New Insights into Herb-Induced Liver Injury

Abstract

Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise, and our understanding of the underlying etiologies is in progress, and hence, an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction [HHI]) or non-herb components (herb-drug interaction [HDI]) has also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focus on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI, and analysis on several types of newly reported "toxic" effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Directions: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail subclassification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on the Roussel Uclaf Causality Assessment Method (RUCAM). Antioxid. Redox Signal. 38, 1138-1149.

Keywords: Roussel Uclaf Causality Assessment Method; hepatotoxicity subtypes; hepatotoxicity-related substance; herb-induced liver injury; oxidative stress.

FIG. 1.

Potential risk factors associated with HILI. The herb-, host-, and environment-related risk factors involved in the pathogenesis of HILI. HILI, herb-induced liver injury.

FIG. 2.

Congenital and acquired factors jointly used to determine the HILI susceptibility of the host. Recent research indicates that host-related risk factors of HILI involve both congenital (gene polymorphisms) and acquired (metabolism and immune hemostasis) factors.

FIG. 3.

The molecular mechanisms of TPL-induced liver injury. The main mechanisms include oxidative stress, apoptosis, mitophagy, and Th17/Treg imbalance. These events can influence each other and finally lead to liver injury. TPL, triptolide.

FIG. 4.

The molecular mechanisms of PM-induced idiosyncratic liver injury. When the susceptible population is under mild immune stress (such as TNF-α, CCl-2, VEGF upregulation), the immune-promoting components of PM—trans-2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside, may enhance the body's immune activation, which increases the susceptibility of the liver to the components of PM—cis-2,3,5,4′-tetrahydroxystilbene-2-O-β-glucoside and emodin-8-O-glucoside, and results in liver injury. Furthermore, the components of PM—emodin and aloe-emodin, can exhaust antioxidants, induce oxidative stress, and contribute to PM-induced liver injury. PM, Polygonum multiflorum.

FIG. 5.

The molecular mechanisms of Epimedium brevicornu-induced indirect liver injury. When maximum non-toxic LPS (in vivo), ATP, or nigericin (in vitro) exist concurrently, the components of E. brevicornu—icariside I or II, can induce NLRP3 inflammasome activation, causing IL-1β production, oxidative stress, pyroptosis, and finally liver injury.