Acute Hepatitis Associated with the Chinese Herbal Product Jin Bu Huan

Estimates of the percentage of patients using alternative medications worldwide range from 4% to 50% [1]. According to a recent U.S. survey, 34% of adult respondents used unconventional therapy and 3% used herbal medicines [2]. In 1990, Americans made 425 million visits to providers of unconventional therapy, which exceeded the number of visits to all primary care physicians, and they spent $13.7 billion, which exceeded the cost of all hospitalizations in the United States [2]. Herbal products are rapidly gaining popularity in North America as remedies for various medical conditions. Jin Bu Huan Anodyne Tablets (Lycopodium serratum), a traditional Chinese herbal remedy, has been used for more than 1000 years as a sedative and analgesic but has only been available in the United States for 10 years [3]. The alkaloid levo-tetrahydropalmatine is responsible for the morphine-like properties of Jin Bu Huan [4]. A recent study [5] described three children who had taken unintentional overdoses of Jin Bu Huan tablets and who developed central nervous system and respiratory depression with bradycardia. We subsequently identified three adult patients with acute hepatitis associated with Jin Bu Huan ingestion and reported this information to the Centers for Disease Control and Prevention and to the Food and Drug Administration [6]. In the present report, we describe the clinical and laboratory features of seven adult patients (including the previously described patients) who ingested Jin Bu Huan and discuss possible mechanisms for Jin Bu Huan hepatotoxicity. Methods Patients All seven patients were white and had no history of hepatic disease, obesity, diabetes mellitus, or atopy. Six of seven patients were women. All denied a history of excessive alcohol or hepatotoxic drug intake. Risk factors for viral hepatitis were absent in all patients. Five patients resided in Los Angeles, California; three patients had purchased Jin Bu Huan Anodyne Tablets (Kwangsi Pai Se Pharmaceutical/Bose Drug Manufactory, Kwangsi, China) at the same drug store. Two other patients resided in Hawaii and Toronto, Canada, respectively. All patients developed symptoms between March 1993 and March 1994 with the exception of patient 7, whose symptoms began in 1991. Ultrasound examinations of the liver and biliary tract were normal in each patient. Serologic test results in all seven patients were negative for antinuclear, anti-smooth muscle, and antimitochondrial antibodies. Prothrombin times were normal throughout the course of illness of each patient. Case Reports Patient 1 A 66-year-old woman presented to her physician with symptoms of fever, nausea, and fatigue for 5 weeks. She was anicteric with a palpable, nontender liver. Stigmata indicating chronic liver disease were absent. She had taken 2 tablets of Jin Bu Huan at night, 2 to 3 times a week for the previous 3 months, for back pain and insomnia. Her medical history included osteoarthritis. She had used nonsteroidal anti-inflammatory drugs during the previous 2 years without adverse effects. Results of serologic tests showed convalescent antibodies for viral hepatitis A and B. A second-generation enzyme-linked immunosorbent assay for anti-hepatitis C virus was negative. Table 1. Liver Test Results in Patients with Jin Bu Huan Toxicity* Two weeks after she stopped taking Jin Bu Huan, maximal levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 9.4 kat/L and 5.2 kat/L, respectively, and were near normal 3 weeks later Table 1 and Figure 1 A. At this time, the patient resumed use of Jin Bu Huan for insomnia (2 tablets each night for 7 days). Two weeks after she resumed taking Jin Bu Huan, symptoms returned and enzyme levels were again increased (ALT, 16.0 kat/L; AST, 9.9 kat/L). Liver test results returned to normal 3 weeks later. A second-generation enzyme-linked immunosorbent assay for anti-hepatitis C virus was repeated, and the result was again negative. Twelve weeks later, she was asymptomatic and liver test results were normal. Figure 1. Effect of Jin Bu Huan Anodyne Tablets on aminotransferase levels. Patient 2 A 24-year-old woman presented to her physician with symptoms of fever, nausea, vomiting, fatigue, and pruritus for 3 weeks. She had deep jaundice, excoriations of her extremities, and tender hepatomegaly. Stigmata indicating chronic liver disease were absent. She was hospitalized for 5 days. She had taken 4 tablets of Jin Bu Huan at night for insomnia, 4 times a week for the previous 2 months. She stopped taking Jin Bu Huan 1 week after the onset of symptoms. She had used an oral contraceptive pill daily for the previous 8 years. No other medical illness was present. In-hospital results of liver tests showed the following maximal levels: ALT, 24.5 kat/L; AST, 14.9 kat/L; alkaline phosphatase, 2.2 kat/L; and total bilirubin, 479 mol/L. Results from ultrasound examination of the liver and biliary tract were normal. Results of serologic tests for viral hepatitis A, B, and C; cytomegalovirus; and Epstein-Barr virus were negative. The level of serum ceruloplasmin was normal. The peripheral leukocyte count increased to 10.8 109/L with 7% eosinophils (normal, <3% eosinophils). The liver biopsy specimen showed acute hepatitis with focal necrosis, cholestasis, and inflammation with numerous eosinophils in the portal tracts, results consistent with a drug reaction (Figure 2). Pruritus improved with cholestyramine treatment. Nine weeks after discontinuing Jin Bu Huan use, she was asymptomatic and anicteric, showed resolution of eosinophilia, and had normal liver test results (Table 1). Figure 2. Liver biopsy specimen from patient 2. arrow arrows arrows arrows Patient 3 A 45-year-old woman, a friend of patient 2, presented to her physician with symptoms of nausea, anorexia, fatigue, pruritus, and right upper quadrant abdominal pain. Physical examination showed tender hepatomegaly. Stigmata indicating chronic liver disease were absent. She had taken 4 tablets of Jin Bu Huan at night for insomnia, 3 to 4 times a week for the previous 12 weeks. During the previous 6 months, she had intermittently used another Chinese herbal product, Ma Huang (active ingredients are ephedrine and pseudoephedrine), without adverse effects. She had used no other medications and had no medical illness. She stopped taking both herbal products because of her illness. Two weeks later, she noted jaundice. Results from liver tests showed the following maximal levels: ALT, 21.8 kat/L; AST, 16.7 kat/L; alkaline phosphatase, 3.8 kat/L; and total bilirubin, 58 mol/L. Results of serologic tests for viral hepatitis A, B, and C and Epstein-Barr virus were negative. During the next 4 weeks, symptoms resolved and liver tests showed decreased levels of enzymes (Table 1). However, 12 weeks after she stopped taking the herbal product, she developed an unidentified illness and increased aminotransferase levels. She denied using Jin Bu Huan, alcohol, or other hepatotoxic drugs. Tests for viral hepatitis A, B, and C and Epstein-Barr virus were repeated, and the results were negative for these viruses. Results from liver tests were maximal 7 weeks later (ALT, 10.2 kat/L; AST, 6.5 kat/L) and were normal by 19 weeks (a total of 30 weeks after cessation of Jin Bu Huan). Patient 4 A 48-year-old woman residing in Hawaii presented to her physician with fatigue and a temperature of 40.6 C. The physical examination was normal, and stigmata indicating chronic liver disease were absent. She had taken 3 tablets of Jin Bu Huan nightly for 7 weeks for insomnia. She had used no other medications and had no other medical illness. Liver test results were abnormal (ALT, 3.2 kat/L; AST, 1.2 kat/L; and alkaline phosphatase, 9.2 kat/L). Results of serologic tests for viral hepatitis A, B, and C and Epstein-Barr virus were negative, and the serum ceruloplasmin level was normal. The peripheral leukocyte count was 9.3 109/L with 6% eosinophils. After cessation of Jin Bu Huan, she became asymptomatic, her eosinophilia resolved, and liver test results returned to normal within 4 weeks (Table 1). Patient 5 A 46-year-old man presented to his physician with a temperature of 40.6 C, headaches, fatigue, and tender hepatomegaly. Stigmata indicating chronic liver disease were absent. He had taken 3 tablets of Jin Bu Huan for insomnia, 3 times a week intermittently for 6 months. He had used no other medications and had no other medical illness. Aminotransferase levels were abnormal 2 weeks after stopping Jin Bu Huan (ALT, 6.7 kat/L; AST, 4.7 kat/L). Results of serologic tests for viral hepatitis A, B, and C were negative, and the serum ceruloplasmin level was normal. Five weeks after he stopped taking Jin Bu Huan, symptoms improved and liver test results were normal Table 1 and Figure 1 B. After reuse of Jin Bu Huan for 4 weeks, the ALT level increased to 1.7 kat/L. A second-generation enzyme-linked immunosorbent assay for anti-hepatitis C virus was negative. After Jin Bu Huan use was discontinued, liver test results returned to normal in 4 weeks. Patient 6 A 31-year-old woman presented to her physician with nausea, vomiting, malaise, and deep jaundice. The physical examination was normal, and stigmata indicating chronic liver disease were absent. She had taken 6 tablets of Jin Bu Huan for insomnia, 4 to 6 times a week intermittently for 10 months and then nightly for 8 weeks. She had used no other medications and had no other medical illness. Liver test results were abnormal (ALT, 35.8 kat/L; AST, 17.4 kat/L; alkaline phosphatase, 2.8 kat/L; and total bilirubin, 262 mol/L). Results of serologic tests for viral hepatitis A, B, and C were negative, and the serum ceruloplasmin level was normal. Two weeks after she stopped taking Jin Bu Huan, liver test results showed that the enzyme levels were decreasing (Table 1). She is presently asymptomatic. Patient 7 A 53-year old woman residing in Toronto, Canada, presented to her physician with