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DOI: 10.1055/s-2006-951606
Serum Markers of Hepatocellular Carcinoma
- ABSTRACT
- AFP AND AFP-L3
- DES-GAMMA-CARBOXY PROTHROMBIN
- OTHER MARKERS
- SUMMARY AND PERSPECTIVES
- ABBREVIATIONS
- REFERENCES
ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with increasing incidence worldwide. Most of patients with HCC are diagnosed at a late stage. Therefore, the prognosis of HCC patients is generally very poor with a 5-year survival rate of less than 5%. Screening strategies including α-fetoprotein (AFP) and ultrasound every 6 months in patients with liver cirrhosis, the major risk factor for HCC development, have been recommended to detect HCC at earlier stages amenable to effective treatment strategies. AFP, however, is a marker with poor sensitivity and specificity and the ultrasound is highly dependent on the operator's experience. Apart from AFP, lens culinaris agglutinin-reactive AFP and des-gamma carboxyprothrombin and several other biomarkers (e.g., glypican-3, human hepatocyte growth factor, and insulin-like growth factor) have been proposed as markers for HCC detection. In addition, with recently employed techniques, such as gene-expressing microarrays and proteomics, it is to be expected that new HCC-specific markers will become available in the near future. For all such proposed markers, however, the clinical usefulness has to be carefully evaluated and validated.
KEYWORDS
Tumor markers - α-fetoprotein - lens culinaris agglutinin-reactive AFP - des-gamma carboxyprothrombin
Chronic hepatitis leads to liver fibrosis and cirrhosis with a high risk for the development of hepatocellular carcinoma (HCC). Various causes for chronic hepatitis have been identified over the past 40 years. The prevention of and therapy for HCC have been central to clinical research and development in hepatology during the last two decades. Despite significant progress, the HCC incidence is still increasing. Worldwide, HCC is one of the most common malignant tumors. Diagnosed at an early stage, surgical options such as resection or liver transplantation or local ablative therapies (e.g., percutaneous alcohol injection, radiofrequency thermoablation) can be applied with an intent to cure. Therefore, patients at risk for HCC should be enrolled in a surveillance program. The definition of patients at risk for HCC has been recently defined in the AASLD guidelines for HCC.[1] According to these guidelines surveillance for HCC development is based on a 6-month α-fetoprotein (AFP) determination and ultrasound examination. AFP is the most widely used marker for HCC. However, its sensitivity and specificity for HCC is poor[2] and varies with the cutoff value, ethnicity of the patient, etiology of liver disease, treatment, and tumor stage. Therefore, there is the need for better HCC markers. The ideal marker should be specific and discriminate HCC from regenerative nodules independent of the cause and the stage of the liver disease. Furthermore, the marker should be sensitive, allowing detection at an early stage, easily measurable, reproducible, and minimally invasive.[3] [4] Recently, new techniques such as gene expression arrays and proteomics have been employed to screen thousands of genes and proteins. The new biomarkers for HCC, however, should be validated by a five-phase program (Table [1]), according to the Early Detection Research Network (EDRN) of the National Cancer Institute, to evaluate these markers for cancer surveillance strategies.[5]
| Phase | Type of Study | Aims |
| 1 | Preclinical exploratory | Promising markers identified |
| 2 | Clinical assay and validation | Assay detects established disease |
| 3 | Retrospective longitudinal | Biomarker detects preclinical disease |
| 4 | Prospective screening | Confirm ability to detect early stage disease |
| 5 | Cancer control | Impact of screening on reducing tumor burden in at-risk population |
In this review, we will give an overview of the so far best characterized HCC markers and will discuss some new markers that promise to become clinically relevant in the near future.
#AFP AND AFP-L3
AFP is a fetal-specific glycoprotein with a molecular weight around 70 kDa produced primarily by the fetal liver. Its serum concentration rapidly declines after birth. During adulthood its synthesis is repressed. As a tumor marker for HCC in humans it has been used for decades, although its sensitivity and specificity varies from 40 to 65% and 76 to 96%, respectively.[6] [7] [8] [9] [10] [11] [12] With increasing cutoff value its specificity rises but sensitivity falls. A cutoff value of 20 ng/mL is commonly used, based on a retrospective study of patients awaiting liver transplantation.[11] AFP values > 400 ng/mL are considered to be diagnostic for HCC.[12] The differential cutoff values and specificities and sensitivities in the studies performed may be due to the diversity of the baseline parameter of the patients included in these studies. It is well known that patients with chronic viral hepatitis have elevated AFP levels even without detectable HCC. In a recent study in chronic hepatitis C virus (HCV)-infected patients using a cut-ff value of 20 ng/mL, the sensitivities ranged from 41 to 66%, with specificities between 80% and 94%.[13] The positive predictive value of AFP is significantly lower in patients with viral hepatitis than with nonviral hepatitis (70% versus 94%, p < 0.05). Therefore, AFP levels seem to be more useful in detecting HCC in patients without viral hepatitis. For all patients at risk for HCC development, a progressively increasing AFP value has to be taken seriously and additional diagnostic tests are warranted.
Besides the total AFP, three different AFP variants differing in their sugar chains (AFP-L1, AFP-L2, AFP-L3) have been described. The variant AFP-L3 has a high binding affinity to the lectin lens culinaris agglutinin and seems to be more specific for HCC than total AFP.[14] [15] AFP-L3 is found in approximately one third of patients with HCC when cutoff values of 10 to 15% are used. Its sensitivities and specificities range from 36 to 96% and 89 to 94%,[16] [17] [18] [19] [20] [21] [22] [23] respectively. However, studies that directly compare the diagnostic accuracy of total AFP versus AFP-L3 in differentiating patients with liver cirrhosis and regenerative nodules from patients with HCC have not been done. Interestingly, most studies correlating the prognosis of patients with HCC and AFP-L3 demonstrated that this marker is associated with reduced liver function, poorer differentiation, and biologically malignant characteristics.[17] [21] Therefore, AFP-L3 seems to be a more reliable and better HCC marker than total AFP and an excellent prognostic parameter in patients with HCC.
#DES-GAMMA-CARBOXY PROTHROMBIN
Liebman et al first described des-gamma-carboxy prothrombin (DCP) as a serum marker in patients with HCC.[24] DCP is an abnormal prothrombin that is produced by the tumor cells, which have reduced gamma-carboxylase activity resulting in a reduced carboxylation of 10 glutamic-acid residues at the N-terminus.[25] [26] It is also known as protein induced by vitamin K absence or antagonist II. DCP levels are usually measured by enzyme immunoassays. A DCP level of 40 mAU/mL is now commonly used as cutoff value. Using this level, DCP sensitivities and specificities range from 28 to 89% and 87 to 96%,[27] [28] [29] [30] [31] [32] [33] [34] [35] [36] respectively. DCP is found to be elevated in ~50 to 60% of patients with HCC. As a marker for HCC, DCP seems to be similar to AFP. However, there are some differences that should be noted. There is no correlation between AFP and DCP. DCP, in contrast to AFP, is more specific for HCC because the liver disease per se (e.g., chronic hepatitis C) can lead to an elevation of AFP but not of DCP. Furthermore, DCP correlates with the HCC stage as well as survival. DCP-positive tumors have a higher rate of intrahepatic metastasis, portal vein invasion, and liver capsule infiltration. The simultaneous detection of serum and tissue DCP is a valuable predictor of the prognosis of HCC patients.[37] [38]
Because AFP (and AFP-L3) and DCP levels do not correlate in patients with HCC, it would be reasonable to determine both markers to improve the accuracy of HCC diagnosis. Indeed, a few studies demonstrated increased specificity and sensitivity by combining both markers.[35] [39] [40] However, a general recommendation to combine markers in HCC surveillance needs further evaluation and general availability of AFP-L3 and DCP assays.
In general, the determination of AFP, AFP-L3, and DCP levels are excellent to monitor tumor progression as well as the efficacy of treatment in marker-positive HCC patients.
#OTHER MARKERS
#Glypican-3
Glypican-3 (GPC3) is a member of the glypican family of glycosyl-phosphatidylinositol-anchored cell-surface heparan-sulfate proteoglycans, and GPC messenger RNA (mRNA) levels are increased in a large proportion of HCC.[41] [42] GPC3 is able to interact with various growth factors and can modulate their activities. The level of GPC3 in the serum has been shown to be significantly higher in patients with HCC as compared with healthy volunteers or patients with nonmalignant liver diseases.[43] [44] [45] GPC3 is detectable in 40 to 53% of patients with HCC and in approximately one third of patients with HCC with normal AFP levels.[45] [46] [47] Therefore, it seems logical that the combination with other markers (AFP, DCP) improves sensitivity from 50 to 72%.[47] In addition, in one report the soluble form of GPC3 seems to be more sensitive than AFP in detecting well-differentiated and moderately differentiated HCC.[47]
#Golgi Protein 73
Golgi protein-73 (GP73) is a resident Golgi protein that has been found to be up-regulated in virus-infected hepatocytes.[48] GP73 is detectable in the serum by immunoblot and can be quantified by densitometric analysis. In one study of 352 patients, serum GP73 levels were significantly higher in patients with HCC compared with those with cirrhosis. GP73 had a sensitivity of 69% and a specificity of 75% at a cutoff value of 10 relative units. For the diagnosis of early HCC, this marker had a significantly higher sensitivity (62%) than AFP (25%). Moreover, serum GP73 levels were elevated in 57% of patients with HCC who had normal AFP levels.[49]
#Hepatocyte Growth Factor
Hepatocyte growth factor (HGF) is produced in various organs of the body and is a multifunctional factor with various biologic activities.[50] Several studies examined the relationship between HGF and liver diseases including the prognosis of fulminant hepatitis and the development of chronic hepatitis and HCC.[51] [52] [53] [54] The serum concentration of HGF can be determined by enzyme-linked immunosorbent assays. In a study of 99 patients with HCV-related liver disease with and without HCC, serum concentrations of HGF were significantly higher in patients with HCC than in patients with chronic hepatitis or cirrhosis without HCC. Interestingly, all patients with a serum HGF concentration > 0.6 ng/mL had an HCC, irrespective of the AFP or DCP level.[55]
#Insulin Growth Factor 1
Experimental and epidemiologic evidence indicates that insulin growth factor (IGF) plays an important endocrine and paracrine role in carcinogenesis. IGF-1 is a potent mitogenic factor, and many cells require it to progress from G1-phase to S-phase of the cell cycle.[56] [57] Moreover, IGF-1 also has antiapoptotic effects in many cell systems.[58] Mazziotti et al prospectively screened 114 patients with HCV-related cirrhosis for 56.4 ± 12.0 months by ultrasound of the liver and AFP determination every 6 months.[59] Serum IGF-1 levels were measured at study entry and at least every 12 months throughout follow-up. Twenty-one patients (19.2%) developed HCC during follow-up. Of note, a significant decrease in IGF-1 levels occurred in patients with HCC, indicating a 70% sensitivity of IGF-1. In addition, the reduction of the IGF-1 level preceded the diagnosis of HCC by 9.3 ± 3.1 months, allowing identification of HCC development.
#Vascular Endothelial Growth Factor
Angiogenesis plays an important role in the progression of HCC.[60] Vascular endothelial growth factor (VEGF) is the most potent known stimulator of angiogenesis. Its expression has been shown to correlate with tumor progression and prognosis in many cancers. The serum VEGF level may be a surrogate marker of tumor VEGF expression and has been shown to have prognostic significance in patients with different cancers. In a recent study, serum VEGF levels were measured by enzyme immunoassay in 108 patients with HCC before surgical resection and in 20 healthy controls.[61] Serum VEGF levels in patients with HCC were significantly higher than those in controls and correlated with venous invasion and advanced tumor stage. Patients with a serum VEGF level > 245 pg/mL had significantly poorer overall and disease-free survival than those with lower levels.
#Transforming Growth Factor-β1
Transforming growth factor-β1 (TGFβ1) is a multifunctional cytokine involved in the regulation of growth and differentiation of both normal and transformed cells. TGFβ1 mRNA and its protein are overexpressed in HCC. TGFβ1 serum levels in patients with HCC are elevated compared with healthy individuals and patients with nonmalignant liver diseases.[62] [63] A cutoff value of 800 pg/mL has been proposed as its specificity and sensitivity have been reported to be > 95% and 68%, respectively, thus being superior to AFP.[63] Furthermore, in 25% of AFP-negative patients with HCC, TGFβ1 was elevated.[62]
#Alpha-L-Fucosidase
Serum activity of alpha-L-fucosidase (ALF), a lysosomal enzyme present in all mammalian cells was found elevated in patients with HCC compared with healthy individuals and patients with cirrhosis without HCC.[64] [65] Its sensitivity and specificity at a cutoff value of 870 nmol/mL an hour are 82% and 71%, respectively. Interestingly, in 85% of patients who eventually developed HCC, the increase in serum ALF > 700 nmol/mL an hour preceded visualization by ultrasound by at least 6 months.[65]
#SUMMARY AND PERSPECTIVES
Serum AFP is presently the most widely and best studied screening test for HCC detection. It has, however, major limitations, because > 20% of patients with HCC do not have elevated AFP levels and AFP levels do not discriminate well between benign liver diseases and HCC. Apart from AFP, serum AFP-L3 and DCP are useful HCC markers. They seem to better differentiate HCC from benign liver diseases and to better predict the prognosis of patients with HCC. However, the studies are difficult to compare, in part due to different assay methods, cutoff values, and study populations. Other markers such as VEGF, IGF-1, and HGF are promising, but most studies published so far are underpowered and need to be confirmed.
Therefore, for the HCC markers identified to date and for potential new biomarkers, evaluation in well-designed studies to determine their diagnostic specificities and sensitivities for the detection of small HCC and preclinical disease according to the structured approach to validate biomarkers in cancer surveillance by the EDRN is of utmost importance.[5]
#ABBREVIATIONS
-
AASLD American Association for the Study of Liver Diseases
-
AFP α-fetoprotein
-
ALF alpha-L-fucosidase
-
DCP des-gamma-carboxy prothrombin
-
EDRN Early Detection Research Network
-
GP73 golgi protein-73
-
GPC3 glypican-3
-
HCC hepatocellular carcinoma
-
HCV hepatitis C virus
-
HGF hepatocyte growth factor
-
IGF insulin growth factor
-
mRNA messenger RNA
-
TGFβ1 transforming growth factor-β1
-
VEGF vascular endothelial growth factor
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P.D. Dr. H.C. Spangenberg
Department of Medicine II, University Hospital
Hugstetter Strasse 55, D-79106 Freiburg, Germany
REFERENCES
- 1 Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005; 42 1208-1236
- 2 Bruix J, Sherman M, Llovet J M et al.. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001; 35 421-430
- 3 Srinivas P R, Kramer B S, Srivastava S. Trends in biomarker research for cancer detection. Lancet Oncol. 2001; 2 698-704
- 4 Srivastava S, Gopal-Srivastava R. Biomarkers in cancer screening: a public health perspective. J Nutr. 2002; 132 2471S-2475S
- 5 Pepe M S, Etzioni R, Feng Z et al.. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001; 93 1054-1061
- 6 Collier J, Sherman M. Screening for hepatocellular carcinoma. Hepatology. 1998; 27 273-278
- 7 Sherman M, Peltekian K M, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology. 1995; 22 432-438
- 8 Trevisani F, D'Intino P E, Morselli-Labate A M et al.. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol. 2001; 34 570-575
- 9 Peng Y C, Chan C S, Chen G H. The effectiveness of serum alpha-fetoprotein level in anti-HCV positive patients for screening hepatocellular carcinoma. Hepatogastroenterology. 1999; 46 3208-3211
- 10 Cedrone A, Covino M, Caturelli E et al.. Utility of alpha-fetoprotein (AFP) in the screening of patients with virus-related chronic liver disease: does different viral etiology influence AFP levels in HCC? A study in 350 western patients. Hepatogastroenterology. 2000; 47 1654-1658
- 11 Gambarin-Gelwan M, Wolf D C, Shapiro R et al.. Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation. Am J Gastroenterol. 2000; 95 1535-1538
- 12 Nguyen M H, Garcia R T, Simpson P W et al.. Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis. Hepatology. 2002; 36 410-417
- 13 Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C: a systematic review and critical analysis. Ann Intern Med. 2003; 139 46-50
- 14 Taketa K, Sekiya C, Namiki M et al.. Lectin-reactive profiles of alpha-fetoprotein characterizing hepatocellular carcinoma and related conditions. Gastroenterology. 1990; 99 508-518
- 15 Johnson P J, Poon T C, Hjelm N M et al.. Structures of disease-specific serum alpha-fetoprotein isoforms. Br J Cancer. 2000; 83 1330-1337
- 16 Taketa K, Okada S, Win N et al.. Evaluation of tumor markers for the detection of hepatocellular carcinoma in Yangon General Hospital, Myanmar. Acta Med Okayama. 2002; 56 317-320
- 17 Khien V V, Mao H V, Chinh T T et al.. Clinical evaluation of lentil lectin-reactive alpha-fetoprotein-L3 in histology-proven hepatocellular carcinoma. Int J Biol Markers. 2001; 16 105-111
- 18 Yoshida S, Kurokohchi K, Arima K et al.. Clinical significance of lens culinaris agglutinin-reactive fraction of serum alpha-fetoprotein in patients with hepatocellular carcinoma. Int J Oncol. 2002; 20 305-309
- 19 Wang S S, Lu R H, Lee F Y et al.. Utility of lentil lectin affinity of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. J Hepatol. 1996; 25 166-171
- 20 Taketa K, Endo Y, Sekiya C et al.. A collaborative study for the evaluation of lectin-reactive alpha-fetoproteins in early detection of hepatocellular carcinoma. Cancer Res. 1993; 53 5419-5423
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P.D. Dr. H.C. Spangenberg
Department of Medicine II, University Hospital
Hugstetter Strasse 55, D-79106 Freiburg, Germany