Home About us Contact
|
Home About us Contact | ||
|
|
||
Liver Failure (liver + failure)
Kinds of Liver Failure Terms modified by Liver Failure Selected AbstractsFulminant Liver Failure After Vancomycin in a Sulfasalazine-Induced DRESS Syndrome: Fatal Recurrence After Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009M. Mennicke DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a rare drug hypersensitivity reaction with a significant mortality. We describe a 60-year-old man with polyarthritis treated with sulfasalazine who developed DRESS and fulminant liver failure after additional vancomycin treatment. Liver histology revealed infiltration of granzymeB+ CD3+ lymphocytes in close proximity to apoptotic hepatocytes. After a superurgent liver transplantation and initial recovery, the patient developed recurrent generalized exanthema and eosinophilia, but only moderate hepatitis. Histology showed infiltration of FasL+ lymphocytes and eosinophils in the transplanted liver. Treatment with high-dose methylprednisolone was unsuccessful. Postmortem examination revealed extensive necrosis of the liver transplant. This case report illustrates that patients with DRESS may develop fulminant liver failure and that DRESS recurrence can recur in the transplanted liver. Histological and immunological investigations suggest an important role of granzymeB and FasL mediated cell death in DRESS associated hepatitis. [source] Effective Bilirubin Reduction by Single-Pass Albumin Dialysis in Liver FailureARTIFICIAL ORGANS, Issue 8 2009Ussanee Boonsrirat Abstract Albumin dialysis is widely accepted as a liver-support technique for patients with liver failure. The Molecular Adsorbent Recirculating System, the widely accepted albumin dialysis technique, has limited use in developing countries because of its technical difficulties and high cost. Therefore, we assessed the efficacy of the more practical modality, the single-pass albumin dialysis (SPAD), in terms of bilirubin reduction, as a marker of albumin-bound toxins removal, as well as the patient outcomes. Twelve acute or acute-on-chronic patients with liver failure who had hyperbilirubinemia (total bilirubin > 20 mg/dL) were treated with SPAD by using 2% human serum albumin dialysate for 6 h. SPAD treatment significantly improved the levels of total bilirubin, conjugated bilirubin, urea, and creatinine (P < 0.001 for all parameters). The reduction ratios of these four parameters were 22.9 ± 3.8%, 20.9 ± 5%, 19.0 ± 4.1%, and 27.7 ± 3.2%, respectively. No significant difference was observed between serum ammonia before and after treatment. No significant changes in mean arterial pressures were noted during the maneuver, representing cardiovascular tolerability. No treatment-related complications were found. The 15-day in-hospital survival was 16.7%. However, a subgroup of the patients who had moderate severity showed 100% 15-day-survival rate (2 of 2 patients). In conclusion, SPAD is salutarily effective in reducing bilirubin in patients with liver failure. The procedure is safe and simply set up. [source] Thermodynamic Considerations in Solid Adsorption of Bound Solutes for Patient Support in Liver FailureARTIFICIAL ORGANS, Issue 7 2008John F. Patzer II Abstract:, New detoxification modes of treatment for liver failure that use solid adsorbents to remove toxins bound to albumin in the patient bloodstream are entering clinical evaluations, frequently in head-to-head competition. While generally effective in reducing toxin concentration beyond that obtainable by conventional dialysis procedures, the solid adsorbent processes are largely the result of heuristic development. Understanding the principles and limitations inherent in competitive toxin binding, albumin versus solid adsorbent, will enhance the design process and, possibly, improve detoxification performance. An equilibrium thermodynamic analysis is presented for both the molecular adsorbent recirculating system (MARS) and fractionated plasma separation, adsorption, and dialysis system (Prometheus), two advanced systems with distinctly different operating modes but with similar equilibrium limitations. The Prometheus analysis also applies to two newer approaches: sorbent suspension reactor and microsphere-based detoxification system. Primary results from the thermodynamic analysis are that: (i) the solute,albumin binding constant is of minor importance to equilibrium once it exceeds about 105 L/mol; (ii) the Prometheus approach requires larger solid adsorbent columns than calculated by adsorbent solute capacity alone; and (iii) the albumin-containing recycle stream in the MARS approach is a major reservoir of removed toxin. A survey of published results indicates that MARS is operating under mass transfer control dictated by solute,albumin equilibrium in the recycle stream, and Prometheus is approaching equilibrium limits under current clinical protocols. [source] Clinical Experience with Molecular Adsorbent Recirculating System (MARS) in Patients with Drug-induced Liver FailureARTIFICIAL ORGANS, Issue 5 2004Xin-min Zhou Abstract:, The molecular adsorbent recirculating system (MARS) is a novel extracorporeal technique for liver support. We report the clinical results in a group of fourteen patients with drug-induced liver failure. Fourteen patients, aged 22,83 years, with acute or subacute liver failure [mean Child,Turcotte,Pugh (CTP) score 11 (range 8,15)] due to the intake of various drugs (diet pill overdose,2; Chinese traditional medicine (CTM),4; antibiotic, paracetamol, tuberculostatic, or vasodilator abuse,8) were treated with one to seven sessions of MARS. Beneficial effects such as the improvement of encephalopathy and prothrombin activity, as well as a reduction of bilirubin and ammonia were recorded during MARS treatments. Thirteen out of fourteen patients survived the hospitalization (93%), and two of the discharged patients died during the follow-up of 6,12 months. The overall survival rate was about 79%. MARS therapy can contribute to the improved treatment of drug-induced liver failure patients. [source] Liver failure in a patient receiving rosiglitazone therapyDIABETIC MEDICINE, Issue 1 2006D.-H. Su No abstract is available for this article. [source] Liver failure following partial hepatectomyHPB, Issue 3 2006Thomas S. Helling Abstract While major liver resections have become increasingly safe due to better understanding of anatomy and refinement of operative techniques, liver failure following partial hepatectomy still occurs from time to time and remains incompletely understood. Observationally, certain high-risk circumstances exist, namely, massive resection with small liver remnants, preexisting liver disease, and advancing age, where liver failure is more likely to happen. Upon review of available clinical and experimental studies, an interplay of factors such as impaired regeneration, oxidative stress, preferential triggering of apoptotic pathways, decreased oxygen availability, heightened energy-dependent metabolic demands, and energy-consuming inflammatory stimuli work to produce failing hepatocellular functions. [source] Liver failure and transplantation after itraconazole treatment for toenail onychomycosisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2 2005A Srebrnik ABSTRACT Three weeks after completing a 4-pulse course of itraconazole for toenail onychomycosis, a 25-year-old woman patient developed severe liver crisis and required an emergency liver transplant. We report the case and discuss the use of itraconazole in onychomycosis and dermatomycoses. [source] Factors Associated with Outcome in Foals with Neonatal Isoerythrolysis (72 Cases, 1988,2003)JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2008A.C. Polkes Background: Neonatal foals with isoerythrolysis (NI) often die, but the risk factors for death have not been identified. Objectives: To identify factors associated with outcome in foals with NI and to identify factors associated with death from liver failure or kernicterus in the same population. Animals: Seventy-two foals with NI examined at referral institutions. Methods: Retrospective case series. Information on signalment, clinical examination findings, laboratory testing, treatment, complications, outcome, and necropsy results were obtained. Results: The overall survival rate was 75% (54 of 72). Liver failure (n = 7), kernicterus (n = 6), and complications related to bacterial sepsis (n = 3) were the 3 most common reasons for death or euthanasia. The number of transfusions with blood products was the factor most strongly associated with nonsurvival in a multivariate logistic regression model. The odds of liver failure developing in foals receiving a total volume of blood products , 4.0 L were 19.5 (95% confidence intervals [CI]: 2.13,178) times higher than that of foals receiving a lower volume (P= .009). The odds of kernicterus developing in foals with a total bilirubin , 27.0 mg/dL were 17.0 (95% CI: 1.77,165) times higher than that of foals with a lower total bilirubin (P= .014). Conclusions and Clinical Importance: Development of liver failure, kernicterus, and complications related to bacterial sepsis are the most common causes of death in foals with NI. Foals administered a large volume of blood products are at greater risk for developing liver failure. [source] Case series of liver failure associated with rosiglitazone and pioglitazone,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 12 2009James S. Floyd MD Abstract Purpose The thiazolidinedione drugs rosiglitazone and pioglitazone are not widely known to be hepatotoxic. We evaluated the FDA Adverse Event Reporting System (AERS) to determine the number of reported cases of liver failure associated with rosiglitazone and pioglitazone between 1997 and 2006, and described their clinical characteristics. Methods Adverse event reports spontaneously submitted to the FDA AERS from 1997 to 2006 were examined. Liver failure associated with rosiglitazone or pioglitazone was defined as liver injury accompanied by hepatic encephalopathy, liver transplantation, placement on a liver transplant list, or death in which all other likely etiologies were excluded. Using prescribing data, the number of reported cases of liver failure per million patient-years of exposure was calculated for each drug. Results Twenty-one cases met our case definition. Clinical characteristics, outcomes, and pathologic data were similar between cases of liver failure associated with rosiglitazone and with pioglitazone. The median duration of therapy was 9 weeks and 85% of cases were acute, defined as symptom onset to liver failure in less than 26 weeks. The case-fatality rate was 81% (17/21), and only 14% (3/21) spontaneously recovered. Accounting for underreporting, the number needed to harm (NNH) for each case of liver failure was 44,000 patient-years of exposure for rosiglitazone and 52,000 patient-years of exposure for pioglitazone. Conclusions This is the largest case series of liver failure associated with rosiglitazone or pioglitazone reported to date, strengthening the evidence that these drugs can cause severe hepatotoxicity. Copyright © 2009 John Wiley & Sons, Ltd. [source] Long-Term Outcomes of Liver Transplantation in Type 1 Gaucher DiseaseAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010R. M. Ayto Gaucher disease (GD) is the most prevalent lysosomal storage disorder. Enzyme replacement therapy (ERT) has demonstrable efficacy in reversing clinical and pathological manifestations of GD. We report four patients with GD and severe hepatic impairment who were successfully treated by orthotopic liver transplantation. Liver failure resulted from GD in two patients and due to a comorbidity in two others (HCV and autoimmune chronic active hepatitis). Following successful liver transplantation, patients received long-term ERT. Liver transplantation is a life-saving treatment for end-stage liver disease in patients with Gaucher disease. All four patients have had excellent outcomes from liver transplantation for up to 10 years postprocedure with no evidence of Gaucher-related pathology in the graft. [source] Ductular Cholestasis, an Unusual Form of Intrahepatic Cholestasis, Associated With Cardiogenic Shock and Ventricular Assist DeviceARTIFICIAL ORGANS, Issue 2 2010Alberto Mohedano-Gómez Abstract Ventricular assist devices have been shown to be effective in advanced heart failure selected patients. They often have borderline end-organ function, what facilitates organ dysfunction. Liver failure is difficult to manage and leads to increased morbidity and mortality. We report a case of ductular cholestasis, an unusual cholestatic hepatic failure with untractable coagulopathy, developed during the use of a magnetic levitation centrifugal pump, implanted as a bridge to heart transplantation, in a patient with cardiogenic shock (as an end-stage disease of idiopathic dilated cardiomyopathy). We discussed the pathophysiology of this entity and the possible related factors, including the assist device. Preemptive interventions have been advocated as the primary way of treatment. Preoperative optimization of heart function and avoidance of visceral hypoperfusion and sepsis may play a major role. [source] A randomized controlled trial of transcatheter arterial chemoembolization with lipiodol, doxorubicin and cisplatin versus intravenous doxorubicin for patients with unresectable hepatocellular carcinomaEUROPEAN JOURNAL OF CANCER CARE, Issue 5 2009M. MABED md, professor Hepatocellular carcinoma (HCC) is a major and often therapeutically frustrating oncological problem. A total of 100 patients with unresectable HCC were recruited and randomized to be treated with either transcatheter arterial chemoembolization (TACE) or systemic chemotherapy. Fifty patients were treated with TACE using lipiodol, doxorubicin and cisplatin, while 50 patients were treated with systemic doxorubicin alone. Patients treated with TACE achieved a significantly higher response rate, with partial response achieved in 16 patients (32%) versus five patients (10%) in the chemotherapy arm (P = 0.007). A significantly more favourable tumour response to chemoembolization was found in patients with single lesions (P = 0.02), Child class A (P = 0.007), Okuda stage 1 (P = 0.005) and ,-feto protein less than 400 ng/mL (P < 0.001). The probability of tumour progression was significantly lower in cases treated with TACE where the median progression free survival was 32 weeks (range, 16,70 weeks) versus 26 weeks (range, 14,54 weeks) for patients treated with systemic chemotherapy (P = 0.03). However, the median overall survival did not differ significantly in cases treated with TACE (38 weeks) compared with those treated with chemotherapy (32 weeks) (P = 0.08), except for patients with serum albumin >3.3 g/dL (60 vs. 36 weeks; P = 0.003). Multivariate Cox regression analysis showed that a rise of serum albumin by 1 g/dL is associated with a decrease in the risk of death by 33% (95% confidence interval: 0.12,0.94, P = 0.038). Mortality in the chemoembolization arm was due to tumour progression in 18 patients (53%), liver failure in 11 patients (32%) and gastro intestinal tract (GIT) bleeding in 5 patients (15%). Mortality in the chemotherapy arm was due to tumour progression in 23 patients (64%), liver failure in 9 patients (25%) and GIT bleeding in 4 patients (11%). Treatment-related mortality was 4% in the TACE arm versus 0% in the chemotherapy arm. In conclusion, the overall survival benefits of TACE and systemic doxorubicin are similar for patients with unresectable HCC amenable to either treatment. It is crucial to optimize the benefit,risk ratio of TACE. In this setting, serum albumin level is a candidate marker for selection of cases who may benefit from this procedure. [source] ME3738 protects from concanavalin,A-induced liver failure via an IL-6-dependent mechanismEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2003Christian Klein Abstract ME3738 is a new compound that attenuates liver disease in several models of acute and chronic liver inflammation. We used the concanavalin,A (Con,A) model to elucidate the molecular mechanismsof ME3738 to block liver cell damage. Pretreatment of BALB/c mice with ME3738 prior to Con,A injection resulted in a significant reduction in liver injury. The protective effect of ME3738 prior to Con,A injection was associated with a reduction in IL-6 serum levels and NF-,B DNA binding in liver nuclear extracts. However, STAT3 DNA binding was induced via ME3738 prior to Con,A injection. Further analysis showed that ME3738 induces IL-6 serum levels and activates STAT3 DNA binding and target gene transcription. The relevance of this finding was assessed in IL-6,/, mice. Inthese animals, ME3738 induced no increase in IL-6 serum expression, and activation of IL-6-dependent pathways was not found. In addition, ME3738 did not protect IL-6,/, animals from Con,A-induced liver failure, while IL-6 injection was still effective. Therefore, we demonstrate that ME3738 triggers IL-6 expression, which activates pathways that are relevant to protect from Con,A-induced liver failure. [source] A reversibly immortalized human hepatocyte cell line as a source of hepatocyte-based biological supportADDICTION BIOLOGY, Issue 4 2001Naoya Kobayashi The application of hepatocyte transplantation (HTX) is increasingly envisioned for temporary metabolic support during acute liver failure and provision of specific liver functions in inherited liver-based metabolic diseases. Compared with whole liver transplantation, HTX is a technically simple procedure and hepatocytes can be cryopreserved for future use. A major limitation of this form of therapy in humans is the worldwide shortage of human livers for isolating an adequate number of transplantable human hepatocyes when needed. Furthermore, the numbers of donor livers available for hepatocyte isolation is limited by competition for their use in whole organ transplantation. Considering the cost of hepatocyte isolation and the need for immediate preparation of consistent and functional cells, it is unlikely that human hepatocytes can be obtained on such a scale to treat a large number of patients with falling liver functions. The utilization of xenogenic hepatocytes will result in additional concerns regarding transmission of infectious pathogens and immunological and physiological incompatibilities between animals and humans. An attractive alternative to primary human hepatocytes is the use of tightly regulated human hepatocyte cell lines. Such cell lines can provide the advantages of unlimited availability, sterility and uniformity. We describe here methods for creating transplantable human hepatocyte cell lines using currently available cell cultures and gene transfer technology. [source] Assessment of drug-induced liver injury in clinical practiceFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 2 2008Ma Isabel Lucena Abstract Currently, pharmaceutical preparations are serious contributors to liver disease, with hepatotoxicity ranking as the most frequent cause for acute liver failure and post-marketing regulatory decisions. The diagnostic approach of drug-induced liver injury (DILI) is still rudimentary and inaccurate because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug's hepatotoxic potential, the exclusion of alternative causes of liver damage, and the ability to detect the presence of subtle data that favour a toxic aetiology. Clinical and laboratory data may also be assessed with algorithms or clinical scales, which may add consistency to the clinical judgment by translating the suspicion into a quantitative score. The CIOMS/RUCAM instrument is considered at present the best method for assessing causality in DILI, although it could be improved through the use of large database of bona fide DILI cases for validation criteria. [source] Immunomodulatory therapy for chronic hepatitis B virus infectionFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2005D. Sprengers Abstract Hepatitis B virus (HBV) is one of the most prevalent viral pathogens of man with around 350 million chronically infected patients. It has been postulated that in persistently infected individuals the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver disease. The primary aim in the treatment of chronic hepatitis B is to induce sustained disease remission and prevent serious complications like liver failure and/or hepatocellular carcinoma. The recent emergence of drug-resistant HBV mutants and post-treatment relapse as a consequence of nucleoside analogue monotherapy emphasizes that the principal goal should be to stimulate a successful immune response. In this paper we will focus on the immune response to HBV and we will review reported data on immunotherapeutic strategies like immunomodulatory drugs (cytokines and Thymic derivates) and vaccine therapies using currently available recombinant anti-HBV vaccines, lipopeptide-based T cell vaccine and newly developed genetic vaccines. [source] Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicityGLIA, Issue 8 2007V. B. R. Pichili Abstract Hepatic encephalopathy (HE) is a major neurological complication that occurs in the setting of severe liver failure. Ammonia is a key neurotoxin implicated in this condition, and astrocytes are the principal neural cells histopathologically and functionally affected. Although the mechanism by which ammonia causes astrocyte dysfunction is incompletely understood, glutamine, a by-product of ammonia metabolism, has been strongly implicated in many of the deleterious effects of ammonia on astrocytes. Inhibiting mitochondrial glutamine hydrolysis in astrocytes mitigates many of the toxic effects of ammonia, suggesting the involvement of mitochondrial glutamine metabolism in the mechanism of ammonia neurotoxicity. To determine whether mitochondriaare indeed the organelle where glutamine exerts its toxic effects, we examined the effect of L -histidine, an inhibitor of mitochondrial glutamine transport, on ammonia-mediated astrocyte defects. Treatment of cultured astrocytes with L -histidine completely blocked or significantly attenuated ammonia-induced reactive oxygen species production, cell swelling, mitochondrial permeability transition, and loss of ATP. These findings implicate mitochondrial glutamine transport in the mechanism of ammonia neurotoxicity. © 2007 Wiley-Liss, Inc. [source] Deletion of interleukin-6 in mice with the dominant negative form of transforming growth factor , receptor II improves colitis but exacerbates autoimmune cholangitis,HEPATOLOGY, Issue 1 2010Weici Zhang The role of interleukin-6 (IL-6) in autoimmunity attracts attention because of the clinical usage of monoclonal antibodies to IL-6 receptor (IL-6R), designed to block IL-6 pathways. In autoimmune liver disease, activation of the hepatocyte IL-6/STAT3 (signal transducer and activator of transcription 3) pathway is associated with modulating pathology in acute liver failure, in liver regeneration, and in the murine model of concanavalin A,induced liver inflammation. We have reported that mice expressing a dominant negative form of transforming growth factor , receptor II (dnTGF,RII) under control of the CD4 promoter develop both colitis and autoimmune cholangitis with elevated serum levels of IL-6. Based on this observation, we generated IL-6,deficient mice on a dnTGF-,RII background (dnTGF,RII IL-6,/,) and examined for the presence of antimitochondrial antibodies, levels of cytokines, histopathology, and immunohistochemistry of liver and colon tissues. As expected, based on reports of the use of anti,IL-6R in inflammatory bowel disease, dnTGF,RII IL-6,/, mice manifest a dramatic improvement in their inflammatory bowel disease, including reduced diarrhea and significant reduction in intestinal lymphocytic infiltrates. Importantly, however, autoimmune cholangitis in dnTGF,RII IL-6,/, mice was significantly exacerbated, including elevated inflammatory cytokines, increased numbers of activated T cells, and worsening hepatic pathology. Conclusion: The data from these observations emphasize that there are distinct mechanisms involved in inducing pathology in inflammatory bowel disease compared to autoimmune cholangitis. These data also suggest that patients with inflammatory bowel disease may not be the best candidates for treatment with anti,IL-6R if they have accompanying autoimmune liver disease and emphasize caution for therapeutic use of anti,IL-6R antibody. HEPATOLOGY 2010 [source] Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity,HEPATOLOGY, Issue 4 2010Hua Wang Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. (HEPATOLOGY 2010.) [source] New school in liver development: Lessons from zebrafish,HEPATOLOGY, Issue 5 2009Jaime Chu There is significant overlap in the genes and pathways that control liver development and those that regulate liver regeneration, hepatic progenitor cell expansion, response to injury, and cancer. Additionally, defects in liver development may underlie some congenital and perinatal liver diseases. Thus, studying hepatogenesis is important for understanding not only how the liver forms, but also how it functions. Elegant work in mice has uncovered a host of transcription factors and signaling molecules that govern the early steps of hepatic specification; however, the inherent difficulty of studying embryogenesis in utero has driven developmental biologists to seek new systems. The rapidly developing vertebrate zebrafish is a favorite model for embryology. The power of forward genetic screens combined with live real-time imaging of development in transparent zebrafish embryos has highlighted conserved processes essential for hepatogenesis and has uncovered some exciting new players. This review presents the advantages of zebrafish for studying liver development, underscoring how studies in zebrafish and mice complement each other. In addition to their value for studying development, zebrafish models of hepatic and biliary diseases are expanding, and using these small, inexpensive embryos for drug screening has become de rigueur. Zebrafish provide a shared platform for developmental biology and translational research, offering innovative methods for studying liver development and disease. The story of hepatogenesis has something for everyone. It involves transcriptional regulation, cell-cell interaction, signaling pathways, control of cell proliferation and apoptosis, plus morphogenic processes that sculpt vasculature, parenchymal cells, and mesenchyme to form the multifaceted liver. Decades of research on liver development in mice and other vertebrates offer valuable lessons in how the multipotent endoderm is programmed to form a functional liver. Of equal importance are insights that have illuminated the mechanisms by which hepatic progenitors are activated in a damaged liver, how the adult liver regenerates, and, possibly, the basis for engineering liver cells in vitro for cell transplantation to sustain patients with liver failure. Moreover, processes that are key to liver development are often co-opted during pathogenesis. Therefore, reviewing hepatogenesis is informative for both basic and translational researchers. In this review, we bring to light the many advantages offered by the tropical freshwater vertebrate zebrafish (Danio rerio) in studying hepatogenesis. By comparing zebrafish and mice, we highlight how work in each system complements the other and emphasize novel paradigms that have been uncovered using zebrafish. Finally, we highlight exciting efforts using zebrafish to model hepatobiliary diseases. (HEPATOLOGY 2009.) [source] Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases,HEPATOLOGY, Issue 1 2009Allen D. Brinker Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n = 4) or liver transplantation (n = 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. Conclusion: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion. (HEPATOLOGY 2009;49:250-257.) [source] Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management,HEPATOLOGY, Issue 1 2009Raj Vuppalanchi Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease in the western world. It is now recognized that these patients have myriad of important co-morbidities (e.g., diabetes, hypothyroidism and metabolic syndrome). The workup of patients with suspected NAFLD should consist of excluding competing etiologies and systemic evaluation of metabolic comorbidities. NAFLD is histologically categorized into steatosis and steatohepatitis, two states with fairly dichotomous natural history. While significant progress has been made in terms of noninvasively predicting advanced fibrosis, insufficient progress has been made in predicting steatohepatitis. Currently, liver biopsy remains the gold standard for the histological stratification of NAFLD. While sustained weight loss can be effective to treat NASH, it is often difficult to achieve. Foregut bariatric surgery can be quite effective in improving hepatic histology in selected patients without liver failure or significant portal hypertension. Thiazolidinediones have shown promise and the results from the ongoing, large multicenter study should become available soon. Large multicenter studies of CB, receptor anatagonists are also underway but their results will not be available for several years. Several recent studies have highlighted that cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. Conclusion: Health care providers should not only focus on liver disease but also concentrate on aggressively modifying and treating their cardiovascular risk factors. (HEPATOLOGY 2009;49:306-317.) [source] Ammonia impairs neutrophil phagocytic function in liver disease,HEPATOLOGY, Issue 4 2008Debbie L. Shawcross Hyperammonemia is a feature of liver failure, which is associated with increased risk of infection. The aims of the present study were to determine in vitro, in rats fed an ammoniagenic diet and in patients with cirrhosis, whether induction of hyperammonemia results in neutrophil dysfunction. As hyperammonemia produces cell swelling, we explored the role of the osmoregulating, p38 mitogen-activated protein kinase (p38MAPK) pathway in mediating this neutrophil dysfunction. Neutrophils were isolated from blood of healthy volunteers and incubated with either 75 ,M ammonia or phosphate-buffered saline. Both groups were studied under hyponatremic conditions and/or with the addition of p38MAPK modulators. Neutrophil phagocytosis was measured in naive rats and rats fed an ammoniagenic diet and in patients with stable cirrhosis given placebo (n = 8) or an amino acid solution inducing hyperammonemia (n = 8). Cell volume and phagocytosis was analyzed by fluorescent-activated cell sorting using fluorescein isothiocyanate,labeled E. coli. p38MAPK phosphorylation was measured by western blotting. In healthy neutrophils incubated with ammonia and in rats fed an ammoniagenic diet, neutrophils showed evidence of swelling, impaired phagocytosis, and increased spontaneous oxidative burst compared to controls. Phagocytosis was significantly impaired in patients with induced hyperammonemia compared to placebo. The effects of hyperammonemia and hyponatremia were synergistic. The p38MAPK intracellular signaling pathways were activated in healthy neutrophils exposed to ammonia in association with increased burst activity. Neutrophil phagocytic dysfunction was abrogated by the addition of a p38MAPK agonist. Conclusion: Ammonia produces neutrophil swelling and impairs neutrophil phagocytosis. The p38MAPK intracellular signaling pathway has been shown to be important in mediating the ammonia-induced neutrophil dysfunction. (HEPATOLOGY 2008.) [source] Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development,HEPATOLOGY, Issue 2 2008Silke Marhenke In tyrosinemia type 1 (HT1), accumulation of toxic metabolites results in oxidative stress and DNA damage, leading to a high incidence of hepatocellular carcinomas. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor important for cellular protection against oxidative stress and chemical induced liver damage. To specifically address the role of Nrf2 in HT1, fumarylacetoacetate hydrolase (Fah)/Nrf2,/, mice were generated. In acute HT1, loss of Nrf2 elicited a strong inflammatory response and dramatically increased the mortality of mice. Following low grade injury, Fah/Nrf2,/, mice develop a more severe hepatitis and liver fibrosis. The glutathione and cellular detoxification system was significantly impaired in Fah/Nrf2,/, mice, resulting in increased oxidative stress and DNA damage. Consequently, tumor development was significantly accelerated by loss of Nrf2. Potent pharmacological inducers of Nrf2 such as the triterpenoid analogs 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole have been developed as cancer chemoprevention agents. Pretreatment with 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole dramatically protected Fah,/, mice against fumarylacetoacetate (Faa)-induced toxicity. Our data establish a central role for Nrf2 in the protection against Faa-induced liver injury; the Nrf2 regulated cellular defense not only prevents acute Faa-induced liver failure but also delays hepatocarcinogenesis in HT1. (HEPATOLOGY 2008;48:487,496.) [source] Disease-specific autoantibodies in patients with acute liver failure: The King's College London Experience,HEPATOLOGY, Issue 3 2008William Bernal No abstract is available for this article. [source] Mitochondrial hepatopathies: Advances in genetics and pathogenesis,HEPATOLOGY, Issue 6 2007Way S. Lee Hepatic involvement is a common feature in childhood mitochondrial hepatopathies, particularly in the neonatal period. Respiratory chain disorders may present as neonatal acute liver failure, hepatic steatohepatitis, cholestasis, or cirrhosis with chronic liver failure of insidious onset. In recent years, specific molecular defects (mutations in nuclear genes such as SCO1, BCS1L, POLG, DGUOK, and MPV17 and the deletion or rearrangement of mitochondrial DNA) have been identified, with the promise of genetic and prenatal diagnosis. The current treatment of mitochondrial hepatopathies is largely ineffective, and the prognosis is generally poor. The role of liver transplantation in patients with liver failure remains poorly defined because of the systemic nature of the disease, which does not respond to transplantation. Prospective, longitudinal, multicentered studies will be needed to address the gaps in our knowledge in these rare liver diseases. (HEPATOLOGY 2007;45:1555,1565.) [source] Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis,HEPATOLOGY, Issue 1 2006Raoul Poupon Primary biliary cirrhosis (PBC),autoimmune hepatitis (AIH) overlap syndrome is a clinical entity characterized by the occurence of both conditions at the same time in the same patient. In addition to PBC-AIH overlap syndrome, transitions from one autoimmune disease to another have been reported, but no systematic series have been published. We report a series of 12 patients with consecutive occurrence of PBC and AIH (i.e., PBC followed by AIH). Among 282 PBC patients, 39 were identified who fulfilled criteria for probable or definitive AIH. AIH developed in 12 patients (4.3%). The baseline characteristics of the patients were similar to those of patients with classical PBC. Time elapsed between the diagnosis of PBC and the diagnosis of AIH varied from 6 months to 13 years. Patients with multiple flares of hepatitis at the time of diagnosis of AIH had cirrhosis on liver biopsy. Ten patients were given prednisone ± azathioprine; short-term as well as sustained remissions were obtained in 8 of these, while two had multiple relapses and eventually died 8 and 7 years after diagnosis of AIH. In conclusion, the development of superimposed AIH could not be predicted from baseline characteristics and initial response to UDCA therapy. If not detected early, superimposed AIH can result in rapid progression toward cirrhosis and liver failure in PBC patients. (HEPATOLOGY 2006;44:85,90.) [source] An inhibitor of cyclin-dependent kinase, stress-induced p21Waf-1/Cip-1, mediates hepatocyte mito-inhibition during the evolution of cirrhosis,HEPATOLOGY, Issue 6 2005John G. Lunz III During the evolution of cirrhosis, there is a relative decrease in volume percentage of hepatocytes and a relative increase in biliary epithelial cells and myofibroblasts. This is recognized histopathologically as a ductular reaction and leads to gradual distortion of the normal hepatic architecture. The final or decompensated stage of cirrhosis is characterized by a further decline in hepatocyte proliferation and loss of functional liver mass that manifests clinically as ascites, encephalopathy, and other signs of liver failure. In this report, we tested the hypothesis that p21-mediated hepatocyte mito-inhibition accelerates the evolution of cirrhosis using an established mouse model of decompensated biliary cirrhosis, p21-deficient mice, and liver tissue from humans awaiting liver replacement. Despite the same insult of long-term (12-week) bile duct ligation, mice prone to decompensation showed significantly more oxidative stress and hepatocyte nuclear p21 expression, which resulted in less hepatocyte proliferation, an exaggerated ductular reaction, and more advanced disease compared with compensation-prone controls. Mice deficient in p21 were better able than wild-type controls to compensate for long-term bile duct ligation because of significantly greater hepatocyte proliferation, which led to a larger liver mass and less architectural distortion. Mito-inhibitory hepatocyte nuclear p21 expression in humans awaiting liver replacement directly correlated with pathological disease stage and model of end-stage liver disease scoring. In conclusion, stress-induced upregulation of hepatocyte p21 inhibits hepatocyte proliferation during the evolution of cirrhosis. These findings have implications for understanding the evolution of cirrhosis and associated carcinogenesis. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005.) [source] Bioartificial liver in acute liver failure: Impostor or simply misunderstood?HEPATOLOGY, Issue 2 2005FRCPI, John O'Grady M.D. No abstract is available for this article. [source] Nuclear factor ,B decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine modelHEPATOLOGY, Issue 2 2003Ichiro Ogushi Endotoxin syndrome is a systemic inflammatory response mediated by inflammatory cytokines. Nuclear factor ,B (NF-,B) is the dominant regulator of the production of these cytokines by inflammatory cells. The aim of this study was to assess the efficacy of in vivo transfer of synthetic double-stranded oligodeoxynucleotides (ODN) with high affinity against NF-,B (NF-,B/decoy/ODN) as a therapeutic strategy for treating endotoxin-induced fatal liver injury. Liver injury was induced by administration of lipopolysaccharide (LPS) to Propionibacterium acnes -primed BALB/C mice. NF-,B/decoy/ODN was transferred into the portal vein using a fusigenic liposome with hemagglutinating virus of Japan. NF-,B/decoy/ODN was preferentially transferred to Kupffer cells, and activation of NF-,B after the LPS challenge was suppressed, leading to decreased inflammatory cytokine production. As a result, the massive necrosis and hepatocyte apoptosis observed in the control mice was dramatically attenuated and the survival rate improved. In conclusion, NF-,B/decoy/ODN transfer in vivo effectively suppressed endotoxin-induced fatal liver injury in mice. [source] | ||||||||||||||||||||||||||||||||||||||||