Jin Bu Huan Toxicity in Adults -- Los Angeles, 1993

Jin Bu Huan (JBH) is a traditional Chinese herbal product used as a sedative and analgesic. During 1993, public health and health-care providers in Colorado reported three children with unintentional overdoses of JBH that caused central nervous system and respiratory depression with rapid onset of life-threatening bradycardia (1). Subsequently, the first cases of acute hepatitis attributed to use of JBH were diagnosed in three women in Los Angeles during July and August 1993. Patients 1 and 2 were referred to a Los Angeles hepatology clinic by their physicians; patient 3 was identified by patient 2. All three patients had purchased JBH at the same health-food store. This report summarizes the investigation of these cases. Patient 1

In July, a 66-year-old woman sought care from her physician for fever, nausea, and fatigue of 2-3 days' duration. She was anicteric and had a palpable, nontender liver. Liver test results were elevated. Serologic tests for hepatitis A and hepatitis B indicated complete resolution of past infection; the test for hepatitis C infection was negative.

During May-July, she had used two JBH tablets at night, two to three times per week, for back pain and insomnia. In mid-July, she reportedly discontinued use of JBH because of her illness, and her alanine aminotransferase level was 786 U/L (normal: less than 40 U/L); aspartate aminotransferase (AST), 463 U/L (normal: less than 35 U/L); alkaline phosphatase, 176 U/L (normal: less than 108 U/L); and total bilirubin, 0.7 mg/dL (normal: less than 1.2 mg/dL). By mid-August, her liver test results had improved to slightly above normal; however, 4 weeks later, her alanine aminotransferase level was 961 U/L; AST, 595 U/L; alkaline phosphatase, 169 U/L; and total bilirubin, 0.4 mg/dL. Three weeks before these tests, the patient had resumed use of JBH (two tablets each night) for 1 week. She discontinued use of JBH a second time in early September. Three weeks later, she was asymptomatic, and liver enzymes had returned to normal. Patient 2

In August, a 24-year-old woman sought care from her physician for fever, nausea, vomiting, fatigue, and pruritus of 2-3 days' duration; she had jaundice, excoriations of her limbs, and tender hepatomegaly. She was hospitalized for 5 days. Serologic tests were negative for hepatitis A, hepatitis B, and hepatitis C; cytomegalovirus; Epstein-Barr virus; and human immunodeficiency virus. Serum ceruloplasmin was normal. The peripheral white blood cell count was 10,800 per mm3 with 7% eosinophils.

During June and July, she had used four JBH tablets at night, four times per week, for insomnia. She noted onset of jaundice in mid-July but continued use of JBH for 2 additional weeks. Two weeks after she reportedly discontinued use of JBH because of her illness, her alanine aminotransferase level was 1468 U/L; AST, 895 U/L; alkaline phosphatase, 133 U/L; and total bilirubin, 28.0 mg/dL (indirect bilirubin, 17 mg/dL {normal: less than 0.3 mg/dL}. Liver biopsy revealed acute hepatitis with many eosinophils in the portal tracts and cholestasis consistent with a drug reaction. To treat pruritus, cholestyramine therapy was initiated during her hospital stay; pruritus improved slightly. Nine weeks after discontinuing use of JBH, the patient was asymptomatic, and liver enzymes had returned to normal. Patient 3

In August, a 45-year-old woman sought care from her physician for nausea, anorexia, fatigue, pruritus, and abdominal (right upper-quadrant) pain of 2-3 days' duration. Physical examination revealed tender hepatomegaly. Liver test results were elevated. Serologic tests for hepatitis A, hepatitis B, and hepatitis C were negative.

During May-August, she had used four JBH tablets at night, three to four times per week, for insomnia. During January-August, she had intermittently used another Chinese herbal product, Ma Huang (active ingredients include ephedrine and pseudoephedrine). She noticed onset of jaundice in mid-September, and her alanine aminotransferase level was 1308 U/L; AST, 1002 U/L; alkaline phosphatase, 225 U/L; and total bilirubin, 3.4 mg/dL. In late September, she reportedly discontinued use of both herbal products because of her illness. During the next 2 weeks, her symptoms resolved, except for mild pruritus. Nine weeks after discontinuing use of JBH, the patient was asymptomatic, and her liver test results had improved. Summary Findings

No patient reported alcohol abuse. Ultrasound examination of the liver and biliary tract was normal for all patients; tests for antinuclear, antismooth muscle, and anti-mitochondrial antibodies were negative. All patients had normal prothrombin times throughout the course of their illnesses. Follow-Up Investigation

The package insert for JBH tablets recommends use to treat pain and insomnia and indicates a composition of 70% starch and 30% levo-alkaloid from the plant Polygala chinensis. Tablets from patients 1 and 2 were analyzed at Colorado State University, using nuclear magnetic resonance and gas chromatography/mass spectroscopy; the tablets contained 36% (28.8 mg) levo-tetrahydropalmatine (L-THP), a chemical present in plants of the genera Stephania and Corydalis but not present in the genus Polygala (the plant of origin indicated on the package insert) (2,3). The remaining constituents were inert and no other plant materials or chemicals were identified. The Food and Drug Administration (FDA) is investigating this product. Reported by: GM Woolf, MD, SE Rojter, MD, FG Villamil, MD, JM Vierling, MD, Section of Hepatology, Cedars-Sinai Medical Center, Los Angeles; W Katkov, MD, St. Johns Hospital, Santa Monica. FR Stermitz, MD, JJ Beck, Dept of Chemistry and Agricultural Experiment Station, Colorado State Univ, Fort Collins. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Health Studies Br, Div of Environmental Hazards and Health Effects, National Center for Environmental Health, CDC.

Editorial Note

Editorial Note: The ingredients identified in the JBH tablets from two of the three case-patients in this report were identical to those extracted from the JBH tablets retrieved from the previously reported cases of overdose in children (1). The findings in this report suggest that JBH (or one of its components) may be hepatotoxic; therefore, JBH should be avoided by persons with known liver disease.

The severity of the adverse health effects in these three cases underscores the potential health risks associated with use of herbal products. Based on surveys in Australia, England, the Netherlands, and New Zealand, the reported proportion of adult patients who seek consultations with and treatment by providers of unconventional therapy * varies from 4% to 50% (4). In a recent survey of U.S. adults, 34% of respondents reported using unconventional therapy, and 3% reported using herbal products (5). In addition, during 1990, U.S. residents made an estimated 425 million office visits to providers of unconventional therapy; expenditures associated with such therapies totaled approximately $13.7 billion (5). In North America, Chinese herbal products are sold as over-the-counter remedies for a variety of ailments. Although package inserts claim the safety of herbal products, previous reports have documented the risk of adverse health effects associated with use of these products (1,4-7).

Because the marketers of herbal products maintain that these products are dietary supplements rather than drugs, herbal products generally are not subject to standard testing for safety and efficacy. For the three cases in this report, the plant source and percentage of the active ingredient indicated on the JBH labels were incorrect. Such inaccuracies mislead consumers and health-care providers and can impede prompt and proper medical treatment. In addition, consumers should be warned that the term "natural" on a label does not ensure product safety (8).

Reporting systems have not been available to collect data about adverse reactions to dietary supplements, including botanical products. However, FDA's newly implemented MEDWATCH program, which monitors reports of adverse reactions to FDA-regulated products, may enhance surveillance because it specifically requests reports of adverse reactions to dietary supplements (9). National surveillance programs such as this can assist in identifying and monitoring the adverse health effects of JBH and other herbal products and dietary supplements. To report cases of serious adverse reactions to dietary supplements, health-care providers should contact MEDWATCH (telephone {800} 332-1088) to request a reporting form.

References

1. CDC. Jin Bu Huan toxicity in children -- Colorado, 1993. MMWR 1993;42:633-6.

2. Guo-Zhang J. Tetrahydropalmatine and its analogues as new dopamine receptor antagonists. Trends Pharmacol Sci 1987;8:81-2.

3. Zhen-Gang W, Gan-Zhong L. Advances in natural products in China. Trends Pharmacol Sci 1985;6:423-6.

4. Voerhoef MJ, Sutherland LR, Brkich L. Use of alternative medicine by patients attending a gastroenterological clinic. Can Med Assoc J 1990;142:121-5.

5. Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States: prevalence, costs and patterns of use. N Engl J Med 1993;328:246-

7. McGee JO, Patrick RS, Wood CB. A case of veno-occlusive disease of the liver in Britain associated with herbal tea consumption. J Clin Pathol 1976;29:788-94.

8. CDC. Chaparral-induced toxic hepatitis -- California and Texas, 1992. MMWR 1992;41:812-4.

9. Food and Drug Administration. Unsubstantiated claims and documented health hazards in the dietary supplement marketplace. Rockville, Maryland: US Department of Health and Human Services, Public Health Service, Food and Drug Administration, July 1993.

10. Kessler DA. Introducing MEDWATCH: a new approach to reporting medication and device adverse effects and product problems. JAMA 1993;269:2765-8.

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