Original Article
Early Recognition of Hepatocellular Carcinoma Based on Altered Profiles of Alpha-Fetoprotein
N Engl J Med 1993; 328:1802-1806June 24, 1993
- Abstract
Background
The sugar-chain structures of circulating alpha-fetoprotein in patients with hepatocellular carcinomas differ from those in patients with cirrhosis. We studied the reactivity of alpha-fetoprotein with two lectins, Lens culinaris agglutinin A and erythroagglutinating phytohemagglutinin, to monitor the evolution of hepatocellular carcinoma in patients with cirrhosis.
Methods
Among 361 patients with cirrhosis caused mainly by chronic hepatitis B or hepatitis C virus infection, 33 with base-line serum alpha-fetoprotein concentrations ≥ 30 ng per milliliter were found to have hepatocellular carcinomas during a mean follow-up of 35 months. The lectin-reactive profiles of the alpha-fetoprotein in the serum of these 33 patients were analyzed and compared with those in the serum of 32 patients with cirrhosis who had increased base-line serum alpha-fetoprotein concentrations and were followed for at least 24 months but in whom hepatocellular carcinoma did not develop.
Results
At the time of tumor detection, 24 (73 percent) of the 33 patients with cirrhosis and hepatocellular carcinoma had higher percentages of L. culinaris agglutinin A-reactive alpha-fetoprotein (alpha-fetoprotein L3), erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein (alpha-fetoprotein P4+P5), or both than the 32 patients with cirrhosis but no hepatocellular carcinoma. Among the 24 patients, one or both of the markers were first elevated 3 to 18 months before the hepatocellular carcinoma was detected by imaging techniques.
Conclusions
Measurements of the alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 fractions of serum alpha-fetoprotein allow the differentiation of hepatocellular carcinoma from cirrhosis in some cases and serve as predictive markers for the development of hepatocellular carcinoma during the follow-up of patients with cirrhosis.
Media in This Article
Figure 1
Representative Patterns of Alpha-Fetoprotein Bands Separated by Lectin-Affinity Electrophoresis in the Serum of a Patient with Cirrhosis Who Had Hepatocellular Carcinoma and the Serum of One Who Did Not.Figure 2
Proportions of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in the Serum of Patients Who Had Cirrhosis with and without Hepatocellular Carcinoma.Article Activity
- Article
Hepatocellular carcinoma is the seventh most common form of cancer in men worldwide and the ninth most common in women1. In Japan, the incidence of hepatocellular carcinoma has increased steadily in the past 10 years, resulting in an increase in the mortality rate from 9.5 per 100,000 population per year in the period from 1968 to 1977 to 16.0 per 100,000 in the period from 1984 to 1985,2 and it is now the third most common cancer in men and the fifth most common in women. Since the development of hepatocellular carcinoma is closely associated with chronic liver disease, particularly cirrhosis,3-5 patients with cirrhosis should be examined regularly with imaging techniques such as ultrasonography or computed tomography, in combination with determinations of serum alpha-fetoprotein, a substance produced by virtually all hepatocellular carcinomas. In fact, close follow-up of patients with cirrhosis with imaging techniques and serum alpha-fetoprotein assays has led to the identification of hepatocellular carcinomas at an early stage4,6. Serum alpha-fetoprotein concentrations, however, are elevated both in patients with hepatocellular carcinomas and in those with benign chronic liver diseases, and there is wide overlap between the two groups,7,8 causing monitoring with serum alpha-fetoprotein measurements alone to be inefficient9,10.
Human alpha-fetoprotein has one asparagine-linked biantennary oligosaccharide per molecule11. On the basis of this structure, microheterogeneity of the sugar component of alpha-fetoprotein was studied by affinity chromatography and affinity electrophoresis, with several lectins having specificity for different oligosaccharides12-14. The serum alpha-fetoprotein of patients with hepatocellular carcinoma is characterized by greater proportions of alpha-fetoprotein that reacts with Lens culinaris agglutinin A and erythroagglutinating phytohemagglutinin than the serum alpha-fetoprotein of patients with benign chronic liver diseases15-19. The methods used to determine the lectin reactivity of alpha-fetoprotein in these studies were cumbersome and insensitive, with detection limits of 100 ng per milliliter. Recently, more sensitive methods using lectin-affinity electrophoresis coupled with antibody-affinity blotting were developed to detect reactions of alpha-fetoprotein with these lectins20. We undertook this study to determine the lectin reactivity of alpha-fetoprotein, using kits based on these methods that had a detection limit of 20 to 30 ng per milliliter, in patients with cirrhosis who had hepatocellular carcinomas and those who did not.
Methods
We studied 361 patients with cirrhosis who were admitted to our hospital between 1980 and 1990 and were regularly followed, with measurements of serum alpha-fetoprotein and ultrasonography or computed tomography of the liver every three months. The diagnosis of cirrhosis was made by liver biopsy in all the patients. Seventy-six of the 361 patients had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line (Table 1Table 1
Clinical Characteristics of 361 Patients with Cirrhosis at Base Line, According to Measurement of Serum Alpha-Fetoprotein.). Of these 76 patients, 33 (43 percent) were found to have hepatocellular carcinomas during a mean follow-up period of 35 months (range, 3 to 91); 24 were men and 9 were women, and they were 36 to 73 years of age (mean [±SD], 54 ±9). Tests for hepatitis B surface antigen and anti-hepatitis C antibody (second generation) were positive in 10 and 23 of these 33 patients, respectively. The diagnosis of hepatocellular carcinoma was based on histologic findings in tissue obtained at the time of surgery or ultrasonography-guided tumor biopsy in 20 patients, and on characteristic appearances on ultrasonography, computed tomography, and angiography in 13 patients.Hepatocellular carcinomas also developed during follow-up in 23 of 285 patients (8 percent) who had base-line serum alpha-fetoprotein concentrations of less than 30 ng per milliliter. During the same period, there were 32 patients with cirrhosis (26 men and 6 women), 28 to 81 years of age (mean, 50 ±14), who had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line and who were followed for at least 24 months but in whom hepatocellular carcinomas did not develop. Tests for hepatitis B surface antigen and anti-hepatitis C antibody were positive in 13 and 18 of these patients, respectively; both tests were negative in the remaining patient. The patients with cirrhosis in whom hepatocellular carcinomas did not develop during follow-up served as controls. Another 11 patients had base-line serum alpha-fetoprotein concentrations similar to those of the controls and did not have hepatocellular carcinomas, but were not studied in detail during follow-up.
Serum alpha-fetoprotein concentrations were measured in duplicate by radioimmunoassay with kits obtained from Dainabot Radioisotope (Tokyo, Japan). The coefficient of variation of the assay was less than 7 percent, and the values in normal subjects were less than 10 ng per milliliter. Serum samples with values of 30 ng per milliliter or more were stored at -20 °C for the later analysis of lectin-reactive profiles. The proportions of L. culinaris agglutinin A-reactive alpha-fetoprotein (alpha-fetoprotein L3) and erythroagglutinating phytohemagglutinin-reactive alpha-fetoprotein (alpha-fetoprotein P4+P5) were measured by lectin-affinity electrophoresis, coupled with antibody-affinity blotting with alpha-fetoprotein Differentiation Kits L and P (Wako Pure Chemical Industries, Osaka, Japan). Alpha-fetoprotein L3 is considered to have sugar chains fucosylated at the core of asparagine-linked N-acetylglucosamine, whereas the sugar-chain structure of alpha-fetoprotein P4+P5 remains to be determined21. In the assay used, serum alpha-fetoprotein was separated by lectin-affinity electrophoresis with 1 percent agarose gels containing either 0.2 mg of L. culinaris agglutinin A or 0.26 mg of erythroagglutinating phytohemagglutinin per milliliter of solution.
The bands of alpha-fetoprotein thus separated were transferred to nitrocellulose membranes precoated with affinity-purified polyclonal horse antihuman alpha-fetoprotein antibodies20. The membranes were washed with TRIS-buffered saline containing 0.05 percent Tween 20 and treated with F(ab')2 fragments of rabbit antihuman alpha-fetoprotein antibodies for 30 minutes at 37 °C. After washing with Tween 20-TRIS-buffered saline, the membranes were allowed to react with horseradish peroxidase-conjugated goat antirabbit IgG antibodies for 30 minutes at 37 °C. The membranes were again washed, and the alpha-fetoprotein bands were visualized by the tetrazolium method of Taketa22.
The intensities of the bands of alpha-fetoprotein were quantitated by densitometry. From the intensities thus determined, the percent distribution of alpha-fetoprotein was calculated. The results for individual bands were expressed as percentages of the intensity of total alpha-fetoprotein binding to each lectin. With the electrophoretic numbering system proposed by Taketa et al.,23 the major bands of alpha-fetoprotein were numbered consecutively from the anode, and the band numbers suffixed to the capitalized initial letters of the lectins used: for example, alpha-fetoprotein L1, L2, and L3 for L. culinaris agglutinin A, and alpha-fetoprotein P1, P2, P3, P4, and P5 for erythroagglutinating phytohemagglutinin. The bands of alpha-fetoprotein in serum are shown in Figure 1Figure 1
Representative Patterns of Alpha-Fetoprotein Bands Separated by Lectin-Affinity Electrophoresis in the Serum of a Patient with Cirrhosis Who Had Hepatocellular Carcinoma and the Serum of One Who Did Not.. Among patients with alpha-fetoprotein P4+P5, approximately 70 percent had discrete bands for P4 and P5; in the remaining patients, these two bands were incompletely resolved. Although alpha-fetoprotein L2 and alpha-fetoprotein P1 and P3 were not detected in this study, alpha-fetoprotein L2 and alpha-fetoprotein P1 are characteristically present in patients who have alpha-fetoprotein-producing extrahepatic tumors, and alpha-fetoprotein P3 is frequently found in patients who have fulminant hepatitis24. The variabilities of the values for alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 in the same subjects were less than 8 percent25.Statistical Analysis
All the results are expressed as means ±SD. The statistical analyses were performed with Student's t-test and the chi-square test. All P values were two-tailed, and P values of less than 0.05 were considered to indicate statistical significance.
Results
Clinical Features of Hepatocellular Carcinomas Detected by Imaging Techniques
The clinical features of the hepatocellular carcinomas in the 33 patients when first detected by ultrasonography or computed tomography are shown in Table 2Table 2
Clinical Features of Hepatocellular Carcinomas in 33 Patients with Cirrhosis at the Time of Detection of the Tumor.. Twenty-nine patients (88 percent) had unifocal tumors, and the rest had multifocal tumors. The tumors were 3 cm or less in diameter in 21 (72 percent) of the 29 patients with unifocal tumors, as were 7 of the 9 tumors in the 4 patients with multifocal tumors.Comparison of Serum Alpha-Fetoprotein Concentrations in Patients with Cirrhosis with and without Hepatocellular Carcinoma
The serum alpha-fetoprotein concentrations ranged from 30 to 460 ng per milliliter (median, 72) at base line in the 32 patients with cirrhosis who were followed for at least two years but in whom hepatocellular carcinoma did not develop. The values in this group fluctuated during follow-up, and ranged from 5 to 270 ng per milliliter (median, 32) after two years. The serum alpha-fetoprotein concentrations ranged from 30 to 1240 ng per milliliter (median, 75) at base line and from 30 to 7080 ng per milliliter (median, 275) at the time of tumor detection in the 33 patients with cirrhosis in whom hepatocellular carcinoma developed during follow-up. Only 8 (24 percent) of the 33 patients with cirrhosis in whom hepatocellular carcinoma developed had serum alpha-fetoprotein concentrations above 500 ng per milliliter at the time of detection of the tumor.
Proportions of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in Patients with Cirrhosis with and without Hepatocellular Carcinoma
The mean proportion of alpha-fetoprotein L3 in the 33 patients with cirrhosis and hepatocellular carcinoma at the time of tumor detection was significantly higher than the base-line values in the 32 patients with cirrhosis without hepatocellular carcinoma at base line (22 ±19 percent vs. 5 ±5 percent, P<0.001) (Figure 2Figure 2
Proportions of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in the Serum of Patients Who Had Cirrhosis with and without Hepatocellular Carcinoma.). Similarly, the mean proportion of alpha-fetoprotein P4+P5 was significantly higher in the patients with cirrhosis and hepatocellular carcinoma than in the patients with cirrhosis without hepatocellular carcinoma (22 ±14 percent vs. 8 ±5 percent, P<0.001) (Figure 2). The percentage of alpha-fetoprotein L3 did not correlate with the percentage of alpha-fetoprotein P4+P5 in the patients with cirrhosis and hepatocellular carcinoma (P>0.05) (Figure 3Figure 3
Correlation between the Percentages of Alpha-Fetoprotein L3 and Alpha-Fetoprotein P4+P5 in Patients with Cirrhosis and Hepatocellular Carcinoma.).When the cutoff values for alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 were set at 15 percent and 18 percent, respectively, which were the mean base-line percentages plus 2 SD in the 32 patients with cirrhosis who did not have hepatocellular carcinoma, none of the patients in whom hepatocellular carcinoma later developed had elevated values at base line. In contrast, 18 (55 percent) of the 33 patients with cirrhosis and hepatocellular carcinoma had elevated percentages of alpha-fetoprotein L3 and 18 (55 percent) of them had elevated percentages of alpha-fetoprotein P4+P5 at the time of diagnosis of hepatocellular carcinoma. Consequently, 24 (73 percent) of 33 patients with cirrhosis and hepatocellular carcinoma had elevated percentages of one or both of these forms of alpha-fetoprotein at the time of tumor detection. The total follow-up period before the detection of hepatocellular carcinoma in these 24 patients was 32 ±25 months, whereas the total follow-up period in the remaining 9 patients in whom hepatocellular carcinoma developed was 43 ±17 months (P>0.05). The serum alpha-fetoprotein concentrations at the time of detection of hepatocellular carcinoma did not differ between the two groups (P>0.05). Of the 23 patients with cirrhosis who had base-line serum alpha-fetoprotein concentrations of less than 30 ng per milliliter and in whom hepatocellular carcinoma later developed, 12 had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at the time of tumor detection. When the fractions of alpha-fetoprotein were analyzed in serum obtained from these 12 patients at the time of tumor detection, 8 (67 percent) had elevated percentages of alpha-fetoprotein L3, alpha-fetoprotein P4+P5, or both.
Among the 24 patients with cirrhosis who had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line and elevated percentages of alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 when hepatocellular carcinoma was detected, serum samples obtained before the detection of the tumor by imaging techniques were analyzed retrospectively. An elevated percentage of alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 was first detected in eight patients (33 percent) in samples obtained 3 months before the tumor was detected, in six patients (25 percent) in samples obtained 6 months before detection, in seven patients (29 percent) in samples obtained 12 months before detection, and in three patients (12 percent) in samples obtained 18 months before detection.
Discussion
Hepatocellular carcinomas develop during the natural history of cirrhosis, with an annual incidence of 3 to 10 percent4,26. To detect hepatocellular carcinomas at an early stage,4,6 close follow-up of patients with cirrhosis is therefore important in order to provide optimal therapy27. In addition, liver transplantation is a promising treatment for small hepatocellular carcinomas detected on regular clinical monitoring, but not for those that have become symptomatic28. Serum alpha-fetoprotein concentrations are often elevated in patients with hepatocellular carcinomas, but they can also be elevated in patients with benign chronic liver disease29,30. More specific markers are therefore needed to evaluate patients with cirrhosis who have increased serum alpha-fetoprotein concentrations, when tumors cannot be detected by imaging techniques.
We found 33 patients with cirrhosis who had serum alpha-fetoprotein concentrations of 30 ng per milliliter or more at base line and in whom hepatocellular carcinomas developed during follow-up periods averaging 35 months, but 43 patients with cirrhosis in whom hepatocellular carcinomas did not develop during follow-up had similar base-line serum alpha-fetoprotein concentrations. At the time of tumor detection, the serum alpha-fetoprotein concentrations were nearly four times higher than at base line, but in 76 percent of patients the values were similar to those in the patients with cirrhosis who did not have hepatocellular carcinoma. Measurement of the different fractions of alpha-fetoprotein permitted a better distinction between these two groups. When we used cutoff values for alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 based on the results in the patients with cirrhosis in whom hepatocellular carcinoma did not develop and who had elevated ( ≥ 30 ng per milliliter) serum alpha-fetoprotein concentrations at base line, the specificity of alpha-fetoprotein L3 and alpha-fetoprotein P4+P5 for hepatocellular carcinoma was very high, as evidenced by the exclusion of all 32 patients with cirrhosis but no hepatocellular carcinoma. These two markers were expressed independently in the patients with cirrhosis and hepatocellular carcinoma, and their combined use yielded a sensitivity of 73 percent for hepatocellular carcinoma. These results are similar to those described by Taketa et al.,24 although the sensitivity was slightly lower in our study. The difference was probably due to differences in the stage of hepatocellular carcinoma, because the study by Taketa et al. included more patients with advanced hepatocellular carcinomas. Aoyagi et al.31 reported a similar sensitivity, and a specificity of 96 percent, for the proportion of alpha-fetoprotein L3, measured as the fucosylation index of alpha-fetoprotein, in patients with hepatocellular carcinoma.
Among the patients with cirrhosis and hepatocellular carcinoma who had elevated percentages of either alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 at the time of detection of the cancer, we found that the markers were first elevated 3 to 18 months before the tumor was detected by imaging techniques. These results suggest that a patient with cirrhosis who has an elevated percentage of alpha-fetoprotein L3 or alpha-fetoprotein P4+P5 either has hepatocellular carcinoma or will have a clinically detectable lesion in 12 to 18 months, although the absence of an increase in these markers does not exclude the diagnosis of hepatocellular carcinoma.
Source Information
From the First Department of Internal Medicine, Nagasaki University School of Medicine (Y.S., K.N., Y.K., M.S., S.N.), and the Health Research Center, Nagasaki University (N.I., T.K.), both in Nagasaki; the Department of Public Health, Okayama University Medical School, Okayama (K.T.); and Sanraku Hospital, Tokyo (Y.E.) -- all in Japan.
Address reprint requests to Dr. Nagataki at the First Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852, Japan.
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