Integrative Cell and Tissue Dynamics
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Staff member publications
Tantai, Xinxing, Liu, Yi, Yeo, Yee Hui, Praktiknjo, Michael, Mauro, Ezequiel, Hamaguchi, Yuhei, Engelmann, Cornelius, Zhang, Peng, Jeong, Jae Yoon, van Vugt, Jeroen Laurens Ad, Xiao, Huijuan, Deng, Huan, Gao, Xu, Ye, Qing, Zhang, Jiayuan, Yang, Longbao, Cai, Yaqin, Liu, Yixin, Liu, Na, Li, Zongfang, Han, Tao, Kaido, Toshimi, Sohn, Joo Hyun, Strassburg, Christian, Berg, Thomas, Trebicka, Jonel, Hsu, Yao-Chun, IJzermans, Jan Nicolaas Maria, Wang, Jinhai, Su, Grace L., Ji, Fanpu, Nguyen, Mindie H., ( 2021 ). impression of sarcopenia on survival of patients with cirrhosis : A meta-analysis Journal Of Hepatology 76, 588-599
The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this sketch, we aimed to quantify the association between sarcopenia and the risk of deathrate in patients with cirrhosis, by sexual activity, underlying liver-colored disease etiology, and badness of hepatic dysfunction.PubMed, Web of Science, EMBASE, and major scientific league sessions were searched without language restriction through 13 January 2021 with extra manual search of bibliographies of relevant articles. Cohort studies of ? 100 patients with cirrhosis and ? 12 months of follow-up that evaluated the association between sarcopenia, muscle multitude and the hazard of deathrate were included.22 studies with 6965 patients with cirrhosis were included. The pool prevalence of sarcopenia in patients with cirrhosis was 37.5 % overall ( 95 % CI 32.4 % -42.8 % ), higher in male patients, patients with alcohol associated liver disease ( ALD ), patients with CTP mark C, and when sarcopenia was defined in patients by lumbar 3- skeletal muscle index ( L3-SMI ). Sarcopenia was associated with the increased risk of mortality in patients with cirrhosis ( adjusted-hazard ratio [ aHR ] 2.30, 95 % CI 2.01-2.63 ), with exchangeable findings in sensitivity psychoanalysis of cirrhosis patients without HCC ( aHR 2.35, 95 % CI 1.95-2.83 ) and in subgroup analysis by sex, liver disease etiology, and badness of liverwort dysfunction. The association between quantitative muscle bulk index and mortality farther supports the inadequate prognosis for patients with sarcopenia ( aHR 0.95, 95 % CI 0.93-0.98 ). There was no significant heterogeneity in all analyses.Sarcopenia was highly and independently associated with higher hazard of deathrate in patients with cirrhosis.The prevalence of sarcopenia and its association with death in patients with cirrhosis remain ill-defined. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50 % in patients with ALD or Child ‘s course C cirrhosis. Sarcopenia was independently associated with about 2-fold higher gamble of deathrate in patients with cirrhosis. The mortality rate increased with greater asperity or longer period of having sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized.Copyright © 2021. Published by Elsevier B.V.
Keywords : alcohol associated liver disease, cirrhosis, prognosis, sarcopenia, Alcohol-associated liver disease, Cirrhosis, Prognosis, Sarcopenia, Skeletal muscle index Queck, A., Fink, A. F., Sirait-Fischer, E., Rüschenbaum, S., Thomas, D., Snodgrass, R. G., Geisslinger, G., Baba, H. A., Trebicka, J., Zeuzem, S., Weigert, A., Lange, C. M., Brüne, B., ( 2020 ). Alox12/15 insufficiency exacerbates, while lipoxin A4 ameliorates hepatic inflammation in murine alcoholic hepatitis Frontiers in Immunology 11, 1447 dipsomania is one of the leading and increasingly prevailing reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis ( AH ) constitutes a hard disease with presently no satisfying treatment options. Lipoxin A4 ( LXA4 ), a 15-lipoxygenase ( ALOX15 ) -dependent lipid mediator involved in settlement of inflammation, showed promise pre-clinical results in the therapy of several inflammatory diseases. Since ignition is a chief driver of disease progress in alcoholic hepatitis, we investigated the impingement of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse mannequin for alcoholic steatohepatitis ( NIAAA model ) was tested in Alox12/15+/+ and Alox12/15−/− shiner, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver-colored disease, increased liverwort immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic ignition. Interestingly, i.p. injections of LXA4 importantly lowered transaminase levels only in Alox12/15−/− mouse and reduce liverwort immune cell percolation a well as systemic incendiary cytokine construction in both genotypes, even though steatosis progressed. frankincense, while LXA4 injection attenuated choose parameters of disease progression in Alox12/15−/− mouse, its beneficial shock on unsusceptibility was besides apparent in Alox12/15+/+ mouse. In decision, pro-resolving lipid mediators may be beneficial to reduce excitement in alcoholic hepatitis.
Keywords : Alcoholic hepatitis, Arachidonate 12/15-lipoxygenase ( Alox12/15 ), Lipoxin A4, Resolution of inflammation, Specialized pro-resolving lipid mediators ( SPMs ) Praktiknjo, M., Monteiro, S., Grandt, J., Kimer, N., Madsen, J. L., Werge, M. P., William, P., Brol, M. J., Turco, L., Schierwagen, R., Chang, J., Klein, S., Uschner, F. E., Welsch, C., Moreau, R., Schepis, F., Bendtsen, F., Gluud, L. L., Møller, S., Trebicka, J., ( 2020 ). Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure Liver International 40, ( 6 ), 1457-1466 Background & Aims : Acute-on-chronic liver failure ( ACLF ) is characterized by high short-run mortality and systemic excitement ( SI ). recently, different cardiodynamic states were shown to independently predict outcomes in cirrhosis. The relationship between cardiodynamic states, SI, and portal site high blood pressure and their impingement on ACLF exploitation remains unclear. The bearing of this study was therefore to evaluate the interplay of cardiodynamic state and SI on fateful ACLF development in cirrhosis. Results : At inclusion, hemodynamic measures including cardiac exponent ( CI ) and liverwort venous atmospheric pressure gradient of 208 patients were measured. Patients were followed prospectively for fateful ACLF development ( basal end point ). SI was assessed by proinflammatory markers such as interleukins ( ILs ) 6 and 8 and soluble IL-33 receptor ( sIL-33R ). Patients were divided according to CI ( < 3.2 ; 3.2-4.2 ; > 4.2 L/min/m2 ) in hypo- ( normality = 84 ), normo- ( newton = 69 ) and hyperdynamic group ( nitrogen = 55 ). After a medial follow-up of 3 years, the highest gamble of fateful ACLF was seen in hyperdynamic ( 35 % ) and hypodynamic patients ( 25 % ) compared with normodynamic ( 14 % ) ( P = .011 ). Hyperdynamic patients showed the highest rate of SI. The detectable level of IL-6 was an mugwump predictor of fatal ACLF development. Conclusions : Cirrhotic patients with hyperdynamic and hypodynamic circulation have a higher risk of fatal ACLF. Therefore, the cardiodynamic submit is strongly associated with SI, which is an independent forecaster of exploitation of black ACLF.
Keywords : Acute-on-chronic liver failure, Circulation, Cirrhosis, Hemodynamic, Inflammation Klein, L. M., Chang, J., Gu, W., Manekeller, S., Jansen, C., Lingohr, P., Praktiknjo, M., Kalf, J. C., Schulz, M., Spengler, U., Strassburg, C., Cárdenas, A., Arroyo, V., Trebicka, J., ( 2020 ). The development and consequence of acute-on-chronic liver failure after surgical interventions Liver Transplantation 26, ( 2 ), 227-237 Acute-on-chronic liver failure ( ACLF ) is a syndrome with high short-run mortality. Precipitating events, including bleeding and infections, put up to ACLF development, but the role of operation remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and testing ground data were collected prior to and on days 1-2, 3-8, and 9-28, and at 3 and 12 months after surgery. Surgery type was classified as limited or across-the-board, a well as liver and nonliver operation. A total of 39 patients had baseline ACLF. operation was performed during acute decompensation in 35 % of the rest of the 330 patients, and 81 ( 24.5 % ) developed ACLF within 28 days after operating room. Surrogate markers of systemic ignition were exchangeable in patients who developed ACLF or not. Age, arouse, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were autonomous predictors for the exploitation of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher deathrate at 3, 6, and 12 months. Survival did not differ between patients with ACLF at operating room and those developing ACLF after operating room. Development of ACLF within 28 days after operation and elevated alkaline phosphatase and international normalized ratio were autonomous predictors of 90-day mortality. mugwump predictors of 1-year all-cause deathrate were alkaline phosphatase, Model for End-Stage Liver Disease score, and preoperative liverwort brain disorder, whereas nonliver operation was associated with better survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, specially in those with active bacterial infection, lower serum sodium, and kidney or curdling dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be cautiously managed perioperatively.
Trebicka, J., Sundaram, V., Moreau, R., Jalan, R., Arroyo, V., ( 2020 ). Liver transplant for acute-on-chronic liver failure : science or fiction ? Liver Transplantation 26, ( 7 ), 906-915 Acute clinical deterioration of a affected role with chronic liver disease remains a decisive clock luff both in terms of medical management and prognosis. This circumstance, besides known as acute decompensation ( AD ), is an important event determining a intersection in the trajectory of patients. A significant number of patients with AD may develop hepatic or extrahepatic organ failure, or both, which defines the syndrome acute-on-chronic liver-colored bankruptcy ( ACLF ), and ACLF is associated with a high morbidity and short-run deathrate. ACLF may occur at any phase during chronic liver-colored disease and is pathogenetically defined by systemic excitement and immune metabolic dysfunction. When electric organ failures develop in the presence of cirrhosis, specially extrahepatic organ failures, liver transplant ( LT ) may be the only curative treatment. This reappraisal outlines the testify supporting LT in ACLF patients, highlighting the function of time, bridging to LT, and possible indicators of futility. importantly, prospective studies on ACLF and transplant are urgently needed.
Cullaro, G., Sharma, R., Trebicka, J., Cárdenas, A., Verna, E. C., ( 2020 ). Precipitants of acute-on-chronic liver failure : An opportunity for preventive measures to improve outcomes Liver Transplantation 26, ( 2 ), 283-293 Acute-on-chronic liver failure ( ACLF ) is a fear complication that can develop at any stage of chronic liver disease. The incidence of ACLF is increasing, leading to a significant load to both the moved individual and health care systems. To date, our sympathy of ACLF suggests that it may be initiated by precipitants such as systemic infection, alcohol habit, or viral hepatitis. The preponderance of these vary significantly by geography and underlying liver disease, and these precipitants have a varying impact on patient prognosis. Herein, we present a review of our current understand of the precipitants of ACLF, including gaps in stream data and opportunities for meaningful intervention and areas of future research.
Madsen, B. S., Thiele, M., Detlefsen, S., Sørensen, M. D., Kjærgaard, M., Møller, L. S., Rasmussen, D. N., Schlosser, A., Holmskov, U., Trebicka, J., Sorensen, G. L., Krag, A., ( 2020 ). prediction of liver fibrosis austereness in alcoholic liver disease by human microfibrillar-associated protein 4 Liver International 40, ( 7 ), 1701-1712 background : alcoholic liver disease ( ALD ) is a populace health concern that is the lawsuit of half of all cirrhosis-related deaths. early on detection of fibrosis, ideally in the precirrhotic stage, is a cardinal strategy for improving ALD outcomes and for preventing progress to cirrhosis. previous studies identified the blood-borne marker human microfibrillar-associated protein 4 ( MFAP4 ) as a biomarker for detection of hepatitis C virus ( HCV ) -related fibrosis. aim : To evaluate the diagnostic accuracy of MFAP4 to detect ALD-induced fibrosis. method : We performed a prospective, liver biopsy-controlled study involving 266 patients with prior or current alcohol overexploitation. Patients were split into a prepare and a validation cohort. Results : MFAP4 was present in fibrotic liverwort tissue and serum MFAP4 levels increased with fibrosis grade. The area under the receiver operating characteristic arch ( AUROC ) for signal detection of cirrhosis was 0.91 ( 95 % CI 0.85-0.96 ) in the train cohort and 0.91 ( 95 % CI 0.79-1.00 ) in the establishment cohort. For detection of advanced fibrosis, the AUROC was 0.88 ( 95 % CI 0.81-0.94 ) in the education cohort and 0.92 ( 95 % CI 0.83-1.00 ) in the validation cohort. The diagnostic accuracy did not differ between MFAP4 and the enhance liver fibrosis ( ELF ) test or transient elastography ( TE ) in an intention-to-diagnose psychoanalysis. MFAP4 did not predict liverwort decompensation in a time-to-decompensation analysis in a subgroup of patients with cirrhosis. termination : MFAP4 is a novel biomarker that can detect ALD-related fibrosis with high accuracy.
Keywords : Biomarker, Cirrhosis, Extracellular matrix protein, Liver biopsy, Non-invasive test Trebicka, J., Gu, W., Ibañez-Samaniego, L., Hernández-Gea, V., Pitarch, C., Garcia, E., Procopet, B., Giráldez, Ã, Amitrano, L., Villanueva, C., Thabut, D., Silva-Junior, G., Martinez, J., Genescà, J., Bureau, C., Llop, E., Laleman, W., Palazon, J. M., Castellote, J., Rodrigues, S., Gluud, L., Ferreira, C. N., Barcelo, R., Cañete, N., Rodríguez, M., Ferlitsch, A., Mundi, J. L., Gronbaek, H., Hernández-Guerra, M., Sassatelli, R., Dell’Era, A., Senzolo, M., Abraldes, J. G., Romero-Gómez, M., Zipprich, A., Casas, M., Masnou, H., Primignani, M., Weiss, E., Catalina, M. V., Erasmus, H. P., Uschner, F. E., Schulz, M., Brol, M. J., Praktiknjo, M., Chang, J., Krag, A., Nevens, F., Calleja, J. L., Robic, M. A., Conejo, I., Albillos, A., Rudler, M., Alvarado, E., Guardascione, M. A., Tantau, M., Bosch, J., Torres, F., Pavesi, M., Garcia-Pagán, J. C., Jansen, C., Bañares, R., ( 2020 ). Rebleeding and deathrate risk are increased by ACLF but reduced by preemptive TIPS Journal of Hepatology 73, ( 5 ), 1082-1091 Background & Aims : The relationship between acute-on-chronic liver failure ( ACLF ) and acute variceal shed blood ( AVB ) is ill understand. specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the function of transjugular intrahepatic portosystemic shunt ( TIPS ) in the management in patients with ACLF has not been described to date. Methods : A multicenter, international, experimental report was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. placement of preemptive TIPS ( pTIPS ) was based on individual center policy. Patients were followed-up for 1 class, until death or liver transplant. Cox regression and competing gamble models ( Gray ‘s trial ) were used to identify independent predictors of rebleeding or mortality. Results : At admission, 380/2,138 ( 17.8 % ) patients had ACLF according to EASL-CLIF criteria ( grad 1 : 38.7 % ; grade 2 : 39.2 % ; grade 3 : 22.1 % ). The 42-day rebleeding ( 19 % vs. 10 % ; p < 0.001 ) and mortality ( 47 % vs. 10 % ; p < 0.001 ) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and deathrate. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was besides observed in leaning score equal analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. Conclusions : This large multicenter external real-life report identified ACLF at entree as an independent predictor of rebleeding and mortality in patients with AVB. furthermore, pTIPS was associated with better survival in patients with ACLF and AVB. Lay drumhead : acute variceal shed blood is a deadly complicatedness of liver cirrhosis that results from severe portal high blood pressure. This learn demonstrates that the presence of acute-on-chronic liver failure ( ACLF ) is the strongest predictor of mortality in patients with acute variceal bleeding. importantly, patients with ACLF and acute variceal ( re ) bleeding benefit from preemptive ( early ) placement of a transjugular intrahepatic portosystemic shunt. Keywords : Acute variceal bleed, Acute-on-chronic liver failure, Cirrhosis, Rebleeding Torres, S., Abdullah, Z., Brol, M. J., Hellerbrand, C., Fernandez, M., Fiorotto, R., Klein, S., Königshofer, P., Liedtke, C., Lotersztajn, S., Nevzorova, Y. A., Schierwagen, R., Reiberger, T., Uschner, F. E., Tacke, F., Weiskirchen, R., Trebicka, J., ( 2020 ). holocene advances in practical methods for liver-colored cell biology : A short-circuit overview International Journal of Molecular Sciences 21, ( 6 ), 2027 molecular and cellular research modalities for the study of liver pathologies have been enormously improved over the recent decades. Advanced technologies offer novel opportunities to establish cellular telephone isolation techniques with excellent honor, paving the path for 2D and 3D microscopy and high-throughput assays ( for example, bulk or single-cell RNA sequence ). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between diverse parenchymal and non-parenchymal liver-colored cells. furthermore, sophisticate animal models of liver disease let for the in vivo appraisal of fibrogenesis, portal site high blood pressure and hepatocellular carcinoma ( HCC ) and for the preclinical test of curative strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th touch of the European Club for Liver Cell Biology ( ECLCB-8 ) in October of 2018 in Bonn, Germany.
Keywords : Fibrogenesis, Hepatic radial cells, Hepatocellular cancer, In vitro models, Steatosis Schierwagen, R., Uschner, F. E., Ortiz, C., Torres, S., Brol, M. J., Tyc, O., Gu, W., Grimm, C., Zeuzem, S., Plamper, A., Pfeifer, P., Zimmer, S., Welsch, C., Schaefer, L., Rheinwalt, K. P., Clària, J., Arroyo, V., Trebicka, J., Klein, S., ( 2020 ). The function of macrophage-inducible C-type lectin in different stages of chronic liver disease Frontiers in Immunology 11, 1352 The macrophage-inducible C-type lectin ( mincle ) is part of the unconditioned immune system and acts as a radiation pattern recognition receptor for pathogen-associated molecular patterns ( PAMPS ) and damage-associated molecular patterns ( DAMPs ). Ligand binding induces mincle energizing which consequently interacts with the signaling arranger Fc sense organ, SYK, and NF-kappa-B. There is besides testify that mincle expressed on macrophages promotes intestinal barrier integrity. however, little is known about the role of mincle in liverwort fibrosis, particularly in more advanced disease stages. Mincle construction was measured in human liver samples from cirrhotic patients and donors collected at liver transplant and in patients undergoing bariatric surgery. human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver bankruptcy ( ACLF ). In these models, the function of mincle was investigated in liver samples deoxyadenosine monophosphate well as in peripheral blood monocytes ( PBMC ), tissues from the kidney, irascibility, humble intestine, and center. additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis ( NASH ) by treatment with mincle protagonist trehalose-6,6-dibehenate ( TDB ). In human NASH, mincle is upregulated with increase collagen production. In ApoE deficient mouse fed high-fat western diet ( NASH model ), mincle energizing significantly increases liverwort collagen output. In human cirrhosis, mincle expression is besides importantly upregulated. furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downriver signaling via FC sense organ gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to excitement and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver-colored disease.
Keywords : ACLF, Bacterial translocation, Fibrosis, Inflammation, NASH Pose, E., Napoleone, L., Amin, A., Campion, D., Jimenez, C., Piano, S., Roux, O., Uschner, F. E., de Wit, K., Zaccherini, G., Alessandria, C., Angeli, P., Bernardi, M., Beuers, U., Caraceni, P., Durand, F., Mookerjee, R. P., Trebicka, J., Vargas, V., Andrade, R. J., Carol, M., Pich, J., Ferrero, J., Domenech, G., Llopis, M., Torres, F., Kamath, P. S., Abraldes, J. G., Solà, E., Ginès, P., ( 2020 ). safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis ( LIVERHOPE-SAFETY ) : a randomized, double-blind, placebo-controlled, phase 2 trial The Lancet Gastroenterology and Hepatology 5, ( 1 ), 31-41 background Statins have beneficial effects on intrahepatic circulation and decrease portal high blood pressure and rifaximin modulates the catgut microbiome and might prevent bacterial translocation in patients with cirrhosis. consequently, this drug combination might be of remedy benefit in patients with decompensated cirrhosis. however, there is business regarding the safety of statins in patients with decompensated cirrhosis. We assessed the condom of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. Methods We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six european countries ( Italy, France, Holland, Germany, the UK, and Spain ). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients ( 1:1:1 ) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. randomization was stratified according to Child-Pugh class ( B vs C ) and restricted using blocks of multiples of three. The chief end point was development of liver-colored or brawn perniciousness, as defined by changes in liver aminotransferases ( aspartate transaminase [ AST ] and alanine transaminase [ ALT ] ), alkaline phosphastase, and creatine kinase. The learn is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. Findings The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day ( n=18 ), simvastatin 20 mg/day plus rifaximin 1200 mg/day ( n=16 ), or placebo of both medications ( n=16 ). Six patients ( two from each group ) were excluded. consequently, the full moon analysis set included 44 patients ( 16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group ). After a safety analyses when the beginning ten patients completed treatment, discussion was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data condom monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group ( beggarly differences between the groups at the end of treatment for AST 130 IU/L [ 95 % CI 54 to 205 ; p=0·0009 ] and for ALT 61 IU/L [ 22 to 100 ; p=0·0025 ]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group ( for AST −14 IU/L [ –91 to 64 ; p=0·728 ] and for ALT −8 IU/L [ –49 to 33 ; p=0·698 ] ). We observed no meaning differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of discussion compared with patients in the placebo group ( 1009 IU/L [ 208 to 1809 ] ; p=0·014 ). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group ( 4·2 IU/L [ –804 to 813 ] ; p=0·992 ). Three ( 19 % ) patients in the simvastatin 40 mg/day group developed liver-colored and muscle toxicity reproducible with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was importantly higher in the simvastatin 40 mg/day plus rifaximin group ( nine [ 56 % ] of 16 patients ) compared with the other two groups ( two [ 14 % ] of 14 for both groups ; p=0·017 ). There were no good unexpected adverse reactions reported during the survey. Interpretation Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, peculiarly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the drug to be used in studies investigating the function of statins in patients with decompensated cirrhosis.
Benz, F., Bogen, A., Praktiknjo, M., Jansen, C., Meyer, C., Wree, A., Demir, M., Loosen, S., Vucur, M., Schierwagen, R., Tacke, F., Trebicka, J., Roderburg, C., ( 2020 ). Serum levels of bone sialoprotein correlate with portal site pressure in patients with liver cirrhosis PLoS ONE 15, ( 4 ), e0231701 Liver cirrhosis represents the common end-stage of chronic liver diseases careless of its etiology. Patients with compensate disease are by and large asymptomatic, however, progress to a decompensated disease degree is common. The available stratification strategies are often inapplicable to identify patients with a higher gamble for disease progress and a specify prognosis. SIBLINGs, soluble glycophosphoproteins, are secreted into the rake by immune-cells. While osteopontin, the most big extremity of the SIBLINGs family, has been repeatedly associated with liver cirrhosis, data on the diagnostic and/or predictive value of bone sialoprotein ( BSP ) are scarce and partially inconclusive. In this study, we analyzed the diagnostic and predictive likely of circulating BSP in comparison to other standard testing ground markers in a large cohort of patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt ( TIPS ). Serum levels of BSP were similar in patients with different disease stages and were not indicative mood for prognosis. Interestingly, BSP serum levels did correlate inversely with portal site pressure, american samoa well as its surrogates such as platelet count, the portal vein vein cross-sectional area and correlated positively with the portal vein venous speed. In summary, our data highlight that BSP might represent a previously unrecognized marker for portal vein high blood pressure in patients with liver cirrhosis.
Torner, M., Mangal, A., Scharnagl, H., Jansen, C., Praktiknjo, M., Queck, A., Gu, W., Schierwagen, R., Lehmann, J., Uschner, F. E., Graf, C., Strassburg, C. P., Fernandez, J., Stojakovic, T., Woitas, R., Trebicka, J., ( 2020 ). Sex specificity of kidney markers to assess prognosis in cirrhotic patients with TIPS Liver International 40, ( 1 ), 186-193 Background & Aims : nephritic affair assessed by creatinine is a key predictive agent in cirrhotic patients. however, creatinine is influenced by respective factors, rendering interpretation difficult in some situations. This is particularly significant in early stages of nephritic dysfunction where nephritic stultification might not be accompanied by an increase in creatinine. other parameters, such as cystatin C ( CysC ) and beta‐trace protein ( BTP ), have been evaluated to fill this gap. however, none of these studies have considered the character of the patient ‘s sex. The deliver sketch analysed CysC and BTP to evaluate their omen value and differentiate them according to sexual activity. Patients and methods : CysC and BTP were measured in 173 transjugular intrahepatic portosystemic shunt ( TIPS ) -patients from the NEPTUN-STUDY ( NCT03628807 ) and analysed their relationship with mortality and sexual activity. Propensity score for age, MELD, etiology and TIPS indication was used. Results : Cystatin C and BTP showed excellent correlations with creatinine values at service line and follow-up. CysC was an freelancer predictor of overall deathrate ( HR = 1.66 ( 1.33-2.06 ) ) with an AUC of 0.75 and identified a cut-off of 1.55 mg/L in the solid cohort. Interestingly, CysC was significantly lower in females, besides after leaning sexual conquest meet. In males, the entirely independent predictor was the creatinine level ( HR = 1.54 ( 1.25-1.58 ) ), while in females CysC levels independently predicted mortality ( HR = 3.17 ( 1.34-7.52 ) ). conclusion : This study demonstrates for the beginning meter that in TIPS-patients creatinine predicts mortality in males better than in females, whereas CysC is a better forecaster of deathrate in females. These results may influence future clinical decisions on remedy options for example, allocation for liver transplant in TIPS-patients.
Keywords : Beta-trace protein, Cirrhosis, Cystatin C, Portal high blood pressure, Renal function Cremonese, C., Schierwagen, R., Uschner, F. E., Torres, S., Tyc, O., Ortiz, C., Schulz, M., Queck, A., Kristiansen, G., Bader, M., Sauerbruch, T., Weiskirchen, R., Walther, T., Trebicka, J., Klein, S., ( 2020 ). short-run western diet aggravates non-alcoholic fatso liver-colored disease ( NAFLD ) with portal high blood pressure in TGR ( mREN2 ) 27 rats International Journal of Molecular Sciences 21, ( 9 ), 3308 Non-alcoholic fatso liver-colored disease ( NAFLD ) is gaining in importance and is linked to fleshiness. particularly, the exploitation of fibrosis and portal high blood pressure in NAFLD patients requires treatment. Transgenic TGR ( mREN2 ) 27 rats overexpressing shiner renin ad lib develop NAFLD with portal high blood pressure but without fleshiness. This learn investigated the extra function of fleshiness in this model on the development of portal high blood pressure and fibrosis. Obesity was induced in twelve-week erstwhile TGR ( mREN2 ) 27 rats after receiving western diet ( WD ) for two or four weeks. Liver fibrosis was assessed using standard techniques. liverwort formula of transforming increase factor-β1 ( TGF-β1 ), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, angstrom well as the chemoattractant Ccl2, interleukin-1β ( IL1β ) and tumor necrosis factor-α ( TNFα ) were analyzed. Assessment of portal site and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced fleshiness and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feed of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor ( Emr1 ) mRNA expression levels. Of eminence, portal atmospheric pressure increased with the duration of WD compared to animals that received a normal chow. Besides fleshiness, WD feeding increased systemic vascular resistance reflecting systemic endothelial and visceral vascular dysfunction. We conclude that transgenic TGR ( mREN2 ) 27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal high blood pressure. leaning towards elevated expression of Emr1 is associated with macrophage activity point to a meaning function of macrophages in NAFLD pathogenesis, credibly due to a switch of the renin–angiotensin system towards a higher activation of the classical music nerve pathway. The hepatic injury induced by WD in TGR ( mREN2 ) 27 rats is suitable to evaluate different stages of fibrosis and portal site high blood pressure in NAFLD with fleshiness.
Keywords : ADGRE1, EMR1, F4/80, Immunity, Liver fibrosis, Macrophage, NAFLD, Portal high blood pressure, TGR ( mREN2 ) 27, western diet Praktiknjo, M., Simón-Talero, M., Römer, J., Roccarina, D., Martínez, J., Lampichler, K., Baiges, A., Low, G., Llop, E., Maurer, M. H., Zipprich, A., Triolo, M., Maleux, G., Fialla, A. D., Dam, C., Vidal-González, J., Majumdar, A., Picón, C., Toth, D., Darnell, A., Abraldes, J. G., López, M., Jansen, C., Chang, J., Schierwagen, R., Uschner, F., Kukuk, G., Meyer, C., Thomas, D., Wolter, K., Strassburg, C. P., Laleman, W., La Mura, V., Ripoll, C., Berzigotti, A., Calleja, J. L., Tandon, P., Hernandez-Gea, V., Reiberger, T., Albillos, A., Tsochatzis, E. A., Krag, A., Genescà, J., Trebicka, J., ( 2020 ). sum sphere of ad-lib portosystemic shunts independently predicts hepatic brain disorder and mortality in liver cirrhosis Journal of Hepatology 72, ( 6 ), 1140-1150 Background & Aims : spontaneous portosystemic shunts ( SPSS ) frequently develop in liver cirrhosis. Recent data suggested that the bearing of a single large SPSS is associated with complications, particularly overt hepatic brain disorder ( oHE ). however, the presence of > 1 SPSS is common. This study evaluates the impact of entire cross-section SPSS area ( TSA ) on outcomes in patients with liver cirrhosis. Methods : In this retrospective international multicentric report, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and lab data were recorded. Each detected SPSS radius was measured and TSA calculated. annual survival was the primary end point and acute decompensation ( oHE, variceal bleed, ascites ) was the secondary end point. Results : A full of 301 patients ( 169 male ) were included in the aim cohort. Thirty percentage of all patients presented with > 1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with belittled or large TSA ( S-/L-TSA ). Patients with L-TSA presented with higher model for end-stage liver disease score ( 11 vs. 14 ) and more normally had a history of oHE ( 12 % vs. 21 %, phosphorus < 0.05 ). During follow-up, patients with L-TSA experienced more oHE episodes ( 33 % vs. 47 %, p < 0.05 ) and had lower 1-year survival than those with S-TSA ( 84 % vs. 69 %, phosphorus < 0.001 ). Multivariate analysis identified L-TSA ( venture ratio 1.66 ; 95 % CI 1.02–2.70, p < 0.05 ) as an mugwump forecaster of deathrate. An autonomous multicentric establishment age group of 607 patients confirmed that patients with L-TSA had lower 1-year survival ( 77 % vs. 64 %, p < 0.001 ) and more oHE development ( 35 % vs. 49 %, phosphorus < 0.001 ) than those with S-TSA. conclusion : This study suggests that TSA > 83 mm2 increases the hazard for oHE and mortality in patients with cirrhosis. Our results support the clinical manipulation of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. Lay summary : The prevalence of ad-lib portosystemic shunts ( SPSS ) is higher in patients with more gain chronic liver disease. The presence of more than 1 SPSS is coarse in advanced chronic liver disease and is associated with the exploitation of liverwort brain disorder. This sketch shows that total cross-section SPSS area ( quite than diameter of the single largest SPSS ) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of entire cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.
Keywords : ACLF, Acute decompensation, Acute-on-chronic liver failure, Ascites, Cirrhosis, Computed imaging, Hepatic brain disorder, Liver, Portal high blood pressure, spontaneous portosystemic shunt, SPSS, TIPS Pose, Elisa, Trebicka, Jonel, Mookerjee, Rajeshwar P., Angeli, Paolo, Ginès, Pere, ( 2019 ). Statins : Old drugs as new therapy for liver diseases ? Journal of Hepatology 70, ( 1 ), 194-202 In accession to lowering cholesterol levels, statins have pleiotropic effects, particularly anti-inflammatory, antiangiogenic, and antifibrotic, that may be beneficial in some chronic incendiary conditions. Statins have only recently been investigated as a likely treatment option in chronic liver-colored diseases because of concerns related to their condom in patients with impaired liver routine. A number of experimental studies in animal models of liver diseases have shown that statins decrease liverwort inflammation, fibrogenesis and portal vein pressure. In addition, retrospective cohort studies in bombastic populations of patients with cirrhosis and pre-cirrhotic conditions have shown that treatment with statins, with the determination of decreasing high cholesterol levels, was associated with a reduce risk of disease progress, liverwort decompensation, hepatocellular carcinoma exploitation, and end. These beneficial effects persisted after adjustment for disease severity and other likely confounders. last, a few randomised controlled trials have shown that treatment with simvastatin decreases portal site pressure ( two studies ) and mortality ( one study ). Statin discussion was broadly well tolerated but a few patients developed dangerous side effects, particularly rhabdomyolysis. Despite these promising beneficial effects, far randomised controlled trials in big serial of patients with hard clinical endpoints should be performed before statins can be recommended for use in clinical practice.
Schierwagen, Robert, Alvarez-Silva, Camila, Madsen, Mette Simone Aae, Kolbe, Carl Christian, Meyer, Carsten, Thomas, Daniel, Uschner, Frank Erhard, Magdaleno, Fernando, Jansen, Christian, Pohlmann, Alessandra, Praktiknjo, Michael, Hischebeth, Gunnar T., Molitor, Ernst, Latz, Eicke, Lelouvier, Benjamin, Trebicka, Jonel, Arumugam, Manimozhiyan, ( 2019 ). Circulating microbiome in blood of different circulatory compartments Gut 68, ( 3 ), 578-580 Rao, T. N., Hansen, N., Hilfiker, J., Rai, S., Majewska, J. M., Lekovic, D., Gezer, D., Andina, N., Galli, S., Cassel, T., Geier, F., Delezie, J., Nienhold, R., Hao-Shen, H., Beisel, C., Di Palma, S., Dimeloe, S., Trebicka, J., Wolf, D., Gassmann, M., Fan, T. W. M., Lane, A. N., Handschin, C., Dirnhofer, S., Kröger, N., Hess, C., Radimerski, T., Koschmieder, S., Cokic, V. P., Skoda, R. C., ( 2019 ). JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms Blood 134, ( 21 ), 1832-1846 Increased energy necessity and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2–driven myeloproliferative neoplasms ( MPNs ). We found that expression of mutant JAK2 augmented and subverted metabolic action of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose weave atrophy, and early mortality. Hypoglycemia in MPN shiner models correlated with hyperactive erythropoiesis and was due to a combination of promote glycolysis and increased oxidative phosphorylation. Modulating alimentary supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem turn and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulative enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small atom 3PO reversed hypoglycemia and reduce hematopoietic manifestations of MPNs. These effects were linear with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. inhibition of glycolysis by 3PO altered the oxidation-reduction homeostasis, leading to accumulation of reactive oxygen species and augment apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.
Hernández-Gea, V., Procopet, B., Giráldez, Ã, Amitrano, L., Villanueva, C., Thabut, D., Ibañez-Samaniego, L., Silva-Junior, G., Martinez, J., Genescà, J., Bureau, C., Trebicka, J., Llop, E., Laleman, W., Palazon, J. M., Castellote, J., Rodrigues, S., Gluud, L. L., Noronha Ferreira, C., Barcelo, R., Cañete, N., Rodríguez, M., Ferlitsch, A., Mundi, J. L., Gronbaek, H., Hernández-Guerra, M., Sassatelli, R., Dell’Era, A., Senzolo, M., Abraldes, J. G., Romero-Gómez, M., Zipprich, A., Casas, M., Masnou, H., Primignani, M., Krag, A., Nevens, F., Calleja, J. L., Jansen, C., Robic, M. A., Conejo, I., Catalina, M. V., Albillos, A., Rudler, M., Alvarado, E., Guardascione, M. A., Tantau, M., Bosch, J., Torres, F., Garcia-Pagán, J. C., ( 2019 ). Preemptive-TIPS improves result in bad variceal run : An experimental study Hepatology 69, ( 1 ), 282-293 Patients admitted with acute variceal run ( AVB ) and Child-Pugh C mark ( CP-C ) or Child-Pugh B plus active run at endoscopy ( CP-B+AB ) are at high risk for treatment failure, rebleeding, and deathrate. A preemptive transjugular intrahepatic portosystemic shunt ( p-TIPS ) has been shown to improve survival in these patients, but its habit in clinical practice has been challenged and not routinely incorporated. The give discipline aimed to further validate the function of preemptive TIPS in a big number of bad patients. This multicenter, external, experimental study included 671 patients from 34 centers admitted for AVB and eminent risk of discussion failure. Patients were managed according to current guidelines, and consumption of drugs and endoscopic therapy ( D+E ) or p-TIPS was based on individual center policy. p-TIPS in the set of AVB is associated with a lower mortality in CP-C patients compared with D+E ( 1 class deathrate 22 % vs. 47 % in D+E group ; P = 0.002 ). Mortality rate in CP-B+AB patients was low, and p-TIPS did not improve it. In CP-C and CP-B+AB patients, p-TIPS reduced treatment failure and rebleeding ( 1-year accumulative incidence function probability of remaining detached of the complex end point : 92 % vs. 74 % in the D+E group ; P = 0.017 ) and exploitation of de novo or worsening of former ascites without increasing rates of hepatic brain disorder. termination : p-TIPS must be the treatment of choice in CP-C patients with AVB. Because of the firm benefit in preventing far bleed and ascites, p-TIPS could be a beneficial treatment scheme for CP-B+AB patients ..
Abraldes, J. G., Trebicka, J., Chalasani, N., D’Amico, G., Rockey, D. C., Shah, V. H., Bosch, J., Garcia-Tsao, G., ( 2019 ). Prioritization of remedy targets and trial design in cirrhotic portal high blood pressure Hepatology 69, ( 3 ), 1287-1299 portal high blood pressure ( PH ) is the main driver of cirrhosis decompensation, the chief determinant of end in patients with cirrhosis. PH results initially from increased intrahepatic vascular underground. Subsequently, increased inflow from visceral vasodilation and increased cardiac output signal lead to a far increase in portal site atmospheric pressure ( PP ). Reducing PP in cirrhosis results in better outcomes. Removing the causal agent of cirrhosis might improve PP. however, this is a decelerate procedure and patients may continue to be at risk of decompensation. additionally, for some chronic liver-colored diseases, such as nonalcoholic fatty liver disease ( NAFLD ), etiological treatments are not yet available. therefore, there is a indigence to develop better therapies specifically aimed at reducing PP. For over 35 years, the anchor of such therapy has been the use of nonselective beta-blockers ( NSBBs ) that act by reducing portal vein venous inflow. recently, many drugs ( chiefly targeting intrahepatic mechanism ) have shown predict in preclinical and early on clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position wallpaper is to propose a fresh framework for the design of clinical trials ( phase 1, 2, and 3 ) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this fix. We have focused the discussion on patients with compensate cirrhosis. The wallpaper summarizes discussions held at The American Association for the Study of Liver Diseases ( AASLD ) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulative professionals, and diligence partners.
Trebicka, J., Bastgen, D., Byrtus, J., Praktiknjo, M., Terstiegen, S., Meyer, C., Thomas, D., Fimmers, R., Treitl, M., Euringer, W., Sauerbruch, T., Rössle, M., ( 2019 ). Smaller-diameter covered transjugular intrahepatic portosystemic shunt stents are associated with increase survival Clinical Gastroenterology and Hepatology 17, ( 13 ), 2793-2799.e1 Background & Aims : We studied the effects of diameter of shroud, self-expandable, nitinol stents on survival times of patients with a transjugular intrahepatic portosystemic shunt ( TIPS ). Methods : We collected data from 185 patients ( median long time, 55 y ; 30 % female ) who received a cover nitinol stent, from February 2006 through September 2010, using the on-line multicenter german TIPS register. TIPS were given to 107 patients for refractory ascites and to 78 patients for variceal bleed. Patients at risk of hepatic brain disorder ( owing to advanced long time, prior episodes ) or liver failure ( bilirubin degree, > 3 mg/dL ), and bleeding patients receiving variceal embolization at TIPS, received 8-mm stents ( n = 53 ). The remaining patients received 10-mm stents ( n = 132 ). Eighty-one of the 10-mm stents were underdilated using 8-mm dilation balloons. clinical and biochemical data were collected after TIPS placement at 1 calendar month, 3 months, 6 months, 9 months, 1 year, and thereafter every 3 to 6 months. Groups were compared using proclivity score analysis. Results : Patients who received 8-mm stents survived significantly longer ( 34 ± 26 molybdenum ) than patients who received 10-mm stents ( 18 ± 19 moment ), careless of whether they were in full dilated or underdilated. When we compared 10-mm stents with or without underdilation, we found that a significantly higher proportion of patients who received underdilated stents survived for 1 calendar month after TIPS placement ( 95 % five 84 % ; P = .03 ), but not for 3 months ( P = .10 ). In multivariate psychoanalysis, 1-year mortality correlated with full dilation of the stent to 10 millimeter ( luck proportion [ HR ], 2.0 ; 95 % CI, 1.1–3.5 ) and with serum creatinine concentration at service line ( HR, 1.5 ; 95 % CI, 1.0–1.7 ). Five-year mortality was associated with consumption of the 10-mm stents ( HR, 1.8 ; 95 % CI, 1.4–2.7 ) and service line concentration of creatinine ( HR, 1.3 ; 95 % CI, 1.1–1.6 ). Conclusions : A smaller stent ( noun phrase diameter of 8 millimeter, but not underdilation of a 10-mm stent ) is associated with a drawn-out survival compared with 10-mm stents, mugwump of liver-specific predictive criteria.
Keywords : cirrhosis, Comparison, Covered, Portal Hypertension Jansen, C., Trebicka, J., ( 2019 ). column : diastolic dysfunction seems not to be critical for survival after transjugular intrahepatic portosystemic stent-shunt Alimentary pharmacology & therapeutics 49, ( 8 ), 1101-1102 Armstrong et al take a closer look at cardiac diagnostics in patients evaluated for transjugular intrahepatic portosystemic stent-shunt ( TIPSS ) insertion. Although highly selected in their patients, presence of diastolic dysfunction was not associated with survival, but Model for End-Stage Liver Disease ( MELD ) score remained the best predictor of survival. The clinical “ gut-feeling ” and pathophysiological understanding propose that the cardiac function should play a function and should be investigated anterior to TIPSS interpolation in these patients. therefore, the question arises, is echocardiography relevant for selection of patients to TIPSS and if yes what parameters are the relevant ones ?
Lehmann, J., Praktiknjo, M., Nielsen, M. J., Schierwagen, R., Meyer, C., Thomas, D., Violi, F., Strassburg, C. P., Bendtsen, F., Moller, S., Krag, A., Karsdal, M. A., Leeming, D. J., Trebicka, J., ( 2019 ). Collagen type IV remodelling gender-specifically predicts mortality in decompensated cirrhosis Liver International 39, ( 5 ), 885-893 Background & Aims : Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute accent decompensation. Extratracellular matrix is compiled of deposition of diverse components. The function of basement membrane collagen type IV in advance cirrhosis and acute decompensation is ill-defined and investigated in this study. Methods : Patients with decompensated cirrhosis from the prospective NEPTUN cohort ( ClinicalTrials.gov Identifier : NCT03628807 ), who underwent transjugular intrahepatic portosystemic shunt procedure were included. Clinical and lab parameters, PRO-C4 and C4M levels were measured in blood samples from portal site and hepatic veins fair before transjugular intrahepatic portosystemic shunt placement. Results : Levels of C4M and PRO-C4 are significantly lower in patients with massive ascites and mar nephritic sodium elimination. C4M and PRO-C4 show gender-specific profiles with significantly lower levels in females compared to males. Females with higher C4M levels show higher deathrate. By contrast, males with higher C4M levels show lower deathrate. In multivariate Cox regression analysis, C4M is an mugwump forecaster of survival in female patients. conclusion : This sketch shows that markers of collagen type IV remodelling do not accumulate in severe nephritic dysfunction. Although collagen type IV abasement markers derive from the liver, portal site venous C4M levels are relevant for survival. furthermore, it demonstrates that circulating C4M shows gender-specific profiles, which can independently bode survival in female patients with decompensated cirrhosis.
Keywords : ACLF, Acute decompensation, Acute-on-chronic liver failure, Cirrhosis, Collagen type IV, Extracellular matrix remodelling, Gender, Liver, Portal high blood pressure, Transjugular intrahepatic portosystemic shunt Praktiknjo, M., Djayadi, N., Mohr, R., Schierwagen, R., Bischoff, J., Dold, L., Pohlmann, A., Schwarze-Zander, C., Wasmuth, J. C., Boesecke, C., Rockstroh, J. K., Trebicka, J., ( 2019 ). Fibroblast emergence agent 21 is independently associated with severe hepatic steatosis in non-obese HIV-infected patients Liver International 39, ( 8 ), 1514-1520 background : Severe liverwort steatosis shows a high prevalence and contributes to morbidity and mortality in human immunodeficiency virus ( HIV ) infected patients. Known hazard factors include fleshiness, dyslipidaemia and features of metabolic syndrome. Fibroblast growth component 21 ( FGF-21 ) is involved with hepatic glucose and lipid metabolism. This cogitation aimed to evaluate FGF-21 as a biomarker for dangerous liverwort steatosis in non-obese HIV-infected patients. Methods : This is a prospective, cross-sectional, monocentric study including HIV-infected out-patients. liverwort steatosis was measured via controlled attenuation parameter ( CAP ) using FibroScan 502 touch ( ECHOSENS, France ). Severe liverwort steatosis was defined at CAP ≥ 253 dB/m. Peripheral rake samples were collected and plasma was analysed for FGF-21. Demographic and clinical characteristics were collected from patient ‘s health records. Results : In sum, 73 non-obese HIV-monoinfected patients were included in this learn. Prevalence of severe hepatic steatosis was 41 %. Patients with dangerous liverwort steatosis showed importantly higher levels of FGF-21. Univariate analysis revealed FGF-21, BMI, lipemia, ALT levels and arterial high blood pressure as significant, while multivariate psychoanalysis showed entirely FGF-21, arterial high blood pressure and ALT levels as significant mugwump hazard factors for severe liverwort steatosis. stopping point : This report presents FGF-21 as an independent and stronger forecaster of austere hepatic steatosis than blood lipids in HIV-infected patients. furthermore, arterial high blood pressure and ALT levels predict hard steatosis even in non-obese HIV-monoinfected patients. furthermore, this report supports existing metabolic gamble factors and expands them to non-obese HIV-infected patients.
Keywords : BMI, CAP, Dyslipidaemia, FGF-21, Fibroscan, HIV, Hyperlipidaemia, Liver, NAFLD, NASH, Steatosis Trebicka, J., Amoros, A., Pitarch, C., Titos, E., Alcaraz-Quiles, J., Schierwagen, R., Deulofeu, C., Fernandez-Gomez, J., Piano, S., Caraceni, P., Oettl, K., Sola, E., Laleman, W., McNaughtan, J., Mookerjee, R. P., Coenraad, M. J., Welzel, T., Steib, C., Garcia, R., Gustot, T., Rodriguez Gandia, M. A., Bañares, R., Albillos, A., Zeuzem, S., Vargas, V., Saliba, F., Nevens, F., Alessandria, C., De Gottardi, A., Zoller, H., Ginès, P., Sauerbruch, T., Gerbes, A., Stauber, R. E., Bernardi, M., Angeli, P., Pavesi, M., Moreau, R., Clària, J., Jalan, R., Arroyo, V., ( 2019 ). Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis Frontiers in Immunology 10, 476 background : Patients with sharply decompensated cirrhosis ( AD ) may or may not develop acute-on-chronic liver bankruptcy ( ACLF ). ACLF is characterized by high-grade systemic inflammation, organ failures ( OF ) and high short-run mortality. Although patients with AD cirrhosis expose distinct clinical phenotypes at baseline, they have moo short-run deathrate, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic ignition in these patients. Methods : Upon hospital entrance fee baseline plasma levels of 15 markers ( cytokines, chemokines, and oxidize albumin ) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes ( AD-1 : Creatinine < 1.5, no HE, no OF ; AD-2 : creatinine 1.5–2, and or HE grade I/II, no OF ; AD-3 : Creatinine < 1.5, no HE, non-renal OF ). Results : Most markers were slenderly abnormal in compensate cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating “ full-blown ” systemic inflammation ( all markers ). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial derivative ( 30 % of the markers ). Mortality related to each clinical AD-phenotype was significantly lower than deathrate associated with ACLF ( p < 0.0001 by grey test ). Among AD-patients service line systemic inflammation ( particularly IL-8, IL-6, IL-1ra, HNA2 independently associated ) was more intense in those who had hapless 28-day outcomes ( ACLF, death ) than those who did not experience these outcomes. Conclusions : Although AD-patients show distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have alone fond energizing of systemic inflammation. however, those with the most extend service line systemic ignition had the highest the risk of ACLF development and death.
Keywords : Acute-on-chronic liver failure, Ascites, Cirrhosis, Cytokines, Microbiome, Myeloid cells, Systemic inflammation Faron, A., Pieper, C. C., Schmeel, F. C., Sprinkart, A. M., Kuetting, D. L. R., Fimmers, R., Trebicka, J., Schild, H. H., Meyer, C., Thomas, D., Luetkens, J. A., ( 2019 ). nonfat muscle area measured by magnetic resonance image predicts overall survival of patients undergoing radioembolization of colorectal cancer liver metastases European Radiology 29, ( 9 ), 4709-4717 Objectives : To investigate the clinical likely of nonfat muscle sphere ( FFMA ) to predict result in patients with liver-predominant metastatic colorectal cancer ( mCRC ) undergoing radioembolization ( RE ) with 90Yttrium microspheres. Methods : Patients with mCRC who underwent RE in our center were included in this retrospective learn. All patients received liver-colored magnetic resonance imaging including standard T2-weighted images. The full erector spinae muscle area and the intramuscular adipose tissue area were measured at the level of the beginning of the lake superior mesenteric artery and subtracted to calculate FFMA. Cutoff values for definition of depleted FFMA were 3644 mm2 in men and 2825 mm2 in women. The independent consequence was overall survival ( OS ). For survival analysis, the Kaplan-Meier method and Cox regressions comparing respective clinic-oncological parameters which potentially may affect OS were performed. Results : seventy-seven patients ( 28 female, mean age 60 ± 11 years ) were analyzed. mean clock between MRI and the follow RE was 17 ± 31 days. medial OS after RE was 178 days. Patients with depleted FFMA had significantly shortened OS compared to patients with high FFMA ( medial OS : 128 vs. 273 days, p = 0.017 ). On multivariate Cox regression analysis, OS was effective predicted by FFMA ( luck proportion ( HR ) 2.652 ; p
Keywords : Brachytherapy, Colorectal cancer, magnetic rapport visualize, Sarcopenia Klein, S., Frohn, F., Magdaleno, F., Reker-Smit, C., Schierwagen, R., Schierwagen, I., Uschner, F. E., van Dijk, F., Fürst, D. O., Djudjaj, S., Boor, P., Poelstra, K., Beljaars, L., Trebicka, J., ( 2019 ). Rho-kinase inhibitor coupled to peptide-modified albumin carrier reduces portal site atmospheric pressure and increases nephritic perfusion in cirrhotic rats Scientific Reports 9, ( 1 ), 2256 Rho-kinase ( ROCK ) activation in liverwort radial cells ( HSC ) is a key mechanism promoting liver fibrosis and portal vein high blood pressure ( PTH ). specific delivery of ROCK-inhibitor Y-27632 ( Y27 ) to HSC targeting mannose-6-phosphate-receptors reduces portal vein blackmail and fibrogenesis. In decompensated cirrhosis, presence of ascites is associated with dilute nephritic perfusion. Since in cirrhosis, platelet-derived growth gene receptor beta ( PDGFRβ ) is upregulated in the liver arsenic well as the kidney, this study coupled Y27 to human serum albumin ( HSA ) substituted with PDGFRβ-recognizing peptides ( pPB ), and investigated its effect on PTH in cirrhotic rats. In vitro collagen compression assays tested biological activeness on LX2 cells. Hemodynamics were analyzed in BDL and CCl4 cirrhotic rats 3 henry, 6 heat content and 24 hydrogen after i.v. administration of Y27pPBHSA ( 0.5/1 mg/kg b.w ). Phosphorylation of moesin and myosin easy chain ( MLC ) assessed ROCK natural process in liver, femoral muscleman, mesenteric artery, kidney and heart. Three Y27 molecules were coupled to pPBHSA as confirmed by HPLC/MS, which was sufficient to relax LX2 cells. In vivo, Y27pPBHSA-treated rats exhibited lower portal vein imperativeness, hepatic vascular resistance without effect on systemic vascular resistance, but a tendency towards lower cardiac output compared to non-treated cirrhotic rats. Y27pPBHSA reduced intrahepatic resistor by decrease of phosphorylation of moesin and MLC in Y27pPBHSA-treated cirrhotic rats. Y27pPBHSA was found in the liver of rats up to 6 hours after its injection, in the HSC demonstrated by double-immunostainings. Interestingly, Y27pPBHSA increased nephritic arterial flow over clock combined with an antifibrotic effect as shown by decrease nephritic acta2 and col1a1 messenger rna expression. consequently, targeting the ROCK inhibitor Y27 to PDGFRβ decreases portal vein coerce with potential beneficial effects in the kidney. This singular overture should be tested in human cirrhosis.
Keywords : liverwort radial cells, Hepatorenal syndrome Klein, S., Kleine, C. E., Pieper, A., Granzow, M., Gautsch, S., Himmit, M., Kahrmann, K., Schierwagen, R., Uschner, F. E., Magdaleno, F., Naoum, M. E., Kristiansen, G., Walther, T., Bader, M., Sauerbruch, T., Trebicka, J., ( 2019 ). TGR ( mREN2 ) 27 rats develop non-alcoholic fatty liver disease-associated portal high blood pressure responsive to modulations of Janus-kinase 2 and Mas receptor Scientific Reports 9, ( 1 ), 11598
preponderance of non-alcoholic fatty liver disease ( NAFLD ) is increasing. Resulting fibrosis and portal site high blood pressure, as a potential secondary event, may necessitate discussion. Overexpression of mouse renin in the transgenic rat model, TGR ( mREN2 ) 27, leads to spontaneous exploitation of NAFLD. consequently, we used TGR ( mREN2 ) 27 rats as a exemplary of NAFLD where we hypothesized increased susceptibility and investigate fibrosis and portal vein high blood pressure and associated pathways. 12-week honest-to-god TGR ( mREN2 ) 27 rats received either cholestatic ( BDL ) or toxic injury ( CCl4 inhalant ). portal site and systemic hemodynamic assessments were performed using microsphere proficiency with and without injection of the Janus-Kinase 2 ( JAK2 ) inhibitor AG490 or the non-peptidic Ang ( 1-7 ) protagonist, AVE0991. The extent of liver fibrosis was assessed in TGR ( mREN2 ) 27 and wild-type rats using standard techniques. Protein and messenger rna levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic radial cells ( HSC ) and hepatocytes. TGR ( mREN2 ) 27 rats developed ad-lib, but balmy fibrosis and portal vein high blood pressure due to the activation of the JAK2/Arhgef1/ROCK nerve pathway. AG490 decreased migration of HSC and portal press in detached liver perfusions and in vivo. fibrosis or portal high blood pressure after cholestatic ( BDL ) or toxic injury ( CCl4 ) was not aggravated in TGR ( mREN2 ) 27 rats, probably due to decreased mouse renin expression in hepatocytes. interestingly, portal site high blood pressure was evening blunted in TGR ( mREN2 ) 27 rats ( with or without extra injury ) by AVE0991. TGR ( mREN2 ) 27 rats are a suitable model of ad-lib liver fibrosis and portal site high blood pressure but not with increased susceptibility to liver damage. After extra injury, the animals can be used to evaluate novel curative strategies targeting Mas.
Keywords : Mechanisms of disease, Molecular medicine Brol, M. J., Rösch, F., Schierwagen, R., Magdaleno, F., Uschner, F. E., Manekeller, S., Queck, A., Schwarzkopf, K., Odenthal, M., Drebber, U., Thiele, M., Lingohr, P., Plamper, A., Kristiansen, G., Lotersztajn, S., Krag, A., Klein, S., Rheinwalt, K. P., Trebicka, J., Galaxy, Consortium, ( 2019 ). combination of CCL4 with alcoholic and metabolic injuries mimics human liver-colored fibrosis American Journal of Physiology – Gastrointestinal and Liver Physiology 317, ( 2 ), G182-G194 Metabolic and alcoholic liver injuries result in nonalcoholic ( NAFLD ) or alcoholic ( ALD ) fatty liver disease, respectively. In detail, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of desirable models with significant fibrosis. The carbon tetrachloride ( CCl4 ) liver fibrosis model does not reflect homo NAFLD or ALD, but CCl4 may serve as a fibrosis catalyst in addition to another injury. Ethanol in drink water ( 16 % ) or western diet ( WD ) were administered for 7 wk in mouse either alone or in combination with CCl4 intoxications. extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection ( newton = 7 ), NAFLD ( newton = 8 ), or ALD ( normality = 7 ). WD or ethanol alone induced entirely meek steatosis and inflammation. combination of CCl4 and WD induced the most severe steatosis together with meaning liver fibrosis and centrist excitement. combination of CCl4 and ethyl alcohol induced the strongest ignition, with significant liver-colored fibrosis and chasten steatosis. The relationship traffic pattern between fibrosis, proliferation, and inflammation of human ALD was largely similar in mouse treated with CCl4 and ethyl alcohol. The combination of CCl4 poisoning with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. specially, CCl4 plus ethyl alcohol for 7 wk induces ALD in mouse, providing a model suitable for foster basic research and drug screen. NEW & NOTEWORTHY Alcoholic fatso liver disease with significant fibrosis is generated within 7 wk using carbon paper tetrachloride as a fibrosis accelerator and administering gradually ethyl alcohol ( up to 16 % ) in mouse. The similarity in the model of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this sneak model desirable as a preclinical model for drug development.
Keywords : ASH, Liver fibrosis, NAFLD, NASH Queck, A., Thomas, D., Jansen, C., Schreiber, Y., Rüschenbaum, S., Praktiknjo, M., Schwarzkopf, K. M., Mücke, M. M., Schierwagen, R., Uschner, F. E., Meyer, C., Clària, J., Zeuzem, S., Geisslinger, G., Trebicka, J., Lange, C. M., ( 2019 ). Pathophysiological character of prostanoids in curdling of the portal site venous organization in liver cirrhosis PLoS ONE 14, ( 10 ), e0222840 background : Prostanoids are important regulators of platelet collection and thrombotic arterial diseases. Their participation in the development of portal site vein thrombosis, patronize in decompensated liver cirrhosis, is still not investigated. Methods : consequently, we used pro-thrombotic venous milieu generation by bare metallic element stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal site and the liverwort vein. Results : While the liverwort vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein vein ( all P < 0.0001 ). Baseline concentrations of thromboxane B2 in the portal vein vein were independently associated with an increase of portal vein liverwort venous pressure gradient during short term follow-up, as an indirect signboard of thrombogenic likely ( multivariable P = 0.004 ). furthermore, badness of liver disease was inversely correlated with portal site a well as hepatic vein levels of prostaglandin D2 and E2 ( all P < 0.0001 ). Conclusions : Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis. Praktiknjo, M., Clees, C., Pigliacelli, A., Fischer, S., Jansen, C., Lehmann, J., Pohlmann, A., Lattanzi, B., Krabbe, V. K., Strassburg, C. P., Arroyo, V., Merli, M., Meyer, C., Trebicka, J., ( 2019 ). Sarcopenia is associated with development of acute-on-chronic liver failure in decompensated liver cirrhosis receiving transjugular intrahepatic portosystemic shunt Clinical and Translational Gastroenterology 10, ( 4 ), e00025 introduction : brawn multitude has been shown to be a omen marker in patients with liver cirrhosis. Transversal psoas muscle thickness normalized by acme ( TPMT/height ) obtained by routine computed imaging is a simple surrogate parameter for sarcopenia. TPMT/height, however, is not arouse specific, which might play a character in risk stratification. Its association with acute-on-chronic liver-colored failure ( ACLF ) has not been established even. ACLF is associated with systemic inflammatory dysregulation. This report aimed at evaluating the function of sarcopenia in ACLF growth of patients with decompensated cirrhosis receiving transjugular intrahepatic portosystemic shunt ( TIPS ) using sex-specific TPMT/height. method acting : One hundred eighty-six patients from the prospective Non-invasive evaluation Program for TIPS and Follow Up Network age group ( experimental, real-world TIPS cohort with integrated follow-up ) were analyzed. TPMT/height was measured from routine computed imaging. The sex-specific cutoff was determined to classify patients as sarcopenic and nonsarcopenic for 1-year deathrate after TIPS. Clinical result was compared. chief end points were ACLF and 1-year mortality after TIPS. secondary conclusion points were development of decompensations ( hepatic brain disorder and ascites ) after TIPS. consequence : The sex-specific shortcut increases the diagnostic accuracy with regard to primary and secondary coil end points compared with the unisex cutoff. Sex-specific sarcopenia classification is an freelancer predictor of 1-year mortality and ACLF development in patients with cirrhosis receiving TIPS. Patients in the sarcopenia group showed importantly higher rates of deathrate, ascites, overt liverwort brain disorder, and ACLF after TIPS compared with the nonsarcopenia group. The Chronic Liver Failure Consortium Acute Decompensation score as a marker of systemic excitement was significantly higher in sarcopenic patients. conclusion : This study demonstrates for the inaugural prison term that sarcopenia is related to ACLF development and systemic inflammation. The omen value of TPMT/height can be improved by using sex-specific cutoffs.
Magdaleno, Fernando, Schierwagen, R., Uschner, Frank E., Trebicka, J., ( 2018 ). “ Tipping ” extracellular matrix remodeling towards regression of liver fibrosis : fresh concepts Minerva Gastroenterologica east Dietologica, 64, ( 1 ), 51-61 Fibrosis development was initially conceived as an ceaseless progressive condition. Nowadays, it has become apparent that fibrotic tissue undergoes a continuous bipartisan summons : fibrogenesis and fibrinolysis, characterizing the remodel of extracellular matrix ( ECM ). however, in established fibrosis, this bipartite summons is tipped towards fibrogenesis and this leads to a self-perpetuating collection of ECM, a discrete metabolic unit, together with other cells and processes promoting fibrosis deposit. several mechanism advertise fibrosis regression, such as abasement of ECM, infiltration of tonic macrophages, prevention of the epithelial-mesenchymal conversion of hepatocytes, renovation of the liver-colored sinusoidal endothelial cells ’ differentiation phenotype, and backsliding to quiescence, apoptosis and agedness of liverwort radial cells ( HSC ). Hence, fibrosis is the leave of an unbalanced bipartite summons of matrix recast. At the late stage of the disease, antifibrotic interventions could become necessity to reverse self-perpetuating fibrogenesis and accelerate regression of fibrosis even if induce and cofactors of liverwort injury have been eliminated. This review outlines some of the crucial mechanisms leading towards regression of liver fibrosis.
Keywords : liverwort radial cells, Extracellular matrix, remodeling, Rho-associated kinases, Janus kinases Luetkens, Julian A., Klein, Sabine, Traeber, Frank, Schmeel, Frederic C., Sprinkart, Alois M., Kuetting, Daniel L. R., Block, Wolfgang, Hittatiya, Kanishka, Uschner, Frank E., Schierwagen, Robert, Gieseke, Juergen, Schild, Hans H., Trebicka, Jonel, Kukuk, Guido M., ( 2018 ). quantitative liver-colored MRI including extracellular volume fraction for non-invasive quantification of liver fibrosis : a prospective proof-of-concept study Gut 67, ( 3 ), 593-594 quantitative liver MRI including extracellular volume fraction for non-invasive quantification of liver fibrosis : a prospective proof-of-concept report.
Praktiknjo, M., Book, M., Luetkens, J., Pohlmann, A., Meyer, C., Thomas, D., Jansen, C., Feist, A., Chang, J., Grimm, J., Lehmann, J., Strassburg, C. P., Abraldes, J. G., Kukuk, G., Trebicka, J., ( 2018 ). nonfat brawn mass in magnetic resonance visualize predicts acute-on-chronic liver failure and survival in decompensated cirrhosis Hepatology 67, ( 3 ), 1014-1026 Muscle mass seems to be a predictive marker in patients with liver cirrhosis. however, reported methods to quantify muscle mass are heterogeneous, consented cutoff values are missing, and most studies have used computed imaging. This study evaluated nonfat muscle area ( FFMA ) as a marker of sarcopenia using magnetic resonance imagination ( MRI ) in patients with decompensated cirrhosis with transjugular intrahepatic portosystemic shunt ( TIPS ). The full erector spinae brawn area and the intramuscular fatty tissue sphere were measured and subtracted to calculate the FFMA in 116 patients with cirrhosis by TIPS and MRI. The train age group of 71 patients compared calculate tomography–measured cross psoas muscleman thickness with FFMA. In 15 patients MRI was performed before and after TIPS, and in 12 patients follistatin serum measurements were carried out. The results on FFMA were confirmed in a establishment age group of 45 patients. FFMA correlated with follistatin and cross psoas muscle thickness and showed slightly better association with survival than cross psoas muscle thickness Gender-specific cutoff values for FFMA were determined for sarcopenia. Decompensation ( ascites, overt liverwort brain disorder ) persisted after TIPS in the sarcopenia group but resolved in the nonsarcopenia group. Sarcopenic patients showed no clinical improvement after TIPS american samoa well as higher deathrate, chiefly due to development of acute-on-chronic liver failure. FFMA was an independent forecaster of survival in these patients. ending : This study offers an easy-to-apply MRI-based measurement of nonfat muscle mass as a marker of sarcopenia in decompensated patients ; while TIPS might improve sarcopenia and thereby survival, doggedness of sarcopenia after TIPS is associated with a reduced response to TIPS and a higher risk of acute-on-chronic liver failure growth and mortality.
Jansen, Christian, Möller, Philipp, Meyer, Carsten, Kolbe, Carl Christian, Bogs, Christopher, Pohlmann, Alessandra, Schierwagen, Robert, Praktiknjo, Michael, Abdullah, Zeinab, Lehmann, Jennifer, Thomas, Daniel, Strassburg, Christian P., Latz, Eicke, Mueller, Sebastian, Rössle, Martin, Trebicka, Jonel, ( 2018 ). Increase in liver stiffness after transjugular intrahepatic portosystemic shunt is associated with inflammation and predicts mortality Hepatology 67, ( 4 ), 1472-1484 Transjugular intrahepatic portosystemic shunt ( TIPS ) efficiently treats complications of portal high blood pressure. Liver and irascibility stiffness might predict clinically significant portal vein high blood pressure. This prospective study investigated liver awkwardness in patients receiving TIPS regardless of reading. Of 83 admit patients, 16 undergo transient elastography immediately before and 30 minutes after TIPS ( acute accent group ), while 67 received shear wave elastography of liver-colored and irascibility 1 day before and 7 days after TIPS ( chronic group ) and were followed promote. In blood samples obtained before TIPS from cubital, portal site, and liverwort veins, levels of several interleukins ( IL1b, IL6, IL8, IL10, IL18 ) and interferon-gamma were analyzed. In 27 patients ( 5 acute, 22 chronic ), it resulted in an increase in liver awkwardness of > 10 %. In 56 patients, liver stiffness decreased or remained unchanged ( < 10 % ). importantly, irascibility stiffness measured by shear wave elastography decreased in all patients ( chronic group ). none of the clinical or testing ground parameters differed between patients with increase in liver awkwardness and those without. Of note, patients with increase liver stiffness showed higher overall and/or hepatic venous levels of proinflammatory cytokines at TIPS and higher incidence of organ failure and worse survival after TIPS. C-reactive protein values and addition of > 10 % in liver awkwardness after TIPS were the only independent predictors of mortality in these patients. conclusion : This study demonstrates that the presence of systemic inflammation predisposes patients to develop increased liver severity after TIPS, a predictor of harmonium failure and end.
Piano, Salvatore, Schmidt, Hartmut H., Ariza, Xavier, Amoros, Alex, Romano, Antonietta, Hüsing-Kabar, Anna, Solà, Elsa, Gerbes, Alexander, Bernardi, Mauro, Alessandria, Carlo, Scheiner, Bernhard, Tonon, Marta, Maschmeier, Miriam, Solè, Cristina, Trebicka, Jonel, Gustot, Thierry, Nevens, Frederik, Arroyo, Vicente, Gines, Pere, Angeli, Paolo, ( 2018 ). Association between grade of acuate on chronic liver failure and reaction to terlipressin and albumin in patients with hepatorenal syndrome Clinical Gastroenterology and Hepatology 16, ( 11 ), 1792-1800 Type 1 hepatorenal syndrome ( HRS ) is the most bad type of nephritic failure in patients with cirrhosis. Terlipressin and albumin are effective treatments for character 1 HRS. however, the effects of acute on chronic liver failure ( ACLF ) grade on response to treatment are not clear. We aimed to identify factors associated with reply to treatment with terlipressin and albumin in patients with type 1 HRS ( decrease in serum horizontal surface of creatinine to below 1.5 mg/dL at the end of treatment ) and factors associated with death within 90 days of HRS diagnosis ( 90-day mortality ).
Luetkens, Julian, A., Klein, Sabine, Träber, Frank, Schmeel, Frederic, C., Sprinkart, Alois M., Kuetting, Daniel L. R., Block, Wolfgang, Uschner, Frank E., Schierwagen, Robert, Hittatiya, Kanishka, Kristiansen, Glen, Gieseke, Juergen, Schild, Hans, H., Trebicka, Jonel, Kukuk, G.M., ( 2018 ). quantification of liver fibrosis at T1 and T2 function with extracellular volume divide MRI : preclinical results Radiology 288, ( 3 ), 748-754 In our animal discipline, quantitative liver MRI including extracellular volume fraction appears to be a valuable and modern diagnostic creature for the signal detection and quantification of diffuse liver fibrosis. Purpose : To evaluate MRI T1 and T2 map with calculation of extracellular volume ( ECV ) for diagnosis and grading of liver fibrosis. Materials and Methods : Different grades of fibrosis were induced in 60 male Sprague-Dawley rats by bile duct ligation ( BDL ) and carbon-tetrachloride ( CCl4 ) poisoning. portal site pressure was measured invasively, whereas liverwort fibrosis was quantified by hydroxyproline content, Sirius red staining, and α smooth brawn actin staining. T1 values, T2 values, and ECV were assessed by using quantitative MRI map techniques. Results : T1 values in animals 4 weeks after BDL were greater than in master animals ( 718 millisecond ± 74 vanadium 578 millisecond ± 33, respectively ; P < .001 ). T2 values at 4 weeks were besides greater in animals that underwent BDL than in command animals ( 46 millisecond ± 6 v 29 millisecond ± 2, respectively ; P < .001 ). similar T1 and T2 findings were observed after CCl4 drunkenness. ECV was greater in animals 4 weeks after BDL compared with control animals ( 31.3 % ± 1.3 v 18.2 % ± 3.5, respectively ; P < .001 ), with alike results after CCl4 drunkenness. high correlations were found between ECV and hepatic hydroxyproline contented ( BDL : roentgen = 0.68, P < .001 ; CCl4 : r = 0.65, P < .001 ), Sirius red stain ( BDL : radius = 0.88, P < .001 ; CCl4 : roentgen = 0.82, P < .001 ), α smooth muscleman actin stain ( BDL : radius = 0.70, P < .001 ; CCl4 : radius = 0.73, P < .001 ), and portal site pressure ( BDL : gas constant = 0.54, P = .003 ; CCl4 : roentgen = 0.39, P = .043 ). conclusion : acme of T1 and T2 values and ECV was associated with severity of liver fibrosis and portal site high blood pressure in an experimental animal model.
Ruiz-Margáin, Astrid, Pohlmann, Alessandra, Ryan, Patrick, Schierwagen, Robert, Chi-Cervera, Luis A., Jansen, Christian, Mendez-Guerrero, Osvely, Flores-García, Nayelli C., Lehmann, Jennifer, Torre, Aldo, Macías-Rodríguez, Ricardo Ulises, Trebicka, Jonel, ( 2018 ). Fibroblast growth gene 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis Liver Transplantation 24, ( 5 ), 595-605 Acute-on-chronic liver failure ( ACLF ) develops in acute decompensation ( AD ) of cirrhosis and shows high deathrate. In critically ill patients, early diagnosis of ACLF could be significant for remedy decisions ( eg, nephritic substitution, artificial liver hold, liver transplant ). This study evaluated fibroblast growth factor 21 ( FGF21 ) as a marker of mitochondrial dysfunction in the context of ACLF. The study included 154 individuals ( 112 critically patients and 42 goodly controls ) divided into a education and a establishment cohort. In the train age group of 42 healthy controls and 34 critically ill patients ( of whom 24 were patients with cirrhosis ), levels of FGF21, interleukin ( IL ) 6, and IL8 were measured. In the validation cohort of 78 patients with cirrhosis, 17 patients were admitted with or developed ACLF during follow-up and undergo day by day clinical and nutritional assessment. Levels of FGF21 were higher in critically ill patients, specially in patients with cirrhosis admitted to the intensive care unit ( ICU ). furthermore, FGF21 adenine well as IL6 and IL8 levels were higher in patients with ACLF, but they did not increase with the austereness of ACLF. Interestingly, in the establishment cohort, FGF21 was besides elevated in the patients who developed ACLF in the adjacent 7 days. In these patients, FGF21 levels were an independent predictor of ACLF bearing and development in multivariate analysis together with Child‐Pugh score. FGF21 levels had no impact on the survival of critically ill patients with cirrhosis. In conclusion, this cogitation demonstrates that FGF21 levels are of specific diagnostic respect regarding the presence and development of ACLF in patients admitted to ICU for AD of liver cirrhosis. further studies are warranted to address pathophysiological and possible curative implications.
Jansen, Christian, Cox, Alexander, Schueler, Robert, Schneider, Matthias, Lehmann, Jennifer, Praktiknjo, Michael, Pohlmann, Alessandra, Chang, Johannes, Manekeller, Steffen, Nickenig, Georg, Berlakovich, Gabriela, Strassburg, Christian P., Hammerstingl, Christoph, Staufer, Katharina, Trebicka, Jonel, ( 2018 ). Increased myocardial contractility identifies patients with decompensated cirrhosis requiring liver transplant Liver Transplantation 24, ( 1 ), 15-25 recently allocation of organs for transplant impairs post–liver transplant ( LT ) survival. Cardiac dysfunction, particularly diastolic and autonomic dysfunction, is patronize and plays an important function in the prognosis of patients with cirrhosis. however, the function of myocardial contractility is undiscovered, and its predictive value is controversially discussed. This discipline analyses the function of myocardial contractility assessed by speckle tracking echocardiography in LT allotment. In sum, 168 patients with cirrhosis ( training cohort, 111 ; validation age group [ VC ], 57 ) awaiting LT in 2 centers were included in this retrospective study. besides, 51 patients from the trail and all patients from the VC were transplanted, 36 patients of the train and 38 of the VC were active at the end of follow-up, and 21 nontransplanted patients died. Contractility of the left ventricle ( LV ) increased with severity of the Child-Pugh score. interestingly, higher LV contractility in the educate cohort patients, particularly in those with Child-Pugh C, was an freelancer predictor of boil down transplant-free survival. In male patients, the effects on survival of increase exit and right ventricular myocardial contractility were more pronounce. notably, competing hazard analysis demonstrated that increase contractility is associated with earlier LT, which could be confirmed in the VC. importantly, LV myocardial contractility had no impact on survival of patients not receiving LT or on post-LT survival. In conclusion, this study demonstrates for the first time that increased myocardial contractility in decompensated patients identifies patients who require LT early, but without increased post-LT deathrate.
Schwabl, Philipp, Brusilovskaya, Ksenia, Supper, Paul, Bauer, David, Königshofer, Philipp, Riedl, Florian, Hayden, Hubert, Fuchs, Claudia Daniela, Stift, Judith, Oberhuber, Georg, Aschauer, Stefan, Bonderman, Diana, Gnad, Thorsten, Pfeifer, Alexander, Uschner, Frank Erhard, Trebicka, Jonel, Rohr-Udilova, Nataliya, Podesser, Bruno Karl, Peck-Radosavljevic, Markus, Trauner, Michael, Reiberger, Thomas, ( 2018 ). The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal site pressure in cirrhotic rats Scientific Reports 8, ( 1 ), 9372 In cirrhotic patients, portal site high blood pressure ( PHT ) deteriorates survival, however treatment options are limited. A major contributor to increased intrahepatic vasoconstriction in PHT is dysfunctional nitric-oxide signal. soluble guanylate cyclase ( sGC ) is the receptor of nitric-oxide and can be stimulated by riociguat. Riociguat is approved for pneumonic high blood pressure but has not been studied in liver-colored cirrhosis. In this study we assessed the effects of riociguat on PHT and liver fibrosis in cholestatic ( bile duct ligation, BDL ) and toxic ( carbon-tetrachloride, CCl4 ) rat models. In cirrhotic livers sGC formulation was upregulated. In BDL rats, riociguat reduced liver fibrosis and decrease portal site imperativeness without affecting systemic hemodynamics. In an early BDL disease phase, riociguat decreased bile duct proliferation, improved sinusoidal vascular dysfunction and inhibit angiogenesis. In advanced BDL riociguat exhibited anti-inflammatory effects. In CCl4 rats the beneficial effects of riociguat treatment were less marked and confined to an early disease stage. similarly, in patients with cholestatic cirrhosis and PHT nitrates ( that induce sGC action ) decreased portal vein press more efficaciously than in patients with non-cholestatic etiology. We besides found an improvement of transaminases in patients with pneumonic high blood pressure receiving riociguat. Our findings support the clinical development of sGC stimulators in patients with cirrhotic PHT.
Beiert, T., Knappe, V., Tiyerili, V., Stöckigt, F., Effelsberg, V., Linhart, M., Steinmetz, M., Klein, S., Schierwagen, R., Trebicka, J., Roell, W., Nickenig, G., Schrickel, J. W., Andrié, R. P., ( 2018 ). chronic lower-dose relaxin government protects from cardiac arrhythmia in experimental myocardial infarct due to anti-inflammatory and anti-fibrotic properties International Journal of Cardiology 250, 21-28 background : The peptide hormone relaxin-2 ( RLX ) exerts beneficial effects during myocardial ischemia, but functional data on lower-dose RLX in myocardial infarct ( MI ) is lacking. therefore, we investigated the impact of 75 μg/kg/d RLX treatment on electric vulnerability and left ventricular function in a mouse model of MI. Methods and results : standardize cryoinfarction of the bequeath anterior ventricular wall was performed in mouse. A two week treatment time period with fomite or RLX via subcutaneously implanted osmotic minipumps was started immediately after MI. The relaxin receptor RXFP1 was expressed on ventricular/atrial cardiomyocytes, myofibroblasts, macrophages and endothelial but not vascular polish muscle cells of belittled coronary vessels. RLX discussion resulted in a significant reduction of ventricular tachycardia inducibility ( vehicle : 91 %, RLX : 18 %, p
Keywords : Arrhythmia, Myocardial infarct, Relaxin-2, Ventricular tachycardia Trebicka, Jonel, ( 2018 ). Non-cirrhotic portal high blood pressure : A possibly benign but complicated disease Digestive and Liver Disease 50, ( 8 ), 845-846 n the last Baveno Consensus Conference held in 2015 a dedicated section described the management of patients with portal vein thrombosis, in presence or absence of cirrhosis [ 1 ]. In this specific collective of patients few studies have described their natural history and consequently new studies are urgently needed in ordain to recommend evidence-based management. so far the recommendation regarding the treatment of complications of portal site high blood pressure are aligned with the recommendation in the bearing of cirrhosis.
Anadol, Evrim, Lust, Kristina, Boesecke, Christoph, Schwarze-Zander, Carolynne, Mohr, Raphael, Wasmuth, Jan-Christian, Rockstroh, Jürgen Kurt, Trebicka, Jonel, ( 2018 ). exposure to previous haul is associated with meaning liver-colored fibrosis and cirrhosis in human immunodeficiency virus-infected patients PLoS ONE 13, ( 1 ), e0191118 introduction Combined antiretroviral therapy ( handcart ) has improved survival in HIV-patients. While the first antiretrovirals, which became available in especial D-drugs ( specially didanosine and stavudine ) and unboosted protease inhibitors, may impair liver function, the modern handcart seems to decrease liver-colored fibrosis. This study assessed the influence of photograph to former antiretrovirals on liver-colored fibrosis in HIV-infected patients. Methods This experimental cross-sectional single-center study recruited 333 HIV patients and assessed liver fibrosis using ephemeral elastography ( TE ). Results 83 % were male with a median old age of 45, while 131 were co-infected with viral hepatitis. Overall, 18 % had significant fibrosis and 7.5 % had cirrhosis. 11 % of HIV mono-infected patients had significant fibrosis and 2 % had cirrhosis. HCV infection ( OR:5.3 ), history of photograph to didanosine ( OR:2.7 ) and HIV load below 40copies/mL ( OR:0.5 ) were independently associated with significant fibrosis, while HCV ( OR:5.8 ), exposure to didanosine ( OR:2.9 ) and azidothymidine ( OR:2.8 ) were independently associated with cirrhosis. Interestingly, in HIV mono-infected patients, a HIV-load below 40copies/mL ( OR:0.4 ) was independently associated with significant fibrosis, and dideoxyinosine ( OR:20.8 ) with cirrhosis. conclusion In ending, history of exposure to didanosine and azidothymidine continues to have an impact on the presence of liver cirrhosis in HIV patients. however, HCV co-infection and ongoing HIV-replication have the strongest effect on development of meaning fibrosis in these patients.
Jansen, Christian, Al-Kassou, Baravan, Lehmann, Jennifer, Pohlmann, Alessandra, Chang, Johannes, Praktiknjo, Michael, Nickenig, Georg, Strassburg, Christian P., Schrickel, Jan W., Andrié, René, Linhart, Markus, Trebicka, Jonel, ( 2018 ). Severe abnormal Heart Rate Turbulence Onset is associated with deterioration of liver-colored cirrhosis PLoS ONE 13, ( 4 ), e0195631 background : In patients with liver cirrhosis, cardiac dysfunction is frequent and is associated with increase unwholesomeness and deathrate. cardiac dysfunction in cirrhosis seems to be linked to autonomic dysfunction. This cogitation investigates the role of autonomic dysfunction assessed by Heart Rate Turbulence ( HRT ) analyses in patients with liver cirrhosis. Methods and patients : Inclusion criteria was ( 1 ) diagnosis of cirrhosis by clinical, imaging or biopsy and ( 2 ) evaluation by standard 12-lead-ECG and 24h holter monitoring and ( 3 ) at least 3 previous ventricular contractions. The exclusion criterion was presence of cardiac diseases, independent of liver cirrhosis. biochemical parameters were analysed using standard methods. HRT was assessed using Turbulence attack ( TO ) and gradient ( TS ). The end point was deterioration of liver cirrhosis defined as increased MELD and readmission for complications of liver cirrhosis. Results : Out of 122 cirrhotic patients, 82 patients ( 63 % male ) with medial Child grade of 6 ( range 5–12 ) and median MELD score of 10 ( range 6–32 ) were included. Increasing Child score, INR and decreasing albumin were correlated with TO. In addition, decompensated patients with ascites showed more abnormal TO and TS. During the observation period, patients with more abnormal TO showed importantly higher rate of rising MELD Score at 6 months ( phosphorus = 0.03 ). however, at least in our collective HRT-parameters were not independent predictors of deterioration of cirrhosis.
Lange, C. M., Bechstein, W. O., Berg, T., Engelmann, C., Bruns, T., Canbay, A., Moreau, R., Trebicka, J., ( 2018 ). Acute-on-chronic liver bankruptcy Visceral Medicine 34, ( 4 ), 296-300 systemic inflammation is a authentication of ( acutely ) decompensated liver cirrhosis and in particular of acute-on-chronic liver failure ( ACLF ). frequently, it is challenging to discriminate infection from aseptic excitement in these patients. Which patient – in the absence of rise infection – do you treat with antibiotics in these scenarios, and are there any prefer antibiotic regimens ?
Trebicka, J., Reiberger, T., Laleman, W., ( 2018 ). Gut-liver axis links portal high blood pressure to acute-on-chronic liver failure Visceral Medicine 34, ( 4 ), 270-275 Acute-on-chronic liver failure ( ACLF ) is considered a clear-cut syndrome in patients with liver disease, with systemic inflammation playing a central function. portal high blood pressure ( PHT ) is besides aggravated by inflammation and may subsequently impact the course of ACLF. PHT is more than good an increase in portal pressure in the portal venous system ; it aggravates the course of liver disease and, thus, besides facilitates the growth of acute decompensation and ACLF. A critical mechanistic link between PHT and ACLF might be the gut-liver bloc, which is discussed in this review.
Madsen, Bjørn Stæhr, Trebicka, Jonel, Thiele, Maja, Israelsen, Mads, Arumugan, Manimozhiyan, Havelund, Troels, Krag, Aleksander, ( 2018 ). Antifibrotic and molecular aspects of rifaximin in alcoholic liver disease : discipline protocol for a randomized controlled test Trials 19, ( 1 ), 143 Alcoholic liver disease is the leading cause of cirrhosis cosmopolitan. Due to an increase in alcohol overexploitation, alcoholic liver disease has become an increased charge on health care systems. abstinence from alcohol remains the cornerstone of alcoholic liver disease treatment ; however, this overture is hampered by frequent relapse and miss of specific therapy for treating advanced cases of liver disease. In the confront study, we hypothesized that gut microbiota drive the exploitation of liver fibrosis and that modulation of catgut microbiota with the gut-selective, nonabsorbable antibiotic rifaximin attenuates alcoholic liver fibrosis.
Mohr, Raphael, Boesecke, Christoph, Dold, Leona, Schierwagen, Robert, Schwarze-Zander, Carolynne, Wasmuth, Jan-Christian, Weisensee, Insa, Rockstroh, Jürgen Kurt, Trebicka, Jonel, ( 2018 ). Return-to-health effect of modern combined antiretroviral therapy potentially predisposes HIV patients to liverwort steatosis Medicine 97, ( 17 ), e0462 prevalence and hazard factors for liverwort steatosis ( HS ) in the human immunodeficiency virus ( HIV ) -positive population of western countries are controversially discussed and potentially confounded by coinfection with viral hepatitis. significant HS ( more than 10 % of hepatocytes ) can be accurately measure using operate attenuation argument ( CAP ) decision. Aim of this study was to assess prevalence and factors associated with meaning HS in HIV monoinfected patients. A entire of 364 HIV-infected patients ( 289 monoinfected ) were included in this prospective, cross-section survey. All patients undergo CAP decision. Steatosis was classified as S1 ( significant steatosis ) with CAP > 238 dB/m, S2 with CAP > 260 dB/m, and S3 with CAP > 292 dB/m. Multivariable logistic arrested development analyses were performed to assess the factors associated with HS in this cohort. Significant HS was detected in 118 monoinfected patients ( 149 in the entire age group ). In the total age group ampere well as in the monoinfected patients alone, HS grade distribution showed a exchangeable traffic pattern ( S1:29 %, S2:34 %, and S3:37 % ). Interestingly, patients with HS had a longer history of HIV infection and combine antiretroviral therapy ( cart ). Interalia, senesce, sex, ethnicity, and metabolic factors were powerfully associated with HS, while body mass index ( BMI ), triglyceride, and glycated hemoglobin ( HbA1c ) levels were independently associated with significant HS. HS is highly prevailing among HIV monoinfected patients. Although metabolic hazard factors, such as fleshiness and ill controlled diabetes, are independently associated with HS in HIV monoinfected patients, cart and control of HIV seem to play an indirect function in the exploitation of HS, probably through the return-to-health effect.
Keywords : CAP, handcart, HIV monoinfection, liver injury, NAFLD Laleman, Wim, Claria, Joan, Van five hundred Merwe, Schalk, Moreau, Richard, Trebicka, Jonel, ( 2018 ). systemic ignition and acute-on-chronic liver bankruptcy : excessively much, not enough Canadian Journal of Gastroenterology and Hepatology 2018, 1027152 ACLF is a specifc, but building complex and multifactorial mannequin of acute decompensation of cirrhosis and is characterized by an extraordinary moral force natural course, quickly evolving organ failure, and high short-run mortality. Dysbalanced immune function is central to its pathogenesis and result with an initial excessive systemic infammatory reception that drives organ failure and mortality. late in its course, immuno-exhaustion/immunoparalysis prevails predisposing the affected role to secondary infectious events and reescalation in end-organ dysfunction and mortality. Te management of patients with ACLF is still ill defned. however, as its pathophysiology is gradually being unravelled, potential therapeutic targets emerge that warrant farther analyze such as restoring or substituting albumin via plasma exchange or via albumin dialysis and evaluating utility of TLR4 antagonists, modulators of gut dysbiosis ( pre- or probiotics ), and FXR-agonists.
Trebicka, J., Gluud, L. L., ( 2017 ). Reply to : “ Adding embolization to TIPS implantation : A better therapy to control bleeding from ectopic varices ? ” Journal of Hepatology 67, ( 1 ), 202-203 We would like to thank the Perricone and colleagues for their letter and for the concern in the article “ Emergency TIPS in a Child-Pugh B patient : When does the window of opportunity open and stopping point ? ” .1 The letter raises an important interrogate, namely the management of bleeding from ectopic varices. Bleeding from ectopic varices other than fundic varices represents a rare and ambitious complicatedness. guidance for clinical practice is needed.
Jansen, C., Thiele, M., Verlinden, W., Krag, A., Francque, S., Trebicka, J., ( 2017 ). prediction of bearing of oesophageal varices just by shear-wave elastography of the liver-colored and spleen Liver International 37, ( 9 ), 1406-1407 Reiberger, T., Trebicka, J., ( 2017 ). New liver – Fresh microbiome : Implications on brain function Liver Transplantation 23, ( 7 ), 873-874 Schierwagen, R., Uschner, F. E., Magdaleno, F., Klein, S., Trebicka, J., ( 2017 ). Rationale for the practice of statins in liver disease American Journal of Physiology – Gastrointestinal and Liver Physiology 312, ( 5 ), G407-G412 The evolution of chronic liver injuries from benign and accomplishable dysfunction to life threatening end-stage liver-colored disease with dangerous complications renders chronic liver disease a ball-shaped health burden. Because of the lack of effective medication, transplant remains the only and final remedy option for end-stage liver disease. Since the demand for organ transplants by far exceeds the add, other treatment options are urgently required to prevent progress and improve end-stage liver disease. Statins are primarily cholesterol-lowering drugs used for primary coil or secondary prevention of cardiovascular diseases. In summation to the basal effect, statins act beneficially through different pleiotropic mechanisms on inflammation, fibrosis, endothelial officiate, thrombosis, and curdling to improve chronic liver diseases. however, concerns remain about the efficacy and base hit of lipid-lowering medicine treatment because of their potential hepatotoxic risks, and as of immediately, these risks impede broader use of statins in the discussion of chronic liver-colored diseases. The draw a bead on of this review is to comprehensively describe the mechanisms by which statins improve prospects for different chronic liver diseases with special focus on the pathophysiological rationale and the clinical experience of lipid-lowering medicine use in the treatment of liver diseases.
Beiert, T., Tiyerili, V., Knappe, V., Effelsberg, V., Linhart, M., Stöckigt, F., Klein, S., Schierwagen, R., Trebicka, J., Nickenig, G., Schrickel, J. W., Andrié, R. P., ( 2017 ). Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties Biochemical and Biophysical Research Communications, 490, ( 3 ), 643-649 Background Relaxin-2 ( RLX ) is a peptide hormone that exerts beneficial anti-fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this learn was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation ( AF ) after myocardial infarct ( MI ). Methods Mice with cryoinfarction of the leave anterior ventricular wall were treated for two weeks with either RLX ( 75 μg/kg/d ) or vehicle ( sodium acetate ) delivered via subcutaneously implanted osmotic minipumps. Results RLX treatment importantly attenuated the addition in AF-inducibility following cryoinfarction and reduced the base duration of AF episodes. furthermore, epicardial function of both atria revealed an increase in conduction speed. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant decrease in atrial messenger rna expression of connective tissue growth divisor. Transcript levels of the proinflammatory cytokines interleukin-6 and interleukin-1β were reduced in RLX treated mouse, but macrophage infiltration into atrial myocardium was alike in the vehicle and RLX treated groups. Conclusion Treatment with RLX in mouse after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new remedy option in the discussion of AF, even when complicating MI.
Keywords : atrial fibrillation, Atrial fibrosis, Myocardial infarct, Relaxin-2 Schwab, S., Lehmann, J., Lutz, P., Jansen, C., Appenrodt, B., Lammert, F., Strassburg, C. P., Spengler, U., Nischalke, H. D., Trebicka, J., ( 2017 ). determine of genic variations in the SOD1 gene on the development of ascites and ad-lib bacterial peritonitis in decompensated liver cirrhosis european Journal of Gastroenterology and Hepatology, 29, ( 7 ), 800-804
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Background The symmetry between generation and elimination of reactive oxygen species by superoxide dismutase ( SOD ) is crucially involved in the pathophysiology of liver-colored cirrhosis. reactive oxygen species damage cells and induce inflammation/fibrosis, but besides play a critical character in immune defense from pathogens. As both processes are involved in the development of liver-colored cirrhosis and its complications, genetic mutant of the SOD1 gene was investigated. Patients and methods Two SOD1 individual nucleotide polymorphism ( rs1041740 and rs3844942 ) were analyzed in 49 cirrhotic patients undergoing liver-colored transplant. In addition, 344 cirrhotic patients with ascites were analyzed in a cohort of 521 individuals in terms of the kinship of these polymorphisms with spontaneous bacterial peritonitis ( SBP ). Results Although rs3844942 showed no associations with complications of cirrhosis, we observed a meaning association between rs1041740 and the presence of ascites and SBP in the discovery cohort of patients with cirrhosis. importantly, the association with SBP was not confirmed in the establishment age group of patients with ascites. By contrast, a tendency toward lower SBP rates was observed in carriers of rs1041740. In this cohort, rs1041740 was not associated with survival. Conclusion These data suggest a complex character of SOD1 in different processes leading to complications of liver-colored cirrhosis. rs1041740 might be associated with the development of ascites and possibly plays a role in SBP once ascites has developed.
Keywords : Ascites, Genetic polymorphism, Liver cirrhosis, Reactive oxygen tension, Spontaneous bacterial peritonitis, Superoxide dismutases Klein, S., Schierwagen, R., Uschner, F. E., Trebicka, J., ( 2017 ). Mouse and denounce models of evocation of liverwort fibrosis and appraisal of portal site high blood pressure Fibrosis ( Methods in Molecular Biology ) ( ed. Rittié, L. ), Humana Press ( New York, USA ) 1627, 91-116