Novel strategies for the treatment of acetaminophen hepatotoxicity.

INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

Incidence and Etiology of Drug-Induced Liver Injury in Mainland China.

BACKGROUND & AIMS: We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. METHODS: We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. RESULTS: Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76-52.03), followed by mixed injury (28.30%; 95% CI 27.73-28.87) and cholestatic injury (20.31%; 95% CI 19.80-20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86-26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. CONCLUSIONS: In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

Interleukin-1α and Interleukin-1ß play a central role in the pathogenesis of fulminant hepatic failure in mice.

BACKGROUND AND AIMS: Fulminant hepatitis failure (FHF) is marked by the sudden loss of hepatic function, with a severe life-threatening course in persons with no prior history of liver disease. Interleukin (IL)-1α and IL-1ß are key inflammatory cytokines but little is known about their role in the development of FHF. The aim of this study was to assess the involvement of IL-1α and IL-1ß in the progression of LPS/GalN-induced FHF. METHODS: WT, IL-1α or IL-1ß deficient mice were injected with LPS/GalN. Blood and liver tissue were collected at different time points, FHF related pathways were examined. RESULTS: After FHF induction the survival of both IL-1α and IL-1ß KO mice was longer than that of WT mice. Lower serum liver enzyme levels, demonstrated reduced hepatic injury in the IL-1α and IL-1ßKO mice. Histologically detected liver injury and apoptotic hepatocytes were significantly reduced in the IL-1αand IL-1ßKO mice compared to WT mice. Reduced hepatic IkB levels and upregulated NFκB activity in WT mice remained inhibited in IL-1α and IL-1ß KO mice. Hepatic expression levels of TNFα and IL-6 were significantly increased in WT mice but not in IL-1α and IL-1ß KO mice. CONCLUSIONS: IL-1α and IL-1ß play a central role in the pathogenesis of LPS/GalN-induced FHF. These interleukins are associated with the activation of NFκB signaling, upregulation of the pro-inflammatory cytokines and liver damage and apoptosis. Since neither IL-1α nor IL-1ß depletions completely rescued the phenotype, we believe that IL-1α and IL-1ß have a similar and probably complementary role in FHF progression.

Direct intrahepatic portocaval shunt for treatment of portal thrombosis and Budd-Chiari syndrome.

Budd-Chiari syndrome (BCS) refers to hepatic venous outflow obstruction that in severe cases can lead to acute liver failure prompting consideration of revascularization or transplantation. Here, a 22 year old female with angiographically proven BCS secondary to JAK2/V617F positive Polycythemia vera on therapeutic warfarin presented with acute liver failure (ALF). Imaging revealed a new, near complete thrombotic occlusion of the main portal vein with extension into the superior mesenteric vein. An emergent direct intrahepatic portocaval shunt (DIPS) was created and liver function promptly normalized. She has been maintained on rivaroxaban since that time. Serial assessment over 1 year demonstrated continued shunt patency and improved flow in the mesenteric vasculature on ultrasound as well as normal liver function. DIPS is a viable alternative in the treatment of ALF from BCS when standard recanalization is not feasible. Improved blood flow may also improve portal/mesenteric clot burden. While further investigation is needed, new targeted anticoagulants may be viable as a long term anticoagulation strategy.

Fialuridine induces acute liver failure in chimeric TK-NOG mice: a model for detecting hepatic drug toxicity prior to human testing.

BACKGROUND: Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers. METHODS AND FINDINGS: Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers. CONCLUSIONS: FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors' Summary.

[Management of severe alcoholic hepatitis]. / Management bei schwerer alkoholischer Hepatitis.

Severe alcoholic hepatitis is still associated with high mortality and presence of liver failure manifested by jaundice, coagulopathy and encephalopathy is a poor prognostic indicator. The management of these patients includes at first hand several supportive measures as treatment of alcohol withdrawal, administration of fluid and vitamins and admission to an intensive care unit in the unstable patient. Glucocorticoids have been since decades the most intensively studied therapy in alcoholic hepatitis and are effective in certain subgroups. Indication for such a therapy is usually defined on a Maddrey Discriminant Function > 32. The Lille score at day 7 is used to decide whether corticosteroid therapy should be stopped or continued for a 1 month course. Nutritional supplementation is also likely to be beneficial. The main progress in better understanding its pathophysiology has come from cytokine studies. Various proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) or interleukin-1 (IL-1) have been proposed to play a role in this disease. This advancement has recently led to pilot studies investigating anti-TNF drugs such as pentoxifylline, infliximab (anti-TNF antibody) or etanercept in the treatment of this disease. These studies revealed besides for pentoxifylline rather negative results. Despite this fact, targeting of certain cytokines such as IL-1 remains an attractive treatment concept for this devastating disorder in the future.

Acute liver failure caused by 'fat burners' and dietary supplements: a case report and literature review.

Globally, people are struggling with obesity. Many effective, nonconventional methods of weight reduction, such as herbal and natural dietary supplements, are increasingly being sought. Fat burners are believed to raise metabolism, burn more calories and hasten fat loss. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. The present report describes a young healthy woman who presented with fulminant hepatic failure requiring emergent liver transplantation caused by a dietary supplement and fat burner containing usnic acid, green tea and guggul tree extracts. Thorough investigation, including histopathological examination, revealed no other cause of hepatotoxicity. The present case adds to the increasing number of reports of hepatotoxicity associated with dietary supplements containing usnic acid, and highlights that herbal extracts from green tea or guggul tree may not be free of adverse effects. Until these products are more closely regulated and their advertising better scrutinized, physicians and patients should become more familiar with herbal products that are commonly used as weight loss supplements and recognize those that are potentially harmful.

Transient acute liver failure complicating transurethral resection syndrome.

Transurethral resection (TUR) syndrome, resulting from dilutional hyponatraemia for excessive absorption of irrigating fluid, represents the most relevant complication of transurethral resection of prostate (TURP). Ethanol is used as a tracer in the irrigant solution to monitor fluid absorption with a breathalyser. An unusual case of transient acute liver failure complicating TUR syndrome is reported. A 54-year-old male patient, without risk factors for the development of toxic hepatitis, was subjected to TURP for treatment of benign prostatic hyperplasia. Fluid absorption (2275 ml), estimated by breathalyser, exceeded maximum allowed absorption (2000 ml) only at the end of the surgical intervention. No signs of possible toxicity were evident in the few hours following the intervention. About 10 h after the end of TURP, the patient developed sweating, vomiting and diarrhoea. Laboratory analysis revealed severe hyponatraemia (116 meq/l) with signs of severe liver impairment (total bilirubin 5.8 mg/dl, alanine aminotransferase 56,500 U/l, aspartate aminotransferase 32,700 U/l), kidney failure (serum creatinine 1.93 mg/dl) and serum ethanol levels of 219 mg/dl (0.2%). The patient was treated with acetylcysteine 150 mg/kg i.v. and furosemide 50 mg i.v. Liver and renal functions improved in few days and recovered completely within 30 days. The TUR syndrome observed in this case was probably extravascular in nature, and could have been identified and prevented by measuring ethanol levels 10 min after ending the surgical procedure. The performance of such a test should be strongly recommended to all surgeons. The clinicians attributed the development of liver impairment in this case to ethanol toxicity. However, further studies are warranted to confirm whether hepatic injury can represent a possible complication of TUR syndrome when ethanol solution is used as irrigant fluid.

Intoxicación pediátrica por fósforo blanco (saltapericos): supervivencia a ingesta de dosis potencialmente letal / Pediatric poisoning with white phosphorus (saltapericos): survival after potentially lethal ingestion

El saltapericos es un juego pirotécnico a base de fósforo inorgánico, cuyo uso está prohibido porque causa daño hepático agudo. Se reporta un caso de intoxicación severa en una niña sobreviviente, quien ingirió una dosis potencialmente letal y recibió asistencia médica tardía. El protocolo terapéutico que se siguió en el presente caso clínico, permitió el logro de una evolución satisfactoria; este tratamiento consistió en descontaminación interna con agua oxigenada y aceite mineral, exsanguinotransfusión y fármacos hipoamonemizantes.

Saltapericos is a pyrotechnic firework containing inorganic phosphorus whose use is banned since causes acute liver damage. A case of severe poisoning is reported in a girl, who consumed a potentially lethal dose and received late medical care. The therapeutic protocol followed in the present clinical case led to a positive outcome; this treatment consisted of internal decontamination with hydrogen peroxide and mineral oil, exchange transfusion and hypoammonemic drugs.

[Therapeutic effect of the latest extracorporal elimination procedure (Prometheus treatment) in acute liver failure caused by intoxication]. / A legújabb extracorporalis eliminációs eljárás (Prometheus-kezelés) terápiás hatékonysága mérgezés okozta akut májelégtelenségben.

INTRODUCTION: Despite intensive therapy the mortality of acute liver failure without organ transplantation is 60-90%. Because of organ shortage in liver transplantation, a significant number of patients dies while being on the waiting list. In order to diminish the mortality, various trials were introduced to remove the albumin-bound and water-soluble toxins in liver failure with the aim to support the spontaneous regeneration of the liver and maintaining the patients alive until liver transplantation. Prometheus treatment is a relatively new technique combining Fractionated Plasma Separation and Adsorption (FPSA) with a high-flux dialysis. During the procedure the patient's own separated albumin-rich plasma passes through special adsorbents making possible the elimination of albumin-bound toxins, while hemodialysis gets rid of water-soluble toxins. AIM: The authors' intention was to demonstrate the efficiency of Prometheus treatment in acute liver failure caused by intoxication. PATIENTS AND METHOD: Prometheus treatment was indicated in three patients who suffered from severe intoxication with paracetamol, potassium permanganate and Amanita phalloides, which resulted in a hepatic failure incurable with conservative therapy. RESULTS: Ten treatments were performed in the three female patients. No serious complication was observed. Due to the treatment the albumin-bound (indirect bilirubin p = 0.048; bile acid p = 0.001) and water-soluble (direct bilirubin p = 0.002; creatinine p = 0.007) toxins were significantly decreased. The level of ammonia, urea nitrogen, fibrinogen and antithrombin III did not change significantly. All the three patients were cured without liver transplantation. CONCLUSION: Prometheus treatment removes efficiently the accumulating toxins in acute liver failure. It is a safe elimination technique. In cases untreatable with conservative therapy it makes possible maintaining the patients alive until the liver regenerates spontaneously, or liver transplantation is feasible.

[The clinical use of blood ultrafiltration in leptospirosis patients with acute kidney and liver failure]. / Klinicheskoe primenenie ul'trafil'tratsii krovi u bol'nykh leptospirozom s ostroi nedostatochnost'iu pochek i pecheni.

The use of ultrafiltration of blood in clinical settings in the treatment of patients with leptospirosis presenting with acute renal failure permits enhancing a detoxicating effect due to elimination with the ultrafiltrate of up to 30% of products of nitrogenous metabolism. This allows the water balance to be corrected, homeostasis, the functional activity of the cardiovascular, respiratory systems to be stabilized. Therapeutic effectiveness is enhanced that is evidenced by a 20% decline in the incidence of complications and in case-fatality rate in grave forms of leptospirosis.

Detection of poisoning by Impila (Callilepis laureola) in a mother and child.

Poisoning with impila (Callilepis laureola) is a recurring phenomenon in South Africa. Cases of poisoning with other plants which contain atractyloside also occur in Europe and the Americas. Since poisoning leads to rapid death from renal and/or hepatic failure, it is suspected that many cases are undiagnosed; this is especially so in South Africa, where patients may die without reaching hospital and do not often admit to ingestion of a traditional remedy. We have developed a thin layer chromatographic method for the detection of impila constituents in urine. We describe the clinical symptoms and the application of the screening method to diagnosis in the case of a mother and child, who both showed symptoms of impila poisoning; the mother died but the child survived. This method is rapid and may be used for the definitive diagnosis in cases of poisoning with atractyloside-containing plants.