O papel da elastografia na hipertensão portal clinicamente significativa / The role of elastography in clinically significant portal hypertension

ABSTRACT This is a narrative review that aims to discuss the importance of elastographic methods in the evaluation of clinically significant portal hypertension (CSPH) in cirrhotic patients, where the authors propose an algorithm for evaluating these patients. In compensated advanced chronic liver disease, the goal is to prevent the development of CSPH and, in those already with CSPH, prevent the appearance of gastroesophageal varices (GEV) and other complications of portal hypertension. In compensated cirrhosis, the prevalence of GEV is 30-40%, of which 10-20% are at risk of bleeding. Therefore, using non-invasive methods would exempt the patient from the need of an endoscopy. Hepatic Elastography is a non-invasive, safe, reproducible method, available through many techniques: Vibration-Controlled Transient Elastography (VCTE), Shear Wave Elastography (SWE) and Magnetic Resonance Elastography (MRE). The Baveno VII presented the "rule of 5" for VCTE: liver stiffness measurement (LSM) ≤15 kPa and platelets >150.000/mm3 exclude CSPH, while an LSM ≥25 kPa is highly suggestive of CSPH. Also, the "rule of 4" for SWE has been proposed: patients with ≥17 kPa could be considered as having CSPH. At last, spleen stiffness measurement (SSM) has been proposed as a more specific technique to predict the presence of CSPH. In conclusion, elastography has gained prestige in the non-invasive evaluation of patients with advanced chronic liver disease by allowing prophylactic measures to be taken when suggesting the presence of CSPH.

RESUMO Trata-se de uma revisão narrativa que visa discutir a importância dos métodos elastográficos na avaliação da hipertensão portal clinicamente significativa (HPCS) em pacientes cirróticos, onde os autores propõem um algoritmo para avaliação desses pacientes. Na doença hepática crônica avançada compensada, o objetivo é prevenir o desenvolvimento de HPCS, e naqueles já com HPCS prevenir o aparecimento de varizes gastroesofágicas (VGE) e outras complicações da hipertensão portal. Na cirrose compensada, a prevalência de VGE é de 30-40% e 10-20% são varizes com risco de sangramento, portanto o uso de métodos não invasivos dispensaria o paciente de endoscopia. A elastografia hepática é um método não invasivo, seguro e reprodutível, disponível através de várias técnicas: elastografia transitória (VCTE), onda de cisalhamento (SWE) e elastografia por ressonância magnética. O Baveno VII apresentou a "regra dos 5" para VCTE: medida da rigidez hepática (LSM) ≤15 kPa e plaquetas >150.000/mm3 excluem HPCS enquanto um LSM ≥25 kPa é altamente sugestivo de HPCS. Além disso, foi proposta a "regra dos 4" para SWE: pacientes com ≥17 kPa podem ser considerados como portadores de HPCS. Por fim, a medição da rigidez do baço (SSM) foi proposta como uma técnica mais específica para prever a presença de HPCS. Em conclusão, a elastografia ganhou prestígio na avaliação não invasiva de pacientes com doença hepática crônica avançada, ao permitir a adoção de medidas profiláticas ao sugerir a presença de HPCS.

Results of transarterial chemoembolization of hepatocellular carcinoma as a bridging therapy to liver transplantation / Resultados da quimioembolização transarterial do carcinoma hepatocelular como terapia ponte para transplante de fígado

Abstract Objective: To evaluate the degree of tumor necrosis after transarterial chemoembolization (TACE), used as a bridging therapy in patients awaiting liver transplantation, and its effect on survival. Materials and Methods: This was a retrospective cohort study involving 118 patients submitted to TACE prior to liver transplantation, after which the degree of tumor necrosis in the explant and post-transplant survival were evaluated. Results: Total necrosis of the neoplastic nodule in the explant was observed in 76 patients (64.4%). Of the patients with total necrosis in the explanted liver, 77.8% had presented a complete response on imaging examinations. Drug-eluting bead TACE (DEB-TACE), despite showing a lower rate of complications than conventional TACE, provided a lower degree of total necrosis, although there was no statistical difference between the two. By the end of the study period, 26 of the patients had died. Survival was longer among the patients with total necrosis than among those with partial or no necrosis (HR = 2.24 [95% CI: 0.91-5.53]; p = 0.078). Conclusion: In patients undergoing TACE as a bridging therapy, total tumor necrosis appears to be associated with improved patient survival.

Resumo Objetivo: Avaliar os resultados da necrose tumoral após quimioembolização transarterial (TACE) como terapia ponte e seu reflexo na sobrevida dos pacientes. Materiais e Métodos: Estudo de coorte retrospectivo, com 118 pacientes que realizaram TACE, em que foram avaliados o grau de necrose tumoral no explante e a sobrevida pós-transplante. Resultados: Necrose total do nódulo neoplásico no explante foi observada em 76 pacientes (64,4%). Observou-se que 77,8% dos pacientes com necrose total no explante hepático tinham apresentado resposta completa nos exames de imagem. A DEB-TACE, apesar de ter demonstrado menor taxa de intercorrências, proporcionou menor grau de necrose total em relação à TACE convencional, a despeito de não haver diferença estatística. Ao final do seguimento do estudo, o número de óbitos foi de 26. A sobrevida foi maior nos pacientes que tiveram necrose total quando comparada com grau de necrose parcial ou ausência de necrose [HR = 2,24 (IC 95%: 0,91-5,53); p = 0,078]. Conclusão: Necrose completa do tumor nos pacientes submetidos a TACE como terapia ponte parece estar associada com melhora da sobrevida.

Transjugular intrahepatic portosystemic shunt in decompensated cirrhotic patients in a tertiary hospital in southern Brazil

SUMMARY OBJECTIVE: The aim of the present study was to evaluate the outcomes of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt. METHODS: A retrospective longitudinal observational study was carried out evaluating 38 cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt. The outcomes were evaluated in an outpatient follow-up period of 3 months. The assumed significance level was 5%. RESULTS: The indications for transjugular intrahepatic portosystemic shunt were refractory ascites in 21 (55.3%), variceal hemorrhage in 13 (34.2%), and hydrothorax in 4 (10.5%) patients. There was development of hepatic encephalopathy in 10 (35.7%) patients after transjugular intrahepatic portosystemic shunt. From the 21 patients with refractory ascites, resolution was observed in 1 (3.1%) patient, and in 16 (50.0%) patients, there was ascites control. Regarding transjugular intrahepatic portosystemic shunt after variceal bleeding, 10 (76.9%) patients remained without new bleeding or hospitalizations in the follow-up period. The global survival in the follow-up period in patients with and without hepatic encephalopathy was 60 vs. 82%, respectively (p=0.032). CONCLUSION: Transjugular intrahepatic portosystemic shunt can be considered in decompensated cirrhotic patients; however, the development of hepatic encephalopathy which can shorten survival should be focused.

Cardiac abnormalities in patients with nonalcoholic fatty liver disease

SUMMARY OBJECTIVE: This study aimed to evaluate the correlation between Nonalcoholic fatty liver disease and cardiac abnormalities. METHODS: Patients with Nonalcoholic fatty liver disease who attended an outpatient clinic in Southern Brazil were prospectively evaluated. Patients should be older than 18 years and have steatosis. RESULTS: A total of 174 patients were evaluated. The mean age was 63±12 years, 65% were women, 71% white, 82.2% hypertensive, 52.3% diabetic, 56.3% obese, and 30% dyslipidemic. There was no association between Nonalcoholic fatty liver disease and cardiac abnormalities, even after adjusting for age, sex, and metabolic syndrome. CONCLUSIONS: The present study did not show a direct correlation between Nonalcoholic fatty liver disease and cardiac abnormalities, regardless of metabolic syndrome.

Avaliação do desempenho do índice triglicerídeo-glicose no diagnóstico e estadiamento da DHGNA em pacientes obesos / Performace of triglyceride-glucose index on diagnosis and staging of nafld in obese patients

ABSTRACT BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the world, and its prevalence is increasing alongside obesity. In United States, NAFLD is already the second leading cause of liver transplantation. The spectrum of the disease ranges from simple steatosis, which has a benign course, to steatohepatitis, which may progress to cirrhosis and its complications. The rising of noninvasive methods for diagnosing and staging non-alcoholic steatohepatitis (NASH) and fibrosis decreases the need of liver biopsy, as well as the costs and the occurrence of complications related to it. OBJECTIVE: To analyze the performance of the triglyceride-glucose index to evaluate steatosis, NASH and liver fibrosis in obese patients with NAFLD. METHODS: This is a retrospective cross-sectional study. Every medical record of patients who were candidates for bariatric surgery at a leading hospital in Southern Brazil were analyzed. The triglyceride-glucose index (TyG Index), a method composed only of two simple laboratory tests (serum triglycerides and fasting glucose levels), was performed prior to surgery. The TyG Index performance regarding the anatomopathological findings was evaluated, and the AUROC curve was calculated to evaluate the best cut-off point for diagnosing steatosis, non-alcoholic steatohepatitis and liver fibrosis grade. Also, the NAFLD fibrosis Score (NFS) was evaluated. RESULTS: A total of 423 patients were evaluated. The TyG Index with a cut-off point of 8.76 excluded significant simple steatosis (grade 2-3) in obese patients, with 67.6% sensitivity, 65.1% specificity, 46.3% positive predictive value (PPV), 81.8% negative predictive value (NPV), 65.8% accuracy and 0.66 AUROC (P=0.005). In the evaluation of NASH, the TyG Index with a cut-off point of 8.82 excluded significant NASH (grade 2-3) with 57.3% sensitivity, 58.6% specificity, 33.7% PPV, 78.8% NPV, 58.2% accuracy and 0.58 AUROC (P=0.022). When evaluating liver fibrosis, the TyG Index with a cut-off point of 8.91 showed a sensitivity of 61.8%, a specificity of 62.5%, a PPV of 13.8 and a NPV of 94.4% for exclusion of advanced fibrosis (F3-4), with a 62.4% accuracy and 0.69 AUROC (P<0.001). When analyzing the performance of NFS in the diagnosis of advanced fibrosis, the cut-off point <-1.455 excluded advanced fibrosis with sensitivity of 59.4%, specificity of 51%, PPV of 11%, NPV of 92.4% and accuracy of 51.7%. However, the cut-off point of 0.676 to diagnose advanced fibrosis presented sensitivity of 21.9%, specificity of 83%, PPV of 11.7%, NPV of 91.2% and 77.3% accuracy. The AUROC was 0.54 (P=0.480). CONCLUSION: TyG Index did not perform well in the diagnosis of significant steatosis and NASH. However, it was able to exclude advanced fibrosis in obese patients who are candidates for bariatric surgery.

RESUMO CONTEXTO: A doença hepática gordurosa não-alcoólica (DHGNA) é a doença hepática mais prevalente no mundo. Nos Estados Unidos, a DHGNA já é a segunda causa de transplante hepático. O espectro da doença abrange desde a esteatose simples, que apresenta curso benigno, até esteato-hepatite não-alcoólica (EHNA), que pode progredir para cirrose e suas complicações. O desenvolvimento de métodos não invasivos para o diagnóstico e estadiamento da EHNA e da fibrose hepática visa diminuir a necessidade de biópsia hepática, um procedimento invasivo e não raro associado a complicações. OBJETIVO: Analisar o desempenho do índice triglicerídeo-glicose (TyG Index) para o diagnóstico e estadiamento da DHGNA em pacientes obesos. MÉTODOS: Este é um estudo transversal retrospectivo. Foram analisados todos os prontuários de pacientes candidatos a cirurgia bariátrica em um hospital de referência do Sul do Brasil e calculado o TyG Index, um escore composto por dois exames laboratoriais (triglicerídeos e glicose de jejum), realizados previamente à cirurgia. O desempenho do TyG Index em relação aos achados anatomopatológicos hepáticos foi avaliado, e calculada a curva ROC para avaliação de esteatose simples, EHNA e fibrose hepática. O NAFLD Fibrosis Score (NFS) também foi avaliado. RESULTADOS: Foram avaliados 423 pacientes. O melhor ponto de corte do TyG Index para a exclusão de esteatose simples significativa (grau 2-3) foi de 8,76, com sensibilidade 67,6%, especificidade 65,1%, valor preditivo positivo (VPP) 46,3%, valor preditivo negativo (VPN) 81,8%, acurácia 65,8% e AUROC 0,66 (P=0,005). Na avaliação de EHNA significativa (grau 2-3), o melhor ponto de corte foi de 8,82 com sensibilidade 57,3%, especificidade 58,6%, VPP 33,7%, VPN 78,8%, acurácia 58,8% e AUROC 0,58 (P=0,022). Em relação à fibrose avançada (grau 3-4), o melhor ponto de corte do TyG Index foi de 8,91 com sensibilidade 61,8%, especificidade 62,5%, VPP 13,8%, VPN 94,4%, acurácia 62,4% e AUROC 0,69 (P<0,001). Ao analisarmos o desempenho do NFS no diagnóstico de fibrose avançada, o ponto de corte de <-1,455 excluiu fibrose avançada com sensibilidade 59,4%, especificidade 51%, VPP 11%, VPN 92,4% e acurácia 51,7%. Entretanto, o ponto de corte de 0,676 para fibrose avançada apresentou sensibilidade de 21,9%, especificidade 83%, VPP 11,7%, VPN 91,2% e acurácia 77,3%. A AUROC foi de 0,54 (P=0,480). CONCLUSÃO: O TyG Index não apresentou bom desempenho para o diagnóstico e estadiamento da esteatose simples e da EHNA. Entretanto, foi capaz de excluir fibrose avançada em pacientes obesos candidatos a cirurgia bariátrica.

Papel da imunohistoquímica no diagnóstico diferencial do carcinoma hepatocelular precoce e dos nódulos com displasia de alto grau em pacientes com cirrose / Results of immunohistochemistry in the differential diagnosis of early hepatocellular carcinoma and nodules with high-grade dysplasia in patients with cirrhosis

ABSTRACT BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and cirrhosis is considered a pre-malignant disease. In this context, the evolutionary sequence from low grade dysplastic nodule and high grade dysplastic nodule (HGDN) to early HCC and advanced HCC has been studied. The differential diagnosis between HGDN and early HCC is still a challenge, especially in needle biopsies OBJECTIVE: To evaluate an immunohistochemistry panel to differentiate dysplastic nodules and HCC. METHODS: Patients with cirrhosis who underwent surgical resection or liver transplantation were included. The sensitivity, specificity and accuracy for the diagnosis of neoplasia were analyzed by evaluating five markers: heat shock protein 70, glypican 3, glutamine synthetase, clathrin heavy chain and beta-catenin. P≤0.05 was considered statistically significant. RESULTS: One hundred and fifty-six nodules were included; of these, 57 were HCC, 14 HGDN, 18 low grade dysplastic nodules and 67 regenerative macronodules. Sensitivity of HCC diagnosis was 64.9% for glypican 3 and 77.2% for glutamine syntetase, while specificity was 96.0% and 96.0% respectively. When the panel of four markers was considered (excluding beta catenin), the specificity ranged from 87.9% for one positive marker to 100% for at least three markers. The best accuracy for HCC diagnosis was obtained with at least two positive markers, which was associated with a sensitivity of 82.5% and specificity of 99%. CONCLUSION: Differential diagnosis of dysplastic nodules and HCC by morphological criteria can be challenging. Immunomarkers are useful and should be used for the differential diagnosis between HCC and HGDN.

RESUMO CONTEXTO: O carcinoma hepatocelular (CHC) é o câncer primário do fígado mais frequente e a cirrose é considerada uma doença pré-maligna. Nesse contexto, a sequência evolutiva do nódulo displásico de baixo grau e nódulo displásico de alto grau (NDAG) para CHC precoce e CHC avançado tem sido estudada. O diagnóstico diferencial entre NDAG e CHC precoce ainda é um desafio, principalmente em biópsias por agulha. OBJETIVO: Avaliar um painel de imunohistoquímica para diferenciar nódulos displásicos de CHC. MÉTODOS: Foram incluídos pacientes com cirrose submetidos à ressecção cirúrgica ou transplante de fígado. A sensibilidade, especificidade e acurácia para o diagnóstico da neoplasia foram analisadas avaliando cinco marcadores: proteína de choque térmico 70kDa, glipican 3, glutamina sintetase, clatrina de cadeia pesada e beta-catenina. P≤0,05 foi considerado estatisticamente significativo. RESULTADOS: Cento e cinquenta e seis nódulos foram incluídos; destes, 57 eram CHC, 14 NDAG, 18 nódulos displásicos de baixo grau e 67 macronódulos regenerativos. A sensibilidade do diagnóstico de CHC foi de 64,9% para glipican 3 e 77,2% para glutamina sintetase, enquanto a especificidade foi de 96,0% e 96,0%, respectivamente. Quando o painel de quatro marcadores foi considerado (excluindo beta catenina), a especificidade variou de 87,9% para um marcador positivo a 100% para pelo menos três marcadores. A melhor acurácia para o diagnóstico de CHC foi obtida com pelo menos dois marcadores positivos, o que foi associado a uma sensibilidade de 82,5% e especificidade de 99%. CONCLUSÃO: O diagnóstico diferencial de nódulos displásicos e CHC por critérios morfológicos pode ser desafiador. Imunomarcadores são úteis e devem ser usados para o diagnóstico diferencial entre CHC e NDAG.

Muscle depletion in cirrhotic patients assessed using computed tomography: a cross-sectional study

ABSTRACT BACKGROUND: Sarcopenia is a common complication in patients with cirrhosis and may lead to increased morbidity and mortality. OBJECTIVE: To investigate the prevalence of sarcopenia and its association with disease severity scores, among patients with cirrhosis. DESIGN AND SETTING: Observational and retrospective cohort study carried out in a tertiary-care hospital in southern Brazil. METHODS: This study was conducted among patients with chronic liver disease who were followed up at the gastroenterology and hepatology outpatient clinic of a tertiary-care hospital in southern Brazil and who underwent computed tomography scans of the abdomen through any indication. RESULTS: We included 83 patients in the study. In the population evaluated, there was a predominance of males (57.80%) and the mean age was 56 years. Hepatitis B or C virus was present in the genesis of the disease in 34.9% of the cases, followed by an etiology of alcohol abuse (30.1%). Sarcopenia was diagnosed in 41 (49.4%) of the patients when the cutoff point for cirrhotic patients was used. There was no significant correlation between the Child-Pugh and MELD severity scores and the occurrence of sarcopenia. CONCLUSION: Sarcopenia presents high prevalence among patients with chronic liver disease, without any association with predictors of severity.

Atualização das recomendações da Sociedade Brasileira de Hepatologia para o diagnóstico e tratamento do carcinoma hepatocellular / Brazilian society of hepatology updated recommendations for diagnosis and treatment of hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.

RESUMO O carcinoma hepatocelular (CHC) é uma das principais causas de mortalidade relacionada a câncer no Brasil e no mundo. A Sociedade Brasileira de Hepatologia (SBH) publicou em 2015 suas primeiras recomendações sobre a abordagem do CHC. Desde então, novas evidências sobre o diagnóstico e tratamento do CHC foram relatadas na literatura médica, levando a diretoria da SBH a promover uma reunião monotemática sobre câncer primário de fígado em agosto de 2018 com o intuito de atualizar as recomendações sobre o manejo da neoplasia. Um grupo de experts foi convidado para realizar uma revisão sistemática da literatura e apresentar uma atualização baseada em evidências científicas visando que pudesse nortear a prática clínica multidisciplinar do CHC. O texto resultante foi submetido a avaliação e aprovação de todos membros da SBH através de sua homepage. O documento atual é a versão final que contêm as recomendações atualizadas e revisadas da SBH.

Razão da contagem de plaquetas ao quadrado/diâmetro do baço-aspartato aminotransferase: avaliação de um novo método não-invasivo para a predição de varizes esofágicas / Platelet count squared/spleen diameter-aspartate aminotransferase ratio: non-invasive method to predict esophageal varices

ABSTRACT BACKGROUND - Variceal bleeding has a high mortality among cirrhotics, and screening with endoscopy is indicated at the diagnosis of cirrhosis. Screening with endoscopy implies discomfort, risks and considerable costs. OBJECTIVE - To evaluate platelet count squared/spleen diameter-aspartate aminotransferase ratio (PS/SA), as a non-invasive predictor of esophageal varices in cirrhotics. METHODS - This cross-sectional study evaluated cirrhotics for PS/SA and presence of esophageal varices. Outpatient records of cirrhotic patients were reviewed for the abovementioned data. Sensitivity, specificity, negative and positive predictive values of PS/SA were calculated. After the univariate analysis, variables with P<0.10 were submitted to a logistic regression. RESULTS - The study included 164 cirrhotics, 59.70% male, with a mean age of 56.7 years. Hepatitis C was the most frequent cause of cirrhosis, being present in 90 patients. Patients were classified as Child-Pugh A in 52.44% and as Child-Pugh B or C in 47.56%. Esophageal varices were present in 72.56% of the patients at endoscopy. PS/SA, with a cutoff of 3x108, had a sensitivity of 95.80% (confidence interval of 95% - 95%CI=0.92-0.99), a specificity of 22.70% (95%CI=0.10-0.35), a positive predictive value of 77.20% (95%CI=0.70-0.84) and a negative predictive value of 66.70% (95%CI=0.42-0.91). In the logistic regression, only platelet count and Child-Pugh score were associated to esophageal varices (P<0.05). CONCLUSION - PS/SA has an excellent sensitivity to predict esophageal varices, allowing almost one fourth of patients without esophageal varices to spare endoscopy. Nevertheless, PS/SA is not independently associated to esophageal varices.

RESUMO CONTEXTO - A hemorragia varicosa tem elevada mortalidade entre cirróticos, e o rastreamento endoscópico de varizes está indicado no momento do diagnóstico da cirrose. O rastreamento endoscópico implica desconforto, riscos e custos consideráveis. OBJETIVO - Avaliar a razão da contagem de plaquetas ao quadrado/diâmetro do baço-aspartato aminotransferase (PQ/BA) como preditor não-invasivo de varizes esofágicas em cirróticos. MÉTODOS - Este estudo transversal avaliou cirróticos quanto ao PQ/BA e à presença de varizes esofágicas. Prontuários ambulatoriais de cirróticos foram revisados quanto a tais dados. Sensibilidade, especificidade e valores preditivos negativo e positivo do PQ/BA foram calculados. Após a análise univariada, variáveis com P<0,10 foram submetidas à regressão logística. RESULTADOS - O estudo incluiu 164 cirróticos, 59,70% masculinos, com média de idade de 56,7 anos. Hepatite C foi a mais frequente causa de cirrose, estando presente em 90 pacientes. Os pacientes foram classificados como Child-Pugh A em 52,44% e em Child-Pugh B ou C em 47,56%. As varizes esofágicas estiveram presentes à endoscopia em 72,56% dos pacientes. PQ/BA, com um ponto de corte de 3x108, teve sensibilidade de 95,80% (intervalo de confiança de 95% - IC95%=0,92-0,99), especificidade de 22,70% (IC95%=0,10-0,35), valor preditivo positivo de 77,20% (IC95%=0,70-0,84) e valor preditivo negativo de 66,70% (IC95%=0,42-0,91). Na regressão logística, apenas a contagem de plaquetas e o escore de Child-Pugh associaram-se às varizes esofágicas (P<0,05). CONCLUSÃO - PQ/BA apresentou excelente sensibilidade para predizer varizes esofágicas, permitido que cerca de um quarto dos pacientes sem varizes esofágicas evitasse a endoscopia. Entretanto, PQ/BA não se associou de maneira independente às varizes esofágicas.

Transient Elastography vs Aspartate Aminotransferase to Platelet Ratio Index in Hepatitis C: A Meta-Analysis

ABSTRACT Background and rationale. Many different non-invasive methods have been studied with the purpose of staging liver fibrosis. The objective of this study was verifying if transient elastography is superior to aspartate aminotransferase to platelet ratio index for staging fibrosis in patients with chronic hepatitis C. Material and methods. A systematic review with meta-analysis of studies which evaluated both non-invasive tests and used biopsy as the reference standard was performed. A random-effects model was used, anticipating heterogeneity among studies. Diagnostic odds ratio was the main effect measure, and summary receiver operating characteristic curves were created. A sensitivity analysis was planned, in which the meta-analysis would be repeated excluding each study at a time. Results. Eight studies were included in the meta-analysis. Regarding the prediction of significant fibrosis, transient elastography and aspartate aminotransferase to platelet ratio index had diagnostic odds ratios of 11.70 (95% confidence interval = 7.13-19.21) and 8.56 (95% confidence interval = 4.90-14.94) respectively. Concerning the prediction of cirrhosis, transient elastography and aspartate aminotransferase to platelet ratio index had diagnostic odds ratios of 66.49 (95% confidence interval = 23.71- 186.48) and 7.47 (95% confidence interval = 4.88-11.43) respectively. Conclusion. In conclusion, there was no evidence of significant superiority of transient elastography over aspartate aminotransferase to platelet ratio index regarding the prediction of significant fibrosis, but the former proved to be better than the latter concerning prediction of cirrhosis.

The Impact of Early Dermatologic Events in the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib

ABSTRACT Background and Aims. The presence of dermatologic reaction as an adverse event to sorafenib treatment in patients with unresectable hepatocellular carcinoma has been indicated as a prognostic factor for survival in a recent prospective analysis. To date, this is the only clinical predictor of treatment response, which can be evaluated earlier in the treatment and, therefore, contribute to a better and more individualized patient management. Material and methods. This retrospective study included 127 patients treated with sorafenib under real-life practice conditions in two hepatology reference centers in Brazil. Demographic data, disease/medical history and time of sorafenib administration as well as adverse events related to the medication were recorded in a database. Results. Cirrhosis was present in 94% of patients, 85.6% were Child-Pugh A, 80.3%BCLC-C, 81% had vascular invasion and/or extrahepatic spread and 95% had a performance status 0 to 1.The median duration of treatment was 10.1 months (range: 0.1-47 months).The most common adverse event within the first 60 days of treatment were diarrhea (62.2%) and dermatological reaction (42%).The median overall survival for the cohort was 20 months, and it was higher for patients who developed dermatological reactions within the first 60 days compared to those who did not present this adverse event. Conclusion. This retrospective analysis showed the use of sorafenib in patients selected according to BCLC staging, and it is the first external validation of early dermatologic adverse events as a predictor of overall survival in patients with advanced hepatocellular carcinoma.

Frequency of the mdr1 gene polymorphism rs1045642 (c3435t) in hcv-hiv co-infected patients / Frequência do polimorfismo rs1045642 (C3435T) do gene MDR1 em pacientes coinfectados HCV-HIV

ABSTRACT Background Due to the high prevalence of co-infection by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) and the severity of these infections, the understanding of the biological mechanisms involved in these processes, including viral behavior and host genetic profile, is of great importance for patient treatment and for public health policies.Some single nucleotide polymorphisms (SNPs) in the human genome, such as the SNP rs1045642 (C3435T) in the MDR1 gene, have been reported to be associated to the sustained virological response (SVR) to HCV treatment in HCV-HIV co-infected patients. Objective The present study analyzes the MDR1 gene C3435T polymorphism in HCV-HIV co-infected patients. Methods A total of 99 HCV-HIV patients were included in the study. The DNA was extracted from blood samples, and the SNP rs1045642 was assessed by Real Time PCR (qPCR). Risk factors for acquiring the virus and the SVR after HCV treatment with pegylated interferon-alpha and ribavirin were also analyzed. Results Among the patients, 54 (54.5%) were male and 45 (45.5%) were female. The average age was 46.1±9.8 years. The SVR after HCV treatment was 40%. The frequencies of MDR1 genotypes CC, CT and TT were 28.3%, 47.5% and 24.2%, respectively. Allele frequencies were 52% for the C allele and 48% for the T allele. No association was found for SNP rs1045642 (C3435T) regarding response to treatment (P=0.308). Conclusion - In this study, the C3435T polymorphism in the MDR1 gene appears not to be associated with SVR in HCV-HIV co-infected individuals.

RESUMO Contexto Em virtude da elevada prevalência da coinfecção pelos vírus da hepatite C (HCV) e da imunodeficiência humana (HIV) e às inúmeras complicações que esses vírus acarretam, é fundamental o maior entendimento do comportamento biológico dos mesmos. O polimorfismo de nucleotídeo único rs1045642 C3435T do gene de resistência a múltiplas drogas MDR1, no qual ocorre modificação do códon ATC para ATT, parece estar relacionado à resposta virológica sustentada ao tratamento do HCV em coinfectados HCV-HIV. Objetivo Mapear o polimorfismo C3435T do gene MDR1 em pacientes coinfectados HCV-HIV e correlacionar com dados clínicos e laboratoriais. Métodos Foram analisados 99 pacientes coinfectados HCV-HIV. A identificação molecular do polimorfismo de nucleotídeo único rs1045642 do gene MDR1 foi realizada pela técnica de PCR em tempo real (qPCR) alelo-específico com primers e sondas específicos para a identificação desse polimorfismo. Fatores de risco para a aquisição do HCV e a resposta virológica sustentada ao tratamento do HCV com interferon-alfa peguilado e ribavirina foram analisados. Resultados Dentre os pacientes avaliados, 54 (54,5%) eram do gênero masculino e 45 (45,5%) do gênero feminino. A média de idade foi de 46,1 anos (±9,8). As frequências dos genótipos CC, CT e TT foram 28,3%, 47,5% e 24,2% respectivamente, e as frequências alélicas foram 52% para alelo C e 48% para alelo T. Não houve associação entre o gene MDR1 e a resposta virológica sustentada (P=0,308). Conclusão Neste estudo, o polimorfismo C3435T no gene MDR1 não apresentou associação com a resposta virológica sustentada ao tratamento em indivíduos coinfectados HCV-HIV.

LIVER BIOPSY: IMPORTANCE OF SPECIMEN SIZE IN THE DIAGNOSIS AND STAGING OF CHRONIC VIRAL HEPATITIS

Liver biopsy is the gold standard method for the grading and staging of chronic viral hepatitis, but optimal biopsy specimen size remains controversial. The aim of this study was to evaluate the quality of liver specimen (number of portal tracts) and to evaluate the impact of the number of portal tracts in the staging of chronic hepatitis. Material and Methods: 468 liver biopsies from consecutive patients with hepatitis C virus and hepatitis B virus infection from 2009 to 2010 were evaluated. Results: The length of fragment was less than 10 mm in 43 cases (9.3%), between 10 and 14 mm in 114 (24.3%), and ≥ 15 mm in 311 (64.4%); of these, in 39 (8.3%) cases were ≥ 20 mm. The mean representation of portal tracts was 17.6 ± 2.1 (5-40); in specimens ≥ 15 mm the mean portal tract was 13.5 ± 4.7 and in cases ≤ 15 mm was 11.4 ± 5.0 (p = 0.002). Cases with less than 11 portal tracts were associated with F3, and cases with 11 or more portal tracts with F2 (p = 0.001). Conclusion: this study demonstrated the good quality of liver biopsy and a relationship between the macroscopic size of the fragment and the number of portal tracts.

Brazilian society of hepatology recommendations for the diagnosis and treatment of hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma is a malignancy of global importance and is associated with a high rate of mortality. Recent advances in the diagnosis and treatment of this disease make it imperative to update the recommendations on the management of the disease. In order to draw evidence-based recommendations concering the diagnosis and management of hepatocellular carcinoma, the Brazilian Society of Hepatology has sponsored a single-topic meeting in João Pessoa (PB). All the invited pannelists were asked to make a systematic review of the literature and to present topics related to the risk factors for its development, methods of screening, radiological diagnosis, staging systems, curative and palliative treatments and hepatocellular carcinoma in noncirrhotic liver. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript containing the recommendations of the Brazilian Society of Hepatology.

RESUMO O carcinoma hepatocelular é uma neoplasia de importância global e associada a altos índices de mortalidade. Recentes avanços no diagnóstico e tratamento da doença tornaram necessárias que se atualizassem as recomendações sobre o manejo da doença. Para definir as recomendações sobre o diagnóstico e tratamento do carcinoma hepatocelular, a Sociedade Brasileira de Hepatologia organizou uma reunião monotemática em João Pessoa (PB). Todos expositores foram solicitados a fazer uma revisão sistemática da literatura e apresentar os temas relacionados a fatores de risco para o desenvolvimento de carcinoma hepatocelular, métodos para rastreamento, diagnóstico radiológico e sistemas de estadiamento da doença, tratamentos curativos e paliativos e carcinoma hepatocelular em fígado não cirrótico. Após o encontro, todos os expositores se reuniram para discussão dos tópico e elaboração dessas recomendações. O texto resultante foi ainda submetido a avaliação e aprovação por todos membros da Sociedade através de sua homepage. O documento atual é a versão final que contêm as recomendações da Sociedade Brasileira de Hepatologia.

HEPATOCELLULAR CARCINOMA IN A NON-CIRRHOTIC PATIENT WITH SUSTAINED VIROLOGICAL RESPONSE AFTER HEPATITIS C TREATMENT / Carcinoma hepatocelular em paciente não cirrótico com resposta virológica sustentada após tratamento para hepatite C

Chronic infection by hepatitis C virus (HCV) is one of the main risk factors for the development of liver cirrhosis and hepatocellular carcinoma. However, the emergence of hepatocellular carcinoma (HCC) in non-cirrhotic HCV patients, especially after sustained virological response (SVR) is an unusual event. Recently, it has been suggested that HCV genotype 3 may have a particular oncogenic mechanism, but the factors involved in these cases as well as the profile of these patients are still not fully understood. Thus, we present the case of a non-cirrhotic fifty-year-old male with HCV infection, genotype 3a, who developed HCC two years after treatment with pegylated-interferon and ribavirin, with SVR, in Brazil.

A infecção crônica pelo vírus da hepatite C é um dos principais fatores de risco para o desenvolvimento de cirrose hepática e carcinoma hepatocelular. Entretanto, o surgimento do carcinoma hepatocelular em pacientes portadores de hepatite C na ausência de cirrose, especialmente após o tratamento e a obtenção de resposta virológica sustentada, é um evento incomum. Recentemente tem sido sugerido que o genótipo 3 do vírus da hepatite C possa ter um mecanismo oncogênico particular, mas todos os fatores envolvidos nestes casos, assim como o perfil destes pacientes, ainda não estão totalmente esclarecidos. Deste modo, apresentamos o caso de um paciente masculino de 50 anos de idade, com infecção pelo vírus da hepatite C genótipo 3a, não cirrótico, que desenvolveu carcinoma hepatocelular dois anos após ter atingido resposta virológica sustentada com o tratamento com interferon peguilado e ribavirina.

Effects of L-arginine and L-NAME on ischemia-reperfusion in rat liver

PURPOSE: To evaluated the effects of L-arginine (a NO donor) and L-NAME (Nw-nitro-L-arginine methyl ester - a NOS inhibitor) on ischemia-reperfusion in rat livers. METHODS: One hundred fifty two male Wistar rats were divided into four groups: control (simulated surgery); hepatic IR; pretreatment with L-arginine plus hepatic IR; and L-NAME plus hepatic IR. The hepatocellular damage was evaluated at the first, third and seventh days after the procedures through the alanine-aminotransferase (ALT) and aspartate-aminotransaminase (AST) levels, as well as histopathological features: vascular congestion (VC); steatosis (STE); necrosis (NEC); and inflammatory infiltration (INF). The mortality rate was also evaluated. RESULTS: The pretreatment with L-NAME significantly worsened the AST levels after hepatic IR (p<0.05) at first day and L-arginine demonstrated an attenuating effect on ALT levels at seventh day (p<0.05). Furthermore, the administration of L-arginine was able to reduce the VC and STE in the seventh day after hepatic IR (p<0.05). The analysis of the mortality rates did not demonstrate any difference between the groups. Nevertheless, there was not effect of L-arginine and L-NAME on the mortality of the animals. CONCLUSION: L-arginine/NO pathway has a role in the hepatic IR because the pretreatment with L-arginine partially had attenuated the hepatocellular damage induced by hepatic IR in rats. .

Analysis of thessurvival of cirrhotic patients nlisted for liver transplantatiion in the pre- and post-meld era in southern Brazil / Análise da sobrevida de pacientes cirróticos listados para transplante ortotópico de fígado nas eras pré e pós MELD no Sul do Brasil

Context Transplantation is the only cure for decompensated cirrhosis. Model for End-Stage Liver Disease (MELD) is used in liver allocation. Objectives Comparing survival of enlisted populations in pre- and post-MELD eras and estimating their long-term survival. Methods This is a retrospective study of cirrhotics enlisted for transplantation during pre- and post-MELD eras. Survival curves were generated using Kaplan-Meier’s model. Cox’s model was used to determine risk factors for mortality. Exponential, Weibull’s, normal-log and Gompertz’s models were used to estimate long-term survival. Results The study included 162 patients enlisted in pre-MELD era and 184 in post-MELD period. Kaplan-Meier’s survival curve of patients enlisted in post-MELD era was better than that of pre-MELD period (P = 0.009). This difference remained for long-term estimates, with a survival of 53.54% in 5 years and 44.64% in 10 years for patients enlisted in post-MELD era and of 43.17% and 41.75% for pre-MELD period. Era in which patients had been enlisted (P = 0.010) and MELD score at enlistment (P<0.001) were independently associated to survival with hazard ratios of 0.664 (95% CI-confidence interval = 0.487-0.906) and 1.069 (95% CI = 1.043-1.095). Conclusions MELD-based transplantation policy is superior to chronology-based one, promoting better survival for enlisted patients, even in long-term. .

Contexto O transplante é a única cura para a cirrose descompensada. O Model for End-Stage Liver Disease (MELD) é usado na alocação de órgãos. Objetivos Comparar a sobrevida da população listada para transplante nas eras pré e pós-MELD e estimar sua sobrevida a longo prazo. Métodos Este é um estudo retrospectivo, de cirróticos listados para transplante nas eras pré e pós-MELD. Curvas de sobrevida foram criadas através do modelo de Kaplan-Meier. O modelo de Cox foi utilizada para determinar fatores de risco para mortalidade. Os modelos exponencial, Weibull, log-normal e Gompertz foram usados para estimar sobrevida de longo prazo. Resultados Incluíram-se 162 pacientes listados na era pré-MELD e 184 listados na pós-MELD. A curva de Kaplan-Meier para os pacientes listados na era pós-MELD foi melhor que a da pré-MELD (P = 0,009). Esta diferença permaneceu nas estimativas de longo prazo, com sobrevida de 53,54% em 5 anos e de 44,64% em 10 anos para pacientes listados na era pós-MELD e de 43,17% e 41,75% no período pré-MELD. A era em que os pacientes eram listados (P = 0,010) e o MELD de inscrição (P<0,001) estiveram associados de maneira independente à sobrevida, com razão de riscos de 0,664 (intervalo de confiança-IC 95% = 0,487-0,906) e de 1,069 (IC 95% = 1,043-1,095). Conclusões A política de transplantes baseada no escore MELD é superior à baseada no tempo de espera em lista, promovendo melhor sobrevida, mesmo em longo prazo. .

Melting curve aaalysis for the screening of heptitis b virus genotypes a, d annd f in patients from a general hospital in southern Brazil / Analise da curva de melting para o screening dos genotipos A, D e F do virus da hepatite B em pacientes de um hospital geral do sul do Brasil.

Context Hepatitis B virus (HBV) can cause fulminant hepatitis, cirrhosis and hepatocellular carcinoma, and is one of the most common causes of acute and chronic liver failure. The genetic variants of HBV can be decisive for the evolution of these diseases as well as for the election of therapy. Objectives The aim of this study was to evaluate and standardize an in house methodology based on the analysis of the melting curve polymerase chain reaction (PCR) of real-time (qPCR) to screen for genotypes A, D and F of HBV in patients from a hospital in Rio Grande do Sul, Brazil. Methods We evaluated 104 patients presumably with HBV chronic infection. Viral DNA was extracted from plasma and viral genotypes and different mutations were determined using PCR-based protocols. Results A PCR-based methodology was standardized for the analysis of genotypes A, D and F of HBV. The technique was based in a nested PCR with the final step consisting of a multiplex real-time PCR, using the melting curve as a tool for the differentiation of fragments. A higher frequency of genotype D (44.4%), followed by genotype A (22.2%) and genotype F (3.7%) was observed. Conclusion The standardized assay, a nested PCR-multiplex qPCR using specific primers, provides a rapid and accurate method for the differentiation of HBV genotypes that are more frequent in Southern Brazil – A, D and F. This method can be applied in the clinical practice. .

Contexto O vírus da hepatite B pode causar hepatite fulminante, cirrose e carcinoma hepatocelular, sendo uma das causas mais frequentes de doença aguda e crônica do fígado. As variantes genéticas do VHB podem ser determinantes para a evolução da doenças assim como para a eleição da terapêutica. Objetivos O objetivo deste estudo foi padronizar e avaliar uma metodologia “in house”, através da utilização da curva de melting de reação em cadeia da polimerase (PCR) em tempo real (qPCR), como rastreamento para análise dos genótipos A, D e F do vírus da hepatite B em pacientes do Rio Grande do Sul. Métodos Foram avaliados 104 pacientes supostamente com infecção crônica pelo VHB. O DNA foi extraído com kit comercial, os genótipos e as mutações foram determinados utilizando diferentes protolocos baseados em PCR. Resultados Foi padronizada uma metodologia baseada em PCR para a análise dos genótipos A, D e F do VHB. A técnica consistiu de uma PCR Nested incluindo uma etapa final de PCR em tempo real Multiplex, utilizando a curva de melting como ferramenta para a definição dos fragmentos. Foi observada uma maior frequência do genótipo D (44,4%), seguido do genótipo A (22,2%) e do genótipo F (3,7%) na amostra analisada. Conclusão O ensaio padronizado fornece um método rápido e preciso para diferenciar genótipos do VHB mais frequentes no sul do Brasil – A, D e F – usando um PCR Nested Multiplex com primers específicos, o qual apresenta potencial aplicação na prática clínica. .

Ascite no paciente cirrótico / Ascites in cirrhotic patient

Este artigo, ao fazer uma revisão da literatura no que tange ao tratamento da ascite no paciente com cirrose, enfatiza a importância da dieta com restrição de sal; do papel da espironolactona no início do tratamento em pacientes com um primeiro episódio de ascite e do tratamento combinado (espironolactona e furosemida) nas ascites recorrentes e da paracentese terapêutica, com reposição de albumina, na ascite tensa. Conclui ressaltando a importância da avaliação do transplante hepático nesta população de doentes.

The present article, reviewing medical literature regarding treatment of ascites in cirrhotic patients, emphasizes the importance of a sodium restricted diet; it also explains the role of espironolactone as the first treatment in a patient with the first episode of ascites, that of the combined treatment with espironolactone and furosemide in cases of recurrent ascites and that of therapeutical paracentesis with albumin replacement in patients with tense ascites. It concludes highlighting the importance of evaluating cirrhotic patients with ascites for liver transplantation.

Risk factors for nonalcoholic steatohepatitis in cryptogenic cirrhosis / Fatores de risco para esteatohepatite não-alcoólica na cirrose criptogênica

CONTEXT: In about 10% of patients with chronic liver disease, it is not possible to identify an etiologic factor. These cases are called cryptogenic cirrhosis. Currently, nonalcoholic steatohepatitis (NASH) is being considered as a possible etiologic factor for a significant segment of patients that presents with cryptogenic cirrhosis. OBJECTIVE: To estimate the prevalence of risk factors for NASH in patients with cryptogenic cirrhosis, in order to verify if there is a causal relationship between them. METHOD: Cross-sectional study, with evaluation of the demographic and laboratorial data of patients with cryptogenic cirrhosis. They were compared with data obtained from a group with NASH and a group with alcoholic and/or hepatitis C (HCV) cirrhosis. RESULTS: Forty seven patients with cryptogenic cirrhosis were evaluated, 47 with NASH and 196 with HCV and/or alcoholic cirrhosis. The mean age of patients with cryptogenic cirrhosis was 52 years, while in those with NASH it was 46.4 years (P = 0,041). The group with cryptogenic cirrhosis had 23 female and 24 male patients. Of the patients who presented with NASH, 68.1% were female. Of the patients who presented with alcoholic/HCV cirrhosis, 64.8% were male. There were no statistically significant differences between the groups. In cryptogenic cirrhosis patients, the following prevalences could be observed: impaired fasting glycemia - 68.2%; obesity - 27.5%; total hypercholesterolemia - 27.9%; low HDL levels - 58.1% (women - 81%; men - 36.4%); hypertriglyceridemia - 16.3%. The results seen in cryptogenic cirrhosis patients showed statistical similarity with the results of the NASH group regarding fasting glycemia (62.8%) and male HDL levels (53.8%). The comparison with the alcoholic/HCV cirrhosis group showed statistical differences regarding fasting glycemia (45.2%), hypercholesterolemia (13.3%) and female HDL levels (50.8%). CONCLUSIONS: It is not possible to establish a causal relationship between cryptogenic cirrhosis and NASH. Only data related to fasting glycemia and HDL levels in male patients showed statistical similarities between both groups of patients.

CONTEXTO: Em aproximadamente 10% dos pacientes com doença hepática crônica não é possível identificar um fator etiológico, sendo então rotulados como tendo cirrose criptogênica. Atualmente a esteatohepatite não-alcoólica (EHNA) tem sido considerada como provável etiologia em parcela significativa desses pacientes. OBJETIVO: Estimar a prevalência de fatores de risco para EHNA em pacientes com cirrose criptogênica com o intuito de verificar uma possível relação causal entre as duas doenças. MÉTODOS: Estudo transversal em que foi avaliado o registro de dados demográficos e laboratoriais de pacientes com cirrose criptogênica com a finalidade de compará-los com aqueles obtidos de um grupo de pacientes com EHNA e de um grupo controle composto de cirróticos por hepatite C (HCV) e/ou álcool. RESULTADOS: Foram avaliados 47 pacientes com cirrose criptogênica, 47 com EHNA e 196 com cirrose por HCV e/ou álcool. A média de idade dos pacientes com cirrose criptogênica foi 52 anos, enquanto a daqueles com EHNA foi 46,4 anos (P = 0,041). No grupo com cirosse criptogênica havia 23 mulheres e 24 homens. Naqueles com EHNA predominou o gênero feminino (68,1%) e nos cirróticos por HCV e/ou álcool predominou o gênero masculino (64,8%), sem diferença estatística entre os grupos. Naqueles com cirrose criptogênica, a prevalência de glicemia de jejum alterada foi 68,2%; obesidade, 27,5%; hipercolesterolemia total, 27,9%; baixos níveis de HDL, 58,1% (81% nas mulheres e 36,4% nos homens); e hipertrigliceridemia, 16,3%. A comparação com dados observados nos pacientes com EHNA mostra semelhança estatística entre o perfil glicêmico (62,8%) e níveis de HDL nos homens (53,8%). A comparação com os cirróticos relacionados ao HCV e/ou álcool mostra diferença estatística no perfil glicêmico (45,2%), colesterol total (13,3%) e HDL nas mulheres (50,8%). CONCLUSÃO: Não foi possível estabelecer uma relação causal entre a EHNA e a cirrose criptogênica. Apenas o perfil glicêmico e os níveis de HDL colesterol nos pacientes masculinos apresentaram semelhanças estatísticas entre os dois grupos de doentes.