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a
Department of Oncology and Hematology, Paracelsus Medical University, Nürnberg, b IBMP – Institute for
Würzburg, and d Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
Established Facts
• Drug-induced liver injury is one of the main reasons for acute liver failure.
• The diagnosis of drug-induced liver injury requires the thorough exclusion of other causes of liver dis-
ease, coupled with a careful review of the patient’s medication history and an awareness of the hepa-
totoxicity profile of the administered drugs.
Novel Insights
• When prescribing potentially hepatotoxic drugs, clinicians should have a low threshold for checking
their patients’ liver function, particularly when the clinical condition deteriorates or indicates a prob-
lem with liver function.
Abstract Introduction
Drug-induced liver injury is one of the main reasons for acute
liver failure. We report the case of a young patient who ex- Acute liver failure (ALF) is a complex multisystemic
perienced a drug-induced liver injury resulting in life-threat- illness that evolves after severe damage and loss of func-
ening acute liver failure after treatment with different anti- tion of most liver cells accompanied by coagulopathy and
biotics (amoxicillin, ciprofloxacin, cefazolin, clindamycin) encephalopathy within a short period of time [1]. Apart
158.232.240.74 - 1/28/2019 1:19:03 PM
E-Mail ibmp @ osn.de
from viral infections, drug-induced liver injury (DILI) is Barr virus, enterovirus, HIV, and influenza B all depicted negative
one of the main reasons for ALF. DILI can either be results. Tests for influenza A and parainfluenza were negative for
IgM and positive for IgA and IgG. Thus, an acute or recent infec-
caused by predictable type A (augmented pharmacologi- tion with influenza A or parainfluenza could not be excluded.
cal) reactions, e.g., to acetaminophen [2–4], or type B (id- There were no signs of autoimmune hepatitis; her copper excre-
iosyncratic) reactions. Type B reactions are not dose de- tion was within the normal range. It is noteworthy that the patient
pendent and occur rarely, and thus are not predictable, as did not receive any further acetaminophen or anti-infective treat-
it is the case with most antibiotics [5]. We report the case ment at our department of oncology and hematology.
Since the patient’s general condition worsened continuously, a
of a young patient in whom different antibiotics, the an- liver transplantation was considered. At this time, her liver values
algesic and antipyretic acetaminophen, or a combination were as follows: total bilirubin 16.9 mg/dL, γ-glutamyltransferase
of these drugs may have led to DILI resulting in life- 84 U/L, ALT 859 U/L, and LDH 606 U/L. The synthesis capacity
threatening ALF. of the liver, shown by blood coagulation, was considerably re-
duced: international normalized ratio 2.62, antithrombin 21%
(normal, 80–120%), factor II 21%, factor V 57%, factor VII 20%,
and factor IX 29%.
Case Report At the department of gastroenterology an endoscopic laparos-
copy with liver biopsy was performed, revealing that 50% of the
A 20-year-old woman was admitted to our hospital because of hepatocytes were necrotic. On the same day liver failure occurred,
hepatitis of unknown origin. The patient’s history was complex: 5 whereupon the patient was transferred to the intensive care unit
weeks before admission to our department a right cervical and nu- (ICU). In view of all findings, a recovery of the liver was not ex-
chal lymph node swelling with odynophagia and fever up to 38.5 ° C pected and the patient was put on the transplant list. The patient
had been observed. An outpatient treatment had been commenced remained stable at a low level with episodes of hepatic encepha-
with amoxicillin (without clavulanic acid) and aspirin. Since no lopathy until at last, after 2 weeks in the ICU, her condition began
improvement occurred after 3 days, the treatment was changed to to improve slowly. Finally, the liver function was sufficiently re-
ciprofloxacin. After 2 more days without signs of recovery, the pa- stored, making a transplant unnecessary. Three weeks after admis-
tient was admitted to the department of otorhinolaryngology the sion to the ICU, the patient could be transferred to the general
following day, where she received intravenous cefazolin, leading to ward and after another 2 weeks she was discharged from the hos-
a rapid improvement of the symptoms and a CRP decrease from pital. Another 3 weeks later, her general condition had recovered
6.7 to 2.9 mg/dL (normal <0.5 mg/dL). At that time there were no very well and also her liver function tests had considerably im-
signs of liver injury. proved: total bilirubin 2.2 mg/dL, alkaline phosphatase 127 U/L,
However, during the treatment she complained of generalized γ-glutamyltransferase 156 U/L, AST 55 U/L, and ALT 52 U/L. On
pruritus and developed fine-spotted red lesions on her trunk. As follow-up examination 1 month later the patient felt well, showing
this rash was supposed to be caused by amoxicillin, the antibiotic completely normalized liver synthesis function tests and transam-
treatment was changed to clindamycin and an antiallergic treat- inases.
ment with prednisone and an antihistaminic drug (levocetirizine)
was initiated. The patient was discharged from the hospital after 4
days. Acetaminophen was prescribed with the recommendation to
take it in case of fever. Two weeks later the patient developed per-
sistent fever up to 40 ° C, which was again treated with acetamino-
Discussion and Review of the Literature
phen for approximately 1 week (2 g/day).
When the patient was admitted to our department 3 weeks after Establishing the diagnosis of DILI can be difficult due
discharge from the department of otorhinolaryngology (and 20 to the lack of specific symptoms or tests. To our knowl-
days after the first intake of acetaminophen), she still had a slight edge, the most recent guideline for the diagnosis and
exanthema, a cervical lymphadenopathy, and signs of hepatitis.
Upon admission, her laboratory values of liver function were as management of DILI has been published by the American
follows: total bilirubin 3.7 mg/dL (normal <1.0), alkaline phospha- College of Gastroenterology (ACG) [6]. The guideline
tase 143 U/L (normal 35–105), γ-glutamyltransferase 201 U/L underlines that the diagnosis of DILI requires the cau-
(normal <40), aspartate aminotransferase (AST) 1,153 U/L (nor- tious exclusion of other causes of liver disease, coupled
mal <35), alanine transaminase (ALT) 1,219 U/L (normal <35), with a careful review of the patient’s medication history
glutamate dehydrogenase 54.2 U/L (normal <5), cholinesterase
2.6 kU/L (normal 3.9–10.3), and lactate dehydrogenase (LDH) and an awareness of the hepatotoxicity profile of the ad-
923 U/L (normal <250). Moreover, coagulation was compromised ministered drugs.
(international normalized ratio 1.57). Due to the highly elevated In order not to go beyond the scope of this report, only
aminotransferase levels and, in contrast, the only slightly increased hepatotoxicity profiles of drugs which are relevant in this
alkaline phosphatase level, the liver damage was classified as hepa- case will be discussed. Involved experts from various
tocellular.
During her 8-day stay, intensive investigations and laboratory fields of internal medicine agreed on the following drugs
tests were performed to exclude a viral origin of her hepatitis. Se- as possible causative agents: amoxicillin, ciprofloxacin,
rologic tests for hepatitis A, B, C, and E, cytomegalovirus, Epstein- cefazolin, clindamycin, and acetaminophen.
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1. Time to onset Reaction occurred before starting the Reaction occurred before starting the
drug or >15 days after stopping the drug or >30 days after stopping the
Unrelated
drug (except for slowly metabolized drug (except for slowly metabolized
- Incompatible drugs) drugs)
Insufficiently
- Unknown No information available to calculate time to onset
documented
1st exposure 2nd exposure 1st exposure 2nd exposure Score
- From drug intake 5 to 90 days 1 to 15 days 5 to 90 days 1 to 90 days +2
<5 or >90 days >15 days <5 or >90 days >90 days +1
- From drug withdrawal 15 days 15 days 30 days 30 days +1
2. Course Difference between the peak of AP
Difference between the peak of ALT
(or TB) and upper limit of normal
and upper limit of normal values
of the reaction after values
cessation of the drug Decrease t50% within 8 days Not applicable +3
Decrease t50% within 30 days Decrease t50% within 180 days +2
Not applicable Decrease <50% within 180 days +1
Lack of information or no Lack of information or no
0
improvement improvement
Decrease <50% after the 30th day or
— –2
recurrent increase
Alcohol Alcohol or pregnancy +1
3. Risk factors
Age 55 years Age 55 years +1
4. Concomitant drug(s) None or no information or concomitant drug with incompatible time to onset 0
Concomitant drug with compatible or suggestive time to onset –1
Concomitant drug known as hepatotoxin and with compatible or suggestive
–2
time to onset
Concomitant drug with evidence for its role in this case (positive
–3
rechallenge or validated test)
5. Exclusion of nondrug causes All causes (group I and group II) reasonably
Group I (6 causes): recent viral infection with ruled out +2
hepatitis viruses (1. HAV; 2. HBV; 3. HCV);
4. biliary obstruction; 5. alcoholism; 6. acute
recent hypotension history The 6 causes of group I ruled out +1
Group II: Complications of underlying disease(s); 5 or 4 causes of group I ruled out 0
clinical and/or biological context suggesting CMV,
Less than 4 causes of group I ruled out –2
EBV, or herpes virus infection
Non-drug cause highly probable –3
7. Response to re- Doubling of ALT with the drug Doubling of AP (or TB) with the
+3
administration alone drug alone
Doubling of ALT with the drugs Doubling of AP (or TB) with the
already given at the time of the drugs already given at the time of +1
first reaction the first reaction
Increase of ALT but less than N in Increase of AP (or TB) but less
the same conditions as for the than N in the same conditions as –2
first administration for the first administration
Other situations Other situations 0
Fig. 1. The CIOMS/RUCAM scale [34]. AP, alkaline phosphatase; TB, total bilirubin; HAV, hepatitis A virus;
HBV, hepatitis B virus; HCV, hepatitis C virus; CMV, cytomegalovirus; N, upper limit of the normal range.
158.232.240.74 - 1/28/2019 1:19:03 PM
1 Time to onset
From beginning of the drug 2 2 2 2 2
From cessation of the drug 1 1 1 1 1
2 Course
After cessation of the drug 2 2 2 2 2
3 Risk factors
Ethanol 0 0 0 0 0
Age of the patient <55 years 0 0 0 0 0
4 Concomitant drugs
Concomitant drug known as hepatotoxin and
with compatible or suggestive time to onset –2 –2 –2 –2 –2
5 Search for nondrug causes
All causes reasonably ruled out 2 2 2 2 2
6 Previous information on the hepatotoxicity of the drug
Reaction labeled in the product characteristics 2 2 2 2 2
7 Response to readministration
Not done or not interpretable 0 0 0 0 0
Total 7 7 7 7 7