Hepatocellular Carcinoma Group Research Articles

The Value of Serum CHI3L1 for the Diagnosis of Chronic Liver Diseases.

ObjectiveTo explore the value of chitinase-3-like protein 1 (CHI3L1) for the diagnosis of patients with chronic liver diseases such as chronic viral hepatitis B, liver cirrhosis and hepatocellular carcinoma (HCC), and analyze the correlation between serum CHI3L1 level and Child–Pugh grading of chronic liver diseases.MethodsThe serum CHI3L1 levels of 154 cases of chronic viral hepatitis B, 132 cases of liver cirrhosis and 88 cases of HCC were detected by ELISA, and 92 healthy subjects were taken as the control.ResultsThe –serum CHI3L1 levels in HCC group, liver cirrhosis group and chronic viral hepatitis B group were higher than in healthy control group (P < 0.001). Serum CHI3L1 level showed a trend of increase in patients with chronic hepatitis to liver cirrhosis and to HCC. The diagnostic efficacy of serum CHI3L1 level on liver cirrhosis showed the sensitivity of 64.4% and the specificity of 96.7%. The diagnostic efficacy of serum CHI3L1 level on HCC showed the sensitivity of 86.8% and the specificity of 97.8%. Serum CHI3L1 level was higher in Child–Pugh grade B and C patients than in Child–Pugh grade A patients, and was positively correlated with Child–Pugh grading of liver function (rs = 0.301, P < 0.001).ConclusionSerum CHI3L1 level increased in chronic liver diseases and showed an increase trend with the progression of liver diseases. Serum CHI3L1 could be a biomarker for the auxiliary diagnosis of chronic liver diseases.

Circular RNA hsa_circ_0000437 may be used as a new indicator for the diagnosis and prognosis of hepatocellular carcinoma

ABSTRACT Circular RNAs (circRNAs) play an essential role in hepatocellular carcinoma (HCC); however, the precise role of circRNAs in the diagnosis and prognosis of HCC remains unclear. The circRNA circ_0000437 was identified in the microarray dataset GSE166678 and was detected in HCC and paired adjacent tissue and serum samples in both the HCC and control groups by reverse transcription quantitative PCR. The association between circ_0000437 expression and clinicopathological characteristics was investigated. Furthermore, the diagnostic and prognostic values of circ_0000437 were determined using receiver operating characteristic (ROC) and Kaplan-Meier curves. Circ_0000437 expression was markedly upregulated in the tumor group compared with the control group and was correlated with tumor node metastasis (TNM) classification, differentiation degree, tumor size, and Barcelona Clinic Liver Cancer (BCLC) stage (P< 0.05) in both the tumor tissues and serum. Furthermore, poor overall survival (OS) was correlated with high circ_0000437 expression, and the area under the ROC curve (AUC) of circ_0000437 for the diagnosis of HCC was 0.9281 in the serum. Our findings suggest that circ_0000437 may be used as a novel biomarker for the diagnosis and prognosis of patients with HCC.

Repurposing PDE5 inhibitor tadalafil and sildenafil as anticancer agent against hepatocellular carcinoma via targeting key events of glucose metabolism and multidrug resistance.

Hepatocellular carcinoma (HCC) has emerged asone of the most common and lethal cancers worldwide and is caused due to contamination of diets with aflatoxin B1 and chronic viral hepatitis. Recent reports suggest that phosphodiesterase-5 inhibitor (PDE5i) exhibits anticancer properties against several forms of cancer but till now has not been evaluated against HCC. We aimed to evaluate the anticancer property of phosphodiesterase-5 inhibitors (PDE5i) tadalafil and sildenafil against aflatoxin B1 HCC. Rats of HCC group were fed with 5% alcohol via drinking water for 3 weeks, followed by administration of AFB1 (1 mg/kg/bw, i.p.) at an interval of two subsequent days. PDE5i (tadalafil and sildenafil, 10 mg/kg bw) was administered along with drinking water after 6 weeks of treatment with AFB1 for 2 weeks. In the present investigation, in HCC elevation in the level of SGOT, SGPT, ALP, and urea vis-à-vis activity of key glycolytic enzyme LDH and mRNA expression of c-myc, Akt, LDH-A, and PFKFB3 was noted. Similarly, the level of multidrug resistance protein (MDR) and breast cancer resistance protein (BCRP/ABCG2) was elevated along with increased expression of angiogenesis marker (HIF-1α, VEGF, andTGF-β1) in HCC. Post-treatment with PDE5 inhibitor (tadalafil and sildenafil) downregulated and brought back the above parameters towards normal and out of two PDE5i (tadalafil and sildenafil), sildenafil effect was more potent as compared to tadalafil. Our findings demonstrate for the first time that PDE5 inhibitors tadalafil and sildenafil are able to prohibit the development and progression of aflatoxin B1 induced HCC.

The diagnostic utility of microRNA 222-3p, microRNA 21-5p, and microRNA 122-5p for HCV-related hepatocellular carcinoma and its relation to direct-acting antiviral therapy

Background and study aimsRecent reports have emphasized the increased risk of hepatocellular carcinoma (HCC) post direct-acting antiviral (DAAs) therapy in chronic hepatitis C virus (HCV) patients. Unfortunately, reliable diagnostic markers for HCC are still lacking. In this context, serum microRNAs have become promising diagnostic targets. Thus, the current study aims to elaborate the diagnostic utility of microRNA 122-5p, microRNA 21-5p, and microRNA 222-3p in the serum of Egyptian patients presenting with HCV infection and HCC post DAA therapy. Patients and methodsQiagen specific microRNA assays were utilized to assess the expression levels of the chosen microRNAs in the serum samples collected from 3 groups: (1) 50 patients with HCV-related HCC, (2) 50 patients with HCC post DAA therapy, and 20 healthy control. ResultsThe mean serum values of microRNA 21-5p and microRNA 122-5p were significantly lower in the HCC post DAA therapy group than in both the group with HCC without prior exposure to DAAs (P < 0.001) and control group (P 0.05 and 0.02, respectively). A significant upregulation was observed for both microRNA 21-5p and microRNA 122-5p in the HCV-related HCC group compared with the control group (P < 0.001 and = 0.011, respectively). On the other hand, the mean serum value of microRNA 222-3p was significantly raised in the HCC post DAA therapy group than in the control group (P = 0.007), whereas no statistically significant difference was observed between both groups with HCC and between the group with HCV-related HCC without prior exposure to DAAs and control group. ConclusionThis is the first study to introduce microRNA 21-5p, microRNA 122-5p and microRNA 222-3p as noninvasive biomarker candidates for HCC post DAA therapy. Their altered expression among treatment-naive HCC and HCC post DAA therapy might assume a different microRNA profiling in both HCC groups.

Hepatitis B virus core-related antigen (HBcrAg) as a prognostic marker for the development of hepatocellular carcinoma: A mini systematic review of the literature.

Chronic hepatitis B (CHB) infection is a risk factor for hepatocellular carcinoma (HCC). Previous studies showed that elevated levels of Hepatitis B Virus (HBV) DNA and HBsAg are associated with increased HCC risk in patients with chronic HBV infection. Multiple studies showed that high levels of HBV DNA and Hepatitis B Surface Antigen (HBsAg) are associated with higher HCC risk in CHB patients. Patients treated with antiviral therapy may have undetectable or low levels of HBV DNA and HBsAg loss. However, HCC may develop in some patients with low-level HBV DNA and HBsAg seroconversion. In this study, we evaluated the role of HBcrAg in predicting HBV related HCC development. We searched PubMed, Scopus, and Web of Science databases using keywords (hepatitis B core-related antigen, hepatocellular carcinoma, liver neoplasm, hepatocellular and hepatic cancer, to identify studies assessing serum level of HBcrAg in patients with CHB and HCC. The search resulted in 184 studies. Seven studies were included: Four of which were retrospective cohort studies, and the rest were prospective cohort, case controls. Six of them reported a higher HBcrAg positivity rate in the HCC group when compared with the HBV DNA assay, yet with similar hazard ratio (HR) in predicting the incidence of HCC. However, four studies found that HBcrAg positivity was an independent risk factor for HCC development with a HR ranging from 3.27 to 7.05. HBV-related HCC has many proposed biomarkers in its prediction, yet our findings revealed HBcrAg to may have superiority over other biomarkers. High quality studies with bigger sample size research is needed to understand the potential role of HBcrAg in CHB induced HCC.

Early Impact of MMaT-3 Policy on Liver Transplant Waitlist Outcomes for Hepatocellular Carcinoma.

Background.To reduce the disparity in access to liver transplant (LT), United Network for Organ Sharing implemented an exception policy in May 2019, which capped hepatocellular carcinoma (HCC) exception score to the median Model for End-Stage Liver Disease (MELD) at transplant within the donor service area minus 3 points (MMaT-3) after the 6-mo wait period. We aimed to evaluate how this policy affected HCC waitlist outcomes.Methods.Using United Network for Organ Sharing data, we analyzed waitlist outcomes in HCC patients at the time they received exception points from in the pre-MMaT era (August 15, 2017, to November 15, 2018) and MMaT era (June 1, 2019, to August 30, 2020). Comparisons were made within the HCC group and HCC versus non-HCC (at time of listing) groups in the pre-MMaT and MMaT eras and regions were grouped as low, medium, and high MELD based on MMaT.Results.HCC group: LT probability within HCC patients decreased by 20% (subhazard ratio [sHR], 0.78; 95% confidence interval [CI], 0.74-0.85) between the eras and decreased by 41% in low MELD regions (sHR, 0.59; 95% CI, 0.52-0.66). Waitlist dropout was unchanged. Matched HCC versus non-HCC groups: HCC patients had 80% higher LT probability (sHR, 1.84; 95% CI, 1.71-1.99) than non-HCC patients in the pre-MMaT era; which decreased to a 14% higher LT probability in MMaT era. In low and medium regions, HCC patients had over twofold higher LT probability in the pre-MMaT era, which decreased to a ~20% higher probability (sHR, 1.14; 95% CI, 1.06-1.23) in the MMaT era. After implementation of the acuity circle policy, HCC patients had lower LT probability (sHR, 0.84; 95% CI, 0.74-0.94) than non-HCC patients.Conclusions.The geographic disparity between HCC and non-HCC patients has improved with the MMaT-3 policy. Despite lower LT probability for HCC patients, waitlist dropout was not adversely impacted.

Circulating Cell-Free DNA and DNA Integrity as Molecular Diagnostic Tools in Hepatocellular Carcinoma.

We assessed the ability to use circulating cell-free DNA (cfDNA) and the DNA integrity index (DNAII) to detect the transition from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). Circulating cfDNA and DNAII were measured in 50 patients with advanced LC and 50 patients with HCC who were followed for 1 month after transarterial chemoembolization (TACE). Fifty healthy participants served as a control group. Real-time quantitative polymerase chain reaction (PCR) was used to measure circulating cfDNA concentration, and Alu-PCR was used to measure the concentration of Alu repeats, both short fragments (115 base pairs [bp]) and long fragments (247 bp). We compared liquid biopsy results with the relevant traditional markers. The HCC group showed significantly higher circulating cfDNA concentrations and DNAII values compared with the LC and control groups. No significant differences were found in circulating cfDNA concentrations and DNAII values between the LC and control groups. Circulating cfDNA concentrations decreased significantly after treatment (TACE); areas under the curve of circulating cfDNA concentration and DNAII values were significantly better than those of ɑ-fetoprotein and vascular endothelial growth factor in discriminating between LC and HCC. The combined use of DNAII with proteins induced by vitamin K absence or antagonist showed better diagnostic performance in HCC. Circulating cfDNA could have a potential role in monitoring HCC treatment.

Acute-phase serum amyloid A for early detection of hepatocellular carcinoma in cirrhotic patients with low AFP level

Regular hepatocellular carcinoma (HCC) surveillance by ultrasonography in combination with the α-fetoprotein (AFP) examination is unsatisfactory in diagnostic sensitivity for early-stage HCC especially in cirrhotic patients. We conducted a prospective study in a tertiary medical center in Taiwan and consecutively collected serum samples from patients with chronic hepatitis, liver cirrhosis (LC), or HCC for new biomarker discovery. Overall, 166 patients were enrolled, including 40 hepatitis, 30 LC, and 96 HCC. Four acute-phase serum amyloid A (A-SAA) derived biomarkers including total A-SAA, A-SAA monomer and oligomer, and protein misfolding cyclic amplification (PMCA) signal were measured and compared between patients with and without HCC. A-SAA biomarkers significantly increased in the HCC group when compared to the hepatitis and LC groups, and generally increased in more advanced tumor stages. Among A-SAA biomarkers, the area under the receiver operator characteristic curves (AUROCs) for PMCA signal in discrimination of all-stage and early-stage HCC were 0.86 and 0.9 in cirrhotic patients, which is comparable to AFP. For cirrhotic patients with low AFP (< 7 ng/mL), PMCA signal maintained good capacity in prediction of early-stage HCC (AUROC: 0.94). Serum A-SAA and its prion-like property showed a potential to complement AFP in detection of early-stage HCC.

Association of the MARCO polymorphism rs6761637 with hepatocellular carcinoma susceptibility and clinical characteristics.

Hepatocellular carcinoma (HCC) remains a significant health problem with a substantial genetic predisposition. The liver harbors the largest proportion of macrophages among all the solid organs. There is considerable controversy regarding the relationship between the macrophage receptor with collagenous structure (MARCO) and tumor development and progression. Accordingly, we performed this case-control study to determine whether associations exist between the MARCO single nucleotide polymorphism rs6761637 and HCC susceptibility and clinical characteristics. We successfully genotyped 586 HCC cases and 647 controls using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The overall genotype distribution of rs6761637 was similar in the HCC and control groups (P = 0.143). However, the CT + CC genotypes of rs6761637 were slightly more common in the HCC group among female (P = 0.021), overweight (body mass index ≥ 24kg/m2, P = 0.003), and nonsmoking (P = 0.022) individuals. The minor C allele carriers had a 1.47-fold increased risk of developing large tumor nodules (P = 0.041). rs6761637 did not affect the recurrence-free or overall survival rate of patients with HCC (P = 0.247 and 0.304, respectively). In conclusion,this is the first report of the association between MARCO genetic variations and HCC risk. These results suggest that the MARCO rs6761637 polymorphism may play a regulatory role in HCC carcinogenesis, but it does not seem to predict prognosis.

Serum clusterin as a promising diagnostic and prognostic marker for hepatocellular carcinoma after locoregional treatment

Hepatocellular carcinoma (HCC) is one of the most common aggressive tumors, with a rising prevalence in Egypt. Clusterin is a secretory heterodimeric glycoprotein linked to cancer development and progression. This study was conducted to evaluate the diagnostic and prognostic role of serum clusterin as a possible biomarker of HCC and correlate its level with the mRECIST scoring system. This study included 45 patients with liver cirrhosis and HCC eligible for locoregional treatment and 20 patients with liver cirrhosis without HCC as controls. All patients underwent standard laboratory tests and abdominal ultrasound. For HCC patients, a triphasic CT scan, alpha-fetoprotein (AFP), and clusterin levels were measured at baseline and one month after intervention. HCC patients had a substantially higher baseline clusterin level than cirrhotic patients (122.291 ± 61.898 vs. 74.015 ± 41.571, P = 0.002). Five patients in the HCC group were not eligible for intervention because they had evidence of portal vein invasion. At one month follow-up after HCC treatment, serum clusterin levels declined significantly from baseline (from 122.291 ± 61.898 to 81.125 ± 62.321, P = < 0.001). According to the mRECIST scoring, baseline clusterin levels were significantly higher among patients with progressive disease than those with partial response than those with complete response (180.722 ± 55.908, 161.310 ± 56.339, 84.810± 41.389, respectively, overall P = < 0.001). Clusterin was a useful marker in detecting HCC with 73.33% sensitivity and 75% specificity at a cutoff of ≥ 86.6 mg/L, and it also had 95.24% sensitivity and 77.78% specificity in detecting tumor progression at a cutoff of ≥ 146.6 mg/L, according to the mRECIST scoring system. In conclusion, clusterin may be a helpful diagnostic and prognostic marker for HCC after locoregional treatment, as its baseline level is useful in predicting response and progression of HCC in correlation with the mRECIST scoring system.

Detection of exosomal miR-18a and miR-222 levels in Egyptian patients with hepatic cirrhosis and hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is known to be the second leading cause of cancer-related mortality worldwide. For improving the prognosis as well as reducing the rate of mortality, early diagnosis of HCC is a must.AimsThis study was conducted to assess the ability of the serum expression of exosomal miR-18a and miR-222 to differentiate and diagnose patients with HCC, patients with liver cirrhosis, and healthy controls.MethodsThis study included 51 patients with liver cirrhosis, 51 patients with HCC on top of hepatitis C virus (HCV) infection, and 50 healthy controls.ResultsmiR-18a and miR-222 were assessed using reverse transcription-polymerase chain reaction. MiR-18a and miR-222 levels were significantly higher in the liver cirrhosis and HCC groups than the control group (p ˂ 0.001). However, no statistically significant difference was found between patients with HCC and liver cirrhosis (p = 0.4 for miR-18a and p = 0.1 for miR-222). ROC curve analyses to evaluate the diagnostic performances of the two miRNAs as important noninvasive diagnostic markers revealed a best cutoff value of 2 for miR-18a to differentiate between liver cirrhosis, HCC, and healthy controls. And for mir-222, a cutoff value of 1.7 and 1.9 showed the highest specificity for discrimination between liver cirrhosis, HCC, and healthy controls, respectively. Moreover, logistic regression model revealed that miR-18a expression was independent predictive factor in HCC patients (p = 0.004), while miR-222 expression was independent predictive factor in liver cirrhosis patients (p < 0.001).ConclusionmiR-18a and miR-222 were significantly discriminative markers between patients with liver cirrhosis and HCC and healthy individuals. Therefore, they have a prognostic rather than a diagnostic value. Moreover, miR-18a and miR-222 could be useful in identifying liver injuries, including fibrosis and cirrhosis.

Assessment of fibroblast growth factor 19 as a non-invasive serum marker for hepatocellular carcinoma.

BACKGROUNDFibroblast growth factor 19 (FGF-19) is one of the founding members of the endocrine FGF subfamily. Recently, it has been the subject of much interest owing to its role in various physiological processes affecting glucose and lipid metabolism and the regulation of bile acid secretion as well as cell proliferation, differentiation, and motility. Additionally, FGF-19 secretion in an autocrine style has reportedly contributed to cancer progression in various types of malignancies including hepatocellular carcinoma (HCC). AIMTo estimate the serum FGF-19 concentrations in HCC cases and assess its diagnostic performance for the detection of HCC.METHODSWe recruited 90 adult participants and divided them into three equal groups: Healthy controls, cirrhosis patients, and HCC patients. Serum FGF-19 concentrations were measured using the Human FGF-19 ELISA kit. RESULTSWe detected a high statistically significant difference in serum FGF-19 levels among the three groups. The highest level was observed in the HCC group, followed by the cirrhosis and control groups (236.44 ± 40.94 vs 125.63 ± 31.54 vs 69.60 ± 20.90 pg/mL, respectively, P ≤ 0.001). FGF-19 was positively correlated with alpha fetoprotein (AFP; r = 0.383, P = 0.003) and international normalised ratio (r = 0.357, P = 0.005), while it was negatively correlated with albumin (r = -0.500, P ≤ 0.001). For the detection of HCC, receiver operating characteristic curve analysis showed that the best cut-off point of AFP was > 8.2 ng/mL with an area under the curve (AUC) of 0.78, sensitivity of 63.33%, specificity of 83.33%, positive predictive value (PPV) of 79.2%, negative predictive value (NPV) of 69.4%, and total accuracy of 78%. However, FGF-19 at a cut-off point > 180 pg/mL had an AUC of 0.98, sensitivity of 100%, specificity of 90.0%, PPV of 90.0%, NPV of 100%, and total accuracy of 98%.CONCLUSIONFGF-19 represents a possible novel non-invasive marker for HCC. It may improve the prognosis of HCC patients due to its utility in several aspects of HCC detection and management.

Influence of AFP on surgical outcomes in non-B non-C patients with curative resection for hepatocellular carcinoma

To study the clinical and prognostic features of non-B non-C alpha-fetoprotein (AFP)(-)-hepatocellular carcinoma (HCC) (NBNC-AFP(-)-HCC) and the relationship between the prognostic features of HCC and hepatitis B virus surface antigen (HBsAg) status and AFP. We enrolled 227 patients who underwent hepatic resection for HCC between January 1998 and December 2007 at Sun Yat-sen University Cancer Center, all of whom were diagnosed with HCC by pathology. All patients were stratified into one of four groups (B-AFP(+)-HCC, B-AFP(-)-HCC, NBNC-AFP(+)-HCC, and NBNC-AFP(-)-HCC) according to AFP levels and HBsAg status. The clinicopathologic and survival characteristics of NBNC-AFP(-)-HCC patients were compared with those of all other three groups. Out of the 105 NBNC-HCC patients, 43 patients (40.9%) had AFP-negative HCC. There were some differences in factors between the B-AFP(+) and NBNC-AFP(-) patients, such as age, body mass index (BMI), diabetes, and ALT (P < 0.05). On univariate analysis, tumour size, secondary tumour, and portal invasion were prognostic factors for overall survival (OS) and disease-free survival (DFS) (P < 0.05). Cox multivariate regression analysis suggested that tumour size and tumour number (P < 0.05) were independent predictors. In addition, compared with the B-AFP(+)-HCC, B-AFP(-)-HCC, and NBNC-AFP(+)-HCC groups, the NBNC-AFP(-)-HCC patients had the best DFS (P < 0.05). Compared with the B-AFP(+)-HCC and NBNC-AFP(+)-HCC groups, the NBNC-AFP(-)-HCC patients had better OS (P < 0.05), and survival rates were similar to those of B-AFP(-)-HCC patients. NBNC-AFP(-)-HCC patients had a relatively favourable prognosis. It can serve as a useful marker in predicting the risk of tumour recurrence in the early stages.

Expression of IER3 in hepatocellular carcinoma: clinicopathology, prognosis, and potential regulatory pathways.

BackgroundImmediate early response 3 (IER3) is correlated to the prognosis of several cancers, but the precise mechanisms underlying the regulation by IER3 of the occurrence and development of hepatocellular carcinoma (HCC) remain unknown.MethodsThe expression level of IER3 was examined by using in-house immunohistochemistry (IHC), public gene chip, and public RNA-sequencing (RNA-seq). The standardized mean difference (SMD) was calculated to compare the expression levels of IER3 between HCC patients and controls. The summary receiver operating characteristics (sROC) was plotted to comprehensively understand the discriminatory capability of IER3 between HCC and non-HCC group. The Kaplan–Meier curves and the combined hazard ratios (HRs) were used to determine the prognostic value of IER3 in HCC. Moreover, differentially expressed genes (DEGs) and co-expression genes (CEGs) were used to explored the molecular mechanisms of IER3 underlying HCC. hTFtarget was used to predict the transcription factors (TFs) of IER3. The binding site of TFs and the IER3 promoter region was forecasted using the JASPAR website. The relevant ChIP-seq data were used to determine whether TF peaks were present in the IER3 transcription initiation.ResultsA significantly increased expression of IER3 protein was found in HCC tissue relative to non-HCC tissue as detected by IHC (p < 0.001). Compared to 1,263 cases of non-HCC tissues, IER3 in 1483 cases of HCC tissues was upregulated (SMD = 0.42, 95% confidence interval [CI] [0.09–0.76]). The sROC showed that IER3 had a certain ability at differentiating HCC tissues (area under the curve (AUC) = 0.65, 95% CI [0.61–0.69]). Comprehensive analysis of the effect of IER3 on the prognosis of patients with HCC demonstrated that higher IER3 expression was associated with poor prognosis in HCC (HRs = 1.30, 95% CI [1.03–1.64]). Pathway enrichment analysis revealed that IER3-related genes were mostly enriched in the PI3K-Akt signaling pathway, cancer-related signaling pathways, the p53 signaling pathway, and other signaling pathways. Regulatory factor X5 (RFX5) was identified as a possible regulator of IER3-related TF.ConclusionIER3 may be a potential prognostic marker for HCC. The molecular mechanisms of IER3 in HCC warrant further study.

Experience of using contrast-enhanced ultrasound examination in the most common malignant neoplasms of the liver

Aim. To study the features of contrast enhancement of malignant neoplasms of the liver in patients with and without cirrhosis (LC), to study the differences in the dynamics of contrast enhancement of liver are metastatic lesions (MTS) and hepatocellular carcinoma (HCC).Material and methods. A retrospective analysis results 58 patients with HCC (group 1) and 51 patients with liver metastases (group 2) was carried out based on morphological data. According to the criterion for the presence of LC, group 1 was divided into two subgroups. The main method of radiological diagnostics was contrast enhancement ultrasound (CEUS).Results. The indicators of the dynamics of the Wash-in of an ultrasound contrast agent into the HCC node and the dynamics of the drug WASH-OUT from the focus in patients with LC did not significantly differ from those in patients without cirrhosis. HCC is characterized by the onset of leaching of the ultrasound contrast agent after 62 seconds from the beginning of the study, which significantly differs from MTS (p &lt;0.05). The parameters in predicting the G3 stage of the tumor were as follows: the parameter “onset of WASH-OUT” of the from the focus &lt;79 sec, the parameter “time of maximum WASH-OUT” of the ultrasound contrast agent &lt;270 seconds. In our opinion, certain difficulties are presented by the diagnosis of highly differentiated carcinomas due to the absence of the WASH-OUT phenomenon in 50% of patients. Differential diagnosis of metastases should be based on a combination of a number of signs, the most important of which, in our opinion, are: early onset of elution of ultrasound contrast agent, “black hole” symptom, peripheral ring-shaped enhancement in arterial phase.Conclusion. The data obtained with the help of CEUS confirm the effect of “arterialization of hepatic blood flow” in patients with LC. Differences in the parameters of contrasting HCC nodes in subgroups of patients with and without LC are not statistically significant. The polymorphism of the signs detected in MTS in the liver is due to the morphology of the primary tumor and the size of the neoplasms. Differential diagnosis should be based on a combination of signs of the dynamics of ultrasound contrast agents.

Autoantibody Against Ferritin Light Chain is a Serum Biomarker for the Detection of Liver Cirrhosis but Not Liver Cancer.

PurposeFerritin is a protein that plays an important role in iron metabolism, it consists of two subunits: heavy chain (FTH) and light chain (FTL). Elevated expression of FTL is observed in multiple malignancies. Recent studies have found that the frequency of circulating autoantibody against FTL (anti-FTL) increased significantly in hepatocellular carcinoma (HCC). The aim of this study is to verify circulating anti-FTL as a biomarker for the early detection of HCC.Patients and MethodsA total of 1565 participants were enrolled and assigned to two independent validation cohorts, including 393 HCC patients, 379 liver cirrhosis (LC) patients, 400 chronic hepatitis (CH) patients, and 393 healthy subjects. The concentration of serum anti-FTL was measured by indirect Enzyme-Linked Immunosorbent Assay (ELISA). Kruskal–Wallis test was used to compare anti-FTL concentrations between HCC group and three control groups. Percentile 95 of anti-FTL absorbance value of healthy group was selected as the cut-off value to calculate the positive rate in each group. The area under receiver operating characteristic curve (AUC) was used to quantitatively describe its diagnostic value.ResultsThe median concentration of anti-FTL in HCC patients was higher than that in CH patients and healthy subjects, but there was no difference between HCC patients and LC patients. Further analysis showed that there was no difference between early stage LC, advanced stage LC, Child-Pugh A HCC, Child-Pugh B HCC and Child-Pugh C HCC. The positive rate of anti-FTL was 12.2% (48/393) in HCC, 13.5% (51/379) in LC, 6.3% (25/400) in CH and 5.1% (20/393) in healthy subjects, respectively. The AUC of anti-FTL to distinguish LC from CH or healthy subjects were 0.654 (95% CI: 0.615–0.692) and 0.642 (95% CI: 0.602–0.681), respectively.ConclusionAnti-FTL is not a biomarker for the early diagnosis of HCC due to specificity deficiency, but may be helpful for the early detection of LC.

Sero-reactivity to three distinct regions within the hepatitis C virus alternative reading frame protein (ARFP/core+1) in patients with chronic HCV genotype-3 infection.

Hepatitis C virus (HCV) infection affects more than 71 million people worldwide. The disease slowly progresses to chronic, long-term liver injury which leads to hepatocellular carcinoma (HCC) in 5 % of infections. The alternative reading frame protein (ARFP/core+1) is encoded by a sequence overlapping the HCV core gene in the +1 reading frame. Its role in hepatitis C pathogenesis and the viral life cycle is unclear, although some observers have related its production to disease progression and the development of HCC. The aim of this study was to determine whether ARFP is immunogenic in patients with chronic HCV genotype 3 infection and to assess whether sero-reactivity is associated with disease progression, particularly to HCC. Immunogenic epitopes within the protein were predicted by a bioinformatics tool, and three −20 aa length-peptides (ARFP-P1, ARFP-P2 and ARFP-P3) were synthesized and used in an avidin-biotin ARFP/core+1 peptide ELISA. Serum samples from 50 patients with chronic HCV genotype 3 infection, 50 genotype-1 patients, 50 HBV patients and 110 healthy controls were tested. Sero-reactivity to the ARFP peptides was also tested and compared in 114 chronic HCV genotype-3 patients subdivided on the basis of disease severity into non-cirrhotic, cirrhotic and HCC groups. Chronic HCV genotype-3 patients showed noticeable rates of reactivity to ARFP and core peptides. Seropositivity rates were 58% for ARFP-P1, 47 % for ARFP-P2, 5.9 % for ARFP-P3 and 100 % for C22 peptides. There was no significant difference between these seroreactivities between HCV genotype-3 patients with HCC, and HCV genotype-3 patients with and without liver cirrhosis. Patients with chronic HCV genotype-3 infection frequently produce antibodies against ARFP/core+1 protein. ARFP peptide reactivity was not associated with disease severity in patients with HCV genotype-3. These results support the conclusion that ARFP/core+1 is produced during HCV infection, but they do not confirm that antibodies to ARFP can indicate HCV disease progression.

Verification of hepatitis B-related hepatocellular carcinoma predictive models to evaluate the risk of HCC in patients with liver cirrhosis under antiviral treatment.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The development of chronic hepatitis B (CHB)-related HCC can be attributed to continuous hepatitis B virus (HBV) infection. It is crucial to identify and monitor patients with CHB at high risk of HCC occurrence so that HCC can be detected early and the patients are able to receive effective treatment promptly to increase the survival rate and improve prognosis. This study aimed to verify hepatitis B-related hepatocellular carcinoma predictive models to evaluate the risk of HCC in patients with liver cirrhosis under antiviral treatment. Patients with HBV-related compensated cirrhosis were treated with lamivudine and adefovir randomly, and then with a combination of two drugs at different time points based on the virologic response. Patients with HCC occurrence during follow-up were categorized as HCC group, whereas others as control group. They were further divided into 2-year HCC, 2-year control, 5-year HCC, and 5-year control groups according to the observation time. The operating curves of the patients were used to verify models before and after antiviral treatment. Using the baseline as a parameter, the area under the curve (AUC) of risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B) after 2 and 5 years was 0.863 and 0.797, respectively. The AUC after 2 and 5 years was 0.839 and 0.747, respectively, for guide with age, gender, HBV DNA, core promoter mutations and cirrhosis (GAG-HCC) and 0.741 and 0.748, respectively, for Taiwanese HBV cohort (TW1). Using 48 weeks as the parameter, it has an optimal critical value of 8 points. The AUC of REACH-B after 2 and 5 years was 0.738 and 0.721, respectively. REACH-B can predict the risk of HCC occurrence in patients with compensated liver cirrhosis before and after antiviral treatment. GAG-HCC and TW1 could predict the risk before antiviral treatment.

Genetic Variations of ALDH (rs671) Are Associated With the Persistence of HBV Infection Among the Chinese Han Population.

Alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), members of the alcohol dehydrogenase family, have important roles in liver diseases. The roles of the polymorphisms of ADH1B rs1229984 and ALDH2 rs671 in hepatitis B virus (HBV) susceptibility and persistent infection were investigated in the present study. Total 1,034 patients with hepatitis B [99 acute hepatitis B (AHB), 521 chronic hepatitis B (CHB), 158 acute-on-chronic liver failure (ACLF), 159 liver cirrhosis (LC), and 97 hepatocellular carcinoma (HCC)] and 1,262 healthy controls (HCs) of the Chinese Han population were recruited, and single nucleotide polymorphisms (SNPs) of rs671 and rs1229984 were genotyped. Independent and joint roles of rs671 and rs1229984 in HBV infection were analyzed. The results showed that rs671 genotypes had a significantly different distribution among different subgroups. Compared with HCs, the frequency of rs671-AA genotype was higher in hepatitis B individuals, especially in the CHB group [adjusted OR (95%CI) = 1.899 (1.232–2.928), p = 0.003, in the co-dominant model], which showed a significant positive association. It was further confirmed that CHB individuals who carried ALDH2 rs671-AA genotype had a higher risk of persistent HBV infection and higher HBV-DNA quantitation compared with those with GG/GA genotype. In addition, the rs671-AA genotype might predict HCC incidence in patients with CHB. There were no different distributions of alleles or genotypes in rs671 mutant among AHB, ACLF, LC, or HCC groups compared with HCs. These data suggested the possible hazardous role of rs671-AA variant in HBV infection and persistence.

Dual hepatitis B and C-associated hepatocellular carcinoma: clinical characteristics, outcome, and prognostic role of albumin-bilirubin grade.

Albumin-bilirubin (ALBI) grade is used to evaluate the outcome of patients with hepatocellular carcinoma (HCC) which is often associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study aimed to investigate the clinical characteristics, outcome, and prognostic role of ALBI grade in dual HBV/HCV-related HCC. A total 3341 HCC patients with viral etiology were prospectively enrolled and retrospectively analyzed. Multivariate Cox proportional hazards model was used to identify independent prognostic predictors. Of all patients, 2083 (62%), 1068 (32%), and 190 (6%) patients had HBV, HCV, and dual HBV/HCV infection, respectively. The mean age of HBV, HCV, and dual virus group was 60, 68, and 64years (p < 0.001), respectively. There was no significant survival difference between HBV, HCV, and dual HBV/HCV-related HCC group (p = 0.712). Multivariate Cox analysis in dual HBV/HCV-related HCC showed that multiple tumors [hazard ratio (HR): 1.537, p = 0.044], tumor size >3cm (HR 2.014, p = 0.044), total tumor volume (TTV) >50 cm3 (HR 3.050, p < 0.001), vascular invasion (HR 3.258, p < 0.001), performance status 2-4 (HR 2.232, p < 0.001), ALBI grade 2-3 (HR 2.177, p < 0.001), and BCLC stage B-D (HR 2.479, p < 0.001) were independent predictors of poor survival. Dual viral infection does not accelerate the development of HCC in HBV carriers. Patient survival is similar between dual HBV/HCV-related HCC and single HBV- or HCV-related HCC group. The ALBI grade is a robust prognostic model in dual virus-related HCC to discriminate patient long-term survival.