Background. Although researchers have consistently demonstrated systemic inflammation in chronic obstructive pulmonary disease (COPD), its origin is yet unknown. We aimed to compare the lung bronchial and parenchymal tissues as potential sources of major acute-phase reactants in COPD patients and resistant smokers.
Methods. Consecutive patients undergoing elective surgery for suspected primary lung cancer were considered for the study. Patients were categorized as COPD or resistant smokers according to their spirometric results. Lung parenchyma and bronchus sections distant from the primary lesion were obtained. C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2 and SAA4) gene expressions were evaluated by RT-PCR. Protein levels were evaluated in paraffin embedded lung tissues by immunohistochemistry and in serum samples by nephelometry.
Results. Our study included 85 patients with COPD and 87 resistant smokers. In bronchial and parenchymal tissues, both CRP and SAA were overexpressed in COPD patients. In the bronchus, CRP, SAA1, SAA2, and SA4 gene expressions in COPD patients were 1.89-fold, 4.36-fold, 3.65-fold, and 3.9-fold the control values, respectively. In the parenchyma, CRP, SAA1, and SAA2 gene expressions were 2.41-, 1.97-, and 1.76-fold the control values, respectively. Immunohistochemistry showed an over-stained pattern of these markers on endovascular cells of COPD patients. There was no correlation with serum protein concentration.
Conclusions. These results indicate an overexpression of CRP and SAA in both bronchial and parenchymal tissue in COPD, which differs between both locations, indicating tissue/cell type specificity. The endothelial cells might play a role in the production of theses markers.
COPD; C-reactive protein; Serum Amyloid A; gene expression; immunohistochemistry.
Chronic obstructive pulmonary disease (COPD) has been recently defined as a systemic pulmonary inflammatory disease, and congenital α1 antitrypsin deficiency is one of the well-established genetic risk factors for chronic obstructive pulmonary disease. The aim of our study was to evaluate the possible associations of α1 antitrypsin with inflammatory markers – CRP, sCD14, TNF-α, sTNFR-1, and sTNFR-2 – in patients with COPD with different α1 antitrypsin genotypes.
Material and methods
Serum biomarkers from patients (n = 355) with COPD, defined according to the GOLD criteria, were analyzed using commercial ELISA kits; α1 antitrypsin concentrations were determined by nephelometry, and α1 antitrypsin phenotyping was carried out by means of isoelectric focusing.
No significant differences in CRP, TNF-α, sTNFR-1, sTNFR-2, and sCD14 levels were found comparing COPD patients with different genotypes. In patients without α1 antitrypsin deficiency (PI*MM), a significant negative correlation between lung function (FEV1) and serum α1 antitrypsin (r = –0.522, p = 0.03) and CRP concentration (r = –0.590, p = 0.011) was detected. The level of α1 antitrypsin positively correlated with: a) CRP concentration (r = 0.671, p = 0.005), b) sCD14 (r = 0.510, p = 0.008) and c) sTNFR-1 (r = 0.567, p = 0.007).
In patients without α1 antitrypsin deficiency, the positive association of α1 antitrypsin concentration with CRP, sCD14, and sTNFR-1 and the negative association with FEV1 show the importance of α1 antitrypsin as a marker of systemic inflammation.
chronic obstructive pulmonary disease; α1 antitrypsin; inflammatory markers
Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from acute exacerbations (AECOPD) and display varying disease severity. However, there is no available biomarker for the classification of AECOPD. This study is aimed at investigating the sputum cellular profiles to classify patients with AECOPD.
A total of 83 patients with AECOPD and 26 healthy controls were recruited. Their demographic and clinical characteristics were recorded, and their lung function was examined. The phenotypes of sputum inflammatory cells were characterised, and the concentrations of sputum and serum amyloid-A (SAA), C-reactive protein (CRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP-9) were measured. Based on the sputum inflammatory cell profiles, individual patients were categorized into one of the four subgroups with inflammatory eosinophilic, neutrophilic, paucigranulocytic, and mixed granulocytic AECOPD. Most AECOPD patients were reevaluated within 12–14 months after discharge.
There were 10 (12%) eosinophilic, 36 (43%) neutrophilic, 5 (6%) mixed granulocytic, and 32 (39%) paucigranulocytic AECOPD patients. The patients with mixed granulocytic or neutrophilic AECOPD had a higher BODE score, more sputum inflammatory cells, lower lung function, and longer hospital stay, accompanied by higher concentrations of sputum MMP-9, IL-6 and CRP, and serum SAA, IL-6 and CRP. Notably, 83% of patients with neutrophilic AECOPD displayed evidence of bacterial infection and many of them responded poorly to standard therapies. In addition, patients with mixed granulocytic or neutrophilic stable COPD remained at lower lung functions and higher levels of inflammation.
Patients with AECOPD display heterogeneous inflammation, and the profiles of sputum inflammatory cells may be used as valuable biomarkers for the classification of AECOPD patients.
AIMS: To investigate whether serum amyloid A protein (SAA) and C-reactive protein (CRP) concentrations could be used in the management of beta thalassaemic patients undergoing bone marrow transplantation (BMT). METHODS: Serum SAA and CRP concentrations were determined in paired samples from 66 patients with beta thalassaemia before and after BMT. Serum SAA concentrations were determined by an enzyme linked immunoassay (EIA); serum CRP concentrations were determined by a nephelometric assay. RESULTS: Serum SAA concentrations before transplantation were significantly higher in the group that subsequently rejected the transplant than the group without complications. SAA concentrations increased after BMT in acute graft versus host disease (GvHD) and rejection. No significant increase in SAA or CRP was found in chronic GvHD. Increases in serum in SAA and CRP concentrations were not related to concomitant infection episodes. CONCLUSIONS: The different acute phase response in acute GvHD and rejection compared with chronic GvHD suggests that different immunopathogenic mechanisms are responsible.
Inflammatory status may be an important prognostic factor for breast cancer. Correlates of markers of inflammation in breast cancer survivors have not been thoroughly evaluated.
Using data from, the Health, Eating, Activity, and Lifestyle (HEAL) Study (a population-based, multiethnic prospective cohort study of female breast cancer patients) we evaluated the associations between circulating markers of inflammation (C-reactive protein [CRP] and serum amyloid A [SAA], measured ~31 months after diagnosis) and several demographic, lifestyle, and clinical characteristics in 741 disease-free breast cancer survivors. Analysis of variance and regression methods were used for statistical analyses of log-transformed values of CRP and SAA.
After adjusting for age, BMI, ethnicity, and study site, higher concentrations of CRP were associated with increasing concentration of SAA (p-trend<0.0001), increasing age (p-trend<0.0001), increasing BMI (p-trend<0.0001), increasing waist circumference (p-trend<0.0001), positive history of heart failure (p=0.0007), decreasing physical activity (p-trend=0.005), Hispanic ethnicity (p=0.05 vs. non-Hispanic white), and current smoking (p=0.03 vs. never smoking). Vitamin E supplementation (p=0.0005), tamoxifen use (p=0.008), and radiation treatment (compared to no chemotherapy or radiation; p=0.04) were associated with reduced CRP. Associations of CRP with clinical characteristics were not significant in the adjusted models. In a multivariate analysis, CRP showed significant associations with waist circumference, BMI, age, history of heart failure, tamoxifen use, and vitamin E supplementation (R2=0.35). Similar, yet fewer, associations were observed for SAA (R2=0.19).
This study highlights important correlates of inflammatory status in breast cancer patients. Our results are consistent with those from similar studies of healthy women.
body mass index (BMI); breast cancer; C-reactive protein (CRP); inflammation; serum amyloid A (SAA)
The serum concentrations of serum amyloid-A protein (SAA), C-reactive protein (CRP), and alpha 1-acid glycoprotein (alpha 1-AGP) have been measured in 185 patients with rheumatoid arthritis. SAA and CRP concentrations correlated well (r = 0.86) both within and above the normal ranges, though SAA showed a greater incremental increase than CRP. All patients with normal SAA levels also had normal CRP and alpha 1-AGP concentrations. In contrast, in 40% of patients with normal CRP and alpha 1-AGP concentrations the SAA was raised, sometimes markedly so. The clinical and serological assessments of disease activity in these patients were not significantly different from those with concomitantly raised levels of CRP. These findings suggest that SAA is a more sensitive marker of inflammation than is CRP. The role of the measurement of SAA as a monitor for inflammatory disease activity is discussed.
The present study aimed to evaluate whether circulating C-reactive protein (CRP) levels are a biomarker of systemic inflammation and a significant predictor of future chronic obstructive pulmonary disease (COPD) outcome. During the study, 116 patients with stable COPD and 35 age- and gender-matched healthy subjects with normal pulmonary function were observed. Patient follow-up was also performed to evaluate the strength of the associations between CRP levels and future outcomes. The observations from the present study showed that serum CRP levels were significantly higher in stable COPD patients than in control subjects (4.48±0.83 vs. 1.01±0.27 mg/l, respectively; P<0.05). In addition, it was identified that a serum CRP concentration of >3 mg/l is a poor prognostic variable of COPD compared with a CRP concentration of ≤3 mg/l [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.05–6.99; P<0.05]. A quantitative synthesis of four studies including 1,750 COPD patients was performed and statistically similar results were obtained (HR, 1.54; 95% CI, 1.14–2.07; P<0.01). The present study showed that circulating CRP levels are higher in stable COPD patients and, therefore, may be used as a long-term predictor of future outcomes. These observations highlight the importance of high sensitivity CRP assays in patients with stable COPD.
C-reactive protein; chronic obstructive pulmonary disease; survival
BACKGROUND—Familial Mediterranean fever (FMF) is a periodic febrile disorder, characterised by fever and serositis. The acute phase response during attacks of FMF results from the release of cytokines, which in turn induce increased expression and changed glycosylation of acute phase proteins. A recent study indicated that attacks in FMF are accompanied by a rise of plasma concentrations of serum amyloid A (SAA) and C reactive protein (CRP), which remain significantly raised during remission relative to healthy controls. Another study suggested that obligatory heterozygotes also display an inflammatory acute phase response.
OBJECTIVE—To determine the state of inflammation in homozygotic and heterozygotic MEFV genotypes.
METHODS—CRP and SAA were studied by enzyme linked immunosorbent assay (ELISA). The glycosylation of the acute phase protein, α1-acid glycoprotein (AGP), was visualised with crossed affinoimmunoelectrophoresis with concanavalin A as diantennary glycan-specific component and Aleuria aurantia lectin as fucose-specific affinity component.
RESULTS—FMF attacks were associated with an increase (p<0.05) in the serum inflammation parameters CRP, SAA, and AGP. The glycosylation of AGP showed an increase (p<0.05) in fucosylated AGP glycoforms, whereas the branching of the glycans remained unaffected. The glycosylation of AGP in the MEFV carrier group, compared with that in a healthy control group, was characterised by a significant increase (p<0.05) in branching of the glycans, whereas the fucosylation remained unaffected.
CONCLUSION—The findings suggest an FMF-specific release of cytokines, resulting in a different glycosylation of AGP between a homozygotic and heterozygotic MEFV genotype.
OBJECTIVES—(1) To determine whether serum concentration of serum amyloid A (SAA) protein is influenced by the SAA1 allele in Japanese patients with rheumatoid arthritis (RA) as previously shown in a healthy control group; and (2) to analyse what factors, based on such an allelic bias, influence the relative SAA values of those patients.
METHODS—SAA and C reactive protein (CRP) concentrations together with SAA1 genotypes were determined in 316 Japanese patients with RA. The relative SAA values were evaluated as an SAA/CRP ratio.
RESULTS—Comparison of the three SAA1 homozygote groups showed that the SAA/CRP ratio was highest in the 1.5/1.5 group (mean 9.0, p<0.01 v the other two homozygote groups) followed by the 1.3/1.3 group (mean 7.2, NS v the 1.1/1.1 group) and the 1.1/1.1 group (mean 4.0). The SAA/CRP ratio was significantly higher in patients receiving corticosteroids regardless of the presence of allele 1.5. No clear differences in the ratio between patients with or without amyloidosis were found.
CONCLUSION—The SAA1.5 allele and corticosteroid treatment had a positive influence on SAA concentrations in serum. These findings are important when evaluating SAA concentration in inflammatory diseases and when considering the cause or treatment of amyloidosis.
The purpose of the study was to determine the relationship between high sensitivity C-reactive protein (hs-CRP) levels and prognostic factors in chronic obstructive pulmonary disease.
We studied 50 stable COPD patients with: spirometry, 6 minute walk distance, body mass index, GOLD stage (spirometric classification) and smoking status. In these patients hs-CRP values were measured and compared with those of 50 healthy controls. Then the serum hs-CRP was subjected to evaluation for any correlation with the predictors of outcomes in COPD subjects.
Hs-CRP levels were higher in COPD patients than in controls (4.82 vs. 0.88 mg/L p < 0.01). Correlation was found between hs-CRP and the following variables: FEV1 (r= −0.813; p < 0.01), 6MWD (r= −0.876; p < 0.01), body mass index (r= −0.710; p < 0.01), GOLD stage (r= 0.797, p < 0.01) and smoking status (r= 0.796; p < 0.01). Using multivariate analysis, FEV1 and 6MWD showed the strongest negative association with hs-CRP levels.
The circulating levels of the inflammatory marker hs-CRP are significantly elevated in patients with COPD, supporting the view that COPD is in part an inflammatory disorder. Hs-CRP levels in stable COPD patients are best correlated with FEV1 and 6-minute walk distance (6MWD). This information should be considered when hs-CRP levels are measured in stable COPD patients.
High sensitivity-C-reactive protein; Chronic obstructive pulmonary disease
Patients with chronic obstructive pulmonary disease (COPD) have raised serum levels of C reactive protein (CRP). This may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as concomitant ischaemic heart disease (IHD) or smoking status. The aim of this study was to evaluate IHD and smoking as potential causes of raised CRP levels in COPD and to test the association between inhaled corticosteroid (ICS) use and serum CRP levels.
Cross sectional analyses comparing cohorts of 88 patients with COPD, 33 smokers (S), and 38 non‐smoker (NS) controls were performed. Clinical assessments included a complete medical history, pulmonary function, 6 minute walk test (6MWT), cardiopulmonary exercise test, and high sensitivity serum CRP measurements.
Serum CRP levels were significantly higher in patients with COPD (5.03 (1.51) mg/l) than in controls (adjusted odds ratio 9.51; 95% confidence interval 2.97 to 30.45) but were similar in the two control groups (S: 2.02 (1.04) mg/l; NS: 2.24 (1.04) mg/l). There was no clinical or exercise evidence of unstable IHD in any of the subjects. CRP levels were lower in COPD patients treated with ICS than in those not treated (3.7 (3.0) mg/l v 6.3 (3.6) mg/l); this association was confirmed in an adjusted regression model (p<0.05).
CRP levels are raised in COPD patients without clinically relevant IHD and independent of cigarette smoking, and reduced in patients with COPD using ICS. CRP may be a systemic marker of the inflammatory process that occurs in patients with COPD.
C‐reactive protein; chronic obstructive pulmonary disease; ischaemic heart disease; smoking; inhaled corticosteroids; systemic inflammation; exercise capacity
The aim of this case control study is to assess the relationship between serum C-reactive protein (CRP) levels and well-known clinical parameters in Chronic obstructive pulmonary disease (COPD) considering the impact of smoking behavior, biomass exposure and accompanying clinical entities, namely pulmonary hypertension, systemic hypertension and diabetes mellitus.
Spirometry, echocardiography, arterial oxygen saturation (SpO2) measurements, BODE scores and serum CRP levels were investigated in stable COPD patients. Associations between CRP levels and clinical parameters were evaluated.
CRP levels are significantly higher in COPD patients than in healthy controls. CRP levels were not significantly different between COPD patients treated with inhaled corticosteroids and those not treated. CRP levels significantly correlated with age, FEV1% predicted, FVC% predicted, SpO2, MMRC, 6 minute walk distance, BODE scores and haemoglobin levels. In multivariate analysis BODE scores and concomitant systemic hypertension manifested the strongest association with CRP levels. CRP levels in COPD patients with and without pulmonary hypertension were significantly different. CRP levels did not differ significantly according to smoking status or biomass exposure, moreover COPD cases due to biomass exposure who never smoked also had higher CRP levels compared to healthy controls.
Systemic inflammation is inherent to COPD independent of ever-smoking status and correlates with disease severity, concomitant systemic hypertension and pulmonary hypertension.
Biomass; C-reactive protein (CRP); chronic obstructive pulmonary disease (COPD); pulmonary artery pressure; smoking behaviour
C reactive protein (CRP) and serum amyloid A protein (SAA) are sensitive and rapid acute phase reactants, and their measurement for monitoring inflammatory disease and assessing the prognosis in secondary amyloidosis is gaining widespread acceptance. The changes in these proteins in eight subjects suffering from natural colds, 15 subjects with experimentally induced colds (rhinoviruses E1, 3, 9, 14, or 31), and eight with experimentally induced influenza (A/Eng/40/83) were studied. SAA concentration increased in 21 of the 23 subjects with natural or experimental rhinovirus colds (mean increase 95 mg/l); CRP concentration increased in 11 (mean increase 11 mg/l). All subjects with influenza showed pronounced increases in SAA concentrations (mean increase 642 mg/l) while six showed increases in CRP concentration (mean increase 22 mg/l). All these increases were highly significant (p less than 0.001). Asymptomatic excretors of both rhinovirus and influenza virus showed significant increases in SAA concentration (p = 0.015 for rhinovirus and p less than 0.001 for influenza virus) but not in CRP concentration. No changes in SAA or CRP values were seen in 12 volunteers after challenge with saline. These observations suggest that caution is required in the interpretation of estimations of SAA concentration and that it may be too sensitive an acute phase protein for clinical use as its concentration may be raised in both trivial and asymptomatic viral infections.
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with significant systemic consequences. Recognition of the systemic manifestations has stimulated interest in identifying circulating biomarkers in these patients. A systematic analysis was undertaken of multiple protein analytes in the serum of well characterised patients with COPD and matched controls using novel protein microarray platform (PMP) technology.
Forty‐eight patients (65% men) with COPD (forced expiratory volume in 1 s <55%) and 48 matched controls were studied. Anthropometric parameters, pulmonary function tests, 6‐minute walk distance, the BODE index and the number of exacerbations were measured and the association of these outcomes with the baseline levels of 143 serum biomarkers measured by PMP was explored.
Thirty biomarker clusters were identified and ranked by computing the predictive value of each cluster for COPD (partial least squares discriminant analysis). From the 19 best predictive clusters, 2–3 biomarkers were selected based on their pathophysiological profile (chemoattractants, inflammation, tissue destruction and repair) and the statistical significance of their relationship with clinically important end points was tested. The selected panel of 24 biomarkers correlated (p<0.01) with forced expiratory volume in 1 s, carbon monoxide transfer factor, 6‐minute walk distance, BODE index and exacerbation frequency.
PMP technology can be useful in identifying potential biomarkers in patients with COPD. Panels of selected serum markers are associated with important clinical predictors of outcome in these patients.
Previous studies reported that serum amyloid A (SAA) is elevated in patients with tumors, including breast cancer, compared to healthy controls. In addition, the levels of SAA increase gradually with tumor progression. In this study, we investigated the blood SAA level of breast cancer patients, and evaluated its potential as a serum biomarker for the early diagnosis of breast cancer and as a staging estimate. SAA protein was determined by enzyme-linked immunosorbent assay in serum samples from 30 healthy women, 21 women with benign diseases and 118 breast cancer patients who were subdivided into 4 groups based on their clinical characteristics. SAA levels were not statistically different in stage I breast cancer patients compared with the healthy controls and benign breast disease patients. SAA concentrations had medians of 0.63 µg/ml in normal healthy women, 0.76 µg/ml in patients with benign disease (p>0.05) and 0.82 µg/ml in stage I breast cancer patients (p>0.05). By contrast, SAA values in stage Ⅱ, Ⅲ and Ⅳ patients had a significantly higher median compared to those of the healthy, benign breast diseases and stage I groups (p<0.05). Breast cancer patients with lymph node (LN) metastasis or distant metastasis were found to have significantly higher SAA concentrations than those without metastases. SAA is not a suitable marker for early breast cancer diagnosis, but its level is correlated with the stage of breast cancer. Thus, it may be a good candidate marker for the staging and prognosis of breast cancer.
serum amyloid A; breast cancer; staging; diagnosis
HIV infection and drugs of abuse such as methamphetamine (METH), cocaine, and alcohol use have been identified as risk factors for triggering inflammation. Acute phase proteins such as C-reactive protein (CRP) and serum amyloid A (SAA) are the biomarkers of inflammation. Hence, the interactive effect of drugs of abuse with acute phase proteins in HIV-positive subjects was investigated.
Plasma samples were utilized from 75 subjects with METH use, cocaine use, alcohol use, and HIV-positive alone and HIV-positive METH, cocaine, and alcohol users, and age-matched control subjects. The plasma CRP and SAA levels were measured by ELISA and western blot respectively and the CD4 counts were also measured.
Observed results indicated that the CRP and SAA levels in HIV-positive subjects who are METH, cocaine and alcohol users were significantly higher when compared with either drugs of abuse or HIV-positive alone. The CD4 counts were also dramatically reduced in HIV-positive with drugs of abuse subjects compared with only HIV-positive subjects.
These results suggest that, in HIV-positive subjects, drugs of abuse increase the levels of CRP and SAA, which may impact on the HIV infection and disease progression.
Drugs of abuse; HIV; Plasma; C-reactive protein; Serum amyloid A
OBJECTIVE--To evaluate the clinical significance of interleukin-6 (IL-6) measurements in relation to laboratory and clinical measures of disease activity and radiological progression in early rheumatoid arthritis (RA). METHODS--A prospective study was performed in 51 patients with early RA during the first three years of the disease, with monthly clinical and laboratory assessments and biannual radiographs of the hands and feet. IL-6 was measured by enzyme linked immunosorbent assay (ELISA). Cross sectional (n = 51) and longitudinal (n = 20) correlations between plasma IL-6 concentrations and values of C reactive protein (CRP), serum amyloid A protein (SAA), erythrocyte sedimentation rate (ESR), haemoglobin (Hb), platelets, and joint scores were calculated, and correlations made between time integrated values of IL-6, CRP and ESR, and radiological progression over three years (n = 20). RESULTS--Significant correlations were found between IL-6 and the acute phase response and platelets, but variable results were obtained for the correlation between IL-6 and Hb. In contrast to a significant correlation between time integrated values of CRP or ESR and radiological progression, time integrated values of IL-6 did not correlate with radiological progression over three years follow up. CONCLUSION--The course of disease activity and the radiological progression of joint damage are better reflected by CRP, SAA, and ESR values than by plasma IL-6 concentrations, particularly in stages of low disease activity.
The distinction between exudates and transudates is very important
in the patient management. Here we evaluate whether the
acute-phase protein serum amyloid A (SAA), in comparison with C
reactive protein (CRP) and total protein (TP), can be useful in
this discrimination. CRP, SAA, and TP were
determined in 36 exudate samples (27 pleural and 9 ascitic) and in
12 transudates (9 pleural and 3 ascitic). CRP, SAA, and TP
were measured. SAA present in the exudate
corresponded to 10% of the amount found in serum, that is, the
exudate/serum ratio (E/S) was 0.10 ± 0.13. For comparison, the
exudate/serum ratio for CRP and TP was 0.39 ± 0.37 and 0.68 ± 0.15, respectively. There was a strong positive correlation
between serum and exudate SAA concentration (r = 0.764;p < 0.0001). The concentration of SAA in transudates was low
and did not overlap with that found in exudates (0.02-0.21 versus
0.8–360.5 g/mL). SAA in pleural and ascitic exudates results
mainly from leakage of the serum protein via the inflamed
membrane. A comparison of the E/S ratio of SAA and CRP points SAA
as a very good marker in discriminating between exudates and
Timely and accurate diagnosis of pancreatic adenocarcinoma (PA) is hampered by the lack of effective circulating biomarkers. No single test has emerged that improves upon the commonly used biomarker, cancer antigen 19-9 (CA 19-9) to effectively discriminate PA from benign conditions. The goals of this study were to validate two acute phase proteins, haptoglobin and serum amyloid A (SAA), as biomarkers for PA and determine if the combination of haptoglobin, SAA and CA 19-9 would improve PA diagnosis over CA 19-9 alone.
Levels of haptoglobin, SAA and CA 19-9 were measured in pre-treatment sera from 75 PA patients, 32 patients with chronic pancreatitis, 42 patients with other benign pancreatic disease or biliary stricture and 150 healthy control subjects by ELISA or colorimetric binding assay. Relative levels of haptoglobin or SAA were compared between groups using ANOVA. The diagnostic accuracy of serum haptoglobin and SAA levels were investigated using receiver operating characteristics analysis. Using classification tree analysis, an algorithm was developed that used haptoglobin, SAA and CA 19-9 in a panel diagnostic screen.
Both haptoglobin and SAA were significantly elevated in sera from PA patients compared to healthy control subjects (P < 0.0001) and patients with chronic pancreatitis (P = 0.01). Haptoglobin was significantly elevated in sera from PA patients relative to patients with other benign diseases (P = 0.0015), whereas SAA fell short of significance in the same comparison (P = 0.0508). Receiver operating characteristic analysis indicated that haptoglobin (AUC = 0.792) was a better diagnostic marker than SAA (AUC = 0.691) over multiple threshold cutoffs. Using specific cutoffs that minimized overall misclassification, haptoglobin yielded a sensitivity of 82.7 % and a specificity of 71.1% and SAA yielded a sensitivity of 34.7% and 90.2% specificity when discriminating PA cases from all non-PA controls. In the same sample set, CA 19-9 yielded a sensitivity of 77.3% and a specificity of 91.1%. Combining data from haptoglobin, SAA and CA 19-9 in a panel diagnostic screen improved overall accuracy over CA 19-9 alone yielding a sensitivity of 81.3% and a specificity of 95.5%.
These data demonstrate that haptoglobin and SAA are useful in discriminating PA from benign conditions as well as healthy controls when used in a panel diagnostic screen. This study supports the use of combined biomarkers for improved accuracy in the diagnosis of PA.
Increase of Serum amyloid A (SAA) level has been observed in patients with a variety of cancers. The objective of this study was to determined whether SAA level could be used as a prognostic parameter in patients with esophageal squamous cell carcinoma (ESCC).
SAA levels were measured by rate nephelometry immunoassay in 167 healthy controls and 167 ESCC patients prior to surgical resection. Statistical associations between clinicopathological observations and SAA levels were determined using the Mann–Whitney U test. The clinical value of SAA level as a prognostic parameter was evaluated using the Cox’s proportional hazards model.
SAA levels were significantly higher in patients with ESCC compared to levels in healthy controls (13.88 ± 15.19 mg/L vs. 2.26 ± 1.66 mg/L, P < 0.001). Elevation of SAA levels (≥ 8.0 mg/L) was observed in 54.5% (91/167) of patients with ESCC but not in healthy controls. SAA levels were associated with tumor size (P < 0.001), histological differentiation (P = 0.015), T classification (P < 0.001), clinical stage (P < 0.001), lymph node metastasis (P < 0.001) and distant metastasis (P < 0.001), but not with the age and gender of the patients or tumor location. Multivariate analysis revealed that patients with an elevated level of SAA (≥ 8.0 mg/L) had significantly lower 5-year survival rate than those with non-elevated SAA (< 8.0 mg/L, log-rank P < 0.0001).
An elevated level of preoperative SAA was found to associate with tumor progression and poor survival in patients with ESCC.
Serum amyloid A; Esophageal squamous cell carcinoma; Prognosis; Biomark
Inflammation and inflammatory biomarkers play an important role in atherosclerosis and cardiovascular disease. Little information is available, however, on time course of serum markers of inflammation after stroke.
First ischemic stroke patients ≥40 years old had levels of high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), and fibrinogen measured in plasma samples drawn at 1, 2, 3, 7, 14, 21 and 28 days after stroke. Levels were log-transformed as needed, and parametric and non-parametric statistical tests were used to test for evidence of a trend in levels over time. Levels of hsCRP and SAA were also compared with levels in a comparable population of stroke-free participants.
Mean age of participants with repeated measures (n = 21) was 65.6 ± 11.6 years, and 13 (61.9%) were men, and 15 (71.4%) were Hispanic. Approximately 75% of patients (n = 15) had mild strokes (NIH Stroke Scale score 0–5). There was no evidence of a time trend in levels of hsCRP, SAA, or fibrinogen for any of the markers during the 28 days of follow-up. Mean log(hsCRP) was 1.67 ± 1.07 mg/L (median hsCRP 6.48 mg/L) among stroke participants and 1.00 ± 1.18 mg/L (median 2.82 mg/L) in a group of 1176 randomly selected stroke-free participants from the same community (p = 0.0252).
Levels of hsCRP are higher in stroke patients than in stroke-free subjects. Levels of inflammatory biomarkers associated with atherosclerosis, including hsCRP, appear to be stable for at least 28 days after first ischemic stroke.
Intravenous administration to human volunteers of a commercial preparation of recombinant human C-reactive protein (CRP) produced in E. coli was recently reported in this journal to induce an acute phase response of serum amyloid A protein (SAA) and of CRP itself, and to activate the coagulation system. The authors concluded that CRP is probably a mediator of atherothrombotic disease. Here we confirm that this recombinant CRP preparation was pro-inflammatory both for mouse macrophages in vitro and for mice in vivo, but show that pure natural human CRP had no such activity. Furthermore mice transgenic for human CRP, and expressing it throughout their lives, maintained normal concentrations of their most sensitive endogenous acute phase reactants, SAA and serum amyloid P component (SAP). The patterns of in vitro cytokine induction and of in vivo acute phase stimulation by the recombinant CRP preparation were consistent with contamination by bacterial products, and there was 46.6 EU of apparent endotoxin activity per mg of CRP in the bacterial product, compared to 0.9 EU per mg of our isolated natural human CRP preparation. The absence of any pro-inflammatory activity in natural CRP for macrophages or healthy mice strongly suggests that the in vivo effects of the recombinant preparation observed in humans were due to pro-inflammatory bacterial products and not human CRP.
C-reactive protein; inflammation; atherosclerosis; atherothrombosis; cardiovascular disease
As an acute-phase protein, serum amyloid A (SAA) is expressed primarily in the liver. However, its expression in extrahepatic tissues, especially in tumor tissues, was also demonstrated recently. In our study, we investigated the expression of SAA in uterine cervical carcinomas, and our results suggested its potential as a serum biomarker.
Quantitative real-time polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the SAA gene and protein expression levels in the tissues and sera of patients with non-neoplastic lesions (NNLs), cervical intraepithelial neoplasia (CIN) and cervical carcinoma (CC).
Compared with NNLs, the SAA gene (SAA1 and SAA4) expression levels were significantly higher in uterine CC (mean copy numbers: 138.7 vs. 5.01, P < 0.000; and 1.8 vs. 0.079, P = 0.001, respectively) by real-time PCR. IHC revealed cytoplasmic SAA protein staining in tissues from adenocarcinoma and squamous cell carcinoma of the cervix. The median serum concentrations (μg/ml) of SAA were 6.02 in patients with NNLs and 10.98 in patients with CIN (P = 0.31). In contrast, the median serum SAA concentration was 23.7 μg/ml in uterine CC patients, which was significantly higher than the SAA concentrations of the NNL group (P = 0.002) and the CIN group (P = 0.024).
Our data suggested that SAA might be a uterine CC cell product. High SAA concentrations in the serum of CC patients may have a role in monitoring disease occurrence and could have therapeutic applications.
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1433263219102962.
Uterine cervical carcinoma; Serum amyloid A; Tumor marker
Concentrations of serum amyloid A protein (SAA) were measured in 254 children with viral diseases, including measles, varicella, rubella, mumps, echo-30 meningitis, chronic hepatitis B and C, and in eight with Kawasaki disease. Latex agglutination nephelometric immunoassay was used for assaying SAA. In 191 out of 195 patients (98%), SAA concentrations became markedly raised in the acute phase of the viral disease: measles (97%), varicella (100%), mumps (95%), and echo-30 meningitis (99%) with mean titres of 82.4, 80.5, 60.2, 75.2, and 101.1 micrograms/ml respectively. This increase in SAA was followed by a rapid return to normal concentrations (< 5 micrograms/ml) during convalescence. Remarkably higher concentrations of SAA (mean 1630 micrograms/ml) were detected in the acute phase of patients with Kawasaki disease, but in most of the children with chronic hepatitis B or C, the titres of SAA remained normal. There was no close correlation between SAA and serum concentrations for alpha 1-acid glycoprotein, beta 2-microglobulin, transferrin, and IgG. There was a clear correlation between SAA and C reactive protein concentrations, although SAA showed a greater incremental change than C reactive protein in the acute phase. In the acute phase of these viral diseases, 56% of the patients had raised SAA concentrations (> or = 5 micrograms/ml) with normal C reactive protein concentrations (< 5 micrograms/ml). These results indicate that SAA could be useful as an inflammatory marker in children with acute viral infections.
To determine if serum amyloid A (A-SAA) could be detected in human osteoarthritic (OA) joints and further clarify if high A-SAA level in joints result from a local production or from a diffusion process from abnormally elevated plasma concentration. Regulatory mechanism of A-SAA expression and its pro-inflammatory properties were also investigated.
A-SAA levels in serum and synovial fluid of OA (n = 29) and rheumatoid arthritis (RA) (n = 27) patients were measured and compared to matched-healthy volunteers (HV) (n = 35). In vitro cell cultures were performed on primary joint cells provided from osteoarthritis patients. Regulatory mechanisms were studied using Western-blotting, ELISA and lentiviral transfections.
A-SAA was statistically increased in OA plasma patients compared to HV. Moreover, A-SAA level in OA plasma and synovial fluid increased with the Kellgren & Lauwrence grade. For all OA and RA patients, A-SAA plasma level was higher and highly correlated with its corresponding level in the synovial fluid, therefore supporting that A-SAA was mainly due to the passive diffusion process from blood into the joint cavity. However, A-SAA expression was also observed in vitro under corticosteroid treatment and/or under IL-1beta stimuli. A-SAA expression was down-regulated by PPAR-γ agonists (genistein and rosiglitazone) and up-regulated by TGF-β1 through Alk1 (Smad1/5) pathway. RhSAA induced proinflammatory cytokines (IL-6, IL-8, GRO-α and MCP-1) and metalloproteinases (MMP-1, MMP-3 and MMP-13) expression in FLS and chondrocytes, which expression was downregulated by TAK242, a specific TLR4 inhibitor.
Systemic or local A-SAA expression inside OA joint cavity may play a key role in inflammatory process seen in osteoarthritis, which could be counteracted by TLR4 inhibition.