Hepatocellular Carcinoma - Alpha-Fetoprotein

8/11/03 (Grant)

Question: What level of serum alpha-fetoprotein definitely indicates hepatocellular carcinoma?

<1>

Unique Identifier:12834318

Authors: Gupta S. Bent S. Kohlwes J.

Institution: University of California, San Francisco, USA.

Title: Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. A systematic review and critical analysis. [Review] [46 refs]

Source: Annals of Internal Medicine. 139(1):46-50, 2003 Jul 1.

Abstract: BACKGROUND: Patients with hepatitis C virus (HCV) are at increased risk for hepatocellular carcinoma. Although serum alpha-fetoprotein (AFP) is often used to detect hepatocellular carcinoma in HCV-infected individuals, its utility is unclear. PURPOSE: To define the test characteristics of AFP for the diagnosis of hepatocellular carcinoma in patients with HCV. DATA SOURCES: MEDLINE search from 1966 to December 2002 for English- and non-English-language articles examining the test characteristics of AFP for identifying hepatocellular carcinoma. STUDY SELECTION: Articles were included if they reported the sensitivity and specificity of AFP for detecting hepatocellular carcinoma in patients with HCV. Articles were excluded if the cause of hepatitis was ambiguous or if 50% or more of the study patients did not have HCV. DATA EXTRACTION: Relevant articles were evaluated for quality of evidence; test characteristics were abstracted and calculated. DATA SYNTHESIS: Five studies met all inclusion criteria and were analyzed. The overall quality of evidence was limited; only one study universally applied an acceptable gold standard test, and three of five studies used a case-control design that potentially overestimates diagnostic accuracy. By using the most commonly reported cutoff value of a positive test result for hepatocellular carcinoma (AFP level > 20 microg/L), the ranges of test characteristics were as follows: sensitivity, 41% to 65%; specificity, 80% to 94%; positive likelihood ratios, 3.1 to 6.8; and negative likelihood ratios, 0.4 to 0.6. CONCLUSIONS: The paucity of high-quality data calls for more rigorous study of AFP and other diagnostic tests for detecting hepatocellular carcinoma in HCV-infected patients with an accepted gold standard applied to the entire cohort. Even if the "best-case" estimates of AFP sensitivity and specificity are accurate, AFP has limited utility for detecting hepatocellular carcinoma. [References: 46] CAS Registry/EC Number 0 (Tumor Markers, Biological). 0 (alpha-Fetoproteins).

<2>

Unique Identifier:12820452

Authors: Soresi M. Magliarisi C. Campagna P. Leto G. Bonfissuto G. Riili A. Carroccio A. Sesti R. Tripi S. Montalto G.

Institution: Cattedra di Medicina Interna, Cattedra di Metodologia Clinica, Dpt di Medicina Clinica e delle Patologie Emergenti, Universita di Palermo, Italy.

Title: Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma.

Source: Anticancer Research. 23(2C):1747-53, 2003 Mar-Apr.

Abstract: With the widespread use of ultrasonography (US) and computerized tomography (CT), the usefulness of alpha-fetoprotein assay in the diagnosis of hepatocellular carcinoma (HCC) has decreased. The aim of our study was to evaluate the best cut-off value for serum alpha-fetoprotein to discriminate between liver cirrhosis (LC) and HCC and the factors influencing levels in a Sicilian population. Three hundred and seventy-two patients with LC and 197 with HCC-associated LC were studied. The etiology was: HCV in 288 cases (77.4%) of LC and 147 cases (75%) of HCC; HBV in 31 cases (8.3%) of LC and 15 cases (7.6%) of HCC; HCV/HBV in 21 cases (5.6%) of LC and 6 cases (3.0%) of HCC; non-viral in 32 cases (8.6%) of LC and 29 cases (15%) of HCC. Hepatic function was estimated by the Child-Pugh's score; the TNM classification was used in HCC. The area under the ROC curve was 0.81 +/- 0.02; the best discriminant cut-off value, calculated as the value of the maximized likelihood ratio, was 30 ng/ml. At this level sensitivity (SE) was 65%, specificity (SP) 89%, positive predictive value (PPV) 74% and negative predictive value (NPV) 79%. When the patients were divided at this cut-off point into two groups according to viral or non-viral etiology, PPV was 70% versus 94%, respectively (p < 0.05). In the non-viral diseases PPV reached 100% for AFP serum levels of 100 ng/ml, while in the viral diseases PPV was 100% when AFP was greater than 400 ng/ml. There were no significant differences in SE, SP or NPV between viral and non-viral liver diseases. Child's classes B and C were more frequent in HCC (chi 2 of MH 7.7, p < 0.0001). There was a correlation between AFP serum values and TNM classification (p < 0.02) and on multiple logistic regression AFP levels > 30 ng/ml correlated positively only with the TNM stage (p < 0.0001). In conclusion, the best cut-off value for serum AFP in our study population was 30 ng/ml, but at this level sensitivity was low. This cut-off value was more useful in detecting non-viral HCC, because PPV was significantly higher than in viral HCC; therefore, our data confirm that the usefulness of AFP in the diagnosis of HCC of viral etiology is limited, being more useful in HCC of non-viral etiology. CAS Registry/EC Number 0 (alpha-Fetoproteins).

<3>

Unique Identifier:12394211

Authors: Nguyen MH. Keeffe EB.

Institution: Division of Gastroenterology and hepatology, Department ofMedicine, Santford, California 94304-1509, USA. mindiehn@hotmail.com

Title: Screening for hepatocellular carcinoma. [Review] [89 refs]

Source: Journal of Clinical Gastroenterology. 35(5 Suppl 2):S86-91, 2002 Nov-Dec.

Abstract: Hepatocellular carcinoma (HCC) is common throughout the world and most often develops as a late complication of chronic viral hepatitis or cirrhosis of any cause. As a result of the high prevalence rate of chronic hepatitis C, the incidence of HCC is rising in the United States, as well as in European and Asian countries. The overall survival rate of HCC is poor, and surgical resection and liver transplantation are the only curative treatment options. Screening for HCC offers the best hope for early detection, eligibility for treatment, and improved survival. Most physicians routinely screen at-risk patients with chronic viral hepatitis and cirrhosis for HCC, despite the lack of official guidelines. The current consensus recommendations are to screen healthy hepatitis B virus carriers with annual or semiannual serum alpha-fetoprotein; carriers with chronic hepatitis or cirrhosis and patients with cirrhosis of any etiology are surveyed with twice yearly serum alpha-fetoprotein and liver ultrasound. This article will review the current recommendations for HCC screening, the rationale that led to these recommendations, and the challenges of cost-effectiveness research in this area. [References: 89] CAS Registry/EC Number 0 (Tumor Markers, Biological). 0 (alpha-Fetoproteins).

<4>

Unique Identifier:12143050

Authors: Nguyen MH. Garcia RT. Simpson PW. Wright TL. Keeffe EB.

Institution: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94304-1509, USA.

Title: Racial differences in effectiveness of alpha-fetoprotein for diagnosis of hepatocellular carcinoma in hepatitis C virus cirrhosis.

Source: Hepatology. 36(2):410-7, 2002 Aug.

Abstract: alpha-Fetoprotein (AFP) is frequently used as a diagnostic marker for hepatocellular carcinoma (HCC). Most available data concerning AFP come from studies of patients with chronic hepatitis B or other chronic liver diseases of mixed etiologies. Limited data concerning the diagnostic value of AFP for hepatitis C virus (HCV)-related HCC have to date come only from Asian and European studies, and results are conflicting. There may be significant differences in AFP levels depending on racial backgrounds and etiologies of primary liver disease. We conducted a multicenter, retrospective, case-control study of 163 HCC patients with HCV infection and 149 control patients with HCV-related cirrhosis. The positive likelihood ratios for AFP at 0 to 20, 21 to 50, 51 to 100, and 101 to 200 ng/mL were 0.46, 1.31, 1.15, and 6.90, respectively. No controls had AFP greater than 200 ng/mL. The sensitivity of AFP for the diagnosis of HCC in African Americans with HCV infection was lower than that of patients of all other ethnic groups combined (57.1% vs. 81.6% for AFP > 10 ng/mL, P =.02, and 42.9% vs. 66.0% for AFP > 20 ng/mL, P =.05). The area under the receiver operating characteristics curve was 0.81 for non-African Americans but only 0.56 for African Americans. In conclusion, AFP greater than 200 ng/mL can be used to confirm HCC in patients with HCV-related cirrhosis and a hepatic mass. However, AFP is insensitive for the diagnosis of HCC in African Americans. CAS Registry/EC Number 0 (Tumor Markers, Biological). 0 (alpha-Fetoproteins).

<5>

Unique Identifier:11508671

Authors: Kashyap R. Jain A. Nalesnik M. Carr B. Barnes J. Vargas HE. Rakela J. Fung J.

Institution: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pennsylvania, USA.

Title: Clinical significance of elevated alpha-fetoprotein in adults and children.

Source: Digestive Diseases & Sciences. 46(8):1709-13, 2001 Aug.

Abstract: The aim of the current study is to identify underlying pathology associated with elevated serum alpha-fetoprotein (AFP; >20 ng/ml) among patients referred to a tertiary-care academic medical center with emphasis in liver diseases, hepatobiliary surgery, and liver transplantation. From May 1992 to April 1997, 386 patients (320 adults and 66 children) with elevated AFP (>20 ng/ml) were identified from the Medical Archival System (MARS) database at the University of Pittsburgh Medical Center. The medical records from all these patients were retrospectively reviewed. Radiological, pathological, and biochemical profiles were obtained at the time of documented elevated AFP. These patients included: 218 adults with malignancies, 102 adults without malignancies, 18 children and infants with malignancies, and 48 children and infants without malignancies. Thirty-two percent of adults were found to have raised AFP with liver disease and without hepatocellular carcinoma and 78% had some type of malignancy, predominantly hepatocellular carcinoma. Seventy-three percent of infants and children had elevated AFP without malignancy. Based on our findings, we recommend that all patients (adults, infants and children) with raised AFP of >20 ng/ml should undergo thorough evaluation to rule out malignant disease. CAS Registry/EC Number 0 (alpha-Fetoproteins).

<6>

Unique Identifier:11394657

Authors: Trevisani F. D'Intino PE. Morselli-Labate AM. Mazzella G. Accogli E. Caraceni P. Domenicali M. De Notariis S. Roda E. Bernardi M.

Institution: Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, University of Bologna, Italy. trevi@unibo.it

Title: Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status.[comment].

Source: Journal of Hepatology. 34(4):570-5, 2001 Apr.

Abstract: BACKGROUND: It is not established whether virological status affects the efficiency of alpha-fetoprotein (AFP) as a hepatocellular carcinoma (HCC) marker among patients with chronic liver disease (CLD). METHODS: We enrolled in a case-control study 170 HCC and 170 CLD patients, matched for age, sex, CLD and HBsAg/anti-HCV status. The AFP sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. PPV and NPV were evaluated for three additional HCC prevalences (5, 10, and 20%). RESULTS: The best discriminating AFP value was 16 ng/ml. A value of 20 ng/ml (above which investigations for HCC are recommended) had equivalent sensitivity (60.0 vs. 62.4%) and specificity (90.6 vs. 89.4%). PPV of 20 ng/ml was 84.6% but decreased to 25.1% at 5% tumor prevalence. NPV was 69.4% and rose to 97.7% at 5% prevalence. In the different groups of infected patients PPV ranged from 80.0 to 90.9%, falling to 17.4-34.5% at 5% prevalence. In noninfected patients PPV was 100% at any HCC prevalence. NPV ranged from 59.0 to 73.0%, reaching 96.5-98.1% at 5% prevalence. CONCLUSIONS: In CLD patients, AFP monitoring misses many HCCs and inappropriately arouses suspicion of malignancy in many patients. Its usefulness is barely affected by the infection responsible for CLD. An AFP elevation could be more indicative of HCC in non-infected patients. CAS Registry/EC Number 0 (Hepatitis B Surface Antigens). 0 (Hepatitis C Antibodies). 0 (alpha-Fetoproteins).

<7>

Unique Identifier:11246354

Authors: Chu CW. Hwang SJ. Luo JC. Lai CR. Tsay SH. Li CP. Wu JC. Chang FY. Lee SD.

Institution: Department of Medicine, Veterans General Hospital-Taipei and National Yang-Ming University School of Medicine, Taiwan, Republic of China.

Title: Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C.

Source: Journal of Clinical Gastroenterology. 32(3):240-4, 2001 Mar.

Abstract: Elevated serum alpha-fetoprotein (AFP) in patients with chronic hepatitis C is not uncommonly seen, but the pathogenesis of this phenomenon remains unclear. The aims of this study were to assess the prevalence of elevated serum AFP in patients with chronic hepatitis C and to evaluate the clinical, virologic, and histopathologic significance of this phenomenon. One hundred and fifteen Chinese patients with a histologic diagnosis of chronic hepatitis C were enrolled. None had evidence of hepatocellular carcinoma by image study at enrollment and for at least 2 years' follow-up. Of the 115 patients, 33 (29%) had elevated serum AFP (more than 12 ng/mL). There was a significantly lower mean serum albumin (4.0 +/- 0.1 vs. 4.3 +/- 0.1 gm/dL, p <0.001) and higher mean scores for periportal necroinflammation (3.3 +/- 0.3 vs. 2.3 +/- 0.2, p = 0.007) and fibrosis (2.3 +/- 0.2 vs. 1.1 +/- 0.1, p < 0.001) in patients with elevated serum AFP when compared with patients without elevated serum AFP. Patients with elevated serum AFP had significantly more incidences of genotype 1b infection when compared with patients without elevated serum AFP (77% vs. 51%, p = 0.021). Mean serum hepatitis C virus (HCV) RNA titer showed no significant difference between the two groups. Multivariate logistic regression analysis showed that as serum albumin of less than 4.2 gm/dL, a histology fibrotic score of more than 3, and HCV genotype 1b infection were significantly independent predictors associated with elevated serum AFP. In conclusion, elevated serum AFP levels were significantly correlated with lower serum albumin levels, advanced fibrosis/cirrhosis, and genotype 1b infection in patients with chronic hepatitis C. CAS Registry/EC Number 0 (alpha-Fetoproteins).

<8>

Unique Identifier:11218912

Authors: Johnson PJ.

Institution: Department of Clinical Oncology, Chinese University of Hong Kong Prince of Wales Hospital, Shatin, Hong Kong SAR, China.

Title: The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. [Review] [63 refs]

Source: Clinics in Liver Disease. 5(1):145-59, 2001 Feb.

Abstract: Forty years after its discovery, estimation of serum AFP remains a useful test for clinicians involved in management of patients with HCC or chronic liver disease. The test, when used with the conventional cut-off point of 500 ng/mL, has a sensitivity of about 50% and a specificity of more than 90% in detecting the presence of HCC in a patient with coexisting liver disease. New tests that can significantly increase the specificity at lower levels (i.e., between 10 and 500 ng/mL) are available but have, to date, been too complex to be widely applied in clinical practice. Serum AFP estimation may also be useful in monitoring response to therapy, particularly as more effective systemic regimens are becoming available. Indeed, there is preliminary evidence that changes in serum AFP may be a more accurate and sensitive way of determining the degree of response to treatment than conventional imaging procedures that rely on physical determination of tumor size. It may, perhaps, be time to add changes in serum AFP to the conventional imaging criteria for assessing response in clinical trials. [References: 63] CAS Registry/EC Number 0 (Protein Isoforms). 0 (alpha-Fetoproteins).

<9>

Unique Identifier:11149026

Authors: Cedrone A. Covino M. Caturelli E. Pompili M. Lorenzelli G. Villani MR. Valle D. Sperandeo M. Rapaccini GL. Gasbarrini G.

Institution: Cattedra ed Istituto di Medicina Interna, Universita Cattolica del Sacro Cuore, Roma, Italy.

Title: 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.

Source: Hepato-Gastroenterology. 47(36):1654-8, 2000 Nov-Dec.

Abstract: BACKGROUND/AIMS: Dosage of serum AFP (alpha-fetoprotein) is widely used for HCC screening in patients with chronic liver disease. Virus-related chronic liver disease is the main cause of cirrhosis and HCC in Western and Far Eastern countries, but the relationship between viral etiology and AFP levels in HCC is still unclear. The aim of this study was to verify, in Western patients with post-viral chronic liver disease, the usefulness of AFP dosage for the detection of HCC, and the influence of viral etiology on AFP levels in HCC. METHODOLOGY: The study population included 350 patients with post viral chronic liver disease that underwent liver biopsy, serum AFP determination and ultrasound liver evaluation. Seven patients had normal liver histology, 197 had chronic hepatitis, 72 had cirrhosis, and 74 had cirrhosis and HCC. ROC (receiver operating characteristic) analysis was used to assess the best diagnostic AFP threshold value for HCC detection. Logistic regression analysis was performed to individuate independent predictors of HCC diagnosis. RESULTS: No difference was observed in AFP levels between HCV- and HBV-positive patients, neither in the whole population nor in the HCC patients only. ROC area under curve for AFP was 0.801 (95% CI: 0.721-0.867). The analysis individuated a best accurate AFP threshold value for HCC diagnosis of 50 ng/mL. HCC was detected with specificity > or = 95% only for AFP > 100 ng/mL. The sensitivity however was poor (25%). Male sex, age > 60, and AFP were independent predictors of HCC diagnosis. CONCLUSIONS: Serum AFP levels in HCC patients are not influenced by virus B or C hepatitis pattern. AFP dosage should not be used for HCC diagnosis in non-cirrhotic patients. Male patients with cirrhosis should be regarded with a more "aggressive" screening program compared to females. CAS Registry/EC Number 0 (Biological Markers). 0 (alpha-Fetoproteins).

<10>

Unique Identifier:11129271

Authors: Tangkijvanich P. Anukulkarnkusol N. Suwangool P. Lertmaharit S. Hanvivatvong O. Kullavanijaya P. Poovorawan Y.

Institution: Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Title: Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels.

Source: Journal of Clinical Gastroenterology. 31(4):302-8, 2000 Dec.

Abstract: The purpose of this study was to determine whether a relation does exist between clinicopathologic features and the prognosis of hepatocellular carcinoma (HCC) with respect to serum alpha-fetoprotein (AFP) levels at diagnosis. We reviewed the clinical data of 309 pathologically proven HCC cases divided into three groups: group 1 with normal AFP (<20 IU/mL), group 2 with moderately elevated AFP (20-399 IU/mL) and group 3 with markedly elevated AFP (> or =400 IU/mL). Of these, there were 76 (24.6%), 78 (25.2%), and 155 patients (50.2%) in groups 1, 2, and 3, respectively. We found that HCC patients with high AFP tended to have greater tumor size, bilobar involvement, massive or diffuse types, and portal vein thrombosis. Nonetheless, we could not establish a correlation between increased AFP and Okuda's stages, degree of tumor differentiation, or extrahepatic metastasis. The median survival rates in groups 1 (6 months) and 2 (7 months) were significantly longer than that of group 3 (3 months). On multivariate logistic regression analysis, positive hepatitis B surface antigen (HBsAg) status and bilobar tumor involvement represented the independent factors for predicting high AFP values. We concluded that AFP is useful not only for diagnosis, but also as a prognostic indicator in patients with HCC . However, it cannot be considered a sensitive tumor marker, particularly during the early stages in HBsAg-negative patients. CAS Registry/EC Number 0 (alpha-Fetoproteins).

<11>

Unique Identifier:10520864

Authors: Hayashi K. Kumada T. Nakano S. Takeda I. Sugiyama K. Kiriyama S. Sone Y. Miyata A. Shimizu H. Satomura S.

Institution: Department of Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan.

Title: Usefulness of measurement of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein as a marker of prognosis and recurrence of small hepatocellular carcinoma.

Source: American Journal of Gastroenterology. 94(10):3028-33, 1999 Oct.

Abstract: OBJECTIVE: Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3%) is a recently described marker of hepatocellular carcinoma (HCC), and its usefulness has been demonstrated in many studies. We evaluated the usefulness of serial measurement of AFP-L3% as a marker of prognosis and recurrence after treatment of small HCC. METHODS: AFP-L3% was measured before and after initial treatment in 60 patients with small HCC (maximum diameter < or = 2 cm). AFP-L3% was taken as the ratio of AFP-L3 to total AFP and multiplied by 100%, and levels > or = 10% were considered positive. Outcomes and recurrence were compared between patients AFP-L3%-negative after initial treatment (Group A, n = 43) and patients who were AFP-L3%-positive after initial treatment (Group B, n = 17). RESULTS: Before treatment, AFP-L3% was positive in 14 (23.3%) of the 60 patients. The cumulative survival rate of Group A was significantly longer (p = 0.0091) than that of Group B. The recurrence rate was significantly higher in Group B (p = 0.0104) than in Group A. When recurrence was limited to intrahepatic metastasis, the recurrence rate was significantly higher in Group B (p = 0.0064). However, the recurrence rate of multicentric occurrence did not differ significantly between Groups A and B. CONCLUSIONS: Measurement of AFP-L3% after treatment may be useful for understanding prognosis and recurrence of HCC. CAS Registry/EC Number 0 (Lectins). 0 (alpha-Fetoproteins). 0 (lentil lectin).

<12>

Unique Identifier:10382636

Authors: Johnson PJ.

Institution: Department of Clinical Oncology, Chinese University of Hong Kong, Shatin.

Title: Role of alpha-fetoprotein in the diagnosis and management of hepatocellular carcinoma. [Review] [33 refs]

Source: Journal of Gastroenterology & Hepatology. 14 Suppl:S32-6, 1999 May.

Abstract: Thirty-five years after its first description, alpha-fetoprotein (AFP) remains the gold standard by which other markers are judged. Serum levels above the reference range of 10 ng/mL occur in approximately 75% of cases of hepatocellular carcinoma (HCC). In individual patients, the serum AFP level behaves as if it reflects tumour mass. However, the specificity of AFP is relatively low because moderately raised levels are also found in some patients with uncomplicated chronic liver disease. Recently, tumour-specific AFP assays have been developed. These are based on the carbohydrate side-chains on the AFP molecule which exhibit characteristic differences in AFP of different origins. Monitoring response to treatment may often be more effectively carried out by serial estimation of AFP than by conventional imaging techniques. The relative specificity of AFP for HCC has also been employed to detect circulating HCC cells and to target gene therapy. [References: 33] CAS Registry/EC Number 0 (alpha-Fetoproteins).

 1.7672.1.63