Diagnosis, management

and
prevention of drug-induced
liver injury

Drug-induced liver injury (DILI) is

increasingly being recognised as a
significant cause of both acute and chronic
liver disease.

The most commonly implicated agents are

paracetamol, antimicrobials, CNS drugs,
NSAIDs, statins, isoniazid , captopril and
herbal remedies.

Drug hepatotoxicity, is the leading cause of

acute liver failure (ALF). [approximately
50% of all cases.]

Drug-induced ALF is also associated with

high morbidity and mortality, [ only a 20%
survival in the absence of liver
transplantation.]

CLASSIFICATION

Hepatotoxicity can be classified as

predictable

unpredictable (idiosyncratic).

predictable
This form is dose related.
has a high incidence.
and occurs with a short latency (within a
few days).

The classical example of predictable drug

toxicity is paracetamol.

idiosyncratic reactions
occur with variable latency (1 week to 1
year
or more),
with low incidence,
may or may not be dose related.

The majority of hepatotoxic drugs cause

idiosyncratic reactions.

OTHER CLASSIFICATION

DILI can also be classified as:

1)immune mediated (allergic)

2) non-immune mediated (non- allergic)

Immune-mediated idiosyncratic
reactions can be characterised by
presence of:

fever,
rash,
eosinophilia and
autoantibodies (such as antinuclear and smooth
muscle antibodies).

Severe cases may be accompanied by

StevensJohnson syndrome,
toxic epidermal necrolysis, and
haematological features such as granulocytopenia,
thrombocytopenia or haemolytic anaemia.

DIAGNOSIS

The key to causality is to assess :

1) the temporal relationship between
drug initiation and development of an
abnormal liver panel,
2) the individual susceptibility to DILI
3) and to diligently exclude other causes
of liver diseases.

Be carefull

In a cohort study of patients with suspected

DILI:
(21%) had a Positive HEV serology.
(23.1%) were subsequently diagnosed
with AIH .

Lab tests

Laboratory tests that might aid diagnosis of

immune-mediated reactions include :
the lymphocyte-stimulation test.

In atypical cases of paracetamol overdose:

detection of serum paracetamol
adducts.

Finally

individual drugs exhibit a characteristic clinical

signature, which may assist in the diagnosis of DILI:
(1)the pattern of the abnormal liver panel
(hepatitis,
cholestasis or mixed);
(2) duration of latency to symptomatic
presentation;
(3) presence or absence of immune-mediated
hypersensitivity (ie, immune or non-immune
reaction)
(4) response to drug withdrawal.

PATTERNS OF LIVER PANEL

ABNORMALITY

HEPATITIS PATTERN OF
DILI

hepatitis form most likely to be

associatedwith acute liver failure.

Indicator of severity

There is usually poor correlation between

degree of ALT elevation and the severity of
the liver disease.

histology being a more accurate indicator.

However, jaundice is a good predictor of

mortality in drug-induced hepatitis.

Hys law

A consistent serum bilirubin 3 ULN, ( in the

absence of biliary obstruction or Gilberts syndrome,) is
associated with a mortality of approximately
10%. (range, 550%)

Mixed pattern

This pattern of liver injury probably has the

lowest mortality.

MANAGEMENT

prompt discontinuation of the offending

drug,

supportive and symptomatic therapy,

monitoring for the development of ALF.

Treatment

Use of glucocorticoids for immunemediated reactions and ursodeoxycholic

acid (UDCA) for cholestatic liver injury
remain controversial therapies

Treatment
in the subset with DILI, there was a trend
towards a worse prognosis in those on
steroid therapy
it may be reasonable to treat prolonged
cholestasis due to DILI with UDCA in a dose
of 1315 mg/kg.
in drug-induced hepatitis with allergic
features, with no improvement after drug
withdrawal, a short course of steroids may
be justifiable.

Treatment
Antioxidants have also been proposed as a
treatment modality for severe DILI
N-acetylcysteine (NAC) is the treatment of
choice for paracetamol overdose.
At the earliest signs of liver failure (INR.1.5,
development of ascites, or any grade of
hepatic encephalopathy), prompt referral to
a liver transplant unit is indicated.

More accurate predictors of liver failure are:

an ALT of 10ULN (rarely observed in

placebo-treated patients), or

an ALT of 3ULN accompanied by

serumbilirubin of .2ULN (modified Hys
law).

The higher the serum bilirubin, the more

severe the liver injury

ALT Monitoring

Drugs that result in predictable injury would

not qualify for monthly monitoring, since
such reactions occur early.(within a few
days)

The apparent non-immune cases associated

with delayed toxicity may be suitable for
such a risk management strategy

ALT Monitoring
though there may still be a number of
concerns:
1)compliance with monthly monitoring is
poor.
2 ) such a strategy may lead to premature
termination of drugs in patients who would
otherwise benefit from their use.
3) Finally, serious DILI can occur despite
monitoring of the liver panel

ALT Monitoring

where a benefitrisk analysis would favour

continued therapy, monthly monitoring may
be beneficial compared with no monitoring
at all

Prevention of drug-induced liver

injury includes:
vigilance,
identification of risk factors,
ALT monitoring with certain drugs, and
safer marketing strategies.
the most useful way to prevent DILI would
be to educate our patients about the
warning signs of severe drug injury such as
abdominal pain, nausea, vomiting and
jaundice.

CONCLUSION
drug-induced liver injury must be included
as a differential diagnosis in all patients
with an abnormal liver panel.
Management of patients with drug induced
liver injury needs increased vigilance, as

once liver failure develops spontaneous survival

(in the absence of liver transplantation) is rare,
except in those with paracetamol-induced
hepatotoxicity

Thanks for your

attention

Thanks for your attention