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DRUG RECORD

 

COMFREY

(SYMPHYTUM OFFICINALE)

OVERVIEW
Comfrey

 

Introduction

Comfrey is an plant belonging to the Borganinaceae family, extracts of the leaves and roots of which has been used as an herbal to treat wounds and to decrease pain and inflammation associated with arthritis, sprains and bone fractures.  Comfrey, however, also contains pyrrolizidine alkaloids and, when taken orally, can cause sinusoidal obstruction syndrome and severe liver injury.

 

Background

Common comfrey (Symphytum officinale) is a perennial herb belonging to the family Borganinaceae which is native to Europe and Asia, but is now found worldwide.  Leaf and root extracts have many constituents including allantoin, rosmarinic acid, triterpene saponins, silicic acid, and tannins, believed to be the basis for its antiinflammatory and wound healing activity.  However, comfrey also contains several pyrrolizidine alkaloids (symphytine, echimidine, symglandine and lycopsamine) which are toxic and capable of causing sinusoid obstruction syndrome (previously called veno-occlusive disease) and severe liver injury.  Comfrey has been shown to cause similar liver injury in laboratory animals and has also been linked to liver cancer.  Comfrey products are marketed as herbal teas, root powders and as capsules.  Oral comfrey has been banned or restricted in most countries, but topical forms (ointments, creams and liniments) are available and advertised as useful for wound healing sprains and bone fractures.  Human studies have shown that comfrey creams have mild analgesic effects and decreases muscle and joint pain.

 

Hepatotoxicity

Several cases of acute liver injury resembling sinusoidal obstruction syndrome due to oral comfrey have been published.  The injury usually arises within 1 to 2 months of starting the comfrey product (either extract in tablet form or large amounts of comfrey tea) with onset of right upper quadrant pain, nausea, and weight gain (from fluid retention) followed by jaundice.  Serum aminotransferase levels are usually only mildly elevated with a hepatocellular pattern of injury, although they may be markedly increased if tested during the early phases of the injury.  Immunoallergic and autoimmune features are usually not present.  The injury can be severe and rapidly lead to acute liver failure (acute sinusoidal obstruction syndrome), but more commonly presents insidiously with weight gain, ascites, weakness, and minimal serum aminotransferase elevations (subacute or chronic sinusoidal obstruction syndrome).

 

Mechanism of Injury

The pyrrolizidine alkaloids contained in comfrey include intermedine, lycopsamine, symphtine and echnimidine, which are metabolized by the cytochrome P450 enzymes into highly toxic pyrrole metabolites which have alkylating properties that can damage hepatic endothelial cells and can cause sinusoidal obstruction.  The amount of pyrrolizidine alkaloids in comfrey varies by the part of the plant used, its age and time of harvesting.  The toxicity of pyrrolizidine containing substances is increased by microsomal enzyme inducers such as phenobarbital.  Infants appear to be particularly susceptible to pyrrolizidine alkaloid injury.

 

Outcome and Management

Hepatotoxicity from comfrey is now rare, as it is widely accepted as being toxic when taken internally and oral formulations are restricted or banned in most countries.  Management should be directed at limiting further injury and specific treatment of complications (ascites, variceal bleeding).  Anticoagulants have not been shown to be beneficial.  More extensive description of sinusoidal obstruction syndrome and its management are given in the introductory section and in discussion of the antineoplastic alkylating agents.

 

Other Names:  Black root, common comfrey, knitbone

 

Drug Class:  Herbals and Dietary Supplements

 

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REPRESENTATIVE TRADE NAMES
Comfrey – Generic

 

DRUG CLASS
Herbals and Dietary Supplements

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Comfrey 84696-05-9 Herbal mixture Not applicable

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REFERENCES
Comfrey

 

References updated: 12 May 2014

  1. Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.  (Expert review of hepatotoxicity published in 1999; comfrey is discussed as a pyrrolizidine containing herbal that has been linked to veno-occlusive disease which is now referred to as sinusoidal obstruction syndrome [SOS]).

  2. Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58. (Review of hepatotoxicity of herbal and dietary supplements [HDS] mentions that comfrey is one of more than 350 plant species that contain pyrrolizidine alkaloids and is capable of causing sinusoidal obstruction syndrome).

  3. Comfrey. In, PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007: pp. 291-22.  (Compilation of short monographs on herbal medications and dietary supplements).

  4. McGee JO, Patrick RS, Wood CB, Blumgart LH. A case of veno-occlusive disease of the liver in Britain associated with herbal tea consumption. J Clin Pathol 1976; 29: 788-94. PubMed Citation  (26 year old woman developed abdominal pain and ascites, having used herbal tea for 2 years [bilirubin 0.8 mg/dL, ALT 28 U/L, Alk P 303 U/L], with splenomegaly, varices and intractable ascites, biopsy showing sinusoid obstruction syndrome; dying after failed portocaval shunt, analysis of tea showed pyrrolizidine alkaloids).

  5. Stillman AE, Huxtable R, Consroe P, Kohnen P, Smith S. Hepatic venoocclusive disease due to pyrrolizidine(Senecio) poisoning in Arizona. Gastroenterology 1977; 73: 349-52. PubMed Citation  (6 month old developed distended abdomen and vomiting [bilirubin 0.5 mg/dL, AST 794 U/L] and was found to have ascites and biopsy showed sinusoidal obstruction syndrome; child had been fed large quantities of locally brewed tea which was made from Senecio longilobus).

  6. Fox DW, Hart MC, Bergeson PS, Jarrett PB Stillman AE, Huxtable RJ. Pyrrolizidine (Senecio) intoxication mimicking Reye’s syndrome. J Pediatr 1978; 93: 980-2. PubMed Citation  (2 month old boy developed vomiting and hematemesis and hepatic encephalopathy after being given herbal tea [gordolobo] for 4 days [bilirubin normal, but rising to 19.3 mg/dL, ALT 1860 U/L] initially diagnosed as Reye syndrome, dying after 3 days, autopsy showing severe acute sinusoidal obstruction syndrome).

  7. Mattocks AR. Toxic pyrrolizidine alkaloids in comfrey. Lancet 1980: 2: 1136-7. PubMed Citation  (Measured pyrrolizidine alkaloids in dried comfrey leaves, finding lowest concentration in mature large leaves and variation by time of harvesting).

  8. Roitman JN. Comfrey and liver damage. Lancet 1981; 1: 944. PubMed Citation  (Analysis of tea made from commercially available comfrey found a cup to contain 26 mg of pyrrolizidine alkaloids, well above the amount that has been linked to serious hepatic injury when taken long term).

  9. Editorial. Pyrrolizidine alkaloids. Lancet 1984; 1: 201. PubMed Citation  (Plants have evolved poisons that are toxic to insects, but can also cause hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in grazing animals and in humans who ingest these in teas and herbal medications: “a disastrous discontinuity of tradition”).

  10. Ridker PM, Ohkuma S, McDermott WV, Trey C, Huxtable RJ. Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements. Gastroenterology 1985; 88: 1050-4. PubMed Citation  (49 year old woman developed edema and ascites after taking comfrey capsules and tea for 6 months [no liver test results provided], biopsy showing sinusoidal obstruction syndrome, ultimately requiring portocaval shunt with subsequent slow clinical improvement after stopping comfrey ingestion).

  11. Kumana CR, Ng M, Lin HJ, Ko W, Wu PC, Todd D. Herbal tea induced hepatic veno-occlusive diseases; quantification of toxic alkaloid exposure in adults. Gut 1985; 25: 101-4. PubMed Citation  (Four young women brewed Indian herbal tea to treat psoriasis and 3 developed ascites from sinusoidal obstruction syndrome 19-45 days later [bilirubin 0.6, 0.6 and 3.3 mg/dL, ALT 63, 122 and 69 U/L], one dying of hepatic failure, analysis of tea revealed pyrrolizidine alkaloids).

  12. Culvenor CCJ. Pyrrolizidine alkaloids: some aspects of the Australian involvement. Trends Pharmacol Sci 1985; 6: 18-22. Not in PubMed.  (Presence of pyrrolizidine alkaloids in several common Australian weeds is a health hazard to livestock and humans; these include Heliotropium europaeum, Echium plantagineum, Senecio and Crotalaria species).

  13. Huxtable RJ, Luethy J, Zweifel U. Toxicity of comfrey-pepsin preparations. N Engl J Med 1986; 315: 1095. PubMed Citation  (Analysis of two commercial brands of comfrey-pepsin preparations sold as a digestive aid demonstrated pyrrolizidine alkaloids [symphytine and symglandine] in concentrations that could cause sinusoidal obstruction syndrome after a few months of regular intake).

  14. Weston CFM, Cooper BT, Davies JD. Veno-occlusive disease of the liver secondary to ingestion of comfrey. Br Med J 1987; 295: 183. PubMed Citation  (13 year old boy developed fever, abdominal pain and ascites after several years of treatment with an herbal tea containing comfrey for Crohn’s disease [bilirubin 1.5 mg/dL, AST 87 U/L, Alk P normal], biopsy showing sinusoidal obstruction syndrome).

  15. Roulet M, Laurini R, Rivier L, Calame A. Hepatic veno-occlusive disease in a newborn infant of a woman drinking herbal tea. J Pediatr 1988; 112: 433-6. PubMed Citation  (5 day old girl found to have jaundice, hepatomegaly and ascites [bilirubin 9.6 mg/dL, ALT 760 U/L, protime 13%], biopsy and autopsy showing severe sinusoidal obstruction syndrome and analysis of an herbal tea taken daily by the mother during pregnancy revealed pyrrolizidine alkaloids).

  16. Bach N, Thung SN, Schaffner F. Comfrey herb tea-induced hepatic veno-occlusive disease. Am J Med 1989; 87: 97-9. PubMed Citation  (47 year old woman developed liver test abnormalities and ascites having taken comfrey pills and tea daily for more than a year [bilirubin 1.2 mg/dL, ALT 24 U/L, Alk P 27 U/L], biopsy showing chronic sinusoidal obstruction syndrome).

  17. Ridker PN, McDermont WV. Hepatotoxicity due to comfrey herb tea. Am J Med 1989; 87: 701. PubMed Citation  (Letter in response to Bach [1989] reviewing the history of the association of comfrey and pyrrolizidine alkaloids and sinusoidal obstruction syndrome).

  18. Huxtable RJ, Awang DV. Pyrrolizidine poisoning. Am J Med 1990; 89: 547-8. PubMed Citation  (Letter in response to Bach [1989] and Ridker [1989] calling for better documentation of components of implicated hepatotoxic herbs in view of the variable amounts of pyrrolizidine alkaloids found in different comfrey samples due to different species of Symphytum, problems of contamination, mislabeling, use of leaves vs roots and variability in alkaloid content by time of harvest and growing conditions).

  19. Ridker PM, McDermott WV. Comfrey herb tea and hepatic veno-occlusive disease. Lancet 1989; 1: 657-8. PubMed Citation  (Concise review of the hepatotoxicity of comfrey herb tea and its association with sinusoidal obstruction syndrome, probably due to the presence of pyrrolizidine alkaloids which comprise more than 180 compounds and occur in at least 8 plant families; four genera – Heliatropium, Crotalaria, Senecio and Symphytum – accounting for most toxic ingestions).

  20. Yeong ML, Swinburn B, Kennedy M, Nicholson G. Hepatic veno-occlusive disease associated with comfrey ingestion. J Gastroenterol Hepatol 1990; 5: 211-4. PubMed Citation  (23 year old man who had eaten young comfrey leaves for 1-2 weeks developed fatigue and abdominal pain followed in the next 2 months by swelling and edema [bilirubin 1.6 mg/dL, AST 365 U/L, Alk P 475 U/L, INR 1.4], with intractable ascites and hepatic failure; autopsy showed sinusoidal obstruction syndrome).

  21. Carlsson C. Herbs and hepatitis. Lancet 1990; 336: 1068. PubMed Citation  (Analysis of laboratory results from 395 patients found higher ALT levels among 53 patients taking herbals [55 U/L] than among those who did not [12 U/L]).

  22. Huxtable RJ. The myth of beneficient nature: the risks of herbal preparations. Ann Intern Med 1992; 117: 165-6. PubMed Citation  (Editorial on problems of herbal poisoning highlighting pyrrolizidine alkaloids, comfrey, germander, and suggesting guidelines on their use [never during pregnancy or while nursing, avoiding daily and high doses of a single agent, using products from reputable sources and never using comfrey]).

  23. Miskelly FG, Goodyer LI. Hepatic and pulmonary complications of herbal medicines. Postgrad Med J 1992; 68: 935. PubMed Citation  (77 year old woman developed fatigue followed by jaundice 6 months after starting an herbal product with comfrey and skullcap [bilirubin 3.5 mg/dL, AST 520 U/L, Alk P 390 U/L], resolving within 6 months of stopping).

  24. Sperl W, Stuppner H, Gassner J, Judmaier W, Dietze O, Vogel W. Reversible hepatic veno-occlusive disease in an infant after consumption of pyrrolizidine-containing herbal tea. Eur J Pediatr 1995; 154: 112-6. PubMed Citation  (18 month old boy treated with locally prepared herbal tea for over a year presented with ascites and hepatic encephalopathy [bilirubin 2.8 mg/dL, ALT 124 rising to 923 U/L], biopsy showing sinusoidal obstruction syndrome, but gradual improvement and resolution of clinical symptoms and signs after stopping the tea; the plant leaves were likely Adenostyles alliariae [Alpendost] which is known to contain pyrrolizidine alkaloids).

  25. Stickel F, Seitz HK. The efficacy and safety of comfrey. Public Health Nutr 2000; 3(4A): 510-8. PubMed Citation  (Review of comfrey which has a long tradition as an external treatment for inflammatory arthritis and trauma; for internal application it was claimed to be beneficial for gastritis, ulcers, diarrhea and various allergies including asthma; the pyrrolizidine content of comfrey products varies greatly, and hepatic toxicity largely associated with daily intake of tablets or multiple cups of tea).

  26. Stickel F, Seitz HK, Hahn EG, Schuppan D. [Liver toxicity of drugs of plant origin]. Z Gastroenterol 2001; 39: 225-32, 234-7. German. PubMed Citation  (Review of hepatotoxicity of botanicals including comfrey, pyrrolizidine alkaloids, germander, celandine, chaparral, Chinese herbs and pennyroyal).

  27. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22: 195-206. PubMed Citation  (Review and description of patterns of liver injury, including discussion of potential risk factors, and herb-drug interactions; comfrey is listed as a health tonic that contains toxic pyrrolizidine alkaloids capable of causing sinusoidal obstruction syndrome).

  28. Schiano TD. Hepatotoxicity and complementary and alternative medicines. Clin Liver Dis 2003; 7: 453-73. PubMed Citation  (Comprehensive review of herbal associated hepatotoxicity; discusses comfrey as a cause of sinusoidal obstruction syndrome).

  29. Pak E, Esrason KT, Wu VH. Hepatotoxicity of herbal remedies: an emerging dilemma. Prog Transplant 2004; 15: 91-6. PubMed Citation  (Review of hepatotoxicity of herbal medications stressing the recent rise in numbers of cases, with literature review of comfrey).

  30. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. PubMed Citation  (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, including 7 [5%] for herbal medications, but comfrey is not mentioned as a cause).

  31. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis 2007; 11: 577-96. PubMed Citation  (Review of herbal induced hepatotoxicity, with detail of specific herbal compounds including review of the literature on comfrey hepatotoxicity).

  32. García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by “natural remedies”: an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. PubMed Citation  (Among 521 cases of drug-induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals but none were attributed to comfrey).

  33. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 9% of cases were attributed to herbal medications, but none were linked to comfrey).

  34. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-82. PubMed Citation  (Overview of the regulatory environment, clinical patterns, and future directions in research with HDS; comfrey is discussed in the context of pyrrolizidine alkaloid hepatotoxicity).

  35. Giannetti BM, Staiger C, Bulitta M, Predel HG. Efficacy and safety of a Comfrey root extract ointment in the treatment of acute upper or low back pain: results of a double-blind, randomized, placebo-controlled, multi-centre trial. Br J Sports Med 2009; 44: 637-41. PubMed Citation  (Controlled trial of comfrey root extract ointment versus placebo in 120 patients with acute back pain found significant effect of comfrey ointment on pain intensity and movement; side effects were mild and transient and no more common than with placebo).  

  36. Mei N, Guo L, Fu PP, Fuscoe JC, Luan Y, Chen T. Metabolism, genotoxicity, and carcinogenicity of comfrey. J Toxicol Environ Health B Crit Rev 2010; 13: 509-26. PubMed Citation  (Overview of the metabolism and toxicity of comfrey, which refers to several species in the genus Symphytum, most frequently "common comfrey" or S. officinale; the herbal is prepared from leaves and dried roots but is a potential health risk due to pyrrolizidine alkaloids such as retronecine mono- and diesters and is hepatotoxic and carcinogenic in laboratory animals).

  37. Staiger C. Comfrey: a clinical overview. Phytother Res 2012; 26: 1441-8. PubMed Citation  (Review of the efficacy and safety of topical comfrey in treatment of arthritis, myalgias, conusions and strains).

  38. Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a
    tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. PubMed Citation  (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, herbal drugs and supplements including five publications on comfrey).

  39. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement
    hepatotoxicity. Aliment Pharmacol Ther 2013; 37: 3-17. PubMed Citation  (Systematic review of literature on HDS associated liver injury discusses pyrrolizidine alkaloids including comfrey as causing sinusoidal obstruction syndrome). 

  40. Abdualmjid RJ, Sergi C. Hepatotoxic botanicals - an evidence-based systematic review. J Pharm Pharm Sci 2013; 16 (3): 376-404. PubMed Citation  (A systematic review of hepatotoxic botanicals mentions that comfrey is a common garden plant and consists of several species which contain pyrrolizidine alkaloids that can lead to sinusoidal obstruction syndrome, when taken orally and brewed as teas).

  41. Navarro VJ, Seeff LB. Liver injury induced by herbal complementary and alternative medicine. Clin Liver Dis 2013; 17: 715-35. PubMed Citation  (Review of herbal hepatotoxicity mentions that comfrey is used topically for pain relief, but when taken orally or brewed as a tea it can be associated with sinusoidal obstruction syndrome).

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OTHER REFERENCE LINKS
Comfrey
  1. PubMed logoRecent References on Comfrey

  2. Clinical Trials logoTrials on Comfrey

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