Prediction Of Hepatocellular Carcinoma Development Research Articles

Make platelet count great again: Direct‐acting antiviral agent therapy in patients with chronic hepatitis C

Hepatitis C virus (HCV) infection is an endemic disease in Taiwan, which causes adverse liver events, including development of cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). Among the chronic hepatitis C (CHC) patients, sustained virological response (SVR) after antiviral therapy has been shown to be associated with prolonged overall survival and the reduced risks of HCC and liver-related mortality.1 The combination of pegylated interferon (Peg-IFN) plus ribavirin therapy was the standard of care before 2011. However, its use was limited by various disadvantages, including decrease in platelet count during therapy. With the introduction of novel direct-acting antiviral agents (DAAs) targeting the replication process of HCV, this IFN-free therapy has become the standard of care and has higher response rates and fewer side effects. Thrombocytopenia is a common complication of chronic liver diseases, but the pathophysiology of thrombocytopenia in CHC patients is not yet completely understood yet. Regardless of the underlying mechanisms, it has been reported that peripheral platelet count reflects the degree of fibrosis in CHC patients.2 In this study, Hsu et al first investigated the temporal relationship between platelet count and alanine aminotransferase (ALT) level in CHC patients who received DAA therapy. In this retrospective study, the SVR rate at 12 weeks after therapy (SVR12) was 98.7% (77/78). In patients without cirrhosis (n = 70), a 7.5% increase of mean platelet count was noted within 2 weeks after the initiation of DAA therapy. The increased platelet count remained stable throughout the treatment and follow-up periods. In contrast, no obvious changes in platelet count were noted among patients with cirrhosis (n = 8). The underlying mechanism to induce thrombocytopenia in CHC patients is complex. It has been considered that splenic congestion as a consequence of portal hypertension is the major etiology.3 Other possible mechanisms included autoimmune reaction with the production of antiplatelet antibodies, direct bone marrow suppression by HCV, decreased production of thrombopoietin, and endothelial dysfunction.4 This study demonstrated that platelet count increased within 2 weeks after DAA therapy, which has not been observed during Peg-IFN-based therapy as Peg-IFN itself causes thrombocytopenia. Such a rapid recovery could be attributed to the suppression of HCV replication instead of fibrosis regression, which usually takes years to develop. However, we still need more studies to address how suppressed viral replication induces recovery of platelet count. The most challenging issue in the DAA era is how to predict HCC development after SVR12 is achieved. Previous studies have shown that host and liver factors, such as platelet count, are important HCC predictors. Based on this study, the pretreatment platelet count can be affected by viral replication, while the posttreatment platelet count is more stable and can be more representative of the liver fibrosis severity. This also echoes the finding that posttreatment biomarkers, compared to pretreatment biomarkers, serve as better predictors for long-term HCC development in CHC patients treated with curative antivirals.5, 6 Considering all lines of data together, we believe that biomarkers measured after treatment are more appropriate in predicting long-term outcomes than those measured before treatment. There are also some limitations of this study. First, the patient number was small, and there were only eight patients with cirrhosis. The insignificant change of platelet count in cirrhotic patients could be attributed to the small patient number. Second, the study only collected information from baseline to 12 weeks after treatment. It is still unclear whether there is a consistent improvement of platelet count after a long-term follow up, which is more likely to be attributed to liver fibrosis regression. A large-scale study with a long-term follow up is needed to address this issue. In summary, DAA therapy is associated with increased platelet count shortly after suppressing HCV replication in CHC patients without cirrhosis. Further research is needed to assess the long-term effects of DAAs therapy on platelet count and the biological basis for these findings. The authors declare no conflict of interest.

Liver stiffness measurement at complete virological response in hepatoma prediction for HBV-related cirrhosis patient with potent antiviral agent.

Hepatocellular carcinoma (HCC) development is ameliorated with nucleos(t)ide agent (NA) therapy for hepatitis B virus (HBV)-related cirrhosis patients. This study investigates whether liver stiffness (LS) measurement at complete virological response (CVR) was useful in predicting HCC development. Between July 2006 and August 2016, HBV-related cirrhosis patients with potent NA (entecavir/tenofovir) with the first LS measurement during CVR and with serial LS were enrolled. Patients developing HCC 6 months after potent NA or before the first LS measurement were excluded. Three hundred and seventy-one patients were enrolled. The median follow-up was 5.6 and 3.8 years from potent NA treatment and the first LS measurement respectively. Twenty-seven patients developed HCC. The 1-, 3-, 5- and 7-year cumulated incidences of HCC occurrence were 0%, 2.8%, 5.8% and 9%, respectively. In addition to age > 57 years, LS > =21.5 kPa (HR: 3.86, 95%CI: 1.67-8.94) was an independent factor associated with HCC occurrence in multivariate analysis. However, the magnitude of change in LS was not associated with HCC development. For the first LS in HCC prediction, the performance was 0.636. There were two to thirteen LS measurements during CVR. The change in LS was classified into four patterns stratified by the first and serial LS. Compared with those with serial LS < 21.5 kPa, patients with LS > =21.5 kPa tend to have higher HCC occurrence (P = .062). In summary, LS at CVR was an independent factor associated with HCC development for HBV-related cirrhosis patients with potent NA. However, LS was not satisfactory in the prediction performance of HCC development.

Effectiveness of Noninvasive Fibrosis Markers for the Prediction of Hepatocellular Carcinoma in Chronic Hepatitis B and Chronic Hepatitis B+D Induced Cirrhosis

PurposeDespite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, the incidence and mortality of hepatocellular carcinoma (HCC) continue to rise. To obtain the best treatment result for HCC, early diagnosis is the key. In this study, we investigated the accuracy of noninvasive fibrosis markers, which have been typically used to predict liver fibrosis in recent years, in the prediction of HCC development in patients with chronic hepatitis B and chronic hepatitis B + D–induced cirrhosis. MethodsBetween 2004 and 2018, 1216 patients with chronic liver disease were retrospectively reviewed, and 331 patients (27%) with hepatitis B and hepatitis B+D virus–related cirrhosis were enrolled in our study. Patients were divided into 2 groups based on HCC diagnosis (HCC and non-HCC group). Eleven noninvasive fibrosis markers were evaluated in the groups. These markers included 3 alpha-fetoprotein (AFP)-based models (PAPAS index, Fibro-alpha, and BRC score) and 8 non-AFP based models (Lok index, FIB–4, Fibro-O index, APRI, King’s score, Forns index, Bonacini score, and HUI model) for each Child-Pugh score in the prediction of HCC. ResultsAFP-based models were higher in HCC group patients, and statistically significant outcomes were detected with these methods in each Child-Pugh score group for HCC prediction (P < .05). Non-AFP based–methods showed different and inconsistent results in each Child-Pugh score group. ConclusionThese easily applied fibrosis markers, particularly AFP-based models, may provide an effective, simple, and low-cost way to predict HCC development in patients with hepatitis B and hepatitis B + D cirrhosis.

Aspartate Aminotransferase-to-Platelet Ratio or Fibros-4 Index Predicts the Development of Hepatocellular Carcinoma in Chronic Hepatitis C Patients with Sustained Virologic Response to Interferon Therapy.

The risk of hepatocellular carcinoma (HCC) is not completely eliminated in chronic hepatitis C (CHC) patients even after viral eradication. There are few studies in predicting the development of HCC using biomarker in CHC patients with sustained virologic response (SVR). We evaluated the role of the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) in predicting HCC development in 295 patients with SVR after interferon therapy. The annual incidence of HCC was 0.55% (95% confidence interval: 0.31-0.96). It was higher in patients with a pretreatment APRI ≥2.0 than in those with an APRI <2.0 (1.82% versus 0.17%; P = 0.0001) and in patients with a FIB-4 ≥ 3.25 compared with those with a FIB-4 < 3.25. (1.50% versus 0.07%; P = 0.0001). The annual incidence of HCC was higher in patients with a post-treatment APRI ≥0.5 than in those with an APRI <0.5 (1.67% versus 0.07%; P < 0.0001) and in patients with a post-treatment FIB-4 ≥ 2.5 compared with those with a FIB-4 < 2.5 (1.49% versus 0.01%; P = 0.0003). Among pretreatment variables, male gender, albumin, APRI, or FIB-4 were independent predictors for HCC. Among post-treatment variables, APRI or FIB-4 was an independent predictor for HCC. HCC surveillance should be performed in these high-risk patients.

Risk assessment of hepatocellular carcinoma development by magnetic resonance elastography in chronic hepatitis C patients who achieved sustained virological responses by direct-acting antivirals.

Prediction of hepatocellular carcinoma (HCC) development after sustained virological response (SVR) is clinically important, and the usefulness of noninvasive markers for prediction HCC have been reported. The aim of this study was to compare the prediction accuracy for HCC development by noninvasive markers. A total of 346 patients with chronic hepatitis C without history of HCC who achieved SVR through direct-acting antivirals were included. Magnetic resonance elastography (MRE) and serum fibrosis markers were measured 12weeks after the end of treatment, and the subsequent HCC development was examined. The mean observation period was 26.4±7.9months, and 24 patients developed HCC. Area under the receiver operating characteristic curve of liver stiffness by MRE, Wisteria floribunda agglutinin-positive mac-2 binding protein and FIB-4 for predicting HCC within 3years was 0.743, 0.697 and 0.647, respectively. The 1/2/3-year rates of HCC development in patients with liver stiffness ≥3.75 KPa were 6.6%, 11.9% and 14.5%, whereas they were 1.4%, 2.5% and 2.5% in patients with liver stiffness <3.75 KPa (P<0.001). Multivariate analysis revealed that liver stiffness ≥3.75 was an independent predictive factor for HCC development (hazard ratio, 3.51; 95% confidence interval, 1.24-9.99). In subgroup analysis, there were 132 patients who were <73years old and had liver stiffness <3.75 KPa, and no HCC development was observed in these patients. Diagnostic accuracy for predicting HCC development was higher in MRE than serum fibrosis markers and measurement of liver stiffness by MRE could identify patients with high and low risk of HCC development after SVR.

Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis.

Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.

Serum aldo–keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is associated with liver inflammation in patients with nonalcoholic fatty liver disease, and it can progress to liver fibrosis at an advanced stage, as well as hepatocellular carcinoma (HCC) and portal hypertension. Although liver fibrosis is accurately diagnosed via biopsy, noninvasive methods are preferable. Aldo-keto reductase family 1 member B10 (AKR1B10) is associated with HCC and is secreted into the blood by liver cells via a lysosome-mediated nonclassical pathway. Accordingly, we analyzed whether secretion of AKR1B10 protein is associated with advanced NASH. We performed histological staging in 85 Matteoni classification type III and IV NASH patients and evaluated the incidence of HCC, formation of gastroesophageal varices, and prognosis according to serum AKR1B10 and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP)(M2BPGi) and by comparison with conventional markers of fibrosis. A positive correlation was found between the Brunt classification and serum AKR1B10 level. In Brunt stage 4 patients, AKR1B10 levels were higher than those of other liver fibrosis markers, with higher specificity. The cutoff values for AKR1B10 and WFA(+)-M2BP for stage 4 fibrosis were 1.03 and 3.11, respectively. The rates of stage 4 fibrosis, HCC incidence, and gastroesophageal varix formation were significantly different between the two groups subdivided according to these cutoff levels. Moreover, the patients in the higher value group had significantly worse prognosis after NASH diagnosis CONCLUSION: AKR1B10 is a useful serum biomarker for advanced liver fibrosis in NASH and, combined with serum WFA(+)-M2BP, can predict HCC development, gastroesophageal varix formation, and poor prognosis.

Serum hepatitis B core-related antigen for the prediction of hepatocellular carcinoma development

Serum hepatitis B core-related antigen for the prediction of hepatocellular carcinoma development

Liver stiffness measurements in chronic hepatitis C: Treatment evaluation and risk assessment.

Liver stiffness (LS), measured by transient elastography, has been validated as a non-invasive surrogate for liver fibrosis. We investigated the long-term predictive ability of LS for hepatocellular carcinoma (HCC) development and overall survival in 1146 patients with chronic hepatitis C by using LS value at enrollment. We also investigated chronological changes in LS based on antiviral therapy and its outcome in 752 patients. During the mean follow-up period of 6.6years, 190 patients developed HCC. Cumulative HCC incidence rates at 5years were clearly stratified as 1.7% in the ≤5kPa, 3.3% in 5.1-10kPa, 16.7% in 10.1-15kPa, 24.4% in 15.1-20kPa, 36.3% in 20.1-25kPa, and 43.7% in >25kPa subgroups (P<0.001). Overall survival was also stratified: 10-year survival rates were 99.3% in the ≤5kPa, 95.4% in 5.1-10kPa, 81.4% in 10.1-15kPa, 79.5% in 15.1-20kPa, 66.1% in 20.1-25kPa, and 49.1% in >25kPa subgroups (P<0.001). LS decreased at a rate of 8.1% per year in those who achieved sustained virological responses, but increased at 0.1% per year in those who could not achieve sustained virological response instead of antiviral therapy, and increased at 3.7% per year in those who did not undergo antiviral therapy. Liver stiffness measurements can be useful in the prediction of HCC development and overall survival and in the evaluation of chronological changes in liver fibrosis grade during and after antiviral therapy.

Von Willebrand factor is a useful biomarker for liver fibrosis and prediction of hepatocellular carcinoma development in patients with hepatitis B and C.

Several noninvasive biomarkers are available for diagnosing liver fibrosis stage and predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis and liver cirrhosis. However, these biomarkers are not sufficiently accurate. Recently, von Willebrand factor (VWF) has been related to angiogenesis and apoptosis. Furthermore, VWF is associated with hepatic spare ability and HCC. We aimed to determine whether VWF is a potential biomarker for liver fibrosis and HCC development. Two hundred and twelve patients with chronic hepatitis B and C were recruited. VWF antigen (VWF: Ag) levels in each patient were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were used to determine the risk factor of HCC. The VWF: Ag levels were higher in patients with severe liver fibrosis stage and/or HCC development than in those without. The area under the curve of VWF: Ag for diagnosis of severe liver fibrosis stage was 0.721. Multivariable analysis showed that only VWF: Ag was a predictive biomarker for HCC development. VWF: Ag is related to liver fibrosis and may be useful for predicting HCC development. VWF is a potentially useful biomarker to diagnose severe liver fibrosis and predict HCC development.

Validation of modified fibrosis-4 index for predicting hepatocellular carcinoma in patients with compensated alcoholic liver cirrhosis.

Recently, modified fibrosis-4 index (mFIB-4) and the easy liver fibrosis test (eLIFT) were developed for predicting liver fibrosis in chronic liver disease patients. We evaluated whether the 2 tests can predict hepatocellular carcinoma (HCC) risk in alcoholic liver cirrhosis (ALC) patients.A retrospective cohort of 924 ALC patients was assessed for HCC development. Four non-invasive serum biomarkers, mFIB-4, the eLIFT score, fibrosis-4 index (FIB-4), and aspartate aminotransferase to platelet ratio index (APRI) were tested using time-dependent analysis of areas under receiver operating characteristic curve (AUROC), DeLong, and log-rank tests.During a median 4.8 years of follow-up, HCC occurred in 83 patients (9.0%). For predicting HCC development at 3 years, the mFIB-4 showed a significantly higher AUROC than APRI and eLIFT scores (0.71 vs 0.61 and 0.56, respectively, all P < .05). The AUROCs of the mFIB-4 for HCC development were not significantly different from those of the FIB-4. According to the mFIB-4, the risk of HCC development was significantly stratified by low index (≤4)/high index (>4) (P < .001 by log-rank test).The mFIB-4 showed better predictability of HCC development than APRI and eLIFT scores, and significantly stratified HCC risk in Asian ALC patients.

Predictive Markers for Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis C Virus Genotype4a

Background: Egypt has the highest prevalence of hepatitis C virus worldwide. Monitoring hepatitis C-infected patients for hepatocellular carcinoma development is an important clinical issue to diagnose these patients during the potentially curable early-stage of disease. This study aims to evaluate the role of N-terminal procollagen III, matrix metalloproteinase- 2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests as predictors of hepatocellular carcinoma development upon long-term followup of non-responding hepatitis C virus patients.Methods: The study included 850 treatment-naive hepatitis C virus genotype 4a adult patients; after treatment, 360 achieved sustained viral response while 490 did not. Nonresponding patients had a 5-year rate for hepatocarcinogenesis of 8.4% and a 10-year rate of 27.5%. N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, alpha-fetoprotein, and conventional liver function tests were evaluated in all patients before and after treatment, and after hepatocellular carcinoma development. The study also included a group of 50 hepatocellular carcinoma patients who were negative for hepatitis C and hepatitis B viruses, and a group of 50 healthy subjects as controls.Results: The non-responders had significantly higher age, stage, grade, viral load, alanine aminotransferase, and aspartate aminotransferase than responders. Also N-terminal procollagen III, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-1, and alphafetoprotein were significantly higher in non-responders; after treatment they decreased in responders. In non-responders they remained higher than the control. The most significant risk factors for hepatocellular carcinoma development in non-responding hepatitis C virus patients were male gender and increased age, stage, grade, aspartate aminotransferase, Nterminal procollagen III, and tissue inhibitor of matrix metalloproteinase-1. Patients with viral-hepatocellular carcinoma were of significantly lower age, higher grade, stage, γ-glutamyltransferase, N-terminal procollagen III, and matrix metalloproteinase-2 than non-viral hepatocellular carcinoma patients. Percent positive N-terminal procollagen III, tissue inhibitor of matrix metalloproteinase-1, and alpha-fetoprotein were significantly higher in viral hepatocellular carcinoma patients.Conclusion: Data suggest that high N-terminal procollagen III and tissue inhibitor of matrix metalloproteinase-1levels after treatment might be particularly important as markers of hepatitis C virus-non-responding patients who are at higher risk of developing hepatocellular carcinoma, especially in older males with high stage and grade liver disease. However, studies of larger scale are needed to verify this suggestion.

Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy

Recently, the PAGE-B score and Toronto HCC risk index (THRI) have been developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB). We aimed to validate PAGE-B scores and THRI in Asian patients with CHB and suggested modified PAGE-B scores to improve the predictive performance. From 2007 to 2017, we examined 3,001 Asian patients with CHB receiving entecavir/tenofovir therapy. We assessed the performances of PAGE-B, THRI, CU-HCC, GAG-HCC, and REACH-B for HCC development. A modified PAGE-B score (mPAGE-B) was developed (derivation set, n = 2,001) based on multivariable Cox models. Bootstrap for internal validation and external validation (validation set, n = 1,000) were performed. The five-year cumulative HCC incidence rates were 6.6% and 7.2% in the derivation and validation datasets after entecavir/tenofovir onset. In the derivation dataset, age, gender, serum albumin levels, and platelet counts were independently associated with HCC. The mPAGE-B score was developed based on age, gender, platelet counts, and serum albumin levels (time-dependent area under receiver operating characteristic curves [AUROC] = 0.82). In the validation set, the PAGE-B and THRI showed similar AUROCs to CU-HCC, GAG-HCC, and REACH-B at five years (0.72 and 0.73 vs. 0.70, 0.71, and 0.61 respectively; all p >0.05 except REACH-B), whereas the AUROC of mPAGE-B at five years was 0.82, significantly higher than the five other models (all p <0.01). HCC incidence rates after initiation of entecavir/tenofovir therapy in patients with CHB were significantly decreased in all risk groups in long-term follow-up periods. Although PAGE-B and THRI are applicable in Asian patients with CHB receiving entecavir/tenofovir therapy, mPAGE-B scores including additional serum albumin levels showed better predictive performance than the PAGE-B score. PAGE-B scores and Toronto HCC risk index were developed to predict the risk of hepatocellular carcinoma (HCC) in Caucasian patients with CHB under potent antiviral therapy. This study validated these two scores in Asian patients with CHB and suggested that modified PAGE-B scores could improve the predictive performance. A modified PAGE-B score, which is based only on a patient's age, gender, baseline platelet counts, and serum albumin levels at treatment initiation, represents a reliable and easily available risk score to predict HCC development during the first five years of antiviral treatment in Asian patients with CHB. With a scoring range from 0 to 21 points, a modified PAGE-B score differentiates the HCC risk. A modified PAGE-B score significantly differentiates the five-year HCC risk: low ≤8 points and high ≥13 points.

Remaining hepatocellular carcinoma risk in chronic hepatitis B patients receiving entecavir/tenofovir in South Korea.

We aimed to identify the incidence rate of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with entecavir or tenofovir in South Korea, and to identify predictors of HCC development in these patients. Between January 2007 and December 2015, 582 CHB patients initially received entecavir (n = 406, 69.8%) or tenofovir (n = 176, 30.2%) for CHB. During a median follow-up of 57.1months, HCC developed in 38 (6.5%) of the 582 patients, regardless of antiviral agent type. Entecavir- and tenofovir-treated patients had similar HCC development rates (P = 0.471). For the 582 patients, 2-, 4-, and 6-year cumulative HCC development rates were 2.6%, 4.4%, and 8.3%, respectively, and the 2-, 4-, and 6-year cumulative HCC development rates of patients with liver cirrhosis were significantly greater than those of patients without liver cirrhosis (6.2%, 9.8%, and 18.4% vs. 0.3%, 1.1%, and 2.2%, respectively; P < 0.001). Older (≥60years) patients, regardless of the presence of cirrhosis, and cirrhotic patients aged ≥40years showed significantly higher risk of HCC development compared to others (both P < 0.05). Multivariate analysis showed that an older age (≥50years; hazard ratio [HR] 5.02, P = 0.009), and the presence of cirrhosis (HR 4.95, P = 0.002) independently predicted HCC development. The 6-year cumulative HCC development rate was 6.5% in CHB patients treated with entecavir or tenofovir. Age ≥50years and liver cirrhosis were found to predict HCC development in these patients.

Predictive value of the preoperative neutrophil-to-lymphocyte ratio for the development of hepatocellular carcinoma in HBV-associated cirrhotic patients after splenectomy.

The neutrophil to lymphocyte ratio (NLR), a simple marker of inflammation, has recently been showed to predict tumor recurrence in hepatocellular carcinoma (HCC) patients after hepatic resection or liver transplantation. However, whether it can be used to predict HCC development in cirrhotic patients remained unknown. The aim of this study was to evaluate the predictive value of the preoperative NLR for the development of HCC in cirrhotic patients who underwent splenectomy. A total of 230 HBV-associated cirrhotic patients who underwent splenectomy in our hospital from January 2000 to December 2012 were included in this study. Detailed clinical data included patients’ general characteristics, laboratory tests and imaging studies, surgical procedures and complications. Information on patients’ follow-up data was also obtained. We found that 38 (16.52%) patients developed HCC after splenectomy during the follow-up period. An elevated preoperative NLR was associated with increased risk of developing HCC in cirrhotic patients after splenectomy. The optimal cutoff value of NLR for HCC development was 2.27. In patients who developed HCC during the follow-up period, NLR scores showed no predictive value in overall survival after splenectomy. However, NLR scores appeared to have a much better predictive value in overall survival in patients who did not develop HCC. In conclusion, cirrhotic patients who underwent splenectomy remain at a relatively high risk of developing HCC, and an elevated preoperative NLR is associated with HCC development in cirrhotic patients who underwent splenectomy for hypersplenism.

Stagnation of histopathological improvement is a predictor of hepatocellular carcinoma development after hepatitis C virus eradication.

BackgroundHepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients.MethodsOf 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ± 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed.ResultsAt baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group.ConclusionStagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.

Hepatocellular carcinoma risk assessment by the measurement of liver stiffness variations in HCV cirrhotics treated with direct acting antivirals

BackgroundDirect-acting antivirals (DAA) are an effective treatment for hepatitis C virus infection. However, sustained virologic response (SVR) after DAA treatment does not seem to reduce the risk of hepatocellular carcinoma (HCC) development in these patients. Liver stiffness measurement (LSM) may predict the risk of developing HCC in liver cirrhosis patients. AimsThe aim of our study was to evaluate the role of LSM variation as predictor of HCC development in patients treated with DAA. MethodsIn 139 HCV-related cirrhotic patients, LSM and laboratory tests were carried out at baseline (BL) and at the end of DAA treatment (EOT). Patients were followed for at least 6 months after the EOT. LSM reduction was expressed as Delta LS (∆LS). Cox regression analysis was used to identify prognostic factors for HCC development after DAA. ResultsMedian LSM values were significantly reduced from BL to EOT (from 18.6 to 13.8 kPa; p < 0.001). The median ∆LS was −26.7% (IQR: −38.4% −13.6%). During a median follow-up of 15 months after DAA treatment, 20 (14.4%) patients developed HCC. Significant LSM reduction was observed both in patients who developed HCC and in those who did not, but this was significantly lower in the patients who developed HCC (−18.0% vs −28.9% p = 0.005). At multivariate analysis, ∆LS lower than −30%, Child-Turcotte-Pugh-B and history of HCC were independently associated with HCC development. ConclusionOur results indicate that ∆LS is a useful non-invasive marker for predicting HCC development after DAA treatment.

Post-treatment alpha fetoprotein and platelets predict hepatocellular carcinoma development in dual-infected hepatitis B and C patients after eradication of hepatitis C.

We investigated the long-term risk of hepatocellular carcinoma (HCC) in dual-infected hepatitis B and C patients after eradication of hepatitis C virus (HCV). A total of 164 (62% male, median age, 50.5 years) hepatitis B and C dual-infected patients who achieved HCV sustained virological response were recruited. Half the patients were HCV genotype 1 with a median viral load of 5.5 log10 IU/mL, and 22.6%had an HBV DNA level ≥ 2000 IU/mL before therapy. HCC developed in 14 patients (8.5%), with an annual incidence of 1.38% per person-year. The 3-year, 5-year, 10-year, and 15-year cumulative probabilities were 2.5%, 5.1%, 12.6%, and 22.7%, respectively. Six months after treatment, a Cox regression hazard analysis revealed platelet level (HR: 0.98, 95% CI: 0.957–0.999, P = 0.038) and AFP level (HR: 1.20, 95% CI: 1.031–1.400, P = 0.019) to be independent factors in HCC. A higher 10-year cumulative risk of HCC was detected in patients with 6-month post-treatment AFP levels > 5.0 ng/mL and platelet levels < 130 x1000/µL (54.9%), compared to patients with neither (8.6%). Although the risk of HCC is low, surveillance of HCC is encouraged in dual-infected patients after eradication of HCV. Post-treatment AFP and platelet levels predict HCC development.

Predicting hepatocellular carcinoma development for cirrhosis patients via methylation detection of heparocarcinogenesis-related genes.

Background: Most hepatocellular carcinoma (HCC) patients have undergone a progression from chronic hepatitis, then liver cirrhosis (LC), and finally to carcinoma. The objective of this study was to elucidate risk factors to predict HCC development for cirrhosis patients.Methods: Multiple methylated specific PCR (MSP) was applied to determine methylation status of heparocarcinogenesis-related genes in 396 tissue and plasma specimens and multivariate cox model was used to analyze the relationship between risk variables and HCC development among cirrhosis patients, followed up in a median period of 30 months.Results: Among 105 LC cases, HCC incidence rate at 30 months was 30.48% (32/105), which were statistically associated with patients' age and aberrant methylation of p16, SFRP, and LINE1 (p<0.05). Receiver operating characteristic (ROC) curve showed the overall predictive accuracy reached the highest (90.7%) if the four risk variables were concurrent to predict HCC development. Moreover, along with the growth of age from 0-40, 40-55, to 55-70 years or the increased number of aberrantly-methylated gene from 0-1 to 2-3, the HCC incidence rate of cirrhosis patients rised from 10.00%, 12.28% to 82.14% and 17.44% to 89.47%, separately. Thus, based on combined analysis with diverse age and number of aberrantly-methylated gene, 105 cases were divided into five groups and computed their respective HCC incidecne rate to categorize them into different risk groups. Of note, A significant lifting of HCC incidence rate in the high-risk group (40-55 years coupled with 2-3 aberrantly-methylated genes, 55-70 years coupled with 0-1 aberrantly-methylated gene, 55-70 years coupled with 2-3 aberrantly-methylated genes; n=33) was observed compared with the low-risk group (0-40 years coupled with 0-1 aberrantly-methylated gene, 40-55 years coupled with 0-1 aberrantly-methylated gene; (n=72) (p<0.01).Conclusions: Ultimately, high-risk cirrhosis patients with 55-over years or 2-3 aberrantly-methylated genes should be paid more attention to be regularly screened with HCC development.

Isolated anti-HBc: The Relevance of Hepatitis B Core Antibody-A Review of New Issues.

Hepatitis B core antibody (anti-HBc) is considered the most sensitive serological marker for history of hepatitis B virus (HBV) infection. In a subset of anti-HBc carriers, anti-HBc is present in the absence of hepatitis B surface antigen and hepatitis B surface antibody-a serological pattern known as "isolated anti-HBc" (IAHBc). IAHBc has been of clinical interest over the past several years, with growing data to suggest its role as a serological marker for occult HBV infection (OBI). This article reviews the clinical significance and association of IAHBc with hepatitis C virus (HCV) co-infection, risk of HBV reactivation during direct-acting antiviral therapy for HCV as well as immune suppression, and development of hepatocellular carcinoma (HCC). Hepatitis B core-related antigen is also highlighted as an emerging laboratory assay that may identify OBI and predict HCC development in non-cirrhotic patients receiving nucleoside/nucleotide analog therapy.