Serum Alpha-Fetoprotein Has High Specificity for the Early Detection of Hepatocellular Carcinoma After Hepatitis C Virus Eradication in Patients

Alpha-fetoprotein (AFP) has not played a large role in the surveillance of hepatocellular carcinoma due to inadequate sensitivity and specificity for active chronic hepatitis or cirrhosis. The aim of this study was to evaluate the diagnostic accuracy of AFP in small hepatocellular carcinomas after hepatitis C virus eradication to determine the optimal cutoff value.We conducted a case–control study of 29 cases and 58 controls, matched for age, gender, and platelet counts.The AFP cutoff was 5 ng/mL in patients after hepatitis C virus eradication and 17 ng/mL in those without hepatitis C virus eradication. The areas under the receiver operating characteristic curve were 0.86 (95% confidence interval, 0.76–0.96) in patients after hepatitis C virus eradication and 0.83 (95% confidence interval, 0.74–0.91) in those without hepatitis C virus eradication. In patients after hepatitis C virus eradication, the sensitivity and specificity of AFP levels were 24.1% and 100%, respectively, using a cutoff value of 17 ng/mL. Using a lower cutoff value of 5 ng/mL, the sensitivity increased to 75.9%, although the specificity decreased to 89.0%.AFP is a specific tumor marker for the diagnosis of hepatocellular carcinoma after hepatitis C virus eradication when using the optimal cutoff value of 5 ng/mL.     

Retinal Complications During Interferon Therapy for Chronic Hepatitis C

Objectives: Various side effects of interferon (IFN) therapy have been reported. In this study, we examined retinal change during IFN therapy. Methods: We performed ophthalmological examinations before, during, and after therapy on 63 patients with chronic hepatitis C who were receiving either natural IFN-a or recombinant IFN-α 2a or 2b. Results: No retinal lesion was detected before IFN therapy, but, during therapy, retinal abnormality or retinopathy developed in 36 (57.1%) of 63 patients, including retinal hemorrhage in 25 patients and cotton-wool spots in 28 patients. They were noted early in the course of IFN therapy, within the first 4 wk in 67% (24/36) and within 8 wk in 86% (31/36). The incidence was not influenced by the type of IFN but was higher among diabetic (11/12, 92%, p < 0.05) or hypertensive patients (4/5, 80%, not significant) than among patients without either diabetes or hypertension (24/49, 49%). There was no relation between the incidence of retinopathy and the level of ALT activity or white blood cell or platelet counts. However, retinopathy occurred in most patients receiving IFN therapy after white blood cell count and platelet count reached a nadir. The levels of L DK -cholesterol and the atherosclerotic index in patients with retinopathy were slightly higher than those in the patients without retinopathy. Conclusions: These results suggest that retinopathy often occurs in patients with chronic hepatitis C who are receiving IFN and that we should closely monitor patients for retinal complications during IFN therapy.     

Necessities of Interferon Therapy in Elderly Patients with Chronic Hepatitis C

Background

The significance of antiviral therapy for elderly patients with chronic hepatitis C virus (HCV) infection has not been elucidated.

Patients and Methods

Among 5645 patients with HCV-related chronic liver disease, the prognosis of 1917 elderly patients aged 60 years or more was analyzed. A total of 454 patients underwent interferon (IFN) therapy. By using multivariate analysis, carcinogenesis and survival were analyzed according to initial findings.

Results

At 10 and 15 years, cumulative survivals in untreated elderly patients were 90.7% and 72.7% in the high platelet (≥150,000/mm³) group, 78.6% and 47.8% in the intermediate (100,000-149,000/mm³) group, and 52.5% and 25.0% in the low platelet group (<100,000/mm³), respectively. At 5 and 10 years, hepatocarcinogenesis rates in the intermediate and low platelet groups were 10.9% and 21.6% in the IFN group (N = 217) and 19.5% and 43.0% in the untreated group (N = 459), respectively (P = .0005). IFN independently decreased carcinogenesis risk with a hazard ratio of 0.56 (P = .035). In the high platelet group, 5- and 10-year carcinogenesis rates were 3.7% and 8.3% in the IFN-treated group (N = 228) and 5.1% and 14.0% in the untreated group (N = 585), respectively (P = .69). IFN treatment significantly increased cumulative survivals in the lower platelet subgroup (P = .0001) but did not affect the higher platelet subgroup (P = .08). IFN was independently associated with a longer survival in the lower platelet subgroup (hazard ratio 2.33, P = .005).

Conclusion

In elderly patients with chronic HCV, IFN for a subgroup with intermediate and low platelet counts had significant advantages in regard to hepatocarcinogenesis and survival.     

Significance of Prior Hepatitis B Virus Infection in the Development of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

To clarify the clinical significance of prior hepatitis B virus (HBV) infection in the development of C-viral hepatocellular carcinoma (HCC), we conducted two studies: (1) Two hundred thirty-four patients with C-viral HCC and 320 patients with C-viral chronic liver disease without HCC admitted to our hospital between 1990 and 1994 were analyzed for the association of hepatitis B core antibody (HBcAb) positivity with HCC by multivariate logistic regression analysis, and this revealed HBcAb positivity as an independent risk factor for development of HCC adjusted for age and sex. (2) Four hundred fifty-nine patients with biopsy-proven hepatitis C virus-related chronic liver disease between 1986 and 1998 were enrolled in the cohort study and followed for the development of HCC. During an average follow-up of 6.6 ± 3.3 years, HCC developed in 63 patients, 37 of 160 patients positive for HBcAb and 26 of 299 patients negative for HBcAb. Multivariate Cox proportional regression analysis showed that the incidence of HCC increased by age, advanced stage of liver fibrosis, mean alanine aminotransferase value of more than 80 IU/liter, and positivity of HBcAb. Sustained virological responders after interferon therapy revealed a reduced risk for HCC development. In conclusion, prior HBV infection was shown to be one of the independent risk factors for development of HCC in C-viral chronic liver disease.     

The Role of Interferon Therapy in Patients with Hepatocellular Carcinoma

Interferon (IFN) not only may have antiviral properties against hepatitis C, but also may reduce the risk of hepatocellular carcinoma (HCC) through anticarcinogenic properties or indirectly by antifibrotic effects. Because patients with chronic hepatitis C and cirrhosis are at risk for HCC, IFN was used to prevent or treat HCC in patients with hepatitis C. Studies demonstrate that the risk of HCC in hepatitis C patients who are sustained viral responders is substantially reduced but not eliminated. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial demonstrated that maintenance therapy with IFN does not reduce the risk of HCC in patients with bridging fibrosis or cirrhosis. Other studies suggest the risk of HCC is reduced with IFN maintenance therapy in older patients or in patients whose ??-fetoprotein levels decline. A randomized clinical trial demonstrated IFN therapy is not effective against HCC. Few studies suggest IFN may reduce the risk of recurrent HCC or reduce tumor burden after ablation or resection. Larger trials are needed to determine if IFN can prevent tumor recurrence after resection or locoregional therapy in patients with hepatitis C cirrhosis and HCC.     

Serum Soluble Interleukin-2 Receptor Levels Before and During Interferon Treatment in Patients with Chronic Hepatitis B Virus Infection

To determine the role of serum solubleinterleukin-2 receptor (sIL-2R) in chronic hepatitis Bvirus (HBV) infection, the level of serum sIL-2R wasmeasured in sera of 105 patients with chronic HBVinfection and in 21 healthy controls, using enzyme-linkedimmunosorbent assay. Serum sIL-2R levels weresignificantly higher in chronic HBV-infected patientswith chronic hepatitis (508 ± 310 units/ml) andliver cirrhosis (543 ± 283 units/ml) than inhealthy controls (331 ± 106 units/ml, P <0.05). Moreover, serum sIL-2R levels were significantlyhigher in patients with chronic hepatitis or livercirrhosis than in asymptomatic HBV carriers (341 ±150 units/ml, P < 0.01). There was no difference inserum sIL-2R levels between asymptomatic HBV carriersand healthy controls or between patients with chronic hepatitis and liver cirrhosis. A significantrelationship was found between serum sIL-2R and ALTlevels (P < 0.05) in patients with chronic HBVinfection, although there was no correlation betweensIL-2R and HBV DNA levels. Serum sIL-2R levels in mostpatients decreased to the same level as asymptomatic HBVcarriers and healthy controls at 48 weeks after the endof treatment, and serum ALT and HBV DNA levels were decreased to within the normal range at 96weeks. Thus, serum sIL-2R levels indicate the degree ofliver damage among patients with chronic HBV infection.The serum sIL-2R levels one year after interferon administration may be a useful marker ofdetermined at the effectiveness by thistreatment.     

Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

Independent Risk Factors for Hepatocellular Carcinoma Recurrence after Direct-Acting Antiviral Therapy in Patients with Chronic Hepatitis C

Background/AimsThis study was performed to evaluate the efficacy of direct-acting antivirals (DAAs) in Korean patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and to investigate the risk factors associated with HCC recurrence.MethodsA total of 100 patients with HCV-related HCC, who were treated with DAAs between May 2015 and December 2016, were recruited from seven university hospitals in Korea. Claim data of 526 patients with HCC obtained from the Health Insurance Review and Assessment Service in South Korea were used for external validation of the results.ResultsAmong the 100 patients, 88% achieved a sustained virological response (SVR) 12 weeks after the end of DAA therapy (SVR12), and 37% experienced HCC recurrence after DAA therapy. Short last HCC treatment durability (<12 months) before DAA commencement was independently associated with HCC recurrence (hazard ratio [HR], 2.89; p=0.011). In the nationwide validation cohort, 20.3% of the patients experienced HCC recurrence. The last HCC treatment with a noncurative method, a short last HCC treatment durability (<12 months), and a longer total duration of HCC treatment (≥18 months) were independently related with HCC recurrence (HR 3.73, p<0.001; HR 3.34, p<0.001; and HR 1.74, p=0.006; respectively).ConclusionsDAA therapy showed an acceptable SVR12 rate in patients with HCV-related HCC. Short last HCC treatment durability (<12 months) was associated with HCC recurrence after DAA therapy. This finding suggests that the last HCC treatment durability is an important predictor of HCC recurrence after DAA therapy. (Gut Liver 2021;15-419)     

Acute Pancreatitis Associated with Interferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

Acute pancreatitis is a rare complication of interferon (IFN) and ribavirin (RBV) therapy. The aim of this study was to determine the incidence, clinical presentation, and outcome of acute pancreatitis in patients with chronic hepatitis C virus (HCV) infection treated with IFN and RBV combination therapy. We conducted a retrospective review of 1706 HCV-infected patients treated with IFN alpha-2b and RBV. The diagnosis of drug-induced acute pancreatitis was made based on the presence of epigastric pain, elevated amylase and lipase levels, and the absence of other identifiable causes of pancreatitis. Acute pancreatitis was diagnosed in 7 of 1706 HCV-infected patients (0.4%; 95% CI, 0.2 to 0.8%) who were treated with IFN alpha-2b and RBV. The mean age of the patients (four males and three females) was 51.4 +/- 4.7 years and the median duration of therapy prior to development of pancreatitis was 12.0 weeks (range, 4.0-21.0 weeks). All patients presented with epigastric pain associated with nausea, vomiting, and/or fever. The median amylase and lipase values at the time of diagnosis of pancreatitis were 330.0 U/L (range, 182.0-1813.0 U/L) and 500.0 U/L (range, 171.0-2778.0 U/L), respectively. IFN and RBV were discontinued in all patients at the time of diagnosis and six of the seven patients were hospitalized; one patient refused hospital admission. Pancreatitis resolved in all seven patients and none of these individuals had recurrent pancreatitis during a median follow-up of 18.0 months (range, 3.0-27.0 months). In conclusion, IFN and RBV combination therapy is a potential cause of drug-induced pancreatitis in patients with chronic HCV. In these individuals, pancreatitis is often severe enough to warrant hospital admission, although symptoms resolve promptly after discontinuation of antiviral therapy.     

Early Loss of Serum Hepatitis C Virus RNA Can Predict a Sustained Response to Interferon Therapy in Patients with Chronic Hepatitis C

Objectives : We evaluated whether the loss of serum hepatitis C virus (HCV) RNA early in interferon (IFN) therapy would indicate a subsequent response to IFN therapy. Methods : One hundred fourteen patients with chronic hepatitis C were treated with IFN-α for 24 weeks. All patients were positive for anti-HCV antibodies and serum HCV RNA. Serum HCV RNA was measured by highly sensitive and specific RT-PCR (modified Amplicor HCV). Results : Of 114 patients who were treated with IFN-α for 24 weeks, 22 of 29 patients (75.9%) who lost HCV RNA at the first week of treatment, 5 of 14 patients (35.7%) who lost HCV RNA at the second week, and 2 of 16 patients (12.5%) who lost HCV RNA at fourth week were judged as sustained responder (SR). The SR rate was significantly higher in patients who lost HCV RNA at the first week of therapy ( p < 0.05). On the contrary, none of 55 patients who retained HCV RNA during the first 4 weeks of IFN therapy were judged as SR. Concerning the patients who lost HCV RNA at the first week of therapy, there were no significant differences in the SR rate in either HCV genotype (1b, 2a, and 2b). Conclusions : Our study confirms that the early response to IFN (loss of HCV RNA at the end of the first week of IFN therapy) can be a predictor of the subsequent sustained response to IFN therapy. Additionally, positivity of HCV RNA at the fourth week of IFN therapy can be a predictor of the subsequent non-sustained response to IFN therapy.     

Prognostic Significance of Serum Galectin-3 Levels in Patients with Hepatocellular Cancer and Chronic Viral Hepatitis

Background/Aim:

Galectins affect diverse physiological and pathophysiological processes such as development, inflammation, and tumor growth. We aimed to compare serum galectin-3 levels in three patient groups with chronic hepatitis B and C virus (HBV, HCV), cirrhosis secondary to HBV or HCV, and hepatocellular carcinoma (HCC) secondary to HBV or HCV and evaluate the role of galectin-3 during HCC progression.

Patients and Methods:

Nineteen patients with hepatocellular cancer, 22 patients with cirrhosis, and 24 patients with chronic hepatitis B and C were included in this study. Serum galectin-3 levels in different liver diseases were assessed by enzyme-linked immunosorbent assay.

Results:

The mean galectin-3 levels were 4.61 ng/mL (±2.32) in HCC patients, 5.68 ng/mL (±2,2) in cirrhotic patients, 1.98 ng/mL (±1.50) in chronic viral hepatitis group. There were no statistical differences between HCC and cirrhotic patients (P = 0.5), but lower in chronic hepatitis group statistically compared with cirrhosis and HCC (P < 0.001, P = 0.002, respectively). In case of cirrhotic patients, galectin-3 levels were significantly higher in patients with cirrhosis secondary to HCV compared with HBV (P = 0.03). When we evaluated galectin-3 levels in HCC patients, it was found to be 3.92 ng/mL in HCC secondary to hepatitis B and 5.37 ng/mL in HCC secondary to hepatitis C.

Conclusion:

Serum galectin-3 levels in patients with chronic HBV or HCV may guide us about progression to cirrhosis or HCC and prognosis of the disease. Especially, galectin-3 levels may be more pronounced in case of HCV.     

Combined Therapy with Interferon and Ribavirin in Chronic Hepatitis C Does Not Affect Serum Quasispecies Diversity

Our aim was to investigate if interferon plus ribavirin has any effect on serum HCV quasispecies distribution and the relationship between diversity of HCV quasispecies and treatment response. In all, 21 patients were treated with interferon plus ribavirin for 48 weeks. The presence of HCV quasispecies was determined in serum samples at baseline and at the fourth week of treatment by SSCP analysis of the hypervariable region. SSCP pattern was defined as single or multiple band. A single band was found in six patients and multiple bands in nine. No significant difference was found between SSCP pattern in pretreatment samples and response to the therapy. In none of the patients were observed changes in number of SSCP bands between samples taken at baseline and in the fourth week of the therapy. In conclusion, the complexity of HCV quasispecies before the therapy was not related to treatment response; combined therapy did not affect serum HCV quasispecies.