Many conventional drugs (for example, isoniazid and valproic acid) are well recognized as possible hepatotoxins.1 Several herbal medicines have also been reported to have hepatotoxic effects. However, herbal medicines may not always be considered as the etiologic agent in cases of unexplained liver injury. Current mechanisms to track adverse effects of herbal medicines are inadequate.2 Consumers generally consider herbal medicines to be safe and view them as natural alternatives to traditional medications. A recent study showed that only 40% of people who use herbal medicines informed their primary care physicians.3 Therefore, cases of herbal medicine toxicity may go unrecognized. Establishing a diagnosis of herbal hepatotoxicity can be difficult. Even when herbal-related toxicity is suspected, a definitive diagnosis is difficult to establish without proper analysis of the product or plant material.
In the following case review, we contrast one case of herbal-induced hepatotoxic reaction that received thorough and systematic follow-up with a second case complicated by poor history and multiple product use to illustrate the challenges in diagnosing herb-related hepatitis.
METHODS
In 1999, we investigated 2 reports to the California Poison Control System, San Francisco division (CPCS-SF), of persons who sustained significant liver injury after taking herbal remedies for specific medical purposes. Both had previously been healthy with no history of drug or alcohol abuse and no risk factors for viral hepatitis (that is, neither had recently traveled abroad or received blood products). The patients were interviewed, medical records were reviewed, and the implicated herbal products were submitted to the California Department of Health Services (CDHS) for identification and analysis.
We also conducted a MEDLINE search to identify other reported cases of herbal-induced hepatotoxic effects. We searched the literature from 1966 to the present using search terms herbal hepatitis, toxic hepatitis and plants, herbal hepatotoxicity, and liver failure and medicinal herbs.
We included English-language case reports, case series, case-control studies, and clinical reviews.
Patient 1
A previously healthy 42-year-old woman began taking 3 herbal medicines for insomnia on the advice of a homeopathic practitioner. The products were an shu ling (Stephaniae sinica), “Ignatia Amara” and “Relaxed Wanderer.”
She took the products as directed for about 10 weeks and then developed nausea, abdominal pain, and jaundice. She stopped using the herbal products and was seen by her primary care physician, who diagnosed acute hepatitis. Her liver function test results are shown in table 1. Results of other laboratory tests, including a complete blood cell count, electrolyte levels, and coagulation times, were within normal limits. Viral serologic markers for hepatitis A, B, and C viruses were absent. She had no known occupational or environmental exposures to hepatotoxins.
WHAT AGENTS ARE ASSOCIATED WITH TOXIC HEPATITIS, AND WHAT ARE THE MECHANISMS OF TOXIC REACTIONS?
Hepatotoxins may have intrinsic, idiosyncratic, or immune-mediated mechanisms of liver injury. Intrinsic hepatotoxins, such as acetaminophen, amanitin (found in Amanita phalloides mushrooms), or carbon tetrachloride, produce liver damage in a predictable, dose-dependent manner.1 On the other hand, when there is no apparent dose-response relationship or predictable physiologic mechanism and relatively few cases of hepatitis occur among a large group of persons exposed to an agent, the mechanism of hepatotoxic reaction is characterized as idiosyncratic. Many drugs and chemicals are idiosyncratic hepatotoxins: isoniazid, amiodarone, tetracycline, methyldopa, bromobenzene, valproic acid, and halothane. Toxic hepatitis may also occur sporadically due to differences in individual susceptibility related to factors such as age, sex, underlying disease, concomitant medications, and genetic influences.
Hypersensitivity or immune-mediated hepatitis may develop after repeated exposure to a causative agent. Immune-mediated hepatitis may manifest with systemic findings such as fever, rash, eosinophilia, or atypical lymphocytosis and recur with reexposure. Liver injury due to drugs such as sulfonamides, chlorpromazine, erythromycin, and phenytoin is thought to be immune-mediated.
The patient called the CPCS-SF when the cause of the hepatitis could not be identified and her physician suspected the herbal products might be responsible. The herbal products were sent to the CDHS Food and Drug Branch for laboratory analysis. Poison specialists at the CPCS-SF searched the Poisindex (Micromedex, Englewood, CO) toxicology database and found the synonym jin bu huan listed for an shu ling (S sinica). Chemical analysis of an shu ling identified L-tetrahydropalmatine, the hepatotoxic constituent of jin bu huan. The product lot was confiscated from the importer-seller, and a public health warning was issued by the CDHS. Ignatia Amara and Relaxed Wanderer contained no suspected hepatotoxins.
WHICH HERBAL MEDICINES HAVE BEEN ASSOCIATED WITH CLINICALLY SIGNIFICANT LIVER INJURY?
Some herbs are thought to be intrinsic hepatotoxins and show dose-related liver toxicity, either through direct hepatocellular damage, such as with Atractylis gummifera, or through the generation of a reactive metabolite, as is the case with pennyroyal oil (Mentha pulegium).4
In many instances, herbal hepatotoxins are thought to cause a hypersensitivity or idiosyncratic reaction. This appears to be true of L-tetrahydropalmatine. Seven cases of hepatitis have been reported in adults who used jin bu huan.5 Liver disease occurred after a mean duration of use of 20 weeks (range, 7-52 weeks). Six of the 7 patients showed complete resolution of symptoms within 8 weeks. Two patients had a recrudescence of symptoms with re-exposure to the herb.
Chaparral ingestion has been associated with at least 16 cases of hepatitis, including 2 cases of fulminant liver failure that required transplantation.2 In 4 patients, there was progression to cirrhosis. The duration of chaparral use ranged from 3 to 52 weeks. The predominant pattern of liver injury was cholestatic hepatitis.
Other cases of herbal-related liver injury have been described in the medical literature.6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42Table 2 summarizes recent reports of herbal-induced hepatotoxic reaction in the English-language literature. Often the mechanism of herbal-induced liver injury is unknown, and the pathologic findings are nonspecific, with cholestasis, hepatocyte necrosis, and acute and chronic inflammatory cell infiltrate. In general, the documentation of reported cases of herbal toxicity is inadequate and does not provide definitive proof of causality. For example, the report of hepatotoxic reaction due to mistletoe was merely speculative and created significant controversy because the implicated product also contained skullcap.23,24,25,26 In addition, herbs are sometimes sold under different common names or adulterated with a toxic substance (for example, germander substituted for skullcap in some US products).7,37 Few case reports are supported by experimental studies or animal models demonstrating hepatotoxicity, as in the case of the herb valerian.6 There are likely more extensive data on herbal medicine toxicity in the foreign language literature that were not evaluated in this review, including possibly human and animal experimental data.
Table 2.
Reports of cases of herbal-induced hepatotoxicity in the English-language literature
| Herbal product and reference no. | Plant | Cases reported, no. | Suspected mechanism of liver injury |
|---|---|---|---|
| Asian herbs for eczema and psoriasis8,9,10,11,12 | Dictamnus dasycarpus, Rehmannia glutimosa, Paeonia species, Glycyrrhiza species, Lophatherum species | 6 | Unknown |
| Atractylis13 | Atractylis gummifera | 1 | Direct hepatotoxin; inhibits oxidative phosphorylation |
| Chaparral2,14,15,16,17 | Larrea tridentata | 16 | Unknown mechanism; cholestasis, hepatocyte necrosis |
| Germander18,19,20 | Teucrium chamaedrys | 10 | Unknown; may be immune-mediated |
| Greater celandine21 | Chelidonium majus | 10 | Unknown, possibly idiosyncratic |
| Jin bu huan5 | Lycopodium serratum, Stephania species, Corydalis species | 7 | Unknown |
| Ma huang22 | Ephedra species | 1 | Unknown |
| Mistletoe23,24,25,26 | Viscum album | 1 | Unknown |
| Pennyroyal4,27,28,29,30 | Mentha puleguim, Hedeoma pulegoides | 5 | Reactive oxidative metabolite causes hepatocyte necrosis |
| Coltsfoot31* | Tussilago farfara | 1 | Direct hepatotoxin; veno-occlusive disease; portal hypertension; centrilobular necrosis; and hepatocellular carcinoma |
| Comfrey32,33,34,35* | Symphytum officinale, Symphytum asperum, or Symphytum uplandicum | 5 | Direct hepatotoxin; veno-occlusive disease; portal hypertension; centrilobular necrosis; and hepatocellular carcinoma |
| Bush tea36* | Crotalaria | † | Direct hepatotoxin; veno-occlusive disease; portal hypertension; centrilobular necrosis; and hepatocellular carcinoma |
| Senecio37,38* | Senecio longilobus | 2 | Direct hepatotoxin; veno-occlusive disease; portal hypertension; centrilobular necrosis; and hepatocellular carcinoma |
| Senna39 | Cassia angustifolia | 1 | May be direct hepatotoxin; centrilobular necrosis is predominant pattern of injury |
| Skullcap-valerian combination40,41,42 | Scutelleria lateriflora and Valeriana officinalis | 6 | Possible hypersensitivity reaction |
Pyrrolizidine alkaloids.
Whereas no cases of toxicity related to bush tea have been reported in the United States, epidemics have been reported to occur, primarily in the developing world, when certain pyrrolizidine alkaloids have contaminated foods.
HOW IS A DEFINITIVE DIAGNOSIS OF HERBAL-RELATED TOXIC HEPATITIS MADE?
Establishing a diagnosis of herbal-related toxic hepatitis is difficult because the effects of herbs are often chronic and nonspecific and may not become clinically apparent for some time. Proper documentation of adverse effects of herbal medicines is hindered by several factors. Physicians may not ask patients about their use of herbal medicines, or patients may be reluctant to discuss their use of alternative remedies. As a result, many cases of herbal-related toxic hepatitis may go unrecognized and unreported. Inadequate product labeling, multiple-ingredient herbal products, batch-to-batch variation, and adulterants or contaminants may complicate attempts to accurately identify the toxic component. Because the English-language literature consists mostly of case reports of herbal toxicity rather than scientific studies, there is often little sound evidence to support a clinical diagnosis of herbal-related hepatitis.
HOW CAN THE PRESENCE OF A HEPATOTOXIC SUBSTANCE IN A HERBAL PRODUCT BE CONFIRMED?
When a physician suspects a toxic reaction from an herbal medicine, the patient should be urged to provide the product in its original packaging, along with the date and place of purchase. Because herbal products are sometimes poorly labeled or contain misinformation, a definitive diagnosis can be established only with laboratory confirmation of a hepatotoxin. Unfortunately, access and availability of such assays are limited. State and county health departments may provide such analytic testing free of charge. Specimens of the patient's urine and blood should also be obtained and frozen for possible future testing to confirm the presence of the hepatotoxin.
The patient was presumed to have chemical-induced hepatitis due to the ingredient L-tetrahydropalmatine in the herbal sedative an shu ling. Six weeks later, her serum aminotransferase levels had decreased significantly and she was completely asymptomatic. No additional cases of hepatitis associated with the use of this product were reported. Although jin bu huan is banned from importation into the United States, this shipment of an shu ling reportedly cleared US customs because the shipping invoice contained only the Chinese botanical name.
Patient 2
A 39-year-old female office worker began taking several herbal products for “detoxification” after she noticed her eyes appeared yellow. She reportedly felt well at the time and did not have nausea, vomiting, fever, or abdominal pain. When she was a teenager, she had hepatitis associated with infectious mononucleosis but had since been healthy. She did not seek medical care but sought advice from a local nutrition store and a self-help herbal therapy book on how to detoxify her liver. One month before presentation, she began taking several herbal products that reportedly included milk thistle extract (Silybum marianum) in her tea and 2 cleansing products called Liv-Alive and DeTox caps. However, her jaundice gradually progressed.
About 2 weeks before she was admitted to the hospital, she reportedly took chaparral (Larrea tridentata), 500 mg daily, for 2 days as a liver “tonic,” then stopped it when she noticed a marked worsening in jaundice. About 1 week later, she was found at home, obtunded and disoriented. On being seen in the emergency department, she was cool and lethargic with marked jaundice and scleral icterus. Her blood pressure was 160/88 mm Hg; pulse rate, 94 beats per minute; respiratory rate, 24 per minute; and temperature, 35.1°C (95°F). Findings of the physical examination and laboratory values (table 3) were consistent with fulminant hepatic failure with hepatorenal syndrome and progressive encephalopathy.
An endotracheal tube was inserted, red blood cells and fresh frozen plasma were transfused, and continuous hemodialysis was started. On the second hospital day, the patient underwent orthotopic liver transplantation. Examination of the liver specimen showed massive hepatic necrosis with mixed inflammatory cell infiltrate and moderate cholestasis. Fibrosis and steatosis were not evident. Histopathologic examination did not reveal the cause of the fulminant hepatic failure.
WHAT ARE THE TREATMENT AND PROGNOSIS OF HERBAL-INDUCED LIVER INJURY?
Treatment includes removing exposure to the toxic agent and supportive patient care. Often, herbal-related acute hepatitis will resolve spontaneously once ingestion of the offending product is discontinued. Rarely, acute liver injury progresses to fulminant failure, necessitating transfer to a tertiary care facility with a liver transplantation service. Clinical deterioration may develop rapidly in toxin-induced hepatic failure, so the decision to transfer the patient should be made quickly. N-Acetylcysteine, the antidote commonly used for acetaminophen poisoning, may also be of benefit in selected cases of fulminant hepatic failure due to other toxins, such as carbon tetrachloride and herbs such as pennyroyal oil.43 Some hepatotoxic herbs cause chronic pathologic liver changes. Herbs such as coltsfoot, comfrey, bush tea, and senecio contain pyrrolizidine alkaloids, direct hepatotoxins that can cause centrilobular necrosis, veno-occlusive disease, portal hypertension, and an increased risk of hepatocellular carcinoma.31,32,33,34,35,36,37,38
The patient's postoperative course was complicated, but she eventually recovered and was discharged from the hospital 21 days after transplantation. Although her recall of the events before her hospital admission was poor, she reported occasionally taking a cold and allergy combination product with acetaminophen, chlorpheniramine for allergic rhinitis, echinacea daily for 1 year, glucosamine for 1 month, multivitamins, and the herbal products described. The Liv-Alive and Detox caps contained 11 and 20 herbal ingredients, respectively, none of which were suspected hepatotoxins. She drank ethanol rarely and used no other drugs. The results of a urine toxicology screen were negative. Her serum acetaminophen level was lower than 70 μmol/L (10 μg/mL). Serologic tests for viral hepatitis A, B, and C were negative. Chemical analysis of the herbal products showed no pharmaceutical adulterants or contaminants. Although the cause of her initial painless jaundice remained unknown, the rapid progression to massive liver failure was suspected to be related to the use of the herbal products, most likely chaparral. However, the amount and duration of chaparral use was less than reported in previous cases of liver injury.2,14,15,16,17
WHAT IS THE IMPORTANCE OF DRUG-HERB AND HERB-HERB INTERACTIONS IN CAUSING TOXIC REACTION?
Possible drug-herb interactions are of concern to primary care physicians, but published clinical studies are scarce.44 Recent studies show that Saint-John's-wort has pharmacokinetic interactions with drugs that are substrates for cytochrome P-450 enzymes and P-glycoprotein transport mechanisms, such as cyclosporine, ethinyl estradiol, and digoxin.45,46 Herbs that induce hepatic cytochrome P-450 enzymes could potentiate the toxicity of intrinsic hepatotoxins such as acetaminophen. Other herbs may have clinically relevant drug interactions or synergistic actions with other botanicals. For example, herbs with anticoagulant effects such as ginkgo biloba, ginseng, and garlic could increase the risk of bleeding in patients taking warfarin or platelet inhibitors.46 There are few published data in the English-language literature to support the practice of combining numerous active herbal ingredients in a single product, and yet, such products are widely available in nutrition and health food stores, retail pharmacies, and supermarkets, potentially increasing the risk of serious herb-herb interactions. For instance, there is growing concern about combination products that contain several cardiovascular stimulant herbs such as ephedra, guarana, and Citrus aurantium that could increase the risk of adverse effects, including hypertension, cardiac arrhythmia, and stroke.47,48
HOW IS A CASE OF SUSPECTED HERBAL-RELATED HEPATITIS REPORTED?
Suspected adverse events related to herbal products should be reported immediately to a regional poison control center for advice on medical management and product testing. A state or county health department should also be notified to investigate the importing, sales, and distribution of the implicated herbal product. Under the Dietary Supplement Health and Education Act of 1994, manufacturer reporting of adverse events related to herbal medicines is not mandated. Underreporting of adverse effects of herbal products hinders effective federal surveillance of dangerous alternative remedies.
Health care providers and consumers are urged to report any suspected adverse effect of an herbal product to MEDWATCH (Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20852-9787, 1-800-332-1088 or www.fda.gov).
CONCLUSIONS
The first case illustrates how systematic and thorough case follow-up can aid in making a clinical diagnosis and possibly prevent further cases of herb-related toxicity. In this case, the patient was forthcoming about her use of alternative medicines. The physician considered the possibility of herbal-induced hepatitis and recommended contacting the local poison control center. A collaborative investigation between CPCS-SF and CDHS, including chemical confirmation of the suspected toxin, resulted in prompt removal of a known, dangerous herbal product.
The second case shows some of the difficulties encountered in making a definitive diagnosis of herbal-related liver toxic effects. Poor patient recall about her pattern of herbal medicine use before the onset of hepatic failure hindered establishing the temporal sequence of events. The amount and duration of use of chaparral, the suspected hepatotoxin, was less than reported in previous cases. Finally, the use of multiple herbs and medications raises the possibility of drug-herb and herb-herb interactions that could have contributed to liver injury.
Both of these patients had a specific medical condition that warranted health care consultation and intervention. The decision to self-treat with herbal remedies was associated with substantial morbidity and delay in receiving necessary treatment. All patients should be informed about the risks of unregulated herbal medicines and urged to seek qualifed advice on the use of any alternative remedy.
Figure 1.
Ingestion of chaparral (from the plant Larrea tridentata) has been associated with 16 cases of hepatitis
Mimi Kamp
Table 1.
Liver function test results for patient 1*
| AST, U/L | ALT, U/L | Alkaline phosphatase, U/L | Total bilirubin, μmol/L (mg/dL) | GGT, U/L | LDH, U/L | Albumin, g/L (g/dL) | |
|---|---|---|---|---|---|---|---|
| Patient | 1,309 | 3,386 | 100 | 20 (1.2) | 144 | 313 | 46 (4.6) |
| Reference range | 0-41 | 0-45 | 36-125 | 2-20 (0.1-1.2) | 0-45 | 60-200 | 32-55 (3.2-5.5) |
| AST = aspartate aminotransferase; ALT = alanine aminotransferase; GGT = γ-glutamyltransferase; LDH = lactate dehydrogenase. | |||||||
Values are given in SI units with conventional units in parentheses, unless both have the same numerical value.
Table 3.
Laboratory test results for patient 2*
| AST, U/L | ALT, U/L | Total bilirubin, μmol/L (mg/dL) | Prothrombin time (INR), sec | Ammonia, μmol/L (μg/dL) | BUN, mmol/L (mg/dL) | Creatinine, μmol/L (mg/dL) | |
|---|---|---|---|---|---|---|---|
| Patient | 502 | 349 | 730 (42.7) | 41.4 (3.9) | 109 (78) | 15.4 (43) | 239 (2.7) |
| Reference range | 12-42 | 9-50 | 2-20 (0.1-1.2) | 11.0-14.5 (0.8-1.2) | 11-35 (15-49) | 3.6-8.6 (10-24) | 44-124 (0.5-1.4) |
| AST = aspartate aminotransferase; ALT = alanine aminotransferase; INR = international normalized ratio; BUN = blood urea nitrogen. | |||||||
Except for prothrombin time, values are given in SI units with conventional units in parentheses, unless both have the same numerical value.
Funding: This work was supported in part by a Veterans Affairs Medical Toxicology fellowship (CAH)
Competing interests: None declared
- Some herbs used as alternative medicines may be hepatotoxic
- Recent cases of herbal-related hepatoxic effects in the United States have involved the use of jin bu huan, chaparral, pennyroyal, comfrey (Symphytum species), and germander (Teucrium species)
- Diagnosing herbal-related hepatitis may be hindered by patients' reluctance to disclose the use of alternative medicines and the failure to recognize or chemically identify hepatotoxic herbs
- The use of herbal medicines should be considered in patients with unexplained hepatitis
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