Usnic acid is a furandione found uniquely in lichen that is used widely in cosmetics, deodorants, toothpaste and medicinal creams as well as some herbal products. Taken orally, usnic acid can be toxic and has been linked to instances of clinically apparent, acute liver injury.
Usnic acid is a dibenzo-furandione which is uniquely found in lichen (Usnea) species, which are distributed worldwide. In vitro usnic acid has antibacterial, antifungal and antiviral activities, and lichen extracts containing usnic acid have been used in folk medicine externally for wound healing and athlete’s foot and internally for sore throat, toothache and fever. Usnic acid has also found several commercial uses, largely in perfumery and cosmetic products, but also in medicinal creams. However, usnic acid appears to be toxic when taken orally in high doses and, for instance, can cause ataxia and paralysis in animals grazing on lichen contaminated crops and grains. Usnic acid has been purified and extensively studied in vitro and has been shown to uncouple oxidative phosphorylation in isolated mitochondria, which may account for its broad antimicrobial activity. Uncoupling of oxidative phosphorylation by decreasing the efficacy of energy use and causing increased thermogenesis has been proposed as an approach to treatment of obesity. However, this approach is potentially dangerous and has not been shown to be effective in causing weight loss other than by extreme toxicity. Nevertheless, usnic acid has been used in several commercial over-the-counter weight loss products.
Several cases of clinically apparent acute liver injury have been attributed to commercial dietary supplements that contain usnic acid. “LipoKinetix” was one such supplement advertised as a weight loss and body building supplement. Each tablet contained sodium usniate (100 mg), norephedrine (25 mg), diiodothyronine (100 mg), yohimbine (3 mg) and caffeine (100 mg). The product has been linked to multiple instances of acute liver injury. The time to onset was 2 to 12 weeks and the clinical presentation resembled acute viral hepatitis with onset of fatigue and nausea, followed by jaundice. The pattern of serum enzyme elevations was hepatocellular, with marked elevations in serum ALT and minimal increases in alkaline phosphatase levels. Liver biopsy demonstrated acute hepatocellular necrosis and inflammation. Immunoallergic features (fever, rash and eosinophilia) were not common and autoantibodies were usually not present. Recovery was rapid with stopping the dietary supplement, but some cases were severe and led to acute liver failure and either death or need for emergency liver transplantation. Rare instances of hepatotoxicity have also been reported with use of lichen based teas known as Kombucha tea, but whether these were due to usnic acid or another contaminant of the tea was not shown.
Mechanism of Injury
The hepatotoxicity of usnic acid is probably caused by uncoupling of oxidative phosphorylation in the liver, which can produce hepatocyte lysis and apoptosis and induces acute liver injury in animal models.
Outcome and Management
Hepatotoxicity attributed usnic acid and products such as LipoKinetix is often clinically apparent, but is usually reversible with prompt discontinuation of the nutritional supplement. Usnic acid is a direct hepatotoxin and thus is unlikely to share cross sensitivity to liver injury with other agents.
Case 1. Acute liver failure due to usnic acid.
[Modified from case 1 of: Sanchez W, Maple JT, Burgart LJ, Kamath PS. Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid. Mayo Clinic Proc 2006; 81: 541-4. PubMed Citation].
A 38 year old woman developed fatigue, abdominal discomfort and jaundice 3 months after starting a multiingredient health supplement called UCP-1, which contained usnic acid. She was previously well and had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. She had been on oral contraceptives and received a 2 week course of tinidazole 3 weeks before presentation. She was a fitness trainer at a health club in Asia, and she and her husband started taking the health supplement UCP-1 as an aid to body building in the recommended dose of 3 capsules 3 times daily, each capsule containing usnic acid (150 mg), L-carnitine (525 mg) and calcium pyruvate (1050 mg). She was hospitalized at which time her bilirubin was 23.0 mg/dL and serum aminotransferase levels markedly elevated (ALT 1636 U/L, AST 1536 U/L), while alkaline phosphatase levels were minimally increased (195 U/L) (Table). When she developed signs of hepatic encephalopathy, she was transferred to a liver transplant center in the United States. Over the next few days she developed worsening hepatic failure and underwent emergency liver transplantation. Tests for hepatitis A, B and C were negative as were autoimmune markers and tests for Wilson disease. The explant demonstrated massive necrosis and collapse. She recovered after transplant and was discharged a week later. Her husband had also used the nutritional supplement and, although not symptomatic, had marked elevations in serum aminotransferase values (ALT 1462 U/L, AST 451 U/L) with normal bilirubin levels. After stopping the supplement, his serum liver tests began to improve and were normal four months later.
|Medication:||UCP-1 (Usnic acid: ~1350 mg daily)|
|Pattern:|| Hepatocellular (R=25.1)|
||5+ (acute liver failure, liver transplantation)
||Oral contraceptives, tinidazole (an antiprotozoal agent similar to metronidazole)
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Protime 22.7 seconds
||Emergency liver transplantation
Usnic acid taken as a weight loss supplement has been associated with at least a dozen published cases of acute liver injury which, as in this case, can be severe, leading to acute liver failure and death or need for emergency liver transplantation. The fact that both husband and wife developed liver injury while on UCP-1 is in favor of its role in causing the injury, but they also shared common exposures and therefore the episode could also be due to common infectious agent. Nevertheless, the clinical presentation and course were entirely compatible with usnic acid associated hepatotoxicity.
REPRESENTATIVE TRADE NAMES
Usnic Acid – Generic
Herbal and Dietary Supplements
||CAS REGISTRY NUMBER
References updated: 28 November 2013
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Favreau JT, Ryu ML, Braunstein G, Orshansky G, Park SS, Coody GL, Love LA, Fong TL. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136: 590-5. PubMed Citation (7 patients, 4 women and 3 men, ages 20-32 years, developed symptoms and jaundice [n=5] or liver test abnormalities [n=2], 1-12 weeks after starting LipoKinetix [norephedrine, usniate, diiodothyronine, yohimbine, caffeine] for weight loss [peak bilirubin 2.2-14.6 mg/dL, ALT 438-14,150 U/L], resolving in 1 to 3 months of stopping).
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Han D, Matsumaru K, Tettori D, Kaplowitz N. Usnic acid-induced necrosis of cultured mouse hepatocytes: inhibition of mitochondrial function and oxidative stress. Biochem Pharmacol 2004; 67: 439-51. PubMed Citation (Usnic acid caused necrosis of isolated mouse hepatocytes probably by uncoupling of electron transport in mitochondria, oxidative stress and depletion of glutathione).
Hsu LM, Huang YS, Chang FY, Lee SD. ‘Fat burner’ herb, usnic acid, induced acute hepatitis in a family. J Gastroenterol Hepatol 2005; 20: 1138-9. PubMed Citation (3 sisters with toxicity from herbal “fat burner” consisting of soybean extract and usnic acid; 36 year old woman had abdominal pain 2 weeks after starting herbal [bilirubin normal, ALT 442 U/L, Alk P 217 U/L], resolving within 6 weeks; 32 year old sister developed jaundice after 4 weeks of use [bilirubin 29 mg/dL, ALT 778 U/L, Alk P 118 U/L, INR 2.6], resolving in 4 months; third sister stopped the herbal after 3 days because of fatigue).
Arneborn P, Jansson A, Böttiger Y. [Acute hepatitis in a woman after intake of slimming pills bought via Internet]. Lakartidningen 2005; 102: 2071-2. Swedish. PubMed Citation (20 year old overweight woman developed nausea followed by jaundice 4 weeks after starting a weight loss agent [Termoxical, containing usnic acid] purchased over the Internet [bilirubin 4.9 mg/dL, ALT 1320 U/L, Alk P 198 U/L], resolving within a month of stopping).
Sanchez W, Maple JT, Burgart LJ, Kamath PS. Severe hepatotoxicity associated with use of a dietary supplement containing usnic acid. Mayo Clinic Proc 2006; 81: 541-4. PubMed Citation (Two cases: 38 year old woman developed jaundice 3 months after starting UCP-1 in a dose of 1350 mg daily [bilirubin 23.0 mg/dL, ALT 1636 U/L, Alk P 195 U/L, protime 22.7 sec], progressing to hepatic failure and successful liver transplantation [Case 1]; 38 year old husband of previous case developed back pain 3 months after starting UCP-1 [bilirubin 0.6 mg/dL, ALT 1462 U/L], with rapid resolution on stopping and normal values 4 months later).
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but none were linked to usnic acid containing products specifically).
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