OBJECTIVE: To evaluate the effectiveness and safety of first-generation protease inhibitors for the treatment of genotype 1 hepatitis C virus-infected patients at Brazilian reference centers. METHODS: This multicenter cross-sectional study included hepatitis C virus genotype 1 monoinfected patients treated with Peg-interferon, ribavirin, and either boceprevir (n=158) or telaprevir (n=557) between July 2013 and April 2014 at 15 reference centers in Brazil. Demographic, clinical, virological, and adverse events data were collected during treatment and follow-up. RESULTS: Of the 715 patients, 59% had cirrhosis and 67.1% were treatment-experienced. Based on intention-to-treat analysis, the overall sustained viral response was 56.6%, with similar effectiveness in both groups (51.9% for boceprevir and 58% for telaprevir, p=0.190). Serious adverse events occurred in 44.2% of patients, and six deaths (0.8%) were recorded. Cirrhotic patients had lower sustained viral response rates than non-cirrhotic patients (46.9% vs. 70.6%, p<0.001) and a higher incidence of serious adverse events (50.7% vs. 34.8%, p<0.001). Multivariate analysis revealed that sustained viral response was associated with the absence of cirrhosis, viral recurrence after previous treatment, pretreatment platelet count greater than 100,000/mm3, and achievement of a rapid viral response. Female gender, age>65 years, diagnosis of cirrhosis, and abnormal hemoglobin levels/platelet counts prior to treatment were associated with serious adverse events. CONCLUSION: Although serious adverse events rates were higher in this infected population, sustained viral response rates were similar to those reported for other patient cohorts.

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.

Inosine triphosphatase (ITPA) single nucleotide polymorphisms (SNPs) are strongly associated with protection against ribavirin (RBV)-induced anaemia in European, American and Asian patients; however, there is a paucity of data for Brazilian patients. The aim of this study was to evaluate the ITPA SNP (rs7270101/rs1127354) frequency in healthy and hepatitis C virus (HCV)-infected patients from Brazil and the association with the development of severe anaemia during antiviral therapy. ITPA SNPs were determined in 200 HCV infected patients and 100 healthy individuals by sequencing. Biochemical parameters and haemoglobin (Hb) levels were analysed in 97 patients who underwent antiviral therapy. A combination of AArs7270101+CCrs1127354 (100% ITPase activity) was observed in 236/300 individuals. Anaemia was observed in 87.5% and 86.2% of treated patients with AA (rs7270101) and CC genotypes (rs1127354), respectively. Men with AA (rs7270101) showed a considerable reduction in Hb at week 12 compared to those with AC/CC (p = 0.1475). In women, there was no influence of genotype (p = 0.5295). For rs1127354, men with the CC genotype also showed a sudden reduction in Hb compared to those with AC. Allelic distribution of rs7270101 and rs1127354 shows high rates of the genotypes AA and CC, respectively, suggesting that the study population had a great propensity for developing RBV-induced anaemia. A progressive Hb reduction during treatment was observed; however, this reduction was greater in men at week 12 than in women.

Single nucleotide polymorphisms (SNPs) in the interleukin (IL)28B locus have been associated with a sustained virological response (SVR) in interferon-ribavirin (IFN-RBV)-treated chronic hepatitis C virus (HCV)-infected patients in European and African populations. In this study, the genotype frequency of two IL28B SNPs (rs129679860 and rs8099917) in a cohort of chronic HCV-monoinfected patients in Brazil was evaluated and the SNP sufficient to predict the treatment response outcome was determined. A total of 66 naïve genotype-1 chronic HCV-infected patients were genotyped and the associated viral kinetics and SVR were assessed. The overall SVR was 38%. Both the viral kinetics and SVR were associated with rs129679860 genotypes (CC = 62% vs. CT = 33% vs. TT = 18%, p = 0.016). However, rs8099917 genotypes were only associated with SVR (TT = 53% vs. TG = 33% vs. GG = 18%; p = 0.032). In this population, the analysis of a single SNP, rs12979860, successfully predicts SVR in the IFN-RBV treatment of HCV.

Data concerning the relationship between hepatitis B virus (HBV) genotypes and liver histology are scarce. The aim of this study was to compare HBV non-B and non-C genotypes according to demographic features, clinical status, HBV-DNA levels and liver histology in Rio de Janeiro. One hundred twenty one consecutive chronic HBV-infected patients were enrolled during two-year period and data were prospectively collected. Sera were tested for HBV genotyping using restriction fragment length polymorphism. Liver biopsy was obtained from patients with either increased alanine aminotransferase (ALT) or HBV-DNA levels. Genotype A was the most common, found in 82 (68%) patients, followed by F in 19 (15%), D in 17 (14%), B in one (1%) and C in two (2%). There was no association between HBV genotypes A, D and F and gender (p = 0.37), age (p = 0.78), race (p = 0.22), mode of infection (p = 0.94), HB "e" antigen status (p = 0.37) and HBV-DNA levels (p = 0.47). The ALT levels were lower in genotype D (75%) compared with A (47%) and F (55%) (p = 0.05). Liver biopsy showed lower inflammation [histological activity index (HAI) = 4] and fibrosis (F) (= 0) scores in genotype D than in genotypes A (HAI = 5, p < 0.001; F = 2, p = 0.008) or F (HAI = 5, p = 0.009; F = 2, p = 0.01). Genotype A was the most prevalent in chronic HBV-infected patients and genotype D patients presented with less intense liver disease.

RACIONAL: A hipertensão porta que acomete os pacientes com cirrose hepática é causa de varizes de esôfago, ascite e edema. Alguns estudos têm sido realizados para avaliar a importância das varizes de esôfago no desenvolvimento dos distúrbios motores esofagianos e do refluxo gastroesofágico anormal neste grupo de pacientes. A ascite pode ser um fator promotor de refluxo gastroesofágico e tem sido questionado se o refluxo anormal poderia favorecer a rotura das varizes de esôfago. Entretanto, são poucos os estudos que utilizam a pHmetria esofagiana prolongada ambulatorial na avaliação destes pacientes. OBJETIVO: Avaliar a presença de refluxo anormal a pHmetria esofagiana prolongada ambulatorial em pacientes cirróticos com varizes de esôfago e seus possíveis fatores preditivos. MÉTODOS: Cinqüenta e um pacientes (28 homens, 23 mulheres, média de idade de 54 anos) com cirrose hepática diagnosticada por métodos clínicos, laboratoriais, de imagem e histopatológicos foram avaliados de forma prospectiva. Todos os pacientes apresentavam varizes de esôfago à endoscopia digestiva alta e foram submetidos a um questionário para avaliação da presença de sintomas típicos da doença do refluxo gastroesofágico (pirose e/ou regurgitação ácida). pHmetria esofagiana prolongada ambulatorial foi realizada posicionando-se o cateter 5 cm acima do limite superior do esfíncter esofagiano inferior, determinado previamente pela esofagomanometria. Refluxo anormal (% tempo total com pH < 4 >4,5%) foi relacionado com o tamanho das varizes, gastropatia congestiva, ascite, gravidade da cirrose e presença de sintomas típicos da doença do refluxo gastroesofágico. RESULTADOS: O calibre das varizes foi considerado pequeno em 30 pacientes (59%), médio em 17 (33%) e grosso em 4 (8%), 21 (41%) gastropatia congestiva. Ascite foi observada em 17 (33%); 32 pacientes (63%) foram classificados com Child-Pugh A, 17 (33%) Child-Pugh B e 2 (4%) Child-Pugh C. Vinte e sete pacientes (53%) apresentavam sintomas típicos da doença do refluxo gastroesofágico. Refluxo anormal a pHmetria esofagiana prolongada ambulatorial foi demonstrado em 19 pacientes (37%). Apenas um deles apresentava esofagite erosiva à endoscopia digestiva alta. Não houve relação entre ascite, calibre das varizes, gastropatia congestiva e classificação de Child-Pugh com refluxo anormal. Houve correlação entre a presença dos sintomas típicos da doença do refluxo gastroesofágico e refluxo anormal. CONCLUSÃO: Refluxo anormal foi demonstrado em 37% dos pacientes com cirrose hepática e varizes de esôfago. Apenas os sintomas típicos foram preditores de refluxo anormal.

BACKGROUND: Portal hypertension in patients with liver cirrhosis causes manifestations such as esophageal varices, ascites and edema. Some studies have been conducted about the role of esophageal varices in the development of esophageal motor disorders and abnormal gastroesophageal reflux in these patients. Ascites could be a factor promoting gastroesophageal reflux and it has been questioned whether reflux would favor the rupture of varices. However there are a few studies using ambulatory esophageal pH recording in the evaluation of these patients. AIMS: Evaluate gastroesophageal reflux by pH recording in cirrhotic patients with esophageal varices and possible predictors. METHODS: Fifty one patients (28 men, 23 women, mean age of 54 years) with liver cirrhosis, diagnosed by clinical, laboratorial, image and histological findings were prospectively evaluated. All patients had esophageal varices confirmed by endoscopy and were submitted to a questionnaire about typical gastroesophageal reflux disease symptoms (heartburn and or acid regurgitation). pH recording was performed with the probe placed 5 cm above the superior lower esophageal sphincter limit, as determined by manometry. Abnormal reflux (% total time with pH < 4 >4.5%) was related to the size of varices, congestive gastropathy, ascites, severity of cirrhosis and typical gastroesophageal reflux disease symptoms. RESULTS: The caliber of the varices was considered to be small in 30 patients (59%), medium in 17 (33%) and large in 4 (8%), 21 (41%) congestive gastropathy. Ascites was observed in 17 (33%), 32 patients (63%) were classified as Child-Pugh A, 17 (33%) Child-Pugh B and 2 (4%) Child-Pugh C. Twenty seven patients (53%) presented with typical gastroesophageal reflux disease symptoms. Abnormal reflux at pH recording was found in 19 patients (37%). One of them presented with erosive esophagitis at endoscopy. There was no relation between ascites, variceal size, congestive gastropathy and Child-Pugh score and abnormal reflux. There was a correlation between typical gastroesophageal reflux disease symptoms and abnormal reflux. CONCLUSION: Abnormal gastroesophageal reflux was found in 37% of the patients with hepatic cirrhosis and esophageal varices. Only typical gastroesophageal reflux disease symptoms predicted these findings.

O fígado é um órgão estratégico no metabolismo de macro e de micronutrientes e, portanto, é de esperar que o comprometimento de sua função seja acompanhado de alterações no estado nutricional de vitamina A. O objetivo deste artigo é revisar na literatura evidências científicas sobre o metabolismo hepático da vitamina A, o efeito das interações entre a vitamina A e o etanol sobre a morfologia hepática, além das alterações do metabolismo dessa vitamina na doença hepática alcoólica. Os dados foram selecionados na base de dados Medline no período de 1979 a 2005. O fígado é o principal órgão responsável pelo armazenamento, metabolismo e distribuição da vitamina A para os tecidos periféricos. Esse órgão utiliza retinol para seu funcionamento normal como proliferação e diferenciação celular. Dessa forma, a deficiência dessa vitamina parece alterar a morfologia hepática. Baixos níveis de retinol hepático têm sido encontrados em todos os estágios da doença hepática alcoólica. A deficiência de vitamina A na doença hepática alcoólica pode resultar da diminuição da sua ingestão ou absorção, na redução da síntese de ácido retinóico ou na diminuição da sua degradação. A ingestão crônica de álcool resulta em níveis reduzidos de ácido retinóico, o que favorece a formação de tumor hepático. Logo, em etilistas crônicos o estado nutricional de vitamina A deve ser monitorado, para evitar sua deficiência e seus sintomas clínicos, embora a suplementação deva ser feita com cautela, pois doses comumente usadas podem ser tóxicas para aqueles que consomem etanol.

The liver is a strategic organ in the metabolism of macro and micronutrients; when its functioning is compromised, it may cause some change in the nutritional status of vitamin A. The purpose of this article is to review scientific evidence in literature on the liver metabolism of vitamin A, the role of ethanol and retinol interactions on hepatic morphology, besides the alterations in the metabolism of this vitamin in alcoholic liver disease. Data were collected from Medline database. The liver is the main organ responsible for the storage, metabolism and distribution of vitamin A to peripheral tissues. This organ uses retinol for its normal functioning such as cell proliferation and differentiation. This way, vitamin A deficiency seems to alter liver morphology. Patients with alcoholic liver disease have been found to have low hepatic levels of retinol in all stages of their disease. In alcoholic liver disease, vitamin A deficiency may result from decreased ingestion or absorption, reduction in retinoic acid synthesis or increased degradation. Long-term alcohol intake results in reduced levels of retinoic acid, which may promote the development of liver tumor. So, in chronic alcoholic subjects, vitamin A status needs to be closely monitored to avoid its deficiency and clinical effects, however its supplementation must be done with caution since the usual dose may be toxic for those who consume ethanol.

RACIONAL: A cirrose hepática apresenta como uma das principais causas de morbimortalidade, a hipertensão porta com o desenvolvimento de varizes esofagianas, possibilidade de hemorragia digestiva alta e agravamento da insuficiência hepática. É importante identificar fatores preditivos causais ou agravantes desta condição e se possível, preveni-los. Nos últimos anos tem se observado a associação de distúrbios motores de esôfago e de refluxo gastroesofágico em pacientes cirróticos com varizes de esôfago. OBJETIVOS: Estudar a prevalência dos distúrbios de motilidade esofagiana e, entre eles, da motilidade esofagiana ineficaz, neste grupo de pacientes e seus possíveis fatores preditivos. MÉTODOS: Avaliaram-se de maneira prospectiva, 74 pacientes com cirrose hepática e varizes esofagianas diagnosticadas por endoscopia digestiva alta, virgens de tratamento endoscópico terapêutico. Todos foram submetidos a um protocolo de investigação clínica, a esofagomanometria e 55 pacientes também realizaram pHmetria esofagiana ambulatorial. RESULTADOS: Alterações da motilidade esofagiana foram observadas em 44 pacientes (60%), sendo a mais prevalente a motilidade esofagiana ineficaz, verificada em 28%. Refluxo anormal foi encontrado em 35% dos pacientes. Não houve correlação entre anormalidade manométrica em geral e motilidade esofagiana ineficaz, em particular, e a presença de sintomas esofagianos ou típicos de doença do refluxo, refluxo anormal, a gravidade da doença, a presença de ascite e o calibre das varizes. CONCLUSÕES: A maioria dos cirróticos com varizes esofagianas não submetidos a tratamento endoscópico apresenta distúrbios motores do esôfago, sem fatores preditivos identificáveis. A importância clínica desses achados necessita de maior aprofundamento na questão, para elucidar seu papel definitivo.

BACKGROUND: The hepatic cirrhosis has as one of the main morbid-mortality causes, the portal hypertension with the development of esophageal varices, the possibility of a digestive hemorrhage and worsening of hepatic insufficiency. It is important to identify causal predictive or aggravating factors and if possible to prevent them. In the last years, it has been observed the association of esophageal motor disorders and gastro-esophageal reflux in cirrhotic patients with esophageal varices. AIMS: To study the prevalence of the esophageal motility disorders and among them, the ineffective esophageal motility, in patients with hepatic cirrhosis and esophageal varices, without previous endoscopic therapeutic and the predictives factors. METHODS: Prospectively, it has been evaluate 74 patients suffering from liver cirrhosis and esophagic varices, without previous endoscopic treatment. All of them were submitted to a clinical protocol, esophageal manometry and 55 patients also held the ambulatory esophageal pHmetry. RESULTS: Esophageal motility disorders have been found in 44 patients (60%). The most prevalent was the ineffective esophageal motility, observed in 28%. The abnormal reflux disease was diagnosed through the pHmetry in 35% of the patients. There were no correlation between the manometrical abnormality in general and the ineffective esophageal motility in particular and the esophageal or gastroesophageal reflux disease symptoms, the abnormal reflux, the disease seriousness, the ascites presence and the gauge of the varices. CONCLUSIONS: The majority of cirrhotic patients with non-treated esophageal varices present esophageal motor disorders. No predictive factor was found. The clinical relevance of these findings need more researches in the scope to define the real meaning of theses abnormalities.

Racional - Foram estudados 125 pacientes com hepatite crônica ativa e cirrose pós-hepatite por vírus B ou C, e diferentes graus de acometimento funcional hepático. Objetivo - Traçar um perfil hormonal tiroidiano nesses pacientes. Material e Métodos - Os pacientes foram divididos em quatro grupos: a) 31 com hepatite crônica ativa; b) 41 com cirrose pós-hepatite Child A; c) 35 com cirrose pós-hepatite Child B e d) 18 com cirrose pós-hepatite Child C. Além das dosagens séricas de albumina e bilirrubina, determinação do tempo de atividade da protrombina e avaliação da presença de ascite e encefalopatia hepática, todos foram submetidos a dosagens séricas de triiodotironina (T3), tiroxina (T4), hormônio estimulador da tiróide (TSH), tiroxina livre (FT4), triiodotironina reversa (rT3), cálculo do índice rT3/T3 (IrT3) e realização do teste do TRH. Resultados - Quando se compararam as médias dos resultados dos testes entre os diferentes grupos, observou-se que o T3 foi o exame mais expressivo, gradativamente mais baixo, quanto mais avançada a doença (hepatite crônica ativa: 149,2 ± 42,3 ng/dL; cirrose pós-hepatite Child A: 137,4 ± 37,2 ng/dL; cirrose pós-hepatite Child B: 88,0 ± 28,4 ng/dL e cirrose pós-hepatite Child C: 41,8 ± 21,9 ng/dl). Os níveis do TSH, T4 e FT4 foram normais na maioria dos pacientes, porém níveis séricos baixos do T4 (4,5 ± 2,0 µg/dL) e FT4 (0,7 ± 0,4 ng/dL) e elevados do TSH (7,2 ± 11,5 µIU/mL), rT3 (60,8 ± 52,1 ng/dL) e IrT3 (2,2 ± 2,6) eram mais freqüentes nos pacientes com cirrose pós-hepatite Child C. O teste do TRH foi normal na maioria dos pacientes. Conclusão - O estudo mostra relação direta entre os níveis séricos baixos do T3 e elevados do rT3 e do IrT3 com o grau de disfunção hepática, segundo a classificação de Child-Pugh.

Background - One hundred and twenty five patients with virus B or C chronic active hepatitis and postnecrotic cirrhosis and different degrees of liver dysfunction were studied. Aim - 1) To determine a thyroid hormonal profile; 2) to evaluate the prognostic value of these tests in relation to the progression of the disease and mortality; 3) compare these findings with Child-Pugh classification. Patients and Methods - The patients were divided in four groups: a) 31 with chronic active hepatitis; b) 41 with postnecrotic cirrhosis Child A; c) 35 with postnecrotic cirrhosis Child B and d) 18 with postnecrotic cirrhosis Child C. The protocol comprised serum measurements of albumin and bilirrubin, estimates of prothrombin time and clinical evaluation of ascites and encephalopathy, measurement of total serum triiodothyronine, thyroxine, thyroid-stimulating hormone, free thyroxine, reverse triiosothyronine, calculated rT3/T3 index (IrT3) and thyrotropin-releasing hormone test. Results - Total serum triiodothyromnine showed the most significant difference among the groups, gradually lower as the disease became more advanced (CAH: 149,2 ± 42,3 ng/dL; PNC-A: 137,4 ± 37,2 ng/dL; PNC-B: 88,0 ± 28,4 ng/dL and PNC-C: 41,8 ± 21,9 ng/dL). Low levels of T4 (4,5 ± 2,0 µg/dL) and FT4 (0,7 ± 0,4 ng/dL) and elevated levels of thyroid-stimulating hormone (7,2 ± 11,5 µIU/mL), reverse triiosothyronine (60,8 ± 52,1 ng/dL) and calculated rT3/T3 index (2,2 ± 2,6) were more frequent in patients with postnecrotic cirrhosis Child C. Thyrotropin-releasing hormone test was normal in the majority of the patients. Conclusion - The present study shows a positive relationship between the low serum levels of T3 and elevated serum levels of rT3 and IrT3/T3 with the degree of hepatic dysfunction according to the Child-Pugh classification.

O vírus da hepatite C é o principal responsável pela hepatite pós-transfusional e sua progressão para hepatite crônica, cirrose e carcinoma hepatocelular é muito comum. A fim de avaliar frequência, tempo e fatores relacionados à progressão da hepatite C, estudamos 175 pacientes com hepatite C pós-transfusional. Estes foram divididos em 2 grupos com cirrose (n = 92) e sem cirrose (n = 83). O tempo médio de desenvolvimento de cirrose foi de 11 ± 6 anos. Pacientes com cirrose eram mais velhos à época da transfusão, apresentavam maior prevalência de alcoolismo e tinham tempo de evolução mais longo. O prognóstico foi pior no grupo com cirrose com 28,4% de mortalidade e 9,1% de carcinoma hepatocelular, comparados a 5,5% e 0% no grupo sem cirrose, respectivamente. Concluímos que a hepatite C pós-transfusional é uma doença progressiva, que se agrava com o passar do tempo, progridindo mais rapidamente em idosos e pacientes com outros fatores de agressão hepática.

Hepatitis C virus is the main agent responsable for post-transfusion hepatitis. Progression to chronic hepatitis, cirrhosis and hepatocellular carcinoma is very commom. The aim of this study was to evaluate the frequency, timing and factors related to progression of hepatitis C. One hundred seventy five patients with chronic post-transfusion hepatitis C were grouped in a cirrhosis group (n = 92) and a non-cirrhosis group (n = 83). The medium time of development to cirrhosis was 11 ± 6 years. Patients with cirrhosis were older at the time they received transfusion, used more alcohol and had longer times of evolution. The prognosis was worse in the cirrhosis group with a mortality rate of 28.4% and 9.1% of evolution towards hepatocellular carcinoma, comparing with 5.5% and 0% in the non-cirrhosis group respectively. It is shown that post-tranfusion hepatitis C is slowly developing progressive disease which progress is much more rapidly in elderly patients and patients with others factors of liver damage.