Drug-induced liver injury (DILI) is the most common cause for acute liver failure
in the USA and Europe. DILI is also a leading cause of attrition of compounds in drug
development and one of the two most frequent causes for drug withdrawals, restrictions,
and project terminations. Whereas liver signals that escape detection during drug
approval result in postmarketing restrictions (e. g., pazopanib, temozolomide and
flupirtine in 2013), the risk of false-positive DILI adjudication may lead to unnecessary
attrition, thereby contributing to the considerable economic issues associated with
DILI [1].
It is crucial to discriminate two types of DILI, intrinsic and idiosyncratic DILI.
Intrinsic DILI is dose-dependent and occurs with a rather short latency. Prime example
for intrinsic DILI is acetaminophen (APAP). Patients who consume APAP at a single
dose exceeding 7.5 g experience acute liver toxicity. Intrinsic DILI is reproducible
in preclinical models and much insight has been gained into the underlying mechanisms.
In contrast to intrinsic DILI, the occurence of idiosyncratic DILI, which is very
rare but nonetheless responsible for about 10 – 15% of acute liver failures in the
USA, is almost impossible to predict. This type of DILI is characterised by a variable
latency to onset (weeks to months) and a lack of clear dose-dependency. Idiosyncratic
DILI may be triggered by many drugs and herbal and dietary supplements and is a diagnostic
challenge due to the lack of an in vitro test [1], [2]. Diagnosis is based on exclusion of other causes of acute liver injury, scoring
systems such as RUCAM, drug signatures which can be found in registries such as livertox.nih.gov
[3], and on expert adjudication.
No specific treatment has been established for idiosyncratic DILI. Severe cases of
acute liver failure may need liver transplantation. The immediate consequence upon
diagnosis of DILI is withdrawal of the causal drug. Unfortunately, identification
of the culprit drug may be impossible in polypharmacy which is typical in DILI patients.
Moreover, the differential diagnosis of autoimmune hepatitis is a big practical challenge
with major therapeutic implications [4].
Whereas longterm steroid treatment is key for autoimmune hepatitis it has no proven
benefit in DILI but still is fraught with the well known side effects.
On this background, diagnostic and prognostic biomarkers of DILI are urgently needed.
Several serum markers and an in vitro causality test based on blood cells of individual
affected patients are currently under investigation [5].
