Case 5 -

Herbal Remedy-induced Hepatotoxicity Julia C. Iezzoni

Clinical History The patient, a 44-year-old male who recently emigrated from Saudi Arabia, presented with complaints of jaundice. Physical examination demonstrated mild right upper quadrant pain, jaundice and mild ascites. Laboratory studies demonstrated markedly elevated aminotransferases, alkaline phosphatase, and total bilirubin, and a prolonged prothrombin time. Viral serologies, autoantibodies, and toxin screens were negative, and copper studies were normal. The patient was on no prescription or over-the-counter medications. Upon further questioning, the patient described that for several weeks he had regularly ingested large quantities of an "herbal tea" as a "health tonic". The specific contents of this herbal formulation could not be determined at the time of the patient's clinical presentation. A liver biopsy was performed. Diagnosis: Herbal Remedy-induced Hepatotoxicity Case 5 - Figure 1 - H&E Case 5 - Figure 2 - H&E Case 5 - Figure 3 - H&E Pathologic findings: The liver biopsy demonstrates extensive hemorrhagic necrosis, without inflammation, of the zone 3 hepatocytes. The surrounding parenchyma demonstrates hepatocyte ballooning degeneration, bile duct injury with bile plugs, and a portal chronic inflammatory infiltrate. Discussion Over the past decade, the use of herbal remedy and dietary supplements in the United States has skyrocketed. It is estimated that more than 20,000 botanical products are currently on the market. Approximately 4 billion dollars is spent on these products in the United States each year, and this figure is predicted to increase to at least a 7-billion-dollar annual market by the year 2004. While exact figures vary between surveys, an estimated 12% to 18% of adults in the United States use herbal remedies; in selected groups, this figure is greater than 50%. Contrary to popular belief, the majority of herbal therapy users are not "naturalists" or "health nuts" but rather are average adults who incorporate botanical therapies into their total health care. Research has shown that many patients of conventional medicine also use herbal therapies, and 18% of patients who take long-term prescription medications simultaneously use at least one herbal remedy. Adults who use alternative therapies themselves are more likely to use these therapies for their children. In addition, members of some cultural or ethnic groups who have traditionally practiced herbal-based medicine (e.g. South African, Chinese, Native American), frequently continue to rely heavily on these products. As such, the use of herbal therapies in the United States is widespread and is expected to increase. While there is considerable anecdotal evidence about the efficacy of some botanicals, and plants have been and will continue to be a rich source of conventional pharmaceuticals, little is known about the safety of these herbal preparations. Few, if any of them, have been subjected to rigorous scientific evaluation for possible adverse effects, and there is only limited information about dose-related toxicity. Despite these obvious deficiencies, the general population often believes that herbal products are inherently safe and free of side effects because they are "natural". Accordingly, these products typically are used in unspecified quantities and without medical supervision. Just as with any chemical agent, however, botanicals have the potential to be toxic and to interact with prescription medications. Furthermore, as with pharmaceuticals, the liver is at unique risk for the herbal remedy-induced toxicity because it is a major site of drug/chemical uptake, metabolism and excretion. Therefore, with the widespread use of botanicals, we may expect to see increased numbers of cases of suspected herbal remedy-induced hepatotoxicity, and pathologists will be called upon to assess the liver biopsies performed as part of the diagnosis and clinical evaluation of these patients. A brief review of the current regulatory status of herbal products is useful to understand some of the toxicity issues unique to these agents. In response to the burgeoning interest in alternative medicines, in 1992 the Office of Alternative Medicine was established as a branch of the National Institutes of Health, and in 1998, this office was expanded to become the National Center of Complementary and Alternative Medicine (NCCAM). The NCCAM was assigned the charge of standardizing the alternative medicine industry, developing research programs that integrate proven alternative medicine modalities into conventional medical care, and providing the public with a reliable assessment of the safety and efficacy of alternative therapies. Despite the formation of this office, botanical products remain relatively unregulated. In large part, this is due to the Dietary Supplement Health and Education Act, legislation passed in 1994 by the United States Congress, which permits the classification of botanicals as "dietary supplements", not pharmaceuticals, as long as these products are not marketed as preventing or treating disease. By avoiding the designation of "pharmaceutical", these "dietary supplements" are considered "foods", and thus may be marketed without prior submission of efficacy and safety data to the United States Food and Drug Administration (FDA). Consequently, the labeling on many of these "dietary supplements" euphemistically describe the use of the product for organ "wellness" or "health" or to "support" or "maintain" normal function or structure (e.g. saw palmetto to "promote prostate wellness", horse chestnut seed extract for "leg vein health", butterbur to "support urinary bladder muscle strength"). However, the intended medical and disease-specific uses of these products often are well known to the general public through books and pamphlets (often kept in health food stores alongside the products) as well as a myriad of Internet sites. As such, in practical terms, these botanical "dietary supplements" are being used as drugs to treat specific diseases, but legally they are not required to meet the efficacy and safety standards of conventional pharmaceuticals. Ironically, the very over-the-counter availability of these products helps to foster the perception that they are implicitly safe. Assurance of the quality control and safety of these products is particularly difficult because of characteristics inherent to the very nature of herbal remedies. Botanicals typically are prepared from plants by simple processes, such as pulverization or aqueous or alcohol extraction, methods typically devoid of extensive purification steps or standardization. Consequently, herbal remedies are often crude mixtures of many chemical compounds. These chemical constituents may not be well characterized or even known, and typically, the full spectrum of their biologic activity is undocumented. Environmental conditions, such as climate, geographic location, and season of the year in which the plant is harvested, may result in dramatically different levels of pharmacologically active constituents in the plants. As such, there is little consistency in dosage or standardization of the quantity of the active ingredient. In addition, herbal preparations lack purity standards and may contain a variety of other ingredients, such as pesticides, heavy metals (e.g. arsenic, mercury, lead), non-declared prescription medications, or microbial or fungal growth due to incorrect storage. Additional problems with herbal medications include botanical misidentification and formulations composed of complex mixtures of ingredients that are not specifically identified (e.g. Chinese medicinal teas). These quality control and safety issues inherent to herbal remedies are potentiated by the relatively unregulated "dietary supplement" status of botanicals. Pathogenetically, chemical agents (whether synthetic or natural) that can damage the liver are classified as either intrinsic hepatotoxins or idiosyncratic hepatotoxins. As with conventional drugs that cause liver injury, some hepatotoxic herbal agents are intrinsic hepatotoxins whereas others cause liver damage through idiosyncratic means. Intrinsic hepatotoxins predictably cause liver damage in virtually every exposed individual. As such, their incidence of hepatic injury is high, and this toxicity is dose dependent. The latent period between exposure to the agent and the onset of hepatic injury typically is short and is relatively consistence between individuals. These agents, or their metabolites, are cytotoxic, and cause cellular injury by direct physiochemical or structural damage. Callilepis laureola, germander, atractlysis, and pyrrolizidine alkaloids (present in a number of medicinal plants, e.g. comfrey) cause liver injury in a pattern characteristic of intrinsic hepatoxins. Perhaps the most widely studied of these are the pyrrolizidine alkaloids, which cause veno-occlusive disease in a dose-dependent manner. The alkaloid is metabolized by cytochrome P450 to a reactive and toxic intermediate. This metabolism can occur in both hepatocytes and sinusoidal endothelial cells, but the greater susceptibility of the latter cells may be critical in the pathogenesis of the injury. In contrast, the toxicity of idiosyncratic hepatotoxins is non-predictable. They produce hepatic injury in a small proportion of exposed individuals, and this toxicity is not dose dependent. The latent period usually is long and is variable between individuals. These agents are thought to cause injury due through either metabolic or immunologic means. Metabolic idiosyncrasy results from a unique metabolic aberration in an individual that permits production of or accumulation of injurious amounts of hepatotoxic metabolites of the agent. A familial lack of an enzyme necessary for metabolism of a drug is an example of metabolic idiosyncrasy. Most cases of immunologic idiosyncratic injury are believed to result from a hypersensitivity (i.e. allergic) response of an individual to the agent. Such cases may demonstrate clinical manifestations of hypersensitivity (fever, rash, peripheral eosinophilia) as well as abundant eosinophils in the hepatic inflammatory infiltrate. Another possible mechanism of immunologic idiosyncrasy is an autoimmune-type response that involves formation of a neoantigen by the reaction of a metabolite of the drug with a hepatocellular protein; presumably, the immune response to the neoantigen accounts for the autoimmune-type hepatic injury. As such, idiosyncratic hepatotoxins are not directly hepatotoxic; instead, they are dependent on the unique metabolic or immunologic features of the individual. Greater celandine (Chelidonim majus) and Jin Buan Huan (a traditional Chinese medicinal) appear to cause hepatotoxicity through a hypersensitivity idiosyncratic reaction. Dai-saiko-to, a Japanese herbal preparation, may trigger an autoimmune-type hepatitis through an immunologic idiosyncratic mechanism. Pathology Liver injury caused by conventional drugs may result in virtually any histologic pattern of hepatobiliary disease. The injury may be hepatocellular, cholestatic, or mixed in type. The degree of injury may vary from mild and reversible to fulminant hepatic necrosis. While the majority of cases present as an acute liver injury, sometimes the clinical presentation and histologic appearance is that of a chronic liver disease, such as chronic hepatitis or even cirrhosis. In addition to the more common hepatitic and cholestatic lesions, some drugs may cause steatosis, vascular changes or neoplasms. Similar to conventional drugs, herbal agents also cause a diverse variety of morphologic patterns of hepatic injury (Table 1). Just as with pharmaceuticals, varying degrees of hepatocyte necrosis may be seen, which range from individual hepatocyte necrosis to zonal necrosis (typically zone 3) to fulminant, panacinar hepatic necrosis. Alternatively, the damage may manifest as either an acute or chronic hepatitis; depending on the offending agent, this injury may have a cholestatic, hepatocellular, autoimmune, or giant cell hepatitic appearance. Sometimes cirrhosis may be present at the time of clinical presentation. Vascular injury, such as the veno-occlusive disease, is a well-documented injury caused by pyrrolizidine alkaloids, which are present in a number of botanicals. Steatosis, either macrovesicular or microvesicular, has been described in association with certain herbal agents. Due to this diversity of morphologic appearances, herb-induced hepatoxicity would be considered in the differential diagnosis of many histologic patterns of liver injury. Differential diagnosis If present, certain uncommon patterns of liver injury should arouse suspicion for drug or herbal hepatotoxicity. These include zonal hepatic necrosis (typically zone 3), necrotic lesions with steatosis or bile duct injury, and vascular injury, especially veno-occlusive disease. Similar to liver injury caused by conventional drugs, however, the diagnosis of herbal remedy-induced hepatoxicty usually is made by circumstantial evidence. Because there are no specific diagnostic tests and herb-induced liver injury may resemble a diverse variety of hepatobiliary diseases, the diagnosis requires exclusion of other etiologies of liver injury, a high degree of clinical suspicion, and a detailed drug history (both pharmaceuticals and herbal remedies). This latter information may be difficult to obtain, because upon questioning, up to 70% of patients do not report their intake of herbal preparations. This reluctance may be due to fear of the physician's disapproval or the belief that intake of "natural remedies" is not relevant to a question about drug exposure. Once this information is obtained, however, consideration of the chronological relationships between herbal intake and onset of the liver disease, as well as the response after stopping the herb, are important considerations in establishing this diagnosis. Deliberate re-challenge with the agent is rarely indicated for ethical reasons (it can be hazardous) but inadvertent re-challenge may have occurred and can provide important supportive evidence. Table 1: Hepatoxicity of herbal products (selected list) Herbal Product Species Type of Hepatic Injury Comfrey Symphytum Sp Veno-occlusive disease Gordolobo herbal tea Veno-occlusive disease Chinese herbal preparations and medicinal teas: complex mixtures of a variety of ingredients) Veno-occlusive disease; chronic cholestasis with vanishing bile duct syndrome Jin Bu Huan: includes Lycopodium serratum and Polygala chinensis Acute and chronic hepatitis; cholestatic hepatitis; microvesicular steatosis; fulminant hepatic failure Germander Teucrium chamaedrys Acute and chronic hepatitis; cirrhosis; hepatocellular or cholestatic liver injury; hepatocellular necrosis - zone 3; fulminant hepatic failure Callilepis laureola Hepatocellular necrosis - zone 3 Atractylis gummifera Hepatitis; hepatocellular necrosis; fulminant hepatic failure; steatosis Chaparral Larria tridanta Acute and chronic hepatitis; hepatocellular necrosis - zone 3; fulminant hepatic failure, cholestatic hepatitis Greater celandine Chelidonim majus Acute cholestatic hepatitis Kava Acute hepatitis; hepatocellular necrosis - panacinar; fulminant hepatic failure Mistletoe Viscus album Chronic hepatitis Dai-saiko-to: a Japanese herbal preparation that includes extracts from a variety of plants Autoimmune hepatitis; hepatocellular necrosis - zonal or bridging; microvesicular steatosis Isabgol: mixture which includes Plantago ovata and Emblica officinalis Giant cell chronic hepatitis Cascara sagrada - a mixture of ingredients Cholestatic hepatitis Saw palmetto Chronic hepatitis Ma-huang Acute hepatitis; autoimmune hepatitis The diagnosis of herbal-induced hepatotoxcity is facilitated by information regarding whether a particular botanical causes liver damage, and if so, the specific type(s) of hepatic injury. To this end, the NCCAM sponsors an educational website (www.nccam.nih.gov), and MedWatch is an FDA-sponsored program available for physicians to report adverse events associated with products monitored by the FDA, including special nutritional products (telephone 1-800-FDA-1088; Internet at www.fda.gov/medwatch/). The latter website also provides a searchable database that allows users to identify adverse events associated with a specific "dietary supplement", making this a very useful tool to identify possible herbal remedy-induced hepatotoxicity. References Brent J. Three new hepatotoxic syndromes. Clin Toxicol 1999;37:715-9. Buck ML, Michel RS. Grand Rounds: Talking with families about herbal therapies. J Pediatri 2000;136:673-8. Kumana CR, Ng M, Lin HJ, Ko W, Wu P-C, Todd D. Herbal tea induced hepatic veno-occlusive disease: quantification of toxic alkaloid exposure in adults. Gut 1985;26:101-4. Larrey D. Hepatoxicty of herbal remedies. J Hepatol 26 Suppl 1;1997:47-51. Marrone CM. 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