Response to Ursodeoxycholic Acid May Be Assessed Earlier to Allow Second-Line Therapy in Patients with Unresponsive Primary Biliary Cholangitis.

BACKGROUND: Response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has been traditionally assessed 1 to 2 years after treatment initiation. With the development of new drugs, some patients may benefit from an earlier introduction of second-line therapies. AIMS: This study aims to identify whether well-validated response criteria could correctly identify individuals likely to benefit from add-on second-line therapy at 6 months. METHODS: Analysis of a multicenter retrospective cohort which included only patients with clear-cut PBC. RESULTS: 206 patients with PBC (96.6% women; mean age 54 ± 12 years) were included. Kappa concordance was substantial for Toronto (0.67), Rotterdam (0.65), Paris 1 (0.63) and 2 (0.63) criteria at 6 and 12 months, whereas Barcelona (0.47) and POISE trial (0.59) criteria exhibited moderate agreement. Non-response rates to UDCA was not statistically different when assessed either at 6 or 12 months using Toronto, Rotterdam or Paris 2 criteria. Those differences were even smaller or absent in those subjects with advanced PBC. Mean baseline alkaline phosphatase was 2.73 ± 1.95 times the upper limit of normal (× ULN) among responders versus 5.05 ± 3.08 × ULN in non-responders (p < 0.001). CONCLUSIONS: After 6 months of treatment with UDCA, the absence of response by different criteria could properly identify patients who could benefit from early addition of second-line therapies, especially in patients with advanced disease or high baseline liver enzymes levels.

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.

Usefulness of collagen type IV in the detection of significant liver fibrosis in nonalcoholic fatty liver disease.

INTRODUCTION/AIMS: Liver fibrosis assessment is a key issue in the evaluation of nonalcoholic fatty liver disease (NAFLD) patients. In the present study, we aimed to validate a noninvasive marker panel to assess significant and advanced fibrosis in these patients. METHOD: 126 biopsy-proven NAFLD patients were included. NAFLD diagnosis was based on histological criteria. Fibrosis stages were determined according to NASH-Clinical Research Network criteria. Clinical and laboratorial data were collected during the interval of three months before or after liver biopsy. Histological fibrosis stages were classified as significant fibrosis (F2-F4) and advanced fibrosis (F3-F4). Five serum biomarkers [hyaluronic acid (HA), collagen type IV (cIV), procollagen type III (PC III), laminin (LN) and cholylglycine (CG)] were assessed by chemiluminescence immunoassays. RESULTS: Most patients were female (61.61%), mean age: 55.7 ±â€¯9.13 years old and mean BMI was 32.1 ±â€¯5.9 kg/m2. Prevalence of diabetes, dyslipidemia, arterial hypertension, and metabolic syndrome was 68.75%, 82.29%, 63.54% and 81.05%, respectively. Patients with cIV above 30 ng/mL had a 5.57-times (IC: 1.86-16.69) the chance of having significant fibrosis and 7.61-times (IC: 2.27-25.54) the chance of having advanced fibrosis versus patients with values below 30 ng/mL. HA, PC III, LN and CG did not detect the presence of significant and advanced fibrosis. The AUROC of clV for detection of significant (0.718) and advanced fibrosis (0.791) was better than that of other serum biomarkers. CONCLUSION: Type 4 collagen could predict the presence of significant and advanced fibrosis in NAFLD patients and it would be a useful tool in routine clinical practice.

Diagnostic performance of three non-invasive fibrosis scores (Hepamet, FIB-4, NAFLD fibrosis score) in NAFLD patients from a mixed Latin American population.

INTRODUCTION AND AIMS: Several non-invasive scoring systems have been developed and validated worldwide to predict the risk of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). However, information about the performance of these systems in Latin American populations is scarce. Our aim was to evaluate the performance of the Hepamet Fibrosis Score, Fibrosis-4 (FIB-4) and the NAFLD Fibrosis Score (NFS) in a mixed Latin American group of NAFLD patients. METHODS: Clinical, laboratory and liver biopsy data collected from 379 biopsy-proven NAFLD patients from Latin American tertiary health centers were reviewed. Histological fibrosis stages were classified using the Kleiner score. Accuracy was determined, and new fibrosis score thresholds were calculated to better compare the performances of non-invasive tests and to explore their usefulness in excluding fibrosis. RESULTS: The distribution of fibrosis stages among the sample population was as follows: F0 (45%), F1 (27%), F2 (8%), F3 (16%) and F4 (4%). Using modified thresholds, the areas under the ROC curves (AUROC) for Hepamet and FIB-4 (0.73 and 0.74, respectively) to detect significant fibrosis were higher than that of NFS (0.58). However, the AUROCs of the three scores were not significantly different in advanced fibrosis and cirrhosis. To exclude fibrosis, we calculated lower cutoffs than standard thresholds for Hepamet, FIB-4 and NFS with similar performances. CONCLUSION: Thresholds of non-invasive fibrosis scores (Hepamet, FIB-4 and NFS) can be modified to maximize diagnostic accuracy in Latin American patients with NAFLD.

Bioactivities of Centaurium erythraea (Gentianaceae) Decoctions: Antioxidant Activity, Enzyme Inhibition and Docking Studies.

Centaurium erythraea is recommended for the treatment of gastrointestinal disorders and to reduce hypercholesterolemia in ethno-medicinal practice. To perform a top-down study that could give some insight into the molecular basis of these bioactivities, decoctions from C. erythraea leaves were prepared and the compounds were identified by liquid chromatography-high resolution tandem mass spectrometry (LC-MS/MS). Secoiridoids glycosides, like gentiopicroside and sweroside, and several xanthones, such as di-hydroxy-dimethoxyxanthone, were identified. Following some of the bioactivities previously ascribed to C. erythraea, we have studied its antioxidant capacity and the ability to inhibit acetylcholinesterase (AChE) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR). Significant antioxidant activities were observed, following three assays: free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) reduction; lipoperoxidation; and NO radical scavenging capacity. The AChE and HMGR inhibitory activities for the decoction were also measured (56% at 500 µg/mL and 48% at 10 µg/mL, respectively). Molecular docking studies indicated that xanthones are better AChE inhibitors than gentiopicroside, while this compound exhibits a better shape complementarity with the HMGR active site than xanthones. To the extent of our knowledge, this is the first report on AChE and HMGR activities by C. erythraea decoctions, in a top-down analysis, complemented with in silico molecular docking, which aims to understand, at the molecular level, some of the biological effects ascribed to infusions from this plant.

Prevalence and significance of antimitochondrial antibodies in autoimmune hepatitis (AIH): Results from a large multicentre study of the International AIH Group.

BACKGROUND & AIMS: Antimitochondrial antibodies (AMA) are specific markers for the diagnosis of primary biliary cholangitis (PBC) but can also be found occasionally in patients with autoimmune hepatitis (AIH). The present large multicentre cohort study assessed the prevalence and significance of AMA in AIH-patients. METHODS: 123 AMA-positive AIH-patients were investigated and compared with 711 age-matched AMA-negative AIH-patients and 69 patients with AIH/PBC variant. RESULTS: AMA prevalence in AIH-patients was 5.1% (range: 1.2%-11.8%). AMA-positivity was associated with female sex (p = 0.031) in AMA-positive AIH-patients but not with liver biochemistry, bile duct injury on liver biopsy, disease severity at baseline and response to treatment compared to AMA-negative AIH-patients. Comparing AMA-positive AIH-patients to those with AIH/PBC variant, there was no difference in disease severity. Regarding liver histology, AIH/PBC variant patients were characterized by the presence of at least one feature of bile duct damage (p<0.001). Response to immunosuppressive treatment was similar among groups. From AMA-positive AIH patients only those with evidence of non-specific bile duct injury had higher risk to progress to cirrhosis (HR=4.314, 95%CI: 2.348-7.928; p<0.001). During follow-up, AMA-positive AIH-patients had higher risk to develop histological bile duct injury (HR 4.654, 95%CI 1.829-11.840; p = 0.001). CONCLUSIONS: AMA presence is relatively common among AIH-patients, but their clinical significance seems important only when they co-exist with non-specific bile duct injury at the histological level. Therefore, a careful evaluation of liver biopsy seems of utmost importance in these patients.

Fibrates for the Treatment of Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid: An Exploratory Study.

Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC. Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria. Results: In total, 27 patients (100% women, mean age 48.9 ± 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39-76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria. Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients.

Effect of Food Preparations on In Vitro Bioactivities and Chemical Components of Fucus vesiculosus.

Fucus vesiculosus is a brown macroalgae used in food and generally considered safe to be consumed, according to EU Directive (EC 258/97). The aim of this study is to analyze the effect of food preparation on F.vesiculosus of different origins on what concerns its chemical constituents and final bioactivities. The aqueous extract of the seaweeds were obtained at different temperatures, similar to food preparation and then purified by SPE. The compound identification was carried out by Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS/MS) and algae extracts microstructure were observed by Scanning Electron Microscopy (SEM). The activities were determined by using antioxidant activity, inhibition of acetylcholinesterase (AChE) and 3-hidroxi-3-methyl-glutaril-CoA (HMG-CoA) reductase (HMGR) together with Caco-2 cells line simulating the intestinal barrier. The activity of AChE and the HMGR were inhibited by the extracts giving IC50 values of 15.0 ± 0.1 µg/mL and 4.2 ± 0.1 µg/mL, respectively and 45% of the cholesterol permeation inhibition. The main compounds identified were phlorotannins and peptides derivatives. The mode of preparation significantly influenced the final bioactivities. Moreover, the in vitro results suggest that the preparation of F. vesiculosus as a soup could have hypercholesterolemia lowering effect.

Epidemiologia das hepatites virais por classificação etiológica / Epidemiology of viral hepatitis by etiological classification

OBJETIVO: Descrever e analisar a epidemiologia das hepatites virais. MÉTODOS: Estudo epidemiológico descritivo realizado por meio da análise de dados obtidos do banco de dados da plataforma do Departamento de Informática do Sistema Único de Saúde relativos ao Estado de Minas Gerais, com as variáveis número de casos, hepatite viral CID 10 (B15 a B19), faixa etária, forma de transmissão, sexo e etnia no período de 2010 a 2017. RESULTADOS: Somaram-se 14.308 casos de hepatite A, B e C entre 2010 e 2017 em Minas Gerais. A hepatite C foi a mais prevalente com 50%, seguido da hepatite B com 39% e da hepatite A com 11%. O sexo masculino (70,2%) contrastou com o feminino (50,8%) no panorama geral. Quanto à etnia, foram obtidos 38% na parda e 37,5% na branca, em contraste com 0,4% na indígena. A faixa etária mais acometida foi de 40 a 59 anos com 54% dos casos. Surpreendeu a manutenção do número de casos registrados de vírus C transmitidos via transfusão sanguínea, provavelmente antes do reconhecimento do vírus, nos anos 1990 (1.002 casos), além da existência de casos de vírus A transmitidos via sexual (30 casos). CONCLUSÃO: Em Minas Gerais, a epidemiologia das hepatites virais seguiu a tendência global em faixa etária e número de casos. Todavia tornase imprescindível considerar novas abordagens de prevenção e controle com foco em educação sexual em saúde independente, principalmente nas faixas etárias jovens e avançadas. (AU)

OBJECTIVE: To describe and analyze the epidemiology of viral hepatitis. METHODS: This is a descriptive epidemiological study based on the analysis of data from the Department of Informatics of the Unified Health System in the state of Minas Gerais, with the following variables: viral hepatitis ICD 10 (B15-B19), age range, way of transmission, gender, and ethnicity, from 2010 to 2017. RESULTS: There were 14,308 cases of hepatitis A, B, and C from 2010 to 2017 in the state of Minas Gerais. Hepatitis C vírus was the most prevalent with 50%, followed by hepatitis B virus with 39%, and hepatitis A virus with 11%. The male gender (70.2%) contrasted with the female (50.8%) in the general panorama. As for ethnicity, 38% were in the brown people, and 37.5% in the white people, compared to 0,4% in the indigenous people. The most affected age group was 40-59 years, with 54% of the cases. Surprisingly, the number of registered cases of C virus transmitted by blood transfusion was steady, probably before the virus was recognized in the 1990s (1002 cases), and there were cases of virus A transmitted via sexual intercourse (30 cases). CONCLUSION: In Minas Gerais, the epidemiology of viral hepatitis follows the global trend in terms of age range and number of cases; however, it is imperative to consider new approaches in prevention and control, focusing on sexually independent health education, mainly in the young and advanced age groups. (AU)

Tripla infecção com HTLV-1, leishmaniose visceral e estrongiloidíase complicada por pancreatite aguda / Triple infection with HTLV-1, visceral leishmaniasis and strongyloidiasis complicated by acute pancreatitis

lntrodução: a estrongiloidíase tem grande importância médica devido à capacidade de o Strongyloides stercoralis completar seu ciclo de vida no homem e gerar a síndrome de hiperinfecção principalmente em imunocomprometidos. Devido à dificuldade em estruturar a resposta Th2, os pacientes infectados com o Vírus Linfotrópico de Células T Humanas Tipo 1 (HTLV-1) têm maior tendência a apresentar infecção maciça. A leishmaniose visceral, doença relevante em países em desenvolvimento, causa alterações imunológicas semelhantes, porém há poucos relatos de suscetibilidade específica ao Strongyloides stercoralis nos infectados por Leishmania sp. O presente trabalho tem objetivo de relatar um caso de coinfecção HTLV e calazar, que apresentou-se como pancreatite aguda e enteropatia perdedora de proteínas secundárias à estrongiloidíase maciça. Relato de caso: trata-se de um paciente de 34 anos com história de leishmaniose prévia que deu entrada no nosso Serviço com pancreatite aguda idiopática leve, além de história de diarreia crônica há um ano com anasarca e hipoalbuminemia associadas. Apresentou endoscopia digestiva alta com atrofia duodenal importante, tendo sido identificados Strongyloides stercoralis em biópsia, além de sorologia para HTLV positiva. Apresentou translocação bacteriana com sepse grave de foco abdominal, após início do tratamento com ivermectina, tendo posteriormente evoluído com melhora clínica importante e remissão dos sintomas. Fez investigação com punção de medula óssea, em que foram identificadas as formas amastigotas da leishmania. Discussão e conclusão: a presença de HLTV é um fator de risco para a síndrome de hiperinfecção por Strongyloides stercoralis, tendo predisposto o paciente às manifestações graves e raras descritas. A identificação de leishmania na medula óssea, entretanto, é um fator de risco ainda pouco conhecido para estrongiloidíase disseminada, porém com plausibilidade biológica por afetar o sistema imunológico do hospedeiro.(AU)

Introduction: strongyloidiasis has great medical importance because of the ability of the Strongyloides stercoralis to complete its life cycle in man and cause hyperinfection syndrome especially in immunocompromised hosts. Because of the difficulty in triggering The response, Human T-cell lymphotropic virus type 1 (HTLV-1) infected patients has susceptibility for massive infection. Visceral leishmaniasis, a relevant disease in developing countries, causes similar immunological changes, but there are few reports of specific susceptibility to Strongyloides stercoralis on infected by Leishmania sp. This study aimed to report a case of HTLV and kala azar coinfection, presenting as acute pancreatitis and protein losing enteropathy secondary to massive strongyloidiasis. Case report: a 34-year-old patient previously treated for leishmaniasis has presented at our service with idiopathic acute pancreatitis and chronic diarrhea for one year with anasarca and hypoalbuminemia. Upper endoscopy revealed duodenal atrophy in which biopsy identified Strongyloides stercoralis, and HLTV serology was positive. He presented with bacterial translocation and severe sepsis after first dose of ivermectin, but has clinical improvement and remission of symptoms afterwards. Bone marrow aspiration identified amastigote forms of Leishmania. Discussion and Conclusion: the presence of HLTV is a risk factor for Strongyloides stercoralis hyperinfection, and predisposed this patient to the serious and rare events described. The identification of Leishmania in bone marrow, however, is an poorly known risk factor for disseminated strongyloidiasis, but with biological plausibility because it affects the immune system of the host.(AU)

Irradiaçäo de corpo inteiro usando-se uma unidade de telecobaltoterapia com seus colimadores removidos / Total body irradiation using a cobalt unit with its collimators removed

A técnica de radiaçäo de corpo inteiro requer campos suficientemente grandes a fim de englobar todo o paciente. Existem vários métodos que podem ser utilizados para a obtençäo dos campos requeridos por essa técnica de tratamento, entre os quais a construçäo de uma unidade exclusiva, o deslocamento do paciente ao longo de uma unidade fixa ou a modificaçäo de uma unidade construída para o tratamento convencional. No Instituto Nacional de Câncer o problema foi resolvido por meio de remoçäo dos colimadores de uma unidade construída para o tratamento convencional que possibilita a obtençäo de um campo circular de 2,25 , de diâmetro a 147 cm da fonte. O processo de remoçäo e reposiçäo dos colimadores é extremamente rápido e näo interfere no funcionamento normal do aparelho. A homogeneidade do campo de um filtro achatador, de simples construçäo e fácil colocaçäo. Os parâmetros dosimétricos e relevantes foram mantidos nas condiçöes geométricas de tratamento

Estudo da dose superfície e regiäo de bluild-up de um feixe de fótons de 18 MV / Surface dose and build-up region from a 18 MV photon beam

Foi realizado um estudo do comportamento da dose superfície e da regiäo de build-up em funçäo de diversos parâmetros de intersse clínico para o feixe de fótons de 18 MV do acelerador linear Saturne (Therac 20). As curvas de dose em profundidade foram obtidas, com uma câmara de ionizaçäo de placas paralelas de 0,03 cm3, para ambas as polaridades, em um fantoma de acrílico, no eixo central do feixe, além de pontos fora do eixo correspondentes a regiöes anatômicas de interesse quando da irradiaçäo de campos irregulares. Foi estudada a variaçäo da dose superfície em funçäo do tamanho de campo, da distância fonte superfície e da presença da bandeja e da placa de mylar do tampo eda mesa quando da irradiaçäo póstero-anterior. Foram também feitas medidas no eixo central variando-se o ângulo de incidência do feixe