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1.
J Hepatol ; 2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33508376

RESUMO

BACKGROUND AND AIM: TIPS implantation is an effective and safe treatment for complications of portal hypertension. Prediction of survival is important in these patients as they constitute a high-risk population per se. Therefore, the aim of our study was to develop an alternative prognostic model for accurate survival prediction after planned TIPS implantation. METHODS: A total of 1871 patients with de novo TIPS implantation for ascites or secondary prophylaxis of variceal bleeding were recruited retrospectively. The study cohort was divided in a training set (80% of study patients; n=1496) and a validation set (20% of study patients; n=375). Further, patients with early (preemptive) TIPS implantation due to variceal bleeding were included as another validation cohort (n=290). Medical data and overall survival (OS) were assessed. A Cox regression model was performed to create an alternative prediction model, which includes significant prognostic factors. RESULTS: Age, bilirubin, albumin and creatinine were the most important prognostic factors. These parameters were included in a new score named the Freiburg index of post-TIPS survival (FIPS). The FIPS score was able to identify high-risk patients with a significantly reduced prognosis of a median survival of 5.0 [3.1 - 6.9] months after TIPS implantation in the training set. These results were confirmed in the validation set (median survival of 3.1 [0.9 - 5.3] months). The FIPS score showed better prognostic discrimination compared to the Child-Pugh-, MELD-, MELD-Na-score and the bilirubin-platelet model. However, the FIPS score showed insufficient prognostic discrimination in patients with early TIPS implantation. CONCLUSIONS: The FIPS score is superior to established scoring systems for identifying high-risk patients with a reduced prognosis in patients with elective TIPS implantation.

2.
Hepatology ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33421158

RESUMO

Rifaximin is an oral non-systemic antibiotic, with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both grampositive and gramnegative organisms. Rifaximin is currently worldwide used in patients with cirrhosis for preventing recurrent hepatic encephalopathy because its efficacy and safety has been proved by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which, in turn, can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted as evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas, in the second part, its clinical effects are critically discussed. It clearly emerges that, due to its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than hepatic encephalopathy deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure and mortality, are therefore eagerly awaited.

3.
Z Gastroenterol ; 59(1): 24-34, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33429447

RESUMO

INTRODUCTION: In the management of patients with decompensated liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) insertion is well-established but common recommendations in the follow up management are inconsistent. Doppler sonography is commonly used for detection for TIPS dysfunction whilst data on the impact of elective invasive examinations are scarce. AIM: The aim of this retrospective analysis is to evaluate potential benefits of elective invasive examinations in the follow up management of patients after TIPS insertion METHODS: Data of all patients receiving TIPS at the university hospitals of Muenster and Bonn between 2013 and 2018 (n = 534) were collected. The impact of performance of elective invasive examinations at 12 months after TIPS insertion on the occurrence of liver related events (LREs) and frequency of TIPS revisions within 24 months after TIPS insertion was analyzed. RESULTS: No significant differences were found concerning occurrence of liver related events after 24 months depending on whether an elective invasive examination was performed. Occurrence of hepatic encephalopathy, relapse of initial indication for TIPS, as well as death or liver transplantation all did not differ. These findings were verified by a subgroup analysis including only patients who did not experience a LRE or TIPS revision within the first 12 months after TIPS procedure. CONCLUSION: The analyzed data suggest no evidence for a beneficial impact due to implementation of an elective invasive examination program after TIPS insertion. Invasive examinations should remain reserved to patients with suspected TIPS dysfunction.


Assuntos
Procedimentos Cirúrgicos Eletivos/efeitos adversos , Varizes Esofágicas e Gástricas/cirurgia , Hipertensão Portal/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Varizes Esofágicas e Gástricas/etiologia , Seguimentos , Encefalopatia Hepática , Humanos , Hipertensão Portal/complicações , Derivação Portossistêmica Transjugular Intra-Hepática/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento
4.
Gut ; 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479052

RESUMO

OBJECTIVE: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients. DESIGN: This international multicentre cohort study included a derivation ACLD patient cohort with valid two-dimensional shear wave elastography (2D-SWE) results. Clinical and laboratory parameters at baseline and during follow-up were recorded. LSM by transient elastography (TE) was also recorded if available. The primary outcome was overall mortality. The secondary outcome was the development of first/further decompensation. RESULTS: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM. CONCLUSION: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.

5.
PLoS One ; 16(1): e0245091, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33481811

RESUMO

OBJECTIVES: Rising prevalence of multidrug-resistant organisms (MDRO) is a major health problem in patients with liver cirrhosis. The impact of MDRO colonization in liver transplantation (LT) candidates and recipients on mortality has not been determined in detail. METHODS: Patients consecutively evaluated and listed for LT in a tertiary German liver transplant center from 2008 to 2018 underwent screening for MDRO colonization including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant gram-negative bacteria (MDRGN), and vancomycin-resistant enterococci (VRE). MDRO colonization and infection status were obtained at LT evaluation, planned and unplanned hospitalization, three months upon graft allocation, or at last follow-up on the waiting list. RESULTS: In total, 351 patients were listed for LT, of whom 164 (47%) underwent LT after a median of 249 (range 0-1662) days. Incidence of MDRO colonization increased during waiting time for LT, and MRDO colonization was associated with increased mortality on the waiting list (HR = 2.57, p<0.0001. One patients was colonized with a carbapenem-resistant strain at listing, 9 patients acquired carbapenem-resistant gram-negative bacteria (CRGN) on the waiting list, and 4 more after LT. In total, 10 of these 14 patients died. CONCLUSIONS: Colonization with MDRO is associated with increased mortality on the waiting list, but not in short-term follow-up after LT. Moreover, colonization with CRGN seems associated with high mortality in liver transplant candidates and recipients.

6.
Gut ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431576

RESUMO

OBJECTIVE: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) pathophysiology remains unclear. This study aims to characterise the molecular basis of HBV-ACLF using transcriptomics. METHODS: Four hundred subjects with HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC) or chronic hepatitis B (CHB) and normal controls (NC) from a prospective multicentre cohort were studied, and 65 subjects (ACLF, 20; ACHD, 10; LC, 10; CHB, 10; NC, 15) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs). RESULTS: The functional synergy analysis focusing on seven bioprocesses related to the PBMC response and the top 500 differentially expressed genes (DEGs) showed that viral processes were associated with all disease stages. Immune dysregulation, as the most prominent change and disorder triggered by HBV exacerbation, drove CHB or LC to ACHD and ACLF. Metabolic disruption was significant in ACHD and severe in ACLF. The analysis of 62 overlapping DEGs further linked the HBV-based immune-metabolism disorder to ACLF progression. The signatures of interferon-related, neutrophil-related and monocyte-related pathways related to the innate immune response were significantly upregulated. Signatures linked to the adaptive immune response were downregulated. Disruptions of lipid and fatty acid metabolism were observed during ACLF development. External validation of four DEGs underlying the aforementioned molecular mechanism in patients and experimental rats confirmed their specificity and potential as biomarkers for HBV-ACLF pathogenesis. CONCLUSIONS: This study highlights immune-metabolism disorder triggered by HBV exacerbation as a potential mechanism of HBV-ACLF and may indicate a novel diagnostic and treatment target to reduce HBV-ACLF-related mortality.

7.
Epigenomics ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33432840

RESUMO

Aim: This study aimed to identify novel miRNAs (miRs) as regulators of UGT1A gene expression and to evaluate them as potential risk factors for the development of liver fibrosis/cirrhosis. Materials & methods: miRNA target sites in UDP-glucuronosyltransferase 1A (UGT1A) 3'-UTR were predicted and confirmed by luciferase assays, quantitative real-time PCR and western blot using HEK293, HepG2 and Huh7 cells. UGT1A and miRNA expression were analyzed in cirrhotic patients and a mouse model of alcoholic liver fibrosis. Results: miR-214-5p and miR-486-3p overexpression reduced UGT1A mRNA, protein levels and enzyme activity in HepG2 and Huh7 cells. miR-486-3p was upregulated in cirrhotic patients and fibrotic mice livers, whereas UGT1A mRNA levels were reduced. Conclusion: In conclusion, we identified two novel miRNAs capable to repress UGT1A expression in vitro and in vivo. Furthermore, miR-486-3p may represent a potential risk factor for the development or progression of liver fibrosis/cirrhosis by means of a reduced UGT1A-mediated detoxification activity.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33257833

RESUMO

The human gut microbiome has emerged as a major player in human health and disease. The liver, as the first organ to encounter microbial products that cross the gut epithelial barrier, is affected by the gut microbiome in many ways. Thus, the gut microbiome might play a major part in the development of liver diseases. The common end stage of liver disease is decompensated cirrhosis and the further development towards acute-on-chronic liver failure (ACLF). These conditions have high short-term mortality. There is evidence that translocation of components of the gut microbiota, facilitated by different pathogenic mechanisms such as increased gut epithelial permeability and portal hypertension, is an important driver of decompensation by induction of systemic inflammation, and thereby also ACLF. Elucidating the role of the gut microbiome in the aetiology of decompensated cirrhosis and ACLF deserves further investigation and improvement; and might be the basis for development of diagnostic and therapeutic strategies. In this Review, we focus on the possible pathogenic, diagnostic and therapeutic role of the gut microbiome in decompensation of cirrhosis and progression to ACLF.

11.
J Hepatol ; 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33301825

RESUMO

Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy (HE) and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left-ventricular dysfunction, HE to hyperammonemia, and variceal hemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the Systemic Inflammation Hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system functions through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. This cascade of events may therefore have deleterious effects on organ function. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritization of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequent impairment in organ functions.

12.
J Hepatol ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33227350

RESUMO

INTRODUCTION: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes. PATIENTS AND METHODS: The PREDICT study included 1273 non-electively hospitalized patients with AD (No-ACLF=1071; ACLF=202). Medical history, clinical and laboratory data were collected at enrolment and during 90-day follow up, with particular attention to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, four distinct events were precipitants consistently related to AD, including proven bacterial infections, severe alcoholic hepatitis, gastrointestinal (GI) bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. In both AD phenotypes, patients with proven bacterial infections or severe alcoholic hepatitis had a similar survival. The number of precipitants was associated with significantly increased 90-day mortality, and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD and specific preventive and therapeutic strategies targeting these events may improve outcome in decompensated cirrhosis.

14.
Sci Rep ; 10(1): 20682, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33244180

RESUMO

Transjugular intrahepatic portosystemic shunt (TIPS) can treat portal hypertensive complications and modifies hepatic hemodynamics. Modification of liver perfusion can alter contrast enhancement dynamics of liver nodules. This study investigated the diagnostic performance of contrast-enhanced ultrasound (CEUS) to diagnose hepatocellular carcinoma (HCC) in cirrhosis with TIPS. In this prospective monocentric observational study, CEUS was used to characterize focal liver lesions in patients at risk for HCC with and without TIPS. Times of arterial phase hyperenhancement (APHE) und washout were quantified. Perfusion-index (PI) and resistance-index (RI) of hepatic artery and portal venous flow parameters were measured via doppler ultrasonography. Diagnostic gold standard was MRI/CT or histology. This study included 49 liver lesions [23 TIPS (11 HCC), 26 no TIPS (15 HCC)]. 26 were diagnosed as HCC by gold standard. Sensitivity and specificity of CEUS to diagnose HCC with and without TIPS were 93.3% and 100% vs. 90.9% and 93.3%, respectively. APHE appeared significantly earlier in patients with TIPS compared to patients without TIPS. TIPS significantly accentuates APHE of HCC in CEUS. CEUS has good diagnostic performance for diagnosis of HCC in patients with TIPS.

15.
J Clin Med ; 9(11)2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33238576

RESUMO

Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, eventually induced and/or aggravated by TIPS, that remains a clinical challenge especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HE. TIPS procedural parameters regarding stent size and invasive portosystemic pressure gradient measurements thereby have an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HE molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HE.

17.
Artigo em Inglês | MEDLINE | ID: mdl-33079784

RESUMO

BACKGROUND: Gastrointestinal bleedings (GIBs) are frequent in cirrhotic patients and lead to high morbidity and mortality. Lately, there have been conflicting reports on the role of and bleeding type [variceal bleeding and nonvariceal bleeding (NVB)]. This study investigated the predictors of mortality in patients with variceal bleeding and NVB with relationship to sex differences. MATERIALS AND METHODS: A total of 271 patients with suspected upper GIB who underwent endoscopy were included. Patients were followed up at 1 week, 6 months and 1 year after admission. Univariate and multivariate logistic or Cox regression analyses investigated correlations of predictive factors and clinical outcomes. Propensity score matching was performed to control for severity of disease and compare groups for sex and bleeding type. RESULTS: A total of 42 patients were excluded (cirrhosis or bleeding not confirmed). The remaining patients were classified by bleeding type into patients with variceal bleeding (n = 115) or NVB (n = 156). Males (n = 155) had higher mortality in variceal bleeding than in NVB, while in females (n = 116) mortality was similar in the two bleeding types. This was confirmed after matching in males (n = 116) and females (n = 82). Further independent predictors of mortality in males were model for end-stage liver disease (MELD) at baseline, blood urea nitrogen, alanine aminotransferase, while in females age, leukocytes, MELD, history of ascites and hepatic encephalopathy. CONCLUSION: This study shows that variceal bleeding has higher mortality in males compared to NVB, while in females the type of GIB does not impact the outcome. This highlights that sex-specific clinical management should be based on bleeding type after endoscopy.

18.
J Clin Med ; 9(11)2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33114543

RESUMO

BACKGROUND: Bariatric surgery is a widely used treatment for morbid obesity. Prediction of postoperative weight loss currently relies on prediction models, which mostly overestimate patients' weight loss. Data about the influence of Non-alcoholic fatty liver disease (NAFLD) on early postoperative weight loss are scarce. METHODS: This prospective, single-center cohort study included 143 patients receiving laparoscopic gastric bypass surgery (One Anastomosis-Mini Gastric Bypass (OAGB-MGB) or Roux-en-Y Gastric Bypass (RYGB)). Liver biopsies were acquired at surgery. NAFLD activity score (NAS) assigned patients to "No NAFLD", "NAFL" or "NASH". Follow up data were collected at 3, 6 and 12 months. RESULTS: In total, 49.7% of patients had NASH, while 41.3% had NAFL. Compared with the No NAFLD group, NAFL and NASH showed higher body-mass-index (BMI) at follow-up (6 months: 31.0 kg/m2 vs. 36.8 kg/m2 and 36.1 kg/m2, 12 months: 27.0 kg/m2 vs. 34.4 and 32.8 kg/m2) and lower percentage of total body weight loss (%TBWL): (6 months: 27.1% vs. 23.3% and 24.4%; 12 months: 38.5% vs. 30.1 and 32.6%). Linear regression of NAS points significantly predicts percentage of excessive weight loss (%EWL) after 6 months (Cologne-weight-loss-prediction-score). CONCLUSIONS: Histopathological presence of NAFLD might lead to inferior postoperative weight reduction after gastric bypass surgery. The mechanisms underlying this observation should be further studied.

19.
Hepatol Commun ; 4(10): 1477-1486, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33024917

RESUMO

Sphingosine-1-phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute-on-chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF (P < 0.001). S1P levels further decreased with progression to ACLF grade 3 (P < 0.05), and S1P highly inversely correlated with the Model for End-Stage Liver Disease score (r = -0.508; P < 0.001). In multivariate analysis, S1P remained an independent predictor of 7-day mortality with high diagnostic accuracy (area under the curve, 0.874; P < 0.001). Conclusion: In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF.

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