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GERMANDER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Germander, an herbal medicine, is the common name for Teucrium chamaedrys. Recently, this has been promoted as an adjuvant therapy for weight control. Use of the tea and capsules have been associated with hepatotoxicity.

Specific Substances

    1) Germander
    2) Teucrium chamaedrys
    3) T. chamaedrys
    4) Teucrium micropodioides
    5) Wall germander

Available Forms Sources

    A) FORMS
    1) Preparations include: herbal teas, 1 g per bag; medicinal liquor, 75 mg to 150 mg germander per 100 mL; capsules, 200 mg or 270 mg; and capsules mixed with green tea, 150 mg germander and 250 mg tea per capsule (Larrey et al, 1992). Crude germander is also available.
    B) SOURCES
    1) Leaves and flower heads from the plant, Teucrium chamaedrys, are used in germander herbal medicine preparations (Larrey et al, 1992).
    2) Several incidences of the sedative herbal product, skullcap, being substituted with germander have been reported in Europe (Phillipson & Anderson, 1984). Hepatotoxicity cases thought due to skullcap may in fact be caused by germander.
    C) USES
    1) The most common current use of germander in the past few decades is for the treatment of obesity. It is used as a slimming decoction and anoretic remedy, however there are no scientific studies to support its efficacy (Gori et al, 2011).
    2) In the past, germander was widely employed in Cypriot folk medicine as a cure for stomach aches, with an infusion prepared from leaves and flower heads. It was also used for the treatment of liver disorders. Choleretic and antiseptic properties have been attributed to germander.
    a) In addition, it has been used as an antidepressant, diuretic, antipyretic and in the treatment of asthma and bronchitis (Gori et al, 2011).
    3) In France, germander preparations were banned in May, 1992 after 26 cases of acute hepatitis due to ingestion of either germander capsule or tea were reported (Laliberte & Villeneuve, 1996). Based on these findings, T. chamaedrys was later banned in Italy and Belgium (Gori et al, 2011).
    4) In the United States germander is regulated as an allowable flavoring agent (hydroalcoholic extract) in alcoholic beverages including wines, bitters and liqueurs only (Gori et al, 2011). In Canada, germander is NOT allowed as a non-medicinal ingredient for oral use products (McGuffin et al, 1997).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Germander, an aromatic plant from the mint family, is used in teas and as a diuretic, antipyretic, choleretic, and for abdominal disorders and wounds. It is most commonly used as a slimming decoction.
    B) PHARMACOLOGY: The T. chamaedrys species (the most common species studied) contains saponins, glycosides, flavonoids and furano neoclerodane diterpenoids.
    C) TOXICOLOGY: Furano neoclerodane diperpenoids are thought to be responsible for the hepatotoxicity observed. Clerodane diterpenoids are natural toxins; tecurin A and teuchamaedryn A are considered the major toxic substances of diterpenoid fraction of T. chamedrys.
    D) EPIDEMIOLOGY: Overdose is uncommon.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Toxic effects are reported following chronic ingestions of germander (Teucrium chamedrys), which have produced hepatotoxicity and hepatic necrosis in humans, usually with a time delay of 6 weeks to 6 months, and in animal studies.
    2) OTHER: Nausea, vomiting and abdominal pain may occur in patients who develop liver dysfunction. Malaise and fever have been reported in patients who develop hepatitis.
    3) ANIMAL DATA: Evidence of hepatic necrosis is apparent within 24 hours of toxic dosing in mice.
    F) WITH POISONING/EXPOSURE
    1) Toxicity has not been reported after acute ingestions. Clinical events are anticipated to be similar to adverse effects reported with normal use of germander, primarily hepatotoxicity.
    0.2.7) NEUROLOGIC
    A) Fatigue has been reported in patients developing hepatitis.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting and abdominal pain may occur in patients who develop liver dysfunction.
    0.2.9) HEPATIC
    A) Centrilobular hepatic necrosis, which is usually reversible, has been reported in patients after chronic ingestions of germander.
    0.2.13) HEMATOLOGIC
    A) Coagulation disorders, including decreased prothrombin and factor V levels, may occur in patients developing germander-induced hepatitis.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Laboratory Monitoring

    A) Determine the SGOT (AST), SGPT (ALT), total bilirubin, and INR (or PT) for all symptomatic patients. If significant abnormalities in liver function are present, monitor creatinine, BUN, urinalysis, electrolytes, glucose, hemoglobin, hematocrit, amylase, and ECG as clinically indicated.
    B) Obtain serum electrolytes in symptomatic patients. Patients who are acidotic should also have ABGs drawn.
    C) Monitor vital signs.
    D) Obtain blood clotting studies (PT or INR, PTT) in patients with evidence of hepatitis or clinical bleeding.
    E) Monitor weight, abdominal girth, fluid intake, and urine output in patients with hepatotoxicity and ascites.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Of the limited reports of adverse events, most occurred following chronic consumption of germander for at least 6 weeks to 6 months. Monitor liver function in patients with a new onset of nausea, jaundice, malaise or other signs of hepatitis or hepatic impairment.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is supportive and directed at signs and symptoms of hepatitis, portal hypertension, ascites, and coagulation disorders. In theory, N-acetylcysteine may offer some heptoprotection and should be considered in patients with severe hepatotoxicity or those who are deteriorating despite discontinuing germander. This therapy has not been studied in humans or animals with germander hepatotoxicity.
    C) ENHANCED ELIMINATION
    1) No studies have addressed the utilization of extracorporeal elimination techniques following germander poisoning. They are unlikely to be useful as toxicity is reported after chronic exposure.
    D) DECONTAMINATION
    1) PREHOSPITAL: Most cases of toxicity reported have involved chronic ingestion of germander. It is not known, if activated charcoal will be useful in treating an ingestion.
    2) HOSPITAL: Activated charcoal may be indicated following a recent ingestion if coingestants are suspected and the patient is not vomiting and able to protect the airway.
    E) PATIENT DISPOSITION
    1) HOME CRITERIA: An child with a minor ingestion of a herbal product (ie, one capsule) containing germander is unlikely to develop symptoms and can be monitored at home with adult supervision. An adult is not likely to develop symptoms following a minor (ie, several capsules or tea containing germander) unintentional ingestion.
    2) OBSERVATION CRITERIA: Symptomatic patients with chronic exposure, and those with deliberate overdose should be referred to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients who develop significant hepatic impairment should be admitted.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center if the diagnosis is unclear. Consult a hepatologist for patients with severe hepatotoxicity.
    F) PHARMACOKINETICS
    1) Teucrium chamaedrys (the most common species studied) contains saponins, glycosides, flavonoids and furano neoclerodane diterpenoids. It is thought that the furano neoclerodane diperpenoids are responsible for the hepatotoxicity observed.
    G) PITFALLS
    1) Clinical history should include use of herbal products. Little is known about a significant acute exposure; symptoms may be delayed requiring monitoring and follow-up of the patient. Avoid other drugs that undergo hepatic metabolism.
    H) DIFFERENTIAL DIAGNOSIS
    1) Coingestion of other known hepatotoxins (acetaminophen, alcohol). Viral or autoimmune hepatitis.

Range Of Toxicity

    A) TOXICITY: Limited data. Toxic hepatitis has been reported after chronic use and most individuals recover completely; there have been rare reports of cirrhosis and death following T. chamaedrys use. Liver necrosis and fibrosis have occurred after germander doses of 250 mg/day and up to 1620 mg/day for 1 to 6 months.

Clinical Effects

Summary Of Exposure

    A) USES: Germander, an aromatic plant from the mint family, is used in teas and as a diuretic, antipyretic, choleretic, and for abdominal disorders and wounds. It is most commonly used as a slimming decoction.
    B) PHARMACOLOGY: The T. chamaedrys species (the most common species studied) contains saponins, glycosides, flavonoids and furano neoclerodane diterpenoids.
    C) TOXICOLOGY: Furano neoclerodane diperpenoids are thought to be responsible for the hepatotoxicity observed. Clerodane diterpenoids are natural toxins; tecurin A and teuchamaedryn A are considered the major toxic substances of diterpenoid fraction of T. chamedrys.
    D) EPIDEMIOLOGY: Overdose is uncommon.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Toxic effects are reported following chronic ingestions of germander (Teucrium chamedrys), which have produced hepatotoxicity and hepatic necrosis in humans, usually with a time delay of 6 weeks to 6 months, and in animal studies.
    2) OTHER: Nausea, vomiting and abdominal pain may occur in patients who develop liver dysfunction. Malaise and fever have been reported in patients who develop hepatitis.
    3) ANIMAL DATA: Evidence of hepatic necrosis is apparent within 24 hours of toxic dosing in mice.
    F) WITH POISONING/EXPOSURE
    1) Toxicity has not been reported after acute ingestions. Clinical events are anticipated to be similar to adverse effects reported with normal use of germander, primarily hepatotoxicity.

Vital Signs

    3.3.3) TEMPERATURE
    A) Fever has been reported in adults who developed hepatitis after chronic use of germander (Legoux et al, 1992).

Neurologic

    3.7.1) SUMMARY
    A) Fatigue has been reported in patients developing hepatitis.
    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Asthenia has been reported in adults who developed hepatitis after chronic use of germander (Goksu et al, 2012; Laliberte & Villeneuve, 1996; Larrey et al, 1992; Dao et al, 1993; Diaz et al, 1992).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting and abdominal pain may occur in patients who develop liver dysfunction.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Nausea, vomiting, and abdominal pain have been described in patients who developed hepatitis associated with the chronic use of germander (Goksu et al, 2012; Laliberte & Villeneuve, 1996; Larrey et al, 1992; Legoux et al, 1992).

Hepatic

    3.9.1) SUMMARY
    A) Centrilobular hepatic necrosis, which is usually reversible, has been reported in patients after chronic ingestions of germander.
    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Hepatic centrilobular necrosis has occurred following use of germander, usually with a delay of 6 weeks to 6 months, averaging 9 weeks, characterized by jaundice and high aspartate and alanine aminotransferase levels, and sometimes resulting in fatalities or the necessity of liver transplants. Viral serological tests and tests for tissue antibodies are generally negative. The liver injury resembles that seen in cases of acute cytolytic hepatitis caused by viruses or drugs. Recovery usually occurs within 6 weeks to 6 months following the discontinuation of germander. Toxic hepatitis may recur very soon after germander therapy is resumed (Goksu et al, 2012; Mostefa-Kara et al, 1992; Laliberte & Villeneuve, 1996; Larrey et al, 1992; Castot & Larrey, 1992; Mattei et al, 1992; Pauwels et al, 1992; Larrey, 1994; Dao et al, 1993; Diaz et al, 1992).
    b) PATHOLOGY: Hepatoxicity is mediated via its furano neoclero-dane diterpenoids, mainly teucrin A. Germander-induced hepatitis may be related to both direct toxicity and secondary immune reactions, which likely varies by individual (Goksu et al, 2012; Gori et al, 2011; Kaya et al, 2009).
    c) CASE SERIES: A review of the literature, there have been 52 cases of toxic hepatitis following the ingestion of Teucrium genus, most patients recovered completely following discontinuation of the plant. However, one death, 2 cases of cirrhosis and one case of liver transplantation following severe acute liver injury have been reported (Gori et al, 2011).
    d) CASE REPORTS: A couple (66-year-old man and 65-year-old woman) developed repeated episodes of asthenia, nausea without jaundice and elevated liver enzymes after drinking a decoction containing T. chamaedrys L., which was confirmed by laboratory analysis. Hepatic function rapidly returned to normal after discontinuation of the decoction (Gori et al, 2011).
    e) CASE REPORT: A 69-year-old healthy man presented with jaundice and fatigue after a 2 month history of drinking Germander plant tea for hemorrhoid symptoms. He noticed jaundice one month after discontinuing the tea. Liver enzymes were elevated, viral serology testing and antibody testing were negative, and ultrasound of the liver and biliary tract were normal. Liver function gradually improved within a month (Goksu et al, 2012).
    f) CASE REPORT: A 68-year-old woman, with no risk factors for hepatitis, presented with elevated liver enzyme levels, jaundice, and fatigue. Six weeks previously she had taken Tealine(R), an herbal for weight loss at a dose of 3 tablets daily and dexfenfluramine, 3 tablets daily (45 mg), for 7 to 14 days 6 weeks previously. Six months earlier, she had taken the same dose of Tealine(R) for about 2 weeks. No signs of chronic liver disease or hepatosplenomegaly were present. Her condition deteriorated and she died about 2 weeks later. Massive hepatic necrosis was apparent at necropsy (Mostefa-Kara et al, 1992).
    g) CASE REPORT: A 55-year-old woman developed bridging necrosis and collapse, lobular and portal-tract inflammatory infiltration and mild portal-tract fibrosis, as shown with liver biopsy, following dosing with germander, 1600 mg/day for 6 months. Concomitant drugs included calcium, conjugated estrogens, vitamin C, levothyroxine, and gemfibrozil. There was no history of risk factors for liver disease. Liver function tests returned to normal over the following 2 months after germander was discontinued (Laliberte & Villeneuve, 1996).
    h) CASE REPORT: A 36-year-old woman presented with fever, arthralgias and vomiting. She had been treated with wild germander (Tealine(R)), 900 mg/day for 8 months, prior to admission. Liver enzyme levels were markedly elevated. Liver enzymes returned to normal 6 to 10 weeks after stopping germander. Symptoms recurred on rechallenge with germander, 440 mg/day for 3 days. Liver biopsy was notable for centrilobular necrosis, compatible with chronic hepatitis (Legoux et al, 1992).
    B) CIRRHOSIS OF LIVER
    1) WITH THERAPEUTIC USE
    a) A case of active cirrhosis following the chronic use of wild germander has been reported. Following discontinuation of the herbal medicine, a favorable outcome resulted (Ben Yahia et al, 1993).
    C) PORTAL HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Portal hypertension, with esophageal varices, jaundice, and ascites, may accompany germander-induced liver damage. Portal hypertension may be persistent even after liver function tests have normalized (Dao et al, 1993).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC NECROSIS
    a) MICE: Doses of 2 to 4 g of Washington germander in an ethanolic extract resulted in marked increases in ALT concentrations and histopathological evidence of mid-zonal hepatic necrosis, extending to centrilobular necrosis at the highest dose, within 24 hours of dosing (Kouzi et al, 1994).

Hematologic

    3.13.1) SUMMARY
    A) Coagulation disorders, including decreased prothrombin and factor V levels, may occur in patients developing germander-induced hepatitis.
    3.13.2) CLINICAL EFFECTS
    A) BLOOD COAGULATION PATHWAY FINDING
    1) WITH THERAPEUTIC USE
    a) Abnormal coagulation values, including decreased prothrombin and factor V levels, have been reported in adults who developed hepatitis after chronic use of germander (Larrey et al, 1992; Dao et al, 1993; Mostefa-Kara et al, 1992; Diaz et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of this agent.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, no data were available to assess the carcinogenic potential of this agent.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the carcinogenic potential of this agent.

Genotoxicity

    A) At the time of this review, no data were available to assess the mutagenic or genotoxic potential of this agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Determine the SGOT (AST), SGPT (ALT), total bilirubin, and INR (or PT) for all symptomatic patients. If significant abnormalities in liver function are present, monitor creatinine, BUN, urinalysis, electrolytes, glucose, hemoglobin, hematocrit, amylase, and ECG as clinically indicated.
    B) Obtain serum electrolytes in symptomatic patients. Patients who are acidotic should also have ABGs drawn.
    C) Monitor vital signs.
    D) Obtain blood clotting studies (PT or INR, PTT) in patients with evidence of hepatitis or clinical bleeding.
    E) Monitor weight, abdominal girth, fluid intake, and urine output in patients with hepatotoxicity and ascites.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Overdose experience is limited. It may be advisable to monitor serum liver function tests as hepatotoxicity has been associated with the therapeutic use of germander.
    2) Monitor serum electrolytes in symptomatic patients.
    B) ACID/BASE
    1) Monitor ABGs in patients with metabolic acidosis.
    C) HEMATOLOGIC
    1) Monitor coagulation parameters and monitor for bleeding in all symptomatic patients. Obtain PT or INR, PTT in patients with evidence of hepatitis or clinical bleeding.
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Monitor ECG in all symptomatic exposures.
    2) OTHER
    a) Weight, abdominal girth, fluid intake and urine output should be monitored in all patients with ascites.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop significant hepatic impairment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An child with a minor ingestion of a herbal product (ie, one capsule) containing germander is unlikely to develop symptoms and can likely be monitored at home with adult supervision. An adult is not likely to develop symptoms following a minor (ie, several capsules or tea containing germander) unintentional ingestion.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center if the diagnosis is unclear. Consult a hepatologist for patients with severe hepatotoxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients with chronic exposure, and those with deliberate overdose should be referred to a healthcare facility for evaluation.

Monitoring

    A) Determine the SGOT (AST), SGPT (ALT), total bilirubin, and INR (or PT) for all symptomatic patients. If significant abnormalities in liver function are present, monitor creatinine, BUN, urinalysis, electrolytes, glucose, hemoglobin, hematocrit, amylase, and ECG as clinically indicated.
    B) Obtain serum electrolytes in symptomatic patients. Patients who are acidotic should also have ABGs drawn.
    C) Monitor vital signs.
    D) Obtain blood clotting studies (PT or INR, PTT) in patients with evidence of hepatitis or clinical bleeding.
    E) Monitor weight, abdominal girth, fluid intake, and urine output in patients with hepatotoxicity and ascites.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Most cases of toxicity reported have involved chronic ingestion of germander. GI decontamination is generally not necessary after ingestion.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Most reported cases of toxicity have involved chronic ingestion of germander. GI decontamination is unlikely to be useful. Activated charcoal may be indicated following a recent ingestion if coingestants are suspected and the patient is not vomiting and able to protect the airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most reported cases of toxicity have involved chronic ingestion of germander contained in alternative or herbal medicine sources. Treatment is supportive and directed at signs and symptoms of progressive hepatitis.
    2) Corticosteroids have empirically been used to treat germander-induced hepatitis, but there is no direct evidence to substantiate the value of this treatment.
    B) MONITORING OF PATIENT
    1) Monitor liver and renal function tests and electrolytes in symptomatic patients. Determine the SGOT (AST), SGPT (ALT), total bilirubin, and INR (or PT) for all symptomatic patients. If significant abnormalities in liver function are present, monitor creatinine, BUN, urinalysis, electrolytes, glucose, hemoglobin, hematocrit, amylase, and ECG as clinically indicated.
    2) Because of the possibility of progressive hepatitis following chronic use of germander, all symptomatic patients should be monitored for portal hypertension, ascites, and possible bleeding or coagulation disorders. When ascites is present, fluid restriction should be initiated along with monitoring the patient's weight.
    C) ACETYLCYSTEINE
    1) Animal studies have suggested that glutathione depletion enhances the hepatotoxicity of teucrin A, one of the furanoneoclerodane diterpenes of germander (Kouzi et al, 1994). Thus, N-acetylcysteine may in theory offer some heptoprotection and should be considered in patients with severe hepatotoxicity or those who are deteriorating despite discontinuing germander. This therapy has not been studied in humans or animals with germander hepatotoxicity.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques following germander poisoning. They are unlikely to be useful as toxicity is reported after chronic exposure.

Abstracts

Case Reports

    A) ADULT
    1) A 68-year-old woman, who had taken germander (450 mg/day for 7 to 14 days) and dexfenfluramine (45 mg/day for 7 to 14 days) presented with jaundice, asthenia and elevated serum liver enzymes. The germander had been taken about 6 weeks prior to presentation, and was the second administration after a first treatment for 2 weeks, 6 months previously. Viral serological tests and tests for tissue antibodies were negative. No hepatic or biliary abnormality was visible on ultrasonography. She deteriorated over the next 2 weeks (prothrombin and factor V less than 10%) and became comatose. She died shortly afterward. Massive hepatic necrosis was seen on necropsy (Mostefa-Kara et al, 1992).

Range Of Toxicity

Summary

    A) TOXICITY: Limited data. Toxic hepatitis has been reported after chronic use and most individuals recover completely; there have been rare reports of cirrhosis and death following T. chamaedrys use. Liver necrosis and fibrosis have occurred after germander doses of 250 mg/day and up to 1620 mg/day for 1 to 6 months.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) WEIGHT CONTROL - Recommended doses have included 600 to 1620 milligrams/day taken as capsules or as germander mixed with green tea extracts (Laliberte & Villeneuve, 1996; Larrey et al, 1992).

Minimum Lethal Exposure

    A) CASE REPORT
    1) ADULT
    a) A 68-year-old woman, with no risk factors for hepatitis, presented with elevated liver enzyme levels, jaundice, and fatigue. Six weeks previously she had taken Tealine(R), an herbal for weight loss at a dose of 3 tablets daily and dexfenfluramine, 3 tablets daily (45 mg), for approximately 7 to 14 days 6 weeks previously. Six months earlier, she had taken the same dose of Tealine(R) for about 2 weeks. No signs of chronic liver disease or hepatosplenomegaly were present. Her condition deteriorated and she died about 2 weeks later. Massive hepatic necrosis was apparent at necropsy (Mostefa-Kara et al, 1992).
    b) CASE REPORTS: In a review of the literature, there have been 52 cases of toxic hepatitis following the ingestion of Teucrium genus (predominantly T. chamaedrys L.), most patients recovered completely following discontinuation of the plant. However, one death, 2 cases of cirrhosis and one case of liver transplantation following severe acute liver injury have been reported. Germander-induced hepatitis may be related to both direct toxicity and secondary immune reactions, which likely varies in individuals (Gori et al, 2011).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) ADULT
    a) A 69-year-old healthy man presented with jaundice and fatigue after a 2 month history of drinking Germander plant tea for hemorrhoid symptoms. He noticed jaundice one month after discontinuing the tea. Liver enzymes were elevated, viral serology testing and antibody testing were negative, and ultrasound of the liver and biliary tract were normal. Liver function gradually improved within a month (Goksu et al, 2012).
    b) A 56-year-old woman took germander capsules (1620 mg/day) for 6 weeks, then had a 5 week break and resumed therapy for 2 more weeks. Treatment was stopped due to nausea. Serum aminotransferase levels were significantly elevated. Clinical signs/symptoms cleared promptly and liver function tests returned to normal within 1.5 months (Larrey et al, 1992).
    c) A 54-year-old woman was reported to develop centrilobular hepatic necrosis 1 month following a 2 month course of germander therapy (600 mg/day). Liver function tests returned to normal 2.5 months after the onset of hepatitis (Larrey et al, 1992).
    d) A 36-year-old woman developed marked increases in liver enzymes following germander therapy (900 mg/day for 8 months). Enzyme levels normalized within 10 weeks after discontinuing germander. On rechallenge with 440 mg/day for 3 days, liver enzymes were again elevated. Liver biopsy results showed centrilobular hepatic necrosis consistent with chronic hepatitis (Legoux et al, 1992).

Pharmacology Toxicology

Toxicologic Mechanism

    A) The mechanism of germander-induced hepatotoxicity has not been established. Larrey et al (1992) reported an absence of hypersensitivity manifestations, blood hypereosinophilia, and serum anti-tissue antibodies in patients with hepatitis, probably due to germander. These authors, however, suspected an immuno-allergic mechanism may have been involved. Following a re-challenge with germander, there was a recurrence of hepatitis in a relatively short duration of germander use in 3 patients, consistent with an immuno-allergic mechanism.
    B) One of the major furanoneoclerodane diterpenes, teucrin A, was investigated for its hepatotoxic effects in mice. The same mid-zonal hepatic necrosis was seen with this compound as with extracts of the powdered plant material. Test results indicated the mechanism of hepatic injury appeared to involve cytochrome P450-mediated formation of reactive electrophilic, oxidative products of the furan ring of teucrin A (Kouzi et al, 1994). In turn, activation of the furano diterpenoids depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in hepatocytes in rat studies (Lekehal et al, 1996).
    1) This may be one of the mechanisms of toxicity; however, this compound represents only a fraction of the total furanoneoclerodane diterpenoids found in germander. Other compounds in this class may exist that are more potent hepatotoxins and may contribute to cellular injury (Kouzi et al, 1994).

References

General Bibliography

    1) Castot A & Larrey D: Acute hepatitis following administration of germander-containing products: 26 cases. Gastroenterol Clin Biol 1992; 16:916-922.
    2) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    3) Dao T, Peytier A, & Galateau F: Chronic active hepatitis progressing to cirrhosis after germander administration. Gastroenterol Clin Biol 1993; 17:609-610.
    4) Diaz D, Ferroudji S, & Heran B: Wild germander-induced acute hepatitis. Gastroenterol Clin Biol 1992; 16:1006-1007.
    5) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
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