Acute hepatitis-like injury in a patient taking isoniazid. The hepatocyte in the center of the field is undergoing apoptosis, while the other liver cells are swollen or ballooned. The inflammatory response is predominantly lymphocytic.
Submassive (zone 3) hepatic necrosis, lytic type, following halothane anesthesia. There is loss of hepatocytes and stromal collapse surrounding terminal hepatic venules (“central veins”) with central-central and sometimes central-portal bridging.
Submassive (zone 3) coagulative necrosis caused by an overdose of acetaminophen. Viable hepatocytes surround the portal areas, while the terminal hepatic venules (arrows) are surrounded by necrotic tissue. Inset (lower right) shows the necrotic hepatocytes at high magnification.
Cholestatic injury. The biopsy on the left has relatively ‘bland” cholestasis with numerous canalicular bile plugs (arrows) but relatively little hepatocellular injury. The biopsy on the right shows a combined hepatocellular and cholestatic injury with canalicular bile plugs (arrows), as well as hepatocyte ballooning and dropout, producing disarray of the liver cell plates.
Hepatocellular and canalicular cholestasis. Bile is present within transversely (open arrow) or longitudinally sectioned bile canaliculi (long arrows). Several hepatocytes at upper right (curved arrows) contain bile (hematoxylin and eosin, original magnification × 400).
Granulomatous hepatitis in a patient taking phenylbutazone. There are two young granulomas (arrows) composed of epithelioid histiocytes, lymphocytes, and a few eosinophils, and the surrounding parenchyma also has spotty hepatocyte dropout and lymphocytic inflammation.
Severe chronic hepatitis in a patient who had taken α-methyldopa for 3 months. The biopsy resembles autoimmune hepatitis with diffuse hepatocellular ballooning, portal expansion, and fibrosis. There are numerous plasma cells in the portal inflammatory infiltrate, and there is marked interface hepatitis around the circumference of the expanded portal tract.
Severe liver injury in an atypical pattern, suggesting a drug-induced cause. The liver biopsy shows confluent zone 3 necrosis and collapse (left) but the surrounding inflammation consists of epithelioid histiocytes and giant cells (upper right) and numerous plasma cells. Because the combination of histologic features was so unusual and unlike any naturally occurring liver disease, a drug reaction was suspected. Further inquiry into the history revealed that the patient had been taking trovafloxacin before becoming ill.
Amiodarone phospholipidosis. A, Black and white photomicrograph (H and E x 160) showing foam cells in right upper corner and Mallory bodies (arrows).B, A closer view of area with foam cells in the same patient. C, Electron microphotograph (x22,600) of the same case showing multiple dense, laminated inclusions (myelin figures) in the hepatocyte cytoplasm. Another cardiac medication that may cause toxicity to the liver and other organs is amiodarone, an antiarrhythmia agent. Dose-related hepatotoxicity, with an incidence of 15% to 50%  may become manifest 1 month to more than 1 year of therapy. The clinical picture varies from asymptomatic transaminase elevation to fulminant hepatic failure . Severe cholestasis may be present and fatal cirrhosis can ensue. The hepatic accumulation of amiodarone can be detected by CT because the drug is iodinated; however, the increased density does not correlate with the degree of liver damage . Unlike alcoholic hepatitis, in which the damage tends to be centrilobular, amiodarone hepatotoxicity is mainly periportal . The possible mechanism of the steatosis is discussed in Figure 6-33. (Courtesy of K. Ishak.)
Gastrocon 2016 - Drug Induced Liver Disease
DRUG INDUCED LIVER DISEASEDRUG INDUCED LIVER DISEASE
S. P. SINGHS. P. SINGH
The liver diseaseThe liver disease resulting from the inhalation,resulting from the inhalation,
ingestion or parenteral administrationingestion or parenteral administration of anyof any
pharmacological or chemical agent is called drugpharmacological or chemical agent is called drug
induced liver diseaseinduced liver disease (DILD)(DILD)
Drug Induced Liver DisordersDrug Induced Liver Disorders
• When Liver Biopsy has been
performed: lesion should be named
according to histological findings,
e.g. ‘cirrhosis’, ‘CLD’,’hepatic
necrosis’ or ‘hepatitis’.
• In the absence of histological data:
such terms should not be used. The
preferred term is “liver injury”.
• This term should be used if there is an
increase in over 2 N in ALT [alanine
aminotransferase] or CB [Conjugated
• Combined increase in AST [aspartate
aminotransferase], AP [Alk Phos] & TB
[Total Bil] provided one of them is above 2N.
• Hepatocellular: Increase of over 2N in
ALT alone or R ≥ 5 [R = serum activity of
ALT/serum activity of AP – each
expressed as multiple of N]
• Cholestatic: Increase in over 2N in AP
alone or R ≤ 2.
• Mixed: Both ALT above 2N & AP are
increased, & 2 < R < 5
• Isolated increase even over 2N in AST, AP
or TB should be considered only a
biochemical abnormality and not
necessarily a sign of liver injury
• When the increase in ALT, AST, AP or TB
is between N & 2N, the term –
‘abnormality of liver tests’ should be used
& not ‘liver injury’.
CLINICAL FEATURESCLINICAL FEATURES
Drugs can cause nearly any
type of liver disorder and can
mimic many well-recognized
• Intrinsic hepatotoxins
• Idiosyncratic hepatotoxins
• Damage to the genome?
The hepatocyte in the center of the field is under-
going apoptosis, while the other liver cells are swollen
or ballooned. The inflammatory response is predomi-
Acute hepatitis-like injury in a patient taking
Submassive (zone 3) coagulative necrosis
caused by an overdose of acetaminophen
The biopsy on the left has relatively ‘bland”
Cholestasis. Biopsy on the right shows a com
-bined hepatocellular and cholestatic injury
HEPATOCELLULAR & CANALICULAR CHOLESTASIS
Bile is present within transversely (open arrow) or long-
itudinally sectioned bile canaliculi (long arrows). Several
hepatocytes at upper right (curved arrows) contain bile
Granulomatous hepatitis in a
patient taking phenylbutazone
Severe chronic hepatitis in a patient who
had taken α-methyldopa for 3 months
Severe liver injury in an atypical pattern,
suggesting a drug-induced cause
Amiodarone phospholipidosis: foam cells and Mallory bodies
LIVER BIOPSY FINDINGS THAT
SUGGEST DRUG HEPATOTOXICITY
• Prominent Eosinophils in inflammatory
• Granulomatous Hepatitis with
granulomas + hepatitis-like
• Cholestatic Hepatitis: combined
hepatocellular & cholestatic injury
• Severe acute injury
• Any unusual combination of histologic
findings, atypical for any of the
common primary liver diseases.
NAILING THE CULPRIT
• Drug induced Liver disease can simulate
nearly any clinical syndrome or pathologic
• Diagnosis can not be made on
morphologic grounds alone or on the
basis of specific laboratory test !
• Careful correlation of history with
clinical, laboratory & histologic data.
In every instance, the morphologic findings
must be correlated with the following
• A complete drug or chemical history:
All exposures must be considered.
• Specific and detailed time-related
drug information: It is essential to
know exactly when the drug was taken
in relation to the signs, symptoms, and
laboratory evidence of liver disease.
• The results of the laboratory tests:
These are essential in determining
the onset, duration, and degree of
The following should be determined
from the history and lab studies:
• Temporal eligibility
• Exclusion of other causes
• Pattern of injury
• Dechallenge and rechallenge
• Toxicologic analysis
• Did the administration of the drug precede the
onset of the liver disease by a reasonable time
interval (latent period) for that drug?
• An obvious but often overlooked point is that if the
patient was already ill when he or she began taking
the suspected drug, then the drug could not have
caused the illness
• It is also important to recognize that each drug
that can cause liver injury does so after a latent
period that is characteristic for that drug. In most
cases, this is approximately 3 weeks to 3 months
• If a drug has been taken regularly with no problems
for years, it is extremely unlikely that it is
responsible for a newly recognized injury
“Other causes besides the
suspected drug need to be
carefully considered and
excluded if possible”
• Any drug that has been in use for some time
will have a record that can be used to
assess the likelihood of its having caused
the suspected injury
• However, any newly marketed drugs that
the patient has taken should be considered
too although they will not have a track
• When a list of drugs and dates has been
assembled, each drug should be checked for
• Resources: Physicians' Desk Reference &
Medline-PubMed database [
PATTERN OF INJURY
• Pattern of injury produced by each
drug tends to be consistent, or at
least falls within a defined range.
• For example, some drugs, such as
erythromycin, typically produce
cholestatic injury, wherease others,
such as isoniazid, are nearly always
• The literature search is often helpful
in establishing whether the type of
injury seen in an individual case is
typical or unusual for the suspected
drug and will contribute to the
assessment of the likelihood of a
• Dechallenge and rechallenge are very
helpful in the final analysis
• If the patient recovers after the
drug is stopped, the likelihood that
the drug was the cause is increased
• However, lack of recovery does not
always exclude the drug. In
particular, recovery from a
cholestatic injury can be very
• Deliberate rechallenge is never
recommended, because it puts the patient
at risk for a more serious injury
• However if a drug is inadvertently
readministered (eg, before it was
suspected), the prompt return of the
injury is extremely strong evidence that
the drug is the causative agent
• Toxicologic analysis of blood, tissue, or
other body fluids can establish direct
toxicity (overdose or poisoning) in
selected cases only.
• In most cases, however, drug
hepatotoxicity is caused by
idiosyncratic reactions, and so
toxicology is of no use.
INTERNATIONAL CONSENSUS CRITERIA
for Diagnosis of drug induced hepatotoxicity
• The time from drug intake and withdrawal to the apparent
onset of the reaction was "suggestive" (5-90 days from
initial drug intake) or "compatible" (less than five or more
than 90 days from initial drug intake and not more than
15 days of drug withdrawal for "hepatocellular" reaction
and not more than 30 days of drug withdrawal for
cholestatic reaction) with drug hepatotoxicity.
• Course of the reaction after cessation of the drug was
"very suggestive" (decrease in the liver enzymes by at
least 50% of the excess over the upper limit of normal
within eight days) or "suggestive" (decrease in the liver
enzymes by at least 50% within 30 days for
"hepatocellular" reaction and 180 days for "cholestatic"
reaction) of drug reaction.
• Alternative cause of the reaction had been excluded by
detailed investigations, including a liver biopsy in each
• There was a positive response to rechallenge (at least a
doubling of liver enzymes) when such information was
J Hepatol 1990;11:272-276
FINALLY AFTER A CASE HAS BEEN
EVALUATED, IT CAN BE CLASSIFIED
ON THE BASIS OF ‘CERTAINTY’
• Causative: Cases in which toxicologic analysis
establishes a drug level in the toxic range.
• Probable: Cases in which the drug is temporally
eligible and in which the type of tissue injury is
the same as that observed in previous experience
with the drug.
• Possible: Cases in which the type of injury can be
associated with the drug but in which other
factors or possible causes cannot be excluded.
• Coincidental: Cases in which drug-induced disease
appears to be most unlikely but cannot be
• Negative: Cases in which the possibility of a drug
injury can be clearly eliminated.
• Council for International Organizations
of Medical Sciences (CIOMS) scale
• Maria & Victorino (M&V) Clinical scale or
CDS [Clinical Diagnostic Scale]
CLINICAL DIAGNOSTIC SCALE
I. Temporal relationship between drug
intake and the reaction
II. Exclusion of alternative causes
IV. Intentional or accidental re-exposure to
V. Previous report in the literature of
cases of hepatotoxicity associated with
Maria & Victorino (M&V)
Scores for Individual Axes of
the M&V Diagnostic Scale
• From drug intake until onset event +1 to+3
• From drug withdrawal until onset event -3 to +3
• Course of the reaction 0 to +3
• Exclusion alternative causes -3 to +3
• Extrahepatic manifestations 0 to +3
• Bibliographic data -3 to +2
• Rechallenge 0 to +3
TEMPORAL RELATIONSHIP BETWEEN
DRUG INTAKE & REACTION
• Time: Intake – Onset of 1st
clinical or Lab
4 Days – 8 Weeks 3
< 4 Days or > 8 Weeks 1
• Time: Drug withdrawal – Onset of
0 – 7 Days 3
8 – 15 Days 0
> 15 Days -3
• Time: Drug withdrawal – Normalization of Lab
values [Decrease to values 2 x ULN]
< 6 mo [Chole/mixed] or 2 mo [Hep] 3
> 6 mo [Chole/mixed] or 2 mo [Hep] 0
Clinical Diagnostic Scale
• Complete Exclusion: 3
• Partial Exclusion: 0
• Possible alternate cause detected -1
• Probable alternative cause detected -1
[rash, fever, arthralgia, eosinophilia, cytopenia]
• 4 or more 3
• 2 or 3 2
• 1 1
• None 0
CLINICAL DIAGNOSTIC SCALE:
• INCIDENTAL / ACCIDENTAL RE-EXPOSURE
Positive re-challenge test 3
Negative or absent re-challenge test 0
• PREVIOUS REPORT IN LITERATURE OF DILI
No [drugs marketed for up to 5 years] 0
No [drugs marketed for > 5 years] -3
• CDS score of > 9 identified the cases
of drug-related hepatotoxicity with
88% sensitivity and 92% specificity.
• Patients with scoring ≤ 9 on CDS
scale require further investigation
& / or follow-up.
• CDS scoring useful in evaluation of
suspected hepatotoxic drug reactions
Aithal et al, J Hepatol 2000
Scores for Individual Axes of the
• From drug intake until onset event +2 to+1
• From drug withdrawal until onset event +1 to 0
• Course of the reaction +1 to 0
• Age +1 to 0
• Alcohol +1 to 0
• Concomitant therapy -3 to 0
• Exclusion non-drug-related causes -3 to +2
• Bibliographic data 0 to +2
• Rechallenge -2 to +3
Summary of “Diagnosis”
• Drug-induced liver disease is a relatively
common, but often unrecognized, cause of
• Drugs are great imitators, capable of
producing nearly any clinical scenario and
• When dealing with a liver biopsy from a
patient with an undiagnosed liver disease,
the diagnosis of drug hepatotoxicity is
made by first having a high index of
suspicion, and then by careful correlation
PREVENTION OF DILD
• With the exception of acetaminophen
hepatotoxicity , there is little effective
treatment for drug-induced liver disease.
• All physicians must report suspected
adverse effects to monitoring agencies or
• Minimize DILI through avoidance of
overuse of hepatotoxic drugs; avoid
• For dose-dependent hepatotoxins,
prevention depends on adherence to
dosage guidelines or use of blood levels.
• Active management might include removal
of the drug and the administration of
antidotes and anti-inflammatory and
cytoprotective agents. In practice,
management is usually confined to
discontinuation of hepatotoxic drugs.
• For ingested toxins like metals, poisonous
mushrooms, and acetaminophen,removal of
unabsorbed drug through the aspiration of
stomach contents may be appropriate.
• Thiol replacement therapy, usually N-
acetylcysteine (NAC), is indicated as an
antidote for acetaminophen poisoning .
• Beyond discontinuation of the
offending agent, the management of
drug hepatitis and cholestasis is
symptomatic and supportive.
• In cases of acute liver failure,
hepatic transplantation should be
• Ursodeoxycholic acid has some promise for
chronic cholestasis and pruritus.
• Glucocorticoids have little role in the
management of drug-induced cholestasis or
hepatitis and are ineffective in
chlorpromazine-, methyldopa-, and
isoniazid-induced hepatitis and in drug-
induced fulminant hepatic failure.
• Case reports attest to their occasional
effectiveness in protracted cases of
hepatitis caused by etretinate, allopurinol,
diclofenac, or ketoconazole.
• Glucocorticoids should be reserved for
atypical and refractory cases, particularly
those with vasculitis.
For all queries, write to:
Measures proposed to reduce risk of severe
hepatic adverse effects during ATT
• First, patients with underlying liver test
abnormalities should not be given pyrazinamide.
• Second, isoniazid & pyrazinamide should be
administered at the lowest dosage within their
respective therapeutic ranges.
• Third, Se transaminase levels should be determined
twice weekly during first 2 wks of treatment, every 2
wks during the rest of the first 2 mos, and every mo
Durand et al, 1996
Measures proposed to reduce risk of
severe hepatotoxicity during ATT
• When Se transaminase ↑to > 3 times ULN,
therapy with isoniazid, rifampicin and
pyrazinamide should be stopped.
• After Se transaminase levels have returned
to normal, INH can be re-introduced at a low
daily dose, without rifampicin.
• Pyrazinamide may not be re-introduced: risk
of recurrence & poor prognosis of
• Although nephrotoxic, streptomycin is an
alternative in patients with LFT abnormalities
during ATT. Durand et al, 1996
Challenge Reintroduction Dosages
Introduce at 50 mg/day; increase sequentially to
300 mg/day after 2–3 days if no reaction occurs, and
Added after a further 2–3 days without reaction: 75
mg/day increase to 300 mg after 2–3 days, & then
to 450 mg (<50 kg) or 600 mg (>50 kg) as
appropriate after further 2–3 days without reaction,
and then continued.
Added finally: 250 mg/day, increase to 1.0 g after
2–3 days; then to 1.5 g (<50 kg) or 2 g (>50 kg).
Three Different Regimens for Reintroduction of Anti-Tuberculosis
SK Sharma et al. Clinical Infectious Diseases 2010
SK Sharma et al. Clinical Infectious Diseases 2010
Summary of the ATT Re-introduction Study
Acetaminophen induced DILI
• N-acetylcysteine reduces mortality
even if commenced late
• Reduces Inotrope Requirements
• Decreases Cerebral Edema
• Increases the rate of survival by
* Keays et al. IV NAC in paracetamol induced FHF: A prospective controlled trial.
Valproate induced DILI
• IV Carnitine*
• Overcomes inhibition of β-oxidation
of Fatty Acids caused by Valproate
• Also es↑ β-oxidation of Valproate
• IV is better than Oral
• ↑ Survival*
* Bohan et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity.
• Silymarin alone or combination of
Silymarin + Benzylpenicillin for
Mushroom (Amanita phalloides)
can be attempted in cholestatic
hepatitis with f/o hypersensitivity
(rash & fever)2
1. Enjalbert et al. Treatment of amatoxin poisoning: 20-yr retrospective analysis. J Toxicol
Clin Toxicol 2002