Review of Abnormal Laboratory Test Results and Toxic Effects Due to Use of Herbal Medicines

Amitava Dasgupta, PhD

Disclosures

Am J Clin Pathol. 2003;120(1) 

In This Article

Effect of Herbal Medicines on Clinical Laboratory Testing

Abnormal laboratory test results due to the use of herbal medicines can be classified in 3 categories:

  1. Abnormal test results due to direct interference of a component of the herbal medicine with the assay

  2. Unexpected concentration of a therapeutic drug due to drug-herb interactions

  3. Abnormal test results due to toxic effects of the herbal product

Interference of Chinese Medicines With Digoxin Immunoassays

The Chinese medicine Chan Su is prepared from the dried white secretion of the auricular glands and the skin glands of Chinese toads (Bufo melanostictus Schneider or Bufo bufo gargarzinas Gantor). Chan Su also is a major component of the traditional Chinese medicines Lu-Shen-Wan and kyushin.[2,3] These medicines are used as remedies for tonsillitis, sore throat, furuncle, and palpitations. Chan Su also is used for stimulation of myocardial contraction and pain relief.[4] The cardiotonic effect of Chan Su is due to its major bufadienolides, such as bufalin, cinobufagin, and resibufogenin.[5] Bufalin is known to block vasodilatation and increases vasoconstriction and vascular resistance and, thus, blood pressure by inhibiting Na+,K+-ATPase.[6] At high dosages, Chan Su causes cardiac arrhythmia, breathlessness, seizure, and coma. The death of a Chinese woman after ingestion of Chinese herbal tea containing Chan Su has been reported.[7]

Structural similarity between bufadienolides and digoxin accounts for the toxic effects and serum digoxin-like immunoreactivity of Chan Su. Fushimi and Amino[8] reported a serum concentration of 0.4 ng/mL (0.51 nmol/L) in a healthy volunteer after ingestion of kyushin tablets containing Chan Su as the major component. Panesar[9] reported an apparent digoxin concentration of 0.88 ng/mL (1.1 nmol/L) in healthy volunteers who ingested Lu-Shen-Wan pills. The author used the fluorescence polarization immunoassay (FPIA) of digoxin for the study. An apparent digoxin concentration of 4.9 ng/mL (6.3 nmol/L) was reported in 1 woman who died of ingestion of Chinese herbal tea containing Chan Su.[7] Although Chan Su falsely elevates the serum digoxin concentration when the FPIA is used, negative interference of Chan Su in serum digoxin measurement has been reported with the microparticle enzyme immunoassay (MEIA, Abbott Laboratories, Chicago, IL). However, interfering components in Chan Su are bound very strongly to serum proteins, while digoxin is only 25% protein bound. Therefore, monitoring the free digoxin concentration eliminates this interference. Another way to eliminate this interference is to use the chemiluminescent assay (Bayer Diagnostics, Tarrytown, NY).[10]

Dan Shen is a Chinese medicine prepared from the root of the Chinese medicinal plant Salvia miltiorrhiza. This herb has been in use in China for many centuries for treating various cardiovascular diseases, including angina pectoris, and it now is available in the United States. More than 20 diterpene quinones known as "tanshinones" have been isolated from Dan Shen. These compounds have structural similarity with digoxin. Feeding Dan Shen to mice caused digoxin-like immunoreactivity in serum when measured by the FPIA. The presence of Dan Shen falsely elevated serum digoxin concentrations as measured by the FPIA and falsely lowered the digoxin concentrations when measured by the MEIA. However, no interference was observed when the chemiluminescent assay was used.[11,12] Interference of Dan Shen in the FPIA and MEIA can be eliminated by measuring free digoxin because the digoxin-like immunoreactive components of Dan Shen have much higher serum protein binding than digoxin. The EMIT 2000 digoxin assay and a recently FDA-approved turbidimetric digoxin immunoassay (Bayer Diagnostics) also are free from interference from Dan Shen. Interestingly, the same Chinese medicine prepared by different manufacturers showed significantly different digoxin-like immunoreactivity, presumably because Chinese medicines are not prepared by following rigorous standardization processes as used in the preparation of Western medicines.[13]

McRae[14] reported a case in which ingestion of Siberian ginseng was associated with elevated digoxin concentrations in a 74-year-old man. In this patient, the serum digoxin concentrations had been maintained between 0.9 and 2.2 ng/mL (1.2-2.8 nmol/L) for a period of 10 years. After ingestion of Siberian ginseng, his serum digoxin concentration increased to 5.2 ng/mL (6.7 nmol/L), although the patient did not experience any signs of digoxin toxicity. The patient stopped taking Siberian ginseng, and the serum digoxin concentration returned to a normal value.[14]

Our study indicates that Siberian ginseng produces only modest interference in the digoxin FPIA and MEIA. Asian ginseng also showed modest positive (FPIA) and modest negative (MEIA) interference.[15] Interferences of herbal products in therapeutic drug monitoring of digoxin are given in Table 2 .

Abnormal Drug Concentrations Due to Use of Herbal Medicines

Several herbal medicines lower the seizure threshold maintained by phenobarbital, offsetting the beneficial anticonvulsant activity. Evening primrose oil is used as a remedy for premenstrual syndrome, diabetic neuropathy, and attention-deficit/hyperactivity disorder. Evening primrose oil contains gamolenic acid that lowers the seizure threshold maintained by several anticonvulsants.[16] Borage oil (starflower) also contains gamolenic acid. Shankhapushpi, an ayurvedic medicine for epilepsy, has adversely affected the effectiveness of phenytoin. Dandekar et al[17] observed 2 patients experience loss of seizure control after self-medication with shankhapushpi. The serum phenytoin concentration dropped from 9.6 µg/mL (38.0 µmol/L) to 5.1 µg/mL (20.2 µmol/L) after ingestion of this herbal product (1 teaspoon 3 times a day).17

Warfarin. Warfarin is an anticoagulant with a narrow therapeutic range. The drug has potentially serious consequences if bleeding complications develop or if a subtherapeutic level occurs, thus failing to protect the patient from thromboembolic events. Several herbs interact with warfarin. The herbs that may increase the risk of bleeding (potentiate effects of warfarin) include angelica root, arnica flower, ansine, bogbean, borage seed oil, capsicum, feverfew, garlic, ginger, ginkgo, horse chestnut, licorice root, and willow bark. The herbs with documented interaction with warfarin include Dan Shen, ginseng, Siberian ginseng, Devil's claw, and dong quai, among others.[18]

A 47-year-old man with a mechanical heart valve took warfarin for 5 years and had an average international normalized ratio (INR) of 4. Within 2 weeks of using ginseng, his INR dropped to 1.5, but 2 weeks after discontinuing ginseng use, it returned to 3.3. Fortunately, no adverse effects occurred during the 2 weeks with a subtherapeutic INR.[19] A subtherapeutic INR due to the intake of soy protein in the form of soy milk also has been reported in a 70-year-old man. INR values returned to normal 2 weeks after discontinuation of soy milk.[20] Conversely Dan Shen caused inappropriately increased anticoagulation (INR values ranging from 5.5-8.4) in patients taking warfarin.[21,22] Apart from inhibition of platelet aggregation, Dan Shen also promotes fibrinolysis due to antithrombin III-like activities. Dan Shen increases the concentration of warfarin owing to a decrease in clearance.[22]

Dong quai is a Chinese medicine used for treatment of menstrual cramps, irregular menses, and menopausal symptoms. A 46-year-old woman with stabilized atrial fibrillation who was taking warfarin experienced a greater than 2-fold rise in prothrombin time (23.5 seconds; baseline, 16.2 seconds) and INR (4.05, baseline value, 1.89) after taking dong quai for 4 weeks. A month later, her INR was 4.9 and the prothrombin time was 27.0 seconds. At that time, the patient admitted taking dong quai. The patient was advised to discontinue dong quai, and her INR was 2.48 and the prothrombin time was 18.5 seconds 4 weeks after withdrawal of the herb.[23] Dong quai contains coumarins, which are natural vitamin K antagonists.[24] Boldo-fenugreek also increases INR and bleeding time in patients taking warfarin.[25]

Licorice. Licorice may offset the ability of spironolactones to reduce blood pressure. Licorice is used as an anti-inflammatory herb and also as a remedy for gastric and peptic ulcers. Carbenoxolone, one of the components of licorice, can elevate blood pressure and cause hypokalemia. However, discontinuation of licorice results in the return of blood pressure to normal.[26]

Significantly Lower Concentrations of Drugs Due to Concurrent Use of St John's Wort

St John's wort is prepared from Hypericum, a perennial aromatic shrub with bright yellow flowers that bloom from June to September. The flowers are believed to be most abundant and brightest around June 24, the day traditionally believed to be the birthday of John the Baptist. Therefore, the name St John's wort became popular for this herbal product. Many chemicals have been isolated from St John's wort, including hypericin, pseudohypericin, quercetin, isoquercitrin, rutin, amentoflavone, hyperforin, other flavonoids, and xanthones. Interestingly melatonin, a human pineal gland hormone, is also found in St John's wort.[27] The mechanism of action of St John's wort is not well established.[28]

Several reports describe unexpected low concentrations of certain therapeutic drugs due to concurrent use of St John's wort. Johne et al[29] reported that 10 days' use of St John's wort resulted in a decrease of trough serum digoxin concentrations by 33% and peak digoxin concentration by 26%. Durr et al[30] confirmed the lower digoxin concentrations in healthy volunteers who concurrently took St John's wort. The authors also demonstrated that St John's wort activates cytochrome P-450 mixed-function oxidase liver enzymes (CYP3A4) responsible for metabolism of digoxin and many other drugs.[30] Barone et al[31] reported 2 cases in which renal transplant recipients started self-medication with St John's wort. Both patients experienced subtherapeutic concentrations of cyclosporine, and in 1 patient, acute graft rejection developed owing to the low cyclosporine concentration. In both patients, termination of the use of St John's wort returned the cyclosporine concentrations to therapeutic levels.[31] St John's wort also reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% and decreased the extrapolated trough by 81%. A reduction in indinavir concentration of this magnitude could lead to treatment failure.[32] A case report describes an interaction between St John's wort and theophylline. After she began taking St John's wort, a patient who had been taking 300 mg of theophylline twice daily required a dosage increase to 800 mg twice daily to maintain a serum theophylline concentration of 9.2 µg/mL (51 µmol/L). Seven days after discontinuation of St John's wort, her theophylline concentration increased to 19.6 µg/mL (109 µmol/L).[33]

Fugh-Berman[34] and later Fugh-Berman and Ernst[35] have written reviews on interactions between herbs and drugs. The most common interactions between herbs and drugs are summarized in Table 3 .

Unexpected Presence of a Drug in a Patient Who Never Used That Drug: Herbal Medicines Adulterated With Western Medicines

The adulteration of Chinese herbal products with Western drugs is a serious problem. Of 2,069 samples of traditional Chinese medicines obtained from 8 hospitals in Taiwan, 23.7% contained pharmaceuticals, most commonly caffeine, acetaminophen, indomethacin, hydrochlorothiazide, and prednisolone.[36] Nonsteroidal anti-inflammatory drugs and benzodiazepines have been found in many Chinese medicines sold outside Asia. These herbs include Miracle-Herb, tung shueh, and Cuifong Toukuwan.[37] Heavy metal contamination also was found in herbal products. Ko[38] reported that 24 of 254 Asian patented medicines obtained from herbal stores in California contained lead, 36 products contained arsenic, and 35 products contained mercury.

Nelson et al[39] reported a case of aplastic anemia associated with the use of herbal medication in a 12-year-old boy. The authors demonstrated the presence of phenylbutazone in the herbal preparation, but that medication was not listed as an ingredient in the package insert. The boy had a hemoglobin concentration of 8 g/dL (80 g/L), a neutrophil count of 200/mL, and a platelet count of 5,000/mL. These hematologic abnormalities are related to phenylbutazone toxicity.[39] Lau et al[40] reported a case in which a 33-year-old patient had a serum phenytoin concentration of 48.5 µg/mL (192 µmol/L). The patient had a history of a seizure disorder that was managed with 400 mg sodium valproate 3 times a day, 200 mg of carbamazepine twice a day, and 150 mg of phenobarbital every evening. No phenytoin was given. The patient consumed a proprietary Chinese medicine before admission to the hospital. The manufacturer's information leaflets stated that the capsules contained pure Chinese medicines and were effective for controlling epilepsy.[40] Goudie and Kaye[41] reported a case of severe hypoglycemia in a patient (fasting glucose level, 37.8 mg/dL [2.1 mmol/L]) due to use of a Chinese medicine, ZhenQi, for diabetes. Analysis of this herbal medicine showed the presence of glyburide, a sulfonylurea. A sulfonylurea overdose can lead to profound hypoglycemia.[41]

Abnormal Laboratory Test Results Due to Toxic Effects of Herbal Medicines

Kava-Kava and Abnormal Liver Function Test Results. Kava is an herbal sedative with a purported antianxiety or calming effect. Kava is prepared from a South Pacific plant (Piper mesthysticum). The main bioactive compounds include yangonin, desmethoxyyangonin, 11-methoxyyangonin, kavain, and dihydroxykavin. These components are present in the lipid-soluble kava extract or kava resin.[42]

Kava can have additive effects with central nervous system depressants. A patient who was taking alprazolam (Xanax), cimetidine, and terazosin became lethargic and disoriented after ingesting kava.[43] Kava lactones can inhibit cytochrome P-450 activities and have a potential for interaction with drugs that are metabolized by the liver.[44] Heavy consumption of kava has been associated with increased concentrations of -glutamyltransferase. Escher et al[45] 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 aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations. Blood tests were negative for hepatitis, cytomegalovirus, and HIV. The patient eventually received a liver transplant.[45] Because of the potential for toxic effects on the liver, the FDA warned the public against the use of kava-kava.[46]

Chaparral and Abnormal Liver Function Test Results. Chaparral can be found in health food stores as capsules and tablets and is used as an antioxidant and an anticancer herbal product. Leaves, stems, and bark also are available in bulk for brewing tea. Chaparral-associated hepatitis has been reported. A 45-year-old woman who took 160 mg/d of chaparral for 10 weeks sought care because of jaundice, anorexia, fatigue, nausea, and vomiting. The results of liver enzyme and other liver function tests were abnormally high (ALT, 1,611 U/L; AST, 957 U/L; alkaline phosphatase, 265 U/L; g-glutamyltransferase, 993 U/L; and bilirubin, 11.6 mg/dL [198 µmol/L]). Viral hepatitis, cytomegalovirus, and Epstein-Barr virus were ruled out. Liver biopsy showed acute inflammation with neutrophil and lymphoplasmacytic infiltration, hepatic disarray, and necrosis.[47] Gordon et al[48] reported a case in which hepatitis developed in a 60-year-old woman owing to the use of chaparral for 10 months. Despite aggressive therapy, the condition of the patient deteriorated, and she required orthotopic liver transplantation.[48] Other cases of toxic effects on the liver due to chaparral have been reported.[49] The FDA has warned the public about the dangers of consuming chaparral.

Mistletoe and Liver Damage. Mistletoe is a parasitic evergreen plant that lives on trees such as oaks, elms, firs, pines, and apple. Mistletoe was used in folk medicine as a digestive aid, heart tonic, and sedative. Mistletoe berries are poisonous. In a 49-year-old woman with nausea, general malaise, and dull abdominal pain, the results of liver function tests suggested hepatitis (ALT, 123 U/L; lactate dehydrogenase, 395 U/L; AST, 250 U/L). Liver biopsy also suggested hepatitis. However, all serologic tests for hepatitis were negative. The patient had drug-induced hepatitis probably due to mistletoe.[50]

Germander and Elevated Liver Enzyme Levels. Germander has been used as a remedy for weight loss and as a general tonic. Germander tea is made from the aerial parts of the plant and has been in use for centuries. Capsules made from germander powder also are available in health food stores. Twenty-six cases of germander-induced hepatotoxicity have been reported in Europe. A 55-year-old woman taking 1,600 mg per day of germander became jaundiced after 6 months. Laboratory results were as follows: bilirubin concentration, 13.9 mg/dL (238 µmol/L); AST, 1,180 U/L; ALT, 1,500 U/L; alkaline phosphatase, 164 U/L. Serologic tests for all types of hepatitis were negative. A liver biopsy suggested drug-induced hepatitis. Germander therapy was discontinued, and the hepatitis resolved in 2 months.[51] Acute cholestatic hepatitis with the transient appearance of antimitochondrial antibody also has been reported due to germander.[52]

Comfrey and Liver Damage. The regular use of comfrey is a potential health risk owing to the presence of pyrrolizidine alkaloids. These alkaloids have hepatotoxic effects in animals and humans and also induce tumors in animals.[53] Ridker et al[54] documented hepatic veno-occlusive disease associated with consumption of comfrey roots. Long-term studies in animals have confirmed the carcinogenicity of comfrey in animal models.[55] A study showed that phenobarbital induced the metabolism of pyrrolizidine alkaloids to a lethal metabolite.[56] Stickel and Seitz[57] commented on serious hazards associated with the use of comfrey.

Kelp and Abnormal Thyroid Profile. Kelp (seaweed) tablets are available in health food stores and are used as a thyroid tonic, an anti-inflammatory, and a metabolic tonic. Kelp tablets are rich in vitamins and minerals but also contain a substantial amount of iodine (each tablet contains approximately 0.7 mg of iodine). A 72-year-old woman with no history of thyroid disease had the typical symptoms of hyperthyroidism. She had been taking 4 to 6 kelp tablets a day for 1 year. Her thyrotropin concentration was low (1.3 µIU/L); the total thyroxine level was 14.4 µg/dL (185.3 nmol/L; reference range, up to 12.4 µg/dL [160 nmol/L]); and the total triiodothyronine level was 284 ng/dL (4.38 nmol/L; reference range, 69-219 ng/dL [1.07-3.38 nmol/L]). After discontinuing the kelp tablets, her hyperthyroidism resolved, and thyroid function test results returned to normal (thyrotropin, 3.1 µIU/L; total thyroxine, 8.4 µg/dL [108.1 nmol/L]; total triiodothyronine, 140 ng/dL [2.15 nmol/L]).[58]

Chromium and Hypoglycemic Herbs: Abnormally Low Glucose Concentrations. Athletes and body builders use chromium for improving performance. Chromium is a trace metal that has an effect on the glucose-insulin system. Bunner and McGinnis[59] described a case in which a 29-year-old man was referred to the outpatient neuropsychiatry clinic because of his unusual behavior at work. The patient had been diagnosed with diabetes mellitus at the age of 20 years and was taking 9 U of NPH insulin (Humulin N) per day. His blood glucose concentrations ranged between 90 and 120 mg/dL (5.0-6.7 mmol/L). During the episode, he was agitated, and on admission to the hospital, his blood glucose concentration was 30 mg/dL (1.7 mmol/L). The patient was taking 200 to 300 µg of chromium 2 to 3 times per week for bodybuilding, and the hypoglycemic episode most likely was linked to chromium use.[59] Anderson[60] reviewed the effect of chromium on the glucose-insulin system in subjects with hypoglycemia, hyperglycemia, diabetes mellitus, and hyperlipidemia. Ginseng, whose activity has been attributed to 2% to 3% ginsenosides, has been associated with hypoglycemic properties. Fenugreek, ginger, nettle, sage, and devil's claw also can affect glucose levels. Karela has been shown to improve glucose tolerance.[61]

Zhang et al[62] reported that male subjects showed a significant reduction in the glucose concentration after taking garlic oil, but female subjects showed an increase. However, a small adverse effect on the lipid profile was observed in male subjects, while females had beneficial effects on the lipid profile following the use of garlic oil for 11 weeks.[62]

Licorice and Hypokalemia. Fifty-nine licorice-induced hypokalemic myopathy cases have been reported. Laboratory findings include a mean serum potassium concentration of 1.98 mEq/L (1.98 mmol/L), a mean total creatine kinase concentration of 5,383 U/L, plasma aldosterone activity of 2.92 ng/dL (0.08 nmol/L), and a mean plasma renin activity of 0.17 ng/mL/h (0.13 · L-1 · h-1).[63] Licorice-induced pseudoaldosteronism also has been reported.[64] Licorice contains glycyrrhizic acid, which inhibits the enzyme 11- -hydroxysteroid dehydrogenase (converts cortisol to cortisone). Therefore, concentrations of cortisol may increase. Renin activity and aldosterone concentrations in serum usually decrease.

Lead Poisoning Due to Herbs: Abnormal Laboratory Test Results. Unexpected lead poisoning may occur owing to the use of herbal medicines contaminated with lead.[38] Anderson et al[65] reported a case of lead poisoning in a 23-year-old man with a 5-day history of severe, diffuse abdominal pain, vomiting, and diarrhea followed by constipation. The laboratory investigation showed elevated bilirubin and alanine transaminase concentrations, but the alkaline phosphatase activity was normal. The urinary porphyrin screen was positive, indicating the possibility of acute porphyria. Further investigation showed elevated concentrations of zinc protoporphyrin (145 µmol/L; reference range, <70 µmol/L) and lead (77 µg/dL [3.7 µmol/L]). The patient was taking an herb purchased in India. After discontinuation of the herbal medicine, his blood concentrations of lead and zinc protoporphyrin were reduced significantly.[65] Wu et al[66] reported 2 cases of lead poisoning due to the Chinese herbal medicine Cordyceps. One patient had a blood lead concentration of 130 µg/dL (6.3 µmol/L), and another patient had a lead concentration of 46 µg/dL (2.2 µmol/L). The lead content in the Chinese medicine was found to be as high as 20,000 ppm.[66]

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