Cause Of Acute Liver Injury Research Articles

A Multicenter Study Into Causes of Severe Acute Liver Injury

The differential diagnosis of an increase in alanine aminotransferase (ALT) level and/or aspartate aminotransferase (AST) level of ≥1000 IU/L often is stated to include 3 main etiologies: ischemic hepatitis, acute viral hepatitis (typically hepatitis A and hepatitis B), and drug-induced (more specifically, acetaminophen/paracetamol) liver injury (DILI).1 Unfortunately, there are a paucity of studies examining the most common causes of acute liver injury (ALI) and those that have been published have been small,2 single-center,2 or examined less severe increases in ALT or AST levels.3,4 We conducted a multicenter study of all patients with an ALT and/or AST level ≥1000 IU/L. Our study had 3 main goals: (1) to determine the most common causes of an ALT and/or AST level ≥1000 IU/L, along with their relative frequencies; (2) todetermine differences in etiology based on hospital type (liver transplant center, community hospital, Veterans Affairs hospital); and (3) to confirm or disprove the differential heuristic that ischemic hepatitis, acute viral hepatitis, and acetaminophen toxicity are the most common etiologies.

Genetic Association of Single Nucleotide Polymorphisms with Acetaminophen-Induced Hepatotoxicity

Acetaminophen is commonly used to reduce pain and fever. Unfortunately, overdose of acetaminophen is a leading cause of acute liver injury and failure in many developed countries. The majority of acetaminophen is safely metabolized in the liver and excreted in the urine; however, a small percentage is converted to the highly reactive N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is inactivated by glutathione S-transferases, but at toxic levels, excess NAPQI forms reactive protein adducts that lead to hepatotoxicity. Individual variability in the response to both therapeutic and toxic levels of acetaminophen suggests a genetic component is involved in acetaminophen metabolism. In this review, we evaluate the genetic association studies that have identified 147 single nucleotide polymorphisms linked to acetaminophen-induced hepatotoxicity. The identification of novel genetic markers for acetaminophen-induced hepatotoxicity provides a rich resource for further evaluation and may lead to improved prognosis, prevention, and treatment.

Paracetamol and Cardiac Congenital Malformations in Prediabetic Pregnancy Women

Hyperglycemia can influence the development of the fetal heart, affecting both its structure and its function. Prospective and retrospective cohort studies have demonstrated an increased risk of congenital abnormalities with gestational diabetes. This observation is probably related to the inclusion of women with unrecognized type 2 diabetes [1, 2]. Substantial literature indicates that diabetes in pregnant rats and mice induces embryo lethality, growth retardation and a variable incidence of birth defects. Then, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy. Acetaminophen overdose is the most often cause of acute liver injury and obese women are in particular risk, because is able to induce mitochondrial oxidative stress [3]. Acetaminophen (Paracetamol) over doses decreased embryonic low-molecularweight thiols (glutathione and cysteine), compounds that play a vital role in the detoxication of exogenous and endogenous chemicals [3-5]. The apparent safety of Paracetamol drug, a useful analgesic only (with no anti-inflammatory properties) is compromised by its widespread and extensive chronic use, particularly in Peruvian population, where its analgesic is doing without control [6-9]. In fact, paracetamol though considered safe at a considerable low dose, especially in women could cause kidney derangement and cardiac malformations during pregnant state if the drug is ingested in the first trimester [8]. Major congenital malformations, including those affecting the cardiovascular system, remain the leading cause of mortality and morbidity in infants of diabetic mothers [10]. Thus, there is overcome potential maternal acetaminophen (paracetamol) toxicity [11].

Atypical Presentation of Cardiac Tamponade as a Cause of Acute Liver Injury: Case Report and Review of Literature.

Pericardial tamponade is a rare cause of acute liver injury due to the compressive effects of an effusion resulting in a poor cardiac output which ultimately leads to ischemia-induced injury. We present a patient with chronic hepatitis C infection and end-stage renal disease who was transferred to our center for further evaluation and management of acute liver injury after presenting to an outside hospital with left upper quadrant abdominal pain, nausea and vomiting. The patient was discovered to have tamponade physiology on transthoracic echocardiogram as an underlying cause of his acute liver injury despite lack of clinical tamponade features. He required pericardiocentesis which eventually led to resolution of the acute liver injury and he was discharged home on day twelve after full recovery. We review the existing literature regarding the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of ischemic hepatitis, which is associated with high mortality; therefore early recognition and treatment of the underlying cause are paramount.

Novel Protective Role of Nicotinamide Phosphoribosyltransferase in Acetaminophen-Induced Acute Liver Injury in Mice

Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the United States. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild-type (Nampt+/+), heterozygous knockout (Nampt+/-), and overexpression (NamptOE) mice were treated with overdose of acetaminophen, followed by histologic, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen-induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt+/- mice, whereas the effects in NamptOE mice were least severe relative to Nampt+/+ mice. Treatment of P7C3-A20, a small chemical molecule up-regulator of Nampt, ameliorated acetaminophen-induced mouse ALI over the reagent control. These findings support the fact that NAMPT protects against acetaminophen-induced ALI.

Regulation of HMGB1 in Hepatocytes by MyD88 and Type‐I interferon (IFN‐I) During Ehrlichia‐induced acute liver injury.

BackgroundLiver is the major target organ in Human Monocytic ehrlichiosis (HME), an undifferentiated febrile illness that is life‐threatening and caused by intracellular bacterial pathogen, Ehrlichia, that target liver and infect macrophages, hepatocytes and endothelial cells. Severe Hepatic inflammation is the common cause of acute liver injury following systemic infection with Ehrlichia. Our previous studies have shown that Myeloid differentiation primary response gene 88 (MYD88) and type I IFN (IFN‐I) promotes excessive inflammation and liver damage following fatal Ehrlichia infection. In this study, we explored the role of the MyD88 and IFN‐I in liver inflammation.ResultsIn this study, we provide evidence to support that high mobility group box 1 (HMGB1), a chromosomal protein and damage‐associated molecular patterns (DAMPs), plays a role in the regulation of innate responses and autophagy during Ehrlichia infection. Wild‐type (WT) mice infected with virulent Ehrlichia develop sepsis and liver injury marked by excessive systemic production of pro‐inflammatory cytokines and chemokines as well as HMGB1. To determine the cellular source of HMGB1 and regulatory mechanisms, we infected hepatocytes (HC) from WT and MYD88−/− knockout mice with virulent Ehrlichia. To mimic paracrine effect of IFN‐I cytokines produced by immune cells on HC response to Ehrlichia infection, we cultured infected HC in the presence or absence of IFN‐β (100 IU/mL). Our data indicate that in‐vitro infected HC produces low levels of IFN‐beta compared to uninfected cells. Exogenous stimulation of infected HC with IFN‐β induced elevated expression and cytoplasmic translocation of HMGB1 in WT‐HC. This was associated with increased autophagy and higher expression of IL‐23R, IFNAR, and heightened JAK/STAT signaling. Importantly, the effect of high dose IFN‐I on autophagy and HMGB1 was MYD88‐dependent. Interestingly, infection of MYD88−/− HC with Ehrlichia, in the absence of exogenous IFN‐β, enhanced autophagy induction and cytosolic translocation of HMGB1, suggesting that MYD88 negatively regulate HMGB1 and autophagy in HC in the absence of the paracrine effect of IFN‐β.ConclusionTogether, our data suggest that autophagy regulation and HMGB1 response in hepatocytes during Ehrlichia‐induced sepsis is controlled by the strength of IFN‐I signaling and dependent on interplay between MYD88 and IFN‐I pathways.Support or Funding InformationThis work was supported by grants from NIAMS, NIGMD, and NIAID (AR68317 CCY, RO1‐GM102146 MS, and R56A1097679 NI)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Interventions for paracetamol (acetaminophen) overdose.

Interventions for paracetamol (acetaminophen) overdose.

Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women

Acetaminophen overdose is the leading cause of acute liver injury (ALI) and acute liver failure (ALF) in the developed world. Sex differences in acetaminophen-induced hepatotoxicity have not been described. We collected data from the Acute Liver Failure Study Group cohort, a national registry of 32 academic medical centers in North America of adults with ALI or ALF, including 1162 patients with acetaminophen-induced ALI (n= 250) or acetaminophen-induced ALF (n= 912) from January 2000 through September 2016. We analyzed data on patient presentation, disease course, demographics, medical and psychiatric history, medication use, substance use, and details of acetaminophen ingestion. Sex differences in continuous and categorical variables were evaluated by Wilcoxon rank-sum and χ2 analysis or the Fisher exact test. Our primary aim was to evaluate sex differences in the presentation and clinical course of acetaminophen-induced acute liver injury or liver failure, and our secondary goal was to compare overall and transplant-free survival between sexes. Most patients with acetaminophen-induced ALI (68%) or ALF (76%) were women. Higherproportions of women than men had psychiatric disease (60% of women vs 48% ofmen, P < .01) and had co-ingestion with sedating agents (70% of women vs 52% of men, P<.01)-more than half of which were opioids. Higher proportions of women had severehepatic encephalopathy (HE) (68% of women vs 58% of men), and required intubation (67% of women vs 59% of men, P values <.03). Higher proportions of women used vasopressors (26% of women vs 19% of men, P= .04) or mannitol (13% of women vs 6% of men, P < .01); proportions of male vs female patients with transplant-free survival were similar (68%). On adjusted analysis, women had higher risk of severe HE (adjusted odds ratio[AOR], 1.66; 95% CI, 1.17-2.35). We found a significant interaction between sex and co-ingestion of sedating agents (P < .01); co-ingestion increased odds of severe HE in women 2-fold (AOR, 1.86; 95% CI, 1.28-2.69; P < .01) but not in men (AOR; 0.62; 95% CI, 0.34-1.13; P= .12). In an analysis of the Acute Liver Failure Study Group cohort, we found acetaminophen-induced ALI and ALF to be more common among women. Women have greater critical care needs than men, and increased risk for severe HE, which could be due in part to increased use of sedatives. Future studies should investigate sex differences in acetaminophen metabolism and hepatotoxicity, particularly among users of opioids.

Fast food diet-induced non-alcoholic fatty liver disease exerts early protective effect against acetaminophen intoxication in mice

BackgroundAcetaminophen (APAP) is a readily available and safe painkiller. However, its overdose is the most common cause of acute liver injury (ALI). Many predisposing factors contribute to susceptibility to APAP-induced ALI. Non-alcoholic fatty liver disease (NAFLD), the major cause of chronic liver disease, is considered an important predictor of APAP-induced ALI, although the exact mechanism controversial. In this study, we aimed to elucidate the effects of NAFLD on APAP-induced ALI.MethodsTwo groups of mice, normal chow (NC) diet-fed and fast food (FF) diet-fed mice for 14 weeks, were further divided into two subgroups: intraperitoneally injected with either saline (NC-S and FF-S groups) or APAP (NC-A and FF-A groups). Biochemical tests, histological analysis, quantitative PCR, and western blotting were conducted.ResultsAlanine aminotransferase (ALT) level (199.0 ± 39.0 vs. 63.8 ± 7.4 IU/L, p < 0.05) and NAFLD activity score (0 vs. 4.5 ± 0.22) were significantly higher in mice in FF-S group than those in NC-S group. ALI features such as ALT level (8447.8 ± 1185.3 vs. 836.6 ± 185.1 IU/L, p < 0.001) and centrizonal necrosis were prominent and mRNA levels of Trib3 (RR, 1.81) was high in mice in the NC-A group. Levels of CYP2E1 and anti-inflammatory molecules such as PPAR-γ, p62, and NRF2 were high in mice in the FF-A group.ConclusionsOur results showed that while the FF diet clearly induced non-alcoholic steatohepatitis and metabolic syndrome, NAFLD also attenuates APAP-induced ALI by inducing anti-inflammatory molecules such as PPAR-γ.

MyD88-dependent inflammasome activation and autophagy inhibition contributes to Ehrlichia-induced liver injury and toxic shock.

Severe hepatic inflammation is a common cause of acute liver injury following systemic infection with Ehrlichia, obligate Gram-negative intracellular bacteria that lack lipopolysaccharide (LPS). We have previously shown that type I IFN (IFN-I) and inflammasome activation are key host-pathogenic mediators that promote excessive inflammation and liver damage following fatal Ehrlichia infection. However, the underlying signals and mechanisms that regulate protective immunity and immunopathology during Ehrlichia infection are not well understood. To address this issue, we compared susceptibility to lethal Ixodes ovatus Ehrlichia (IOE) infection between wild type (WT) and MyD88-deficient (MyD88-/-) mice. We show here that MyD88-/- mice exhibited decreased inflammasome activation, attenuated liver injury, and were more resistant to lethal infection than WT mice, despite suppressed protective immunity and increased bacterial burden in the liver. MyD88-dependent inflammasome activation was also dependent on activation of the metabolic checkpoint kinase mammalian target of rapamycin complex 1 (mTORC1), inhibition of autophagic flux, and defective mitophagy in macrophages. Blocking mTORC1 signaling in infected WT mice and primary macrophages enhanced bacterial replication and attenuated inflammasome activation, suggesting autophagy promotes bacterial replication while inhibiting inflammasome activation. Finally, our data suggest TLR9 and IFN-I are upstream signaling mechanisms triggering MyD88-mediated mTORC1 and inflammasome activation in macrophages following Ehrlichia infection. This study reveals that Ehrlichia-induced liver injury and toxic shock are mediated by MyD88-dependent inflammasome activation and autophagy inhibition.

Acute-on-chronic liver failure in a multi-ethnic Asian city: A comparison of patients identified by Asia-Pacific Association for the Study of the Liver and European Association for the Study of the Liver definitions.

AIMTo explore the applicability of the Asia-Pacific Association for the Study of the Liver (APASL) and European Association for the Study of the Liver (EASL) guidelines for acute-on-chronic liver failure (ACLF) in profiling patients and determining the outcome.METHODSPatients admitted to a tertiary hospital in Singapore with acute decompensation of liver disease from January 2004 to July 2014 are screened for ACLF according to the APASL and EASL criteria. The patients’ data (including basic demographics, information about existing chronic liver disease, information about the acute decompensation, relevant laboratory values during admission, treatment, and outcome) are retrospectively analyzed to determine the background, precipitating factors and outcome.RESULTSA total of 458 liver patients is analyzed, and 78 patients with ACLF are identified. Sixty-three patients (80.8%) meet the APASL criteria, 64 patients (82.1%) meet the EASL criteria, and 49 patients (62.8%) fulfilled both criteria. The most common causes of acute liver injury are bacterial infections (59.0%), hepatitis B flare (29.5%), and variceal bleeding (24.4%). The common aetiologies of the underlying chronic disease included hepatitis B (43.6%), alcoholic (20.5%) and cryptogenic (11.5%) liver disease. The overall mortality rate is 61.5%. Increased age, the number of organ failures (as per CLIF-SOFA score), peak creatinine, INR, and amylase levels are associated with increased mortality or the need for liver transplantation. 14.3% of patients undergo liver transplantation with a 100% 1-year survival rate.CONCLUSIONBoth APASL and EASL criteria have identified ACLF patients with high three-month mortality, but those who fulfill APASL criteria alone have a better survival.

Cardiohepatic interactions in heart failure: clinical and therapeutic implications

AbstractLiver involvement in chronic heart failure has long been recognized and reflects the systemic hemodynamic changes that occur during the evolution of heart failure syndrome. Apart from venous congestion and backward failure, other fundamental mechanisms also exist such as decreased hepatic blood flow, decreased arterial saturation, and sinusoidal thrombosis. In the acute setting, the decrease in cardiac output, accompanied by severe and profound hypotension is the main cause of acute liver injury, whereas increased venous pressure also plays an important role. The biochemical dominance of a cholestatic profile is rather related to congestion and increased systemic venous pressures, whereas the hepatotoxic profile is rather related to hypoperfusion.Answer questions and earn CME: https://wileyhealthlearning.com/Activity2/5608949/Activity.aspx

Ginsenoside Rk1 ameliorates paracetamol-induced hepatotoxicity in mice through inhibition of inflammation, oxidative stress, nitrative stress and apoptosis

BackgroundFrequent overdose of paracetamol (APAP) has become the major cause of acute liver injury. The present study was designed to evaluate the potential protective effects of ginsenoside Rk1 on APAP-induced hepatotoxicity and investigate the underlying mechanisms for the first time. MethodsMice were treated with Rk1 (10 mg/kg or 20 mg/kg) by oral gavage once per d for 7 d. On the 7th d, all mice treated with 250 mg/kg APAP exhibited severe liver injury after 24 h, and hepatotoxicity was assessed. ResultsOur results showed that pretreatment with Rk1 significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor, and interleukin-1β compared with the APAP group. Meanwhile, hepatic antioxidants, including superoxide dismutase and glutathione, were elevated compared with the APAP group. In contrast, a significant decrease in levels of the lipid peroxidation product malondialdehyde was observed in the ginsenoside Rk1-treated group compared with the APAP group. These effects were associated with a significant increase of cytochrome P450 E1 and 4-hydroxynonenal levels in liver tissues. Moreover, ginsenoside Rk1 supplementation suppressed activation of apoptotic pathways by increasing Bcl-2 and decreasing Bax protein expression levels, which was shown using western blotting analysis. Histopathological observation also revealed that ginsenoside Rk1 pretreatment significantly reversed APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress, such as 3-nitrotyrosine, were also inhibited after pretreatment with Rk1 compared with the APAP group. ConclusionThe results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of ginsenoside Rk1 in APAP-induced hepatotoxicity may be due to its antioxidation, antiapoptosis, anti-inflammation, and antinitrative effects.

A Sinister Cause of Extreme Hepatitis

Background and Aim: Acute liver injury/failure is a life threatening medical emergency which if promptly recognized and managed can be life saving. History of drugs and dietary supplements including herbals is of paramount importance in the management of acute liver injury as they are potentially avertible. Here we report one such case of acute liver injury. Methods: A 35-year-old male presented to Gastroenterology OPD with anorexia, nausea, vomiting for 3 days. Apart from mild icterus, rest of the general and systemic examination was unremarkable. His initial liver function tests showed acute hepatitis pattern. He denied any history of habits and his past history was significant for diabetes of 2 yrs duration. Various other causes of liver disease including acute viral hepatitis (A,B,C,E), Wilson's disease and autoimmune hepatitis were ruled out by relevant investigations. Careful history review revealed he was taking green tea extract for 7 days prior to the onset of symptoms, which was stopped since then. In view of coagulopathy, he underwent transjugular liver biopsy, which showed hepatocyte disarray with feathery degeneration, micro and macrovescicular steatosis, pseudo glandular and giant cell transformation, spotty necrosis with acidophil bodies. He was treated with N-Acetyl Cysteine, insulin basal bolus regime and UDCA. Results: There was improvement in liver function parameters with bilirubin trending down up to 1.3 and INR to 1.2. This case demonstrates a rare cause of acute liver injury (Table 1).Table 1Liver Function Tests.DateT. Bil mg/dlD. Bil mg/dlAST IU/mlALT IU/mlPT/INR16/01/173.72.37538911523.2/2.0619/01/179.358.21928520826.4/2/3420/1/1710.518.563491469925.6/2.2721/01/1710.678.092568449424.1/2.1423/01/179.458.22528231416.8/1.4924/01/1710.058.6268169416.0/1.4227/01/1713.0710.5910566115.2/1.35 Open table in a new tab Conclusion: Though rare, green tea extracts can potentially lead to severe acute liver injury and probably acute liver failure if unaddressed. In the present era of increasing usage of herbal and dietary supplements for health benefits/weight loss patients and physicians should become more aware regarding the hepatotoxicity of GTE/HDS. Clinical history still plays a vital role in identifying offending agent and avoiding unnecessary management in idiopathic acute liver injury/failure (Figure 1). The authors have none to declare.

Ameliorative Effects and Possible Molecular Mechanism of Action of Black Ginseng (Panax ginseng) on Acetaminophen-Mediated Liver Injury.

Background: Frequent overdosing of acetaminophen (APAP) has become the major cause of acute liver injury (ALI). The present study aimed to evaluate the potential hepatoprotective effects of black ginseng (BG) on APAP-induced mice liver injuries and the underlying mechanisms of action were further investigated for the first time. Methods: Mice were treated with BG (300, 600 mg/kg) by oral gavage once a day for seven days. On the 7th day, all mice were treated with 250 mg/kg APAP which caused severe liver injury after 24 h and hepatotoxicity was assessed. Results: Our results showed that pretreatment with BG significantly decreased the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST) compared with the APAP group. Meanwhile, hepatic antioxidant including glutathione (GSH) was elevated compared with the APAP group. In contrast, a significant decrease of the levels of the lipid peroxidation product malondialdehyde (MDA) was observed in the BG-treated groups compared with the APAP group. These effects were associated with significant increases of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) levels in liver tissues. Moreover, BG supplementation suppressed activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax protein expression levels according to western blotting analysis. Histopathological examination revealed that BG pretreatment significantly inhibited APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress like 3-nitrotyrosine (3-NT) were also inhibited after pretreatment with BG, compared with the APAP group. Conclusions: The results clearly suggest that the underlying molecular mechanisms of action of BG-mediated alleviation of APAP-induced hepatotoxicity may involve its anti-oxidant, anti-apoptotic, anti-inflammatory and anti-nitrative effects.

Acute Liver Injury Associated with Anorexia Nervosa

While mild to moderate elevation of liver transaminases is common with anorexia nervosa, acute hepatic injury with severe elevation of transaminases and coagulopathy is rare . We report a 24-year male with anorexia nervosa who was presented with acute liver injury. Alanine transferase and aspartate transferase peaked at 2033 IU/ml and 1410 IU/ml respectively. More common causes of acute liver injury were ruled out. Liver biopsy did not show centrilobular necrosis or congestion which are the hallmarks of ischemic liver injury. The patient has improved on re-institution of proper nutrition. In conclusion, acute liver injury can occasionally be caused by anorexia nervosa. The pathophysiologic mechanism involved, on contrary to what previously reported, is unlikely tissue hypoperfusion.

Predictors of poor outcomes in patients with wild mushroom-induced acute liver injury.

AIMTo identify early predictive markers of poor outcomes in patients with acute liver injury from wild mushroom intoxication.METHODSThis observational, retrospective record review involved adults aged ≥ 18 years admitted to emergency department with mushroom intoxication from January 2005 to December 2015. The diagnosis of mushroom intoxication was based on the following: (1) a positive history of recent wild mushroom intake (either raw or cooked); (2) the onset of gastrointestinal symptoms, such as watery diarrhea, vomiting, and/or abdominal pain, after ingestion; and (3) the exclusion of other possible causes of acute liver injury. Acute liver injury was defined by a > 5-fold elevation of liver enzymes or moderate coagulopathy [international normalized ratio (INR) > 2.0]. Clinical and laboratory findings were compared in survivors and non-survivors.RESULTSOf 93 patients with mushroom intoxication, 23, 11 men (47.8%) and 12 women (52.2%), of median age 61 years, developed acute liver injury. The overall in-hospital mortality rate was 43.5% (10/23). Among the laboratory variables, mean serum alkaline phosphatase (73.38 ± 10.89 mg/dL vs 180.40 ± 65.39 mg/dL, P < 0.01), total bilirubin (2.312 ± 1.16 mg/dL vs 7.16 ± 2.94 mg/dL, P < 0.01) concentrations and indirect/direct bilirubin (2.45 ± 1.39 mg/dL vs 0.99 ± 0.45 mg/dL, P < 0.01) ratio as well as prothrombin time (1.88 ± 0.83 mg/dL vs 10.43 ± 4.81 mg/dL, P < 0.01), and activated partial thromboplastin time (aPTT; 32.48 ± 7.64 s vs 72.58 ± 41.29 s, P = 0.01), were significantly higher in non-survivors than in survivors. Logistic regression analysis showed that total bilirubin concentration (OR = 3.58, 95%CI: 1.25-10.22), indirect/direct bilirubin ratio (OR = 0.14, 95%CI: 0.02-0.94) and aPTT (OR = 1.30, 95%CI: 1.04-1.63) were significantly associated with mortality. All patients with total bilirubin > 5 mg/dL or aPTT > 50 s on day 3 died.CONCLUSIONMonitoring of bilirubin concentrations and aPTT may help in predicting clinical outcomes in patients with acute liver injury from wild mushroom intoxication.

STAT3, a Key Parameter of Cytokine-Driven Tissue Protection during Sterile Inflammation - the Case of Experimental Acetaminophen (Paracetamol)-Induced Liver Damage.

Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol) overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger-associated molecular patterns (DAMPs) from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT)-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL)-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients, standard therapy may fail and APAP intoxication can proceed toward a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions.

Caspase-3/7-mediated Cleavage of β2-spectrin is Required for Acetaminophen-induced Liver Damage.

The ubiquitously expressed β2-spectrin (β2SP, SPTBN1) is the most common non-erythrocytic member of the β-spectrin gene family. Loss of β2-spectrin leads to defects in liver development, and its haploinsufficiency spontaneously leads to chronic liver disease and the eventual development of hepatocellular cancer. However, the specific role of β2-spectrin in liver homeostasis remains to be elucidated. Here, we reported that β2-spectrin was cleaved by caspase-3/7 upon treatment with acetaminophen which is the main cause of acute liver injury. Blockage of β2-spectrin cleavage robustly attenuated β2-spectrin-specific functions, including regulation of the cell cycle, apoptosis, and transcription. Cleaved fragments of β2-spectrin were physiologically active, and the N- and C-terminal fragments retained discrete interaction partners and activity in transcriptional regulation and apoptosis, respectively. Cleavage of β2-spectrin facilitated the redistribution of the resulting fragments under conditions of liver damage induced by acetaminophen. In contrast, downregulation of β2-spectrin led to resistance to acetaminophen-induced cytotoxicity, and its insufficiency in the liver promoted suppression of acetaminophen-induced liver damage and enhancement of liver regeneration. Conclusions: β2-Spectrin, a TGF-β mediator and signaling molecule, is cleaved and activated by caspase-3/7, consequently enhancing apoptosis and transcriptional control to determine cell fate upon liver damage. These findings have extended our knowledge on the spectrum of β2-spectrin functions from a scaffolding protein to a target and transmitter of TGF-β in liver damage.

The Incidence and Outcomes of Ischemic Hepatitis: A Systematic Review with Meta-analysis

BackgroundIschemic hepatitis is a devastating cause of acute liver injury. Data are limited regarding its incidence and outcomes. MethodsSystematic review and meta-analysis of studies from PubMed, EMBASE, and Web of Science with specific search terms. Inclusion criteria included case series with >10 patients and clear case definition (especially liver enzyme levels >10 times the upper limit of normal). ResultsTwenty-four papers met inclusion criteria. A total of 1782 cases were identified in these papers (mean 78 per paper, range 12-322). The pooled average age of the included patients was 64.2 years, and their mean peak aspartate aminotransferase level, alanine aminotransferase level, and total bilirubin were 2423 IU/L, 1893 IU/L, and 2.55 mg/dL, respectively. Ischemic hepatitis was present in 2 of every 1000 admissions; including 2.5 of every 100 intensive care unit admissions and 4 of 10 admissions associated with an aminotransferase level >10 times the upper limit of normal. The pooled proportions of patients with ischemic hepatitis who had a predisposing acute cardiac event or sepsis were 78.2% and 23.4%, respectively. The proportion of patients with a documented hypotensive event of any duration was 52.9%. Overall, the pooled rate of survival to discharge was 51% (range 23.1%-85.7%). ConclusionsIschemic hepatitis is a common cause of severe acute liver injury and is associated with a significant risk of in-hospital death. A major opportunity in the management of ischemic hepatitis is recognition of the condition without documented hypotension.