Basal core promoter and precore mutations among hepatitis B virus circulating in Brazil and its association with severe forms of hepatic diseases

BACKGROUND In Brazil, few studies have investigated the prevalence of infection with the precore (PC) and basal core promoter (BCP) mutants of the hepatitis B virus (HBV). OBJECTIVES This study aimed to analyse the frequency of PC and BCP mutations among patients infected with HBV and to evaluate the association between the variants and advanced hepatic disease. METHODS A total of 161 patients infected with HBV were studied. To identify PC and BCP mutations, a 501-bp fragment of HBV DNA was amplified and sequenced. FINDINGS PC and BCP regions from HBV strains were successfully amplified and sequenced in 129 and 118 cases, respectively. PC and BCP mutations were detected in 61.0% and 80.6% of the cases, respectively. The A1762T/G1764A variant was identified in 36.7% of the patients with grade 1 and 2 liver fibrosis (29/79) and in 81.8% of the patients with grade 3 and 4 liver fibrosis (9/11) (p < 0.01); in 76.9% of the patients with cirrhosis (10/13) and in 38.1% of the patients without cirrhosis (40/105) (p = 0.01); and in 77.8% of the patients with hepatocellular carcinoma (HCC) (7/9) and in 39.4% of the patients without HCC (43/109) (p = 0.03). MAIN CONCLUSIONS A high prevalence of HBV PC and BCP mutants was found. The A1762T/G1764A variant was independently associated with advanced forms of liver fibrosis, hepatic cirrhosis, and HCC.

Distribution of HBV subgenotypes in Ribeirão Preto, Southeastern Brazil: a region with history of intense Italian immigration

Abstract Hepatitis B virus (HBV) is distributed worldwide, with geographical variations regarding prevalence of the different genotypes. The aim of this study was to determine the HBV genotypes and subgenotypes circulating in Southeast Brazil and compare the genetic sequences found with HBV sequences previously described in the world. Sequences from 166 chronic HBV carriers were analyzed using the fragment constituted by 1306 base pairs comprising surface and polymerase regions of the HBV genome. The sequences obtained were submitted to phylogenetic analysis. HBV subgenotypes A1, A2, D1-D4, F2a, and F4 were found. HBV genotype D was the most frequent, found in 99 patients (58.4%). Within this group, subgenotype D3 was the most prevalent, in 73 patients (42.9%). HBV genotype A was identified in 58 (36%) patients, subgenotype A1, in 48 (29.8%) subjects. Genotype F was identified in 9 (5.4%). According to the phylogenetic analysis, the sequences found were grouped with sequences from Europe, Asia and Middle East (subgenotypes D1, D2, D3) and sequences from Latin America and Africa (subgenotype A1). HBV D3 grouped in different clusters inside D3 clade, several of them with sequences isolated in Italy. We also identified eight families whose relatives were infected with the same HBV subgenotype, most with high similarity between sequences. In conclusion, the distribution of the HBV sequences obtained interweaved with sequences from other continents, corresponding to regions from where many immigrants came to this region, in accordance to the hypothesis that the HBV detected over there were brought during the colonization times.

Addition of n-butyl cyanoacrylate to classic transarterial chemoembolization may improve the radiological response in patients with hepatocellular carcinoma

OBJECTIVE: Transarterial chemoembolization is the treatment of choice for intermediate-stage hepatocellular carcinoma. However, there are no clear data supporting transarterial chemoembolization vs . transarterial embolization or regarding the best chemotherapeutic agent, which may suggest a preponderant role of ischemia over chemotherapeutic action. This study sought to evaluate the radiological response and outcome of transarterial chemoembolization modified by n-butyl cyanoacrylate addition compared to conventional transarterial chemoembolization in hepatocellular carcinoma patients. MATERIALS AND METHODS: A retrospective review identified forty-seven patients who underwent modified chemoembolization and thirty-three who underwent conventional chemoembolization between June 2006 and December 2011. The radiological response was reassessed using the modified Response Evaluation Criteria in Solid Tumors. The sustained complete response, time to progression and overall survival rates were also analyzed. RESULTS: Complete response rates were significantly higher in patients who had undergone modified chemoembolization compared to those who had undergone conventional treatment (61.7% and 24.3%, respectively; p <0.001). The rate of sustained complete response was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 236 and 37 days, respectively; p <0.001). Time to progression was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 424 and 201 days, respectively; p =0.042). Overall survival rates revealed no difference between patients who received modified chemoembolization and conventional chemoembolization (median of 483 and 399 days, respectively; p =0.316). CONCLUSION: Transarterial chemoembolization modified by n-butyl cyanoacrylate addition was superior to conventional transarterial chemoembolization in terms of the radiological response in the first imaging control. Although the sustained complete response and time to progression rates were higher for the modified chemoembolization group, no differences in overall survival rates were observed.

Prospective analysis of 44 consecutive liver transplants performed at a university hospital

PURPOSE: To analyze the intraoperative and immediate postoperative biochemical parameters of patients submitted to orthotopic liver transplantation. METHODS: Forty four consecutive orthotopic liver transplants performed from October 2009 to December 2010 were analyzed. The patients (38 male and eight female) were divided into two groups: group A, survivors, and group B, non-survivors. Fifty percent of group A patients were Chid-Pugh C, 40% Chid-Pugh B and 10% Chid-Pugh A. In group B, 52% of the patients were Chid-Pugh C, 41% Chid-Pugh B, and 17% Chid-Pugh A. All orthotopic liver transplants were performed by the piggy-back technique without a portacaval shunt in an anhepatic phase. ALT, AST, LDH and lactate levels were determined preoperatively, at five, 60 minutes after arterial revascularization of the graft and 24 and 48 hours after the end of the surgery.( or: after the surgery was finished). RESULTS: There were no preoperative clinical differences (Child and Meld) between the two groups. The times of warm and hypothermal ischemia were similar for both groups (p>0.05). Serum aminotransferases levels at five and 60 minutes after arterial revascularization of the graft were similar (p>0.05) for both groups, as also were lactate levels at the time points studied. There was no significant difference in Δ lactate between groups at any time point studied (p>0.05). No significant difference was observed between groups during the first 24 and 48 hours after surgery (p>0.05). CONCLUSION: No significant difference in any of the parameters studied was observed between groups. Under the conditions of the present study and considering the parameters evaluated, no direct relationship was detected between the intraoperative situation and the type of evolution of the patients of the two groups studied.

Analysis of 83 consecutive liver transplants performed at a tertiary care reference hospital in the interior of the state of Sao Paulo / Analise de 83 transplantes hepáticos consecutivos realizados em hospital universitário de referência terciária do interior do estado de São Paulo

PURPOSE: To analyze pre-, intra- and immediate postoperative parameters of patients submitted to liver transplantation. METHODS: Eighty-three consecutive orthotopic liver transplants performed from January 2009 to July 2011 were analyzed. The patients were divided into 2 groups: A, survivors (MELD between 9 and 60) and B, non-survivors (MELD between 14 and 40), with 30.6 percent of group A patients being CHILD C, 51℅ CHILD B and 18,4℅ CHILD A. In group B ,32.1℅ of the patients were CHILD C, 42,9℅ CHILD B, and 25℅ CHILD A. All orthotopic liver transplantations were performed using the piggyback technique without a portacaval shunt. Systemic arterial pressure and serum ALT and AST levels were determined preoperatively and 5, 60 and 1440 minutes after arterial graft revascularization. Serum ALT and AST profiles were evaluated for seven days after surgery. RESULTS: Systemic arterial blood pressure levels, time of hot and hypothermic ischemia and time of graft implant were statistically similar for the two groups (p>0.05). Serum levels (U/L) of ALT and AST at the 5, 60 and 1440 minute time points after arterial revascularization of the graft were also similar for the two groups studied, as also were the serum ALT and AST profiles. CONCLUSIONS: No statistically significant difference in any of the parameters studied was detected between the two groups. Under the conditions of the present study and on the basis of the parameters evaluated, no direct relation was detected between the intraoperative period and the type of patient outcome in the two groups studied.

OBJETIVO: Analisar parâmetros do pré, intra e pós-operatório imediato de pacientes submetidos ao transplante de fígado. MÉTODOS: Foram analisados 83 transplantes ortotópicos de fígado realizados consecutivamente no período janeiro de 2009 a julho de 2011. Os pacientes foram dividos em dois grupos: A, survivors (MELD entre 16 e 60), e B, non-survivors (MELD entre 14 e 40) sendo que 30,6℅ dos pacientes do grupo A eram CHILD C, 51℅ CHILD B e 18,4℅ CHILD A. No grupo B, 32,1℅ dos pacientes eram CHILD C, 42,9℅ CHILD B, e 25℅ CHILD A. Todos os transplantes ortotópicos de fígado foram feitos com a técnica de piggyback sem "shunt" porto cava. Foram analisados os valores de pressão arterial sistêmica e os níveis séricos de ALT e AST, no pré-operatório, 5, 60 e 1440 minutos após revascularização arterial do enxerto. Avaliaram-se os perfis séricos da ALT e AST durante sete dias de pós-operatorio. RESULTADOS: Verificou-se que em ambos os grupos, os níveis de pressão arterial sistêmica, os tempos de isquemia normotérmica, hipotérmica e de implante do enxerto foram estatisticamente semelhantes (p>0,05). Os níveis séricos (U/L) de ALT e AST nos tempos de 5, 60 e 1440 minutos após a revascularização arterial do enxerto também foram semelhantes nos grupos estudados. Os perfis séricos da ALT e AST foram semelhantes nos dois grupos estudados. CONCLUSÕES: Não se verificou diferença estatisticamente significante entre todos os parâmetros estudados, em ambos os grupos. Nas condições do presente estudo, não se verificou relação direta do intra-operatório com o tipo de evolução (outcome) dos pacientes nos dois grupos estudados.

Clinical, demographic and epidemiological characteristics of patients with hepatitis B followed at a university hospital in southeastern Brazil: predominance of HBeAg negative cases / Características clínicas, demográficas e epidemiológicas dos pacientes com hepatite B em seguimento em hospital universitário no sudeste do Brasil: predominância de casos HBeAg negativos

INTRODUCTION: Hepatitis B is common in Brazil, although there are regional differences regarding the degree of endemicity, the most frequent forms of transmission and the presence of different evolutive stages of chronic disease. The present study aimed to determine the clinical, demographic and epidemiological characteristics of patients chronically infected with hepatitis B virus (HBV) residing in the Ribeirão Preto region, southeastern Brazil. METHODS: A total of 529 medical records of individuals with HBV monoinfection were reviewed. RESULTS: More than 60 percent of the subjects were males, with a mean age of 38 years-old. The HBeAg-negative serological pattern was verified in 84.4 percent of the patients, among whom the risk of vertical/intrafamily transmission was 43.2 percent (p = 0.02). The consumption of alcohol in amounts exceeding 20g a day was observed in 21.3 percent of the subjects and was more frequent among men (33 percent) (p < 0.001). Among patients with cirrhosis, 54.1 percent were alcohol abusers (p = 0.04), all of them males. The presence of cirrhosis was more frequent in the HBeAg-positive group (24.4 percent) than in the HBeAg-negative group (10.2 percent) (p < 0.001). CONCLUSIONS: High proportions of HBV-infected subjects with an HBeAg-negative pattern were observed, with a higher risk of vertical/intrafamily transmission. Alcohol abuse was associated with male subjects and with cirrhosis of the liver in this group. A tendency toward an increase in the number of HBeAg-negative cases was observed over time.

INTRODUÇÃO: No Brasil, a hepatite B é comum. No entanto, há diferenças regionais no que diz respeito ao grau de endemicidade, as formas de transmissão mais encontradas e a presença dos diferentes estágios evolutivos da doença crônica. O objetivo deste trabalho foi o de conhecer características clínicas, demográficas e epidemiológicas de pacientes cronicamente infectados pelo vírus da hepatite B (HBV), residentes na região de Ribeirão Preto, no sudeste do Brasil. MÉTODOS: Foi realizada a análise retrospectiva de 529 prontuários de indivíduos com monoinfecção pelo HBV. RESULTADOS: Mais de 60 por cento eram masculinos, a média de idade foi de 38 anos. O padrão sorológico HBeAg negativo foi encontrado em 84,4 por cento dos pacientes, entre os quais o risco para transmissão vertical/intrafamiliar foi de 43,2 por cento (p = 0,02). Verificou-se uso de álcool em quantidades maiores que 20g ao dia em 21,3 por cento dos indivíduos, sendo mais frequente entre os homens (33 por cento) (p < 0,001). Entre os pacientes com cirrose, 54,1 por cento faziam uso abusivo de bebidas alcoólicas (p = 0,04), sendo todos estes do gênero masculino. A presença de cirrose foi maior no grupo HBeAg positivo (24,4 por cento) que no grupo HBeAg negativo (10,2 por cento) (p < 0,001). CONCLUSÕES: Observaram-se elevadas proporções de indivíduos com infecção pelo HBV com padrão sorológico HBeAg negativo, entre os quais houve maior risco para a transmissão vertical/intrafamiliar. O uso abusivo de álcool esteve associado a indivíduos do sexo masculino e, neste grupo, à cirrose hepática. Observou-se tendência ao aumento no número de casos HBeAg negativo ao longo do tempo.

Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon

BACKGROUND AND AIM: The durability of the sustained virologic response (SVR) in patients with chronic hepatitis C after treatment and the ideal follow-up time for these patients remains undefined. The objective of the study was to evaluate the durability of the virologic response in patients with chronic hepatitis C followed up for at least 12 months after SVR at HCFMRP-USP. METHODS: The study was conducted on 174 patients with chronic hepatitis C treated with different antiviral regimens who had achieved SVR. Qualitative serum HCV-RNA was determined by the commercial kit (COBAS AMPLICOR HCV, v2.0). RESULTS: There was predominance of male (73 percent) with a mean age of 45.6 ± 10 years. Liver cirrhosis was present in 16.1 percent of the study subjects. Mean follow-up time after SVR was 47 months (12-156 months). Twenty-two patients received monotherapy with interferon; 94 received interferon plus ribavirin, and 58 received pegylated interferon plus ribavirin. A total of 134 patients (77.0 percent) received one treatment course, 29 (16.7 percent) received two courses, and 11 (6.3 percent) received three courses. The distribution of HCV genotypes was: genotype 1 (40.2 percent), genotype 3 (40.8 percent) and genotype 2 (10.3 percent). Genotype was undetermined in 8.7 percent of cases. None of the 174 patients had recurrence of HCV infection. Two cirrhotic patients developed hepatocellular carcinoma (HCC) during follow-up. CONCLUSIONS: Among patients with SVR there was no recurrence of HCV infection or evidence of liver disease progression in any patient followed up for a mean of 47 months after SVR, except for patients with advanced hepatic disease before treatment, who may develop HCC despite SVR. Therefore, one can assume that SVR is associated with long term good prognosis.

Clinical and regulatory protocol for the treatment of jaundice in adults and elderly subjects: a support for the health care network and regulatory system / Protocolo clínico e de regulação para o tratamento de icterícia no adulto e idoso: subsídio para as redes assistenciais e o complexo regulador

PURPOSE: Clinical interventions and controlled access to the health care system can be improved by a Regulatory System (RS) and Clinical and Regulatory Protocols (CRPs). The objective of the present paper is to present the methodology used for elaborating the CRPs. METHODS: The process used to elaborate the CPRs involved a scientific co-operation between university and health care system. Workshops were held and attended by primary care practitioners, RS team, and matrix team (university specialists supporting primary care practitioners). RESULTS: The treatment of jaundice in adults and elderly subjects is amongst the themes selected for elaborating the CRPs since jaundice is a medical sign frequently seen in four clinical scenarios involving distinctive diagnostic and therapeutic interventions which can be performed in different health care settings. Evaluation guidelines as well as the clinical and regulatory procedures were established for different health care settings. The most relevant clinical and regulatory interventions were expressed as algorithms in order to facilitate the use of CRPs by health care practitioners. CONCLUSION: It is expected that the implementation of this protocol will minimise the imbalance between the icteric patients' needs and the treatment modalities being offered, thus contributing to a more co-operative health care network.

OBJETIVO: As ações clínicas e de ordenação do acesso à rede de saúde podem ser aperfeiçoadas pelo Complexo Regulador (CR) e pelos Protocolos Clínicos e de Regulação (PCR). Nesse trabalho apresenta-se a metodologia de elaboração dos PCR mediante cooperação entre universidade e sistema de saúde. MÉTODOS: O processo utilizado para a elaboração dos PCR envolve oficinas com a participação de profissionais da atenção básica, do CR e das equipes matriciais (especialistas da universidade que dão suporte às equipes de atenção básica). RESULTADOS: Dentre os temas selecionados para elaboração dos PCR, incluiu-se a icterícia no adulto e no idoso. Trata-se de um sinal clínico que comporta quatro cenários de apresentação com distintos percursos diagnósticos e terapêuticos passíveis de serem executados em diferentes pontos da rede assistencial. As diretrizes de avaliação, bem como as decisões e ações clínicas e reguladoras cabíveis para os diferentes cenários foram estabelecidas desde a atenção básica até o hospital terciário. As ações clínicas e reguladoras mais relevantes foram colocadas em algoritmo para facilitar o emprego do protocolo pelos profissionais de saúde. CONCLUSÃO: Há a expectativa que a implementação desse protocolo possa minimizar o descompasso entre as necessidades dos pacientes ictéricos e a modalidade de serviço oferecida e, assim, contribuir para a configuração de uma rede assistencial mais cooperativa.

Liver transplantation: expectation with MELD score for liver allocation in Brazil / Transplante hepático: expectativas com escore MELD para alocação de fígado no Brasil

Liver transplantation represents the most effective therapy for patients suffering from chronic end-stage liver disease. Until very recently, in Brazil, liver allocation was based on the Child-Turcotte-Pugh score and the waiting list followed a chronological criterion. In February 2002 the Model for End-stage Liver Disease (MELD) score was adopted for the allocation of donor livers in the US. After that change, an increased number of patients with more severe liver disease was observed, although there was no difference in 1-year patient and graft survival. A reduction in waiting-list mortality was also observed. In Brazil, the MELD score was adopted on May 31st, 2006. Good results are expected regarding the new criterion for allocation.

O transplante de fígado representa o tratamento mais eficiente disponível no momento para pacientes com doença hepática crônica terminal. Em fevereiro de 2002 o escore - Model for End-stage Liver Disease (MELD), o qual determina a gravidade da doença com estimativa de mortalidade em três meses, foi implantado para alocação de doadores de fígado nos Estados Unidos. Conseqüentemente foi observado um maior número de pacientes graves transplantados, com redução de mortalidade na lista de espera e não houve diferença de sobrevida em um ano de paciente e enxerto. Até recentemente no Brasil a alocação de órgãos era baseada no critério cronológico de acordo com a inclusão em lista de espera para transplante de fígado, doador cadáver. Há poucos dias (31 de maio de 2006), foi publicada a portaria que institui o critério de gravidade para alocação de fígado. Expectativas quanto aos resultados e o impacto dessa mudança na realidade brasileira são aguardados.

Hepatitis C: a challenge to hepatologists and to the liver transplantation team / Hepatite C: um desafio aos hepatologistas e à equipe de transplante de fígado

Hepatitis C is the main cause of cirrhosis and hepatocellular carcinoma and the leading indication of liver transplantation. The aim of this article was to review specific epidemiological, clinical and therapeutic aspects of hepatitis C and theirs implication for the hepatologists belonging to liver transplantation services. These specific aspects were reviewed in the literature mainly using Medline. Data regarding the epidemiological, clinical and therapeutic aspects of hepatitis C are discussed, with emphasis on their consequences for the liver transplantation team. Hepatitis C is a challenge for hepatologists and for the liver transplantation team. The burden we observe today is the late consequence of infection that occurred in the past. Measures for early recognition of complications of liver disease are recommended. HCV treatment should always be performed before liver transplantation if possible, but if not, HCV recurrence should be recognized and treated early after transplantation.

O objetivo deste artigo foi revisar aspectos epidemiológicos, clínicos e terapêuticos da hepatite C e suas implicações para a equipe de transplante de fígado. Esses aspectos específicos foram revisados na literatura usando principalmente o Medline.Dados relativos a aspectos epidemiológicos, clínicos e terapêuticos da hepatite C foram discutidos com ênfase nas suas conseqüências para a equipe de transplante de fígado. A hepatite C é um desafio para hepatologistas e para a equipe de transplante de fígado. A epidemia que observamos atualmente é a conseqüência tardia da infecção que ocorreu no passado. São recomendadas medidas para o reconhecimento precoce das complicações da infecção. Recomenda-se que o tratamento da hepatite C deve ser feito sempre que possível e de preferência, antes do transplante, mas se isso não for possível, esforços devem ser feitos para o reconhecimento precoce da reinfecção e instituição do tratamento.

Impact of blood salvage during liver transplantation on reduction in transfusion requirements / Impacto do uso do cell saver na redução de transfusão sanguínea durante o transplante de fígado

PURPOSE: The aim of this study was to analyse the changes in transfusion requirements, in patients submitted to orthotopic liver transpantation from cadaveric donors, with the use of intraoperative red blood cell salvage (Cell Saver). METHODS: Data from 41 transplants were analysed. Intraoperative blood loss was calculated from the cell salvage, suction and the swabs. The autologous and heterologous transfusions were recorded The red blood salvage was performed using the Cell Saver 5 System (Haemonetics).. For analysis the patients were divided in two groups: one that used the Cell Saver and another that didn't. RESULTS: The median age of the patients was 50 years and the main indication for liver transplantation was cirrhosis (35 cases - 85.3 percent). The median blood loss was 8362 + 3994 ml (with the Cell Saver) and 10824 + 7002 ml (without the Cell Saver) and the median transfusion of heterologous packed red blood cells was 9,6 + 8 units (with the Cell Saver) compared to 22,3 + 21 units (without the Cell Saver). CONCLUSIONS: The Cells Saver has the potential to reduce the need for heterologous blood transfusion reducing the risks of transmissible diseases.

OBJETIVO: O objetivo desse estudo foi analisar as mundanças na quantidade de transfusão necessária com uso do Intraoperative red blood cell salvage (Cell saver), em pacientes submetidos a transplante ortotópico de fígado, doador cadáver. MÉTODOS: Foram avaliados dados de 41 pacientes submetidos a transplante de fígado. O sangramento foi calculado de acordo com débito do aspirador, compressas e captação do Cell saver. A reposição necessária foi avaliada de acordo com a quantidade de transfusão heteróloga e autóloga. Para análise dos dados os pacientes foram dividos em dois grupos: com e sem uso de Cell saver. RESULTADOS: A mediana de idade foi 50 anos e principal indicação de transplante foi cirrose hepática com 35 casos (85,3 por cento). A mediana de sangramento durante o procedimento cirúrgico 8362 + 3994 ml (com cell saver) e 10824 + 7002 ml (sem cell saver) e a mediana de transfusão de concentrado de hemácias heterólogo, durante o período de internação hospitalar 9,6 + 8 unidades (com cell saver) compar 22,3 + 21 unidades (sem cell saver). CONCLUSÃO: Uso de Cell Saver tem um potential para reduzir a quantidade de transfusão heteróloga, dimuindo o risco de transmissão de doenças.