Possible Development Of Hepatocellular Carcinoma Research Articles

Five-Year Follow-Up of Cured HCV Patients under Real-World Interferon-Free Therapy.

Simple SummaryHepatitis C virus (HCV) is the major factor responsible for hepatocellular carcinoma (HCC). Currently available treatments for HCV infection are short, simple, effective and safe. Long-term monitoring of patients is essential to demonstrate the efficacy of antiviral therapy, including the risk of HCC development. Since highly effective treatment options only became available in the middle of the past decade, we evaluated patients treated during this period five years after treatment. We have shown that the risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful treatment. Therefore, longer follow-up is necessary to assess the long-term risk of developing HCC, especially in patients with cirrhosis.(1) Background: Treatment of hepatitis C virus (HCV) infections with direct-acting antivirals (DAA) has demonstrated high efficacy and an excellent safety profile. The cured patients showed a sustained virological response and improved liver function, but also a continued risk of hepatocellular carcinoma (HCC) during the 2–3 years of follow-up after treatment; (2) Methods: A total of 192 patients out of 209 of the primary AMBER study were analyzed five years after treatment with ombitasvir/paritaprevir/ritonavir with or without dasabuvir and with or without ribavirin. Results: We confirmed that HCV clearance after DAA treatment is stable regardless of baseline liver fibrosis. We found that sustained virologic response is associated with a gradual but significant reduction in liver stiffness over 5 years. Liver function improved during the first 2 years of follow-up and remained stable thereafter. The risk of death due to HCC as well as death due to HCV persists through 5 years of follow-up after successful DAA treatment. However, in non-cirrhotic patients, it appears to clear up 3 years after treatment; (3) Conclusions: Monitoring for more than 5 years after curing HCV infection is necessary to assess the long-term risk of possible development of HCC, especially in patients with cirrhosis of the liver.

A Simple Noninvasive Index Can Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B

Screening for possible development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is essential for risk prediction and early therapy. This study reported a novel model comprised of routine laboratory variables for predicting HCC from CHB. A retrospective study was performed among 463 participants. alpha-fetoprotein (AFP), platelet and alanine aminotransferase (ALT) ratio (APAR) was constructed to differentiate HCC from CHB or non-cancer with area under the receiver operating characteristic curves (AUC) of 0.815 and 0.868 in the training set, 0.831 and 0.861 in the validation set, respectively. In participants with low or normal AFP (<100 ng/mL), the diagnostic efficacy of APAR measured by AUC were 0.817 and 0.809 for predicting HCC from CHB or non-cancer, and at a cutoff of 0.47, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 89%, 60%, 67% and 86%, respectively. For participants with normal AFP (<20 ng/mL), the AUC of APAR were 0.839 and 0.746 accompanied by a cutoff of 0.36 with sensitivity, specificity, PPV, and NPV of 88%, 69%, 71%, and 87%, respectively. In conclusion, APAR is an effective model for HCC screening especially in those with low even normal serum AFP levels.

Do occupational exposures to vinyl chloride cause hepatocellular carcinoma and cirrhosis?

Controversy exists about the association between occupational exposures to vinyl chloride and hepatocellular carcinoma and cirrhosis. Two large multicentre mortality cohort studies, one American and another European, reported higher mortality for primary cancer of liver and biliary tract. However, the American study was not able to rule out misclassification, because based on death certificates and under the heading primary liver cancers, some angiosarcomas, the typical neoplasia associated with vinyl chloride, may have been included. The American study does not report on cirrhosis mortality. The European study also reports higher mortality of primary liver cancer, but contrary to the American study in a further analysis based on 10 verified cases of hepatocellular carcinoma, an exposure-response trend with duration of employment and with cumulative exposure to vinyl chloride was detected. A smaller cohort belonging to this multicentre cohort confirmed these results. Meta-analyses based on the two large cohorts concluded for a small excess of primary liver cancer, although misclassification could not be ruled out. Excess risk of cirrhosis was reported in the European cohort, in a subcohort and in a cross-sectional study. However, a meta-analysis did not confirm this excess. Several critical appraisals of the literature reached antithetical conclusions about hepatocellular carcinoma, cirrhosis and occupational exposures to vinyl chloride. For both hepatocellular carcinoma and cirrhosis, a study suggests an additive and multiplicative effect of vinyl chloride exposure with viral hepatitis and alcohol consumption respectively. Pathology reports seem to indicate a possible development of hepatocellular carcinoma but not of cirrhosis after high exposures to vinyl chloride.

Promising Anti-Hepatitis C Virus Compounds from Natural Resources

Hepatitis C virus (HCV) infection is a major worldwide problem, which involves approximately 170 million people. High morbidity of patients is caused by chronic infection, which leads to liver cirrhosis, hepatocellular carcinoma and other HCV-related diseases. The sustained virological response (SVR) has been markedly improved to be >90% by the current standard interferon (IFN)-free treatment regimens with a combination of direct-acting antiviral agents (DAAs) targeting the viral NS3 protease, NS5A multi-function protein and NS5B RNA-dependent RNA polymerase, compared with 50-70% of SVR rates achieved by the previous standard IFN-based treatment regimens with or without an NS3 protease inhibitor. However, the emergence of DAA-resistant HCV strains and the limited access to the DAAs due to their high cost could be major concerns. Also, the long-term prognosis of patients treated with DAAs, such as the possible development of hepatocellular carcinoma, still needs to be further evaluated. Natural resources are considered to be good candidates to develop anti-HCV agents. Here, we summarize anti-HCV compounds obtained from natural resources, including medicinal plant extracts, their isolated compounds and some of their derivatives that possess high antiviral potency against HCV.

Aqueous extract of Corchorus olitorius decreases cytotoxicity of aflatoxin B1and fumonisin B1in H4IIE-luc cells

75 ABSTRACT Aim: Afl atoxin B1 (AFB1) and fumonisin B1 (FB1) are important food-borne mycotoxins. Co-contamination of foodstuffs with these two mycotoxins is well-known and has been implicated in a possible development of hepatocellular carcinoma in humans living in regions of the world where exposures to these mycotoxins in grain are greatest. The aim of the current study was to evaluate the potential protective effects of an aqueous extract of Cochorus olitorius (C. olitorius, moroheiya) against cytotoxicity of AFB1 and/or FB1 in H4IIE-luc rat hepatoma cells, using assays to measure cell viability and disruption of DNA integrity. Although this transactivation assay was originally developed to specifi cally respond to aryl hydrocarbon agonists, this cell line was used because of its hepatic origin. Methods: H4IIE-luc cells were incubated with different concentrations of AFB1 and/or FB1 for 24 and 48 h with or without aqueous extract of C. olitorius. Results: Both mycotoxins decreased cell viability and increased DNA damage. Cytotoxicity was more pronounced when cells were exposed simultaneously to AFB1 and FB1. Conclusion: Aqueous extract of C. olitorius protected cells against cytotoxicity of mycotoxins. C. olitorius contains a water-soluble, natural chemo-preventative agent for cancer that should be isolated and identifi ed.

Current management options for tyrosinemia

Correspondence: Mortada Hassan El-Shabrawi Pediatric Hepatology, Cairo University, 3 Nablos Street, off Shehab Street, Mohandesseen, Cairo 12411, Egypt Tel +201 2313 3705 Fax +202 3761 9012 Email melshabrawi@medicine.cu.edu.eg Abstract: Hypertyrosinemia is observed in three inherited disorders of tyrosine metabolism. Hereditary Tyrosinemia Type I (HTT-I), or hepatorenal tyrosinemia, is an autosomal recessive disorder caused by mutation in the fumarylacetoacetate hydrolase (FAH) gene. HTT-I is associated with severe involvement of the liver, kidneys, and central nervous system, and is due to toxic accumulation of metabolites of tyrosine, such as succinylacetone. HTT-I is the inborn error with the highest incidence of progression to hepatocellular carcinoma. Elevated succinylacetone, in dried filter paper blood samples, or in plasma or urine, is pathognomonic and diagnostic for HTT-I and is the most reliable neonatal screening method. Liver transplantation is the definitive management, but the need for this is markedly decreased by the combined dietary and drug management. A diet low in tyrosine and phenylalanine, plus nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione) (NCTB) are considered the gold standard management options. Carnitine and 1,25-OH-vitamin D are adjuvant therapy. Strict follow up with succinylacetone level for monitoring of treatment should be done. Abdominal ultrasonography and abdominal computerized tomography scan or magnetic resonance imaging should also be done for surveillance of the possible development of hepatocellular carcinoma.

Occurrence of Hepatocellular Carcinoma Was Not a Rare Event during and Immediately after Antiviral Treatment in Japanese HCV-Positive Patients

Advanced chronic hepatitis C patients with sustained virolological response by antivirals remain at risk for hepatocellular carcinoma (HCC). We investigated the incidence of HCC during and immediately after peginterferon-alfa-2a and ribavirin (RBV) treatment in patients with chronic hepatitis C in Japan. HCC was detected in 8 of 238 patients during and after these treatments (mean follow-up period: 572 ± 252 days). In conclusion, occurrence of HCC is not a rare event during and immediately after peginterferon-alfa-2a plus RBV treatment. In cases with cirrhosis, higher α-fetoprotein levels, old age, or a previous history of HCC treatment, clinicians should be especially alert for the possible development of HCC during and immediately after peginterferon-alfa-2a and RBV treatment. Clinicians should regularly check for the possible development of HCC even in chronic hepatitis C patients under treatment.

Liver Transplantation to Treat Suspected Hepatocellular Carcinoma in Iron-Free Foci in Congenital Hemochromatosis: Case Report

Hepatocellular carcinoma (HCC) commonly develops in cirrhotic or noncirrhotic livers affected by congenital hemochromatosis. In patients with congenital hemochromatosis and HCC, liver transplantation is a therapeutic option with a 5-year posttransplantation survival rate as high as 80%. Herein is reported congenital hemochromatosis in a 37-year-old man. During a routine checkup, 2 liver nodules were detected. Signal characteristics at magnetic resonance imaging indicated the presence of iron-free foci (IFF). The serum α-fetoprotein concentration was within the range of normal, and repeated liver biopsy did not show histomorphologic signs of malignancy but confirmed the presence of IFF in surrounding siderosis. The patient was listed for liver transplantation with match MELD (Model of End-Stage Liver Disease including exceptions) because of suspected HCC. After 173 days on the waiting list, liver transplantation was performed successfully. Histologic examination of the explanted liver confirmed 2 HCC lesions with a diameter of 0.9 cm in the exact projection as the IFF detected at magnetic resonance imaging. At 20 months of rapamycin-based immunosuppression therapy, there were no signs of HCC recurrence. This is, to our knowledge, the first report of liver transplantation performed to treat suspected HCC based on the finding of IFF in congenital hemochromatosis, with histopathologic confirmation of the diagnosis of HCC after transplantation. According to this case and the current literature, IFF in patients with congenital hemochromatosis should be considered preneoplastic lesions vulnerable to possible development of HCC.

Pathological analysis of oxyphilic granular hepatocytes and hepatocellular mitochondria in chronic hepatitis C

Oxyphilic granular hepatocyte (OGH) results from hepatocellular changes associated with chronic hepatitis. The histopathological significance of OGH has not been clarified. The subjects consisted of two groups of patients with hepatitis C: one group of patients who had undergone liver biopsy 3.8 times on average, and were followed for 8 years on average, and one group of hepatocellular carcinoma (HCC) patients who had undergone hepatectomy. The following items were examined: frequency of OGH, relationship between OGH and the degree of fibrosis and inflammation; amount of mitochondria in resected tissues; activity of mitochondrial enzymes; relationship between the development of HCC and OGH; and relationship between the duration of infection and OGH in the post-transfusion patients. The incidence of OGH was 35.3% in liver biopsy patients and 46.9% in resected patients. A higher stage of fibrosis was associated with a higher frequency of OGH. Not only OGH but also hepatocyte mitochondria in the peripheral zone increased with the progression of fibrosis. Hepatocytes with or without increased mitochondria were randomly distributed. The mitochondrial enzyme activity was increased in hepatocytes with increased mitochondria. In the post-transfusion patients, a longer duration of infection and a higher stage of fibrosis were associated with a higher frequency of OGH. A high percentage of patients with OGH developed HCC. Mitochondrial changes are important histological findings related to the progression of liver lesions and the possible development of HCC.

Clinical Outcomes of Delayed Clearance of Serum HBsAg in Patients with Chronic HBV Infection

BackgroundSpontaneous delayed clearance of hepatitis B surface antigen (HBsAg) in patients with chronic HBV infection is a rare event. The aim of this study was to investigate the incidence of delayed clearance of serum HBsAg in chronic HBV infection and to determine the characteristics and clinical outcomes of HBsAg delayed clearance in Korean patients.MethodsFrom April 1981 to June 2003, 4,061 patients who were positive for HBsAg were evaluated retrospectively. The following assessments were undertaken in 47 patients who had spontaneous delayed clearance: liver biochemistry, viral markers, α-fetoprotein levels, and radiographic examinations including ultrasonography every three to six months for 6-264 months (median 87.9 months).ResultsTwenty-four of 47 patients were asymptomatic carriers. The others included seven patients with chronic hepatitis, seven with liver cirrhosis and nine with hepatocellular carcinoma. The estimated annual incidence of HBsAg seroclearance was 0.4%. The time span from positive HBsAg to HBsAg seroclearance in the AHC, CH, LC, and HCC was 62.9, 141, 63, and 95.3 months during follow up. Twenty-four of 24 AHC remained normal, 5 of 7 CH remained as CH and 2 patients remained normal, 1 of 7 with LC developed HCC and 6 of the LC remained as LC, and 4 of 9 HCC patients died.ConclusionThe clinical course following delayed clearance of HBsAg had diverse outcomes from AHC to HCC. Therefore, these patients require close follow up for the possible development of hepatocellular carcinoma following HBsAg clearance.

Hepatocellular Carcinoma in Hereditary Tyrosinemia Type I Despite 2-(2 Nitro-4-3 Trifluoro- Methylbenzoyl)-1, 3-Cyclohexanedione Treatment

Hepatocellular Carcinoma in Hereditary Tyrosinemia Type I Despite 2-(2 Nitro-4-3 Trifluoro- Methylbenzoyl)-1, 3-Cyclohexanedione Treatment

Liver tissue examination.

Histopathological study of the liver biopsy in viral hepatitis B allows to diagnose acute hepatitis, its severity and stage of evolution. Prediction of chronicity is feasible after two months. In chronic disease, histopathology allows to diagnose chronic hepatitis, its aetiology, grade of severity and stage of progression. Interface hepatitis and bridging confluent necrosis are important prognostic features. Severity is graded according to extent of necro-inflammatory lesions, which include portal inflammation, interface hepatitis, intralobular liver cell damage and death, and confluent (bridging) necrosis. Staging of progression is based on extent of fibrosis and lobular architectural changes (cirrhosis). Semiquantitative scoring of grade and stage is useful in trials of new drugs, in clinical research, and for comparison of preand post-treatment biopsies. It is not recommendable in routine diagnostic practice. In situ hybridization and (immuno-)electron microscopy are less practical and mostly used in research. Immunohistochemical staining for HBV antigens, especially for HBcAg and HBsAg, is useful for specifying the aetiology and the viral phase of the disease. The viral replicative phase is characterized by mild activity, nuclear localization of HBcAg, cytoplasmic HBeAg and membranous expression of HBsAg; the viral clearance phase features more severe inflammation and necrosis, possibly including the bridging type, whereas immunostaining reveals nuclear, cytoplasmic and membranous HBcAg; HBsAg stains in the cytoplasm of some cells, and in cellular membranes; the residual integration phase reveals no or only mild activity and cytoplasmic HBsAg, without demonstrable HBcAg. Attention for and reporting of premalignant lesions is important in improving adequate patient surveillance for possible development of hepatocellular carcinoma. Recognizable lesions include large cell and small cell liver cell dysplasia in dysplastic foci and nodules.

Long-term outcome of chronic hepatitis B in adolescents or young adults in follow-up from childhood.

It has not yet been defined whether children with chronic hepatitis B are likely to develop severe liver disease in the future. The purpose of this study was to evaluate the evolution of chronic hepatitis B acquired in childhood. Fifty-two children in the age range of 0 to 15 years who were positive for hepatitis B surface antigen and hepatitis B e antigen in serum for at least 6 months were enrolled in this study. In the majority of the 52 children, hepatitis B virus infection was acquired by perinatal transmission. All 52 showed abnormal liver function test findings for more than 6 months before enrollment, and the subjects were followed up longitudinally for 3 to 22 years (mean, 11 years). They are now more than 15 years of age (15-27 years old). During the follow-up period, 26 (50%) children had spontaneous seroconversion to anti-hepatitis B e. Serum levels of alanine aminotransferase normalized in these 26 children. In one child of these children, hepatocellular carcinoma developed at the age of 21 years, 16 years after seroconversion, although his liver function profiles remained normal. The other 26 children remained hepatitis B e antigen positive, most with unchanged biochemical features. Sixteen (62%) children among these 26 children were treated with interferon-alpha. Eleven (69%) children had seroconversion to anti-hepatitis B e within the first year after the cessation of therapy. Hepatocellular carcinoma developed in 1 of these 11 children at the age of 16 years, 6 years after interferon therapy. Thus, hepatocellular carcinoma developed in two children in an anti-hepatitis B e positive phase. All children carrying hepatitis B surface antigen should be observed carefully to monitor the possible development of hepatocellular carcinoma, especially in the antihepatitis B e-positive phase after spontaneous seroconversion or even after interferon treatment.

Liver transplantation for glycogen storage disease types I, III, and IV.

Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy have dramatically improved the outcome of GSD type I by reducing the incidence of liver adenoma and renal insufficiency. Nine type I and 3 type III patients have received liver transplants because of poor metabolic control, multiple liver adenomas, or progressive liver failure. Metabolic abnormalities were corrected in all GSD type I and type III patients, while catch-up growth was reported only in two patients. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in both GSDIb patients post liver transplantation necessitating continuous granulocyte colony stimulating factor treatment. Thirteen GSD type IV patients were liver transplanted because of progressive liver cirrhosis and failure. All but one patient have not had neuromuscular or cardiac complications during follow-up periods for as long as 13 years. Four have died within a week and 5 years after transplantation. Caution should be taken in selecting GSD type IV candidates for liver transplantation because of the variable phenotype, which may include life-limiting extrahepatic manifestations. It remains to be evaluated, whether a genotype-phenotype correlation exists for GSD type IV, which may aid in the decision making. Liver transplantation should be considered for patients with glycogen storage disease who have developed liver malignancy or hepatic failure, and for type IV patients with the classical and progressive hepatic form.