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1.
J Autoimmun ; 149: 103325, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39413503

RESUMO

INTRODUCTION AND AIMS: mRNA vaccines against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) infection have been associated with immune-related adverse reactions. We aimed at investigating whether SARS-CoV-2 vaccines may worsen autoimmune reactions in patients with autoimmune liver diseases. METHODS: We centrally tested a large panel of liver- and non-liver-related autoantibodies in patients with primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and in healthcare workers (HW) before and after SARS-CoV-2 mRNA vaccines. RESULTS: 49 PBC, 35 AIH, 9 PSC and 38 HW were included. The proportion of subjects with at least one autoantibody positivization after vaccination was 11 % for HW, 37 % for AIH, 35 % for PBC and 56 % for PSC patients, patients having a significantly higher frequency of positivization as compared to HW. The proportion of seropositive subjects before vaccination who had at least one autoantibody negativization was 25 % for HW, 57 % for AIH, 40 % for PBC and 50 % for PSC, AIH patients having a significantly higher frequency of negativization as compared to HW. In the AIH group, the number of autoantibody negativizations was higher than the number of positivizations. The BNT162b2 vaccine was associated with a higher risk of developing new autoantibodies as compared to the mRNA-1273 vaccine. No new-onset autoimmune disease was observed after one year. One AIH patient had a relapse after vaccination. CONCLUSION: mRNA SARS-CoV-2 vaccines do not induce short-term worsening of autoimmunity in patients with autoimmune liver diseases.

2.
Hepatology ; 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38079352

RESUMO

BACKGROUND AND AIMS: The clinical spectrum of human infection by HEV ranges from asymptomatic to severe acute hepatitis. Furthermore, HEV can cause diverse neurological manifestations, especially Parsonage-Turner syndrome. Here, we used a large-scale human genomic approach to search for genetic determinants of severe clinical presentations of HEV infection. APPROACH AND RESULTS: We performed whole genome sequencing in 3 groups of study participants with PCR-proven acute HEV infection: (1) 24 patients with symptomatic acute hepatitis E; (2) 12 patients with HEV-associated Parsonage-Turner syndrome; and (3) 16 asymptomatic blood donors (controls). For variant calling and annotation, we used GATK4 best practices followed by Variant Effect Predictor (VEP) and Annovar. For variant classification, we implemented the American College of Medical Genetics and Genomics/Association for Molecular Pathology Bayesian classification framework in R. Variants with a probability of pathogenicity >0.9 were considered damaging. We used all genes with at least 1 damaging variant as input for pathway enrichment analyses.We observed a significant enrichment of type I interferon response pathways in the symptomatic hepatitis group: 10 out of 24 patients carried a damaging variant in one of 9 genes encoding either intracellular viral sensors ( IFIH1 , DDX58 , TLR3 , POLR3B , POLR3C ) or other molecules involved in type I interferon response [interferon regulatory factor 7 ( IRF7 ), MYD88 , OAS3 , GAPDH ]. We did not find any enriched pathway in the Parsonage-Turner syndrome group or in the controls. CONCLUSIONS: Our results highlight the essential role of type I interferon in preventing symptomatic acute hepatitis E.

3.
Liver Int ; 42(2): 330-339, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34839578

RESUMO

BACKGROUND: Switzerland has made strides towards hepatitis C virus elimination, but as of 2019, elimination was not guaranteed. However, political interest in viral hepatitis has been increasing. We sought to develop a better understanding of Switzerland's progress towards HCV elimination and the profile of remaining HCV-RNA-positive patients. METHODS: A previously described Markov model was updated with recent diagnosis and treatment data and run to generate new forecasts for HCV disease burden. Two scenarios were developed to evaluate HCV morbidity and mortality under the status quo and a scenario that achieves the Swiss Hepatitis Strategy Elimination targets. Next, an analysis was conducted to identify population segments bearing a high burden of disease, where future elimination efforts could be directed. RESULTS: At the beginning of 2020, an estimated 32 100 viremic infections remained in Switzerland (0.37% viremic prevalence). Adult (≥18 years of age) permanent residents born abroad represented the largest subpopulation, accounting for 56% of HCV infections. Thirteen countries accounted for ≥60% of viremic infections amongst permanent residents born abroad, with most people currently residing in Zurich, Vaud, Geneva, Bern, Aargau and Ticino. Amongst Swiss-born HCV-RNA-positive persons, two-thirds had a history of IDU, corresponding to 33% of total infections. CONCLUSIONS: In Switzerland, extra efforts for diagnosis and linkage to care are warranted in foreign-born populations and people with a history of drug use. Population-level measures (eg increasing the number of providers, increase screening) can identify patients who may have otherwise fallen through the gaps or avoided care because of stigma.


Assuntos
Hepacivirus , Hepatite C , Adulto , Antivirais/uso terapêutico , Efeitos Psicossociais da Doença , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Humanos , Suíça/epidemiologia
4.
J Hepatol ; 74(2): 419-427, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33065168

RESUMO

BACKGROUND & AIMS: CT may miss up to 30% of cases of colorectal liver metastases (CRLMs). We assessed the impact of contrast-enhanced ultrasound (CEUS) on the detection of CRLMs and on changes to the therapeutic strategy; additionally, we assessed the accuracy of CEUS in differentiating unclear focal liver lesions (FLLs) compared to staging-CT. METHODS: We prospectively analyzed all patients with newly diagnosed and histologically confirmed colorectal cancer (CRC) at our tertiary gastroenterological center between December 2015 and May 2019. CEUS was performed in a total of 296 patients without CRLMs after staging-CT using the contrast agent (SonoVue®). Standard of reference was obtained by MRI or histology to diagnose CRLMs missed by CT. Benign FLLs were confirmed by MRI or follow-up CT (mean follow-up interval: 18 months). RESULTS: Eight additional CRLMs were detected by CEUS (overall 2.7%; sensitivity 88.9%, specificity 99.0%, positive predictive value 100%, negative predictive value 99.6%). All patients with CRLMs detected only by CEUS were in tumor stage T3/T4 (4.0% additionally detected CRLMs). The number needed to screen to detect 1 additional CRLM by CEUS was 37 in all patients and 24.5 in T3/T4-patients. When results were reviewed by a board-certified radiologist and oncologist, the therapeutic strategy changed in 6 of these 8 patients. Among the 62 patients (20.9%) with unclear FLLs after staging-CT, CEUS determined the dignity (malignant vs. benign) of 98.4% of the FLLs. CONCLUSION: Overall, CEUS detected 2.7% additional CRLMs (including 4.0% in tumor stage T3/T4) with a significant impact on the oncological therapeutic strategy for 75% of these patients. Patients with tumor stage T3/T4 would particularly benefit from CEUS. We propose CEUS as the first imaging modality for CT-detected lesions of unknown dignity. LAY SUMMARY: In patients with newly diagnosed colorectal cancer, contrast-enhanced ultrasound (CEUS) detected additional liver metastases after computed tomography (CT). In the majority of these patients, the oncological therapy was changed after obtaining the CEUS results. After staging-CT, 21% of hepatic lesions remained unclear. In these cases, CEUS was accurate to either reveal or exclude liver metastasis in nearly all patients and could reduce costs (e.g., number of MRI scans).


Assuntos
Neoplasias Colorretais/patologia , Aumento da Imagem/métodos , Neoplasias Hepáticas , Metástase Neoplásica/diagnóstico por imagem , Fosfolipídeos/farmacologia , Hexafluoreto de Enxofre/farmacologia , Ultrassonografia/métodos , Idoso , Neoplasias Colorretais/terapia , Meios de Contraste/farmacologia , Feminino , Humanos , Fígado/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Imageamento por Ressonância Magnética/métodos , Masculino , Oncologia/métodos , Oncologia/normas , Estadiamento de Neoplasias , Melhoria de Qualidade , Reprodutibilidade dos Testes , Tomografia Computadorizada por Raios X/métodos
5.
Clin Gastroenterol Hepatol ; 19(1): 195-198.e2, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706062

RESUMO

Hepatitis C virus infection is causing chronic liver disease, cirrhosis, and hepatocellular carcinoma. By combining direct-acting antivirals (DAAs), high sustained virologic response rates (SVRs) can be achieved. Resistance-associated substitutions (RASs) are commonly observed after DAA failure, and especially nonstructural protein 5A (NS5A) RASs may impact retreatment options.1-3 Data on retreatment of DAA failure patients using first-generation DAAs are limited.4-7 Recently, a second-generation protease- and NS5A-inhibitor plus sofosbuvir (voxilaprevir/velpatasvir/sofosbuvir [VOX/VEL/SOF]) was approved for retreatment after DAA failure.8 However, this and other second-generation regimens are not available in many resource-limited countries or are not reimbursed by regular insurance, and recommendations regarding the selection of retreatment regimens using first-generation DAAs are very important. This study aimed to analyze patients who were re-treated with first-generation DAAs after failure of a DAA combination therapy.


Assuntos
Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Antivirais/uso terapêutico , Farmacorresistência Viral , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Retratamento , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Proteínas não Estruturais Virais/genética
6.
J Autoimmun ; 116: 102578, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33229138

RESUMO

BACKGROUND & AIM: The diagnosis of primary biliary cholangitis (PBC), an uncommon immune-mediated cholestatic liver disease, is based on positive circulating anti-mitochondrial (AMA) and/or PBC-specific anti-nuclear autoantibodies (ANA), coupled with elevated serum alkaline phopsphatase (ALP) levels. Timely initiation of treatment with ursodeoxycholic acid prevents progression to cirrhosis and liver failure. We aimed at investigating liver histology in patients with normal ALP level and positive AMA and/or PBC-specific ANA. METHODS: We searched the Swiss PBC Cohort Study database, which includes subjects with positive PBC autoimmune serology and normal ALP levels, for patients who underwent a liver biopsy. Histological slides were centrally reviewed by an expert liver pathologist, and sera were centrally re-tested for AMA and ANA. RESULTS: 30 patients were included; 90% females, median age 53 (range 27-72) years. Twenty-four (80%) had liver histology typical for (n = 2), consistent with (n = 16) or suggestive of (n = 6) PBC, including three of four AMA-negative ANA-positive patients. Among 22 ursodeoxycholic acid treated patients, 14 had elevated GGT levels before treatment; a significant decrease of the median GGT level between pre- (1.46 x ULN) and post- (0.43 x ULN) treatment (p = 0.0018) was observed. CONCLUSIONS: In our series, a high proportion of AMA positive patients with normal ALP levels have PBC. For the first time we show histological diagnosis of PBC in AMA-negative/PBC-specific ANA-positive subjects and the potential role of GGT as a biomarker in PBC patients with normal baseline ALP levels. Current guidelines for the diagnosis of PBC do not cover the whole extent of PBC presentation, with important clinical implications in terms of timely treatment initiation.


Assuntos
Fosfatase Alcalina/sangue , Autoanticorpos/sangue , Colangite/tratamento farmacológico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Idoso , Fosfatase Alcalina/imunologia , Fosfatase Alcalina/metabolismo , Autoanticorpos/imunologia , Colangite/imunologia , Colangite/metabolismo , Estudos de Coortes , Feminino , Humanos , Cirrose Hepática Biliar/imunologia , Cirrose Hepática Biliar/metabolismo , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Prognóstico , Resultado do Tratamento , Ácido Ursodesoxicólico/imunologia , gama-Glutamiltransferase/sangue , gama-Glutamiltransferase/imunologia , gama-Glutamiltransferase/metabolismo
7.
J Gastroenterol Hepatol ; 36(4): 936-942, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32790935

RESUMO

BACKGROUND AND AIM: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). METHODS: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. RESULTS: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P < 0.001) and seropositive for anti-mitochondrial antibodies (88% vs 84%, P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8% vs 43.6%, P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76 vs 1.98 × upper limit of normal [ULN], P = 0.006), aspartate aminotransferase (1.29 vs 1.50 × ULN, P < 0.001), and total bilirubin (0.53 vs 0.58 × ULN, P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3% vs 16.1%, P = 0.07) and Paris II response (71.4% vs 69.4%, P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8% vs 90.7%, P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjögren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. CONCLUSIONS: Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.


Assuntos
Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Cirrose Hepática Biliar/complicações , Fosfatase Alcalina/sangue , Anticorpos Antinucleares/sangue , Aspartato Aminotransferases/sangue , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Bilirrubina/sangue , Biomarcadores/sangue , Feminino , Humanos , Cirrose Hepática Biliar/diagnóstico , Masculino , Mitocôndrias/imunologia , Prevalência , Prognóstico , Fatores Sexuais
8.
J Cell Mol Med ; 23(6): 3916-3926, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30950188

RESUMO

The precise mechanisms of SDF-1 (CXCL12) in angiogenesis are not fully elucidated. Recently, we showed that Notch inhibition induces extensive intussusceptive angiogenesis by recruitment of mononuclear cells and it was associated with increased levels of SDF-1 and CXCR4. In the current study, we demonstrated SDF-1 expression in liver sinusoidal vessels of Notch1 knockout mice with regenerative hyperplasia by means of intussusception, but we did not detect any SDF-1 expression in wild-type mice with normal liver vessel structure. In addition, pharmacological inhibition of SDF-1/CXCR4 signalling by AMD3100 perturbs intussusceptive vascular growth and abolishes mononuclear cell recruitment in the chicken area vasculosa. In contrast, treatment with recombinant SDF-1 protein increased microvascular density by 34% through augmentation of pillar number compared to controls. The number of extravasating mononuclear cells was four times higher after SDF-1 application and two times less after blocking this pathway. Bone marrow-derived mononuclear cells (BMDC) were recruited to vessels in response to elevated expression of SDF-1 in endothelial cells. They participated in formation and stabilization of pillars. The current study is the first report to implicate SDF-1/CXCR4 signalling in intussusceptive angiogenesis and further highlights the stabilizing role of BMDC in the formation of pillars during vascular remodelling.


Assuntos
Quimiocina CXCL12/metabolismo , Intussuscepção/metabolismo , Neovascularização Patológica/metabolismo , Receptor Notch1/metabolismo , Receptores CXCR4/metabolismo , Animais , Benzilaminas , Células da Medula Óssea/metabolismo , Adesão Celular/genética , Quimiocina CXCL12/genética , Embrião de Galinha , Ciclamos , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , Hepatócitos/metabolismo , Compostos Heterocíclicos/farmacologia , Intussuscepção/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/genética , Receptor Notch1/antagonistas & inibidores , Receptor Notch1/genética , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais/genética
9.
Am J Gastroenterol ; 114(7): 1101-1108, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31241547

RESUMO

INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.


Assuntos
Colagogos e Coleréticos/uso terapêutico , Progressão da Doença , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Adulto , Fatores Etários , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Internacionalidade , Estimativa de Kaplan-Meier , Cirrose Hepática Biliar/mortalidade , Cirrose Hepática Biliar/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Análise de Sobrevida , Resultado do Tratamento
10.
J Autoimmun ; 102: 89-95, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31047768

RESUMO

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection is associated with a wide range of immunopathological manifestations, which are significantly improved by successful interferon-based treatment. There is paucity of data on the impact of interferon-free HCV clearance on immunopathological manifestations, which might be expected to disappear more frequently as compared to what reported in interferon-induced HCV-clearance. We have investigated liver autoimmune serology before and after interferon-free clearance of HCV by treatment with direct acting antiviral agents (DAA). METHOD: Patients within the Swiss Hepatitis C Cohort Study who underwent successful (SVR 12) HCV treatment with DAA were tested for autoimmune liver serology according to dedicated guidelines before and at least 6 months after end of treatment. RESULTS: A total of 235 patients were included; 62% males; median age 56 years; 27% with cirrhosis. Median time between end of DAA treatment and post-treatment serum sampling was 17 months. At least one autoantibody before treatment was found in 175 (74%) patients ; 32 (14%) were positive for 2 autoantibodies; no patient was positive for anti-SLA, anti-LC1 or typical AMA before or after DAA. ANA disappeared in 34%, SMA in 52% and anti-LKM1 in one of two patients after successful treatment, but, unexpectedly, one or more autoantibodies appeared in 27% of pre-treatment negative subjects. CONCLUSION: HCV clearance by DAA is associated with autoantibody disappearance in more than one third of the patients who were positive before treatment. However, the majority of the patients remain autoantibody-positive and 27% of those who were negative before treatment developed autoantibodies after DAA-induced HCV clearance. These data confirm that HCV infection is associated with autoimmunity and show that the autoimmune imprint persists after viral clearance by DAA, suggesting that long-term follow-up may be warranted.


Assuntos
Autoanticorpos/sangue , Autoimunidade/imunologia , Hepatite C Crônica/patologia , Cirrose Hepática/patologia , Fígado/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Linhagem Celular , Feminino , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Humanos , Fígado/imunologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Liver Int ; 38(4): 619-626, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28834649

RESUMO

BACKGROUND: Autochthonous hepatitis E is increasingly recognized as zoonotic infection in western countries. Serological assays have varying sensitivity and specificity. METHODS: We implemented molecular testing to identify and characterize acute hepatitis E acquired in Switzerland. RESULTS: Ninety-three cases of mostly symptomatic acute hepatitis E acquired in Switzerland were documented by PCR between November 2011 and December 2016. Median HEV RNA was 7.5 x 104 IU/mL (range, 5.3 to 4.7 x 107 IU/mL). HEV genotyping was successful in 78 patients, revealing genotype 3 in 75 and genotype 4 in three patients. Phylogenetic analyses revealed a few limited geographical and temporal clusters. Of the 91 patients with available anti-HEV IgM serology, four were negative; three of these were also IgG-negative, likely as a result of immunosuppression, and one was IgG-positive, a constellation compatible with HEV reinfection. Median age of the patients was 58 years (range, 20-80 years); 71 (76.3%) were men and 49 of these (69.0%) were ≥ 50 years old. The clinical course was particularly severe in patients with underlying chronic liver disease, with fatal outcome in two patients. Six patients (6.5%) presented with neuralgic amyotrophy. CONCLUSIONS: Nucleic acid-based diagnosis reveals HEV as a relevant cause of acute hepatitis in Switzerland. Middle-aged and elderly men constitute the majority of symptomatic patients. Testing for HEV should be included early in the diagnostic workup of acute hepatitis and of neuralgic amyotrophy, a typical extrahepatic manifestation of HEV genotype 3 infection.


Assuntos
Vírus da Hepatite E/isolamento & purificação , Hepatite E/diagnóstico , Hepatite E/epidemiologia , Doença Aguda , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Neurite do Plexo Braquial/complicações , Feminino , Genótipo , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite E/genética , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Viral/sangue , Distribuição por Sexo , Suíça/epidemiologia , Adulto Jovem
14.
Scand J Gastroenterol ; 53(9): 1114-1120, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30270688

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is defined by liver inflammation and consecutive fibrotic damage caused by a deposition of fat in the liver. No licensed medical treatments exist and lifestyle modification is difficult to incorporate into everyday life. We investigated the efficacy and safety of a 48-week treatment with vitamin D3 in NASH patients. METHODS: Histologically determined NASH patients with elevated alanine aminotransferase (ALT) and decreased 25-OH vitamin D level at baseline received vitamin D3 or placebo orally over a 48-week period. The primary endpoint of this study was the change in ALT from baseline to the end-of-treatment. Steatohepatitis was categorized according to the Steatosis, Activity and Fibrosis Score and disease activity was assessed using the NAFLD activity score. RESULTS: Serum 25-OH vitamin D levels significantly increased only in the vitamin D3 group over the 48-week treatment phase indicating compliance. In contrast to placebo, patients in the vitamin D group had markedly decreased ALT levels after the end-of-treatment phase. A significant decrease during treatment with vitamin D was also observed for cytokeratin-18 fragments compared with placebo. The study was not powered to detect changes in histological score, hence only descriptive results for histopathological characteristics are available. CONCLUSIONS: Treatment with 2100 IE vitamin D q.d. over 48 weeks was well tolerated and led to a significant improvement of serum ALT levels in patients with hypovitaminosis D and histology-proven NASH as the primary endpoint together with a trend toward reduction of hepatic steatosis, which was not significant due to a small number of available biopsy specimens.


Assuntos
Alanina Transaminase/sangue , Calcifediol/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Projetos Piloto , Índice de Gravidade de Doença , Suíça , Resultado do Tratamento , Deficiência de Vitamina D/sangue , Adulto Jovem
15.
J Hepatol ; 67(3): 471-479, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28412294

RESUMO

BACKGROUND & AIMS: Although hepatitis E constitutes a substantial disease burden worldwide, surprisingly little is known about the localization of hepatitis E virus (HEV) in the human liver. We therefore aimed to visualize HEV RNA and proteins in situ. METHODS: A panel of 12 different antibodies against HEV open reading frame (ORF) 1-3 proteins was evaluated for immunohistochemistry (IHC) and two probes for in situ hybridization (ISH) in formalin-fixed, paraffin-embedded (FFPE) HuH7 cells transfected with HEV ORF1-3 expression vectors. IHC (and partly ISH) were then applied to Hep293TT cells replicating infectious HEV and liver specimens from patients with hepatitis E (n=20) and controls (n=134). RESULTS: Whereas ORF1-3 proteins were all detectable in transfected, HEV protein-expressing cells, only ORF2 and 3 proteins were traceable in cells replicating infectious HEV. Only the ORF2-encoded capsid protein was also unequivocally detectable in liver specimens from patients with hepatitis E. IHC for ORF2 protein revealed a patchy expression in individual or grouped hepatocytes, generally stronger in chronic compared to acute hepatitis. Besides cytoplasmic and canalicular, ORF2 protein also displayed a hitherto unknown nuclear localization. Positivity for ORF2 protein in defined areas correlated with HEV RNA detection by ISH. IHC was specific and comparably sensitive as PCR for HEV RNA. CONCLUSIONS: ORF2 protein can be reliably visualized in the liver of patients with hepatitis E, allowing for sensitive and specific detection of HEV in FFPE samples. Its variable subcellular distribution in individual hepatocytes of the same liver suggests a redistribution of ORF2 protein during infection and interaction with nuclear components. LAY SUMMARY: The open reading frame (ORF) 2 protein can be used to visualize the hepatitis E virus (HEV) in the human liver. This enabled us to discover a hitherto unknown localization of the HEV ORF2 protein in the nucleus of hepatocytes and to develop a test for rapid histopathologic diagnosis of hepatitis E, the most common cause of acute hepatitis worldwide.


Assuntos
Vírus da Hepatite E/isolamento & purificação , Fígado/virologia , RNA Viral/análise , Proteínas Virais/análise , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Hibridização In Situ , Análise Serial de Tecidos
16.
Liver Int ; 37(3): 369-376, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27678216

RESUMO

BACKGROUND: Novel direct antiviral agents (DAA) targeting hepatitis C virus (HCV) have revolutionized the treatment of chronic hepatitis C infection (CHC). Rates of sustained virological response (SVR) to treatment have drastically improved since introduction of DAA. Transient Elastography (TE) is an ultrasound based, non-invasive technique to assess liver stiffness (LS). We examined the changes in TE values and fibrosis scores FIB-4 and APRI after DAA treatment of CHC. METHODS: 549 patients who received a DAA based treatment for CHC were screened and 392 were included. TE values recorded prior to therapy and within 18 months after therapy were evaluated. In addition, FIB-4 and APRI scores were calculated and histopathological results were recorded if available. RESULTS: Median TE prior to DAA treatment was 12.65 kPa (IQR 9.45-19.2 kPa) and decreased to 8.55 kPa (IQR 5.93-15.25) post-treatment. This finding is statistically significant (P<.001) and equals a TE regression of 32.4% after DAA treatment. Median FIB-4 and APRI values significantly decreased from 2.54 (IQR 1.65-4.43) and 1.10 (IQR 0.65-2.43) to 1.80 (IQR 1.23-2.84, P<.001) and 0.43 (IQR 0.3-0.79, P<.001) respectively. CONCLUSION: Patients with SVR after DAA therapy showed significant regression of TE values. Rapid decrease in TE was in concordance with regression of validated fibrosis scores FIB-4 and APRI. It remains to be examined whether this indicates a true regression of fibrosis or merely resolution of chronic liver inflammation with subsequent improvement of TE values and laboratory parameters.


Assuntos
Antivirais/uso terapêutico , Aspartato Aminotransferases/sangue , Plaquetas/citologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/diagnóstico por imagem , Biomarcadores/sangue , Progressão da Doença , Quimioterapia Combinada , Técnicas de Imagem por Elasticidade , Feminino , Hepacivirus , Humanos , Fígado/diagnóstico por imagem , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Resposta Viral Sustentada , Suíça
17.
Liver Int ; 37(10): 1431-1445, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28261910

RESUMO

While hepatitis C exemplifies the role of host genetics in infectious diseases outcomes, there is no comprehensive overview of polymorphisms influencing spontaneous and/or treatment-induced hepatitis C virus clearance. We performed a systematic review and meta-analysis of host polymorphisms associated with these phenotypes. Literature search was conducted using combinations of keywords in three databases. Studies were reviewed and relevant data systematically extracted for subsequent meta-analyses. Polymorphisms from candidate gene studies were tested in two cohorts of HCV-infected patients with available genomic data. The literature search yielded 8'294 citations, among which 262 studies were selected. In the meta-analysis of 27 HLA studies, the most significant associations with spontaneous hepatitis C virus clearance included DQB1*02, DQB1*03, DRB1*04 and DRB1*11. In the meta-analysis of 16 studies of KIR genes and their HLA-ligands, KIR2DS3 was associated with both spontaneous and treatment-induced clearance, and the HLA-C2 ligand with failure to spontaneously clear the virus. In a pooled analysis of 105 candidate genes and two genome-wide association studies, we observed associations of single nucleotide polymorphisms from nine genes (EIF2AK2, IFNAR2, ITPA, MBL2, MX1, OASL, SPP1, TGFB1, TNK2) with response to interferon-based therapy. Meta-analysis of 141 studies confirmed the association of IFNL3/4 polymorphisms with spontaneous and treatment-induced hepatitis C virus clearance, even in previously underpowered groups, such as hepatitis C virus genotypes 2/3-infected patients. This study may contribute to a better understanding of hepatitis C virus immunopathogenesis and highlights the complex role of host genetics in hepatitis C virus clearance.


Assuntos
Antígenos HLA/genética , Hepacivirus/patogenicidade , Hepatite C/genética , Hepatite C/virologia , Polimorfismo de Nucleotídeo Único , Receptores KIR/genética , Antivirais/uso terapêutico , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Interações Hospedeiro-Patógeno , Humanos , Razão de Chances , Fenótipo , Resposta Viral Sustentada , Resultado do Tratamento
18.
Liver Int ; 37(5): 694-699, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27778440

RESUMO

BACKGROUND: Direct-acting oral anticoagulants (DOACs) are used in patients with splanchnic vein thrombosis (SVT) and cirrhosis, but evidence for safety and efficacy in this setting is limited. Our aim was to identify indications and reasons for starting or switching to DOACs and to report adverse effects, complications and short-term outcome. METHODS: Data collection including demographic information, laboratory values, treatment and complications through the Vascular Liver Disease Interest Group Consortium. RESULTS: Forty-five centres (90%) of the consortium completed the initial eCRF. We report here a series of 94 patients from 17 centres. Thirty-six patients (38%) had cirrhosis. Child-Pugh score was 6 (range 5-8), and MELD score 10.2 (range 6-19). Indications for anticoagulation were splanchnic vein thrombosis (75%), deep vein thrombosis (5%), atrial fibrillation (14%) and others (6%). DOACs used were rivaroxaban (83%), dabigatran (11%) and apixaban (6%). Patients were followed up for a median duration of 15 months (cirrhotic) and 26.5 months (non-cirrhotic). Adverse events occurred in 17% of patients and included one case of recurrent portal vein thrombosis and five cases of bleeding. Treatment with DOACs was stopped in three cases. The major reasons for choosing DOACs were no need for monitoring or inadequacy of INR to guide anticoagulation in cirrhotic patients. Renal and liver function did not change during treatment. CONCLUSIONS: A consistent number of patients with SVT and/or cirrhosis are currently treated with DOACs, which seem to be effective and safe. These data provide a basis for performing randomized clinical trials of DOACs vs. low molecular weight heparin or vitamin K antagonists.


Assuntos
Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Cirrose Hepática/complicações , Trombose Venosa/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Circulação Esplâncnica/fisiologia , Vitamina K/antagonistas & inibidores , Adulto Jovem
19.
Lab Invest ; 96(9): 972-80, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27428080

RESUMO

Notch signaling pathways have recently been implicated in the pathogenesis of metabolic diseases. However, the role of hepatic Notch signaling in glucose and lipid metabolism remains unclear and needs further investigation as it might be a candidate therapeutic target in metabolic diseases such as nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). We used hepatocyte-specific Notch1 knockout (KO) mice and liver biopsies from NASH and NAFLD patients to analyze the role of Notch1 in glucose and lipid metabolism. Hepatocyte-specific Notch1 KO mice were fed with a high fat diet (HFD) or a regular diet (RD). We assessed the metabolic phenotype, glucose and insulin tolerance tests, and liver histology. Hepatic mRNA expression was profiled by Affymetrix Mouse Gene arrays and validated by quantitative reverse transcription PCR (qPCR). Akt phosphorylation was visualized by immunoblotting. Gene expression was analyzed in liver biopsies from NASH, NAFLD, and control patients by qPCR. We found that Notch1 KO mice had elevated fasting glucose. Gene expression analysis showed an upregulation of glucose-6-phosphatase, involved in the final step of gluconeogenesis and glucose release from glycogenolysis, and perilipin-5, a regulator of hepatic lipid accumulation. When fed with an HFD KO mice developed overt diabetes and hepatic steatosis. Akt was highly phosphorylated in KO animals and the Foxo1 target gene expression was altered. Accordingly, a reduction in Notch1 and increase in glucose-6-phosphatase and perilipin-5 expression was observed in liver biopsies from NAFLD/NASH compared with controls. Notch1 is a regulator of hepatic glucose and lipid homeostasis. Hepatic impairment of Notch1 expression may be involved in the pathogenesis of human NAFLD/NASH.


Assuntos
Diabetes Mellitus/genética , Fígado Gorduroso/genética , Predisposição Genética para Doença/genética , Glucose-6-Fosfatase/genética , Perilipina-1/genética , Receptor Notch1/genética , Animais , Diabetes Mellitus/etiologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Perfilação da Expressão Gênica/métodos , Hepatócitos/metabolismo , Humanos , Immunoblotting , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
20.
Hepatology ; 62(5): 1375-87, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26250868

RESUMO

UNLABELLED: Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction. CONCLUSION: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity.


Assuntos
Hepatite C Crônica/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Genótipo , Células HEK293 , Humanos , Interferon-alfa/biossíntese , Interferons , Quinases Associadas a Receptores de Interleucina-1/fisiologia , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Fator 6 Associado a Receptor de TNF/metabolismo , Receptores Toll-Like/fisiologia , Ubiquitinação
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