Polygonum Multiflorum

Publication Details

OVERVIEW

Introduction

Polygonum multiflorum is an herb native to China, extracts of which has been used for centuries as a treatment for a wide range of conditions including backache, dizziness, liver disease, graying of the hair and constipation. P. multiflorum is also known as Shou Wu Pian, He Shou Pian, Fo-Ti and Chinese knotweed. Polygonum multiflorum has been implicated in numerous reports of clinically apparent acute liver injury which can be severe and even fatal.

Background

Polygonum multiflorum is a commonly used and ancient Chinese herbal remedy prepared from the root of the tuber, Polygonum multiflorum, known as the Chinese climbing knotweed (Fo Ti). Fo Ti is a plant native to China which has been cultivated widely elsewhere, including the United States. Extracts of the roots of Polygonum multiflorum have been used for centuries in traditional Chinese medicine for a multitude of conditions and as an agent to prevent aging. Some of the historical uses include cancer, tuberculosis, diabetes, hypertension, infections, erectile dysfunction, infertility, and muscle soreness. It is also used as a tonic in liver and kidney conditions and to fortify muscles and bones. The extract has been marketed as a pill and claimed to be beneficial for headache, dizziness, graying of the hair, constipation and liver disease. Polygonum multiflorum can also be brewed in teas, and extracts are used in topical creams or ointments for skin conditions and muscle soreness. The efficacy of Polygonum multiflorum has not been proven in prospective, controlled trials but it is widely available over the counter. The active components of Polygonum multiflorum are believed to be anthraquinones including chrysophanol, emodin and rhein. Anthraquinones may also account for its effect in constipation but may also account for its hepatotoxicity. Various oral formulations are available, and it is also taken as a tea using extracts of dried Polygonum roots. Common side effects are abdominal pain, diarrhea, nausea and vomiting. Serious adverse events are rare, although hepatotoxicity has been increasingly reported, particularly from China and East Asia.

Hepatotoxicity

Several published cases and a large case series from China, Korea and Japan of clinically apparent acute liver injury have been attributed to use of Polygonum multiflorum. Indeed, in China Polygonum multiflorum is reported to be the most common cause of herbal product related liver injury. The latency to onset is usually short, but ranges from a few days to as long as 6 months. The pattern of serum enzyme elevations is typically hepatocellular or mixed and the clinical presentation resembles acute viral hepatitis with onset of fatigue, nausea and right upper quadrant pain followed by dark urine and jaundice. Immunoallergic features are uncommon as are autoantibodies. Liver biopsy shows changes typical of acute hepatitis. The course is usually self-limited, resolving rapidly once the herbal is discontinued, but up to 10% of clinically apparent cases have been fatal or led to urgent liver transplantation. Recurrence upon re-exposure with a more rapid time to onset has been reported. Recent case series have identified the HLA allele B*35:01 as a risk factor, being found in 70% to 88% of cases compared to 5% of controls in Chinese populations. A similar HLA-association has been found for green tea in the United States.

Likelihood score: A (well established cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of hepatotoxicity of Polygonum multiflorum is not known, but the injury is usually attributed to the anthraquinones (such as emodin) which are major constituents in Polygonum multiflorum. In a single report, the major compound identified in the recovered tablets was a stilbene glycoside, tetrahydroxystilbene-glucopyranoside. The HLA allele B*35:01 appears to be a major risk factor for liver injury from Polygonum multiflorum suggesting that the injury is immunologically mediated.

Outcome and Management

Hepatotoxicity from Polygonum multiflorum is usually self-limited but can be prolonged and is occasionally fatal. Recurrence with restarting the herb is common and rechallenge should be avoided. There is little evidence for cross sensitivity to the hepatotoxic effects of other herbal medications. Use of corticosteroids has not been reported to be effective.

Other Names: Fo Ti, Chinese climbing knotweed, Fleece-flower root, Chinese cornbind, Ho Shou Wu, Shou Wu Pian, Shen Min, Zi Shou Wu

Drug Class: Herbal and Dietary Supplements

Other herbals in the Subclass: Chinese and Other Asian Herbal Medicines

CASE REPORT

Case 1. Recurrent hepatitis due to Shou Wu Pian.(1)

A 5 year old girl developed jaundice and dark urine 4 months after her parents started her on Shou Wu Pian (3 tablets daily) for hair loss. She was otherwise healthy, with normal growth and development and no history of liver disease or risk factors for viral hepatitis. She was taking no conventional medications and her family initially did not mention the herbal use. Physical examination showed jaundice and mild hepatomegaly without fever, rash, abdominal tenderness or splenomegaly. Laboratory results showed raised serum bilirubin levels (4.9 mg/dL), and elevations in serum aminotransferases (ALT 1543 U/L, AST 1938 U/L) and gamma-glutamyl transpeptidase levels (GGT 67, normal <17 U/L). Tests for hepatitis A, B and C were negative as were tests for cytomegalovirus and Epstein Barr virus infection. Abdominal ultrasound showed normal liver and biliary tract. Liver tests improved without specific therapy and one month later liver tests were normal (Table). However, she returned with recurrence of jaundice 2 months later and at this point the history of herbal use was obtained. After recovering from the initial liver injury, the Shou Wu Pian had been restarted at a lower dose (2 tablets per day) and she redeveloped jaundice within a month of restarting. She again began to improve once the herbal medication was stopped, but liver test abnormalities did not completely resolve until 5 months later. Analysis of residual tablets of the Shou Wu Pian demonstrated the stilbene glycoside, tetrahydrostilbine-glucopyranoside, as the major constituent with only trace amounts of anthraquinones.

Key Points

Laboratory Values

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Table

months months

Comment

The case history is somewhat typical of herbal induced liver injury, in that the family did not inform the physicians that the child was receiving Shou Wu Pian (Polygonum multiflorum) and did not consider it harmful or imagine that it was the cause of the hepatitis. The clinical features resembled acute hepatitis, but the recurrence (with a shorter latency) on restarting the herbal makes this a convincing case for Polygonum multiflorum induced acute liver injury.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Shou Wu Pian – Generic

DRUG CLASS

Herbal and Dietary Supplements

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Shou Wu Pian – Generic

DRUG CLASS

Herbal and Dietary Supplements

CHEMICAL FORMULA AND STRUCTURE

CITED REFERENCE

1.
Panis B, Wong DR, Hooymans PM, De Smet PAMG, Rosias PPR. Recurrent toxic hepatitis in a Caucasian girl related to the use of Shou-Wu-Pian, a Chinese herbal preparation. J Pediatr Gastroenterol Nutr. 2005;41:256–8. [PubMed: 16056110]

ANNOTATED BIBLIOGRAPHY

References updated: 15 August 2020

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    (31 year old woman from Hong Kong developed jaundice several weeks after starting Shou Wu Pian for hair loss [bilirubin 4.0 rising to 6.1 mg/dL, ALT 870 U/L, Alk P 108 U/L], resolving within 3 weeks of stopping).
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    (46 year old woman developed pruritus and jaundice 2 weeks after starting Shou Wu Pian [bilirubin 12.6 mg/dL, ALT 876 U/L, Alk P 185 U/L], resolving within a month of stopping).
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    (78 year old man developed jaundice 1 month after starting Shou Wu Pian for chronic prostatitis [bilirubin 25.5 mg/dL, ALT 1276 U/L, Alk P 409 U/L], resolving rapidly upon stopping).
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    (5 year old girl developed jaundice 4 months after being started on Shou Wu Pian [bilirubin 4.9 mg/dL, ALT 1543 U/L, Alk P normal], resolving within 5 weeks and recurring within 4 weeks of restarting, resolving this second time only after 5 months: Case 1).
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    (Among 45 patients from Hong Kong with chronic hepatitis B who had an acute exacerbation of disease, the cause appeared to be an exacerbation of hepatitis B in 28, acute hepatitis A in 2, acute hepatitis E in 3, conventional drug induced liver injury in 3, alcohol in 2 and use of Traditional Chinese Medicines in 7, one of whom had been taking Polygonum multiflorum for weight loss for 6 weeks and developed a severe hepatitis, ultimately requiring liver transplantation).
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    (35 year old man developed jaundice “several months” after starting “NuHair” [containing Polygonum multiflorum] for hair loss [bilirubin 4.6 rising to 13.7 mg/dL, ALT 2714 U/L, Alk P 137 U/L, INR 1.3], resolving 4 months after stopping).
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    (34 year old man developed jaundice 30 days after starting daily use of Polygonum multiflorum tea and extract [bilirubin 25.3 mg/dL, ALT 1452 U/L, Alk P 111 U/L] with neutropenia [and pulmonary tuberculosis], liver injury resolving slowly after stopping herbal product).
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    (53 year old Japanese woman developed fatigue after taking Shou Wu Pian for 8 months [bilirubin 1.2 mg/dL, ALT 417 U/L, Alk P 1425 U/L, ANA 1:320], resolving within 2 months of stopping).
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    (35 year old Italian woman developed fatigue, abdominal pain and jaundice 4 weeks after starting 3 herbal products for hair loss including Shou Wu Pian [Polygonum multiflorum], glycyrrhizin and black cohosh [bilirubin 3.3 mg/dL, ALT 1540 U/L, Alk P 1020 U/L, normal INR], resolving within 2 months of stopping).
  • Bae SH, Kim DH, Bae YS, Lee KJ, Kim DW, Yoon JB, Hong JH, Kim SH. Korean J Hepatol. 2010;16:182–6. [Toxic hepatitis associated with Polygoni multiflori] [PubMed: 20606503]
    (54 year old Korean woman developed fatigue 1 month after starting Shou Wu [ALT 1136 U/L, Alk P 324 U/L], resolving rapidly but recurring upon re-exposure).
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    (Case series of 25 patients with suspected hepatotoxicity from Polygonum multiflorum seen between 2007 and 2009 at a single Korean hospital; ages 24 to 65 years, presenting with jaundice after taking herbal as a tea or liquid extract for 2 to 180 days [bilirubin 1.6-32.9 mg/dL, ALT 271-1706 U/L, Alk P 81-465 U/L], injury pattern being hepatocellular [n=18] or mixed [n=7], liver biopsies showing acute hepatocellular injury, resolving in most, one patient died, one underwent liver transplantation, and one had recurrence on re-exposure).
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  • Banarova A, Koller T, Payer J. Toxicka hepatitida po Polygonum multiflorum. Vnitr Lek. 2012;58:958–62. [Toxic hepatitis induced by Polygonum multiflorum] Slovak. [PubMed: 23691566]
    (33 year old woman developed nausea and jaundice 4 weeks after starting Polygonum multiflorum [bilirubin 6.1 mg/dL, ALT 1163 U/L, Alk P 131 U/L], resolving within 4 weeks of stopping).
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    (Middle aged Asian-American woman developed fatigue and confusion 2-3 months after starting an herbal mixture called Ban Tu Wan for hair loss [bilirubin 4.1 mg/dL, ALT 5386 U/L, Alk P 199 U/L], with coagulopathy and renal dysfunction progressing to hepatic failure and death within a few days; Ban Tu Wan was labelled as having 9 botanical ingredients including Polygonum multiflorum).
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    (Among 18 patients with Polygonum multiflorum [Fo-Ti] hepatotoxicity seen at a Chinese referral center between 2005 and 2012, median age was 42 years, latency 27 days [range 1-120 days], 16 [89%] with jaundice, all hepatocellular [ALT 601 to 4095 U/L, Alk P 89 to 816 U/L], all recovered and none died; frequently ingested as a decoction with alcohol or as a tea).
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    (Review of the preparation, chemical constituents, pharmacology, clinical efficacy and hepatotoxicity of Polygonum multiforum).
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    (26 year old Chinese man developed fatigue followed by jaundice one month after starting Qibao Meiran Wan for hair growth [bilirubin 3.2 mg/dL, ALT 1674 U/L, Alk P 110 U/L], resolving within a month of stopping the herbal product which was labelled as containing 8 different botanicals, one of which was Polygonum multiflorum).
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    (Among 198 patients with suspected drug induced liver injury seen at Berlin Hospitals and enrolled in a prospective database, 10 were attributed to herbal supplements but none were attributed to Shou Wu Pian or Polygonum multiflorum).
  • Brown AC. Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 2 of 5 series. Food Chem Toxicol. 2017;107:472–501. [PubMed: 27402097]
    (Description of an online compendium of cases of liver toxicity attributed to HDS products, lists 8 cases of jaundice and “numerous” cases of hepatitis associated with Polygonum multiflorum and Shou Wu Pian).
  • Li H, Wang X, Liu Y, Pan D, Wang Y, Yang N, Xiang L, et al. Hepatoprotection and hepatotoxicity of Heshouwu, a Chinese medicinal herb: Context of the paradoxical effect. Food Chem Toxicol. 2017;108:407–418. [PubMed: 27484243]
    (Review of the methods of preparation and in vivo and in vitro effects of two forms of Polygonum multiflorum—Sheng Shou Wu [dried roots] and Zhi He Shou Wu [boiled roots with black soybean] used in Traditional Chinese Medicine which have different concentrations of basic constituents and have both hepatoprotective and hepatotoxic potential).
  • Li CY, He Q, Gao D, Li RY, Zhu Y, Li HF, Feng WW, et al. Idiosyncratic drug-induced liver injury linked to Polygonum multiflorum: A case study by pharmacognosy. Chin J Integr Med. 2017;23:625–30. [PubMed: 28523534]
    (41 year old man developed fatigue 2 weeks after starting Polygonum multiflorum for blackening of his hair followed in a week by jaundice [bilirubin 9.6 mg/dL, ALT 766 U/L, Alk P 132 U/L, INR 1.1], resolving within a month of stopping the product which tested positive for the herb).
  • Wang Y, Wang L, Saxena R, Wee A, Yang R, Tian Q, Zhang J, et al. Clinicopathological features of He Shou Wu-induced liver injury: This ancient anti-aging therapy is not liver-friendly. Liver Int. 2019;39:389–400. [PubMed: 30066422]
  • (Among 547 patients hospitalized for drug induced liver injury, 29 cases were attributed to He Shou Wu [Polygonum multiflorum] all of which were hepatocellular with median initial bilirubin of 6.0 mg/dL, ALT 995 U/L, Alk P 165 U/L, median latency of 40 days [range 4-300], 79% were jaundiced, 86% recovered, 1 recurred on rechallenge, 2 had chronic injury and 1 [3%] died) .
  • Jing J, Wang RL, Zhao XY, Zhu Y, Niu M, Wang LF, Song XA, et al. Association between the concurrence of pre-existing chronic liver disease and worse prognosis in patients with an herb- “Polygonum multiflorum” thunb. induced liver injury: a case-control study from a specialised liver disease center in China. BMJ Open. 2019;9:e023567. [PMC free article: PMC6340630] [PubMed: 30782709]
    (Among 5703 patients hospitalized for drug induced liver injury, 145 were attributed to Polygonum multiflorum, among whom those with preexisting liver disease [n=33: 23%] had a higher mortality rate [9% vs 1%]).
  • Liu Y, Wang W, Sun M, Ma B, Pang L, Du Y, Dong X, Yin X, Ni J. "Polygonum multiflorum"-induced liver injury: clinical characteristics, risk factors, material basis, action mechanism and current challenges. Front Pharmacol. 2019;10:1467. [PMC free article: PMC6923272] [PubMed: 31920657]
    (Review of the clinical uses and hepatotoxicity of Polygonum multiflorum also called Ho Shou Wu in China which is used for detoxification and bowel relaxation and which “tonifies the liver and kidney” and benefits “black beard”).
  • Li C, Rao T, Chen X, Zou Z, Wei A, Tang J, Xiong P, et al. HLA-B*35:01 allele Is a potential biomarker for predicting Polygonum multiflorum-Induced liver injury in humans. Hepatology. 2019;70:346–57. [PubMed: 30985007]
    (Among 26 cases of Polygonum multiflorum hepatotoxicity 88% had at least one copy of the HLA-B*35:01 allele compare to 12% of 33 patients with other forms of drug induced liver injury and 5% of normal controls).
  • Aithal GP. Of Potions, poisons, Polygonum, and pre-emptive polymorphism. Hepatology. 2019;70:8–10. [PubMed: 31155733]
    (Editorial in response to Li [2019]).
  • Zhang L, Niu M, Wei AW, Tang JF, Tu C, Bai ZF, Zou ZS, et al. Risk profiling using metabolomic characteristics for susceptible individuals of drug-induced liver injury caused by Polygonum multiflorum. Arch Toxicol. 2020;94:245–56. [PubMed: 31630224]
    (Metabolomics identified 25 metabolites in pretreatment serum that separated 6 Polygonum multiflorum treated subjects who developed evidence of hepatoxicity from 30 who tolerated therapy, the metabolites being involved in glycerophospholipid, sphingolipid, fatty acid, histidine and aromatic amino acid metabolic pathways).
  • Yang WN, Pang LL, Zhou JY, Qiu YW, Miao L, Wang SY, Liu XZ, et al. Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population. World J Gastroenterol. 2020;26:1329–39. [PMC free article: PMC7109278] [PubMed: 32256020]
    (Use of single-nucleotide polymorphisms identified HLA-B*35:01 to be associated with73 cases of polygonum multiflorum hepatotoxicity [allele frequency 0.41] compared to 118 cases if other drug induced liver injury [0.12] and to Han population controls [0.027]).