Hepatotoxicity due to herbal medications and dietary supplements

INTRODUCTION — Complementary and alternative medical (CAM) therapies encompass a diverse group of practices that include the use of herbal and dietary supplements (HDS) (table 1) [1]. The use of CAM therapies in the United States (US) and worldwide has been increasing steadily; however, the prevalence is unknown [2]. In the US, out-of-pocket costs in 2008 were $14.8 billion, and by 2012 costs exceeded $30.2 billion [3-6]. Survey data have suggested that use of HDS ranges from 10 percent to over 75 percent depending on the country [7-12]. The most commonly used CAM therapies are herbal and dietary supplements [5,13]. The most common reason reported for their use is for health improvement and health maintenance [14]. Women, persons younger than age 65 years, and individuals with a higher annual household income have been reported to be more likely to use CAM therapies [1,3,5,15,16].

Use of herbal preparations can be traced back as far as ancient Egypt, China, India, and Sumeria, and formulations have been expanded upon over the centuries [17,18]. Many patients consider herbal remedies to be completely free of unwanted side effects [19-21]. This is concerning since herbal products have biologic activity that can lead to severe hepatotoxicity or that interact with one other or with prescription medications. Fewer than 40 percent of patients disclose to their clinician that they are using these products, either alone or in conjunction with conventional drugs [1,3,22].

DATABASE OF DRUGS, HERBS, AND SUPPLEMENTS ASSOCIATED WITH HEPATOTOXICITY — Over 1000 medications and herbal products have been implicated in the development of drug-induced liver injury, and the list continues to grow [12,23]. A searchable database of drugs, herbal medications, and dietary supplements associated with hepatotoxicity has been developed by the National Institutes of Health (NIH) [24]. Additionally, the NIH has developed a dietary supplement label database, containing over 40,000 products [25].

REGULATION — Regulation of herbal and dietary supplements (HDS) varies by country. In 1962, the US Kefauver-Harris Drug Amendment required that all over-the-counter and prescription products show proof of safety and efficacy [26]. Complementary and alternative medicines (CAMS) were assigned to the food supplement category and had a lower threshold of required evidence for safety [26]. An attempt by the US Food and Drug Administration (FDA) in the early 1990s to develop more strict regulations was met with significant opposition by supplement manufacturers, lobbyists, and consumers.

The Dietary Supplement Health and Education Act (DSHEA) of 1994 was an amendment to the US Federal Food, Drug, and Cosmetic Act (FD&C) [27,28]. The DSHEA defines a dietary ingredient as a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use by humans to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of the preceding substances [17,27,29]. These products may be in the form of tablets, capsules, soft gels, gel caps, liquids, teas, or powders. The United States Pharmacopeia–National Formulary (USP–NF) is the official reference for herbal preparations [27]. The United States Pharmacopeia is an official public standards-setting authority for all prescription and over-the-counter medicines and other healthcare products manufactured or sold in the United States [30]. The USP also sets standards for food ingredients and dietary supplements.

Under the DSHEA, the FDA is responsible for proving whether or not there are safety concerns and taking action against any unsafe dietary supplement product only after it reaches the market. Products in distribution prior to 1994 were allowed to remain on the market; their use justified based upon experience from trial and error, not rigorous scientific scrutiny. Supplement manufacturers are not required to register themselves or their product with the FDA prior to distribution or to obtain FDA approval before producing or selling supplements [27,31]. They are also responsible for reporting any side effect and ensuring that their product has not been adulterated. The FDA monitors product information, such as labeling and claims, and also monitors safety through a voluntary dietary supplement adverse event reporting system. Over the years, the FDA has issued warnings on products that have been reported to have hepatotoxicity [32]. The Federal Trade Commission regulates advertising of dietary supplements [31].

The DSHEA requires that manufacturers establish product safety before marketing. Manufacturers must also ensure that the product label is truthful and not misleading. The label must contain a complete list of all ingredients contained in the product and the identity of the manufacturer. Manufacturers must also limit the claims that can be made (health claims, nutrient content claims, and structure/function claims) [33]. Structure/function claims are those which claim that the nutrient or dietary ingredient is intended to affect normal structure or function in humans (ie, "calcium builds strong bones"). They may also describe the means by which a nutrient or dietary ingredient acts to maintain such structure/function (ie, "fiber maintains bowel regularity"), or they may describe general wellbeing from consumption of the nutrient or dietary ingredient. Structure/function claims may also express a benefit related to a nutrient deficiency disease (ie, "vitamin C prevents scurvy"). In this last setting, they must include a statement telling how widespread the disease is in the United States. If a manufacturer makes a structure/function claim, the DSHEA requires a disclaimer: "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease."

If a manufacturer makes a structure/function claim on the supplement label, the DSHEA requires a disclaimer: "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease."

The Final Rule for Current Good Manufacturing Practices for Dietary Supplements was passed in 2007 as a further step in attempting to ensure the safety of herbal and dietary supplements (HDS) [34]. This rule requires that manufacturers follow certain standards in the production of HDS. Manufacturers are required to verify the contents of the product (ie, identify the ingredients, strength) and ensure that the product is contamination free. However, the Final Rule does not address the safety or efficacy of the product ingredient itself.

The DSHEA requires that a product's label accurately reflect its contents. However, there may be significant discrepancies between the ingredients listed on the label and the actual contents of the preparation. This is especially true of preparations containing multiple plants or herbs (ie, Chinese remedies), which may be adulterated either unintentionally or intentionally by cheaper, more toxic herbs, heavy metals, microbials, and pharmaceutical medicines (such as acetaminophen, aspirin, benzodiazepines, sildenafil, or steroids) [19,20,35-50]. As many as one-third or more of products can be adulterated [39,51-53]. There can also be variations between batches of the same herbal product from the same manufacturer [35,54-56]. It can be difficult to identify the agent actually responsible for the hepatotoxicity [57].

The widespread use of mixed remedies and the lack of randomized trials make any review of the safety and efficacy of herbal remedies difficult. In addition, conformity to the USP standards is voluntary, and there are no regulatory standards for HDS. The European Food Safety Authority (EFSA) monitors claims made on herbal products [58]. Across the world, regulation and safety monitoring remain limited, and the World Health Organization has developed a Traditional Medicine Strategy [59].

FREQUENCY OF HEPATOTOXICITY — There are no precise estimates of the frequency of hepatotoxicity attributable to herbal and dietary supplements (HDS). Patients often do not report the use of herbal products to their clinicians, and they self-medicate with large amounts [3,47]. As a result, hepatotoxicity associated with herbal use may be missed. The United States Drug-Induced Liver Injury Network (DILIN) found that approximately 15 to 20 percent of cases of drug-induced liver injury (DILI) could be attributed to HDS [60]. Additionally, this proportion of DILI cause by HDS increased from 7 to 20 percent between 2004 and 2013 [60]. Others, depending on the geographic location, have implicated HDS in up to 73 percent of cases of DILI [51,60-71]. Additionally, it has been estimated that fewer than 1 percent of adverse reactions to dietary supplements are reported [27].

DIAGNOSIS — Patients are often reluctant to discuss use of herbal and dietary supplements (HDS)/complementary and alternative medicines (CAMs) or do not recognize them as medications [47]. It is important for the clinician to discuss the use of these products with the patient in a nonjudgmental manner. Patients can then be educated on the potential adverse effects and herb-herb or drug-herb interactions that may occur. This may prevent the development of hepatotoxicity. However, the unreported use of herbal remedies must be considered as a possible etiology in any setting of clinical manifestations of liver injury.

Herb-induced liver injury (HILI) typically presents as acute hepatocellular injury with extremely elevated aminotransferases and bilirubin and jaundice [72]. However, it may also present as asymptomatic liver enzyme elevations, acute or chronic hepatitis (symptomatic malaise, nausea, vomiting, abdominal pain, etc.), acute liver failure with coagulopathy and encephalopathy, or with signs and symptoms of cirrhosis.

Continued use of the offending product increases morbidity once hepatotoxicity has developed [36,73]. The patient may even increase the use of the herbal preparation to help manage the new symptoms, further worsening the liver injury. For patients with elevated liver enzymes, other causes of liver disease must be ruled out. Patients often use herbal remedies to treat their chronic disease and may, in fact, exacerbate it [4,5,54]. Continued ingestion of the herbal preparation in the face of ongoing hepatotoxicity may lead to acute liver failure, sinusoidal obstruction syndrome, or cirrhosis [20,63,74].

The pattern of liver injury is similar to that seen with other forms of drug-induced liver injury (DILI). It can be hepatocellular, cholestatic, a mixture of the two, or vascular (ie, sinusoidal obstruction syndrome). Hepatocellular injury is more frequent with HILI than is seen with DILI secondary to conventional medications [32,63,75]. In addition, patients presenting with a hepatocellular pattern of injury, particularly in women, have a poorer prognosis [65,76,77]. (See "Drug-induced liver injury".)

The diagnosis of HILI can be difficult. Clinical history may be helpful but is not always reliable. The relationship between the exposure and the hepatic toxicity is not always clear. In addition, patients may be taking multiple preparations, making identification of a single offending agent impossible. They may also have concomitant liver disease, such as alcohol use disorder or nonalcohol-associated steatohepatitis (NASH), which can produce similar clinical and laboratory features. There is no gold standard, and no specific tests or serum biomarkers exist to confirm a diagnosis of drug-induced liver injury from either a prescription medication or an herbal remedy. Proving that an HDS causes HILI relies on both chronologic and clinical criteria [78,79].

The Council for International Organizations of Medical Sciences (CIOMS) developed a series of standard designations of drug-induced liver disorders and classification of injury [80]. The US Food and Drug Administration (FDA) Drug Hepatotoxicity Steering Committee proposed modifications to the CIOMS classification scheme for classifying hepatotoxicity in clinical trials (table 2) [81]. These guidelines are used as markers of hepatotoxicity in clinical trials.

A number of scales have been developed that attempt to codify causality of drug toxicity into objective criteria [82]. The best known scale is the Roussel Uclaf Causality Assessment Method (RUCAM) scale, also called the Council for International Organizations of Medical Sciences (CIOMS) scale. Other scales including the Maria & Victorino scale and the Naranjo scale are simpler clinical diagnostic scales [79,83-85]. Studies that have compared these models suggest that the RUCAM (CIOMS) scale may have better discriminative ability [78,82,86]. While these scales have not been validated in the setting of herbal medications, they may be useful (table 3). None of these scales address all risk factors in all patients, and none are used routinely in clinical practice [79]. One of the most important diagnostic criteria remains the exclusion of other causes of liver injury. RUCAM (CIOMS) has been validated independently in the setting of drug rechallenge [84]. The Drug-Induced Liver Injury Network (DILIN) developed the DILIN Causality Scoring System to adjudicate the causality of drug-induced injury for patients enrolled into its prospective clinical trial [87]. This model relies on structured expert opinion, and when compared with the RUCAM, it produces higher agreement rates and likelihood scores. However, intraobserver variability remains significant. Unfortunately, the DILIN scale is not a clinically viable option of determining causality since it relies on expert opinion.

Features suggesting HILI include lack of illness prior to ingesting the HDS, clinical illness or biochemical abnormalities developing after beginning the offending agent, and improvement after the product is withdrawn. If an immunologic reaction is suspected, the illness will generally recur upon reintroduction of the offending substance. For patients with suspected HILI, rechallenge is not advised. Nonspecific symptoms developing after introduction of an HDS (such as nausea, anorexia, malaise, fatigue, right upper quadrant pain, or pruritus) may indicate HILI and should prompt evaluation. Unlike the more stereotypic presentations seen with hepatotoxicity due to most drugs, the clinical presentations of injury secondary to HDS are less typical and have been less well-defined [32]. Exceptions to this are hepatotoxicity to anabolic steroids and pyrrolizidine alkaloid-containing products.

Key elements for attributing liver injury to an HDS are similar to those for other drug products and include [88]:

●Exposure must precede the onset of liver injury (although the latent period is highly variable).

●Underlying liver disease should be excluded.

●Injury may improve when the HDS is stopped (although, in some cases, injury may initially worsen for days or weeks while, in fulminant cases, declining liver biochemical tests may indicate deterioration rather than improvement).

●Liver injury may have recurred more rapidly and severely after repeated exposure.

TREATMENT — The mainstay of therapy for HILI is withdrawal of the offending toxin. Early recognition of toxicity is important to permit assessment of severity and monitoring for acute liver failure. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)

Glucocorticoids are of uncertain benefit for most forms of drug hepatotoxicity, although they may have a role for treating patients with hypersensitivity reactions [89]. Our practice is to give glucocorticoids to patients with hypersensitivity reactions who have progressive cholestasis despite herbal and dietary supplements (HDS) withdrawal and who have biopsy features that resemble those seen in autoimmune hepatitis. In addition, we give glucocorticoids to patients with extrahepatic manifestations of a hypersensitivity reaction that warrant glucocorticoid treatment (eg, severe pulmonary involvement in patients with DRESS [drug reaction with eosinophilia and systemic symptoms]). (See "Overview of autoimmune hepatitis", section on 'Histology' and "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Management'.)

Patients should be followed by serial biochemical measurements. Hepatology consultation may be warranted.

Recovery should be expected in the majority of patients after discontinuing the HDS. More advanced disease requires supportive therapy, with acute liver failure often leading to death or need for liver transplantation. In this setting, mortality can be over 80 percent. The development of jaundice (bilirubin greater than two times the upper limit of normal in the setting of an alanine aminotransferase greater than three times the upper limit of normal) following introduction of a HDS potentially portends a poor outcome and should also prompt immediate referral to a center with expertise in hepatology [65,90,91]. Patients who recover from HDS induced hepatotoxicity generally have a favorable prognosis.

In the United States, the Food and Drug Administration records HDS toxicity. Cases of HDS hepatotoxicity should be reported to 1-800-332-1088 or https://www.fda.gov/safety/reporting-serious-problems-fda/reporting-health-professionals.

SPECIFIC HEPATOTOXIC HERBS — The many reports in the literature of the toxic effects of herbal remedies underscore the view that not all natural products are harmless. Hepatotoxicity may be the most frequent adverse reaction to herbal remedies [92,93]. Some of the more frequently reported offending herbs include Chinese remedies and teas (Jin Bu Huan [94,95], Ma-Huang [96-98]), germander [74,99-104], valerian [105], mistletoe [106], skullcap [105-107], chaparral [108-112], comfrey [113-117], herbal teas containing toxic alkaloids [115,118-120], pennyroyal oil [121], and kava (table 4) [93,122-126]. Although liver abnormalities are frequently transient, cases of chronic liver disease and acute liver failure have been described [19,20,126,127].

The list that follows includes some of the herbs that have been associated with hepatotoxicity. However, the list of herbal medications, dietary supplements, and medications associated with hepatic injury is long. A more complete listing can be found in the searchable database of drugs, herbal medications, and dietary supplements developed by the National Institutes of Health [128].

Pyrrolizidine alkaloids — Pyrrolizidine alkaloids (PAs) are a group of naturally occurring alkaloids based on the structure of pyrrolizidine. More than 660 PAs and PA N-oxides have been identified in over 6000 plant species throughout the world (3 to 5 percent of the world's flowering plants) (table 5) [129,130]. They are used for a variety of complaints, including arthritis, gout, and a number of infections. Over 50 percent of PAs exhibit hepatotoxicity [119,130]. Their hepatotoxicity, which has been long recognized, is predominantly observed after exposure to the following plant families: Boraginaceae (Heliotropium, Trichodesma, Symphytum [Comfrey]), Compositae (Senecio [Bush Teas], Eupatorium), Crotalaria (Leguminosae), Echinacea (Echinacea purpurea) [131], Germander (Teucrium chamaedrys), Greater Celandine (Chelidonium majus), and Scrophul-ariaceae (Castilleja) [113-115,118-120,132-134]. PA poisoning is common in areas where traditional remedies are frequently used (such as Africa and India) [135,136]. In Western countries, it is seen more sporadically. Comfrey has been removed from the market in France following numerous reports of liver damage. It remains widely available in the United States despite US Food and Drug Administration (FDA) requests to remove comfrey products from the market [115,137].

Alkaloid toxicity usually results in moderate to severe liver damage, particularly to the hepatic central vein and sinusoidal endothelium. Hemorrhagic necrosis, hepatomegaly, ascites, and endothelial cell proliferation are also seen. This can lead to occlusion of the hepatic veins, resulting in hepatic sinusoidal obstruction syndrome (formerly veno-occlusive disease), a progressive form of portal hypertension, which often progresses to hepatic failure [138,139]. Sinusoidal obstruction syndrome is the characteristic histologic feature of PA hepatotoxicity [134]. (See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

The precise mechanism of hepatic injury is unknown but appears to result from accumulation of highly reactive electrophilic metabolites produced via the cytochrome P450 (CYP450) enzyme system [19,113,121]. The increased concentration of P450 enzymes within the hepatic centrilobular region correlates with the changes seen histologically. The pyrrolic metabolite, dehydro riddelliine, covalently binds to cellular DNA, which have been identified in the blood [134]. The damage is compounded by depletion of glutathione or induction of CYP450 3A4 [17,140]. PAs have also been shown to induce apoptosis [140,141].

Nonthrombotic luminal occlusion of the small centrilobular veins leads to hepatic congestion and subsequent hemorrhagic parenchymal necrosis [19,142]:

●With acute injury, patients typically present with sudden onset abdominal pain, jaundice, conjugated hyperbilirubinemia, and elevated aminotransferases. Hepatomegaly and ascites are common.

●The subacute and chronic forms are more insidious and may mimic cirrhosis and portal hypertension from other causes. However, histology shows a distinctive pattern of centrilobular injury [138].

Hepatotoxicity from PAs is dose and time dependent and reproducible [143]. Approximately one-half of patients with hepatotoxicity develop limited lesions and generally proceed to complete recovery once the offending herb has been discontinued [138,144]. More extensive disease can lead to cirrhosis, hepatic failure, and death [19,21,144]. The acute form is rapidly fatal in 20 to 40 percent of patients (with worse prognosis in adults compared with children). Approximately 15 percent with acute disease will progress to subacute or chronic injury, succumbing within several years to end stage liver disease. Of the remainder, most develop cirrhosis and portal hypertension [36,138,144,145]. Death may occur two weeks to more than two years after poisoning, but patients may recover almost completely if the herb intake is discontinued and liver damage is not severe.

Ayurvedic herbs — Ayurvedic medicine originated in ancient India. These herbal and dietary supplements (HDS) have been used most commonly on the Indian subcontinent in the practice of traditional medicine (Ayurveda), but their use is expanding worldwide. Ayurveda uses many medicinal plants that contain toxic pyrrolizidine alkaloids [146,147]. They include Psoralea corylifolia, Centella asiatica, Acacia catechu, Eclipta alba, and Vetivexia [64,148-150]. Both acute and chronic hepatitis have been reported. Additionally, many of these products have been found to be adulterated with heavy metals, including lead, mercury, or arsenic [48,151].

Germander — The blossoms of germander (Teucrium chamaedrys) have been used for thousands of years for a variety of symptoms [152]. It is used in tea form or alcohol-based extracts. The herb is said to have choleretic properties, although this has never been scientifically proven. It is also used for dyspepsia, hypertension, diabetes, gout, and obesity [129]. Liver injury can present as acute hepatitis, chronic hepatitis, or acute liver failure [74,99,100,152,153]. The herb has been removed from the market in France because of its hepatotoxicity [102,103]. The majority of cases of hepatotoxicity have occurred at the manufacturers' recommended doses (600 to 1600 mg/day). Clinical symptoms generally occur after approximately two to three months of ingestion and include a nonspecific hepatitis, which generally runs a benign course [19]. Typical features include anorexia, nausea, abdominal pain, and jaundice associated with a marked elevation in serum aminotransferases. Complete recovery is usually seen within two to six months following discontinuation of the herb. Fatal cases have been described, as have more insidious presentations with progression to cirrhosis [17,19,74,101]. Cirrhosis generally develops in patients who have ingested the offending herb for longer periods of time or in larger quantities.

Germander contains toxic alkaloids, the furanic neoclerodane diterpenes (NCDs), which are oxidized by the cytochrome P450 3A4 enzyme system into hepatotoxic reactive metabolites [99,154]. The toxic metabolites accumulate and covalently bind to cellular proteins, which in association with the depletion of the free-radical scavenger glutathione, leads to acute centrilobular hepatocyte necrosis in vivo. In vitro studies have revealed progressive apoptosis and cytoskeletal disorganization [20,154].

Poley (Teucrium polium) is in the same genus as germander and is used for diabetes (in Israel), gastric complaints (in North Africa), fever (in Italy), and as a poultice (in Spain). It has also been linked to hepatotoxicity and acute liver failure [104,155,156]. Teucrium capitatum and T. viscidum have also been reported to cause hepatotoxicity [157,158].

Greater celandine — Greater Celandine (Chelidonium majus) is a member of the poppy family that grows mainly in Europe and Asia but has been introduced into North America. It is considered a cleansing herb and is said to stimulate pancreatic enzymes and bile. In fact, it has been shown to increase biliary flow in experimental models [159]. Therefore, it is often used for hepatobiliary (jaundice, hepatitis, and gallbladder) and digestive tract (dyspepsia, gastroenteritis, irritable bowel syndrome, constipation, anorexia, stomach cancer, intestinal polyps) complaints [160]. The plant contains over 20 alkaloids [160]. When used orally, it has been implicated numerous cases of liver injury [133,160-167]. Jaundice is generally the predominant symptom, but anorexia, nausea, vomiting, abdominal pain and itching have been reported. Liver enzyme elevations range from 100 to over 4,000 units/L, and injury is hepatocellular and idiosyncratic in the majority of cases [167]. However, cholestatic hepatitis has also been reported [133,161]. The mechanism of hepatotoxicity is unclear. Liver injury appears to show a female predominance [167,168]. Histologic examination of the involved liver has suggested metabolic hepatotoxicity [133,161,167]. There have been no reports of fatalities and discontinuing generally leads to resolution of liver injury over two to six months. Greater celandine has been banned from use in many European countries.

Chaparral — Chaparral (Larrea tridentata) is indigenous to the southwestern United States and is derived from the leaves of the creosote bush (greasewood). It is said to have antiamebic, antibacterial, antifungal, and antiviral properties. It is used for diarrhea, cramps, chest pain, upper respiratory tract infections, rheumatism, cutaneous venereal lesions, chronic skin disorders, and weight loss [144]. It has been popular among patients with HIV infection [169]. It is available in the form of tea, capsules, tablets, and salves [108]. Scientific evidence regarding chaparral’s effectiveness is lacking.

Patients with chaparral-induced hepatotoxicity typically present with acute hepatitis [108]. Marked elevation in the serum aminotransferase and bilirubin values may be seen. Alkaline phosphatase may be mildly elevated. Acute hepatocellular injury of varying degrees of severity has been reported, including mild cholestatic hepatitis, severe collapse of parenchymal architecture, hepatic fibrosis, and massive liver failure requiring transplantation [108-112,170]. The onset of disease occurs 3 to 52 weeks after the ingestion and resolves in 1 to 17 weeks in most cases [108]. Progression to cirrhosis or acute liver failure requiring liver transplantation has been reported [108].

Atractylis gummifera and callilepis laureola — Atractylis gummifera grows in the Mediterranean and is used as an antipyretic, emetic, abortifacient, and diuretic, and hepatotoxicity continues to be reported [19,171,172]. Toxicity is secondary to two diterpenoid glucosides: atractyloside and carboxyatractyloside [173]. These toxins inhibit mitochondrial oxidative phosphorylation by interacting with a mitochondrial adenine nucleotide translocator, inducing oxidative stress [173,174]. The onset of toxicity is rapid, occurring within hours after ingestion. It often leads to acute liver and kidney failure and subsequent death.

Callilepis laureola (Impila) is native to South Africa [175,176]. Like A. gummifera, it contains atractyloside. Its toxicity has been linked to depletion of cellular glutathione. It has a similar rapid onset of action and mortality rates are over 90 percent by five days after ingestion. There have been reports that supplementation with N-acetylcysteine may reduce its toxicity [175].

Pennyroyal — Pennyroyal (Mentha pulegium) is a highly toxic agent that can cause both hepatic and neurologic injury. It is frequently used to flavor herbal remedies and teas (particularly mint teas) and is often used for digestive disorders, liver disorders, amenorrhea, gout, colds, increased micturition, and for skin diseases. It also continues to be used as an abortifacient. Acute toxicity leads to gastrointestinal distress and central nervous system (CNS) effects within one to two hours of ingestion (up to 10 mL of the oil), and fatal ingestions can occur with ingestion of >15 mL of the oil [177].

The P450-induced oxidative metabolites (menthofuran) of the active compound pulegone are associated with severe hepatic toxicity from centrilobular degeneration and massive necrosis [144]. These metabolites bind to cellular proteins and deplete hepatic glutathione [121,178,179]. The use of N-acetylcysteine may help minimize hepatic injury [177].

Mistletoe — Mistletoe (Viscum album) is purported to be effective in treating asthma, epilepsy, arteriosclerosis, cardiac arrhythmia, cramps, blood loss, nervous conditions, high blood pressure, joint pain, dizziness, and infertility [106]. There have been case reports of hepatitis [106]. Lectins in the product induce apoptosis and can also stimulate the immune system [32]. However, controversy remains as to whether mistletoe actually causes disease. In reported cases, the ingested capsules were also laced with Skullcap (Scutellaria galericulata). Skullcap and Valerian (Valeriana officinalis) have been implicated in liver injury, although there are no experimental data supporting their toxicity [19,21,105].

Kava kava — Kava kava (Piper methysticum) is used as a dietary supplement and has been used in the South Pacific for centuries for complaints of anxiety, sleeplessness, and menopausal symptoms. Numerous reports of severe hepatotoxicity and liver failure have been described in Europe and the United States [93,122-126,180-182]. Hepatotoxicity has been reported within a few weeks to up to two years (average 4.5 months) following ingestion [180].

Clinically, reports of toxicity range from transient elevation in aminotransferases to acute liver failure and death [93]. Liver injury has been characterized histologically with hepatic necrosis, cholestatic hepatitis, and lobular hepatitis. The mechanism of hepatotoxicity is unclear, but multiple hepatotoxic components have been identified, including pipermethystine and flavokavain B [183,184]. The aerial portions of the plant contain the toxic alkaloid pipermethysticin and are generally not consumed [183,184].

Based upon case reports of serious toxicity, the US Food and Drug Administration issued a consumer advisory regarding this toxic herbal product. Details of the advisory are available online. The product has been banned from many European markets. The link of toxicity to Kava kava remains debated [183]. Some propose that the aqueous preparation is safe [185], while others have shown that even this preparation leads to hepatotoxicity [186].

Green tea extracts — Extracts of Chinese green tea (Camellia sinensis L.) are commonly used and have been associated with hepatocellular injury [187-189]. In general, drinking green tea in moderation appears to be safe and may have beneficial effects. However, numerous supplement extracts are available and have been reported to cause liver injury. These extracts have been used in multiple weight-loss products, many of which have been removed from the market due to toxicity. The mechanism of hepatotoxicity remains unclear. Catechins such as epigallocatechin-3-gallate (EGCG) are likely to be involved. EGCG induces reactive oxygen species similar to other herbal products [190]. A genetic predisposition may also predispose to injury, and women are more susceptible than men [187,191]. Hepatotoxicity is increased in those who are fasting [131]. The pattern of injury is predominantly hepatocellular, but mixed and cholestatic presentations have been reported [190,192]. Liver injury generally develops within three months of use and usually resolves with discontinuation of the product.

Androgenic anabolic steroids — Anabolic steroid use has long been associated with many types of liver injury, including hepatitis, intrahepatic cholestasis, peliosis hepatis, hepatocellular adenoma, and hepatocellular carcinoma [193,194]. They were first identified and synthesized in the 1930s, classified as a class III controlled substance in 1991, and further regulated in 2004 [27]. Despite their regulation and well-known hepatic toxicity, their use remains widespread, and patients continue to present with hepatotoxicity [195,196]. The classic presentation is one of hepatocellular injury with severe jaundice a median of approximately 70 days following use [197]. Patients who present with markedly elevated bilirubin levels are also prone to acute renal injury [32]. The FDA issued a public health advisory warning consumers to stop using any body building products containing anabolic steroids or steroid-like substances [198].

Black cohosh — Black cohosh (Actaea racemosa) is indigenous to eastern North America. It is widely available and the rhizomes and roots are commonly used for the treatment of peri- and postmenopausal symptoms. The product contains many compounds, including phenolic acids, flavonoids, volatile oils, triterpene glycosides, and tannins [131]. There have been multiple reports of hepatotoxicity and adulteration [199,200]. Generally, this HDS results in an autoimmune-type of liver injury, and liver failure necessitating transplantation has been reported [131,199,201-204]. However, the causality between black cohosh and hepatotoxicity remains uncertain.

Flavocoxid — Flavocoxid is a prescription medical food that is a blend of two flavonoids, baicalin and catechins (derived from the plants Scutellaria baicalensis and Acacia catechu, respectively). It has been used to treat osteoarthritis. The United States Food and Drug Administration recommended discontinuation of flavocoxid because of reports of serious adverse events, including drug-induced liver injury [205]. In a prospective study of 877 patients, four patients (0.4 percent) developed liver injury [206]. The association between flavocoxid use and liver injury was deemed highly likely in three cases and possible in one. In all four cases, liver tests returned to normal within 3 to 12 weeks of discontinuing the flavocoxid.

CHINESE HERBAL REMEDIES — Over 11,000 species of medicinal plants are used in China [131]. Use of traditional Chinese medicines (TCM) has grown globally. Many TCMs have beneficial effects [38]. However, published reports on hepatotoxicity with TCM have been increasing [38,93,94,98,207-210]. Evidence regarding the incidence and prevalence rates of hepatotoxicity with these products is uncertain [211]. Studies of drug-induced liver injury which include TCMs report widely varying data, with TCMs accounting for 4 to 55 percent of cases, depending on the patient cohort [210].

Much of HILI due to TCMs are believed to be due to herbs containing pyrrolizidine alkaloids [212]. TCMs that have been shown to cause sinusoidal obstruction syndrome include Jing Tian San Qi (Sedum aizoon, syn. Stonecrop), Shan Chi (Gynura segetum), and Senecio vulgaris [213-215]. The TCM Shi Can contains Teucrium chamaedrys (Germander) or other Teucrium species which are a known cause of HILI [74].

The clinical course for patients with hepatotoxicity ranges from elevated liver enzymes [207,208] to acute liver failure and death or need for liver transplantation [127]. Up to 70 percent of these products produce reactive metabolites which cause hepatotoxicity [216]. It is often difficult to identify the agent responsible for the hepatotoxicity since most Chinese preparations are either mixtures of multiple herbal preparations (typically four to six different herbs) or have been adulterated with substituted herbs, heavy metals, or pharmaceutical medicines [19-21,35,37,39-42,52,53,64]. Generally, a single herb is considered primary (the "king" or "sovereign"), while the additional herbs are thought to act synergistically with the main product or to modify its toxicity [12]. Toxicity is generally observed with preparations that contain aconitine, podophyllin, or anticholinergics [208].

Jin Bu Huan — Jin Bu Huan (Lycopodium serratum) has been used for over 1000 years as a sedative and analgesic [94,152,153]. It has morphine-like properties due to the alkaloid levo-tetrahydropalmatine. It was banned for use in the United States in the 1990s following multiple reports of toxicity [94,95,217].

Both acute and chronic hepatotoxicity have been reported [94,95,217]. Patients with hepatotoxicity present at a mean of 20 weeks (7 to 52 weeks) after ingestion with acute hepatitis associated with fever, nausea, vomiting, fatigue, pruritus, abdominal pain, hepatomegaly, and jaundice. Plasma aminotransferase levels are significantly elevated. The liver biopsies that have been performed appear consistent with a drug-induced liver injury, demonstrating eosinophils and focal hepatocellular necrosis [94,95]. Fibrosis and microvesicular steatosis have also been reported [94].

Symptoms resolve over a mean of eight weeks (2 to 30 weeks) with discontinuation of the herb and have promptly recurred when patients were rechallenged [94,95]. The hepatotoxic mechanism is not known but may be immunologic given the histologic presentation [152].

Ma-Huang (ephedra) — Ma-Huang (Ephedra sinica), an ephedra alkaloid, has been used for centuries for cough, bronchitis, fever, joint symptoms, edema, bone pain, to induce weight loss, and as a central nervous system (CNS) stimulant [96,98]. The active ingredient is ephedrine, and has been associated with psychiatric and autonomic system adverse events. Reports of hepatotoxicity have also been associated with use of the drug, including hepatitis, acute liver failure, and exacerbation of autoimmune hepatitis [96-98,218,219]. The mechanism of toxicity is not known.

Affected patients present in similar fashion to those taking Jin Bu Huan [96,98]. Biopsies revealed diffuse severe hepatocellular necrosis and polymorphonuclear cell infiltrates with occasional eosinophils. Abnormal liver tests usually normalize within four months of discontinuation of drug [219]. Ephedra has been withdrawn from the United States market.

Syo-saiko-to — Syo-saiko-to (Dai-saiko-to, xiao-chai-hu-tang, da-chai-hu-tang, TJ-19) is a Chinese herbal product used in Japan that contains numerous herbs (Bupleuri root, Pinelliae tuber, Scutellaria root, ginseng root, ginger rhizome, glycyrrhiza root, and jujube fruit). The components in this product differ in their proportion of herbal products. It has been used in the treatment of hepatitis C virus infection. There is some evidence that these products may have anti-inflammatory, antifibrotic, and antitumorigenic activity [220]. There have been multiple reports of hepatotoxicity associated with this product; however, some occurring up to three months after ingestion and recurring with rechallenge [221-223]. The histologic picture is one of centrilobular confluent or spotty necrosis, microvesicular steatosis, acidophil bodies, and possibly granulomas [221]. Patients should be cautioned against using this herbal remedy.

Chaso or Onshido — Chaso and Onishido are used for weight loss. The toxic ingredient in these formulations is thought to be N-nitroso-fenfluramine, which depletes adenosine triphosphate (ATP) and impairs mitochondrial oxidative phosphorylation [32]. This results in diffuse hepatic necrosis and nonspecific inflammation. Cases of acute liver failure, death, and liver transplantation have been reported [224].

Shui-zhi-zi or sansisi — These products contain Gardenia jasminoides and are used to treat fever, liver disease or cancer. This product contains geniposide which has been shown to have dose dependent hepatotoxicity [225].

WEIGHT LOSS PRODUCTS — Numerous proprietary preparations have been associated with hepatotoxicity, including Hydroxycut [226-231], Herbalife [46,232-237], Enzyte [238], N.O.-XPLODE [197], OxyELITE [239], SlimQuick [191], Exolise [191,192].

Herbalife products — These products are sold worldwide in the form of drinks, tablets, capsules, and energy bars. There are multiple reports of hepatotoxicity with these products, ranging from mild to severe enough to require liver transplantation [46,232,234-236,240,241]. The pattern of liver injury is hepatocellular in the majority of cases; however, there are also reports of both mixed and cholestatic injury. The mechanism of toxicity remains unknown.

Hydroxycut — Hydroxycut is a weight loss product that contains multiple herbal products. Again, most had hepatocellular injury, but other patterns were reported as well. The original formulation included Camellia sinensis (117 mg EGCG). In 2009, the FDA issued a warning regarding the product’s potential hepatotoxicity and recommended that consumers discontinue use of the products carrying the brand name Hydroxycut [230,231,240,242]. The manufacturer voluntarily recalled all of its products, reformulated the herbal mix, and this new formulation has been sold [240].

Supplements containing Garcinia cambogia — Dietary supplements containing Garcinia cambogia are widely marketed for weight loss. As their use has gained popularity in the United States, cases of acute hepatitis and acute liver failure requiring liver transplantation have been reported [243-245]. It has been postulated that the active ingredient, hydroxycitric acid, is the cause of liver injury. This ingredient was banned by the US Food and Drug Administration (FDA) because of hepatotoxicity. Additionally, the FDA has recommended that specific products containing Garcinia cambogia be avoided as they are contaminated with sibutramine [246]. In a case report, sibutramine was associated with hepatotoxicity, and it was removed from the US market for cardiovascular toxicity [247]. (See "Obesity in adults: Drug therapy", section on 'Therapies not recommended'.)  

OxyELITE Pro — Following a report of seven patients who developed severe hepatitis or acute liver failure while taking the product OxyELITE Pro [248], further investigation identified an additional 52 cases of acute hepatitis. The FDA initiated an investigation into the manufacturing and distribution of OxyELITE Pro [239]. They identified multiple reports of toxicity in the United States, the majority of whom were young (mean age 33.9 years) and male (60 percent). Sixty-nine patients had consumed OxyELITE Pro, and 32 patients required hospitalization, three patients required liver transplantation, and one patient died [239]. The original product contained 1,3-dimethylamylamine (DMAA), which had been noted to have caused acute liver injury [249]. The formulation was changed in 2013 by the manufacturer to remove DMAA, and add aegeline [250]. Aegeline is extracted from Aegle marmelos (bael), and has been used in Ayurvedic medicine. Its main alkaloid is N-[2-hydroxy-2(4-methoxyphenyl) ethyl]-3-phenyl-2-propenamide The FDA had not been informed of this change and the manufacturer issued a recall in November 2013.

OTHER HEPATOTOXIC HERBS — There are many case reports of hepatotoxicity with other herbal preparations. These include Aloe (A. vera; A. barbadensis, A. arborescens), Bajiaolian, Borage (Borago officinalis), Broom Corn (Sorghum vulgare), Camphor oil, Centella asiatica (gotu kola), Margosa oil (Azadirachza indica), Cocaine, Coltsfoot, Copaltra (Coutarea latiflora and Centaurium erythraea), Kombucha tea, LipoKinetix (a capsule used for weight loss that contains multiple ingredients including usnic acid from the lichen Usnea barbata), Noni juice (Morinda citrifolia), Cascara sagrada, Sassafras (Sassafras albidum), and Senna (Cassia angustifolia) [19,21,36,93,144,149,152,153,161,192,224,233,251-261].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Drug-induced liver injury".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Toxic hepatitis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Herbal remedies may be associated with hepatotoxicity, making it important to discuss the use of herbal and dietary supplements (HDS) and complementary and alternative medical (CAM) therapies with patients to prevent potential complications, such as herb-drug interactions. (See "Overview of herbal medicine and dietary supplements".)

●The use of herbal remedies should be considered as a possible etiology in any setting of clinical manifestations of liver injury.

●Proving that an herbal or dietary supplement causes liver injury relies on both chronologic and clinical criteria. Features suggesting drug toxicity include lack of illness prior to ingesting the drug, clinical illness or biochemical abnormalities developing after beginning the drug, and improvement after the product is withdrawn. (See 'Diagnosis' above.)

●Obtaining a sample of the implicated HDS or CAM therapies for testing is possible, but expertise is not widely available. Costs are generally prohibitive, and most research laboratories are capable of testing only for certain compounds.

●The mainstay of therapy for herbal hepatotoxicity is withdrawal of the offending toxin and supportive care. (See 'Treatment' above.)

●A searchable database of drugs, herbal medications, and dietary supplements has been developed by the National Institutes of Health.