Making a Diagnosis of Herbal-Related Toxic Hepatit

liver411

Making a Diagnosis of Herbal-Related Toxic Hepatitis from Western Journal of Medicine Christine A Haller, Jo Ellen Dyer, Richard Ko, Kent R Olson Introduction 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. ****** Section 1 of 11 Christine A Haller, California Poison Control System and Department of Medicine Division of Clinical Pharmacology, Jo Ellen Dyer, California Poison Control System and School of Pharmacy, Richard Ko, Food and Drug Branch, California Department of Health Services Sacramento and Kent R Olson, California Poison Control System, School of Pharmacy and School of Medicine 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. 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. Figure 1. (click image to zoom) Ingestion of chaparral (from the plant Larrea tridentata) has been associated with 16 cases of hepatitis. 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. 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.[6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42]Table 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. 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 herb