Drug-induced liver injury (DILI) is a rare but potentially life-threatening condition,
which accounts for the majority of acute liver failure cases in the US and EU. Unlike
direct hepatoxicity, which is mainly caused by acetaminophen, idiosyncratic DILI is
unpredictable and occurs unrelated to the dose or frequency of the medication. Interestingly,
DILI cannot only be caused by a large variety of prescription drugs, but also by herbal
and dietary supplements (HDS). While HDS-DILI has already played a role in Asian countries
like China or Korea for a long time, there is also an increasing incidence of HDS-DILI
in countries with formerly less HDS-DILI cases such as the US, presumably due to a
rising usage of those remedies (1).
With those rising incidence rates, the recognition of HDS as potential hepatotoxic
agents is also increasing. Consequently, an updated American Association for the Study
of Liver Diseases (AASLD) practice guidance on drug, herbal, and dietary supplement–induced
liver injury has recently been published by Fontana et al. (2). The guideline nicely
points out a well-known problem for DILI experts: DILI is a diagnosis of exclusion
and therefore remains a diagnostic challenge (3). Due to the lack of standardized
diagnostic test or validated biomarkers, the current gold standard of DILI diagnosis
is still expert consensus opinion (2,4). In addition, causality assessment tools can
assist in establishing DILI diagnosis since they provide a systemic approach for the
evaluation of the likelihood that a specific medication has caused liver injury. Moreover,
such tools can help identifying the causative agent in polymedicated patients. There
are several causality assessment methods available with the Roussel Uclaf Causality
Assessment Method (RUCAM) being most frequently used. The RUCAM scores the likelihood
of DILI according to different items comprised of latency from drug intake, evolution
upon drug withdrawal, known risk factors, previous information on hepatoxicity and
outcome upon rechallenge (5). However, when it comes to evaluating HDS-induced DILI,
application of RUCAM has major limitations especially concerning the items previous
hepatotoxicity and reaction to re-exposure.
With regards to the information on previous hepatoxicity the importance of researching
for comparable DILI cases in medical databases, such as LiverTox was highlighted in
the AASLD practice guidance (6). LiverTox gives a brief synopsis on typical patterns
of liver injury reported for a large number of drugs. Moreover, a grading for the
likelihood of hepatotoxicity caused by the specific drug according to the number of
available reports on previous DILI cases is provided. However, with more than 100,000
different HDS sold alone in the USA (2), it is obvious that case reports most likely
have not been reported for every HDS available. Moreover, an underreporting of previous
cases in the medical literature has to be expected, since patients might not mention
HDS intake and physicians might not ask about such intake since they do not perceive
HDS as possibly harmful. Accordingly, Fontana et al. point out that while LiverTox
provides information for more than 1,000 prescription drugs, only 60 HDS are listed
in the database (2). Interestingly, we have previously shown that in addition to conventional
medical databases, information on HDS-induced hepatotoxicity can also be gained from
commercial websites: while only six cases of ashwagandha-induced liver injury could
be found in medical databases (6), eleven consumers reported liver problems in the
customers’ reviews of one of major commercial websites selling Ashwagandha. Now, two
of them even stating to have suffered from acute liver failure (7). Thus, in addition
to focusing on professionally published case reports, previous information on hepatotoxicity
should also be extracted from consumers’ reviews.
Another challenge in diagnosis and identify HDS-DILI is the uncertainty of the actual
HDS components. Due to changes in cultivation conditions, undeclared ingredients or
contamination with bystander components, the composition of HDS can vary even within
the same HDS preparation (1,2). In addition, intentional adulteration with pharmaceuticals
with the aim to enhance the therapeutic effect the HDS is marketed with, has been
described (1,2). Thus, evaluation of previous hepatoxicity and re-exposure can be
complicated by incomplete knowledge of the specific ingredients. Even in the case
of a (deliberate) re-exposure it cannot be assured that the patient is treated with
the same type of compounds, on the other hand unintentional re-exposure might occur
even when a supposedly different HDS is used. Therefore, RUCAM can be misleading in
patients with suspected HDS-DILI and might favour prescription drugs over HDS as the
underlying cause in patients with polymedication.
To overcome some of the limitations of the RUCAM, the so-called RECAM, an updated
electronic version of the RUCAM is now available. This scale expands the scope of
alternative diagnosis that should be excluded and excludes risk factors which according
to newer data are in fact not related with increased DILI risk (8). However, RECAM
was developed and validated within the US, validation in other geographical regions
with different drug spectrums causing DILI and evaluation in HDS-induced DILI cases
is still outstanding (8).
With regards to the exclusion of alternative diagnoses, Fontana et al. mention the
importance of testing and excluding viral hepatitis. In line with this, it was stated
that of all suspected DILI cases in the US DILI network (DILIN) 1.3% and 3% were later
tested positive for hepatis C or E, respectively (2). However, while testing for and
therefore excluding viral hepatis can be routinely performed in suspected DILI case,
exclusion of autoimmune hepatitis (AIH) can pose greater challenges. Regarding this
topic, the AASLD guidance recommends to test for autoantibodies, e.g., antinuclear
and anti-smooth muscle antibodies (ANA and ASMA) as well as serum Ig levels during
the hepatological work-up. Moreover, it is mentioned that DILI with an AIH-like phenotype
can occur, however, without further specification on definition, diagnosis or management
(2). The acceptance of drug-induced autoimmune-like hepatitis (DI-ALH) as an independent
entity which should be differentiated from idiopathic AIH and DILI has been recently
underscored by an expert meeting report published on the nomenclature, diagnosis and
management of DI-ALH (9). Nevertheless, distinguishing DILI from AIH and also from
DI-ALH can be challenging and even impossible in some cases, since clinical, laboratory
and histopathological features might be indistinguishable (9-11). While Fontana et
al. focus on testing for antibodies presumably specific for AIH, it has been previously
shown that DILI as well as DI-ALH can also present with positive autoantibodies especially
ANA (12). Thus, the presence of autoantibodies in acute liver injury does not exclude
DILI as a diagnosis. Nevertheless, differentiating DILI and DI-ALH from AIH is of
high importance for the individual patient, since patients with DILI or DI-ALH rarely
need lifelong immunosuppression in contrast to idiopathic AIH (9). Moreover, while
in some DI-ALH cases, liver injury might resolve upon discontinuation of the drug
without immunosuppression, a relevant proportion of patients with DI-AIH require extended
immunosuppression when compared to conventional DILI (11). In the absence of diagnostic
tests for DILI or validated DILI biomarkers the only reliable diagnostic criterion
in those unclear cases is the evolution under immunosuppression and tapering of such.
In this regard, it has been previously shown that rapid reduction of alanine aminotransferase
(ALT) indicates towards DILI rather than AIH being the cause of liver injury (13).
Thus, positive testing for autoantibodies in suspected DILI or HDS-DILI should not
per se exclude the possibility DILI or DI-ALH and tapering of immunosuppression with
close monitoring of liver parameters, especially ALT, should be considered early on,
in particular in the cases with rapid ALT decline.
The practice guidance also discusses the natural history and management of idiosyncratic
DILI in general and of HDS-DILI in specific, highlighting the poor outcome of patients
with drug-induced liver failure as well as emphasizing the importance of referral
of those cases to transplant centres (2,4). Most likely due to delay in identification
of HDS as the causative agent in DILI, patients with HDS-induced liver failure have
an even higher risk of needing liver transplantation or death when compared to patients
with DILI caused by prescription drugs (2,14). However, while liver injury can be
life-threatening in a relevant number of cases, treatment options are limited. In
drug-induced liver failure, treatment with N-acetylcysteine in accordance with recommendations
for acetaminophen-induced liver injury is suggested (2). In addition, positive effects
for corticosteroids or ursodeoxycholic acid have been described (2,13), however, randomized
controlled trials are still missing. In the current AASLD guidance statements, the
use of methylprednisolone as the corticosteroid of choice is mentioned, possibly in
accordance with international recommendations on treatment of immune checkpoint inhibitor-induced
liver injury. Nevertheless, while being a rare condition, methylprednisolone-induced
liver injury has been observed as highlighted by case series recently published by
us (15). Therefore, we recommend using prednisolone rather than methylprednisolone
in case corticosteroid treatment is initiated in a potential DILI patient.
In conclusion, the AASLD guidance shows us that despite the numerous limitations and
obstacles in the diagnosis of HDS-related DILI, early recognition of HDS-DILI cases
is of high importance, in particular due to the poor outcome of HDS-induced liver
failure.
Supplementary
The article’s supplementary files as
10.21037/hbsn-23-329