Drug Induced Liver Injury (DILI)

E-learning Course
Lesson 1A: What is DILI?

Council for International Organizations of Medical Sciences

Uppsala Monitoring Centre

2022-09-26

Hello, I am Raul Andrade, I am professor of Medicine at the University of Malaga, in

Spain, and on behalf of the CIOMS Hepatotoxicity Working Group, I am going to
present this podcast entitled “What is Drug-Induced Liver Injury (DILI)?”

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 Learning Goal
Understand the meaning of
DILI and be able to classify
cases according to categories
and severity.

The learning goal of this module is to be able to understand the meaning of drug-
induced liver injury and be able to classify cases according to categories and severity.

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Learning Objectives
• Explain what is meant by DILI, and recognise its frequency and risk factors
• Classify cases according to categories and severity and be able to calculate the R
value
• Describe drugs/drug groups commonly implicated in the various types of DILI

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 Drug-induced liver injury is an unintended effect on the liver
of not only medications but also herbal products and dietary

1.1 DILI Categories

supplements, which can be serious eventually leading to acute
liver failure and death

Intrinsic Indirect Idiosyncratic

Dose- Yes/Yes/High No (generally) No(with some
related/Predictable /Occasionally/Intermediate exceptions)/No/Low
/Rate of occurrence
Implicated drugs Acetaminophen, nicotinic High-dose corticosteroids, Isoniazid, amox-clav,
acid, aspirin, some anti-cancer agents: Macrolide antibiotics,
cocaine,chemotherapies, ICIs, protein kinase inhibitors, fluoroquinolones, statins,
amiodarone, MTX (IV), monoclonal antibodies flucloxacillin, diclofenac, some
Pyrrolizidine alkaloids (infliximab, anti-CD20), HDS (e.g. Green tea extracts,
daclizumab Polygonum multiflorum)
Pathologic Liver damage occurs if What the “drug does” rather Adaptive immune response,
mechanisms parent drug or metabolite than what the “drug is” (e.g. Mitochondrial damage and
concentrations in liver immune drug-induced hepatic steatosis may also be
cells exceed a threshold autoreactivity or increased observed
insulin resistance)

Hoofnagle & Bjornsson. N Engl J Med 2019; 381: 264-273.

The types of drug-induced liver injury have been divided classically into intrinsic and
idiosyncratic. Intrinsic type, includes drugs that produce DILI in a dose-related fashion
with a predictable capacity and the rate of occurrence is high, providing the drug is
given in high doses and this includes drugs such as acetaminophen, a few other drugs
used in clinical practice, but also, herbs, for example those containing pyrrolizidine
alkaloids.
In these cases, liver damage occurs if parent drug or metabolite concentrations in
liver cells exceed a threshold. But the bulk of DILI cases are called idiosyncratic. In
these cases, the drug reaction is unpredictable and not related to the known
pharmacological action of the drug, and the rate of occurrence is low. And this
category includes many drugs, for example, isoniazid, many antibiotics, statins or
some herbs and dietary supplements.
Recent evidence suggests that the adaptive immune response is important in this
mechanism, in the pathogenesis of idiosyncratic DILI, because GWAS have identified
that carriers of some HLA Class 1 and 2 alleles are at higher risk of developing DILI
when exposed to specific drugs.
In some cases, for example, mitochondrial damage can be also important, and
recently a third type, indirect DILI had been proposed. This shows characteristics
which are intermediate between intrinsic and idiosyncratic and include high dose
corticosteroids or immune checkpoint inhibitors or other immunomodulating drugs
and in this case, the mechanism seems to be that related to what the drug does
rather than what the drug is. For example, the immune drug-induced autoreactivity in
the liver caused by immune checkpoint inhibitors.

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 1. 1.2 Liver biochemistry and R value
Serum ALT generally have greater liver tissue specificity than serum AST.
-In some patients with alcoholic liver disease or cirrhosis, peak AST levels
may be higher than ALT making AST a more sensitive biomarker of DILI
Increased ALP levels due to liver injury in the absence of bone pathology are accompanied
by elevations in gamma-glutamyl transferase (GGT).
-When the source of increased ALP is bone, GGT levels are generally normal.

Liver enzyme estimates from the same samples and the first set of measurements available
are used to calculate R value.
ALT (case)/ALT (ULN) = ALT-activity; ALP (Case)/ALP (ULN) = ALP activity,
R value = ALT/ALP ratio = ALT-activity/ ALP -activity.
Bénichou C. J Hepatol. 1990; 11: 272-6.
Fontana RJ, et al. Hepatology 2010;52:730-42.
Aithal GP, et al. Clin Pharmacol Ther 2011; 89:806-15

To identify and classify drug-induced liver injury today, the values of

aminotransferases and alkaline phosphatase (ALP) and total bilirubin (TBL) are used
and serum alanine aminotransferase (ALT) has greater liver tissue specificity than
serum aspartate aminotransferase (AST) with some exceptions. For example, patients
with alcoholic liver disease or cirrhosis in which peak AST can be a more sensitive
biomarker of DILI.
Regarding ALP, it should be accompanied with elevation of gamma-glutamyl
transferase (GGTP) to make sure that the origin is the liver, and the calculation of the
R value is made using always the same samples and the first set of measurements
available. This is calculated by dividing the ALT activity (ALT(case)/ALT(ULN)) by the
ALP activity (ALP(case)/ALP(ULN)).

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 1. 1.2 Biochemical patterns of liver injury and R value
• HEPATOCELLULAR: Alanine
aminotransferase (ALT)
predominantly raised (ALT/ALP
≥ 5 xULN)

• CHOLESTATIC: Alkaline
phosphatase (AP)
predominantly raised (ALT/ALP
≤ 2 xULN)

• MIXED ALT & ALP are

increased, and 2<ALT/ALP<5 Bénichou C. J Hepatol. 1990; 11: 272-6.
Fontana RJ, et al. Hepatology 2010;52:730-42.
Aithal GP, et al. Clin Pharmacol Ther 2011; 89:806-15

Using this classification, the drug-induced liver injury can be classified as

hepatocellular when there is a predominantly elevation of ALT and as cholestatic
when the ALP is mostly elevated and mixed type of liver damage when the elevation
is in between.

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 1. 1.3 DILI phenotypes
 Acute hepatitis (resembling viral-hepatitis) isoniazid, ketoconazole, ximelagatran
 Cholestatic or mixed hepatitis amoxicillin-clavulanate, macrolides
 Acute hepatic necrosis acetaminophen, IV amiodarone
 Hypersensitivity syndrome (DRESS*) phenytoin, carbamazepine
 Chronic steatosis/ steatohepatitis methotrexate, tamoxifen, irinotecan
 Acute fatty liver with metabolic acidosis stavudine, tetracycline, sodium valproate
 Drug-induced autoimmune hepatitis minocycline, nitrofurantoin
 Sinusoidal obstruction syndrome cyclophosphamide, azathioprine
 Nodular regenerative hyperplasia azathioprine, HAART, bleomycin
 Immune-mediated liver injury ipilimumab, pembrolizumab, nivolumab
*Drug reaction with eosinophilia and systemic symptoms
 Different clinical manifestations
 Different biochemical abnormalities
 Different clinical outcomes (See Table 2 of CIOMS DILI monograph)

According to the presentation in clinical practice, DILI can produce also a myriad of
phenotypes, and these include, for example, phenotypes that resemble viral
hepatitis, phenotypes of cholestatic or mixed hepatitis, acute hepatic necrosis,
hepatitis with hypersensitivity features, chronic liver syndromes including, for
example, steatosis, steatohepatitis or drug-induced autoimmune hepatitis or vascular
lesions in the liver such as sinusoidal obstruction syndrome. And what is interesting is
that several drugs, different drugs, can produce the same phenotype, but also a given
drug can produce different phenotypes, and this list is not intended to be exhaustive,
so many more other drugs are able to produce the phenotypes here shown. And this
leads to different clinical manifestations, different biochemical abnormalities and
different clinical outcomes.

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 1.2 DILI Clinical manifestions
 Drug-induced liver injury can be asymptomatic and detected in routine liver tests
monitoring
 Clinical manifestations of DILI are unspecific and include fatigue, nausea,
abdominal pain and immunoallergic signs such as fever, rash and adenopathy
 Such manifestations will downgrade the threshold requested for ALT to > 3 x ULN
to be considered as significant liver injury
 Uncommon clinical features linked to sinusoidal endothelial injury may include
ascites or variceal bleeding.
 DILI superimposed in cirrhosis may lead to manifestations of decompensation

What are the clinical manifestations of DILI?

It's important to know that in many instances drug-induced liver injury can be
asymptomatic and only detected in routine liver test monitoring, for example. That is
what normally happens in clinical trials but in some cases, DILI produces specific
clinical manifestations including fatigue, nausea, abdominal pain, and immunologic
signs such as fever, rash, and adenopathy.
And what is also important to know is that the presence of such manifestations will
downgrade the threshold requested for ALT above three times the upper limit normal
to be considered a significant liver injury. In other instances, it can be detected by
uncommon clinical features linked, for example, to sinusoidal endothelial injury,
which produces portal hypertension and manifests as ascites or variceal bleeding.
And also, it's important to know that DILI superimposed on cirrhosis can be expressed
only by the manifestation of decompensation.

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Uppsala Monitoring Centre (UMC)
Box 1051, SE-751 40 Uppsala, Sweden
Email: [email protected], www.who-umc.org