1. Drug-induced liver injury (DILI) has an incidence of 14 to 19 cases per 100,000 persons and is responsible for 3 to 5% of hospital admissions for jaundice. 2. DILI can be caused by direct hepatotoxicity from intrinsically toxic agents or idiosyncratic hepatotoxicity from agents that rarely cause injury. 3. Risk factors for DILI include old age, female sex, metabolic syndrome, and chronic hepatitis B or C. Drugs that cause DILI often have hepatic metabolism by cytochrome P450 enzymes and form reactive metabolites.

1. DRUG-INDUCED LIVER
INJURY – EASL 2019
GUIDELINES
Ahmed Elmoughazy
Assistant lecturer in
Hepato-Gastroenterology
unit, Internal Medicine
department, MRI

2. EPIDEMIOLOGY
Incidence is estimated to be 14 to 19 cases per
100,000 persons.
Drug-induced liver injury is responsible for 3
to 5% of hospital admissions for jaundice and is
the most frequent cause of acute liver failure in
most Western countries, accounting for more
than half of cases.

3. TYPES
Direct hepatotoxicity is
caused
by agents that are intrinsically
toxic to the liver.
The injury is common,
predictable, dose-dependent,
and reproducible in animal
models.
The latency period is
typically short, usually with an
onset within 1 to 5 days after
high therapeutic or
supratherapeutic doses, as in
the case of an intentional or
accidental overdose.

4. DIRECT
HEPATOTOX
ICITY
Acute hepatic necrosis
is the most common
form of clinically
apparent direct
hepatotoxicity.
Serum alanine
aminotransferase levels
rise to high values,
whereas alkaline
phosphatase levels are
minimally elevated.

5. TYPES
Idiosyncratic
hepatotoxicity is caused
by agents that have little
or no intrinsic toxicity and
that cause liver injury only
in rare cases, typically
after 1 in 2000 to 1
in100,000 patient-
exposures.
 The injury is
unpredictable, not dose-
dependent, and not
reproducible in animal
models

6. IDIOSYNCRA
TIC
HEPATOTOXI
CITYAcute hepatocellular
hepatitis is the most
common manifestation of
idiosyncratic liver injury.
The symptoms and course
resemble those of acute
viral hepatitis, with
prominent alanine
aminotransferase
elevations (increased by a
factor of 5 to 50), whereas
alkaline phosphatase
levels are only modestly
increased.

9. The focus of these guidelines is idiosyncratic drug-induced liver
injury (DILI).

10. RISK FACRTORS
Old age
Female sex
Metabolic syndrome
Chronic hepatitis B and C can be considered risk factors for DILI from
anti-HIV and anti-TBC therapy.

11. POTENTIAL DRUGS TO CAUSE DILI
A daily dose of >100 mg whatever the drug:
1. Predominant hepatic metabolism by cytochrome P450 enzymes.
2. The formation of reactive metabolites.
3. Dual inhibition of mitochondria and bile salt export pump function.

13. DRUG-
INDUCED AIH
In cohorts of cases with
the diagnosis of AIH, 2–9%
were considered to be
induced by drugs and
conversely, drug-induced
AIH accounts for 9% of all
DILI.
Suspected drug-induced
AIH should be evaluated
in detail including
causality assessment,
serology, genetic tests
and liver biopsy whenever
possible.

14. DRUG-
INDUCED
AIH
In cases where even liver histological features
cannot establish drug aetiology with certainty, it is
reasonable to institute corticosteroid therapy in
patients who do not show recovery despite drug
cessation, with an intention to avoid progression
of liver injury.
However, once remission has been achieved,
withdrawal of immunosuppression and close
monitoring would resolve the diagnosis in the
majority as drug-induced AIH do not relapse over
a follow-up of 3–4 years.

15. SECONDAR
Y
SCLEROSIN
G
CHOLANGIT
IS
Following transarterial infusion of
chemotherapeutic agents, as a result of
ischaemic injury to the biliary tract
rather than toxicity from
chemotherapeutic agents themselves.

16. FATTY
LIVER AND
DILI
Acute fatty liver: This is a rare
form of acute hepatotoxicity
referred to as ‘Reye’s
syndrome’ when seen in
children treated with salicylate.

17. FATTY
LIVER AND
DILI
Drug-associated fatty liver
disease.

18. IMMUNE CHECKPOINT INHIBITORS
(ICIS)
Immunotherapeutic agents that act as immune blockades increase T
cell responses and restore potent anti- tumour immune responses
that are suppressed in cancer, with the goal of inducing tumour
rejection.

21. LIVER
TUMOURS

22. DX

23. ROLE OF
BIOPSY

24. TREATMENT
The most important initial step in terms of
management of suspected DILI is to discontinue the
implicated agent. In the large majority of DILI,
spontaneous recovery occurs, without the need for any
treatment or specific measure. In fact, spontaneous
recovery after discontinuation of the offending drug is
an important criterion in the causality assessment.
However, improvement may not begin immediately
and ongoing or even worsening injury can occur
despite withdrawal of the causative agent.
Patients with concomitant jaundice should be kept
under active surveillance with frequent testing of liver
biochemistries.

25. TREATMENT
 Short administration of cholestyramine may be used
to decrease the course of hepatotoxicity induced by
very selected drugs, such as leflunomide and
terbinafine.
Carnitine may be used to improve the course of
valproate hepatotoxicity.
The efficacy of Ursodeoxycholic acid to reduce the
severity of liver injury may not be substantiated.

26. TREATMENT
Corticosteroids are often given when all else fails to
produce results.
Early trials of corticosteroid treatments demonstrated
limited benefits.
Corticosteroids can be used to treat drug-induced
cholestatic hepatitis, in particular associated with
hypersensitivity features such as eosinophilia, rash
and fever (antiepileptic drugs).

27. TREATMENT
•N-acetylcysteine used
early in the course of
Acute liver failure (ALF)
may prevent
progression to more
severe encephalopathy
and may also exert renal
protective effects.