILI and mechanism-based treatments for the disease are lacking.13
References 1 Bénichou C. Criteria of drug-induced liver disorders. Report of an
international consensus meeting. J Hepatol 1990;11(2):272–276 2 Suk KT, Kim DJ. Drug-induced liver injury: present and future. Clin
Mol Hepatol 2012;18(3):249–257 3 Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-
4
5 6
7
8
9 10
onset jaundice: how often is it caused by idiosyncratic druginduced liver injury in the United States? Am J Gastroenterol 2007;102(3):558–562, quiz 693 Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;52(6):2065–2076 Reuben A. Hy’s law. Hepatology 2004;39(2):574–578 Zimmerman H. Hepatotoxicity - The Adverse Effects of Drugs and Other Chemicals on the Liver. Philadelphia: Lippincott, Williams & Wilkins; 1999:606, 616–618 Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002;22(2): 145–155 Stine JG, Lewis JH. Drug-induced liver injury: a summary of recent advances. Expert Opin Drug Metab Toxicol 2011;7(7): 875–890 Bleibel W, Kim S, D’Silva K, Lemmer ER. Drug-induced liver injury: review article. Dig Dis Sci 2007;52(10):2463–2471 Rockey DC, Seeff LB, Rochon J, et al; US Drug-Induced Liver Injury Network. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the RousselUclaf causality assessment method. Hepatology 2010;51(6): 2117–2126
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
250
Levine et al.
11 Andrade RJ, Lucena MI, Fernández MC, et al; Spanish Group for the
18 Questions and Answers on Trovafloxacin Public Health Advisory. U.S.
Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005;129(2):512–521 Aithal PG, Day CP. The natural history of histologically proved drug induced liver disease. Gut 1999;44(5):731–735 Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology 2010;52(2): 730–742 Ostapowicz G, Fontana RJ, Schiødt FV, et al; U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137(12):947–954 Orman ES, Conjeevaram HS, Vuppalanchi R, et al; DILIN Research Group. Clinical and histopathologic features of fluoroquinoloneinduced liver injury. Clin Gastroenterol Hepatol 2011;9(6): 517–523, e3 Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J Med 2005;118(3):259–268 Licata A, Randazzo C, Morreale I, Butera G, D’Alessandro N, Craxì A. Fluoroquinolone-induced liver injury: three new cases and a review of the literature. Eur J Clin Pharmacol 2012;68(5):525–532
Food and Drug administration website. Available at: http://www.fda. gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053104.htm. Accessed September 28, 2013 Karim A, Ahmed S, Rossoff LJ, Siddiqui RK, Steinberg HN. Possible levofloxacin-induced acute hepatocellular injury in a patient with chronic obstructive lung disease. Clin Infect Dis 2001;33(12): 2088–2090 Spahr L, Rubbia-Brandt L, Marinescu O, Armenian B, Hadengue A. Acute fatal hepatitis related to levofloxacin. [letter]J Hepatol 2001; 35(2):308–309 Robinson W, Habr F, Manlolo J, Bhattacharya B. Moxifloxacin associated vanishing bile duct syndrome. [letter]J Clin Gastroenterol 2010;44(1):72–73 Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease. J Hepatol 1997;26(Suppl 1):31–35 Levy C, Lindor KD. Drug-induced cholestasis. Clin Liver Dis 2003; 7(2):311–330 Reau NS, Jensen DM. Vanishing bile duct syndrome. Clin Liver Dis 2008;12(1):203–217, x Bataille L, Rahier J, Geubel A. Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn’s disease. J Hepatol 2002;37(5):696–699
12 13
14
15
16
17
19
20
21
22 23 24 25
Seminars in Liver Disease
Vol. 34
No. 2/2014
251
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Levofloxacin-Induced Cholestasis and Ductopenia
Copyright of Seminars in Liver Disease is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Severe Ductopenia and Cholestasis from Levofloxacin Drug-Induced Liver Injury: A Case Report and Review Calley Levine, MD1
Anshu Trivedi, MD2
Swan N. Thung, MD2
1 Department of Medicine, Icahn School of Medicine at Mount Sinai,
New York, New York 2 The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York
Ponni V. Perumalswami, MD1
Address for correspondence Calley Levine, MD, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 (e-mail: [email protected]).
Semin Liver Dis 2014;34:246–251.
Abstract
Keywords
► antibiotics ► drug-induced liver injury ► hepatotoxicity ► levofloxacin ► vanishing bile duct syndrome
A 67-year-old woman with hypertension, hypothyroidism, and glaucoma was referred for jaundice and elevated liver function tests. She was treated for streptococcal endophthalmitis with 2 weeks of intravenous (IV) levofloxacin followed by 2 months of oral levofloxacin. The patient had no prior history of liver disease and denied alcohol intake. Her physical exam was remarkable for jaundice and scleral icterus without any stigmata of liver disease. Viral hepatitis serologies and antibodies, including myeloperoxidase, proteinase 3, and antinuclear, antimitochondrial, antiliver kidney microsome, antismooth muscle antibodies, were all within normal limits. The liver biopsy revealed severe cholestasis, extensive bile duct loss, and fibrosis. The patient had no known exposure to any other systemic medications or inciting factors other than levofloxacin. Although there are a few reported cases of drug-induced liver disease (DILI) related to levofloxacin, this case is believed to be the first reported case of ductopenia or vanishing bile duct syndrome (VBDS) associated with levofloxacin. Although fluoroquinolones, such as levofloxacin, are generally considered safe antibiotics, health practitioners must be aware of their association with DILI, as the diagnosis of DILI is one of exclusion and requires a high index of suspicion.
Case History A 67-year-old woman with history of hypertension, hypothyroidism, and glaucoma presented to the liver faculty practice at the Mount Sinai Medical Center (MSMC) in New York City for further evaluation of jaundice and elevated liver function tests. Several months prior to presentation, she developed eye swelling and redness on a return flight from India to the United States. She was admitted to a local New York hospital, where she was diagnosed with streptococcal endophthalmitis, which ultimately resulted in loss of vision in her left eye. During her 2-week long hospitalization, she received IV
Issue Theme Drug-Induced Liver Injury; Guest Editors, Naga Chalasani, MD, and Paul H. Hayashi, MD, MPH
steroids and antibiotics, including intravitreous vancomycin and ceftazidime, as well as IV levofloxacin 500 mg daily. She was discharged home on levofloxacin 500 mg oral daily for 2 months, prednisone 60 mg oral twice daily, and moxifloxacin ophthalmic solution. She was scheduled to return 2 months later for follow-up with ophthalmology for a possible surgical intervention. Eight weeks postdischarge, the patient presented to her primary care physician (PCP) for routine preop testing and was found to be jaundiced on exam. Upon questioning, she admitted to voiding dark urine for the past week. Her blood tests revealed a total bilirubin (TB) 16.3 mg/dL, direct bilirubin (DB) 9.4 mg/dL, aspartate aminotransferase (AST) 273 IU/L, alanine aminotransferase
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1375964. ISSN 0272-8087.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
246
247
1.0
Levine et al.
Seminars in Liver Disease
Vol. 34
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; DB, direct bilirubin; INR, international normalized ratio; TB, total bilirubin.
1.0 1.0 1.0 1.0 1.0 1.0 1.1 1.1 1.0 1.0 0.9 INR
0.9
389
13.0 13.2
476 448
13.7 15.1
432 380
12.2 14.0
419 382
14.8 19.4
349 304
15.1 23.6
315 299
19.2 16.3
ALP (IU/L)
483
0.4
60
TB (mg/dL)
8.4 9.1 9.0 9.0 11.0 12.8 13.4 >9 13.8 21.6 9.4 – DB (mg/dL)
17.5
132
97 108
126 129
105 112
124 120
110 131
151 210
187 187
220 209
158 166
167 196
ALT (IU/L)
273
614
14
16
AST (IU/L)
239
60 55 50 45 40 34 29 25 21 16 13 0 Number of weeks since discontinuation of levofloxacin
65 60 55 50 44 39 35 31 26 23 10 Baseline from prior year Number of weeks since initiation of levofloxacin
Table 1 Summary of laboratory data
(ALT) 614 IU/L, alkaline phosphatase (ALP) 483 U/L, total protein 6.3 g/dL, albumin 3.8 g/dL, and international normalized ratio (INR) of 0.9. Her laboratory data from the prior year was within normal limits. She had no evidence of ascites or asterixis on exam. Following treatment with intraocular injections, the patient was admitted to a local New York hospital for evaluation of her abnormal liver tests. The ophthalmologic surgery was deferred. The workup included several diagnostic exams. An initial abdominalultrasound and computed tomography (CT) scan revealed no biliary ductal dilatation or stigmata of chronic or advanced liverdisease. A subsequent magnetic resonance cholangiopancreatography (MRCP) also excluded any ductal dilatation or mechanical obstruction. A transjugular liver biopsy revealed severe cholestasis, extensive bile duct loss, and portal fibrosis. These findings were consistent with druginduced liver injury (DILI). The patient was started on a course of steroids with minimal improvement in her laboratory values. She was soon discharged home with instructions to continue her steroid course and was provided an outpatient referral to MSMC. At her initial outpatient visit at MSMC, approximately 3 months after the elevated liver tests were discovered, she was asymptomatic except for jaundice and hair loss over the previous few months. She denied any nausea, vomiting, weight loss, fevers, chills, and abdominal pain. She had no known history of liver disease and her family history was only significant for cardiac disease. She had no signs or symptoms of liver failure, and no evidence of gastrointestinal bleeding, fluid overload, encephalopathy, coagulopathy, or renal dysfunction. She was on amlodipine and metoprolol for hypertension, levothyroxine for hypothyroidism, and prednisone since her most recent hospitalization. She denied taking any other medications, and a thorough history failed to reveal exposure to any other toxins. She denied taking any herbal or over-the-counter supplements, including teas, powders, and oils. She has a known allergic reaction to penicillin manifesting with a rash. She denied any alcohol, tobacco, or drug use. The patient was hemodynamically stable and afebrile. Her exam was significant for deeply icteric sclera. She had no signs of chronic liver disease: no palmar erythema, asterixis, ascites, or peripheral edema. There was no evidence for hepatosplenomegaly. Serologies for hepatitis A, B, C, and E viruses, myeloperoxidase, proteinase 3, antinuclear, antimitochondrial, antiliver kidney microsome, antismooth muscle antibodies were all negative. Immunoglobulin IgA, IgM, and IgG were low at 43 mg/dL, 411 mg/dL, and 28 mg/dL, respectively. The patient was started on ursodiol and tapered off the prednisone within a few weeks. She was also referred for evaluation at the MSMC liver transplant program in case she developed subfulminant liver failure. The patient never progressed to liver failure and was not listed for a liver transplant. She has been followed monthly in our liver practice; serial laboratories have shown slow, but steady improvement in her cholestasis and hyperbilirubinemia (see ►Table 1). Clinically, she continues to do well, with resolution of hair loss and placement of a prosthetic eye.
70
Levofloxacin-Induced Cholestasis and Ductopenia
No. 2/2014
Levofloxacin-Induced Cholestasis and Ductopenia
Levine et al.
Pathology Findings A liver needle biopsy was performed approximately 4 months afterexposure to levofloxacin. The specimen showed severe cholestasis, mainly canalicular, with canaliculi being dilated by inspissated thick bile, and intrahepatocytic bile pigment resulting in feathery degeneration of hepatocytes (►Fig. 1A). Few scattered lobular inflammatory infiltrates are present (►Fig. 1B). Portal areas are remarkable for extensive bile duct loss without significant inflammation and only minimal ductular reaction (►Figs. 2A and B). CK7 immunostain shows bile duct loss in 25 of 27 portal tracts and formation of metaplastic hepatocytes in periportal zones, the latter indicative of chronic cholestasis (►Fig. 3). Portal and periportal fibrosis are present. The conglomeration of these findings are consistent with cholestatic hepatitis with paucity of intrahepatic bile ducts (ductopenia), most likely drug induced. There is no evidence of sclerosing cholangitis.
Discussion Based on the laboratory values and histological results, this patient was diagnosed with DILI, consistent with a vanishing bile duct pattern along with predominant cholestatic injury.
Fig. 2 (A) Portal tract with an artery (arrow) and no accompanying bile duct (hematoxylin and eosin [H&E], 200 ). (B) Another portal tract with mild fibrosis and bile duct loss (H&E, 200 ).
Levofloxacin was determined to be the most likely culprit as she had not started any other new medications prior to the development of DILI. She completed a 10-week-long course of levofloxacin comprised of 2 weeks of intravenous therapy followed by 2 months of oral therapy immediately preceding the diagnosis of abnormal liver tests and jaundice, as
Fig. 1 (A) Liver biopsy specimen with hepatocellular cholestasis and dilated bile canaliculi (arrows) (hematoxylin and eosin [H&E], 200 ), and (B) lobular necroinflammation (long arrow) and apoptotic body (short arrow) formation (H&E, 400 ). Seminars in Liver Disease
Vol. 34
No. 2/2014
Fig. 3 CK7 immunostain confirms the absence of bile duct and shows minimal ductular reaction (dark brown) and cholestatic hepatocyte formation (light brown) (Immunostain, 200 ).
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
248
summarized in ►Table 1. She reported no prior history of liver injury prior to these preoperative laboratories. Since the cessation of levofloxacin, our patient’s liver tests remained elevated, but demonstrated improvement. Her AST and ALT have decreased slowly over time, with ALT decreasing over fivefold within a 9-month period. Similarly, her ALP and bilirubin levels have remained elevated, but with slow improvement. There have been multiple case reports and review articles in the literature describing the association of fluoroquinolones and hepatotoxicity. However, there are only a few reported cases describing prolonged cholestasis associated with levofloxacin. To our knowledge, this is the first reported case of levofloxacin induced vanishing bile duct syndrome (VBDS). “Liver injury” is defined as an increase in ALT or TB of over 2 times () the upper limit of normal (ULN), or a combined increase in AST, ALP, and TB provided one of them is over 2 ULN.1 A consensus reached at the Fogarty International Center Conference on Hepatotoxicity in 1978 characterized elevations in liver enzymes, AST, and ALT more than 3 ULN or ALP more than 1.5 ULN in combination with elevated bilirubin (> 3 the ULN) as a sign of serious liver injury any time after a new medication is initiated.2–4 Now known as “Hy’s law” or “Hy’s rule,” named after Dr. Hyman Zimmerman, DILI that is significant enough to lead to AST or ALT elevations in the presence of jaundice (bilirubin elevations) can be very ominous and can lead to death, especially if the implicated drug is not stopped. The associated fatality rate of DILI in the presence of clinical jaundice has been reported to be 10%.5,6 The annual incidence of DILI is reported to be one in 10,000 to 100,000.7 Over 1,100 drugs, including medications and supplements, have been reported to cause hepatotoxicity.8 Moreover, DILI is the most common reason for withdrawing drugs from the market and for “black box” warnings by the U. S. Food and Drug Administration (FDA).4,9 Obtaining a thorough and accurate history of drug allergies and prior medications is crucial to the diagnosis of DILI. In determining the inciting agent, there are several important factors to consider: the latency or time to onset of DILI, clinical features, prior cases of DILI with the implicated drug, risk factors, exclusion of other causes, liver biopsy results, and the course after cessation of the drug. A positive rechallenge (i.e., readministration of the drug) is considered the gold standard in determining a causal relationship, but is regarded as clinically dangerous.2 Scoring systems, including the Roussel Uclaf Causality Assessment Method (RUCAM) Scale, have been used to assess causality. However, a comparison in 2010 revealed considerable variability between the RUCAM Scale and structured expert opinion.10 Risk factors that have been associated with DILI include genetic susceptibility (especially related to P450 enzymes), female gender (although more recent studies have found no difference between genders), age over 55 years, history of prior drug reactions, drug dose, concomitant alcohol use, extremes of nutritional status (obesity and malnutrition), and pregnancy.9,11 The pattern of injury can be classified in many ways, but most commonly as either hepatocellular,
Levine et al.
cholestatic, or mixed. The pattern is determined by the ratio (R) of ALT/ALP. Hepatocellular damage is consistent with R > 5, cholestatic pattern with R < 2, and a mixed pattern if R > 2 but < 5.2 In an analysis of 461 DILI cases submitted to a Spanish Registry, hepatocellular pattern was the most prevalent (58%) and was associated with ALT values 30 ULN in 22% of cases. The cholestatic pattern was associated with jaundice in 81% of cases.11 The first step in treatment is to discontinue the offending agent. Cessation of the implicated agent (i.e., dechallenge) as soon as possible is critical to spontaneous recovery and generally followed by clinical improvement. The recovery time can vary and is often extended in the cholestatic type of DILI.2,9 After stopping a culprit drug, hepatocellular damage is considered “very suggestive” if ALT levels decrease by at least 50% of the excess above the ULN within 8 days and ALT levels return to normal within one month. A cholestatic or mixed pattern, however, is considered “suggestive” if the ALP or TB decreases by at least 50% of the excess above the ULN within 6 months.2 However, in a study performed in United Kingdom of 44 patients with DILI identified over an 18-year period, 39% of patients had persistent abnormalities in their liver blood tests and/or imaging (including abdominal ultrasounds and isotope scans) at 1 to 19 year (median 5-y) followup.12 Additionally, if a patient develops a chronic liver injury or acute liver failure secondary to DILI, improvement during dechallenge may be negligible.13 Drug-induced liver disease can be very severe, in some instances leading to prolonged jaundice, acute liver failure, and transplant or death. Druginduced liver disease can be very difficult to diagnose and causality is very difficult to determine. As a result, DILI is often is a diagnosis of exclusion.2,4,10 Drug-induced liver disease should always be on the differential diagnosis for a patient who presents with liver dysfunction, whether acute or chronic. Drug-induced liver disease accounts for 13% of acute liver injury cases in the United States, with antibiotics as the most common cause, especially antituberculosis therapies and amoxicillin-clavulanate.2,4,9,11,14 Fluoroquinolones are frequently used in both the inpatient and outpatient settings in the United States, becoming the most commonly prescribed antibiotic class among adults in 2002.15,16 They are generally well tolerated, have a safe side effect profile, are easily dosed, have broad antibiotic coverage, and are highly bioavailable when given orally.15 Fluoroquinolone-induced hepatotoxicity is uncommon, but when it occurs, is usually transient and associated with minimal liver symptoms and injury. However, rare cases have been reported in which patients with fluoroquinolone-induced DILI required liver transplant or suffered death secondary to acute liver failure.17 Of note, the FDA restricted the distribution of trovafloxacin, a third-generation fluoroquinolone, due to serious hepatotoxicity, resulting in transplant or death.18 Licata et al reviewed 35 cases of reported hepatotoxicity associated with fluoroquinolone use, with ciprofloxacin implicated in 45.7%, levofloxacin in 31.4%, moxifloxacin in 20.0%, and norfloxacin in 2.9% of cases. The time between Seminars in Liver Disease
Vol. 34
No. 2/2014
249
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Levofloxacin-Induced Cholestasis and Ductopenia
Levofloxacin-Induced Cholestasis and Ductopenia
Levine et al.
initiation of the fluoroquinolone and the discovery of hepatic injury ranged from 1 to 39 days (median 8 d). Fluoroquinolones were found to be associated with hepatocellular (51.4%), cholestatic (28.6%), and mixed (20.0%) patterns.17 Histologic findings often had immunoallergic features consistent with a hypersensitivity reaction, including fevers, rash, and eosinophilia.4,15 These features were not seen in our patient. The first reported case of severe hepatotoxicity associated with levofloxacin use was in 2001. A 74-year-old received IV levofloxacin for treatment of a lower respiratory tract infection. Within 2 days of drug initiation, she was found to have significant elevation of transaminases consistent with hepatocellular DILI, which resolved after discontinuation of levofloxacin.19 In 2001, the first reported case of fatal levofloxacin-associated acute liver failure was also reported. A 99-year-old man progressed to acute fatal liver failure after exposure to levofloxacin 500 mg daily for treatment of a urinary tract infection. His biopsy showed hepatocellular necrosis and a mixed cellular infiltrate, which included numerous eosinophils. At that time, it was believed that the rarity of levofloxacin-induced liver injury and presence of eosinophils on biopsy supported an immunoallergic reaction.20 Since 2001, several more cases of levofloxacin-related liver injury have been reported, predominantly consistent with the hepatocellular pattern of injury.17 There were no cases, however, of levofloxacin-induced liver injury leading to VBDS. Vanishing bile duct syndrome, also referred to as ductopenia, is defined by the histologic appearance on liver biopsy: the absence of interlobar bile ducts in 50% or more small portal tracts, with characteristic sparing of the larger extrahepatic biliary tree. It results from the destruction of intrahepatic bile ducts and their progressive disappearance from the liver parenchyma.21 Over 40 medications have been associated with causing VBDS, including chlorpromazine, ajmaline and arsenical derivatives, phenytoin, clindamycin, trimethoprim-sulfamethoxazole, and tetracyclines.21–23 More commonly, these medications cause varying degrees of drug-induced cholestasis. Drug-induced cholestasis can persist for several months following removal of the offending agent and rarely can progress to the development of VBDS. Liver tests and jaundice may gradually improve in some cases, even in the setting of persistent ductopenia.24 As in this case, the patient many continue to suffer from prolonged jaundice or chronic liver disease despite cessation of the drug.9 Liver failure may progress in some cases following cessation of the drug, eventually leading to secondary biliary cirrhosis, liver failure, transplantation, or death. Antibiotics, including amoxicillin/ clavulanic acid, ampicillin, clindamycin, erythromycin, and tetracyclines, have been reported to cause VBDS.24 Only a handful of case reports have linked fluoroquinolone usage with the development of VBDS. Robinson et al reported a case of VBDS after a short course of moxifloxacin.21 Additionally, Orman et al described a case of a 46-year-old woman who presented with a cholestatic pattern of elevated liver tests beginning 8 days after starting a course of moxifloxacin. This patient had 1.3 years of prolonged jaundice and eventuSeminars in Liver Disease
Vol. 34
No. 2/2014
ally developed hepatic failure, requiring a liver transplant. The biopsy of the explanted liver was consistent with VBDS.15 Another case reported ductopenia in a patient after 6 months of daily ciprofloxacin usage.25 To our knowledge, our patient’s case is the first reported case of VBDS following the use of levofloxacin. Fluoroquinolones make up a widely used and generally safe class of antibiotics. However, health care providers should be aware of the rare association of fluoroquinolones, such as levofloxacin, with severe hepatotoxicity. It is crucial for health care providers to obtain an accurate history of drug allergies and to only prescribe fluoroquinolones (or any other drugs and/or medications) when appropriate. Unfortunately, the pathophysiology of fluoroquinoloneinduced drug injury is not yet well understood. As hepatotoxicity associated with fluoroquinolone usage has a short latency and patients often manifest features consistent with an immunoallergic reaction, a hypersensitivity reaction may be a possible mechanistic explanation. Further research, including determination of genetic risk factors, is needed to establish which patients are most at risk of DILI and to predict which patients are likely to develop a reaction to a particular drug. Research, such as that being performed by the Drug Induced Liver Injury Network is vitally needed to develop specific and mechanism-based treatment options for patients with DILI. Current management consists of removing the offending agent and supportive care. Neither a course of steroids nor ursodiol or antioxidant therapy has been shown to be efficacious in the treatment of DILI and mechanism-based treatments for the disease are lacking.13
References 1 Bénichou C. Criteria of drug-induced liver disorders. Report of an
international consensus meeting. J Hepatol 1990;11(2):272–276 2 Suk KT, Kim DJ. Drug-induced liver injury: present and future. Clin
Mol Hepatol 2012;18(3):249–257 3 Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-
4
5 6
7
8
9 10
onset jaundice: how often is it caused by idiosyncratic druginduced liver injury in the United States? Am J Gastroenterol 2007;102(3):558–562, quiz 693 Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;52(6):2065–2076 Reuben A. Hy’s law. Hepatology 2004;39(2):574–578 Zimmerman H. Hepatotoxicity - The Adverse Effects of Drugs and Other Chemicals on the Liver. Philadelphia: Lippincott, Williams & Wilkins; 1999:606, 616–618 Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002;22(2): 145–155 Stine JG, Lewis JH. Drug-induced liver injury: a summary of recent advances. Expert Opin Drug Metab Toxicol 2011;7(7): 875–890 Bleibel W, Kim S, D’Silva K, Lemmer ER. Drug-induced liver injury: review article. Dig Dis Sci 2007;52(10):2463–2471 Rockey DC, Seeff LB, Rochon J, et al; US Drug-Induced Liver Injury Network. Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the RousselUclaf causality assessment method. Hepatology 2010;51(6): 2117–2126
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
250
Levine et al.
11 Andrade RJ, Lucena MI, Fernández MC, et al; Spanish Group for the
18 Questions and Answers on Trovafloxacin Public Health Advisory. U.S.
Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005;129(2):512–521 Aithal PG, Day CP. The natural history of histologically proved drug induced liver disease. Gut 1999;44(5):731–735 Fontana RJ, Seeff LB, Andrade RJ, et al. Standardization of nomenclature and causality assessment in drug-induced liver injury: summary of a clinical research workshop. Hepatology 2010;52(2): 730–742 Ostapowicz G, Fontana RJ, Schiødt FV, et al; U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137(12):947–954 Orman ES, Conjeevaram HS, Vuppalanchi R, et al; DILIN Research Group. Clinical and histopathologic features of fluoroquinoloneinduced liver injury. Clin Gastroenterol Hepatol 2011;9(6): 517–523, e3 Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J Med 2005;118(3):259–268 Licata A, Randazzo C, Morreale I, Butera G, D’Alessandro N, Craxì A. Fluoroquinolone-induced liver injury: three new cases and a review of the literature. Eur J Clin Pharmacol 2012;68(5):525–532
Food and Drug administration website. Available at: http://www.fda. gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053104.htm. Accessed September 28, 2013 Karim A, Ahmed S, Rossoff LJ, Siddiqui RK, Steinberg HN. Possible levofloxacin-induced acute hepatocellular injury in a patient with chronic obstructive lung disease. Clin Infect Dis 2001;33(12): 2088–2090 Spahr L, Rubbia-Brandt L, Marinescu O, Armenian B, Hadengue A. Acute fatal hepatitis related to levofloxacin. [letter]J Hepatol 2001; 35(2):308–309 Robinson W, Habr F, Manlolo J, Bhattacharya B. Moxifloxacin associated vanishing bile duct syndrome. [letter]J Clin Gastroenterol 2010;44(1):72–73 Desmet VJ. Vanishing bile duct syndrome in drug-induced liver disease. J Hepatol 1997;26(Suppl 1):31–35 Levy C, Lindor KD. Drug-induced cholestasis. Clin Liver Dis 2003; 7(2):311–330 Reau NS, Jensen DM. Vanishing bile duct syndrome. Clin Liver Dis 2008;12(1):203–217, x Bataille L, Rahier J, Geubel A. Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn’s disease. J Hepatol 2002;37(5):696–699
12 13
14
15
16
17
19
20
21
22 23 24 25
Seminars in Liver Disease
Vol. 34
No. 2/2014
251
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Levofloxacin-Induced Cholestasis and Ductopenia
Copyright of Seminars in Liver Disease is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
