Hepatotoxic Herbs

Summary

Hepatotoxic Herbs

introduction:
Possible hepatotoxic reactions caused by herbal medicine are a matter of obvious concern, albeit one which receives excessively zealous attention from sections of the medical community and popular press. Recently, erroneous attributions of hepatoxicity caused by herbs have been published, for example the unfounded claim of Echinacea hepatoxicity by Lucinda Miller in 1998.
(Miller LG. Arch Intern Med 1998;158:2200-2210.)

Hepatotoxicity can take a number of forms. Since most drugs, as well as compounds derived from herbal medicines and foodstuffs are largely detoxified via hepatic metabolism, any compromise to the functional status of hepatic detoxification may cause problems, ranging from short term intoxications to long term carcinogenesis.

Overwhelming necrotic toxicosis that can result in fulminant hepatic failure within hours or days is not unusual in relation to chemical exposures but has not been reported with normal doses of herbal medicines. The much reported case of a fatality due to ingestion of a substantial quantity of Mentha pulegium (Pennyroyal) essential oil is perhaps a case in point. Essential oils are not generally used as internal medicines in herbal therapeutics; they are regarded as often toxic, always highly concentrated extracts of certain volatile fractions of plant chemistry. Excessive doses of concentrated extracts and isolated compounds are not considered here, nor are excessively high doses of otherwise therapeutically safe plant extracts.

Toxicity, including hepatoxicity arising from various factors in traditional Chinese patent medicines is discussed in a separate section: Chinese Herbs: Adulteration and Contaminants

Short term compromise of detoxification functionality can result in moderate hepatocellular inflammation, causing symptoms ranging from mild pruritis and skin rash to frank hepatitis and transaminase enzyme level elevation, with symptoms usually reversing on cessation of exposure to the provocative agent. Inter-individual differences in microsomal enzyme status may contribute in part to the apparent idiosyncrasy of such reactions, whilst popular mythologies about natural "healing crises" may be responsible for some under-reporting of such adverse reactions.

Hepatic veno-occlusive disease, (VOD), a very specific form of hepatotoxic pathology related to the Budd-Chiari syndrome, is of great concern. This is, firstly, because its silent onset and progress can remain undetected. By the time it becomes symptomatic, extensive irreversible damage may have been sustained, which may lead to progressive cirrhosis with the potential of fulminant failure. Secondly, it is uniquely associated with the ingestion of certain kinds of pyrrolizidine alkaloids (PA's), that are present in a variety of herbs.

Pyrrolizidine Alkaloids:
• mechanism: Pyrrolizidine alkaloids (PA's) are found in over 240 species, mostly amongst the Asteraceae (Daisy) and Boraginaceae (Borage) families. The toxicity of PA's has been known since the nineteenth century; Senecio "hepatitis" in cattle was described in 1884. The mechanisms of toxicity are well documented have been reviewed recently. (See, for example, Denham A.1996). Hepatotoxicity among PA's varies with minor differences in chemical structure. It is most marked among macrocyclic diesters; these form highly reactive pyrrole intermediates upon metabolism by CYP3A4. Subsequent conjugation of the pyrroles is via glutathione. The reactive pyrrole intermediates form covalent bonds with nucleic acids and disrupt cellular protein synthesis and cell replication which initiates the pathological process. DNA crosslinking may also lead to carcinogenesis.

• herbal concern: Evaluation of the risks from ingestion of PA containing herbs is a complex, controversial and unresolved subject. PA's vary in toxicity, not only by distribution in different species of the same genera, but in their distribution in different plant parts (leaf, root etc.) of the same species. Regulatory authorities in some countries have proscribed the use of all PA-containing herbs such as Tussilago farfara (Coltsfoot) and Borago officinalis (Borage) despite complete lack of any evidence for toxicity in normal usage, along with Symphytum spp. (Comfrey) for which there is more compelling evidence of hepatoxicity - with four reports worldwide associating possible VOD with comfrey use at normal dose levels. In the USA, cautions are recommended by AHPA (American Herbal Products Association) to restrict use of PA-containing herbs to external use on unbroken skin and to avoid consumption during pregnancy and nursing.
(Denham A. Eur J Herb Med 1996;2(3):27-38; McGuffin M, et al.(eds.) 1997, p149-151; Whitelegg M. Eur J Herb Med 1994;1(1)11-17.)

overview of interactions :
• Detoxification of PA's depends initially on the CYP3A4 enzyme subsystem and subsequently on hepatic glutathione (GSH) status. Although age, genetic variation, nutritional status and other factors account for large inter-individual differences, it is known which drugs inhibit CYP3A4 and which drugs are substrates by CYP3A4. Use of these drugs would require an even greater vigilance concerning the concurrent ingestion of PA-containing herbs.

• Drugs inhibiting CYP3A4 include fluoxetine, itraconazol, fluconazole, ketoconazole, erythromycin, clarithromycin, troleandomycin. See also Grapefruit Juice.

• Drugs metabolized by CYP3A4 include quinidine, carbamazepine, astemizole, terfanadine, fluoxetine, alprazolam, midazolam, triazolam, diltiazem, nifedipine, cisapride, cyclosporine, lidocaine, lovastatin, lydrocortisone, lexamethsone.
(Bland JS. 1997, 17.)

other hepatotoxic herbs:
• Teucrium chamaedrys (Germander) has been associated with hepatoxicity in humans including at least one fatality, and is restricted in the USA and several other countries. Teucrium is not in general use or available in commerce, although adulteration of other species with Teucrium due to mistaken identification has been reported. Evidence suggests that the relevant diterpenoids are metabolized via CYP3A4.
(De Smet PAGM, et al. 1997, 137.)

• Larrea tridentata (Chapparal) was subject of FDA warning following several reports of hepatotoxicity. Controversy surrounded the reports of Chaparral toxicity and four cases reviewed by Watts C, et al. in 1994 were also associated with pre-existing liver conditions.
(McGuffin M, et al.(eds.) 1997, 67.)

• Acorus spp. and Asarum spp. both contain beta-asarone, a volatile allylbenzene which can form a hepatotoxic and genotoxic epoxide metabolite when activated by hepatic microsomal enzymes. Adverse reactions of nausea and vomiting have been reported. These herbs are used primarily by professional herbalists: they are considered safe providing therapeutic dose ranges are observed.
(McGuffin M, et al.(eds.) 1997, 134.)

hepatotoxicity: scope of problem:
Even taking into account the possibility of under reporting of adverse effects caused by herbs, the scale of the problem of hepatotoxicity due to herbal remedies should nevertheless be seen in perspective. In the time scale that the four reported cases of Comfrey associated hepatotoxicity world-wide were noted, thousands of cases of acetaminophen poisoning took place; an OTC drug regarded as safe within normal dose range. In 1994 the London Royal College of Physicians reported acetaminophen poisoning to be the second biggest etiological cause for liver transplant procedure. Acetaminophen is considered safe within normal dose range and calls for its removal from OTC status are absent.



Herbs

Pyrrolizidine alkaloid-containing herbs:
• Alkanna tinctoria (Alkanet, Anchusa)
• Borago officinalis (Borage)
• Cynoglossum officinale (Hound'stongue)
• Eupatorium purpureum (Queen of the Meadow)
• Lithospermum officinale (Stoneseed)
• Petasites spp. (Butterburr)
• Senecio spp. (Liferoot)
• Symphytum asperum (Prickly Comfrey)
• Symphytum caucasicum (Comfrey)
• Symphytum officinale (Comfrey)
• Symphytum tuberosum (Comfrey)
• Symphytum x uplandicum (Russian Comfrey)
• Tussilago spp. (Coltsfoot)




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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Bland JS. The Inflammatory Disorders. Gig Harbor WA: HealthComm Seminar, 1997.

Bone K. Safety of Herbal Medicines: Melbourne, Australia: MediHerb Seminar.1996.

Denham A. Using herbs that contain pyrrolizidine alkaloids.Eur J Herb Med 1996;2(3):27-38.

DeSmet PAGM, et al.(eds.) Adverse Effects of Herbal Drugs 3. NY: Springer Verlag, 1997.

Duke JA. Handbook of Phytochemical Constituents of GRAS Herbs and Other Economical Plants. CRC Press, 1994.

McGuffin M, et al.(eds.) AHPA Botanical Safety Handbook .CRC Press, 1997.

Miller LG. Herbal medicinals. Arch Intern Med 1998;158:2200-2210.

Whitelegg M. In defence of Comfrey. Eur J Herb Med 1994;1(1)11-17.