Obesity has become a global struggle, leading individuals to seek various weight reduction methods. Among these, herbal and natural dietary supplements, including fat burners, have gained popularity. While often perceived as safe, it's crucial to understand the potential adverse effects associated with these supplements.
The Appeal of Fat Burners
Fat burners are marketed as a way to boost metabolism, burn more calories, and accelerate fat loss, essentially mimicking the effects of exercise. Because they are not subject to regulatory testing by the United States Food and Drug Administration (FDA), herbal remedies continue to be a popular choice due to their perceived safety and easy availability.
The Dark Side: Hepatotoxicity
Despite the perception that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. Several slimming aids and herbal medications associated with severe hepatotoxicity have been reported in the literature.
A Case Study of Fulminant Hepatic Failure
A previously healthy 28-year-old female bodybuilder with no risk factors for liver disease presented to her local emergency centre with fatigue, malaise, inability to exercise and new-onset jaundice. Her symptoms worsened over a span of one week before hospitalization. The patient was a professional bodybuilder taking a multi-ingredient, nonstimulant health supplement and fat burner (Somalyz and Lipolyz, Species Nutrition, USA).
The supplements contained a combination of ingredients, including:
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- Somalyz: usnic acid (4 mg), propionyl-L-carnitine (167 mg), phosphatidylcholine/phosphatidylethanolamine (50 mg), gamma-aminobutyric acid (667 mg) and vitamin E (27 IU) per capsule.
- Lipolyz: usnic acid (12 mg), propionyl-L-carnitine (500 mg), green tea extract (300 mg), guggulsterone Z and guggulster-one E (10 mg), cyclic adenosine monophosphate (2 mg) and vitamin E (20 IU) per capsule
She was taking one to two capsules of Somalyz at bedtime and one capsule of Lipolyz with meals three times a day as recommended for one month before illness.
Upon evaluation, blood work revealed significantly elevated levels of bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase, indicating severe liver damage. Extensive toxicology screening was negative, with no features of acetaminophen toxicity (acidosis, high lactate or renal failure). She had normal levels of ferritin, ceruloplasmin and alpha-1 antitrypsin. A pregnancy test was negative. A computed tomography scan of her abdomen revealed a normal size liver with a patent portal vein, hepatic artery, hepatic vein and normal biliary anatomy. The patient’s encephalopathy worsened and she remained unresponsive. A computed tomography scan of her head was normal. An intracranial pressure monitor was placed, which measured an intracranial pressure of 19 mmHg and a cerebral perfusion pressure of 77 mmHg to 82 mmHg. She underwent successful cadaveric orthotopic liver transplantation on hospital day 2. By postoperative day 4, she was awake and alert.
Histology of the native explanted liver showed confluent necrosis resulting in parenchymal collapse, confirming the extensive liver damage.
Identifying the Culprit: Usnic Acid
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.
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. It is derived from a lichen species of the genus Usnea and 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.
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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 . 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.
Several previous reports described liver failure associated with the use of LipoKinetix, a multi-ingredient preparation containing usnic acid. In 2002, Favreau et al 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. Sanchez et al 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.
Other Potential Contributors: Green Tea and Guggul
While usnic acid appears to be the primary culprit, other ingredients in the supplements, such as green tea extract and guggul, may have contributed to the liver damage.
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. Similar cases have been reported from France and Spain resulting in the removal of the green tea extract ‘Exolise’ from the market. Two cases of fulminant hepatic failure associated with green tea extracts have been reported. Mitochondrial toxicity and the formation of reactive oxygen species have been demonstrated with epigallocatechin-3-gallate, a key constituent of green tea extracts.
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.
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Regulatory Loopholes and Continued Availability
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). Usnic acid is still available and advertised on the Internet as an ingredient in various other dietary supplements and fat burners.