Herbal Medicine : Effect of clinical laboratory test

1. Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard 521
Herbal Remedies
Effects on Clinical Laboratory Tests
Amitava Dasgupta, PhD; David W. Bernard, MD, PhD
● Context.—Complementary and alternative medicine
(herbal medicines) can affect laboratory test results by sev-
eral mechanisms.
Objective.—In this review, published reports on effects
of herbal remedies on abnormal laboratory test results are
summarized and commented on.
Data Sources.—All published reports between 1980 and
2005 with the key words herbal remedies or alternative
medicine and clinical laboratory test, clinical chemistry
test, or drug-herb interaction were searched through Med-
line. The authors’ own publications were also included. Im-
portant results were then synthesized.
Data Synthesis.—Falsely elevated or falsely lowered di-
goxin levels may be encountered in a patient taking digoxin
and the Chinese medicine Chan Su or Dan Shen, owing to
direct interference of a component of Chinese medicine
with the antibody used in an immunoassay. St John’s wort,
a popular herbal antidepressant, increases clearance of
many drugs, and abnormally low cyclosporine, digoxin,
theophylline, or protease inhibitor concentrations may be
observed in a patient taking any of these drugs in combi-
nation with St John’s wort. Abnormal laboratory results
may also be encountered owing to altered pathophysiolo-
gy. Kava-kava, chaparral, and germander cause liver tox-
icity, and elevated alanine aminotransferase, aspartate ami-
notransferase, and bilirubin concentrations may be ob-
served in a healthy individual taking such herbal products.
An herbal product may be contaminated with a Western
drug, and an unexpected drug level (such as phenytoin in
a patient who never took phenytoin but took a Chinese
herb) may confuse the laboratory staff and the clinician.
Conclusions.—Use of alternative medicines may signifi-
cantly alter laboratory results, and communication among
pathologists, clinical laboratory scientists, and physicians
providing care to the patient is important in interpreting
these results.
(Arch Pathol Lab Med. 2006;130:521–528)
Herbal medicines are readily available in the United
States without a prescription. Chinese medicines are
an important component of the herbal medicines available
today. In developing countries, as much as 80% of the in-
digenous populations depend on a local traditional system
of medicine. Within the European market, herbal medi-
cines represent an important pharmaceutical market with
annual sales of US $7 billion. In the United States, the sale
of herbal medicines increased from US $200 million in
1988 to more than US $3.3 billion in 1997.1
Most people
who use herbal medicines in the United States have a col-
lege degree and fall in the age group of 25 to 49 years. In
one study, 65% of people thought that herbal medicines
were safe.1
In another recent study, Honda and Jacobson2
reported that individual psychological characteristics,
such as personality, coping mechanisms, and perceived
social support, may influence the use of herbal medicines.
Accepted for publication December 7, 2005.
From the Department of Pathology and Laboratory Medicine, Uni-
versity of Texas–Houston Medical School, Houston (Dr Dasgupta); and
the Department of Pathology, Methodist Hospital, Houston, Tex (Dr
Bernard).
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Amitava Dasgupta, PhD, Department of Pathology and Lab-
oratory Medicine, University of Texas–Houston Medical School, 6431
Fannin, MSB 2.292, Houston, TX 77030 (e-mail: Amitava.Dasgupta@
uth.tmc.edu).
The general concept often portrayed in marketing and
media that anything natural is safe is not true, and herbal
medicines like manufactured Western pharmaceuticals
can be toxic and can have significant side effects. Inap-
propriate use or overuse of herbal medicine may even
cause death. Many herbal products have been shown to
be able to cause severe toxicity (Table 1). Despite the po-
tential toxicity, there is widespread use among patients.
Gulla et al3
performed a survey of 369 patient-escort pairs
because sometimes patients coming to emergency depart-
ments are unconscious. Of these, 174 patients used herbs.
Most common was ginseng (20%) followed by echinacea
(19%), Ginkgo biloba (15%), and St John’s wort (14%).3
REGULATORY ISSUES AFFECTING HERBAL MEDICINES
The US Food and Drug Administration regulates drugs
and requires that they be both safe and effective. Most
herbal products are classified as dietary supplements or
foods and are marketed pursuant to the Dietary Supple-
ment Health and Education Act of 1994. The Food and
Drug Administration requires these products to be safe
for consumers but does not require demonstration of ef-
ficacy, as long as they are not marketed for prevention or
treatment of disease.4,5
Herbal products are regulated differently in other coun-
tries. In the United Kingdom, any product not granted a
license as a medical product by the Medicines Control
Agency is treated as a food and cannot carry any health

2. 522 Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard
Table 1. Potentially Toxic and Toxic Herbs
Herb Toxicity Intended Use (Should Anyone Use?)
Ephedra
Chan Su
Kava-kava
Comfrey
Cardiovascular
Cardiovascular
Hepatotoxicity
Hepatotoxicity
Herbal weight loss
Tonic for heart
Sleeping aid, antianxiety
Repairing of bone and muscle, prevention of kidney
stones
Germander
Chaparral
Hepatotoxicity
Hepatotoxicity, nephrotoxicity, carcinogenic
Weight loss, general tonic
General cleansing tonic, blood thinner, arthritis reme-
dies, and weight loss product
Borage Hepatotoxicity, hepatocarcinogenic Source of essential fatty acids, rheumatoid arthritis, hy-
pertension
Calamas Carcinogenic Psychoactive, not promoted in United States
Senna
Licorice
Carcinogenic, hepatotoxic
Pseudoadosteronism (sodium and water retention, hyper-
tension, heart failure)
Laxative
Treatment of peptic ulcer, flavoring agent
claim or medical advice on the label. Similarly, herbal
products are sold as dietary supplements in the Nether-
lands. In Germany, herbal monographs called the German
Commission E Monographs are prepared by an interdisci-
plinary committee using historic information; chemical,
pharmacologic, clinical, and toxicological studies; case re-
ports; epidemiologic data; and unpublished manufactur-
er’s data. If an herb has an approved monograph, it can
be marketed. Australia created a Complementary Medi-
cine Evaluation Committee in 1997 to address regulatory
issues regarding herbal remedies, and Canada has created
a Natural Health Products Directorate after restructuring
its Therapeutic Products and Foods Branch in 2000.4,5
HERBAL MEDICINES AND CLINICAL
LABORATORY TESTS
An herbal medicine can affect laboratory test results by
1 of 3 mechanisms.
1. Direct assay interference, most commonly with the
immunoassays, due to cross-reactivity of a component or
components present in the preparation. For example, a
falsely elevated digoxin level may be observed using the
fluorescence polarization immunoassay (FPIA) for digoxin
due to ingestion of the Chinese medicines Chan Su, Lu-
Shen-Wan, or Dan Shen.
2. Physiologic effects either through toxicity or enzyme
induction due to an herbal product. For example, kava-
kava causes liver toxicity, and elevated alanine amino-
transferase (ALT), aspartate aminotransferase (AST), and
bilirubin concentrations may be observed in healthy in-
dividuals taking kava-kava.
3. Effects of contaminants, since an herbal product may
contain undisclosed drugs and an unexpected drug level
(such as phenytoin in a patient who never took phenytoin
but took a Chinese herb) may confuse the laboratory staff
and the clinician.
CHINESE MEDICINE AND INTERFERENCE WITH
VARIOUS DIGOXIN IMMUNOASSAYS
Digoxin immunoassays available commercially use ei-
ther monoclonal or polyclonal antibodies directed toward
digoxin. In general, assays using polyclonal antibodies
against digoxin, such as the FPIA (rabbit polyclonal anti-
body) and microparticle enzyme immunoassay (MEIA;
both marketed by Abbott Laboratories, Abbott Park, Ill)
are more susceptible to interference by Chinese medicines
than digoxin immunoassays that use monoclonal antibod-
ies.6
Chan Su, a Chinese medicine, is prepared from the
dried white secretion of the auricular glands and the skin
glands of Chinese toads (Bufo melanostictus Schneider or
Bufo bufo gargarizans Gantor) and is a major component of
traditional Chinese medicines Lu-Shen-Wan and Kyu-
shin.7
These medicines are used for the treatment of a va-
riety of conditions, such as tonsillitis, sore throat, furuncle,
heart palpitations, and others, because of their anesthetic
and antibiotic action. Additional effects of use of Chan Su
given in small doses include stimulation of myocardial
contraction, antiinflammatory effect, and pain relief.8
The
cardiotonic effect of Chan Su is mostly due to its major
bufadienolides, such as bufalin, cinobufagin, and resibu-
fogenin. At high dosage, Chan Su causes cardiac arrhyth-
mia, breathlessness, convulsion, and coma.9
Death of a
woman after ingestion of Chinese herbal tea containing
Chan Su has been reported.10
Structural similarity be-
tween bufadienolides and digoxin accounts for the toxicity
and serum digoxin-like immunoreactivity of Chan Su.6
Fu-
shimi and Amino11
reported an apparent serum concen-
tration of digoxin of 0.51 nmol/L (0.4 ng/mL) in a healthy
volunteer after ingestion of Kyushin tablets containing
Chan Su as the major component. Panesar12
reported an
apparent digoxin concentration of 1124 pmol/L (0.88 ng/
mL) in healthy volunteers who ingested Lu-Shen-Wan
pills that contained Chan Su.
Ingestion of Chan Su and related drugs prepared from
toad venom has been shown to cause digoxin-like im-
munoreactivity in serum. Moreover, it can cause positive
interference (falsely elevated serum digoxin levels) in se-
rum digoxin measurement by FPIA (Abbott Laboratories)
and negative interference (falsely lowered serum digoxin
values) by the MEIA (Abbott Laboratories).6
Other digoxin
immunoassays, such as EMIT 2000 (Dade Behring, Deer
Park, Ill), Synchron LX system (Beckman, Brea, Calif),
Tina-quant (Roche Diagnostics, Indianapolis, Ind), and
turbidimetric (Bayer Diagnostics, Tarrytown, NY) are also
affected, but the magnitudes of interference are less sig-
nificant compared to the FPIA assay. The chemilumines-
cent assay marketed by Bayer Diagnostics is free from
such interferences.13
The interfering components in Chan
Su are very strongly bound to serum proteins and are
absent in protein-free ultrafiltrates. In contrast, digoxin is
only 25% bound to serum protein and is present in the
ultrafiltrate. Therefore, monitoring free digoxin concentra-
tion can minimize interference of Chan Su in serum di-
goxin measurements.6
Dan Shen is a Chinese medicine prepared from the root

3. Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard 523
Table 2. Interference of Herbal Products in Therapeutic Drug Monitoring of Digoxin
Herbal Product Interference Comments*
Chan Su High Chan Su has active components like bufalin that cross-react with FPIA, MEIA, Roche,
Beckman, and turbidimetric (Bayer) digoxin assay. Only Bayer’s CLIA assay has no inter-
ference.
Lu-Shen-Wan High–moderate It also has active components like bufalin that cross-react with FPIA, MEIA, Roche, Beck-
man, and turbidimetric (Bayer) digoxin assay. Only Bayer’s CLIA assay has no interfer-
ence.
Siberian ginseng Moderate Falsely elevated digoxin (FPIA) or falsely low digoxin (MEIA). No interference with EMIT,
Bayer (CLIA and turbidimetric), Roche, or Beckman assays.
Asian ginseng Moderate Falsely elevated digoxin (FPIA) or falsely low digoxin (MEIA). No interference with EMIT,
Bayer (CLIA and turbidimetric), Roche, or Beckman assays.
Dan Shen Moderate Falsely elevated digoxin (FPIA) or falsely low digoxin (MEIA). No interference with EMIT,
Bayer (CLIA and turbidimetric), Roche, or Beckman assays.
* FPIA indicates fluorescence polarization immunoassay (marketed by Abbott Laboratories), MEIA, microparticle enzyme immunoassays; CLIA,
chemiluminescent immunoassay (marketed by Bayer Diagnostics, Tarrytown, NY).
of the Chinese medicinal plant Salvia miltiorrhiza.14
This
herb has been in use in China for many centuries for treat-
ment of various cardiovascular diseases, including angina
pectoris. Dan Shen caused modest interference with poly-
clonal antibody–based digoxin immunoassays, such as
MEIA and FPIA. Chemiluminescent assay (Bayer), EMIT
2000 digoxin assay, and Roche and Beckmann digoxin as-
says are also free from interference from Dan Shen.15
In-
terference of various Chinese medicines with digoxin im-
munoassays is summarized in Table 2.
McRae16
reported an interesting case of interference of
digoxin measurement in a 74-year-old man, which was
supposedly due to ingestion of Siberian ginseng. The pa-
tient had been compliant with chronic digoxin therapy
and had maintained therapeutic levels between 0.9 and
2.2 ng/mL during a period of 10 years. However, after
ingestion of Siberian ginseng, his serum digoxin level in-
creased to 5.2 ng/mL in the absence of any signs or symp-
toms of digoxin toxicity. Following cessation of ingestion
of the ginseng, his serum digoxin level returned to pre-
vious therapeutic levels. The patient resumed taking gin-
seng and several months later, his serum digoxin level was
again elevated. Digoxin therapy was maintained at a con-
stant daily dose, the ginseng was stopped once more, and
the serum digoxin concentration again returned to thera-
peutic level.16
This is an interesting case for a number of
reasons, including that in our experience, Siberian ginseng
produces only modest interference in the FPIA and MEIA
digoxin assays.17
Asian ginseng also showed modest pos-
itive (FPIA) and modest negative (MEIA) interference.
Again EMIT 2000, Bayer (both turbidimetric and chemi-
luminescent assay), Roche (Tina-quant), and Beckman
(Synchron LX system) digoxin assays are free from inter-
ference from both Asian ginseng and Siberian ginseng.13,17
A likely explanation for the findings in this case is the
possibility that the patient ingested Siberian ginseng,
which was in reality a misidentified Chinese herb. High
interferences in digoxin measurement are more consistent
with use of Chan Su or Lu-Shen-Wan.
INTERACTION BETWEEN VARIOUS DRUGS
AND ST JOHN’S WORT
Lower Serum Levels of Drugs
Most commercially available St John’s wort preparations
in the United States are dried alcoholic extracts of hyper-
icin. Other preparations are liquid extracts of the plant.18
St John’s wort is licensed in Europe for treatment of de-
pression and anxiety, and is sold over the counter in the
United Kingdom.18
The active components of St John’s
wort induce the cytochrome P450 mixed function oxidase
(CYP3A4) enzyme system that is responsible for metabo-
lism of many drugs in the liver.19
In particular, hyperforin
is thought to be responsible for CYP3A4 induction
through activation of a nuclear steroid/pregnane and xe-
nobiotic receptor.20
St John’s wort also induces P-glycopro-
tein drug transporter and may reduce the efficacy of
drugs for which hepatic metabolism may not be the major
pathway of clearance. The component, hypericin, may be
the active ingredient that activates P-glycoprotein.21
There-
fore, self-medication with St John’s wort may cause treat-
ment failures due to increase in clearance of many pre-
scribed drugs. These include drugs in the classes of im-
munosuppressant (cyclosporine and tacrolimus), human
immunodeficiency virus (HIV) protease inhibitors, HIV
nonnucleoside reverse transcriptase inhibitors metabo-
lized via CYP3A4, and antineoplastic drugs, such as iri-
notecan and imatinib mesylate.22–24
Increased clearance of
oral contraceptives has also been reported. Unrecognized
use of St John’s wort is frequent and may have important
influences on the effectiveness and safety of drug therapy
during hospital stays.25
Examples of clinical problems encountered with use of
St John’s wort are abundant in the literature. One report
describes a 50-year-old woman who had taken St John’s
wort in a powder form (600 mg per day for 10 days) and
then took 20 mg paroxetine (Paxil). She complained of
nausea, weakness, and fatigue and became incoherent and
lethargic. She had been previously stable on paroxetine for
8 months (40 mg dose) without adverse reactions.26
Barone et al27
reported 2 cases in which renal transplant
recipients started self-medication with St John’s wort. Both
patients experienced subtherapeutic concentrations of cy-
closporine, and 1 patient developed acute graft rejection
due to low cyclosporine level. On termination of use of St
John’s wort, both patients’ cyclosporine concentrations re-
turned to therapeutic levels.27
Interaction between St John’s
wort and cyclosporine is well documented in the litera-
ture.28
Bauer et al29
concluded that St John’s wort caused
rapid and significant reduction in plasma cyclosporine
concentrations. Additionally, substantial alteration in cy-
closporine metabolite kinetics was observed.29
Mai et al30
reported that hyperforin content of St John’s wort deter-
mines the magnitude of interaction between St John’s wort

4. 524 Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard
and cyclosporine. Significant reduction in area under the
curve for tacrolimus was also observed in 10 stable renal
transplant patients receiving St John’s wort. Interestingly,
no interaction was observed with another immunosup-
pressant, mycophenolic acid.31,32
St John’s wort was shown to reduce the area under the
curve of the HIV-1 protease inhibitor indinavir by a mean
of 57% and decreased the extrapolated trough by 81%.
Reduction in indinavir levels of this magnitude are clini-
cally significant and could lead to treatment failure.33
Busti
et al34
reported that atazanavir therapy can also be affect-
ed due to simultaneous use of St John’s wort. Coadmin-
istration of lopinavir/ritonavir with St John’s wort is also
not recommended because of substantial reduction in lo-
pinavir plasma concentrations.35
Interaction between St John’s wort and theophylline has
been reported. A patient taking 300 mg of theophylline
twice daily required a dosage increase to 800 mg twice
daily to maintain her theophylline concentration at a se-
rum level of 9.2 ␮g/mL after she began taking St John’s
wort. Seven days after discontinuation of St John’s wort,
her theophylline level increased to 19.6 ␮g/mL.36
Reduced plasma level of methadone was also observed
in the presence of St John’s wort, resulting in reappearance
of withdrawal symptoms.37
Clearance of imatinib mesylate
is also increased due to administration of St John’s wort,
resulting in compromise of imatinib’s clinical efficacy.38
St
John’s wort also has significant interaction with oral con-
traceptives.39
Sugimoto et al40
reported that St John’s wort
significantly reduces plasma concentration of the choles-
terol-lowering drug simvastatin, which is metabolized by
CYP3A4 in the intestinal wall and liver. On the other
hand, St John’s wort did not influence plasma pravastatin
concentration.40
Interestingly, St John’s wort does not in-
teract with carbamazepine.41
Interaction between St John’s wort and digoxin is of clin-
ical significance. Johne et al42
reported that 10 days’ use of
St John’s wort could result in a decrease of trough serum
digoxin concentrations by 33%, and of peak digoxin con-
centrations by 26%. Digoxin is a substrate for P-glycopro-
tein, which is induced by St John’s wort. Durr et al43
also
confirmed the lower digoxin concentrations in healthy vol-
unteers who concurrently took St John’s wort. Dose and
preparation of St John’s wort also affect pharmacokinetics
of digoxin.44
Tannergren et al45
recently reported that re-
peated administration of St John’s wort significantly de-
creases bioavailability of R- and S-verapamil. This effect
is caused by induction of first-pass metabolism by
CYP3A4, most likely in the gut.45
Herbal remedies are not prepared following rigorous
pharmaceutical standards. Wide variations in the active
component of St John’s wort in various commercial prep-
arations have been reported. Draves and Walker46
reported
that in commercial tablets of St John’s wort, the percentage
of active components varied from 31.3% to 80.2% of the
claim of active ingredients on labeling on the bottle. More-
over, hyperforin, an active ingredient of St John’s wort, is
photosensitive, and active components of St John’s wort
are unstable in aqueous solution, while degradation is de-
pendent on the pH of the solution.47
Major degradation
products of hyperforin in acidic solution have been iden-
tified as furohyperforin, furohyperforin hydroperoxide,
and furohyperforin isomer a, using liquid chromatogra-
phy–mass spectrometry/mass spectrometry and nuclear
magnetic resonance.47
Because interaction between St
John’s wort and drugs may depend on the concentrations
of active components of St John’s wort, measurement of
active components of St John’s wort in human serum may
have clinical implications. Bauer et al48
described a high-
performance liquid chromatographic (HPLC) method (is-
ocratic reverse-phase HPLC) for determination of hyperi-
cin, pseudohypericin using fluorometric detection, and hy-
perforin by UV detection. The limit of detection was 0.25
ng/mL of hypericin and pseudohypericin and 10 ng/mL
for hyperforin in human plasma.48
Pirker et al49
also used
liquid extraction using n-hexane and ethyl acetate (70:30
by volume) and reverse-phase HPLC with UV fluores-
cence and mass spectrometric (electrospray ionization) de-
tection for quantification of active components of St John’s
wort in human plasma. The linearity for hypericin deter-
mination was 8.2 to 28.7 ng/mL for hypericin and 21.6 to
242.6 ng/mL for hyperforin.49
Several liquid chromato-
graphic methods have also been reported for determina-
tion of active components of St John’s wort in various com-
mercial preparations.50,51
INTERACTION OF WARFARIN WITH
HERBAL SUPPLEMENTS
Warfarin acts by antagonizing the cofactor function of
vitamin K.52
Variability in the anticoagulant response to
warfarin is an ongoing clinical dilemma. Clinical efficacy
of warfarin varies with intake of vitamin K and clearance
of warfarin via CYP2C9, which is a polymorphic gene
with variable expression. In addition, several warfarin-
herb interactions may have significant effects on warfarin
therapy. St John’s wort and ginseng can diminish warfa-
rin’s anticoagulation effect by increasing clearance through
inducing CYP2C9.53,54
Herbal remedies containing coumarin can increase the
anticoagulation of patients on warfarin. The international
normalization ratio (INR) was increased in a patient treat-
ed with warfarin for atrial fibrillation when he started tak-
ing coumarins containing herbal products boldo and fenu-
greek. Following discontinuation of herbal supplements,
his INR returned to normal after 1 week.55,56
Increased
anticoagulation due to interaction between warfarin and
Dan Shen has been reported.57–59
Two cases of increased
INR were reported after coadministration of curbicin (a
preparation containing saw palmetto, pumpkin, and vi-
tamin E). The INR normalized after discontinuation of the
herbal supplement.60
Conversely, supplements containing
vitamin K, such as green tea, can antagonize the antico-
agulant effect of warfarin.61
Samuels62
recently discussed
the effects of herbal medicines on anticoagulation therapy.
Major drug-herb interactions are summarized in Table 3.
HERBAL REMEDIES AND ABNORMAL LIVER
FUNCTION TESTS
Kava-kava is an herbal remedy taken for anxiety. How-
ever, the use of this remedy can cause severe hepatotox-
icity.63
Heavy consumption of kava has been associated
with increased concentrations of ␥-glutamyltransferase,
suggesting potential hepatotoxicity. Escher and Desmeu-
les63
described a case in which severe hepatitis was asso-
ciated with kava use. A 50-year-old man took 3 to 4 kava
capsules daily for 2 months (maximum recommended
dose 3 capsules). Liver function tests showed 60- to 70-
fold increases in AST and ALT. Tests for viral hepatitis
(hepatitis A virus, hepatitis B virus, and hepatitis C virus)
were all negative, as were tests for cytomegalovirus and

5. Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard 525
Table 3. Common Drug-Herb Interactions
Herbal Product Interacting Drug Comments
Ginseng Warfarin Ginseng may decrease effectiveness of warfarin
St John’s wort Paxil Lethargy, incoherence, nausea
Digoxin Decreased area under the curve, peak, and trough concentration of digoxin;
may reduce effectiveness of digoxin
Cyclosporine/FK 506 Lower cyclosporine: FK506 concentrations due to increased clearance; may
cause transplant rejection
Theophylline Lower concentration, thus decreases the efficacy of theophylline
Indinavir, lopinavir, ritonavir,
atazanavir
Lower concentration may cause treatment failure in patients with human im-
munodeficiency virus
Statins Reduced plasma concentrations of simvastatin, but no effect on pravastatin
Irinotecan, imatinib Reduced efficacy
R- and S-verapamil Increased clearance
Oral contraceptives Lower concentration/failed birth control
Ginkgo biloba Aspirin Bleeding because ginkgo can inhibit platelet aggregation factor
Warfarin
Thiazide
Hemorrhage
Hypertension
Kava Alprazolam Additive effects with central nervous system depressants, alcohol
Garlic Warfarin Increases effectiveness of warfarin, bleeding
Ginger Warfarin Increases effectiveness of warfarin, bleeding
Feverfew Warfarin Increases effectiveness of warfarin, bleeding
Dong quai Warfarin Dong quai contains coumarin; dong quai increases international normalized
ratio for warfarin, causes bleeding
Dan Shen Warfarin Increases effectiveness of warfarin due to reduced elimination of warfarin
Comfrey Phenobarbital Increases metabolism of comfrey, producing a lethal metabolite from pyrroli-
zidine, severe hepatotoxicity
Evening primrose
oil
Phenobarbital May lower seizure threshold, need dose increase
HIV. The patient eventually received a liver transplant.63
Humberston et al64
also reported a case of acute hepatitis
induced by kava-kava. Other cases of hepatotoxicity due
to the use of kava have been documented.65
In January
2003, kava extracts were banned in the entire European
Union and Canada, and in the United States, the Food and
Drug Administration strongly cautioned against using
kava. There have been at least 11 cases of serious hepatic
failure and 4 deaths directly linked to kava extract con-
sumption, as well as 23 reports indirectly linking kava
with hepatotoxicity.66
Anke and Ramzan67
recently re-
viewed hepatotoxicity due to use of kava.
In addition to hepatitis and liver failure due to chronic
use of kava, a recent publication reports a case of acute
kava overdose resulting in altered mental status and ataxia
similar to that seen with ethanol intoxication.68
Also, sev-
eral kava lactones may act as inhibitors of the CYP450
system (CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A9/11).
Therefore, potential drug interactions with kava are likely.
Interactions between kava and central nervous system de-
pressants, alcohol, levodopa, caffeine, anticonvulsants,
and monoamine oxidase inhibitors have been reported
and summarized in a recent review article, also by Anke
and Ramzan.69
Chaparral can be found in health food stores as cap-
sules and tablets, and is used as an antioxidant and an-
ticancer herbal product. Leaves, stems, and bark in bulk
are also available for brewing tea. However, this product
can cause severe hepatotoxicity. Several reports of chap-
arral-associated hepatitis have been reported. A 45-year-
old woman who took chaparral (160 mg/day for 10
weeks) presented with jaundice, anorexia, fatigue, nausea,
and vomiting. Liver enzymes and other liver function tests
showed abnormally high values (ALT, 1611 U/L; AST, 957
U/L; alkaline phosphatase, 265 U/L; ␥-glutamyltransfer-
ase, 993 U/L; and bilirubin, 11.6 mg/dL). Viral hepatitis,
cytomegalovirus, and Epstein-Barr virus were ruled out.
Liver biopsy showed acute inflammation with neutrophil
and lymphoplasmacytic infiltration, hepatic disarray, and
necrosis. The diagnosis was drug-induced cholestatic hep-
atitis, which in this case was due to use of chaparral.70
Gordon et al71
reported a case in which a 60-year-old
woman took chaparral for 10 months and developed se-
vere hepatitis for which no other cause was found. On
admission, her bilirubin was 12.4 mg/dL; ALT, 341 U/L;
AST, 1191 U/L; and alkaline phosphatase, 186 U/L. All
tests for viral hepatitis were negative. Eventually, this pa-
tient received a liver transplant.71
Germander has been used as a remedy for weight loss
and as a general tonic. Germander is an aromatic plant in
the ‘‘mint family,’’ and germander tea made from the ae-
rial parts of the plant has been in use for many centuries.
Several cases of liver toxicity have been reported in Eu-
rope due to ingestion of germander.72
A 55-year-old wom-
an taking 1600 mg per day of germander became jaun-
diced after 6 months. Her bilirubin was 13.9 mg/dL; AST,
1180 U/L; ALT, 1500 U/L; and alkaline phosphatase, 164
U/L. Serologic tests for all types of hepatitis were nega-
tive. Liver biopsy suggested drug-induced hepatitis. Ger-
mander therapy was discontinued and hepatitis resolved
in 2 months.73
Bosisio et al74
described an HPLC method
for detection of teucrin A, the active component of ger-
mander in beverages.
Mistletoe is a parasitic evergreen plant that lives on
trees, such as oaks, elms, firs, pines, and apple. Mistletoe
was used in the folk medicine as a digestive aid, heart
tonic, and a sedative. It was also used in treating arthritis,
hysteria and other mental disturbances, and in the treat-
ment of cancer. Usually, leaf of mistletoe is used in herbal
remedies. A 49-year-old woman presented with nausea,
general malaise, and a dull pain in the abdomen. Liver
tests suggested hepatitis (ALT, 123 U/L; lactate dehydro-

6. 526 Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard
genase, 395 U/L; and AST, 250 U/L). Liver biopsy also
suggested hepatitis. However, all tests for viral hepatitis
were negative. The patient was diagnosed with a drug-
induced hepatitis due to the use of mistletoe.75
KELP AND HYPERTHYROIDISM
Kelp (seaweed) tablets are available in health food stores
and are used as a thyroid tonic, antiinflammatory and
metabolic tonic, and also as a dietary supplement. Kelp
tablets are rich in vitamins and minerals, but also contain
substantial amounts of iodine. Teas et al76
reported that
iodine content varied widely among various commercially
available seaweed preparations, and some Asian seaweed
dishes may exceed tolerable upper iodine intake of 1100
␮g/d.
A 72-year-old woman with no history of thyroid disease
presented with typical symptoms of hyperthyroidism. She
was taking 4 to 6 kelp tablets a day for 1 year. Her thyroid-
stimulating hormone was low, 1.3 mIU/L; total T4, 14.4
␮g/dL (185.3 nmol/L), normal range up to 12.4 ␮g/dL;
and total T3, 284.2 ng/dL (4.38 nmol/L), normal range,
69.4 to 219.3 ng/dL. After cessation of ingestion of kelp
tablets, her hyperthyroidism resolved and thyroid func-
tion tests returned to normal (thyroid-stimulating hor-
mone, 3.1 mIU/L; total T4, 8.4 ␮g/dL (108.1 nmol/L); total
T3, 139.5 ng/dL (2.15 nmol/L).77
Clark et al78
studied the
effect of kelp supplementation on thyroid function in eu-
thyroid subjects and concluded that short-term dietary
supplementation with kelp significantly increases both
basal and poststimulation thyroid-stimulating hormone.
LICORICE AND HYPOKALEMIA
Several cases of licorice-induced hypokalemic myopathy
have been reported.79
Laboratory findings include mean
serum potassium level of 1.98 mEq/L, mean total creatine
kinase of 5383 U/L, plasma aldosterone activity of 2.92
ng/dL, and mean plasma rennin activity of 0.17 ng/mL/
h.79
Cheng et al80
reported a case of hypokalemia leading
to paralysis in a patient with prostate cancer. On admis-
sion, the patient’s potassium level was 1.7 mEq/L, and he
also had metabolic alkalosis (bicarbonate, 42.6 mEq/L).
Other abnormal findings were low plasma rennin activity
and a low aldosterone level in the presence of a normal
cortisol level, indicating a state of pseudohyperaldoster-
onism. The patient had consumed 8 packs of Korean herb-
al tonic (100 mL per pack) daily to treat his prostate cancer
for 2 months. A significant amount of glycyrrhizic acid
(0.23 mg/mL), an active ingredient of licorice, was de-
tected in the tonic.80
Glycyrrhizic acid inhibits the enzyme
11-␤-hydroxysteroid dehydrogenase.81
HERBAL MEDICINE AND PERIOPERATIVE PATIENTS
Use of herbal remedies by perioperative patients is a
significant problem due to potential interactions between
herbal supplements and anesthetic, as well as risk of
bleeding during and after surgery.82
In a recent survey of
patients scheduled for elective surgery, 57% of respon-
dents had used herbal supplements at some point in their
lives. Thirty-eight percent of respondents had used herbal
supplements in the previous 2 years, and 1 in 6 respon-
dents had used an herbal supplement during the month
of their surgery.83
Multiple authors have made suggestions
regarding the cessation of use of herbal supplements.
Ang-Lee et al84
recommended that garlic and ginseng
should be discontinued at least 7 days prior to surgery
because both herbs have been reported to cause bleeding.
Ginkgo biloba should also be discontinued 3 days prior to
surgery because ginkgo also inhibits platelet aggregation,
causing bleeding. Kava should be discontinued at least 24
hours before surgery because kava can increase the sed-
ative effect of anesthetics. Ma Huang (ephedra) should be
discontinued 24 hours prior to surgery because Ma Huang
increases blood pressure and heart rate. St John’s wort
should be discontinued 5 days prior to surgery because St
John’s wort induces cytochrome P450 mixed function oxi-
dase of liver that metabolizes many drugs. Therefore, con-
centrations of many drugs, such as cyclosporine, warfarin,
and steroids, can be significantly reduced by the presence
of St John’s wort. This is particularly important for trans-
plant surgery because cyclosporine is used as an immu-
nosuppressant.84
The American Society of Anesthesiolo-
gists recommends that all herbal supplements should be
discontinued 2 to 3 weeks before elective surgery.82,85
MISIDENTIFICATION AND ADULTERATION OF
HERBAL PRODUCTS
Labeling of herbal products may not accurately reflect
its content, and adverse events or interactions attributed
to a specific herb may be due to misidentification of
plants, contamination of plants with pharmaceuticals or
heavy metals, and manufacturing or quality control prob-
lems, including substitution of one herb for another.86
The
addition of pharmaceuticals to Chinese herbal products is
a serious problem. Of 2069 samples of traditional Chinese
medicines collected from 8 hospitals in Taiwan, 23.7%
contained pharmaceuticals, most commonly caffeine, acet-
aminophen, indomethacin, hydrochlorothiazide, and pred-
nisolone.86,87
Lau et al88
reported a case of phenytoin poi-
soning in a patient after using Chinese medicines. This
patient was treated with valproic acid, carbamazepine,
and phenobarbital for epilepsy, but was never prescribed
phenytoin. She consumed 3 bottles of a Chinese proprie-
tary medicine in addition to her prescribed medicines. She
showed a toxic phenytoin level of 48.5 ␮g/mL in her
blood. Analysis of her Chinese medicines showed adul-
teration with phenytoin, although the product leaflet stat-
ed that the preparation contained only Chinese herbs.88
A
fatal case of hepatic failure due to contamination of an
herbal supplement with nitrosofenfluramine has been re-
ported. Analysis of the herbal supplement also revealed
the presence of fenfluramine.89
Cole and Fetrow90
reported
the presence of colchicines in Ginkgo biloba and echinacea
preparations. They also reported a case of a 23-year-old
woman who showed a serum digoxin level of 3.66 ng/mL
after taking an herbal cleansing product. One product
named plantain was found to contain Digitalis lantana as
an unlabeled constituent.90
Heavy metal contamination is a major problem with
Asian medicines. Ko91
reported that 24 of 254 Asian patent
medicines collected from herbal stores in California con-
tained lead, 36 products contained arsenic, and 35 prod-
ucts contained mercury. Lead and heavy metal contami-
nations are common with Indian ayurvedic medicines.92
Lead poisoning due to use of ayurvedic medicine has been
documented in the literature.93,94
Cadmium, mercury, and
lead are found in various herbal products sold in Brazil.95
CONCLUDING REMARKS
Herbal medicines are crude products, often with both
active ingredients and toxic components present. Heavy

7. Arch Pathol Lab Med—Vol 130, April 2006 Herbal Medicines and Laboratory Testing—Dasgupta & Bernard 527
metal contamination, adulteration with Western pharma-
ceuticals, and prohibited animal and plant ingredients are
regularly reported in herbal remedies.96
While many man-
ufacturers of herbal remedies attempt to provide products
with consistent levels of suspected active ingredients, the
standardization techniques have uncertain effects on the
safety and efficacy of the final product.97
Therefore, phy-
sicians need to be aware of the potential use of such herbal
medicines by their patients, and abnormal laboratory tests
may serve as a clue to the clinician for relevant lines of
investigation in their patients in whom symptoms may be
related to the use of herbal products. A multidisciplinary
team approach with pharmacist, chemical pathologist, sci-
entific officer, and physician may be appropriate to deal
with toxicity and related problems due to use of herbal
medicines.98
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