Reappraisal of the diagnostic value of alpha‐fetoprotein for surveillance of HBV‐related hepatocellular carcinoma in the era of antiviral therapy

This study was designed to explore if antiviral treatment influences the performance of serum alpha‐fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high‐risk chronic HBV‐infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non‐antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non‐antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut‐off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high‐risk population of CHB and LC patients.     

Development of HCC in patients receiving adefovir dipivoxil for lamivudine‐resistant hepatitis B virus mutants

Aim: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add‐on lamivudine for treatment of lamivudine‐resistant hepatitis B virus (HBV) mutants. Methods: A total of 247 patients who developed lamivudine‐resistant HBV mutants, with an increase of HBV DNA ≥ 1 log copies/mL, received adefovir dipivoxil 10 mg add‐on lamivudine 100 mg daily during a median of 115 weeks (range: 25–282 weeks). They were followed for the development of HCC by imaging modalities every 3?6 months. Results: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and α‐fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan‐Meier analysis, AST levels ≥ 70 IU/L, YIDD mutants, cirrhosis and age ≥ 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). Conclusion: HCC can develop in cirrhotic patients receiving adefovir add‐on lamivudine. Hence, the patients with baseline AST ≥ 70 IU/L and YIDD mutants would need to be monitored closely for HCC.     

Survival impact of lymphocyte infiltration into the tumor of hepatocellular carcinoma in hepatitis B virus‐positive or non‐B non‐C patients who underwent curative resection

Aim

The prognostic value of lymphocyte infiltration into hepatocellular carcinoma (HCC) is still controversial, and it has not been reported in hepatitis B virus (HBV)‐positive or non‐B non‐C (NBNC) HCC. The aim of this study is to assess the prognostic significance of lymphocyte infiltrate in tumor for HBV‐positive and NBNC HCC patients.

Methods

This study investigated 145 HBV‐positive or NBNC patients who underwent hepatectomy for HCC between January 2001 and May 2009. Cumulative recurrence rate, overall survival (OS), and clinicopathological parameters were analyzed according to lymphocyte infiltration in tumor.

Results

In patients with low lymphocyte infiltration, the 5‐year recurrence rate was higher and OS was poor (86.4 and 44.1%, respectively) than that of the patients with high lymphocyte infiltration (55.3 and 83.7%, respectively). Multivariate analyses revealed that independent risk factors for recurrence were low albumin value (hazard ratio [HR] 2.33, P = 0.009), high American Joint Committee on Cancer (AJCC) T stage (HR 2.31, P < 0.0001), high α‐fetoprotein (AFP) value (HR 2.06, P = 0.005), and low lymphocyte infiltration (HR 2.50, P = 0.0001). The independent risk factors for OS were low albumin value (HR 3.69, P = 0.003), high AJCC T stage (HR 2.10, P = 0.049), high AFP value (HR 3.98, P < 0.001), and low lymphocyte infiltration (HR 3.47, P = 0.001).

Conclusions

Lymphocyte infiltrate in tumor is significantly associated high recurrence rate and poor overall survival. Evaluation of the infiltrating lymphocyte could improve the prediction of prognosis in HCC patients after curative resection.     

Usefulness of serum alpha-fetoprotein (AFP) as a marker for hepatocellular carcinoma (HCC) in hepatitis C virus related cirrhosis: analysis of the factors influencing AFP elevation without HCC development]

BACKGROUND/AIMS: Serum alpha-fetoprotein (AFP) is frequently used for the diagnosis of hepatocellular carcinoma (HCC). Most available data concerning AFP came from studies of patients with chronic hepatitis B or mixed etiologies. Studies concerning the diagnostic value of AFP for HCV-related liver cirrhosis (LC) are limited. We evaluated the factors influencing AFP elevation in the absence of HCC and analyzed the diagnostic value of serum AFP in HCC surveillance of HCV-related LC patients. METHODS: We enrolled 55 patients of HCV-related LC with HCC and 62 patients without HCC as a case-control study were analyzed. The sensitivity and specificity were calculated and the clinical and biochemical factors influencing serum AFP levels. RESULTS: The sensitivities and specificities of serum AFP for the detection of HCC in HCV-related LC were 72.7% and 59.7% for AFP>or=20 ng/mL, and 47.3% and 92.5% for AFP>or=100 ng/mL, respectively. Elevated serum AST was independently associated with elevated serum AFP level in HCV-related LC. In cases of ASTor=100 ng/mL for the diagnosis of HCC was 100%. However, in case of AST>2 ULN, the specificity was 85.0% for AFP>or=100 ng/mL and 95.0% for AFP>or=200 ng/mL. CONCLUSIONS: Serum AST levels influence serum AFP level in HCV-related LC. In cases of AST2 ULN.     

Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein

Background and Aim: Fucosylated alpha‐fetoprotein (AFP‐L3) is known to be a marker of poor prognosis in patients with hepatocellular carcinoma (HCC). However, it has been difficult to measure AFP‐L3 under low AFP (≤ 20 ng/mL). The aim of this study was to elucidate the role of AFP‐L3 in HCC patients with low AFP conditions. Methods: One hundred and ninety six consecutive newly developed HCC patients with low AFP (≤ 20 ng/mL) were examined for serum AFP‐L3 expression by a newly‐developed micro‐total analysis system that could stably measure AFP‐L3 in low AFP circumstances, and its clinical importance was analyzed. Results: Positivity of AFP‐L3 in HCC patients was 13.3% at a cut‐off level of 10%. Five‐year survivals of HCC patients with AFP‐L3 (< 10%) and AFP‐L3 (≥ 10%) were 69.4% and 41.1%, respectively (P = 0.001). Among 18 clinical parameters, low alanine aminotransferase, large tumor size, presence of portal vein tumor thrombus, high AFP and high des‐gamma carboxy prothrombin were observed in the high AFP‐L3 (≥ 10%) group. Multivariate analysis revealed that high aspartate aminotransferase (AST) (risk ratio [RR] = 3.24, 95% confidence interval [CI] = 1.27–8.26), the presence of ascites (RR = 3.44, 95% CI = 1.22–9.34), multiple tumor number (RR = 3.06, 95% CI = 1.33–7.17), and high AFP‐L3 (RR = 8.36, 95% CI = 2.79–25.5) were risk factors for survival. High AFP‐L3 was also a risk factor for survival in HCC patients who received radiofrequency ablation (P = 0.048). Conclusions: AFP‐L3 is a strong prognostic factor for survival even in HCC patients with low AFP (≤ 20 ng/mL).     

Significance of hepatitis B virus surface antigen, hepatitis C virus expression in hepatocellular carcinoma and pericarcinomatous tissues

AIM： To investigate the correlation between hepatitis B virus surface antigen （HBsAg）, hepatitis C virus （HCV） expression in hepatocellular carcinoma （HCC）, the HAI score of the noncancerous region of the liver and the serum Alpha fetoprotein （AFP） level.
METHODS： The patterns of HBsAg and HCV in 100 cases of HCC and their surrounding liver tissues were studied on paraffin-embedded sections with immunohistochemistry, the histological status was determined by one pathologist and one surgeon simultaneously using the hepatitis activity index （HAIl score, and AFP was detected by radioimmunity. The study included 100 consecutive patients who underwent curative resection for HCC. Based on HBsAg and HCV expression, the patients were classified into 4 groups： patients positive for HBsAg （HBsAg group）, patients positive for HCV （HCV group）, patients negative for both HCV and HBsAg （NBNC group） and patients positive for both HBsAg and HCV （BC group）.
RESULTS： The BC group had significantly higher HAI scores than the other three groups. （BC 〉 HCV 〉 HBsAg 〉 NBNC）. HBV and HCV virus infection was positively correlated with HAI （rs = 0.39, P = 0.00011. The positive rate of AFP （85.7%） and the value of AFP （541.2 ng/mL） in the group with HBV and HCV co-infection were the highest among the four groups. The positive rate （53.3%） of AFP and the value of AFP （ 53.3 ng/mL） in the group with none-infection of HBV and HCV were the lowest. HBV and HCV virus infection was positively correlated with AFP（rs = 0.38, P = 0.0001）.
CONCLUSION： The AFP increase in patients with liver cancer was positively correlated with the infection of HBV and HCV. The-serum AFP elevation by the infection of HBV and HCV is one of mechanisms which lead to hepatocarcinogenesis, and the antivirus intervening treatment of hepatitis is significant for the prognosis of liver cancer. From our Spearman＇s rank correlation analysis, we can conclude that the severity of virally induced     

Utility of the FIB‐4 Index for hepatocarcinogenesis in hepatitis C virus carriers with normal alanine aminotransferase levels

The FIB‐4 index is a simple formula using age, aspartate aminotransferase, alanine aminotransferase (ALT) and platelet count to evaluate liver fibrosis. We investigated the ability of the FIB‐4 index for hepatocarcinogenesis in hepatitis C virus (HCV) carriers with normal ALT levels. A total of 516 patients with ALT levels persistently at or below 40 IU/L during an observation period of over 3 years were included. Factors associated with the development of HCC were determined. Hepatocellular carcinoma (HCC) developed in 60 of 516 patients (11.6%). The incidence rate of HCC at 5 and 10 years was 2.6% and 17.6%, respectively. When patients were categorized according to the FIB‐4 index as ≤2.0 (n = 226), >2.0 and ≤4.0 (n = 169), and >4.0 (n = 121), the cumulative incidence of HCC at 5 years was 0.5%, 1.3% and 8.0%, respectively, and 2.8%, 25.6% and 37.1% at 10 years, respectively. Patients with FIB‐4 index >4.0 were at the highest risk (P < 0.001). Factors that were significantly associated with HCC in the multivariate analysis were FIB‐4 index >2.0 (hazard ratio (HR), 7.690), FIB‐4 index >4.0 (HR, 8.991), α‐fetoprotein (AFP) >5 ng/mL (HR, 2.742), AFP >10 ng/mL (HR, 4.915) and total bilirubin >1.2 mg/dL (HR, 2.142). A scoring system for hepatocarcinogenesis that combines the FIB‐4 index and AFP predicted patient outcomes with excellent discriminative ability. The FIB‐4 index is strongly associated with the risk of HCC in HCV carriers with normal ALT levels.     

Clinical features of hepatitis C virus-related hepatocellular carcinoma and their association with alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II.

PURPOSE: We investigated the differences in clinical features between alpha-fetoprotein (AFP)-predominant hepatocellular carcinoma (HCC) and protein induced by vitamin K absence or antagonist-II (PIVKA-II)-predominant HCC, especially regarding host factors thought to contribute to hepatocarcinogenesis in chronic hepatitis C virus (HCV) infection. METHODS: HCV-related HCC patients (n=306) were divided into four groups according to median AFP (48.1 ng/ml) and PIVKA-II (60 mAU/ml). Host factors, tumor factors, survival, and risk factors affecting survival were compared. RESULTS: Aspartate aminotransferase (AST; IU/L), alanine aminotransferase (ALT; IU/L), and platelet count (x 10(4)/ml) were, respectively, 81, 67, and 8.2 in AFP-predominant HCC (group A; n=66) vs. 50, 42, and 11.4 in PIVKA-II-predominant HCC (group P; n=52). Tumor sizes (mm) in groups A and P were 20 and 37, respectively. Significant differences were evident. Survival was identical between the two groups. Factors affecting survival were total bilirubin, portal tumor thrombus and number of nodule in group A, and albumin and tumor distribution in group P. CONCLUSIONS: PIVKA-II-predominant HCC had a milder hepatitis and a better-preserved platelet count compared with AFP-predominant HCC. Considering the strong relation between hepatocarcinogenesis and hepatic inflammation with chronic HCV infection, these differences indicate that hepatocarcinogenic mechanisms in PIVKA-II-predominant HCC may differ from those in AFP-predominant HCC.     

Combined pre‐S deletion and core promoter mutations related to hepatocellular carcinoma: A nested case‐control study in China

Aim: To investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) in Qidong, China. Methods: A total of 2387 males (aged 20–65 years) who were seropositive for the hepatitis B surface antigen (HBsAg), but had not been diagnosed with HCC, were recruited to a community‐based HCC screening study from August, 1996. Evaluation of virological parameters at recruitment was determined for 196 HCC patients during 10 years of follow‐up and 323 controls. Results: After adjustment for age at recruitment, history of cigarette smoking and alcohol consumption, alanine aminotransferase (ALT) elevation, alpha‐fetoprotein (AFP) levels >20 ng/mL, hepatitis B e antigen positive, HBV DNA levels ≥4.00 log₁₀ copies/mL, pre‐S deletion, T1653 mutation, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with subsequent risk of HCC. A significant biological gradient of HCC risk by HBV DNA levels from less than 2.69 log₁₀ copies/mL to 6.00 log₁₀ copies/mL or greater was observed. HBV with a complex mutation combination pattern (pre‐S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations) rather than a single mutation was associated with the development of HCC. The longitudinal observation demonstrated a gradual combination of pre‐S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC. Conclusions: AFP levels >20 ng/mL, high HBV DNA levels, pre‐S deletion, and T1762/A1764 double mutations at recruitment were independent risk factors of HCC. Combination of pre‐S deletion and core promoter mutations increased the risk of HCC.     

Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection

BACKGROUND/AIMS:  To identify the risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after resection.
METHODS:  Seventy-two patients who underwent liver resection for HBV-related HCC were recruited. Demographic, biochemical, tumor, and viral factors at the time of resection were evaluated by univariate and multivariate analyses to identify risk factors associated with recurrence after resection.
RESULTS:  The median follow-up period was 18.9 months and the median age was 53 yr, with male-to-female ratio of 59:13. Age >60 yr, tumor size >5 cm, poorly differentiated tumor, lymphovascular permeation, the presence of microsatellite lesions, α-fetoprotein (AFP) level >1,000 ng/mL and HBV viral load >2,000 IU/mL (4 log₁₀ copies/mL) at the time of tumor resection, HBV genotype C, core promoter mutations, and patients with no antiviral treatment after tumor resection were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV viral load >2,000 IU/mL (4 log₁₀ copies/mL) ( P = 0.001, odds ratio [OR] 22.3), AFP >1,000 ng/mL ( P = 0.02, OR 7.4), tumor size >5 cm ( P = 0.02, OR 5.1), and age >60 yr ( P = 0.01, OR 4) at the time of tumor resection remained to be the independent risk factors.
CONCLUSIONS:  Viral load of >2,000 IU/mL (4 log₁₀ copies/mL) is the most important correctable risk factor for HCC recurrence after resection. Whether antiviral therapy in these patients can decrease tumor recurrence requires further investigations.     

The risk of hepatocellular carcinoma among chronic hepatitis B virus‐infected patients outside current treatment criteria

We assessed the incidence of hepatocellular carcinoma (HCC) in those outside of current treatment recommendations and risk factors associated with HCC development. A multi‐centre, retrospective cohort of 3624 patients who were monitored without antiviral treatment was analysed. Incident HCC risk according to the Asian Pacific Association for the study of the Liver (APASL), the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) treatment recommendations was assessed. A risk score was developed using independent factors associated with HCC development among patients who were outside current treatment criteria. During a median follow‐up of 4.6 years, incident HCC was diagnosed in 161 (4.4%) patients. The proportions of patients who developed HCC outside treatment recommendation according to APASL, AASLD and EASL criteria were 64.0%, 46.0% and 33.5%, respectively. The 5‐year cumulative HCC incidence rate was 13.9% for cirrhotic patients with low‐level viremia and 6.1 ~ 7.3% for chronic hepatitis patients with elevated HBV DNA levels plus mildly elevated alanine aminotransferase levels. Among patients who were outside treatment recommendation, age, sex, hepatitis B e antigen, cirrhosis, alanine aminotransferase and platelet levels were independent factors associated with HCC development. When these factors were used to calculate the risk score for each patient, those with a score ≥8 had a higher HCC incidence rate (14.3% at 5‐year), although they were currently outside treatment recommendations. Thus, HCC was observed among patients who were outside current treatment criteria indicating that careful monitoring for HCC and efforts to identify patients at risk are required.     

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.     

Predictors of alpha-fetoprotein elevation in patients with chronic hepatitis C, but not hepatocellular carcinoma, and its normalization after pegylated interferon alfa 2a-ribavirin combination therapy

BACKGROUND AND AIM: Elevated serum alpha-fetoprotein (AFP) levels are noted in patients with chronic hepatitis C (CHC) without hepatocellular carcinoma (HCC). The change in AFP levels after treatment with pegylated interferon and ribavirin (Peg-IFN/RBV) combination therapy is still unknown. The aim of this study was to investigate the predictors of elevated serum AFP in patients with CHC, and its change after Peg-IFN/RBV therapy. METHODS: A total of 123 patients, intended to receive pegylated interferon alfa-2a plus ribavirin therapy, were enrolled. Eighty-three patients had complete treatment and received follow up for and additional 24 weeks. The factors that may affect the elevation of pretreatment AFP and the normalization of post-treatment AFP were determined. RESULTS: The mean AFP level was 18.5 +/- 63.0 ng/mL (range, 1.3-676.0 ng/mL); 41 (33.3%) of the 123 patients had elevated serum AFP (more than 10 ng/mL) at baseline. A multivariate logistic regression analysis disclosed that older age (odds ratio [OR], 1.093; 95% confidence interval [CI], 1.015-1.177; P = 0.018), more advanced METAVIR fibrosis stage (OR, 5.237; 95% CI, 1.244-22.037; P = 0.024), a higher aspartate aminotransferase (AST) level (IU/L) (OR, 1.020; 95% CI, 1.008-1.033; P = 0.001), and lower platelet count (x10(9)/L, OR, 0.985; 95% CI, 0.968-0.994; P = 0.003) were independent determinants of pretreatment AFP elevation. After treatment, 72 of 83 (86.7%) cases were found to have normal post-treatment AFP levels (<10 ng/mL) at the end of follow up (EOF). Post-treatment negativity of the chronic hepatitis C virus (HCV)-RNA (OR, 10.014; 95% CI, 1.000-100.329; P = 0.050) and the post-treatment platelet count (x10(9)/L) (OR, 1.025; 95% CI, 1.001-1.050; P = 0.040) were associated with normal AFP at EOF. AFP progressively decreased with significant differences starting from the 12th week after treatment to the end of treatment, and was lowest at the EOF date for the sustained viral response (SVR) group. On the contrary, the non-SVR group did not have an AFP change during and after treatment. CONCLUSION: Older age, low platelet count, higher AST levels, and advanced fibrosis predisposed chronic hepatitis C patients without HCC to have elevated serum AFP levels. After Peg-IFN/RBV combination therapy, a higher platelet count and HCV viral eradication were determinants of normal AFP at EOF. Serial AFP levels decreased after treatment, presenting in a time-dependent manner, specifically for the SVR group.     

Association of mannose‐binding lectin‐2 gene polymorphism with the development of hepatitis C‐induced hepatocellular carcinoma

Background: Development of end‐stage liver and graft disease is suspected to be partially determined by the individual genetic background. Mannose‐binding lectin (MBL) is an important immunomodulatory factor, which is supposed to be involved in complement activation and oncogenesis. Genetic polymorphisms of MBL‐2 alter MBL functionality. The aim of our study was to determine the prevalence of MBL‐2 polymorphism (rs7096206) in hepatitis C virus (HCV)‐induced hepatocellular carcinoma (HCC) based on histological analysis of explanted livers in patients undergoing liver transplantation (LT). Methods: One hundred and seventy‐seven patients, who underwent LT for HCV‐induced liver disease, were genotyped for MBL‐2 by TaqMan genotyping assay. Sixty‐two patients with histologically confirmed HCC were compared with 115 patients without HCC. MBL‐2 genotypes were corelated with the growth patern, tumour size and pretransplant α‐fetoprotein (AFP) level of HCC patients. Results: The prevalence of GG/GC genotypes was significantly higher among HCC patients compared with tumour‐free explanted livers (P=0.004; odds ratio 2.5; 1.3–4.8). GG/GC genotype group was significantly associated with the size of HCC (P=0.022), higher pretransplant AFP level (P=0.010) and bilobar tumour growth (P=0.038). Furthermore, CC genotype was found to be significantly more frequent in AFP‐negative HCCs (P=0.002). Conclusion: Mannose‐binding lectin‐2 polymorphism seems to be involved in the development of pretransplant HCV‐induced HCC and should be further investigated as potential risk factor for HCV‐associated carcinogenesis.     

Screening for cancer in viral hepatitis

Early diagnosis of HCC is possible because certain risk factors for this tumor are known and because sensitive and relatively inexpensive diagnostic tools are available. Early diagnosis of HCC is also possible because of the long phase of asymptomatic tumor growth and the tumor's tendency to grow as a solitary mass in many patients. In two consensus development conferences held in Anchorage, Alaska and in Milan, Italy, chronic carriers of HBsAg, patients with cirrhosis, patients with rare metabolic liver diseases, and individuals with family histories of HCC were identified as patients at high risk for HCC and therefore as candidates for periodic screening. At the Anchorage conference, it was recommended that healthy carriers have at least yearly determinations of serum AFP and that carriers with additional risk factors (e.g., cirrhosis) be screened every 6 months by abdominal US scans and determination of serum AFP levels. No specific recommendations were released for HBsAg-negative patients with chronic liver disease. At the Milan conference, it was recommend that patients with cirrhosis or with certain congenital metabolic conditions known to be at risk for HCC should be screened by AFP determination and US scan twice a year. It was also recommended that HBsAg carriers older than 35 years or with family histories of HCC should be screened for HCC by determinations of serum AFP levels and aminotransferase levels once a year.     

Clinical characterization of patients developing histologically‐proven fibrosing cholestatic hepatitis C post‐liver transplantation

Aim: Fibrosing cholestatic hepatitis C (FCH) post‐liver transplantation (LT) is an uncommon disorder with extremely poor outcome. Using stringent histological criteria, we sought to identify cases of FCH to better characterize its incidence, clinical features and outcomes. Methods: From January 1991 to December 2007, 973 LT for hepatitis C virus (HCV) were performed at our center. Using the pathology database, 51 cases with a provisional diagnosis of FCH were identified. FCH was diagnosed histologically by cholestasis accompanied by thin periportal fibrous septa, ductular reaction and mild inflammation. Results: FCH was reconfirmed in 24 recipients; seven had concurrent biliary problems. Twenty‐seven cases were excluded; biopsy was unavailable in nine cases, 15 did not meet the histological criteria of FCH and three had missing clinical information. All received deceased donors at a mean age of 64.4 years (15/17 aged >50 years). Mean time from LT to FCH was 7.6 months with 16 of 17 diagnosed within 1 year of LT. At diagnosis, mean viral load was 14.4 million IU/mL, bilirubin 16.2 mg/dL, aspartate aminotransferase 262 IU/mL, alanine aminotransferase 192 IU/mL and alkaline phosphatase 299 IU/mL. All 17 patients died or required re‐LT a mean of 7.8 months after the FCH diagnosis. Conclusion: FCH occurs infrequently and is typified by hyperbilirubinemia, donor age of more than 50 years, extremely high HCV RNA and specific histological changes occurring within the first several months post‐LT with extremely poor patient and graft survival. Histology alone is not reliable for the diagnosis of FCH, especially in the setting of recurrent HCV with concurrent biliary problems.     

Correlation between clinical indication for treatment and liver histology in HBeAg‐negative chronic hepatitis B: a novel role of α‐fetoprotein

Background: It is unclear whether clinical indication for antiviral treatment is in agreement with histological indication in HBeAg‐negative chronic hepatitis B (CHB). This study aimed to clarify this relationship and identify factors associated with liver histology. Patients and methods: We investigated 152 consecutive, treatment‐naïve, HBeAg‐negative CHB patients who had undergone liver biopsies at a tertiary medical centre in Taiwan. Clinical indications for treatment included a serum alanine aminotransferase level more than twice the upper limit of normal and an hepatitis B virus DNA level >2000 IU/ml. Factors associated with the histological indication (Ishak's grade ≥7 and/or stage ≥2) were analysed. Results: The association between the clinical and the histological indications was significant (P=0.011). However, the agreement was poor (κ value=0.197). In patients satisfying the clinical indication, age >52 years [odds ratio (OR)=2.669, P=0.042], serum α‐fetoprotein (AFP) level >7 ng/ml (OR=7.070, P<0.001) and platelet count <130 × 10⁹/L (OR=11.720, P=0.025) were identified to be independent factors associated with histological indication. In patients who did not satisfy the clinical indication, multivariate analysis revealed that only an AFP level >7 ng/ml (OR=10.345, P=0.021) was independently associated with histological indication. Combining the clinical indication and/or AFP level >7 ng/ml to predict liver histology, the sensitivity and the negative predictive value could improve from 86 to 94.4% and 66.7 to 81% respectively. Conclusion: AFP level is associated with liver histology in HBeAg‐negative CHB. Serum AFP level can serve as a surrogate indicator to identify patients who need antiviral treatment.     

Noninvasive diagnostic criteria for hepatocellular carcinoma in hepatic masses >2 cm in a hepatitis B virus‐endemic area

Background: Noninvasive criteria for diagnosing hepatocellular carcinoma (HCC) suggested by the American Association for the Study of Liver Diseases (AASLD) in 2005 consisted of serum α‐fetoprotein (AFP) level >200 ng/ml or a typical enhancement pattern (arterial enhancement and portal/delayed washed out) on dynamic imaging of hepatic mass(es) >2 cm in a cirrhotic liver. Aims: To validate these criteria in a Korean population and to evaluate whether these criteria are applicable to patients without cirrhosis at a high risk of developing HCC. Methods: We prospectively investigated 206 consecutive patients with hepatic mass(es) >2 cm who underwent biopsy or surgical resection. Patients were evaluated by four‐phase dynamic computed tomography (CT) and by assays of serum AFP concentrations at baseline. Patients were classified according to the presence of risk factors or cirrhosis, and the diagnostic accuracy of each test was determined. Results: The positive predictive values (PPV) of typical CT findings or serum AFP >200 ng/ml were 97.8% in cirrhotic patients, 89.6% in high‐risk patients without cirrhosis and 82.4% in low‐risk patients. The PPVs of typical CT findings alone in these groups were 98.8, 97.6 and 87.5% respectively. In high‐risk patients without cirrhosis, the addition of serum AFP levels to typical CT findings minimally increased the diagnostic sensitivity from 81.6 to 87.8% but reduced the PPV from 97.6 to 89.6%. Conclusions: Serum AFP concentration is not a suitable diagnostic criterion for HCC. Typical CT findings can be used to diagnose HCC >2 cm both in cirrhotic patients and in high‐risk patients without cirrhosis.     

Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial

BACKGROUND/AIMS: Alpha-fetoprotein (AFP) has been useful in the diagnosis of hepatocellular carcinoma (HCC) but lacks specificity. We assessed serum AFP among patients with chronic hepatitis C and advanced fibrosis to establish predictors of AFP elevations and changes with antiviral therapy. METHODS: Serum AFP was measured at baseline and on therapy in patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C). AFP levels were correlated with patient demographic and clinical features. RESULTS: Baseline AFP was > or = 20 ng/mL in 191 of 1145 patients (16.6%). Mean AFP values were significantly higher in patients with cirrhosis than in those with bridging fibrosis (22.5 vs. 11.4 ng/mL, P < 0.0001). Factors independently associated with raised serum AFP in patients with cirrhosis were female gender, black race, decreased platelet count, increased serum AST/ALT ratio, serum ferritin, and Mallory bodies in liver biopsies. Serum AFP levels decreased significantly during therapy with pegylated interferon alpha-2a and ribavirin. HCC was identified in six subjects, only three of whom had AFP > 20 ng/mL. CONCLUSIONS: Among patients with advanced chronic hepatitis C, serum AFP values are frequently elevated, even in the absence of HCC. Factors associated with raised AFP include severity of liver disease, female gender and black race. Serum AFP levels decline during antiviral therapy.     

Alpha-fetoprotein before and after pegylated interferon therapy for predicting hepatocellular carcinoma development

AIM: To investigate factors that accurately predict hepatocellular carcinoma (HCC) development after antiviral therapy in chronic hepatitis C (CHC) patients.METHODS: CHC patients who received pegylated interferon and ribavirin were enrolled in this cohort study that investigated the ability of alpha-fetoprotein (AFP) to predict HCC development after interferon (IFN) therapy.RESULTS: Of 1255 patients enrolled, 665 developed sustained virological response (SVR) during mean follow-up period of 5.4 years. HCC was occurred in 89 patients, and 20 SVR patients were included. Proportional hazard models showed that HCC occurred in SVR patients showing AFP ≥ 5 ng/mL before therapy and in non-SVR patients showing AFP ≥ 5 ng/mL before and 1 year after therapy besides older age, and low platelet counts. SVR patients showing AFP ≥ 5 ng/mL before therapy and no decrease in AFP to < 5 ng/mL 1 year after therapy had significantly higher HCC incidence than non-SVR patients showing AFP ≥ 5 ng/mL before therapy and decreased AFP (P = 0.043). AFP ≥ 5 ng/mL before therapy was significantly associated with low platelet counts and high values of alanine aminotransferase (ALT) in stepwise logistic regression analysis. After age, gender, platelet count, and ALT was matched by propensity score, significantly lower HCC incidence was shown in SVR patients showing AFP < 5 ng/mL before therapy than in those showing AFP ≥ 5 ng/mL.CONCLUSION: The criteria of AFP < 5 ng/mL before and 1 year after IFN therapy is a benefical predictor for HCC development in CHC patients.