Mercedes Robles

Drug-induced liver injury: insights from genetic studies

Drug-induced liver injury (DILI) is an increasing health problem and a challenge for physicians, regulatory bodies and the pharmaceutical industry, not only because of its potential severity and elusive pathogenesis but also because it is often inaccurately diagnosed, commonly missed entirely and more often not reported. The general view is that idiosyncratic DILI, which is not predictable whether based on the pharmacology of the drug or on the dose administered, is determined by the presence in the recipient of variants in, or expression of, genes coding for key metabolic pathways and/or the immune response, and the interaction of these genetic variants with environmental variables. Furthermore, idiosyncratic DILI is an example of a complex-trait disease with two or more susceptibility loci, as reflected by the frequency of genetic variants in the population often being higher than the occurrence of significant liver injury. Polymorphisms of bioactivation/toxification pathways via the CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III), together with immunological factors that might determine DILI are reviewed. Challenges such as gene-trait association studies and whole-genome studies, and future approaches to the study of DILI are explored. Better knowledge of the candidate genes involved could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity, development of new diagnostic tools and new treatment strategies with safer drugs.

Rechallenge in drug-induced liver injury: the attractive hazard

Progress in the understanding of drug-induced liver injury (DILI) is clearly hampered by the lack of specific markers of the disease. In this scenario, recrudescence of the liver injury upon re-exposure to the suspicious drug is considered the more reliable evidence of DILI. On-purpose re-exposure, however, entails both practical and ethical issues because the bulk of situations in clinical practice are non-immunoallergic DILI in which a provocation test frequently would give negative results. Besides, deliberate re-exposure with a drug that is not considered vital or essential is potentially harmful and, hence, hardly justified in DILI, and rechallenge is more commonly described in an unintentional basis. The causes, characteristics and consequences of rechallenge have been specifically addressed recently. For causality assessment, a positive rechallenge test carries the strong value, and is accordingly scored by clinical algorithms. Such clinical scales, however, reward drugs that are associated with a positive rechallenge response, but might be considered biased against those where re-administration fails to elicit a response or, more commonly, for which no rechallenge is attempted.

Antibiotic-Induced Liver Toxicity: Mechanisms, Clinical Features and Causality Assessment

Antibiotics are the therapeutic agents most often associated with hepatotoxicity. However, this is mainly due to the widespread prescription of these drugs. The relative risk of antibiotic-related hepatotoxicity is low. Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult, particularly because some cases occur long after the drug has been stopped. Among the penicillins, amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations. Flucloxacillin ranks as the second highest cause of DILI in many countries. The severity of antibiotic-induced DILI varies widely, with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestatic/mixed type. The pattern is strongly influenced by age. Recently telithromycin (a new generation macrolide) has been linked with DILI, with a typical pattern, which includes abrupt commencement of fever, abdominal pain, jaundice and, in some cases, ascites. Antibiotic-induced DILI appears, in most instances, to be idiosyncratic. Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity.

Hepatotoxicity in 2011--advancing resolutely.

Liver toxicity from drugs, and also from alternative medicine products such as herbalist’s remedies and dietary supplements, is currently an increasingly relevant health issue. A great majority of hepatic adverse reactions seen in clinical practice are unpredictable (unrelated to a drug’s pharmacological characteristics) and basically result from an interaction of three circumstances: a drug with potential to generate hepatotoxic radicals in a genetically susceptible individual under certain environmental factors. This type of reaction, which occurs only rarely, goes undetected during a drug’s development process, and hence typically manifests when dozens of thousands of patients are exposed to it post-marketing; this still represents the first cause for a drug’s market withdrawal. On the other hand, the absence of objective diagnostic tests and variable clinical presentation commonly entail a delayed diagnosis of liver toxicity. In the present article, we review recent advances in this area and new consensus as result of investigators from different countries. EPIDEMIOLOGY

Idiosyncratic drug hepatotoxicity: a 2008 update

Pharmaceutical preparations, and also herbal products and dietary supplements, are emerging contributors to severe forms of liver disease. Although acetaminophen intoxication is still the reason for many cases of drug-induced liver injury (DILI) in Western countries, the bulk of hepatic reactions to drugs are idiosyncratic. Only a small fraction of individuals exposed to a drug associated with liver injury will develop hepatotoxicity. Indeed, the rarity of this serious adverse event prevents its detection in clinical trials. The pathogenesis of idiosyncratic DILI is not well known because of a lack of reliable animal models, although it probably involves the metabolism of the drug and/or activation of the immune system. Different databases have described antibiotics, NSAIDs and anticonvulsants as the main group of drugs incriminated in DILI. Clinical presentation of DILI includes predominantly a hepatocellular type of damage, yet cholestatic and mixed types are also common; the determinants of the type of damage induced by a given drug are poorly understood. Analysis of pooled data has recently underlined the influence of older age in the cholestatic/mixed expression of liver injury, as well as the independent association of female gender, older age, aspartate aminotransferase levels with hepatocellular type of damage and high bilirubin levels with the risk of fulminant liver failure/death. In the long term (providing the patient survives the initial episode), persistent damage may occur in at least 6% of patients, with the cholestatic mixed type of damage more prone to becoming chronic, while in the hepatocellular pattern the severity is greater, with further likelihood of evolution to cirrhosis. Cardiovascular and CNS drugs are the main groups leading to chronic liver damage. The diagnosis of hepatotoxicity remains a difficult task owing to the lack of reliable markers for use in general clinical practice. Diagnostic algorithms may add consistency to clinical judgment by translating a suspicion into a quantitative score. Currently, the Council for International Organizations of Medical Sciences/Roussel Uclaf Causality Assessment Method instrument is considered the gold standard in causality assessment of hepatotoxicity, although there is probably room for improvement. Current efforts in collecting bona fide cases will make refinements of existing scales feasible. Efforts should also be directed towards the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be taken. The treatment of idiosyncratic DILI is largely supportive. Early suspicion and withdrawal of the offending agent is the most important therapeutic measure.

A survey of zoonotic pathogens carried by house mouse and black rat populations in Yucatan, Mexico

The house mouse (Mus musculus) and the black rat (Rattus rattus) are reservoir hosts for zoonotic pathogens, several of which cause neglected tropical diseases (NTDs). Studies of the prevalence of these NTD-causing zoonotic pathogens, in house mice and black rats from tropical residential areas are scarce. Three hundred and two house mice and 161 black rats were trapped in 2013 from two urban neighbourhoods and a rural village in Yucatan, Mexico, and subsequently tested for Trypanosoma cruzi, Hymenolepis diminuta and Leptospira interrogans. Using the polymerase chain reaction we detected T. cruzi DNA in the hearts of 4·9% (8/165) and 6·2% (7/113) of house mice and black rats, respectively. We applied the sedimentation technique to detect eggs of H. diminuta in 0·5% (1/182) and 14·2% (15/106) of house mice and black rats, respectively. Through the immunofluorescent imprint method, L. interrogans was identified in 0·9% (1/106) of rat kidney impressions. Our results suggest that the black rat could be an important reservoir for T. cruzi and H. diminuta in the studied sites. Further studies examining seasonal and geographical patterns could increase our knowledge on the epidemiology of these pathogens in Mexico and the risk to public health posed by rodents.