Toxic hepatitis due to a food supplement: “Natural” is no synonym for “harmless”

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Clinics and Research in Hepatology and Gastroenterology (2016) xxx, xxx.e1—xxx.e6

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CASE REPORT

Toxic hepatitis due to a food supplement: ‘‘Natural’’ is no synonym for ‘‘harmless’’ Filip J. Couturier a,b, Luc J. Colemont a, Herbert Fierens a, Veronique M. Verhoeven c,∗ a

Department of Gastroenterology and Hepatology, Sint-Vincentius Hospital, Sint-Vincentiusstraat 20, 2018 Antwerpen, Belgium b Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium c Academic Center for Primary and Interdisciplinary care, Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium

Summary Background/aims: Herbal products are increasingly used in modern medicine for numerous indications. They are not considered as drugs and thus often not linked to side effects. Material: A 77-year-old patient presented with silent icterus and biochemical evidence of hepatocellular damage. Because of dyslipidaemia, he was recently prescribed Controchol® , a food supplement containing red yeast and green tea extracts. Results: Liver biopsy showed necro-inflammatory destruction of liver parenchym, collapse of reticulin matrix, cholestasis and gall duct damage, compatible with toxic hepatitis. After discontinuation of Controchol® , there was a gradual normalisation of the liver function tests. Liver injury is a known side effect of both red yeast and green tea extracts. After exclusion of other causes, we therefore concluded our patient had suffered from Controchol® -induced toxic hepatitis. Conclusion: Products that are conceived as ‘‘natural’’ alternatives for pharmacological drugs, like food supplements, are not free of side effects per se, and should not be considered as ‘‘harmless’’. © 2016 Elsevier Masson SAS. All rights reserved.

Introduction ∗

Corresponding author. E-mail address: [email protected] (V.M. Verhoeven).

One of the independent risk factors for cardiovascular disease, being the number one cause of death globally, is dyslipidaemia. Depending on the individual cardiovascular risk profile, drug therapy, in addition to lifestyle changes, is

http://dx.doi.org/10.1016/j.clinre.2015.12.016 2210-7401/© 2016 Elsevier Masson SAS. All rights reserved.

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xxx.e2 necessary in the management of a lipid disequilibrium. While the array of pharmacological options expands, statins are still most frequently used to tackle hypercholesterolaemia in primary and secondary prevention of cardiovascular disease [1]. The elevation of hepatic transaminases is a well-known side effect of statin therapy, although the risk appears to be relatively low (0—3%), and progression to liver failure uncommon, even in patients with underlying liver disease [2]. In this modern era of unlimited information and mistrust of the pharmaceutical industry, patients and medical practitioners are looking for ‘‘natural alternatives’’ for conventional drugs. These products are often not perceived as drugs and considered to be innocuous. Also in the treatment of dyslipidaemia, a myriad of herbal products is being used, some of them containing substances that are chemically identical to statins. As illustrated in several case reports, ‘‘natural products’’ are not always harmless and can cause life threatening side effects such as acute liver failure. We report the case of a patient having developed a toxic hepatitis due to therapy with a lipid-lowering food supplement.

Case report A 77-year-old Caucasian male was admitted to the department of Gastroenterology because of new onset painless jaundice since one day with darkening of the urine. He mentioned no other complaints nor anamnestic features suggestive of a recent cardiovascular event (like an episode of hypotension). The patient had a history of gouty arthritis, ethylism, laparoscopic cholecystectomy (for symptomatic gallstone disease) and an impaired glucose tolerance. He reported no recent use of analgesics, alcohol or illicit drugs (which was confirmed by his family). Besides his chronic medication (allopurinol 300 mg o.d.) the patient was prescribed the lipid-lowering product Controchol® (Neocare N.V., Brussels, Belgium) one tablet daily, a month before presentation because of dyslipidaemia. Controchol® is a food supplement containing red yeast and green tea extracts. Before starting this supplement, the values of the following liver function tests were within normal limits: alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (␥GT), bilirubin and prothrombin time (PT). Clinically, we saw a moderately overweight (weight 85 kg, BMI 27.1 kg/m2 ) male with normal vital signs (blood pressure 125/75 mmHg, heart rate 57 beats per minute, temperature 36.7 ◦ C, 97% blood oxygen saturation breathing ambient air) and a prominent icterus at presentation (without other clinical abnormalities). The initial laboratory work-up revealed evidence of hepatocellular damage (ALT 1742 U/L, normal values < 40 U/L; AST 1634 U/L, normal values < 48 U/L; LDH 1683 U/L, normal values 313—618 U/L; ferritin 871 ␮g/L, normal values 18—646 ␮g/L), cholestasis (ALP 198 U/L, normal values 38—126 U/L; ␥GT 686 U/L, normal values 15—73 U/L) and hyperbilirubinaemia (total bilirubin 4.86 mg/dL, normal values < 1.4 mg/dL; direct bilirubin 3.87 mg/dL, normal values < 0.3 mg/dL). There was a mildly lower cholinesterase level (cholinesterase 4866 U/L, normal values 5320—12,920 U/L), elevated immunoglobulin A (IgA) level (IgA 4.4 g/L, normal values 0.7—4 g/L) and marked

F.J. Couturier et al. hypertriglyceridaemia (triglycerides 368 mg/dL, normal values < 150 mg/dL). Haemoglobin, leukocyte and thrombocyte levels were normal, just as coagulation tests. Ethanol, albumin, fasting glucose, total cholesterol, lipase and thyroid stimulating hormone (TSH) levels were within normal limits. The abdominal ultrasonography showed a steatotic liver and normal findings postcholecystectomy but no common bile duct dilatation, ascites nor abnormalities of other organs. Results of extended laboratory testing disclosed no serological arguments for viral hepatitis (hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis E virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus and varicella zoster virus) or autoimmune liver disease (antinuclear, anti-mitochondrial, anti-liver/kidney microsomal and anti-smooth muscle antibodies). Serum levels of ␣-1-antitrypsin, free copper and ceruloplasmin were also normal. Consequently, our tentative diagnose was Controchol® -induced toxic hepatitis, with predominantly hepatocellular injury (ALT > 2 times the upper limit of normal, and ALT/ALP > 5). Besides Controchol® also allopurinol was stopped due to its possible hepatotoxic properties. Because of persistence of the biochemical abnormalities after withdrawal of Controchol® and allopurinol, a liver biopsy was performed 1 week later. Microscopically, there was prominent necro-inflammatory destruction of the liver parenchyma with hepatocyte ballooning, collapse of the reticulin matrix, intracellular and intracanalicular cholestasis and gall duct damage, indicative of toxic hepatitis (Figs. 1 and 2). Sixty days after medication adjustments, we still noted a subtle icteric discolouration of the skin with hyperbilirubinaemia (total bilirubin 4.14 mg/dL, direct bilirubin 3.19 mg/dL), but normalisation of other liver function tests (ALT 40 U/L, AST 35 U/L, ALP 102 U/L, ␥GT 58 U/L). A followup ultrasonography showed unchanged findings. Another 4 months later, all clinical and biochemical abnormalities had resolved (e.g. total bilirubin 0.79 mg/dL).

Figure 1 Hematoxylin and eosin stain: liver biopsy showed portal inflammation (asterisk) with lymphocytes, macrophages, neutrophilic and prominent eosinophilic granulocytes. A small bile duct is seen in the upper right hand corner. There is obvious ballooning of the hepatocytes (arrows) and both intracellular and intracanalicular cholestasis.

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Toxic hepatitis due to a food supplement: ‘‘Natural’’ is no synonym for ‘‘harmless’’

Figure 2 Periodic acid-Schiff (PAS) stain after diastase of the liver biopsy showed both interface and lobular inflammation (asterisks) with loss of hepatocytes and numerous ceroid macrophages (arrows).

Discussion In this report, we present a case of toxic hepatitis following consumption of Controchol® , a food supplement that is used to lower plasma lipid levels. According to the manufacturer each tablet of Controchol® contains 200 mg of red yeast rice extract (with 5% monacolin K) and 400 mg of green tea extract (with 21% epigallocatechin gallate). It was a challenge to establish the link between the clinical manifestations and the causal agent, especially because the patient considered the intake of this functional food as irrelevant to his clinical symptoms, and did not mention it at first even after a thorough anamnesis. Red yeast rice (RYR) is widely used in the Asian food industry as a red colourant in sake, candy, meat and fish. Furthermore, it is used in traditional Chinese medicine since ancient times ‘‘to invigorate the body, aid in digestion, and revitalise the blood’’ [3]. In the past decade, RYR has attracted increasing research interest because of its lipidlowering potential. Red yeast rice is produced by culturing the yeast Monascus Purpureus on rice grain products. This fermentation process generates a mixture of monacolins, which act as inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase and thus inhibit the synthesis of cholesterol in the liver. Monacolin K is chemically identical to the statin commercialised as lovastatin. Like RYR, green tea has been part of Asian culture for thousands of years. This ubiquitous beverage, which is made from the processed (non-fermented) leaves of the plant Camellia sinensis Theaceae, is considered to contain several health-promotion properties (e.g. anticancer, anti-obesity, anti-atherosclerotic, antidiabetic, antibacterial). The beneficial effects of green tea extracts (GTE) are mainly related to the activities of epigallocatechin gallate (EGCG), a major component of catechin, which is a polyphenolic flavonoid compound (plant pigment). Intake of catechins is associated with enhanced cardiovascular and metabolic health [4]. Several trials have shown a reduction in total cholesterol, low-density lipoprotein (LDL) cholesterol and triglycerides (next to blood-lowering effects) in patients taking green tea compared to placebo. Observational studies suggest an

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inverse association between GTE-intake and cardiovascular disease. However, no randomised controlled trial on this matter has studied cardiovascular events or mortality as a primary outcome yet. Besides, due to the varying doses of green tea (extracts) consumed in different studies, it remains impossible for now to determine what cumulative dose should be ingested to reduce cardiovascular morbidity [5]. A growing number of studies confirm that RYR products effectively lower plasma lipids [6—9]. Most studies are short-term studies that use LDL and total cholesterol as primary outcome parameters. Furthermore, a large multicenter, randomised, double blind placebo-controlled study in 4870 Chinese patients with a history of myocardial infarction and moderate hypercholesterolemia showed, over a period of 4.5 years, a reduction by one third in cardiovascular deaths and in the need for coronary revascularisation. In high-risk subgroups (diabetes, hypertension), a reduction in coronary events was shown [10,11]. In 2011, the European Food Safety Authority (EFSA) affirmed a health claim of a cause-and-effect relationship between daily consumption of 10 mg of monacolin K from fermented red yeast rice preparations and maintenance of normal blood LDL cholesterol concentrations [12]. While the possible position of RYR products in the current range of lipid-lowering substances is still being studied, dietary supplement manufacturers have proceeded promptly to commercialise a number of over-the-counter RYR formulations, which are being marketed and mediatised as a ‘‘natural’’ alternative to lipid-lowering drugs and as a solution for patients who experience statin-associated side effects. RYR products indeed seem to be relatively well tolerated, even in statin-intolerant patients [13,14]. However, there is probably an underreporting of side effects. A causal link between symptoms and food supplements is often not obvious, and until now most research was focused on effectiveness of RYR formulations, and sample sizes are generally too small to assess side effects and long-term effects. Whereas the prevalence of side effects seems lower than in statins, there are anecdotal reports of myopathy [15] including rhabdomyolysis [16], of anaphylactic reactions [17], and, as in this case, of toxic hepatitis [18,19] associated with use of RYR products. Toxic hepatitis occurred in the first 6 months after initiation of RYR intake (a time pattern common to liver injury caused by most drugs) [18,19]. Statins themselves are relatively safe for the liver; although a mild, dose-dependent and transient aminotransferase elevation is often (0—3%) associated with initiation of statin therapy, hepatoxicity is uncommon, even in patients with underlying liver disease [2]. Next to hepatotoxic effects, some cases of statin-induced autoimmune hepatitis have been described [20,21]. Different steps can be taken for the management of statin-intolerant patients. Possible strategies include changing statins, lowering the dose of statins, intermittent dosing, or substitution of statins by other lipid-lowering drugs such as ezetimibe, bile acid sequestrants, red rice products, or coenzyme Q10 supplementation [22]. Although GTE has been shown to exhibit hepatoprotective effects in animal and (predominantly Asian) epidemiological studies, its use has also been linked to liver injury in humans, ranging from acute hepatitis to fulminant liver failure requiring transplantation. The minimal

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F.J. Couturier et al.

cumulative dose needed to provoke hepatotoxicity seems to be highly variable and unpredictable. Liver damage mostly occurs within three months of ingestion [4,23—25]. As with statin-associated hepatoxicity, the genetic background and pathophysiology of liver injury due to GTE are not well understood. Next to the unjustified perception of the public that ‘‘natural’’ functional foods are innocuous and at all times free of side effects, other problems exist on the

Table 1

food supplement market. The lack of governmental regulation in the food industry makes it difficult to assess the exact composition and quality of products. What is written on the labels and the actual content of the product may differ. The composition of red yeast rice products for instance, varies depending on the yeast strains and culture conditions used to manufacture them, and can be changed due to stability issues (degradation) while very high levels might suggest

Updated Council for International Organizations of Medical Sciences scale for the hepatocellular type of injury [29]. Possible score

Patient’s score

Time from drug intake until reaction onset

5 to 90 days < 5 or > 90 days

+2 +1

+2 —

Time from drug withdrawal until reaction onset

≤ 15 days

+1

—

Risk factors

Alcohol Age ≥ 55 years

+1 +1

0 +1

Course of the reaction

> 50% improvement within 8 days > 50% improvement within 30 days Lack of information or decrease ≥ 50% after the 30th day Worsening or < 50% improvement after 30 days

+3 +2 0 −2

— — 0 —

Concomitant drug(s)

None or no information Concomitant herb or drug with incompatible time to onset Concomitant herb or drug with compatible or suggestive time to onset Concomitant herb or drug known as hepatotoxin and with compatible or suggestive time to onset Concomitant herb or drug with evidence for its role in this case (positive rechallenge or validated test)

0 0

— 0

−1

—

−2

—

−3

—

Non-drug causes Group I (6 causes)a Group 2 (6 causes)b

All causes — groups I and II — reasonably ruled out The 6 causes of group I ruled out 5 or 4 causes of group I ruled out Less than 4 causes of group I ruled out Non-herb cause highly probable

+2 +1 0 −2 −3

+2 — — — —

Previous information on hepatotoxicity of the herb

Reaction labelled in the product characteristics Reaction published but unlabelled Reaction unknown

+2 +1 0

— +1 —

Response to readministration

Doubling of ALT with the herb alone, provided ALT below 5N before reexposure Doubling of ALT with the herb(s) and drug(s) already given at the time of first reaction Increase of ALT but less than N in the same conditions as for the first administration Other situations

+3

—

+1

—

−2

—

0

— 6

Total score for patient

ALT: alanine transaminase. The compilation of the individual items is adapted from the updated version of the Council for International Organizations of Medical Sciences (CIOMS) scale and the original CIOMS scale. Total score and resulting causality grading: ≤ 0, excluded; 1—2, unlikely; 3—5, possible; 6—8, probable; ≥ 9, highly probable. a Group I causes: (1) anti-HAV-IgM; (2) HBsAg, anti-HBc-IgM, HBV-DNA; (3) anti-HCV, HCV-RNA; (4) hepatobiliary sonography/colour Doppler sonography of liver vessels/endosonography/CT/MRC; (5) alcoholism (AST/ALT ≥ 2 IU/L); and (6) acute recent hypotension history (particularly if underlying heart disease). b Group II causes: (1) complications of underlying disease(s); and (2) infection suggested by PCR and titre change for CMV (antiCMV-IgM, anti-CMV-IgG), EBV (anti-EBV-IgM, anti-EBV-IgG), HEV (anti-HEV-IgM, anti-HEV-IgG), HSV (anti-HSV-IgM, anti-HSV-IgG), VZV (anti-VZV-IgM, anti-VZV-IgG).

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Toxic hepatitis due to a food supplement: ‘‘Natural’’ is no synonym for ‘‘harmless’’ that they are not the result of a natural fermentation process and that the product has been spiked with chemical lovastatin [26,27]. Standardised production and control are urgently needed. Summarizing, GTE and naturally occurring statins in RYR represent a risk of side effects, although the risk appears to be low. The link between symptoms and consumption of food supplements is often not obvious, and patients regularly forget to mention the intake of these functional foods because they do not consider them as drugs. It is a challenge for clinicians to establish such link through thorough and repeated history-taking. On the other hand, attributing hepatotoxicity to a food supplement remains a cumbersome venture because of the difficulty in excluding alternative causes such as potentially hepatotoxic co-medications [28]. In our case, we also took allopurinol in account as a possible culprit. Since there was an obvious temporal association between the Controchol® therapy and the evolution of the toxic hepatitis (while the patient had been taken allopurinol for 30 years), we reckoned that the food supplement was the causative agent in this case. Our diagnose was supported by a ‘‘probable’’ score (Table 1) using the updated ‘Council for International Organizations of Medical Sciences’ (CIOMS) scale (for hepatocellular liver injury), the preferred tool to assess causality in herb induced liver injury (HILI) [29]. Which compound (RYR and/or GTE) exactly was responsible for the marked hepatotoxicity, remains unclear. And because of a lack of control procedures regarding the production process of food supplements, liver injury due to contamination by other toxic substances remains a possibility. Rigorous study of adverse effects is warranted, but as long as it is not imposed by any legal control organism, the chances that the nutraceutical industry will invest in this kind of studies are low. At present, there is a lack of regulation for quality control and surveillance of side effects of dietary supplements in Belgium and in many other countries. Establishing a legal framework in this context is urgently needed. In the meantime, case reports like ours are important to get a more realistic estimate of the burden of adverse effects associated with food supplements. We strongly recommend the supervision of a healthcare professional when using a (possible toxic) herbal or dietary supplement. Products containing several substances that are capable of causing liver toxicity should be avoided.

Disclosure of interest

[2] [3]

[4] [5] [6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

The authors declare that they have no competing interest. [15]

Acknowledgements We are indebted to Dr. C. Colpaert (Department of Pathology, Sint-Vincentius Hospital, Sint-Vincentiusstraat 20, 2018 Antwerpen, Belgium) for the histological images.

[16]

Source of funding: none declared.

[17]

References

[18]

[1] European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I,

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Taskinen MR, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32(14):1769—818. Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther 2007;25:1135—51. Ying Sing S, T’ien Jung K’ai W. Chinese technology in the seventeenth century. Sun E-T and Sun S-C, transl. London: Pennsylvania State University Press; 1966. p. 291—4. Khan N, Mukhtar H. Tea and health: studies in humans. Curr Pharm Des 2013;19:6141—7. Hartley L, et al. Green and black tea for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013;6. Verhoeven V, Lopez Hartmann M, Remmen R, Wens J, Apers S, Van Royen P. Red yeast rice lowers cholesterol in physicians — a double blind, placebo-controlled randomized trial. BMC Complement Altern Med 2013;13:178. Bogsrud MP, Ose L, Langslet G, Ottestad I, Strøm EC, Hagve TA, et al. HypoCol (red yeast rice) lowers plasma cholesterol — a randomized placebo-controlled study. Scand Cardiovasc J 2010;44:197—200. Cicero AF, Derosa G, Parini A, Maffioli P, D’Addato S, Reggi A, et al. Red yeast rice improves lipid pattern, high-sensitivity C-reactive protein, and vascular remodeling parameters in moderately hypercholesterolemic Italian subjects. Nutr Res 2013;33:622—8. Verhoeven V, Van der Auwera A, Van Gaal L, Remmen R, Apers S, Stalpaert M, et al. Can red yeast rice and olive extract improve lipid profile and cardiovascular risk in metabolic syndrome? A double blind, placebo-controlled randomized trial. BMC Complement Altern Med 2015;15:52. Lu Z, Kou W, Du B, Wu Y, Zhao S, Brusco OA, et al. Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol 2008;101:1689—93. Li JJ, Lu ZL, Kou WR, Chen Z, Wu YF, Yu XH, et al. Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS). J Clin Pharmacol 2009;49:947—56. EFSA. Scientific opinion on the substantiation of health claims related to monacolin K from red yeast rice and maintenance of normal blood LDL cholesterol concentrations (ID 1648, 1700) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J 2011;9:2304 http://www.efsa.europa.eu/en/efsajournal/ doc/2304.pdf accessed 21/07/2014. Venero CV, Venero JV, Wortham DC, Thompson PD. Lipidlowering efficacy of red yeast rice in a population intolerant to statins. Am J Cardiol 2010;105:664—6. Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med 2009;150:830—9 [W147—9]. Lapi F, Gallo E, Bernasconi S, Vietri M, Menniti-Ippolito F, Raschetti R, et al. Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products. Br J Clin Pharmacol 2008;66:572—4. Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation 2002;74:1200—1. Wigger-Alberti W, Bauer A, Hipler UC, Elsner P. Anaphylaxis due to Monascus purpureus-fermented rice (red yeast rice). Allergy 1999;54:1330—1. Grieco A, Miele L, Pompili M, Biolato M, Vecchio FM, Grattagliano I, et al. Acute hepatitis caused by a natural lipid-lowering product: when ‘‘alternative’’ medicine is no ‘‘alternative’’ at all. J Hepatol 2009;50:1273—7.

Please cite this article in press as: Couturier FJ, et al. Toxic hepatitis due to a food supplement: ‘‘Natural’’ is no synonym for ‘‘harmless’’. Clin Res Hepatol Gastroenterol (2016), http://dx.doi.org/10.1016/j.clinre.2015.12.016

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xxx.e6 [19] Roselle H, Ekatan A, Tzeng J, Sapienza M, Kocher J. Symptomatic hepatitis associated with the use of herbal red yeast rice. Ann Intern Med 2008;149:516—7. [20] Pelli N, Setti M, Ceppa P, Toncini C, Indiveri F. Autoimmune hepatitis revealed by atorvastatin. Eur J Gastroenterol Hepatol 2003;15:921—4. [21] Alla V, Abraham J, Siddiqui J, Raina D, Wu GY, Chalasani NP, et al. Autoimmune hepatitis triggered by statins. J Clin Gastroenterol 2006;40:757—61. [22] Vandenberg BF, Robinson J. Management of the patient with statin intolerance. Curr Atheroscler Rep 2010;12:48—57. [23] Sarma DN. Safety of green tea extracts: a systematic review by the US Pharmacopeia. Drug Saf 2008;31:469—84. [24] Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006;144:68—71.

F.J. Couturier et al. [25] Yin X, Yang J, Li T, Song L, Han T, Yang M, et al. The effect of green tea intake on risk of liver disease: a meta analysis. Int J Clin Exp Med 2015;8(6):8339—46. [26] Li YG, Zhang F, Wang ZT, Hu ZB. Identification and chemical profiling of monacolins in red yeast rice using high-performance liquid chromatography with photodiode array detector and mass spectrometry. J Pharm Biomed Anal 2004;35:1101—12. [27] Hsin-Ping O, Chiun CRW, Lih-Shiuh L. Thermal degradation kinetics analysis of monacolin K in Monascus-fermentated products LWT. Food Sci Technol 2009;42:292—6. [28] Teschke R, et al. Herbal hepatotoxicity: suspected cases assessed for alternative causes. Eur J Gastroenterol Hepatol 2013;25:1093—8. [29] Teschke R, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol 2013;19(19):2864—82.

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