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Abstract
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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...
Language: en |