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Clinical studies on α1-acid glycoprotein glycosylation - with focus on fucose
Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

α1-Acid glycoprotein (AGP, orosomucoid) is a heavily glycosylated protein found in blood plasma in all humans. AGP is one of the major acute phase proteins, and its concentration is frequently measured in clinical laboratories as a marker for inflammatory disease. For several years it has been known that the glycosylation of AGP is altered in different physiological and pathological conditions. However, methods for analysis of the glycosylation changes have been time-consuming and at best semi-quantitative. Consequently, clinical studies have been limited to small numbers of patients, and have not confirmed the usefulness of routine analysis of A GP glycosylation in clinical investigations. In the present study, two major issues were addressed: the need for new methods that would allow quantitative measurements of specific glycosylation changes, and the need for clinical studies with sufficient numbers of study subjects to evaluate the potential advantages and drawbacks of analyzing AGP glycosylation in a clinical laboratory.

High-pH anion-exchange chromatography (HPAEC) separates oligosaccharides with high resolution and was used to study N-linked oligosaccharides (N-glycans) released from AGP obtained from patients with different inflannnatory conditions. We showed that HPAEC is a very reproducible and useful method for profiling of AGP N-glycans, providing infmmation on N-glycan sialylation and fucosylation simultaneously. In particular, we found a typical pattern with a sharp increase in fucosylated, tri-sialylated N-glycans in patients with rheumatoid arthritis (RA). The laborious preparation of samples prior to analysis is a drawback for the use ofHPAEC as a routine method in a clinical laboratory. However, HPAEC has a great potential as a tool for profiling AGP glycosylation in different pathologic conditions, and it was used as a reference for the development of other analytical methods. In order to analyze a larger number of patient samples, we developed a lectin immunoassay using a fucose specific lectin from the A!euria aurantia mushroom. The lectin immunoassay was well suited for use in a clinical laboratory and was used to study AGP fucosylation in patients with severe bmns, recent onset rheumatoid arthritis (RA), liver disease, and alcohol abuse. In a time study of 10 patients with severe bums, changes in AGP fucosylation showed a typical pattern, without con-elation to acute phase protein synthesis. This confirmed the results of previous studies indicating that glycosylation is regulated independently from protein synthesis in the acute phase response.

We studied AGP fucosylation in 131 patients with recent onset RA. In these patients, AGP fucosy lation was increased, but the con elation with disease activity according to a clinical score (DAS28) was not superior to previously used biochemical markers of inflammation. However, in men with RA who had increased AGP fucosylation at the time of diagnosis, the degree of fucosylation conelated to disease progression during the first year following diagnosis. It remains to be confumed whether AGP fucosylation can provide prognostic information for this patient category.

When we studied AGP fucosylation in 261 patients investigated for suspected liver disease, fucosylation was heavily increased in patients with histopathological signs of liver cirrhosis. In addition, AGP fucosylation coiTelated to the severity of disease. By calculating an AGP fucosylation index (AGP-Fl, AGP fucosylation/AGP serum concentration), a high diagnostic accuracy was found for liver cinhosis. Even in patients with cinhosis without any symptoms related to liver disease, AGP-FI was significantly higher than in patients with steatosis or chronic hepatitis. When compared with other biochemical markers of liver disease, AGP fucosylation was among the most specific in discriminating liver cin·hosis, and may be useful in clinical investigations of liver disease.

We also studied AGP fucosylation in 21 patients with heavy alcohol abuse admitted to hospital for detoxification. fu the 16 male patients that were studied, AGP fucosylation was significantly increased compared to healthy controls. Furthermore, in these men there was a significant con·elation between AGP fucosylation and other biochemical markers previously used for detection of liver cirrhosis. This study should be extended with a larger number of patients, and histopathological examination following liver biopsy, in order to confirm the value of increased AGP fucosylation as an early marker for cirrhosis in this patient categmy.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2002. , 35 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 750
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25706Local ID: 10082ISBN: 91-7373-195-1 (print)OAI: oai:DiVA.org:liu-25706DiVA: diva2:246254
Public defence
2002-11-08, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-20Bibliographically approved
List of papers
1. Glycosylation of α1-acid glycoprotein in inflammatory disease: analysis by high-pH anion-exchange chromatography and concanavalin A crossed affinity immunoelectrophoresis
Open this publication in new window or tab >>Glycosylation of α1-acid glycoprotein in inflammatory disease: analysis by high-pH anion-exchange chromatography and concanavalin A crossed affinity immunoelectrophoresis
1997 (English)In: Glycoconjugate Journal, ISSN 0282-0080, E-ISSN 1573-4986, Vol. 14, no 4, 481-488 p.Article in journal (Refereed) Published
Abstract [en]

High-pH anion-exchange chromatography with pulsed amperometric detection is a highly sensitive technique that can be used for detecting changes in sialylation and fucosylation, as well as different branching patterns of N-linked oligosaccharides in glycoproteins. We examined the N-glycans of α1-acid glycoprotein obtained from twelve patients with various inflammatory conditions with this technique, as well as traditional concanavalin A crossed affinity immunoelectrophoresis. We found the chromatographic profiles of N-glycans in all patients with rheumatoid arthritis to be very similar, but significantly different from normal controls. N-glycans from patients with ulcerative colitis also showed specific alterations in their chromatographic profiles. However, some heterogeneity was found between these patients, perhaps reflecting changes in glycosylation secondary to certain states of the disease, or to medical treatment. We conclude that this technique is useful for detailed mapping of glycosylation changes in α1-acid glycoprotein in clinical samples, and that it may be used to further increase our knowledge about glycosylation changes in response to inflammatory disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81671 (URN)10.1023/A:1018503602681 (DOI)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2017-12-07Bibliographically approved
2. Lectin ELISA for Analysis of α1-Acid Glycoprotein Fucosylation in the Acute Phase Response
Open this publication in new window or tab >>Lectin ELISA for Analysis of α1-Acid Glycoprotein Fucosylation in the Acute Phase Response
1999 (English)In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 45, no 11, 2010-2012 p.Article in journal (Refereed) Published
Abstract [en]

No abtract available.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25261 (URN)9701 (Local ID)9701 (Archive number)9701 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-09-20Bibliographically approved
3. Fucosylation of α1-acid glycoprotein (orosomucoid) compared with traditional biochemical markers of inflammation in recent onset rheumatoid arthritis
Open this publication in new window or tab >>Fucosylation of α1-acid glycoprotein (orosomucoid) compared with traditional biochemical markers of inflammation in recent onset rheumatoid arthritis
2002 (English)In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 317, no 1-2, 221-229 p.Article in journal (Refereed) Published
Abstract [en]

Background: Fucosylation of α1-acid glycoprotein (AGP, orosomucoid) has previously been found to be increased in patients with rheumatoid arthritis. Furthermore, the degree of fucosylation has been suggested to reflect disease activity. Therefore, we investigated the fucosylation of AGP in 131 patients (96 women and 35 men) with recent onset rheumatoid arthritis (RA). We compared the results with traditional biochemical markers of inflammation, i.e. plasma concentrations of AGP (P-AGP), and C-reactive protein (P-CRP).

Methods: AGP fucosylation measured with a novel lectin enzyme-linked immunosorbent assay (ELISA) was compared with a disease activity score (DAS28) and its components, and with P-AGP, and P-CRP at the time of diagnosis, and at a follow-up visit 1 year later.

Results: Both men and women with RA had increased AGP fucosylation compared to healthy individuals. We found a weak correlation between AGP fucosylation and DAS28 only in men. In men with initially increased AGP fucosylation, the level of fucosylation correlated with the change in DAS28 during the first year following diagnosis.

Conclusion: We conclude that AGP fucosylation is not superior to traditional markers of disease activity in RA. However, AGP fucosylation may give some additional information to traditional biochemical markers on the disease progression in men.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25259 (URN)10.1016/S0009-8981(01)00803-8 (DOI)9699 (Local ID)9699 (Archive number)9699 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2015-08-31Bibliographically approved
4. Increased α1-acid glycoprotein fucosylation in patients with liver cirrhosis
Open this publication in new window or tab >>Increased α1-acid glycoprotein fucosylation in patients with liver cirrhosis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Increased fucosylation of serum glycoproteins has previously been reported in patients with liver disease. We analyzed α1-acid glycoprotein (AGP) fucosylation in serum samples from patients investigated for suspected liver disease, in order to evaluate its value as a biochemical marker for liver cirrhosis.

Methods: We used a novel lectin innnunoassay adapted to the Auto-DELFIA system to analyze AGP fucosylation in 261 consecutive patients admitted for liver biopsy at Malmö university hospital in Southern Sweden. The results were compared with histopathological findings. In addition, AGP fucosylation was compared to other biochemical markers described to be useful in the diagnosis of liver cirrhosis. The different biochemical markers were compared by ROC curve analysis.

Results: AGP fucosylation was significantly higher in patients with liver cirrhosis (n=65) than in nmmal controls (n=72), patients with normal histology (n=29), patients with steatosis only (n=38), patients with viral or chronic hepatitis without ciiThosis (n=71), and patients with other liver diseases without histological signs of cirrhosis (n=58). By calculating an AGP fucosylation index (AGP-FI = AGP fucosylation/AGP serum concentration), a high diagnostic accuracy was obtained. The area under the curve for AGP-FI was 0.83 and 0.74 for men and women respectively, compared to 0.82 for hyaluronic acid, and 0.77 for AST/ALT ratio in both men and women.

Conclusion: We conclude that AGP fucosylation appears to be useful in identifying patients with liver cirrhosis among patients investigated for liver disease. The lectin immunoassay showed satisfactory reproducibility, and is suitable for routine use in a clinical laboratory.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81672 (URN)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2012-09-20Bibliographically approved
5. Increased α1-acid glycoprotein fucosylation in patients with high alcohol consumption
Open this publication in new window or tab >>Increased α1-acid glycoprotein fucosylation in patients with high alcohol consumption
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Changes in glycosylation of senun glycoproteins have been described in different pathologic conditions, and increased fucosylation has previously been reported in patients with liver disease. We analyzed serwn samples from patients admitted to hospital for detoxification of excessive alcohol consumption in order to study α1-acid glycoprotein (AGP) fucosylation and its correlation to other biochemical markers of alcoholism and liver damage.

Methods: We used a novel lectin innmmoassay to analyze AGP fucosylation (AGP-F) in a prospective study of 21 consecutive patients admitted for treatment at Linköping University Hospital in the Southeast of Sweden. The results were compared with markers conunonly used for detecting alcoholism and liver cirrhosis, such as carbohydrate deficient transferrin, aminotransferase activity, including aspartate aminotransferase/alanine aminotransferase ratio (AST/ALT), and with hyaluronic acid (HA). In addition, ultrasonography of the liver was performed in 16 of the 21 patients.

Results: AGP-F was significantly higher in the male study patients than in normal controls. In addition, in these patients AGP-F correlated to the levels of AST/ALT-ratio and HA No correlation was found between AGP-F and steatosis of the liver, as indicated by ultrasonography, or between AGP-F and CDT.

Conclusion: We conclude that AGP-F is increased in men with a high alcohol intake and correlates with AST/ALT ratio and HA, which previously have been found to be indictors of liver cirrhosis. AGP-F should be further evaluated as a potential early indicator ofliver cirrhosis in this patient category.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-81673 (URN)
Available from: 2012-09-20 Created: 2012-09-20 Last updated: 2012-09-20Bibliographically approved

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