Kava Hepatotoxicity: Are we any closer to the truth?

In recent years, kava kava ( Piper methysticum, Forst. f., Piperaceae) has been implicated in a number of liver failure cases. Ever since this has kept the scientific world busy. Even though, on closer inspection, the majority of the case reports are probably not connected to kava intake, hepatotoxic effects of kava cannot generally be ruled out. In this article the major theories as to the mechanism of kava hepatotoxicity are summarized. But in spite of all these hypotheses, there is still no satisfactory answer. In any case, further studies, that might hopefully restore the reputation of kava, are required.     

Is the alkaloid pipermethystine connected with the claimed liver toxicity of Kava products?

The pyridone alkaloid pipermethystine has been considered to be responsible for alleged hepatoxicity of Kava products. Investigation of a series of retain samples of finished products from the German market and self-produced extracts from root and stem material of Piper methysticum clearly showed that pipermethystine (1) is absent from all root and retain samples and extracts, with a limit of quantification of 45 ppm. As a positive control, leaves of P. methysticum showed an amount of 0.2% of 1. Thus, if there is any hepatotoxicity, compound 1 should not be the responsible constituent in the case reports with ethanolic extracts produced in Germany.     

Troglitazone hepatotoxicity: are we getting closer to understanding idiosyncratic liver injury?

Idiosyncratic hepatotoxicity is a rare and unpredictable eventof liver injury affecting generally less than 1 in 10,000 patientstreated with certain drugs. However, it is a serious clinicalproblem as it accounts for 10% of all drug-induced liver failurecases (Kaplowitz, 2005). Since idiosyncratic drug reactionsare not detected in preclinical testing and in most cases noteven during clinical trials, the problem surfaces generallyafter the drug is approved and hundreds of thousands of patientsare being treated. Idiosyncratic hepatotoxicities are currentlythe main cause for Food and Drug Administration-mandated warnings,restrictions of use or even withdrawals of drugs from the market(Kaplowitz, 2005). As such, this is a considerable problem forthe pharmaceutical industry and for regulatory agencies worldwide.One of the recent examples of drugs causing idiosyncratic hepatotoxicityand liver failure was the antidiabetic drug Rezulin (troglitazone). Troglitazone, a peroxisome proliferator–activated     

Connexin32: a mediator of acetaminophen-induced liver injury?

Connexin32 is the building block of hepatocellular gap junctions, which control direct intercellular communication and thereby act as goalkeepers of liver homeostasis. This study was set up to investigate whether connexin32 is involved in hepatotoxicity induced by the analgesic and antipyretic drug acetaminophen. To this end, whole body connexin32 knock-out mice were overdosed with acetaminophen followed by sampling at different time points within a 24-h time frame. Evaluation was done based upon a series of clinically and mechanistically relevant read-outs, including protein adduct formation, histopathological examination, measurement of alanine aminotransferase activity, cytokine production, levels of reduced and oxidized glutathione and hepatic protein amounts of proliferating cell nuclear antigen. In essence, it was found that genetic ablation of connexin32 has no influence on several key events in acetaminophen-induced hepatotoxicity, including cell death, inflammation or oxidative stress, yet it does affect production of protein adducts as well as proliferating cell nuclear antigen steady-state protein levels. This outcome is not in line with previous studies, which are contradicting on their own, as both amplification and alleviation of this toxicological process by connexin32 have been described. This could question the suitability of the currently available models and tools to investigate the role of connexin32 in acetaminophen-triggered hepatotoxicity.     

Drug-induced liver injury: Is chronic liver disease a risk factor and a clinical issue?

Introduction: Clinicians and practitioners caring for patients with chronic liver disease are often unsure whether drug therapy is a hazard that increases their patient’s risk for drug-induced liver injury (DILI).

Areas covered: We searched for reports of drug induced liver injury, both idiosyncratic and intrinsic, in patients with chronic liver disease including non-alcoholic and alcoholic liver disease, and cirrhosis. Reports we analyzed include statin treatment in patients with fatty liver, acetaminophen use in alcoholic fatty liver, antituberculous drugs in patients with tuberculosis and viral hepatitis, antiviral medications in hepatitis and antiretroviral medications in HIV/AIDS. The most challenging cases we found are drug therapy in patients with decompensated liver cirrhosis.

Expert opinion: We identified many case reports and case series discussing a potential increased risk of DILI in patients with pre-existing liver disease. However, most of these reports were retrospective and ambiguous. With few exceptions, we conclude that drugs seem to be well tolerated by the majority of patients with pre-existing, non-cirrhotic chronic liver diseases. Special care is needed for some therapies, however, including antiviral therapy in chronic hepatitis B and C and in decompensated liver cirrhosis with impaired drug metabolism. Prospective studies are warranted to valid our conclusions.     

“One-trial tolerance” to the anxiolytic actions of benzodiazepines in the elevated plus-maze,or the development of a phobic state?

Diazepam (5 mg/kg) increased the number of shocks accepted by rats on two successive trials in the punished drinking test. Thus, the phenomenon of one trial tolerance to the anxiolytic effects of benzodiazepines in the elevated plus-maze does not generalise to this other animal test of anxiety. FG 7142 (20 mg/kg) and prior exposure to the odour of a cat had significant anxiogenic effects on two successive trials in the plus-maze. Thus the phenomenon of one trial tolerance does not generalise to these anxiogenic effects in the plus-maze. Furthermore, chlordiazepoxide retained its ability to counteract the anxiogenic effects in the plus-maze of prior exposure to cat odour, over successive trials. On the basis of these and previous experiments it is suggested that the state of anxiety generated on trial 2 in the plus-maze is close to a phobic state, against which benzodiazepines are relatively ineffective. Chlordiazepoxide (5 and 10 mg/kg) was also ineffective against the behavioural responses of rats during exposure to cat odour, another possible animal test of phobia. This contrasted with its efficacy against the anxiogenic effects of cat odour that subsequently generalised to and could be detected in the plus-maze.     

Intravenous immunoglobulin for infectious diseases: back to the pre-antibiotic and passive prophylaxis era?

The dramatic increase in both the number of novel infectious agents and resistance to antimicrobial drugs has incited the need for adjunct therapies in the war against infectious diseases. Exciting recent studies have demonstrated the use of antibodies in the form of intravenous immunoglobulin (IVIg) against infections. By virtue of the diverse repertoire of immunoglobulins that possess a wide spectrum of antibacterial and antiviral specificities, IVIg provides antimicrobial efficacy independently of pathogen resistance and represents a promising alternative strategy for the treatment of diseases for which a specific therapy is not yet available.     

Misspecification in moment inequality models: back to moment equalities?

Summary Consider the linear model where one is interested in learning about β given data on y and x and when y is interval measured; that is, we observe such that . Moment inequality procedures use the implication . As compared to least squares in the classical regression model, estimates obtained using an objective function based on these moment inequalities do not provide a clear approximation to the underlying unobserved conditional mean function. Most importantly, under misspecification, it is not unusual that no parameter β satisfies the previous inequalities for all values of x, and hence minima of an objective function based on these moment inequalities are typically tight. We construct set estimates for β in the linear model that have a clear interpretation when the model is misspecified. These sets are based on moment equality models. We illustrate these sets and compare them to estimates obtained using moment inequality‐based methods. In addition to the linear model with interval outcomes we also analyse the binary missing data model with a monotone instrument assumption (MIV), we find there that when this assumption is misspecified, bounds can still be non‐empty, and can differ from parameters obtained via maximum likelihood. We also examine a bivariate discrete game with multiple equilibria. In sum, misspecification in moment inequality models is of a different flavour than in moment equality models, and so care should be taken with (1) the_interpretation of the estimates and (2) the size of the ‘identified set’.     

Bouncing back: is the bipolar rebound phenomenon peculiar to lithium? A retrospective naturalistic study

In bipolar disorder the discontinuation of lithium prophylaxis is associated with early episode precipitation. Is this ;rebound' phenomenon peculiar to lithium? This naturalistic retrospective case note review investigated the frequency of immediate recurrence after discontinuation of any prophylactic treatment. Bipolar patients who stopped at least one medication after at least 6 months of remission were studied. A total of 310 case notes were examined in a systematic search. A total of 53 cases of discontinuation in 48 subjects were found. Discontinued medications included lithium, valproate, carbamazepine, typical and atypical antipsychotics and antidepressants. Recurrence occurred within 3 months of medication withdrawal in 39 cases (74%). Over half of the discontinuation episodes involved lithium: recurrence occurred in 86% of these cases. In the groups stopping other prophylactic agents, a majority of subjects suffered recurrence: anticonvulsants (89%), antipsychotics (64%) and antidepressants (58%). However, these groups were small and the clarity of the data was undermined by the simultaneous withdrawal of other agents. Manic and hypomanic episodes were the most common form of recurrences. Depressive episodes occurred proportionately most frequently following antidepressant withdrawal. More than half of recurrences required hospital admission. This study provides preliminary naturalistic evidence that early episode recurrence in bipolar disorder is not peculiar to lithium withdrawal but may occur following withdrawal of medication from all classes recommended in prophylaxis. These findings, if replicated, have important implications for clinical practice and for research.     

Drug-induced liver injury: results from the hospital-based Berlin Case–Control Surveillance Study

Aim

Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case–control study to determine the hepatotoxic risk of a wide range of drugs.

Methods

The Berlin Case–Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case–control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis.

Results

The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic.

Conclusions

Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic.     

Highlights of drug - and herb- induced liver injury in the literature from 2016: how best to translate new information into clinical practice?

Introduction: Over 1500 papers on drug-induced liver injury (DILI) and herb-induced liver injury (HILI) were published in 2016, many of which have the potential to impact clinical practice.

Areas covered: Clinical studies and case series that lent themselves to new concepts in diagnosing, and treating DILI were selected for inclusion. Epidemiology of DILI in large prospective registries was highlighted. Causality assessment of drug hepatotoxicity remains challenging, as seen with cases of OxyELITE Pro (OEP). In 2016 updates to the Roussel Uclaf Causality Assessment Method (RUCAM) were published to aid in the accuracy of diagnosing DILI/HILI. New reports of established hepatotoxins were again discussed in 2016, including genetic risk factors for DILI with respect to antituberculous agents.

Expert opinion: 2016 marked a turning point in how much credence should be placed in the current causality assessment for DILI/HILI cases. Many recognized hepatotoxins are backed by a relatively few number of literature reports. Danan and Teschke make a strong case that an updated RUCAM should remain the gold standard for diagnosing DILI/HILI going forward, although the role of expert opinion is often still needed in cases where RUCAM falls short. The field of chemoinformatics continues to evolve while we await a truly predictive and diagnostic DILI biomarker.