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Clinical Chemistry 48: 2195-2201, 2002;
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(Clinical Chemistry. 2002;48:2195-2201.)
© 2002 American Association for Clinical Chemistry, Inc.

Diagnostic Accuracy of {alpha}1-Acid Glycoprotein Fucosylation for Liver Cirrhosis in Patients Undergoing Hepatic Biopsy

Ingvar Rydén1a, Peter Påhlsson2 and Stefan Lindgren3

1 Department of Clinical Chemistry, Kalmar County Hospital, SE 39185 Kalmar, Sweden.

2 Division of Clinical Chemistry, Department of Biomedicine and Surgery, Linköping University, SE 58185 Linköping, Sweden.

3 Gastroenterology-Hepatology Division, Department of Medicine, Malmö University Hospital, SE 20502 Malmö, Sweden.

aAuthor for correspondence. Fax 46-480-81025; e-mail ingvar.ryden{at}telia.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Increased fucosylation of serum glycoproteins has previously been reported in patients with liver disease. We analyzed {alpha}1-acid glycoprotein (AGP) fucosylation in serum samples from patients investigated for suspected liver disease to evaluate its value as a biochemical marker for liver cirrhosis.

Methods: We used a novel lectin immunoassay adapted to the AutoDELFIA 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 histopathologic findings. In addition, AGP fucosylation was compared with other biochemical markers described as useful in the diagnosis of liver cirrhosis. The biochemical markers were compared by ROC curve analysis.

Results: AGP fucosylation was significantly (P <0.05) higher in patients with liver cirrhosis (n = 65) than in healthy controls (n = 72), patients with normal histology (n = 29), patients with steatosis only (n = 38), patients with viral or chronic hepatitis without cirrhosis (n = 71), and patients with other liver diseases without histologic signs of cirrhosis (n = 58). By calculating the AGP fucosylation index (AGP-FI = AGP fucosylation/AGP serum concentration), we obtained a high diagnostic accuracy. The areas under the ROC curves for AGP-FI were 0.83 and 0.74 for men and women, respectively, compared with 0.82 for hyaluronic acid and 0.77 for the aspartate aminotransferase/alanine aminotransferase ratio in both men and women.

Conclusions: 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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In recent years, several studies have reported altered glycosylation of plasma proteins in different pathologic conditions (1). Carbohydrate-deficient transferrin, which lacks one or two complete N-linked complex-type oligosaccharide side chains (N-glycans), is widely used to detect and monitor chronic alcohol abuse (2). {alpha}1-Acid glycoprotein (AGP;1 orosomucoid) is a heavily glycosylated plasma protein with five complex N-glycans. AGP glycosylation has been studied in patients receiving estrogen treatment or with acute and chronic inflammation or different malignant diseases, and changes in branching, sialylation, and fucosylation of the oligosaccharides were found (1)(3)(4)(5)(6). Furthermore, increased AGP fucosylation was found in ascitic fluid from a patient with liver cirrhosis (7). Haptoglobin fucosylation was also increased in alcoholic liver disease (8)(9), and serum cholinesterase fucosylation was increased in liver cirrhosis, but not in viral or chronic hepatitis (10)(11). In other studies, increased fucosylation of {alpha}-fetoprotein and other serum glycoproteins was found mainly in hepatocellular carcinoma (12)(13).

We used a novel lectin immunoassay adapted from Rydén et al. (6) to analyze AGP fucosylation in sera from 261 consecutive patients undergoing liver biopsy as a part of a clinical investigation of liver disease. The aim of the study was to investigate the possible use of AGP fucosylation in the diagnosis of liver cirrhosis and to compare AGP fucosylation with other biochemical markers previously used for detecting cirrhosis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients and controls
We retrospectively studied 261 consecutive patients who underwent liver biopsy during investigation for suspected chronic liver disease at the Department of Gastroenterology at Malmö University Hospital in Southern Sweden during 1990–1996. This is the only hospital in the city of Malmö, which has 250 000 inhabitants; therefore, the patients are representative of the spectrum of liver disease in this population, with the exception of alcoholic liver disease, because many of these patients are cared for at the Alcohol Clinic, and patients with radiologic signs of hepatocellular carcinoma, who usually do not undergo large-needle liver biopsy at Malmö University Hospital. Each serum sample was obtained on the day of liver biopsy, frozen, and stored at -20 °C. The age and sex distributions in the different disease groups are shown in Table 1 . Plasma was collected from healthy donors at the local Blood Transfusion Unit to be analyzed individually. These samples were also pooled and stored at -70 °C to be used as a control in the lectin immunoassay.


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  		Table 1. Median age, age range, and gender distribution of the study patients divided into different groups according to liver biopsy results.

liver biopsy
Liver biopsy was performed according to the Menghini technique, using a 1.4-mm Hepafix® needle. Each liver specimen was fixed in formalin, and paraffin-embedded sections were routinely stained with hematoxylin–eosin, periodic acid–Schiff with and without previous digestion of glycogen by diastase, van Gieson, Perls iron stain, and Gordon–Sweet stain.

routine chemistry
The serum albumin (Alb) concentration was measured with the bromcresol green method, and the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured according to IFCC recommendations (14)(15). During 1990–1991, these tests were performed on a Prisma (LKB), and during 1992–1996, they were performed on a DAX 48 (Technicon). Prothrombin time (PT) was measured with the Stago Prothrombincomplex Assay (Stago). Serum AGP and C-reactive protein were analyzed by turbidimetry on a Cobas Integra 700 (Roche).

hyaluronic acid test
Serum hyaluronic acid (HA) was measured by the HA-test (Pharmacia Diagnostics) according to the manufacturer’s instructions.

lectin immunoassay
A lectin immunoassay using the fucose-specific Aleuria aurantia lectin (AAL) was adapted for use in the Auto DELFIA (Wallac), with europium-conjugated streptavidin used for signal detection. Briefly, the analysis was performed as follows: AAL was purified from mushrooms harvested locally, as detailed previously (16), and AAL fractions were pooled, lyophilized, and stored at -20 °C. AAL was then dissolved in a buffer solution, biotinylated according to the manufacturer’s instructions (ImmunoprobeTM Biotinylation Kit; Sigma), and stored at 4 °C. Microtiter plates (Nunc-Immuno MaxiSorpTM, Nalge Nunc International) were coated with 100 µL of monospecific polyclonal antibodies directed against human AGP (Anti Human Orosomucoid, product no. A0011; Dako), diluted in 10 mL of coating buffer (15 mmol/L Na2CO3, 35 mmol/L NaHCO3, 0.2 g/L NaN3, pH 9.6), for 12 h at 4 °C. The subsequent procedures were performed at room temperature. Blocking agent (200 µL; phosphate-buffered saline, pH 7.4, containing 50 g/L bovine serum albumin) was added to the wells, and the plates were incubated on a shaker for 60 min. The wells were then washed four times with a washing solution (9 g/L NaCl solution containing 2.5 mL/L Tween). For each patient, 10 µL of serum was diluted in 2 mL of DELFIA Diluent II (Wallac). In samples having an AGP concentration >1.1 g/L, the AGP concentration was adjusted to 0.7 ± 0.2 g/L before dilution.

The following steps were then performed in the AutoDELFIA. A 100-µL aliquot of the diluted samples was added to each well and incubated for 60 min. Samples were added in duplicate for each patient. The plates were washed six times with 25 mL of concentrated Wash Solution (Wallac) diluted in 600 mL of distilled water and incubated with 100 µL of biotinylated AAL diluted 1:100 in Assay Buffer (100 µL of biotinylated AAL in 10 mL of Assay Buffer; Wallac) for 60 min. Plates were then washed six times and incubated with 100 µL of streptavidin-europium (Wallac) diluted 1:1000 in Assay Buffer (10 µL of 0.1 g/L streptavidin-europium in 10 mL of Assay Buffer) for 60 min. Enhancement Solution (100 µL; Wallac) was added and, after incubation for 5 min, the plates were read by the AutoDELFIA system. A calibration curve was obtained from preparations made from a pool of patient samples with highly fucosylated AGP by dilution with a pool of patient samples that contained a low degree of AGP fucosylation. The linearity of the calibration curve was tested by dilution of a highly fucosylated sample (AGP concentration, 0.7 g/L), and the assay response was compared with the reference method described by Rydén et al. (6). The calibrators were assigned values of 1, 2, 3, 4, and 5 arbitrary units (AU), approximately corresponding to the mean number of fucose residues per AGP molecule, according to a previously performed monosaccharide analysis (17). The AGP fucosylation index (AGP-FI) was calculated as follows: AGP-FI = AGP fucosylation/AGP serum concentration.

All biochemical tests were performed without knowledge of the biopsy results.

statistics
The Statistica 5.5 software package (StatSoft, Inc.) was used for statistical analysis. For comparison of results among patient groups, the Kruskal–Wallis ANOVA and the Mann–Whitney U-test were used. P <0.05 was considered significant. MedCalc, Ver. 6.10.001, was used for ROC curve analysis. For AGP-FI, the cutoff was 4.5, according to ROC analysis. For the HA-test, the cutoff was set at 110 µg/L, as specified by Guechot et al. (18); for the AST/ALT ratio, the cutoff was set at 1, as described in Dufour et al. (19); and for PT, 85% was used as the cutoff value, as described by Oberti et al. (20). For S-Alb, we adopted the cutoff value of 35 g/L used in local clinical practice. The guidelines suggested by Bruns et al. (21) were followed for the evaluation.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
patients
The 261 patients were divided into five groups according to the histologic findings at liver biopsy (Table 1Up ): no diseased tissue (n = 29); steatosis only (n = 38); hepatitis, including viral, toxic, and autoimmune hepatitis with no histologic sign of cirrhosis (n = 71); cirrhosis, on the basis of alcoholic, metabolic, viral, and autoimmune diseases (n = 65); and others without cirrhosis (n = 58), including large duct cholestatic disease (n = 10), metabolic disease [such as antitrypsin deficiency, hemochromatosis, or Wilson disease (n = 9)], alcoholic hepatitis (n = 7), steatosis with cellular necrosis (n = 6), reticular hyperplasia (n = 6), chronic hepatitis in transition form (n = 4), primary sclerosing cholangitis (n = 1), secondary malignancy (n = 1), and patients with inconclusive biopsy results (n = 14).

agp fucosylation
Reference intervals based on the healthy controls were established for men (n = 36) and women (n = 36), respectively. The reference intervals calculated from the 2.5 and 97.5 percentiles were 1.0–3.7 AU for men and 0.9–2.8 AU for women. The mean value for the pool used as a normal control was 1.8 AU. Reproducibility was tested by repeated measurements of the control and a highly fucosylated sample. The intraassay CVs were 8.0% for the normal control and 5.8% for the highly fucosylated sample. The total CV throughout the study for the normal control was 10%.

Patients with liver cirrhosis verified by liver biopsy had significantly (P <0.05) higher AGP fucosylation (median, 3.9 AU; range, 0.7–11.4 AU) than healthy controls (median, 1.9 AU; range, 0.8–3.7 AU) and the other patients (median, 2.0 AU; range, 0.1–8.2 AU). In 28 patients (10 men and 18 women), AGP fucosylation was increased but evidence of cirrhosis was absent in the liver biopsy. An acute-phase reaction was found in 12 of these cases (3 men and 9 women) as indicated by increased plasma C-reactive protein (>10 mg/L) and/or AGP (>1.1 g/L). To reduce the influence of an inflammatory process, an AGP-FI was calculated based on the formula given in the Materials and Methods.

Eleven of the 28 patients with increased AGP fucosylation without cirrhosis had a normal AGP-FI; thus, the number of "false positives" was reduced. Of the remaining 17 patients with increased AGP-FI without any sign of cirrhosis in liver biopsy, 5 had hepatitis based on viral or chronic autoimmune disease, 3 had large duct cholestatic disease, 3 had alcoholic hepatitis, 3 had steatosis complicated by lobular cell necrosis, 1 had steatosis only, 1 had metabolic liver disease, and 1 had reticular hyperplasia.

The AGP-FI distribution when patients with cirrhosis were further classified into three groups based on clinical signs of the severity of the disease is shown in Fig. 1 (cirrhosis without symptoms related to liver disease, n = 36; patients with symptoms related to liver disease, without portal hypertension or decompensation, n = 16; patients with decompensated liver cirrhosis or signs of portal hypertension, n = 11). The AGP-FI distributions in patients with negative biopsies or steatosis only (n = 67) and in patients with hepatitis (n = 68) are shown in Fig. 1 for comparison. Seven patients were not classified because of missing clinical data, including two patients with cirrhosis and three with hepatitis. The AGP-FI was significantly higher in all groups of cirrhotic patients than in patients without histopathologic signs of cirrhosis. The P for the difference between cirrhotic patients without any symptoms [mean (SD) AGP-FI, 4.5 (3.2)] and patients with hepatitis [mean AGP-FI, 2.8 (1.8)] was 0.003.



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  		Figure 1. Distribution of AGP-FI in patients with cirrhosis, classified according to the degree of symptoms or signs related to liver disease: cirrhosis without symptoms related to liver disease (NS); cirrhosis and symptoms related to liver disease, but without portal hypertension or decompensation (ND); and decompensated liver cirrhosis or signs of portal hypertension (DC).

The distributions of AGP-FI in patients with negative biopsies or steatosis only (NB or steatosis) and in patients with hepatitis are shown for comparison. Box and whisker plots show the median ({square}), quartiles (box), and range (whiskers). {circ} denotes outliers, and + denotes extreme values, defined as follows: outliers are results above/below the 75th/25th percentile ± 1.5(75th - 25th percentile); extreme values are above/below the 75th/25th percentile ± 2(75th - 25th percentile).

Because previous studies and reference intervals have indicated differences in AGP fucosylation between sexes, the following results are presented separately for men and women. The distribution of AGP-FI in different patient groups according to liver biopsy is shown in Fig. 2 . AGP-FI was significantly (P <0.05) higher in patients with liver cirrhosis than in each of the other patient groups. ROC curves for AGP-FI in liver cirrhosis are shown in Fig. 3 . The diagnostic accuracy for all tests is summarized in Table 2 . When men and women with cirrhosis were further stratified according to age, a significantly higher area under the curve (AUC) was found for women >50 years of age compared with women <50 years, as shown in Table 3 .



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  		Figure 2. Distribution of AGP-FI in different patient groups according to liver biopsy results in men (A) and women (B).

Box and whisker plots show the median ({square}), quartiles (box), and range (whiskers). {circ} denotes outliers, and + denotes extreme values, defined as follows: outliers are results above/below the 75th/25th percentile ± 1.5(75th - 25th percentile); extreme values are above/below the 75th/25th percentile ± 2(75th - 25th percentile). Values exceeding scale limits are in parentheses.



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  		Figure 3. ROC curves for AGP-FI in liver cirrhosis, according to liver biopsy, in men (A) and women (B).


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  		Table 2. AUCs with 95% confidence intervals obtained from ROC curve analysis, and diagnostic sensitivities and specificities for AGP-FI, S-Alb, PT, AST/ALT ratio, and HA-test in liver cirrhosis in men and women, respectively, at cutoffs specified.


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  		Table 3. AUCs with 95% confidence intervals obtained from ROC curve analysis, and diagnostic sensitivity and specificity for AGP-FI in men and women above and below 50 years of age.1

other biochemical tests
Although differences were not statistically significant, Alb and PT showed a lower AUC for liver cirrhosis than did the other markers (Table 2Up ). The diagnostic accuracy for liver cirrhosis was similar for the AST/ALT ratio, HA-test, and AGP-FI (Table 2Up ), but the correlation between AGP-FI and AST/ALT ratio was low, 0.26. The correlation between AGP-FI and HA was 0.49 (Fig. 4 ). In 11 of the 17 patients with increased AGP-FI without histologic signs of cirrhosis, HA was also increased. However, in two patients, HA was highly increased (>2500 µg/L) without any histopathologic signs of cirrhosis and with no increase in AGP-FI (Fig. 4 ). No obvious reasons for a false-positive result, such as hypothyroidism, were found in these patients.



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  		Figure 4. AGP-FI plotted vs HA in all patients.

Log scales are shown. {square}, patients with cirrhosis; {circ}, patients without cirrhosis, according to liver biopsy. Dashed lines indicate cutoffs: 4.5 for AGP-FI and 110 µg/L for HA.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
There is a need for accurate biochemical markers to aid in early diagnosis of liver cirrhosis (20)(22). Liver biopsy is usually required to establish a definite diagnosis, but it has limitations in terms of lack of sensitivity, risk of complications, and discomfort for the patient (20); it thus is not suitable for screening for cirrhosis in patients with, e.g., chronic viral hepatitis or alcoholic liver disease. Common procedures include a clinical examination and routine laboratory analyses, such as hematologic indices; coagulation analyses, including PT; serum/plasma proteins, including Alb, immunoglobulins, and "liver enzymes", e.g., AST, ALT, and glutamyltransferase. Analysis of any of the liver enzymes alone is generally not considered sufficient (22), but the AST/ALT ratio has previously been suggested as a marker for cirrhosis (23)(24). Furthermore, several connective tissue substances have been studied as markers for liver fibrosis and cirrhosis, e.g., HA, type III procollagen N-terminal peptide, and laminin (18)(25)(26). Different diagnostic accuracies have been described for these markers, but HA has been considered the most specific marker for liver fibrosis as well as cirrhosis in several studies (18)(20).

In a previous study, increased AGP fucosylation was found in ascitic fluid from a patient with cirrhosis (7). The purposes of the present study were to investigate AGP fucosylation in a large number of patients who were undergoing investigation of suspected liver disease and to compare the diagnostic accuracy for liver cirrhosis with other biochemical markers. We therefore adapted a lectin immunoassay previously developed by us to be used in an automated analyzer (AutoDELFIA) in the routine laboratory. We investigated AGP fucosylation in 261 patients consecutively admitted for liver biopsy.

The reproducibility of the lectin immunoassay in the AutoDELFIA system was satisfactory for routine use in a clinical laboratory, and ROC curve analysis showed a high diagnostic accuracy for AGP fucosylation in discriminating patients with cirrhosis from patients without cirrhosis. Diagnostic accuracy, assessed as the AUC in ROC curve analysis, was similar for AGP-FI, the HA-test, and the AST/ALT ratio. However, diagnostic specificity may be higher for AGP-FI than for the HA-test and AST/ALT ratio (Table 2Up ). Some patients with no evidence of cirrhosis in liver biopsy had very high HA concentrations (Fig. 4Up ). The correlation was not very high between AGP-FI and the HA-test, indicating different mechanisms for the different biochemical markers. Increased fucosylation of AGP in liver cirrhosis may result from increased fucosyltransferase activity in the liver, as was shown in a study of {alpha}-fetoprotein (27).

AGP-FI was significantly higher in cirrhotic patients without any symptoms than in noncirrhotic patients. This indicates that AGP-FI may be useful for early detection of liver cirrhosis. The patients with cirrhosis were older than the other patients (Table 1Up ). This may be explained by the fact that it takes several years for cirrhotic lesions to develop. From this study, we cannot exclude subtle changes in AGP fucosylation with increasing age. However, in a previous study we found no significant difference in AGP fucosylation between regular blood donors 50–65 years of age and donors 18–25 years of age, indicating that no major age-related changes in AGP fucosylation occur (28). In contrast, sex-related differences in AGP fucosylation are well recognized (4)(28). In the present study, there was a significant difference in the diagnostic performance of AGP-FI in detecting cirrhosis between women older and younger than 50 years of age. The AUC was significantly lower in women <50 years, probably because of the influence of higher estrogen concentrations, either naturally occurring or administered as medication. No information was available about ongoing oral contraception or estrogen treatment. Despite this difference, we found no obvious reason for changing the cutoff for AGP-FI in any of the age groups.

The results of liver biopsies were used as reference for the diagnosis of liver cirrhosis. However, sampling variability may frequently lead to false-negative biopsy findings (20), which affect the outcomes of the comparisons among different biochemical markers. In a few cases, more than one of the investigated biochemical tests indicated cirrhosis, which may imply false-negative results for the liver biopsy. Thus, diagnostic accuracy for the biochemical tests may be underestimated. The lower diagnostic accuracy for biochemical markers found in this investigation compared with some previous studies may be attributable to differences in the patient populations studied. In the present study, the patients were included consecutively, which is more representative of clinical practice.

In conclusion, we found a high diagnostic accuracy for AGP fucosylation in discriminating liver cirrhosis in patients investigated for liver disease. In particular, diagnostic specificity for AGP fucosylation for cirrhosis seems to be high enough to be useful in clinical investigations.


   Acknowledgments
 
We thank Ann-Marie Helgesson for skillful technical assistance. This study was supported by grants from the Health Research Council in the Southeast of Sweden.


   Footnotes
 
1 Nonstandard abbreviations: AGP, {alpha}1-acid glycoprotein; Alb, albumin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; HA, hyaluronic acid; AAL, Aleuria aurantia lectin; AU, arbitrary unit(s); AGP-FI, {alpha}1-acid glycoprotein fucosylation index; and AUC, area under the ROC curve.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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