Herbal Traditional Chinese Medicine and suspected liver injury: A prospective study

Table 5 Narratives of the cases 1-26 of the liver injury study cohort

Patients	Narratives
Case 1 male 51 yr (1994)	Patient with asthma (ICD-9 493.9), chronic low back pain (ICD-9 724.2), and reactive depression (ICD-9 300.4) treated with TCM decoctions with 8 drugs for 23 d: Angelicae sinensis radix, Asari herba, Astragali radix, Atractylodis macrocephalae rhizoma, Bupleuri radix, Glycyrrhizae radix, Paeoniae rubrae radix, Poria (parts), Scutellariae radix. Total daily dose: 80 g. Co-medication theophylline, fluocortolon. No alcohol abuse. Adverse events: nausea after drinking the decoction. ALT 293 U/L. First control after 5 d: ALT 341 U/L. Second control 14 d after discharge: ALT 17 U/L. No hepatitis serology RUCAM-based causality for Bupleuri radix, Glycyrrhizae radix and Scutellariae radix: Possible (score +4)
Case 2 male 73 yr (1994)	Patient suffered from unclear paralytic symptoms in both legs after trauma (ICD-9 344). Herbal TCM treatment with 9 drugs: Angelicae sinensis radix, Asari herba, Astragali radix, Atractylodis macrocephalae rhizoma, Bupleuri radix, Glycyrrhizae radix, Paeoniae rubrae radix, Poria (Stücke), Scutellariae radix for 22 d. Total daily dose: 60 g. Co-medication: digoxine, carbochol, nitrofurantoin, and sulfadiazine. No alcohol abuse. No adverse event symptoms. At discharge: ALT 140 U/L. First control 3 d later: ALT 100 U/L. Second control 3 wk later: ALT 22 U/L. No hepatitis serology RUCAM-based causality for Bupleuri radix, Glycyrrhizae radix, and Scutellariae radix: Possible (score +3)
Case 3 female 68 yr 1995	Patient with chronic bronchitis (ICD-9 491), emphysema (ICD-9 492), and sleeping disorder (ICD-9 780.50) was treated with herbal TCM decoctions (10 drugs) for 26 d: Angelicae sinensis radix, Asari herba, Astragali radix, Atractylodis macrocephalae rhizoma, Bupleuri radix, Ephedrae herba, Glycyrrhizae radix, Paeoniae rubrae radix, Poria (Stücke), Scutellariae radix. Total daily dose: 80 g. No co-medication. No alcohol abuse. No adverse event symptoms. ALT at discharge: 234 U/L. First control at 4 wk after discharge: ALT 7 U/L. No hepatitis serology RUCAM-based causality for Bupleuri radix, Ephedrae herba, Glycyrrhizae radix, and Scutellariae radix: Probable (score +7)
Case 4 female 47 yr (1996)	Patient with migraine (ICD-9 346.0) was treated for 28 d with the following herbal TCM decoctions (15 drugs): Angelicae dahuricae radix, Angelicae sinensis radix, Armeniacae amarum semen, Asari herba, Bupleuri radix, Codonopsis pilosulae radix, Evodiae fructus, Forsythiae fructus, Glycyrrhizae radix, Isatidis radix, Ligustici chuanxiong rhizoma, Ligustici rhizoma, Lonicerae flos, Platycodi radix, Prunellae spica. Total daily dose: 130 g. No comedication. No alcohol abuse. No adverse event symptoms. ALT at discharge 168 U/L. At control 4 wk later: 18 U/L; Hepatitis serology post increased ALT detection: anti-HAV (IgM/IgG) negative; HBs-Ag negative; anti-HBs negative; anti-HBc (IgM/IgG) negative RUCAM-based causality for Bupleuri radix and Glycyrrhizae radix: Probable (score +6)
Case 5 male 77 yr (1998)	Patient with post herpes zoster state (ICD-9 053.13), hypertension (ICD-9 401), diabetes mellitus (ICD-9 250) was treated for 12 d with 11 herbal TCM decoctions: Bupleuri radix, Chebulae fructus, Dictamni radicis cortex, Gentianae macrophyllae rhizoma, Margaritifera usta concha (t), Moutan radicis cortex, Myristicae semen, Paeoniae rubrae radix, Rehmanniae radix, Scutellariae radix, Sophorae flavescentis radix. Total daily dose: 110 g. Co-medication with potentially hepatotoxic drugs: zolpidem, anti-factor 10 Xa-activity. No alcohol abuse. Adverse event symptoms: Fever 38.6 °C, erythema, and transient scleral jaundice. At discharge ALT of 330 U/L, at control 12 wk after discharge < 24 U/L. No hepatitis serology RUCAM-based causality for Bupleuri radix, Dictamni radicis cortex, and Scutellariae radix: Excluded (score -1)
Case 6 female 60 yr (1999)	Patient Suffered From Chronic Migraine (ICD-9 346), Cervico-Brachial Pain Syndrome Left Side (ICD-9 723.3), Lower Back Pain Syndrome (ICD-9 724.2), And Diarrhea (ICD-9 787.91) Without Clear Gastrointestinal Diagnosis Since 4 yr. Herbal TCM Medication (22 Drugs) As Decoction For 22 D: Angelicae Dahuricae Radix, Astragali Radix, Atractylodis Rhizoma, Bombyx Batryticatus (T), Chrysanthemi Flos, Cicadae Periostracum (T), Cinnamomi Ramulus, Citri Reticulatae Pericarpium, Codonopsis Pilosulae Radix, Coicis Semen, Euryales Semen, Evodiae Fructus, Ligustici Rhizome, Lycopi Herba, Moutan Radicis Cortex, Myristicae Semen, Pinelliae Praeparatae Rhizome, Poria (Parts), Psoraleae Fructus (Semen), Punicae Granati Pericarpium, Rehmanniae Praeparatae Rhizome, Scutellariae Radix, Uncariae Cum Uncis Ramulus, Viticis Fructus. Total Daily Dose: 150 G. Co-Medication With Potentially Hepatotoxic Drugs: Ibuprofen 800 And Piroxicam 10. Alcohol Consumption 1 Drink Beer Daily. After Treatment For 5 D, Improvement Of Diarrhea, And After 22 D Migraine Attack Treated With Ibuprofen. Directly After Intake Of Ibuprofen, She Noticed Symptoms With Stomach Pain, Nausea, Vomiting. ALT At Discharge 530 U/L, At Control 47 D Later: 14 U/L. Hepatitis Serology Post Increased ALT: Anti-HAV-Igg Positive; Anti-HAV-Igm Negative; Anti-Hbs Negative; Anti-Hbc Negative RUCAM-Based Causality For Bombyx Batryticatus (T), Psoraleae Fructus (Semen), And Scutellariae Radix: Possible (Score +3)
Case 7 female 58 yr (1999)	Patient with lumbosacral plexus syndrome (ICD-9 953.5) and cervico-brachial syndrome (ICD-9 723.3) was treated with 24 drugs for 26 d with decoctions: Angelicae sinensis radix, Asteris radix, Bupleuri radix, Cinnamomi ramulus, Coptidis rhizoma, Dictamni radicis cortex, Ephedrae herba, Farfarae flos, Forsythiae fructus, Ginkgo semen, Glehniae radix, Isatidis folium, Lonicerae flos, Lumbricus (t), Ophiopogonis radix, Paeoniae alba radix, Paeoniae rubra radix, Perillae fructus, Pinelliae praeparatae rhizoma, Platycodi radix, Rehmanniae praeparatae rhizome, Rehmanniae radix, Scutellariae radix. Total daily dose 110 g. Co-medication: theophylline, vitamin E. No alcohol abuse. Adverse event symptoms: Diarrhea, headache, nausea, and vomiting. ALT at discharge: 35 U/L; at first control 5 d later ALT 132 U/L, at second control 4 wk later 8 U/L. No hepatitis serology RUCAM-based causality for Bupleuri radix, Dictamni radices cortex, Ephedrae herba, and Scutellariae radix: Possible (score +5)
Case 8 male 65 yr (2000)	Patient with polyneuropathy (ICD-9 357.2), who was treated with 14 drugs for 22 d with Angelicae pubescentis radix, Astragali radix, Chaenomelis fructus, Cinnamomi ramulus, Coptidis rhizoma, Corydalis rhizoma, Lonicerae caulis, Lumbricus (t), Mori ramulus, Moutan radicis cortex, Paeoniae rubrae radix, Rehmanniae praeparatae rhizoma, Spatholobi caulis, and Trachelospermi caulis. Total daily dose 130 g. Co-medication with potential liver toxicity: allopurinol 300 mg, atorvastatin 10 mg. Alcohol consumption 3-4 drinks beer per day. No adverse events. Safety check after 10 d of treatment: ALT < 24 U/L; at discharge: 193 U/L; first control 16 d later: ALT 24 U/L RUCAM-based causality for all used TCM herbs: Possible (score +3)
Case 9 female 78 yr 2000	Patient with polymyalgia rheumatica (ICD-9 725) and fibromyalgia (ICD-9 74.1), treated with 17 drugs for 23 d with: Astragali radix, Bupleuri radix, Carthami flos, Cinnamomi ramulus, Coptidis rhizoma, Curcumae longae rhizoma, Cyperi rhizoma, Glehniae radix, Ligustri lucidi fructus, Luffae fructus retinervus, Lycopi herba, Mori ramulus, Paeoniae rubrae radix, Rehmanniae praeparatae rhizoma, Scutellariae radix, Sparganii tuber (rhizoma), Trachelospermi caulis. Total daily dose: 84 g. Co-medication with potential liver toxicity: Triamterene, diclofenac. No alcohol abuse. No adverse event symptoms. ALT at discharge 162 U/L; first control 21 d later: 12 U/L. Hepatitis serology post increased ALT: anti-HAV IgG positive: Anti-HAV IgM negative; HBs-antigen negative; anti-HBs 250 U/L, anti-HBc positive RUCAM-based causality for Bupleuri radix and Scutellariae radix: Possible (score +4)
Case 10 female 35 yr (2002)	Patient suffered from migraine (ICD-9 346.0) and tension headache (ICD-9 307) since 20 yr. Treatment with 20 drugs: Albiziae cortex, Amomi cardamomi semen, Angelicae dahuricae radix, Angelicae sinensis radix, Artemisiae argyi folium, Bombyx batryticatus (t), Bupleuri radix, Codonopsis pilosulae radix, Dolichoris album semen, Evodiae fructus, Ligustici rhizoma, Margaritifera usta concha (t), Meliae toosendan fructus, Mori ramulus, Notopterygii rhizoma seu radix, Paeoniae albae radix, Prunellae spica, Puerariae radix, Scutellariae radix, Tribuli fructus as decoctions. Total daily dose: 95 g. Herbal TCM treatment for 28 d. Co-medication with potentially hepatotoxic drug: estradiol. Occasional alcohol use. Adverse event symptoms: abdominal pain and diarrhea. ALT at discharge 195 U/L; at first control 10 d later ALT 56 U/L. No hepatitis serology RUCAM-based causality for Bombyx batryticatus (t), Bupleuri radix, Meliae toosendan fructus, and Scutellariae radix: Possible (score +5)
Case 11 female 74 yr (2003)	Patient with difficulty of walking (ICD-9 719.7), polyneuropathy (ICD-9 357.2), and low back pain (ICD-9 724.2). Herbal TCM treatment with decoctions (25 drugs): Achyranthis bidentatae radix, Albiziae cortex, Amomi cardamomi semen, Angelicae pubescentis radix, Angelicae sinensis radix, Astragali radix, Atractylodis macrocephalae rhizoma, Chaenomelis fructus, Coicis semen, Coptidis rhizoma, Corydalis rhizoma, Glycyrrhizae radix, Margaritifera usta concha (t), Mori ramulus, Moutan radicis cortex, Paeoniae albae radix, Paeoniae rubrae radix, Phellodendri cortex, Rehmanniae praeparatae rhizoma, Salviae miltiorrhizae radix, Sappan lignum, Spatholobi caulis, Trachelospermi caulis, Tribuli fructus, Ziziphi spinosae semen.Total daily dose: 150 g. Co-medication with potentially hepatotoxic drug: candesartan 16 mg/die (regular), enalapril (rare). No alcohol abuse. No adverse event symptoms. Safety check after 14 d: ALT 165 U/L. At discharge: ALT 325 U/L. First control: ALT 61 U/L, Hepatitis serology post increased ALT: hepatitis B and C excluded; anti-HAV (IgG) positive RUCAM-based causality for Glycyrrhizae radix: Excluded (score -1)
Case 12 female 62 yr (2004)	Patient with chronic fatigue (ICD-10 L53), depressive episodes (ICD-10 F32.9), and gastrointestinal symptoms (ICD-10 K59.9) including abdominal pains and flatulence. Treatment with herbal TCM decoctions (18 drugs) for 26 d: Albiziae cortex, Amomi cardamomi semen, Angelicae sinensis radix, Astragali radix, Aurantii fructus, Citri sarcodactylis fructus, Codonopsis pilosulae radix, Coicis semen, Corydalis rhizoma, Curcumae radix, Eriocauli flos, Meliae toosendan fructus, Moutan radicis cortex, Notoginseng radix, Phragmitis rhizoma, Platycodi radix, Poria (parts), Schisandrae fructus. Total daily dose 96 g. Co-medication with clorazepate. No alcohol abuse. ALT at discharge 751 U/L. Seventeen days after cessation of herbal TCM products: ALT 148 U/L. No more subsequent ALT results available. Adverse event symptoms: Directly after discharge from the TCM-hospital, the patient was admitted at another hospital with a department of internal medicine due to deterioration of gastrointestinal symptoms. Serology: EBV-IgG 590 U/L, EBV-IgM negative RUCAM-based causality for Meliae toosendan fructus: probable (score +7)
Case 13 female 57 yr (2004)	Patient with arthralgia (ICD-10 M25.5), lower back pain syndrome (ICD-10 M54.4), and sleeping disorder (ICD-10 G 47.9) was treated with herbal TCM decoctions (14 drugs) for 25 d: Achyranthis bidentatae radix, Albiziae cortex, Angelicae sinensis radix, Astragali radix, Cassiae semen, Cinnamomi ramulus, Curcumae longae rhizoma, Gentianae macrophyllae rhizoma, Loranthi ramulus, Notoginseng radix, Notopterygii rhizoma seu radix, Periploca radicis cortex, Psoraleae fructus (semen), Spatholobi caulis. Total daily dose: 110 g. Co-medication: L-thyroxine, aminophylline. No alcohol abuse. Adverse event symptoms: abdominal pain, loss of appetite, and single vomiting. ALT at discharge 389 U/L; at first control 4 d later: ALT 191 U/L, and at second control 15 d later: ALT 22 U/L. Hepatitis serology post increased ALT: anti-HAV (IgG+IgM) positive; anti-HAV IgM negative; HBs-Antigen negative; anti-HBs positive; anti-HBc negative; HCV ab: negative RUCAM-based causality for Cassiae semen: possible (score +5)
Case 14 Female 52 yr (2006)	Patient with chronic osteomyelitis (ICD-10 M86.99) left leg and a six-year history after open fracture. PMH of hepatitis A 1968. Treatment with herbal TCM decoctions (12 drugs) for 24 d: Achyrantis bidentatae radix, Amomi cardamom semen, Chaenomelis fructus, Citri grandis exocarpium, Coicis semen, Corydalis rhizoma, Mangolie officinalis cortex, Meliae toosendan fructus, Paeoniae rubra radix, Poria (parts), Scutellariae radix, Zingiberis rhizoma. Total daily dose: 155 g. Co-medication with potential hepatotoxicity: use of not overdosed paracetamol (once) and ibuprofen (when needed, but presently no intake). No alcohol abuse. At day 20 after admission, patient showed adverse event symptoms like abdominal pain of the colic type with intestinal cramps, nausea, and mushier diarrhea. No ascites, no splenomegaly, no hyperbilirubinemia. ALT at discharge 1052 U/L. Three days later: 692 U/L and 35 d later: 33 U/L. Normal hepatitis serology with exclusion of hepatitis A, B, and C RUCAM-based causality for Meliae toosendan fructus and Scutellariae radix: Probable (score +7)
Case 15 female 43 yr (2007)	Patient suffered from unclear post-infectious chronic fatigue (ICD-10 G93; 10 F.43) and chronic cephalgia (ICD-10 R51). Known history of EBV infection. Treatment with herbal TCM decoctions containing the following 23 components for 19 d: Albiziae cortex, Anemarrhenae rhizoma, Astragali radix, Bambusae caulis in taeniam, Bupleuri radix, Chaenomelis fructus, Cinnamomi ramulus, Citri reticulatae pericarpium, Curcumae longae rhizoma, Epimedii herba, Leonuri herba, Ligustri lucidi fructus, Lycii fructus, Magnoliae officinalis cortex, Meliae toosendan fructus, Paeoniae rubra radix, Polygalae radix, Poria (parts), Pseudostellariae radix, Pyrrosiae folium, Salviae miltiorrhizae radix, Scutellariae radix, Tribuli fructus. Total daily dose: 69 g. Co-medication: L-thyroxine. No alcohol abuse. Adverse event symptom: abdominal pain. ALT at discharge 290 U/L; 12 d later at first control: ALT 181 U/L. Second control 24 d later: ALT 81 U/L; third control 28 d later: normal ALT values. No hepatitis serology RUCAM-based causality for Bupleuri radix, Meliae toosendan fructus, and Scutellariae radix: Possible (score +4)
Case 16 female 58 yr (2007)	Patient with lichen sclerosus (ICD-10 L90.0) and cervical spondylosis (ICD-10 M47.0) was treated with herbal TCM decoctions (11 drugs) for 25 d: Amomi cardamomi semen, Atractylodis rhizoma, Bambusae caulis in taeniam, Bombyx batryticatus (t), Bupleuri radix, Coicis semen, Kochiae fructus, Phellodendri cortex, Rehmanniae radix, Salviae miltiorrhizae radix, Scutellariae radix. Total daily dose 43 g. No co-medication. No alcohol abuse. No adverse event symptoms. ALT values at discharge normal. Continued use of herbal TCM at home, but at reduced daily dose of 26 g (corresponding to about 60% of the individual hospital dosage). Twenty-one days after hospital stay, safety check: ALT 715 U/L. Cessation of the herb use. Fifteen days after the first control: ALT 113 U/L. Again 14 d thereafter, at a second control: ALT 44 U/L; and at a third control, ALT 23 U/L. Hepatitis serology post first increased ALT values: Hepatitis B and C excluded. Anti-HAV-IgG positive; Anti-HAV-IgM negative RUCAM-based causality for Bombyx batryticatus (t), Bupleuri radix, and Scutellariae radix: Possible (score +5)
Case 17 female 48 yr (2010)	Patient with migraine (ICD-10 G 43.0) and depression (ICD-10 F 32.0) was treated with 11 herbal TCM components as decoctions for 20 d: Angelicae dahuricae radix, Bambusae caulis in taeniam, Bombyx batryticatus (t), Bupleuri radix, Cassiae semen, Curcumae longae rhizoma, Dipsaci radix, Gentianae macrophyllae rhizoma, Scutellariae radix, Siegesbeckiae herba, Trichosanthis fructus. Total daily dose: 60 g. No co-medication. No alcohol, Adverse event symptom: abdominal pain. Safety control: ALT 279 U/L. Cessation of the herb use. Five days after cessation and at discharge: ALT 252 U/L. First control 14 d after hospital discharge: ALT 12 U/L. Hepatitis serology post increased ALT: Hepatitis A, B, C excluded. Anti-EBV-VCA-IgG > 100; EBV-VCA-IgM < 0.9; HBsAb 474 Units; HBc ab negative; HCV ab not reactive; EBV-EBNA1-Ab (IgG) > 100 Units; Anti-HAV (IgM) negative; Anti-HBc (IgM) negative RUCAM-based causality for Bombyx baytryticuatus (t), Bupleuri radix, Cassiae semen and Scutellariae radix: Probable (score +6)
Case 18 female 52 yr (2010)	Patient with depression (ICD-10 F32.1), migraine (ICD-10 G43.0), spondylosis cervical (ICD-10 M47.8), and cephalgia (ICD-10 R51) treated with 16 drugs: Achyranthis bidentatae radix, Angelicae dahuricae radix, Bambusae caulis in taeniam, Bombyx batryticatus (t), Bupleuri radix, Citri reticulatae pericarpium, Coicis semen, Curcumae longae rhizoma, Magnoliae officinalis cortex, Paeoniae rubra radix, Polygalae radix, Poria (Stücke), Scutellariae radix, Tribuli fructus, Viticis fructus, Zingiberis rhizoma. Total daily dose: 96g. Duration of treatment for only 7 d because of adverse event symptoms of diarrhea ad deterioration of headache. Co-medication: L-thyroxine. Safety check 14 d after admission: ALT 76 U/L; At first control 20 d after admission: ALT 233 U/L. At discharge: ALT 198 U/L. Control 30 d after discharge: ALT 35 U/L. Serology post increased ALT: Anti-HAV (IgG, IgM) negative; anti-HAV (IgM) negative; HBs-antigen negative, Anti-HBs < 10 IU/L; Anti-HBc (IgG + IgM) negative; Anti-HCV negative RUCAM-based causality for Bombyx batryticatus (t), Bupleuri radix, and Scutellariae radix: Probable (score +6)
Case 19 female 60 yr (2011)	In 2011, patient with carcinophobia (ICD-10 F45.2), allergic sensitivity (ICD-10 T78.4) and tinnitus (ICD-10 H93.1) was treated with 28 drugs for 19 d with: Achyranthis bidentatae radix, Angelicae sinensis radix, Armeniacae amarum semen, Astragali radix, Atractylodis macrocephalae rhizoma, Aurantii immaturus fructus, Bambusae caulis in taeniam, Bombyx batryticatus (t), Bupleuri radix, Chrysanthemi flos, Cinnamomi ramulus, Curcumae longae rhizoma, Curcumae radix, Ephedrae herba, Edebouriellae radix, Ligustri lucidi fructus, Liquidambaris fructus, Luffae fructus retinervus, Lycii fructus, Menthae herba, Mori ramulus, Paeoniae albae radix, Paeoniae rubrae radix, Persicae semen, Peucedani radix, Polygoni multiflori caulis, Schisandrae fructus, Scutellariae radix. Daily drug dose 119 g. No co-medication. No alcohol. No adverse event symptoms. ALT at discharge 249 U/L; at first control after 3 d 123 U/L; at second control after 69 d 30 U/L. No hepatitis serology RUCAM-based causality in 2011 for Bombyx batryticatus (t), Bupleuri radix, Ephedrae herba, Polygoni multiflori caulis, and Scutellariae radix: Probable (score +6)
63 yr (2014)	In 2014, the patient was treated again with some of the previous herbal components as in 2011, now with 13 drugs: Atractylodis rhizoma; Bupleuri radix; Carthami flos; Clematidis radix; Curcumae longae rhizoma; Curcumae radix; Lycopodii herba; Mori ramulus; Pinelliae praeparatae rhizoma; Poria (parts); Puerariae radix; Sappan lig; Scutellariae radix. Total daily dose: 104 g. No co-medication. No alcohol abuse known. No adverse event symptoms. Because of the previous experience, liver enzyme control already after 7 d: ALT 295 U/L; cessation of all herbal TCM products. Six days later ALT 182 U/L, and 3 d thereafter: ALT 86 U/L. Eleven days later: ALT 34 U/L. No hepatitis serology RUCAM-based causality in 2014 for Bupleuri radix, Puerariae radix, and Scutellariae radix: Probable (score +7)
Case 20 female 53 yr (2012)	Patient with depressive episode (ICD-10 F33.1), migraine (ICD-10 G43.1), and low back-pain (ICD-10 M54.1) was treated for 22 d the with following 12 components: Achyranthis bidentatae radix, Angelicae dahuricae radix, Bupleuri radix, Cuscutae semen, Ligustici chuanxiong rhizome, Liquidambaris fructus, Lycii fructus, Rehmanniae radix, Scutellariae radix, Trachelospermi caulis, Tribuli fructus, Uncariae cum uncis ramulus. Total daily dose: 88 g. Additional wind-heat-mixture: Polygoni cuspidate rhizoma, Glycyrrhizae radix for 3 d. Wind-cold-mixture: Ephedra herba and Polygoni cuspidate rhizoma. Total daily dose: No comedication. No alcohol. No adverse effect symptoms. ALT at discharge 207 U/L, 22 d later at first control 30 U/L. No hepatitis serology RUCAM-based causality for Bupleuri radix, Ephedra herba, Glycyrrhizae radix, Polygoni cuspidate rhizoma, and Scutellariae radix: Possible (score +4)
Case 21 female 53 yr (2013)	Patient with neurasthenia (ICD-10 F48.0) and fibromyalgia (ICD-10 M79.7) received herbal TCM decoction for 18 d with the following 24 herbs: Achyranthis bidentatae radix, Astragali radix; Atractylodis rhizoma; Aurantii immaturus fructus, Bambusae caulis in taeniam, Bupleuri radix, Carthami flos, Citri reticulatae pericarpium, Citri sarcodactylis fructus, Curcumae longae rhizoma, Dipsaci radix, Glycyrrhizae radix, Inulae flos, Loranthi ramulus, Ophiopogonis radix, Paeoniae albae radix, Paeoniae rubrae radix, Persicae semen, Pinelliae praeparatae rhizoma, Pseudostellariae radix, Rehmanniae radix, Rhei radix et rhizoma, Scutellariae radix, Siegesbeckiae herba. Total daily dose: 78 g. No potentially hepatotoxic co-medication (only L-thyroxine). No alcohol. No adverse event symptoms. ALT at discharge 221 U/L and 41 U/L at control 14 d later. No hepatitis serology RUCAM-based causality for Bupleuri radix, Glycyrrhizae radix, Rhei radix et rhizoma, and Scutellariae radix: Possible (score +5)
Case 22 female 52 yr (2013)	Patient with somatoform pain disorder (ICD-10F45.0), drug induced tension headache (ICD-10 G45.2), and polyarthritis (ICD-10 M05.9), who was treated with herbal TCM decoctions for 22 d. The following 35 herbs were applied: Achyranthis bidentatae radix, Anemarrhenae rhizoma, Angelicae pubescentis radix, Astragali radix, Atractylodis rhizoma, Bambusae caulis in taeniam, Chaenomelis fructus, Cinnamomi ramulus, Clematidis radix, Coicis semen, Coptidis rhizoma, Curcumae longae rhizoma, Cyperi rhizoma, Dipsaci radix, Glycyrrhizae radix, Homalomenae rhizoma, Ligustri lucidi fructus, Liquidambaris fructus, Lonicerae caulis, Loranthi ramulus, Luffae fructus retinervus, Magnoliae officinalis cortex, Mori ramulus, Notopterygii rhizoma seu radix, Paeoniae rubrae radix, Pinelliae praeparatae rhizoma, Polygalae radix, Scutellariae radix, Siegesbeckiae herba, Sinomenii caulis, Sparganii tuber (rhizoma), Trachelo-spermi caulis, Tribuli fructus, Trichosanthis fructus, Uncariae cum uncis ramulus. Total daily dose was 78 g. Co-medication with the potentially hepatotoxic drug: omega-3-acidethylester. No alcohol-abuse, Adverse event symptoms: diarrhea, abdominal pain, and flatulence. Hepatitis B serology negative; HBs-Ag negative, Anti-HCV negative. At discharge: ALT 361 U/L and 15 U/L at control 90 d later RUCAM-based causality for Glycyrrhizae radix and Scutellariae radix: Possible (score +3)
Case 23 female 46 yr (2014)	Patient with alopecia cranialis totalis (ICD-10 L63.0) and Hashimoto-thyroiditis (ICD-10 E06.3) was treated for 28 d with a decoction containing 15 TCM herbs: Achyranthis bidentatae radix, Angelicae sinensis radix, Atractylodis macrocephalae rhizoma, Bambusae caulis in taeniam, Bupleuri radix, Citri reticulatae pericarpium, Cuscutae semen, Ledebouriellae radix, Lycii fructus, Periploca radicis cortex, Polygonati rhizoma, Polygoni multiflori radix, Poria (parts), Psoraleae fructus (semen), Testudinis plastrum (t). Total daily dose: 72 g. Co-medication with L-thyroxine. No alcohol. Adverse event symptom: flatulence. At discharge ALT 268 U/L, with 210 U/L on day 20 and 62 U/L on day 30 RUCAM-based causality for Bupleuri radix, Polygoni multiflori radix, and Psoraleae fructus (semen): Possible (score +4)
Case 24 female 51 yr (2014)	Patient with depression (ICD-10 F33.1) and migraine (ICD-10 G43.0) took for 17 d the herbal TCM decoction with the following 18 herbs: Achyranthis bidentatae radix, Angelicae sinensis radix, Bombyx batryticatus (t), Bupleuri radix, Curcumae longae rhizoma, Curcumae radix, Kochiae fructus, Ligustri lucidi fructus, Lycii fructus, Mori radicis cortex, Mori ramulus, Paeoniae rubrae radix, Polygoni multiflori caulis, Salviae miltiorrhizae radix, Scutellariae radix, Sparganii tuber (rhizoma), Spatholobi caulis, Tribuli fructus. Total daily dose was 60 g. Comedication: cimicifuga, zolpidem. No alcohol. Lack of adverse event symptoms. At discharge and control: ALT 210 U/L and 191 U/L. At a subsequent control 19 d later, ALT 36 U/L RUCAM-based causality for Bombyx batryticatus (t), Bupleuri radix, Polygoni multiflori caulis, and Scutellariae radix: Probable (score +6)
Case 25 female 53 yr (2015)	Patient with chronic pain syndrome (ICD-10 F 45.41; G43.9) received for 3 wk (twice daily) herbal TCM decoctions containing 20 different herbs: Angelicae sinensis radix, Aurantii fructus, Bambusae caulis in taeniam, Bupleuri radix, Carthami flos, Citri sarcodactylis fructus, Curcumae longae rhizoma, Curcumae radix, Ligustici chuanxiong rhizoma, Loranthi ramulus, Lycopodii herba, Mori ramulus, Persicae semen, Poria (parts), Puerariae radix, Scutellariae radix, Sparganii tuber (rhizoma), Spatholobi caulis, Tribuli fructus, Viticis fructus. Total daily dose: 87 g. Co-medication: intermittent use of sumatriptane and the potentially hepatotoxic drug paracetamol. No alcohol. No adverse effect symptoms. ALT at discharge 359 U/L, at control 18 d later ALT 69 U/L. Hepatitis A and B were excluded serologically RUCAM-based causality for Bupleuri radix and Scutellariae radix: Possible (score +5)
Case 26 female 61 yr -2015	Patient with unspecified somatization (ICD-10 F45.1), who suffered from abdominal symptoms of nausea, diarrhea, and loss of appetite, received herbal TCM decoction therapy for 23 d with 26 herbs: Amomi cardamomi semen, Amomi fructus, Armeniacae amarum semen, Atractylodis macrocephalae rhizoma, Bambusae caulis in taeniam, Bupleuri radix, Cinnamomi ramulus, Citri sarcodactylis fructus, Codonopsis pilosulae radix, Coicis semen, Corydalis rhizoma, Cyperi rhizoma, Forsythiae fructus, Glehniae radix, Glycyrrhizae radix, Ledebouriellae radix, Meliae toosendan fructus, Mori radicis cortex, Ophiopogonis radix, Paeoniae albae radix, Paeoniae albae radix, Peucedani radix, Pinelliae praeparatae rhizoma, Poria (parts), Scutellariae radix, Zingiberis rhizoma. Total daily dose: 87 g. Intermittent co-medication with the potentially hepatotoxic pantoprazole. Alcohol use with 2 drinks a day. During hospital stay, she experienced deterioration of her gastrointestinal symptoms. At discharge, ALT 182 U/L. Two weeks later, normalization of ALT (30 U/L). No hepatitis serology RUCAM-based causality for Bupleuri radix, Glycyrrhizae radix, Meliae toosendan fructus, and Scutellariae radix: Possible (score +3)

All patients showed normal ALT values at admission and experienced liver injury under therapy with herbal TCM. Indication for TCM treatment was based on diagnoses according to ICD classification. Liver injury is defined as ALT > 5 × ULN. TCM herbs with known hepatotoxicity from literature represented in bold[8-10]. Causality for all bold TCM herbs was assessed using the updated RUCAM[25]. Causality levels are as follows: ≤ 0 points, excluded causality; 1-2, unlikely; 3-5, possible; 6-8, probable; and ≥ 9, highly probable[3]. ALT normal ≤ 24 U/L until 2001 for males and females, thereafter ≤ 35 U/L for females and ≤ 50 U/L for males. ab: Antibodies; ag: Antigen; ALT: Alanine aminotransferase; CMV: Cytomegalovirus; EBV: Epstein Barr virus; HAV: Hepatitis A virus; HBc: Hepatitis B core; HBs: Hepatitis B surface; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; ICD: International Statistical Classification of Diseases and Related Health Problems; PMH: Past medical history; RUCAM: Roussel Uclaf Causality Assessment Method; TCM: Traditional Chinese Medicine.