Histopathology 2017, 70, 8193. DOI: 10.1111/his.
13082
REVIEW
The histopathological evaluation of drug-induced liver injury
David E Kleiner
Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
Kleiner D E
(2017) Histopathology 70, 8193. DOI: 10.1111/his.13082
The histopathological evaluation of drug-induced liver injury
Drug-induced liver injury (DILI) presents unique chal-
lenges to the pathologist. It is not only an uncommon
reason for liver biopsy, but the pathology of DILI is
spread across the entire spectrum of hepatic injury
patterns. It is important for the pathologist to suspect
DILI when the histological changes are unusual or
out of synchronicity with the patients history. A
systematic evaluation approach will yield the most
information. It begins with the characterization of the
general pattern of injury which, for most cases, will
be found in a handful of necroinflammatory and cho-
lestatic patterns. A careful assessment of the severity
Keywords: acute hepatitis, acute liver failure, cholestasis, hepatic necrosis, hepatotoxicity
Introduction
Drug-induced liver injury (DILI) is an uncommon but
important cause of liver injury. Evidence of DILI has
led to the withdrawal of drugs from the market
(troglitazone1), denial of approval (ximelagatran2) or
cessation of drug development (fialuridine3). The US
Food and Drug Administration has issued black box
warning and safety alerts for a number of other drugs
that have been implicated in serious liver injury
(www.fda.gov/Drugs/DrugSafety/default.htm). The
incidence of DILI is hard to assess across the general
population because of difficulties in collecting and
adjudicating cases in a quantitative way. The first
study that attempted to capture all cases of DILI in a
general population was the study by Sgro et al.4 They
Address for correspondence: D E Kleiner, Senior Research
Physician, Chief Post-Mortem Section, Laboratory of Pathology,
National Cancer Institute, 10 Center Drive, Building 10, Room
2S235, MSC1500, Bethesda, MD 20892, USA. e-mail:
kleinerd@mail.nih.gov
Published 2016. This article is a U.S. Government work and is in the public domain in the USA.
of injury across the various anatomic compartments
will provide information on the probable natural his-
tory of the injury. Correlation of liver injury with the
patients medication history and clinical findings will
help to narrow the differential diagnosis, particularly
when it is recognized that most drugs have a limited
range of histological findings and vary in their
propensity to cause injury. This review provides an
overview of the assessment of the liver biopsy and its
use to confirm or exclude particular drugs as con-
tributing to the patients liver injury.
trained general practitioners and specialists to recog-
nize incident cases of DILI in the Ni
evre district of
France. They identified 34 cases in a 3-year period
for a standardized incidence rate of 8.1 per 100 000
population. More recently, Bjornsson et al.5 con-
ducted a population-based study in Iceland, where
the medical system permitted not only a quantitative
estimate of all cases of DILI, but was also able to pro-
vide information on the numbers of prescriptions
filled during the same time-period. A total of 96 cases
were identified in a 2-year period, leading to a crude
annual incidence of 19.1 per 100 000 population.
Population-based estimates are generally higher than
the incidence estimated from reports to regulatory
authorities.4
When the pathologist receives a liver biopsy for
evaluation, DILI may or may not be included in the
differential diagnosis provided in the clinical history.
When a patient presents with acute liver injury, the
clinical work-up may be incomplete at the time of the
biopsy. When a biopsy is ordered by a non-liver dis-
ease specialist, the referring physician may be looking
82 D E Kleiner
for guidance from the pathologist as to next steps.
Therefore, it is important that the pathologist be alert
to the possibility of DILI and proceed to evaluate the
histological changes in a systematic fashion that will
provide the greatest insight into both possible aetiolo-
gies and estimation of severity.
Histological spectrum
The histological spectrum of DILI is broad, and it is
stated frequently that drug injury can mimic any type
of non-drug injury in the liver. While this may be a
true statement, the patterns of injury seen in DILI
vary from what one might observe in a typical sam-
pling of non-DILI cases. In a landmark paper on the
pathology of DILI, Hans Popper categorized the cases
into six basic injury patterns: zonal injury (necrosis),
uncomplicated cholestasis, non-specific hepatitis with
or without cholestasis (acute) viral hepatitis-like
(including progression to massive necrosis), non-
specific reactive hepatitis and steatosis.6 The most
common patterns in this study were the acute viral
hepatitis-like pattern (39%) and hepatitis with
cholestasis (32%). In contrast, in a practice in which
most medical liver disease biopsies are performed to
assess the common chronic liver diseases, these pat-
terns would stand out as unusual. After this initial
study, there have been other histological categoriza-
tions of DILI. Most recently, the Drug-Induced Liver
Injury Network (DILIN) has published histological
findings from its survey of 249 cases of suspected
DILI.7 Table 1 highlights the main histological pat-
terns used in the study and the frequencies of each
pattern. Of note, 5% of cases could not be classified
clearly as one of the predefined patterns, and some
patterns were not used at all. In particular, steatosis
was a common finding (65% of biopsies had at least
5% steatosis), but no cases had steatosis as the sole
dominant pattern. This was also true in Poppers ser-
ies only one of 155 cases showed steatosis as the
only pattern of injury.
The necroinflammatory injury patterns in DILI
include zonal necrosis, submassive to massive necro-
sis, acute and chronic hepatitis and granulomatous
hepatitis. In zonal necrosis, there is confluent or
coagulative necrosis of hepatocytes in zone 3, often
with little or no lymphocytic inflammation in the por-
tal areas or parenchyma (Figure 1A). Macrophages
may accumulate within and around the edges of the
necrotic zones. Acetaminophen (paracetamol) is the
classic cause of zonal necrosis, but this pattern has
been observed with chemotherapeutic agents and
other drugs. In massive necrosis, there is pan-acinar
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
hepatocyte necrosis involving multiple contiguous
acini. It may result either from severe zonal necrosis
that extends to involve whole acini or from severe
acute hepatitis. It was seen in only one biopsy in the
DILIN study, due possibly to the exclusion of patients
with acute liver failure,7 but was a much more fre-
quent finding in the Popper study,6 where it was
included in the acute viral hepatitis pattern and
accounted for 25% of all cases. Sections from livers
with massive necrosis show complete loss of hepato-
cytes, with collapse of parenchyma between the resid-
ual portal areas. Ductular reaction extends from the
edges of the portal areas towards central veins. The
amount of portal inflammation varies from sparse to
aggregates of lymphocytes. The residual parenchyma
may show evidence of regeneration or may show
ongoing injury, depending on when the biopsy was
obtained relative to the event.
The patterns of acute and chronic hepatitis in DILI
mimic their viral counterparts. Acute hepatitis is
characterized by lobular-dominant inflammation (Fig-
ure 1B). At the severe end of the spectrum the foci of
lobular inflammation are so numerous that they
become confluent, and are often associated with areas
of necrosis. In the chronic hepatitis pattern, the
inflammation is located mainly in the portal areas,
similar to the distribution of inflammation in chronic
hepatitis B or C (Figure 1C). In milder cases of either
pattern, the injury approaches that of a mild reactive
hepatitis and it may be difficult to classify the pattern
as either acute or chronic. In the DILIN study, cases
with acute or chronic hepatitis and cholestasis were
lumped into the cholestatic hepatitis pattern, dis-
cussed below, although it is not unreasonable to
group together cases of acute hepatitis whether or
not they show cholestasis. Many drugs have been
implicated in causing both acute or chronic hepatitis
patterns. Classic agents causing an acute hepatitis-
like injury include isoniazid8 and halothane,9 but
more recently the class of statins10 has been associ-
ated with acute hepatitis. In contrast, agents associ-
ated with chronic hepatitis include those with
features of autoimmunity, such as nitrofurantoin and
minocycline.1113 The distinction between idiopathic
autoimmune hepatitis (AIH) and drug-induced
autoimmune hepatitis (DIAIH) can be difficult, and
there are no absolute criteria. In studies that have
compared idiopathic AIH with DIAIH, cases attributed
to drug injury tend to have only early-stage fibro-
sis.11,12 In addition, Suzuki et al. showed that having
a prominent lobular lymphocytic infiltrate or canalic-
ular cholestasis without typical features of AIH (mod-
erate portal inflammation, hepatocyte rosettes, portal
 Drug-induced liver injury 83

Table 1. Histopathological patterns observed in drug-induced liver injury (DILI)

Pattern Characteristic features Non-DILI differential Frequency*

Necroinflammatory patterns

Zonal coagulative Zone 3 or 1 coagulative necrosis, usually Hypoxicischaemic injury (zone 3) 3%

necrosis without significant inflammation

Submassive to Extensive pan-acinar necrosis, variable Fulminant viral or autoimmune hepatitis 0.4%
massive necrosis inflammation

Acute (lobular) Lobular-dominant inflammation with/without Acute viral or autoimmune hepatitis 21%
hepatitis confluent or bridging necrosis; no cholestasis

Chronic (portal) Portal-dominant inflammation, interface Chronic viral or autoimmune diseases, early 14%
hepatitis hepatitis (also includes mononucleosis PBC/PSC, mononucleosis-associated hepatitis
pattern), with or without portal-based fibrosis;
no cholestasis

Granulomatous Inflammation dominated by granulomas (usually Sarcoidosis, PBC, fungal and mycobacterial, 1%
hepatitis non-necrotizing), portal or lobular atypical bacterial infections

Cholestatic injury patterns

Acute cholestasis Hepatocellular and/or canalicular cholestasis in Sepsis, acute large duct obstruction 9%
(intrahepatic, zone 3; may show duct injury, but little
canalicular) inflammation

Chronic cholestasis Periportal cholate stasis, periportal fibrosis, PSC, PBC, chronic cholestatic injury/AIH 10%
copper accumulation, duct sclerosis or injury, overlap, chronic large duct obstruction
duct loss

Cholestatic hepatitis Acute or chronic hepatitis pattern plus zone 3 Acute viral hepatitis, large duct obstruction 29%
cholestasis

Steatotic injury patterns

Steatosis, Predominantly microvesicular steatosis, Alcohol, fatty liver of pregnancy 0.4%

microvesicular inflammation variable

Steatosis, Predominantly macrovesicular steatosis without Very common finding in general population,
macrovesicular significant portal or lobular inflammation, no alcohol, obesity, diabetes
cholestasis

Steatohepatitis Zone 3 ballooning injury, sinusoidal fibrosis, Common finding in general population, alcohol, 2.4%
Mallory bodies, variable inflammation and obesity, diabetes
steatosis, no cholestasis

Vascular injury patterns

Sinusoidal obstruction Occlusion or loss of central veins, thrombosis, 1%

syndrome/veno- with or without central haemorrhage and
occlusive disease necrosis

Hepato-portal Disappearance of portal veins Idiopathic obliterative portal venopathy,

sclerosis idiopathic arteriohepatic dysplasia

Nodular regenerative Diffuse nodular transformation, with or without Collagen-vascular diseases, lymphoproliferative 0.4%
hyperplasia mild inflammation and sinusoidal fibrosis diseases (but perhaps because of DILI)

Sinusoidal dilation/ Sinusoidal alterations with/without mild lobular Artefactual, acute congestion, bacillary
peliosis inflammation, sinusoidal fibrosis angiomatosis, nearby mass lesions

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84 D E Kleiner
Table 1. (Continued)
Pattern Characteristic features
Cytoplasmic alterations
Glycogenosis Diffuse hepatocyte swelling with very pale
bluish-gray cytoplasm
Ground-glass change Diffuse homogenization of cell cytoplasm due to
induction of smooth endoplasmic reticulum
PBC, Primary biliary cholangitis; PSC, Primary sclerosing cholangitis; AIH, Autoimmune hepatitis; HAART, Highly active antiretroviral ther-
apy.
*Frequencies adapted from Kleiner et al.7 Approximately 5% of cases had complex injury pattern not easily categorized.
plasma cells infiltrates or lobular eosinophils)
favoured the diagnosis of drug injury despite clinical
and serological features of AIH.12 The distinction
between AIH and DIAIH is important because of the
clinical implications although both types may
respond to steroids, patients with DIAIH may be able
to be tapered off immunosuppression successfully
while patients with AIH have a high relapse rate.11
Granulomatous hepatitis due to drugs is an unu-
sual finding, although granulomas, particularly
microgranulomas, are a common finding. Epithelioid
granulomas were seen in 5% of the DILIN cohort,
usually as a component of another pattern of injury
(Figure 1D). In case series of hepatic granulomas, the
granulomas were attributed to drug injury in 19%
of cases.14,15 In granulomatous hepatitis, the granu-
lomas are the predominant form of inflammation.
They may be in portal areas or the parenchyma, but
are always non-necrotizing. Certain drugs, such as
phenytoin16 and allopurinol,17 are associated com-
monly with granulomatous inflammation.
Cholestastic patterns of injury constitute the other
major class of drug injury patterns in the liver. Visi-
ble bile in canaliculi or hepatocyte cytoplasm was evi-
dent in just more than half of the DILIN cohort.
Together with the necroinflammatory patterns of
acute and chronic hepatitis, these five patterns
accounted for 83% of all of the cases in the DILIN
cohort. The cholestatic patterns fall into three basic
categories: acute (bland or intrahepatic) cholestasis,
chronic cholestasis and a mixed pattern of inflamma-
tion, hepatocellular injury and cholestasis termed
cholestatic hepatitis. Acute cholestasis is the classic
injury pattern of the sex steroids, both oestrogens
and androgens.18 Sections show bile plugs in canali-
culi and bile accumulation in hepatocytes, particu-
larly in zone 3 (Figure 2G). Inflammation is mild and
consists mainly of collections of macrophages in areas
of cholestasis. Chronic cholestatic DILI shows features
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
Non-DILI differential Frequency*
Type I diabetes 1%
Medications (phenobarbital, HAART)
of chronic cholestasis such as cholate stasis (pseudox-
anthomatous change) and periportal copper accumu-
lation, that may also be seen in diseases such as
primary biliary cholangitis (formerly primary biliary
cirrhosis) or primary sclerosing cholangitis (Fig-
ure 2H). Duct injury is a common finding in DILI,
present to some degree in more than half of biopsies,7
and so cannot be used as a specific feature in chronic
cholestatic DILI; however, duct loss was seen in
56% of the DILIN cohort, and was the most frequent
finding in biopsies from cases of DILI with very pro-
tracted recovery times.19
Cases that combine cholestasis with some degree of
significant inflammation or hepatocellular injury were
the most common pattern of liver injury observed in
the DILIN series.7 This pattern, termed cholestatic
hepatitis, encompasses a wide spectrum of inflamma-
tion and cholestasis, from cases of acute hepatitis that
have a cholestatic component to cases with minimal
inflammation that approach the definition of acute
cholestasis above (Figure 2EF). The degree of inflam-
mation in cholestatic hepatitis tends to be less severe
than is seen in cases of pure acute or chronic hepati-
tis. Similarly, fewer cases have significant numbers of
plasma cells in the infiltrate, but more cases will
show neutrophilic infiltrates. Cholestatic hepatitis is
the typical pattern of injury for many antibacterials,
antipsychotics and the monoamine oxidase inhibitors.
Steatosis is a common finding in many biopsies,
whether due to drug injury or the well-known aetiolo-
gies of obesity, diabetes or alcohol. Some drugs will
induce steatosis via more typical mechanisms, by
leading to weight gain, diabetes or acquired lipodys-
trophy. A limited set of agents has been associated
with steatohepatitis-like injury, most notably
methotrexate,20 tamoxifen21 (Figure 2A) and amio-
darone.22 The distribution of steatosis, fibrosis and
MalloryDenk bodies may differ from the typical zone
3 injury pattern of non-alcoholic steatohepatitis.
 Drug-induced liver injury 85

A B

C D

E F

G H

Figure 1. Common necroinflammatory and cholestatic patterns of injury. A, Zone 3 necrosis associated with mithramycin. There is coagula-
tive necrosis with haemorrhage in zone 3, but little or no inflammation. B, Acute hepatitis associated with nitrofurantoin. There is a diffuse
lobular infiltrate associated with lobular disarray and hepatocyte rosette formation. C, Chronic hepatitis-like injury associated with a green
tea containing herbal. There is dense lymphoid portal inflammation and interface hepatitis with only occasional foci of lobular inflammation.
D, Granulomatous hepatitis associated with allopurinol. Poorly formed granulomas were scattered throughout the biopsy, seen here in a por-
tal area. E, F, Cholestatic hepatitis associated with cefazolin. There is canalicular and hepatocellular cholestasis in zone 3 (E) while the portal
areas show dense inflammation and duct injury (F). G, Acute cholestasis associated with an anabolic steroid. There is prominent cholestasis,
but little inflammation within the parenchyma or the portal areas (not shown). H, Chronic cholestasis due to amoxicillinclavulanate. In a
biopsy taken 8 months after onset due to persistent hepatic abnormalities, there is mild inflammation and only mild pseudoxanthomatous
change; however, the copper stain was strongly positive (inset).

Amiodarone injury is associated with MalloryDenk special subset of steatotic DILI, almost always associ-
bodies in zone 1 and may not show typical ballooning ated with mitochondrial toxicity. In microvesicular
hepatocellular injury.22 Microvesicular steatosis is a steatosis the hepatocyte cytoplasm shows a foamy
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
86 D E Kleiner

A B

C D

Figure 2. Drug-induced liver injury-associated steatohepatitis and vascular injury. A, Steatohepatitis associated with tamoxifen. There is mild
to moderate steatosis and ballooned hepatocytes. B, Peliotic changes associated with anabolic steroids. There is loss of integrity in the sinu-
soids associated with the formation of small irregular cystic spaces. C, Veno-occlusive disease associated with haematopoietic stem cell trans-
plantation preparative regimen. This Masson trichrome stain shows a central vein almost completely occluded by loose collagen, fibroblasts
and trapped red blood cells. The surrounding parenchyma shows haemorrhage and necrosis. D, Nodular regenerative hyperplasia associated
with oxaliplatin. This reticulin stain shows nodular expansion of liver plates bounded by compressed, atrophic liver plates.

change in which the size of the vacuoles is very small
and regular. The change is present in most of the
hepatocytes and can be seen with macrovesicular
steatosis. Patients may present with lactic acidosis and
hepatomegaly, and despite severe hepatic failure do
not have widespread hepatic necrosis.3,23 Microvesicu-
lar steatosis is the characteristic pattern of injury of
certain drugs, including nucleoside analogues (fi-
aluridine, didanosine, zidovudine and stavudine),2326
valproic acid,27 tetracycline (intravenous formula-
tions),28 linezolid29 and aspirin (Reyes syndrome).30
Vascular injury has its roots in endothelial injury,
and may vary from subtle to severe. In veno-occlusive
disease/sinusoidal obstruction syndrome (VOD/SOS),
there is severe damage to sinusoidal and hepatic
venular endothelial cells. This leads to obstruction of
the sinusoids in zone 3 and gradual occlusion of the
hepatic venules with loose collagen and cells (Fig-
ure 2C). Ischaemic necrosis of hepatocytes may follow,
and patients will present with abrupt signs of portal
hypertension and hepatic failure. VOD/SOS is seen
most often as a complication of chemotherapy,31 in
particular the preparative regimens used for bone mar-
row transplantation. At the other end of the spectrum
are the patterns of hepatoportal sclerosis, nodular
regenerative hyperplasia and sinusoidal dilation. In
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
hepatoportal sclerosis there is narrowing or loss of por-
tal veins in some portal areas sometimes coupled with
dilation of veins in other portal areas. Nodular regen-
erative hyperplasia may be a consequence of hepato-
portal sclerosis or it may be seen in cases with
apparently normal portal veins. Reticulin stains are
useful in showing the nodular variation in hepatocyte
plate width (Figure 2D). Chemotherapeutics, particu-
larly oxaliplatin32 and the purine analogues,33,34 are
associated frequently with both of these patterns.
Peliosis is characterized by blood-filled spaces in the
hepatic parenchyma in which the endothelial lining
has been lost (Figure 2B). Peliosis and sinusoidal dila-
tion are uncommon, but may be associated with both
oral contraceptives and anabolic steroids.
The last category of changes that may be seen in
biopsies taken to evaluate DILI are pigment accumu-
lations and alterations of hepatocyte cytoplasm. Of
these, the cytoplasmic alterations of ground glass
cytoplasm and glycogenosis deserve special mention.
Ground glass cell change has been related to prolifer-
ation of endoplasmic reticulum. The hepatocytes dis-
play a homogeneous, finally granular eosinophilic
cytoplasm. This change has been related classically to
phenobarbital therapy, but has also been observed in
other situations, including patients on long-term

highly active antiretroviral therapy.35 Biopsies may
show other non-specific findings, including minimal
inflammation. Glycogenosis, in which hepatocytes are
swollen with lakes of pale-staining glycogen, is seen
in glycogen storage diseases and uncontrolled
diabetes.36 However, glycogenosis may also be seen
following high-dose corticosteroid therapy, where it
can lead to very elevated aminotransferases.37 When
a biopsy is performed for persistently elevated amino-
transferases after steroid therapy, glycogenosis may
be seen as the only finding or in the background of
unresolved hepatitis. The mechanism of glycogen
accumulation is unclear, but may be related to shifts
in glycogen metabolism induced by the corticosteroids
similar to the effects of uncontrolled diabetes.36
Recent highlights on the drugs involved in
liver injury
In the last couple of years there have been a number
of advances in the understanding of DILI. A compre-
hensive survey of case reports and case series by
Bjornsson and Hoofnagle led to an index of the most
frequently reported drugs implicated in liver injury.38
Table 2 highlights the list of drugs with more than
50 cases reported in the literature, organized by drug
class and annotated with the most commonly associ-
ated histological patterns of injury. This list does not
include the few drugs known to cause dose-related
toxicity, including acetaminophen, aspirin, niacin
and vitamin A, as well as the intravenous forms of
tetracycline, methylprednisone and buprenorphine.
A total of 346 drugs were catalogued, mainly from
drugs used for infection, central nervous system disor-
ders or cardiovascular disorders. Although drugs
approved since 2010 were not included, the benefit
of this catalogue is that it relates to the likelihood of
a drug being associated with liver injury. Actual inci-
dence figures (in terms of DILI events/prescription)
are difficult to estimate due to issues involved in iden-
tifying DILI events correctly in a population for which
prescription information is known. Nevertheless, a
recent population-based study from Iceland has shed
light on some DILI risk numbers by individual drugs.5
During a 2-year period, the investigators identified 96
cases of DILI with an age-standardized incidence that
increased from 8.5 per 100 000 inhabitants for
patients aged 1524 years to 41.0 per 100 000 for
those aged more than 80 years. Based on the number
of prescriptions filled during that time-period, they
were able to estimate the incidence of injury for eight
medications. Of these, the incidence varied from six
per 100 000 prescriptions for doxycycline to 752 per
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
Drug-induced liver injury 87
100 000 prescriptions for azathioprine. The drug
combination amoxicillinclavulanate had the highest
number of cases, but had an intermediate incidence
of 43 per 100 000 prescriptions.
A recent case-series on cephalosporin injury from
Alqahtani et al. highlighted previously unrecognized
toxicity from the commonly used drug cefazolin.39
Cephalosporins have generally been considered safer
than other antibacterials with respect to the risk of
DILI, with the class as a whole contributing to fewer
than 1% of cases in large national series.5,40,41 The
US DILIN network recently reported a series of 33
cases of cephalosporin injury, 19 of which were asso-
ciated with a single intravenous dose of cefazolin.39
These patients present with pruritus and jaundice
between 1 and 3 weeks after the drug is given, usu-
ally for minor surgery. Biopsies showed cholestatic
hepatitis with generally mild portal and lobular
inflammation and prominent zone 3 cholestasis.
Because this drug is used for antibacterial prophylaxis
at the time of surgery, it can be overlooked easily in
a drug history.
Examples of DILI due to immunomodulatory agents
and kinase inhibitors have become common in the
last few years as more of these agents are approved
for use. Some immunomodulatory agents, such as the
interferons, have been in use for decades and have
well-described hepatotoxicity.42 The interleukin recep-
tor antagonists anakinra43 and tocilizumab44 have
both been associated with liver injury that manifests
histologically as acute hepatitis with or without
cholestasis. The tumour necrosis factor antagonists,
which include infliximab, etanercept and adali-
mumab, have been reported to cause severe hepatitis
in either an acute or chronic hepatitic pattern,45 as
well as predisposing patients to reactivation of hepati-
tis B infections. The anti-CD33 monoclonal antibody
gemtuzumab has been linked to veno-occlusive dis-
ease,46 even in patients who have not undergone
haematopoietic stem cell transplantation.47 This effect
may be related to direct toxicity of the antibody to
hepatic cells, as CD33 has been demonstrated on both
Kupffer cells and hepatocytes.48 The anti-cytotoxic T
lymphocyte antigen-4 (CTLA-4) monoclonal antibod-
ies ipilimumab and tremelimumab, along with the
anti-programmed death 1 (PD1) antibodies pem-
brolizumab and nivolumab, are recently approved
agents that act by blocking immune checkpoints that
maintain T cell suppression. Ipilimumab has been
implicated in causing acute hepatitis-like injury that
is thought to be due to immune activation rather
than toxicity in the usual sense,49 consistent with its
mechanism of action. In contrast, the anti-PD1
88 D E Kleiner

Table 2. Histopathological injury patterns of drugs associated most frequently with hepatotoxicity38

Drug class Agent Histological injury pattern

GI anti-inflammatory Sulphasalazine Acute hepatitis, cholestatic hepatitis, granulomas, zonal necrosis

Anti-thrombotic Ticlopidine Chronic cholestasis (VBDS), cholestatic hepatitis

Anti-arrhythmic Quinidine Cholestatic hepatitis, granulomas, zonal necrosis

Amiodarone Steatosis, steatohepatitis, phospholipidosis

Anti-hypertensive Methyldopa Acute/chronic hepatitis, zonal necrosis

Hydralazine Acute/chronic hepatitis, cholestatic hepatitis, granulomas

Lipid-lowering Simvastatin Acute hepatitis, cholestatic hepatitis

Atorvastatin

Sex steroids Oestrogens Acute cholestasis, sinusoidal dilation, peliosis, BuddChiari

Androgens Acute cholestasis, Sinusoidal dilation, peliosis, NRH

Anti-thyroidal Propylthiouracil Acute/chronic hepatitis, zonal necrosis

Anti-microbials Minocycline Chronic hepatitis

Floxacillin (flucloxacillin) Acute cholestasis, chronic cholestasis (VBDS)

Amoxicillinclavulanate Cholestatic hepatitis, chronic cholestasis (VBDS)

Sulphonamides Cholestatic hepatitis, acute hepatitis, granulomas,

chronic cholestasis (VBDS)

Trimethoprimsulphamethoxazole Cholestatic hepatitis, acute hepatitis

Erythromycin Acute to chronic cholestasis, acute hepatitis

Telithromycin Acute hepatitis, zonal necrosis

Nitrofurantoin Acute/chronic hepatitis, zonal necrosis

Ketoconazole Cholestatic hepatitis, acute hepatitis, necrosis

Anti-mycobacterial Rifampin Acute hepatitis, zonal necrosis, cholestatic hepatitis

Isoniazid Acute/chronic hepatitis, fulminant hepatitis

Pyrazinamide Acute/chronic hepatitis, necrosis

Anti-viral Didanosine Microvesicular steatosis, granulomas

Nevirapine Acute/chronic hepatitis, cholestatic hepatitis, zonal necrosis

Efavirenz Acute/chronic hepatitis

Anti-neoplastic Busulfan Cholestatic hepatitis, VOD

Methotrexate Acute/chronic hepatitis, steatosis, steatohepatitis, fibrosis/cirrhosis

Mercaptopurine Cholestatic hepatitis, chronic cholestasis, NRH, sinusoidal dilation, SOS

Thioguanine Acute cholestasis, cholestatic hepatitis, NRH, sinusoidal dilation, SOS

Floxuridine Cholestatic hepatitis, chronic cholestasis, VOD

Anti-androgen Flutamide Cholestatic hepatitis

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 Drug-induced liver injury 89

Table 2. (Continued)
Drug class Agent Histological injury pattern

Immunostimulant Interferon alpha Granulomas

Interferon beta Acute/chronic hepatitis

Immunosuppressive Infliximab Acute/chronic hepatitis, cholestatic hepatitis, acute cholestasis, HBV reactivation

Azathioprine Acute cholestasis, cholestatic hepatitis, NRH, sinusoidal dilation, VOD

Anti-inflammatory Sulindac Cholestatic hepatitis, acute hepatitis, necrosis, steatosis

Diclofenac Acute/chronic hepatitis, cholestatic hepatitis

Ibuprofen Acute hepatitis, cholestatic hepatitis, chronic cholestasis (VBDS), necrosis

Nimesulide Acute/chronic hepatitis, cholestatic hepatitis, acute cholestasis, necrosis

Gold Acute hepatitis, cholestatic hepatitis, chronic cholestasis (VBDS), necrosis

Muscle relaxant Dantrolene Acute/chronic hepatitis, cholestatic hepatitis, fibrosis/cirrhosis

Anti-gout Allopurinol Cholestatic hepatitis, acute hepatitis, granulomas

Anaesthetic Halothane Zonal necrosis, acute/chronic hepatitis, cholestatic hepatitis

Anti-convulsant Phenytoin Acute/chronic hepatitis, cholestatic hepatitis, granulomas, chronic cholestasis

Carbamazepine Acute/chronic hepatitis, cholestatic hepatitis, granulomas, necrosis

Valproic acid Zonal necrosis, cholestatic hepatitis, microvesicular steatosis

Anti-addictive Disulfiram Acute hepatitis

VBDS, Vanishing bile duct syndrome; VOD, Veno-occlusive disease; NRH, Nodular regenerative hyperplasia; HBV, Hepatitis B virus;
GI, Gastrointestinal; SOS, Sinusoidal obstruction syndrome.

antibodies have not yet been reported to cause histo-

logical liver injury, although approximately 12%
have significant elevations in aminotransferases.50
The protein kinase inhibitors are a new class of
antineoplastic agents that target specific pathways
that are usually involved in the unrestrained growth
of tumours. Since the introduction of imatinib in
2001, more than 25 protein kinase inhibitors have
been approved for use in the United States, with the
majority approved since 2010. A number of them,
including bortezomib, erlotinib, imatinib, lapatinib,
pazopanib and sorafenib, have been the subject of
case reports and case-series of hepatotoxicity. They
all have a similar spectrum of liver injury. Imatinib
DILI is probably the best-characterized histologically.
It causes a severe acute hepatitis, sometimes with
areas of confluent or multi-acinar necrosis.51,52
Bortezomib53 and pazopanib have also been reported
to cause an acute hepatitis with cholestasis.54 It is
likely that the other members of this class will also
demonstrate some degree of hepatotoxicity, but have
not been in general use long enough for cases to
have been reported.
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
The role of the liver biopsy in DILI
Unlike other liver diseases, such as chronic viral hep-
atitis or non-alcoholic steatohepatitis, the liver biopsy
does not have a defined role in DILI and its utility
has never been assessed formally. Nevertheless, the
biopsy can play an important role in the evaluation
of DILI. A biopsy may be performed to aid in diagno-
sis by eliminating (or confirming) competing causes
of liver injury and by correlation with known pat-
terns of DILI.55 An unsuspected diagnosis of DILI
may be made by the astute pathologist alert to the
possibility particularly when confronted with unu-
sual histological findings. When recently approved
drugs or drugs undergoing premarket evaluation are
associated with DILI, a biopsy can provide informa-
tion on the nature (and possibly the mechanism) of
the injury. In the case of fialuridine toxicity, changes
of microvesicular steatosis in biopsies rapidly drew
the attention of investigators to the possibility of
mitochondrial injury.3 In comparing cases of sus-
pected DILI that were adjudicated eventually as DILI
to those that were deemed less likely, the DILIN
90 D E Kleiner

group found that DILI was associated more often with on biopsy has evidence of a second process, which
eosinophilic infiltrates, and such cases were less likely may be DILI. The histological differential diagnosis
to have ductular reaction or hepatocellular iron.7 may lead to further clinical testing, such as imaging,
However, these findings represented only relative dif- to exclude obstruction, or serological testing for viral
ferences that may not be useful in individual cases. or autoimmune diseases. A National Institutes of
In addition to pattern of injury, the biopsy provides Health (NIH) workshop on clinical evaluation and
information on the severity of the injury, which may reporting of DILI identified a number of clinical find-
inform prognosis. Certain features, including the ings that may be useful in excluding competing
degree of necrosis and fibrosis and presence of neu- causes for liver injury and which may provide useful
trophils, ductular reaction and microvesicular steato- advice to the clinical team considering a potential
sis, are associated with a greater chance of liver case of DILI.60 Table 3 lists some of the more
failure,7,56,57 while the presence of eosinophils and unusual possibilities to consider to explain particular
granulomas is associated with a milder clinical patterns of injury.
course.7,56 Absence of significant injury may permit If the non-DILI competing causes of injury can be
the continued use of a medication. For example, the excluded, the list of recent medications should be
liver biopsy has been used in the past to decide whether reviewed. Herbals and dietary supplements should
methotrexate can be continued safely.58 A biopsy may also be considered, particularly when the biopsy
also provide clues to mechanism. Microvesicular shows acute cholestasis (associated with body-building
steatosis suggests mitochondrial injury,59 while zonal supplements) or acute hepatitis with or without
necrosis in the absence of inflammation suggests the
accumulation of a toxic metabolite.
When DILI is suspected the pathologist should first Table 3. Uncommon competing causes of liver injury
assess the biopsy to determine the overall pattern of
injury. As noted above, most DILI falls into one of the Feature or pattern of injury Differential diagnosis
necroinflammatory or cholestatic patterns of injury. Chronic hepatitis-like EBV-related hepatitis
A careful assessment of all the hepatic compartments or mild non-specific
should be made, with attention to the central veins, hepatitis CMV-related hepatitis
bile ducts and the character of the inflammation. Spe- (mononucleosis pattern)
cial stains can be extremely helpful. In particular, Collagen-vascular disease
staining for copper using either a rhodanine stain or
Coeliac disease
one of the copper-associated protein stains (orcein,
Victoria blue) can help to identify subtle cases of Common variable
chronic cholestasis. Staining for bile ducts and immunodeficiency
ductules using antibodies to keratin 7 or 19 can be Coagulative necrosis Herpetic hepatitis
useful to highlight these structures, particularly in
the presence of marked inflammation. Reticulin and Adenoviral hepatitis
Masson trichrome stains can help to differentiate Granulomatous hepatitis Atypical bacterial infection
necrotic collapse from fibrosis.
Once the pattern of injury has been defined, the Rickettsial infection
patients history should be reviewed both for medica- Acute cholestasis Benign recurrent intrahepatic
tions likely to cause injury and to identify potential cholestasis
competing causes of liver injury. DILI is always a
Chronic cholestasis and Ischaemic cholangitis
diagnosis of exclusion and the pathologist plays an ductopenia
important role in identifying histological changes Idiopathic adulthood ductopenia
that can be explained by pre-existing non-DILI condi- Langerhans cell histiocytosis
tions. In particular, chronic hepatitis and fatty liver
disease are so prevalent in the population that the IgG4-related systemic sclerosis
burden of proof should be on demonstrating that the Progressive familial intrahepatic
changes are not due to a mundane cause. Similarly, cholestasis
it is also possible to identify histological lesions that
Cholestatic hepatitis Progressive familial intrahepatic
are not explained by underlying disease. A patient cholestasis
with early-stage chronic viral hepatitis or non-
alcoholic steatohepatitis and canalicular cholestasis EBV, EpsteinBarr virus; CMV, Cytomegalovirus; Ig, Immunoglobulin.

Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.

cholestasis (associated with green tea containing sup-
plements and other weight loss supplements). Agents
commenced in the prior 6 weeks to 6 months are most
often involved. Some drugs, such as antibiotics, may
have been given in a short course that ended before
any injury became evident. For example, amoxicillin
clavulanate-related injury is recognized typically
1 week to 10 days after the last dose of the medica-
tion.61 Other drugs may cause clinically apparent
injury only after months to years of therapy. This is
particularly true of those that are associated with
DIAIH (e.g. nitrofurantoin and minocycline) or that
are associated with chronic but subclinical injury (e.g.
amiodarone, tamoxifen and methotrexate). Patients
are treated frequently with multiple medications which
may have differing propensities to cause injury. The
drug tables in the literature review by Bjornsson and
Hoofnagle may be useful in eliminating the less likely
possibilities. The online resource LiverTox (http://liver-
tox.nlm.nih.gov/), maintained by the US National
Library of Medicine, is a drug-by-drug description of
clinical presentations with case examples extracted
from the literature. Comparison of the patients clinical
presentation and histological findings can help to nar-
row the list by correlation with known patterns of bio-
chemical and histological injury. Through careful
evaluation of the pathology, elimination of competing
causes of injury and evaluation of the list of medica-
tions for the propensity and patterns of injury, the
pathologist can provide a valuable consultative service
to the clinical team in cases of suspected DILI.
Conclusion
The pathologists evaluation of the liver biopsy in
cases of DILI can provide important information on
pattern and severity of injury, which can be used to
help to narrow down the differential diagnosis and
provide evidence for a causal association between a
particular drug and the patients liver injury. Severity
of injury can provide information on prognosis and
has the potential to help guide therapy at least in
the case of continuing a beneficial drug such as
methotrexate. The initial assessment should be as
unbiased by clinical information as possible, so that
nothing is overlooked. Linking the injury to a partic-
ular agent requires the exclusion of competing causes
of injury and evaluation of the potential for injury of
the suspect agents as well as correlation with the
known patterns of injury and the typical timecourse
and biochemical presentation of the suspect agents.
In this way, the pathologist can make a valuable
Published 2016. This article is a U.S. Government work and is in the public domain in the USA, Histopathology, 70, 8193.
Drug-induced liver injury 91
contribution to diagnosing DILI as part of a multi-
disciplinary team.
Acknowledgement
This review was supported by the Intramural
Research Program of the NIH, National Cancer
Institute.
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