ADVERSE EVENTS INVOLVING CERTAIN CHINESE HERBAL MEDICINES

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ADVERSE EVENTS INVOLVING
CERTAIN CHINESE HERBAL
MEDICINES AND THE
RESPONSE OF THE PROFESSION
Richard Blackwell
JOURNAL OF CHINESE MEDICINE NUMBER 50 JANUARY 1996

Introduction
As Chinese herbal medicine becomes increasingly widely
practised in the West, reports of occasional adverse effects
are appearing in the literature and questions are being
asked about safety. If we are to retain the confidence and
support of the public we must address these issues in a
spirit of openness and with a willingness to learn the
relevant lessons.
In this article I present a wide-ranging, though not exhaustive,
review of reports in the English-language literature
of adverse events involving Chinese herbs. In particular,
I have devoted attention to a series of cases of liver
damage, including two fatalities, which have occurred in
the UK in patients taking Chinese herbs for skin disease.
This is the first time all this information has been gathered
together in one place.
It is important to remember that these adverse events are
extremely unusual. Chinese herbal medicine is generally
both safe and effective, and there are many patients who
have experienced dramatic benefits to their health from
treatment. All medicines are assessed in terms of their riskbenefit
ratio and it should not be surprising that Chinese
herbal medicines may also occasion rare but significant
adverse events. The aim of this article is to assist a process
of debate and development within the profession as we
work to minimise what risks there are.
Kidney Damage from Slimming Treatment
in Belgium
One of the most serious recent occurrences of toxicity
involving Chinese herbs came to light between 1991 and
1992 in Belgium, where a series of young women were
admitted to hospitals suffering from renal failure1. Investigations
initially discovered nine cases and revealed that
they had all been taking medication for slimming from the
same clinic, which was run by doctors not herbalists. The
clinic had been giving slimming treatments for fifteen years
without such problems, but in 1990 the composition of the
slimming capsules was changed and two Chinese herbs
were included.
The slimming clinic claimed that the new formula contained:
Cascara powder 20-150 mg
Acetazolamide 25-45 mg
Belladonna extract 1-2 mg
Hou Po (Cortex Magnolia officinalis) 100-200 mg
Han Fang Ji (Radix Stephania tetrandra) 100-200 mg1
However, as discussed below, it is now certain that the
second Chinese herb was not in fact Han Fang Ji but rather
was either Guang Fang Ji (Radix Aristolochia Fangchi) or an
unknown adulterant.
In addition to the above formulation, most patients at the
clinic were also prescribed a capsule containing the amphetamines
fenfluramine and diethylproprion and the tranquilliser
meprobamate, and were given intradermal injections
of artichoke extract and euphyllin1. Many will consider
such a regimen to constitute extremely dubious practice,
and indeed the Faculties and Medical Board in Belgium
have warned doctors not to prescribe slimming products
composed of appetite inhibitors and diuretics2. Also, it will
be immediately apparent to practitioners of Chinese herbal
medicine that neither Hou Po nor Han Fang Ji are traditionally
indicated for weight loss, and it is also obvious that they
were not being prescribed on an individualised basis following
a diagnosis according to the principles of Chinese
medicine.
It is worth noting that these patients were also put on a
low calorie diet, which might have enhanced the effect of
the medicines they were given.
Since the first published report from Belgium, a total of 53
cases of renal failure have now been reported2. The patients
affected require kidney dialysis with a view to eventual
transplantation. This is clearly an extremely serious situation
and it is important to try to understand what went
wrong. The cases of kidney damage did only occur once the
Chinese herbs were added to the formula, so the toxic
reaction must have involved them in some way.
The first problem concerns the identity of the herbs
involved. Chromatographic studies confirmed the presence
of Hou Po in the capsules1. However, the same studies
showed that the capsules did not contain tetrandrine, which
is a major constituent of Han Fang Ji. These studies also
isolated an unknown alkaloid which was not present in
samples of Han Fang Ji. Finally, microscopic examination
showed the presence of calcium oxalate in both the capsules
and the importer’s sample of Han Fang Ji. Such crystals are
not found in Han Fang Ji according to the Pharmacopoeia of
the PRC3 but they are present in Guang Fang Ji (Radix
Aristolochia Fangchi). The Chinese Medicinal Material
Research Centre (CMMRC) in Hong Kong also studied
samples of the herb supplied as Han Fang Ji by the exporter
in Hong Kong and found aristolochic acid to be present4.
The CMMRC later studied samples of the slimming capsules
themselves and found them to contain aristolochic
acids A and B5.
One very definite possibility therefore is that the herb
actually used in these capsules was not Han Fang Ji (Radix
Stephania Tetrandra) but was in fact Guang Fang Ji (Radix
Aristolochia Fangchi). This herb contains aristolochic acid,
and this chemical in isolation can produce nephrotoxic
reactions6. However, although the potential toxicity of Guang
Fang Ji is known in Chinese medicine2 the whole herb is
used in China without producing such toxicity. It has also
been pointed out that 185 kg of the supposed Han Fang Ji
was distributed to practitioners throughout Belgium, but
only in this one slimming clinic did problems occur. We
have already mentioned that at this clinic the herbs were not
prescribed by properly trained practitioners of Chinese
herbal medicine, nor in accordance with Chinese medical
theories. Furthermore, instead of being combined with
other herbs which may serve to minimise any potential for
toxicity, in this case the herbs were instead combined with
an extraordinary mixture of pharmaceutical drugs.
It is certain then that the herb supposed to be Han Fang Ji
was misidentified by the exporters in Hong Kong, by the
importers in Belgium and by the doctors in the slimming
clinic. It is very likely that the herb used was in fact Guang
Fang Ji and that this herb’s potential for toxicity was massively
amplified by its use in combination with other drugs,
in patients for whom it was not indicated, and by practitioners
untrained in its use.
However, there is definitely some confusion here. The
initial report of studies done in Belgium clearly states that
the slimming capsules did not contain aristolochic acid1,
and instead speaks of the presence of an unknown alkaloid.
Only in the later report from the CMMRC is it claimed that
the capsules did contain aristolochic acid2. There remains
therefore a second distinct possibility, that the capsules
contained neither Han Fang Ji nor Guang Fang Ji, but some
unknown and severely nephrotoxic adulterant.
There are several lessons to be drawn from this tragic
series of cases of kidney damage:
• Chinese herbs should only ever be prescribed by fully
trained practitioners of Chinese herbal medicine, in accordance
with a traditional individualised diagnosis.
• When herbs with some potential for toxicity are mixed
with modern drugs there may be previously unknown
consequences, as a result of the potentiation of the toxicity
of the herb by the metabolic and physiological effects of the
drugs. This is clearly an important issue which requires
further discussion and elaboration. Some important work
has already been done on producing lists of herbs which are
known to have some potential for toxicity7.
• Proper identification and quality control of herbs by
suppliers is a key ingredient in the safe practice of Chinese
herbal medicine.
Toxicity from Patent Medicines-
Jin Bu Huan & Others
Traditionally, patent medicines are based on traditional
herbal formulas and are prescribed according to a traditional
diagnosis. However, modern patents have moved
away from the traditional formulations, and we have begun
to see problems as a result. Reports from the USA in 1993
and 1994 drew attention to toxicity problems with the
patent medicine Jin Bu Huan Anodyne Tablets, made by
Kwangsi Pai Se Pharmaceutical/Bose Drug Manufactory,
Kwangsi, China8,9. Seven adults developed symptoms of
hepatitis after taking Jin Bu Huan for between 7 and 52
weeks. Symptoms and signs included fever, fatigue, nausea,
pruritus, abdominal pain, jaundice and hepatomegaly.
Liver function tests and liver biopsy results confirmed
acute hepatitis and were consistent with a drug reaction.
Two patients later recommenced the use of Jin Bu Huan and
both experienced a rapid return of the symptoms of hepatitis.
All seven patients made gradual but complete recoveries
on ceasing the use of the patent medicine.
The precise mechanism of the hepatitis is not entirely
certain. The abrupt reappearance of symptoms in the patients
who recommenced taking the tablets suggests a hypersensitivity
reaction, and the liver biopsy showed eosinophilia
in two cases, which also suggests an allergic mechanism.
An immunoallergic mechanism therefore seems most
likely9. However, there are also some suggestions of a direct
hepatotoxic effect9.
The package insert for these tablets recommended their
use for pain relief or insomnia and claimed that the ingredients
were 70% starch and 30% levo-alkaloid from Polygala
chinensis (presumably this refers to Yuan Zhi - Radix
Polygalae Tenuifoliae). However, analysis of the tablets
showed that they contained 36% of levotetrahydropalmatine.
This alkaloid is not found in plants of
the genus Polygala, but it is found in the genera Stephania
and Corydalis9. Almost certainly, the alkaloid in these
tablets was actually extracted from Yan Hu Suo (Rhizoma
Corydalis Yanhusuo). This herb is traditionally known to
alleviate pain and we know there have been studies on the
hypnotic and sedative effects of tetrahydropalmatine extracted
from it22 . This herb is also known as Yuan Hu, hence
presumably the confusion with Yuan Zhi (although the
Chinese characters are different).
Several points are evident here:
• The labelling of this product in English was inaccurate. In
addition, the incorrect weight of the active ingredient suggests
poor quality control by the manufacturers.
• Traditionally, Chinese herbs are always used in combination
with other herbs and prescribed in order to treat the
underlying disharmony causing the symptoms. This tablet
was based on only a single herb and indicated purely for
symptomatic relief.
• What is more, these tablets did not even contain the whole
single herb, but a single chemical extracted from a herb.
This is not the practice of traditional medicine, rather it
represents a modern pharmaceutical approach. It is debatable
whether this product could really be described as
“herbal” at all - it is more akin to a novel and unlicensed
drug! The chemistry of whole herbs involves complex
interactions among their constituents which are poorly
understood10, and there is evidence that whole herbs are
significantly less toxic than single “active ingredients” isolated
from them11,12. Certainly, there are no reports in the
literature of any problems with the whole herb Yan Hu Suo.
Also in the USA, in three separate incidents, children
aged two and a half years and 13- and 23- months took
unintentional overdoses of Jin Bu Huan, amounting to 17, 60
and 7 tablets respectively. Each of these children became
seriously ill, with rapid onset of life-threatening bradycardia
and central nervous system and respiratory depression13.
Fortunately each child made a full recovery. These
cases underline the additional dangers from concentrated
single chemical extracts from herbs.
There have also been reports from Hong Kong and the
USA of patent medicines containing paracetamol, aspirin,
antihistamines, theophylline, bromhexine and synthetic
corticosteroids, and from Hong Kong, the USA and Australia
of other patent medicines containing cadmium, lead
and arsenic1. In Malaysia, a woman developed kidney
damage after taking a patent medicine which was found to
contain phenylbutazone14. In the UK, skin creams for eczema
have been found to contain corticosteroids and a
potent antibiotic15,16,17.
What is evident in these cases is that most of these
problems are not being caused by traditional patent medicines
but by modern formulations containing a single chemical
only or combining Chinese herbs with Western drugs.
The advice given to its members by the Register of Chinese
Herbal Medicine (RCHM) in the UK is relevant here:
Never prescribe a patent medicine unless you know all its
ingredients. Avoid all patents containing Western
medicines (it is in any case illegal to prescribe many of
these unless you are a registered medical practitioner).
Patents with added Western drugs can often be identified
by the words Fu Fang or Qiang Li before the name. Avoid
all patents containing heavy metals (they are toxic and
illegal). Use reputable suppliers. Suppliers must be
encouraged to adopt careful quality control measures15.
Toxic Effects from Adulterants or
Erroneous Substitutes
In 1991 a case was reported from Hong Kong of encephalopathy
and neuropathy following ingestion of a decoction
supposedly prepared from Long Dan Cao (Radix Gentiana
longdancao). Investigation showed that the toxicity was in
fact due to adulteration of the herb by the supplier in
mainland China with the roots of Podophyllum emodi,
which contained podophyllotoxin18. Similarly, the Chinese
Medicinal Material Research Centre (CMMRC) in Hong
Kong investigated a case of serious vomiting and abdominal
pain in Kuala Lumpur and a case of serious vomiting
and headache from Taipei. Both people had taken decoctions
supposedly containing Wei Ling Xian (Radix Clematis).
Investigation revealed that the importers in Kuala Lumpur
and Taipei had been persuaded to accept a new source of
Wei Ling Xian and had not realised that the herb supplied
was actually a toxic adulterant, which again proved to be
Podophyllum emodi5.
The CMMRC also investigated four cases of drowsiness
and confusion affecting four women in Hong Kong, all of
whom had obtained their prescriptions from the same herb
shop. In each case the prescription included Ling Xiao Hua
(Flos Campis grandiflora or C. radicans). In Hong Kong and
southern China this herb is commonly replaced with Pao
Tung Hua (Flos Paulownia fortunei or P. tomentosa). However,
in these cases the retailer at the herb shop had mistakenly
used Yang Jin Hua (Datura metel), which contains
atropine and scopolamine and is known to cause symptoms
such as confusion at the doses used5.
In the USA, a man took a traditional herbal prescription
containing 36 ingredients. He become ill with abdominal
colic, muscle pain and fatigue, was hospitalised for 3 weeks,
and was eventually diagnosed as suffering from acute
intermittent porphyria. The cause was traced to lead poisoning
due to contamination of the Hai Ge Fen (Concha
Cyclinae Sinensis, clam shell) in his prescription19.
Expensive herbs such as Ren Shen (Panax ginseng) may
particularly tempt fraudulent substitution. In the 1970s,
Ginseng preparations bought in the USA were found to
contain Mandragora officinarum (toxic component scopolamine),
Rauwolfia serpentia (toxic component reserpine)
and Cola species41. There have also been other reports of
substitution of Ren Shen20, including a famous case involving
Linford Christie at the Seoul Olympics where what was
supposed to be Ren Shen was found to contain ephedrine.
All these cases again point to the crucial need for good
identification checks and quality control by suppliers. A
minimum requirement would probably be the examination
by microscopy and chromatography of each batch of herbs
by trained pharmacognocists.
Problems with Herbs of Known Toxicity
A handful of the hundreds of herbs commonly used in
Chinese herbal medicine have always been known to be
potentially toxic, but they have continued to be used with
care because of their therapeutic value. The most important
examples are the aconites.
A review of reports of toxicity in Hong Kong21 showed
that most of the cases of serious poisoning were due to the
use of Cao Wu (Radix Aconitum kusnezoffi) and Chuan Wu
(Radix Aconitum carmichaeli - the main root). These herbs
contain highly toxic alkaloids, including aconitine, which
activate sodium channels and over-stimulate cell membranes.
Side effects are neurological, cardiovascular and/
or gastro-intestinal and death can occur due to cardiovascular
collapse or ventricular arrhythmia.
Both of these herbs are traditionally known to be very
toxic, and Chinese herbal pharmacopoeias warn of this.
Nonetheless, in some of the Hong Kong cases quite high
doses of 7-11g had been prescribed. This suggests a lack of
appropriate caution to say the least and raises concerns over
the training and competence of practitioners, particularly
since herbal medicine is unregulated in Hong Kong. Even
when the indications and dosage are correct, problems can
arise. The roots may contain variable amounts of toxic
components and patients’ sensitivity may also vary22. Furthermore,
patients are relied upon to boil these herbs for a
long time to reduce their toxicity, and these instructions
may not always be followed correctly. More complex is the
situation relating to Fu Zi (Radix Lateralis Aconiti
Carmichaeli Praeparata - the processed accessory roots).
This herb is less toxic than the main root and is preprocessed
to further reduce its toxicity (the unprocessed
form is called Sheng Fu Zi and is rarely used). Herbalists find
this herb extremely useful - it is warming and drying and it
tonifies yang. However, there have been some reports of
problems with Fu Zi in Hong Kong23.
In the UK, although the legal situation is somewhat
ambiguous, it appears that all forms of aconite are effectively
banned for internal use. It can certainly be argued that
herbs with such clear and established toxicity as Cao Wu and
Chuan Wu should be restricted to use only when patients are
under close medical supervision, probably as in-patients.
This would permit the rapid detection of adverse reactions,
which can then be successfully treated with atropine. In the
case of Fu Zi, one could argue for its use being allowed at
low doses by qualified and regulated practitioners, and
with clear advice to patients about the need to pre-boil Fu Zi
to reduce its toxicity even further.
Toxic Effects from Rare Herbs - Hong Kong
The herbs Yang Jin Hua (Datura metel) and Nao Yang Hua
(Flos Rhododendri mollis) contain scopolamine, hyoscamine
and atropine and they have been reported as the cause of
cases of anticholinergic poisoning in Hong Kong2l. These
herbs are rarely used by practitioners of Chinese herbal
medicine in Europe, although the former can be obtained
from some suppliers7. The related herb Datura stremonium
is used by Western herbalists and in the UK this is allowed
by the 1968 Medicines Act within a restricted dosage range.
It would seem sensible for Yang Jin Hua (Datura metel) and
Nao Yang Hua (Flos Rhododendri mollis) to also be restricted
to use at low doses by qualified and regulated
practitioners.
Cases of Liver Damage in Skin
Disease Patients
In the UK there has been a great surge in the popularity of
Chinese herbal treatment for skin conditions. This followed
considerable media interest, stimulated by two clinical
trials which showed the value of Chinese herbs in the
treatment of eczema24,25.
There have now been several cases in the UK where
patients have become clinically ill with liver problems after
taking Chinese herbs for the treatment of skin conditions,
and a similar case has been reported from New Zealand.
Two of these patients have died.
The details of a number of these cases have now been
published separately. It has often proved difficult to obtain
much information about the herbs prescribed and details of
the Chinese diagnosis have never been obtained, but there
are a number of cases where details are now available of the
prescriptions given. Unfortunately it is very difficult to
identify the species, given a dried specimen of only one part
of the plant, and to compound the difficulty the identification
of the herbs in some of these cases was done by
botanists, not by specialists in Chinese herbs. As a result
some of these prescriptions may contain errors in identification.
Nonetheless, there is enough information here to
allow us to draw some clear conclusions. These are presented
in the discussion section after the individual cases.
Case 1
This is the first fatality to have occurred in the UK which
was linked to Chinese herbs. A letter from the National
Poisons Unit reporting this case was published in the Lancet
in 199226.
The patient, a 28 year old woman, developed jaundice
after taking Chinese herbs for several months and was
admitted to hospital with hepatitis. The symptoms resolved
satisfactorily. Six months later the patient began
taking Chinese herbs again. Two or three weeks after this
she was again admitted with jaundice, and tragically died
of acute liver failure. A post-mortem revealed total necrosis
of the liver.
The hospital was able to exclude the more common
infectious causes, e.g. hepatitis A and B. There was no
history of exposure to hepatotoxic chemicals, and the only
Western drugs being taken prior to the jaundice were
antacids. There were no traces of hepatotoxic drugs in the
urine, nor of heavy metals in the blood or urine.
The Lancet letter also gave details of the herbal prescription
which this patient supposedly was taking. However,
after further investigations by Dr. David Atherton it has
been discovered that the prescription given to the NPU was
in fact for a different patient of the same name27! The NPU
analysed their sample for aflatoxins (toxins from mould on
the herbs) and for pyrrolizidine alkaloids, and found none,
but clearly this particular result is meaningless since the
wrong sample was tested. The possibility of contamination
or adulteration of the herbs therefore remains in this case.
Dr. Atherton has now provided us with details of the
prescription which was actually taken by this woman
throughout her treatment27:
Pinyin Pharmaceutical Botanical Dosage
name name name
Bai Ji Li Fructus Tribuli Tribulus terrestris 3 chien (9g)
Terrestris
Jing Jie Herba seu Flos Schizonepeta 1 chien (3g)
Schizonepetae tenuifolia
Tenuifoliae
Yin Chen Hao Herba Artemisia Artemisia scopariaa 3 chien (9g)
Yinchenhao
Sheng Di Radix Rehmanniae Rehmannia 3 chien (9g)
Huang Glutinosae (not glutinosa
pre-cooked)
Mu Dan Pi Cortex Moutan Paeonia 3 chien (9g)
Radicis suffructicosa
Bai Xian Pi Cortex Dictamni Dictamnus 3 chien (9g)
Dasycarpi Radicis dasycarpus
Gan Cao Radix Glycyrrhizae Glycyrrhiza 1.5 chien
Uralensis uralensis (4.5g)
Dan Zhu Ye Herba Lophatheri Lophatherum 2 chien (6g)
Gracilis gracile
Mu Tong Caulis Akebiaeb Clematis armandiib 2 chien (6g)
a This is the species I was given for this herb. However, both Artemisia
scoparia and Artemisia capillaris are used and it is not entirely clear
which was present here.
b The pharmaceutical name now used is Caulis Mutong. Old
pharmacopoeias most often list Akebia trifoliata and Akebia quinata as
this herb. However, in modern China either Clematis armandi, Clematis
montana, or Aristolochia manshuriensis may be used22.
The above is based on the practitioner’s written prescription,
which gave the herb names in Chinese.
In response to this fatality, and a number of other early
reports of high blood levels of liver enzymes in patients
taking herbs for eczema and psoriasis28,29, the RCHM made
the following recommendations to its members in 1992 and
1993l5,16:
• that all patients with a history of liver or kidney disease in
the last five years should not be treated without regular
blood-testing to monitor liver and kidney function.
• that practitioners should carefully monitor their patients
and be vigilant for any early indications of liver damage.
• that practitioners should take care with dosage in patients
with skin diseases. A total prescription weight of 35 g/day
(or 0.5 g/kg of body weight) was recommended.
• that practitioners should consider regular blood-testing
of all patients with skin diseases. This last recommendation
was only taken up by a handful of practitioners. Many
practitioners were reluctant to import such a non-traditional
measure into the practice of Chinese medicine, and
there were also obstacles of cost and practicality.
Case 2
This case came to the attention of the RCHM Council in May
1994, when we were approached by a woman whose sister
had been admitted to hospital with jaundice whilst taking
a course of Chinese herbs. The hospital had investigated
other possible causes for the jaundice and concluded that
the herbs were probably responsible. The woman approached
the RCHM because the practitioner claimed to be
“a registered practitioner”. However, the practitioner turned
out not to be a member of the RCHM. The practitioner was
initially reluctant to give any details of the prescription, but
after the patient’s sister threatened legal action she divulged
the following details. The dosages are not known.
Pinyin Pharmaceutical Botanical
name name name
Jing Jie Herba seu Flos Schizonepeta tenuifolia
Schizonepetae
Tenuifoliae
Fang Feng Radix Ledebouriellae Ledebouriella divaricataa
Divaricatae
Huang Qin Radix Scutellariae Scutellaria baicalensis
Baicalensis
Ban Lan Gen Radix Isatidis seu Baphicacanthus cusia, lsatidis
Baphicacanthi tinctoria or I. indigotica
Mu Dan Pi Cortex Moutan Radicis Paeonia suffructicosa
Zi Su Ye Folium Perillae Perilla frutescens
Frutescentis
Mai Men Tuber Ophiopogonis Ophiopogon japonicus
Dong Japonici
Gou Qi Zi Fructus Lycii Lycium barbarum or
L. chinense
Bai Shao Radix Paeoniae Paeonia lactiflora
Lactiflorae
Shan Yao Radix Dioscoreae Dioscorea opposita
Oppositae
Mu Tong Caulis Mutong Aristolochia manshuriensis,
Clematis armandi, or
C. montanab
Fu Ling Sclerotium Poriae Poria cocos
Cocos
Chen Pi Pericarpium Citri Citrus reticulata
Reticulatae
Bai Xian Pi Cortex Dictamni Dictamnus dasycarpus
Dasycarpi Radicis
Gan Cao Radix Glycyrrhizae Glycyrrhiza uralensis
Uralensis
Bai Jiang Can Bombyx Batryticatus Bombyx mori infected with
Beauveria bassiana
a Also known as Ledebouriella seseloides or Saposhnikovia divaricata.
b Old pharmacopoeias most often list Akebia trifoliata and Akebia
quinata as this herb. However, in modern China either Clematis
armandi, Clematis montana, or Aristolochia manshuriensis may be
used22.
The above is based on the practitioner’s written prescription,
which gave the herb names in Chinese.
The information available on this case is rather limited,
but it is included here to make the information available to
practitioners, who may particularly wish to study all the
prescriptions which may have been involved in adverse
events.
Case 3
This case, reported by Kane et al.30, was of a 31 year old
white woman who presented to her general practitioner in
September 1991 complaining of loss of appetite, nausea and
fatigue. She had had dark urine and yellow sclerae for the
previous 24 hours. Examination revealed jaundice and an
enlarged liver. Blood tests revealed raised levels of alanine
transaminase, alkaline phosphatase and bilirubin, confirming
liver damage.
The patient was not taking regular prescribed drugs,
drank hardly any alcohol, and had had no recent injections
or blood transfusions. The provisional diagnosis was viral
hepatitis, but blood tests for hepatitis A were negative.
Three months later she was tested for hepatitis B and C and
for auto-antibodies and these tests were also negative.
The patient’ s liver function returned to normal over the
next eight weeks, but after another six weeks she again
complained of malaise, itching and dark urine. She had
mild jaundice, and blood levels of alanine transaminase
and alkaline phosphatase were again raised.
This time the patient was carefully questioned and she
revealed that before the first episode she had taken Chinese
herbs for her psoriasis. The herbs were taken daily for two
months as a decoction. She had begun taking the herbs
again just three days before the second episode of jaundice.
She stopped the herbs again and her liver function returned
to normal after eight weeks. She remained well during 18
months follow up.
In this case, the recurrence of both symptoms and biochemical
evidence of liver damage shortly after resuming
the herbs strongly incriminates the herbs as the cause of the
liver damage.
The herbs showed no evidence of contamination by
heavy metals or fungi. The prescription was examined and
analysed at the Dept. of Pharmacognosy in the School of
Pharmacy of the University of London. They identified the
herbs by their Latin botanical names as:
Pinyin Pharmaceutical Botanical
name name name
Bai Xian Pi Cortex Dictamni Dictamnus dasycarpus
Dasycarpi Radicis
Mu Dan Pi Cortex Moutan Radicis Paeonia suffructicosa
Sheng Di Radix Rehmanniae Rehmannia glutinosa
Huang Glutinosae
(not pre-cooked)
Bai Hua She Herba Hedyotidis Hedyotis diffusaa
She Cao Diffusae
Shan Dou Gen Radix Sophorae Sophora subprostatab
Subprostatae
Long Dan Cao Radix Gentianae Gentiana scabra
Longdancao
Tu Fu Ling Rhizoma Smilacis Smilax glabra
Glabrae
Zao Xiuc Paris polyphylla Paris polyphylla
a Also known as Oldenlandia diffusa.
b There are two types of this herb: the southern type is known as Guang
Dou Gen (Sophora subprostata, also known as S. tonkinensis) and is
considered to be toxic, the northern type is known as Bei Dou Gen
(Menispermum dahuricum) and is mostly recommended for use since
it is without adverse effects31.
c Also known as Qi Ye Yi Zhi Hua .This herb is traditionally considered
to be slightly toxic31.
In this case it is clear that two herbs in the prescription had
some known potential for toxicity.
Case 4
This case was also reported by Kane et al.30 A 61 year old
Chinese woman living in the UK presented with nausea,
malaise, weight loss, dark urine and jaundice. Blood tests
showed raised levels of aspartate transaminase, alkaline
phosphatase and bilirubin, confirming liver damage. She
had no known history of exposure to hepatitis viruses or
other toxins, she drank very little alcohol, and her only
prescribed drugs had been a short course of terfenadine.
Blood tests for hepatitis A, B and C were negative. She had
been taking Chinese herbs for her eczema for 11 months.
This patient was advised to stop the herbal treatment and
her symptoms disappeared within days. Her liver function
returned to normal within three months.
The herbs were identified by the Dept. of Pharmacognosy
in the School of Pharmacy
Pinyin Pharmaceutical Botanical
name name name
Bai Xian Pi Cortex Dictamni Dictamnus dasycarpus
Dasycarpi Radicis
Mu Dan Pi Cortex Moutan Radicis Paeonia suffructicosa
Wu Wei Zi Fructus Schisandrae Schisandra chinensis
Chinensis
Dang Gui Radix Angelicae Sinensis Angelica sinensis
Chai Hu Radix Bupleuri Bupleurum chinense
Huang Bai Cortex Phellodendri Phellodendron chinense
Bai Ji Li Fructus Tribuli Terrestris Tribulus terrestris
Jing Jie Herba seu Flos Schizonepeta tenuifolia
Schizonepetae Tenuifoliae
Chan Tui Periostracum Cicadae Cryptotympana
pustulataa
Fang Feng Radix Ledebouriellae Saposhnikovia
Divaricatae divaricatab
a Also known as Cryptotympana atrata.
b Also known as Ledebouriella divaricata or L. seseloides.
In this case it seems extraordinary that this woman had
been taking Chinese herbs for 11 months without any
apparent problems for most of this time. This raises several
important questions:
• was the prescription changed in the last few weeks? We
only have information about the prescription she was taking
when she became ill. If we knew that a herb had recently
been added, then that herb would be strongly suspect.
• had there recently been a delivery of a new batch of one
of the herbs? If so, there may have been problems with the
correct identification and preparation of the herbs in the
new batch. This would support the suggestion that good
quality control is a key issue.
• had some other factor intervened? We do not know
whether there had been changes in the patient’s diet, or
whether she had been stressed or over-tired etc.
Case 5
Another case of severe hepatitis was reported in 1994 in the
New Zealand Medical Journal32. A 37 year old woman
presented to her doctor with general malaise. Blood tests
showed raised levels of alkaline phosphatase, GGT, ALT
and AST, all consistent with liver damage. Over the next
two weeks her liver function deteriorated and she was
admitted to hospital. The blood levels of liver enzymes rose
to very high levels before beginning to gradually decline.
Her liver function finally returned to normal seven weeks
after the initial presentation. Tests for hepatitis A, B and C
were all negative. She had antibodies to Epstein-Barr virus
showing that she had been exposed to the virus in the past
and was now immune. Tests for other infective agents were
negative. Liver biopsy revealed features most consistent
with toxic or drug induced liver damage.
Thirteen days before presenting to her doctor, this patient
had begun treatment with Chinese herbs for her psoriasis.
She drank alcohol rarely and had no history of intravenous
injection, blood transfusion or recent overseas travel. Interestingly,
she had had a routine blood test three months
previously and at this time the liver function tests were
normal.
The herbs which were prescribed by the herbal practitioner
were as follows. With the exception of Jianqu they are
given by their Latin pharmaceutical or botanical names in
the published report.
Pinyin Pharmaceutical Botanical
name name name
Qing Dai Indigo Pulverata Levisa Processed from: Isatis
tinctoria, I. indigota,
Baphicacanthus cusia,
Polygonum tinctorium or
Clerodendon
cyrtophylluma
Dan Shen Radix Salviae Salvia miltiorrhiza
Miltiorrhizae
Wu Wei Zi Fructus Schisandrae Schisandra chinensis
Chinensis
Bai Zhi Radix Angelicae Angelica dahurica
Dahuricae
Pu Gong Herba Taraxaci Mongolici Taraxacum mongolicum
Ying cum Radice
Tu Fu Ling Rhizoma Smilacis Glabrae Smilax glabra
Bai Xian Pi Cortex Dictamni Dictamnus dasycarpus
Dasycarpi Radicis
Wu Mei Fructus Pruni Mume Prunus mume
Jian Qub Massa Fermentata b
a The published report names this herb as Indigo naturalis. It is not
entirely clear whether this was Da Qing Ye (Folium Daqingye), i.e. the
unprocessed leaf, or Qing Dai, which is woad - a powder made from the
leaf.
b More commonly known as Shen Qu, this is a non-standardised
fermented leaven including various herbs such as Qing Hao (Herba
Atermisiae Annuae), Xing Ren (Semen Pruni Armeniacae), Cang Er Zi
(Fructus Xanthii Sibirici) and Chi Xiao Dao (Semen Phaseoli Calcarati)22,23.
Case 6
This case is the second fatality to have occurred in the UK.
It was reported in a letter to the British Medical Journal in
199533. A 32 year old man was admitted to hospital with
fulminant liver failure, otherwise known as massive hepatic
necrosis. Within a week of presentation he was deeply
jaundiced and went into coma. Liver transplantation was
attempted but did not succeed in saving the patient’s life.
Tests were unable to identify any viral, immunological or
metabolic cause of liver failure. Four weeks before presentation
the patient had begun treatment with Chinese herbs
for lipomas.
The practitioner’s notes reveal that the patient was born
in India and had a history of jaundice as a child. Apparently
he had also had jaundice in his early twenties. He had been
prescribed ten packets of herbs and he had taken one packet
of herbs a day as instructed. Throughout these ten days he
had felt ill and had diarrhoea but he had persisted with
taking the herbs. After three weeks he was still unwell and
began to become jaundiced. At this point he went to his
doctor and was hospitalised.
One of the tragic features of this case is that had this
patient stopped the herbs as soon as the diarrhoea began, he
would probably still be alive. His death could almost certainly
have been prevented if he had been given written and
verbal instructions to stop taking the herbs and contact the
practitioner if he should develop any symptoms like those
of a cold or flu, or any digestive disturbance such as nausea
or diarrhoea.
The following is the herbal prescription as taken from the
practitioner's notes, with the herbs given by their Chinese
names. However, it should be said that the notes are scanty
and not completely clear so we can not be entirely sure of the
prescription given.
Pinyin Pharmaceutical Botanical Dosage
name name name
Bai Xian Pi Cortex Dictamni Dictamnus dasycarpus 9g
Dasycarpi Radicis
Shan Zha Fructus Crataegi Crataegus pinnatifida 9g
or C. cuneata
Zhi Ke Fructus Citri Citrus aurantium 4.5g
Aurantii
Tian Hua Fen Radix Tricho- Trichosanthes kirilowii 9g
santhis Kirilowii
Chen Pi Pericarpium Citri Citrus reticulata 3g
Reticulatae
Chi Shao Yao Radix Paeoniae Paeonia veitchii or P. 6g
Rubrae lactiflora
Dang Gui Wei Radix Angelicae Angelica sinensis 9g
Sinensis
Fang Feng Radix Ledebouriella 9g
Ledebouriellae divaricataa
Divaricatae
Bai Zhi Radix Angelicae Angelica dahurica 6g
Dahuricae
Fu Ling Sclerotium Poriae Poria cocos 12g
Cocos
Bai Zhu Rhizoma Atractylodes 9g
Atractylodis macrocephala
Macrocephalae
Gan Cao Radix Glycyrrhizae Glycyrrhiza uralensis 6g
Uralensis
a Also known as Ledebouriella seseloides or Saposhnikovia divaricata.
The School of Pharmacy in the University of London is
reported to have consulted a Chinese expert in pharmacognosy
about the herbs in this prescription and they concluded
that none of the herbs appears to be directly hepatotoxic,
which probably points to an immunoallergic mechanism.
Further clarification of this report is required.
Discussion of cases
In many of these cases all the other obvious possible causes
of liver damage can be confidently excluded, and it is clear
that something about the herbal treatment is the cause of the
adverse reactions. Adulteration or misidentification of herbs
seems an unlikely explanation since the cases are spread
over several years and involved different practitioners, and
the herbs have been examined and identified in several
cases. The fact that the majority of these cases occurred in
the UK may be due to the large number of patients with skin
diseases being treated in this country. If we conclude then
that something about the herbal treatment is the cause of the
adverse reactions, this raises two important questions:
1. are these adverse reactions being caused by a single herb
or by several?
2. is the herb or herbs directly toxic to liver cells, or is this an
immunoallergic or idiosyncratic reaction?
A careful examination of these prescriptions shows that
one herb is common to them all, namely Bai Xian Pi (Cortex
Dictamni Dasycarpi Radicis), and it has been suggested that
this herb may be the cause of the hepatitis33. Since this herb
is mostly used to treat skin disease, this would explain why
these cases of liver damage have been confined to patients
being treated for skin disease.
However, there are no reports in the literature of Bai Xian
Pi being directly hepatotoxic, and this includes a recently
published Chinese language pharmacopoeia which gives
details of animal research and clinical studies on this herb34.
So if Bai Xian Pi is involved, the mechanism would appear
most likely to be a rare allergic hypersensitivity and not
direct toxicity.
We should note that in two of the above cases (Cases 1 and
3), patients experienced a much more rapid adverse reaction
when they re-started the herbs a second time. This is
also strongly suggestive of an allergic mechanism.
In two controlled clinical trials examining the benefits of
Chinese herbs in the treatment of eczema24 25, all participants
were given liver function tests and there were no
reports of problems. Bai Xian Pi is one of the ten herbs
contained in the standardised herbal remedy Zemaphyte
which was used in these studies. However, the relatively
small numbers involved in these trials make it difficult to
draw firm conclusions, and further clinical research is
clearly needed.
It has been pointed out by practitioners that probably as
many as 70-80% of prescriptions for skin disease contain Bai
Xian Pi. It is possible that this is the reason why this herb
occurs in each of the above prescriptions, and that the
causes of the hypersensitivity reaction are more complex.
Certainly, it has been suggested that several herbs can be
involved in immunoallergic reactions35, and patients with
atopic conditions such as eczema or with a history of liver
disease might be particularly vulnerable to such reactions.
In case 3 in particular, it is clear that other herbs in the
prescription could have been involved in the toxic effect.
We should therefore be cautious about attributing all these
cases of hepatitis to a single herb when there are so many
other variables.
In conclusion, it appears almost certain that the hepatotoxic
effect which occurred in these cases was of an
immunoallergic type and was not due to a herb which is
directly hepatotoxic. This has two major implications: firstly,
that the toxic effect is probably not dose-related, and secondly
that these sorts of herbal prescriptions are only
potentially toxic to certain individuals who have an allergylike
sensitivity to them, and do not do any harm at all to the
vast majority of people. The problem is to devise strategies
to protect those individuals who do have this immunological
sensitivity.
Chinese herbs are widely used in the UK for the treatment
of eczema and psoriasis, so it is clear that the incidence of
adverse events is quite low, probably affecting one person
in tens of thousands. Most individuals definitely appear to
tolerate the herbs without apparent harm, and the clinical
trial results support this conclusion. The problem is that
when the adverse reaction does occur it can clearly be lifethreatening.
No-one fully understands the mechanisms of
such idiosyncratic reactions, which are also known to occur
with some drugs. It is generally suspected that there can be
a genetic susceptibility which makes some individuals
vulnerable.
It is noteworthy that both of the fatalities involved people
of Indian origin. This may indicate a genetic susceptibility,
or it may be that both these individuals already had compromised
liver function, perhaps as a result of infectious
hepatitis earlier in life. In any case, it is clear that people
with poor liver function will be particularly at risk.
However, great caution is undoubtedly needed with all
patients. In Case 5 above the woman is known to have had
perfectly fine liver function three months previously, but
she nonetheless developed severe hepatitis and was hospitalised
after taking the herbs for only 13 days.
In the light of the above, the RCHM has taken the view
that whatever the precise mechanisms and whether or not
a single herb is the cause, the first priority is to protect future
patients. The second fatality in particular (Case 6) could
almost certainly have been prevented by good practice, and
the RCHM has emphasised this by issuing the following
updated guidelines36:
• A detailed case history is essential to determine whether
there is any history of jaundice or hepatitis. Where there is
such a history, patients must be closely monitored and this
must include liver function tests.
• Although hypersensitivity reactions are not directly dosedependent,
continuing caution with dosage is advised for
the time being.
• Patients should be carefully monitored, and in particular
practitioners should be alert to any early signs of liver
damage37.
• All patients should be given written guidelines warning
them to stop taking their herbal medicine and immediately
contact their practitioner if they experience symptoms such
as nausea, vomiting, diarrhoea, flu-like symptoms, and
hypochondriac tenderness.
The practitioners involved in the six cases reported above
appear to have been fully trained, but five of the six were not
members of the RCHM. In the one case where the practitioner
was a member of the RCHM, the Register’s guidelines
had not been followed. Although the numbers are too
small to allow firm conclusions, this may reflect the fact that
a good level of training is not in itself enough to ensure safe
practice, but must be complemented with membership of a
professional body with Codes of Ethics and Practice, complaints
procedures, and channels of regular communication
to keep members informed.
A possible addition to the RCHM’ s guidelines would be
for practitioners to take care to closely monitor patients who
consume a lot of alcohol, and this should probably include
liver function tests. Practitioners should also be aware that
immunoallergic effects are often much worse on re-exposure
to the medicine. A patient who has experienced suspicious
symptoms and stopped taking their herbs may experience
a much more rapid and more severe reaction if they
begin to take the herbs again at a later date. Cases 1 and 3 are
good examples of this.
It is important to stress to practitioners, most of whom
have not experienced any problems with their own patients
being adversely affected, that this does not mean that there
is not a problem. Since it is probable that only one person in
every few thousand is vulnerable to liver damage from the
herbs, this would mean that one would have to treat five or
ten thousand people before one would expect (statistically)
to have one patient become ill with liver damage.
It has been suggested by some agencies that all patients
being treated with Chinese herbs should receive routine
blood tests for liver damage38. However, most practitioners
are resistant to this idea, on grounds of cost and inconvenience
to patients and because many patients dislike giving
blood samples. It is also true that several prescription drugs
carry small risks of liver damage but continue to be used
without resort by doctors to liver function testing of all their
patients. This illustrates the point that adequate training
and good practice are the keys to patient safety.
It is unfortunate that we do not have enough details on
these cases to enable us to analyse them in terms of a
Chinese medicine approach to the individual’s patterns of
disharmony. It is possible that factors in patients’ diet or
lifestyle or constitution may make them more vulnerable to
hypersensitivity reactions to some herbs.
It has also been suggested that the overall balance of the
prescriptions may be inappropriate in some way, and in
particular that they may be focused too much on clearing
pathogenic factors and may not do enough to support the
Spleen or the Liver. However, many experts on herbal
dermatology in China feel that focusing on the pathogenic
factors is the correct strategy. Certainly it is true that some
of the prescriptions given in these six cases are quite strongly
draining, but the prescription used in Case 6 contained a
number of herbs to support the Spleen, and the prescription
used in Case 2 contained a number of herbs to support
blood and yin. Another possible factor is that a high overall
dosage of herbs may put additional stress on the Spleen in
particular. In addition, it has been suggested that herbs
which modern research has shown to have hepato-protective
effects should be added to our prescriptions for skin
diseases. There is a need for further discussion and debate
of all these questions within the profession.
Another question arising from these cases is the absence
of reports of liver damage in patients receiving treatment
for skin diseases in modern China. It is striking that Case 4
above is of a Chinese woman, so there does not appear to be
anything in the way of genetics or diet protecting Chinese
patients. The most likely explanation is that hepatitis A and
B are endemic in China anyway. It is entirely possible that
if there are occasional cases of herb-induced hepatitis in
China these are assumed to be infectious in origin and the
true cause is missed.
A clear lesson from these tragedies is that the profession
must urgently organise national and international reporting
mechanisms in order to detect adverse effects from
Chinese herbs quickly and effectively. Accurate information
is most important. In the UK we are now seeing good
levels of co-operation between the profession and bodies
such as the National Poisons Unit and Schools of Pharmacy,
which will help to improve the flow of information in both
directions.
The second lesson is that good patient management is
essential. In particular we can identify the following:
• good communication with patients. Patients must be
warned both verbally and in writing of potential adverse
effects and of the importance of stopping the herbs and
contacting their practitioner should these occur.
• regular monitoring of patients. Patients should be seen
every week or two at first and generally never less than
every four weeks. Appointments should last for at least 15
minutes to allow time to fully review each case.
Finally, it is important to remember that Chinese herbal
treatment has been shown to be remarkably effective for
stubborn and unpleasant skin diseases such as eczema,
which cause a great deal of suffering and distress24,25. Our
aim must be to continue to offer this beneficial treatment
while protecting potentially vulnerable individuals from
unnecessary and avoidable harm.
Conclusion
In conclusion, we can see that the vast majority of adverse
events involving Chinese herbs which have been reported
in the literature can be avoided by the following measures:
• Chinese herbs should only ever be prescribed by fully
trained practitioners of Chinese herbal medicine, in accordance
with a traditional individualised diagnosis. Training
of practitioners should include the ability to monitor for
and recognise adverse effects. The RCHM has begun the
task of establishing agreed educational standards in the UK
and this is clearly a matter of some urgency. Professional
bodies will increasingly need to be able to guarantee minimum
standards of practice and to enforce codes of ethics
and practice, and legal protection of title and self-regulation
will be necessary to achieve this.
• Chinese herbs should be prescribed in the traditional
manner, according to an individualised diagnosis based on
the theory and practice of Oriental medicine. The herbs
should be used according to their traditional indications
and in established combinations.
• There should be compulsory Codes of Practice for practitioners
which include many of the recommendations made
in this paper, including requirements to monitor patients
regularly, to arrange regular blood tests before treating
patients with a history of liver diseases, to fully inform
patients, etc. In the case of the RCHM such a Code already
exists, but membership is entirely voluntary and as a result
disciplinary procedures are weakened and some practitioners
do not join at all.
• Whenever it is proposed to use herbs in novel ways, for
example in the form of chemical extracts, or for symptomatic
treatment, then careful and thorough clinical research
and monitoring must be undertaken. A similar caution
should be applied to the prescribing of obscure or
unusual herbs.
• A handful of herbs traditionally known to be seriously
toxic, such as Cao Wu and Wu Tao, should probably be
restricted to use in hospital settings only.
• A number of herbs with some potential for toxicity, such
as Fu Zi, should probably be restricted to use at specified
doses by fully trained practitioners only. Herbs with some
potential for toxicity should not be prescribed for patients
who are also taking modern drugs.
• Proper identification and quality control of herbs by
manufacturers and suppliers is a key ingredient in enabling
the safe practice of Chinese herbal medicine. A minimum
requirement would probably be the examination by
microscopy and chromatography of each batch of herbs by
trained pharmacognocists.
• Suppliers should not make available patent medicines
whose ingredients are not certain, and practitioners should
not prescribe them.
It is interesting to note that these suggestions are similar
to the recommendations of the Report of the Working Party
on Chinese Medicine appointed by the Secretary for Health
and Welfare in the Hong Kong administration. The recommendations
include: the registration of herbal practitioners;
the creation of a list of “potent herbs” which should
only be available with a prescription from a herbal practitioner;
licensing of the processing, manufacture, import
and distribution of raw herbs and patent medicines; and
improvements to the training of both practitioners and
dispensers39.
We should remember that adverse effects from Chinese
herbs are rare. In Hong Kong, where the use of Chinese
herbs is both widespread and unregulated, it has been
shown that only 0.2% of the general medical admissions to
the Prince of Wales Hospital were due to adverse reactions
to Chinese medicine, as compared to 4.4% of admissions
caused by Western pharmaceuticals40. As we have seen,
improvements in quality control and in the training and
regulation of practitioners would substantially reduce the
already low incidence of problems involving Chinese medicine.
These improvements will assist greatly in establishing
Chinese herbal medicine in the West as a safe and effective
form of treatment.
Acknowledgements
Many thanks to the following for their valuable assistance
and guidance: Mazin Al-Khafaji, Dr. David Atherton,
Charles Buck, Peter Deadman, Dr. Han Liping, Ken Lloyd,
Michael McIntyre, Dr. Zhong Shouming. The views and
opinions expressed in this article are, however, entirely my
own.
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Biography
Richard Blackwell graduated in Medical Science from the
University of Nottingham Medical School. He is Deputy Principal
of the Northern College of Acupuncture in York, and has
taught Chinese medicine and acupuncture since 1988. He was
a member of the Register of Chinese Herbal Medicine from
1986 to 1991 and its President from 1991 to 1994.