Medical and psychiatric outcomes for patients transplanted for acetaminophen‐induced acute liver failure: a case–control study

Background: Acetaminophen‐induced hepatotoxicity is the most common cause of acute liver failure (ALF) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence. Aims and methods: We compared the severity of pretransplant illness, psychiatric co‐morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999–2004 for acetaminophen‐induced ALF (n=36) with age‐ and sex‐matched patients undergoing emergent LT for non‐acetaminophen‐induced ALF (n=35) and elective LT for chronic liver disease (CLD, n=34). Results: Acetaminophen‐induced ALF patients undergoing LT had a greater severity of pre‐LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) acetaminophen‐induced ALF patients had a formal psychiatric diagnosis before LT (non‐acetaminophen‐induced ALF=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow‐up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (acetaminophen‐induced ALF 1 year 87%, 5 years 75%; non‐acetaminophen‐induced ALF 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two acetaminophen‐induced ALF patients reattempted suicide post‐LT (one died 8 years post‐LT). Conclusions: Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for acetaminophen‐induced ALF were comparable to those transplanted for non‐acetaminophen‐induced ALF and electively for CLD. Multidisciplinary approaches with long‐term psychiatric follow‐up may contribute to low post‐transplant suicide rates seen and low rates of graft loss because of non‐compliance.     

Protection by bicyclol derivatives against acetaminophen‐induced acute liver failure in mice and its active mechanism

Background/Aims: To find a novel drug against acute liver failure, a methionine derivative of bicyclol (WLP‐S‐10) was studied in acetaminophen‐injected mice. Methods: At first, 10 derivatives of bicyclol were tested in male KunMing strain mice injected with CCl₄, acetaminophen or d ‐galactosamine plus lipopolysaccharide (LPS), serum alanine aminotransferase (ALT) and mortality rate were determined. Among the 10 derivatives, a methionine derivative of bicyclol (WLP‐S‐10) was shown to be the most effective. A single dose of WLP‐S‐10 200 mg/kg was intraperitoneally injected 1 h before administration of a lethal dose of acetaminophen; the mortality rate, liver lesions, serum ALT, aspartate aminotransferase (AST) and liver glutathione (GSH) were determined. Mitochondrial GSH and adenosine triphosphate (ATP) levels, cytochrome C and apoptosis‐inducing factor (AIF) leakage, mitochondrial swelling and membrane potential were determined. Results: As a result, WLP‐S‐10 200 mg/kg significantly reduced liver injury induced by CCl₄ and decreased the mortality rate of mice because of acute liver failure caused by lethal dosage of acetaminophen or d ‐galactosamine plus LPS. WLP‐S‐10 200 mg/kg markedly reduced liver necrosis, serum ALT and AST elevation and GSH depletion after injection of acetaminophen. WLP‐S‐10 inhibited mitochondrial swelling, breakdown of membrane potential and depletion of mitochondrial ATP, and also reduced release of cytochrome C and AIF from mitochondria induced by acetaminophen. Conclusions: The results indicate that WLP‐S‐10 is a novel potential compound against acetaminophen‐induced acute liver failure in mice, and its active mechanism is mainly related to protection against necrosis and apoptosis of hepatocytes through inhibition of mitochondrial energy (ATP) depletion and AIF and cytochrome C release.     

Acute liver failure: mechanisms of immune‐mediated liver injury

Acute liver failure (ALF) is a syndrome of diverse aetiology, including hepatic encephalopathy, renal, cardiac and pulmonary failures, which result in a rapid loss of hepatic function. The mechanisms of liver injury contributing to ALF can be summarized into two categories: direct damage and immune‐mediated liver injury. This review summarizes current concepts of immune‐mediated liver injury from both clinical studies and animal models. We highlight immune responses of ALF from the liver injury perspective, which combines a variety of molecular and cellular mechanisms, particularly, the contribution of cytokines and the innate immune system. Hepatic and circulating inflammatory cytokines play a significant role in the pathophysiology of ALF including hepatocyte necrosis, extrahepatic complications and hepatocyte regeneration. Overproduction of cytokines, if unchecked, is hazardous to the host and may cause severe outcomes. Measuring pro‐inflammatory cytokines in ALF may be of value for predictors of outcome. Innate and adaptive immune systems both involved in ALF contribute to immune‐mediated liver injury. The innate immune response is activated much more rapidly compared with adaptive immunity, particularly in acute liver injury where the host has little time to trigger an effective adaptive immune response. From this point of view, the innate immune system may make a more profound contribution than the adaptive immune system. Furthermore, immune responses crosstalk with other physiological or pathophysiological factors, for example, coagulation factors which in turn determine the outcome of ALF and these are discussed.     

Acetaminophen‐induced liver injury in obesity and nonalcoholic fatty liver disease

Although acetaminophen (APAP) is usually considered as a safe drug, this painkiller can lead to acute liver failure after overdoses. Moreover, there is evidence that the maximum recommended dosage can induce hepatic cytolysis in some individuals. Several predisposing factors appear to enhance the risk and severity of APAP‐induced liver injury including chronic alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions linked to obesity. In contrast, obesity by itself does not seem to be associated with a higher risk of APAP‐induced liver injury. Since 1987, seven studies dealt with APAP‐induced hepatotoxicity in rodent models of NAFLD and five of them found that this liver disease was associated with higher APAP toxicity. Unfortunately, these studies did not unequivocally established the mechanism(s) whereby NAFLD could favour APAP hepatotoxicity, although some investigations suggested that pre‐existent induction of hepatic cytochrome P450 2E1 (CYP2E1) could play a significant role by increasing the generation of N‐acetyl‐p‐benzoquinone imine (NAPQI), the toxic metabolite of APAP. Moreover, pre‐existent mitochondrial dysfunction associated with NAFLD could also be involved. In contrast, some investigations suggested that factors that could reduce the risk and severity of APAP hepatotoxicity in obesity and NAFLD include higher hepatic APAP glucuronidation, reduced CYP3A4 activity and increased volume of body distribution. Thus, the occurrence and the outcome of APAP‐induced liver injury in an obese individual with NAFLD might depend on a delicate balance between metabolic factors that can be protective and others that favour large hepatic levels of NAPQI.     

The diagnosis and management of idiosyncratic drug‐induced liver injury

Drug‐induced liver injury (DILI) is an uncommon but important cause of liver disease that can arise after exposure to a multitude of drugs and herbal and dietary supplements. The severity of idiosyncratic DILI varies from mild serum aminotransferase elevations to the development of severe liver injury that can progress to acute liver failure resulting in death or liver transplantation within days of DILI onset. Chronic liver injury that persists for more than 6 months after DILI onset is also becoming increasingly recognized in up to 20% of DILI patients. Host demographic (age, gender, race), clinical and laboratory features at DILI onset have been associated with the severity and outcome of liver injury in DILI patients. In addition to cessation of the suspect drug, other medical interventions including the use of N‐acetylcysteine and corticosteroids in selected patients have shown some clinical benefit, but additional prospective studies are needed. A number of promising diagnostic, prognostic and mechanistic serum and genetic biomarkers may help improve our understanding of the pathogenesis and treatment of idiosyncratic DILI.     

microRNA、细胞自噬与肝纤维化

近年来研究发现微小RNA（microRNA）在肝纤维化发生中起到重要调节作用,明晰miR表达谱的差别有助于揭示肝纤维化发生的分子调节机制、发现肝纤维化诊断的分子标志、并有助于发现新的治疗策略。此外研究还发现自噬（autophagy）信号在肝星状细胞（HSC）激活中起到重要作用,静息HSC通过自噬使含维生素A酯的脂滴释放和被利用,以此产生能量来驱动HSC的活化过程。该发现是肝纤维化发生机制的重要补充。     

Corticosteroid therapy in drug‐induced liver injury: Pros and cons

Drug‐induced liver injury (DILI) is a liver toxicity induced by a drug or its metabolite. The incidence of DILI continues to increase and it has been an enormous challenge worldwide, while the prognosis is not optimistic. Currently, the most effective treatment for DILI is to suspend the offending drug(s) and to avoid re‐exposure, with no definitive therapy available for idiosyncratic DILI with or without acute liver failure. Given the anti‐inflammatory effects of corticosteroids, they have been widely used in DILI in clinical practice, although their efficacy remains controversial. Several studies have shown their beneficial effects but a few reports have refuted the efficacy of corticosteroids in treating patients with DILI. In this review, we summarized the history and current status of corticosteroid use in liver diseases and the pros and cons of corticosteroid treatment in DILI, and we explored the DILI candidates who may benefit from corticosteroid therapy, the administration route and dosage, and the adverse effects related to corticosteroid use.     

Late‐onset acetaminophen‐induced allergic hepatitis with progression to chronicity

Acetaminophen (paracetamol), a widely used antipyretic/analgesic, is a well‐known agent causing acute hepatic injury. Whereas most cases are caused by its intrinsic hepatotoxicity, idiosyncratic hepatitis by the allergic mechanism is extremely rare. We herein report a case of late‐onset acetaminophen‐induced allergic hepatitis with progression to chronicity. This unique case extends the spectrum of acetaminophen‐induced liver injury. Clinicians should be aware of this unusual clinical manifestation. The mechanism underlying the immunological reaction to acetaminophen remains to be elucidated.     

The transformation in biomarker detection and management of drug‐induced liver injury

Drug‐induced liver injury (DILI) is a major concern for patients, care givers and the pharmaceutical industry. Interpretation of the serum biomarkers routinely used to detect and monitor DILI, which have not changed in almost 50 years, can be improved with recently proposed models employing quantitative systems pharmacology. In addition, several newer serum biomarkers are showing great promise. Studies in rodents indicate that the ratio of the caspase cleaved fragment of cytokeratin 18 to total K18 in serum (termed the “apoptotic index”) estimates the relative proportions of apoptosis vs necrosis during drug‐induced liver injury. Glutamate dehydrogenase can reliably differentiate liver from muscle injury and, when serum is properly prepared, may also detect mitochondrial toxicity as a mechanism of liver injury. MicroRNA‐122 is liver‐specific, but recent data suggests it can be actively released from hepatocytes in the absence of overt toxicity limiting enthusiasm for it as a DILI biomarker. Finally, damage associated molecular patterns, particularly high mobility group box 1 and its various modified forms, are promising biomarkers of innate immune activation, which may be useful in distinguishing benign elevations in aminotransferases from those that portend clinically important liver injury. These new biomarkers are already being measured in early clinical trials, but broad acceptance will require widespread archiving of serum from diverse clinical trials and probably pre‐competitive analysis efforts. We believe that utilization of a panel of traditional and newer biomarkers in conjunction with quantitative systems pharmacology modelling approaches will transform DILI detection and risk management.     

细胞自噬在肝脏疾病中的作用

近年来,越来越多的证据表明细胞自噬在慢性肝炎病毒感染、酒精性肝病、脂肪肝等各种类型的肝脏疾病的发生发展中起到重要作用,成为关注和研究的新焦点。自噬是指细胞利用溶酶体大范围降解长寿命蛋白质、大分子物质、核糖体及受损细胞器的过程。简述了各种肝脏疾病与细胞自噬的关系,认为探索细胞自噬在肝病机制中所扮演的角色,将可能成为治疗肝脏疾病的一个新靶点。     

Role of immune dysfunction in drug induced liver injury

Drug-induced liver injury (DILI) is one of the leading causes of liver failure and withdrawal of drugs from the market. A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable. Recent literature suggests that some drugs can alter the liver’s repair systems resulting in injury. The pathophysiology of DILI is complex, and immune dysfunction plays an important role in determining the course and severity of the disease. Immune dysfunction is influenced by the host response to drug toxicity. A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development. This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.