Review of Abnormal Laboratory Test Results (part 2)
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:
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. 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. The cardiotonic effect of Chan Su is due to its major bufadienolides, such as bufalin, cinobufagin, and resibufogenin. Bufalin is known to block vasodilatation and increases vasoconstriction and vascular resistance and, thus, blood pressure by inhibiting Na+,K+-ATPase. 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.
Structural similarity between bufadienolides and digoxin accounts for the toxic effects and serum digoxin-like immunoreactivity of Chan Su. Fushimi and Amino 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 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. 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).
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. 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.
McRae 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.
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. Interferences of herbal products in therapeutic drug monitoring of digoxin are given in Table 2.
FPIA, fluorescence polarization immunoassay; MEIA, microparticle enzyme immunoassay. *Bayer Diagnostics, Tarrytown, NY; Roche Diagnostics, Indianapolis, IN; Beckman Coulter, Fullerton, CA.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
Herbal Product
Level of Interference Comments
Chan Su High Chan Su has active components such as bufalin, which cross-react with digoxin assays; only Bayer assay has
no interference; monitoring free digoxin also eliminates interference Dan Shen Moderate Falsely elevated (FPIA) or falsely low (MEIA) digoxin level; no interference with EMIT, Bayer, Randox, Roche, or Beckman assays; monitoring free digoxin eliminates interference Uzara root
(diuretic) Additive effect with digoxin; also interferes with digoxin assay Siberian
ginsengModerate Falsely elevated (FPIA) or falsely low (MEIA) digoxin level; no interference with EMIT, Bayer, Randox, Roche, or
Beckman assays; monitoring free digoxin does not eliminate interference Asian ginseng Moderate Falsely elevated (FPIA) or falsely low (MEIA) digoxin level; no interference with EMIT, Bayer, Randox, Roche, or
Beckman assays; monitoring free digoxin does not eliminate interference
