Carcinogenesis on the background of liver fibrosis: Implications for the management of hepatocellular cancer

Hepatocellular carcinoma(HCC) is now the second leading cause of cancer-related deaths globally and many patients have incurable disease. HCC predominantly occurs in the setting of liver cirrhosis and is a paradigm for inflammation-induced cancer. The causes of chronic liver disease promote the development of transformed or premalignant hepatocytes and predisposes to the development of HCC. For HCC to grow and progress it is now clear that it requires an immunosuppressive niche within the fibrogenic microenvironment of cirrhosis. The rationale for targeting this immunosuppression is supported by responses seen in recent trials with checkpoint inhibitors. With the impact of immunotherapy, HCC progression may be delayed and long term durable responses may be seen. This makes the management of the underlying liver cirrhosis in HCC even more crucial as studies demonstrate that measures of liver function are a major prognostic factor in HCC. In this review, we discuss the development of cancer in the setting of liver inflammation and fibrosis, reviewing the microenvironment that leads to this tumourigenic climate and the implications this has for patient management.     

Telomere and telomerase in chronic liver disease and hepatocarcinoma

The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma (HCC) whereas others have a benign course. Therefore, a genetic predisposition may contribute to the development of cirrhosis and HCC. Evidence supporting the role of genetic factors as a risk for cirrhosis has been accumulating during the past years. In addition to the results from epidemiological studies, polymorphisms studies and data on twins, the concept of telomere shortening as a genetic risk factor for chronic liver disease and HCC has been proposed. Here we review the literature on telomerase mutations, telomere shortening and liver disease including hepatocellular carcinoma.     

The global impact of hepatic fibrosis and end-stage liver disease

Hepatic fibrosis is an integral part in the progression of chronic liver disease, ultimately leading to cirrhosis and hepatocellular carcinoma. Globally, alcohol consumption, hepatitis B (HBV) and hepatitis C (HCV) have been the main causes of cirrhosis. More recently, the increasing prevalence of obesity and the metabolic syndrome has resulted in increasing incidence of cirrhosis secondary to nonalcoholic fatty liver disease (NAFLD), especially in developed countries. Chronic liver disease and cirrhosis are important causes of morbidity and mortality in the world. Moreover, the burden of chronic liver disease is projected to increase, due in part to the increasing prevalence of end-stage liver disease and HCC secondary to NAFLD and HCV.     

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection

AIM To clarify the prevalence of occult hepatitis B virus(HBV) infection(OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma(HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus(HCV) infection. METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection(chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or moredifferent viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome. RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively(P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase 40 IU/L, Child-Pugh score and sustained virologic response(SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development. CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.     

Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND/AIMS: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan. METHODS: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease. RESULTS: HBV carriers with older age (> 50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22-25, P < 0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.41-12.03, P = 0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.30-14.52, P = 0.02). CONCLUSIONS: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.     

Treatment of chronic hepatitis C virus infection in patients with cirrhosis

Chronic hepatitis C virus (HCV) infection eventually leads to cirrhosis in 20–30% of patients and to hepatocellular carcinoma (HCC) in 1–5% of patients. Rates of sustained virological response with standard interferon-α (IFN-α) are low in patients without cirrhosis (generally < 20%) and are even lower in those with cirrhosis. Combination therapy with IFN and ribavirin improves response rates in patients with chronic hepatitis C without cirrhosis, and the results from subgroups of HCV-infected patients with advanced fibrosis or cirrhosis are encouraging. Importantly, treatment with IFN slows progression of liver fibrosis, regardless of HCV genotype or early response to therapy, and reduces the risk of HCC by two- to fivefold. The risk of development of HCC is also lower in patients who show at least a partial response to IFN therapy compared with those who show no response. There is a clear need for more definitive studies of treatment in patients with chronic hepatitis C and cirrhosis, ideally using therapies with greater efficacy. Nonetheless, based on the potential to slow the progression of liver fibrosis (regardless of treatment response) and to reduce the risk of HCC, a greater number of HCV-infected patients with cirrhosis should be considered as candidates for IFN treatment. Preliminary data indicate that pegylated IFNs have improved virological response rates and may have additional clinical benefits in the prevention or reduction of fibrosis and retardation of progression of cirrhosis and HCC in these patients.     

Subgenotypes of hepatitis B virus genotype C do not correlate with disease progression of chronic hepatitis B in Taiwan.

BACKGROUND: Hepatitis B virus (HBV) genotype C (HBV/C) has two subgenotypes: HBV/Cs and Ce. The prevalence and clinical implications of subgenotype Cs and Ce in Taiwanese HBV carriers remain unknown. METHODS: Subgenotypes of HBV/C were determined in 242 Taiwanese HBV carriers with various stages of liver disease. The clinical as well as virologic features between patients with HBV/Cs and HBV/Ce infection were further compared. RESULTS: HBV/Ce was the predominant subgenotype in Taiwan. The prevalence of HBV/Ce was 93.6% in the inactive carriers group, 84.2% in chronic hepatitis patients, 81.2% in cirrhosis patients, 92.5% in hepatocellular carcinoma (HCC) patients without cirrhosis and 91.9% in HCC patients with cirrhosis. There was no significant difference in the distribution of the HBV/C subgenotypes among patients with different stages of liver disease. CONCLUSIONS: Subgenotypes of HBV/C may not have a clinical impact on the disease progression of chronic hepatitis B in Taiwan.     

Patterns of progression

Hepatitis C virus (HCV) infection appears to have a slow but progressive evolution to chronic hepatitis and cirrhosis in a significant percentage of patients. Chronic hepatitis develops in 60–80% of patients. Worldwide prospective studies have shown that a further 20–30% of patients with chronic active hepatitis will develop cirrhosis regardless of the possible source of HCV infection. The percentage of cirrhotics is generally believed to increase progressively as the length of follow-up increases. In patients with chronic HCV, there also is high risk for the development of hepatocellular carcinoma. Factors influencing the rate of progression from chronic hepatitis to cirrhosis appear to include age at time of exposure, duration of infection, degree of liver damage at initial biopsy, immunological status, and possibly HCV genotype. The mean intervals between the time of initial infection and the diagnosis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma have been estimated to be 10, 20, and 30 years, respectively. The progression of disease is variable and is not always orderly and sequential. Patients can progress from chronic persistent hepatitis or chronic active hepatitis directly to hepatocellular carcinoma without first developing cirrhosis, especially those with genotype 1b. In addition, cirrhosis does not appear to lead to clinically apparent hepatic failure in all patients. Because of the variability in the clinical presentation and clinical progression of chronic HCV, long-term follow-up studies may be necessary to fully assess the sequelae of chronic HCV infection. Most patients with chronic HCV have abnormal liver histology but can present as otherwise healthy individuals. In contrast, patients with chronic HCV who have normal hepatic chemistries can have substantial hepatocellular damage. Consequently, treatment at diagnosis offers the greatest likelihood of eliminating the virus and preventing progression to more severe liver disease.     

Nonalcoholic steatohepatitis and noncirrhotic hepatocellular carcinoma: fertile soil

Nonalcoholic fatty liver disease (NAFLD) is easily the most common cause of chronic liver disease in the United States (U.S.) as the hepatic manifestation of the metabolic syndrome. Although only 5 to 20% of patients with NAFLD are generally considered to meet criteria for nonalcoholic steatohepatitis (NASH), with its inherent risk for progression to cirrhosis, this still represents an alarmingly large number of individuals. The exponentially growing rates of hepatocellular carcinoma (HCC) in the U.S. may be partially attributable to increased numbers of NASH cirrhotics, although recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis. This review focuses on HCC in noncirrhotic NASH with an emphasis on clinical presentation, pathogenesis, and implications for screening.     

Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease

Hepatitis B virus(HBV) infection is a dynamic state ofinteractions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B(CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma(HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.     

Digital image analysis of the distribution of proliferating cell nuclear antigen in hepatitis C virus-related chronic hepatitis,cirrhosis, and hepatocellular carcinoma

Viral dynamic studies in chronic hepatitis C virus (HCV) infection indicate a significantly shortened survival of virus-infected cells. Since at the steady state of chronic viral infection, the rate of infected cell elimination equals new cell regeneration, this would imply a high rate of hepatocyte turnover in chronic HCV liver disease. We estimated the fraction of regenerating hepatocytes in liver biopsy sections in chronic HCV liver disease, cirrhosis, and hepatocellular carcinoma (HCC). We used antibodies to proliferating cell nuclear antigen (PCNA) to detect proliferating cell nuclei in liver biopsy specimen from controls and patients with chronic hepatitis, cirrhosis, and HCC. We also used bis-benzimide to label fluorescently all hepatocyte nuclei simultaneously. Using digital image analysis, we calculated the area occupied by PCNA-stained hepatocyte nuclei, as a fraction of the total area occupied by fluorescently labeled hepatocyte nuclei (labeling index; LI). Antibody staining was negligible in the control specimen. The mean ± SE PCNA LI increased from 0.21 ± 0.1 in chronic hepatitis to 0.63 ± 0.15 in HCC. There was no significant difference between chronic hepatitis and cirrhosis. The fraction of cells undergoing regeneration is increased in chronic HCV liver disease, HCV-related cirrhosis, and HCC. Increased hepatocyte turnover could provide the link between chronic HCV liver disease and HCC.     

Characteristics of hepatitis C viral genome associated with disease progression

The clinical presentations of chronic hepatitis C are not uniform. Some patients show persistently high serum alanine transaminase (ALT) values and develop liver cirrhosis and hepatocellular carcinoma (HCC), whereas serum ALT values stay normal in other patients. The mechanism causing this diversity remains to be elucidated. The aim of this study was to identify genomic characteristics of hepatitis C virus (HCV) genotype 1b associated with disease progression. Full length sequences of HCV were determined in 14 patients who showed persistently normal serum ALT values (normal ALT group) and 13 cirrhotics with HCC (HCC group). Residues in which amino acid usage was different between these 2 groups were extracted, and Progression score was defined as the total number of residues with 7 amino acids, more frequently present in the HCC group than in the normal ALT group. In the validation of this Progression score in 9 patients with normal ALT and 25 with HCC, the score was significantly higher in the HCC group (3.1 +/- 1.1 vs. 2.0 +/- 0.9, P =.019). Finally, the correlation between the score and clinical markers related to disease progression was analyzed. In a total of 107 patients with chronic HCV infection, the Progression score was correlated significantly with platelet counts (r = -0.31, P =.0024) by multivariate analysis. In conclusion, high Progression scores were associated with the presence of HCC and low platelet counts. Sequences of the HCV-1b genome may be related to the progression of chronic hepatitis C.     

Association of Helicobacter species with hepatitis C cirrhosis with or without hepatocellular carcinoma

BACKGROUND AND AIMS: Recent studies have suggested that bacterial coinfection with Helicobacter species in patients already infected with hepatitis C virus (HCV) could be involved in the development of cirrhosis and hepatocellular carcinoma (HCC). A retrospective cross sectional study was performed in order to explore the association between Helicobacter species and HCV associated liver diseases. METHODS: The presence of Helicobacter species was tested by polymerase chain reaction on liver samples from four groups of patients. RESULTS: Helicobacter 16S rDNA was found in only 4.2% of liver samples from control patients (n=24) and in 3.5% of liver samples from patients with non-cirrhotic chronic hepatitis C (n=29) while it was found in 68.0% of liver samples from patients with HCV positive cirrhosis without HCC (n=25) as well as in 61.3% of cirrhotic liver samples from patients with HCV positive cirrhosis and HCC (n=31). In addition, when the HCC tumour tissue was tested (n=21), 90.5% of samples were positive. DNA from Helicobacter pylori- and Helicobacter pullorum-like organisms was found. CONCLUSIONS: There is an association between the presence of Helicobacter species DNA in the liver and hepatitis C cirrhosis, with or without HCC. Indeed, the presence of these bacteria could be the result of structural changes in the liver. Alternatively, Helicobacter species could be a co-risk factor in HCV chronic liver diseases. This result warrants prospective studies to determine the possible causal role of these bacteria in the progression of chronic hepatitis C.     

Correlation between serum galectin‐9 levels and liver fibrosis

Background and Aim

Chronic liver diseases progress from chronic inflammation to fibrosis to tumorigenesis. Galectin‐9, a β‐galactoside‐specific animal lectin, is indicated to contribute to all three steps of progression. The aim of this study was to determine which of the three steps was most dominant in elevating the serum galectin‐9 concentration and to test the possibility of galectin‐9 as a serum biomarker.

Methods

Japanese patients with chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), non‐alcoholic fatty liver disease, or alcoholic liver disease who provided informed consent were enrolled in this study. Serum galectin‐9 levels were measured using a sandwich ELISA. Multiple regression analyses were performed using ezr to identify factors that determined serum galectin‐9 concentration.

Results

One hundred one patients with 50 of chronic hepatitis and 51 of liver cirrhosis were enrolled; the cohort included 45 cases of hepatitis C virus infection, 13 cases of hepatitis B virus infection, and 46 cases with HCC‐related complications. The median serum galectin‐9 concentration was 77.54 pg/mL (interquartile range: 18.89–241.9 pg/mL). Multiple linear regression analyses proved Fibrosis‐4 index and aspartate aminotransferase to platelet ratio index, indexes of liver fibrosis, were able to predict the serum galectin‐9 levels with statistical significance. A multiple logistic regression analysis determined 10 pg/mL increase in the serum galectin‐9 concentration presented an odds ratio of 3.90 for liver fibrosis progression.

Conclusions

The serum galectin‐9 concentration represents a potential biomarker of liver fibrosis in patients with chronic liver diseases, regardless of chronic inflammation or the presence of HCC complications. Furthermore, higher serum galectin‐9 levels are a predictor for liver fibrosis progression.     

Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office

Chronic hepatitis C virus (HCV) infection affects approximately 1.3 % of the United States population and 4 % of veterans who use Department of Veterans Affairs medical services. Chronic HCV is the primary cause of cirrhosis, hepatocellular carcinoma (HCC), and end-stage liver disease requiring liver transplantation in the United States. Management of chronic HCV is aimed at halting disease progression, preventing cirrhosis decompensation, reducing the risk of HCC, and treating extrahepatic complications of the infection. As part of a comprehensive HCV management strategy, peginterferon alfa and ribavirin, along with the addition of a hepatitis C protease inhibitor therapy for many genotype 1-infected patients, are the current standard of care. Antiviral therapy should be provided to those individuals who are clinically stable, have moderate liver disease or compensated cirrhosis, and are motivated to pursue therapy. Many patients have comorbid medical and psychiatric conditions, which may affect their adherence to antiviral therapy or worsen while on antiviral therapy. To optimally manage hepatitis C and associated comorbidities, patients benefit from multidisciplinary teams that can provide HCV-specific care and treatment. Sustained virologic response is associated with "cure" of chronic HCV, and results in improved liver disease outcomes and prolonged survival.     

Chronic hepatitis B virus infection in the Asia-Pacific region and Africa: review of disease progression

Countries in the the Asia-Pacific region and Africa tend to have the highest prevalence of hepatitis B infection worldwide. Hepatitis B infection progresses from an asymptomatic persistently infected status to chronic hepatitis B, cirrhosis, decompensated liver disease and/or hepatocellular carcinoma. The aim of this review was to summarize rates and risk factors for progression between disease states in the Asia-Pacific region and Africa. A literature search was conducted employing MEDLINE and EMBASE (1975-2003) using the following key words: hepatitis B, natural history, disease progression, cirrhosis, hepatocellular carcinoma, mortality, Africa and the Asia-Pacific region. Bibliographies of articles reviewed were also searched. Ranges for annual progression rates were: (i) asymptomatic persistent infection to chronic hepatitis B, 0.84-2.7%; (ii) chronic hepatitis B to cirrhosis, 1.0-2.4%; and (iii) cirrhosis to hepatocellular carcinoma, 3.0-6.6%. Patients with asymptomatic persistent infection and chronic hepatitis B had relatively low 5-year mortality rates (<4%); rates (>50%) were much higher in patients with decompensated liver disease and hepatocellular carcinoma. No data were found for progression rates in African populations. Hepatitis B e antigen was a risk factor for chronic hepatitis B, and bridging hepatic necrosis in chronic hepatitis B increased the risk of cirrhosis. Risk factors for hepatocellular carcinoma included cirrhosis, co-infection with hepatitis C virus, and genetic and environmental factors. In this review, wide ranges of disease progression estimates are documented, emphasizing the need for further studies, particularly in Africa, where progression rates are largely not available. Summarizing information on factors associated with disease progression should assist in focusing efforts to arrest the disease process in those at most risk.     

Surveillance for hepatocellular carcinoma in chronic viral hepatitis: Is it time to personalize it?

Surveillance with abdominal ultrasound with or without alpha-fetoprotein is recommended by clinical practice guidelines for patients who are considered to be at risk of developing hepatocellular carcinoma (HCC), including those with cirrhosis, advanced fibrosis and special subgroups of chronic hepatitis B (CHB). Application of the standard surveillance strategy to all patients with chronic liver disease (CLD) with or without cirrhosis imposes major sustainability and economic burdens on healthcare systems. Thus, a number of HCC risk scores were constructed, mainly from Asian cohorts, to stratify the HCC prediction in patients with CHB. Similarly, even if less than for CHB, a few scoring systems were developed for chronic hepatitis C patients or cirrhotic patients with CLD of different etiologies. Recently, a few newsworthy HCC-risk algorithms were developed for patients with cirrhosis using the combination of serologic HCC markers and clinical parameters. Overall, the HCC risk stratification appears at hand by several validated multiple score systems, but their optimal performance is obtained only in populations who show highly homogenous clinic-pathologic, epidemiologic, etiologic and therapeutic characteristics and this limitation poses a major drawback to their sustainable use in clinical practice. A better understanding of the dynamic process driving the progression from CLD to HCC derived from studies based on molecular approaches and genetics, epigenetics and liquid biopsy will enable the identification of new biomarkers to define the individual risk of HCC in the near future, with the possibility to achieve a real and cost/effective personalization of surveillance.     

Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta‐analysis

Summary. Interferon (IFN) has been used in the treatment of chronic hepatitis B for decades. Beneficial effects including hepatitis B e antigen/HBV DNA seroclearance have been documented. However, the effect of treatment on the prevention of cirrhosis and hepatocellular carcinoma (HCC) development remains controversial. We conducted a meta‐analysis of available literature to evaluate whether IFN reduces the incidence of liver cirrhosis and HCC in patients with chronic hepatitis B. Twelve clinical controlled trials, including 2082 patients and comparing IFN with no treatment, were selected. Data on the incidence of liver cirrhosis and HCC in IFN treated and untreated patients were extracted from each study. The evaluation of preventive effectiveness was performed with an intention‐to‐treat method. The relative risk (RR) and 95% confidence interval (CI) of the main outcomes as a measure of efficacy were used. Meta‐analysis was performed using fixed‐effect or random‐effect methods, depending on absence or presence of significant heterogeneity. Analyses were performed with stata version 9.0 and Review Manager Version 4.2. Five studies including the data on development of liver cirrhosis, and eleven studies including the data on development of HCC were analyzed. There was no evidence for publication bias on the funnel plot or by Egger’s test, and the heterogeneity test indicated that the variation of trial‐specific RR was not statistically significant. A different incidence of liver cirrhosis and HCC was observed between treated and untreated patients. The RR of liver cirrhosis and HCC was 0.65 (95% CI: 0.47, 0.91) and 0.59 (95% CI: 0.43, 0.81), respectively. In conclusion, the results of this meta‐analysis indicate that IFN prevents or delays the development of liver cirrhosis and HCC in patients with chronic hepatitis B.