Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis

OBJECTIVES: Screening for hepatocellular carcinoma (HCC) is advocated in cirrhotic patients to optimize early detection and treatment. However, the cost-effectiveness is not well defined. Our objective was to perform a cost-utility analysis from a third-party payer's perspective of no screening, alpha-fetoprotein (AFP) concentration measurement alone, abdominal ultrasound (US) and AFP, abdominal three-phase CT and AFP, and abdominal magnetic resonance imaging (MRI) and AFP. METHODS: A Markov model was constructed simulating the natural history of hepatitis C-related cirrhosis in a cohort of patients age 50 yr over a time horizon of their remaining life expectancy. Transition probabilities were obtained from published data and U.S. vital statistics. Costs represented Medicare reimbursement data. Costs and health effects were discounted at a 3% annual rate. RESULTS: Screening with ultrasonography and AFP concentration measurement was associated with an incremental cost-utility ratio of 26,689 US dollars per quality-adjusted life year, whereas screening with abdominal three-phase CT and AFP concentration measurement was associated with an incremental cost-utility ratio of 25,232 US dollars per quality-adjusted life year compared with no screening. Compared with three-phase CT and AFP, magnetic resonance and AFP imaging costs 118,000 US dollars per quality-adjusted life year. Sensitivity analysis demonstrated that the results are most sensitive to the annual incidence of HCC, proportion of tumors amenable to treatment, and to transplant candidacy, whereas the choice of screening strategy is most sensitive to the test characteristics and cost. CONCLUSIONS: Screening for HCC with CT is a cost-effective strategy in transplant-eligible patients with cirrhosis secondary to chronic hepatitis C viral (HCV) infection, comparable with other commonly accepted screening interventions such as mammography and colonoscopy.     

Prospective screening increases the detection of potentially curable hepatocellular carcinoma: results in 8900 high-risk patients

Objectives

Historically, only 10% of patients with hepatocellular carcinoma (HCC) are diagnosed with early-stage, potentially curable disease. In this study, chronic hepatitis virus-infected patients were prospectively screened to determine: (i) the proportion of patients diagnosed with potentially curable HCC, and (ii) survival following curative therapy.

Methods

The study included 8900 chronic hepatitis virus-infected patients enrolled in a prospective screening programme, of whom 1335 (15.0%) were infected with hepatitis B virus (HBV), 7120 (80.0%) with hepatitis C virus (HCV), and 445 (5.0%) with both HBV and HCV. Screening was conducted every 6 months and included serum alpha-fetoprotein (AFP) measurement and ultrasonography. Curative treatments included liver transplantation, resection, radiofrequency ablation and/or ethanol injection.

Results

Hepatocellular carcinoma was diagnosed in 765 (8.6%) patients. Of 1602 patients with cirrhosis, 758 (47.3%) developed HCC. Curative treatment was possible in 523 (68.4%) of the 765 HCC patients. Two- and 5-year rates of overall survival in the curative treatment group were 65% and 28%, respectively, compared with 10% and 0% in the advanced disease group (P < 0.001).

Conclusions

Prospective screening of patients at high risk for the development of HCC increases the proportion of patients diagnosed with potentially curable disease. This may result in an increase in the number of longterm survivors. Screening strategies should focus on patients with chronic HBV or HCV infection who have progressed to cirrhosis because more than 40% of these patients will develop HCC.     

Clinical prognostic variables in young patients (under 40 years) with hepatitis B virus-associated hepatocellular carcinoma

OBJECTIVE: The aim of this study was to determine the impact of hepatocelluar carcinoma (HCC) screening in chronic hepatitis B patients who did not meet the current screening recommendations. METHODS: Patients who were admitted to Bellevue Hospital Center with HCC were assessed for risk factors, cirrhosis and tumor‐specific factors. Eligibility for liver transplantation or resection with favorable outcome was determined by applying Milan criteria. RESULTS: In all 93 patients were diagnosed with hepatitis B virus (HBV)‐associated HCC, 18 of whom were under 40 years. Cirrhosis was infrequently associated with HCC in this group, with most cancers occurring in non‐cirrhotic patients (12/18, 66.7%). No patient developed HCC outside the American Association for the Study of Liver Diseases (AASLD) cancer screening recommendations (young age, non‐cirrhotic) were eligible for liver transplantation or resection with favorable outcomes (within Milan criteria). However, HCC patients who were diagnosed within AASLD screening recommendations did meet Milan criteria in 17.3% (14/81) patients. CONCLUSIONS: Current guidelines for HCC screening in patients with HBV may lead to a delay in diagnosis in non‐cirrhotic patients under 40 years. Consideration should be given to modifying current recommendations to advocate entering HBV patients into a cancer‐screening program at young age.     

Efficacy of ultrasonography and alpha-fetoprotein on early detection of hepatocellular carcinoma

AIM: To evaluate the effectiveness of ultrasonographic screening for early detection of hepatocellular carcinoma (HCC). METHODS: The data of 14968 patients who had ultrasonography (US) for chronic liver diseases were collected into a database program from June 1995 to June 2005. The risk factors for HCC were also studied. A total of 6089 patients who had repeated US were enrolled, 264 patients were diagnosed with HCC during follow-up (mean, 39 mo). RESULTS: The detection rate of small HCC (≤3 cm in diameter) was 67.7%. The tumor size detected by screening at the intervals of 6 mo was significantly smaller than that at longer intervals. Only 29.3% of HCC patients had an elevated serum alpha fetoprotein (AFP) level above 400 ng/mL. The risk of HCC development during follow-up was higher in patients with liver cirrhosis (10.9%) and hepatitis C (9.0%) than in patients with chronic hepatitis (4.2%), hepatitis B (4.9%) and non-B, non-C hepatitis (NBNC, 3.9%). CONCLUSION: US screening at a interval of 6 mo is beneficial to high-risk patients over 40 years old and the early detection of HCC prolongs survival.     

Effect of antiviral treatment on alfa‐fetoprotein levels in HBV‐related cirrhotic patients: early detection of hepatocellular carcinoma

Summary. Alpha‐fetoprotein (AFP) is a marker of the presence of hepatocellular carcinoma (HCC), but is also elevated in advanced chronic hepatitis B. The detection and usage of AFP tests need to be improved. A cohort of 101 patients with advanced chronic hepatitis B and elevated AFP values was treated with entecavir (ETV) or peginterferon‐α2a. ETV was more effective in reducing AFP levels; mean time to AFP normalization was 11.9 weeks after ETV treatment initiation vs 22.3 weeks in peginterferon treated patients (P = 0.000). An additional cohort of 93 hepatitis B virus (HBV) cirrhotic patients with elevated AFP were treated with ETV prospectively and maintained under intensive surveillance. HCC developed in 16 (17.2%) patients in whom the strongest independent predictor was a continued AFP rise in spite of ongoing treatment. In this context, nodules of sizes 10–14 mm and 15–20 mm were detected in 40% of patients each. In conclusion, HBV cirrhotic patients with rising AFP levels were at very high risk of HCC development. Early detection of minute lesions may be possible by monitoring AFP levels, whilst patients are on treatment in conjunction with enhanced computed tomography examination.     

Community-based screening for hepatocellular carcinoma in elderly residents in a hepatitis B- and C-endemic area

Background and Aim: The aim of the present study was to elucidate a reasonable model and the efficacy of hepatocellular carcinoma (HCC) screening on an elderly population. Methods: Two‐stage HCC screening was conducted in a hepatitis C virus (HCV)‐endemic area. First, participants underwent blood tests for hepatitis B surface antigen (HBsAg), anti‐HCV antibody, serum α‐fetoprotein (AFP), aspartate aminotransferase, alanine aminotransferase, and platelet count. Patients who were abnormal for any of the six markers were enrolled for second‐stage ultrasonography. Suspected cases were referred for confirmation. HCC cases were followed for 4 years. All patients were linked to national mortality and cancer register databases to identify newly‐developed HCC, 30 months after screening. Results: A total of 461 males and 541 females were screened for HCC, with 15.1% testing positive for HBsAg and 44.3% positive for anti‐HCV. Among them, 619 (61.8%) met the criteria of ultrasonographic screening; 527 (85.1%) responded, and 16 confirmed HCC (male/female = 8/8, 68.8 ± 8 years) cases were detected. All tumor diameters were less than 5 cm, and six were less than 2 cm. AFP and thrombocytopenia were two independent predictive factors of HCC. The overall survival rates of detected cases were 93.8% and 56.3% was 1 and 4 years, respectively. The only good prognostic predictor was “underwent curative treatment”. Another seven non‐HCC residents developed HCC after screening, and five of these were with either thrombocytopenia or AFP elevation. Conclusion: Under economical consideration, AFP and platelet count should be feasible screening markers of risk identification. Early detection and prompt treatment results in good prognosis in an aged population.     

Application of surveillance programs for hepatocellular carcinoma in the Asia–Pacific Region

Hepatocellular carcinoma (HCC) is a potential target for cancer surveillance (or screening) as it occurs in well-defined, at-risk populations and curative therapy is possible only for small tumors. Surveillance has been recommended by regional liver societies and is practiced widely, but its benefits are not clearly established. Hepatic ultrasonography with or without alpha fetoprotein (AFP) performed every 6 months is the preferred program. Surveillance of HCC has been well shown to detect small tumors for curative treatment, which may be translated to improved patient survival. However, most studies are limited by lead-time bias, length bias for early diagnosis of small HCC, different tumor growth rates and poor compliance with surveillance. Cost-effectiveness of surveillance programs depends on the rate of small HCC detected 'accidentally' (routine imaging) in a comparator group, annual incidence of HCC with various etiologies, patient age and the availability of liver transplantation. The incremental cost-effectiveness for 6-monthly AFP and ultrasound has been estimated from approximately $US26 000–74 000/quality adjusted life years (QALY). All cirrhotic patients are therefore recommended for HCC surveillance unless the disease is too advanced for any curative treatment. As chronic hepatitis B can develop into HCC without going through liver cirrhosis, high-risk non-cirrhotic chronic hepatitis B patients are also recommended for HCC surveillance. In conclusion, HCC surveillance could be effective at reducing disease-specific mortality with acceptable cost-effectiveness among selected patient groups, provided it is a well-organized program.     

Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma

Background and Aim: Hepatocellular carcinoma (HCC) is a common complication in patients with chronic viral hepatitis. Detection of HCC at an early stage is critical for a favorable clinical outcome. The study aim was to: (i) compare the levels of des‐γ‐carboxyprothrombin (DCP), α‐fetoprotein (AFP) and AFP‐L3 in HCC patients and in chronic viral hepatitis patients without HCC; (ii) define the level of each tumor marker with the best sensitivity and specificity for HCC diagnosis; and (iii) to correlate the levels of these markers with respect to size and tumor burden. Methods: Two hundred and forty patients with either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection were studied. These included 144 with HCC, 47 with chronic hepatitis (fibrosis stage I–III on liver biopsy) and 49 with cirrhosis. Results: Levels of DCP, AFP and AFP L‐3 were significantly higher in patients with HCC than in those without HCC (P ≤ 0.0001). Receiver–operating curves (ROC) indicated that the cut‐off value with the best sensitivity and specificity for each test was ≥84 mAU/mL for DCP, ≥25 ng/mL for AFP and ≥10% for AFP‐L3. The sensitivity, specificity and positive predictive value (PPV) for DCP was 87%, 85% and 86.8%, for AFP 69%, 87% and 69.8%, and for AFP‐L3 56%, 90% and 56.1%, respectively. DCP levels were below the ROC cut‐off in all patients without HCC. In patients with single lesions, there was a direct correlation of DCP to tumor size. High levels of AFP correlated with diffuse type of HCC. All three markers were significantly elevated in the presence of metastatic HCC. No advantage was observed by combining two or three markers for HCC diagnosis. Conclusion: DCP had the highest sensitivity and PPV for HCC diagnosis, had a direct correlation with tumor size, and was not elevated in any patients without HCC. DCP should be used as the main serum test for HCC detection.     

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

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.     

Cost effectiveness of screening immigrants for hepatitis B

Background: The prevalence of chronic hepatitis B (CHB) infection among the immigrants of North America ranges from 2 to 15%, among whom 40% develop advanced liver disease. Screening for hepatitis B surface antigen is not recommended for immigrants. Aims: The objective of this study is to estimate the health and economic effects of screening strategies for CHB among immigrants. Methods: We used the Markov model to examine the cost‐effectiveness of three screening strategies: (i) ‘No screening’; (ii) ‘Screen and Treat’ and (iii) ‘Screen, Treat and Vaccinate’ for 20–65 years old individuals who were born abroad but are currently living in Canada. Model data were obtained from the published literature. We measured predicted hepatitis B virus (HBV)‐related deaths, costs (2008 Canadian Dollars), quality‐adjusted life‐years (QALYs), and incremental cost‐effectiveness ratio (ICER). Results: Our results show that screening all immigrants will prevent 59 HBV‐related deaths per 10 000 persons screened over the lifetime of the cohort. Screening was associated with an increase in quality‐adjusted life expectancy (0.024 QALYs) and cost ($1665) per person with an ICER of $69 209/QALY gained compared with ‘No screening’. The ‘Screen, Treat and Vaccinate’ costs an additional $81, generates an additional 0.000022 QALYs per person, with an ICER of $3 648 123/QALY compared with the ‘Screen and Treat’. Sensitivity analyses suggested that the ‘Screen and Treat’ is likely to be moderately cost‐effective. Conclusion: We show that a selective hepatitis B screening programme targeted at all immigrants in Canada is likely to be moderately cost‐effective. Identification of silent CHB infection with the offer of treatment when appropriate can extend the lives of immigrants at reasonable cost.     

Hepatocellular carcinoma in Belgium: clinical and virological characteristics of 154 consecutive cirrhotic and non-cirrhotic patients

OBJECTIVE: This study analyses the characteristics of patients with hepatocellular carcinoma (HCC) in a low endemic area with special emphasis on the differences between cirrhotic and non-cirrhotic patients. DESIGN AND SETTING: The files of 154 consecutive patients with HCC observed in a single tertiary care hospital have been investigated to determine epidemiological parameters and diagnostic procedures. RESULTS: Compared to non-cirrhotic cases, cirrhotic patients with HCC are older and have a more pronounced male predominance. Their disease is more advanced, they usually present with multi-focal tumours, rarely located in the left liver lobe. Antibodies to hepatitis C (anti-HCV) are present in 55%, 52% ever had contact with hepatitis B (HBV) and 31% were hepatitis B surface antigen (HBsAg)-positive. Six non-cirrhotic cases were anti-HCV-positive. alpha-Fetoprotein (AFP) elevation > 50 and > 400 microg/l was more frequently observed in cirrhotic patients with HCC (P = 0.016). A striking association was found between enhanced AFP levels and the presence of anti-HCV (P = 0.0006), while no such relation existed for AFP and HBV markers. The sensitivity of a 'routine' ultrasound examination is disappointing for the early detection of HCC in cirrhotic patients. CONCLUSIONS: In our hospital, in a low endemic area for HCC, we have a surprisingly high proportion of non-cirrhotic patients with HCC (40%). In cirrhosis, usually the consequence of alcohol abuse or hepatitis B or C, small tumours can be missed by ultrasonography if not specifically looked for. AFP levels are particularly elevated in hepatitis C-induced HCC.     

Early detection of hepatocellular carcinoma in patients with cirrhosis by alphafetoprotein, ultrasound and fine-needle biopsy

Hepatocellular carcinoma (HCC) may be detected at a relatively early stage in patients with liver cirrhosis regularly followed by screening programs using ultrasonography (US) and alpha-fetoprotein (AFP) measurement. Using both tests in 214 consecutive cirrhotic patients with no clinical signs of liver cancer, we detected HCC in 20 cases (9.4%). The sensitivity of US was greater (85%) than that of AFP (75%), and the combination of the two methods had a sensitivity of 100%. Only 50% of patients with focal liver lesions at US had a final diagnosis of HCC that was obtained in the majority of cases by US-guided fine needle biopsy.     

Hepatocellular carcinoma screening practices and impact on survival among hepatitis B-infected Asian Americans

Asians Americans have a high burden of hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC). HCC screening practices in this population are unknown. We aimed to investigate predictors and patterns of HCC screening and its impact on survival in HBV-infected Asian Americans. Clinical data were obtained from a retrospective cohort of 1870 HBsAg-positive Asians in San Francisco's safety net clinics. In 824 patients at-risk for HCC, screening (≥1 imaging and/or AFP per year) decreased from 67% to 47% to 24% from the 1st to 2nd to 10th year after HBV diagnosis, respectively. AFP, imaging, and imaging plus AFP were used in 37%, 14%, and 49% during the first year after diagnosis, and imaging plus AFP increased to 64% by the 10th year. Among 1431 patients followed in 2007, age 40-64 years, female gender, cirrhosis, hepatologist evaluation, HBV diagnosis after 2003, and testing for HBeAg were associated with HCC screening. Of the 51 patients with HCC, more cirrhotics received screening and were diagnosed with early stage disease. Median survival following HCC diagnosis was higher in screened patients (1624 days vs. 111 days, P = 0.02). MELD score at HCC diagnosis (HR 1.2, 95% CI 1.1-1.3) and receipt of curative therapy (HR 0.3, 95% CI 0.08-0.94) were associated with survival. Screening rates in at-risk Asian Americans, particularly among noncirrhotics, were suboptimal and decreased over time. Among patients with HCC, receipt of prior screening improved survival, and this survival benefit was related to better liver function at HCC diagnosis and receipt of curative therapy.     

High prevalence of multinodular hepatocellular carcinoma in patients with cirrhosis attributable to multiple risk factors.

To see whether or not there is an association between the cause of cirrhosis and the number of hepatocellular carcinoma (HCC) nodules, we analyzed 178 consecutive patients in whom HCC was detected during a prospective screening by abdominal ultrasound (US). The relevant information was obtained from the database of the screening programs operating at four hospitals in the Milan area. One hundred twenty-nine (72%) patients had a single tumor nodule detected by US and 49 (28%) patients had multinodular disease. Ninety-eight (55%) patients had normal serum values of alpha-fetoprotein (AFP). Tumor staging with biphasic computed tomography (CT) scan or hepatic arteriography with lipiodol revealed that 101 (57%) patients had single tumor nodules and 77 (43%) patients had more than one HCC nodule. After staging, multinodular HCC was more common in patients with multiple risk factors than in the hepatitis C virus (HCV) carriers (56% vs. 38%, P =.05). Interestingly, single tumors were as common in the 126 patients undergoing 6-month interval screening as in the 52 patients who were studied at yearly intervals. The former patients, however, had more small tumors than the latter ones (91% vs. 74%, P =.04). The 22 patients who were alcohol abusers had normal levels of serum AFP more often than the hepatitis B virus (HBV) or HCV carriers or those with multiple risk factors (86% vs. 57%, P <.04; vs. 47%, P <.002; vs. 52%, P <.006, respectively). We concluded that multinodular HCC was underdetected by real time US; it prevailed among patients with multiple risk factors. In these patients, screening with US exams every 6 months may be inadequate for early detection of liver cancer.     

Economic evaluation of a surveillance program of hepatocellular carcinoma (HCC) in India

Purpose Surveillance of patients of cirrhosis of liver is practiced for early detection of HCC. No data from any developing country on cost-effectiveness of such a program are available. Methods Economic evaluation of HCC surveillance was embedded in a prospective study undertaken to estimate the incidence of HCC in 194 cirrhotics. The protocol consisted of 6 monthly abdominal ultrasound (US) and serum alphafetoprotein (AFP) estimation, and yearly triple phase CT. Cost was estimated from the hospital and patient perspectives. Cost-effectiveness ratios for detecting a case of HCC were estimated. Modeling was done to estimate cost effectiveness with different combinations of diagnostic tests. Results Cost-effectiveness ratios of HCC surveillance program per HCC case detected were estimated as US$ 280 from the hospital perspective. From patient perspective, these were US$ 9,965 for outstation and US$ 2,808 for local patients. Cost-effectiveness ratio for direct medical cost per case of HCC detected by 6 monthly US and AFP, the EASL protocol, was estimated to be US$ 1,510 in the private sector. Conclusion The cost of HCC surveillance program is exorbitant for India (gross national income per capita US$ 620) and possibly other low/middle income countries.     

Sensitivity of commonly available screening tests in detecting hepatocellular carcinoma in cirrhotic patients undergoing liver transplantation

OBJECTIVE: Recognition of hepatocellular carcinoma (HCC) is important in the management of patients awaiting liver transplantation. HCCs >5 cm in diameter are at high risk to recur after transplant. The goal of this study was to assess the sensitivity of the diagnostic tests employed in a pretransplant screening program. METHODS: The study is a retrospective analysis of charts of 106 consecutive adults transplanted over a 1-yr period. All patients had ultrasonography (US), computerized tomography (CT), and serum alpha fetoprotein (AFP) testing within 6 months of transplantation. Radiographic reports were subdivided into low-risk and high-risk groups, based upon level of suspicion for HCC. The results were compared to explant pathology. RESULTS: Pathological analysis of 106 explants revealed HCC in 19 patients. High-risk US exams had a positive predictive value (PPV) of 0.69 and a negative predictive value (NPV) of 0.91 in the diagnosis of HCC. High-risk CT exams had a PPV of 0.67 and an NPV of 0.90. When patients had either a high-risk US or a high-risk CT, there was a PPV of 0.59 and an NPV of 0.83. Of the 19 patients with HCC, three had high-risk US and low-risk CT; two had high-risk CT and low-risk US. Four patients, all with HCC <4 cm, had low-risk US, CT, and serum AFP. CONCLUSIONS: US, CT, and serum AFP, as single tests, are insensitive for detection of HCC in the cirrhotic liver. However, they are highly specific. Sensitivity and specificity for US are comparable to those for CT. Given its lower cost, US is preferable to CT for routine screening of HCC in patients with end-stage liver disease undergoing liver transplantation.     

Angiopoietin-2 serum levels are elevated in patients with liver cirrhosis and hepatocellular carcinoma

OBJECTIVES: Liver cirrhosis is characterized by remodeling leading to nodules that are difficult to discern from hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) serum levels are used for the screening for HCC, with limited success. We evaluated angiopoietin-2 as a serum marker in patients with cirrhosis and with HCC. METHODS: In a retrospective study, we measured angiopoietin-2 serum levels in 131 patients with HCC, 180 patients with cirrhosis, and 40 healthy controls. We also determined AFP serum levels in patients with HCC and compared the test characteristics of both serum markers. The expression patterns of angiopoietin-2 were determined by in situ hybridization in healthy and cirrhotic livers as well as in HCC. RESULTS: Angiopoietin-2 serum levels were elevated in patients with liver cirrhosis (P < 0.0001) compared with healthy controls. Levels were further elevated in patients with HCC compared with healthy controls (P < 0.0001) and cirrhotic patients (P < 0.0001). The combination with AFP measurements led to improved discrimination between HCC and cirrhosis. Angiopoietin-2 message was present in tumor cells of HCCs but was absent from hepatocytes of cirrhotic and healthy livers. In cirrhosis, message was detected within the strands of fibrous tissue. CONCLUSIONS: Serum angiopoietin-2 levels are elevated in patients with cirrhosis, implicating a possible role of the angiopoietin-Tie-2 system for neoangiogenesis in cirrhosis. Serum levels are further elevated in patients with HCC, suggesting the potential use of angiopoietin-2 as a marker for the detection of cirrhosis and HCC.     

血清标志物在肝炎肝硬化患者中诊断肝癌的价值

目的寻找有效的适合用于肝炎肝硬化患者肝癌诊断的血清肿瘤标志物.方法AFP测定应用竞争性放射免疫技术(RIA),岩藻糖苷酶(AFU)测定应用酶化学技术,唾液酶(SA)测定应用化学法,可溶性白介素2受体(sIL-2R)和肝细胞生长因子(HGF)的测定应用单克隆抗体双夹心酶联免疫吸附试验(ELISA).结果AFU、AFP和SA三项指标肝癌患者显著高于肝硬化患者,P值分别为P=0.027,P＜0.001和P＜0.001.分别以AFU值440nmol/ml·h-1、AFP测定值400 ng/ml、SA测定值590 μg/ml为阳性参考值,测定肝癌组患者阳性率分别为57.57%、68.09%和35.7%.三者假阳性率分别为48%、20%和0,以AFP和SA对41例肝癌进行联合检测,其肝癌患者阳性检出率为80.49%.肝癌患者血清sIL-2R水平与肝硬化患者及肝炎患者比较无显著差异,P＞0.05.肝癌患者血清HGF水平低于肝硬化患者以及重症肝炎患者.结论肝癌患者HGF、sIL-2R和AFU显著高于正常人血清,但其升高的水平受肝脏炎症影响较大,对肝癌的特异性较差,因而不适合应用于肝炎肝硬化患者肝癌的诊断.AFP仍然是最敏感的肝癌血清指标,SA具有肿瘤特异性高和不受肝脏炎症干扰的特点,适合肝炎肝硬化患者肝癌的诊断,联合AFP可以使阳性检出率达80.49%,使肝癌的诊断灵敏性大大提高.     

Combined use of AFP,PIVKA-II,and AFP-L3 as tumor markers enhances diagnostic accuracy for hepatocellular carcinoma in cirrhotic patients

Objective: As data on the effectiveness of tumor markers in detecting hepatocellular carcinoma (HCC) in cirrhotic patients are limited, we investigated the diagnostic accuracy of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3). Material and methods: This retrospective study enrolled 361 cirrhotic patients with HCC, and 276 cirrhotic patients without HCC occurrence. Results: Most patients were men (n?=?431, 67.7%); the median age was 57.0 years. The main etiology of chronic liver disease was chronic hepatitis B (n?=?467, 73.3%). The sensitivity and specificity of combined three biomarkers was 87.0 and 60.1% in overall HCC, and 75.7 and 60.1% in early HCC, respectively (cutoff: 20 ng/mL for AFP, 40 mAU/mL for PIVKA-II, and 5% for AFP-L3). The area under the receiver operating characteristic curve (AUROC) for HCC diagnosis was 0.765 (95% confidence interval [CI], 0.728–0.801) for AFP; 0.823 (95% CI, 0.791–0.854) for PIVKA-II; and 0.755 (95% CI, 0.718–0.792) for AFP-L3. The AUROC for early HCC diagnosis was 0.754 (95% CI, 0.691–0.816) for AFP, 0.701 (95% CI, 0.630–0.771) for PIVKA-II, and 0.670 (95% CI, 0.596–0.744) for AFP-L3. Combining the three tumor markers increased the AUROC to 0.877 (95% CI, 0.851–0.903) for HCC diagnosis, and 0.773 (95% CI, 0.704–0.841) for early HCC diagnosis. Conclusion: Diagnostic accuracy improved upon combining the AFP, PIVKA-II, and AFP-L3 tumor markers compared to each marker alone in detecting HCC and early HCC in cirrhotic patients.     

Cirrhotic Patients With or Without Hepatocellular Carcinoma Harbour AFP-Specific T-Lymphocytes That Can Be Activated in vitro by Human Alpha-Fetoprotein

Background: Alpha-fetoprotein (AFP) is re-expressed in 60%-70% of hepatocellular carcinomas (HCC) and may therefore be a potential target for a prophylactic or therapeutic tumour-specific vaccination. A prerequisite for this approach is the possibility to induce AFP-specific T-lymphocytes in patients with HCC and/or cirrhosis. Methods: Peripheral blood was examined for the presence of AFP-specific T-lymphocytes using a FACS-based interferon- &#110 secretion assay. Results: In a group of healthy volunteers, the presence of AFP-specific CD4- and CD8-lymphocytes was demonstrated. Screening of blood of 14 cirrhotic patients without HCC and 23 cirrhotic patients with HCC showed that patients with liver diseases that represent targets for vaccination also harbour CD4-positive as well as CD8-positive AFP-specific T-lymphocytes. AFP reactivity in patients' lymphocytes was not significantly influenced by soluble serum AFP. The median stimulation factors for CD4-positive T-lymphocytes were significantly higher ( P = 0.0365) in cirrhotic patients without HCC (median 2.08, range 0.50-4.40) compared to cirrhotic patients with HCC (median 1.15, range 0.24-8.50). Conclusion: AFP-specific T-lymphocytes that may be instrumental in HCC vaccination strategies are present in humans. This study suggests that immunopreventive vaccination of cirrhotic patients rather than immunotherapeutic vaccination of HCC patients may be preferable.