Update and Application to Liver Biopsy Interpretation in Clinical Practice
Case 5 -
Herbal Remedy-induced Hepatotoxicity
Julia C. Iezzoni
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
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
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
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.
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.
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)
|Type of Hepatic Injury|
|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|
|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|
|Acute and chronic hepatitis; hepatocellular necrosis - zone 3; fulminant hepatic failure, cholestatic hepatitis|
|Acute cholestatic hepatitis|
|Kava ||Acute hepatitis; hepatocellular necrosis - panacinar; fulminant hepatic failure|
|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.
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