Transcript Diagnosis, management and prevention of drug

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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.
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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.]
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Hepatotoxicity can be classified as
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predictable
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unpredictable (idiosyncratic).
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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.
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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.
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DILI can also be classified as:
1)immune mediated (allergic)
2) non-immune mediated (non- allergic)
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fever,
rash,
eosinophilia and
autoantibodies (such as antinuclear and smooth
muscle antibodies).
Severe cases may be accompanied by
 Stevens–Johnson syndrome,
 toxic epidermal necrolysis, and
 haematological features such as
granulocytopenia,
thrombocytopenia or
haemolytic anaemia.
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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.
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In a cohort study of patients with suspected
DILI:
(21%) had a Positive HEV serology.
(23.1%) were subsequently diagnosed
with AIH .
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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.
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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.
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hepatitis form most likely to be
associatedwith acute liver failure.
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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.
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A consistent serum bilirubin ≥3 ×ULN, ( in the
absence of biliary obstruction or Gilbert’s syndrome,) is
associated with a mortality of approximately
10%. (range, 5–50%)
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This pattern of liver injury probably has the
lowest mortality.
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prompt discontinuation of the offending
drug,
supportive and symptomatic therapy,
monitoring for the development of ALF.
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Use of glucocorticoids for immunemediated reactions and ursodeoxycholic
acid (UDCA) for cholestatic liver injury
remain controversial therapies
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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 13–15 mg/kg.
in drug-induced hepatitis with allergic
features, with no improvement after drug
withdrawal, a short course of steroids may be
justifiable.
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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.
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an ALT of 10×ULN (rarely observed in
placebo-treated patients), or
an ALT of ≥3×ULN accompanied by
serumbilirubin of ≥.2×ULN (modified Hy’s
law).
The higher the serum bilirubin, the more
severe the liver injury
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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
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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
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where a benefit–risk analysis would favour
continued therapy, monthly monitoring may
be beneficial compared with no monitoring at
all
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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.
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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