Soluble Urokinase Plasminogen Activator Receptor is Associated With Progressive Liver Fibrosis in Hepatitis C Infection

Medical Department III, University Hospital Aachen, Aachen, Germany.
Journal of clinical gastroenterology (Impact Factor: 3.5). 09/2011; 46(4):334-8. DOI: 10.1097/MCG.0b013e31822da19d
Source: PubMed


Progressive liver fibrosis is the main predictor of disease outcome in chronic hepatitis C viral (HCV) infection. Although the importance of the coagulation cascade has been suggested in liver fibrogenesis, the role of the fibrinolytic pathway is yet unclear.
We evaluated the association of serum levels of the fibrinolysis-associated soluble urokinase plasminogen activator receptor (suPAR) with the severity of liver fibrosis in HCV infection.
suPAR serum levels were assessed in 146 chronically HCV-infected patients of 2 independent cohorts (64 subjects in the screening cohort, 82 in the validation cohort) by enzyme-linked immunosorbent assay and correlated with biopsy-proven histologic stage of liver fibrosis and noninvasive liver fibrosis markers (aspartate transaminase to platelets ratio index score, transient elastography).
suPAR serum levels were strongly associated with the histologic stage of liver fibrosis in both cohorts (P<0.0001). Although mean suPAR levels in patients with F1 and F2 fibrosis were not different from healthy control subjects, they were significantly increased at higher stages of liver fibrosis (F3 and F4, P<0.0001). suPAR values had a high diagnostic specificity and sensitivity to differentiate mild/moderate fibrosis (F1/F2) from severe fibrosis (F3/F4) with an area under curve of 0.774 (P=0.0001) and for the differentiation of noncirrhosis from cirrhosis (F1/F2/F3 vs. F4, area under curve 0.791, P=0.0001). SuPAR serum levels were also strongly correlated to the noninvasive fibrosis markers aspartate transaminase to platelets ratio index score (r=0.52) and transient elastography (r=0.44, both P<0.0001).
Serum suPAR levels were robust markers of liver fibrosis in 2 cohorts with a comparable diagnostic accuracy for prediction of severe liver fibrosis as established noninvasive marker.

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    • "In patients with Crimean-Congo hemorrhagic fever, suPAR is elevated and also predictive for mortality [42]. Systemic suPAR levels also predict the progression of liver fibrosis to cirrhosis in patients with chronic hepatitis C [45], [46]. Furthermore, elevated suPAR levels have been found in the cerebrospinal fluid of patients with viral meningitis [44]. "
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    ABSTRACT: Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease. A single-centre prospective cohort study. Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA). The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0-18.2 ng/ml vs. median 4.7 ng/ml, range 2.4-12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = -0.325, p = 0.001) and minimum hematocrit (r = -0.369, p<0.001). Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.
    PLoS ONE 08/2013; 8(8):e71335. DOI:10.1371/journal.pone.0071335 · 3.23 Impact Factor
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    • "However, none of the patients in this study were suffering from glomerular disease and it is currently unknown if suPAR has an active role in disease outside FSGS. Two earlier studies found a strong connection between high suPAR and decreased liver biosynthesis and cirrhosis [6,18], and the association between ALAT and suPAR may support these findings: also, patients in the Charlson group 'Liver disease' had a mean suPAR of 11.8 ng/ml, the highest mean value among the groups. If suPAR does not play an active role in disease outside FSGS, it is likely that the suPAR level reflects a conglomerate of negative biological processes such as increased inflammation and fibrosis, organ dysfunction and decreased organ biosynthesis. "
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    ABSTRACT: Soluble urokinase plasminogen activator receptor (suPAR) is the soluble form of the membrane-bound receptor (uPAR) expressed predominantly on various immune cells. Elevated plasma suPAR concentration is associated with increased mortality in various patient groups, and it is speculated that suPAR is a low-grade inflammation marker reflecting on disease severity. The aim of this prospective observational study was to determine if the plasma concentration of suPAR is associated with admission time, re-admission, disease severity/Charlson Comorbidity Index Score, and mortality. We included 543 patients with various diseases from a Danish Acute Medical Unit during a two month period. A triage unit ensured that only medical patients were admitted to the Acute Medical Unit. SuPAR was measured on plasma samples drawn upon admission. Patients were followed-up for three months after inclusion by their unique civil registry number and using Danish registries to determine admission times, readmissions, International Classification of Diseases, 10th Edition (ICD-10) diagnoses, and mortality. Statistical analysis was used to determine suPAR's association with these endpoints. Increased suPAR was significantly associated with 90-day mortality (4.87 ng/ml in survivors versus 7.29 ng/ml in non-survivors, P < 0.0001), higher Charlson Score (P < 0.0001), and longer admission time (P < 0.0001), but not with readmissions. The association with mortality remained when adjusting for age, sex, C-reactive protein (CRP), and Charlson Score. Furthermore, among the various Charlson Score disease groups, suPAR was significantly higher in those with diabetes, cancer, cardiovascular disease, and liver disease compared to those without comorbidities. SuPAR is a marker of disease severity, admission time, and risk of mortality in a heterogeneous cohort of patients with a variety of diseases. The independent value of suPAR suggests it could be of value in prognostic algorithms.
    Critical care (London, England) 07/2012; 16(4):R130. DOI:10.1186/cc11434 · 4.48 Impact Factor
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    ABSTRACT: Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis. We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and short-term mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany. Twenty-eight-day mortality. Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL−1 predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35–6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61–0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis. Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.
    Journal of Internal Medicine 02/2013; 274(1). DOI:10.1111/joim.12054 · 6.06 Impact Factor
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