Christian Frenzel

Review article: herbal hepatotoxicity – an update on traditional Chinese medicine preparations

Although evidence for their therapeutic efficacy is limited, herbal traditional Chinese medicine (TCM) preparations increasingly gain popularity. In contrast to other herbal products, adverse effects by herbal TCM including liver toxicity were rarely reported. In recent years, more cases were published, providing new clinical challenges.

Clinical and causality assessment in herbal hepatotoxicity.

Introduction: Herbal hepatotoxicity represents a poorly understood, neglected and multifaceted disease with numerous confounding variables and missing established causality in the majority of cases. This review discusses overt shortcomings in its clinical and causality assessment and suggests improvements. Areas covered: A selective literature search of PubMed using the terms herbal hepatotoxicity, herb-induced liver injury, drug hepatotoxicity and drug-induced liver injury was performed to identify published case reports, spontaneous case reports, case series and review articles regarding hepatotoxicity due to herbs, herbal drugs and herbal dietary supplements. Covered areas focused on confounding variables related to the documentation of the herbal product and the clinical course, hepatotoxicity and reexposure criteria, temporal association, comedication and alternative causes with special attention to preexisting diseases of the liver, bile ducts and the pancreas. Of particular interest were recent discussions of approaches designed and validated for hepatotoxicity causality, such as the scale of CIOMS (Council for International Organizations of Medical Sciences). Expert opinion: The authors call for substantial improvements in data quality of herbal products and case characteristics and strongly recommend using the CIOMS scale to assess causality in suspected herbal hepatotoxicity.

Herbal hepatotoxicity: a critical review

This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements.

Cutting Edge: A Key Pathogenic Role of IL-27 in T Cell- Mediated Hepatitis

The signals driving T cell activation in T cell-mediated fulminant hepatitis are not fully understood. In this study, we identify the cytokine IL-27p28/EBI3 as a major pathogenic factor in the ConA model of T cell-mediated hepatitis. We found an up-regulation of hepatic EBI3 and p28 expression and augmented levels of IL-27 in wild-type mice after ConA administration, suggesting a potential pathogenic role of this cytokine in ConA hepatitis. Consistently, IL-27 EBI3-deficient mice were almost completely protected from ConA-induced liver damage. Such protection was associated with reduced levels of IFN-γ and its signaling proteins pSTAT-1 and T-bet. Finally, in vivo blockade of IL-27 function using a soluble IL-27 receptor fusion protein led to reduced pSTAT1 levels and suppression of liver injury. Taken together, these data demonstrate a key pathogenic role of IL-27 in T cell-mediated liver injury. Furthermore, in vivo blockade of IL-27 emerges as a novel potential therapy for T cell-mediated hepatitis.

Spontaneous reports of primarily suspected herbal hepatotoxicity by Pelargonium sidoides: Was causality adequately ascertained?

Spontaneous reports of primarily assumed hepatotoxicity in connection with the use of Pelargonium sidoides (PS) have been interpreted by the Drug Commission of the German Medical Association (DCGMA) as showing some hepatotoxic potential of PS used to treat common cold and other respiratory tract infections. Causality for PS was assessed using the liver specific, structured, quantitative, and updated scale of the Council for International Organizations of Medical Sciences (CIOMS). In none of the 15 cases was there a highly probable or probable causality for PS. Analysis revealed confounding factors such as numerous final diagnoses unrelated to PS and poor data quality in virtually all cases. In only a minority of the cases were data provided to consider even common other diseases of the liver. For instance, biliary tract imaging data were available in only 3 patients; data to exclude virus infections by hepatitis A-C were provided in 4 cases and by CMV and EBV in 1 case, whereas HSV and VZV virus infections remained unconsidered. Thus, convincing evidence is lacking that PS was a potential hepatotoxin in the analyzed cases.

Herbal hepatotoxicity: Analysis of cases with initially reported positive re-exposure tests

BACKGROUNDnPositive re-exposure tests are diagnostic hallmarks for hepatotoxicity.nnnOBJECTIVEnTo test validity of positive re-exposures in herb induced liver injury.nnnMETHODSnWe searched Medline database for cases of herb induced liver injury with positive re-exposures and analysed 34 cases for positive re-exposure test criteria of baseline alanine aminotransferase< 5N before re-exposure, and re-exposure alanine aminotransferase ≥ 2× baseline alanine aminotransferase. Re-exposure test was negative, if baseline alanine aminotransferase< 5N combined with re-exposure alanine aminotransferase< 2× baseline alanine aminotransferase, or if baseline alanine aminotransferase≥ 5N regardless of the re-exposure alanine aminotransferase including no available re-exposure alanine aminotransferase result.nnnRESULTSnIn 21/34 cases (61.8%), criteria for a positive re-exposure were fulfilled, with negative tests in 6/34 cases (17.6%) or uninterpretable ones in 7/34 cases (20.6%). Confirmed positive re-exposure tests established potential of herb induced liver injury for Aloe, Chaparral, Chinese herbal mixtures, Chinese Jin Bu Huan, Chinese Syo Saiko To, Germander, Greater Celandine, Green tea, Kava, Mistletoe, Polygonum multiflorum, and Senna, with up to 4 case reports per herb.nnnCONCLUSIONSnAmong 34 cases of herb-induced liver injury with initially reported positive re-exposure tests, 61.8% of the cases actually fulfilled established test criteria and provided firm diagnoses of herb induced liver injury by various herbs.

Letter: herbal hepatotoxicity – an update on traditional Chinese medicine preparations; authors′ reply

plant species for the medicinals Bupleuri Radix and Angelicae Radix than Chinese medicine, namely B. falcatum and A. acutiloba or A. acutiloba var. Sugiyamae. In Table 1 of the article by Teschke et al., A. sinensis is erroneously listed as an ingredient. The reported liver injury, which may only have a ‘possible’ causality association with the formula, can neither simply be related to Chinese medicine nor to a single component of the Kampo formula. What in the article does really concern Chinese Medicine? In one case, the remedy ban tu wan (‘alopecia areata pills’) was taken. This is a combination of nine Chinese medicinal herbs. No identity check was done, no investigation on contaminants or adulteration and no standardised causality assessment. A causality assignment of the fatal liver injury to the ingredient Polygoni multiflori Radix (he shou wu) is vague. An investigation carried out in Taiwan found that there was an increased risk for hepatitis B patients to be hospitalised for liver injury when taking formulas containing Bupleuri Radix (chai hu). Generally, from this nonrandomised study no proof of causality can be derived. Since the two major suspicious formulas contained not only Bupleuri Radix but, among many other ingredients, also Scutellariae Radix, the results cannot be one-sidedly related to Bupleuri Radix. A causal link to Bupleuri Radix thus cannot be verified. The only conclusive association of Chinese medicine with hepatotoxicity presented in this article is the case compilation concerning Polygoni multiflori Radix (he shou wu). In these cases, Polygoni multiflori Radix apparently had been applied as a single herb (although reported differently by Teschke et al.), namely as an unprepared herb. The striking number of cases in which this herb has been ingested as tea, liquid or powder suggests a hepatotoxic risk, even though tests for identity and contaminants or adulteration are missing. The causality assessment has been done according to CIOMS and classified as ‘probable’. In one case, there was even a re-exposure to the herbal preparation with a positive outcome. We, too, considered Polygoni multiflori Radix as potentially hepatotoxic because of the numerous cases reported in the literature. Thus, only a small part of the study applies to the practice of Chinese Medicine as executed in western countries or as taught academically in China.

Effectiveness and safety of minilaparoscopy-guided spleen biopsy: a retrospective series of 57 cases.

BackgroundMinilaparoscopy is an accepted method for liver biopsy. We report our experience with minilaparoscopy for splenic biopsy.MethodsWe reviewed the records of all minilaparoscopy procedures performed from 1996 to 2004 at the University of Mainz Medical Center and from 2005 to mid-2011 at the University of Hamburg Medical Center to identify patients who underwent a minilaparoscopy-guided splenic biopsy. All procedures were performed using the previously described method (2.75-mm trocar, 2.3-mm Veress needle, 1.9-mm laparoscope) with the patient under conscious sedation (midazolam/meperidine/propofol). Splenic biopsies were performed using a second trocar with an 18-G Tru-Cut needle. Argon plasma coagulation (APC) and/or fibrin glue (FG) were used to control postbiopsy bleeding.ResultsFifty-seven patients underwent minilaparoscopy-guided biopsy of the spleen (27 females, 30 males; median agexa0=xa041xa0years, rangexa0=xa016–76). A specimen suitable for histopathologic evaluation was obtained in all patients. Grouped by preprocedure indication, a definitive diagnosis was obtained in 70% (7/10) of patients who had splenic mass lesions in prior imaging (3 B-NHL, 2 hemangioma, 1 tuberculosis, 1 sarcoidosis; pxa0<xa00.01) compared to 29% (10/34) in the group with unexplained fever or suspected lymphoma (3 tuberculosis, 2 B-NHL, 1 hepatosplenic T-cell lymphoma, 1 sarcoidosis, 1 Still’s disease, 1 EBV, 1 Q-fever) and 0/13 with unexplained splenomegaly. Focal lesions noted at laparoscopy yielded to a histologic diagnosis in 38% (11/29) of 42 patients compared to 21% (6/28) without laparoscopic abnormality (pxa0=xa00.25). Bleeding from the biopsy site was noted in 96.5% (55/57) and was classified as brisk in 9. Control of hemorrhage was achieved in all patients (APC: 47, FG: 1, APC/FG: 7). There was no postprocedure bleeding or other complications.ConclusionSplenic biopsy guided by minilaparoscopy can be performed safely. Postprocedure bleeding is readily controlled with APC with or without fibrin glue. The highest diagnostic yield is in patients with focal splenic lesions.