Herbal-Induced Liver Injury (HILI) refers to liver damage caused by traditional Chinese medicines, natural remedies, and related formulations. In recent years, with the widespread global use of herbal medicines and the continuous improvement of adverse drug reaction monitoring systems, reports of HILI have shown an upward trend. Drug-Induced Liver Injury (DILI) caused by herbal factors has garnered increasing attention.
On September 13,at the 2020 Academic Annual Meeting of the Chinese Medical Association Hepatology Branch and Youth Committee Conference, Professor Nan Yuemin from the Department of Hepatology at Hebei Medical University Third Hospital shared key insights based on several large-scale domestic and international studies published in recent years. These included trends in HILI globally, influencing factors, clinical manifestations and classification of HILI, differential diagnosis, similarities and differences between HILI and DILI, diagnostic and treatment principles, and prevention strategies.
01 What factors cause HILI?
According to Asia-Pacific data, DILI occurs at a rate of 1/100,000 to 20/100,000 in the general population, while HILI accounts for 20% of all drug-induced liver injuries, ranking second.In the United States, DILI caused by herbal and dietary supplements has also risen annually, increasing from 7% in 2005 to 19% in 2012.
Classifying drugs by hepatotoxicity, the 2020 edition of the Chinese Pharmacopoeia categorizes 83 potentially toxic Chinese herbal medicines: 31 are low toxicity, 42 are moderately toxic, and 10 are highly toxic.Among these 83 varieties, the most frequently reported cases involved Polygonum multiflorum (He Shou Wu), Rheum officinale (Rhubarb), Psoralea corylifolia (Buzhizhi), and Tripterygium wilfordii (Leigongteng). Within the system, HILI-related reports were most prevalent for orthopedic blood-activating and stasis-resolving agents (mainly containing cinnabar and rhubarb), sedative agents (containing He Shou Wu, Schisandra chinensis, Pinellia ternata, and rhubarb), and exterior-releasing agents (containing cinnabar, Bupleurum chinense, and Mentha haplocalyx).These herbs predominantly contain active components such as alkaloids, glycosides, terpenoid lactones, anthraquinones, and heavy metals, which are the primary causes of drug-induced liver injury.
Beyond the inherent hepatotoxicity of the herbs themselves, improper application of Chinese herbal medicine, irrational combination use leading to excessive intake of certain components, and idiosyncratic reactions are also significant factors contributing to HILI.Furthermore, patients with concomitant dermatological or musculoskeletal conditions are more susceptible to HILI.
02 Why does HILI occur?
The primary mechanisms by which Chinese herbal medicines induce liver injury involve oxidative stress pathways, apoptosis pathways, and bile acid metabolism pathways.
?In the oxidative stress pathway, active drug components are metabolized by CYP450, producing DHR/DHPAs that lead to excessive ROS. Representative drugs include Chinese herbs containing alkaloids such as Polygonum multiflorum, Pinellia ternata, and Evodia rutaecarpa.
?In the apoptosis pathway, DHR/DHPAs activate the BCL-2 family, inducing cell death.
?In the bile acid metabolism pathway, GSH depletion weakens MMP-9 inactivation, leading to massive release into the extracellular matrix and increased degradation, which obstructs bile acid flow and causes bile acid stasis.
03 What manifestations occur with HILI?
The median latency period for herbal-induced liver injury is 1–3 months. HILI clinical manifestations lack specificity and can cause all known types of acute, subacute, and chronic liver injury.
Acute and subacute HILI present with nonspecific and highly variable clinical manifestations, ranging from asymptomatic abnormal liver biochemical markers to hepatocellular injury symptoms like fatigue, anorexia, aversion to greasy foods, nausea, and vomiting.Patients with mixed-type liver injury may develop fever, rash, and peripheral blood eosinophilia indicative of hypersensitivity reactions. Severe cases may involve multi-organ damage, including renal injury.
Chronic HILI may manifest as various chronic liver diseases, including hepatic sinusoidal obstruction syndrome/veno-occlusive disease (HSOS/VOD), chronic hepatitis, cirrhosis, chronic intrahepatic cholestasis, and sclerosing cholangitis.
04 How does liver injury caused by Chinese herbal medicine differ from that caused by Western drugs?
Compared to Western drugs, HILI has a higher incidence in women than men (71% vs. 51%), with higher re-challenge positivity rates and mortality, and predominantly presents as hepatocellular injury.
The RUCAM scale in the "Guidelines for Diagnosis and Treatment of Drug-Induced Liver Injury" is used to evaluate the causal relationship between drugs and liver injury.However, establishing causality between TCM and liver injury is more complex than with DILI from Western drugs. Factors like contraindicated combinations, polypharmacy, and chemical additives in TCM formulations complicate HILI diagnosis. At this conference, Professor Nan also presented assessment methods and criteria for evaluating causality in TCM-induced liver injury.
05 How to Treat HILI?
Timely identification and discontinuation of the causative drug are fundamental measures to prevent HILI progression. For progressive liver injury with significant clinical symptoms, appropriate anti-inflammatory and hepatoprotective agents should be selected alongside symptomatic supportive therapy. For patients with immune-mediated/severe cholestatic HILI, glucocorticoid therapy may be a critical lifesaving intervention.For patients developing ALF/SALF, liver transplantation should be considered.
06 How to prevent HILI?
At the conclusion of the meeting, Professor Nan addressed HILI prevention. She emphasized the importance of recognizing hepatotoxicity in Chinese herbal medicines, enhancing training for healthcare professionals and public education to raise awareness of HILI, while simultaneously improving the overall level of TCM pattern differentiation and treatment among TCM practitioners.
Second, herbal medicines with reported liver toxicity should be used cautiously, with strict dose and duration limitations. Patients with chronic liver disease history who take herbal medicines long-term should undergo regular liver function monitoring.
Finally, patients with prior HILI should avoid re-using herbal medicines containing identical or similar chemical components to those implicated in their previous liver injury.