Review article: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

BACKGROUND: 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. AIM: To summarise comprehensively the literature on herbal TCM hepatotoxicity since 2011. METHODS: PubMed was searched using key words related to TCM, the results were restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic 'Drug record: Chinese and other Asian herbal medicines'. RESULTS: Since 2011, new case reports and case series provided evidence for herbal hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four individual TCM herbs with potential health hazards. These were the TCM products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflorum products, Shan Chi, 'White flood' containing the herbal TCM Wu Zhu Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include the establishment of a new and early diagnostic serum marker for hepatotoxicity caused by pyrrolizidine alkaloids, assessed using ultra performance liquid chromatography-mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. CONCLUSION: Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury.

Kava for the treatment of generalized anxiety disorder RCT: analysis of adverse reactions, liver function, addiction, and sexual effects.

Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n = 75) involving chronic administration of kava (one tablet of kava twice per day; 120 mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240 mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p = 0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample.

[Pharmacovigilance and herbal hepatotoxicity: critical aspects and solutions]. / Pharmakovigilanz und herbale Hepatotoxizität: kritische Aspekte und Lösungswege.

Under clinical aspects and in private practice liver diseases are rarely considered in causal connection with the use of herbal drugs and herbal dietary supplements, but in suspected cases a thorough clinical and regulatory causality assessment is mandatory. In initially assumed herbal hepatotoxicity and associated regulatory evaluations by the German regulatory agency, definitions for hepatotoxicity were consistently lacking, upon which causality assssment may have been based. For the description of a risk, even patients were included with lack of established temporal association between herbal use and the appearance the adverse drug reaction (ADR) or with unknown actual liver values, only slightly increased liver values, isolated increased γ-glutamyltransferase, or overt alternative causes including comedication. This continuously led to regulatory high initial case numbers, which were not fundamentally based on clinical and scientific criteria. Heavily debated is also the regulatory use of the WHO method for causality assessment purposes, because this liver unspecific algorithm is neither validated for liver injury nor for any common ADR; this approach therefore is obsolete for a reproducible causality evaluation. Instead, we urgently recommend to use the scale of CIOMS (Council for International Organizations of Medical Sciences), which is liver specific and validated for hepatotoxicity. This is the only way to circumvent future absolute unnecessary and redundant scientific discussions in the regulatory field.

[Diagnostic approach in cases of herbal hepatotoxicity]. / Diagnostisches Vorgehen bei Lebererkrankungen durch pflanzliche Mittel.

BACKGROUND: Herb-induced liver injuries are rare and often lack careful evaluation by physicians and regulatory agencies, with the consequence that alternative diseases with specific therapeutic modalities are missed. Other shortcomings are low data quality that additionally complicates adequate evaluation. METHODS: Based on our own experience and a selective literature search, recommendations are presented that will substantially improve data acquisition and causality evaluation. RESULTS: Important diagnostic criteria include clinical manifestation, dechallenge, type of liver injury, (unintentional) reexposure, comedication, risk factors, primary disease, and definitive exclusion of alternative causes. Concomitantly, the data quality in cases of primarily assumed herbal hepatotoxicity may be substantially improved merely by strict data acquisition using a liver specific form. To establish the diagnosis of hepatic adverse drug reaction, a liver specific causality assessment method is available, which has been proven valuable for physicians and regulatory agencies for pharmacovigilance issues, and should be used more often. Using additional diagnostic steps, care should be taken that alternative diseases are recognized in time and treated adequately. CONCLUSION: In hospital and outpatient settings, primarily assumed herb-induced liver injury is a particular challenge for physicians and regulatory agencies that requires substantially improved case data quality and causality evaluation.

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

BACKGROUND AND OBJECTIVE: Ingestion of the medicinal herb kava has been associated with hepatotoxicity. We aimed to compare two different quantitative methods of causality assessment of patients with assumed hepatotoxicity by the herb. METHODS: We assessed causality in 26 patients from Germany and Switzerland, using two structured quantitative analytical methods: the system of Maria and Victorino (MV) and that of the Council for International Organizations of Medical Sciences (CIOMS). In all 26 patients, regulatory ad hoc evaluation had suggested a causal relationship between liver disease and kava use. RESULTS AND DISCUSSION: Assessment with the MV scale resulted in no or low graded causality for kava in the 26 patients with liver disease. Causality was probable (n=1), possible (n=2), unlikely (n=7), and excluded (n=16). Causality for kava was more evident with the CIOMS scale: highly probable (n=1), probable (n=2), possible (n=6), unlikely (n=2) and excluded (n=15). However, the results of both quantitative causality assessments are not supportive for most of the regulatory ad hoc causality assessments of the 26 patients. CONCLUSION: Grades of causality for suspected hepatotoxicity by kava were much lower when evaluated by structured quantitative causality assessment scales than by regulatory ad hoc judgements. The quantitative CIOMS scale is the preferable tool for causality assessment of spontaneous reports of hepatotoxcity involving kava.

Kava hepatotoxicity: regulatory data selection and causality assessment.

BACKGROUND: Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster. AIMS: We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts. METHODS: The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation. RESULTS: The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation. CONCLUSION: The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.

[Toxic liver disease due to drugs, herbs and dietary supplements: diagnostic approaches]. / Toxische Leberschäden durch arzneiliche, pflanzliche und nahrungsergänzende Mittel: Diagnostische Möglichkeiten.

Toxic liver diseases caused by drugs, herbs and dietary supplements are often recognized late because their hepatotoxic potency is considered to be minimal or non-existent and specific laboratory parameters to definitively establish the diagnosis are lacking. As gold standard for the diagnosis, a positive (unintentional) re-exposure test is considered which is seldom available. A system for evaluation is therefore necessary which takes into account various parameters and defines the grades of causality. By means of a qualitative pre-test with a few questions a screening may be possible as to whether the causality is not probable or not evaluable. Subsequently, a quantitative assessment of the degree of the causality with a main test should be done; this corresponds to the slightly modified and well validated score of the CIOMS (Council for International Organizations of Medical Sciences). The evaluation is achieved using various criteria such as latency period, time between the end of the therapy and begin of the reaction, course of values for the enzyme activities of the liver after cessation of the therapy, risk factors such as age, alcohol consumption and comedication, exclusion of diseases of other organs including chronic liver disease, previous information about hepatotoxicity of the alleged substance and possible results of an unwanted re-exposure. The various answers to these questions are quantitatively assessed, the resulting scores added, and finally an assignment to one of the grades of causality is made. If, on the basis of the main test, there are still doubts about the correct diagnosis, a further test is required to consider the differential diagnosis of additional diseases and chronic liver diseases of other causes. This stepwise approach is essential since ad-hoc decisions regarding causality are not without problems, and other diseases as causes for increased liver values are easily overlooked and not treated adequately in time. By means of this procedure an improvement in the drug safety can be expected, which is fruitful for the patient and helpful to the physician in charge, the health institutions and the drug companies.

Kava extracts: safety and risks including rare hepatotoxicity.

Kava is a perennial shrub native to some islands of the South Pacific and has been cultivated for centuries to prepare a psychoactive beverage from its rhizoma by means of extraction. Subsequently, kava extracts are commonly used as herbal anxiolytic drugs also in many other countries all over the world including European ones and the USA. Toxicological and clinical studies have shown that kava extracts are virtually devoid of toxic effects with the exception of rare hepatotoxic side effects reported in few patients. When assessed primarily by the British regulatory authority MCA but also by us, a critical analysis of the suspected cases (n = 19) in Germany reveals that only in 1 single patient a very probable causal relationship could be established between kava treatment and the development of toxic liver disease due to a positive result of an unscheduled reexposure test, whereas in another patient there might be a possible association. Out of the remaining 17 cases 12 patients were not yet assessable due to insufficient data and in 5 other cases a causal relationship was unlikely or could be excluded. The German regulatory authority might therefore well be advised to provide now additional information for those 12 patients with so far unsatisfactory data, facilitating a more appropriate assessment of causality. Nevertheless, in the meantime physicians and patients should continue to keep an eye on possible hepatotoxic side effects in the course of kava treatment, to stop the treatment alredy at first suspicion and to start with a careful diagnostic work up ruling out all other causes.

[Kava, kavapyrones and toxic liver injury]. / Kava, Kava-Pyrone und toxische Leberschäden.

Kava extracts are obtained from the rhizoma of the kava shrub (Piper methysticum) and contain various pyrones which are used as herbal anxiolytic remedies for generalized anxiety syndromes of low and intermediate grades. The commonly recommended daily dose of 60-120 mg kavapyrones and the duration of the therapy of up to 3 months should not be increased without consultation of a physician and were not followed by most patients, since herbal drugs are considered by the population not only as effective but also as safe. Whereas kava extracts are well tolerated by most patients and rare side effects are rapidly reversible upon drug discontinuation, there are suspected hepatotoxic reactions reported during the last years in temporal and not necessarily causal association with a therapy with kava extracts. Almost 80 % of the patients took kavapyrones in overdose (maximally 480 mg/d) and/or for a prolonged time of more than 3 months up to 2 years. Additional risks factors include co-medication with up to 5 other chemically defined or herbal drugs with in part potentially hepatotoxic properties as well as a genetic deficiency of the hepatic microsomal cytochrome P450 2D6. Severe clinical courses with liver transplantation and possible fatal outcome occurred in 7 patients with overdose and/or long duration of the therapy with kavapyrones. Preventive measures should therefore include a dose of 120, maximally 210 mg kavapyrones per day for 1 month, maximally 2 months, as well as a prescription by a physician. Laboratory test (ALT and gamma-GT) should be done before and during the therapy, and co-medication and alcohol consumption should be avoided. With these measures the hepatotoxic risks under the treatment with kavapyrones might be minimized which are also available via internet and from abroad with possible severe consequences when taken without medical supervision.

[Drug-induced liver diseases]. / Arzneimittelbedingte Lebererkrankungen.

About 1000 drugs produced world-wide may lead to clinically relevant hepatotoxic reactions which are unpredictable at normal doses and occur at various frequencies. Among these are well established therapeutic drugs which have been in use for years or decades as well as newly introduced drugs, the number of which is steadily increasing. For the development of drug-induced liver disease, various pathogenetic mechanisms, many risk factors and variable latency periods are known. The histological picture may imitate practically all known non-toxic liver diseases from which toxic liver disease needs to be differentiated. Patients under drug therapy require regular medical follow-up with regard to the development of toxic liver disease since the prognosis is only good with early recognition and immediate withdrawal of the alleged drug. Specific therapeutic modalities to prevent toxic liver disease are limited to paracetamol overdosage which is treated by the application of N-acetylcysteine. For other drug-induced liver diseases characterised by a prolonged course, therapy with ursodeoxycholic acid or steroids may be helpful. When fulminant drug-induced liver failure occurs, liver transplantation is the therapy of choice with a better prognosis than a conventional therapy. Despite this therapeutic option more than 40 different drugs are known to have caused lethal forms of toxic liver disease. Physicians have therefore to be alert to early recognize drug-induced liver disease and to withdraw the drug at first suspicion of the diagnosis.

[Duodenal tuberculosis. A rare cause of a covered perforation in the duodenal bulb]. / Duodenaltuberkulose. Seltene Ursache einer gedeckten Perforation im Bulbus duodeni.

Vague upper abdominal pain, weight loss (10 kg) and recurrent bouts of fever had been present for several months in a 77-year-old woman. Abdominal ultrasonography in the region of the head of the pancreas and duodenum had demonstrated several lymphomas, some of them with "air streaking". This finding suggested penetration from the duodenum to neighbouring lymph nodes. Plain film of the abdomen did not show free air, but at gastroscopy a covered perforation into the surrounding lymph nodes was found. At first lymphoma or Crohn's disease were considered in the differential diagnosis. But the finding of acid-fast bacteria in a biopsy from the pelvic crest suggested intestinal tuberculosis with dissemination. This diagnosis was confirmed by the direct demonstration of Mycobacterium tuberculosis in gastric juice. Under tuberculostatic treatment with daily 0.3 g isoniazid, 0.45 g rifampicin, 0.8 ethambutol and 1.5 g pyrazinamide, as well as 50 mg prednisolone to prevent stricture, the size of the tuberculous ulcer had markedly decreased within 2 weeks. Follow-up gastroscopy after 6 months showed almost complete healing without stricture. However rare, gastrointestinal tuberculosis should not be forgotten in the differential diagnosis because it can imitate a large variety of gastrointestinal diseases.

[The liver and alcohol]. / Leber und Alkohol.

The liver is the main organ for alcohol metabolism and is therefore predisposed for various functional changes and irreversible alterations. The alcoholic fatty liver represents the early stage of alcohol-induced liver diseases and is completely reversible upon consequent alcohol abstinence. Already at this early stage a significant increase of gamma-glutamyltransferase activities is commonly found in the serum, which can mainly be attributed to an enzyme induction in the endoplasmic reticulum of the liver cell. Other stages of alcohol-induced liver diseases include the alcoholic hepatitis and the liver cirrhosis, which have a better prognosis upon consequent alcohol abstinence compared to continuous alcohol consumption. Many therapeutic studies with various drugs have been carried out in patients with alcohol-induced liver diseases, but at present a treatment with drugs in a sufficiently great number of patients has not been firmly established. The most important medical goal is to establish the diagnosis of alcohol-induced liver diseases already at the early stage of the fatty liver in order to initiate the necessary therapeutic measures with the aim of a consequent alcohol abstinence.

[The biochemistry of alcohol metabolism]. / Biochemie des Alkoholmetabolismus.

The metabolism of ethanol to acetaldehyde in the liver proceeds via alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MOS), whereas catalase plays no significant role. ADH is an enzyme of the cytosol, requires NAD+ as cofactor and exhibits a pH optimum in the alkaline range. The Km of ADH is about 2 mM for ethanol (equivalent to 0.1%). Thus, the enzyme is already saturated at low ethanol concentrations. Conversely, MEOS resides in the endoplasmic reticulum, requires NADPH and O2, is inhibited by CO and exhibits a km of about 10 mM corresponding to 0.5% ethanol. This enzyme system is therefore primarily the pathway of ethanol metabolism at intermediate to high ethanol concentrations. MEOS has many properties in common with other drug metabolizing enzymes and is characterized by inducibility following chronic ethanol consumption, which suggests the involvement of the microsomal system in the adaptive enhancement of ethanol clearance commonly observed in alcoholics. The product of ethanol oxidation by ADH, MEOS and catalase is acetaldehyde. Acetaldehyde is oxidized in the liver to acetate by NAD dependent aldehyde dehydrogenase. Four isozymes have been identified. Lack of isozyme I is responsible for the "flush-syndrome" commonly observed in asian people following alcohol intake. Ethanol metabolism is affected by the aging process and is decreased with advancing age.

Acquired immunodeficiency syndrome. Magnetic resonance patterns of brain involvement with pathologic correlation.

Magnetic resonance brain scans of 30 patients with either acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were reviewed. Twenty patients had focally abnormal neurological examination results at the time of scanning. Pathological diagnosis was available in nine. Four patterns of abnormality were observed on T2-weighted images. Multiple discrete high-signal foci (pattern A) were found in patients with toxoplasmosis and progressive multifocal leukoencephalopathy. Large, bilateral patchy to confluent high-signal areas within the white matter (pattern B) represented a white matter encephalitis secondary to cytomegalovirus or human immunodeficiency virus. Generalized enlargement of the cortical sulci and ventricles (pattern C) probably reflected atrophic changes from the chronic human immunodeficiency virus infection and prolonged debilitating illness. Solitary high-signal-intensity lesions (pattern D) suggested a nonviral opportunistic infection. Differential diagnosis of brain abnormalities in patients with AIDS can be assisted by recognition of these characteristic patterns.

Enhanced biliary gamma-glutamyltransferase excretion following prolonged alcohol consumption in rats.

In order to study the question of whether chronic ethanol consumption may alter the biliary excretion of gamma-glutamyltransferase (gamma-GT), female rats were pair-fed nutritionally adequate liquid diets containing either ethanol (36% of total calories) or isocaloric carbohydrates for 24 days. Compared to pair-fed controls, the administration of the alcohol-containing diet resulted in an increased biliary excretion of gamma-GT (5.84 +/- 0.73 mU 6 h-1 100 g-1 b.w. vs. 8.82 +/- 0.79, P less than 0.001). This was associated with a corresponding enhanced biliary output of total bile acids. An apparent linear relation between the biliary output rates of gamma-GT and those of total bile acids was observed both in alcohol-fed animals (r = 0.83) and in their pair-fed controls (r = 0.95). In addition, there was a significant increase of gamma-glutamyltransferase activities in the liver homogenate and in liver plasma membranes, both in fractions rich in bile canalicular and basolateral membranes and in those rich in blood sinusoidal site. Serum gamma-glutamyltransferase activities as well as serum bile acid concentrations were also enhanced by 96.8% (P less than 0.001) and 233% (P less than 0.001), respectively. These data show that chronic alcohol consumption enhances hepatic gamma-GT activities, leading to an increased efflux of gamma-GT into the bile and possibly into the blood out of the liver cell. Furthermore, these data suggest the involvement of bile acids with their solubilizing properties for the biliary excretion of gamma-GT.