Development Of Fulminant Hepatic Failure Research Articles

A Dual Role of Complement Activation in the Development of Fulminant Hepatic Failure Induced by Murine-Beta-Coronavirus Infection

With the epidemic of betacoronavirus increasing frequently, it poses a great threat to human public health. Therefore, the research on the pathogenic mechanism of betacoronavirus is becoming greatly important. Murine hepatitis virus strain-3 (MHV-3) is a strain of betacoronavirus which cause tissue damage especially fulminant hepatic failure (FHF) in mice, and is commonly used to establish models of acute liver injury. Recently, MHV-3-infected mice have also been introduced to a mouse model of COVID-19 that does not require a Biosafety Level 3 (BSL-3) facility. FHF induced by MHV-3 is a type of severe liver damage imbalanced by regenerative hepatocellular activity, which is related to numerous factors. The complement system plays an important role in host defense and inflammation and is involved in first-line immunity and/or pathogenesis of severe organ disorders. In this study, we investigated the role of aberrant complement activation in MHV-3 infection-induced FHF by strategies that use C3-deficient mice and intervene in the complement system. Our results showed that mice deficient in C3 had more severe liver damage, a higher viral load in the liver and higher serum concentrations of inflammatory cytokines than wild-type controls. Treatment of C57BL/6 mice with C3aR antagonist or anti-C5aR antibody reduced liver damage, viral load, and serum IFN-γ concentration compared with the control group. These findings indicated that complement system acts as a double-edged sword during acute MHV-3 infection. However, its dysregulated activation leads to sustained inflammatory responses and induces extensive liver damage. Collectively, by investigating the role of complement activation in MHV-3 infection, we can further understand the pathogenic mechanism of betacoronavirus, and appropriate regulation of immune responses by fine-tuning complement activation may be an intervention for the treatment of diseases induced by betacoronavirus infection.

S2564 Cyanoacrylate Embolization Following EGD Resulting in Fulminant Hepatic Failure in a Patient With Cirrhosis

INTRODUCTION: Esophagogastric varices are a common complication of portal hypertension and can present with life-threatening bleeding. Definitive endoscopic therapy is via band ligation or sclerotherapy. The former is preferred for esophageal varices, but efficacy is lower in gastric varices (GV). Sclerotherapy with cyanoacrylate (CA) has shown better efficacy and is now recommended as first line therapy for bleeding GV. Studies on long-term efficacy and complications remain limited. CASE DESCRIPTION/METHODS: A 62-year-old woman with NASH cirrhosis (MELD 11) presented with hematemesis. She denied any history of SBP, varices, or encephalopathy. She endorsed a previous history of COVID-19 and had reactive IgG but PCR probe for SARS-CoV-2 was negative. She underwent EGD and was found to have oozing GV along the lesser curvature, which were treated with 4cc of CA achieving hemostasis. The following night she had altered mentation and the blood lactate was increased to 7.2 mmol/L. AST and ALT were also increased. She received broad spectrum antibiotics, and a CT angiogram showed evidence of embolization of CA into the left lobe of the liver. On day 3 her level of consciousness declined and she was intubated for airway compromise. An MRCP confirmed the presence of CA within the left hepatic lobe with associated ischemia. The lactate increased to 20 mmol/L and the blood ammonia level to 700 mcg/dL, with MELD 45. Continuous hemodialysis was started for anuric renal failure. She underwent evaluation for liver transplantation, but cerebral edema and multiorgan failure with refractory acidosis occurred and she died on day 7. DISCUSSION: We present a case of GV treated with CA and the subsequent embolization of CA into the left lobe of the liver. This precipitated acute on chronic liver failure with features of fulminant hepatic failure (FHF) complicated by severe hyperammonemia, cerebral edema, multiorgan failure, and death. Although she had a recent diagnosis of COVID-19, the time course, relatively normal initial inflammatory markers, and imaging suggest that CA embolization was likely the injury that led to fulminant hepatic failure. Given the lack of case reports of CA embolization to the liver causing infarction and few cases to the brain or distant vessels, further research on its long-term safety is warranted. Another novel aspect to this case is the development of FHF in a patient with known cirrhosis.

Clinical characteristics and molecular analysis of hepatitis B virus reactivation in hepatitis B surface antigen-negative patients during or after immunosuppressive or cytotoxic chemotherapy.

Reactivation of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)-positive patients treated with immunosuppressive or cytotoxic chemotherapy is well known and has emerged as an important clinical issue. The risk is low, but reactivation of HBV in HBsAg-negative patients after resolution of HBV infection also occurs; however, the clinical and virological characteristics remain somewhat unclear. We investigated HBsAg-negative patients who developed HBV reactivation during or after immunosuppressive or cytotoxic chemotherapy to clarify the clinical and virological features. Reactivation of HBV in 30 previously infected that is HBsAg-negative patients during or after immunosuppressive or cytotoxic chemotherapy was examined. Direct sequencing at the time of reactivation was used to evaluate 11 patients. The majority of patients had diffuse large B cell lymphoma treated by rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Fulminant hepatic failure developed in three patients, who did not survive. HBV subgenotypes A2/Ae (n=1), B1/Bj (n=2), and C2/Ce (n=8) were detected. There were no significant differences in the prevalence of BCP/PC variants between HBV reactivation and acute self-limited hepatitis patient groups. BCP and PC variants were not associated with development of fulminant hepatic failure from HBV reactivation. The prevalence of HBV S region variants, including immune-escape mutants, among reactivation patients was significantly higher than that in acute self-limited hepatitis patients. Reactivation risk factors included male sex, advanced age, and hematological malignancy. HBV S gene immune-escape mutants were frequently found in the HBsAg-negative reactivation patients during or after immunosuppressive or cytotoxic chemotherapy.

Employment of digital gene expression profiling to identify potential pathogenic and therapeutic targets of fulminant hepatic failure.

BackgroundThe dysregulated cytokine metabolism and activity are crucial to the development of fulminant hepatic failure (FHF), and many different cytokines have been identified. However, the precise gene expression profile and their interactions association with FHF are yet to be further elucidated.MethodsIn this study, we detected the digital gene expression profile (DGEP) by high-throughput sequencing in normal and FHF mouse liver, and the candidate genes and potential targets for FHF therapy were verified. And the FHF mouse model was induced by D-Galactosamine (GalN)/lipopolysaccharide (LPS).ResultsTotally 12727 genes were detected, and 3551 differentially expressed genes (DEGs) were obtained from RNA-seq data in FHF mouse liver. In FHF mouse liver, many of those DEGs were identified as differentially expressed in metabolic process, biosynthetic process, response to stimulus and response to stress, etc. Similarly, pathway enrichment analysis in FHF mouse liver showed that many significantly DEGs were also enriched in metabolic pathways, apoptosis, chemokine signaling pathways, etc. Considering the important role of nuclear factor-kappa B (NF-κB) in metabolic regulation and delicate balance between cell survival and death, several DEGs involved in NF-κB pathway were selected for experimental validation. As compared to normal control, NF-κBp65 and its inhibitory protein IκBα were both significantly increased, and NF-κB targeted genes including tumor necrosis factor α(TNFα), inducible nitric oxide synthase (iNOS), interleukin-1β, chemokines CCL3 and CCL4 were also increased in hepatic tissues of FHF. In addition, after NF-κB was successfully pre-blocked, there were significant alteration of hepatic pathological damage and mortality of FHF mouse model.ConclusionsThis study provides the globe gene expression profile of FHF mouse liver, and demonstrates the possibility of NF-κB gene as a potential therapeutic target for FHF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0380-9) contains supplementary material, which is available to authorized users.

Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin

Hepatocyte apoptosis plays an important role in the development of fulminant hepatic failure (FHF). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress and unfolded protein response (UPR) inhibition is an underlying mechanism of melatonin anti-apoptotic effects in an animal model of FHF of viral origin induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2×10(4) hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10mg/kg and 20mg/kg at 0hr, 12hr and 24hr postinfection. RHDV infection induced increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin heavy chain binding protein (BiP/GRP78), glucose-regulated protein 94 (GRP94), phospho-c-Jun N-terminal kinase (JNK) and caspase-12. These effects were attenuated by melatonin. Double immunofluorescence staining showed colocalization of CHOP and cleaved caspase-3 in liver sections of RHDV-infected rabbits, while immunostaining decreased markedly with melatonin treatment. RHDV infection resulted in significant increases in the mRNA levels of activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), spliced X-box binding protein-1 (XBP1s) and tumor necrosis factor receptor-associated factor 2 (TRAF2). Melatonin attenuated the extent of the changes. Data obtained provide evidence that in rabbits with experimental infection by RHDV, reduction in apoptotic liver damage by melatonin is associated with attenuation of ER stress through a modulation of the three arms of UPR signaling and further support a potential hepatoprotective role of melatonin in FHF.

Inhibiting the expression of hepatocyte nuclear factor 4 alpha attenuates lipopolysaccharide/D-galactosamine-induced fulminant hepatic failure in mice

Hepatocyte nuclear factor 4 alpha (HNF4alpha) plays an important role in regulating cytokine-induced inflammatory responses. This study aimed to investigate the role of HNF4alpha in the development of fulminant hepatic failure (FHF) induced by lipopolysaccharide/D-galactosamine (LPS/D-GalN). The FHF model was induced by simultaneous intraperitoneal injection of LPS/D-GalN in mice. Three days prior to LPS/D-GalN administration, HNF4alpha short-hairpin interfering RNA expression plasmid or physiological saline was injected via the tail vein with a hydrodynamics-based procedure. The degree of hepatic damage and cumulative survival rate were subsequently assessed. The expression of HNF4alpha was increased in the early stage after LPS/D-GalN administration. Inhibiting the expression of HNF4alpha reduced serum levels of alanine aminotransferase and aspartate aminotransferase, alleviated histological injury, and improved the survival of mice with FHF. In addition, both serum and hepatic tumor necrosis factor alpha expression were suppressed when HNF4alpha expression was inhibited in mice with FHF. Inhibiting HNF4alpha expression protects mice from FHF induced by LPS/D-GalN, but the exact mechanism behind this needs further investigation.

Preterm Delivery in a Parturient Candidate for Emergency Liver Transplantation After Hepatitis B Virus Infection Related Fulminant Liver Failure

This case shows the development of fulminant hepatic failure due to acute hepatitis B virus infection in a multipara (32(nd) week of gestation) candidate for an emergency liver transplantation. Preterm labor began and she delivered a preterm healthy male baby. Postpartum, there were complications including a massive hemorrhage that was managed adequately. We also reviewed the literature regarding causes, complications, and management of acute liver failure during pregnancy and labor.

Dynamic Patterns of serum metabolites in fulminant hepatic failure pigs

Fulminant hepatic failure (FHF) is still an intractable disease associated with serious metabolic disorder. Investigating the dynamic changes of serum metabolites during the development of FHF would facilitate revealing the pathogenesis and also promote its treatment. Therefore, this study characterized the dynamic metabonome of serum from FHF Pigs using ultra performance liquid chromatography–mass spectrometry. Based on multiple statistical analysis of the resulting dataset, three types of up-regulated and one type of down-regulated patterns were delineated. Each pattern demonstrated distinct trends at different stages during the whole process of FHF, implying the differential clinical significance of them. Specifically, aromatic amino acids (Pattern 1) and lysophosphatidylcholines (LPCs) (Pattern 4) might be good markers for evaluating the severity of FHF, while some conjugated bile acids, long chain acylcarnitines (Pattern 2) and Glycocholic acid (Pattern 3) could indicate liver injury in the early stage. Inspired from the PCA plot that the pathogenetic condition of FHF aggravated with sampling time, a linear discriminant analysis (LDA) model based on phenylalanine and LPC 18:1 were further constructed for evaluating the severity of FHF. The leave-one-out cross-validation accuracy of 91.67% for the training set and the prediction accuracy of 92.31% for the external validation set confirmed its excellent performance. In conclusion, findings obtained from the present study, including four types of Dynamic Patterns of serum metabolites during FHF development and an LDA model for evaluating the severity of FHF, will be of great help to the research and management of FHF in the future.

Hypereosinophilia, JAK2V617F, and Budd‐Chiari syndrome: Who is responsible for what?

Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction, which sometimes may be life threatening, with the development of fulminant hepatic failure. In cases of this kind, the most frequent underlying cause of BCS, myeloproliferative neoplasms (MPN), should always be excluded first, and molecular analysis of the Janus Kinase 2 (JAK2) mutation must always be performed [1]. While the association of BCS with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis is well documented, hypereosinophilia has only been described in sporadic cases [2–7]. Furthermore, Jak2 mutation in association with hypereosinophilia has been reported very rarely and its prevalence in this disorder still requires further investigation [8,9]. To the best of our knowledge, cases with the above association occurring together with BCS have not been reported until now. Here, we describe a young woman presenting with idiopathic eosinophilia, JAK2 mutation, and BCS. We also elaborate briefly on the biological mechanism and clinical features of this rare entity. In our opinion, this case supports the formal inclusion of hypereosinophilic syndrome (HES) in the WHO MPN category and also raises the possible pathogenetic contribution of eosinophils, or their products, in MPN-associated splanchnic vein thrombosis.

T1953 Prediction and Early Intervention Improved the Survival Rate of Patients With Fulminant Hepatic Failure

Aim Patients with subacute fulminant hepatic failure (FHF) and late-onset hepatic failure (LOHF) show relatively slow disease progression, although usually suffer serious liver damage. It therefore seems that liver can lose its regenerative capability at the appearance of hepatic coma. No effective treatments have been established for such cases. We advocated that predicting the development of FHF at the stage of severe hepatitis and early intervention with intensive medical treatment for the underlying liver disease could improve the survival rate in these cases. The present study examined the efficacy of our proposed treatment system. Method Inclusion criteria of the present study were as follows: acute hepatitis patients admitted to Showa University Fujigaoka Hospital from 2002 to 2008, prothrombin time below 60% of normal, and absence of hepatic coma on admission. Prediction of FHF was determined based on a previously reported formula (Yoshiba M, J Gastro 2002). Treatment for underlying hepatitis consisted mainly of immunosuppressive therapy using methylpredonisolone withdrawal in combination with continuous cyclosporin A infusion and/or antiviral therapy using interferon beta and/or nucleic acid analogues. Patients were also given artificial liver support immediately after the appearance of hepatic coma; it comprised plasma exchange in combination with hemodiafiltration using huge buffer volumes. Results The inclusion criteria were met by 74 patients with causes of hepatitis listed as HAV (3), HBV (11), HBV carrier (23), HCV (8), drugs (1), and indeterminate (28). Of the total, 34 patients were positive for the prediction formula. Probability of the development of FHF and estimated survival rate were 84% and 40%, respectively. Thirteen of the 34 patients developed FHF with 10 surviving, and 30 of the 34 patients survived (survival rate, 88%). Of the remaining 40 patients who were negative for the prediction formula, 4 developed FHFwith all surviving, and 39 of the 40 patients survived overall (survival rate, 97.5%). One patient died of malignant lymphoma. Conclusion Prediction of FHF and early intervention with intensive medical care are effective in preventing the development of FHF and improving survival rate without liver transplantation in patients with FHF.

T1954 Originally Developed Intensive Medical Care for Fulminant Hepatic Failure Improved Patients' Survival Rate and Also Safely Bridge Fatal Patients to Liver Transplantation

Aim Patients with subacute fulminant hepatic failure (FHF) and late-onset hepatic failure (LOHF) show relatively slow disease progression, although usually suffer serious liver damage. It therefore seems that liver can lose its regenerative capability at the appearance of hepatic coma. No effective treatments have been established for such cases. We advocated that predicting the development of FHF at the stage of severe hepatitis and early intervention with intensive medical treatment for the underlying liver disease could improve the survival rate in these cases. The present study examined the efficacy of our proposed treatment system. Method Inclusion criteria of the present study were as follows: acute hepatitis patients admitted to Showa University Fujigaoka Hospital from 2002 to 2008, prothrombin time below 60% of normal, and absence of hepatic coma on admission. Prediction of FHF was determined based on a previously reported formula (Yoshiba M, J Gastro 2002). Treatment for underlying hepatitis consisted mainly of immunosuppressive therapy using methylpredonisolone withdrawal in combination with continuous cyclosporin A infusion and/or antiviral therapy using interferon beta and/or nucleic acid analogues. Patients were also given artificial liver support immediately after the appearance of hepatic coma; it comprised plasma exchange in combination with hemodiafiltration using huge buffer volumes. Results The inclusion criteria were met by 74 patients with causes of hepatitis listed as HAV (3), HBV (11), HBV carrier (23), HCV (8), drugs (1), and indeterminate (28). Of the total, 34 patients were positive for the prediction formula. Probability of the development of FHF and estimated survival rate were 84% and 40%, respectively. Thirteen of the 34 patients developed FHF with 10 surviving, and 30 of the 34 patients survived (survival rate, 88%). Of the remaining 40 patients who were negative for the prediction formula, 4 developed FHFwith all surviving, and 39 of the 40 patients survived overall (survival rate, 97.5%). One patient died of malignant lymphoma. Conclusion Prediction of FHF and early intervention with intensive medical care are effective in preventing the development of FHF and improving survival rate without liver transplantation in patients with FHF.

Establishment of pig acute liver failure model and the role of pig fibrinogen-like protein 2

To establish a pig model of fulminant hepatic failure for evaluating the pre-clinical efficacy of drug treatment on severe hepatitis, and to detect the expression of fibrinogen-like protein-2 (fgl2) prothrombinase in the model, so as to provide basis for gene therapy targeting to fgl2 for fulminant hepatic failure. D-galactosamine hydrochloride was used to induce pig model of fulminant hepatic failure, and the experiment animals were divided into model group (rapid injection of D-galactosamine hydrochloride by ear vein, a dose of 1.2 g/kg) and negative control group (5% Glucose). Clinical, biochemical and pathological changes of animals were observed. The expression of pigs fgl2 (pfgl2) mRNA in liver tissue was detected by real time RT-PCR, the expression of pfgl2 protein in liver tissue was detected by immunohistochemistry. A pig model of fulminant hepatic failure was successfully established using the D-galactose hydrochloride; Real time RT-PCR of liver fgl2 mRNA showed that fgl2 mRNA expression was increased significantly in liver tissue of fulminant hepatic failure pig model compared with the control group (P = 0.016); Immunohistochemical staining showed that there were fgl2 protein expression in liver tissue of fulminant hepatic failure pig model, mainly in the membrane and cytoplasm of hepatocytes, inflammatory cells, liver sinusoidal endothelial cells and vascular endothelial cells of liver cell necrosis region. However, there are no fgl2 positive staining on negative control. The pig model of fulminant hepatic failure induced by D-galactosamine hydrochloride is similar to human pathological process and can be used to evaluate the pre-clinical efficacy and safety of drug treatment on fulminant hepatic failure. Abnormal expression of pfgl2 at both mRNA level and protein level in the liver of fulminant hepatic failure pig model shows that pfgl2 induced coagulation pathway is also involved in the development of fulminant hepatic failure. Gene therapy targeting fgl2 genes for fulminant hepatic failure may provide a new means for the treatment of fulminant hepatic failure.

Prevalence of Hepatitis B Virus Subgenotypes and Basal Core Promoter, Precore Variants in Patients with Acute Hepatitis B in Central Vietnam

Objective: Hepatitis B virus (HBV) has been classified into 8 genotypes that have different geographic distributions. The clinical outcomes of acute hepatitis are dependent on genotype. The aim of this study was to investigate the distribution of HBV subgenotypes and basal core promoter (BCP)/precore (PC) regions in acute hepatitis patients in Central Vietnam to clarify the distributions and the clinical and virological differences. Methods: 27 patients with acute hepatitis B were studied. HBV subgenotypes and BCP/PC variants were determined by direct sequencing of the preS, BCP/PC regions, respectively. Results: HBV subgenotypes B4/Ba (n = 22) and C1/Cs (n = 5) were detected. Of the 27 patients, 3 developed fulminant hepatic failure, and all were infected with B4/Ba. Three patients had a BCP mutation, and 10 patients had a PC mutation in subgenotype B4/Ba. Three patients with C1/Cs had a BCP mutation. Two of 3 patients who progressed to fulminant hepatic failure had T1762, A1764, and A1896 simultaneously. None of the patients with acute, self-limited hepatitis carried these triple mutations. Conclusion: The prevalent HBV subgenotypes in patients with acute hepatitis B in Central Vietnam were B4/Ba and C1/Cs. BCP/PC variants have an association with the development of fulminant hepatic failure in subgenotype B4/Ba.

Evaluation of prognostic markers in severe drug-induced liver disease

To analyze the outcome of patients with severe drug-induced liver disease (DILD) associated with jaundice classified as hepatocellular, cholestatic or mixed liver injury and to evaluate the validity of Hyos rule and the most important predictors for outcome. The Adverse Drug Reaction Advisory Committee was set up in 1997 in our hospital to identify all suspicions of DILD following a structured prospective report form. Liver damage was divided into hepatocellular, cholestatic, and mixed types according to laboratory and histologic criteria when available. Further evaluation of causality assessment was performed. From January 1997 to December 2004, 265 patients were diagnosed with DILD, and 140 (52.8%) of them were female. hepatocellular damage was the most common (72.1%), the incidence of death was 9.9% in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05). There was no difference in age of dead and recovered patients. The proportion of females and males was similar in recovered and dead patients, no difference was observed in duration of treatment between the two groups. The serum total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and aspartate transaminase (AST) (P = 0.013) values were higher in dead patients than in recovered patients. Chinese herbal medicine was the most frequently prescribed, accounting for 24.2% of the whole series. However, antitubercular drugs (3.4%) were found to be the primary etiological factor for fetal DILD. Factors associated with the development of fulminant hepatic failure were hepatic encephalopathy (OR = 43.66, 95% CI = 8.47-224.95, P < 0.0001), ascite (OR = 28.48, 95% CI = 9.26-87.58, P < 0.0001), jaundice (OR = 11.43, 95% CI = 1.52-85.96, P = 0.003), alcohol abuse (OR = 3.83, 95% CI = 1.26-11.67, P = 0.035) and direct bilirubin (OR = 1.93, 95% CI = 1.25-2.58, P = 0.012). Death occurs in 9.8% of patients with DILD. Chinese herbal medicine stands out as the most common drug for DILD. While antitubercular drugs are found to be the primary etiological factor for fetal DILD, hepatic encephalopathy, ascites, jaundice, alcohol abuse and direct bilirubin levels are associated with the death of DILD patients.

Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

Drug-Induced Liver Injury: An Analysis of 461 Incidences Submitted to the Spanish Registry Over a 10-Year Period

Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.

Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure

Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure. Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg.d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg.d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-alpha (TNF-alpha, an index of liver injury) and 6-keto-PGF(1alpha) (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay. As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs 5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438+/-102 vs 841+/-145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-alpha (indomethacin vs N/S: 22+/-5 vs 10+/-1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1alpha (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S. Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant hepatic failure.

Lebertransplantation bei Tyrosin�mie Typ I

Over the last 10 years the need for liver transplantation in tyrosinaemia type I (TTI) (McKusick Catalogue No. 276700) has considerably changed. Whereas prior to 1992 the development of fulminant hepatic failure, progressive liver dysfunction or hepatocellular carcinoma almost inevitably led to liver transplantation at a very early age of the patient, with the introduction of NTBC [2-(2-nitro-4-trifluoromethyl-benzoyl)-1,3-cyclohexandion], the outcome of the disease has dramatically improved. Only 10% of all children with fulminant hepatic failure secondary to TTI require liver transplantation and very few children in whom NTBC treatment was commenced before the age of 2 years have required liver transplantation for the risk of hepatocellular carcinoma. Following liver transplantation regular surveillance of potentially progressive renal dysfunction needs to be emphasised. However, despite improvements following the introduction of NTBC, close monitoring of morphological changes of the liver and serial α-fetoprotein levels are essential to identify those patients at high risk.

Function and regulation of production of hepatocyte growth factor (HGF)

Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.

Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure.

Hepatic encephalopathy is a complex neuropsychiatric syndrome seen secondary to acute liver failure, chronic parenchymal liver disease, or portal-systemic anastomosis. Vasodilatation induced by nitric oxide (NO) may be involved in the development of hepatic coma. However, there are no comprehensive data concerning the effects of NO inhibition on the severity of hepatic encephalopathy. Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of thioacetamide (TAA, 350 mg kg-1 day-1) for 3 days. Rats were divided into two groups to receive either NG-nitro-L-arginine methyl ester (L-NAME, 20 mg kg-1 day-1 via intragastric gavage) or normal saline (N/S) from 2 days prior to TAA administration for 5 days. Severity of encephalopathy was assessed by counts of motor activity and neurobehaviour test scores. Plasma levels of endotoxin, tumour necrosis factor-alpha and nitrate/nitrite were determined by the chromogenic Limulus assay, enzyme-linked immunosorbent assay and colorimetric assay, respectively. Compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving L-NAME (59% vs. 18%, P < 0.01). Inhibition of NO had detrimental effects on the counts of motor activities (P < 0.05) and neurobehaviour score (P < 0.01). Rats treated with L-NAME had significantly higher plasma levels of endotoxin (26.7 +/- 3.8 pg mL-1) and tumour necrosis factor-alpha (29.4 +/- 6.5 pg mL-1) compared with rats treated with N/S (13.2 +/- 2.7 pg mL-1 and 11.2 +/- 2.6 pg mL-1, respectively, P < 0.01). Plasma levels of endotoxin and tumour necrosis factor-alpha, but not of nitrate/nitrite, were significantly correlated with the severity of hepatic encephalopathy (P < 0.05). Chronic L-NAME administration had detrimental effects on the severity of encephalopathy in TAA-treated rats, suggesting a protective role of NO in the development of fulminant hepatic failure.