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Recurrent Toxic Hepatitis in a Caucasian Girl Related to the Use of Shou‐Wu‐Pian, a Chinese Herbal Preparation

2005; Lippincott Williams & Wilkins; Volume: 41; Issue: 2 Linguagem: Inglês

10.1097/01.mpg.0000164699.41282.67

1536-4801

Bianca Panis, Dennis R. Wong, P. M. Hooymans, Peter A. G. M. De Smet, Philippe Rosias,

Herbal Medicine Research Studies

INTRODUCTION The conditions causing impairment of liver function in pediatric patients vary with age. In neonates, infection, metabolic diseases and anatomic obstructions are most common, while in older children infection or drugs are more likely (1,2). Drugs should always be considered as a cause of acute liver injury. Drugs may be directly cytotoxic to hepatocytes or may produce immune-mediated hepatic injury. Some drugs produce metabolites causing liver injury in a dose-dependent manner, whereas other agents form a product toxic only in susceptible persons (3). Non-conventional or alternative medical therapies are being used more frequently in Western society and should be considered as a possible cause of unexplained abnormal liver function tests (4). Herbal preparations are widely available as supposedly harmless remedies for many complaints. However, an increasing body of literature has emerged concerning the risks of these preparations including hepatotoxicity (5-7). The Chinese herbal product Shou-Wu-Pian is prepared from the root tuber of Polygonum multiflorum. It is marketed for relief of a variety of conditions including early graying of hair and baldness. It is also recommended for enrichment of the liver. We report the first pediatric case of acute liver injury occurring twice in a Caucasian girl after ingestion of Shou-Wu-Pian. CASE REPORT A 5-year-old previously healthy Caucasian girl with normal growth and development presented with a 2-day history of jaundice, dark urine and pale stools. There was no history of malaise, anorexia, fever, pruritus or abdominal pain. She was said not to be taking any medication. The family history was negative for inherited metabolic diseases. She had no history of blood transfusions or hepatitis. No recent overseas travel was reported. General physical examination showed an alert, oriented and cooperative girl. Conjunctivae and skin were jaundiced. The liver was enlarged but splenomegaly was absent. Spider nevi, palmar erythema and scratch marks were absent. Further neurologic and general physical examination was normal. Liver biochemistry showed elevated serum levels of bilirubin and liver enzymes (Table 1). Viral markers for hepatitis A, B and C virus were negative as were markers for Treponema pallidum, cytomegalovirus, herpes simplex virus 1 and 2 and Epstein-Barr virus. Full blood count and coagulation tests were normal. Cultures of blood and urine were negative. Abdominal ultrasound examination showed normal liver and biliary tract. Liver biopsy was not performed in this child because of its invasive character and because elevated liver function tests soon decreased after her visit to the hospital.TABLE 1: Liver function tests of the index patientAfter 1 month, jaundice disappeared and liver function tests normalized. However, 2 months after the first presentation she returned to our hospital with a relapse of jaundice. Serum levels of liver enzymes and bilirubin were elevated again (Table 1). A careful history revealed the use of Shou-Wu-Pian. She used this herbal preparation 4 months before the first episode of jaundice (three tablets a day) and stopped using it after the first presentation. However, after resolution of the first symptoms, she was again treated with Shou-Wu-Pian at a lower dose (two tablets a day) for an additional month. We strongly advised her to stop using this preparation. Cessation of the second exposure was associated with slower recovery of liver tests (Table 1). After 5 months, liver function normalized and she enjoyed excellent health at that time. Nuclear magnetic resonance spectrometry was used to determine the composition of the tablets. The results of nuclear magnetic resonance analysis showed 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside, a stilbene glycoside to be the main constituent. The anthraquinone emodin was present in trace amounts (approximately 50 times less than the stilbene glycoside). In addition to these components, some lipids, glucose and sucrose were detected. DISCUSSION Herbal preparations have become more and more popular in Western society, and their use is not restricted to people of Asian descent. Although the term "natural herbal remedies" sounds harmless, many herbal products have severe toxicities (8-12). To define the risks of herbal preparations, the manufacturer should label all ingredients. Even when labeled, however, there are often significant discrepancies between the ingredients listed and the actual contents. Furthermore, these products are often adulterated with pharmaceuticals or contaminated with heavy metals (13). Shou-Wu-Pian is the tablet form of the root tuber of Polygonum multiflorum, the common name of which is the fleeceflower root. The root tuber was recorded in herbal "Kaibao Bencao" issued by the imperial court of the Song Dynasty (973-974 AD) (14). In China, the tuber is dug in autumn, washed clean and dried. The unprepared root is mixed with black soybean milk and Chinese yellow wine, steamed and dried again. The root is also manufactured as a tonic, which is sold as Shou-Wu-Zhi. Shou-Wu-Pian can be translated as "Mr. Black Hair" and is sold for a variety of symptoms associated with aging, including baldness and graying of hair. Shou-Wu-Pian is also sold under the name "He-Shou-Wu"' (communication from the supplier: "Chinese Medical Center," Amsterdam, the Netherlands). A search in MEDLINE revealed three previous reports of toxicity related to ingestion of Shou-Wu-Pian. In 1996 But et al. reported a patient with acute toxic hepatitis after the use of Shou-Wu-Pian (14). This 31-year-old Chinese woman, 17 weeks pregnant, became jaundiced after using Shou-Wu-Pian for several weeks to treat loss of hair. Liver enzymes were elevated. Serologic tests were negative. Ultrasound examination of the liver was normal. During detailed questioning, the woman described a period of jaundice after using Shou-Wu-Zhi approximately 2 years earlier. Liver functions returned spontaneously to normal after cessation of the preparation. In 2001 Park et al. (15) described a 46-year-old Chinese woman taking Shou-Wu-Pian. She presented with a 10-day history of jaundice and dark urine after using the herb for 2 weeks. Liver enzymes were elevated and abdominal ultrasound was normal. A liver biopsy revealed a lobular inflammatory infiltrate with lymphocytes, histiocytes and some neutrophils. Canalicular and hepatocellular cholestasis and hepatocyte necrosis were reported. One month after stopping the preparation, liver function tests returned to normal. Mazzanti et al. (16) recently reported a 78-year-old Italian man who had taken Shou-Wu-Pian to treat symptoms of chronic prostatitis. He had experienced symptoms of acute hepatitis 4 weeks after the consumption of Shou-Wu-Pian, which improved rapidly after the patient discontinued using it. Liver function tests were elevated. Serologic and virologic markers were negative. Ultrasonography and magnetic resonance imaging were normal. But et al. (14) performed a search using CHIMERA, a database of herbal poisoning reports in China, and found several adverse reactions attributed to Polygonum multiflorum, including rash, fever, abdominal pain, dyspnea, vision problems and palpitations. A recent systematic review of adverse events associated with unconventional therapies in children does not include the presented adverse effects of Shou-Wu-Pian (8). The mechanism of Shou-Wu-Pian induced hepatotoxicity is not understood. The liver is the major site of metabolism of most xenobiotics and is especially vulnerable to injury during biotransformation of these compounds. Since discontinuation of Shou-Wu-Pian was associated with resolution of symptoms and improvement of liver function abnormalities, and since re-use resulted in prompt recurrence of symptoms, drug-induced hypersensitivity reaction seems very likely. But et al. (14) analyzed the tablets with thin-layer chromatography and attributed the adverse reactions to the anthraquinones emodin and physcin. Mazzanti et al. (16) performed thin-layer chromatography of Shou-Wu-Pian as well and determined anthraquinones (0.14% w/w) to be present using a spectrophotometric method. Anthraquinones have been shown to form highly reactive anthrones in the colon that can be hepatotoxic (17). Hepatic injury has been described for several other herbal medicines containing anthraquinones, such as Cascara Sagrada, Cassia siamea and Senna (Cassia angustifolia or C. senna) (18-20). Synthetic anthraquinone derivates such as diacerein, mitoxantrone and dantron have been associated with liver damage as well (21-23). The product information reports the anthraquinone derivates emodin, physcin, chrysophanol, rhein and chrysophanol anthrone and the stilbene derivates 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside and its 2″- and 3″-O-monogalloyl esters to be present in the polygonal tablets. The effects of stilbene glycosides on the liver remain unclear (24,25). In addition to these anthraquinone and stilbene derivates, 3.7% of lecithin and several catechin-polyphenol derivates are reported to be present. Our nuclear magnetic resonance analysis confirmed the presence of only two of the described compounds, the stilbene glycoside 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside and the anthraquinone emodin. The acute hepatitis induced by Shou-Wu-Pian in this case is likely related to the chemical components of the herbal product, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside and/or emodin. However, it is important to realize that the preparation may be adulterated with potentially hepatotoxic components that have not been identified using the nuclear magnetic resonance method. We report the first case of acute toxic hepatitis that occurred twice in a Caucasian girl after ingestion of Shou-Wu-Pian, which was recommended because of hair loss. Complete resolution of symptoms and improvement of liver function parameters followed cessation of herbal therapy, but cessation of the second exposure was associated with slower recovery of liver function parameters. The morbidity associated with ingestion of Shou-Wu-Pian illustrates the danger of using unregulated herbal products that are perceived to be safe. Products from Polygonum multiflorum are easily available from Chinese medical practices, grocery stores in Chinatowns and even from various web sites. Although the first reports of hepatotoxicity secondary to Polygonum multiflorum were published in 1996, product information supplied with these preparations and information on web rarely post appropriate warnings (14). Physicians should routinely consider the use of unconventional therapies like Shou-Wu-Pian when dealing with unexplained liver injury. Acknowledgments: The authors would like to thank Prof. Rob Verpoorte and Young H. Choi, PhD, for the performance of the nuclear magnetic resonance imaging analysis.