Thromboelastometry identifies coagulopathy associated with liver failure and disseminated intravascular coagulation caused by yellow fever, guiding specific hemostatic therapy: a case report. / A tromboelastometria identifica coagulopatia associada à insuficiência hepática e coagulação intravascular disseminada causadas por febre amarela, orientando a terapia hemostática específica: um relato de caso.

This case report a severe case of yellow fever complicated by liver failure and disseminated intravascular coagulation. Thromboelastometry was capable of identifying clotting disorders and guiding hemostatic therapy. We report the case of a 23-year-old male admitted to the Intensive Care Unit with sudden onset of fever, generalized muscle pain associated with liver failure, and disseminated intravascular coagulation. The results of conventional laboratory tests showed thrombocytopenia, whereas thromboelastometry suggested coagulopathy with slight hypofibrinogenemia, clotting factor consumption, and, consequently, an increased risk of bleeding. Unlike conventional laboratory tests, thromboelastometry identified the specific coagulation disorder and thereby guided hemostatic therapy. Both fibrinogen concentrates and vitamin K were administered, and no blood component transfusion was required, even in the presence of thrombocytopenia. Administration of hemostatic drugs, including fibrinogen concentrate and vitamin K, improved thromboelastometric parameters, correcting the complex coagulation disorder. Blood component transfusion was not performed, and there was no bleeding.

Este relato de caso detalha um caso grave de febre amarela complicada por insuficiência hepática e coagulação intravascular disseminada. A tromboelastometria foi capaz de identificar os distúrbios da coagulação e orientar o tratamento hemostático. Relatamos o caso de um homem com 23 anos de idade admitido na unidade de terapia intensiva com quadro com início abrupto de febre e dor muscular generalizada associados a insuficiência hepática e coagulação intravascular disseminada. Os resultados dos exames laboratoriais convencionais revelaram trombocitopenia, enquanto a tromboelastometria sugeriu coagulopatia com discreta hipofibrinogenemia, consumo de fatores de coagulação e, consequentemente, aumento do risco de sangramento. Diferentemente dos exames laboratoriais convencionais, a tromboelastometria identificou o distúrbio de coagulação específico e, assim, orientou o tratamento hemostático. Administraram-se concentrados de fibrinogênio e vitamina K, não sendo necessária a transfusão de qualquer componente do sangue, mesmo na presença de trombocitopenia. A tromboelastometria permitiu a identificação precoce da coagulopatia e ajudou a orientar a terapêutica hemostática. A administração de fármacos hemostáticos, incluindo concentrados de fibrinogênio e vitamina K, melhorou os parâmetros tromboelastométricos, com correção do transtorno da coagulação. Não se realizou transfusão de hemocomponentes, e não ocorreu qualquer sangramento.

A tromboelastometria identifica coagulopatia associada à insuficiência hepática e coagulação intravascular disseminada causadas por febre amarela, orientando a terapia hemostática específica: um relato de caso / Thromboelastometry identifies coagulopathy associated with liver failure and disseminated intravascular coagulation caused by yellow fever, guiding specific hemostatic therapy: a case report

RESUMO Este relato de caso detalha um caso grave de febre amarela complicada por insuficiência hepática e coagulação intravascular disseminada. A tromboelastometria foi capaz de identificar os distúrbios da coagulação e orientar o tratamento hemostático. Relatamos o caso de um homem com 23 anos de idade admitido na unidade de terapia intensiva com quadro com início abrupto de febre e dor muscular generalizada associados a insuficiência hepática e coagulação intravascular disseminada. Os resultados dos exames laboratoriais convencionais revelaram trombocitopenia, enquanto a tromboelastometria sugeriu coagulopatia com discreta hipofibrinogenemia, consumo de fatores de coagulação e, consequentemente, aumento do risco de sangramento. Diferentemente dos exames laboratoriais convencionais, a tromboelastometria identificou o distúrbio de coagulação específico e, assim, orientou o tratamento hemostático. Administraram-se concentrados de fibrinogênio e vitamina K, não sendo necessária a transfusão de qualquer componente do sangue, mesmo na presença de trombocitopenia. A tromboelastometria permitiu a identificação precoce da coagulopatia e ajudou a orientar a terapêutica hemostática. A administração de fármacos hemostáticos, incluindo concentrados de fibrinogênio e vitamina K, melhorou os parâmetros tromboelastométricos, com correção do transtorno da coagulação. Não se realizou transfusão de hemocomponentes, e não ocorreu qualquer sangramento.

Abstract This case report a severe case of yellow fever complicated by liver failure and disseminated intravascular coagulation. Thromboelastometry was capable of identifying clotting disorders and guiding hemostatic therapy. We report the case of a 23-year-old male admitted to the Intensive Care Unit with sudden onset of fever, generalized muscle pain associated with liver failure, and disseminated intravascular coagulation. The results of conventional laboratory tests showed thrombocytopenia, whereas thromboelastometry suggested coagulopathy with slight hypofibrinogenemia, clotting factor consumption, and, consequently, an increased risk of bleeding. Unlike conventional laboratory tests, thromboelastometry identified the specific coagulation disorder and thereby guided hemostatic therapy. Both fibrinogen concentrates and vitamin K were administered, and no blood component transfusion was required, even in the presence of thrombocytopenia. Administration of hemostatic drugs, including fibrinogen concentrate and vitamin K, improved thromboelastometric parameters, correcting the complex coagulation disorder. Blood component transfusion was not performed, and there was no bleeding.

The function of MicroRNA in hepatitis B virus-related liver diseases: from Dim to Bright.

MicroRNAs represent a class of non-coding RNA molecules that negatively regulate gene expression either by repressing translation or by inducing degradation of messenger RNA. Studies have shown that, as regulators of gene expression, microRNAs are widely involved in various human diseases, including hepatitis B virus-related liver diseases. By modulating hepatitis B virus replication, regulating extracellular matrix formation, as well as silencing tumor suppressor genes, these small molecules are implicated in the development of chronic hepatitis, liver fibrosis/cirrhosis, and hepatocellular carcinoma caused by hepatitis B virus infection. In addition, current researches indicated a potential role of microRNA as diagnostic markers and therapeutic targets. In conclusion, microRNAs are promising tools in the diagnosis and treatment of hepatitis B virus -related liver diseases.

The efficacy and safety of entecavir in patients with chronic hepatitis B- associated liver failure: a meta-analysis.

BACKGROUND: The effectiveness of nucleoside analogue (NA) treatment in patients with chronic hepatitis B (CHB) -associated liver failure is still controversial. Severe lactic acidosis has been reported during entecavir (ETV) treatment in patients with impaired liver function. AIM: To investigate the rescuing efficacy and safety of ETV in patients with CHB-associated liver failure. MATERIAL AND METHODS: A literature search was carried out to collect articles dated up to December, 2013 on ETV therapy for patients with CHB-associated liver failure. Risk ratio (RR) and mean difference (MD) were used to measure the effects. Survival rate was used as the primary efficacy measure. The safety of ETV was assessed. RESULTS: Six randomized controlled trials were selected. The overall analysis revealed ETV significantly improved survival at 4 weeks (RR = 1.35; 95% CI [1.16, 1.57]; p < 0.0001), 8 weeks (RR = 1.33; 95% CI [1.07, 1.64]; p = 0.009), 12 weeks (RR = 1.68; 95% CI [1.24, 2.28]; p = 0.0008). Pooled data also showed beneficial effects of antiviral therapy compared with control for HBV DNA negative change (RR = 5.35; 95% CI [2.06, 13.88]; p = 0.0006), TBIL and PTA improvement (TBIL: MD = -69.36; 95% CI [-134.37, -4.36]; p = 0.04. PTA: MD = 16.26; 95% CI [8.59, 23.94]; p < 0.0001). No adverse effect was identified in the examined studies. CONCLUSION: Our results showed that antiviral therapy with ETV improved the short-term survival of patients with CHB-associated liver failure. In addition, ETV was well tolerated during the treatment period. Further studies are still needed to strengthen these results.

Infection by Brazilian and Dutch swine hepatitis E virus strains induces haematological changes in Macaca fascicularis.

BACKGROUND: Hepatitis E virus (HEV) has been described as an emerging pathogen in Brazil and seems to be widely disseminated among swine herds. An autochthonous human case of acute hepatitis E was recently reported. To obtain a better understanding of the phenotypic profiles of both human and swine HEV strains, a experimental study was conducted using the animal model, Macaca fascicularis. METHODS: Six cynomolgus monkeys (Macaca fascicularis) were inoculated intravenously with swine HEV genotype 3 that was isolated from naturally and experimentally infected pigs in Brazil and the Netherlands. Two other monkeys were inoculated with HEV genotype 3 that was recovered from Brazilian and Argentinean patients with locally acquired acute and fulminant hepatitis E. The haematological, biochemical, and virological parameters of all animals were monitored for 67 days. RESULTS: Subclinical hepatitis was observed in all monkeys after inoculation with HEV genotype 3 that was recovered from the infected swine and human patients. HEV RNA was detected in the serum and/or faeces of 6 out of the 8 cynomolgus monkeys between 5 and 53 days after inoculation. The mild inflammation of liver tissues and elevations of discrete liver enzymes were observed. Seroconversions to anti-HEV IgM and/or IgG were detected in 7 animals. Reactivities to anti-HEV IgA were also detected in the salivary samples of 3 animals. Interestingly, all of the infected monkeys showed severe lymphopenia and a trend toward monocytosis, which coincided with elevations in alanine aminotransferase and antibody titres. CONCLUSIONS: The ability of HEV to cross the species barrier was confirmed for both the swine (Brazilian and Dutch) and human (Argentinean) strains, thus reinforcing the zoonotic risk of hepatitis E in South America. Cynomolgus monkeys that were infected with HEV genotype 3 developed subclinical hepatitis that was associated with haematological changes. Haematological approaches should be considered in future studies of HEV infection.

Porphyria cutanea tarda in an HCV-positive liver transplant patient: a case report.

INTRODUCTION: Porphyria cutanea tarda (PCT) is the most common type of porphyria. The strong association between PCT and hepatitis C virus (HCV) infection is well established. Although antiviral treatment of chronic hepatitis C may improve PCT in some cases, de novo onset of PCT has been observed in patients under- going peginterferon/ribavirin treatment. We present a rare case of a genotype 3 HCV-positive liver transplant recipient who developed PCT during antiviral treatment and discuss its probable etiopathogenesis. CASE PRESENTATION: A genotype 3 HCV-positive liver transplant recipient, a 42-year-old man, was treated with peginterferon alfa-2a (180 µg/week) combined with ribavirin (1,200 mg/day) for recurrence of HCV infection after liver transplantation. He presented with hyperferritinemia but tested negative for genetic hemochromatosis (C282Y and H63D mutations). During antiviral therapy, he developed skin lesions on his hands characterized by vesicles and erosions consistent with PCT. PCT was confirmed by skin biopsy and elevated urinary uroporphyrin levels (1,469 mg/24 h). He was treated with chloroquine (200 mg) twice weekly, resulting in gradual regression of the skin lesions. Antiviral treatment was stopped after 48 weeks, and the patient achieved a sustained virological response. In conclusion, we report an extremely rare case of PCT in a genotype 3 HCV-positive liver transplant patient treated with antiviral therapy. We believe that the combination of HCV genotype 3 infection; hemolysis due to ribavirin treatment; and increased plasma levels of cytokines, such as IL-6 and TNFα, could have altered the patient's iron metabolism and thus caused PCT.

Operational tolerance after liver transplantation, more common than we think: a case report.

Operational tolerance after liver transplantation has been described in around 20% of the recipients. These patients are able to maintain a normal graft function in the absence of immunosuppressive drugs, thus being free of adverse effects that are common and frequently severe. Here we present a well-documented case of operational tolerance after liver transplantation and discuss current concepts on this topic with emphasis on recent findings that will potentially allow for identifying graft-tolerant patients.

Does pre-liver transplant HBV DNA level affect HBV recurrence or survival in liver transplant recipients receiving HBIg and nucleos(t)ide analogues?

BACKGROUND AND AIMS: The risk of recurrent hepatitis B virus (HBV) infection and prognosis of liver transplantation in patients with HBV has dramatically changed with the use of prophylaxis including hepatitis B immune globulin (HBIg) and antiviral agents. METHODS: This study analyzes the prognostic value of HBV DNA level before orthotopic liver transplantation (OLT) and the effect of HBV prophylaxis on rates of HBV recurrence and survival. Between 1988 and 2008, 859 patients underwent OLT in our center; 60 patients had HBV-related liver disease and in 49, HBV DNA was determined by real time-PCR before OLT. Survival and HBV recurrence were analyzed according to preoperative viral load (HBV DNA <10(3) IU/mL vs. HBV DNA ≥10(3)) and prophylaxis regimens (HBIg vs HBIg and antivirals). RESULTS: On multivariate analysis, prophylaxis with HBIg alone, but not HBV-DNA levels was independently associated with poor survival, with a relative risk (RR) of death of 6.5 (95% CI 2.1-19.8, P = 0.001). The risk of HBV recurrence, in this small series, was also associated with monoprophylaxis with HBIg (RR 27, 95% CI 5.2-147.2, P < 0.0001), but not with HBV-DNA levels. CONCLUSIONS: When prophylaxis with HBIg and antiviral agents was administered, survival and HBV recurrence were not influenced by HBV-DNA levels determined by real time-PCR prior to OLT.

Post-transplant recurrent hepatitis C: immunohistochemical detection of hepatitis C virus core antigen and possible pathogenic implications.

INTRODUCTION: The mechanisms by which severe cholestatic hepatitis develops after liver transplantation are not fully understood. Reports on immunohistochemical distribution of hepatitis C virus (HCV) antigens are still scarce, but recently, HCV immunostaining was suggested for early diagnosis of cholestatic forms of recurrent hepatitis C in liver grafts. After purification, Rb246 pab anticore (aa1-68) yielded specific, granular cytoplasmic staining in hepatocytes. Signal amplification through the Envision-Alkaline Phosphatase System avoided endogenous biotin and peroxidase. AIMS/METHODS: Rb246 was applied to liver samples of explants of 12 transplant recipients, six with the most severe form of post-transplantation recurrence, severe cholestatic hepatitis (group 1) and six with mild recurrence (group 2). We also assessed immuno-reactivity at two time-points post-transplantation (median 4 and 22 months) in both groups. HCV-core Ag was semiquantified from 0 to 3+ in each time point. Serum HCV-RNA was also measured on the different time points by branched DNA. RESULTS: In the early post-transplant time point, one patient had a mild staining (1+), two patients had a moderate staining (2+) and the other three had no staining in group 1, compared with five patients with no staining (0) and one patient with mild staining (1+) in group 2. Late post-transplant liver samples were available in nine patients, and two out of four samples in group 1 showed a mild staining, compared with no staining patients in five patients in group 2. Strikingly, on the explant samples, HCV immunostaining was strongly positive in group 1, and mildly positive in group 2. Two out of five samples showed 3+ staining, and three samples showed 2+ staining in group 1; two out of five samples showed no staining, two samples showed 1+ staining and one sample showed 2+ staining in group 2. Serum HCV-RNA was significantly higher in group 1, on both time-points post-transplantation. HCV-core Ag was not directly associated with serum HCV-RNA on the different time points. CONCLUSION: These preliminary results suggest that strong HCV immunostaining in the explant is predictive of more severe disease recurrence.

Lamivudine resistance and other mutations in the polymerase and surface antigen genes of hepatitis B virus associated with a fatal hepatic failure case.

BACKGROUND AND AIM: Resistance to lamivudine therapy of chronic hepatitis B virus (HBV) infection occurs by mutation in the YMDD motif of the reverse transcriptase (rt) domain (rtM204V/I) of the virus polymerase, and is usually accompanied by rtL180M mutation. Here we investigated virological factors associated with hepatic failure in a 58-year-old male, chronically HBV-infected patient who died after 33 months of lamivudine therapy. METHODS: Nucleotide sequencing was performed from one sample collected before and two samples collected during lamivudine therapy. RESULTS: A peak of alanine aminotransferase and aspartate aminotransferase levels occurred after 19 months of lamivudine treatment, associated with the rtM204I mutation. After 32 months, the rtM204V mutation was predominant, accompanied by the lamivudine-resistant rtL180M mutation. Furthermore, two rare polymerase (rtS117Y and rtV142A) and three HBsAg (L109I, F134L, and I208T) substitutions were observed. At that time, the patient was hospitalized with hepatic decompensation, followed by hepatic failure, and died one month later. HBV-DNA was detected at moderate levels (8.3 x 10(4)-2.6 x 10(6) copies/mL) throughout. CONCLUSION: The results suggest that substitutions in polymerase (rtS117Y, rtV142A) and surface antigens (L109I, F134L, and I208T), associated with lamivudine-resistant mutations at positions 180 and 204, were involved in this case of fatal hepatitis B.

A new biliodigestive anastomosis technique after hepatic artery thrombosis as bridge to liver retransplantation: a case presentation.

Arterial complications after liver transplantation are frequent. Hepatic artery thrombosis (HAT) is usually associated with biliary complications. Herein we have reported a case of a patient who was admitted for jaundice, itch, and elevated aspartate aminotransferase and alanine aminotransferase levels at 6 weeks after liver transplantation. HAT associated with a biloma was diagnosed and an urgent operation performed requiring a new biliodigestive anastomosis technique. Fourteen months after the first transplant, the patient was retransplanted. The operation performed may be an alternative to treat biliary complications due to late HAT.

Hepatitis B virus and hepatitis C virus co-infection: additive players in chronic liver disease?

Hepatitis B virus (HBV) and hepatitis C virus (HCV) share modes of transmission and their combined infection is a fairly frequent occurrence particularly in areas where the two viruses are endemic and among subjects with a high risk of parenteral infections. Moreover, the number of coinfected patients is likely higher than is usually thought. In fact, many studies have shown that HBV genomes may also be present in HBsAg-negative patients, particularly in those with HCV-related chronic hepatitis. This condition is commonly called "occult HBV infection". Much evidence suggests that coinfection by HBV and HCV may have considerable clinical relevance. In particular, this condition is generally believed to be a factor favouring the progression of liver fibrosis toward cirrhosis and the development of liver cancer, and in case of both overt and occult HBV infection. In spite of its potential clinical impact, however, there is few information about the possible interplay between the two viruses. Here, we concisely reviewed the available data on the virological and clinical features of the dual HBV/HCV infection prospecting the aspects that should be highlighted in the nearest future for improving the knowledge on this important field of the hepatology.

Fulminant hepatic failure in children and adolescents in Northern Brazil.

The histological findings of fulminant hepatic failure were correlated to the demographic, clinical, biochemical and virological features in children and adolescents, native to the Amazonas State in Northern Brazil. 96.2% had evidence of infection by primary hepatotrophic viruses. Histological analysis revealed three distinct patterns of fulminant hepatic failure.

Hepatitis C and liver transplantation.

Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. The aim of this review is to analyze the factors involved in the results in different groups of patients with HCV underwent to liver transplantation. The groups involved those pretransplantation, post-transplant HCV infection, preventive early post-transplantation and with of recurrent hepatitis C.