NotesHistological patterns in drug-induced liver disease

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Histological patterns in drug-induced liver disease

Unread post by nadae.benawi » 20 Apr 2012, 23:27

The diagnosis of drug-induced liver injury (DILI) is a
challenging problem, often confounded by incomplete
clinical information and the difficulty of eliciting exposure
to herbal products, over-the-counter agents and toxins.
The task is further rendered difficult on biopsy, as drugs
can mimic all the patterns found in primary liver disease.
Acute hepatitis, with or without cholestasis, is the most
common histological pattern of DILI, and drugs such as
acetaminophen are the leading causes of acute liver
failure. Most cases of DILI resolve on discontinuation of
the drug, but recovery can take months or rarely the
disease can progress despite drug withdrawal. Drugs
such as methotrexate can lead to chronic hepatitis and
cirrhosis, while others such as minocycline, nitrofurantoin
and methyldopa are implicated in autoimmune hepatitis.
Prolonged cholestasis and ductopenia resembling primary
chronic biliary disease can occur. Drug-induced steatohepatitis
is also an uncommon pattern, but is well
described with drugs such as amiodarone and irinotecan.
In the presence of risk factors such as obesity and
diabetes, some drugs such as tamoxifen, oestrogens and
nifedipine can precipitate or exacerbate steatohepatitis.
Other observed patterns include granulomatous hepatitis,
vascular injury (eg, sinusoidal obstruction syndrome), Ito
cell lipidosis and neoplasms (eg, adenomas).
Evaluation of liver biopsy for adverse drug reaction
is one of the most challenging problems in liver
pathology. Drug-related injury can mimic all the
patterns observed in primary liver disease, and an
unequivocal histological diagnosis is not possible in
the majority of cases. Inadequate clinical history
and multiple drugs being taken simultaneously
often compound the problem. It can be difficult to
elicit information about herbal agents, over-thecounter
medications, and exposure to household or
industrial toxins. The list of drugs associated with
hepatotoxicity is long, although the association of
many drugs with liver injury remains tenuous and
can be found only in case reports.
MECHANISMS OF INJURY
It is widely recognised that drug-induced liver
injury (DILI) is mediated by two chief mechanisms:
intrinsic and idiosyncratic hepatoxicity.
Intrinsic hepatotoxins cause hepatocellular damage
in a predictable dose-dependent manner directly by
the drug or indirectly by its metabolite. Some
drugs, such as acetaminophen, cause intrinsic
hepatotoxicity, but the majority of agents in this
category are industrial, household or environmental
toxins such as carbon tetrachloride and
alkaloids in mushrooms. The majority of drugs
lead to idiosyncratic liver injury and can be
classified into metabolic and immunological categories.
In the former, the drug is metabolised into a
toxic metabolite in predisposed individuals, while
the latter is akin to ‘‘drug allergy’’ or hypersensitivity
following sensitisation to the drug. In
general, intrinsic hepatotoxicity manifests with
hepatocellular necrosis with little inflammation,
while idiosyncratic drug reactions often show
inflammation-dominant hepatic injury.
ESTABLISHING DRUG AS THE CAUSATIVE AGENT
The temporal profile is crucial to establish the
diagnosis of DILI, as the onset of liver disease
follows drug ingestion. However, the manifestation
of liver toxicity may occur weeks or months
after drug ingestion and even after the drug has
been stopped. Liver enzyme elevations can persist
for up to several months after the drug has been
discontinued. In some instances, measurement of
serum levels of the drug or its metabolite can be
helpful in diagnosis, such as in acetaminophen
toxicity. Since the list of drugs capable of causing
liver injury is long, a systematic literature search
for each drug that the patient has been taking is
necessary. The case for DILI is strengthened if the
reported pattern of injury in the literature is in
keeping with the observed clinical and histological
picture. Rechallenge with the drug can help
establish the drug aetiology, but it is often not
done due to the inherent risk involved. Since
diverse histological patterns of DILI can mimic
virtually any primary liver disease, appropriate
imaging and laboratory tests are necessary to
exclude other aetiologies before the diagnosis of
DILI can be accepted.
Liver injury can be classified as hepatocellular,
cholestatic or mixed, based on criteria established
by the Council for International Organizations of
Medical Sciences (CIOMS)1 2 (table 1).
The CIOMS system also is used for causality
assessment of DILI by scoring parameters such as
time to onset of symptoms, laboratory data,
additional drug regimen, known toxicity of suspected
drug, non-drug causes, and response to
rechallenge. The total score is categorised into
ranges of causality: highly probable, probable,
possible, unlikely and excluded.3–5 The remaining
discussion is devoted to the patterns observed in
DILI with emphasis on morphological features,
common drugs and differential diagnosis for each
pattern (table 2).
ACUTE HEPATITIS
DILI accounts for ,10% of acute hepatitis and is
perhaps the most common cause of cholestatic
hepatitis.6 A wide variety of drugs can cause acute
hepatocellular injury (box 1).
Herbal and botanical drugs are an important but
often overlooked cause of hepatotoxicity (table 3).
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These are not regulated by the Food and Drug Administration
and hence are not subject to rigorous testing. More than 20 000
herbal products are marketed in forms including powders,
essential oils and teas, and more than $5 billion are spent on
these annually. Nearly 20% of American adults have used herbal
remedies, and usage is higher in selected groups including
Chinese,20 South African21 and Native American22 cultures.
Definitive identification of an herbal product can require
chemical analysis, as mistranslation or misidentification can
be an issue. Eliciting a detailed herbal history is imperative.23
Certain commonly consumed herbal agents now being investigated
for their hepatoprotective effects, such as turmeric
(Curcuma longa)24 and mate tea (Ilex paraguariensis),25 are listed
as potentially hepatotoxic in various patient literature. Finally,
contaminants of herbal supplements should be considered,
including heavy metals such as arsenic, cadmium, lead or
mercury.26
The following morphological patterns can be observed in
acute hepatocellular injury.
c Acute hepatitis. The hallmarks of acute hepatocellular
injury are portal and parenchymal inflammation, hepatocellular
injury, and/or necrosis (fig 1). By definition, fibrosis
is absent. Regenerative features such as binucleate hepatocytes
and thick cell plates are common. Prominent Kupffer
cells often are present in the sinusoids. The term ‘‘cholestatic
hepatitis’’ is used when these changes are accompanied
by cholestasis (see Acute cholestatic injury).
c Necrosis. Acute hepatocellular injury can result in necrosis
affecting single (spotty necrosis) or groups of hepatocytes
(confluent necrosis). In some cases, confluent necrosis can
be zonal and may be helpful in diagnosis. Centrizonal (zone
3) necrosis is characteristic of acetaminophen and
halothane, and toxins such as carbon tetrachloride.
Isolated necrosis affecting zones 1 and 2 is rare; toxins such
as cocaine and ferrous sulfate typically affect zone 1, while
beryllium has been implicated in zone 2 necrosis. When
extensive, confluent necrosis can lead to acute hepatic
failure.
c Resolving hepatitis. If biopsy is performed later in the
disease course, hepatocellular injury and inflammation may
be minimal (fig 2). The presence of numerous macrophages
in the sinusoids is a helpful clue for the diagnosis of
resolving hepatitis. The stain periodic acid–Schiff with
diastase can be used to highlight the macrophages (fig 3).
Table 1 CIOMS consensus criteria for terminology in drug-induced liver
injury
Terminology Criteria
Hepatocellular injury Isolated increase in ALT .twice normal, or ALT/ALP >5
Cholestatic injury Isolated increase in ALP .twice normal, or ALT/ALP (2
Mixed injury ALT and ALP are increased, and 2,ALT/ALP,5
Acute injury Above changes present for ,3 months
Chronic injury Above changes present for .3 months
Chronic liver disease This term is used only after histological confirmation
ALP, alkaline phosphatase; ALT, alanine aminotransferase; CIOMS, Council for
International Organizations of Medical Sciences.
Table 2 Overview of drug-induced liver injury patterns
Histological pattern Differential diagnosis Common drugs involved
Acute hepatitis and cholestatic hepatitis Viral hepatitis, autoimmune hepatitis, Wilson disease,
idiopathic
See table 3
Acute liver failure
Necrosis with marked inflammation Autoimmune hepatitis, viral hepatitis, Wilson disease Isoniazid, monoamine oxidase inhibitors,
anticonvulsants (phenytoin, valproate),
antimicrobials (sulfonamides, cotrimoxazole,
ketoconazole)
Necrosis with little or no inflammation Herpes simplex or adenoviral hepatitis, Wilson disease,
malignant infiltration
Acetaminophen, cocaine, MDMA (ecstasy),
carbon tetrachloride
Microvesicular steatosis with little or no inflammation Acute alcohol intoxication, Reye syndrome, fatty liver of
pregnancy
Tetracycline, nucleoside analogues
Chronic hepatitis
Autoimmune marker-negative Autoimmune hepatitis. chronic viral hepatitis, Wilson disease Lisinopril, sulfonamides, trazodone, uracil,
tegafur, tamoxifen, methotrexate
Drug-induced autoimmune hepatitis Autoimmune hepatitis Minocycline, nitrofurantoin, methyldopa,
clometacin
Cholestasis
Bland cholestasis Sepsis, cardiac failure, shock, large duct obstruction, benign
intrahepatic cholestasis, intrahepatic cholestasis of pregnancy
Anabolic/androgenic steroids, oestrogenic
steroids, NSAIDs (nimesulide, piroxicam)
Cholestatic hepatitis (cholangiolitic or hypersensitivity
cholestasis)
Viral hepatitis, large duct obstruction Chlorpromazine, clarithromycin
Granulomatous hepatitis Infections, sarcoidosis, primary biliary cirrhosis, talc, metal
toxicity
Isoniazid, interferon, phenytoin, allopurinol (also
see box 2)
Steatosis/steatohepatitis
Macrovesicular steatosis Diabetes, obesity, Wilson disease, hepatitis C Alcohol, steroids, total parenteral nutrition, gold,
chlorinated hydrocarbons, chemotherapeutic
agents (5-fluorouracil)
Microvesicular steatosis Fatty liver of pregnancy, carnitine deficiency, Reye syndrome Cocaine, tetracycline, valproic acid, zidovudine
Steatohepatitis (See macrovesicular steatosis differential) Amiodarone, chemotherapeutic agents
(irinotecan), perhexiline
Vascular abnormalities
Sinusoidal obstruction syndrome Myeloablation, venous outflow obstruction, right heart
disease
Oxaliplatin, pyrrolizidine alkaloids, chemotherapy
for ALL
ALL, acute lymphoblastic leukaemia; MDMA, 3,4-methylenedioxymethylamphetamine; NSAID, non-steroidal anti-inflammatory drug.
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Differential diagnosis
The histological features can be indistinguishable from other
causes of acute hepatitis such as acute viral hepatitis, initial
presentation of autoimmune hepatitis and Wilson disease. The
presence of bile duct injury, prominent eosinophilic infiltrate,
granulomas, sharply defined perivenular necrosis, or cholestasis
out of proportion to hepatocellular injury, favours adverse drug
reaction, but none of these features is specific.
ACUTE LIVER FAILURE (FULMINANT HEPATITIS)
Acute liver failure (ALF) is defined as the onset of hepatic
encephalopathy within 8 weeks of onset of symptoms. Drugs
are the most common cause of ALF in the USA, accounting for
25–50% of cases.27–30
Based on morphological features, ALF can be subdivided into
three categories.
c Extensive microvesicular steatosis. This pattern is rare and
has been observed with tetracycline and nucleoside analogues
such as zidovudine (see Steatosis and steatohepatitis).
c Necrosis with marked inflammatory activity. This is the
most common pattern seen in idiosyncratic adverse drug
reactions. It is similar to the acute hepatitis pattern
discussed above except that the confluent necrosis involves
most of the liver parenchyma (massive/submassive hepatic
necrosis). The most commonly implicated drugs are
isoniazid,31 32 other antimicrobial agents (sulfonamides,
cotrimoxazole, ketoconazole), monoamine oxidase inhibitors,
and anticonvulsants (phenytoin,31 valproate). Any drug
that causes acute hepatitis can potentially cause ALF.
c Necrosis with little or no inflammation. This pattern is
seen with acetaminophen (fig 4), recreational drugs such
as cocaine and 3,4-methylenedioxymethylamphetamine
(MDMA; ecstasy), industrial organic compounds such as
carbon tetrachloride, and some herbal preparations. Necrosis
can be accompanied by steatosis.
Acetaminophen
Acetaminophen toxicity is the leading drug-related cause,
implicated in nearly 40% of ALF, the remaining being attributed
to idiosyncratic drug reactions.27–29 33 Acetaminophen is a very
safe drug within its therapeutic window (3–4 g/day), but can
cause dose-dependent toxicity with overdose whether accidental
(1/3 of cases) or with suicidal intent (2/3 of cases). At low
doses, the drug is conjugated to water-soluble metabolites in the
liver and is excreted in the urine. At higher doses, glutathione
depletion leads to saturation of the conjugation mechanism,
leaving the parent compound to be metabolised to toxic
intermediates. The minimum toxic dose in adults is 7.5–10 g,
but severe liver damage occurs with ingestion of 15–25 g.
Acetaminophen blood levels taken 4–16 h after ingestion are the
best predictor of outcome. Chronic alcohol consumption,
obesity, and drugs that induce the P-450 cytochrome system,
such as isoniazid, phenytoin, carbamazepine or cimetidine, can
lower the toxic threshold of acetaminophen.
Patients typically experience gastrointestinal symptoms for
the first 12–24 h and a latent phase at 24–48 h. The onset of
acute hepatitis/acute liver failure occurs 72–96 h after drug
ingestion. Hepatotoxicity can be prevented with early presentation
and institution of acetyl-cysteine therapy within 12 h. The
highest mortality is encountered in late presenters.
CHRONIC HEPATITIS
Chronic liver disease typically refers to persistent biochemical
abnormalities beyond 6 months.34 In some series, the cut-off of
3 months has been used for hepatocellular injury and 6 months
for cholestatic or mixed injury.35 Progression to chronicity has
been reported in 5–10% of adverse drug reactions and is higher
for the cholestatic/mixed injury pattern.36 Histologically
proven drug-induced chronic hepatitis with fibrosis is a rare
Box 1 Drugs associated with acute hepatitis pattern of
injury
Non-steroidal anti-inflammatory drugs
c Diclofenac*, indomethacin, tolmetin, sulindac, ibuprofen,
ketoprofen, mefenamic acid, celecoxib
Anaesthetic agents
c Halothane,7 methoxyflurane
Anticonvulsants
c Phenytoin, carbamazepine*, valproic acid, chlorpromazine*
Antibacterial agents
c Ampicillin, amoxicillin–clavulanic acid,5 8 9 oxacillin,
cephalosporins, tetracycline, sulfonamides, erythromycin,
trimethoprim–sulfamethoxazole*
Antifungal agents
c Griseofulvin, fluconazole, ketoconazole*
Antiparasitic agents
c Albendazole, thiabendazole, fansidar
Antituberculous agents
c Isoniazid, rifampin
Antiviral agents
c Zidovudine, ribavirin, nevirapine*, efavirenz*
Antitumour agents
c 6-Mercaptopurine, azathioprine, L-asparaginase, mithramycin,
vincristine, cyclophosphamide, carmustine
Antihypertensive agents
c Methyldopa, hydralazine, lisinopril, labetalol
Antiarrhythmic agents
c Quinidine, nifedipine, procainamide
Hypolipidaemics
c Statins, clofibrate, nicotinic acid, ezetimibe*
Hypoglycaemics*
c Rosiglitazone, troglitazone
Antiandrogens*
c Flutamide
Other
c Sulfonylureas, troglitazone, dantrolene, chlorzoxazone,
dextropropoxyphene, allopurinol, gold
Toxins
c Aflatoxin, death cap mushroom (Amanita phalloides), carbon
tetrachloride, ethylene dichloride, allyl compounds, ferrous
sulfate, phosphorus, MDMA (ecstasy)
*Primarily cholestatic pattern
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phenomenon. Some specific patterns and clinicopathological
situations are discussed below.
Chronic hepatitis with negative autoimmune markers
The histological features are indistinguishable from chronic viral
hepatitis, and progression to fibrosis and even cirrhosis can
occur. The features of acute hepatitis may be seen to a variable
degree. Drugs associated with this pattern include lisinopril
(antihypertensive), sulfonamide (antibiotic), trazodone (antidepressant),
and chemotherapeutic agents such as uracil, 5-
fluorouracil prodrug tegafur and tamoxifen. Isolated case
reports implicate numerous other drugs including phenytoin37
and the Chinese herb Jin bu huan.38 Progression to fibrosing
cholestatic hepatitis has been reported in a hepatitisC patient
after administration of cyclophosphamide and corticosteroids
for glomerulonephritis.39 Discontinuation of the drug may lead
to a favourable outcome, but if the fibrosis is advanced the
resolution may be slow or the disease may progress.
Autoimmune hepatitis
Several drugs can cause chronic hepatitis that is serologically
and morphologically indistinguishable from de novo autoimmune
hepatitis (AIH). The hepatic disease may be accompanied
by features of hypersensitivity such as rash, arthralgia and
peripheral eosinophilia.
Minocycline
Long-term use of minocycline, a synthetic tetracycline for
treatment of acne, can lead to hepatitis that can mimic lupusrelated
hepatitis, AIH or overlap syndrome. Autoimmune
disease can develop within days of starting the drug or may
be delayed for many years. High titres of antinuclear antibodies
(ANAs) are common, but smooth muscle (SMA) and other
autoantibodies often are negative. Autoimmune markers may
be elevated in chronic hepatitis due to drugs (drug-induced
autoimmune hepatitis). Inflammatory activity can be minimal
to mild, and eosinophils are typically inconspicuous (fig 5).
Marked fibrosis and cirrhosis are rare, and patients often
improve after drug withdrawal.40 Microvesicular and macrovesicular
steatosis in response to minocycline have been
reported, but these followed high-dose intravenous therapy
rather than oral administration.41
Nitrofurantoin
Nitrofurantoin is used to treat urinary tract infections. The
hepatic injury can manifest as self-limited acute hepatitis,
chronic hepatitis, and rarely as hepatic failure.42 Chronic
hepatitis can be indistinguishable from de novo AIH and is
often associated with ANA and SMA.43 Discontinuation of the
drug generally leads to clinical and biochemical improvement. In
some cases, the disease may progress despite drug withdrawal.
In contrast to minocycline, significant fibrosis and cirrhosis can
occur.
Figure 1 Atorvastatin-induced acute hepatitis. Mixed parenchymal
inflammation is present, consisting of lymphocytes, plasmahistiocytic
cells, and neutrophils. There is no bile duct damage or fibrosis. H&E,
6200.
Table 3 Herbal products with known hepatotoxicity
Herbal product10 11 Intended use Biopsy findings
Chaparral leaf (creosote bush, Larrea tridentata),12 teas and
capsules
Antimicrobial, anti-aging, skin conditions Acute hepatitis, cholestasis, hepatocellular
necrosis
Germander (Teucrium genus),13 14 teas and tablets Antiseptic, antipyretic, abdominal ailments, obesity Acute hepatitis, centrizonal necrosis, rarely
chronic liver disease with cirrhosis
Pennyroyal (Mentha pulegium, Hedeoma pulegioides),15
‘‘squaw mint’’ oil
Emmenagogue, abortifacient, anti-flea agent for pets Centrizonal necrosis
Glue thistle (Atractylis gummifera),16 found in Mediterranean
region and North Africa
Emetic, diuretic, antipyretic Centrizonal necrosis, panacinar necrosis
Jin bu huan (Lycopodium serratum),17 marketed as anodyne
tablets in 1990s
Sleeping aid, analgesic Acute hepatitis, chronic hepatitis,
microvesicular steatosis
Kava (Piper methysticum)2 18 Stress relief, anti-anxiety, sleeping aid, premenstrual syndrome Acute hepatitis, fulminant hepatitis
Mistletoe (Phoradendron and Viscum geni)19 Digestive aid, heart tonic, sedative Acute hepatitis
Figure 2 Resolving hepatitis. Parenchymal infiltrate is diminished in
comparison to acute hepatitis. Hepatocellular injury is minimal. Pigment
accumulation in sinusoidal macrophages is prominent. H&E, 6200.
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Others
Other drugs implicated in AIH include methyldopa (antihypertensive)
44 and clometacin non-steroidal anti-inflammatory drug
(NSAID).45 Antibodies to liver-kidney-microsomal antibodies,
akin to type 2 AIH, have been described in hepatitis related to
hydralazine (antihypertensive) and tienilic acid (ticrynafen, a
diuretic withdrawn from the American market), but this
association is not clearly defined.46
Methotrexate
Methotrexate is a folate antagonist that is used for long-term
treatment of rheumatoid arthritis, psoriasis and inflammatory
bowel disease. The canals of Hering may be the target of
methotrexate-related scarring.47 The risk of liver toxicity is
exacerbated with heavy alcohol use, pre-existing liver disease,
daily dosing and high cumulative dose.48 Minor elevation in liver
enzymes occurs in 20–50% of patients but does not necessarily
imply significant toxicity.
The histological features of methotrexate-related toxicity
range from minor fatty change, hepatocyte anisonucleosis, mild
portal-based inflammation, and focal necrosis to more severe
hepatocellular necrosis, fibrosis and cirrhosis (fig 6).
Methotrexate may exacerbate or precipitate steatohepatitis in
patients with risk factors such as obesity and diabetes. Some
patients with high cumulative dose can have steatohepatitis-like
histology without other risk factors.49
Patients on long-term methotrexate need close monitoring.
Liver biopsy is necessary in patients who develop deranged liver
function following methotrexate therapy. A grading scheme has
been proposed to assess toxicity (Roenigk classification50–52;
table 4).
ACUTE CHOLESTATIC INJURY
Drug-induced cholestatic injury can manifest clinically with
jaundice, pruritus, dark urine and pale stools. Liver enzyme
studies typically reveal elevation of alkaline phosphatase and cglutamyl
transferase. Transaminases can be variably elevated. A
Danish study of 1100 cases of drug-associated injury reported
16% with the acute cholestatic pattern.53
The histological patterns of injury can be divided into two
forms. (1) Pure (bland) cholestasis in which bile plugs are seen in
hepatocytes or canaliculi and are most prominent in zone 3.
Inflammation and hepatocellular injury are not observed. This
pattern is typically observed with anabolic steroids (fig 7) and
oral contraceptives. Other drugs that have been incriminated
include prochlorperazine, thiabendazole54 and warfarin. (2)
Cholestatic hepatitis in which the cholestasis is accompanied
by inflammation and hepatocellular injury. Bile ductular
reaction may be present. This pattern also has been referred
to as cholangiolitic or hypersensitivity cholestasis.55 This pattern
manifests as mixed-type injury on liver biochemical tests.
Figure 3 Resolving hepatitis. Sinusoidal macrophages are evident with
periodic acid–Schiff (PAS)-positive diastase-resistant cytoplasmic
contents. PAS with diastase, 6200.
Figure 4 Acetaminophen toxicity. Marked hepatocellular necrosis is
present in a zonal, centrilobular pattern, while the inflammatory infiltrate
is minimal. Residual viable hepatocytes show some steatosis. H&E,
6100. (Image courtesy of Dr Linda Ferrell, University of California, San
Francisco, California, USA.)
Figure 5 Minocycline-induced autoimmune hepatitis. Marked
necroinflammatory activity with numerous plasma cells. H&E, 6200.
Figure 6 Methotrexate toxicity. Prominent macrovesicular steatosis
and periportal fibrosis. H&E,6100. (Image courtesy of Dr Linda Ferrell,
University of California, San Francisco, California, USA.)
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Cholestatic hepatitis can result from a wide variety of drugs; it
is the classic pattern seen with toxicity due to macrolide
antibiotics such as erythromycin56 (fig 8) and the antipsychotic
agent chlorpromazine (see box 1).
Differential diagnosis
Drug-induced cholestatic injury can be histologically indistinguishable
from obstructive biliary disease. While the latter
typically results in portal tract oedema and ductular reaction
with inflammation, cholestasis may be the only significant
feature in early stages. Drug-induced cholestatic hepatitis also
needs to be distinguished from autoimmune hepatitis and acute
viral hepatitis.
Bland cholestasis can occur in several systemic disorders such
as sepsis, cardiac failure and shock, and hence clinical information
is necessary to establish the aetiology. In the appropriate
clinical setting, benign recurrent intrahepatic cholestasis, postoperative
cholestasis and intrahepatic cholestasis of pregnancy
have to be considered. Benign recurrent intrahepatic cholestasis
is a mild, non-progressive variant of bile transporter disorder
characterised by intermittent episodes of cholestasis.57
Intrahepatic cholestasis of pregnancy also is due to bile
transporter gene variation, although it additionally appears
affected by hormonal status, as twin pregnancies and patients
on oral contraceptives are reported to be more susceptible to
intrahepatic cholestasis of pregnancy.58
Chronic biliary diseases such as primary biliary cirrhosis and
primary sclerosing cholangitis do not show cholestasis on
biopsy early in the course of the disease; serological tests such
as antimitochondrial antibodies and cholangiography, respectively,
can more definitely rule out these diagnoses.
CHRONIC CHOLESTASIS AND DUCTOPENIA
Cholestatic symptoms and biochemical findings usually resolve
with cessation of the offending drug but may persist in some
instances. Drugs causing prolonged cholestasis (defined as
greater than 3 months in duration)1 59 and ductopenia include
antibiotics such as amoxicillin–clavulanic acid60 61 and flucloxacillin,
62 63 antifungals such as terbinafine64 and, rarely, oral
contraceptives.65 Amiodarone can also cause prolonged disease.66
Vanishing bile duct syndrome
Cholestasis with variable degree of inflammation, bile duct
injury and hepatocellular damage is seen early in the course of
the disease (fig 9). If the disease persists for a few months or
beyond, loss of bile ducts and overt ductopenia may be
observed, termed ‘‘vanishing bile duct syndrome’’. Persistent
inflammation and bile ductular reaction also may be present.
Rare cases can progress to cirrhosis. Vanishing bile duct
syndrome can be triggered by anticonvulsants such as carbamazepine
67 and zonisamide,68 antipsychotics such as chlorpromazine
69 and sulpiride,70 NSAIDs such as ibuprofen71 72 and
tenoxicam,73 and antibiotics such as amoxicillin,74 flucloxacillin,
75 clindamycin and trimethoprim-sulfamethoxazole.76 The
histological picture can mimic primary biliary cirrhosis or
obstructive biliary disease. Absence of antimitochondrial antibodies
and normal imaging of the biliary tree help in establishing
drug-related aetiology.
Other patterns
Biliary sclerosis can result from intra-arterial infusion of 5-
fluorodeoxyuridine for treatment of hepatic metastasis of
colorectal carcinoma.77 Ischaemic injury to the large intrahepatic
and extrahepatic bile ducts can lead to strictures that resemble
Table 4 Roenigk classification system51
Roenigk grade Fatty change Nuclear pleomorphism Necroinflammatory damage Fibrosis
I Mild or none Mild or none Mild or none None
II Moderate or severe Moderate or severe Moderate or severe portal
inflammation
None
IIIa With or without With or without With or without Mild
IIIb With or without With or without With or without Moderate or
severe
IV With or without With or without With or without Cirrhosis
A score of IIIb or IV is an indication to discontinue the drug. Early detection and discontinuation of the drug is associated with a
favourable outcome.
Figure 7 Anabolic-steroid-induced pure cholestasis. Prominent bile
plugs are present in hepatocytes and canaliculi without inflammation or
hepatocellular damage. H&E, 6200.
Figure 8 Erythromycin-related cholestatic hepatitis. Features similar to
acute hepatitis are present, as well as bile plugs in hepatocytes and
canaliculi. H&E, 6100.
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primary sclerosing cholangitis radiologically and histologically.
Similar injury can occur with other agents such as formaldehyde
and sodium chloride injected into hydatid cysts.
GRANULOMATOUS HEPATITIS
The most common causes of granulomas in the liver are
infections, sarcoidosis, primary biliary cirrhosis and drugs (box
2).
Granulomas are uncommon in hepatitis C but can occur in
patients treated with interferon. Talc granulomas can occur in
intravenous drug users and can be detected by viewing under
polarised light. Other systemic granulomatous disease such as
chronic metal toxicity (such as beryllium or copper) can also
involve the liver.55 Finally, a study of granulomatous hepatitis
cases over a 13-year period identified 11% as idiopathic.79 These
cases can present with fever of unknown origin and generally
respond favourably to steroids.
The granulomas can be present in the portal tracts or the
parenchyma and lack necrosis. Unlike in primary biliary
cirrhosis, the granulomas are not centred on the bile ducts.
Granulomas also can occur with other patterns of liver injury
such as acute hepatitis, cholestasis or steatosis.
The term fibrin-ring granuloma has been used for small
granulomas that consist of a ring of fibrin arranged around a
central fat vacuole (fig 10). Epithelioid histiocytes are present
around the ring of fibrin. In atypical cases, the fibrin is
intermixed with the histiocytes and does not form a welldefined
ring. More typical granulomas without the fibrin ring
generally are present in other areas of the biopsy. Fibrin-ring
granulomas have been described with allopurinol, BCG vaccination
and intravesical therapy for carcinoma. These granulomas
were first described in the rickettsial disease Q fever (Coxiella
burnetti) but also occur in boutonneuse fever (Rickettsia conorii),
leishmaniasis, toxoplasmosis, cytomegalovirus infection and
Hodgkin lymphoma.
STEATOSIS AND STEATOHEPATITIS
Macrovesicular steatosis
Macrovesicular steatosis includes large and small droplet fat.
The term ‘‘large droplet fat’’ is used when at least half the
hepatocyte cytoplasm is occupied by a single lipid vacuole,
while multiple lipid vacuoles are seen in small droplet fat. The
latter often is confused with true microvesicular steatosis
which, unlike small droplet fat, affects the liver in a diffuse
fashion (see below). Macrovesicular steatosis can be seen in
association with steroids,80 nitrofurantoin, gold, methotrexate,
NSAIDs such as ibuprofen, indomethacin and sulindac, and
antihypertensives such as metoprolol, chlorinated hydrocarbons
such as carbon tetrachloride and chloroform,81 or chemotherapeutic
agents such as 5-fluorouracil, cisplatin and tamoxifen.82
Microvesicular steatosis
Exclusive or predominant microvesicular steatosis diffusely
affecting the liver is a result of mitochondrial injury and often
occurs as an adverse effect of drugs/toxins such as cocaine,
tetracycline, valproic acid and zidovudine (fig 11). Acute
exposure to alcohol (alcohol foamy liver degeneration)83 and
paediatric Reye syndrome also show diffuse microvesicular
steatosis.84 Other non-drug related aetiologies include acute
fatty liver of pregnancy and genetic diseases such as carnitine
deficiency.
Steatohepatitis
By definition, steatohepatitis is characterised by steatosis,
lobular inflammation and hepatocellular injury in the form of
hepatocellular ballooning (with or without acidophil bodies or
Mallory hyaline) or pericellular fibrosis. A few drugs (notably
amiodarone and irinotecan) play a direct aetiological role in
steatohepatitis. Most other drugs exacerbate or precipitate
steatohepatitis in the presence of other risk factors such as
obesity and diabetes.
Figure 9 Prolonged cholestasis. Persistence of canalicular bile plugs
accompanied by feathery degeneration of periportal hepatocytes (cholate
stasis). H&E, 6200.
Box 2 Drugs implicated in granulomatous hepatitis
Antimicrobials
c Isoniazid, penicillin, sulfonamides, cephalexin, dapsone,
dicloxacillin, oxacillin, interferon
Anticonvulsants/antipsychotic agents
c Phenytoin, diazepam, chlorpropamide, chlorpromazine,
procarbazine, carbamazepine
Others
c Allopurinol, gold, procainamide, quinidine, methyldopa,
diclofenac, diltiazem, BCG therapy for cancer, nitrofurantoin,
mesalamine, phenylbutazone (veterinary use, use in humans
limited due to side effect of aplastic anaemia)78
Figure 10 Fibrin-ring granulomas. Fat vacuole surrounded by a ring of
fibrin deposition and epithelioid cells. H&E, 6200.
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Amiodarone
Amiodarone, a potent antiarrhythmic agent, causes elevated
liver enzymes in up to 30% of patients85 86 and steatohepatitis in
1–2%87 of patients. The majority of cases display liver enzyme
abnormalities within 24 h of intravenous infusion.88 Even low
oral dosing (200 mg daily) may trigger steatohepatitis with
cumulative use.89 Occasionally, jaundice is the major clinical
presentation. These cases often show hepatocellular necrosis
and fibrosis, and have a poor prognosis.66
Amiodarone steatohepatitis is characterised by prominent
Mallory hyaline (occasionally in zone 1) and neutrophilic
satellitosis, while steatosis is less conspicuous (fig 12). The
findings can be similar to alcoholic steatohepatitis. Reversal of
liver injury often occurs with discontinuation of the drug but
may be delayed by weeks or months. In addition, amiodarone is
also associated with a different type of lipid accumulation called
‘‘phospholipidosis’’ characterised by accumulation of drug in the
lysosomes.90 91 This leads to ‘‘foamy’’ appearance of hepatocytes
and Kupffer cells. The foamy areas show lamellar lysosomal
inclusion bodies on electron microscopy92 (fig 13).
Phospholipidosis is not always seen in amiodarone toxicity90
and is independent of steatohepatitis.93
Perhexiline maleate (Pexid), an antianginal drug, and diethylaminoethoxyhexestrol
(Coralgil), a vasodilator, have been used
extensively in Europe and Japan, respectively. Both drugs can
cause steatohepatitis and phospholipidosis similar to amiodarone.
94 95
Chemotherapy-induced steatohepatitis
Steatosis and steatohepatitis have been reported with chemotherapeutic
agents. The latter especially is associated with
irinotecan, a drug often used preoperatively in colorectal cancer
with hepatic metastases. This has been referred to as
chemotherapy-associated steatohepatitis in the oncology literature.
82 96 Other chemotherapeutic agents such as oxaliplatin
have been variably implicated.82 97
Others
Drugs such as tamoxifen, steroids, oestrogen and diethylstilbestrol
often lead to hepatic steatosis, but steatohepatitis is rare.
These drugs may exacerbate or precipitate steatohepatitis in
patients with risk factors for steatohepatitis rather than play an
aetiological role. The evidence linking steatohepatitis and
calcium channel blockers such as nifedipine also is anecdotal.
Risk factors for steatohepatitis were present in many reported
cases, creating uncertainty about the association of these drugs
with steatohepatitic injury.98
VASCULAR ABNORMALITIES
Several vascular patterns of injury are recognised, each with
distinctive morphological features and drug associations.
Sinusoidal obstruction syndrome
Sinusoidal obstruction syndrome (SOS; veno-occlusive disease)
is due to endothelial cell injury to small hepatic venules that
manifests histologically as endothelial swelling and thrombosis
(fig 14). The resultant venous outflow obstruction leads to
sinusoidal dilatation, congestion, hepatocellular necrosis, and
can result in centrilobular fibrosis.
Cytotoxic/chemotherapeutic drugs such as oxaliplatin (used
in colorectal cancer) can cause injury to sinusoidal endothelial
cells and hepatic stellate cells.97 99 100 SOS can also occur due to
myeloablation before stem cell transplantation, chemotherapy
for acute lymphocytic leukaemia, bone marrow transplantation
101 and pyrrolizidine alkaloids.97 Genetic polymorphisms in
methylenetetrahydrofolate reductase have been implicated in
SOS in post-transplant patients.102 Recently, defibrotide has
been used with success to resolve cases of SOS,103 although in
some cases, transplantation can be required.104
Figure 12 Amiodarone steatohepatitis. Marked hepatocyte ballooning,
numerous Mallory hyaline and minimal steatosis. H&E, 6100.
Figure 13 Phospholipidosis. Formation of lysosomal inclusion bodies
due to accumulation of amiodarone. Electron micrograph. (Image
courtesy of Dr Linda Ferrell, University of California, San Francisco,
California, USA.)
Figure 11 Microvesicular steatosis. Numerous small lipid droplets are
present throughout the hepatocytic cytoplasm. H&E, 6400.
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Peliosis hepatis
Peliosis is characterised by blood-filled cavities without an
endothelial lining in the hepatic parenchyma (fig 15). This
phenomenon most commonly is associated with androgens105 or
contraceptive steroids.106 Thiopurine-derived chemotherapeutic
drugs also have been implicated.107 108 Peliosis also occurred with
the intravenous contrast agent thorium dioxide (Thorotrast),
which has been discontinued due to the high risk of
angiosarcoma.109 110 Sinusoidal dilatation may accompany peliosis
or may occur independently, particularly with androgenic or
oestrogenic steroid use.111
Hepatic vein thrombosis
Hepatic vein thrombosis is a rare complication of some drugs,
including oral contraceptives112 113 and dacarbazine,114 and
presents clinically as Budd-Chiari syndrome.
OTHER PATTERNS
Stellate cell lipidosis
Hepatic stellate cells (Ito cells) are modified fibroblasts that
store lipids and vitaminA in the normal liver. They are located
in the space of Disse between the sinusoidal endothelium and
the hepatocytes but generally are not easily visible.115 In certain
conditions, especially hypervitaminosis A, excessive lipid gets
stored in the stellate cells (stellate cell lipidosis, fig 16). The
nuclei of stellate cells are crescent shaped, dark staining, and
indented by the lipid droplets. Thin strands of cytoplasm
separate the lipid droplets. These lipid-laden cells easily can be
mistaken for hepatocytes with steatosis. Their characteristic
morphology and location along the sinusoids between the
hepatic plates distinguishes them from steatotic hepatocytes.116
Hypervitaminosis A results from excess dietary/supplementary
vitaminA intake or use of oral/topical retinoids (such as
etretinate for acne). Stellate cell lipidosis also has been reported
with methotrexate, valproate and steroids, as well as in other
clinical settings such as cholestasis, alcoholic liver disease and
hepatitis C.
It is important to recognise this condition, as activation of
stellate cells can lead to fibrosis, non-cirrhotic portal hypertension
and, rarely, cirrhosis. One case of liver transplantation for
subacute vitaminA toxicity has been reported.117 Early recognition
can prompt reduced intake of vitaminA to avert progression
and fibrosis. The contribution of stellate cell lipidosis to
disease progression when present with other disease processes
such as alcoholic liver disease and chronic hepatitisC is
unknown.
Cytoplasmic inclusions
Ground glass change in the cytoplasm occurs in a minority of
patients with hepatitis B and is characterised by pale eosinophilic
Figure 14 Sinusoidal obstruction syndrome. Endothelial injury in small
hepatic venules leads to luminal occlusion due to endothelial swelling
and thrombosis, and results in sinusoidal dilatation and congestion. H&E,
6100.
Figure 15 Peliosis. The hepatic parenchyma contains blood-filled
cavities that lack an endothelial lining (arrows). H&E, 666. (Image
courtesy of Dr Linda Ferrell, University of California, San Francisco,
California, USA.)
Figure 16 Stellate cell (Ito cell) lipidosis. Fat-laden stellate cells
showing multiple lipid vacuoles with indentation of the nucleus. Note the
location of Ito cells along the sinusoids in the space of Disse. H&E,
6400.
Figure 17 Ground-glass hepatocytes. This change can be seen with
drugs such as cyanamide (used for treating alcohol abuse), diazepam
and barbiturates, and in patients on insulin or intravenous glucose
therapy. H&E, 6200.
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cytoplasmic inclusions in hepatocytes. Similar changes (often
termed ‘‘pseudo ground glass change’’, fig 17) can be seen with
drugs such as cyanamide, a drug used in alcohol treatment
programs.118 119 This phenomenon has also been described with
other drugs such as barbiturates and diazepam, diabetic patients
on insulin, and transplant patients on multiple immunosuppressive
drugs such as steroids, tacrolimus and mycophenolate
mofetil.119 120 Similar to hepatitis B, this change reflects hypertrophy
of smooth endoplasmic reticulum with use of drugs such
as barbiturates, while most other drug-induced cases are due to
accumulation of abnormal glycogen.118–120 Rare metabolic disorders
such as type IV glycogenosis, hypofibrinogenaemia, and
Lafora disease can lead to the same morphological findings.
Pigments
Some drugs/toxins such as gold, titanium and thorium dioxide
(Thorotrast) can be deposited as pigments in the liver. Drugs
that cause prolonged cholestasis can lead to copper accumulation
in periportal hepatocytes. Lipofuscin, a lysosomal pigment
often seen in centrizonal hepatocytes, can be increased with
exposure to anticonvulsant drugs such as phenothiazine and
phenacetin.
Hepar lobatum
This term generally refers to liver abnormalities in tertiary
syphilis. In some instances, chemotherapy for metastatic liver
cancer (especially from the breast) can lead to similar changes.
The liver shows a lobulated contour with capsular indentations
from which fibrous septa extend deep into the parenchyma.121
The fibrous septa can surround the degenerated centre of
tumour nodules and may contain macrophages and residual
tumour. Typical features of cirrhosis such as regenerative
nodules are not observed. These features probably result from
tissue collapse due to chemotherapy-related tumour regression
that is followed by an organising phase of healing and scar
contraction.121
Drug-related neoplasms
The association of oral contraceptives and hepatic adenomas is
well recognised.122 Association with focal nodular hyperplasia
and hepatocellular carcinoma also has been reported,123 124 but
the link is less convincing. Other agents such as anabolic
steroids used by sportsmen, clomiphene, danazol and carbamazepine
have also been associated with hepatic adenoma.125 126
Exposure to vinyl chloride (an industrial chemical) and
thorium dioxide (a discontinued radiographic contrast agent)
can lead to angiosarcoma, sometimes after long latent periods
exceeding 20 years.127 Hepatocellular carcinoma and cholangiocarcinoma
also have been reported with thorium dioxide.128
Competing interests: None.
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c Acute hepatitis, with or without cholestasis, is the most
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