María Isabel Lucena

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.

Norfloxacin-Induced Cholestatic Jaundice

1. Verschraegen G, Claeys W, Meeus G, et al. Pseudomonas pickettii as a cause of pseudobacteremia. J Clin Microbiol 1985;21:278–9. 2. McNeil MM, Solomon SL, Anderson RL et al. Nosocomial Pseudomonas pickettiicolonization associated with a contaminated respiratory therapy solution in a special care nursery. J Clin Microbiol 1985;22:903–7. 3. Jumaa PA, Chattopadhyay B. Pseudobacteraemia. J Hosp Infect 1994; 27:167–77. 4. King A, Holmes B, Philips I, et al. A taxonomic study of the clinical isolates ofPseudomonas pickettii , P. thomasiiand group IVd bacteria. J Gen Microbiol 1979;114:137–47. 5. Lacy S, Want SV.Pseudomonas pickettii infections in a paediatric oncology unit. J Hospital Infect 1992;17:45–51. 6. Graber CD, Jervey L, Ostrander WE, et al. Endocarditis due to a lanthanic, unclassified Gram-negative bacterium (group IVd). Am J Clin Pathol 49;220–3. 7. Fass RJ, Barbishan J. Acute meningitis due to Pseudomonas -like group Va-1 bacillus. Ann Intern Med 84:51–52. 8. Wertheim WA, Markovitz D. Osteomyelitis and intervertebral discitis caused byPseudomonas pickettii . J Clin Microbiol 1992;30:2506–8. 9. Fujita S, Yoshida T, Matsubara F. Pseudomonas pickettii bacteremia. J Clin Microbiol 1981;13:781–2. 10. Philips I, Eykyn S, Laker M. Outbreak of hospital infection caused by contaminated autoclaved fluids. Lancet 1972;ii:1258–60. 11. Kahan A, Philippon A, Paul G, et al. Septicaemia cause by Pseudomonas VA-1 . Clin Microbiol Newsl. 1981;3:124. 12. Oie S, Kamiya A. Bacterial contamination of commercially available ethacridine lactate (acrinol) products. J Hosp Infect 1996;34:51–8. 13. Fernandez C, Wilhelmi I, Andradas E, et al. Nosocomial outbreak of Burkholderia pickettii infection due to a manufactured intravenous product used in three hospitals. Clin Infect Dis 1996;22:1092–5. 14. Raveh D, Simhon A, Gimmon Z, et al. Infection caused by Pseudomonas pickettiin association with permanent indwelling intravenous devices: Four cases and a review. Clin Infect Dis 1993;17:877–80. 15. Chetoul H, Melin P, Struelens MJ, et al. Comparison of biotyping, ribotyping and pulsed-field gel electrophoresis for investigation of a common-source outbreak of Burkholderia pickettiibacteremia. J Clin Microbiol 1997;35:1398–1403.

Chronic hepatitis C, ibuprofen, and liver damage.

were normal except for jaundice. Serum chemistry showed total bilirubin of 28.45 mg/dl (normal 0.3–1.3); conjugated bilirubin, 20.6 mg/dl (normal 0–0.4); ALP, 249 U/L (normal 35–120); AST, 37 U/L (normal 5–40), and ALT, 58 U/L (normal 5–40). Abdominal ultrasonography, CT scan, and cholangiography magnetic resonance were normal and ruled out obstruction of the bile ducts. Serology excluded viral causes. Screening for autoantibodies and metabolic diseases was negative. A liver biopsy specimen showed predominantly casts in canaliculi and mild portal inflammatory infiltrates with lymphocytes and eosinophils. Results of liver tests became normal during the subsequent 2 months. Trovafloxacin, another new quinolone, has been withdrawn from the market in Europe and limited to life-threatening conditions in the United States because of hepatic toxicity (3–6). This is, to our knowledge, the first published report of liver injury due to moxifloxacin. Other causes of liver injury were ruled out. The histological picture was consistent with drug-induced hepatic injury. It is noteworthy that there was a delay of 3 wk between the end of the treatment and the onset of jaundice that may hinder the diagnosis.

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

Toward a clinical practice guide in pharmacogenomics testing for functional polymorphisms of drug-metabolizing enzymes. Gene/drug pairs and barriers perceived in Spain

The development of clinical practice recommendations or guidelines for the clinical use of biomarkers is an issue of great importance with regard to adverse drug reactions. The potential of pharmacogenomic biomarkers has been extensively investigated in recent years. However, several barriers to implementing the use of pharmacogenomics testing exist. We conducted a survey among members of the Spanish Societies of Pharmacology and Clinical Pharmacology to obtain information about the perception of such barriers and to compare the perceptions of participants about the relative importance of major gene/drug pairs. Of 11 potential barriers, the highest importance was attributed to lack of institutional support for pharmacogenomics testing, and to the issues related to the lack of guidelines. Of the proposed gene/drug pairs the highest importance was assigned to HLA-B/abacavir, UGT1A1/irinotecan, and CYP2D6/tamoxifen. In this perspective article, we compare the relative importance of 29 gene/drug pairs in the Spanish study with that of the same pairs in the American Society for Clinical Pharmacology and Therapeutics study, and we provide suggestions and areas of focus to develop a guide for clinical practice in pharmacogenomics testing.

Drug-Induced Autoimmune-Like Hepatitis: A Diagnostic Challenge

Dear Editor,We have read with interest the excellent review byCzaja [1] titled ‘‘Drug-Induced Autoimmune-Like Hepati-tis’’. We would like to add some comments to highlight thecomplexities faced when approaching a diagnosis of thisdisorder.Firstly, it is stated under the subheading ‘‘Drug-InducedHepatitis Within the Spectrum of Immune-Mediated Hep-atitis’’ that the best estimate of the frequency of drug-induced autoimmune-like hepatitis (AIH-DILI) amongpatients with classical features of autoimmune hepatitis is9% [2]. To our knowledge, there are other reports thatshow higher figures. Heurgue´ et al. [3] in France identifiedin a consecutive series of 65 patients with autoimmunehepatitis (AIH) eight cases (12%) with drug-induced AIH,fulfilling all requirements recommended in the review toconfirm the diagnosis. In Gipuzkoa (Deba Valley, totalcatchment of 140,000 people), Spain, from 1994 to 2009,29 cases of AIH were diagnosed, and five were consideredas AIH-DILI, which represents 17% [4]. We think thatthese differences in frequency may be explained by the factthat AIH-DILI is often misdiagnosed. Indeed, the diagnosisof AIH is often made in the setting of a patient beingtreated with multiple drugs. If the diagnostic scale indicatesa probable AIH, the possible role of the drug is generallyunderscored, and immunosuppressive treatment is started.On the other hand, if the AIH scale is not conclusive and/orhistology findings are more consistent with drug-inducedliver injury (DILI), the case is assumed to be an AIH-DILIcase, particularly if after discontinuation of the suspecteddrug the clinical symptoms resolve (AIH-DILI may be aself-limiting process), and the possibility of unmaskingAIH by the action of a drug is subsequently disregarded. Tofurther complicate the differentiation between AIH andDILI, we must underline the fact that there does not seemto be any specific histological features for either of theprocesses and the pathological features may show onlysubtle differences, pointing toward an immune mediatesliver disease versus hepatic toxicity [5]. These consider-ations lead us to suggest that AIH-DILI might be under-reported nowadays.Secondly, it is said that most drugs produce a self-lim-ited acute hepatitis, which is unusual in true AIH [1], butthat others seem to trigger a chronic hepatitis that isindistinguishable from classical AIH. In a recent study,Bjo¨rnsson et al. [2] published 24 cases of AIH-DILI, 22being minocycline and nitrofurantoin cases (11/11). Dis-continuation of steroid therapy was tried in 14 cases, withno relapses. Of the AIH cases in this series, 65% relapsed.In a French series [3], one patient had a spontaneous

Effect of cyclosporin a on platelet aggregation and thromboxane/prostacyclin balance in a model of extrahepatic cholestasis in the rat

Cyclosporin A (CsA), a potent immunosuppressor used in organ transplants and autoimmune diseases, is associated with adverse effects in the kidney, liver, and nervous system. This drug was recently shown to stimulate platelet aggregation, to increase thromboxane synthesis, and to decrease vascular prostacyclin synthesis. In experimental cholestasis, thrombocyte function is altered. The present study was designed to assess the effects of CsA on platelet function in extrahepatic biliary obstruction (EBO) in rats. Cyclosporin or its excipient (Cremaphore El, polyethoxylated castor oil) did not modify collagen-induced platelet aggregation. In animals with EBO, platelet aggregation decreased by 50%. The administration of CsA (5 or 10 mg/kg) or Cremaphore El increased aggregation by 163%, 253% and 123% respectively. Thromboxane production increased by 119% after Cremaphore El was administered, but was not significantly modified by CsA. Cholestasis increased thromboxane synthesis by 48.4%, whereas CsA showed a direct dose-dependent effect, and excipient had no significant effect. Excipient inhibited the vascular synthesis of 6-keto-PFG1 alpha by 67.2%, as did 5 mg/kg (56.8%) and 10 mg/kg CsA (27.6%). EBO led to a nonsignificant increase in the vascular synthesis of 6-keto-PFG1 alpha. Cremaphore EI inhibited prostacyclin synthesis by 79%; inhibition by CsA was dose-dependent (31% at 5 mg/kg, 60% at 10 mg/kg). Our findings show that cholestasis enhances the effects of CsA on platelet aggregation and thromboxane/prostacyclin balance. These results may reflect the vascular effects of CsA, which in turn may be enhanced by cholestasis.

“Drug-Induced Liver Injury Clinical Consortia: a global research response for a worldwide health challenge”

The hepatic safety of drugs is a major concern of the pharmaceutical industry throughout the whole process of drug development. Whereas the intrinsic toxicity of a few drugs will become evident during the early stages of this process (i.e. in cellular cultures or animal studies), for the bulk of hazardous medications, which will injure the liver in rare occasions, the hepatotoxicity profile may remain hidden in both preclinical and clinical phases. Actually, clinical trials are able to identify relatively common adverse reactions (i.e. occurring at a rate greater than 1 per 1000 exposed subjects), but are generally underpowered to detect the low incidence of idiosyncratic drug-induced liver injury (DILI).[1] The multifactorial nature of the idiosyncratic chemical damage targeting the liver depends on the interaction of the drug physicochemical properties with the host factors that make the subjects susceptible on rare instances.[2] No reliable methods for accurately predicting the occurrence of toxic liver damage on a given individual are still available. Hence, information on the true hepatic safety profile for the bulk of drugs relies on observational studies and requires the exposure of hundreds of thousands of subjects once the medication reaches the market. If an ‘outbreak’ of reports of liver damage linked to a particular drug use were detected, regulatory measures, including warnings and withdrawals, to limit the number of affected individuals would follow. Nowadays, however, many old drugs with hepatotoxic potential still remain in therapeutic use either because their true risk figures have not been fully recognized or due to a favorable benefit/risk balance (i.e. flucloxacillin, amoxicillin-clavulanate). Until recently, hepatotoxicity had not received enough attention from the academic investigators due to its relative rarity and data on hepatotoxicity of drugs were mostly compiled by the pharmaceutical industry under restrictive access rules or were simply unavailable. Indeed, the absence of valid diagnostic biomarkers means that DILI remains a ‘diagnosis of exclusion’, which limits the ‘scientific’ accuracy of the information retrieved and may discourage investigators from being involved on this topic. All these limitations represent an important barrier for proper case identification and characterization as well as for the availability of consistent epidemiological data.

The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury

Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen.Acetaminophen-induced liver injury is one of the most common causes of liver failure and has to be treated within hours of the overdose. Here Barbier-Torres et al. show that targeting MCJ, a mitochondrial negative regulator, even 24 h after the overdose protects liver from acetaminophen-induced damage.

Protective role of c-Jun N-terminal kinase-2 (JNK2) in ibuprofen-induced acute liver injury: Role of JNK2 in ibuprofen-induced acute liver injury

Ibuprofen is a worldwide used non‐steroidal anti‐inflammatory drug which may cause acute liver injury (ALI) requiring liver transplantation. We aimed to unveil the molecular pathways involved in triggering ibuprofen‐induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen‐induced ALI. Next, we assessed the cytotoxicity of ibuprofen in vitro and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c‐Jun N‐terminal kinase 1 (Jnk1−/−) or Jnk2 (Jnk2−/−) expression and included investigations using animals with hepatocyte‐specific Jnk deletion either genetically (Jnk1Δhepa) or by siRNA (siJnk2Δhepa). We found in human and murine samples of ibuprofen‐induced acute liver failure that JNK phosphorylation was increased in the cytoplasm of hepatocytes and other non‐liver parenchymal cells (non‐LPCs) compared with healthy tissue. In mice, ibuprofen intoxication resulted in a significantly stronger degree of liver injury compared with vehicle‐treated controls as evidenced by serum transaminases, and hepatic histopathology. Next, we investigated molecular pathways. PKCα, AKT, JNK and RIPK1 were significantly increased 8 h after ibuprofen intoxication. Constitutive Jnk1−/− and Jnk2−/− deficient mice exhibited increased liver dysfunction compared to wild‐type (WT) animals. Furthermore, siJnk2Δhepa animals showed a dramatic increase in biochemical markers of liver function, which correlated with significantly higher serum liver enzymes and worsened liver histology, and MAPK activation compared to Jnk1Δhepa or WT animals. In our study, cytoplasmic JNK activation in hepatocytes and other non‐LPCs is a hallmark of human and murine ibuprofen‐induced ALI. Functional in vivo analysis demonstrated a protective role of hepatocyte‐specific Jnk2 during ibuprofen ALI. Copyright