ABSTRACT
BACKGROUND AND AIMS: Cystic Fibrosis (CF) lung disease is characterized by progressively declining lung function and represents a major factor contributing to the high morbidity and mortality associated with CF. However, apart from spirometry, respiratory disease surrogate markers reliably indicating CF lung disease and the occurrence of pulmonary exacerbations (PEx) are still lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CF lung disease. METHODS: 54 adult and 26 pediatric CF patients were included in the study and serum concentrations of MMP-1, -2, -8, -9, -13, TIMP-1, TIMP-2, YKL-40, hyaluronic acid, procollagen III peptide were quantified by ELISA. CF lung disease was diagnosed by lung function test, PEx was defined based on a clinical scoring established by Rosenfeld in 2001. RESULTS: Adults and children with moderate to severe CF lung disease exhibited significantly increased serum expression of MMP-8, MMP-9, YKL-40 and TIMP-1. Further, MMP-8, MMP-9 and YKL-40 were significantly increased in adult CF patients suffering from PEx compared to those without clinical signs of respiratory exacerbation. MMP-8, MMP-9, YKL-40, and TIMP-1 serum levels were unaffected by the presence or absence of CF liver disease or pancreatic insufficiency. CONCLUSIONS: MMP-8, MMP-9, and YKL-40 might serve as novel non-invasive biomarkers of CF lung disease and PEx.
Subject(s)
Biomarkers/metabolism , Cystic Fibrosis/metabolism , Lung/metabolism , Neutrophil Activation/physiology , Adipokines/metabolism , Adolescent , Adult , Child , Chitinase-3-Like Protein 1 , Female , Humans , Lectins/metabolism , Lung/pathology , Male , Matrix Metalloproteinase 8/metabolism , Matrix Metalloproteinase 9/metabolism , Pulmonary Fibrosis/metabolism , Young AdultABSTRACT
BACKGROUND AND AIMS: Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools for CFLD are lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CFLD. METHODS: 45 CF patients were included in the study and received transient elastography. Differential regulation of 220 different serum proteins was assessed in a subgroup of patients with and without CFLD. Most interesting candidate proteins were further quantified and validated by ELISA in the whole patient cohort. To assess a potential relation of biomarker expression to the degree of hepatic fibrosis, serum biomarkers were further determined in 18 HCV patients where liver histology was available. RESULTS: 43 serum proteins differed at least 2-fold in patients with CFLD compared to those without liver disease as identified in proteome profiling. In ELISA quantifications, TIMP-4 and Endoglin were significantly up-regulated in patients with CFLD as diagnosed by clinical guidelines or increased liver stiffness. Pentraxin-3 was significantly decreased in patients with CFLD. Serum TIMP-4 and Endoglin showed highest values in HCV patients with liver cirrhosis compared to those with fibrosis but without cirrhosis. At a cut-off value of 6.3 kPa, transient elastography compassed a very high diagnostic accuracy and specificity for the detection of CFLD. Among the biomarkers, TIMP-4 and Endoglin exhibited a high diagnostic accuracy for CFLD. Diagnostic sensitivities and negative predictive values were increased when elastography and TIMP-4 and Endoglin were combined for the detection of CFLD. CONCLUSIONS: Serum TIMP-4 and Endoglin are increased in CFLD and their expression correlates with hepatic staging. Determination of TIMP-4 and Endoglin together with transient elastography can increase the sensitivity for the non-invasive diagnosis of CFLD.
Subject(s)
Cystic Fibrosis/complications , Liver Diseases/blood , Liver Diseases/complications , Proteomics , Adolescent , Adult , Biomarkers/blood , Child , Child, Preschool , Female , Gene Expression Regulation , Humans , Liver Cirrhosis/blood , Liver Cirrhosis/complications , Liver Cirrhosis/diagnosis , Liver Cirrhosis/metabolism , Liver Diseases/diagnosis , Liver Diseases/metabolism , Male , Middle Aged , Tissue Inhibitor of Metalloproteinases/blood , Young Adult , Tissue Inhibitor of Metalloproteinase-4ABSTRACT
BACKGROUND: Cystic fibrosis (CF) associated liver disease develops in approximately 30% of CF patients. However, routine sensitive diagnostic tools are lacking. AIMS: We aimed to compare the value of transient elastography and experimental fibrosis markers for the detection of liver disease in CF patients. METHODS: 145 CF patients (75 children, 70 adults) were prospectively studied and received transient elastography. CF liver disease was diagnosed according to recent guidelines. Serum concentrations of YKL-40, HA, PIIIP, MMP-9, TIMP-1 and TIMP-2 were determined by ELISA. RESULTS: Transient elastography was increased in adults and children with CF hepatopathy compared to those without and exhibited a high diagnostic accuracy for CF liver disease. In adults with portal hypertension, elastography was further enhanced. TIMP-2 was elevated in adults with CF hepatopathy associated portal hypertension and exhibited a high diagnostic accuracy for portal hypertension in adults and for CF hepatopathy in children. TIMP-1 had a high diagnostic accuracy for CF hepatopathy in adults. Diagnostic sensitivities were increased when elastography and respective biomarkers were combined for the detection of CF hepatopathy and portal hypertension. CONCLUSIONS: TIMP-1 and TIMP-2 represent powerful biomarkers for CF associated liver disease and portal hypertension. Their determination may confirm and improve the diagnostic accuracy of transient elastography.
