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Severe Hepatotoxicity Associated With Use of a Dietary Supplement Containing Usnic Acid

2006; Elsevier BV; Volume: 81; Issue: 4 Linguagem: Inglês

10.4065/81.4.541

1942-5546

William Sánchez, John T. Maple, Lawrence J. Burgart, Patrick S. Kamath,

Plant Toxicity and Pharmacological Properties

Dietary supplements containing usnic acid are marketed for weight loss and have been associated with hepatotoxicity. The specific ingredient responsible for the hepatotoxicity is currently unknown. We describe 2 patients who developed severe hepatotoxicity within 3 months of taking a dietary supplement containing usnic acid. One patient developed fulminant hepatic failure requiring emergency liver transplantation; the other developed submassive hepatic necrosis but did not require transplantation. Thorough investigation, including histopathological examination of the liver, revealed no other cause of acute liver injury. Usnic acid hepatotoxicity should be considered as a possible etiologic factor in patients presenting with fulminant hepatic failure, especially if they have been taking dietary supplements for weight reduction. Dietary supplements containing usnic acid are marketed for weight loss and have been associated with hepatotoxicity. The specific ingredient responsible for the hepatotoxicity is currently unknown. We describe 2 patients who developed severe hepatotoxicity within 3 months of taking a dietary supplement containing usnic acid. One patient developed fulminant hepatic failure requiring emergency liver transplantation; the other developed submassive hepatic necrosis but did not require transplantation. Thorough investigation, including histopathological examination of the liver, revealed no other cause of acute liver injury. Usnic acid hepatotoxicity should be considered as a possible etiologic factor in patients presenting with fulminant hepatic failure, especially if they have been taking dietary supplements for weight reduction. Herbal dietary supplement use has become increasingly common in the United States. An estimated 83 million Americans report using alternative medical therapies, including herbal and dietary supplements.1Eisenberg DM Davis RB Ettner SL et al.Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.JAMA. 1998; 280: 1569-1575Crossref PubMed Scopus (5987) Google Scholar Most of the approximately $5.1 billion spent on herbal supplements each year in the United States is out-of-pocket.1Eisenberg DM Davis RB Ettner SL et al.Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey.JAMA. 1998; 280: 1569-1575Crossref PubMed Scopus (5987) Google Scholar Moreover, the use of complementary and alternative medicines and health supplements is believed to be widely underreported.2Eisenberg DM Kessler RC Van Rompay MI et al.Perceptions about complementary therapies relative to conventional therapies among adults who use both: results from a national survey.Ann Intern Med. 2001; 135: 344-351Crossref PubMed Scopus (539) Google Scholar Unlike prescription medications, herbal supplements do not need to be established as safe and efficacious before marketing. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are known to be associated with severe toxicities, including hepatotoxicity.3Barnes J Quality, efficacy and safety of complementary medicines: fashions, facts and the future, part I: regulation and quality.Br J Clin Pharmacol. 2003; 55: 226-233Crossref PubMed Scopus (134) Google Scholar, 4Larrey D Pageaux GP Hepatotoxicity of herbal remedies and mushrooms.Semin Liver Dis. 1995; 15: 183-188Crossref PubMed Scopus (84) Google Scholar, 5Nadir A Agrawal S King PD Marshall JB Acute hepatitis associated with the use of a Chinese herbal product, ma-huang.Am J Gastroenterol. 1996; 91: 1436-1438PubMed Google Scholar Weight loss agents including mahuang,5Nadir A Agrawal S King PD Marshall JB Acute hepatitis associated with the use of a Chinese herbal product, ma-huang.Am J Gastroenterol. 1996; 91: 1436-1438PubMed Google Scholar, 6Estes JD Stolpman D Olyaei A et al.High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.Arch Surg. 2003; 138: 852-858Crossref PubMed Scopus (148) Google Scholar germander,4Larrey D Pageaux GP Hepatotoxicity of herbal remedies and mushrooms.Semin Liver Dis. 1995; 15: 183-188Crossref PubMed Scopus (84) Google Scholar kava,6Estes JD Stolpman D Olyaei A et al.High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.Arch Surg. 2003; 138: 852-858Crossref PubMed Scopus (148) Google Scholar, 7Centers for Disease Control and Prevention Hepatic toxicity possibly associated with kava-containing products—United States, Germany, and Switzerland, 1999-2002.MMWR Morb Mortal Wkly Rep. 2002; 51: 1065-1067PubMed Google Scholar and LipoKinetix (Syntrax Innovations, Inc, Cape Girardeau, Mo)6Estes JD Stolpman D Olyaei A et al.High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.Arch Surg. 2003; 138: 852-858Crossref PubMed Scopus (148) Google Scholar, 8Favreau JT Ryu ML Braunstein G et al.Severe hepatotoxicity associated with the dietary supplement LipoKinetix.Ann Intern Med. 2002; 136: 590-595Crossref PubMed Scopus (165) Google Scholar have been associated with hepatotoxicity. LipoKinetix is a multi-ingredient product (containing norephedrine hydrochloride, sodium usniate, 3,5-diiodothyronine, yohimbine hydrochloride, and caffeine) that was marketed as a weight-loss aid and has been associated with several cases of severe hepatotoxicity, including 1 death.6Estes JD Stolpman D Olyaei A et al.High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure.Arch Surg. 2003; 138: 852-858Crossref PubMed Scopus (148) Google Scholar, 8Favreau JT Ryu ML Braunstein G et al.Severe hepatotoxicity associated with the dietary supplement LipoKinetix.Ann Intern Med. 2002; 136: 590-595Crossref PubMed Scopus (165) Google Scholar These adverse effects prompted the Food and Drug Administration (FDA) to issue a warning to consumers urging discontinuation of the use of LipoKinetix,9FDA Warns Consumers Not to Use the Dietary Supplement LipoKinetix. US Food and Drug Administration Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements, College Park, MdNovember 19, 2001Available at: www.cfsan.fda.gov/~dms/dslipo.htmlGoogle Scholar which has subsequently been voluntarily withdrawn from the market by the distributor. In their report of 7 cases of reversible hepatotoxicity associated with use of LipoKinetix, Favreau et al8Favreau JT Ryu ML Braunstein G et al.Severe hepatotoxicity associated with the dietary supplement LipoKinetix.Ann Intern Med. 2002; 136: 590-595Crossref PubMed Scopus (165) Google Scholar commented that a specific hepatotoxin was not clearly identified and cited multiple possible mechanisms to explain the liver injuries. More recently, Durazo et al10Durazo FA Lassman C Han SHB et al.Fulminant liver failure due to usnic acid for weight loss.Am J Gastroenterol. 2004; 99: 950-952Crossref PubMed Scopus (100) Google Scholar reported a case of fulminant hepatic failure in a 28-year-old woman taking usnic acid supplements for weight reduction. To our knowledge, no published reports have described hepatotoxicity associated with any of the other ingredients in LipoKinetix.8Favreau JT Ryu ML Braunstein G et al.Severe hepatotoxicity associated with the dietary supplement LipoKinetix.Ann Intern Med. 2002; 136: 590-595Crossref PubMed Scopus (165) Google Scholar We describe 2 patients who developed severe hepatotoxicity while using a dietary supplement containing usnic acid, one of whom experienced fulminant hepatic failure requiring emergency liver transplantation. A previously healthy 38-year-old woman with no risk factors for liver disease was hospitalized in an Asian country (Singapore) for new-onset malaise, abdominal discomfort, and jaundice. Her symptoms had progressed slowly over a 2-week period. Prescription medication use was limited to an oral contraceptive and a 2-week course of tinidazole (500 mg orally twice daily) completed 3 weeks previously. The patient was a fitness trainer at an athletic club. She and her husband (case 2) had been taking a multi-ingredient health supplement, UCP-1 (BDC Nutrition, Richmond, Ky), for 3 months. Marketed as a weight-loss product, UCP-1 contains 150 mg of usnic acid, 525 mg of l-carnitine, and 1050 mg of calcium pyruvate per capsule. She and her husband had taken the recommended dosage of 3 capsules 3 times a day in 2-week cycles. At initial hospitalization, laboratory investigations revealed the following (reference ranges shown parenthetically): total bilirubin, 23.0 mg/dL (0-1.5 mg/dL); alkaline phosphatase, 195 U/L (35-120 U/L); aspartate aminotransferase, 1536 U/L (0-40 U/L); and alanine aminotransferase, 1636 U/L (3-40 U/L). Synthetic liver function was impaired with a prolonged prothrombin time of 22.7 seconds (10-14 seconds). During hospitalization, the patient developed earlyhepatic encephalopathy (grade 1-2). Oral lactulose and parenteral vitamin K supplementation were administered, and she underwent 3 sessions of albumin dialysis using MARS (molecular adsorbent recirculating system) therapy. Despite these measures, the encephalopathy worsened, and the patient was transferred to the Mayo Clinic in Rochester, Minn, for possible liver transplantation. On arrival at the Mayo Clinic, the patient was found to be deeply jaundiced and encephalopathic (grade 2-3). Laboratory studies revealed the following: international normalized ratio, 3.9; alkaline phosphatase, 113 U/L (37-98 U/L); aspartate aminotransferase, 602 U/L (12-31 U/L); alanine aminotransferase, 884 U/L (9-29 U/L); total bilirubin, 38.8 mg/dL (0.1-1.0 mg/dL); and serum ammonia, 132 μg/dL (<50 μg/dL). Drug screening was negative for acetaminophen or other hepatotoxic medications, and clinical features suggestive of acetaminophen toxicity (acidosis, renal insufficiency) were not present. Investigations were negative for viral hepatitis (hepatitis A virus IgM, hepatitis B virus surface antigen and core antibody, hepatitis C virus by polymerase chain reaction, and cytomegalovirus and Epstein-Barr virus IgM), autoimmune hepatitis (antinuclear antibody, anti-smooth muscle antibody, and serum γ-globulin), and Wilson disease. The patient underwent successful emergency liver transplantation (cadaveric donor). Explant pathology revealed a shrunken liver that weighed 451 g (predicted weight, 1240 g) with diffuse parenchymal necrosis. Microscopically, most of the hepatectomy specimen consisted of collapsed stroma, bile-stained histiocytes, and lymphocytes (Figure 1). Trichrome staining revealed massive collapse but no hepatic fibrosis. The patient's postoperative course was complicated only by mild acute cellular rejection and minor stricturing of the biliary anastomosis that was treated endoscopically. She was discharged from the hospital on the seventh postoperative day. She continued to do well and had normal hepatic allograft function 1 year posttransplantation. A previously healthy 38-year-old man, the husband of the patient described in case 1, was hospitalized at the Mayo Clinic in Rochester, Minn, for evaluation of intractable back pain with radicular symptoms at the time of his wife's liver transplantation. He had no symptoms attributable to liver disease. He had sustained a weight lifting-related injury 4 weeks earlier, and the back pain was exacerbated during the 16-hour flight from Singapore, Asia, to the Mayo Clinic. Magnetic resonance imaging of the spine showed an extruded L5-S1 disk. Laboratory studies performed before a planned neurosurgical intervention for the disk extrusion revealed the following: aspartate aminotransferase, 451 U/L (12-31 U/L); alanine aminotransferase, 1462 U/L (10-45 U/L); total bilirubin, 0.6 mg/dL (0.1-1.0 mg/dL); and international normalized ratio, 1.0. He had no history of liver disease, elevated liver enzyme levels, jaundice, gastrointestinal bleeding, or ascites; no family history of liver disease; and no other risk factors for liver disease. An amateur bodybuilder, the patient had been using multiple dietary supplements, including creatine, glutamine, α-lipoic acid, ephedrine, and caffeine on a daily basis for several years. Approximately 3 months before presentation, he and his wife (case 1) began using UCP-1. During the preceding 4 weeks, his prescription medications were limited to desloratidine, famotidine, and naproxen on an as-needed basis. He had taken acetaminophen/oxycodone and cyclobenzaprine in recommended doses during the 6 days before admission for back pain. The patient reported only social use of alcohol on weekends and had no history of heavier drinking. However, he had consumed about 120 g of alcohol over a 16-hour period 7 days before hospitalization in an attempt to relieve his back pain during the flight transporting his wife to the United States for evaluation of fulminant hepatic failure. Serologic testing was negative for hepatitis A, B, and C virus, Epstein-Barr virus, and cytomegalovirus. Autoantibodies, including antinuclear antibodies and anti-smooth muscle antibodies, were absent. The serum ceruloplasmin level was normal, and acetaminophen was undetectable. One week after presentation, he remained asymptomatic, but the serum alanine aminotransferase elevation persisted (1240 U/L). Percutaneous liver biopsy was performed to determine the cause and prognosis of the liver disease because the patient urgently needed neurosurgery for his radicular symptoms. The biopsy revealed severe acute panacinar hepatitis characterized by marked lymphoplasmacytic portal infiltrates, prominent periportal and lobular inflammation, and bridging necrosis (grade 4/4) (Figure 2). Masson trichrome stain showed no evidence of preexisting chronic liver disease. Although less extensive than the acute hepatic damage noted in case 1, the disease pattern in this patient suggested a common etiologic insult. The patient was monitored closely, and no evidence of hepatic decompensation was observed. Serum aminotransferase levels began to decline over a 3-week period, allowing the patient to undergo neurosurgery for the extruded disk. Biochemical test results had returned to normal when checked 4 months later. The patient remained symptom-free with normal biochemical test results 1 year later. We report the development of severe hepatotoxicity in 2 young patients, a husband and wife, who were taking a multi-ingredient preparation containing usnic acid, l-carnitine, and calcium pyruvate. The differential diagnosis of fulminant hepatitis includes viral, metabolic, and toxic exposures. Our patients had no evidence of common (hepatitis A or B) or uncommon (Epstein-Barr virus, herpes simplex virus) viral infection, and neither patient presented with symptoms (fever, myalgia) suggestive of an infectious cause. Other than the herbal supplement, the patients took no common medications. Because they shared a household, a potential environmental toxin could be implicated, although the relationship of the onset of illness to the herbalsupplement exposure strongly suggests that the supplement was the toxic agent. The similar histology in both patients strengthens this hypothesis. Although the possible role of unknown ingredients in the dietary supplement cannot be discounted, the findings in our patients suggest that the hepatotoxic agent may be usnic acid. Several previous reports have described severe hepatotoxicity associated with the use of LipoKinetix, a multi-ingredient preparation containing usnic acid.8Favreau JT Ryu ML Braunstein G et al.Severe hepatotoxicity associated with the dietary supplement LipoKinetix.Ann Intern Med. 2002; 136: 590-595Crossref PubMed Scopus (165) Google Scholar, 9FDA Warns Consumers Not to Use the Dietary Supplement LipoKinetix. US Food and Drug Administration Center for Food Safety and Applied Nutrition, Office of Nutritional Products, Labeling, and Dietary Supplements, College Park, MdNovember 19, 2001Available at: www.cfsan.fda.gov/~dms/dslipo.htmlGoogle Scholar, 11Neff GW Reddy KR Durazo FA Meyer D Marrero R Kaplowitz N Severe hepatotoxicity associated with the use of weight loss diet supplements containing ma huang or usnic acid [letter].J Hepatol. 2004; 41: 1062-1064Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Additionally, Durazo et al10Durazo FA Lassman C Han SHB et al.Fulminant liver failure due to usnic acid for weight loss.Am J Gastroenterol. 2004; 99: 950-952Crossref PubMed Scopus (100) Google Scholar reported the occurrence of severe hepatoxicity requiring liver transplantation in a healthy woman taking usnic acid as a dietary supplement. Usnic acid is a secondary metabolite derived from several genera of lichens that have a broad range of biologic properties. Usnic acid and its derivatives have been studied for their antibacterial, antifungal, and antiprotozoal effects. In addition, usnic acid has been found to have in vitro antiproliferative activity.12Ingolfsdottir K Usnic acid.Phytochemistry. 2002; 61: 729-736Crossref PubMed Scopus (434) Google Scholar Despite the available research regarding potential pharmacological uses for usnic acid, data regarding human toxicity are scarce. Durazo et al10Durazo FA Lassman C Han SHB et al.Fulminant liver failure due to usnic acid for weight loss.Am J Gastroenterol. 2004; 99: 950-952Crossref PubMed Scopus (100) Google Scholar described a healthy 28-year-old woman who developed fulminant hepatic failure requiring transplantation 1 month after ingesting 500 mg/d of usnic acid in an effort to lose weight. No other cause for the fulminant hepatic failure was identified. Allergic contact conjunctivitis and dermatitis also have been reported after topical use of usnic acid-containing products.12Ingolfsdottir K Usnic acid.Phytochemistry. 2002; 61: 729-736Crossref PubMed Scopus (434) Google Scholar, 13Plants-usnic acid. POISINDEX® System. Vol 127 [expires 3/2006].Google Scholar Usnic acid has been shown to uncouple oxidative phosphorylation in a murine mitochondrial model, with resultant loss of mitochondrial respiratory control and inhibition of adenosine triphosphate synthesis.14Abo-Khatwa AN al-Robai AA al-Jawhari DA Lichen acids as uncouplers of oxidative phosphorylation of mouse-liver mitochondria.Nat Toxins. 1996; 4: 96-102Crossref PubMed Scopus (98) Google Scholar A recent study duplicated this finding in isolated rat liver mitochondria.15Pramyothin P Janthasoot W Pongnimitprasert N Phrukudom S Ruangrungsi N Hepatotoxic effect of (+) usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria.J Ethnopharmacol. 2004; 90: 381-387Crossref PubMed Scopus (86) Google Scholar These investigators also identified a directly hepatotoxic effect of usnic acid on isolated rat hepatocytes in a mechanism similar to carbon tetrachloride, which involves free radical generation with resultant cell membrane and mitochondrial injury, lipid peroxidation, disturbed calcium homeostasis, and cell death. Regarding the other ingredients in UCP-1, hepatotoxicity has not been described with l-carnitine, which has been used therapeutically in some forms of liver injury including valproate-associated hepatotoxicity.16Bohan TP Helton E McDonald I et al.Effect of l-carnitine treatment for valproate-induced hepatotoxicity.Neurology. 2001; 56: 1405-1409Crossref PubMed Scopus (157) Google Scholar Calcium pyruvate likewise has not been associated with liver injury. One of our patients (case 2) had used ephedrine, caffeine, and α-lipoic acid for more than 3 years; however, none of these substances have been clearly associated with liver injury. Caffeine was shown to enhance acetaminophen-mediated hepatotoxicity in a rat hepatocyte model in which the hepatocytes were pretreated with ethanol, but no data suggest toxicity in humans or in the absence of alcohol use and supratherapeutic doses of acetaminophen.17DiPetrillo K Wood S Kostrubsky V et al.Effect of caffeine on acetaminophen hepatotoxicity in cultured hepatocytes treated with ethanol and isopentanol.Toxicol Appl Pharmacol. 2002; 185: 91-97Crossref PubMed Scopus (23) Google Scholar Given the undetectable levels of acetaminophen, the fact that UCP-1 was the only substance used by both of our patients, the temporal sequence of events in relationship to UCP-1 ingestion and liver injury, and previous experience with LipoKinetix, it is likely that usnic acid was the hepatotoxic agent in both cases. The Dietary Supplement Health and Education Act of 1994 defined dietary supplements as products containing minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites meant to supplement the diet. Under this legislation, supplements are not subject to the same regulation by the FDA as drugs or food products. The company marketing the supplement is responsible for the safety of the product. New supplements do not need FDA approval before marketing. Manufacturers need not be registered with the FDA, nor are they required to provide the FDA with data regarding the safety or efficacy of their products.18Overview of Dietary Supplements. US Food and Drug Administration Center for Food Safety and Applied Nutrition, College Park, MdJanuary 3, 2001Available at: http://vm.cfsan.fda.gov/~dms/ds-oview.htmlGoogle Scholar Therefore, despite the withdrawal of LipoKinetix from the market, its components—including usnic acid—can still be ordered easily by consumers. Health care professionals may voluntarily report adverse events associated with dietary supplements to the FDA's MedWatch hotline (1-800-FDA-1088; www.fda.gov/medwatch/report/hcp.htm). Although BDC Nutrition is no longer manufacturing UCP-1, the supplement taken by our patients, many retailers still stock the product, and it remains available for purchase over the Internet. Health care professionals should continue to be vigilant in inquiring about the use of health supplements and alternative medicines by patients who have liver injury with no obvious cause. The use of usnic acid must be considered a potential risk factor for fulminant hepatic failure.