Abstract
Background and AimsCystic 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.Methods45 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.Results43 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.ConclusionsSerum 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.
Highlights
Cystic fibrosis associated liver disease (CFLD) has a cumulative incidence of approximately 30% [1,2] and accounts for 2.5% of the overall mortality of CF patients, thereby representing the third most common cause of death in CF patients [3].Due to the high prevalence, the early onset and the often progressive course of CFLD, the reliable recognition of CF patients at risk of developing CFLD is of urgent clinical necessity [4]
To identify potential candidate proteins which might act as biomarkers of hepatic fibrosis we initially screened a broad range of differentially regulated serum proteins in patients with CFLD and those without
Serum of 4 patients with CFLD and of 4 patients without CFLD was applied to 4 different serum proteome profilers, thereby assessing key proteins and enzymes involved in angiogenesis (Figure 1), soluble receptors and related proteins released by non-hematopoietic cells and including key proteins involved in the metabolism of the extracellular matrix (Figure 2 and 3) and chemokines regulating the migration of monocytes, neutrophils, and lymphocytes (Figure 4)
Summary
Cystic fibrosis associated liver disease (CFLD) has a cumulative incidence of approximately 30% [1,2] and accounts for 2.5% of the overall mortality of CF patients, thereby representing the third most common cause of death in CF patients [3].Due to the high prevalence, the early onset and the often progressive course of CFLD, the reliable recognition of CF patients at risk of developing CFLD is of urgent clinical necessity [4]. Cystic fibrosis associated liver disease (CFLD) has a cumulative incidence of approximately 30% [1,2] and accounts for 2.5% of the overall mortality of CF patients, thereby representing the third most common cause of death in CF patients [3]. As only 1/50000 of the liver volume is evaluated with liver biopsy, it is controversially discussed in focally distributed liver disease and thereby not generally recommended for the assessment of CFLD [4,5]. Current guideline criteria recommend a combination of physical examination, liver biochemistry and ultrasound to diagnose CFLD [4]; the reliable identification of CF patients at risk of developing CFLD remains a major clinical challenge [4]. Cystic Fibrosis associated liver disease (CFLD) develops in approximately 30% of CF patients. We aimed to identify new experimental biomarkers for the detection of CFLD
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