部分中药肝毒

标签：

Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2036.2006.03111.x/full

• First published: 20 September 2006Full publication history
• DOI: 10.1111/j.1365-2036.2006.03111.xView/save citation
• Cited by: 30 articles

Background

Despite the lack of controlled studies to validate the clinical efficacies and safety profiles of traditional Chinese medicine (TCM), TCM has become more frequently used recently, both in Asian and Caucasian populations.^1, 2 One study has shown that more than 40% Americans take TCM.³ One of the main reasons for taking TCM is that TCM are perceived to have much less side effects and more ‘harmonizing and balancing’ power to the body compared with western medicine. However, there is increasing number of reports showing that several TCM can lead to toxicity.^2, 4, 5 Systematic and comprehensive study of the toxicities related to TCM is difficult to conduct because of several reasons. These include incomprehensive understanding of the modes of action, lack of standardization in the preparatory procedure with different formulations, lack of quality control and high complexity of the ingredients, particularly those from herbal extracts.

Since the currently approved agents for the treatment of chronic hepatitis B (CHB) are usually unable to completely eradicate the hepatitis B virus (HBV), many CHB patients opt for alternative therapies such as TCM for the protection and optimization of liver function. One report finds that 39% of patients with chronic liver diseases admitted to using some form of complementary and alternative medicine.⁶ Another report shows that 21% and 13% of patients attending liver clinics have taken TCM previously or are currently using TCM to treat the liver condition, respectively.⁷ According to a recent study from Hong Kong, 32% of patients with CHB infection admitted a history of TCM usage.⁸ There are two important issues concerning TCM in patients with CHB. First, being the major organ for drug biotransformation, the liver is at a unique and the highest risk for TCM toxicity of the body. According to the reports of the National Poisons Information Service in the United Kingdom, hepatotoxicity is the most frequent adverse event among the possible or confirmed TCM-associated toxicity.⁹ Secondly, the hepatotoxic effects of TCM may be augmented in CHB patients because of the background HBV infection, just as the increased hepatotoxicity of isoniazid in CHB patients.¹⁰ These patients may therefore be at a higher risk for liver decompensation.

The present study aimed to study the clinical outcome of TCM-induced hepatotoxicity in patients with CHB.

Patients and methods

From January to December 2004, all patients with known CHB infection [defined as positivity of hepatitis B surface antigen (HBsAg) for more than 6 months] admitted to Queen Mary Hospital, The University of Hong Kong, Hong Kong because of liver biochemistry derangement were prospectively screened. The inclusion criteria were HBsAg positivity, intake of TCM within 6 months prior to admission, elevated bilirubin levels of more than two times upper limit of normal (ULN) or elevated level of at least one of the liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST) to more than five times ULN, or alkaline phosphatase (ALP) and γ-glutamyltranspeptidase (GGT) to more than two times ULN. The exclusion criteria included: (i) evidence of HBV exacerbation defined by elevated ALT levels associated with HBV-DNA level more than 10⁶ copies/mL with or without positive IgM antibody to hepatitis B core antigen (anti-HBc IgM); (ii) evidence of other acute or chronic hepatitis virus infections including hepatitis A, C, D and E [confirmed by antibodies against the hepatitis A virus (anti-HAV IgM), the hepatitis C virus (anti-HCV IgG), the hepatitis D virus (anti-HDV IgG) and the hepatitis E virus (anti-HEV IgM)]; (iii) evidence of recent severe sepsis; (iv) intake of western medication with known hepatotoxicity; (v) history of significant alcohol intake (>20 g/day for women and >30 g/day for men); (vi) history of ultrasonographic evidence of steatohepatitis and (vii) evidence of autoimmune hepatitis, Wilson‘s disease and primary biliary cirrhosis. The likelihood of TCM-induced hepatotoxicity was decided with reference to the international consensus criteria.¹¹

For patients with TCM-induced hepatotoxicity, details of the TCM including the drug formulae prescribed by the herbalists, the doses and the frequency of intake were analysed. Extensive literature search through PubMed; Medline; Electronic Knowledge Gateway of the Hospital Authority, Hong Kong; Chinese Medicine Library of the Baptist University, Hong Kong; books on TCM written in Chinese and English^12, 13 were performed to determine the hepatotoxicity associated with individual TCM element. Complete blood count, liver biochemistry, renal function test and prothrombin time were monitored. Hepatic decompensation is defined as prolonged prothrombin time to more than 5 s of controls and elevated bilirubin level to more than two times ULN, or development of ascites and/or hepatic encephalopathy.

Results

Between January and December 2004, 45 patients with CHB were admitted with derangement of liver biochemistry. Of these, seven patients (15.6%) had liver derangement attributable to the intake of TCM. The causes of liver biochemical derangement for the remaining 38 patients are as follows: HBV exacerbation (n = 28; eight had TCM intake which were not known to have hepatotoxicity); acute hepatitis A infection (n = 2); acute hepatitis E infection (n = 3); liver toxicities because of other medications including carbimazole and isoniazid (n = 3) and acute alcoholic hepatitis (n = 2). The clinical information and the progress of the seven patients with TCM-associated liver derangement are as follows.

Patient 1

A 33-year-old female (CSM) HBV carrier was admitted with 5 days history of jaundice, associated with nausea and anorexia. She had been taking two capsules of a Chinese proprietary medicine three times daily for weight reduction for 6 weeks. Physical examination was normal except for jaundice. The liver biochemistry on presentation was as follows: albumin 35 g/L (normal 42–54), bilirubin 173 μm (normal 7–19), ALT 3002 U/L (normal 5–31), AST 2371 U/L (normal 12–28), ALP 133 U/L (normal 34–104) and GGT 110 U/L (normal 9–42). The prothrombin time was 15.7 s (control 13.2 s). She was positive for the antibody to hepatitis B e antigen (anti-HBe) but negative for IgM antibody to the hepatitis B core antigen (anti-HBc IgM). HBV-DNA was undetectable with the Digene Hybrid II Capture assay (Gaithersburg, MD, USA; lower limit of detection 1.42 × 10⁵ copies/mL). Ultrasonogram of abdomen did not show evidence of cirrhosis with normal liver and spleen size. The liver function continued to deteriorate with prothrombin time reaching 53 s and bilirubin level 710 μm. In view of the irreversible hepatic decompensation, living-related liver transplantation was performed 4 weeks after admission. The explanted liver revealed confluent necrosis with marked cholestasis and sparse lymphocytic aggregates without any significant fibrosis. The histological features were compatible with drug-induced injury. The Chinese propriety medicine contained 12 herbal items, two of which, Heshouwu and Juemingzi, listed in Table 1 contain anthraquinones (approximately 1% by weight) are known to be hepatotoxic on prolonged intake.^14–17 In addition, with further laboratory analysis, the prescribed TCM formula is found to be adulterated with N-nitrosofenfluramine which is highly hepatotoxic.^18, 19 The patient recovered well after the liver transplantation.

Table 1.   Details of the elements of the traditional Chinese medicines for the first five patients

Patient 2

A 45-year-old man (LTS) with known CHB complaining of epigastric discomfort. The liver biochemistry was normal (albumin 39 g/L, bilirubin 13 μm, ALT 23 U/L) 4 weeks before presentation to our hospital. Ultrasonogram of abdomen did not show evidence of cirrhosis with normal liver and spleen size. He consulted an herbalist for epigastric discomfort and was prescribed five different formulae of TCM. One month later, he developed ascites with derangement of liver function: albumin 30 g/L, bilirubin 450 μm (conjugated bilirubin 372 μm), ALT 27 U/L, ALP 247 U/L and GGT 190 U/L. The prothrombin time was prolonged to 24.2 s. He was positive for anti-HBe and negative for anti-HBc IgM. The HBV-DNA level was undetectable by bDNA assay (Bayer HealthCare LLC, Tarrytown, NY, USA; lower limit of detection 2000 copies/mL). He also developed acute renal failure [creatinine level 990 μm (normal 82–126), urea level 45.6 mm (normal 3.2–7.5)] requiring supportive haemodialysis. The platelet count decreased from 147 to 36 × 10⁹/L. Bone marrow examination revealed reactive change only. The prothrombin time and bilirubin level continued to increase and the renal function failed to improve. He finally died of sepsis and multiorgan failure 2 weeks after admission. Of the five TCM formulae, several identifiable elements were potentially hepatotoxic and nepthrototoxic (Table 1): Chuanlianzi contains a hepatotoxic alkaloid, toosendanin.²⁰ Dajuang contains a hepatotoxic anthraquinone (0.7–4.2% by weight) as in patient 1 (anthraquinone is also nepthrotoxic).²¹ Wugong from dried powder of centipedes, causes fatal cases of multiorgan failure (reported in Chinese literature only). There are at least four others (Quanxie, Baihuagshe, Wushaoshe, Jiangcan) that contain animal toxins that are potentially hepatotoxic.

Patient 3

A 59-year-old man (CTK) with HBeAg-positive liver cirrhosis presented to our hospital with gum bleeding and bilateral lower limbs petechiae. Baseline liver biochemistry during routine follow-up 2 months previously was: albumin 30 g/L, bilirubin level 32 μm, ALT level 113 U/L, ALP level 122 U/L. The platelet count was 72 × 10⁹/L. The creatinine level was 74 μm. Ultrasonogram of abdomen showed small-size cirrhotic liver and splenomegaly. He also had oesophageal varices, which had been endoscopically banded prophylactically. He took eight doses of a Chinese herbal formula daily for leg cramps 3 weeks prior to admission. On admission, the liver biochemistry was grossly deranged: albumin 21 g/L, bilirubin level 484 μm (conjugated bilirubin 339 μm), ALT level 41 U/L, ALP level 123 U/L and GGT level 54 U/L. He developed severe coagulopathy with extremely low platelet count of 2 × 10⁹/L, prolonged prothrombin time of 15.1 s and activated partial thromboplastin time of 52.8 s, and increased D-dimer level of 1971 ng/mL (normal <500). Peripheral blood film showed occasional fragmented red cells. Direct Coomb‘s test was positive. He also developed acute renal failure with elevation of creatinine level to 503 μm. His HBV-DNA level was 3.2 × 10³ copies/mL (measured by bDNA assay). Bone marrow examination revealed a hypocellular marrow with the presence of ring siderblasts suggestive of recent drug/toxin exposure. The overall clinical picture was compatible with drug-induced systemic toxicity involving the haematological (disseminated intravascular coagulopathy, haemolytic anaemia), hepatic and renal systems. He finally succumbed 4 weeks after admission. There were 11 different herbal elements in the drug formula. One of the elements, Zexie listed in Table 1, has been reported to have hepatotoxicity on liver and other organs in studies with mice in the Chinese literature.

Patient 4

A 45-year-old man (CKS) with HBeAg-positive CHB infection was first seen 4 months prior to admission. The liver biochemistry in the first clinic visit was: albumin 42 g/L, bilirubin 27 μm, ALT 70 U/L, AST 44 U/L, ALP 102 U/L and GGT 180 U/L. One month later, he started to take a TCM formula named ‘Lingyang Qingfei Keli’ for its ‘cooling’ effect on the lungs and relief of pharyngeal discomfort. He took 6 g three times daily till the onset of jaundice 3 months later. Physical examination revealed ascites. The liver biochemistry was found to be grossly deranged: albumin 24 g/L, bilirubin 288 μm, ALT 414 U/L, AST 495 U/L, ALP 135 U/L and GGT 178 U/L. The prothrombin time was 22.2 s. Ultrasonogram of abdomen showed small-size cirrhotic liver, splenomegaly and ascites. The HBV-DNA level was low at 290 copies/mL (by Cobas Amplicor HBV Monitor test, Roche Diagnostics, Branchburg, NJ, USA). Anti-HBc IgM was negative. The liver biochemistry gradually improved after the cessation of the TCM and became static with albumin level of 29 g/L, bilirubin level of 94 μm and prothrombin time of 20 s after 3 months. The patient was subsequently put on the waiting list for liver transplantation. There were 12 elements identified in the TCM formula ‘Lingyang Qingfei Keli’. Of these, three are known to be hepatotoxic (Table 1). These include Zudahuang that is a processed Dahuang (mentioned in patient 2), Gancao with its active ingredient, glycyrrhizin, being potentially hepatotoxic on prolonged intake and Bohe (Mentha haplocalyx) a kind peppermint known to be hepatotoxic in Chinese literature. Pennyroyal oil derived from the same genus, Metha pulegium contains several monoterpenes, principally pulegone, known to have toxic effects on the liver and lungs. Several reports of hepatitis because of pennyroyal oil have been reported.^22–25

Patient 5

A 46-year-old man (CCK) had known history of IgA nephropathy and HBeAg-positive CHB infection followed up in the renal clinic for 8 years. The liver biochemistry was completely normal all along. He complained of malaise and loss of appetite, and took two doses of a TCM formulae prepared by his friend in China 2 days before the onset of jaundice. The liver biochemistry on admission was: albumin 36 g/L, bilirubin level 132 μm, ALT level 1324 U/L, AST level 1599 U/L, ALP level 144 U/L and GGT level 165 U/L. The prothrombin time was mildly elevated to 18.1 s. HBV-DNA level was 4.7 × 10⁵ copies/mL (measured by bDNA assay). Anti-HBc IgM was negative. Ultrasonogram of abdomen revealed a small liver with features suggestive of cirrhosis, and mild splenomegaly. The formulae contained 11 elements in which Gancao (Table 1; mentioned in patient 4) is likely the toxic agent for the hepatotoxicity. The liver biochemistry gradually returned to normal 2 months later.

Patient 6

A 37-year-old man (STW) with anti-HBe-positive CHB infection had liver biochemistry on presentation as follows: albumin level 49 g/L, bilirubin 24 μm, ALT 403 U/L, AST 204 U/L, ALP 87 U/L and GGT 23 U/L. The HBV-DNA level was 3.6 × 10⁵ copies/mL. One month later, he was admitted because of a significant increase in the ALT level to 851 U/L with a normal albumin level of 47 g/L and bilirubin level of 19 μm. The prothrombin time was also normal. He had been taking Phyllanthus urinaria extracts for 5 months for its supposed anti-HBV effect. HBV-DNA level remained static at 2 × 10⁵ copies/mL. Anti-HBc IgM was negative. Ultrasonogram of abdomen did not show evidence of cirrhosis with normal liver and spleen size. The liver biochemistry returned to normal 2 months after stopping of the drug. The possibility of spontaneous HBV reactivation was unlikely because of the relative low and static HBV-DNA levels, checked on two occasions 1 month apart. Though P. urinaria extracts have been reported to have anti-HBV effect,²⁶ meta-analysis disproves this.²⁷ Several studies using P. amarus (same genus but different species) have been conducted to determine its efficacy for treating CHB.^28–32 The findings are conflicting and inconsistent, but largely indicate the lack of efficacy for CHB.

Patient 7

A 38-year-old man (TKF) with CHB had regular follow-up in our clinic with documented HBeAg seroconversion 6 years prior to admission. The liver biochemistry remained completely normal until he presented with tea-colour urine, malaise and right upper quadrant discomfort in 2004. He took Ji Gu Cao (Abrus cantonienesis Hance) for 3 days 1 week prior to admission. Physical examination revealed jaundice. The liver biochemistry on admission was: albumin 39 g/L, bilirubin 197 μm, ALT 3070 U/L, AST 1470 U/L, ALP 145 U/L and GGT 173 U/L. Prothrombin time was 17.5 s. He was negative for anti-HBc IgM. The HBV-DNA level was 4.3 × 10⁵ copies/mL by the Digene Hybrid Capture II assay. Ultrasonogram of abdomen did not show evidence of cirrhosis with normal liver and spleen size. After reaching the peak bilirubin level of 404 μm 6 weeks after admission, the liver function became normal after 5 months. The possibility of spontaneous HBV exacerbation was unlikely because of the persistent normal ALT levels for 6 years after stable HBeAg seroconversion, relatively low HBV-DNA level and anti-HBc IgM negativity on admission. Abrus cantonienesis Hance is prepared from the dried stems and roots of a plant named Abrus leguminosiae. Contamination with the seeds of these plants, which contain a toxoalbumin, Abrin, and a toxic glycoside, Abric acid, which are highly toxic to the liver and kidney, may occur during the preparatory procedures.

The clinical features and outcome of these seven patients are summarized in Table 2.

Table 2.   Summary of the clinical features of the seven patients with TCM-induced hepatotoxicity

Discussion

Of the 45 admissions because of liver derangement in patients with CHB infection, 15.6% were attributed to the TCM-induced hepatotoxicity. This figure is likely to be an underestimation at first, because patients do not always own up to the use of herbal medicines. Secondly, liver derangement in CHB patients is often simply attributed to hepatitis B exacerbation without detailed enquiry into the drug history. Thirdly, even with a documented history of herbal intake, doctors are often uncertain as to the culpability of the herbs because of the lack of detailed information on Chinese herbs. It is also not always easy to differentiate HBV exacerbation from herb-induced hepatotoxicity in CHB patients. Detailed history of drugs or herbs intake including dietary supplements to identify the offending elements, for example, those listed in Table 1, and tests for diagnosing acute exacerbation of HBV including HBV-DNA levels and anti-HBc IgM may be of great value. Involvement of other systemic organs in the initial stage of the disease as shown in patients 2 and 3 favours the diagnosis of drug-induced hepatotoxicity.

In patients 6 and 7, the diagnosis of herb-induced hepatotoxicity was based on the temporal relationship of the intake of herbs and the onset of liver derangement together with the absence of convincing evidence of acute exacerbation of the CHB, although specific liver toxic elements were not found in the herbal formulae. There may be several reasons for this. First, it is difficult to get the complete herbal formulae as patients may not recall correctly or fail to disclose fully their herbal intake. Secondly, impurities adulterating the herbs during the process of preparation remain a concern because of the lack of quality control and standardization during the preparatory procedure (as illustrated in patient 1). Thirdly, the amount of the herbs taken by patients may far exceed the safety limit, particularly in patients who take the TCM continually as daily supplements. Fourthly, interactions between different elements of the TCM and also between western medications may occur when they are taken at the same time. Finally, the possibility of synergistic hepatotoxicity of herbal preparation and HBV is largely unknown.

In the present study, five patients (patients 1, 4, 5, 6 and 7) had marked elevation of ALT levels ranging from 414 to 3070 U/L and all except patient 6 were followed by marked cholestasis. The remaining two patients (patients 2 and 3) presented with marked cholestasis (bilirubin levels of 450 and 484 μm respectively) with relatively normal ALT levels (27 and 41 U/L respectively). All seven patients had either normal or only mildly elevated levels of ALP (range: 102–247 U/L) and GGT levels (range: 54–190 U/L). The predilection for elevation of parenchymal enzymes in TCM-induced liver derangement makes it difficult to differentiate from HBV exacerbation in CHB patients. Cases of TCM-induced hepatotoxicity have been clinically confused with acute viral hepatitis.³³

Of the seven CHB patients reported, three had hepatic decompensation resulting in two deaths and one liver transplant. In patients with pre-existing cirrhosis as in patient 3, any insult to the liver; however mild, can easily lead to hepatic decompensation and mortality. In addition, the threshold for hepatotoxicity of different elements of TCM may be lower in CHB patients. Finally, some TCM may contain steroids and immunosuppressives that will enhance the HBV replication leading to severe HBV flares once they are taken off. To determine whether the clinical outcome of CHB patients with TCM toxicity are more severe compared with non-HBV subjects require further studies.

In patient 4, though the liver function gradually improved after cessation of the offending TCM, it did not return to baseline level. The liver function was irreversibly worsened after the added insult of the TCM. This suggests that TCM can potentially accelerate the cirrhotic process in patients with CHB infection.

In conclusion, several elements of TCM had been identified to be associated with hepatotoxicity, often with other systemic toxicity. TCM-related hepatotoxicity resulted in high mortality/requirement for liver transplantation in patients with CHB infection. Randomized-controlled trials with the same stringent criteria as trials in western medicine are required to document the efficacies and safety of various TCM before they can be advocated for the treatment of diseases. In addition, strict quality control for the preparation of TCM should be universally adopted to avoid adulteration with other toxic elements.

Acknowledgement

This study was funded by a grant from the Hepatology Research Fund, The University of Hong Kong.

部分中药肝毒

标签：

原文地址：http://www.cnblogs.com/biopy/p/5796176.html