Risk factors for cancer in patients with primary biliary cholangitis and autoimmune hepatitis and primary biliary cholangitis overlap syndrome.

INTRODUCTION AND OBJECTIVES: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC. MATERIALS AND METHODS: The Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer. RESULTS: Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p≤0.001), smoking (55% vs. 12.3%, p≤0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p= <0.001), AMA positivity (96.6% vs 80.1%, p≤0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk. CONCLUSIONS: The prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC.

Choosing wisely recommendations regarding the top five list of procedures to avoid in the treatment of viral hepatitis: A position statement from the Brazilian Society of Hepatology endorsed by the Latin American Association for the Study of the liver.

INTRODUCTION AND OBJECTIVES: The Choosing Wisely (CW) initiative aims to improve daily practice supported by evidence concerning unnecessary medical tests, procedures, and treatments. This philosophy is essential in managing viral hepatitis (VH), which primary care physicians increasingly carry out. It is also essential to achieving disease elimination. Thus, the aim of our study was to propose evidence-based CW recommendations in VH. MATERIALS AND METHODS: The Brazilian Society of Hepatology (SBH) formed a panel of experts in VH who selected evidence-based CW recommendations, which were subsequently scrutinized and ranked by all members of SBH using a web-based approach. RESULTS: Five recommendations were chosen in order of importance: 1) do not order anti-HCV testing after achieving sustained virological response; 2) do not request serial HCV viral load to evaluate HCV progression, 3) do not add ribavirin to direct-acting antivirals in non-cirrhotic, naïve HCV patients; 4) do not screen for hepatocellular carcinoma in HCV patients with none to moderate fibrosis (≤ F2); 5) do not request anti-HBs after HBV vaccination, except for children born to HBV-infected mothers, hemodialysis patients, healthcare professionals, people who have had sexual contact with chronic HBV carriers, HIV-positive persons and immunocompromised individuals (hematopoietic stem-cell transplant recipients or persons receiving chemotherapy). CONCLUSIONS: CW recommendations may help general practitioners adopt a more rational and cost-effective approach in managing patients with VH in Brazil and Latin America, leading to lesser waste or harm to patients.

Transferrin saturation as a surrogate marker for assessment of labile nontransferrin bound iron in chronic liver disease.

BACKGROUND: Increased transferrin saturation (TS) and ferritin are common in hereditary hemochromatosis (HH) but also in chronic liver diseases (CLD). Nontransferrin bound iron (NTBI) is believed to be associated with iron-induced cell damage. We aimed to evaluate NTBI in CLD and their relationship with liver damage. METHODS: Two groups of patients were studied. Group 1 (G1): 94 CLD patients from an Outpatient Hepatology Unit. Group 2 (G2): 36 healthy individuals form a Medical Checkup Clinic. Transferrin iron-binding capacity, TS, ferritin, AST, ALT, and red cell count were performed using standard tests. NTBI was assessed as enhanced labile plasma iron (eLPi). Levels of eLPi less than 0.4 µmol/l were considered within the normal range. RESULTS: Prevalence of increased iron tests (elevated TS and ferritin) was 14% in G1 and 5.5% in G2 ( P = 0.19). Positive NTBI was found in 12 patients (11 in G1 and 1 in G2). Positivity to NTBI was associated with increased iron tests ( P = 0.03), cirrhosis ( P = 0.03) and AST index (ASTI) ( P = 0.03). NTBI was associated with TS of more than 70% ( P = 0.002) but not to elevated ferritin ( P = 0.74). Variables strongly associated with a positive NTBI in univariate analysis (TS > 70%, cirrhosis and ASTI) were submitted to binary regression analysis. TS of more than 70% was the only independent predictive factor ( P = 0.049; odds ratio, 6.8). CONCLUSION: NTBI was associated with TS in CLD, but not with ferritin. NTBI testing could be useful for CLD patients with increased iron tests. Alternatively, a TS of more than 70% can be used as a surrogate marker.

Brazilian registry for the elimination of hepatitis C in dialysis units: a call to action for Nephrology / Registro brasileiro para eliminação da hepatite C nas unidades de diálise: um chamado para a Nefrologia

Abstract Infection by the hepatitis C virus is more prevalent in patients on dialysis than in the general population in Brazil, and has been associated with worse outcomes. Current therapy for hepatitis C is highly effective, safe, and widely available in Brazil, with coverage provided to dialysis patients with chronic kidney disease, which makes the elimination of hepatitis C a viable target. The Brazilian Society of Nephrology, the Brazilian Society of Hepatology, and the Brazilian Liver Institute developed the "Brazilian Registry for the Elimination of Hepatitis C in Dialysis Units". This project aims to identify, treat, and monitor the response to treatment of patients on chronic dialysis infected with the hepatitis C virus in Brazil. This article presents the issue and invites Brazilian nephrologists to rally around the achievement of a significant goal.

Resumo A infecção pelo vírus da hepatite C é mais prevalente em pacientes em diálise do que na população geral no Brasil e implica um pior prognóstico. O tratamento atual para hepatite C é altamente eficaz, seguro e disponível no país, inclusive para a população de pacientes crônicos em diálise, o que torna a eliminação do vírus da hepatite C uma meta viável. A Sociedade Brasileira de Nefrologia, a Sociedade Brasileira de Hepatologia e o Instituto Brasileiro do Fígado desenvolveram o "Registro Brasileiro para Eliminação da Hepatite C nas Unidades de Diálise". O projeto visa identificar pacientes em diálise crônica com vírus da hepatite C no Brasil, além de tratar e monitorar a resposta virológica após o tratamento. Este breve artigo apresenta o problema e convida os nefrologistas brasileiros a unirem forças nesse objetivo comum.

Alterações hepáticas em transplantados renais do maior centro de transplante do Brasil / Hepatic alterations in kidney transplant recipients from the largest kidney transplant center in brazil

ABSTRACT Background Kidney transplant is the treatment of choice for patients with end-stage renal disease and is associated with lower mortality when compared to dialysis methods. Brazil is the country with the second largest number of kidney transplants in the world and among these patients it has been observed that liver abnormalities are common. The frequency of liver abnormalities ranges from 20-50% post-transplantation, and have an important impact on the survival and quality of life of these patients. There are scarce data about the frequency, causes and characteristics of these alterations. Objective To determine the prevalence of the different causes of hepatic abnormalities in kidney transplant recipients, to associate the characteristics of these abnormalities with demographic, epidemiological and clinical variables, to compare the characteristics of hepatic alterations between different etiologies, and to evaluate possible changes in diagnosis over two different periods of time. Methods Descriptive, cross-sectional observational, epidemiological study was conducted at the outpatient "Hepato-Rim"clinic of Hospital São Paulo (EPM/UNIFESP), a center providing specialized care for patients with hepatic abnormalities and underlying kidney diseases. Results Five-hundred eighty-one transplant patients were evaluated. The most prevalent etiologies of liver abnormalities were hepatitis C and B, iron overload, nonalcoholic fatty liver disease (NAFLD), and drug-induced liver injury (DILI). The most common cause — hepatitis C — was analyzed in greater detail. Compared to the other causes, this infection was more frequent in older patients, female patients, and patients with a longer time since transplantation and hemodialysis. Analysis of the two periods showed that patients of period 1 (P1 — 1993 to 2005) were older and were more frequently referred because of positive serology; referral due to aminotransferases abnormalities predominated during period 2 (P2 — 2006 to 2018). The predominant diagnoses were hepatitis C and B during P1 and NAFLD and DILI during P2. Conclusion Assessment of the main hepatic alterations in kidney transplant recipients is important because it permits better management of these patients in terms of diagnostic investigation and treatment and contributes to the prevention of complications in this special population.

RESUMO Contexto O transplante renal é o tratamento de escolha para pacientes com doença renal terminal e está associado a menor mortalidade quando comparado aos métodos dialíticos. O Brasil é o país com o segundo maior número de transplantes renais do mundo e, entre esses pacientes, observa-se que as alterações hepáticas são comuns. A frequência das alterações hepáticas varia de 20 a 50% pós-transplante e tem importante impacto na sobrevida e qualidade de vida desses pacientes. Existem poucos dados sobre a frequência, causas e características dessas alterações. Objetivo Determinar a prevalência das diferentes causas de anormalidades hepáticas em receptores de transplante renal, associar as características dessas anormalidades a variáveis demográficas, epidemiológicas e clínicas, comparar as características das alterações hepáticas entre diferentes etiologias e avaliar possíveis alterações no diagnóstico em dois períodos diferentes de tempo. Métodos Estudo epidemiológico descritivo, transversal, observacional, realizado no ambulatório "Hepato-Rim" do Hospital São Paulo (EPM/UNIFESP), centro de atendimento especializado a pacientes com anormalidades hepáticas e doenças renais de base. Resultados Quinhentos e oitenta e um pacientes transplantados foram avaliados. As etiologias mais prevalentes de anormalidades hepáticas foram hepatite C e B, sobrecarga de ferro, doença hepática gordurosa não alcoólica e lesão hepática induzida por drogas. A causa mais comum — hepatite C — foi analisada em maiores detalhes. Em comparação com as outras causas, essa infecção foi a mais frequente em pacientes mais velhos, pacientes do sexo feminino e pacientes com mais tempo de transplante e hemodiálise. A análise dos dois períodos mostrou que os pacientes do período 1 (P1 — 1993 a 2005) eram mais velhos e encaminhados com maior frequência devido à sorologia positiva; encaminhamento devido a anormalidades de aminotransferases predominou durante o período 2 (P2 — 2006 a 2018). Os diagnósticos predominantes foram hepatite C e B durante P1 e doença hepática gordurosa não alcoólica e lesão hepática induzida por drogas durante P2. Conclusão A avaliação das principais alterações hepáticas em receptores de transplante renal é importante, pois permite melhor manejo desses pacientes na investigação diagnóstica e no tratamento e contribui para a prevenção de complicações nesta população especial.

National Brazilian survey on the outcomes of hepatitis c retreatment in patients non-responders to direct antiviral agents

ABSTRACT Background and aims: Treatment of hepatitis C with direct antiviral agents (DAA) is associated with almost 95% of sustained virological response. However, some patients need retreatment. In Brazil, it should be done according to the Ministry of Health guidelines, frequently updated to include newly available drugs. This study aimed to conduct a national survey about the characteristics and outcomes of retreatment of hepatitis C in previously non-responders to DAAs. Patients and methods: Institutions from all over the country were invited to participate in a national registry for retreatment, including information about clinical and epidemiological characteristics of the patients, type and outcomes of retreatment regimens. Only patients previously treated with interferon-free regimens were included. Results: As previous treatments the distribution was: SOF/DCV (56%), SOF/SIM (22%), 3D (11%), SOF/LED (6%) and SOF/RBV (5%). For retreatment the most frequently used drugs were SOF/GP (46%), SOF/DCV (23%) and SOF/VEL (11%). From 159 patients retreated, 132/159 (83%) had complete information in the registry and among them only seven patients were non-responders (SVR of 94.6%). All retreatments were well tolerated, without any serious adverse events or interruptions. Conclusion: The retreatment of patients previously non-responders to DAAs was associated with high rate of SVR in this sample of Brazilian patients. This finding allows us to conclude that the retreatment options available in the public health system in Brazil are effective and safe and are an important component of the strategy of elimination of hepatitis C in our country.

Screening for hepatitis C in urgent and emergency units: a systematic review. / Triagem para hepatite C em unidades de urgência e emergência: revisão sistemática.

OBJECTIVE: Identifying studies that performed screening for hepatitis C and that also assessed the virus prevalence in urgency and emergency unit users. METHOD: A systematic review performed on the LILACS, MEDLINE databases via PubMed, SciELO and Virtual Health Library. RESULTS: After careful search and analysis, 19 publications were part of the results, in compliance with the pre-defined criteria. Publication dates were concentrated between 1992 and 2018. The main journal to publish such articles was the Annals of Emergency Medicine (26.31%). Regarding the origin of publications, the following stand out: United States (63.15%), Europe (31.57%), and Asia (5.28%). Regarding prevalence, in the United States, a variation between 1.4% to 18% was observed. In Europe, in turn, the prevalence ranged from 0 to 5%. In the Asian study, the prevalence was 1.8%. CONCLUSION: The screening performed in urgent and emergency units proved to be efficient in identifying new cases, especially when associated with the age factor, which proves to be superior to the strategy based only on risk factors. Thus, for greater effectiveness, the association of three strategies is recommended: screening location, age group, and risk factors.

Tratamento da hepatite C em pacientes com doença renal crônica e pós-tranplante renal: eficácia e segurança dos esquemas de antivirais de ação direta contendo sofosbuvir / Hepatitis c treatment of renal transplant and chronic kidney disease patients: efficacy and safety of direct-acting antiviral regimens containing sofosbuvir

ABSTRACT BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.

RESUMO CONTEXTO: Os antivirais de ação direta revolucionaram o tratamento da hepatite C, inclusive para os pacientes com doença renal crônica (DRC), porém ainda há divergências no emprego do sofosbuvir (SOF) quando taxa de filtração glomerular (TFG) <30 mL/min. OBJETIVO: Avaliar a eficácia e segurança desses esquemas no tratamento da hepatite C em pacientes com DRC e pós-transplante renal, além de avaliar o impacto do SOF sobre a função renal dos não-dialíticos. MÉTODOS: Todos os pacientes com hepatite C e DRC ou transplante renal que realizaram tratamento com antivirais de ação direta em centro referenciado do Brasil no período de janeiro/2016 a agosto/2017 foram incluídos. A eficácia foi avaliada por meio da carga viral (HCV-RNA), considerando-se cura uma resposta virológica sustentada (RVS) com resultado indetectável após 12 e/ou 24 semanas do término do tratamento (RVS12 e RVS24). A segurança foi determinada pelos eventos adversos e a ribavirina, quando associada, foi introduzida de forma escalonada em todos os pacientes com TFG <60 mL/min. Para determinação do impacto do SOF sobre a função renal, foram observadas as dosagens de creatinina basal, durante e após término do tratamento com seu incremento avaliado por meio da classificação de AKIN (acute kidney injury network). RESULTADOS: Foram incluídos 241 pacientes, sendo 52,7% do sexo feminino, com média de idade de 60,72±10,47 anos. A associação de SOF+daclatasvir predominou em 75,6% dos casos e anemia esteve presente em 28% dos pacientes que utilizaram ribavirina (P=0,040). As taxas de RVS12 e RVS24 foram de 99,3% e 97,1%. O tratamento foi bem tolerado, com eventos adversos pouco relevantes, sendo os mais prevalentes: astenia (57,7%), prurido (41,1%), cefaleia (40,7%) e irritabilidade (40,2%). Entre os pacientes em tratamento conservador e transplantados renais, os valores de creatinina sofreram oscilações AKIN I em 12,5% dos casos, durante o tratamento, persistindo em apenas 8,5% da amostra após o término, dos quais 2,0% apresentavam TFG <30 mL/min inicialmente, com queda para 1,1% após uso do SOF. Apenas 0,5% e 1,6% evoluíram com elevação AKIN II e AKIN III. CONCLUSÃO: Os antivirais de ação direta foram seguros e eficazes em pacientes com DRC tratados com esquemas contendo SOF, apresentando altas taxas de RVS, boa tolerabilidade e poucos eventos adversos graves. A associação com ribavirina aumentou o risco de anemia, portanto sua introdução de forma escalonada parece ser útil nos pacientes com TFG <60 mL/min. Em pacientes com TFG <30 mL/min o SOF não apresentou impacto renal significativo, com creatinina sérica retornando a valores próximos ao basal após o tratamento.

Triagem para hepatite C em unidades de urgência e emergência: revisão sistemática / Tamizaje de la hepatitis C en unidades de urgencia y emergencia: revisión sistemática / Screening for hepatitis C in urgent and emergency units: a systematic review

RESUMO Objetivo Identificar estudos que realizaram rastreio para hepatite C e que também avaliaram a prevalência do vírus em usuários de unidades de urgência e emergência. Método Revisão sistemática realizada nas bases de dados LILACS, MEDLINE via PubMed, SciELO e Biblioteca Virtual em Saúde. Resultados Após criteriosa busca e análise, fizeram parte dos resultados 19 publicações, essas em conformidades com os critérios pré-definidos. As datas de publicação se concentraram entre 1992 e 2018. A principal revista a publicar tais artigos foi a Annals of Emergency Medicine (26,31%). Em relação à origem das publicações, destacam-se: Estados Unidos (63,15%), Europa (31,57%) e Ásia (5,28%). Em relação à prevalência, nos Estados Unidos, se observou uma variação entre 1,4% e 18%. Por sua vez, na Europa, a prevalência variou de 0 a 5%. No estudo asiático, a prevalência foi de 1,8%. Conclusão O rastreio realizado em unidades de urgência e emergência se mostrou eficiente na identificação de novos casos, especialmente quando associado ao fator idade, que demonstra ser superior à estratégia baseada apenas em fatores de risco. Assim, para maior efetividade, recomenda-se a associação das três estratégias: local do rastreio, faixa etária e fatores de risco.

RESUMEN Objetivo Identificar los estudios que realizaron pruebas de detección de hepatitis C y que también evaluaron la prevalencia del vírus en usuarios de unidades de urgencia y emergencia. Método revisión sistemática realizada en bases de datos LILACS, MEDLINE a través de PubMed, SciELO y la Biblioteca Virtual en Salud. Resultados Después de una cuidadosa búsqueda y análisis, 19 publicaciones fueron parte de los resultados, estos cumplieron con los criterios predefinidos. Las fechas de publicación se concentraron entre 1992 y 2018. La revista principal para publicar dichos artículos fue el Annals of Emergency Medicine (26,31%). En cuanto al origen de las publicaciones, destacan las siguientes: Estados Unidos (63,15%), Europa (31,57%) y Asia (5,28%). Con respecto a la prevalencia, en los Estados Unidos, se observó una variación entre 1.4% y 18%. En Europa, a su vez, la prevalencia varió de 0 a 5%. En el estudio asiático, la prevalencia fue de 1,8%. Conclusión La evaluación realizada en las unidades de urgencias y emergencias demostró ser eficiente en la identificación de nuevos casos, especialmente cuando se asocia con el factor de edad, que demuestra ser superior a la estrategia basada solo en factores de riesgo. Por lo tanto, para una mayor efectividad, se recomienda la asociación de las tres estrategias: ubicación del examen, grupo de edad y factores de riesgo.

ABSTRACT Objective Identifying studies that performed screening for hepatitis C and that also assessed the virus prevalence in urgency and emergency unit users. Method A systematic review performed on the LILACS, MEDLINE databases via PubMed, SciELO and Virtual Health Library. Results After careful search and analysis, 19 publications were part of the results, in compliance with the pre-defined criteria. Publication dates were concentrated between 1992 and 2018. The main journal to publish such articles was the Annals of Emergency Medicine (26.31%). Regarding the origin of publications, the following stand out: United States (63.15%), Europe (31.57%), and Asia (5.28%). Regarding prevalence, in the United States, a variation between 1.4% to 18% was observed. In Europe, in turn, the prevalence ranged from 0 to 5%. In the Asian study, the prevalence was 1.8%. Conclusion The screening performed in urgent and emergency units proved to be efficient in identifying new cases, especially when associated with the age factor, which proves to be superior to the strategy based only on risk factors. Thus, for greater effectiveness, the association of three strategies is recommended: screening location, age group, and risk factors.

Hepatitis C in Hemodialysis Units: diagnosis and therapeutic approach / Hepatite C nas Unidades de Hemodiálise: diagnóstico e abordagem terapêutica

Abstract According to data from the last census of the Brazilian Society of Nephrology (SBN), the prevalence of hepatitis C virus (HCV) in Brazilian hemodialysis units (HU) is 3.3%, about three times higher than what is reported for the Brazilian general population. Often, professionals working in HU are faced with clinical situations that require rapid HCV diagnosis in order to avoid horizontal transmission within the units. On the other hand, thanks to the development of new antiviral drugs, the cure of patients with HCV, both in the general population and in patients with chronic kidney disease and the disease eradication, appear to be very feasible objectives to be achieved in the near future . In this scenario, SBN and the Brazilian Society of Hepatology present in this review article a proposal to approach HCV within HUs.

Resumo De acordo com os dados do último censo da Sociedade Brasileira de Nefrologia (SBN), a prevalência de portadores do vírus da hepatite C (HCV) nas unidades de hemodiálise (UH) no Brasil é de 3,3%, cerca de três vezes maior do que é observado na população geral brasileira. Muitas vezes, os profissionais que trabalham nas UH deparam-se com situações clínicas que demandam rápido diagnóstico do HCV, a fim de evitar uma transmissão horizontal dentro das unidades. Por outro lado, a cura dos pacientes portadores do HCV, tanto na população geral como na portadora de doença renal crônica e a erradicação da doença, em virtude do desenvolvimento de novas drogas antivirais, parecem ser objetivos bastante factíveis, a ser alcançados em futuro próximo. Nesse cenário, a SBN e a Sociedade Brasileira de Hepatologia apresentam neste artigo de revisão uma proposta de abordagem do HCV dentro das UH.

Pruritus in cholestasis / Prurido na colestase

Pruritus represents one of the main clinical complaints in medical practice, and leads to significant impairment of life quality and some discomfort. Although the knowledge of its main primary and secondary etiologies is well-established in Internal Medicine, especially in Hepatology, its pathophysiological basis and specific therapeutic-directed approaches are still very complex and need a proper systematization for comprehension. This review aims to present the main current themes regarding the main clinical, pathophysiological, therapeutical and management aspects of cholestasis-associated pruritus. METHODS: The authors performed a wide review of practical clinical guidelines, review articles and original articles from manuscripts published and indexed in PubMed. CONCLUSIONS: Pruritus in cholestasis represents a complex symptom in clinical practice and can be secondary to different pathophysiological mechanisms; its early recognition allows a proper therapeutic approach in most cases.

O prurido representa uma das principais queixas clínicas na prática médica e origina importante comprometimento da qualidade de vida, além de desconforto. Apesar de suas principais etiologias primárias e secundárias serem de conhecimento bem estabelecido na Clínica Médica, em especial na Hepatologia, suas bases fisiopatológicas e os princípios da terapêutica específica direcionada são bastante complexos e necessitam uma sistematização adequada para sua compreensão apropriada. Esta revisão objetiva abordar os principais temas atuais referentes às bases clínicas, fisiopatológicas, terapêuticas e de manejo do prurido relacionados à colestase. Os autores realizaram ampla revisão em diretrizes clínicas práticas, artigos de revisão e publicações originais de artigos publicados e indexados na base PubMed. O prurido na colestase representa um sintoma complexo na prática clínica e pode decorrer de diferentes mecanismos fisiopatológicos secundários. Seu reconhecimento precoce possibilita a abordagem terapêutica apropriada na maioria dos casos.

Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies.

Some HCV patients using ribavirin and interferon alpha (IFN-α) develop anti-rods and rings (RR) autoantibodies, the main target of which is inosine monophosphate dehydrogenase (IMPDH), the rate-determining enzyme in de novo GTP biosynthesis. In vitro inhibition of IMPDH by ribavirin induces RR formation. Here we investigate whether other commonly used drugs that interfere with GTP biosynthesis can induce RR structures in vitro and vivo and elicit generation of autoantibodies. HEp-2 cells treated for 24h with ribavirin, mycophenolic acid (MPA), azathioprine, methotrexate or acyclovir were positive for RR structures. However, adefovir, entecavir, tenofovir and lamivudine did not induce RR structures in these cells. Structures induced by ribavirin in HEp-2 cells are stable after 24h drug-washout, while structures induced by other drugs are relatively labile, disappearing within 2h. Looking at patients treated with these drugs, HCV patients treated with ribavirin (n=17) showed higher average percentage of RR-positive peripheral mononuclear cells than autoimmune patients treated with RR-inducing immunosuppressant drugs (n=21). Serum from 173 autoimmune patients who had been treated with MPA, azathioprine or methotrexate was tested for presence of anti-RR autoantibodies, and only one sample was found to be positive. Conversely, of 48 anti-RR autoantibody positive samples identified at Fleury Laboratories over 30months, 94% were from HCV patients treated with ribavirin plus IFN-α. These data indicate that RR structures can be induced by a variety of drugs in vitro and in vivo, but anti-RR autoantibody production is mostly restricted to HCV patients under ribavirin+IFN-α treatment.

Hematological and dermatological adverse events during hepatitis C treatment with peg-interferon and ribavirin / Eventos adversos hematológicos e dermatológicos durante o tratamento da hepatite C com interferon peguilado e ribavirina

Objective: To evaluate frequency and impact of adverse events, mainly the hematological and dermatological ones, on sustained virological response, and compliance to hepatitis C treatment. Methods: Patients were treated according to the guidelines of the Brazilian Ministry of Health. Variables associated with hematological and dermatological adverse events were: age, gender, stage of fibrosis, type of Pegylated interferon, dose reductions, temporary discontinuation and early interruption of treatment. Results: Two hundred and twenty two patients were studied (58% females; age 49±11 years). Dose reductions, temporary interruptions, and early discontinuations were observed in 21%, 8% and 9.5% of patients, respectively. The main adverse events were hematological (anemia, neutropenia and thrombocytopenia) and dermatological (pruritus and alopecia). Anemia (Hemoglobin <10g/dL) was associated with female gender (p<0.001), advanced fibrosis (p=0.047) and dose reductions (p<0.001); neutropenia with advanced fibrosis (p=0.003) and temporary discontinuation (p=0.002); thrombocytopenia with advanced fibrosis (p<0.001) and pegylated interferon α2a (p=0.05). Pruritus and alopecia were associated to female gender (p=0.008 and p=0.02) and treatment interruption (p=0.029 and p=0.02).Conclusion: Hematological and dermatological adverse events are frequent in hepatitis C patients treated with pegylated interferon and ribavirin. However, despite frequent dose reductions and interruptions, these adverse events did not affect the sustained virological response.

Objetivo: Avaliar a frequência e o impacto de eventos adversos, principalmente hematológicos e dermatológicos, na resposta virológica sustentada e na aderência ao tratamento para hepatite C. Métodos: Os pacientes foram tratados de acordo com diretriz do Ministério da Saúde. Variáveis associadas com eventos adversos hematológicos e dermatológicos foram: idade, sexo, grau de fibrose, tipo de interferon peguilado, reduções de dose, descontinuação temporária e interrupção precoce do tratamento. Resultados: Foram estudados 232 pacientes (58% mulheres; idade 49±11 anos). Reduções de dose, interrupções temporárias e descontinuações precoces foram observadas em 21%, 8% e 9,5% dos pacientes, respectivamente. Os principais eventos adversos foram hematológicos (anemia, neutropenia e plaquetopenia) e dermatológicos (prurido e alopecia). Anemia (hemoglobina <10g/dL) se associou a sexo feminino (p<0,001), fibrose avançada (p=0,047) e reduções de doses (p<0,001); neutropenia com fibrose avançada (p=0,003) e interrupção temporária (p=0,002); plaquetopenia com fibrose avançada (p<0,001) e interferon peguilado α2a (p=0,05). Prurido e alopecia se associaram ao sexo feminino (p=0,008 e p=0,02) e interrupção do tratamento (p=0,029 e p=0,02). Conclusão: Eventos adversos hematológicos e dermatológicos foram frequentes em pacientes tratados com interferon peguilado e ribavirina. Entretanto, a despeito de frequentes reduções de dose e interrupções, estes eventos adversos não afetaram a resposta virológica sustentada.

Reativação de leishmaniose durante tratamento de hepatite b crônica com alfainterferona 2b / Leishmaniasis reactivation during treatment of chronic hepatitis B with interferon alpha 2b - case report

Descreve-se aqui um caso de reativação de leishmaniose cutaneomucosa durante o tratamento com alfainterferona 2b (IFN) para hepatite B crônica (HBV). Relato do caso: Paciente masculino, 52 anos, natural da Bahia, procedente de São Paulo onde vivia há 30 anos, encaminhado por HBV. Na história epidemiológica, referiu-se a uma viagem há cinco anos para Porto Seguro-BA, sem apresentar outros fatores de risco. No exame físico para admissão, não havia evidências de doença hepática crônica. Sorologias pré-tratamento: HBsAg e HBeAg positivos, biópsia A0F0 (Metavir). Foi submetido a tratamento com IFN 5 milhões de UI/dia por 24 semanas. No final, apresentava-se HBV DNA detectável, sem soroconversão de HBeAg, porém evoluiu no quarto mês de tratamento com perda ponderal de 10 kg, astenia, sinais e sintomas de sinusite sem melhora clínica após antibioticoterapia. Foi encaminhado para a otorrinolaringologia com rouquidão persistente, destruição de septo nasal, com áreas de crostas, necrose local, alargamento nasal e lesão em palato mole, cuja biópsia mostrou processo inflamatório granulomatoso com necrose caseosa, sugestivo de leishmaniose. Sorologia para leishmaniose IgG 1/80 (IFI) e intradermorreação de Montenegro de 30 mm. Indicado antimoniato de meglumina IV por 30 dias, obteve melhora da rouquidão e das lesões de palato. Conclusão: O quadro clínico sugere reativação da leishmaniose induzida pelo IFN. Acredita-se que este seja o primeiro relato na literatura de reativação de leishmaniose muco-cutânea por uso de IFN, semelhantemente ao que ocorre com a tuberculose. Screening para leishmaniose deve ser realizado em paciente de região endêmica no pré-tratamento com IFN diante da possibilidade de reativação de infecção latente

Clinical and epidemiological profile of female blood donors with positive serology for viral hepatitis B

ABSTRACTINTRODUCTION:Since women are frequently the minority among blood donors worldwide, studies evaluating this population usually reflect male features. We assessed the features of female blood donors with positive serology for HBV and compared them with those of men.METHODS The study comprised consecutive blood donors referred to a specialized liver disease center to be evaluated due to HBsAg- and/or anti-HBc-positive tests.RESULTS: The study encompassed 1,273 individuals, 219 (17.2%) of whom were referred due to positive HBsAg test and 1,054 (82.8%) due to reactive anti-HBc test. Subjects' mean age was 36.8±10.9 years, and 28.7% were women. Female blood donors referred for positive HBsAg screening tests demonstrated higher prevalence of healthcare workers (9.3% vs 2.5%) and lower prevalence of sexual risk behaviors (15.1% vs 41.1%) and alcohol abuse (1.9% vs 19.8%) compared to men. Women had lower ALT (0.6 vs 0.8×ULN), AST (0.6 vs 0.8×ULN), direct bilirubin (0.2 vs 0.3mg/dL), and alkaline phosphatase (0.5 vs 0.6×ULN) levels and higher platelet count (223,380±50,293 vs 195,020±53,060/mm3). Women also had a higher prevalence of false-positive results (29.6% vs 17.0%). No differences were observed with respect to liver biopsies. Female blood donors referenced for reactive anti-HBc screening tests presented similar clinical, epidemiological, and biochemical characteristics to those reported for positive HBsAg screening tests and similarly had a higher prevalence of false-reactive results.CONCLUSIONS: Compared to men, female blood donors with positive HBsAg and/or anti-HBc screening tests demonstrated higher prevalence of professional risk and false-positive results and reduced alteration of liver chemistry.

Disease burden of chronic hepatitis C in Brazil

Background: Hepatitis C virus infection is a major cause of cirrhosis; hepatocellular carcinoma; and liver transplantation. The aim of this study was to estimate hepatitis C virus disease progression and the burden of disease from a nationwide perspective.Methods: Using a model developed to forecast hepatitis C virus disease progression and the number of cases at each stage of liver disease; hepatitis C virus-infected population and associated disease progression in Brazil were quantified. The impact of two different strategies was compared: higher sustained virological response and treatment eligibility rates (1) or higher diagnosis and treatment rates associated with increased sustained virological response rates (2).Results: The number of infected individuals is estimated to decline by 35% by 2030 (1,255,000 individuals); while the number of cases of compensated (n= 325,900) and decompen- sated (n= 45,000) cirrhosis; hepatocellular carcinoma (n= 19,100); and liver-related deaths (n= 16,700) is supposed to peak between 2028 and 2032. In strategy 2; treated cases increased over tenfold in 2020 (118,800 treated) as compared to 2013 (11,740 treated); with sustained virological response increased to 90% and treatment eligibility to 95%. Under this strategy; the number of infected individuals decreased by 90% between 2013 and 2030. Compared to the base case; liver-related deaths decreased by 70% by 2030; while hepatitis C virus-related liver cancer and decompensated cirrhosis decreased by 75 and 80%; respectively.Conclusions: While the incidence and prevalence of hepatitis C virus in Brazil are decreasing; cases of advanced liver disease continue to rise. Besides higher sustained virological response rates; new strategies focused on increasing the proportion of diagnosed patients and eligibility to treatment should be adopted in order to reduce the burden of hepatitis C virus infection in Brazil.

Disease burden of chronic hepatitis C in Brazil.

BACKGROUND: Hepatitis C virus infection is a major cause of cirrhosis; hepatocellular carcinoma; and liver transplantation. The aim of this study was to estimate hepatitis C virus disease progression and the burden of disease from a nationwide perspective. METHODS: Using a model developed to forecast hepatitis C virus disease progression and the number of cases at each stage of liver disease; hepatitis C virus-infected population and associated disease progression in Brazil were quantified. The impact of two different strategies was compared: higher sustained virological response and treatment eligibility rates (1) or higher diagnosis and treatment rates associated with increased sustained virological response rates (2). RESULTS: The number of infected individuals is estimated to decline by 35% by 2030 (1,255,000 individuals); while the number of cases of compensated (n=325,900) and decompensated (n=45,000) cirrhosis; hepatocellular carcinoma (n=19,100); and liver-related deaths (n=16,700) is supposed to peak between 2028 and 2032. In strategy 2; treated cases increased over tenfold in 2020 (118,800 treated) as compared to 2013 (11,740 treated); with sustained virological response increased to 90% and treatment eligibility to 95%. Under this strategy; the number of infected individuals decreased by 90% between 2013 and 2030. Compared to the base case; liver-related deaths decreased by 70% by 2030; while hepatitis C virus-related liver cancer and decompensated cirrhosis decreased by 75 and 80%; respectively. CONCLUSIONS: While the incidence and prevalence of hepatitis C virus in Brazil are decreasing; cases of advanced liver disease continue to rise. Besides higher sustained virological response rates; new strategies focused on increasing the proportion of diagnosed patients and eligibility to treatment should be adopted in order to reduce the burden of hepatitis C virus infection in Brazil.

Acute exacerbation of chronic hepatitis B virus infection in renal transplant patients

Introduction: There is scarce information regarding clinical evolution of HBV infection in renal transplant patients. Aims: To evaluate the prevalence of acute exacerbation in HBV-infected renal transplant patients and its association with the time after transplantation, presence of viral replication, clinical evolution, and use of antiviral prophylaxis. Materials and methods: HBV infected renal transplant patients who underwent regular follow-up visits at 6-month intervals were included in the study. The criteria adopted to characterize exacerbation were: ALT >5 × ULN and/or >3 × baseline level. Predictive factors of exacerbation evaluated were age, gender, time on dialysis, type of donor, post-transplant time, ALT, HBeAg, HBV-DNA, HCV-RNA, immunosuppressive therapy, and use of antiviral prophylaxis. Results: 140 HBV-infected renal transplant patients were included (71% males; age 46 ±10 years; post-renal transplant time 8 ±5 years). During follow-up, 25% (35/140) of the patients presented exacerbation within 3.4 ±3 years after renal transplant. Viral replication was observed in all patients with exacerbation. Clinical and/or laboratory signs of hepatic insufficiency were present in 17% (6/35) of the patients. Three patients died as a consequence of liver failure. In univariate analysis variables associated with exacerbation were less frequent use of prophylactic/preemptive lamivudine and of mycophenolate mofetil. Lamivudine use was the only variable independently associated with exacerbation, with a protective effect. Conclusions: Acute exacerbation was a frequent and severe event in HBV-infected renal transplant patients. Prophylactic/preemptive therapy with antiviral drugs should be indicated for all HBsAg-positive renal transplant patients. .

Do differences exist between chronic hepatitis C genotypes 2 and 3?

Introduction Six genotypes of the hepatitis C virus (HCV) have been identified thus far, and their distribution is well defined. Genotype 1, which is the most prevalent worldwide, is always compared to genotypes 2 and 3, particularly in terms of treatment response. However, little is known about the differences between genotypes 2 and 3 because these genotypes are analyzed together in most studies. Therefore, the aim of this study was to evaluate differences in the clinical, epidemiological, laboratory, and histological parameters between HCV-2 and HCV-3. Methods Patients with chronic hepatitis C infected with genotypes 2 and 3 were studied retrospectively and compared according to clinical, laboratory, and histological aspects. Hepatitis C virus-ribonucleic acid (HCV-RNA) was analyzed quantitatively by TaqMan® real-time PCR, and the HCV genotype was determined by sequencing the 5′-untranslated region. Results A total of 306 patients with chronic HCV-2 (n=50) and HCV-3 (n = 256) were studied. Subtype 2b (n=17/50) and subtype 3a (n=244/256) were the most prevalent among patients infected with HCV-2 and HCV-3, respectively. The mean age was 47 ± 10 years, and there was a predominance of men in the group studied (61%). Comparative analysis between HCV-2 and HCV-3 showed a younger age (p=0.002), less prevalence of arterial hypertension (p=0.03), higher serum albumin levels (p=0.01), more advanced stage of liver fibrosis (p=0.03), and higher frequency of steatosis in patients with HCV-3 (p=0.001). After multivariate regression analysis, all the variables, except serum albumin, remained as variables associated with HCV-3 in the final model. Conclusions Clinical and histological differences exist between HCV-2 and HVC-3, which suggests the need for separate analyses of these genotypes. .