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 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 Med- line. The authors’ own publications were also included. Im- portant 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 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 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;130:521–528) 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 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 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 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 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 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

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 remedies, and weight loss product Borage Hepatotoxicity, hepatocarcinogenic Source of essential fatty acids, rheumatoid arthritis, hypertension Calamas Carcinogenic Psychoactive, not promoted in United States Senna Licorice Carcinogenic, hepatotoxic Pseudoadosteronism (sodium and water retention, hypertension, 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 reports; 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 aminotransferase (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 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 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 between bufadienolides and digoxin accounts for the toxicity and serum digoxin-like immunoreactivity of Chan Su.6 Fu- shimi 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

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 interference. 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 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 antibody–based 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 In- terference 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 con- stant 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. 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 hypericin. 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 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 xe- nobiotic receptor.20 St John’s 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 There- fore, self-medication with St John’s wort may cause treatment failures due to increase in clearance of many prescribed drugs. These include drugs in the classes of im- munosuppressant (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.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 cyclosporine, 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 returned to therapeutic levels.27 Interaction between St John’s wort and cyclosporine is well documented in the literature.28 Bauer et al29 concluded that St John’s 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 John’s wort determines 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 affected 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 lopinavir 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 serum 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 contraceptives.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 interact with carbamazepine.41 Interaction between St John’s wort and digoxin is of clinical 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 concentrations by 26%. Digoxin is a substrate for P-glycoprotein, which is induced by St John’s wort. Durr et al43 also confirmed the lower digoxin concentrations in healthy volunteers 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 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 John’s wort in various commercial preparations 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 chromatography–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 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 John’s 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 John’s 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 warfarin- herb interactions may have significant effects on warfarin therapy. St John’s wort and ginseng can diminish warfarin’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 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.57–59 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. How- ever, 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 Desmeu- les63 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 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 immunodeficiency 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 consumption, 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, 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 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 chaparral-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; ␥-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 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 woman 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 negative. 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 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-

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 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 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 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 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 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 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 John’s wort should be discontinued 5 days prior to surgery because St John’s 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 John’s wort. This is particularly important for transplant 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 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, acet- aminophen, indomethacin, hydrochlorothiazide, and pred- nisolone.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 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 adulteration 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 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 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 pharmaceuticals, 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, 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. 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