Liver injury due to herbal and dietary supplements: A review of individual ingredients

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

ALF

acute liver failure

ANA

anti‐nuclear antibody

ASMA

anti–smooth muscle actin

GTE

green tea extract

HDS

herbal and dietary supplements

Diagnosing liver injury caused by herbal and dietary supplements (HDS) and establishing causality is challenging. These topics are discussed and reviewed in an accompanying article within this current publication. In this review, we focus on dietary supplement ingredients that have hepatotoxic potential (Table 1).

Table 1.

Hepatotoxic Ingredients

Hepatotoxic Ingredient (species name)	Common Uses	Predominant Injury Pattern	Comments
Black cohosh (Cimicifuga racemosa, rhizome of Actaea racemosa)	Menopausal symptoms	Unknown, autoimmune features	Liver damage ranges from transient increases in liver enzymes to acute liver failure.
Ma huang (Ephedra sinica, Ephedra sp.)	Weight loss	Hepatocellular*	Autoimmune features (ANA and ASMA positive) observed.
Green tea (Camellia sinensis)	Weight loss	Hepatocellular	Toxicity has been found to be dose dependent and may be increased in the fasting state.
Garcinia cambogia	Weight loss	Oxidative stress	Associated with hepatic fibrosis and inflammation.
Kava (Piper methysticum)	Sedation, anxiolytic	Cholestatic*	Significant cholestatic hepatitis demonstrated. Liver damage ranged from transient elevation in liver enzymes to ALF leading to death and transplant.
Saw palmetto	Benign prostatic hypertension	Hepatocellular	Hepatotoxicity rare and self‐limited. Idiosyncratic reaction is possible.
Senna glycosides (Cassia senna)	Constipation	Hepatocellular	Damage caused by an active metabolite produced by intestinal breakdown of the ingredient. Hepatotoxicity is self‐limited and rare.
Skullcap (Scutellaria baicalensis)	Sedation, anti‐inflammatory	Hepatocellular	Injury is self‐limited.
Usnic acid	Weight loss	Hepatocellular and mixed*	Hepatotoxicity has led to fulminant liver failure.
Noni juice (Morinda citrifolia)	Seasonal flu, colds, diabetes, high blood pressure	Hepatocellular	Cases of acute liver failure that required liver transplant have been reported.

Abbreviations: ALF, acute liver failure; ANA, anti‐nuclear antibody; ASMA, anti–smooth muscle actin.

Often, it is difficult to identify the culprit ingredient that is responsible for liver damage among a multitude of different components within a particular supplement. However, some ingredients have been associated with hepatotoxicity. We aim to review those ingredients that have been implicated in liver injury and, in doing so, give the practitioner a rationale to implicate a supplement containing them as a cause for injury.

We highlight the fact that, although these substances have been implicated in liver injury, the specific mechanism of injury in many cases has not been fully clarified. In fact, in rare instances of liver injury, the underlying mechanism may be idiosyncratic, that is, unpredictable.

Suspected Toxic Ingredients in Herbal and Dietary Supplements

Black Cohosh

An herbal remedy extracted from the plant Actaea racemosa, black cohosh's uses vary from alleviation of menopausal symptoms to malaria. The mechanism of injury is unknown, and some reports suggest that liver injury is an idiosyncratic reaction. However, case reports support an immune‐meditated reaction because patients presented with high levels of autoantibodies and exhibited a clinical response to prednisone.1 A review performed by the US Pharmacopeia did not reveal convincingly unfavorable clinical pharmacokinetic and animal toxicological data. Nonetheless, it determined that black cohosh products should be labeled with a cautionary statement.2

Ephedrine

Ephedra is a genus of plants, of which a commonly known species is ma huang (Ephedra sinica). The active component of ma huang is ephedrine, which is a sympathomimetic alkaloid with thermogenic properties.3 Traditionally used in Chinese medicine, ephedrine has commonly been prepared in weight‐loss supplements, resulting in liver injury as suggested by case reports.4 Ephedrine has been a suspected hepatotoxic agent causing a hepatocellular pattern of injury with massive necrosis on histological examination.5, 6

Green Tea Extract

Extracted from the plant Camellia sinensis, green tea extract (GTE) is composed of catechins and flavanols. As the most abundant form of catechin, epigallocatechin gallate is thought to be the active component in GTE and is often touted to have weight‐loss benefits. Epigallocatechin gallate has also been found to cause significant liver injury through mitochondrial damage and formation of reactive oxygen species.7, 8 The toxicity is dose dependent in animal models.9 Liver injury has also been linked to the fasting state in dogs and mice.10, 11 Case reports featuring liver injury caused by GTE have been associated with the use of multi‐ingredient weight‐loss supplements.12, 13 Although it is unknown whether hepatotoxicity was due to GTE alone or a combination of multiple ingredients, reports in patients with previous liver injury thought secondary to GTE revealed repeated liver injury after inadvertent re‐exposure to GTE.

Garcinia Cambogia

A fruit found in Asia and Africa, G. cambogia contains the active ingredient hydroxycitric acid, which has the ability to inhibit the conversion of carbohydrates to fat, as well as alter adipogenesis.14, 15 This ingredient is commonly found in multi‐ingredient weight‐loss supplements such as Hydroxycut, Exilis, and Herbalife. Several case reports have documented liver injury after use of Hydroxycut, although direct injury due to G. cambogia is difficult to assess given the multitude of ingredients within these supplements.16 In laboratory studies, hepatotoxicity caused by G. cambogia has been linked to hepatic fibrosis, inflammation, and oxidative stress.17

Kava Kava

Indigent to the Hawaiian, Polynesian, and Fiji islands, Kava root, Piper methysticum rhizoma, has traditionally been used for anxiolytic and antidepressant purposes. Injury has led to cholestatic hepatitis. In 1 report, of 36 patients studied, 9 patients experienced fulminant liver failure, resulting in 8 subsequent liver transplantations.18 Given that marked eosinophilic infiltrates were observed in some liver biopsies and there was lack of dose association with liver injury, the authors of this series speculate that the mechanism of injury may be both immunogenic and idiosyncratic.

Saw Palmetto

Saw palmetto is used for urinary hesitancy or urgency because of benign prostatic hypertension.19 Hepatotoxicity caused by saw palmetto is rare and self‐limited. In the few published cases, the mechanism of injury was not reported.20

Senna Glycosides

Commonly used for constipation, sennosides are broken down to an active metabolite, rhein anthrone, which can cause hepatocellular injury through mitochondrial damage. Hepatotoxicity is self‐limited and rare, although a recurrence of liver injury after re‐exposure has been observed in one case, giving greater confidence in attribution of injury to this ingredient.21

Skullcap

Often used as a relaxant, Scutellaria baicalensis is a plant that belongs to the mint family. Clinical reports have documented use of this herbal remedy for various reasons from sedation to osteoarthritis.22 A case of hepatotoxicity has been documented, but injury was self‐limited after discontinuation.23

Usnic Acid

A common ingredient previously found in weight‐loss products, usnic acid has been shown to uncouple oxidative phosphorylation in mitochondria, thereby increasing thermogenesis and theoretically possessing antiobesity properties. Despite its purported weight‐loss effects, usnic acid has been labeled as a direct hepatotoxin, leading to fulminant liver failure as documented in previously published case reports.24, 25

Noni Juice

Extracted from the Noni fruit, Morinda citrifolia, the juice has been used for a variety of purposes from the seasonal flu to diabetes. Cases of acute liver failure, with one patient requiring liver transplantation, have been reported.26, 27 Despite reported cases of associated liver injury, the true hepatotoxic potential of M. citrifolia requires further investigation.

Conclusion

Liver injury caused by HDS has become increasingly recognized by clinical investigators. Initial clinical assessment depends on a careful diagnostic approach and being aware of the array of potentially hepatotoxic ingredients. We have focused on several common ingredients that have been implicated in liver injury. Recognition of these ingredients within HDS consumed by patients with liver injury should heighten the clinician's suspicion of a causal association. In cases in which a mechanism of injury could not be identified or even surmised from the clinical reports, one could conjecture idiosyncrasy. However, a more confident understanding of the mechanism of injury requires further toxicological study.