Serum Levels Of Acute Phase Proteins Research Articles

The Endotoxin Receptor TLR4 Polymorphism Is Not Associated With Diabetes or Components of the Metabolic Syndrome

The gene coding for the endotoxin receptor TLR4 (toll-like receptor 4) has been sequenced recently, and the polymorphic spectrum of the gene has been elucidated (1). A polymorphism in the gene affects the inflammatory response to lipopolysaccharide (LPS) (2,3), with impact on the risk of gram-negative infections and septic shock (4,5). We have analyzed two cosegregating mutations in the gene region coding for the extracellular domain of the endotoxin receptor TLR4, characterized by a substitution at amino acid position 299 (glycine for aspartate) and another at position 399 (isoleucine for threonine). The 299Gly form of TLR4 affects the inflammatory response to LPS by exhibiting attenuated signaling leading to a dampened response to LPS (4,5). Polymorphisms in the TLR4 protein show an increased risk to develop a septic shock with gram-negative microorganisms (6), premature birth (7), and graft versus host disease after hematopoietic stem cell transplantation (8). Polymorphisms in the TLR4 gene, however, did not reveal any association with severity of menigococcal disease (9), risk of premature rupture of membranes caused by infections (10), or asthma- and atopy-related diseases (11). TLR4 interacts with endogenous ligands such as the stress protein hsp60 (12). Since hsp60 is an important player in chronic inflammatory conditions (12), the TLR4 polymorphism may regulate the subclinical inflammation underlying the pathogenesis of arteriosclerosis. Indeed, a recent study reported an association of the TLR4 polymorphism with atherogenesis (13). Subjects carrying the rare 299Gly allele exhibited a lower risk of carotid atherosclerosis and a smaller intima-media thickness in the common carotid artery (13). Parameters of mild systemic inflammation observed in association with atherosclerosis are strikingly similar to what is seen in subjects with metabolic syndrome or type 2 diabetes, notably elevated serum levels of acute-phase proteins, some inflammatory …

Impact of albumin synthesis rate and the acute phase response in the dual regulation of fibrinogen levels in hemodialysis patients

Fibrinogen is a risk factor for cardiovascular disease. It also is an acute phase protein (APP) and its plasma concentration increases with inflammation. Fibrinogen synthesis correlates with albumin synthesis in nephrotic patients and in patients with an expanded plasma volume even when serum albumin is normal and there is no inflammatory disease. The relationships among albumin synthesis, the acute phase response and plasma fibrinogen levels in hemodialysis patients are unknown. In 74 hemodialysis patients, albumin synthesis, plasma volume (PV) and acute phase proteins (APPs) C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1 AG), ceruloplasmin (Cer), and interleukin 6 (IL-6) were measured in serum and fibrinogen in plasma, and the results analyzed by multiple regression analysis. CRP, IL-6, alpha1 AG, Cer and fibrinogen were measured monthly, which enabled us to determine whether changes in these APPs correlated with the levels of and variability in plasma fibrinogen over time using a longitudinal modeling approach. Length of follow-up for the 74 patients ranged from 3.25 to 67.5 months. Baseline fibrinogen (548.6 +/- 106. 4 mg/dL) was significantly greater than levels reported for normal adults and correlated positively with albumin synthesis (P < 0.001), age (P < 0.001) and log CRP (P = 0.002) and negatively with PV (P < 0.001). Longitudinally, fibrinogen varied positively with long-lived APPs, Cer and alpha1 AG, as well as the short-lived APP, CRP. Plasma fibrinogen concentration is high in HD patients and directly correlates with increased albumin synthesis rates and the serum levels of APPs. Fibrinogen levels also correlate negatively with PV. Fibrinogen levels vary over time in synchrony with levels of other long-lived APPs, supporting the hypothesis that fibrinogen is regulated in part as a component of the acute phase response and in part by factors that increase albumin synthesis.

Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study.

Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.

The acute-phase response varies with time and predicts serum albumin levels in hemodialysis patients

Cross sectional studies have established that the serum albumin level is dependent on serum levels of acute-phase proteins (APPs) or cytokine levels in hemodialysis patients. While the acute-phase response is generally associated with acute inflammatory events, a cross sectional analysis relating laboratory values to outcomes assumes these values to be unchanging. The longitudinal relationship among laboratory measurements and how they vary over time in a population of patients are unknown. Patients who were enrolled in the HEMO Study were recruited into an ancillary longitudinal study to establish the predictive effect of temporal variation in the levels of APPs and of temporal variation in normalized protein catabolic rate (nPCR) on the serum albumin concentration. nPCR was measured monthly using a double-pool method. The positive APPs-C-reactive protein (CRP), alpha1 acid glycoprotein (alpha1-AG), and ceruloplasmin-and the negative APP-transferrin (Trf)-were measured in serum obtained before each dialysis session for six weeks and then monthly in 37 hemodialysis patients. A random coefficient regression analysis was used to assess the association of serum albumin with other measured parameters at each time point, as well as fixed patient characteristics. The within-subject coefficients of variation of albumin (median, range of 25th to 75th percentiles; median, 0.0614; range, 0.0485 to 0.0690) were significantly less than that of APPs (CRP, median, 0.878; range, 0.595 to 1.314, P < 0. 05; and alpha1 AG, median, 0.173; range, 0.116 to 0.247, P < 0.05). The levels of APPs and albumin varied considerably over time. The primary predictor of current albumin was the current CRP level (P = 0.0014). nPCR also was a significant predictor for albumin levels (P = 0.0440) after controlling for the effect of APPs, suggesting an effect of nPCR on serum albumin concentration irrespective of the acute-phase response. Age and the presence of an arteriovenous graft were significant predictors that were associated with reduced albumin. The acute-phase response is intermittent and is not a continuous feature in individual dialysis patients. Levels of APPs are the most powerful predictors for the levels of albumin concentration in hemodialysis in a longitudinal setting. Since variations in albumin are small, measurement of variations in APPs may provide greater insight into the dynamics of clinically relevant processes.

A profile of acute-phase proteins after severe burns

Transport proteins and acute-phase proteins, including complement factors C3 and C4, immunoglobulin A (IgA), IgM, albumin (ALB), prealbumin (PAB), transferrin (TRF), ceruloplasmin (CER), haptoglobin (HAG), and alpha antitrypsin (AAT), were examined in 29 patients with severe burns with a total burn surface area (TBSA) ranging from 30% to 97% (mean, 50.03%±21.16%). Samples from each patient were obtained at days 2, 7, 14, and 21 postburn and were analyzed using a 3M 300 special automatic analyzing system (Sanofi, France). A population of normal individuals served as controls. Statistical analyses were performed using multivariate and regression analyses. The postburn values of C3, C4, PAB, ALB, TRF, and CER were significantly lower compared to controls (P>0.01). Slow postburn recovery was observed for C3 and C4, which was negatively correlated with burn severity. TAF, TAB, and ALB values decreased significantly within the first week postburn (P<0.01); TAF, PAB, and ALB values demonstrated a steady recovery between days 14 and 21 postburn. The recovery was negatively correlated to the severity of the burns. IgA and IgM markedly decreased after 2 days postburn (P<0.01). After the initial decrease, the levels of IgM slowly increased, whereas the levels of IgA remained depressed for the first postburn week. The levels of AAT rose significantly throughout the entire study period and were positively correlated with the severity of the burns (P<0.01). This study demonstrates a pattern of certain reactive/acute-phase proteins in the postburn period. It can be concluded that severe burns directly affect the production of serum levels of acute-phase proteins, thereby impairing important physiological functions such as the immune system, protein transportation, metabolism, and repair processes.

Augmented enhancement of in vitro production of inflammatory cytokines in peripheral blood mononuclear cells in patients undergoing simultaneous resection of the liver and gastrointestinal tract.

To determine changes in the production of inflammatory cytokines and acute-phase proteins, and in the priming of peripheral blood mononuclear cells (PBMC), as mechanisms for the high incidence of postoperative complications in patients who have undergone hepatectomy simultaneously with resection of the gastrointestinal tract. Prospective, clinical study for 3 wks after operation. A surgical department in a university hospital. Twenty-one consecutive adult patients with synchronous and metachronous hepatic metastases from gastrointestinal malignancies, curatively resected by simultaneous resection (group A, n = 9) or by hepatectomy alone (group B, n = 12), and 15 patients with gastrointestinal malignancies undergoing curative resection (group C). Peripheral venous blood samples collected before operation and on days 1, 3, 5, 7, 10, 14, and 21 after operation. The serum and plasma levels of acute-phase proteins, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and endotoxin were measured. The in vitro production of IL-1beta and TNF-alpha by PBMC was also determined by the stimulation of lipopolysaccharide. The incidence of postoperative complications was significantly higher in group A than in groups B and C. The serum levels of IL-6 increased significantly, with a peak at postoperative day 1 in all groups, and the peak levels of IL-6 in groups A and B were significantly higher than that in group C. The serum levels of all acute-phase proteins measured in this study (alpha1-antitrypsin, haptoglobin, and C-reactive protein) increased markedly after operation in group C (p < .05). In group A, only C-reactive protein increased after operation, but its peak level was lower than in groups B and C (p < .05). Although IL-1beta and TNF-alpha in the serum were not detectable in any of the groups during the entire study period, the lipopolysaccharide-induced in vitro production of IL-1beta and TNF-alpha by PBMC in all groups was significantly elevated after operation, with a peak at days 1 and 3 after operation, respectively. In addition, the elevation of the in vitro production of IL-1beta and TNF-alpha in group A was significantly greater than that in group C, lasting until postoperative day 5 (IL-1beta) and postoperative day 10 (TNF-alpha). The levels of plasma endotoxin increased significantly in all groups, with a peak at day 1 after operation, and the peak levels were significantly higher in group A than in groups B and C. There was a significant correlation between the peak levels of in vitro TNF-alpha production and the peak levels of plasma endotoxin (r2 = .331, p< .01). The augmented enhancement of the priming of PBMC as a result of surgery in patients undergoing simultaneous resection of the liver and gastrointestinal tract, together with the reduced synthesis of the acute-phase reactants and impaired host defense mechanisms, might be responsible for the high incidence of postoperative complications, possibly because subsequent exposure of primed macrophages/monocytes to triggering substances such as endotoxin and bacterial components after operation results in inappropriate production of inflammatory cytokines.

Acute-phase proteins and levels of interleukin 1B, interleukin 6, tumor necrosis factor alpha, and interleukin 8 in children with pertussis.

To determine serum levels of acute-phase proteins and interleukin 1B, interleukin 6, tumor necrosis factor alpha, and interleukin 8 in children with pertussis. Cross-sectional study. Divisions of Infectious Diseases, Regional Hospital, and Pediatrics, University of Pavia, Varese, Italy. Eight children with pertussis, six with acute febrile infections, and eight healthy control children matched for sex, age, and time presentation over a 32-month study period. None. An immunoenzymatic assay was used to detect serum levels of all cytokines. Normal values of C-reactive protein, alpha 1-acid glycoprotein, and erythrocyte sedimentation rate were observed in the serum of patients with pertussis. The mean (+/- SD) detectable levels of tumor necrosis factor alpha (65.0 +/- 50.4 pg/mL) and interleukin 6 (32.3 +/- 17.8 pg/mL) were observed in the serum of patients with pertussis. In contrast, a nonsignificant increment of interleukin 1B levels (66.5 +/- 83.7 pg/mL) and interleukin 8 levels (12.7 +/- 17.8 pg/mL) was noted in the serum of the same patients. Increased and significant levels of all four cytokines were noted in most of the serum samples of patients with acute febrile infections. Acute-phase response is absent in patients with pertussis, whereas detectable and significant serum levels of tumor necrosis factor alpha and interleukin 6 were observed in some such patients.

Acute-phase proteins in patients with head and neck cancer treated with interleukin 2/interferon alfa.

Circulating acute-phase proteins may mediate adverse reactions in patients receiving biologic response modifiers, including inhibition of immune responsiveness and clinical toxic effects. Nine patients with unresectable head and neck squamous cell carcinoma were prospectively examined for levels of acute-phase proteins during interleukin 2/interferon alfa immunotherapy and for clinical toxic effects. Simultaneous determination of the in vitro immunomodulatory capacity of autologous serum on the induction of lymphokine-activated killer cells was assessed in 4-hour chromium release assays. Of the seven acute-phase proteins analyzed, haptoglobin and C-reactive protein levels were elevated before therapy was started. Toxic events leading to cessation of interleukin 2/interferon alfa therapy had a high correlation with elevated C-reactive protein and lowered C3 component of complement levels. No relationship was noted between serum levels of acute-phase proteins and induction inhibition of lymphokine-activated killer cell cytotoxicity. The role of C-reactive protein and complement degradation products in mediating interleukin 2/interferon alfa toxicity requires further investigation.

Effect of Prostaglandin E in Multiple Experimental Models. III. Effect on Response to Septic Challenge

Severe thermal injuries result in significant physiologic alterations. These alterations have been attributed in part to the elevated prostaglandin E levels that follow traumatic injuries. We evaluated the physiologic sequelae of elevated prostaglandin E levels by administering a long-acting prostaglandin E2 derivative, 16,16-dimethyl-prostaglandin E2 (dPGE), to rats with septic burns. The dPGE was found to increase gut translocation of bacteria. Administration of dPGE had no significant effect on resting metabolic rate. In rats with nonseptic burns the administration of dPGE resulted in increased serum levels of acute-phase proteins. In conclusion prostaglandin E may have both detrimental and beneficial effects on traumatized persons.

Total enteral nutrition versus total parenteral nutrition after major torso injury: Attenuation of hepatic protein reprioritization: Peterson VM, Moore EE, Jones TN, et al. Surgery 104:199, 1988

Reprioritization of hepatic protein synthesis, a process involving accelerated production of acute-phase proteins at the expense of constitutive proteins, accompanies major trauma. The impact of isocaloric, isonitrogenous total enteral nutrition (TEN) versus total parenteral nutrition (TPN) on hepatic reprioritization was investigated in a prospective, randomized trial. Of the 59 patients with an abdominal trauma index (ATI) greater than 15 but not more than 40, 45 evaluable patients were followed. Results from 36 (18 TEN, 18 TPN) evaluable patients revealed that mean serum levels of acute-phase proteins increased, whereas mean serum levels increased to a greater extent in the TPN group. The maximal increase from baseline for the acute-phase response in both groups occurred at postinjury day 5 and was significantly higher for alpha 1-antitrypsin (alpha 1AT, p = 0.03) and orosomucoid (p = 0.02) in the TPN group. Nonacute-phase proteins reached a nadir at day 10 in the TPN group and increased in the TEN group; significant differences between TEN and TPN groups appeared for albumin (p = 0.004) and retinol-binding protein (RBP, p = 0.03); alpha 2-macroglobulin (alpha 2M) approached significance at day 10 (p = 0.07). When change from baseline values was compared, day 10 increases in alpha 2M were significantly higher (p = 0.04) in the TEN group. These data suggest that postinjury TEN attenuates reprioritization of hepatic protein synthesis in patients sustaining major trauma.

Serum glycoproteins and immunoglobulins in nasopharyngeal carcinoma: Correlations with Epstein-Barr virus associated antibodies and clinical tumor stage

The consistent association of elevated antibody titers to the Epstein-Barr virus associated antigens in patients with nasopharyngeal carcinoma has led to correlations of antibody titers with tumor presence and extent. Recently, serum levels of specific glycoproteins and immunoglobulins have been correlated with tumor presence and extent in patients with head and neck squamous carcinomas, and elevation of the immunoglobulin IgA has been described in patients with nasopharyngeal carcinoma. These correlations prompted a study of 69 untreated patients with nasopharyngeal carcinoma and 53 healthy normal subjects in Taiwan to determine the relations among specific proteins (haptoglobin, α 1-acid glycoprotein, α 1-antitrypsin, α 2-HS-glycoprotein, prealbumin, and albumin), immunoglobulin levels (IgA, IgG, IgM), anti-EBV associated antibody titers, and clinical tumor stage. Elevated antibody titers to EBV-associated antigens (EBV-associated nuclear antigen, viral capsid antigen, and early antigen) were related to tumor presence but not significantly related to clinical tumor stage. Compared with the levels in normal subjects, serum levels of acute-phase proteins (haptoglobin, α 1-acid glycoprotein, α 1-antitrypsin) were significantly increased (p < 0.001) in patients with nasopharyngeal carcinoma, and levels of α 2HS-glycoprotein were significantly decreased (p < 0.001). Uniquely, serum levels of acute-phase proteins, particularly haptoglobin, were directly related to clinical tumor stage (p < 0.05 − 0.001). Furthermore, serum haptoglobin levels correlated directly with anti-EBNA antibody titers (p < 0.03) and serum levels of IgA (p < 0.01). Serum levels of α 2HS-glycoprotein correlated inversely with titers of IgA antibodies to early antigen (p < 0.03). The findings demonstrate that measurement of specific serum glycoprotein and immunoglobulin levels may be useful adjuncts to anti-EBV antibody titers in the serodiagnosis and monitoring of response to treatment of nasopharyngeal carcinoma and aid in the derivation of improved staging systems for these tumors.