Kava Hepatotoxicity: Comparative Study of Two Structured Quantitative Methods for Causality Assessment

Journal of Clinical Pharmacy and Therapeutics (2010) 35, 545–563 doi:10.1111/j.1365-2710.2009.01131.x

ORIGINAL ARTICLE Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment

R. Teschke MD,J.FuchsMD,R.BahreMD,A.GenthnerMD and A. Wolff MD PhD Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Johann Wolfgang Goethe-University Frankfurt ⁄ Main, Hanau, Germany

Keywords: causality assessment methods, herbal SUMMARY hepatotoxicity, kava, kava hepatotoxicity Background and objective: Ingestion of the medicinal herb kava has been associated with hepatotoxicity. We aimed to compare two differ- INTRODUCTION ent quantitative methods of causality assessment of patients with assumed hepatotoxicity by the Chemical drugs, herbal remedies and dietary sup- herb. plements are commonly considered as safe and Methods: We assessed causality in 26 patients devoid of major side effects, but in usually rare from Germany and Switzerland, using two struc- instances hepatotoxic reactions may emerge in a few tured quantitative analytical methods: the system susceptible individuals despite adherence to the of Maria and Victorino (MV) and that of the recommended daily dose and treatment duration Council for International Organizations of Medi- (1–4). Under these conditions, the diagnosis of toxic cal Sciences (CIOMS). In all 26 patients, regulatory liver disease represents a major clinical challenge ad hoc evaluation had suggested a causal and may only be established when other causes of relationship between liver disease and kava use. the observed liver disease have been excluded with Results and discussion: Assessment with the MV certainty. Indeed, there is no biomarker or surrogate scale resulted in no or low graded causality for marker commonly available which might facilitate kava in the 26 patients with liver disease. Causality the diagnosis of toxic liver disease (4). By clinical was probable (n = 1), possible (n = 2), unlikely criteria a differentiation between toxic and genuine (n = 7), and excluded (n = 16). Causality for kava liver disease is commonly not possible, because was more evident with the CIOMS scale: highly symptoms and clinical ﬁndings are similar in both probable (n = 1), probable (n = 2), possible (n = 6), conditions, including icterus, fatigue, right upper unlikely (n = 2) and excluded (n = 15). However, abdominal discomfort, dark urine, pale stool, pru- the results of both quantitative causality assess- ritus and weight loss (3, 4). ments are not supportive for most of the regulatory In the last few years, a world-wide discussion ad hoc causality assessments of the 26 patients. emerged on whether and, if so, to what extent, Conclusion: Grades of causality for suspected treatment with the anxiolytic herb kava is hepato- hepatotoxicity by kava were much lower when toxic (5–15). Kava has been used as ethanolic and evaluated by structured quantitative causality acetonic extracts of the rhizome of the pepper plant assessment scales than by regulatory ad hoc Piper methysticum G. Forster (5, 9). The initial cau- judgements. The quantitative CIOMS scale is the sality assessment was a regulatory one achieved on preferable tool for causality assessment of spon- an ad hoc basis. An association was assumed in 26 taneous reports of hepatotoxcity involving kava. patients from Germany and Switzerland (16). Based on identical data, the regulatory judgement Received 21 July 2009, Accepted 31 August 2009 of causality was not substantiated by another reg- Correspondence: R. Teschke, MD, Department of Internal ulatory agency (17) and health institute (18). It was Medicine II, Klinikum Hanau, Teaching Hospital of the Johann Wolfgang Goethe University of Frankfurt ⁄ Main, Leimenstraße criticized by various scientiﬁc groups (7–14), 20, D-63450 Hanau, Germany. Tel.: +49 6181 ⁄ 2964200; fax: especially when additional data were evaluated +49 6181 ⁄ 2964211; e-mail: [email protected] (5, 7, 12–14). Moreover, quantitative causality

2010 The Authors. JCPT 2010 Blackwell Publishing Ltd 545 546 R. Teschke et al. assessments yielded conflicting results in two CIOMS (20). The scale was applied to kava and reports (14, 15). Supportive data in favour of the each co-medicated chemical drug, herbal remedy regulatory assessment were obtained in one study and dietary supplement. If there was more than (15) using the quantitative scale of MV, acronym one co-medication, only the co-medicated com- for the authors Maria and Victorino (MV) (19), but pound with the highest total score was considered not in another assessment (14) using the quantita- in the final assessment. tive scale of Council for International Organiza- The scores of the MV system relate to temporal tions of Medical Sciences (CIOMS), the acronym for relationships regarding onset of clinical or labora- the Council for International Organizations of tory manifestation, and normalization of laboratory Medical Sciences (20). values after drug discontinuation, exclusion of In the present study, we have evaluated causal- alternative causes, extrahepatic immuno-allergic ity for all 26 patients with liver disease, assumed in manifestations, results of re-exposure and previous a regulatory assessment to be causally associated published reports of cases of drug-induced liver with kava treatment. We retrieved additional data injury with the alleged drug (19). It provides for and used both the quantitative MV method and the each of these items a range of scores. The total score quantitative CIOMS scale. We found that, in the is then computed and used to assign causality as setting of regulatory evaluation of the observed being highly probable, probable, possible, unlikely liver disease in assumed relationship with kava, or excluded. the MV scale performed poorly compared with the CIOMS scale. With a few exemptions, both scales CIOMS scale failed to support the regulatory ad hoc causality assessments for kava. It appears that the CIOMS The quantitative CIOMS scale (20) was applied to scale is the preferred tool for causality assessment all 26 patients (14, 16). Causality assessment for in a setting of assumed kava hepatotoxicity. kava and co-medication was as described for the MV evaluation. The quantitative CIOMS uses items such as time to onset, course of improvement of PATIENTS AND METHODS laboratory data, risk factors, concomitant drugs, Patients search for non-drug causes, previous information on hepatotoxicity of the drug and response to Twenty-six patients originating from Germany re-administration (20). It provides with each of (n = 20) and Switzerland (n = 6) were studied. In these parameters a range of scores. The total score all patients, liver disease was causally attributed to is then computed and this is used for causality treatment with kava extracts, and the regulatory assessment as described above for the MV scale. assessment of causality for kava gave scores rang- ing from certain (n = 3) and probable (n = 15) to possible (n = 8) (16). For each of the patients, Comparative assessment essential data were collected from various sources The results presently obtained with the MV scale including the German and Swiss regulatory agen- were compared with the CIOMS scores for kava cies, drug manufacturers, primary-care physicians, and co-medications for all 26 patients (14). treating hospital physicians and pharmacists as described previously (14). Additional data were obtained from published reports quoted by the RESULTS regulators (16). General characteristics In the mostly female patients, daily overdose of MV scale kavapyrones (kavalactones), prolonged treatment All 26 patients underwent the structured quanti- and co-medication were common features tative causality assessment reported by MV (19). (Table 1), considering that the regulatory recom- The MV scale is a short and modified version of the mendation includes 60–120 mg kavalactones daily structured quantitative causality assessment of as maximum intake for no longer than 3 months.

2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 545–563 00TeAtos JCPT Authors. The 2010

Table 1. Clinical data of all patients (n = 26) with regulatory suspected liver disease in assumed association with the treatment by kava extracts f=fvual,d=died) = d favourable, = (f 00BakelPbihn Ltd, Publishing Blackwell 2010 diinlreferences Additional Patient Identification (years) Age Sex extract Kava (months) therapy of Duration Kavapyrones Co-medication Outcome information Regulatory information Additional Regulatory

(mg/day) ad hoc causality assessment Kava Co-medication ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal

01 BfArM 38 f Acetonic 3Æ5 210 Oral f Exclusion of Daily kava overdose ++ ) (7, 12, 13) 93015209 contraceptive non-kava Prolonged kava treatment Diazepam causes not Exclusion of hepatitis A, B, C, L-Thyroxine reported CMV, EBV, but not of HSV Exclusion of biliary obstruction and alcoholism Course of ALT not sufﬁciently documented, still increased after 6 weeks Normalisation of ALT not documented Autoimmunological parameters , 35 not assessed hepatotoxicity Kava 545–563 , Wilson‘s disease not excluded 547 548 .Teschke R.

Table 1. (Continued) tal. et 00TeAtos JCPT Authors. The 2010 02 BfArM 68 f Acetonic 24 210 St John’s wort f Exclusion of non-kava causes Daily kava overdose + ) (7, 12, 18) 94006568 Aluminium not communicated Prolonged kava treatment hydroxide Observed recurrent increase (2 years) of ALT during kava Exclusion of hepatitis A, B, C, discontinuation not CMV, EBV, but not of HSV mentioned and its relevance Ultrasonography data not for kava unrelated causality presented (qualitative CIOMS Kava unrelated causality due

00BakelPbihn Ltd, Publishing Blackwell 2010 assessment) not discussed to recurrent increase of ALT Existing increased ANA and ALT normalisation AMA titres not mentioned documented after 3 months Alternative diagnosis of AIH Alternative diagnosis of AIH, and PBC or overlap PBC or overlap syndrome syndrome not discussed 03 BfArM 50 f Acetonic 1Æ5 210 Furosemide f Exclusion of non-kava causes Daily kava overdose ++ + (7, 12–14) 94901308 Atenolol not documented ALT normalisation not Terfenadine Existing recurrent increase of documented after 2 months ALT during kava Kava unrelated cause due to ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal discontinuation not recurrent increase of ALT mentioned and its relevance Known terfenadine overdose for a kava unrelated with up to 300 mg daily causality (qualitative CIOMS (allowed maximal 120 mg) assessment) not discussed Complete exclusion Daily overdose of terfenadine diagnostic work-up, but not reported and not HSV-IgM positive assessed Cessation of initial steroid Existing increased HSV-IgM treatment at time when HSV titre not reported and hepatitis was diagnosed alternative diagnosis of HSV-hepatitis as alternative herpetic hepatitis not cause evaluated , 35 545–563 , 00TeAtos JCPT Authors. The 2010

Table 1. (Continued)

04 BfArM 81 f Ethanolic 10 120 Hydrochlorothiazide d Exclusion of non-kava Prolonged kava treatment ++ ) (12–14) 98004297 Crataegus extract causes not reported (10 months) Observed recurrent increase No exclusion of hepatitis A

of ALT during kava and C, CMV, EBV, HSV, but 00BakelPbihn Ltd, Publishing Blackwell 2010 discontinuation not LKM positive mentioned and its relevance No ultrasound results for kava unrelated causality Chronic pancreatitis at (qualitative CIOMS autopsy assessment) not discussed Recurrent ALT increase Existing increased titres of despite kava cessation, LKM antibodies not recorded suggesting kava and alternative independent cause diagnosis of LKM-AIH not No further ALT follow up ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal evaluated due to early death LKM positive AIH as alternative diagnosis 05 BfArM 33 f Ethanolic 4 180 Cisapride f Exclusion of non-kava causes Daily kava overdose ++ ++ (7, 12–14) 99006005 not documented Prolonged kava treatment Not further speciﬁed Exclusion of non-kava causes antibodies described and not presented attributed to a kava induced Course of ALT under AIH but not discussed cortisone therapy for AIH regarding a genuine AIH fails to represent the natural Normalisation of liver values enzyme course, therefore not under cortisone treatment assessable Diagnosis of genuine AIH, ,

35 suggested by reporting aahepatotoxicity Kava

545–563 , physician without information of speciﬁc antibodies AIH as alternative diagnosis accepted 549 550

Table 1. (Continued) .Teschke R.

06 BfArM 35 f Ethanolic 3 120 St John¢s wort f Exclusion of non-kava causes not Data for exclusion of non-kava ++ ) (7, 12) 99006200 communicated and also not causes not available tal. et 00TeAtos JCPT Authors. The 2010 available Exact ALT course and date of Nevertheless, the regulator states normalisation not reported that non-kava causes are not Multiple sclerosis as comorbidity evident Possible treatment also with acetaminophen Poorly documented case 07 BfArM 50 f Ethanolic 7 60 Estrogens LTX Exclusion of non-kava causes not Prolonged kava treatment ++ ++ (7, 12–14) 00005994 Gestagens reported (7 months)

00BakelPbihn Ltd, Publishing Blackwell 2010 Metformin Existing increased titres of ALT course not assessable due to Glimepiride EBV-IgM antibodies, ANA and LTX St John¢s wort SMA not mentioned and Exclusion of hepatitis A, B, C, CMV, alternative diagnosis of EBV EBV, HSV, biliary obstruction, hepatitis, EBV-AIH or genuine alcoholism AIH not discussed Positive titres for EBV-IgM, ANA, ASMA and signiﬁcant increases of VZV-IgG Cortisone treatment Alternative diagnosis of AIH, ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal EBV-AIH, EBV hepatitis, possibly also of VZV hepatitis 08 BfArM 23 f Ethanolic 4 240 Rizatriptan LTX Exclusion of non-kava causes not Daily kava overdose ++ ) (7, 12–14) 00008627 Oral d documented Prolonged duration of kava contraceptive Observed recurrent increase of treatment ALT during kava discontinuation Kava unrelated cause due to not mentioned and its relevance recurrent increase of ALT for a kava unrelated causality Further ALT course not assessable (qualitative CIOMS assessment) due to LTX not discussed Exclusion of hepatitis A, B, C, Existing increased titres of biliary obstruction, alcoholism, CMV-IgM antibodies not Wilson‘s disease recorded and alternative No exclusion of EBV and HSV, ,

35 diagnosis of CMV hepatitis not positive titre for CMV-IgM 545–563 , discussed CMV hepatitis as alternative diagnosis 00TeAtos JCPT Authors. The 2010

Table 1. (Continued)

09 BfArM 48 f ? ? ? ? f Virtually no data reported No data available ? ? (7, 12, 13) 01003950 Brand name of the kava Unassessable case extract unknown No information of time to

onset from the beginning of 00BakelPbihn Ltd, Publishing Blackwell 2010 kava and from cessation of kava presented Course with actual ALT values not mentioned Exclusion of non-kava causes not reported Unclear case, not suitable as index case for a possible subsequent re-administration

ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal (see case 10, identical patient) 10 BfArM 56 f Ethanolic ? ? L-Thyroxine f Exclusion of non-kava causes Daily dose of kava and +++ + (7, 12, 13) 01003951 Estradiol only for HBV, HCV, CMV, duration of treatment Omeprazole EBV and HSV, but not for unknown Losartan HAV reported Course of ALT not evaluable No information of time to Hepatitis A not excluded onset from the beginning of Exclusion of hepatitis B and C, kava and from cessation of CMV, EBV, HSV kava presented Titre of ANA not increased, Course with actual ALT other autoimmune parameters values not given not assessed ALT values just before Treatment with cortisone for

, questionable kava unknown reason 35 aahepatotoxicity Kava

545–563 , re-administration not Various other co-medicated presented dietary supplements This case and the former one (identical patient) are unsuitable for assessment as a positive rechallenge test 551 552 .Teschke R. Table 1. (Continued)

) 11 BfArM 32 m Ethanolic 3 240 Valerian LTX(2x) Exclusion of non-kava causes Daily kava overdose ++ (7, 12, 14) tal. et 00TeAtos JCPT Authors. The 2010 01006229 extract incomplete, details also Exclusion of hepatitis A, B, C, regarding hepatitis and AIH CMV, biliary obstruction not presented EBV and HSV not excluded Recurrent increase of ALT Recurrent ALT increase, during kava cessation not suggesting kava independent mentioned and its relevance cause for a kava unrelated Adipositas causality (quantitative Cortisone treatment for

00BakelPbihn Ltd, Publishing Blackwell 2010 CIOMS assessment) not unknown indication discussed Increased AMA titres Existing increased AMA titres Alternative diagnosis of PBC not reported and alternative diagnosis of PBC not discussed 12 BfArM 36 m Acetonic 1Æ5 70 – f Exclusion of non-kava causes Exclusion of hepatitis A, B, C, E, ++ (12) 01006939 incompletely communicated, CMV, EBV, alcoholism, bile details also regarding virus duct obstruction and negative and autoimmune genesis results for ANA, AMA, LKM, ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal not reported c-ANCA, p-ANCA, SLA, ASMA Existing hepato-splenomegaly, HSV not excluded increased MCV and ALT normalisation not pancytopenia (anaemia, documented after 2 months leucopenia, thrombocytopenia) Thickening of wall of not mentioned and not gallbladder, suspected evaluated regarding another cholecystolithiasis, liver underlying disease histology also with cholangitis and bile duct proliferations Cholecystitis and ⁄ or cholangitis as possible alternative diagnosis Myelodysplastic syndrome as , 35 possible alternative diagnosis 545–563 , 00TeAtos JCPT Authors. The 2010 Table 1. (Continued)

13 BfArM 45 f Ethanolic 4 45 Cynara f Exclusion of non-kava causes Exclusion of hepatitis A, B, C, ++ ) (12) 01010536 scolymus incompletely documented bile duct obstruction, extract The information that alcoholism serological results were CMV, EBV and HSV not negative is not precise excluded and autoimmune enough parameters not assessed 00BakelPbihn Ltd, Publishing Blackwell 2010 ALT course not described in detail 14 BfArM 50 f Ethanolic 3Æ5 240 Oral f Exclusion of non-kava causes Daily kava overdose + ) (12) 02000370 contraceptive incompletely documented Prolonged duration of kava Cyclandelat An infection and an treatment autoimmune disease Virtually no data available excluded without further ALT course not details documented Report came from pharmacist, Case not assessable ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal not from treating physician Preexisting cryptogenic liver who denied a possible cirrhosis as alternative causality for kava diagnosis Cryptogenic liver cirrhosis diagnosed in spring 1998, start with kava treatment 20 February 1998 15 BfArM 46 f Ethanolic 1 360 ) f Exclusion of non-kava causes Daily kava overdose ++ (12, 14) 02001414 incompletely presented Course of ALT poorly and regarding speciﬁc parameters normalisation not for hepatitis A–C and lack of documented HSV as well as Exclusion of hepatitis A, B, ultrasonography results C mentioned, but no details , 35

Existing chronic epigastric documented hepatotoxicity Kava 545–563 , pain, increased lipase and EBV and HSV not excluded decreasing under i.v. Ultrasound data not reported infusion therapy, increased Pancreatitis as alternative y-GT and ALP not diagnosis mentioned, alternative diagnosis of pancreatitis not

discussed 553 554 Table 1. (Continued)

16 BfArM 26 f Ethanolic 0Æ25 50 Sulfasalazine f Age not assessed by regulator but ALT course poorly ++ ) (12, 13) Teschke R. 02002090 Diclofenac generally known documented Progesterone Exclusion of non-kava causes not Exclusion of hepatitis A, B, tal. et

00TeAtos JCPT Authors. The 2010 Omeprazole documented C, EBV, CMV mentioned Butylscopolaminium- but speciﬁc data not bromide documented AMA, SLA ⁄ LP, LKM with negative results, but ANA not reported Known Bechterew¢s disease and adipositas as co-morbiditiy 00BakelPbihn Ltd, Publishing Blackwell 2010 17 BfArM 61 f Ethanolic 3 120 Omeprazole LTXd Time to onset from cessation of kava Virtually no data available ++ ) (7, 12) 02002378 Hymecromon not documented The use of hymecromon Ginkgo biloba extract Exclusion of non-kava causes not suggests pre-existing presented hepato-biliary disease Case is not assessable 18 BfArM 48 f Ethanolic 6 850 Silymarin LTX Partial exclusion of non-kava causes Daily kava overdose + ) (12–14) 02003010 Rheumeda with not clearly documented Prolonged duration of (homeopathic antibodies (HAV, HBV, HCV, CMV) kava treatment preparation) and lack of ultrasonography results Well documented case ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal Gelum (mineral Recurrent increase of ALT during kava with all necessary details supplement) discontinuation not mentioned and Recurrent ALT increase Polilevo (amino acid its relevance for a kava unrelated suggests kava complex) causality (qualitative CIOMS independent cause assessment) not discussed Increased AMA titres and Known regular alcohol consumption y-globulins not documented and not discussed PBC or pre-existing liver Existing data of cirrhosis and fatty cirrhosis of unknown liver not mentioned and not discussed cause as alternative Existing increased lipase and diagnosis edematous pancreatitis shown by ultrasound examination not reported and not discussed ,

35 Existing increased y-globulins and

545–563 , enhanced AMA titres not documented and not discussed regarding PBC as an alternative diagnosis 00TeAtos JCPT Authors. The 2010

Table 1. (Continued)

19 BfArM 39 f Ethanolic 6 60 Oral contraceptive f Exclusion of non-kava Well documented case with +++ ) (7, 12–14)

NN Paroxetine causes not presented exclusion of all relevant kava 00BakelPbihn Ltd, Publishing Blackwell 2010 St John¢s wort Existing positive rechallenge independent causes test reported Positive re-challenge test, thereby highly probable causality

20 BfArM 60 f Ethanolic 12 1200 Etilefrine LTX Exclusion of non-kava Daily kava overdose ++ ) (7, 12)14) NN Piretanide causes fairly well reported, Prolonged duration of kava except results of ultrasound treatment examination, ANA and Well documented case

ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal urinary copper Negative results for AMA excretion ⁄ 24 h and LMA, data for ANA not BMI 31Æ8kg⁄ m2 not available mentioned Adipositas (BMI 31Æ8kg⁄ m2) as comorbidity

21 IKS 50 m Acetonic 2 280 – LTX Daily overdose of kava Exclusions of hepatitis E ++ (12)14) 2000–3502 Fever, rash Denied alcohol consumption Asthenia as ﬁrst symptom, MCV, amylase and lipase not continuation of kava reported treatment for one more week ALT course not available Occasional alcohol Exclusion of biliary consumption obstruction

, Exclusion of hepatitis A, B No exclusion of HSV, AIH or 35 aahepatotoxicity Kava

545–563 , and C, EBV, CMV Wilson¢s disease LTX 9 days after hospitalization 555 556 Table 1. (Continued)

22 IKS 33 f Acetonic 1Æ5 210 Exsepta f Daily overdose of kava Recurrent increase of ALT ++ ) (12–14) Teschke R. 2000–0014 (homeopathic Continuation of kava treatment 16 days after kava cessation, medication) for another week despite in line with kava unrelated tal. et

00TeAtos JCPT Authors. The 2010 symptoms liver disease Still slightly increased Increased EBV-IgM with aminotransferases 5 months normal EBV-IgG, suggestive after kava cessation for alternative diagnosis of Occasional alcohol consumption, EBV-hepatitis 60 g alcohol the day before Histology includes clinical symptoms destruction of interlobular Persistent increased titres of bile ducts, suggesting EBV-IgM alternative diagnosis of bile 00BakelPbihn Ltd, Publishing Blackwell 2010 Not further specified tests for duct destruction of autoantibodies and virus unknown cause negative Normalization of ALT Exclusion of biliary obstruction 2 months after kava cessation Lymphocyte transformation test reactive for kavapyrones. CYP 2D6 deficiency Hepatitis A and C as well as ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal CMV and HIV sufficiently excluded HBc-IgM, HEV and HSV not assessed ANA, AMA, SMA, c-ANCA, p-ANCA all negative 23 IKS 46 f Acetonic 3 140 Hydrochlorothiazide f Daily overdose of kava Not further specified + )) (12–14) 1999–2596 Valsartan Not further declared exclusion exclusion of hepatitis and Propanolol of common drug unrelated causes EBV Improvement of laboratory values Not reported data on CMV, starting 13 days after cessation of HSV and autoimmune all medications including kava parameters Course of ALT values not ,

35 reported

545–563 , Normal ultrasound results Poorly documented case

00TeAtos JCPT Authors. The 2010 Table 1. (Continued)

24 IKS 59 f Acetonic 2 70 Estradiol LTX Suspected AIH with positive No further data available + ) (14) 2000–2330 Norethisterone ANA and AMA (anti-M2 Poorly documented case acetate negative) AIH, PBC or overlap syndrome Celecoxib Liver cirrhosis, Child C as alternative diagnosis Increased y-globulins and MCV MCV increased, possibly alcohol

Not further speciﬁed exclusion related

00BakelPbihn Ltd, Publishing Blackwell 2010 of acute hepatitis A, B, C and HSV not excluded negative IgM titres for CMV Question of cortisone treatment and EBV Course of ALT not mentioned Course of ALT values not Overweight reported LTX 7 months after kava cessation Insigniﬁcant alcohol consumption Exclusion of biliary obstruction ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal 25 IKS 39 f Acetonic 0Æ3 140 – f Daily overdose of kava Poorly documented case + (14) 2001–2046 ALT 100 U ⁄ L, AST 44 U ⁄ L Kava medication August 2000 (date not listed) for 8–10 days Denied alcohol consumption Nervosity as indication for kava Not further speciﬁed hepatitis Increased liver values 2 months serology, negative 11 months after kava cessation, before increased ALT concomitant with diagnosis of Kava treatment August 2000 hyperthyreosis (Basedow) for 10 days Rapid regression of ALT due to First symptoms October 2000 carbimazole treatment Carbimazole since 26 October Thyreotoxic hepatopathy as 2000 alternative diagnosis Normal liver values 2 Retrospective assessment , 35 November 2000 includes nervosity in August hepatotoxicity Kava 545–563 , 2000 due to hyperthyreosis, treatment by kava ineffective, cessation of kava, 2 months later diagnosis of hyperthyreosis with increased ALT, subsiding under thyreostatic therapy

No causal relationship for kava 557 558 .Teschke R.

Table 1.

(Continued) tal. et 00TeAtos JCPT Authors. The 2010 26 IKS 56 f Acetonic 1 70 St John¢s wort f ALT 115 U ⁄ L, AST 53 U ⁄ L Adipositas as co-morbidity + ) (14) 2000–0219 Silymarin Increased liver values in January declared 2000 Increased ALT values obviously Kava treatmnet from December not ascribed primarily to kava 1999 until 8 September 2000, no since no cessation was considered discontinuation despite slightly Poorly documented case increased ALT Increased ALT values due to

00BakelPbihn Ltd, Publishing Blackwell 2010 Denied alcohol consumption adipositas as alternative diagnosis Hypocaloric diet, reduction of body weight by 18 kg down to 52 kg in the 4 months preceding increased ALT values Not further speciﬁed negative results for hepatitis serology and autoimmune antibodies Normal ultrasound results Liver biopsy 9 months after initial ora fCiia hrayadTherapeutics and Pharmacy Clinical of Journal ALT increase with balooning liver cell degeneration without inﬂammation or necrosis Normalization of ALT 3 months after kava cessation

Basic data were obtained from various sources (7, 12–14, 16). Regulatory information and ad hoc causality assessment was presented by the database of BfArM (16) and the Swiss regulatory agency. Regulatory causality assessment was highly probable (+++), probable (++), possible (+), unlikely ()) or excluded ())). Regarding additional informations, a recurrent increase of ALT was found in some patients, indicating a kava independent cause of the liver disease as outlined previously in the qualitative CIOMS assessment (20). AIH, autoimmune hepatitis; AMA, antimitochondrial antibodies; ALT, alanine aminotransferase; ANA, antinuclear antibodies; BMI, body mass index; CIOMS, Council for International Organization of Medical Sciences; CMV, cytomegalovirus; EBV, Epstein Barr virus; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; LKM, liver kidney microsomal antibodies; LTX, liver transplantation; MCV, median cell volume; PBC, primary biliary cirrhosis; SMA, smooth muscle antibodies. , 35 545–563 , Kava hepatotoxicity 559

Details described for the individual cases implicate The low MV scores may be attributed to various poor regulatory data presentation in some of the conditions such as the presence of several alterna- patients as well as laboratory and clinical mani- tive kava-independent causes of the observed liver festations suggestive of kava- and drug-unrelated disease, giving a )3 point score; only partial causes in others. Moreover, in a few patients a exclusion of kava-independent causes, resulting in temporal association between kava use and the 0 point; missed extrahepatic manifestations like development of liver disease was not convincingly rash, fever, arthralgia, peripheral eosinophilia and presented in the regulatory data information. cytopenia, yielding 0 points; and latency period of mostly >8 weeks, giving only 1 point (Table S1). Laboratory signs of acute drug-induced hepato- MV causality assessment for kava cellular toxicity commonly subside within a short Using the MV scale for all 26 patients, there were time, and ALT values are normalized 2 months only three cases with a score ‡10, implying cau- after drug discontinuation. This results in 3 points, sality for kava (Table S1 and Table 2). Causality but was applicable to only some patients. Instead, was probable for one patient with 16 points (case the others reached only 0 points on various 19) and possible for two of the cases with 10 points grounds. For instance, ALT values were still high (case 16) and 13 points (case 21). The score for the or unknown 2 months after kava cessation, or the remaining 23 patients was low, suggesting kava to natural course of ALT within 2 months was not be an unlikely or excluded cause in another seven assessable because of early death, liver transplan- and 16 patients, respectively. tation (LTX) or cortisone treatment of autoimmune

Table 2. Comparison of causality assessments of 26 suspected cases MV causality MV causality for CIOMS causality CIOMS causality of kava or co-medication hepato- Patient for kava co-medication for kava for co-medication toxicity using the MV and the 1 Excluded Excluded Possible Possible CIOMS scales 2 Excluded Excluded Excluded Excluded 3 Excluded Excluded Excluded Excluded 4 Excluded Excluded Excluded Excluded 5 Excluded Excluded Excluded Excluded 6 Unlikely Excluded Unlikely Excluded 7 Excluded Excluded Excluded Excluded 8 Excluded Excluded Excluded Excluded 9 Excluded Excluded 10 Excluded Excluded Unlikely Possible 11 Excluded Excluded Excluded Excluded 12 Unlikely Probable 13 Unlikely Excluded Possible Possible 14 Excluded Excluded Excluded Excluded 15 Excluded Possible 16 Possible Excluded Possible Possible 17 Unlikely Unlikely Excluded Excluded 18 Excluded Excluded Excluded Excluded 19 Probable Unlikely Highly probable Excluded 20 Unlikely Unlikely Probable Probable 21 Possible Possible 22 Unlikely Excluded Excluded Excluded 23 Excluded Excluded Possible Possible 24 Unlikely Excluded Excluded Excluded 25 Excluded Excluded 26 Excluded Excluded Excluded Excluded

2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 545–563 560 R. Teschke et al. hepatitis (AIH) as a kava-unrelated disease. Low excluded or unlikely (Tables 2 and S2). On the scores were also obtained when co-medication was other hand, using the scores of the quantitative considered as possible or probable cause for the CIOMS scale, causality for kava was highly prob- observed liver disease. It therefore appears that in able for one case, probable for two cases and pos- some patients various confounding conditions sible for six cases. The causality grades were preclude a high ranking of causality for kava. sometimes shared with the co-medication (Table 2). It was evident that the MV system and the CIOMS scales (Table 2) produced results with poor MV causality assessment for co-medication concordance. In analogy to kava (Table S1), MV scores were also Previous studies have shown that the MV and low for co-medication (Table S2). Co-medication CIOMS scales perform equally well in the presence was observed in 21 of 26 patients. As MV scores of signs of hypersensitivity such as rash, fever, were all £9 (Table S2), causality for co-medication arthralgia, peripheral eosinophilia and cytopenia. was either unlikely (n = 2) or excluded (n = 19) In all other cases, the CIOMS system performs (Table 2). The causes of low MV scores for better than the MV scale (21, 22). Accordingly, as co-medication were similar to those previously the patients of the present study, with few outlined for kava. exemptions, lacked signs of hypersensitivity (Tables S1 and S2), the CIOMS scale is the preferred tool for kava causality assessment, at least in Comparison of MV with CIOMS scales the present setting of regulatory assumed liver There is poor concordance of causality grades disease by kava and co-medication. obtained using the MV and CIOMS scales for both The regulatory causality assessment (16) seemed kava and co-medication (Table 2). In general, cau- to have been conﬁrmed in one single publication sality assessment by CIOMS resulted in higher (15). The latter study reports that the data of all the grades of causality for kava and co-medication. patients were analysed systematically using a Moreover, disagreement prevails relative to the clinical diagnostic scale (CDS). Reference was regulatory ad hoc causality assessment for kava and provided for CDS being identical with the MV scale co-medication (Table 1) compared with the struc- (15, 23). This scale was obviously applied without tured causality evaluation by MV or CIOMS scales item by item analysis with an additional qualitative (Table 2). In particular, the regulatory assessment assessment (15). Such causality assessment has of certain, probable or possible causality for kava been criticized for drug-induced liver injury (4, 24). for all 26 patients (Table 1) was not substantiated by The MV scale in the present study on 20 patients the structured quantitative evaluation using either from Germany (cases 1–20) (Table 1), recorded the MV or CIOMS scales (Table 2). These data causality as follows: probable (n = 1), possible suggest that in a setting of suspected kava hepato- (n = 1), unlikely (n = 5) and excluded (n = 13) toxicity, causality assessment with the quantitative (Table 2 and Table S1). Using the CDS approach, CIOMS scores should be preferred over evaluation which corresponded to the MV scale, gave all the using an ad hoc basis or the MV scale. cases a causality of certain, probable or possible (15). It appears that in the latter study not all information (Table 1) (7, 12–14) required for DISCUSSION a sound causality assessment was available or The present study shows that the extent of cau- considered. sality varied widely depending on the system used Causality assessment on an ad hoc basis is obvi- for the quantitative evaluation (Table 2). This is a ously not the appropriate approach for evaluation known phenomenon already described in another of whether a chemical drug, herbal remedy or study of patients with liver disease because of dietary supplement may have caused a hepatotoxic chemical drugs (21, 22). With the quantitative MV reaction in a given patient (4, 22). For instance, system, causality for kava was probable and when treating physicians report cases of liver possible in only one or two patients, respectively diseases, assumed to be related to treatment with (Tables 2 and S1) and that for co-medication chemical drugs on an ad hoc basis, to the World

2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 545–563 Kava hepatotoxicity 561

Health Organization (WHO), causality of these suggest that the initial step in causality assessment cases included in the WHO database could not be should begin with the application of the quantita- re-evaluated (25). Similarly, the European Medi- tive CIOMS scale using data provided by the cines Agency (EMEA) dismissed causality in 38 of treating physicians, who are responsible for 42 cases of spontaneous liver disease assumed by reporting the individual CIOMS data item by item others before to be causally associated with black to their respective national regulatory agencies for cohosh in ad hoc assessments (26). Causality for the further evaluation. The itemized CIOMS data remaining four patients was also dismissed when should be in drug-regulatory agency databases and item by item scoring of the quantitative CIOMS should be publicly available to all. scale was used (27). There have also been problems with ad hoc causality assessment of cases of sus- DISCLOSURE pected kava hepatotoxicity (5–14, 28–31) presented to the German regulatory agency (16). Causality No conflicts of interest exist. re-evaluations by both the EMEA and the British Medicines Control Agency yielded quite different REFERENCES results despite identical data for each individual patient (12, 13, 17, 18). Therefore, a systematic 1. Chang CY, Schiano TD (2007) Review article: drug diagnostic approach is obviously required. hepatotoxicity. Alimentary Pharmacology and Thera- It is of note that problems in causality assess- peutics, 25, 1135–1151. 2. Teschke R, Bahre R (2009) Severe hepatotoxicity by ment have also been reported (32–35) for adverse Indian Ayurvedic herbal products; a structured cau- effects other than hepatotoxicity. In particular, no sality assessment. Annals of Hepatology, 8, (in press). systematic decisional algorithms gave results in 3. Zimmerman HJ (1999) Hepatotoxicity. Philadelphia, agreement with those of ad hoc causality assess- PA: Lippincott Williams & Wilkins. ment, because of confounding factors which 4. Teschke R, Schwarzenboeck A, Hennermann KH compromised the sensitivity and specificity of the (2008) Causality assessment in hepatotoxicity by former methods (32). Moreover, without opera- drugs and dietary supplements. British Journal of tional procedures, agreement between experts was Clinical Pharmacology, 66, 758–766. low (33, 34). For general adverse drug reactions, 5. Denham A, McIntyre M, Whitehouse J (2002) Kava – decisional causality algorithms are sensitive but the unfolding story: report on a work-in-progress. they have poor specificity (35). Journal of Alternative Complementary Medicine, 8, 237– Certainly, the main problem in causality assess- 263. 6. Stevinson C, Huntley A, Ernst E (2002) A systematic ment of potential drug-induced liver injury relates review of the safety of kava extract in the treatment to the treating physicians (4). They should collect of anxiety. Drug Safety, 25, 251–261. all the necessary data for causality assessment by 7. Teschke R, Gaus W, Loew D (2003) Kava extracts: the quantitative CIOMS scale for submission to the safety and risks including rare hepatotoxicity. appropriate regulatory agency and the drug man- Phytomedicine, 10, 440–446. ufacturer concerned. The individual data in the 8. Schulze J, Raasch W, Siegers CP (2003) Toxicity of CIOMS scale should be presented in the regulatory kava pyrones, drug safety and precautions – a case database, and then made available to both health- study. Phytomedicine, 10(Suppl. IV), 68–73. care providers and the scientific community. 9. Loew D, Franz G (2003) Quality aspects of traditional Regulatory transparency is mandatory for drug and industrial kava-extracts. Phytomedicine, 10, 610– safety. 612. In conclusion, the CIOMS scale is the preferred 10. Clouatre DL (2004) Kava kava: examining new reports of toxicity. Toxicology Letters, 150, 85–96. tool for causality assessment of liver disease possi- 11. Block KI, Gyllenhaal C, Mead MN (2004) Safety and bly caused by kava. Grades of causality for potential efficacy of herbal sedatives in cancer care. Integrative kava hepatotoxicity were much lower when evalu- Cancer Therapies, 3, 128–148. ated by methods such as MV or CIOMS than by 12. Schmidt M, Morgan M, Bone K, McMillan J (2005) regulatory ad hoc judgements for the 26 patients Kava: a risk-benefit assessment. In: Mills M, Bone K, considered. Regulatory ad hoc causality assessments eds. The essential guide to herbal safety. St Louis, MO: appear to be inadequate and lack transparency. We Elsevier Churchill Livingstone, 155–221.

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2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 545–563 Kava hepatotoxicity 563 with suspected kava-induced liver disease and Please note: Wiley-Blackwell are not responsible assured to be so by regulatory agencies. In section 4 for the content or functionality of any supporting (exclusion of alternative causes), the symbol ()) materials supplied by the authors. Any queries denotes a negative result whereas (+) denotes a (other than missing material) should be directed to positive result. Total points: <6 = causality exclu- the corresponding author for the article. ded; 6–9 = causality unlikely; 10–13 = causality possible; 14–17 = causality probable; >17 = causality highly probable.

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