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BACKGROUND: Predictors of poor outcome associated with variceal bleeding remain suboptimal. In patients with cirrhosis, serum lactate combined with Model for End-Stage Liver Disease (MELD-LA) improved prediction across heterogeneous populations. However, prognostic properties have not yet been assessed in the context of variceal bleeding. AIMS: We aimed to evaluate the predictive performance of MELD-LA compared to MELD, lactate, and nadir hemoglobin in cirrhosis patients with variceal bleeding. METHODS: In this multicenter study, we identified 472 patients with variceal bleeding from a German primary cohort (University Hospitals Hamburg/Frankfurt/Cologne), and two independent external validation cohorts [Veterans Affairs (VA), Baylor University]. Discrimination for 30-day mortality was analyzed and scores were compared. MELD-LA was evaluated separately in validation cohorts to ensure consistency of findings. RESULTS: In contrast to nadir hemoglobin, MELD and peak-lactate at time of bleeding were significantly higher in 30-day non-survivors in the primary cohort (p = 0.708; p < 0.001). MELD-LA had excellent discrimination for 30-day mortality (AUROC 0.82, 95% CI 0.76-0.88), better than MELD and peak-lactate (AUROC 0.78, 95% CI 0.71-0.84; AUROC 0.73, 95% CI 0.66-0.81). MELD-LA predicted 30-day mortality independently of age, sex, severity of liver disease and vasopressor support (HR 1.29 per 1-point-increase of MELD-LA; 95% CI 1.19-1.41; p < 0.001). Similarly, MELD-LA demonstrated excellent discrimination for 30-day mortality in the VA (AUROC = 0.86, 95% CI 0.79-0.93) and Baylor cohort (AUROC = 0.85, 95% CI 0.74-0.95). CONCLUSIONS: MELD-LA significantly improves discrimination of short-term mortality associated with variceal bleeding, compared to MELD, peak-lactate and nadir hemoglobin. Thus, MELD-LA might represent a useful and objective marker for risk assessment and therapeutic intervention in patients with variceal bleeding.
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Enfermedad Hepática en Estado Terminal , Várices Esofágicas y Gástricas , Humanos , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/complicaciones , Ácido Láctico , Enfermedad Hepática en Estado Terminal/complicaciones , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/terapia , Índice de Severidad de la Enfermedad , Cirrosis Hepática , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Prophylactic endoscopic variceal band ligation (EVL) is frequently performed in patients with liver cirrhosis. The aim of our study was to identify factors associated with early upper gastrointestinal bleeding (UGIB) in cirrhosis patients after prophylactic EVL. METHODS: 787 nonemergency EVLs performed in 444 patients in two German University medical centers were analyzed retrospectively. RESULTS: Within 30 days after EVL, 38 UGIBs were observed (4.8â% of all procedures). Bilirubin levels (hazard ratio [HR] 1.5, 95â% confidence interval [CI] 1.2-2.0 for a 2-fold increase) and presence of varices grade III/IV according to Paquet (HR 2.6, 95â%CI 1.3-5.0 compared with absence or smaller sized varices) were independently associated with UGIB following EVL. International normalized ratio (INR) was associated with bleeding events in the univariate analysis but did not reach statistical significance after adjustment for bilirubin and presence of varices grade III/IV (HR 1.2, 95â%CI 0.9-1.6 for an increase by 0.25). There was no statistically significant association between platelet count or fibrinogen levels and UGIB. Substitution of coagulation products did not affect incidence of bleeding after EVL, which also applied to patients with "coagulopathy" (INRâ>â1.5 and/or platelet countâ<â50â×â109/L). No association between proton pump inhibitor therapy and post-EVL UGIB was observed. CONCLUSIONS: EVL is a safe procedure and immediate bleeding complications are rare. Serum bilirubin levels and size of varices, rather than coagulation indices, are associated with UGIB after EVL. Our data do not support the preventive substitution of blood or coagulation products.
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Várices Esofágicas y Gástricas , Várices Esofágicas y Gástricas/complicaciones , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/prevención & control , Humanos , Ligadura/efectos adversos , Cirrosis Hepática/complicaciones , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3+ regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell-mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation.
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Colitis/inmunología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Hígado/patología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Células Cultivadas , Sulfato de Dextran , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
BACKGROUND: Limited data exists concerning the coincidence of chronic pancreatitis (CP) and liver cirrhosis with respect to the patient outcome after liver transplantation (LT). The aim of the study was to identify risk factors for graft loss after liver transplantation and to evaluate the impact of CP on graft survival. METHODS: We analyzed the data of 421 cirrhotic patients who underwent evaluation for primary liver transplantation from January 2007 to January 2014. Diagnosis of CP based on morphologic findings which were graded according to the Cambridge and Manchester classification. (Graft) survival after LT was analyzed by Cox regression analysis. Recipient- and donor-related risk factors for graft loss were evaluated using univariate and multivariate analysis. RESULTS: 40/421 cirrhotic patients suffered from CP (9.5%). 250/421 (59.4%) patients underwent LT between January 2007 and January 2014. In total, 89 patients died or were in need of a re-transplantation during follow-up until August 2017. Patients with CP (N = 26) were at increased risk for graft loss after LT (hazard ratio = 2.183; 95% confidence interval = 1.232-3.868). CP (P = 0.001), a MELD score ≥24 (P = 0.021), absence of esophageal or gastrical varices (P = 0.018), the age of the donor (P = 0.008) and infections after transplantation (P = 0.030) were independent risk factors for organ loss after transplantation in the multivariate Cox regression analysis. CONCLUSION: Patients with chronic pancreatitis are at increased risk for graft loss after LT. A high MELD score, the absence of esophageal or gastrical varices, an advanced donor age and post-transplant infections negatively affect graft survival, too.
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Supervivencia de Injerto/fisiología , Cirrosis Hepática/terapia , Pancreatitis Crónica/complicaciones , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
BACKGROUND: Primary sclerosing cholangitis (PSC) is a progressive liver disease associated with inflammatory bowel disease (IBD). The percentage of PSC patients diagnosed with concomitant IBD varies considerably between studies. This raises the question whether all PSC patients would show intestinal inflammation if screened thoroughly, even in the absence of symptoms. METHODS: To address this question, we collected intestinal biopsies of healthy controls (n = 34), PSC (n = 25), PSC-IBD (n = 41), and IBD (n = 51) patients in a cross-sectional study and carried out cytokine expression profiling, 16S sequencing, in-depth histology, and endoscopy scoring. RESULTS: We found that the vast majority of PSC patients even without clinically manifest IBD showed infiltration of immune cells and increased expression of IL17A and IFNG in intestinal biopsies. However, expression of IL10 and FOXP3 were likewise increased, which may explain why these PSC patients have intestinal inflammation only on a molecular level. This subclinical inflammation in PSC patients was focused in the distal colon, whereas PSC-IBD patients showed inflammation either at the distal colon or on the right side of the colon and the terminal ileum. Furthermore, we observed that PSC patients without IBD showed signs of dysbiosis and exhibited a distinct microbial profile compared with healthy controls. CONCLUSIONS: We found a gradient of intestinal inflammation in the vast majority of PSC patients even in the absence of IBD. Thus, further studies evaluating the effect of anti-inflammatory therapies in PSC patients and their impact on the emergence of clinically manifest IBD and colorectal cancer development are needed.
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The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-ß-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-ß, both CCK and gastrin inhibit proliferation in PSC.
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Colágeno/biosíntesis , Regulación de la Expresión Génica , Páncreas/metabolismo , Células Estrelladas Pancreáticas/metabolismo , Receptor de Colecistoquinina B/biosíntesis , Receptores de Colecistoquinina/biosíntesis , Animales , Butadienos/farmacología , Colágeno Tipo I/metabolismo , Inhibidores Enzimáticos/farmacología , Gastrinas/metabolismo , Masculino , Nitrilos/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-ß1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-ß signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-ß1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-ß signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-ß signaling. We show that TGF-ß, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.
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Colitis/complicaciones , Neoplasias del Colon/etiología , Interleucinas/biosíntesis , Células Th17/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinogénesis/inmunología , Diferenciación Celular , Colitis/inmunología , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/inmunología , Células Th17/patología , Factor de Crecimiento Transformador beta1/metabolismo , Interleucina-22RESUMEN
Anti-α4ß7 therapy with vedolizumab (VDZ) has been suggested as possible immune intervention in HIV. Relatively little is known about the α4ß7-integrin (α4ß7) expression of different T-cell subsets in different anatomical compartments of healthy individuals, patients with HIV or inflammatory bowel disease (IBD). Surface expression of α4ß7 as well as the frequency of activation, homing and exhaustion markers of T cells were assessed by multicolour flow cytometry in healthy volunteers (n = 15) compared to HIV infected patients (n = 52) or patients diagnosed with ulcerative colitis (UC) (n = 14), 6 of whom treated with vedolizumab. In addition, lymph nodal cells (n = 6), gut-derived cells of healthy volunteers (n = 5) and patients with UC (n = 6) were analysed. Additionally, we studied longitudinal PBMC samples of an HIV patient who was treated with vedolizumab for concomitant UC. Overall, only minor variations of the frequency of α4ß7 on total CD4+ T cells were detectable regardless of the disease status or (VDZ) treatment status in peripheral blood and the studied tissues. Peripheral α4ß7+ CD4+ T cells of healthy individuals and patients with UC showed a higher activation status and were more frequently CCR5+ than their α4ß7- counterparts. Also, the frequency of α4ß7+ cells was significantly lower in peripheral blood CD4+ effector memory T cells of HIV-infected compared to healthy individuals and this reduced frequency did not recover in HIV patients on ART. Conversely, the frequency of peripheral blood naïve α4ß7+ CD4+ T cells was significantly reduced under VDZ treatment. The results of the current study will contribute to the understanding of the dynamics of α4ß7 expression pattern on T cells in HIV and UC and will be useful for future studies investigating VDZ as possible HIV cure strategy.
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Linfocitos T CD4-Positivos/inmunología , Colitis Ulcerosa/metabolismo , Infecciones por VIH/metabolismo , Integrinas/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Estudios de Casos y Controles , Colitis Ulcerosa/tratamiento farmacológico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Integrinas/antagonistas & inhibidores , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Receptores CCR5/metabolismo , Adulto JovenRESUMEN
IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation.
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Linfocitos T CD4-Positivos/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-10/metabolismo , Animales , Humanos , Ratones Endogámicos C57BL , Análisis de la Célula Individual , TranscriptomaRESUMEN
OBJECTIVES: There is growing evidence that extracellular nucleotide-induced signaling confers to fibrogenesis in liver and pancreas. Pancreatic stellate cells (PSC) are the most important cell type in pancreatic fibrosis. P2 purine and pyrimidine receptors, again, are pivotal mediators of inflammatory and profibrogenic signals. Our aim was to elucidate the underlying signaling components in activated PSC. METHODS: We performed expression analysis of calcium ion (Ca(2+)) signaling components and monitored real-time intracellular Ca(2+) responses to nucleotides in rat PSC. RESULTS: Adenosine monophosphate, adenosine diphosphate, and adenosine-5'-triphosphate elicited detectable rises in intracellular Ca(2+) concentrations. Stimulation of PSC by ATP led to intracellular Ca signals mediated through both P2X and P2Y receptors. Whereas uridine triphosphate-mediated Ca(2+) signals were generated by activation of P2Y receptors only, uridine diphosphate stimulated P2X receptors as well. Of the phospholipase C (PLC)/inositol-1,4,5-trisphosphate pathway, all PLC-facilitating Gα subunits were present in activated cells as were all 3 inositol-1,4,5-trisphosphate receptor isoforms. In addition, transcripts of PLC-ß and PLC-δ isoforms were also strongly detectable. CONCLUSIONS: Activated PSC feature a plethora of elements from the Ca signaling toolkit and functionally express a subset of P2 nucleotide receptors. Purines and pyrimidines elicit robust intracellular Ca(2+) signals likely contributing to the fibrogenetic potential of these cells.