Application of acoustic radiation force impulse elastography combined with serum markers in Child-Pugh grading

OBJECTIVES: Acoustic radiation force impulse (ARFI) elastography, the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and the fibrosis-4 (FIB-4) index are widely used to assess liver fibrosis. However, efficacies of these methods in the evaluation of hepatic functional reserve remain unclear. In this study, we investigated the relationship between ARFI elastography combined with either AAR, APRI, or FIB-4 index and Child-Pugh (CP) class for the evaluation of hepatic functional reserve in patients with chronic hepatitis B (CHB)-related cirrhosis. METHODS: The shear wave velocities of 104 patients with clinically confirmed CHB-related cirrhosis were determined using the ARFI; and clinical serum markers (e.g. ALT, AST, PLT) were used to calculate the AAR, APRI, and FIB-4 index. Cirrhosis patients were scored according to their CP class. The ARFI, AAR, APRI, and FIB-4 index were compared with the CP class. The efficacy of each indicator in diagnosis was analyzed using the receiver operating characteristic (ROC) curve and the ARFI combined with either the AAR, APRI, or FIB-4 index, which is used to predict decompensated cirrhosis. RESULTS: No significant differences were observed in gender and age among CP classes A, B, and C patients (p>0.05). The ARFI values and the AAR, APRI, and FIB-4 index of patients with CP classes A, B, and C were significantly different (p<0.05). With an increasing CP class, the ARFI, AAR, APRI, and FIB-4 values increased. The correlation between the ARFI and the CP class was stronger than that between the AAR, APRI, and FIB-4 index and the CP class. The area under the ROC curve for the diagnosis of decompensated cirrhosis using the ARFI was 0.841, which was higher than that for the AAR, APRI, and FIB-4 index. According to the area under the curve results, no significant differences were found when the ARFI was combined with either the AAR, APRI, or FIB-4 index and when the ARFI alone was used. CONCLUSIONS: The ARFI value has a strong correlation with the CP class. Therefore, ARFI elastography complements CP class in the assessment of the hepatic functional reserve in patients with CHB-related cirrhosis.

Association of serum levels of C-reactive protein with CRP-717 T/C polymorphism and viremia in HCV and HBV carriers

Abstract INTRODUCTION: The present study investigated the association of the rs2794521 polymorphism in the CRP gene in individuals with chronic hepatitis B and C, correlating it with markers of hepatic inflammation, fibrosis scores, viral load, and plasma protein levels. METHODS: The study analyzed 185 blood samples obtained from patients with hepatitis B (n=74) and hepatitis C (n=111) and 300 samples from healthy donors. Genotyping was performed by real-time polymerase chain reaction, and protein levels were quantified using the automated immunoturbidimetric method. RESULTS: The TT genotype was the most frequent in all studied groups and was associated with higher plasma levels of the protein but not with the progression of liver disease. Low levels of C-reactive protein were associated with increased viremia and scores indicative of severe fibrosis and cirrhosis. CONCLUSIONS: The present results demonstrated a close relationship between the ability of the virus to replicate and cause liver damage and low serum concentrations of C-reactive protein. Future research may determine if these results can be interpreted as a possible form of escape for the virus by decreasing its action as an opsonin and decreasing phagocytosis, which are functions of C-reactive protein in the immune response.

Monitoring of coagulation by intraoperative thromboelastometry of liver transplantation in a patient using warfarin - case report / Monitoração da coagulação pela tromboelastometria no intraoperatório de transplante hepático em um paciente usando varfarina - relato de caso

Abstract Introduction: Advanced hepatic disease may - in addition to the widely recognized hemorrhagic complications - occur with thrombotic events. We describe the case of a cirrhotic patient taking warfarin and whose coagulation management during liver transplantation was guided by thromboelastometry (ROTEM®). Case report: A 56 year-old male patient diagnosed with alcohol cirrhosis using warfarin (2.5 mg.day−1) for partial portal vein thrombosis with the International Normalized Ratio (INR) of 2.14. At the beginning of surgery, the ROTEM® parameters were all normal. In the anhepatic phase, EXTEM and INTEM remained normal, but FIBTEM showed reduction of amplitude after 10 min and maximum clot firmness. Finally, in the neohepatic phase, there was a slight alteration in the hypocoagulability of most of the parameters of the EXTEM, INTEM and FIBTEM, besides a notable correction of the Coagulation Time (CT) in HEPTEM compared to the CT of the INTEM. Therefore, the patient did not receive any transfusion of blood products during surgery and in the postoperative period, being discharged on the 8th postoperative day. Discussion: Coagulation deficit resulting from cirrhosis distorts INR as a parameter of anticoagulation adequacy and as a determinant of the need for blood transfusion. Thus, thromboelastometry can provide important information for patient management.

Resumo Introdução: A doença hepática avançada pode, além das complicações hemorrágicas amplamente reconhecidas, ocorrer com eventos trombóticos. Descrevemos o caso de um paciente cirrótico em uso de varfarina, cujo manejo da coagulação durante o transplante de fígado foi guiado por tromboelastometria (ROTEM®). Relato de caso: Paciente do sexo masculino, 56 anos, diagnosticado com cirrose alcoólica, recebendo varfarina (2,5 mg.dia−1) para trombose parcial da veia porta, com razão normalizada internacional (INR) de 2,14. No início da cirurgia, os parâmetros ROTEM® estavam todos normais. Na fase não hepática, EXTEM e INTEM permaneceram normais, mas FIBTEM mostrou redução da amplitude após 10 min e firmeza máxima do coágulo. Por fim, na fase neo-hepática houve uma ligeira alteração da hipocoagulabilidade na maioria dos parâmetros de EXTEM, INTEM e FIBTEM, além de uma correção notável do tempo de coagulação (CT) de HEPTEM em comparação com o CT de INTEM. Portanto, o paciente não recebeu transfusão de hemoderivados durante a cirurgia e no período pós-operatório, obteve alta no oitavo dia de pós-operatório. Discussão: O déficit de coagulação resultante da cirrose distorce o INR como um parâmetro da adequação da anticoagulação e como um determinante da necessidade de transfusão de sangue. Portanto, a tromboelastometria pode fornecer informações importantes para o manejo do paciente.

Correlações entre características da doença hepática gordurosa não-alcoólica e os níveis de adipocinas e citocinas inflamatórias em indivíduos submetidos à cirurgia bariátrica / Correlation between nonalcoholic fatty liver disease features and levels of adipokines and inflammatory cytokines among morbidly obese individuals

ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the commonest hepatopathy worldwide. OBJECTIVE: To investigate the correlations between NAFLD histopathological features and the levels of adipokines (adiponectin, leptin, and resistin) and circulating inflammatory markers (interleukin-6 [IL-6], interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-α], and C-reactive protein [CRP]). METHODS: This is an exploratory cross-sectional study, which enrolled 19 women with obesity who underwent bariatric surgery. Biochemical characteristics evaluated included the levels of adiponectin, leptin, resistin, IL-6, IL-8, TNF-α, and CRP. NAFLD was assessed through histological examination of liver biopsies carried out during the surgical procedures. RESULTS: The mean age of the study group was 37.3±8.2 years old; mean BMI was 36.2±2.5 kg/m2. Among individuals with liver fibrosis, the levels of IL-8 were significantly higher (24.4 ± 9.7 versus 12.7 ± 6.6; P=0.016726). The intensity of fibrosis presented a significant negative correlation with the levels of adiponectin (R= -0.49379; P=0.03166); i.e. the higher the levels of adiponectin, the lower the intensity of fibrosis. The intensity of steatohepatitis presented a significant negative correlation with the levels of adiponectin (R= -0.562321; P=0.01221); this means that the higher the levels of adiponectin, the lower the intensity of steatohepatitis. CONCLUSION: Adiponectin levels were inversely correlated with the severity of fibrosis and steatohepatitis, whereas IL-8 levels were higher in individuals with liver fibrosis among individuals with obesity and NAFLD undergoing bariatric surgery. The use of these markers to assess NAFLD may bring significant information within similar populations.

RESUMO CONTEXTO: A doença hepática gordurosa não-alcoólica (DHGNA) é a hepatopatia mais comum no mundo. OBJETIVO: Investigar correlações entre as apresentações histopatológicas da DHGNA e os níveis de adipocinas (adiponectina, leptina e resistina) e marcadores sistêmicos de inflamação (interleucina-6 [IL-6], interleucina-8 [IL-8], fator de necrose tumoral alfa [TNF-α] e proteína C reativa [PCR]). MÉTODOS: Estudo transversal exploratório envolvendo 18 mulheres com obesidade submetidas à cirurgia bariátrica. As características bioquímicas avaliadas incluíram os níveis de adiponectina, leptina, resistina, IL-6, IL-8, TNF-α e PCR. A DHGNA foi avaliada através de exams histológicos de biópsias hepáticas realizadas durantes as cirurgias. RESULTADOS: A idade média foi 37,3±8,2 anos; o índice de massa corporal (IMC) médio foi 36,2±2,5 kg/m2. Entre os indivíduos com fibrose hepática, os níveis de IL-8 foram significativamente mais altos (24,4±9,7 versus 12,7±6,6; P=0,016726). A intensidade da fibrose apresentou uma correlação negativa significativa com os níveis de adiponectina (R= -0,49379; P=0,03166), demonstranso que, quanto maiores os níveis de adiponectina, menor a intensidade da fibrose. A intensidade da esteato-hepatite apresentou uma correlação negativa significativa com os níveis de adiponectina (R= -0,562321; P=0,01221), demonstrando que quanto mais altos os níveis de adiponectina, menor a intensidade da esteato-hepatite. CONCLUSÃO: Os níveis de adiponectina correlacionaram-se negativamente com a severidade da fibrose e da esteato-hepatite, enquanto os níveis de IL-8 foram maiores entre os indivíduos com fibrose hepática. O uso destes marcadores pode trazer informações significativas sobre a DHGNA em populações com obesidade.

El polimorfismo rs12979860 C> T en el gen Interferón lambda 4 no está asociado a riesgo de fibrosis hepática en pacientes chilenos con hepatitis crónica por virus C / Interferon Lambda 4 RS12979860 C> T polymorphism is not associated with liver fibrosis in patients with hepatitis C

Background. Host genetic predispositions may be important determinants of liver fibrosis in patients with chronic hepatitis C (CHC). The association between Interferon-L 4 (IFNL4) rs12979860 C>T polymorphism and risk of liver fibrosis in CHC is contradictory. Aim: To evaluate the impact of IFNL4 rs12979860 polymorphism on the risk of fibrosis in patients with CHC. Material and Methods: One hundred fifty patients with CHC aged 50 ± 11 years (89 females) were genotyped for IFNL4 rs12979860 using real time PCR. Fibrosis present in liver biopsies was assessed using the METAVIR score, comparing patients with either no fibrosis, mild fibrosis, or intermediate fibrosis (F0+F1+F2, n = 96), with patients with severe fibrosis or cirrhosis (F3+F4, n = 54). Results: In F0-F2 patients the distribution of rs12979860 genotypes was 22 CC, 57 CT and 17 TT, whereas in patients F3-F4 the distribution was 10, 29 and 15, respectively. No association between IFNL4 rs12979860 genotype and risk of fibrosis was observed in uni or multivariate analyses. Conclusions: IFNL4 rs12979860 C>T polymorphism is not associated with risk of liver fibrosis in this group of patients with CHC.

IL-6, TNF-α, IL-10, and nutritional status in pediatric patients with biliary atresia / IL-6, TNF-α, IL-10 e estado nutricional em pacientes pediátricos com atresia biliar

Abstract Objectives: The objective of the present study is to evaluate whether IL-6, TNF-α, IL-10 are associated with nutritional status in patients with cirrhosis secondary to biliary atresia and compare to healthy controls. Methods: The parameters used for nutritional assessment were the standard deviation scores of height-for-age and of triceps skinfold thickness-for-age. The severity of cirrhosis was evaluated using the Child-Pugh score and PELD/MELD. Serum cytokines were measured using Cytometric Bead Array flow cytometry. Results: IL-6, TNF-α, and IL-10 were significantly higher in the cirrhosis group when compared with the control group (2.4 vs. 0.24 (p < 0.001), 0.21 vs. 0.14 (p = 0.007), and 0.65 vs. 0.36 (p = 0.004), respectively. IL-6 and IL-10 were positively correlated with disease severity (0.450 [p = 0.001] and 0.410; [p = 0.002], respectively). TNF-α did not show a significant correlation with disease severity (0.100; p = 0.478). Regarding nutritional evaluation, IL-6 was negatively correlated with the standard deviation score of height-for-age (−0.493; p < 0.001) and of triceps skinfold thickness-for-age (−0.503; p < 0.001), respectively. IL-10 exhibited a negative correlation with the standard deviation score of height-for-age (−0.476; p < 0.001) and the standard deviation score of triceps skinfold thickness-for-age (−0.388; p = 0.004). TNF-α did not show any significance in both anthropometric parameters (−0.083 (p = 0.555) and −0.161 (p = 0.253). Conclusion: The authors suggest that, in patients with cirrhosis secondary to biliary atresia, IL-6 could be used as a possible supporting biomarker of deficient nutritional status and elevated IL-10 levels could be used as a possible early-stage supporting biomarker of deteriorating nutritional status.

Resumo Objetivos: Avaliar se há associações entre a IL-6, o TNF-α, a IL-10 e a estado nutricional em pacientes com cirrose secundária a atresia biliar e comparar com controles saudáveis. Métodos: Os parâmetros usados na avaliação nutricional foram desvio padrão de estatura para a idade e espessura da prega cutânea do tríceps para a idade. A gravidade da cirrose foi avaliada por meio da classificação de Child-Pugh e do PELD/MELD. As citocinas no soro foram medidas por citometria de fluxo - técnica de Cytometric Bead Array. Resultados: A IL-6, o TNF-α e a IL-10 foram significativamente maiores no grupo de cirrose em comparação com o grupo de controle [2,4 em comparação com 0,24 (p < 0,001)], [0,21 em comparação com 0,14 (p = 0,007)] e [0,65 em comparação com 0,36 (p = 0,004)], respectivamente. A IL-6 e a IL-10 demonstraram correlação positiva com a gravidade da doença (0,450; p = 0,001) e (0,410; p = 0,002), respectivamente. O TNF-α não mostrou relevância na gravidade da doença (0,100; p = 0,478). Com relação à avaliação nutricional, a IL-6 demonstrou correlação negativa com o desvio padrão de estatura para a idade (−0,493; p < 0,001) e o desvio padrão de espessura da prega cutânea do tríceps para a idade (−0,503; p < 0,001), respectivamente. A IL-10 demonstrou correlação negativa com o desvio padrão de estatura para a idade (−0,476; p < 0,001) e o desvio padrão de espessura da prega cutânea do tríceps para a idade (−0,388; p = 0,004), respectivamente. O TNF-α não mostrou relevância em ambos os parâmetros antropométricos [(−0,083; p = 0,555); (−0,161; p = 0,253)]. Conclusão: Assim, sugerimos que, em pacientes com cirrose secundária a atresia biliar, IL-6 pode ser usado como um possível biomarcador de suporte do estado nutricional deficiente e níveis aumentados de IL-10 podem ser usados como um possível biomarcador de suporte, em fase inicial, de deterioração do estado nutricional.

Accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI) imaging, the enhanced liver fibrosis (ELF) test, APRI, and the FIB-4 index compared with liver biopsy in patients with chronic hepatitis C

OBJECTIVES: Although liver biopsy is the gold standard for determining the degree of liver fibrosis, issues regarding its invasiveness and the small amount of liver tissue evaluated can limit its applicability and interpretation in clinical practice. Non-invasive evaluation methods for liver fibrosis can address some of these limitations. The aim of this study was to evaluate the accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI), enhanced liver fibrosis (ELF), the aspartate aminotransferase-to-platelet ratio index (APRI), and the FIB-4 index compared with liver biopsy in hepatitis C. METHODS: We evaluated chronic hepatitis C patients who were followed at the Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology of University of São Paulo School of Medicine, São Paulo, Brazil, and who underwent liver biopsy. The accuracy of each method was determined by a receiver operating characteristic (ROC) curve analysis, and fibrosis was classified as significant fibrosis (≥F2), advanced fibrosis (≥F3), or cirrhosis (F4). The Obuchowski method was also used to determine the diagnostic accuracy of each method at the various stages of fibrosis. In total, 107 FibroScan®, 51 ARFI, 68 ELF, 106 APRI, and 106 FIB-4 analyses were performed. RESULTS: A total of 107 patients were included in the study. The areas under the ROC curve (AUROCs) according to fibrosis degree were as follows: significant fibrosis (≥F2): FibroScan®: 0.83, FIB-4: 0.76, ELF: 0.70, APRI: 0.69, and ARFI: 0.67; advanced fibrosis (≥F3): FibroScan®: 0.85, ELF: 0.82, FIB-4: 0.77, ARFI: 0.74, and APRI: 0.71; and cirrhosis (F4): APRI: 1, FIB-4: 1, FibroScan®: 0.99, ARFI: 0.96, and ELF: 0.94. The accuracies of transient elastography, ARFI, ELF, APRI and FIB-4 determined by the Obuchowski method were F0-F1: 0.81, 0.78, 0.44, 0.72 and 0.67, respectively; F1-F2: 0.73, 0.53, 0.62, 0.60, and 0.68, respectively; F2-F3: 0.70, 0.64, 0.77, 0.60, and 0.67, respectively; and F3-F4: 0.98, 0.96, 0.82, 1, and 1, respectively. CONCLUSION: Transient elastography remained the most effective method for evaluating all degrees of fibrosis. The accuracy of all methodologies was best at F4.

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.

Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C? / Existe associação entre vitamina D e fibrose hepática em pacientes com hepatite C crônica?

ABSTRACT BACKGROUND Vitamin D is known for its immunomodulatory, anti-inflammatory and antifibrotic properties, which are quite relevant in the pathogenesis and treatment of many causes of chronic liver disease. OBJECTIVE This study aimed to evaluate the association between serum vitamin D levels and the histopathological findings in patients with chronic hepatitis C virus infection. METHODS Cross-sectional study composed of patients with chronic hepatitis C. All patients underwent vitamin D 25 dosage and anthropometric data analysis. Liver biopsy was performed in a maximum 36-month period before inclusion in the study. RESULTS Of the 74 patients included in the study, 45 (60.8%) were women, mean age was 57.03±9.24 years, and 63 (85.1%) were white. No association was observed between the serum levels of vitamin D and inflammatory activity (P=0.699) nor with the degree of liver fibrosis (P=0.269). CONCLUSION In this study, no association was observed between vitamin D and inflammatory activity, as well as the degree of liver fibrosis, in patients with chronic hepatitis C.

RESUMO CONTEXTO A vitamina D é conhecida por possuir propriedades imunomoduladoras, anti-inflamatórias e antifibróticas, relevantes na patogênese e tratamento de muitas causas de doença hepática crônica. OBJETIVO Este estudo tem como objetivo avaliar a associação entre os níveis séricos de vitamina D e os achados histopatológicos em pacientes com infecção crônica do vírus da hepatite C. MÉTODOS Estudo transversal, composto por pacientes com hepatite C crônica. Todos os pacientes foram submetidos à dosagem de vitamina D 25 e análise de dados antropométricos. A biópsia hepática foi realizada em um período máximo de 36 meses antes da inclusão no estudo. RESULTADOS Dos 74 pacientes incluídos no estudo, 45 (60,8%) eram mulheres, média de idade de 57,03±9,24 anos e 63 (85,1%) eram brancos. Não foi observada associação entre os níveis séricos de vitamina D e atividade inflamatória (P=0,699), nem com o grau de fibrose hepática (P=0,269). CONCLUSÃO No presente estudo, não foi observada associação entre a vitamina D e a atividade inflamatória, bem como com o grau de fibrose hepática, em pacientes com hepatite C crônica.

New index for the diagnosis of liver fibrosis in Schistosomiasis mansoni / Novo índice biológico para o diagnóstico da fibrose hepática na Esquistossomose mansoni

ABSTRACT BACKGROUND Periportal fibrosis is the major pathological consequence of the Schistosoma mansoni infection. OBJECTIVE To evaluate the accuracy of serum markers and to construct an index to assess fibrosis. METHODS Patients (n=116) with schistosomiasis were evaluated by ultrasound scan and measurements of serum levels of aminotransferases, γ-glutamyl transferase, alkaline phosphatase, hyaluronic acid, cytokines and platelets. Ultrasound images were used to evaluate the fibrosis using Niamey's classification and identified 19 patients without periportal fibrosis (patterns A and B), 48 with mild to moderate fibrosis (C and D) and 49 with advanced fibrosis (E and F). RESULTS Using multivariate analysis, a model was created, which involved alkaline phosphatase and platelets and could separate patients with different patterns of fibrosis. This index showed a better performance in separating patients without fibrosis from with advanced periportal fibrosis. The biological index showed an area under the ROC curve of 1.000. Using values below the lowest or above the highest cut-off point, the presence or absence of advanced fibrosis could be predicted in all patients. CONCLUSION The index constructed can be used to separate patients with different patterns of periportal fibrosis, specially to predict advanced fibrosis in schistosomiasis patients.

RESUMO CONTEXTO A fibrose periportal é a maior consequência patológica da infecção pelo Schistosoma mansoni. OBJETIVO Avaliar a acurácia de marcadores séricos e construir um índice para avaliar a fibrose. MÉTODOS Pacientes (n=116) com esquistossomose foram avaliados pela ultrassonografia e dosados os níveis de aminotransferases, γ-glutamil transferase, fosfatase alcalina, ácido hialurônico, citocinas e plaquetas. Imagens de ultrasom foram utilizadas para avaliar a fibrose através de classificação de Niamey e identificados 19 pacientes sem fibrose periportal (padrão A e B), 48 com fibrose média a moderada (C e D) e 49 com fibrose avançada (E e F). RESULTADOS Através de análise multivariada, um modelo foi criado, que envolveu a fosfatase alcalina e plaquetas e conseguiu separar pacientes com diferentes padrões de fibrose periportal. Este índice mostrou um melhor desempenho em separar pacientes sem fibrose dos pacientes com fibrose avançada. O índice biológico mostrou uma área sob a curva ROC de 1,000. Usando valores infereiores e acima do ponto de corte, a presença ou ausência de fibrose avançada pode ser prevista em todos os pacientes. CONCLUSÃO O índice construído pode ser usado para separar os pacientes com diferentes padrões de fibrose periportal, especialmente para prever fibrose avançada em pacientes com esquistossomose.

Platelet-derived growth factor A mRNA in platelets is associated with the degree of hepatic fibrosis in chronic hepatitis C

Abstract: INTRODUCTION: Transforming growth factor beta 1 (TGFB1) and platelet-derived growth factor (PDGF) are the main cytokines related to hepatic fibrogenesis. METHODS: RNA isolated from the platelets and hepatic tissue of 43 HCV carriers was used for quantitative polymerase chain reaction to determine TGFB1, PDGFA, and PDGFB RNA expression. RESULTS: The mRNA expression of PDGFA in platelets was significantly lower in the group with advanced fibrosis than in the group with early-stage fibrosis. TGFB1 was more frequently expressed in platelets than in hepatic tissue, which was different from PDGFB. CONCLUSIONS: A pathway mediated by overexpression of TGFB1 via PDGFA in megakaryocytes could be involved in the development of fibrosis.

The regulatory role of IL-6R in hepatitis B-associated fibrosis and cirrhosis

This study investigated the expression and regulation of IL-6R in hepatitis B-associated moderate hepatic fibrosis and cirrhosis. Liver tissues, peripheral blood monocytes (PBMs) and serum were collected from 26 hepatitis B patients with liver fibrosis and 35 hepatitis B patients with liver cirrhosis. The levels of Il-6r mRNA expression in these samples were examined by quantitative real-time PCR and IL-6R protein levels were analyzed by western blot and ELISA. MiRNAs that regulate IL-6R expression were predicted by bioinformatics analysis, and validated by dual luciferase reporter assay. Compared with the hepatic fibrosis group, IL-6R was significantly upregulated at both mRNA and protein levels in liver tissues, PBMs and serum samples from the hepatic cirrhosis group (P<0.05). The 3′UTR of Il-6r mRNA was predicted to contain a miR-30b binding site and IL-6R was identified as a possible target of miR-30b. MiR-30b expression was significantly downregulated in samples from hepatic cirrhosis patients compared with hepatic fibrosis patients (P<0.05). In conclusion, IL-6R was upregulated while miR-30b was decreased in patients with liver cirrhosis. The miR-30 can directly regulate the expression of IL-6R.

Trace elements in plasma and nutritional assessment in patients with compensated cirrhosis on a liver transplant list

ABSTRACT Background - In chronic liver disease, trace element levels in plasma are usually low. However, the specific cause and functional implications of this abnormality are yet not well understood. These element levels may decrease as a result of abnormal liver function in patients with cirrhosis and/or malnutrition. Objective - To evaluate the nutritional status and the profile of trace elements in plasma of patients with cirrhosis on a liver transplant list and to correlate them with disease severity. Methods - This cross-sectional study evaluated 31 male patients diagnosed with compensated liver cirrhosis on a waiting list for liver transplant. Nutritional status was objectively evaluated through anthropometry using Mendenhall score and Blackburn classification, subjectively through the Detsky questionnaire and severity of the disease by MELD and CTP score. Trace elements (Zn, Se, Cu, Ca, Fe, Mg and Mn) in plasma were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Statistical analysis was performed using Mann-Whitney test. Results - According to the nutritional assessment 19 (61.3%) were malnourished and 12 (38.7%) were overweight. Regarding disease severity 12 (39%) were classified as Child A, 17 (55%), Child B and 2 (6%) Child C, with 46.9% of patients with MELD score >17. The trace element analysis indicated that 31 (100%) had Mn levels above the reference range, 23 (74.2%) low levels of Cu, 29 (93.5%) with deficiency of Se, and 31 (100%) low levels of Ca and Mg. Disease severity did not show statistical difference between the studied trace elements, in contrast to the nutritional status, in which the malnourished group showed higher levels of Mn (P=0.01) and Fe (P=0.01) and low levels of Zn (P=0.03) when compared to the overweight group. Conclusion - The results showed that the trace elements in plasma are altered in chronic liver disease; without significant correlation to disease severity, but correlated to nutritional status. Malnutrition is present in the patients studied, nonetheless a new scenario with an increase in the prevalence of overweight was verified regardless of the degree of hepatic decompensation.

RESUMO Contexto - Na doença hepática crônica os níveis plasmáticos de oligoelementos normalmente apresentam-se baixos, mas a causa específica e implicações funcionais desta anormalidade ainda não estão bem esclarecidas. Estes elementos podem estar diminuídos em consequência da função hepática alterada em pacientes com cirrose e/ou desnutrição. Objetivo - Avaliar o estado nutricional e o perfil de oligoelementos plasmáticos dos pacientes com cirrose hepática em lista para transplante e correlacionar com a gravidade da doença. Métodos - Trata-se de um estudo transversal, no qual foram avaliados 31 pacientes do sexo masculino com diagnóstico de cirrose hepática compensada em lista de espera para transplante de fígado. O estado nutricional foi avaliado objetivamente por medidas antropométricas através do escore de Mendenhall e classificado segundo Blackburn, subjetivamente por um questionário sistematizado por Detsky e a gravidade da doença pelo escore MELD e CTP. Os oligoelementos plasmáticos (Zn, Se, Cu, Ca, Fe, Mg e Mn) foram analisados pelo método de espectrometria de massas com fonte de plasma indutivamente acoplado (ICP-MS). Para análise estatística foi utilizado o Teste de Mann-Whitney. Resultados - De acordo com a avaliação nutricional 19 (61,3%) estavam com desnutrição e 12 (38,7%) com sobrepeso. Em relação à gravidade da doença 12 (39%) foram classificados como Child A, 17 (55%), Child B e 2 (6%) Child C, sendo 46,9% dos pacientes com o escore MELD >17. Na análise dos oligoelementos 31 (100%) apresentaram níveis de Mn acima dos valores de referência, 23 (74,2%) níveis baixos de Cu, 29 (93,5%) com deficiência de Se, e 31 (100%) níveis baixos de Ca e Mg. Em relação à gravidade da doença não houve diferença estatística entre os oligoelementos estudados, já em relação ao estado nutricional o grupo desnutrido apresentou níveis maiores de Mn (P=0,01) e Fe (P=0,01) e níveis diminuídos de Zn (P=0,03) quando comparado ao grupo sobrepeso. Conclusão - Os resultados mostraram que os oligoelementos estão alterados na doença hepática crônica, sem associação significativa com a gravidade da doença, mas sim com o estado nutricional. A desnutrição está presente nos pacientes estudados, porém um novo cenário com aumento na prevalência de sobrepeso foi verificado independente do grau de descompensação hepática.

Hepatic Venous Pressure Gradient Predicts Long-Term Mortality in Patients with Decompensated Cirrhosis

PURPOSE: The present study aimed to investigate the role of hepatic venous pressure gradient (HVPG) for prediction of long-term mortality in patients with decompensated cirrhosis. MATERIALS AND METHODS: Clinical data from 97 non-critically-ill cirrhotic patients with HVPG measurements were retrospectively and consecutively collected between 2009 and 2012. Patients were classified according to clinical stages and presence of ascites. The prognostic accuracy of HVPG for death, survival curves, and hazard ratios were analyzed. RESULTS: During a median follow-up of 24 (interquartile range, 13-36) months, 22 patients (22.7%) died. The area under the receiver operating characteristics curves of HVPG for predicting 1-year, 2-year, and overall mortality were 0.801, 0.737, and 0.687, respectively (all p17 mm Hg, respectively (p=0.015). In the ascites group, the mortality rates at 1 and 2 years were 3.9% and 17.6% with HVPG 17 mm Hg, respectively (p=0.044). Regarding the risk factors for mortality, both HVPG and model for end-stage liver disease were positively related with long-term mortality in all patients. Particularly, for the patients with ascites, both prothrombin time and HVPG were independent risk factors for predicting poor outcomes. CONCLUSION: HVPG is useful for predicting the long-term mortality in patients with decompensated cirrhosis, especially in the presence of ascites.

Bleeding complications in critically ill patients with liver cirrhosis

BACKGROUND/AIMS: Patients with liver cirrhosis (LC) are at risk for critical events leading to Intensive Care Unit (ICU) admission. Coagulopathy in cirrhotic patients is complex and can lead to bleeding as well as thrombosis. The aim of this study was to investigate bleeding complications in critically ill patients with LC admitted to a medical ICU (MICU). METHODS: All adult patients admitted to our MICU with a diagnosis of LC from January 2006 to December 2012 were retrospectively assessed. Patients with major bleeding at the time of MICU admission were excluded from the analysis. RESULTS: A total of 205 patients were included in the analysis. The median patient age was 62 years, and 69.3% of the patients were male. The most common reason for MICU admission was acute respiratory failure (45.4%), followed by sepsis (27.3%). Major bleeding occurred in 25 patients (12.2%). The gastrointestinal tract was the most common site of bleeding (64%), followed by the respiratory tract (20%). In a multivariate analysis, a low platelet count at MICU admission (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99) and sepsis (OR, 8.35; 95% CI, 1.04 to 67.05) were independent risk factors for major bleeding. The ICU fatality rate was significantly greater among patients with major bleeding (84.0% vs. 58.9%, respectively; p = 0.015). CONCLUSIONS: Major bleeding occurred in 12.2% of critically ill cirrhotic patients admitted to the MICU. A low platelet count at MICU admission and sepsis were associated with an increased risk of major bleeding during the MICU stay. Further study is needed to better understand hemostasis in critically ill patients with LC.

Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor beta Secretion

BACKGROUND/AIMS: The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. METHODS: Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor beta (TGF-beta) immunohistochemistry was analyzed. RESULTS: Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-beta-secreting cells. CONCLUSIONS: Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-beta via the blockage of alpha1- and beta-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved.

Clinical Implications of the Serum Apelin Level on Portal Hypertension and Prognosis of Liver Cirrhosis

BACKGROUND/AIMS: Levels of serum apelin (s-apelin), an endogenous ligand for angiotensin-like receptor 1, have been shown to be related to hepatic fibrosis and hemodynamic abnormalities in preclinical studies. We investigated the clinical implications of s-apelin as a noninvasive prognostic biomarker for chronic liver disease (CLD). METHODS: From January 2009 to December 2012, 215 CLD patients were enrolled and underwent clinical data collection, hepatic venous pressure gradient (HVPG) measurement, and liver biopsy. s-apelin was detected with a human total apelin enzyme-linked immunosorbent assay kit. All patients were prospectively observed during the median follow-up period of 23.0±12.9 months for decompensation and mortality. RESULTS: A total of 42 patients (19.5%) died during the follow-up period. s-apelin was significantly correlated with measurements of liver stiffness (R2=0.263, p<0.001) and collagen proportional area (R2=0.213, p<0.001) measured from liver biopsy tissue and HVPG (R2=0.356, p<0.001). In a multivariate analysis using a Cox regression hazard model, s-apelin was a weakly significant predictor of decompensation (hazard ratio [HR], 1.002; p<0.001) and mortality (HR, 1.003; p<0.001). CONCLUSIONS: s-apelin showed a significant relationship with CLD severity. However, its significance as a noninvasive biomarker for disease severity and prognosis was weak.

LIPID PROFILE OF CIRRHOTIC PATIENTS AND ITS ASSOCIATION WITH PROGNOSTIC SCORES: a cross-sectional study / Perfil lipídico de pacientes cirróticos e sua associação com escores prognósticos: um estudo transversal

BackgroundIn cirrhosis the production of cholesterol and lipoproteins is altered.ObjectiveEvaluate the lipid profile by measuring total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and triglyceride levels in patients with cirrhosis caused by alcoholism and/or hepatitis C virus infection and determine its association with Child-Pugh and MELD scores.MethodsCross-sectional retrospective study of patients treated at the outpatient clinic in Porto Alegre, Brazil, from 2006 to 2010.ResultsIn total, 314 records were reviewed, and 153 (48.7%) met the inclusion criteria, of which 82 (53.6%) had cirrhosis that was due to hepatitis C virus infection, 50 (32.7%) were due to alcoholism, and 21 (13.7%) were due to alcoholism and hepatitis C virus infection. The total cholesterol levels diminished with a Child-Pugh progression (P<0.001). Child-Pugh C was significantly associated with lover levels of low-density lipoprotein (<70 mg/dL; P<0.001), high-density lipoprotein (<40 mg/dL; P<0.001) and triglyceride (<70 mg/dL; P=0.003). MELD>20 was associated with lower total cholesterol levels (<100mg/dL; P<0.001), very low-density lipoprotein (<16 mg/dL; P=0.006), and low-density lipoprotein (<70 mg/dL; P=0.003). Inverse and statistically significant correlations were observed between Child-Pugh and all the lipid fractions analyzed (P<0.001). The increase in MELD was inversely correlated with reduced levels intotal cholesterol (P<0.001), high-density lipoprotein (P<0.001), low-density lipoprotein (P<0.001), very low-density lipoprotein (P=0.030) and triglyceride (P=0.003).ConclusionA reduction in the lipid profile in patients with cirrhosis due to hepatitis C virus infection and/or alcoholism was significantly associated with the Child-Pugh and MELD prognostic markers. These results suggest that the lipid profile may be used as a tool to assist in evaluating liver disease.

ContextoNa cirrose a produção de colesterol e de lipoproteínas está alterada.ObjetivoAvaliar o perfil lipídico - através da dosagem do colesterol total, lipoproteína de muito baixa densidade, lipoproteína de baixa densidade, lipoproteína de alta densidade e triglicerídeos - de pacientes com cirrose, por álcool e/ou vírus da hepatite C, e verificar sua associação com os escores Child-Pugh e MELD.MétodosEstudo transversal, retrospectivo de pacientes em acompanhamento ambulatorial no Complexo Hospitalar Santa Casa de Porto Alegre, Brasil, no período de 2006 a 2010.ResultadosForam revisados 314 prontuários, destes 153 (48,7%) preencheram os critérios de inclusão, sendo que 82 (53,6%) tinham cirrose por vírus da hepatite C, 50 (32,7%) por álcool e 21 (13,7%) por álcool e vírus da hepatite C. Os níveis de colesterol total reduziram com a progressão do Child-Pugh (P<0,001). Child-Pugh C associou-se significativamente aos níveis mais baixos de lipoproteína de baixa densidade (<70 mg/dL; P<0,001), lipoproteína de alta densidade (<40 mg/dL; P<0,001) e triglicerídeos (<70 mg/dL; P=0,003). MELD>20 esteve associado aos menores valores de colesterol total (<100 mg/dL; P<0,001), lipoproteína de muito baixa densidade (<16 mg/dL; P=0,006), lipoproteína de baixa densidade (<70 mg/dL; P=0,003). Correlações inversas e estatisticamente significativas foram observadas entre Child-Pugh e todas as frações lipídicas analisadas (P<0,001). O aumento do MELD esteve correlacionado inversamente com a redução do colesterol total (P<0,001), lipoproteína de alta densidade (P<0,001), lipoproteína de baixa densidade (P<0,001), lipoproteína de muito baixa densidade (P=0,030) e triglicerídeos (P=0,003).ConclusãoA redução do perfil lipídico, nos pacientes com cirrose por vírus da hepatite C e ou álcool, associou-se significativamente com os marcadores de prognóstico Child-Pugh e MELD. Tais resultados sugerem que o perfil lipídico poderá ser utilizado como uma ferramenta para auxiliar na avaliação da hepatopatia.

Lipid profile in cirrhotic patients and its relation to clinical outcome / Perfil lipídico de pacientes cirróticos e sua relação com o desfecho clínico

BACKGROUND: Carriers of hepatitis C virus have lower levels of total cholesterol, high density lipoprotein-cholesterol, low density lipoprotein- cholesterol and triglycerides compared to uninfected patients. With the progression of liver disease, the values ​​for cholesterol and its fractions reduce linearly, with reduction ratio of lipid profile and markers Child-Pugh and MELD. AIM: To determine the relationship between decrease dlipid profile with clinical outcome presented (liver transplantation or death pre-transplant). METHODS: Was conducted a cross sectional analytical study of a follow-up study performed by reviewing medical records. Cirrhotic patients treated at theClinic of Gastroenterology from a large tertiary hospital with cirrhosis of viral etiology and/or alcohol were studied. The clinical characteristics (gender, age and etiology of cirrhosis) and lipid profile data from150 patients were collected in the year 2010.To analyze the occurrence of clinical outcomes (liver transplantation or death pre-transplant) patients were evaluated after four years. RESULTS: The prevalent cause was hepatitis C virus (53,3%), followed by alcohol (32%) and hepatitis C and alcohol (14,6%). Males represented 62% of the sample and the average age was 63.1±9.11 years. The prevalent lipid changes were hypocholesterolemia associated with hypotriglyceridemia (36,6%) and isolated hypocholesterolemia (34,6%). Analyzing groups of patients that showed abnormalities related to lipid profile, was identified a significant association between isolated hypocholesterolemia and clinical outcome-liver transplant(p <0.025) and 18% probability of performing liver transplantation in this group of patients. There was no association between decreased lipid profile and death. CONCLUSION: Isolated hypocholesterolemia contributes to assess the progression of liver disease, because of the association between lowering cholesterol and its fractions and ...

RACIONAL: Portadores do vírus da hepatite C apresentam menores valores de colesterol total, lipoproteína de alta densidade, lipoproteína de baixa densidade e triglicerídeos, quando comparados aos pacientes não infectados. Com a progressão da hepatopatia, os valores de colesterol e suas frações reduzem linearmente, havendo relação entre redução do perfil lipídico e os marcadores Child-Pugh e MELD. OBJETIVO: Verificar a relação entre redução do perfil lipídico e o desfecho clínico apresentado (transplante hepático ou óbito pré-transplante). MÉTODOS: Análise transversal de um estudo de acompanhamento, realizado através da revisão de prontuários médicos. Foram estudados pacientes cirróticos, acompanhados no Ambulatório de Gastroenterologia de um hospital terciário de grande porte com cirrose de causa viral e/ou alcoólica. As características clínicas (sexo, idade e etiologia da cirrose) e dados de perfil lipídico dos 150 pacientes estudados foram coletados no ano de 2010. Para análise da ocorrência dos desfechos clínicos, os pacientes foram avaliados após quatro anos. RESULTADOS: A causa prevalente foi vírus da hepatite C (53,3%), seguida de álcool (32%) e vírus da hepatite C e álcool (14,6%). O sexo masculino representou 62% da amostra e a média de idade foi de 63,1±9,11 anos. As alterações lipídicas prevalentes foram hipocolesterolemia associada à hipotrigliceridemia (36,6%) e hipocolesterolemia isolada (34,6%). Analisando-se os grupos de pacientes que apresentaram alteração referente ao perfil lipídico, identificou-se associação significativa entre hipocolesterolemia isolada e o desfecho clínico - transplante hepático (p<0,025), sendo 18% a probabilidade de realização de transplante hepático neste grupo de pacientes. Não houve associação entre redução do perfil lipídico e óbito. CONCLUSÃO: A hipocolesterolemia isolada contribui para avaliação da progressão da hepatopatia, devido à associação entre redução do colesterol e suas frações ...

Hepatocellular Carcinoma Risk of Compensated Cirrhosis Patients with Elevated HBV DNA Levels according to Serum Aminotransferase Levels

Sometimes, hepatitis B virus (HBV)-related cirrhotic patients with normal aminotransferase levels are closely followed-up for the elevation of aminotransferase levels instead of prompt antiviral therapy (AVT). We analyzed the long-term hepatocellular carcinoma (HCC) risk according to the aminotransferase levels in a retrospective cohort of 1,468 treatment-naive, HBV-related, compensated cirrhosis patients with elevated HBV DNA levels (> or =2,000 IU/mL). Based on aminotransferase levels, patients were categorized into normal ( or =40 U/L, n = 1,104). During a median of 5.3 yr of follow-up (range: 1.0-8.2 yr), HCC developed in 296 (20%) patients. The 5-yr cumulative HCC incidence rate was higher in patients with elevated aminotransferase level, but was not low in normal aminotransferase level (17% vs. 14%, P = 0.004). During the follow-up, 270/364 (74%) patients with normal aminotransferase levels experienced elevation of aminotransferase levels, and AVT was initiated in 1,258 (86%) patients. Less patients with normal aminotransferase levels received AVT (70% vs. 91%, P < 0.001) and median time to start AVT was longer (17.9 vs. 2.4 months, P < 0.001). AVT duration was an independent factor associated with HCC, and median duration of AVT was shorter (4.0 vs. 2.6 yr, P < 0.001) in patients with normal aminotransferase levels. The HCC risk of compensated cirrhosis patients with normal aminotransferase level is not low, and AVT duration is associated with lowered HCC risk, indicating that prompt AVT should be strongly considered even for those with normal aminotransferase levels.