Drug-Induced Liver Injury - AACN
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AACN Advanced Critical Care
Volume 27, Number 4, pp. 430-440
© 2016 AACN
Drug-Induced Liver Injury
Leslie A. Hamilton, PharmD, BCPS, BCCCP
Angela Collins-Yoder, RN, PhD, CCNS, ACNS-BC
Rachel E. Collins, BS
ABSTRACT
Drug-induced liver injury (DILI) can result medications varies, and the resulting dam-
from both idiosyncratic and intrinsic mech- age can be cholestatic, hepatocellular, or
anisms. This article discusses the clinical mixed. The primary treatment of IDILI is to
impact of DILI from a broad range of medi- discontinue the causative agent. DILI due to
cations as well as herbal and dietary sup- acetaminophen is intrinsic because the liver
plements. Risk factors for idiosyncratic DILI damage is predictably aligned with the dose
(IDILI) are the result of multiple host, envi- ingested. Acute acetaminophen ingestion
ronmental, and compound factors. Some can be treated with activated charcoal or
triggers of IDILI often seen in critical care N-acetylcysteine. Future areas of research
include antibiotics, antiepileptic medica- include identification of mitochondrial
tions, statins, novel anticoagulants, proton stress biomarkers and of the patients at
pump inhibitors, inhaled anesthetics, non- highest risk for DILI.
steroidal anti-inflammatory agents, metho- Keywords: drug-induced liver injury, clinical
trexate, sulfasalazine, and azathioprine. practice guidelines, adverse drug reactions,
The mechanism of IDILI due to these herbal and dietary supplements
P atients with drug-induced liver injury
(DILI) display a continuum of diverse
signs and symptoms of hepatic injury after
Incidence of DILI is estimated to range from
1 to 10 in every 10 000 exposed persons.3 The
incidence of liver injury caused by HDSs has
taking a xenobiotic.1 Xenobiotics encompass been reported to be 0.9% in a Korean cohort
“pharmacologically, endocrinologically, or of patients with DILI4 and up to 10% in a
toxicologically active substances.”2 Types of US cohort of patients with DILI.5,6 Prescrip-
xenobiotics associated with DILI in critical tion medications and HDSs typically cause
care include prescription medications, herbal idiosyncratic DILI (IDILI). Dose-dependent
and dietary supplements (HDSs), and over-the- DILI, also known as intrinsic DILI, is
counter medications. DILI is a recognized type
of adverse drug reaction linked to more than Leslie Hamilton is Associate Professor of Clinical Pharmacy,
1000 medications.3 University of Tennessee Health Science Center College of
Liver injury greatly affects the development Pharmacy, Knoxville, Tennessee.
of new drug and HDS products. Directly caus- Angela Collins-Yoder is Clinical Professor, Capstone College
ing toxic effects on the liver is a primary rea- of Nursing, and Critical Care Nurse Specialist, Sacred Heart
son that many medications and HDSs have Pensacola Hospital, 8370 Foxtail Loop, Pensacola, FL 32526
been removed from the market. One function (acollins-yoder@ua.edu).
of the liver is chemical detoxification of cir- Rachel E. Collins is a PharmD candidate, Auburn University
culating substances, and this detoxification Harrison School of Pharmacy, Auburn, Alabama.
function makes the liver vulnerable to injury. The authors declare no conflicts of interest.
Extensive hepatic metabolism of a xenobiotic
is associated with hepatotoxic effects.1,3 DOI: http://dx.doi.org/10.4037/aacnacc2016953
430VOLU ME 27 • N U MB ER 4 • OCTOBER-DECEM BER 2016 D RUG- IND UCE D LIVE R INJURY
associated with medications that, because with IDILI. Clinical utility and interpretation
of their chemical design and dosage toxicity, of individual DNA analyses to predict adverse
accrue recognized patterns of hepatocellular drug reactions with liver injury is not a cur-
injury.6 Acetaminophen is an example of a rent clinical practice recommendation nor is
medication with an intrinsic dose-linked its cost reimbursed by insurance.8,9 Genome-
injury manifestation of DILI and is the most wide association studies suggest that the human
common cause of DILI.3 About 46% of all leukocyte antigen (HLA) gene 6 coding may
persons with acute liver failure in the United play an important role.1,3
States have liver damage associated with Another observed host factor is that most
acetaminophen.3 Acetaminophen is combined patients with idiosyncratic DILI are women.
with many over-the-counter medications and In 4 prospective cohorts, the incidence of
multiple oral prescription pain medications, IDILI in women from the United States,
making it easier for patients to unknowingly Iceland, Spain, and France was 49% to 60%.3
take higher dosages of acetaminophen than The reason for this gender predominance is
they realize. The most common causes of DILI unknown.7,8 In addition, the Drug Induced
due to acetaminophen are long-term dosage Liver Injury Network registries noted that
above recommended levels and dosage of Asian race was an independent risk factor
acetaminophen greater than 150 mg/kg as a for IDILI patients who required transplant,
short-term intake. Patients with both types and African American race was associated
of DILI can experience a clinical course char- with chronic liver dysfunction after IDILI.3,9,10
acterized as mild, moderate, or severe requir-
ing liver transplant, with some patients Environmental Factors
rapidly progressing to severe encephalopathy Environmental risk factors discussed in the
and death. literature with IDILI are alcohol consumption
Evaluation and treatment of DILI are based and associated infection.1 Alcohol consumption
on guidelines targeted specifically to either may have a synergistic effect, predisposing
IDILI or DILI due to acetaminophen. This the patient to greater hepatotoxic effects
article discusses both the unpredictable clini- with antitubercular medications, antivirals,
cal course of IDILI and the predictable clini- and antibiotics.8 Infection is believed to change
cal course of DILI caused by acetaminophen. the dose response of the liver through immuno-
This article delineates the risk factors for modulation that sets the stage for the
DILI, diagnosis and management of DILI, inflammatory aspects of IDILI.9
and selected DILI-associated xenobiotics that
are often used in critical care. Compound-Related Factors
Compound-related factors have been iden-
Risk Factors for DILI tified from study of substances that trigger
Risk factors that predispose people to IDILI. Lipophilia is a predominating charac-
development of DILI can be grouped into 3 teristic of medications that trigger IDILI.
categories: host-related factors, environmental Hepatic conversion of a lipophilic medication
factors, and compound-related factors. Deter- to a hydrophilic form requires multiple meta-
mining which patients are most susceptible bolic degradation pathways so that the kid-
to toxic effects on the liver is an excellent neys can excrete the metabolites. Additional
primary prevention for DILI development. characteristics of compounds that are associ-
ated with liver damage are formation of reac-
Host-Related Factors tive metabolites, molecular weight, induction
The susceptibility of a host to DILI is of oxidative stress, and inhibition of hepatic
believed to be genetic. Multiple genes con- transporters10,11 (Figure 1).
trol immunological and liver processes that
set the stage for DILI development.1,3,7,8 Idiosyncratic DILI
Cheek-swab DNA tests are currently available When drugs are tested in Food and Drug
to provide analysis of selected cytochrome Administration (FDA) trials, IDILI often goes
P-450 pathways that affect drug metabolism. unrecognized. This problem is a matter of
This information can be helpful, for example, numeracy. A clinical trial that has fewer than
before prescription of more than 150 behavio- 3000 patients will not detect the population
ral and seizure medications that are associated risk for an adverse drug reaction with an
431H A MILTON E T A L W W W .AACN ACCON LIN E .ORG
Host Factors
Environmental Factors Genetic
• Viral co-infection • Ethnicity
(Epstein-Barr, hepatitis B and C, HIV) • Sex
• Products of mitochondrial stress • Comorbidity
• Co-prescription of immunomodulators • HLA alleles
• Alcohol consumption • Polymorphisms
• Mitochondrial variations
Metabolics
• Alteration in drug transport
and clearance
• Detoxification process errors
• Enzyme inhibitions
• Age
Compound Factors
• Molecular weight
• Dose
• Chemical structure
• Lipophilicity
Figure 1: Risk factors for development of drug-induced liver injury (DILI). Original art: graphic art created
by Roger Yoder Iconic Images, provided by PresenterMedia.
expected incidence of 1 in 10 000 patients.3,4 to direct the processes of diagnosis and
HDSs are not considered drugs and do not management needed for these patients.8 Two
undergo rigorous testing and scrutiny before online resources are available to provide
marketing; therefore, liver-associated adverse guidance through the diagnostic and manage-
drug reactions are even more difficult to antic- ment process. One is the Livertox database
ipate and predict with use of these xenobiot- at http://livertox.nih.gov.12 The other is the
ics. FDA-mandated recalls for HDSs occur only Drug Induced Liver Injury Network, which is
after adverse drug reactions are identified in available for consultation and provides a data
the postmarketing period. Because of its low registry for cases at http://www.dilin.org.13
frequency of occurrence and the total number Critical to IDILI diagnosis is meticulous col-
of xenobiotics that can trigger liver injury, lection of a medical history focused on time
IDILI is a diagnostic conundrum.6 Research is intervals between each suspected xenobiotic
currently focusing on using prospective data administration, onset of signs and symptoms,
from digital registries with the hope of earlier and total dosage interval. One difficulty with
identification of hepatotoxic medications and obtaining an accurate history is that patients
HDSs.1 Big data registries are also helpful for do not consistently report HDS use. It has
identification of subpopulations at higher risk been reported that 50% of persons in the
for IDILI. United States and greater than 60% to 70%
of military personnel use HDSs.14,15 Data from
Diagnosis and Management of analyses of electronic medical records show
IDILI that only approximately 40% of patients are
The American College of Gastroenterol- reporting this information.14,16
ogists’ clinical practice document for the care As the patient’s medical history unfolds, the
of patients with IDILI is the compass document health care provider should listen attentively
432VOLU ME 27 • N U MB ER 4 • OCTOBER-DECEM BER 2016 D RUG- IND UCE D LIVE R INJURY
Abnormal liver enzymes
Thorough history and physical
Complete review of medications and
herbals and dietary supplements
Calculate R value*
R value = Serum (ALT/ALT ULN) ÷ (Alk P/Alk P ULN)
R value > 5 2 < R value < 5 R value < 2
(Hepatocellular) (Mixed) (Cholestatic)
1st-line tests: Acute viral hepa- 1st-line tests: Acute viral hepa-
titis serologies, HCV RNA & titis serologies, HCV RNA &
1st-line test: imaging studies
autoimmune hepatitis serolo- autoimmune hepatitis serolo-
(abdominal ultrasound)
gies; imaging studies (eg, gies; imaging studies (eg,
2nd-line tests on a case by case
abdominal ultrasound) abdominal ultrasound)
basis: cholangiography (either
2nd-line tests on a case by 2nd-line tests on a case by
endoscopic or MR based),
case basis: ceruloplasmin, case basis: ceruloplasmin,
serologies for primary biliary
serologies for less common serologies for less common
cirrhosis, liver biopsy
viruses (HEV, CMV, and EBV), viruses (HEV, CMV, and EBV),
liver biopsy liver biopsy
Assessment of data, causality assessment, and diagnosis:
1. Assessment of data
a. Completeness: (Table 4) (non-DILI etiologies reasonably excluded)
b. Literature review by use of LiverTox (22) and PubMed
2. Clinical judgment for final DILI diagnosis
3. Expert consultation if doubt persists
Figure 2: An algorithm to evaluate suspected idiosyncratic drug-induced liver injury (DILI). The R-value
cutoff numbers of 2 and 5 serve only as a guideline. Which tests and their order must be based on the
overall clinical picture, including risk factors for competing diagnosis (eg, recent travel to hepatitis E virus
[HEV] endemic area), associated symptoms (eg, abdominal pain, fever), and timing of laboratory tests (ie,
the R value may change as the DILI evolves). Abbreviations: ALT, alanine aminotransferase; Alk P, alkaline
phosphatase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HCV, hepatitis C virus; HSV, herpes simplex
virus; MR, magnetic resonance; ULN, upper limit of normal. Reprinted from Chalasani et al.8 Used with per-
mission from the American Journal of Gastroenterology.
for a history of allergy and sensitivity to medi- calculated as follows: upper limit of normal
cation classifications, particularly antibiotics for alanine transaminase divided by the upper
and antiepileptic medications. History of limit of normal for alkaline phosphatase. This
prior liver disease, especially viral hepatitis number is used clinically to categorize injury
or co-infection with Epstein-Barr virus, with patterns into 3 types: hepatocellular (R > 5),
increased fatigue are common findings.8,12 mixed (R = 2–5), and cholestatic (R < 2).8,12
The clinical signs and symptoms of IDILI The diagnostic workup then proceeds by the
mirror those of hepatitis, so ruling out an decision tree arms determined by the R score.
infectious origin is critical. The American College of Gastroenterologists
The next step is to evaluate the laboratory has developed a diagnostic clinical decision
test results relevant to liver biochemistries and tree (Figure 2, Table 1).8 This useful clinical
eosinophil activation. A useful determination reasoning tool aids in data collection for this
for treatment is to determine the R value, diagnosis of exclusion.
433H A MILTON E T A L W W W .AACN ACCON LIN E .ORG
Table 1: Terminology and Definitionsa
Term or Concept Technique
Intrinsic DILI Hepatotoxicity with potential to affect all individuals to varying
degrees. Reaction typically stereotypic and dose dependent (eg,
acetaminophen).
Idiosyncratic DILI Hepatotoxicity affecting only rare susceptible individuals. Reaction
less dose dependent and more varied in latency, presentation,
and course.
Chronic DILI Failure of return of liver enzymes or bilirubin to pre-DILI baseline,
and/or other signs or symptoms of ongoing liver disease (eg,
ascites, encephalopathy, portal hypertension, coagulopathy)
6 months after DILI onset
Latency Time from medication (or HDS) start to onset of DILI
Washout, resolution, or dechallenge Time from DILI onset to return of enzymes and/or bilirubin to
pre-DILI baseline levels
Rechallenge Readministration of medication or HDS to a patient who already
had a DILI to the same agent
Hy’s law Observation made by late Hyman Zimmerman suggesting a 1 in 10
mortality risk of DILI if the following 3 criteria are met:
1. Serum ALT or AST > 3 × ULN
2. Serum total bilirubin elevated to > 2 × ULN, without initial fin -
ings of cholestasis (elevated serum alkaline phosphatase)
3. No other reason can be found to explain the combination of
increased aminotransferases and bilirubin, such as viral hepa-
titis A, B, C, or other preexisting or acute liver disease
Temple’s corollary An imbalance in the frequency of ALT > 3 × ULN between active
treatment and control arms in a randomized controlled trial.
This is used to assess for hepatotoxic potential of a drug from
premarketing clinical trials
R value ALT/ULN ÷ AP/ULN. Used to defined hepatotoxi- city injury patterns:
hepatocellular (R > 5), mixed (R = 2–5), and cholestatic (R < 2)
RUCAM Diagnostic algorithm that uses a scoring system based on clinical
data, preexisting hepatotoxicity literature on the suspected agent
and rechallenge
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; HDS,
herbal and dietary supplement; RUCAM, Roussel Uclaf Causality Assessment Method; ULN, upper limit of normal.
a
Reprinted from Chalasani et al.8 Used with permission from the American Journal of Gastroenterology.
Specific Triggering antiviral agents.17 In a recent Icelandic study
Medications and IDILI by Björnsson et al,18 amoxicillin-clavulanate
Knowing which types of medications are was the most commonly implicated agent
associated with IDILI assists critical care health in IDILI, causing liver damage in 22% of
professionals to assess patterns of injury patients studied. The type of damage inflicted
associated with these prescription and over- by amoxicillin-clavulanate is usually cholestatic,
the-counter medications. Discussed next are but the damage can also occur as a mixed
some of the prescription medications, HDSs, type of liver injury, especially if amoxicillin-
and over-the-counter medications that are clavulanate is combined with another agent
often associated with IDILI reports. that is known to cause IDILI. Liver damage
caused by amoxicillin-clavulanate is more
Antibiotic-Associated IDILI likely to be caused by the clavulanate portion
Some of the most frequent causes of of the agent, as the incidence of IDILI is much
IDILI stem from the use of antibiotics and lower when amoxicillin is used as a single
434VOLU ME 27 • N U MB ER 4 • OCTOBER-DECEM BER 2016 D RUG- IND UCE D LIVE R INJURY
agent.19 In a study by García Rodríguez et warning is placed in the package insert of
al,19 the incidence of IDILI for amoxicillin- valproic acid, warning of potential fatal
clavulanate per 10 000 prescriptions was hepatic failure in all patients and recommend-
1.7 (95% CI, 1.1-2.7) cases compared with ing extreme caution with the use of valproic
0.3 (95% CI, 0.2-0.5) cases for amoxicillin acid in children less than 2 years of age.10
alone. Because prescriptions for amoxicillin- Recent studies have shown associations with
clavulanate are usually short-term, the onset a higher risk of liver injury induced by valp-
of IDILI is commonly diagnosed after the roic acid in patients with genetic metabolic
course of the agent has been completed.20 mutations or a carnitine deficiency.10 Valproic
Another antibiotic that has often been acid is unique in that it has multiple mecha-
implicated in IDILI is sulfamethoxazole- nisms by which it can cause DILI. One of
trimethoprim, with the sulfonamide compo- the first aberrations seen with valproic acid
nent serving as the main culprit.21 As with is hyperammonemia, which manifests in
amoxicillin-clavulanate, IDILI caused by patients as encephalopathy or coma. Discon-
sulfamethoxazole-trimethoprim is usually tinuing valproic acid allows ammonia levels
cholestatic, but hepatocellular injury has to normalize.8 Valproic acid can also cause
occurred.8,17 In a study by Björnsson,17 a acute hepatocellular damage that is associ-
small number of patients who had IDILI ated with jaundice. In addition, in children,
develop after intake of sulfamethoxazole- valproic acid can cause a Reye’s-like syndrome
trimethoprim either died or required a liver with symptoms of fever and lethargy and ele-
transplant. Liver injury caused by sulfameth- vated aminotransferase and ammonia levels.8
oxazole-trimethoprim is often accompanied Carbamazepine is also commonly associated
by fever, rash, and eosinophilia.8 with IDILI and can cause transiently elevated
Nitrofurantoin is regularly listed as a aminotransferase levels in up to 61% of
common cause of IDILI and can cause an patients.23 Hypersensitivity to carbamazepine
acute or chronic hepatocellular injury that can occur and is associated with fever and
can resemble hepatitis.8 Risk factors associ- eosinophilia; it can even lead to Stevens-
ated with nitrofurantoin-induced liver injury Johnson syndrome. Carbamazepine is linked
include older age, female sex, and prolonged with anticonvulsant hypersensitivity syn-
exposure to the agent.21 DILI from short-term drome and can result in hepatocellular or
use of nitrofurantoin can be accompanied cholestatic injury.23
by a fever or rash, while chronic use of nitro- Like carbamazepine, lamotrigine is also
furantoin is often associated with an immuno- connected with anticonvulsant hypersensitivity
logic mechanism that resembles autoimmune syndrome associated with fever, eosinophilia,
hepatitis.21 Reported cases of DILI from nitro- and Stevens-Johnson syndrome.8 Rapid dose
furantoin include symptoms that have ranged titration and younger age are risk factors for
from mild elevations in aminotransferase levels the development of IDILI from lamotrigine.23
to jaundice and fulminant liver failure.21
Isoniazid is a commonly used agent in the Statins
treatment of tuberculosis and has been asso- Idiosyncratic DILI from statins has been
ciated with hepatocellular injury that resem- reported, although it is rare.17 With most
bles viral hepatitis. Because of the protracted statins, patients may see a mild elevation in
course of isoniazid required to treat tubercu- aminotransferase level that is usually tran-
losis, exposure to this agent occurs over an sient.24 However, patients with hepatocellular
extended period of time.8 Elevations in ami- damage or cholestatic injury after taking
notransferase levels are often seen and signs statins have been reported.24 Because of the
and symptoms of the onset of injury are often rare incidence of IDILI from statins, routine
delayed.22 Interestingly, pharmacogenetic impli- monitoring of aminotransferase levels in
cations have been reported in isoniazid-induced patients on long-term statin therapy is not
liver injury, especially in those patients who recommended unless signs or symptoms of
are slow acetylators of isoniazid.22 liver injury are apparent.24
Antiepileptic Agents Novel Anticoagulants
Valproic acid is the antiepileptic agent most The novel anticoagulants include rivar-
commonly associated with IDILI.8 A black-box oxaban, dabigatran, apixaban, and edoxaban.
435H A MILTON E T A L W W W .AACN ACCON LIN E .ORG
These medications are indicated for use in agents are metabolized by the liver and
many different diagnoses owing to updates often have highly reactive metabolites that
in many clinical practice guidelines and pro- can potentially cause hepatic injury.29,30
files of fewer adverse effects compared with Inhaled anesthetics also can stimulate an
traditional anticoagulants. These drugs act immune response that can result in damaging
by directly inhibiting clotting factors as inflammation in the liver and other organs.29
opposed to traditional oral anticoagulants Because inhaled anesthetics are used during
such as warfarin, which inhibits clotting surgery and trauma, it can be difficult to
factor synthesis. All novel anticoagulants differentiate if liver injury is the result of
have shown some incidence of hepatotoxic these agents or is the result of injury or sur-
effects, but only limited data are available gery. Isoflurane in particular has been associ-
for apixaban and edoxaban.25 The mecha- ated with hepatotoxic effects after repeat
nism of IDILI with these drugs is not well exposures.29 Two types of hepatotoxic effects
understood but has not been determined to are seen: mild dysfunction and life-threatening
be exclusively dose related. Animal models hepatitis.30 The mild dysfunction is charac-
and postmarket evaluation have shown terized by elevations in serum levels of ami-
immune-mediated IDILI as well as IDILI notransferases in patients who are otherwise
resulting from potentially toxic metabo- asymptomatic; patients with mild dysfunction
lites.25,26 Most reported cases of IDILI have experience complete recovery.30 Fulminant liver
been at therapeutic doses of all agents.25 failure characterized by extensive hepatocellular
Evaluation of recent studies has shown necrosis leads to a need for urgent transplant.
rivaroxaban to have the highest incidence
of IDILI, but the incidence is not signifi- Nonsteroidal Anti-inflammatory Drugs
cantly greater than the incidence seen with Nonsteroidal anti-inflammatory drugs
warfarin. The majority of IDILI cases had (NSAIDs) are a large class of analgesics availa-
asymptomatic elevations in levels of alanine ble as prescription and over-the-counter med-
aminotransferase, aspartate aminotransferase, ications. These medications include ibuprofen,
and bilirubin.25 Patients often recover rapidly naproxen, meloxicam, diclofenac, etodolac,
after discontinuation of drug therapy with- and ketorolac as well as others. Several NSAIDs
out further intervention or long-term dam- (eg, bromfenac, ibufenac, and benoxaprofen)
age.26 Although the risk of IDILI with novel have been withdrawn from the market because
anticoagulants is minimal, further postmar- of the increased risk of hepatotoxic effects
keting evaluations are needed to determine associated with them.31
the risk accurately. NSAIDs have long been associated with
hepatotoxic effects, although such effects
Proton Pump Inhibitors occur in less than 0.1% of the population of
Although proton pump inhibitors (PPIs) patients.32 The precise mechanism of NSAID-
have a warning of hepatotoxicity, evidence induced liver injury is not well understood.
for liver injury due to PPI therapy is extremely The most widely accepted explanation is
limited. The majority of case reports have that the injury is due to the electrophilicity
noted elevated serum levels of aminotrans- of the chemical structure of most NSAIDs.32
ferases due to pantoprazole therapy specifi- The electrophilic structure results in reactive
cally.27 Most PPIs, including pantoprazole, are metabolites that can cause hepatotoxic effects
metabolized in the liver by various cytochrome and cellular necrosis.33 One of the additional
enzymes, and that may be the mechanism by proposed mechanisms is the suppression of
which IDILI occurs.27 The highest incidence inflammatory cytokines and decreased immune
of IDILI with PPI therapy has been seen when response that can potentiate hepatocellular
a PPI is combined with azathioprine.28 IDILI injury.33 The incidence of IDILI varies depend-
due to PPI therapy resolves quickly upon ing on the specific NSAID used. In a recent
discontinuation of the drug. prospective study, Schmeltzer et al34 determined
that diclofenac therapy resulted in the most
Inhaled Anesthetics cases of acute liver failure when compared with
Inhaled anesthetics such as isoflurane, several other prescription NSAIDs. Ibuprofen
desflurane, and sevoflurane have shown and naproxen have shown the lowest incidence
some potential for hepatotoxicity. These of IDILI and are considered to be the most
436VOLU ME 27 • N U MB ER 4 • OCTOBER-DECEM BER 2016 D RUG- IND UCE D LIVE R INJURY
frequently used NSAIDs thanks to their avail- effects of use of antioxidants on the prevention
ability without a prescription.34 and treatment of sulfasalazine IDILI, but
evidence for use of this treatment is minimal
Methotrexate at this time.38
Methotrexate is an immunosuppressive
agent that acts by inhibiting folate metabo- Azathioprine
lism and can be used for a variety of different Azathioprine is widely used as an antire-
indications. Methotrexate IDILI occurs in more jection medication for patients who have
than 10% of patients receiving methotrexate undergone organ transplant or who have
and varies from elevated aminotransferase rheumatoid arthritis. It has been linked to
levels to fibrosis and cirrhosis that can be mild hepatotoxic effects indicated by an
life-threatening.35 The mechanism of metho- asymptomatic increase in serum aminotrans-
trexate’s hepatotoxic effects is linked to the ferase levels. The type of damage associated
depletion of folate stores in the liver.36 Folate with moderate to severe hepatotoxic effects
plays a vital role in cellular reproduction, is mixed type including cholestatic hepatitis
and its depletion causes improper DNA repli- and hepatocellular injury.39 The hepatic
cation within hepatocytes. The hepatocytes metabolism of azathioprine results in the
that develop are unable to function effectively, development of reactive oxygen species and
resulting in a buildup of toxins and elevated mitochondrial dysfunction within the liver,
aminotransferase levels.35 Although higher which has been associated with IDILI.40
doses over longer duration have a higher
risk of IDILI, injury can occur with both Herbal and Dietary Supplements
short- and long-term therapy. Liver transplant registries note that 5%
Hepatotoxic effects of methotrexate are of liver transplants are a consequence of
treated by discontinuation of the drug and HDS-induced ILIDI.10,41 In HDS-suspected
administration of folic acid to replenish the injuries, the process of diagnosis is different.
nutrient necessary for the liver to function The same data are gathered and evaluated,
and repair.36 Unfortunately, if IDILI is not but expert opinion and review of the litera-
identified before cirrhosis or fibrosis develops, ture for similar HDS case reports are used.
it can cause permanent damage and require Use of a Roussel Uclaf Causality Assessment
a liver transplant.35 Patients with transient Method (RUCAM) instrument to gauge the
elevations of aminotransferase levels while likelihood of HDS-triggered IDILI is also rec-
undergoing methotrexate therapy usually do ommended.8,42,43 This tool is an algorithm that
not suffer long-term hepatic damage.35 Serum uses a scoring system based on clinical data,
aminotransferase levels should be monitored preexisting publications on the hepatotoxicity
frequently throughout methotrexate therapy to of the suspected agent, and rechallenge with
identify potential IDILI and take preventative the substance. Health care providers look for
measures such as folic acid supplementation patterns of hepatic injury within matched host
or methotrexate dose adjustment. factors and xenobiotic exposure.
A good example of this diagnosis detective
Sulfasalazine work was in Hawaii with the cluster of liver
Sulfasalazine is primarily used to treat failure associated with the use of OxyElite Pro
rheumatoid arthritis and Crohn disease. (USPLabs LLC).43 The health care providers
Although the mechanism is not well under- used the RUCAM and expert opinion to diag-
stood, treatment with sulfasalazine has been nosis the cases. The Hawaii Department of
linked to hepatotoxic and nephrotoxic effects. Health and the Centers for Disease Control
A widely accepted mechanism of injury is the and Prevention carefully examined the cluster
increased oxidative stress that sulfasalazine of IDILI cases, determining that the common
imposes on the liver during treatment.37 Case factor was the use of the weight-loss supple-
reports have shown that IDILI due to sulfasala- ment. The FDA issued a recall of the product
zine therapy can occur over a wide range of with specific attention to one ingredient in
doses and various durations of therapy.38 the product, aegeline, which had not been
The primary treatment for sulfasalazine IDILI tested for safety in humans. This HDS prod-
is drug discontinuation. Researchers in several uct highlights the difficulty for toxicologists
recent studies have sought to determine the who are trying to identify which component
437H A MILTON E T A L W W W .AACN ACCON LIN E .ORG
Table 2: Signs and Symptoms Associated With Progressive Acetaminophen
Hepatotoxicitya
Stage Time Interval Signs and Symptoms
I 24 h Nausea, vomiting, diaphoresis, fatigue
II 24-72 h Latent period
Elevation in liver enzyme levels
Possible for acute tubular necrosis to develop
III 72-96 h Nausea, vomiting, fatigue
Marked elevation in liver enzyme levels, jaundice, lactic acidosis
Level of consciousness declines
Cerebral edema
Hypoglycemia
Bleeding
IV 96 h to 2 weeks Recovery of systems dependent on resolution of multiple organ failure associated
with stage III
a
Based on information from Yoon et al.45
or combination of components are the source acetaminophen. Each toxicology center and
of hepatic injury. Herbal formulas can vary acute care facility may follow an internal pro-
in potency with every lot or dose because tocol for the use of activated charcoal and
the soil, altitude, and season can change the infusion of N-acetylcysteine. One of the tools
potency of the herb.41-43 most commonly used in the decision to use
N-acetylcysteine is the Rumack-Matthew nom-
Diagnosis, Management, and ogram for acute overdose.45 This tool is a
Treatment of Acetaminophen- mathematical algorithm appropriately used
Associated DILI for acute, single overdose ingestions of aceta-
Acetaminophen-associated DILI is a conse- minophen. This tool accounts for the variable
quence of both the dosage of the drug and that 4 hours after ingestion is typically the
the metabolic pathways that take place in zenith of the level of toxic metabolites gen-
the microsomes within hepatocytes. Therefore, erated from a single overdose, allowing the
it is considered an intrinsic type of DILI clinician to predict the optimal dose of
because liver damage is predictably aligned N-acetylcysteine. N-acetylcysteine works to
with dosage. Acetaminophen-associated liver replenish hepatic stores of cysteine, the ele-
failure accounts for approximately half of ment needed to detoxify the toxic metabolites
the patients who have acute liver failure diag- of acetaminophen. Other descriptors of the
nosed each year.44,45 This situation is attributed action of N-acetylcysteine with acute acetami-
to the excessive use of acetaminophen as an nophen overdose are immunological active,
over-the-counter medication and in combina- antioxidant, and antiapoptic functions. Prompt
tion with prescription opioid medications. intervention with N-acetylcysteine has reduced
Acetaminophen metabolism requires 3 sets mortality to 0.7% of patients who have over-
of metabolic detoxifications in the liver. dosed on acetaminophen.45
Hepatotoxicity results from the breakdown The signs and symptoms of the 5 stages of
of acetaminophen to a noxious metabolite acetaminophen overdose are summarized in
N-acetyl-p-benzoquinone imine, which leads Table 2.45 Each stage requires that the critical
to mitochondrial dysfunction and diminishes care team carefully evaluate the patient for
levels of adenosine triphosphate within the resolution of the liver dysfunction or prompt
hepatic cells.45 Additionally, peroxynitrite, a transfer to an acute care liver transplant eval-
toxic free radical, is generated and structurally uation center. Research on acetaminophen-
damages the mitochondria. Acetaminophen- associated DILI focuses on the optimal dosing
triggered cell death is characterized by necrosis. and duration of treatment with N-acetylcysteine
Diagnosis is made by history of ingestion, and on identifying biomarkers that will predict
time and doses of medication viewed within excessive mitochondrial damage leading to
a weight calculation, and serum level of acute liver failure.42
438VOLU ME 27 • N U MB ER 4 • OCTOBER-DECEM BER 2016 D RUG- IND UCE D LIVE R INJURY
Treatment of IDILI and ACKNOWLEDGMENT
Acetaminophen-Induced DILI This article was presented in part at American
The treatment of DILI is guided by the Association of Critical-Care Nurses National
degree of hepatic dysfunction and comorbid Teaching Institute, New Orleans, May 2016.
conditions.45 Consultations with a toxicolo-
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CE Test Instructions
This article has been designated for CE contact hour(s). The evaluation tests your knowledge of the
following objectives:
1. Summarize the classifications of idiosyncratic drug-induced liver injury (DILI) and dose-dependent DILI.
2. Examine the American College of Gastroenterologist’s clinical diagnostic algorithm for idiosyncratic DILI.
3. Compare and contrast selected medications that trigger idiosyncratic DILI in the acute care setting.
4. Recognize the clinical course and high incidence of acetaminophen-associated DILI.
Contact hour: 1.0
Pharmacology contact hour: 0.75
Synergy CERP Category: A
To complete evaluation for CE contact hour(s) for test #ACC6342, visit www.aacnacconline.org and
click the “CE Articles” button. No CE test fee for AACN members. This test expires on October 1, 2019.
American Association of Critical-Care Nurses is an accredited provider of continuing nursing education by the American
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