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 several 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 Medline. The authors own publications were also included. Important results were then synthesized.
Data Synthesis.Falsely elevated or falsely lowered digoxin 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 Johns 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 combination with St Johns wort. Abnormal laboratory results
may also be encountered owing to altered pathophysiology. Kava-kava, chaparral, and germander cause liver toxicity, and elevated alanine aminotransferase, aspartate aminotransferase, and bilirubin concentrations may be observed 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 significantly 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;130:521528)

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. Inappropriate 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 potential toxicity, there is widespread use among patients.
Gulla et al3 performed a survey of 369 patient-escort pairs
because sometimes patients coming to emergency departments are unconscious. Of these, 174 patients used herbs.
Most common was ginseng (20%) followed by echinacea
(19%), Ginkgo biloba (15%), and St Johns wort (14%).3

erbal 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 indigenous populations depend on a local traditional system
of medicine. Within the European market, herbal medicines 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 college 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.

REGULATORY ISSUES AFFECTING HERBAL MEDICINES

Accepted for publication December 7, 2005.

From the Department of Pathology and Laboratory Medicine, University of TexasHouston 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 Laboratory Medicine, University of TexasHouston Medical School, 6431
Fannin, MSB 2.292, Houston, TX 77030 (e-mail: Amitava.Dasgupta@
uth.tmc.edu).

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 Supplement 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 efficacy, as long as they are not marketed for prevention or
treatment of disease.4,5
Herbal products are regulated differently in other countries. 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

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Table 1. Potentially Toxic and Toxic Herbs

Herb

Toxicity

Intended Use (Should Anyone Use?)

Ephedra
Chan Su
Kava-kava
Comfrey

Cardiovascular
Cardiovascular
Hepatotoxicity
Hepatotoxicity

Germander
Chaparral

Hepatotoxicity
Hepatotoxicity, nephrotoxicity, carcinogenic

Borage

Hepatotoxicity, hepatocarcinogenic

Calamas
Senna
Licorice

Carcinogenic
Carcinogenic, hepatotoxic
Pseudoadosteronism (sodium and water retention, hypertension, heart failure)

claim or medical advice on the label. Similarly, herbal

products are sold as dietary supplements in the Netherlands. In Germany, herbal monographs called the German
Commission E Monographs are prepared by an interdisciplinary committee using historic information; chemical,
pharmacologic, clinical, and toxicological studies; case reports; epidemiologic data; and unpublished manufacturers data. If an herb has an approved monograph, it can
be marketed. Australia created a Complementary Medicine 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, LuShen-Wan, or Dan Shen.
2. Physiologic effects either through toxicity or enzyme
induction due to an herbal product. For example, kavakava causes liver toxicity, and elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and
bilirubin concentrations may be observed in healthy individuals 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 either monoclonal or polyclonal antibodies directed toward
digoxin. In general, assays using polyclonal antibodies
against digoxin, such as the FPIA (rabbit polyclonal antibody) 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 antibodies.6
522 Arch Pathol Lab MedVol 130, April 2006

Herbal weight loss

Tonic for heart
Sleeping aid, antianxiety
Repairing of bone and muscle, prevention of kidney
stones
Weight loss, general tonic
General cleansing tonic, blood thinner, arthritis remedies, and weight loss product
Source of essential fatty acids, rheumatoid arthritis, hypertension
Psychoactive, not promoted in United States
Laxative
Treatment of peptic ulcer, flavoring agent

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 Kyushin.7 These medicines are used for the treatment of a variety 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 resibufogenin. At high dosage, Chan Su causes cardiac arrhythmia, breathlessness, convulsion, and coma.9 Death of a
woman after ingestion of Chinese herbal tea containing
Chan Su has been reported.10 Structural similarity between bufadienolides and digoxin accounts for the toxicity
and serum digoxin-like immunoreactivity of Chan Su.6 Fushimi and Amino11 reported an apparent serum concentration 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 immunoreactivity in serum. Moreover, it can cause positive
interference (falsely elevated serum digoxin levels) in serum 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 significant compared to the FPIA assay. The chemiluminescent 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 concentration can minimize interference of Chan Su in serum digoxin measurements.6
Dan Shen is a Chinese medicine prepared from the root
Herbal Medicines and Laboratory TestingDasgupta & Bernard

Table 2. Interference of Herbal Products in Therapeutic Drug Monitoring of Digoxin

Herbal Product

Chan Su

Interference

Comments*

High

Chan Su has active components like bufalin that cross-react with FPIA, MEIA, Roche,
Beckman, and turbidimetric (Bayer) digoxin assay. Only Bayers CLIA assay has no interference.
Lu-Shen-Wan
Highmoderate
It also has active components like bufalin that cross-react with FPIA, MEIA, Roche, Beckman, and turbidimetric (Bayer) digoxin assay. Only Bayers CLIA assay has no interference.
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 treatment of various cardiovascular diseases, including angina
pectoris. Dan Shen caused modest interference with polyclonal antibodybased digoxin immunoassays, such as
MEIA and FPIA. Chemiluminescent assay (Bayer), EMIT
2000 digoxin assay, and Roche and Beckmann digoxin assays are also free from interference from Dan Shen.15 Interference of various Chinese medicines with digoxin immunoassays 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 patient 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 increased to 5.2 ng/mL in the absence of any signs or symptoms of digoxin toxicity. Following cessation of ingestion
of the ginseng, his serum digoxin level returned to previous therapeutic levels. The patient resumed taking ginseng and several months later, his serum digoxin level was
again elevated. Digoxin therapy was maintained at a constant daily dose, the ginseng was stopped once more, and
the serum digoxin concentration again returned to therapeutic 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 positive (FPIA) and modest negative (MEIA) interference.
Again EMIT 2000, Bayer (both turbidimetric and chemiluminescent assay), Roche (Tina-quant), and Beckman
(Synchron LX system) digoxin assays are free from interference 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.

Most commercially available St Johns wort preparations

in the United States are dried alcoholic extracts of hypericin. Other preparations are liquid extracts of the plant.18

St Johns wort is licensed in Europe for treatment of depression and anxiety, and is sold over the counter in the
United Kingdom.18 The active components of St Johns
wort induce the cytochrome P450 mixed function oxidase
(CYP3A4) enzyme system that is responsible for metabolism 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 xenobiotic receptor.20 St Johns wort also induces P-glycoprotein 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 Therefore, self-medication with St Johns wort may cause treatment failures due to increase in clearance of many prescribed drugs. These include drugs in the classes of immunosuppressant (cyclosporine and tacrolimus), human
immunodeficiency virus (HIV) protease inhibitors, HIV
nonnucleoside reverse transcriptase inhibitors metabolized via CYP3A4, and antineoplastic drugs, such as irinotecan and imatinib mesylate.2224 Increased clearance of
oral contraceptives has also been reported. Unrecognized
use of St Johns 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 Johns wort are abundant in the literature. One report
describes a 50-year-old woman who had taken St Johns
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 Johns wort. Both
patients experienced subtherapeutic concentrations of cyclosporine, and 1 patient developed acute graft rejection
due to low cyclosporine level. On termination of use of St
Johns wort, both patients cyclosporine concentrations returned to therapeutic levels.27 Interaction between St Johns
wort and cyclosporine is well documented in the literature.28 Bauer et al29 concluded that St Johns wort caused
rapid and significant reduction in plasma cyclosporine
concentrations. Additionally, substantial alteration in cyclosporine metabolite kinetics was observed.29 Mai et al30
reported that hyperforin content of St Johns wort determines the magnitude of interaction between St Johns wort

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INTERACTION BETWEEN VARIOUS DRUGS

AND ST JOHNS WORT
Lower Serum Levels of Drugs

523

and cyclosporine. Significant reduction in area under the

curve for tacrolimus was also observed in 10 stable renal
transplant patients receiving St Johns wort. Interestingly,
no interaction was observed with another immunosuppressant, mycophenolic acid.31,32
St Johns 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 clinically significant and could lead to treatment failure.33 Busti
et al34 reported that atazanavir therapy can also be affected due to simultaneous use of St Johns wort. Coadministration of lopinavir/ritonavir with St Johns wort is also
not recommended because of substantial reduction in lopinavir plasma concentrations.35
Interaction between St Johns 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 serum level of 9.2 g/mL after she began taking St Johns
wort. Seven days after discontinuation of St Johns wort,
her theophylline level increased to 19.6 g/mL.36
Reduced plasma level of methadone was also observed
in the presence of St Johns wort, resulting in reappearance
of withdrawal symptoms.37 Clearance of imatinib mesylate
is also increased due to administration of St Johns wort,
resulting in compromise of imatinibs clinical efficacy.38 St
Johns wort also has significant interaction with oral contraceptives.39 Sugimoto et al40 reported that St Johns wort
significantly reduces plasma concentration of the cholesterol-lowering drug simvastatin, which is metabolized by
CYP3A4 in the intestinal wall and liver. On the other
hand, St Johns wort did not influence plasma pravastatin
concentration.40 Interestingly, St Johns wort does not interact with carbamazepine.41
Interaction between St Johns wort and digoxin is of clinical significance. Johne et al42 reported that 10 days use of
St Johns wort could result in a decrease of trough serum
digoxin concentrations by 33%, and of peak digoxin concentrations by 26%. Digoxin is a substrate for P-glycoprotein, which is induced by St Johns wort. Durr et al43 also
confirmed the lower digoxin concentrations in healthy volunteers who concurrently took St Johns wort. Dose and
preparation of St Johns wort also affect pharmacokinetics
of digoxin.44 Tannergren et al45 recently reported that repeated administration of St Johns wort significantly decreases 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 Johns wort in various commercial preparations have been reported. Draves and Walker46 reported
that in commercial tablets of St Johns wort, the percentage
of active components varied from 31.3% to 80.2% of the
claim of active ingredients on labeling on the bottle. Moreover, hyperforin, an active ingredient of St Johns wort, is
photosensitive, and active components of St Johns wort
are unstable in aqueous solution, while degradation is dependent on the pH of the solution.47 Major degradation
products of hyperforin in acidic solution have been identified as furohyperforin, furohyperforin hydroperoxide,
and furohyperforin isomer a, using liquid chromatographymass spectrometry/mass spectrometry and nuclear
magnetic resonance.47 Because interaction between St
524 Arch Pathol Lab MedVol 130, April 2006

Johns wort and drugs may depend on the concentrations

of active components of St Johns wort, measurement of
active components of St Johns wort in human serum may
have clinical implications. Bauer et al48 described a highperformance liquid chromatographic (HPLC) method (isocratic reverse-phase HPLC) for determination of hypericin, pseudohypericin using fluorometric detection, and hyperforin 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 fluorescence and mass spectrometric (electrospray ionization) detection for quantification of active components of St Johns
wort in human plasma. The linearity for hypericin determination was 8.2 to 28.7 ng/mL for hypericin and 21.6 to
242.6 ng/mL for hyperforin.49 Several liquid chromatographic methods have also been reported for determination of active components of St Johns wort in various commercial 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 warfarinherb interactions may have significant effects on warfarin
therapy. St Johns wort and ginseng can diminish warfarins 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 treated with warfarin for atrial fibrillation when he started taking coumarins containing herbal products boldo and fenugreek. 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.5759 Two cases of increased
INR were reported after coadministration of curbicin (a
preparation containing saw palmetto, pumpkin, and vitamin E). The INR normalized after discontinuation of the
herbal supplement.60 Conversely, supplements containing
vitamin K, such as green tea, can antagonize the anticoagulant 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. However, the use of this remedy can cause severe hepatotoxicity.63 Heavy consumption of kava has been associated
with increased concentrations of -glutamyltransferase,
suggesting potential hepatotoxicity. Escher and Desmeules63 described a case in which severe hepatitis was associated 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 70fold 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
Herbal Medicines and Laboratory TestingDasgupta & Bernard

Table 3. Common Drug-Herb Interactions

Herbal Product

Ginseng
St Johns wort

Interacting Drug

Warfarin
Paxil
Digoxin
Cyclosporine/FK 506

Kava
Garlic
Ginger
Feverfew
Dong quai

Theophylline
Indinavir, lopinavir, ritonavir,
atazanavir
Statins
Irinotecan, imatinib
R- and S-verapamil
Oral contraceptives
Aspirin
Warfarin
Thiazide
Alprazolam
Warfarin
Warfarin
Warfarin
Warfarin

Dan Shen
Comfrey

Warfarin
Phenobarbital

Evening primrose
oil

Phenobarbital

Ginkgo biloba

Comments

Ginseng may decrease effectiveness of warfarin

Lethargy, incoherence, nausea
Decreased area under the curve, peak, and trough concentration of digoxin;
may reduce effectiveness of digoxin
Lower cyclosporine: FK506 concentrations due to increased clearance; may
cause transplant rejection
Lower concentration, thus decreases the efficacy of theophylline
Lower concentration may cause treatment failure in patients with human immunodeficiency virus
Reduced plasma concentrations of simvastatin, but no effect on pravastatin
Reduced efficacy
Increased clearance
Lower concentration/failed birth control
Bleeding because ginkgo can inhibit platelet aggregation factor
Hemorrhage
Hypertension
Additive effects with central nervous system depressants, alcohol
Increases effectiveness of warfarin, bleeding
Increases effectiveness of warfarin, bleeding
Increases effectiveness of warfarin, bleeding
Dong quai contains coumarin; dong quai increases international normalized
ratio for warfarin, causes bleeding
Increases effectiveness of warfarin due to reduced elimination of warfarin
Increases metabolism of comfrey, producing a lethal metabolite from pyrrolizidine, severe hepatotoxicity
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 consumption, as well as 23 reports indirectly linking kava
with hepatotoxicity.66 Anke and Ramzan67 recently reviewed 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, several 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 depressants, 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 capsules and tablets, and is used as an antioxidant and anticancer herbal product. Leaves, stems, and bark in bulk
are also available for brewing tea. However, this product
can cause severe hepatotoxicity. Several reports of chaparral-associated hepatitis have been reported. A 45-yearold 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; -glutamyltransferase, 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 hepatitis, 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 severe 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 patient 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 aerial parts of the plant has been in use for many centuries.
Several cases of liver toxicity have been reported in Europe due to ingestion of germander.72 A 55-year-old woman taking 1600 mg per day of germander became jaundiced 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 negative. Liver biopsy suggested drug-induced hepatitis. Germander 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 germander 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 treatment 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-

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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 druginduced 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 thyroidstimulating 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 function tests returned to normal (thyroid-stimulating hormone, 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 euthyroid 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 admission, the patients 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 pseudohyperaldosteronism. The patient had consumed 8 packs of Korean herbal 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 detected 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 respondents 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 respondents 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
526 Arch Pathol Lab MedVol 130, April 2006

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 sedative effect of anesthetics. Ma Huang (ephedra) should be
discontinued 24 hours prior to surgery because Ma Huang
increases blood pressure and heart rate. St Johns wort
should be discontinued 5 days prior to surgery because St
Johns wort induces cytochrome P450 mixed function oxidase of liver that metabolizes many drugs. Therefore, concentrations of many drugs, such as cyclosporine, warfarin,
and steroids, can be significantly reduced by the presence
of St Johns wort. This is particularly important for transplant surgery because cyclosporine is used as an immunosuppressant.84 The American Society of Anesthesiologists 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 problems, 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, acetaminophen, indomethacin, hydrochlorothiazide, and prednisolone.86,87 Lau et al88 reported a case of phenytoin poisoning 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 proprietary 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 adulteration with phenytoin, although the product leaflet stated 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 reported. 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 contained lead, 36 products contained arsenic, and 35 products contained mercury. Lead and heavy metal contaminations 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
Herbal Medicines and Laboratory TestingDasgupta & Bernard

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metal contamination, adulteration with Western pharmaceuticals, and prohibited animal and plant ingredients are
regularly reported in herbal remedies.96 While many manufacturers 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, physicians 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, scientific officer, and physician may be appropriate to deal
with toxicity and related problems due to use of herbal
medicines.98
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