Hindawi Publishing Corporation
Case Reports in Pediatrics
Volume 2014, Article ID 156389, 7 pages
http://dx.doi.org/10.1155/2014/156389
Case Report
A Challenge for Diagnosing Acute Liver Injury with
Concomitant/Sequential Exposure to Multiple Drugs:
Can Causality Assessment Scales Be Utilized to Identify
the Offending Drug?
Roxanne Lim, Hassan Choudry, Kim Conner, and Wikrom Karnsakul
Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Correspondence should be addressed to Wikrom Karnsakul; wkarnsa1@jhmi.edu
Received 25 August 2014; Revised 1 November 2014; Accepted 2 November 2014; Published 24 November 2014
Academic Editor: Nan-Chang Chiu
Copyright © 2014 Roxanne Lim et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of druginduced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of
acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin,
ampicillin/sulbactam, and clindamycin) for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy
specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only)
drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the
International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM),
Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although
clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.
1. Introduction
Acute drug-induced liver injuries (DILI) predominate (about
90% of cases) [1] and are classified into 3 categories [2], acute
hepatocellular injury, acute cholestatic liver injury, and mixed
pattern acute liver injury. When a single drug is involved, the
diagnosis is relatively simple. The administration of multiple
concomitant drugs however can pose a difficult implication
for which a specific agent would be the cause of DILI. The
administration of multiple concomitant drugs can, however,
pose a conundrum as to which specific agent is the cause of
DILI. Several algorithms/clinical scales have been developed
to improve the accuracy, consistency, and objectiveness in
identifying the offending drug for the causality assessment of
adverse drug reactions. Examples include the Maria and
Victorino scale [3] and Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM) scale [3–5],
which are used primarily to quantify the strength of association between a liver injury and a particular drug being
implicated. However, it must be emphasized that these diagnostic scales should not be substituted for clinical judgment.
We report a 12-year-old boy who received multiple antibiotics for the treatment of cervical lymphadenitis, retropharyngeal cellulitis, and developed signs and symptoms of cholestatic hepatitis. Causality assessment scales of adverse drug
reactions including Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM), Maria and
Victorino scale, and Digestive Disease Week-Japan (DDW-J)
were utilized to identify the most probable offending drug.
2. Case Report
A previously healthy 12-year-old Hispanic boy presented with
a history of sore throat and swelling in the right submandibular region without history of sick contact, travel, tick bites,
or uncooked or raw food consumption. Amoxicillin was
started to treat a probable streptococcal infection. Three days
850
800
750
700
650
600
550
500
450
400
350
300
250
200
150
100
50
0
14
12
10
8
6
Bilirubin (mg/dL)
later he developed anorexia, dysphagia with liquids, and
neck swelling with fever. He was brought to the Emergency
Department of a nearby hospital and subsequently admitted.
A computed tomography scan of the neck and chest showed
a retropharyngeal fluid collection without features of an
abscess or foreign body and lymphadenopathy throughout
the neck and upper mediastinum. Ceftriaxone and vancomycin were started to treat diffuse facial and neck cellulitis
for 3 days. While the neck swelling progressed, he was intubated. Ceftriaxone and vancomycin were discontinued, and
ampicillin/sulbactam and steroid were started. The following day he was extubated due to improved neck swelling.
Results from laboratory tests were all within normal limits
except for mild anemia (hemoglobin 9.9 g/dL); however, liver
function tests (LFT) were not performed at the time. Ampicillin/sulbactam and steroid were given for 2 days and
discontinued. He was discharged home with a planned 10-day
course of oral clindamycin 300 mg three times a day.
Over 5 days after the hospital discharge, he had developed
fever, fatigue, headache, and dark urine. At the Emergency Department he had severe dehydration, fever (maximum temperature of 101∘ F), physical findings of mild hepatosplenomegaly, and right upper quadrant tenderness. LFT
results included alanine aminotransferase (ALT), 406 IU/L
(normal range 0–40); aspartate aminotransferase (AST),
98 IU/L (normal range 0–37); alkaline phosphatase (ALP),
404 IU/L (normal range 100–390); total bilirubin, 3.0 mg/dL
(normal range 0.1–1.2); direct bilirubin, 2.7 mg/dL (normal
range 0.0–0.4); prothrombin time (PT), 15.3 seconds; international normalized ratio (INR), 1.12; activated partial thromboplastin time (aPTT), 35.2 seconds. At this point, clindamycin was suspected as a cause of hepatic injury and ampicillin/sulbactam was started for 2 weeks because of the lower
risk of hepatotoxicity. Infectious workups were all negative
for hepatitis A, B, C, and E, Herpes, Epstein-Barr virus and
cytomegalovirus viruses, Leptospira, Bartonella henselae, and
blood culture. Three days after his admission in the Emergency Department, repeat LFTs were ALT, 232 IU/L; AST,
94 IU/L; ALP, 465 IU/L; total bilirubin (TB), 4.0 mg/dL; direct
bilirubin (DB), 2.8 mg/dL. The patient was discharged home
with clinical improvement.
Two days later at a follow-up with his pediatrician due
to abdominal pain, enlarged liver was noted on examination
and LFTs worsened: ALT, 152 IU/L; AST, 120 IU/L; ALP,
737 IU/L; TB, 8.8 mg/dL with peripheral eosinophilia with an
absolute count of 900/𝜇L. Referral was made to pediatric liver
specialist 5 days later when TB was at 9.9 mg/dL.
At the Pediatric Liver Center at Johns Hopkins Hospital
the patient complained of chest pain, fatigue, pruritus, and a
recent onset of acholic stools. Physical examination was unremarkable except icteric sclera and mild hepatomegaly. Further investigation was promptly started; ALT, 185 IU/L with
upper limit normal of normal ULN at 34; AST, 208 IU/L; ALP,
812 IU/L; TB, 11.8 mg/dL; PT, 11 seconds; INR, 1.1; aPTT, 28.6
seconds; amylase, 26 U/L; lipase, 33 U/L; normal ammonia
level, glucose, and thyroid function tests. Since serum ALT
elevated > 3X ULN and serum bilirubin > 2X ULN and DILI
is one of the possible liver injury causes, by Hy’s Law he had
the potential for development of acute liver failure. However
Case Reports in Pediatrics
International units
2
4
2
0
50
100
150
Time after start of illness (days)
ALT
Alkaline phosphatase
GGT
200
Total bilirubin
Direct bilirubin
ALT, alanine aminotransferase; GGT, gamma glutamyl transferase;
all values except direct and total bilirubin are given in international units.
Figure 1: Evolution of laboratory values of liver function tests of
patients with time.
his other liver synthetic function was normal and clinically
he did not have hepatic encephalopathy. All-out efforts
were made to look for every possible contributing cause of
his acute liver injury. Specific liver investigations revealed
normal ceruloplasmin, serum ferritin level, normal alpha-1
antitrypsin level, negative alpha-1 antitrypsin mutation analysis, and negative liver autoantibodies (antimitochondrial,
antinuclear, antismooth-muscle, and antiliver-kidney microsomal antibodies).
Magnetic resonance cholangiopancreatography excluded
abnormal gallbladder, intra- and extrahepatic bile duct system, and intrahepatic lesions as possible causes of cholestasis.
Vanishing bile duct syndrome was suspected. At approximately day 48 after illness a percutaneous liver biopsy was
performed. Histopathologic findings demonstrated moderate
lobular cholestasis, mild patchy lobular chronic inflammation, and mild portal fibrosis without features of viral cytopathic effects, autoimmune hepatitis, bile duct injury or loss,
and iron storage. Ursodeoxycholic acid was used to treat
cholestasis (20 mg/kg/day). Fat soluble vitamins were supplemented. At six-month and 4-year follow-up after the onset
of illness his liver chemistry profiles did not indicate ongoing
cholestatic jaundice or hepatocellular injury.
Over the following 5 months, jaundice and pruritus
gradually improved with a more than 50% improvement
in transaminases and bilirubin values. Clindamycin-induced
hepatic injury is highly suspected with evidence of previous
reports in the literature, and using clinical judgement as
displayed in Table 1, Figure 1 summarizes correlation between
clinical/biochemical manifestations and drug administration, trends of transaminases and bilirubin values, and
timeline of events. The question of drugs other than clindamycin possibly causing DILI in this case was raised for the
appropriate information for future drug use in the future.
Since multiple antibiotics were administered in the same
Case Reports in Pediatrics
3
Table 1: Correlation between clinical and biochemical manifestations and drug administration.
Time from onset of Signs/symptoms
illness
−5
0
3–5
5–10
10
16–23
25–30
48
53
67
83
111
Drug exposure
Sore throat
Amoxicillin started
Fever, anorexia,
dysphagia, neck
Ceftriaxone and
swelling, and cervical vancomycin started
lymphadenopathy
Ceftriaxone and
Worsening of neck
vancomycin discontinued,
swelling
and ampicillin/sulbactam
and steroid started
Ampicillin/sulbactam and
steroid discontinued,
Diarrhea
and clindamycin and
probiotics started
Fever, headache,
dizziness, chest pain
on coughing, and
Clindamycin switched to
dark urine.
ampicillin/sulbactam
Hepatosplenomegaly,
RUQ tenderness
Generalized
maculopapular rash Ampicillin/sulbactam
and pruritus
Abdominal pain,
Ampicillin/sulbactam
vomiting.
Hepatomegaly
Chest pain, fatigue,
pruritus, acholic
stools, and jaundice
Increasing pruritus,
anorexia
Anorexia, pruritus
Anorexia
No anorexia
Laboratory values
Total
Direct
bilirubin
bilirubin
ALT
ALP
406
404
3.0
152
737
8.8
124
780
9.9
138
713
13.4
8.8
Cholesterol
1044, GGT
347,
117
651
12.7
8.5
GGT 294
48
83
51
493
497
670
12.6
8.3
2.3
8.7
5.5
1.2
GGT 77
GGT 273
GGT 507
Misc.
2.7
AST 130
Time is in days. ALP = alkaline phosphatase, units used for ALT, ALP, and GGT used are IU. Bilirubin and cholesterol are displayed in mg/dL. Misc. =
miscellaneous lab values.
temporal sequence, the probability of the hepatotoxicity
being secondary to an adverse drug reaction from the other
antibiotics administered prior to clindamycin was assessed
using 3 scales (Table 2). Liver-specific causality assessment
scales including CIOMS/RUCAM scoring system, Maria and
Victorino scale, and DDW-J scale were applied to seek an
offending drug but rated all the antibiotics as being equally
“possible” and “probable” in causing the liver damage except
amoxicillin showing lower score in Maria and Victorino
clinical diagnostic scale.
3. Discussion
A period of 5–10 days after administration of multiple antibiotics, our patient had an acute presentation of cholestasis
described by dark urine, icteric sclerae, and abnormal liver
chemistry. Based on his history and physical examination,
all known causes for cholestasis in the pediatric population
were excluded by extensive investigations. Therefore, druginduced liver injury (DILI) was proposed as a probable
etiology. This was further supported as follows: (1) the development of cholestasis after the introduction of the antibiotics,
(2) clinical and biochemical improvement after withdrawal of
the drugs, (3) hepatotoxicity as a known adverse side effect of
each of the antibiotics, and (4) histopathologic findings excluding other causes of cholestatic hepatitis.
DILI is a well-recognized problem that accounts for up
to 10 percent of all adverse drug reactions. Two main mechanisms of DILI have been proposed: predictable injury (intrinsic hepatotoxins) and unpredictable injury (idiosyncratic
reactions). In our case, an idiosyncratic reaction is likely to be
the case. Many experts would suggest that the liver injury
could have been primarily caused by clindamycin and that
subsequent medications played no role in the presentation.
Although fever, abdominal pain, and hepatomegaly followed
4
Case Reports in Pediatrics
Table 2: Comparison of three liver-specific causality assessment scales on multiple sequential drug exposure.
Causality assessment
scales and criteria
CIOMS/RUCAM
Maria and Victorino clinical
diagnostic scale
(DDW-J) scale
Chronological criteria
From drug intake
until onset
Score range: +1 to +2
(i) 5–90 days: +2
(ii) <5 or >90 days: +1
Withdrawal until
onset
Score range: 0 to +1
(i) ≤30 d: +1
(ii) 0–29 d: 0
Score range: +1 to +3
(i) 4 d–8 wks: +3
(ii) <4 d or >8 wks: +1
Score range: −3 to +3
(i) 0–7 d: +3
(ii) 8–15 d: 0
(iii) >15 d: –3
Score range: +1 to +2
(i) 5–90 d/1–90 days: +2
(ii) <5 or >90 d/>15 days: +1
Score range: 0 to +1
(i) ≤30 d: +1
(ii) >30 d: 0
Score range: −2 to +3
Improvement in 180 days:
(i) >50%: +2
(ii) <50%: +1
(iii) Lack of info or no
improvement: +0
Score range: 0 to +3
(i) <6 mths (cholestatic/mixed)
or <2 mths (hepatocellular): +3
(ii) >6 or 2 mths: +0
Score range: −2 to +3
After cessation of drug
Difference in ALP peak and ULN
(i) not applicable: +3
(ii) decrease in liver enzymes
≥50% in 180 d: +2
decrease <50% in 180 d: +1
(iii) no information/
persistence/increase: +0
(iv) N/A: −2
N/A
Score range: 0 to +3
(rash, fever, arthralgia,
eosinophilia >6%, and cytopenia)
(i) ≥4: +3
(ii) 2 or 3: +2
(iii) 1: +1
(iv) None: 0
Score range: 0 to+1
Eosinophilia (≥6%)
(i) present: +1
(ii) absent: +0
N/A
Score range: 0 to +1
(i) alcohol/pregnancy: +1
N/A
N/A
Exclusion of other causes
Score range: −3 to +2
(i) ruled out: +2
(ii) “possible” to “not
investigated”: −2 to +1
(iii) probable: −3
Score range: −3 to +3
(i) complete: +3
(ii) partial: +0
(iii) possible alt cause: −1
(iv) probable alt cause: −3
Previous information or
known reaction
Score range: 0 to +2
Reaction:
(i) unknown: +0
(ii) published but unlabelled: +1
(iii) labeled in the product’s
characteristics: +2
Score range: −3 to +2
(i) yes: +2
(ii) no (drug marketed for
≤5 yrs): +0
(iii) no (drug marketed for
<5 yrs): −3
Score range: −3 to +2
(i) ruled out: +2
(ii) 6 causes of Group I ruled out:
+1
(iii) 5/4 causes of Group I ruled
out: +0
(iv) <4 causes of Group I ruled
out: −2
(v) nondrug cause highly
probable: −3
Course of the reaction
Extrahepatic
manifestations
Risk factors
Concomitant therapy
Score range: 0 to +2
(i) Age ≥55: +1
(ii) Alcohol or pregnancy: +1
Score range: −3 to 0
Time to onset:
(i) incompatible: +0
(ii) compatible but with
unknown reaction: −1
(iii) compatible but known
reaction: −2
(iv) role proved in this case: −3
(v) none or information not
available: +0
Score range: 0 to +1
(i) reaction labelled in product
characteristics or published: +1
(ii) reaction unknown: +0
Case Reports in Pediatrics
5
Table 2: Continued.
Causality assessment
scales and criteria
CIOMS/RUCAM
Rechallenge
Score range: −2 to +3
(i) positive: +3
(ii) compatible: +1
(iii) negative: −2
(iv) Not available/interpretable:
+0
(v) plasma conc. of drug toxic: +3
Score range: 0 to +3
(i) positive: +3
(ii) negative/absent: +0
DLST
N/A
N/A
Scores interpretation
(i) >8 points: definite
(ii) 6–8 points: probable
(iii) 3–5 points: possible
(iv) 1-2 points: unlikely
(v) <0 points: excluded
(i) >17 points: definite
(ii) 14–17 points: probable
(iii) 10–13 points: possible
(iv) 6–9 points: unlikely
(v) <6 points: excluded
(i) >4 points: definite
(ii) 3-4 points: probable
(iii) <3 points: unlikely
7 probable
7 probable
7 probable
7 probable
7 probable
10 possible
13 possible
13 possible
13 possible
13 possible
7 high possibility
7 high possible
7 high possibility
7 high possibility
7 high possibility
Our case scores
Amoxicillin
Ceftriaxone
Vancomycin
Ampicillin/sulbactam
Clindamycin
Maria and Victorino clinical
diagnostic scale
(DDW-J) scale
Score range: 0 to +3
(i) ALP/TB ≥ 2x with drug alone:
+3
(ii) ALP/TB ≥ 2x with drug
already given at time of 1st
reaction: +1
(iii) ALP/TB increases but
< 𝑁 − 2: −2
(iv) Other situations: +0
Score range: 0 to +2
DLST
(i) positive: +2
(ii) semipositive: +1
(iii) negative/unavailable: +0
CIOMS, Council for the International Organization of Medical Sciences; DDW-J, Digestive Disease Week-Japan; DLST, Drug lymphocyte stimulation test;
N/A, not available; d, days.
5–10 days after administration of several antibiotics, clindamycin is the immediate agent that started right before the
presentation. The causality assessment scales for DILI were
used as tools, for this reason, to give more clues as to which
antibiotic would more likely be the offending agent.
In order to facilitate causality assessments for DILI, several methods have been developed, including expert judgement, probabilistic approaches, and algorithms/scales [6–8].
The latter can be divided into general and liver-specific scales.
As strength in general any of standardized causality assessment scales enhance objectivity in case assessments, grade
the strength of probability in broad categories, and can provide warning signs for drug regulatory measurements. However these scales are often complex and time consuming to
operate. They do not provide a certain diagnosis of DILI. Each
of these has its own strengths and weaknesses. For example,
although the CIOMS/RUCAM scale is cumbersome and lacks
intra- and interrater reliability, it is however the preferred
method as a result of simple and practical use [9–11]. Absolute
agreement between the scales could be low [3]. All scales are
not designed to evaluate DILI when concomitant drugs are
used to solve this particular problem. Therefore the scales do
not replace clinical judgement. Exposure to multiple drugs
during the same period is a challenging factor in identifying
a single agent as a probable offending drug and poses a
dilemma for future recommendation for drug use.
At the time of consultation on this case, we recommended
holding off the use of clindamycin unless there was no
available option for the prospective infection patient might
have. Unfortunately, even for IgE mediated drug allergy,
testing is very limited, and for this kind of situation there
is not any commercial testing that would be helpful given
most likely idiosyncratic mechanism in nature. When we look
at cases like this, all that can be done is to consider which
drugs are more likely to have this type of side effect and then
proceed cautiously. However for an idiosyncratic reaction, it
is unpredictable as the same drug(s) may not do the same
thing in the future. DDW-J was the recently proposed scale in
Japan which was modified from CIOMS adding in vitro drug
lymphocyte stimulation test (DLST) [12]. The test demonstrates an immunological mechanism for the DILI by demonstrating the existence of a subset of T lymphocytes which
recognize and are activated by the drug [13]. Recent findings
on HLA allele associations with DILI via adaptive immune
response suggested the benefit of DLST utilization [13]. DLST
was not performed in their patient as it is not currently commercially available in the United States. The pros of DLST are
that we will have a clue which drugs would be the prime candidate causing the reaction and the information could be used
as a guide for an avoidance of the suspected drug. In theory
DLST is the ideal and objective way to understand the immunologic response to the offending drug; however, many
6
reactions are idiosyncratic, so the same drug(s) may not cause
the same reaction in the future. As demonstrated in Table 2,
each of the antibiotics administered has an almost equal
probability of causing DILI. When we assessed the causality
by different scales for ceftriaxone, vancomycin, clindamycin,
and ampicillin/sulbactam (Table 2), scores for each were in
similar category as a “possible” or “probable” cause of liver
injury.
A search of the literature revealed that all five antibiotics
have been known to be implicated in DILI. Most of isolated
adult cases, however, may not reflect on the clinical aspect
in children [14]. Although the reports in pediatric cases were
limited, there was a recent pediatric report comparing several
antibiotic uses with a focus on hepatic injury [14].
Maraqa et al. reported a 13-year-old child with clindamycin related DILI. The time to onset was 17 days and time
to resolution was 10 days [15]. As for LiverTox database it
only speaks of case reports in adults for hepatic toxicity from
clindamycin. The rest of journal articles only relate hepatotoxicity to clindamycin in adult patients. A 42-year-old
woman developed fatigue, nausea, vomiting, anorexia, pruritus, and jaundice 6 days after administration of the last clindamycin dose for a dental infection [16]. Transaminases were
markedly elevated and liver biopsy revealed centrilobular and
portal cholestatic hepatitis without fibrosis or necrosis. There
is also another case of a 67-year-old man who received a 10day course of oral clindamycin for a skin abscess. One week
after the last clindamycin dose, he developed icterus accompanied by pale stools, dark urine, and pruritus [17]. Liver
biopsy revealed marked cholestasis, portal inflammation, bile
duct injury, and ductopenia. A second biopsy five months
after the first one showed resolved cholestasis but persistent
ductopenia.
Molleston et al. reported two cases of DILI secondary to
amoxicillin use among pediatric patients in the DILIN prospective study [18]. Kim et al. presented a case of a 39-yearold woman who developed cholestatic hepatitis with bile duct
damage and hepatocellular injury eight weeks after initiation
of amoxicillin treatment for abdominal actinomycosis [19]
and became asymptomatic fourteen weeks after drug discontinuation.
Several articles have been published in the literature
documenting the association between ceftriaxone and DILI.
Peker et al. reported a 12-year-old boy who complained of
weakness 3 days and had elevated transaminases 6 days after
ceftriaxone was given for tonsillitis [20]. Transaminases
eventually returned to baseline within 10 weeks after discontinuing the drug. Bickford and Spencer described a case of a
53-year-old man who had elevated total and direct bilirubin
levels after a week therapy of ceftriaxone [21]. Discontinuing
ceftriaxone led to normalization of the LFTs within 2 weeks.
Chen et al. conducted a meta-analysis of 20 published
randomized controlled trials involving 7419 patients [22]. An
increased incidence of hepatic events, specifically elevated
serum aminotransferase levels, was observed in patients
receiving vancomycin (6.8%) compared to those who were
not (3.9%). The majority of events were mild to moderate in
nature and progressive or severe DILI has not been associated
with vancomycin use.
Case Reports in Pediatrics
Ampicillin/sulbactam, in a rare incident, was reported in
a 74-year-old man with Hodgkin’s disease in remission, who
developed a 3-month period of cholestasis after a week treatment with ampicillin/sulbactam 750 mg twice daily for sore
throat [23]. Abnormal liver enzymes prompted liver biopsy
showing diffuse canalicular and mild hepatocellular cholestasis, mild and mixed inflammation in the portal area, and
diffuse necroinflammatory areas in the liver parenchyma.
Liver function tests eventually normalized 7 months after
discontinuing the drug.
In DILI cases with concomitant or sequential drug exposure the CIOMS/RUCAM scale may not be able to differentiate between offending drugs and would require individual
assessments for each of the drugs. These causality assessment
scales disregard differences in metabolic pathways utilized by
concomitant drugs and potential pharmacokinetic drug-drug
or drug-disease interactions [3]. DLST in DDW-J scale on
any drugs could predict the hepatotoxic potential of such a
drug making it the prime candidate causing DILI. CIOMS has
many shortcomings which render it inaccurate in assessing
causality in a multipharmacy situation. A consensus on
criteria for excluding nondrug-related cases will establish a
standardized evidence based database of drugs causing DILI.
This knowledge would allow physicians to apply a uniform
scoring system in the sections of “concomitance therapy” and
previous information on hepatotoxicity [24]. A “multihit”
process could explain idiosyncratic drug reaction in this
patient as a result from a succession of events or exposure to
multiple drugs [25]. It is unlikely that genetic variants in
isoenzymes or cytochrome 450 pathway alone would predispose to severe hepatotoxicity from toxic byproducts given
that severe liver toxicity is a rare event. In addition there could
be suppressor or attenuator pathways which could play a role
in idiosyncratic hepatotoxicity.
In summary, we report on a case of probable DILI with
concomitant use of several antibiotics. None of the known
causality assessment scoring systems was developed for identifying an offending drug for DILI cases with concomitant
drug use in the same temporal sequence. Close monitoring
of liver functions could eliminate certain drugs as offending
agents if an abnormal LFT is present before and after certain
drugs. Obviously this still continues to pose us a challenge in
determining which of the drugs is/are allowed to be utilized in
this child in the future. Whenever suspected, the offending
drug should be discontinued immediately as complete recovery is still possible with prompt drug discontinuation. A
different model using knowledge of drug metabolism and
interaction via genetic variant isoenzymes, cytochrome P450
pathway, and application of in vitro DLST could be considered to aid in identifying offended drug causing DILI.
Ethical Approval
All procedures followed were in accordance with the ethical
standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki
Declaration of 1975, as revised in 2008 (5).
Case Reports in Pediatrics
Consent
Informed consent was obtained from all patients for being
included in the study.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
References
[1] H. J. Zimmerman, Hepatotoxicity: The Adverse Effects of Drugs
and Other Chemicals on the Liver, Lippincott Williams &
Wilkins, 1999.
[2] C. Benichou, J. P. Benhamou, and G. Danan, “Criteria of druginduced liver disorders,” Journal of Hepatology, vol. 11, no. 2, pp.
272–276, 1990.
[3] M. Garcia-Cortes, C. Stephens, M. I. Lucena, A. FernandezCastañer, and R. J. Andrade, “Causality assessment methods in
drug induced liver injury: strengths and weaknesses,” Journal of
Hepatology, vol. 55, no. 3, pp. 683–691, 2011.
[4] G. Danan and C. Benichou, “Causality assessment of adverse
reactions to drugs—I: a novel method based on the conclusions of international consensus meetings: application to druginduced liver injuries,” Journal of Clinical Epidemiology, vol. 46,
no. 11, pp. 1323–1330, 1993.
[5] C. Benichou, G. Danan, and A. Flahault, “Causality assessment
of adverse reactions to drugs—II: an original model for validation of drug causality assessment methods: case reports with
positive rechallenge,” Journal of Clinical Epidemiology, vol. 46,
no. 11, pp. 1331–1336, 1993.
[6] D. Larrey, “Drug-induced liver diseases,” Journal of Hepatology,
vol. 32, supplement 1, pp. 77–88, 2000.
[7] B. K. Gunawan and N. Kaplowitz, “Mechanisms of druginduced liver disease,” Clinics in Liver Disease, vol. 11, no. 3, pp.
459–475, 2007.
[8] P. Zapater, J. Such, M. Pérez-Mateo, and J. F. Horga, “A new poisson and Bayesian-based method to assign risk and causality in
patients with suspected hepatic adverse drug reactions: a report
of two new cases of ticlopidine-induced hepatotoxicity,” Drug
Safety, vol. 25, no. 10, pp. 735–750, 2002.
[9] P. H. Hayashi, “Causality assessment in drug-induced liver
injury,” Seminars in Liver Disease, vol. 29, no. 4, pp. 348–356,
2009.
[10] M. A. Shapiro and J. H. Lewis, “Causality assessment of druginduced hepatotoxicity: promises and pitfalls,” Clinics in Liver
Disease, vol. 11, no. 3, pp. 477–505, 2007.
[11] M. Garcı́a-Cortés, M. I. Lucena, K. Pachkoria, Y. Borraz, R.
Hidalgo, and R. J. Andrade, “Evaluation of naranjo adverse drug
reactions probability scale in causality assessment of druginduced liver injury,” Alimentary Pharmacology and Therapeutics, vol. 27, no. 9, pp. 780–789, 2008.
[12] H. Takikawa, Y. Takamori, T. Kumagi et al., “Assessment of 287
Japanese cases of drug induced liver injury by the diagnostic
scale of the International Consensus Meeting,” Hepatology
Research, vol. 27, no. 3, pp. 192–195, 2003.
[13] P. B. Watkins, “Biomarkers for the diagnosis and management of
drug-induced liver injury,” Seminars in Liver Disease, vol. 29, no.
4, pp. 393–399, 2009.
7
[14] D. Serranti, C. Montagnani, G. Indolfi, E. Chiappini, L. Galli,
and M. de Martino, “Antibiotic induced liver injury: what about
children?” Journal of Chemotherapy, vol. 25, no. 5, pp. 255–272,
2013.
[15] N. F. Maraqa, M. M. Gomez, M. H. Rathore, and A. M. Alvarez,
“Higher occurrence of hepatotoxicity and rash in patients treated with oxacillin, compared with those treated with nafcillin
and other commonly used antimicrobials,” Clinical Infectious
Diseases, vol. 34, no. 1, pp. 50–54, 2002.
[16] C. Aygün, O. Kocaman, Y. Gürbüz, Ö. Şentürk, and S. Hülagü,
“Clindamycin-induced acute cholestatic hepatitis,” World Journal of Gastroenterology, vol. 13, no. 40, pp. 5408–5410, 2007.
[17] I. Altraif, L. Lilly, I. R. Wanless, and J. Heathcote, “Cholestatic
liver disease with ductopenia (vanishing bile duct syndrome)
after administration of clindamycin and trimethoprim-sulfamethoxazole,” The American Journal of Gastroenterology, vol. 89,
no. 8, pp. 1230–1234, 1994.
[18] J. P. Molleston, R. J. Fontana, M. J. Lopez, D. E. Kleiner, J. Gu, and
N. Chalasani, “Characteristics of idiosyncratic drug-induced
liver injury in children: results from the DILIN prospective
study,” Journal of Pediatric Gastroenterology and Nutrition, vol.
53, no. 2, pp. 182–189, 2011.
[19] J. S. Kim, Y. R. Jang, J. W. Lee et al., “A case of amoxicillininduced hepatocellular liver injury with bile-duct damage,” The
Korean Journal of Hepatology, vol. 17, no. 3, pp. 229–232, 2011.
[20] E. Peker, E. Cagan, and M. Dogan, “Ceftriaxone-induced toxic
hepatitis,” World Journal of Gastroenterology, vol. 15, no. 21, pp.
2669–2671, 2009.
[21] C. L. Bickford and A. P. Spencer, “Biliary sludge and hyperbilirubinemia associated with ceftriaxone in an adult: case report and
review of the literature,” Pharmacotherapy, vol. 25, no. 10 I, pp.
1389–1395, 2005.
[22] Y. Chen, X. Y. Yang, M. Zeckel et al., “Risk of hepatic events in
patients treated with vancomycin in clinical studies: a systematic review and meta-analysis,” Drug Safety, vol. 34, no. 1, pp.
73–82, 2011.
[23] S. Köklü, A. Ş. Köksal, M. Asil, H. Kiyici, Ş. Çoban, and M.
Arhan, “Probable sulbactam/ampicillin-associated prolonged
cholestasis,” Annals of Pharmacotherapy, vol. 38, no. 12, pp.
2055–2058, 2004.
[24] R. J. Fontana, L. B. Seeff, R. J. Andrade et al., “Standardization of
nomenclature and causality assessment in drug-induced liver
injury: summary of a clinical research workshop,” Hepatology,
vol. 52, no. 2, pp. 730–742, 2010.
[25] W. M. Lee, “Drug-induced hepatotoxicity,” The New England
Journal of Medicine, vol. 349, no. 5, pp. 474–485, 2003.
MEDIATORS
of
INFLAMMATION
The Scientific
World Journal
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Gastroenterology
Research and Practice
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Journal of
Diabetes Research
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
International Journal of
Journal of
Endocrinology
Immunology Research
Hindawi Publishing Corporation
http://www.hindawi.com
Disease Markers
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Submit your manuscripts at
http://www.hindawi.com
BioMed
Research International
PPAR Research
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Journal of
Obesity
Journal of
Ophthalmology
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Evidence-Based
Complementary and
Alternative Medicine
Stem Cells
International
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Journal of
Oncology
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Parkinson’s
Disease
Computational and
Mathematical Methods
in Medicine
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
AIDS
Behavioural
Neurology
Hindawi Publishing Corporation
http://www.hindawi.com
Research and Treatment
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Oxidative Medicine and
Cellular Longevity
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014