Usnic acid is a component of nutritional supplements that are promoted for weight loss and have been associated with liver-related adverse events including mild hepatic toxicity, chemical hepatitis and liver failure requiring liver transplantation. Usnic acid is derived from a lichen species of the genus Usnea
. It has been investigated for diverse uses as an antimicrobial, an anti-inflammatory, an antioxidant, an analgesic/antipyretic, an antiproliferative and as a natural supplement for weight loss. There are no adequate or well-controlled trials to substantiate any claims of effectiveness in humans for any indication (5
Several previous reports described liver failure associated with the use of LipoKinetix, a multi-ingredient preparation containing usnic acid (6
). In 2002, Favreau et al (6
) reported on seven patients who developed acute hepatitis after using LipoKinetix. This dietary supplement contains sodium usniate, norephedrine, yohimbine, 3-5-diiodothyronine and caffeine; both usnic acid and ephedra alkaloids have been associated with severe hepatotoxicity. LipoKinetix withdrew the product from the market.
Durazo et al (7
) reported on a healthy 28-year-old woman who developed acute liver failure within one month of commencing usnic acid (Pure Usnic acid, Industrial strength; AAA Services, USA) 500 mg/day for two weeks (7
Sanchez et al (8
) reported severe hepatotoxicity in a husband and wife (both 38 years of age) who were bodybuilders taking the multi-ingredient health supplement UCP-1 (BDC Nutrition, USA) for three months. UCP-1 contains usnic acid (150 mg), L-carnitine (525 mg) and calcium pyruvate (1050 mg) per capsule. The wife developed fulminant hepatic failure requiring liver transplantation. The husband experienced submassive necrosis but did not require liver transplantation. Another herbal remedy containing usnic acid – well known to be hepatotoxic – is kombucha tea. This is a beverage made by brewing kombucha mushrooms in sweet black tea (9
Usnic acid has been shown to uncouple oxidative phosphorylation in a murine model, with resultant loss of mitochondrial respiratory control and inhibition of ATP synthesis. A direct hepatotoxic effect analogous to carbon tetrachloride-induced liver toxicity has also been described (10
). Based on a case report (11
) detailing three sisters with acute hepatitis after consumption of a ‘fat burner’ herb containing usnic acid, it was suggested that an inherent susceptibility was present.
Usnic acid is a weak inhibitor of cytochrome CYP2D6 and a potent inhibitor of cytochrome CYP2C19. Based on potent inhibition of CYP2C enzymes, usnic acid has significant potential to interact with other medications (5
). Hepatotoxicity due to usnic acid appears to be idiosyncratic and is possibly due to a ‘convergence of risk factors’ (12
Chinese green tea extracts are derivatives of the leaves of Camellia sinensis
, which belongs to the aceae family. Green tea extracts have been marketed as effective weight-loss supplements, and for the prevention and cure of solid tumours. Although there is little scientific evidence supporting the effectiveness of green tea extracts, serious side effects, including acute liver failure, are increasingly being reported (13
). Similar cases have been reported from France and Spain resulting in the removal of the green tea extract ‘Exolise’ from the market (15
). Two cases of fulminant hepatic failure associated with green tea extracts have been reported (16
). Mitochondrial toxicity and the formation of reactive oxygen species have been demonstrated with epigallocatechin-3-gallate, a key constituent of green tea extracts. The possibility of an allergic reaction to green tea itself has also been reported (18
Gum guggul and its constituents are increasingly being used as dietary supplements. Gum guggul is the oleoresin of Commiphora mukul,
a plant native to India. Its extracts include compounds known for their hypolipidemic properties – the Z and E isomers of guggulsterone and its regulated guggulsterols. Human exposure to gum guggul most often occurs from ingesting herbal remedies or pharmaceuticals, and from the use of cosmetics. Side effects include skin rashes, irregular menstruation, diarrhea, headache, mild nausea and, with very high doses, liver toxicity. Guggulsterol was associated with acute hepatitis in a 63-year-old woman taking the natural lipid-lowering agent Equisterol (Istituto Farmacoterapico Italiano SpA, Italy), which also contains red yeast rice extract (19
Based on the temporal relationship between the use of the dietary supplements and onset of liver failure, literature supporting reports of hepatotoxicity associated with dietary supplements and exclusion of other causes, it is fair to assume that the patient developed fulminant hepatic failure due to dietary supplements. In view of the bulk of the literature, of all the ingredients, usnic acid may have been predominantly responsible for the hepatoxicity. Although usnic acid was the main hepatotoxic agent, its effect was possibly perpetuated by other hepatotoxins, including green tea and gum guggul, also contained in the dietary supplements taken by the patient.
According to the Dietary Supplement Health and Education Act of 1994, dietary supplements are regulated as foods and are not subject to regulation as drugs by the FDA; manufacturers are not compelled to provide safety data to the FDA. However, increasing reports of liver failure due to usnic acid have triggered a regulatory warning and one voluntary product withdrawal (LipoKinetix) (20
). Usnic acid is still available and advertised on the Internet as an ingredient in various other dietary supplements and fat burners. Usnic acid, green tea and guggul tree extracts are a few of the many herbal and dietary supplements associated with significant liver injury.