clinicopathological features of he shou wu‐induced liver ... · persistent liver injury....

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This article has been accepted for publication and undergone full peer review but has not been

through the copyediting, typesetting, pagination and proofreading process, which may lead to

differences between this version and the Version of Record. Please cite this article as doi:

10.1111/liv.13939

This article is protected by copyright. All rights reserved.

DR. XINYAN ZHAO (Orcid ID : 0000-0002-8016-4368)

Article type : Original Articles

Editor : Raul Andrade

Clinicopathological features of He Shou Wu-Induced Liver Injury: This Ancient Anti-Aging Therapy

Is Not Liver-Friendly

Yan Wang1, Lan Wang1, Romil Saxena2, Aileen Wee3, Ruiyuan Yang1, Qiuju Tian1, Jiping Zhang4,

Xinyan Zhao1*, Jidong Jia1*

1 Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key

Laboratory on Translational Medicine on Cirrhosis, National Clinical Research Center for Digestive

Disease, Beijing, China

2Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA.

3Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore,

National University Hospital, Singapore, Singapore

4Department of Pathology, Guangzhou Kingmed Center for Clinical Laboratory, Guangzhou, China

http://crossmark.crossref.org/dialog/?doi=10.1111%2Fliv.13939&domain=pdf&date_stamp=2018-08-01

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Yan Wang and Lan Wang contributed equally to this study.

*Correspondence to:

Xinyan Zhao, MD, PhD, Liver Research Center, Beijing Friendship Hospital, Capital Medical University,

Beijing Key Laboratory on Translational Medicine on Cirrhosis, National Clinical Research Center for

Digestive Disease, 95 Yong An Road, Xi Cheng District, Beijing, China.

Phone: +86 10 63138435; Fax: +86 10 63169246; email: [email protected]

Jidong Jia, MD, PhD, Liver Research Center, Beijing Friendship Hospital, Capital Medical University,

Beijing Key Laboratory on Translational Medicine on Cirrhosis, National Clinical Research Center for

Digestive Disease, 95 Yong An Road, Xi Cheng District, Beijing, China.

Tel: +86 10 63138435; Fax: +86 10 63169246; email: [email protected]

Conflicts of interest: All authors declare that we have no conflict of interest.

Financial support: This work was supported by Beijing Health System Talents Plan (2013-3-069).

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Abbreviations:

AIH autoimmune hepatitis

ALP alkaline phosphatase

ALT alanine aminotransferase

ANA antinuclear antibody

AST aspartate aminotransferase

DB direct bilirubin

DILI drug-induced liver injury

GGT gamma-glutamyl transferase

HILI herb-induced liver injury

IgG immunoglobulin G

INR international normalized ratio

PMT Polygonum Multiflorum Thumb

RUCAM Roussel Uclaf Causality Assessment Method

TB total bilirubin

TBA total bile acid

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TCM Traditional Chinese Medicine

ULN upper limit of normal

Abstract

Background and Aims

Polygonum Multiflorum Thumb (PMT), an ancient anti-aging Chinese herb known traditionally as He

Shou Wu, has side effects of liver toxicity. To determine the main clinical and pathological

characteristics of liver toxicity induced by PMT and the clinical course after its cessation.

Methods

Data of patients, diagnosed as drug-induced liver injury and hospitalized in Beijing Friendship

Hospital from August 2005 to August 2017, were retrospectively reviewed. Clinical, pathological data

and outcome after cessation of He Shou Wu were obtained and analyzed. Kruskal–Wallis and

Chi-square (χ2) tests were performed.

Results

Twenty-nine patients with He Shou Wu-induced liver injury were enrolled. The median age was 53

years (range 15–74) and 75.9% (22/29) were women. The most common symptom was jaundice

(79.3%, 23/29). Of nine patients with liver biopsies, six showed acute cholestatic hepatitis, two acute

and one chronic hepatocellular injury pattern. The latency, liver chemistries and outcomes were

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comparable between pure He Shou Wu (5 patients) and its compounds (24 patients). Twenty-five of

29 patients (86.2%) had normal serum alanine aminotransferase levels after 45 days (range: 10–138

days) and total bilirubin of 46 days (range: 0–551 days). One patient was rechallenged with He Shou

Wu and two developed autoimmune features. One patient died of liver failure and three had chronic

persistent liver injury.

Conclusions

The main clinicopathological injury pattern of He Shou Wu-induced liver injury is moderate to severe

hepatitis with or without cholestasis. Most patients recover completely; however, chronic disease

and death do occur. (249 words).

Key words: He Shou Wu; Polygonum Multiflorum Thumb; drug-induced liver injury; clinical course.

Lay summary:

He Shou Wu, an anti-aging herb, has liver toxicity. Patients usually present with jaundice and a

significant minority has dismal prognosis.

Introduction

Herbal products have been trusted and widely used since antiquity in Northeast Asia, resulting in a

high incidence of herbal-induced liver injury (HILI) in these countries. HILI accounts for up to 50% of

all cases of drug induced liver injury (DILI) in mainland China1 and 20% of cases in South Korea2.

Herbs and nutritional supplements which may contain undeclared/unrecognized herbal constituents

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are now being increasingly consumed in Western countries3 due to the widespread accessibility and

availability over the internet and in local Chinatowns. As reported, the amount of money spent in

consumption of herbal and dietary supplements had increased from $4 billion to $5.6 billion from

1999 to 2012 in America3. Not surprisingly, the incidence of herbal and dietary supplement-induced

liver injury has increased notably in tandem with widespread usage in countries such as United

States4 and Spain5. The massive Chinese/Asian diaspora has also created a global impact for this

health issue. Furthermore, the prognosis of HILI is worse than that of liver injury caused by

well-characterized modern drugs because of the complex ingredients of herbal compounds, possible

and undefined interactions between different components, and the longer durations of herb

consumption due to widespread belief of lay persons that herbs are “natural” harmless compounds

that can be taken long term without regular monitoring for adverse effects6. Hence, there is an

urgent need for greater awareness and further research of HILI.

However, attributing liver injury to the umbrella term “herb” does not result in timely diagnosis,

treatment, prevention or exploration of the underlying mechanisms of HILI. As is available for

modern drug(s) from hepatology textbooks7, recent publications8, 9 and the LiverTox website10, it is

time to summarize the chief clinical and histological characteristics of herbal hepatic toxicity and its

natural history for specific herbs. Such data would improve hepatologists’ understanding of the

characteristics of hepatotoxic effects of a given herb, which in turn would contribute to early

recognition of disease, provision of optimal care, and establishment of a comprehensive database to

facilitate study of the underlying mechanisms of such toxicity.

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He Shou Wu is one of the most common herbs that can cause liver injury as reported. It is believed

to have anti-aging properties and can enhance general health, Thus, it has been used as a tonic for

various conditions, including premature greying of hair, insomnia, backache, dizziness,

hyperlipidemia, coronary heart disease, diabetes and many others11.This drug is fairly easily available

in various herbal forms, such as Ban Tu Wan, Shou Wu Pian, Shen Min, Yangxueshengfa granules and

Qibaomeiran tablets 12; and can be procured online in western countries too, notably, as fo-ti.

However, its safety is questionable due to the fact that reports of He Shou Wu-induced liver

toxicities have increased worldwide in the past several years. Up until 2016, 612 patients with liver

injury induced by He Shou Wu had been reported (Pubmed and www.cnki.net, both in Chinese and

English literature)11, 13. Of these patients, four had cirrhosis13, 14, five had liver failure, four had

undergone liver transplantation15-17,and seven had died13, 15, 16, 18, 19. However, most of these studies

were case reports or reports of small series of patients, and lacked data on causality assessment,

latency, histological features, and long term follow-up after cessation of the herb. Furthermore, the

dominant clinicopathological pattern of liver injury induced by He Shou Wu and the clinical course

after its cessation had not been thoroughly elucidated.

In the study, we treated the herb He Shou Wu as a single medication and hypothesized that it has a

dominant liver injury pattern. Our objective was to elucidate the main clinical and histological

characteristics and clinical outcome of He Shou Wu-induced liver injury.

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Patients and Methods

Study population

Medical records of patients who had been diagnosed with DILI and hospitalized at Beijing Friendship

Hospital from August 2005 to August 2017 were retrospectively reviewed. DILI associated with He

Shou Wu alone or herbal compounds containing He Shou Wu with Roussel Uclaf Causality

Assessment Method (RUCAM) scores≥3 were included20. Patients with concomitant liver diseases

were excluded, including those with hepatotropic viral hepatitis (Hepatitis A, B, C and E viruses),

non-hepatotropic viral infections (cytomegalovirus and Epstein–Barr virus), liver injury induced by

other drugs, primary biliary cholangitis, biliary obstruction, metabolic liver diseases, and ischemic

hepatitis. No patient had history of excessive alcohol consumption (>40g/day of alcohol for men and

>20g/day for women, lasting for 5 years)21. Fatty liver disease was excluded by abdominal ultrasound

in all patients within one month of presentation. Autoimmune liver disease was excluded based on

medical history, status of serum autoantibodies, serum levels of immunoglobulin G (IgG) and

immunoglobulin M, and clinical follow up. This study complied with the Helsinki Declaration of 1975

revised in 1983 and was approved by Ethic review board of Beijing Friendship Hospital, Capital

Medical University. The requirement of informed consent from patients was waived.

Data collection

Detailed medical histories, time frame of exposure to He Shou Wu, and clinical and laboratory

findings were obtained from medical records. For patients who had undergone liver biopsy, the

histological sections were stained with H&E, Masson trichrome, reticulin, periodic acid-Schiff with

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diastase, Perls stain for iron, rhodanine stain for stainable copper. Additionally,

immunohistochemical stains for cytokeratin 7 and cytokeratin 19 were performed. These sections

were reviewed by two liver pathologists (RS, AW) and one hepatologist (XZ), who were blinded to

the clinical information. RUCAM scores were calculated for each patient. A causal relationship

between He Shou Wu and liver injury was categorized as highly probable (>8), probable (6–8), and

possible (3–5).The pattern of injury was defined according to the R value [ratio of serum alanine

aminotransferase (ALT)/upper limit of normal (ULN) to serum alkaline phosphatase (ALP)/ULN] as

hepatocellular when R ≥ 5, mixed as 2 <R < 5, and cholestatic as R ≤ 222. Disease severity was graded

as mild, moderate, moderate–severe, severe, or fatal according to standard criteria 23.

All patients had been followed up until normalization of liver chemistries [ALT or aspartate

aminotransferase (AST)<1×ULN and total bilirubin (TB)<1.5×ULN], chronic persistent abnormality of

liver chemistries, or occurrence of endpoint events such as cirrhosis, liver transplantation, liver

failure, or death. Liver chemistries, complete blood count, and coagulation profiles of each individual

during follow-up (if any) were collected.

Statistical analysis

Continuous variables are shown as median and quartiles and categorical variables data as

percentages. Kruskal–Wallis and Chi-square (χ2) tests, respectively, were performed to assess these

types of variables. All tests were two-tailed and P< 0.05 was considered to denote significant

differences. Data were analyzed using SPSS software (version 22.0; SPSS, Chicago, IL, USA).

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Results

Characteristics of patients with He Shou Wu-induced liver injury

From August 2005 to August 2017, there were 547 individuals with discharge diagnoses of DILI. Of

the 547 patients, 316 (57.8%) cases had DILI due to Traditional Chinese Medicine (TCM), 156 (28.5%)

due to prescription medication, 60 (11.0%) due to both prescription medication and TCM. The

remaining cases were attributed to dietary supplements [9 (1.6%)], chemical poisons [4 (0.7%)],

combination of prescription medication and dietary supplements [1 (0.2%)], or the combination of

TCM and chemical poisons [1 (0.2%)] (Figure 1 and Figure 2). Twenty-nine patients suffered liver

injury due to ingestion of He Shou Wu. The median age was 53 years (range 15-74) and 75.9%

(22/29) were women (Table 1). The most common symptom was jaundice (79.3%), followed by

fatigue (55.2%), nausea (48.3%), abdominal distension (27.6%), itching (24.1%), fever (20.7%), and

abdominal pain (10.3%). The median time to onset of disease after consuming He Shou Wu was 40

days (range 4–300) and median duration of herb consumption was 30 days (range 1–300) (Table2).

The median follow-up was 33.0 months (1.5-93.0). Liver biopsies were available for review in nine

(Cases 7, 18-20, 23-26, 28) of these 29 patients. Five had taken pure He Shou Wu, while the

remaining 25 had taken compounds containing He Shou Wu.

Biochemical features of He Shou Wu-induced liver injury

All 29 patients showed (Table 2, supplementary table S1) marked increases in ALT (median 995.0,

range 308.0-2052.0 U/L) and AST levels (median 585.0; range 260.6-1500.0 U/L), whereas ALP

(median 165.0, range 75.2-440.0 U/L) and gamma-glutamyl transferase (GGT) levels (median 200.0,

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range 29.7-693.0 U/L) were only moderately increased. Because of the marked increase in ALT and

moderate increase in ALP, R ratios of all patients were greater than 5, indicating hepatocellular

injury. Interestingly, 79.3% (23/29) of the study cohort showed serum elevations of TB

(median103.3, range 11.5-527.4umol/L), direct bilirubin (DB), (median 68.8, range 2.6-396.8umol/L),

and total bile acid (TBA) (median 112.8, range2.2-388.3umol/L). Prolonged coagulation

[international normalized ratio (INR)>1.5] was noted in three patients. Sixty-five percent (19/29) of

the patients were negative or borderline positive (1:80) for antinuclear antibody (ANA), 20.7% (6/29)

were moderately positive (1:160), and 6.9% (2/29) strongly positive (1:320). The serum ANA levels

are tested by indirect immunofluorescence and the positive cut-off value is 1:80 rather than 1:40 in

our hospital, which may be different from other medical centers. Furthermore, 21 of the 29 patients

who were tested for antibodies to smooth muscle actin, soluble liver antigen, anti-liver-kidney

microsomal-1 and anti-liver cytoplasmic antigen-1, were negative. IgG was increased (>1.1 ULN) in

five patients.

Patient characteristics according to severity of He Shou Wu-induced liver injury

According to well-defined criteria, seven patients (24.2%) had mild liver injury, 13 (44.8%) moderate,

six (20.7%) moderate–severe, two (6.9%) severe, and one (3.4%) fatal. Table 2 provides a

comparison of patients’ characteristics according to severity of liver injury. Age, sex, and clinical

symptoms were similar in these three groups, as were peak ALT, AST, ALP, and GGT levels. As

expected, patients with moderate, moderate–severe, severe, and fatal liver damage were more

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likely to have jaundice than those with mild liver injury. Furthermore, peak TB, DB, TBA and INR

values at onset were significantly higher in the moderate-severe and fatal than the mild liver injury

group. The interval between peak TB and 50% peak was significantly longer in those with severe

disease than in other groups. The AST/ALT ratio was higher in the severe and fatal (median, 1.2;

range 1.1-1.4) than mild (median, 0.7; range, 0.4-1.2), moderate, and moderate-severe groups

(median, 0.7; range 0.4-1.4); however, these differences were not significant. IgG was also higher in

the severe and fatal (median, 2590.0; range 672.0-2790.0mg/dL) than mild (median, 1110.0; range

855.0-1,900.0 mg/dL) and moderate and moderate–severe groups (median, 1240.0; range,

900.0-2310.0 mg/dL); however, these differences were not significant, possibly because there were

so few patients with severe disease. The proportion of ANA positivity was similar among the groups.

Histopathological injury patterns of He Shou Wu-induced liver injury

Nine of the 29 patients with He Shou Wu injury had liver biopsies. The median time from onset of

symptoms to liver biopsy was 30 days (range, 6-37 days). There were no significant differences in

major clinical and biochemical variables at onset between those who had had liver biopsies and

those who did not (Supplementary Table S2). Patients whose TB declined slowly were more likely to

have undergone biopsy than those whose TB recovered quickly, perhaps reflecting the clinical need

to rule out bile duct damage and loss.

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Predominant histological pattern was moderate to severe hepatitis with (4 cases) or without

cholestasis (3 cases). It was seen in seven biopsies, and was characterized by a moderate to severe

portal and lobular inflammation. The inflammatory infiltrate consisted mostly of lymphocytes; some

cases contained a few intermingled eosinophils; but plasma cells were not excessive. The patient

who improved only after administration of prednisone showed moderate to severe interface activity

with septal fibrosis (Figure 3A). Perivenultitis characterized by variable degrees of inflammation and

necrosis around central veins was seen. (Figure 3B-3C). Some of these areas of necrosis were

replaced by clusters of pigment-laden macrophages (Figure 3D). Ballooning of hepatocytes was also

seen. There was no significant steatosis or demonstration of cholate stasis or hemosiderosis.

The predominant finding in Cases 26 and 28 was severe canalicular cholestasis (Figure 3E). Portal

and lobular inflammation was only mild and consisted predominantly of lymphocytes. There was no

interface hepatitis. The canalicular cholestasis in these two cases was out of proportion to the

degree of inflammation and hepatocellular damage. Ductular reaction (Figure 3F) and sinusoidal

lymphocytic infiltration were observed in seven cases. None of the biopsies showed any obvious

inflammation of interlobular bile ducts or bile duct loss, apart from focal bile duct tortuosity and the

ductal epithelium exhibiting either reactive changes or minimal cytoplasmic damage. Detailed scores

for each patient are shown in Table 3.

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Comparison of patients who had taken He Shou Wu alone versus compounds containing He Shou

Wu

Five of the 29 patients had taken He Shou Wu alone and the remaining 24 compounds containing He

Shou Wu. Supplementary Table S3 provides a comparison of patients who had taken pure He Shou

Wu and those who had taken herbal compounds containing He Shou Wu. Interestingly, these two

groups did not differ significantly in age, sex, clinical symptoms, or laboratory findings, including

peak ALT, AST, AST/ALT ratio, ALP, GGT, peak TB, DB, TBA, INR, IgG, and ANA positive ratio. The

latency, duration of drug consumption, time taken for ALT and TB to decrease to 50% and to normal

levels was also similar between the groups, suggesting that He Shou Wu was the chief culprit of liver

injury. Details of the components of those herbal compounds are listed in Supplementary Table S4.

Clinical course and outcomes of He Shou Wu-induced liver injury

The 29 patients were followed up for a median of 33.0 months (range: 1.5-93.0). Details of follow-up

duration and final outcomes are shown in Table 1. Most of the patients (25/29) recovered

completely in a median time of 45 days (range 10-138 days) for ALT/AST normalization (Figure

4A-4B) and 46 days (range 0-551 days) for TB/ALP normalization (Figure 4C-4D). Patients with

moderate and moderate–severe liver injury took significantly longer to recover than the those with

mild disease (median, 57; range 17-551 days) vs. (median, 0; range 0-38 days), P<0.001). Of those

who recovered, there were four cases of note comprising (i) Case 11 was rechallenged with He Shou

Wu, (ii) Case 20 with autoimmune features responded to corticosteroids, (iii) Case 21 had another

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episode of HILI due to TCM, and (iv) Case 24 had another episode of DILI due to antibiotic treatment

for Helicobacter pylori infection.

There were four patients with poor outcomes, namely (i) Case 25 had a protracted clinical course

with three episodes of liver injury (two attributed to He Shou Wu and one to other herbs) (Figure

5A), (ii) Case 26 had persistent cholestasis11 months after stopping He Shou Wu (Figure 5B), (iii)

Case 27 had chronic liver injury with possible autoimmune features but had not received any steroid

treatment (Figure 5C), (iv) Case 29 died of liver failure (Figure 5D).

Discussion

He Shou Wu, also known as Polygonum multiflorum Thumb (PMT), is a popular Chinese herb that

has been used as an anti-aging agent and a “cure-all” panacea tonic for various conditions including

alopecia and graying of hair, cancer, diabetes, atherosclerosis, sleep disorders, and

neurodegenerative diseases24.The root of PMT was first recorded in the herbal “Kaibaobencao”

issued by the Imperial Court of the Song Dynasty (973–974 AD). Because herbs, including He Shou

Wu, are often assumed to be natural and safe, growing numbers of individuals consume herbal

products worldwide. However, increasing numbers of patients with He Shou Wu-induced liver injury

have been reported in recent years. Review of the published reports in Pubmed and CNKI databases

showed that by 2016, 612 cases of liver injury associated with He Shou Wu had been reported (most

in Chinese), including reports of cirrhosis, liver transplantation, and death8-9, 25.

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In our study, the number of women affected by He Shou Wu was larger than that of men.

Middle-aged women also appeared to be more liable to He Shou Wu-induced liver injury. One

possibility is that middle-aged women are more likely than men to procure herbal products. On the

other hand, gender-based biological differences may also be a confounding factor. Jaundice is the

presenting feature in most cases; other common symptoms include fatigue and nausea. The pattern

of injury is hepatocellular, based on both, the R-value (>5) and the histological findings of moderate

to severe hepatitis with areas of necrosis. Almost half of the patients also have increased TB

>100umol/L (5.8mg/dL), with a quarter of them having serum TB >171umol/L (10mg/dL). Those with

persistently high TB have more severe disease and longer duration of hospitalization.

Histological manifestations of He Shou Wu-induced liver injury have been reported; however, the

major histopathological injury pattern has yet to be determined. Our biopsies show that the findings

appear to be related to the timing of biopsy with the onset of symptoms and severity of disease. In

early disease or more severe disease, the pattern is that of a moderate to severe hepatitis. The

inflammatory infiltrate is present in both portal tracts and the lobular parenchyma, and is composed

mostly of lymphocytes. Interface hepatitis is moderate to severe. Areas of necrosis are found, either

around the central veins or scattered randomly in the parenchyma. Canalicular cholestasis may be

prominent. In patients with less severe disease or when the biopsy is taken later in the course, the

inflammation tends to be mild and is overshadowed by canalicular cholestasis. The interlobular bile

ducts do not appear to be targets of injury and although mild and focal biliary epithelial injury may

be seen, bile duct loss was not seen in our series. It thus appears that liver injury induced by He Shou

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Wu is primarily inflammatory in nature. As the inflammation subsides, canalicular cholestasis

becomes apparent in the absence of significant bile duct injury or loss.

Our results concur with other studies in that most patients with He Shou Wu-induced liver injury

manifest with jaundice and markedly increased TB, ALT and AST levels and that most of these

patients recover fully 11, 13, 16, 17, 26-31. We found that 27.6% of patients (8/29) were ANA positive

(1:160 or 1:320), indicating that immunological disturbances may be involved in the pathogenesis of

liver injury, in addition to direct toxicity. In other words, He Shou Wu-induced liver injury is

idiosyncratic rather than intrinsic. This hypothesis is further supported by marked CD8 T lymphocytic

infiltration (data not shown) and moderate to severe interface activity in most of our biopsied cases.

Patient 20, whose liver injury persisted after cessation of He Shou Wu, achieved complete remission

of disease with immunosuppressive therapy. At most recent follow-up, she has been on continuous

prednisone therapy for the last 12 months. We are therefore unable to conclude whether this

patient represents (autoimmune hepatitis) AIH-like DILI, drug-induced AIH, or typical AIH unmasked

by the DILI episode. Disease course after cessation of prednisone will ultimately shed light on the

correct diagnosis.

Twenty-five of the 29 patients recovered fully at various intervals after cessation of He Shou Wu.

Although most patients recovered, one died of liver failure and three had persistent chronic HILI.

Combining our data with previous studies, eight patients have died, four undergone liver

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transplantation, and four progressed to cirrhosis, underscoring that He Shou Wu can induce severe

and fatal liver injury that requires careful monitoring and intensive care. Liver transplantation should

be considered in patients with persistently high TB who are unresponsive to conventional therapy.

Although cases of cirrhosis due to He Shou Wu have been previously reported in literature, none of

our patients progressed to cirrhosis. Interestingly, 18 out of 29 patients satisfied Hy’s Law32; among

these, one patient had a fatal outcome. The mortality approximates 10%, which suggests that Hy’s

Law can be applied to He Shou Wu induced liver injury to predict outcome.

The present study only includes those patients with He Shou Wu-induced HILI who were sick enough

to be hospitalized. Asymptomatic patients or those with mild liver disease are not included; thus, the

entire spectrum of liver injury from this extremely popular herbal compound in the general

population remains unknown. Furthermore, whereas all studied patients had ingested He Shou Wu,

the majority had taken compounds with complex ingredients that also included He Shou Wu. The

present study shares these two drawbacks with other previously reported series on He Shou Wu

toxicity.

The main bioactive ingredients of He Shou Wu are believed to be anthraquinones, especially,

emodin and 2,3,5,4’-tetrahydroxystilbene-2-O-β-D-glucoside. The mechanisms may be associated

with arresting the cell cycle and inducing apoptosis, necroinflammation, and steatosis33. The exact

mechanism of He Shou Wu-induced injury remains to be defined.

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Finally, there is an urgent need for public education on the harmful effects of He Shou Wu. Liver

chemistries should be monitored regularly during and after consumption, and the drug withdrawn

with the first signs of symptoms. Furthermore, governments should adopt stricter regulations or

require that specific warnings be posted on herbal products containing He Shou Wu.

Conclusions

We report 29 patients with He Shou Wu-induced liver injury. All patients presented with

hepatocellular injury patterns with varying levels of hyper bilirubinemia. The histological findings

appear to be related to the timing of liver biopsy with the course and severity of liver disease. The

initial injury is a moderate to severe hepatitis. As the inflammation resolves, canalicular cholestasis

becomes more apparent. Although most patients recover completely after cessation of He Shou Wu,

a small but significant minority progress to chronic liver disease and rare cases may develop liver

failure leading to death or requiring liver transplantation.

Acknowledgments

We thank Shaofei Su (China) for the kind assistance in providing statistical analysis and Chen Shao

(China) for scanning pathological slides.

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patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther

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Mol Sci 2015;17: pii: E14.

21. National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of

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drug- induced liver injuries. J Clin Epidemiol 1993;46:1323-1330.

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assessment in drug- induced liver injury: summary of a clinical research workshop. Hepatology

2010;52:730-742.

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toxicology of Polygonum multiflorum Thunb.: a review. J Ethnopharmacol 2015;159:158-183.

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manufactured from Polygonum multiflorum. Vet Hum Toxicol 1996;38:280-282.

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derived from Polygonum multiflorum. J Gastroenterol Hepatol 2001; 16:115-117.

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2012;2012.

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liver injury: exemplification of a well-known liver-restorative herb Polygonum

multiflorum.Front Med 2015;9:457-467.

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consumption of Shou Wu Pian, a Chinese herbal product derived from Polygonum

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Table1. Characteristics of 29 patients with He Shou Wu-induced liver injury

Case Age/G

ender

Indication

for

consumpti

on

Single

drug or

compoun

d

Latenc

y

(days)

Durati

on of

consu

mptio

n

(days)

RUC

AM

Severity of

disease

Follow

-up

(mont

hs)

Clinical/pathol

ogical

diagnosis;

timing of liver

biopsy, if any,

after onset

(days)

Final outcome

1 62/M Coronary

heart

disease

Compoun

d

45 45 8 Mild 69.0 Acute

hepatitis; no

biopsy

Recovery

2 42/F Abdominal

distention

Compoun

d

60 14 7 Mild 61.0 Acute

hepatitis; no

biopsy

Recovery

3 30/F Coordinatio

n

Compoun

d

90 90 8 Mild 60.0 Acute

hepatitis; no

biopsy

Recovery

4 55/F Gastritis Single 25 2 6 Mild 55.0 Acute

hepatitis; no

biopsy

Recovery

5 60/F Insomnia Compoun

d

60 20 10 Mild 49.0 Acute

hepatitis; no

biopsy

Recovery

6 52/F Fatigue Compoun 30 30 7 Mild 33.0 Acute Recovery

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d hepatitis; no

biopsy

7 53/F Treatment

of grey hair

Single 30 30 10 Mild 65.0 Acute

hepatitis; 37

Recovery

8 65/F Palpitation Compoun

d

45 51 9 Moderate 15.0 Acute

cholestatic

hepatitis;

no biopsy

Recovery

9 42/M Alopecia

seborrheic

Compoun

d


cholestatic

hepatitis;

no biopsy

Recovery


d


cholestatic

hepatitis;

no biopsy

Recovery

11 47/F Mammary

cancer

Compoun

d


cholestatic

hepatitis;

no biopsy

Recovery,

Rechallenge by He Shou

Wu


d


cholestatic

hepatitis;

no biopsy

Recovery

13 41/F Hair loss Compoun

d


cholestatic

hepatitis;

Recovery

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no biopsy

14 61/F Coronary

heart

disease

Compoun

d


cholestatic

hepatitis;

no biopsy

Recovery

15 28/F Menoxenia Compoun

d


cholestatic

hepatitis;

no biopsy

Recovery

16 23/M Neuroderm

itis

Compoun

d


cholestatic

hepatitis;

no biopsy

Recovery

17 27/M Chest

distress

Compoun

d


hepatitis;

no biopsy

Recovery

18 44/F Treatment

of grey hair

Compoun

d


cholestatic

hepatitis; 6

Recovery

19 32/F Gastritis Compoun

d


cholestatic

hepatitis; 25

Recovery

20* 56/F Backache Single 4 1 10 Moderate 12.0 Acute

hepatitis; 16

Recovery with prednisone

treatment

(Autoimmune features)

21 63/F Insomnia Compoun 16 30 8 Moderate-se 42.0 Acute Recovery,

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d vere hepatitis;

no biopsy

Another TCM-induced DILI

22 74/M Fatigue Compoun

d

94 94 8 Moderate-se

vere

88.0 Acute

hepatitis;

no biopsy

Recovery

23 51/M Arthritis Compoun

d

20 20 10 Moderate-se

vere

32.0 Acute

hepatitis; 34

Recovery

24 60/F Coordinatio

n

Compoun

d

14 14 9 Moderate-se

vere

93.0 Acute

cholestatic

hepatitis; 37

Recovery

Another DILI induced by

antibiotics for Helicobacter

pylori

25 55/M Coordinatio

n

Compoun

d

60 60 8 Moderate-se

vere

91.0 Acute

cholestatic

hepatitis; 30

Protracted clinical course

Rechallenge by He Shou

Wu and other TCM

26 46/F Menopaus

e

Compoun

d

300 300 7 Moderate-se

vere

12.0 Acute

cholestatic

hepatitis; 18

Chronicity

Another TCM-induced DILI

27 53/F Treatment

of grey hair

Single 25 25 5 Severe 7.0 Acute

cholestatic

hepatitis;

no biopsy

Chronicity

(Autoimmune features)

28 15/F Coordinatio

n

Single 120 150 4 Severe 2.0 Acute

cholestatic

hepatitis; 36

Recovery

29 58/F Coronary

heart

Compoun

d

24 24 9 Fatal 1.5 Acute

cholestatic

Died of liver failure

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disease hepatitis;

no biopsy * Cessation of prednisone planned in due course. AIH-like He Shou Wu-induced liver injury favored over He Shou Wu-induced AIH or unmasked AIH should

the liver tests remain normal.

TCM, Traditinal Chinese medicine; RUCAM, Roussel Uclaf Causality Assessment Method.

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Table2. Stratification of patients with He Shou Wu-induced liver injury according to severity of liver damage

Parameters Total Mild Moderate and

moderate-severe

Severe and fatal P value

Female 22/29 6/7 13/19 3/3 0.387

Age 53 (15-74) 53 (30-62) 52 (23-74) 53 (15-58) 0.880

BMI (kg/m2) 21.72 (17.21-27.36) 22.48 (19.18-25.26) 21.72 (17.21-27.36) 20.50 (20.00-21.01) 0.599

Symptoms

Fatigue 16/29 4/7 10/19 2/3 0.895

Abdominal distension 8/29 1/7 6/19 1/3 0.663

Jaundice 23/29 1/7 19/19 3/3 <0.001

Nausea 14/29 2/7 11/19 1/3 0.357

Itching 7/29 0/7 6/19 1/3 0.230

Abdominal pain 3/29 1/7 1/19 1/3 0.308

Fever 6/29 2/7 2/19 2/3 0.070

ALT max (U/L) 995.0 (308.0-2052.0) 1099.0 (354.0-1483.0) 995.0 (308.0-2052.0) 765.0 (340.7-1281.0) 0.831

AST max (U/L) 585.0 (260.6-1500.0) 554.0 (260.6-966.0) 585.0 (262.0-1500.0) 1071.0 (406.4-1356.0) 0.601

AST max/ALTmax 0.8 (0.4-1.4) 0.7 (0.4-1.2) 0.7 (0.4-1.4) 1.2 (1.1-1.4) 0.055

ALP max (U/L) 165.0(75.2-440.0) 163.5(87.0-357.0) 165.0 (125.0-440.0) 188.0 (75.2-304.0) 0.954

GGT max (U/L) 200.0 (29.7-693.0) 216.2(76.0-505.0) 172.0 (44.0-693.0) 502.0 (29.7-527.0) 0.829

TB max (μmol/L) 103.3 (11.5-527.4) 16.3 (11.5-42.1) 106.0 (49.0-378.1) 406.4 (116.0-527.4) <0.001

DB max (μmol/L) 68.8(2.6-396.8) 4.4 (2.6-31.8) 73.6 (29.8-316.0) 275.4 (68.8-396.8) <0.001

TB Amax (μmol/L) 112.8 (2.2-388.3) 23.8 (2.2-168.0) 147.8 (11.6-366.4) 304.7 (279.1-388.3) 0.004

INR at onset 1.05 (0.89-1.64) 1.00 (0.89-1.18) 1.05 (0.92-1.29) 1.57 (1.20-1.64) 0.010

IgG (mg/dl) 1240.0(672.0-2790.0) 1110.0 (855.0-1900.0) 1240.0 (900.0-2310.0) 2590.0(672.0-2790.0) 0.555

EO% (%) 3.0 (0.7-10.7) 4.0 (1.4-10.5) 2.9 (0.7-8.6) 1.8 (1.2-10.7) 0.261

ANA 0.287

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Negative 4 2 1 1

1:80 15 4 11 0

1:160 6 1 4 1

1:320 2 0 1 1

Not available 2 0 2 0

Latency (days) 40 (4-300) 45 (25-90) 40 (4-300) 25 (24-120) 0.938

Time of drug consumption

(days)

30 (1-300) 30 (2-90) 40 (1-300) 25 (24-150) 0.449

Time for ALT decrease to

50% at peak ALT (days)

7 (1-35) 7 (3-23) 7 (1-23) 23(11-35) 0.168

Time for ALT

normalization(days)

45 (10-138) 31 (10-138) 45 (24-118) 47 (47-47) 0.686

Time for TB decrease to

50% at peak TB (days)

8 (0-66) 0 (0-8) 9 (1-33) 39 (12-66) 0.002

Time for TB normalization

(days)

46 (0-551) 0 (0-38) 57 (17-551) - <0.001

Follow-up time (months) 33.0 (1.5-93.0) 60.0 (33.0-69.0) 26.0 (3.0-93.0) 2.0 (1.5-7.0) 0.007

Data are expressed as n or median (minimum, maximum).

ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate aminotransferase; BMI, body mass index; DB, direct

bilirubin; EO%, eosinophile granulocyte; GGT, gamma-glutamyl transferase; IgG, immunoglobulin G; INR, international normalized ratio; TB, total bilirubin;

TBA, total bile acid; ULN, upper limit of normal.

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Table 3. Histopathological injury pattern in He Shou Wu-induced liver injury

Case

no.

Lobular changes Portal changes Inflammat

ory

infiltrate

(compositi

on)

Fibros

is

(locat

ion)

Histological

pattern of

liver injury

Clinicopath

ological

diagnosis Chol

estas

is

Lobular

necro-

inflamm

ation

Central

periven

ulitis

Confluent

necrosis

(location)

Bridging

hepatic

necrosis

Portal

inflam

matio

n

Periport

al

(interfac

e)

inflamm

ation

Ductul

ar

reactio

n

Bile

ducts

7 - ++ ++ ++

Perivenul

ar

hepatocyt

e dropout

with focal

confluent

necrosis

+ ++ ++ + Reacti

ve and

tortuo

us

with

focal

damag

e

Mixed +,

portal

Lobular and

portal

hepatitis

Acute

hepatitis

18 + ++ ++ ++

Perivenul

ar

hepatocyt

e dropout

and

confluent

necrosis-

+/- ++ +++ ++ Reacti

ve

Mixed +,

Portal

Cholestatic

lobular and

portal

hepatitis

Acute

cholestatic

hepatitis

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19 ++ ++ ++ +

Perivenul

ar

hepatocyt

e dropout

+ ++ + + Reacti

ve

with

focal

damag

e

Mixed - Cholestastic

lobular and

portal

hepatitis

Acute

cholestatic

hepatitis

20 - +++ +++ ++

Perivenul

ar

hepatocyt

e dropout

and

confluent

necrosis

+++ +++,

lymph

oid

aggreg

ates

+++ ++ Reacti

ve

Lymphocyt

ic

predomina

nce

++Por

tal

and

septal

lobular and

portal

hepatitis

Acute

hepatitis

23 - ++ + - + (focal) + to ++ + ++ Reacti

ve and

tortuo

us

Lymphocyt

ic

predomina

nce

- lobular and

portal

hepatitis

Acute

hepatitis

24 +++ +++ ++ +++ + + ++ ++ Reacti

ve and

tortuo

us

Mixed - Cholestatic

lobular and

portal

hepatitis

Acute

cholestatic

hepatitis

25

++ +++ +++ +++ ++ ++ +++ ++ Focally

damag

ed and

tortuo

us

Mixed +

Portal

Cholestatic

lobular and

portal

hepatitis

Acute

cholestatic

hepatitis

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26

+++ + - - - - - - Intact Mononucl

ear

- Bland

cholestasis

Acute

cholestatic

28

++ + + +

Perivenul

ar focal

confluent

necrosis

- + + + - Mixed - Cholestatic

hepatitis

Acute

cholestatic

hepatitis

Score 0/+/++/+++ (absent/mild/moderate/severe) Lobular necroinflammation, lobular disarray due to hepatocyte swelling, apoptosis, spotty necrosis with

aggregates of lymphohistiocytes, Kupffer cell/macrophage hypertrophy / ceroid-laden, increase in sinusoidal lymphocytes.

Central perivenulitis: centrilobular inflammation +/- hepatocyte dropout or confluent necrosis

Bridging hepatic necrosis (portal-central, portal-portal): 0/+/++/+++

Bile ducts (comment): “-”: No injury of bile duct; “+”:Irregular ductal epithelium; “++”:Degenerated and atrophic ductal epithelium. (choose from- Intact

epithelium. Reactive epithelium. Damaged epithelium. Ductopenia)

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Figure legends

Figure 1. Flow chart of the retrospective study of 547 hospitalized patients diagnosed with DILI. Of

the 316 patients who had consumed traditional Chinese medicines (TCM), 29 were attributed to He

Shou Wu with 9 undergoing liver biopsies.

Figure 2. Categories of drugs implicated in the 547 patients who were discharged with a diagnosis of

DILI. TCM: Traditional Chinese Medicine.

Figure 3. He Shou Wu-induced liver injury showing

(A) Moderate portal inflammation and interface hepatitis (Case 20) (H&E, 400×),.

(B) Central perivenulitis with hepatocyte dropout and surrounding lobular inflammation (Case 20)

(H&E, 400×),.

(C) Centrilobular hepatocyte necrosis and dropout (Case 19) (Reticulin, 400×), .

(D) Clusters of PAS-positive diastase-resistant ceroid-laden macrophages. (Case 24, PAS-D, 400×),.

(E) Prominent hepatocellular and canalicular cholestasis (Case 26) (H&E, 400×), and .

(F) Brisk ductular reaction at the portal interface. The interlobular bile duct is preserved (Case 18)

(cytokeratin 19 immunostain, 200×).

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Figure 4. Liver chemistry test results which normalized in 25 patients. (A) ALT; (B) AST; (C) TB; (D)

ALP. ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TB,

total bilirubin; ULN: upper limit of normal.

Figure 5. Changes in liver chemistries in three patients with poor outcomes and one with eventful

clinical course.

(A) Case 25: Relapses due to rechallenge with He Shou Wu and another episode of TCM-induced DILI

before eventual recovery after 35 months.

(B) Case 26: Developed chronicity after another episode of TCM-induced DILI in the 5th month of

follow-up.

(C) Case 27: Progressed to chronicity by 10 months.

(D) Case 29: TB increased despite cessation of drugs and the patient eventually died.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; TB,

total bilirubin; TCM, Traditional Chinese Medicine; ULN: upper limit of normal.

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clinicopathological features of he shou wu‐induced liver ... · persistent liver injury....

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