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Acute cholestatic hepatitis caused by Teucrium polium L.



Key words: cholestatic hepatitis, hepatotoxicity hepatotoxicity (hepˑ··tō·t , herbal medicine, Teucrium polium

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The use of herbal remedies can pose serious direct and indirect health risks (De Smet, 2002). The plant Teucrium polium (family Lamiaceae), used worldwide in traditional and herbal medicine (Rasekh et al. 2001) has been reported, in a few reports, to cause hepatotoxicity in humans (Polymeros et al. 2002; Mattei et al. 1995). On the contrary, there are several reports of hepatotoxicity caused by related species in the literature (Larrey et al. 1992; Ben Yahia et al. 1993; Castot and Larrey 1992; Perez Alvarez et al. 2001). In this letter we describe an interesting case of acute cholestatic hepatitis after prolonged use of Teucrium polium as a hypolipidemic herbal remedy.

A 67 year old man was admitted to hospital after a 5-day period of painless jaundice, pruritus pruritus /pru·ri·tus/ (proo-ri´tus) itching.prurit´ic

pruritus a´ni  intense chronic itching in the anal region.

pruritus hiema´lis  xerotic eczema.
, dark urine and light stools. His medical history included fatty liver, associated with hyperlipidemia and the consumption of ethanol (20-30 gr per day), which was confirmed by an abdominal ultrasound scan and liver biopsy performed the previous year. Consumption of Teucrium polium in the form of tea for the treatment of hyperlipidemia during the previous 6 months period (increasing to 2 lt per day the preceding month) was also mentioned. Physical examination revealed yellow pigmentation of the sclera sclera: see eye.  and skin. Laboratory tests showed the following values: hematocrit, 46%; WBCs, 7000 cells/m[m.sup.3] (neutrophils 53%, lymphocytes 29.3%, monocytes 10.2%, eosinophils 6.6%); MCV MCV mean corpuscular volume.

MCV
abbr.
mean corpuscular volume


Mean corpuscular volume (MCV)
A measure of the average volume of a red blood cell.
, 106 fl (normal range: 80-99 fl); platelet count, 133000/m[m.sup.3] (normal range: 150000-450000/m[m.sup.3]); international normalized ratio International Normalized Ratio Hematology A method of reporting prothrombin time–PT results for Pts receiving oral anticoagulant therapy; the INR is defined by the formula, PTPatient/PTMNPT , 2.9 (normal value: <1.7); erythrocyte sedimentation rate Erythrocyte Sedimentation Rate Definition

The erythrocyte sedimentation rate (ESR), or sedimentation rate (sed rate), is a measure of the settling of red blood cells in a tube of blood during one hour.
, 7 mm/h; alanine aminotransferase, 1272 U/L (normal range: 5-40 U/L); aspartate aminotransferase, 1739 U/L (normal range: 5-40 U/L); [gamma]-glutamyl transpeptidase, 302 U/L (normal range: 10-75 U/L); alkaline phosphatase, 190 U/L (normal range: 35-125 U/L); total bilirubin, 11.37 mg/dl (normal range: 0.1-1.3 mg/dl)--direct bilirubin, 7.97 mg/dl; albumin, 3.3 gr/dl (normal range: 3.5-5.0 g/dl); lactate dehydrogenase, 380 U/L (normal range: 80-230 U/L); total cholesterol, 284 mg/dl (normal range: 140-200 mg/dl), Triglycerides, 299 mg/dl (normal range: 40-160 mg/dl), HDLC, 34 mg/dl (normal range: 35-80 mg/dl), LDL-C, 189 mg/dl (normal value: <130 mg/dl); bilirubin and urobilinogen in the urine. An electrocardiogram and a chest X-ray were both within normal limits. Serological and immunologic tests, such as tests for hepatotropic viruses (hepatitis A, B and C viruses, Epstein-Barr virus, cytomegalovirus virus) were also negative. Histopathology his·to·pa·thol·o·gy
n.
The science concerned with the cytologic and histologic structure of abnormal or diseased tissue.


Histopathology
The study of diseased tissues at a minute (microscopic) level.
 of a liver biopsy revealed cholestatic hepatitis compatible with drug induced hepatitis (Fig. 1).

The management of the patient was successful mainly consisted of careful parenteral administration of suitable fluids and vitamin K, per os administration ursodeoxycholic acid and a frequent assessment of the liver function tests Liver Function Tests Definition

Liver function tests, or LFTs, include tests for bilirubin, a breakdown product of hemoglobin, and ammonia, a protein byproduct that is normally converted into urea by the liver before being excreted by the kidneys.
. Liver dysfunction was restored one month after his admission.

Diagnosis was based on the excessive consumption of Teucrium polium tea during the month previous to admission, and the exclusion of other cholestatic syndromes. The histopathological change in the findings of the liver biopsy, taken before and after the consumption of the excessive amount of tea was also conclusive evidence of the cause of cholestatic hepatitis.

[FIGURE 1 OMITTED]

Although the mechanism of Teucrium polium hepatotoxicity is unclear, teucrin A and several neoclerodane diterpenoids, present in the aerial parts of the plant, have been reported as the probable hepatotoxic hep·a·to·tox·ic
adj.
Damaging or destructive to the liver.



hepatotoxic

causing liver damage.
 precursors of this herb (De Berardinis et al. 2000; Fau et al. 1997; Loeper et al. 1994; Lekehal et al. 1996). In some instances, the liver injury has been associated with the presence of autoantibodies in the serum (Polymeros et al. 2002; Ben Yahia et al. 1993; De Berardinis et al. 2000). It has also been reported that some flavonoids flavonoids,
n.pl common plant pigment compounds that act as antioxidants, enhance the effects of vitamin C, and strengthen connective tissue around capillaries.
 have antihyperlipidemic properties, while some terpenoids could inhibit lipid peroxidation (Rasekh et al. 2001). Polymeros et al. (2002) have described a case of acute cholestatic hepatitis with transient appearance of antimitochondrial antibody in a woman after the prolonged use of Teucrium polium as an herbal remedy for symptoms of diabetes mellitus. In 1995 Mattei et al reported massive hepatocyte necrosis predominantly in the centrilobular areas of the liver in a patient with acute liver failure Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease (such as jaundice), and indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells).  after the consumption of Teucrium polium. Considering the temporal relationship between the increase of the dose and the occurrence of hepatitis in our patient, further research is required to evaluate the potential value of Teucrium polium for the management of hyperlipidemia and establish safety profiles of Teucrium polium products.

In conclusion, both the medical community and consumers must be better informed of the hepatotoxicity of this plant. Clinicians should suspect herbal remedies in cases of unexplained hepatitis, considering that herbal medicine is now a common form of alternative therapy and herbal remedies continue to have a great appeal to patients, not only in Greece, but worldwide.

References

Ben Yahia M, Mavier P, Metreau JM, Zafrani ES, Fabre M. Gatineau-Saillant G, Dhumeaux D, Mallat A (1993) Chronic active hepatitis chronic active hepatitis 1. Obsolete term. See Chronic hepatitis2. Chronic viral hepatitis  and cirrhosis induced by wild germander: 3 cases. Gastroenterol Clin Biol 17: 956-962

Castot A, Larrey D (1992) Hepatitis observed during a treatment with a drug or tea containing Wild Germander. Evaluation of 26 cases reported to the Regional Centers of Pharmacovigilance. Gastroenterol Clin Biol 16: 916-922

De Berardinis V, Moulis C, Maurice M, Beaune P, Pessayre D, Pompon D, Loeper J (2000) Human microsomal microsomal

pertaining to or emanating from microsome.
 epoxide hydrolase is the target of germander-induced autoantibodies on the surface of human hepatocytes. Mol Pharmacol 58: 542-551

De Smet PAGM (2002) Herbal remedies. N Engl J Med 347: 2046-2056

Fau D, Lekehal M, Farrell G, Moreau A, Moulis C, Feldmann G, Haouzi D, Pessayre D (1997) Diterpenoids from germander, an herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 113: 1334-1346

Larrey D, Vial T, Pauwels A, Castot A, Biour M, David M, Michel H (1992) Hepatitis after germander (Teucrium chamaedrys) administration: another instance of herbal medicine hepatotoxicity. Ann Intern Med 117: 129-132

Lekehal M, Pessayre D, Lereau JM, Moulis C, Fouraste I, Fau D (1996) Hepatotoxicity of the herbal medicine germander: metabolic activation of its furano diterpenoids by cytochrome P450 3A Depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in rat hepatocytes. Hepatology 24: 212-218

Loeper J, Descatoire V, Letteron P, Moulis C, Degott C, Dansette P, Fau D, Pessayre D (1994) Hepatotoxicity of germander in mice. Gastroenterology 106: 464-472

Mattei A, Rucay P, Samuel D, Feray C, Reynes M, Bismuth H (1995) Liver transplantation for severe acute liver failure after herbal medicine (Teucrium polium) administration. J Hepatol 22: 597

Perez Alvarez J, Saez-Royuela F, Gento Pena E, Lopez Morante A, Velasco Oses A, Martin Lorente J (2001) Acute hepatitis due to ingestion of Teucrium chamaedrys infusions. Gastroenterol Hepatol 24: 240-243

Polymeros D, Kamberoglou D, Tzias V (2002) Acute cholestatic hepatitis caused by Teucrium polium (golden germander) with transient appearance of antimitochondrial antibody. J Clin Gastroenterol 34: 100-101

Rasekh HR, Khoshnood-Mansourkhani MJ, Kamalinejad M (2001) Hypolipidemic effects of Teucrium polium in rats. Fitoterapia 72: 937-939

E. Mazokopakis (1), S. Lazaridou (1), M. Tzardi (2), J. Mixaki (1), I. Diamantis (1), and E. Ganotakis (1)

(1) Division of Internal Medicine, University General Hospital of Heraklion Crete, Greece

(2) Division of Pathology, University General Hospital of Heraklion Crete, Greece

Address

Elias E. Mazokopakis (M.C.), Division of Internal Medicine, University Hospital of Heraklion Crete, P.O. Box 1352, Voutes, 71 110 Heraklion, Crete, Greece Tel.: +30 281 0 392359; Fax: +30 281 0 392847; e-mail: elmazokopakis@yahoo.gr or ganotak@med.uoc.gr
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Title Annotation:Short Communication
Author:Mazokopakis, E.; Lazaridou, S.; Tzardi, M.; Mixaki, J.; Diamantis, I.; Ganotakis, E.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:4EUGR
Date:Jan 1, 2004
Words:1265
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