An analysis of risk factors for developing Hepatocellular carcinoma in a group of Hepatitis C patients with stage 3 fibrosis following interferon therapy.

The risk of Hepatocellular carcinoma (HCC) is high in HCV-infected patients who have biochemically and histologically active chronic hepatitis. To observe the long prognosis of Chronic Hepatitis C (CHC) patients with stage 3 fibrosis (F3), 55 CHC patients after initial Interferon (IFN) therapy were followed up for up to 12 years (average 9.8 +/- 2.3 years). According to the annual average alanine aminotransferase (ALT) levels, patients were grouped into, low (ALT 30 <80 IU/l) and high (ALT >or= 80 IU/l) ALT groups. Eleven patients were re-treated with IFN. During the follow-up period of 12 years, HCC developed in 26 patients with an average annual incidence of 3.9%. Biochemical responders to initial IFN therapy (n = 8) and those re-treated with IFN (n = 10), except 1, did not develop HCC. Cox regression analysis to evaluate risk factors for HCC occurrence, found development of Liver Cirrhosis within 3 years of initial IFN therapy(P = 0.05) and the 3 year annual average ALT post initial IFN therapy (P = 0.033) to be significant. The 12 year annual average ALT was also found to be significantly related to HCC occurrence (P = 0.016), on univariate analysis. Patients belonging to the continuously low ALT group (ALT or=3 years), did not develop HCC or receive IFN re-treatment. In CHC patients with F3, after initial IFN therapy, keeping ALT continuously low, below 30 IU/l for 3 years or more seems important. Continuing treatment with anti-inflammatory drugs along with subsequent IFN re-treatment may prevent or delay HCC even in elderly patients.

Influence of viral load and genotype in the progression of Hepatitis B-associated liver cirrhosis to hepatocellular carcinoma.

AIM/BACKGROUND: Hepatitis B virus (HBV) is an important factor in the development of hepatocellular carcinoma (HCC). We studied the influence of HBV viral load on HCC occurrence in HBV related liver cirrhosis (LC). PATIENTS AND METHODS: Ninety-one LC patients were followed up over a period of 7 years. Twenty three patients received Interferon (IFN) therapy. RESULTS: In 7 years, 23 patients developed HCC. Of them twenty-two (95.6%) were of genotype C. HBV DNA was found to be the only significant variable associated with HCC occurrence on both univariate (P = 0.029) and multivariate analysis (odds ratio 2.33; P < 0.033). The cumulative survival at 5 years was 83% and the annual rate of hepatitis B surface antigen clearance was 0.9 %. All of 17 HCC patients observed over a period of 5 years or more belonged to the continuously high HBV DNA group (annual average >3.7 log copies/ml) and all but one belonged to the continuously high alanine aminotransferase group (annual average >40 IU/l). CONCLUSION: Patients with genotype C and a continuously high HBV DNA for 5 years or more are at a high-risk group for HCC development. Maintaining continuously low HBV DNA for 3 years or more with anti-viral therapy, may be useful in preventing or delaying HCC occurrence.

Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C.

Oxidative stress (OS) plays a major role in chronic hepatitis C. Various OS markers have been found to be elevated in hepatitis C virus (HCV)-related liver disease. This study detected the presence of OS in serum and liver biopsy specimens of HCV patients. Reactive oxygen molecules (ROM) in sera of 54 HCV patients were compared with 23 controls. OS markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal, malondialdehyde, and thioredoxin were measured in liver biopsy specimens of 18 HCV patients with fibrosis staging F1 (six); F2 (two), F3 (four), and F4 (six). The interferon (IFN) response and hepatocellular carcinoma (HCC) occurrence in the presence of OS markers were also evaluated. The level of ROM in HCV patients was 318 +/- 56.7 Carr compared with 248 +/- 40.8 Carr in controls (p=0.032). Multivariate analysis found age (p=0.0236) to be the only independent variable associated with increase in ROM in sera. In liver biopsy specimens, OS markers were found mainly around the area of piecemeal necrosis or the periportal area. The presence of OS markers seemed to increase with fibrosis staging, although not significantly. The OS DNA damage marker 8-OHdG was detected in the nucleus of hepatocytes. Thirteen patients received IFN therapy. During the 4-year follow-up period, HCC developed in four nonresponders to IFN and in one untreated patient. OS markers were stained in both HCC cells and non-HCC cells in HCC patients. OS markers were found in serum and liver specimens of HCV-associated liver disease and in HCC tissue. Detection of OS markers may be important for monitoring disease progression in HCV patients. Antioxidant therapy in combination with antiviral therapy may minimize liver damage and aid in the prevention and subsequent development of HCC.

Effect of vitamin E on serum aminotransferase and thioredoxin levels in patients with viral hepatitis C.

OBJECTIVES: Oxidative stress induces cellular responses such as cell death, gene activation and cell proliferation, in the liver. Vitamin E (Vit. E) has been found to protect the liver against oxidative stress in animal experiments. Thioredoxin (TRX) is a stress inducible, multifunctional protein, secreted during oxidative stress. This study evaluated effects of Vit. E on serum TRX and aminotransferase levels in hepatitis C virus (HCV) patients, partly non-responsive to initial interferon (IFN), with higher than average level of serum alanine aminotransferase (ALT) after receiving anti-inflammatory drug treatment. METHODS: Seventeen HCV patients (male = 3; female = 14) of age 62 +/- 7.65 years receiving anti-inflammatory drug therapy, at least 6 months prior to Vit. E administration, were given d-alpha-tocopherol 500 mg/day, orally, for a period of 3 months. ALT, aspartate aminotransferase (AST), TRX and Vit. E were measured at 0, 1, 2 and 3 months and 1 month after end of treatment. As controls, the same patients biochemical data, 3 months from the start of therapy were used. Patients were divided into three categories: total patients "T", low ALT group "L" (ALT < 70 IU/l) and high ALT group "H" (ALT > 70 IU/l), respectively. RESULTS: The ALT level was lowered, significantly in group H, in the 1st, 2nd, 3rd and 1-month post therapy, compared to the initial value. But group L showed little or no change in ALT. Post Vit. E therapy, in groups T and H, the TRX level was elevated but remained below initial levels, whereas in group L, TRX level remained significantly lower than the pretreatment value. Groups T and L, showed significant reduction (p < 0.05) in serum TRX levels in the 2nd and 3rd month. Group H showed a tendency towards TRX reduction, but not significantly. Serum Vit. E levels increased significantly (p < 0.0001) from the 1st to 3rd month in all three T, H and L groups. CONCLUSION: Oxidative stress induced liver damage is reduced by Vit. E in patients with viral hepatitis C, particularly those with initial ALT levels > 70 IU/l. Vit. E treatment causes reduction of oxidative stress markers as TRX and ALT in sera. Therefore, Vit. E can act as a supportive therapy to combat liver damage caused by oxidative stress, in such patients with continuously high levels of ALT even after anti-viral and anti-inflammatory drug therapy.

Clinical significance of intrahepatic interleukin-8 in chronic hepatitis C patients.

Background/AIM: Interleukin-8 (IL-8) is known as a chemotactic and angiogenetic cytokine and is a potential mediator of host response to injury or inflammation. In order to identify the role of IL-8 in the pathogenesis of chronic hepatitis C (CHC), we assessed semiquantitatively the messenger RNA (mRNA) expression of IL-8 and other cytokines in liver biopsy specimens of CHC patients. METHOD: Liver biopsy specimens were obtained under peritoneoscopy from 35 patients with CHC. The mRNA expression of IL-8 and other cytokines in the liver were determined by real-time PCR and the correlation between the mRNA expression and histological classification of liver were studied. Liver histology was classified by both staging of fibrosis (F0-F4) and grading of activity (A1, mild; A2, moderate and A3, severe). RESULTS: Patients were classified into F1, 8; F2, 9; F3, 9 and F4, 9 and A1, 6; A2, 14 and A3, 15, by staging of fibrosis and grading of activity, respectively. Expression of IL-8 mRNA increased with staging of fibrosis (F1, 0.402+/-0.65; F2, 0.413+/-0.246; F3, 1.388+/-2.166; F4, 1.991+/-1.879) and grading of activity (A1, 0.560+/-0.808; A2, 0.780+/-1.268; A3, 1.548+/-1.957). The mRNA expressions of IL-2, IL-1alpha, IL-1beta, IL-15 and TNF-alpha were found to be closely correlated with IL-8 mRNA (R=0.638; 0.522; 0.487; 0.465 and 0.495, respectively, in all P<0.05). CONCLUSION: In CHC, intra-hepatic expression of both IL-8 and IL-2 increased with fibrosis and inflammatory activity. Positive correlations were found between IL-8 and other cytokines and between cytokines themselves. These findings suggest that these interacting cytokines play an active role in the pathogenesis of CHC, and maybe involved in the upregulation or induction of one and other.