Herbal and Dietary Supplement-Induced Liver Injury

Herbal and dietary supplements (HDS) are used by nearly 1 in 5 Americans, but their use is not commonly reported to, or detected by, healthcare providers.^1,2 HDS use is even more common outside the United States.^3,4 Patterns of liver injury are highly variable, even among cases where injury is purported to result from the same product. The liver is often the target of HDS toxicity, given its integral role in metabolism, and HDS-induced liver injury is a common cause of acute liver failure in the United States.^5,6

Determining causality in HDS-induced liver injury is often difficult, as patients frequently take supplements along with many prescribed and nonprescribed medications. As such, the interaction between HDS and other medications often cannot be gauged. Further confounding the attribution of causality in cases of hepatotoxicity among patients consuming HDS are the potential multiplicity of ingredients within any given product (some of which may not be identified on the label) and seasonal variations in the harvesting of natural products, which could affect their strength and composition.

The diagnosis of hepatotoxicity associated with HDS is typically made after excluding viral, autoimmune, metabolic, and anatomic causes of liver test abnormalities. Several models to assess causality exist in the literature, including the Roussel Uclaf Causality Assessment Model (RUCAM) and the Maria & Victorino (M&V) scale.^7,8 Still, expert opinion remains the gold standard for diag-nosis.⁹ RUCAM is the most frequently referenced scoring system, but it is not commonly used in clinical practice. The M&V scale is more specific but less sensitive, and it gives weight to prior reports in the literature for medications that have been in existence for less than 5 years. The M&V scale tends to underattribute causality compared to RUCAM, while RUCAM tends to underattribute causality compared to expert opinion.^9,10 Expert opinion can also vary significantly between evaluators. To help minimize this variation, consensus expert opinion can be sought, although interobserver variability can still exist, even at this level of adjudication.¹⁰

Since the holy grail of causality continues to be elusive, many efforts are underway worldwide to better understand the mechanisms behind drug-induced liver injury (DILI). These efforts include investigation of host factors using pharmacogenetic and proteomic testing, as well as other diagnostic tools.¹¹ In the United States, the Drug-Induced Liver Injury Network (DILIN) was created to identify a large number of patients with bona fide DILI and to collect epidemiologic and biologic data for future studies.¹² Additionally, the DILIN focuses on developing and testing causality assessment measures for drug, herbal, and over-the-counter medication—induced liver injury.¹²

While the case reported by Inoue and colleagues lacks a formal causality assessment, causality is more straightforward in this case than in most cases of HDS-induced liver injury, as this patient was taking no other supplements or medications preceding the acute liver injury.¹³ However, like many HDS implicated in hepatotoxicity, kamishoyosan is not just one ingredient. Rather, it is comprised of 10 different extracts, including glycyrrhizin—the same supplement that the authors used to treat the liver injury they surmised was related to this supplement. Thus, attribution of the liver injury to one ingredient is quite problematic. Among the noted ingredients of kamishoyosan, glycyrrhizin and mentha (pennyroyal) are the 2 ingredients that are most often associated with liver test abnormali-ties.^14,15 In a large study conducted in Germany that examined the incidence of liver test abnormalities among recipients of traditional Chinese medicines, glycyrrhizin and Atractylodis were the ingredients most commonly associated with liver test abnormalities, occurring with a frequency approaching 1%.¹⁶ Additionally, the patient described by Inoue and coauthors was taking kamishoyosan for the second time.¹³ Liver test results during her first exposure were not reported; had they been elevated, however, a rechallenge may not have been recommended. To conclude that the second exposure may have led to injury due to a rechallenge, despite a lack of knowledge about the first exposure, is a tenable but risky assumption.

Two problems that complicate assessment of HDS-induced liver injury related to traditional Chinese and Japanese medicines are contamination and adulteration. In the United States, governmental oversight of HDS is less stringent than for prescription pharmaceuticals, so contamination and/or adulteration of HDS is not uncommon. In one study, heavy metals or pharmaceuticals not listed on the package label were detected in 32% of traditional Chinese medicines collected in California.¹⁷ Among the most frequently measured adulterants and contaminants were methyltestosterone, ephedrine, phenacetin, arsenic, and mercury. For these reasons, monitoring of liver tests should be strongly considered in patients who are taking HDS, especially traditional Chinese and Japanese medicines.

Inoue and colleagues are likely accurate in concluding that hepatotoxicity was due to kamishoyosan in this case, given the exclusion of other causes of acute liver injury, timing, biopsy findings, and improvement with dechallenge, but confidence in the diagnosis could have been increased by using a formal causality assessment and providing baseline liver test information.¹³ The assignment of attribution to suspected DILI in case reports can be more confidently endorsed by incorporating all of the essential elements for diagnosis.¹⁸

In summary, HDS-induced liver injury is not common, but it remains a real concern worldwide. With increasing prevalence of HDS use, the incidence of acute liver failure and liver test abnormalities attributable to HDS should be expected to continue to rise. Clinicians should have a heightened suspicion for HDS-induced liver injury, especially when common causes of liver disease have been excluded.