Risk Of Hepatocellular Carcinoma Occurrence Research Articles

Risk of hepatocellular carcinoma occurrence after antiviral therapy for patients with chronic hepatitis C Infection: a systematic review and meta-analysis.

The risk of hepatocellular carcinoma (HCC) occurrence following antiviral therapy in patients with chronic hepatitis C (CHC) remains unclear. The current study aims to compare: (1) the HCC occurrence rate following sustained virological response (SVR) versus non-response (NR); (2) the HCC occurrence rate following direct-acting antiviral (DAA) therapy versus interferon (IFN)-based therapy, and (3) the HCC occurrence rate in SVR patients with or without cirrhosis. A search was performed for articles published between January 2017 and July 2022. Studies were included if they assessed HCC occurrence rate in CHC patients following anti-HCV therapy. Random effects meta-analysis was used to synthesize the results from individual studies. A total of 23 studies including 29,395 patients (IFN-based = 6, DAA = 17; prospective = 10, retrospective = 13) were included in the review. HCC occurrence was significantly lower in CHC with SVR (1.54 per 100 person-years (py, 95% CI 1.52, 1.57) than those in non-responders (7.80 py, 95% CI 7.61, 7.99). Stratified by HCV treatment regimens, HCC occurrence following SVR was 1.17 per 100 py (95% CI 1.11, 1.22) and 1.60 per 100 py (95% CI 1.58, 1.63) in IFN- and DAA treatment-based studies. HCC occurrence was 0.85 per 100 py (95% CI 0.85, 0.86) in the non-cirrhosis population and rose to 2.47 per 100 py (95% CI 2.42, 2.52) in the cirrhosis population. Further meta-regression analysis showed that treatment types were not associated with a higher HCC occurrence rate, while cirrhosis status was an important factor of HCC occurrence rate. HCC occurrence was significantly lower in the SVR population than in the NR population. HCC risk following SVR occurred three times more frequently in patients with cirrhosis than patients without cirrhosis. However, we found no significant difference in HCC occurrence risk following SVR between DAA and IFN therapies. CRD42023473033.

Response to antiviral therapy for chronic hepatitis C and risk of hepatocellular carcinoma occurrence in Japan: a systematic review and meta-analysis of observational studies

In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33–0.43) for sustained virologic response (SVR) and 1.70 (1.61–1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19–0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19–0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence.

Who Should Not Be Surveilled for HCC Development after Successful Therapy with DAAS in Advanced Chronic Hepatitis C? Results of a Long-Term Prospective Study.

Background and aims: The identification of patients with Hepatitis C Virus (HCV)-positive advanced chronic liver disease (aCLD) successfully treated by Direct Acting Antiviral Agents (DAAs) who really benefit from Hepatocellular Carcinoma (HCC) surveillance programs is still a matter of debate. We performed a long-term prospective cohort study on F3-F4 HCV-positive patients achieving Sustained Virologic Response (SVR) after DAAs treatment in order to identify patients who can safely suspend surveillance. Methods: 1000 patients with HCV-positive aCLD obtaining SVR by DAAs from January 2015 to December 2017 were divided into four groups according to baseline elastographic, ultrasonographic, clinical and biochemical features: (1) Group 1: 324 patients with Liver Stiffness Measurement (LSM) ≥ 9.5 ≤ 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (2) Group 2: 133 patients with LSM ≥ 9.5 ≤ 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5 (3) Group 3: 158 patients with LSM > 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (4) Group 4: 385 patients with LSM > 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5. FIB-4 and APRI scores were calculated at baseline and at SVR achievement. Each patient was surveiled twice-yearly by ultrasound for a median follow-up of 48 months. Results: among Group 1 patients, 1/324 (0.3%) developed HCC (0.09/100 patients/year [PY]), compared to 6/133 (4.5%) Group 2 patients (1.22/100 PY, p = 0.0009), 10/158 (6.3%) Group 3 patients (1.68/100 PY, p = 0.0001), 54/385 (14.0%) Group 4 patients (4.01/100 PY, p < 0.0001). HCC incidence was significantly lower in Group 2 compared to Group 3 (p = 0.004) and in Group 3 compared to Group 4 (p = 0.009). HCC risk fell in patients showing a decrease of FIB-4/APRI scores. Conclusions: the risk of HCC occurrence is negligible in about 90% of HCV-positive patients with baseline LSM ≥ 9.5 ≤ 14.5 kPa plus FIB-4 < 3.25 and APRI < 1.5 achieving SVR. Among this particular subset of patients, FIB-4/APRI scores may represent an accurate and inexpensive tool to distinguish patients not needing long-term HCC surveillance.

Update on the role of elastography in liver disease.

The diagnosis of liver fibrosis and the assessment of its severity are important to provide appropriate management, to determine the prognosis or the need for surveillance. Currently, for fibrosis staging, liver stiffness measurement (LSM) with the shear wave elastography (SWE) techniques is considered a reliable substitute for liver biopsy in several clinical scenarios. Nonetheless, it should be emphasized that stiffness value is a biomarker of diffuse liver disease that must be interpreted taking into consideration anamnesis, clinical and laboratory data. In patients with diffuse liver disease, it is more clinically relevant to determine the likelihood of advanced disease rather than to obtain an exact stage of liver fibrosis using a histologic classification. In this regard, a 'rule of five' for LSMs with vibration-controlled transient elastography (VCTE) and a 'rule of four' for LSMs with the acoustic radiation force impulse (ARFI)-based techniques have been proposed. In patients with advanced chronic liver disease (CLD), the risk of liver decompensation increases with increasing liver stiffness value. SWE has been proposed as a tool to predict the risk of death or complications in patients with CLD. LSM by VCTE combined with platelets count is a validated non-invasive method for varices screening, with very good results in terms of invasive procedures being spared. ARFI-based techniques also show some promising results in this setting. LSM, alone or combined in scores or algorithms with other parameters, is used to evaluate the risk of hepatocellular carcinoma occurrence. Due to the high prevalence of CLD, screening the population at risk is of interest but further studies are needed.

Neutrophil-lymphocyte ratio and the risk of hepatocellular carcinoma in patients with hepatitis B-caused cirrhosis.

The neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic marker of hepatocellular carcinoma (HCC); however, the relationship between NLR and risk of HCC occurrence has yet to be systematically elucidated. We aimed to investigate the association between NLR and HCC risk in patients with hepatitis B-caused cirrhosis (HBC) undergoing antiviral therapy. A total of 1599 patients with HBC receiving entecavir or tenofovir at three tertiary hospitals between June 2014 and November 2017 were included. Cox proportional hazards regression was used to identify the association between NLR and risk of HCC occurrence by adjusting for potential risk factors. The cumulative incidence of HCC was evaluated using Kaplan-Meier analysis. At study enrollment, the median NLR was 2.0 (interquartile range, 1.4-3.0). The 3-year cumulative probabilities of HCC were 4.8, 8.4, 13.2, and 18.0% across the NLR quartiles, respectively (P < 0.001). Compared with the lowest quartile, higher NLR correlated with an increased HCC occurrence [NLR 1.4-2.0: adjusted hazard ratio (aHR), 1.18 (95% confidence interval (CI), 1.11-1.25); NLR 2.0-3.0: aHR, 2.09 (95% CI, 1.19-3.66); NLR > 3.0: aHR, 2.80 (95% CI, 1.59-4.95); P for trend = 0.001] in the fully adjusted models. In the subgroup analysis, elevated NLR was associated with increased HCC risk, regardless of stratification criteria. Elevated NLR is an independent risk factor for HCC occurrence in patients with HBC undergoing antiviral therapy.

Impacts of the SOAT1 genetic variants and protein expression on HBV-related hepatocellular carcinoma

BackgroundHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains a major public health problem and its pathogenesis remains unresolved. A recent proteomics study discovered a lipid enzyme Sterol O-acyltransferase (SOAT1) involvement in the progression of HCC. We aimed to explore the association between SOAT1 genetic variation and HCC.MethodsWe genotyped three exonic SOAT1 variants (rs10753191, V323V; rs3753526, L475L; rs13306731, Q526R) tagging most variations in the gene, in 221 HCC patients and 229 healthy individuals, to assess the impact of SOAT1 gene variation on risk of HCC occurrence. We further conducted immunohistochemistry to compare SOAT1 protein expression levels in 42 paired tumor and adjacent non-tumor tissues.ResultsWe found that rs10753191 (Odds ratio (OR) = 0.58, P = 0.04) and a haplotype TGA (OR = 0.40, P = 0.01) were associated with reduced HCC risk after adjusting for lipid levels. In the immunohistochemistry experiment, we found that the protein expression of SOAT1 was significantly increased in the tumor compared with adjacent tissue (P < 0.001).ConclusionThis study revealed for the first time SOAT1 genetic variation that associates with host susceptibility to HCC occurrence. Our results suggest a role of SOAT1 in the HCC development, which warrants further elucidation.

Precision pathology analysis of the development and progression of hepatocellular carcinoma: Implication for precision diagnosis of hepatocellular carcinoma.

Outcomes for patients with hepatocellular carcinoma (HCC) remain poor because the condition is often unresponsive to the available treatments. Consequently, the early and precise diagnosis of HCC is crucial to achieve improvements in prognosis. For patients with chronic liver disease, the assessment of liver fibrosis is also important to ascertain both the staging of fibrosis and the risk of HCC occurrence. Early HCC was first described in 1991 in Japan and was defined internationally in 2009. As the concept of early HCC spread, the multistage hepatocarcinogenesis process became accepted. Consequently, improvements in imaging technology made the early diagnosis of HCC possible. At present, the most appropriate therapeutic strategy for HCC is determined using an integrated staging system that assesses the tumor burden, the degree of liver dysfunction and the patient performance status; however, pathological and molecular features are not taken into account. The recent introduction of several new therapeutic agents will change the treatment strategy for HCC. Against this background, HCC subclassification based on tumor cellular and microenvironmental characteristics will become increasingly important. In this review, we give an overview of how pathological analysis contributes to understanding the development and progression of HCC and establishing a precision diagnosis of HCC.

Hepatocellular carcinoma in the post-hepatitis C virus era: Should we change the paradigm?

Hepatocellular carcinoma (HCC) is a common and deadly malignancy. The disease usually develops on a background of chronic liver disease. Until recently, the most common etiology was infection with the hepatitis C virus (HCV). The advent of direct-acting antiviral (DAA) therapies has been a major breakthrough in HCV treatment. Sustained virologic response can now be achieved in almost all treated patients, even in patients with a high risk for the development of HCC, such as the elderly or those with significant fibrosis. Early reports raised concerns of a high risk for HCC occurrence after DAA therapy both in patients with previous resection of tumors and those without previous tumors. As the World Health Organization’s goals for eradication of HCV are being endorsed worldwide, the elimination of HCV seems feasible. Simultaneous to the decrease in the burden of cirrhosis from HCV, non-alcoholic fatty liver disease (NAFLD) incidence has been increasing dramatically including significant increased incidence of cirrhosis and HCC in these patients. Surprisingly, a substantial proportion of patients with NAFLD were shown to develop HCC even in the absence of cirrhosis. Furthermore, HCC treatment and potential complications are known to be influenced by liver steatosis. These changes in etiology and epidemiology of HCC suggest the beginning of a new era: The post–HCV era. Changes may eventually undermine current practices of early detection, surveillance and management of HCC. We focused on the risk of HCC occurrence and recurrence in the post–HCV era, the surveillance needed after DAA therapy and current studies in HCC patients with NAFLD.

Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis

More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients' inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5-95.4), 80.3% (95% CI 76.9-83.9), and 3.2% (95% CI 1.6-4.8) respectively. This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening.

Association of genetic variants in the interleukin-18 gene promoter with risk of hepatocellular carcinoma and metastasis in patients with hepatitis C virus infection.

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, characterized by high vascularization and rapid tumor progression. The current case-control study aimed to analyze the influence of -607C/A and -137G/C polymorphisms in the interleukin-18 (IL-18) promoter on the risk of HCC occurrence and metastasis in Egyptian patients infected with hepatitis C virus (HCV). Both genetic variations were genotyped in 279 subjects including HCV patients with and without HCC and unrelated healthy subjects, using the allele-specific polymerase chain reaction (AS-PCR) method. The relationship between clinico-laboratory parameters including serum level of alpha-fetoprotein (AFP) and these polymorphisms was evaluated in HCC patients. The IL-18-607A allele and AA genotype were significantly related to a higher risk of developing HCC when comparing patients with HCC and controls, and were significantly related to a higher risk of metastasis when comparing metastatic and nonmetastatic groups in the Egyptian patients. In contrast, the IL18-137C allele and GC genotype were significantly related to a lower risk of developing HCC when comparing patients with HCC and controls, and HCV patients with and without HCC. A significant association was found between multinodular HCC and IL-18-607AA genotype, while, uninodular HCC was significantly associated with IL-18-137GG genotype. In addition, IL18-607AA and -137GG genotypes showed significant association with higher level of serum AFP. The detection of polymorphisms in the IL-18 promoter, in a combination with an evaluation of level of serum AFP, could be used as a molecular biomarker in the early diagnosis of HCC, which would aid the early management of the disease, thus decreasing the rate of mortality of this disease. © 2018 IUBMB Life, 70(2):165-174, 2018.

PS-160 - No evidence for higher risk of hepatocellular carcinoma occurrence or recurrence following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression

PS-160 - No evidence for higher risk of hepatocellular carcinoma occurrence or recurrence following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression

BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease.

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10−4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 ‘AAA’ haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19–3.39); false discovery rate (FDR)-P=1.31×10−2]. In the Derivation#2 study, results were confirmed for the BRIP1 ‘GGG’ haplotype [OR, 0.53 (0.36–0.79); FDR-P=3.90×10−3]. In both Validation#1 and #2 studies, BRIP1 ‘AAA’ haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09–2.68); FDR-P=7.30×10−2; and OR, 6.45 (4.17–9.99); FDR-P=2.33×10−19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.

Hepatocellular carcinoma screening is indicated even after sustained virological response: -Moroccan University Hospital Experience-

Introduction: Hepatitis C is the first aetiologic agent for HCC in Morocco. Antiviral treatment reduces the risk of developing HCC in patients with chronic hepatitis C but few cases of HCC have been still reported. We aimed to define population with high risk of HCC occurrence, confirm the protective role of SVR and to identify predictive factors of developing HCC after SVR. We'll try to present suggestions about screening strategies (indications and interval) after antiviral therapy according to level of HCC occurrence risk. Patients and Methods: We included all patients with chronic hepatitis C treated in our department from January 2002 to April 2010. We compare HCV-treated patients with no developed HCC to HCC population using khi-2 and Fisher Exact analysis. Results: 369 patients treated for hepatitis C were considered, and 20 HCC were reported. The risk of HCC occurrence was not significant according to gender and genotypes. Advanced age and severe fibrosis were significant risk factors. HCC was reported in 2.3% of sustained virological responders versus 12.5% of non responders. SVR is a significant protective factor. Conclusion: In our series, 5% of previously treated HCV carriers developed HCC and 2.3% of sustained virological responders developed. Achieving SVR after antiviral therapy is a protective factor. Advanced age (&gt; 50 y. o), severe fibrosis (F&gt;2) and lack of SVR at HCV diagnosis are predictive factors of HCC development in treated patients. Regular bi-annual ultrasonography screening should be indicated necessarily in patients with advanced fibrosis stage (F3- F4) even after SVR, particularly when co-morbid conditions are associated (advanced age, NASH, diabetes mellitus,...). Screening interval in sustained virological responders with reduced fibrosis stage may be limited to annual surveillance. Establishing guidelines about consensual strategy to survey sustained virological responders is now necessary especially with high rates of SVR and the extension of treatment indications in era of DAA drugs. Keywords: Hepatocellular Carcinoma (HCC), Screening, Sustained Virological Response (SVR)

Optimization of risk-predicting models for hepatitis B virus-related hepatocellular carcinoma

Objective The present study aimed to optimize the established predictive models (REACH-B scoring model) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods The hepatitis B surface antigen (HBsAg) positive (> 6 months) patients who were firstly admitted in the Liver Center of First Affiliated Hospital, Fujian Medical University between Oct 1st 2004 and May 1st 2014 were selected as the subjects and divided into two groups, namely, the case group (HCC group) and the control group (non-HCC group). Clinical data of all the subjects were retrospectively collected and analyzed. Receiver operating characteristic curves were used to evaluate the predictive values of the various models. Results To predict the development of HBV-related HCC within 3 years, a total of 627 patients (151 HCC cases and 476 non-HCC controls) were enrolled. Area under curve (AUC) of HBV-related HCC (REACH-B) scoring model was 0.78 (95%CI: 0.74-0.82), with the sensitivity of 73.00% and specificity of 78.70% in predicting 3-year risk of HCC occurrence. By combining alpha-fetoprotein (AFP) and REACH-B, the R-AFP scoring model was constructed. The AUC increased to 0.80 (95%CI: 0.76-0.83, Z=2.50, P=0.01), with the sensitivity of 71.03% and specificity of 79.13% in predicting 3-year HCC development. By combining AFP isoform 3 (AFP-L3%) and REACH-B, the R-AFP-L3% scoring model was constructed. The AUC further increased to 0.83 (95%CI: 0.80-0.87, Z=2.45, P=0.01), with the sensitivity of 75.01% and specificity of 79.32% in predicting 3-year HCC development. To predict the development of HBV-related HCC within 5 years, a total of 159 (65 HCC cases and 94 non-HCC controls) were enrolled. The AUC of REACH-B scoring model was 0.79 (95%CI: 0.72-0.87), with the sensitivity of 73.60% and specificity of 75.43%. The R-AFP scoring model had an AUC of 0.84 (95%CI: 0.77-0.90, Z=2.70, P=0.006), with the sensitivity of 83.12% and specificity of 77.89%. Conclusion Combination of AFP or AFP-L3% may optimize the predictive values of REACH-B scoring model in predicting 3-year and 5-years risks of developing HBV-related HCC. Key words: Hepatitis B virus; Carcinoma, hepatocellular; alpha-Fetoproteins; Forecasting

Evaluation of hepatocellular carcinoma development in patients with chronic hepatitis C by EOB-MRI.

To evaluate the efficacy of ethoxibenzyl-magnetic resonance imaging (EOB-MRI) as a predictor of hepatocellular carcinoma (HCC) development. Between August 2008 and 2009, we studied 142 hepatitis C virus-infected patients (male 70, female 72), excluding those with HCC or a past history, who underwent EOB-MRI in our hospital. The EOB-MRI index [liver-intervertebral disc ratio (LI)] was calculated as: (post-liver intensity/post-intervertebral disc intensity)/(pre-liver intensity/pre-intervertebral disc intensity). The median follow-up period was 3.1 years and the patients were observed until the end of the study period (31 December, 2012). In the follow-up period, HCC occurred in 21 patients. The cumulative occurrence rates were 2.1%, 9.1%, and 14.1% at 1, 2, and 3 years, respectively. Using the optimal cut-off value of LI 1.46, on univariate analysis, age, aspartate amino transferase (AST), α-fetoprotein (AFP) ≥ 10, albumin, total cholesterol, prothrombin time, platelets, and LI < 1.46 were identified as independent factors, but on multivariate analysis, LI < 1.46: risk ratio 6.05 (1.34-27.3, P = 0.019) and AFP ≥ 10: risk ratio 3.1 (1.03-9.35, P = 0.045) were identified as independent risk factors. LI and Fib-4 index have higher area under the receiver operating characteristic curves than other representative fibrosis evaluation methods, such as Forn's index and AST-to-platelet ratio index. LI is associated with the risk of HCC occurrence in hepatitis C patients. LI may be a substitute for liver biopsy when evaluating this risk and its combined use with Fib-4 is a better predictive method of HCC progression.

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

Perturbation of transforming growth factor (TGF)-β signaling in hepatocytes persistently infected with hepatitis viruses promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights into hepatocytic fibro-carcinogenesis have emerged from recent detailed analyses of context-dependent and cell type-specific TGF-β signaling processes directed by multiple phosphorylated forms (phospho-isoforms) of Smad mediators. In the course of hepatitis virus-related chronic liver diseases, chronic inflammation, ongoing viral infection, and host genetic/epigenetic alterations additively shift hepatocytic Smad phospho-isoform signaling from tumor suppression to fibro-carcinogenesis, accelerating liver fibrosis and increasing risk of hepatocellular carcinoma (HCC). After successful antiviral therapy, patients with chronic hepatitis can experience less risk of HCC occurrence by reversing Smad phospho-isoform signaling from fibro-carcinogenesis to tumor suppression. However, patients with cirrhosis can still develop HCC owing to sustained, intense fibro-carcinogenic signaling. Recent progress in understanding Smad phospho-isoform signaling should permit use of Smad phosphorylation as a tool predicting the likelihood of liver disease progression, and as a biomarker for assessing the effectiveness of interventions aimed at reducing fibrosis and cancer risk.

PNPLA3 Gene Polymorphism is Associated with Alcohol-Related Liver Injury with Increased Progression to Cirrhosis and Hepatocellular Carcinoma

Purpose: Alcohol abuse is a common cause of liver disease (ALD) and indication for liver transplantation in the US. Clinical spectrum of ALD may range from simple steatosis or fatty liver (FL), alcoholic hepatitis, alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Only 10-20% of heavy drinkers develop alcoholic cirrhosis (AC), implicating the role of other factors in development of ALD and progression to AC and HCC. Recently, a genetic polymorphism with an isoleucine to methionine substitution at position 148 (rs738409 C>G) in the palatin-like phospholipase domain (PNPLA3) gene has been shown to predispose to steatosis. Data has shown association of this genetic polymorphism with ALD and its progression to more advanced disease. We performed a systematic review and meta-analysis of studies evaluating association of this polymorphism (G instead of C) in ALD. Methods: Search of electronic databases revealed six studies examining association of PNPLA3 gene polymorphism and ALD. Data were reported as pooled odds ratio (OR), with 95% confidence interval (CI). Fixed effects model of comprehensive meta-analysis program software was used to pool data. I2 statistics and Egger's tests were used to assess data heterogeneity and publication bias, respectively. Results: Compared to non-drinkers, drinkers were assessed for risk of AC in five studies, ALD in three, HCC in two, and FL in one. Among alcohol drinkers, association of PNPLA3 genetic polymorphism was assessed for risk of AC compared to ALD or to FL (one study each), and risk of HCC occurrence in AC in two studies. Pooled data shown in Table 1 were homogeneous, without any publication bias.Table 1Conclusion: PNPLA3 genetic polymorphism (rs738409 C>G) confers an increased risk for the development of ALD among drinkers, and an increased propensity for AC and HCC in those with ALD. Studies are needed to clarify association of PNPLA3 and steatosis in alcohol drinkers. PNPLA3 gene may be a potential therapeutic target in ALD and in selecting donor organs for transplanting patients with ALD.

Association of polymorphism in MicroRNA 219‐1 with clearance of hepatitis B virus infection

Polymorphisms in the primary microRNA region may be associated with natural course of hepatitis B virus (HBV) infection. This study evaluated if the mircoRNA 219-1 (miR-219-1) polymorphism can influence the susceptibility towards persistence of HBV infection and the progression to hepatocellular carcinoma (HCC) in patients with chronic HBV infection. A total of 1,439 individuals having either past or present evidence of HBV infection were enrolled for the study. The subjects were divided into four groups; (1) spontaneous recovery (n = 404), (2) chronic HBV carrier (n = 313), (3) chronic HBV carrier with cirrhosis (n = 305), and (4) hepatocellular carcinoma (n = 417). Genotyping was performed at three polymorphic variants (rs421446, rs107822, and rs213210) in the pri-miRNA region of miR-219-1. The rs421446 T allele was found to be strongly associated with HBV clearance (OR = 0.73, P = 0.0005 in a codominant model and OR = 0.67, P = 0.0009 in a dominant model, OR = 0.69, P = 0.04 in a recessive model, respectively). The rs107822 G allele was also found to be associated with HBV clearance (OR = 0.79, P = 0.008 in a codominant model and OR = 0.72, P = 0.01 in a dominant model, respectively). In haplotype analysis, ht2 (T-G-T) and ht1 (C-A-C) were found to be in significant association with the clearance of HBV. However, no significant association was observed between miR-219-1 polymorphism and the risk of HCC occurrence. This result suggests that polymorphisms in the pri-miRNA region of miR-219-1 might be a genetic factor for HBV clearance after infection.

Association of polymorphism in pri-microRNAs-371-372-373 with the occurrence of hepatocellular carcinoma in hepatitis B virus infected patients.

BackgroundMicro RNAs-371-372-373 (miRNAs-371-373), originating from the same pri-miRNA transcript, are reported to be upregulated in hepatocellular carcinoma (HCC) and to be related to the regulation of hepatitis B virus (HBV) infection. Our study investigated whether pri-miRNAs-371-373 polymorphisms are associated with the risk of HCC occurrence and HBV clearance.MethodsGenetic variations were identified through direct DNA sequencing using TaqMan assay. Three sequence variants of pri-miRNAs-371-373 were identified. Genetic associations of those with HCC occurrence and HBV clearance among patients with HBV infection were analyzed using logistic regression analyses with adjustment for age and gender (n = 1439).ResultsFor the occurrence of HCC, polymorphism rs3859501C>A acted as a protective factor both in chronic carriers (OR = 0.75, P = 0.005 in a codominant model; OR = 0.71, P = 0.02 in a dominant model; OR = 0.66, P = 0.03 in recessive model) and liver cirrhosis patients (OR = 0.69, P = 0.001 in a codominant model; OR = 0.60, P = 0.003 in a dominant model; OR = 0.63, P = 0.03 in a recessive model). The pri-miRNAs-371-373_ht2 [C-A-C] also showed a protective effect on HCC occurrence both in the chronic carrier and liver cirrhosis groups (P<0.05 in both). However, there was no significant association between pri-miRNAs-371-373 polymorphisms and HBV clearance.ConclusionsIn conclusion, among chronic carriers and liver cirrhosis patients, the A allele of rs3859501 and the haplotype pri-miRNAs-371-373_ht2 were more protective to HCC than other genotypes and haplotypes. Further studies into the roles of rs3859501 and pri-miRNAs-371-373_ht2 haplotype in hepatocarcinogenesis are needed.

Manganese Superoxide Dismutase Dimorphism and Iron Overload, Hepatocellular Carcinoma, and Death in Hepatitis C Virus–Infected Patients

A genetic dimorphism encodes for either alanine (Ala) or valine (Val) in the mitochondrial targeting sequence of manganese superoxide dismutase (MnSOD), and modulates its mitochondrial import and activity. It has been shown that the presence of at least 1 Ala-encoding allele is more frequent in alcoholic patients with cirrhosis than in controls, and increases the risks of liver iron overload, hepatocellular carcinoma (HCC), and death in these patients. The aim of this study was to assess the influence of the Ala-9Val MnSOD dimorphism on the same parameters and events in hepatitis C virus (HCV)-infected patients. We compared the MnSOD genotypic distributions in 94 control subjects and 165 patients with HCV-related cirrhosis. Patients were included at the time of liver biopsy examination showing cirrhosis, and were followed-up prospectively. The mean time of follow-up evaluation was 85.7 +/- 43.8 months. The distribution of MnSOD genotypes in HCV-infected patients (25% Val/Val homozygotes, 44% Ala/Val heterozygotes, and 31% Ala/Ala homozygotes) did not differ from the distribution in controls (P = .3). MnSOD genotypes did not influence survival (log-rank test, P = .6; relative risk 1.0; 95% confidence interval, 0.6-1.6) or the risk of HCC occurrence (log-rank test, P = .3; relative risk, 1.1; 95% confidence interval, 0.8-1.6). Contrary to previous findings in French alcoholic patients, the Ala-encoding MnSOD allele is represented equally in controls and patients with HCV-related cirrhosis, and it does not significantly influence the risks of liver iron overload, HCC, or death in these patients.