Drug‐induced liver injury caused by herbal and dietary supplements: where to next?

Collaboration and education are critical to understanding and managing this mounting public health problem

Drug‐induced liver injury (DILI) is a major cause of acute liver failure, leading to liver transplantation and death,1 and it is one of the most frequent safety‐related causes of drug marketing withdrawals.2 DILI poses a growing challenge for clinicians, researchers, and regulatory bodies, with a vast array of new medications and herbal and dietary supplements constantly becoming available. Despite decades of experience with drug hepatotoxicity and the relatively recent development of clinical guidelines, registries, and other collaborative resources, much is still to be learned in this important field of medicine.

In contrast to intrinsic DILI (eg, paracetamol‐induced DILI), idiosyncratic DILI (iDILI) is unpredictable, affecting only susceptible individuals, and it is difficult to diagnose and manage. It is also difficult to quantify the incidence of iDILI, as only severe cases are generally diagnosed and reported. Other cases may be misdiagnosed or entirely missed because they are symptom‐free or attributed to other causes. For most drugs, iDILI is thought to affect 1:100 000 to 1:10 000 of treated patients, but the true incidence is probably much higher.3

In this issue of the MJA, Nash and colleagues4 report their retrospective analysis of data for all adults admitted to their metropolitan liver transplant centre with DILI during 2009–2020. They found that the proportion of non‐paracetamol admissions for DILI linked with herbal and dietary supplements had more than trebled during this period (from 15% to 47%), and that the patients involved had poorer outcomes (90‐day transplant‐free survival: 59%; 95% confidence interval [CI], 34–85%) than people admitted with DILI caused by paracetamol (86%; 95% CI, 79–93%) or other prescription medicines (74%; 95% CI, 62–87%). Seven of 15 patients with supplement‐related DILI had non‐European ethnic backgrounds (47%), compared with eight of 54 with DILI linked with non‐paracetamol medications (15%). Traditional Chinese medicines (four cases) and anabolic steroids and bodybuilding supplements (five cases) were the two most frequently implicated supplement types. The findings of Nash and her colleagues4 are of significant public health concern and highlight the need for improved education and regulatory oversight of herbal and dietary supplements, as well as for local and international registries to support health authorities.

The use of complementary medicines, including herbal and dietary supplements, is increasing in Australia and overseas,5,6 and this poses new challenges for our assessment and understanding of DILI. Herbal and dietary supplements are implicated in more than 20% of DILI cases.6 Even the most commonly used supplements, such as green tea and turmeric, can cause hepatotoxicity, despite their marketing as safe agents and few published reports of adverse events.6,7 In Australia, the Therapeutic Goods Administration (TGA) regulates complementary medicines, as defined in the Therapeutic Goods Regulations 1990, as therapeutic goods in a risk‐based, two‐tier system: lower risk products are “listed” and higher risk medicines “registered” with the Australian Register of Therapeutic Goods.8 Extensive post‐marketing regulatory activities and compliance reviews include pharmacovigilance programs for assessing adverse events reported to the TGA. Products purchased from overseas, however, are not regulated by the TGA, and their safety cannot be guaranteed.

Outcomes for patients with DILI cannot be reliably predicted, and the diagnosis is one of exclusion, after other potential aetiologies of liver injury have been eliminated. Identifying the drug involved, even with standard approaches (eg, the Roussel–Uclaf causality assessment method [RUCAM] and expert opinion), can be difficult, especially in cases of polypharmacy. For this reason, the European Medicines Agency and other international initiatives have sought specific biomarkers of DILI. The first in vitro test, using monocyte‐derived hepatocyte‐like (MH) cells to identify iDILI and the causative drugs (including in people taking several medications), was described in 2016.9

Building on the establishment of DILI registries overseas, including the United States DILI Network (US DILIN)10 and LiverTox,11 the Gastroenterology Society Clinical Research Network established a local Australian network, AusDILIN, in 2020 to prospectively collect and analyse data; more than 100 cases have since been reported by 14 participating hospitals. International networks have also been proposed, to enhance patient and provider education, research, collaboration, and knowledge about the epidemiology of DILI.12

The paucity of knowledge about and epidemiologic data for DILI remains a problem. Collaboration via multicentre and multinational DILI registries, biobanks, and other networks is imperative for ensuring robust scientific and regulatory guidance on the hepatic safety of medications and herbal and dietary supplements. In the meantime, community education and awareness programs on the potential dangers of supplements should be given priority to alleviate this mounting public health problem.