Landscape of Liver Injury From Herbal and Dietary Supplements in Europe, Latin America, and Asia

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Abbreviations

DILI

drug‐induced liver injury

HILI

herbal and dietary supplement hepatotoxicity

Key Points

• Herbal and dietary supplement hepatotoxicity (HILI) is scarcely reported in Europe and has a particular signature of hepatocellular pattern of liver injury, female sex predominance, and a greater severity compared with drug‐induced liver injury (DILI) because of conventional medications.

• In Latin America, preliminary unpublished data suggest that the relative prevalence of HILI with regard to DILI is greater than in Europe and the signature is similar.

• In Asian countries, HILI, showing a similar signature than in the other continents, is the first cause of hepatotoxicity, except in India, despite the wide use of Ayurvedic medicine, although case series are increasingly being reported.

The burden of HILI is just emerging as a growing concern in Western countries. However, the magnitude of the problem is probably greater in other areas of the world where data are scarcer. In fact, new initiatives in Latin America are starting to yield information on the relative prevalence of HILI among the agents responsible for hepatotoxicity. Asian countries report a quite variable incidence of HILI, although prospective studies with strict definitions and robust inclusion criteria are still lacking.

Europe

In Europe, herbal products may also be classified as food supplements and marketed as such. An herb may be considered a medicinal product when it is described as having properties for treating or preventing diseases in human. The European Food Safety Authority oversees health claims made on herbal products marketed as food supplements. These products should comply with the Directive 2002/46/EC, which establishes a simplified regulatory procedure for these medicinal products. The value of market for herbs and dietary supplements in Europe substantially varies across countries, being most important in Western Europe, and forecasts an increase in sales by 2020 as compared with the previous years.

Data on HILI incidence in a general population came from a 2‐year population‐based study in Iceland, which estimated the overall annual incidence of idiosyncratic DILI to be 19 cases per 100,000 inhabitants, with an estimated incidence of acute liver injury caused by herbal products of 3 cases per 100,000 persons.1

In the Spanish DILI Registry, the yearly proportion of HILI was 1.5% in 1998 and increased steadily to 6% of the cases identified from 2010 to 2013, as well as 2014 to 2016. Herbal and dietary supplements products were responsible for 4% (32 cases) of the 856 DILI cases in the Spanish DILI Registry. The HILI group showed a particular signature: a female predominance (63%), hepatocellular type of injury (94%), and greater severity evolving more frequently into acute liver failure (6%) than conventional DILI (4%); it was also more frequently associated with rechallenge (9% versus 6%).2

Latin America

In Latin America, there is an extended traditional market for herbs and dietary supplements. However, there are notable differences in policies and regulations for traditional medicines, making the market more heterogeneous and scarcely regulated. The World Health Organization Traditional Medicine Strategy 2014‐2023 is expected to change the landscape by strengthening the regulatory framework and safety monitoring in the continent.

The ongoing Spanish Latin DILI Network will certainly contribute to providing a picture of HILI in Latin America. Preliminary unpublished data indicate a higher relative prevalence of HILI in this continent than in Europe and a similar signature of HILI cases with greater severity compared with DILI.

Asia

In some Asian countries such as China and India, and even in others more technologically advanced such as Korea and Singapore, traditional medicines including herbs and dietary supplements are official and are integrated into their health care system. The relative prevalence of HILI from traditional medicines and dietary supplements shows notable differences across the Asian countries, with 17.1% in Japan,3 18.6% in China,4 71% in Singapore,5 and 72.7% in Korea.6 In the prospective, nationwide study of DILI undertaken in South Korea over a 2‐year period in 17 referral university hospitals, the extrapolated incidence of hospitalization because of DILI was 12 per 100,000 persons per year. Traditional and herbal medicines were the most common cause of hepatotoxicity, being implicated in more than 72% of the cases.6 In India, Ayurvedic medicines, which are part of the health care system and are considered traditionally safe when purchased via the Internet, contain detectable lead, mercury, or arsenic (19.5%‐21.7%),7 and cases of hepatotoxicity are being increasingly detected and reported.8 In China, a large, retrospective, single‐center study including more than 1900 DILI cases showed that Chinese herbal medicine accounted for the 28.4% of the cases with a signature similar to that reported in a prospective series.9