Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells.

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related deaths worldwide. Sorafenib has been used as a first-line systemic treatment for over a decade. However, resistance to sorafenib limits patient response and presents a major hurdle during HCC treatment. Lenvatinib has been approved as a first-line systemic treatment for advanced HCC and is the first agent to achieve non-inferiority against sorafenib. Therefore, in the present study, we evaluated the inhibition efficacy of lenvatinib in sorafenib-resistant HCC cells. Only a few studies have been conducted on this topic. Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance, and in vitro and in vivo studies were employed. Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling. Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.

Long-Term Outcomes and Evaluation of Hepatocellular Carcinoma Recurrence after Hepatitis C Virus Eradication by Direct-Acting Antiviral Treatment: All Kagawa Liver Disease Group (AKLDG) Study.

There are limited studies that have evaluated the long-term outcomes in patients with hepatocellular carcinoma (HCC) recurrence after direct-acting antiviral (DAA) treatment. In this retrospective study, we aimed to investigate the recurrence rates, recurrence factors, and prognosis of 130 patients who were treated with IFN-free DAA treatment after treatment for HCC. The median observation time was 41 ± 13.9 months after DAA treatment. The recurrence rates of HCC were 23.2%, 32.5%, 46.3%, and 59.4% at 6, 12, 24, and 36 months, respectively. A multivariate analysis showed that palliative treatment prior to DAA treatment (HR = 3.974, 95% CI 1.924-8.207, p = 0.0006) and alpha-fetoprotein at sustained virological response 12 (HR = 1.048, 95% CI 1.016-1.077, p = 0.0046) were associated with independent factors for HCC recurrence (HCC-R). The 12-, 24-, and 36-month overall survival rates were 97.6%, 94.0%, and 89.8%, respectively. The 12-, 24-, and 36-month survival rates of the non-recurrence and recurrence groups were 97.7%, 97.7%, and 94.1% and 97.6%, 92.3%, and 87.9%, respectively (p = 0.3404). The size of the main tumor lesion and the serological data were significantly improved at the time of HCC-R after DAA treatment. This study showed an improved prognosis regardless of recurrence rate, which suggests that DAA treatment in HCV patients should be considered.

Efficacy of daily abdominal self-massage for the prevention of recurrent common bile duct stones after endoscopic biliary sphincterotomy.

Recurrent common bile duct stones (CBDS) can occur after endoscopic biliary sphincterotomy (EST). Bile flow through the papilla of Vater could be improved by means of abdominal massage. We report the results of self-abdominal massage in four patients who had previously undergone cholecystectomy and experienced multiple CBDS recurrences after EST.

Association between microRNA-527 and glypican-3 in hepatocellular carcinoma.

The present study aimed to identify the specific microRNAs (miRNAs/miRs) and their corresponding target genes involved in hepatocellular carcinomas (HCCs). Microarray analysis was performed to examine the miRNA expression profiles of four paired HCC and corresponding non-cancerous (N) liver tissues using 985 miRNA probes. The Human miRNA Target database was used to identify the target genes of differentially expressed miRNAs between the HCC and N tissues. The protein expression levels of target genes in the HCC tissues and cell lines were evaluated using western blotting. miRNA-mediated suppression of target gene expression was evaluated by transiently transfecting the miRNA into the HCC cell lines. Of the 985 miRNAs evaluated, four miRNAs were differentially expressed (three upregulated and one downregulated miRNAs). Of these four miRNAs, miRNA-527 was highly downregulated in the HCC tissues. Glypican-3 (GPC-3) was predicted as a target gene of miRNA-527. Western blotting revealed that GPC-3 protein is highly expressed in the HCC tissues and HCC cell lines compared with N and normal cell lines. Transfection with miR-527 resulted in suppression of GPC-3 protein expression in the Cos7 cells. Furthermore, transfection with miR-527 also inhibited the intrinsic expression of GPC-3 in the Huh-7 cell line. This indicated that miR-527 in the HCC tissues may be an important novel miRNA that targets the GPC-3 gene expression. GPC-3, whose expression is regulated by miR-527, may be involved in the development and progression of HCC.

Aspirin inhibits cholangiocarcinoma cell proliferation via cell cycle arrest in vitro and in vivo.

Cholangiocarcinoma is the most common biliary duct malignancy and the second most common primary liver cancer, accounting for 10­20% of hepatic malignancies. With high mortality and poor prognosis, the 5­year survival rate of cholangiocarcinoma is only 10%. A previous study demonstrated a significant association between aspirin use and a decreased risk of cholangiocarcinoma. However, the effect of aspirin on cholangiocarcinoma remains unknown. Therefore, the aim of the present study was to investigate the effects of aspirin on cholangiocarcinoma in vitro and in vivo. Three cholangiocarcinoma cell lines were used to analyze the effect of aspirin on cell proliferation, cell cycle progression, apoptosis, and the regulation of microRNAs. MicroRNAs are known to regulate the development and progression of various types of cancer. An HuCCT­1 xenograft model was used for the in vivo study. It was determined that aspirin inhibited the proliferation of human cholangiocarcinoma cells (except TKKK cells). Aspirin induced cell cycle arrest in the G0/G1 phase and regulated cell­cycle related proteins in cholangiocarcinoma cells (HuCCT­1 cells) but did not induce apoptosis. The expression of miR­340­5p was significantly upregulated after treatment, and overexpression of miR­340­5p inhibited the proliferation of HuCCT­1 cells and decreased the levels of cyclin D1. TKKK cells had low miR­340­5p expression, which may explain why aspirin had no effect on their proliferation. In vivo, aspirin reduced the growth of xenografted tumors. In conclusion, the present study indicated that aspirin partially inhibited cholangiocarcinoma cell proliferation and tumor growth by inducing G0/G1 phase cell cycle arrest, potentially through the miR­340­5p/cyclin D1 axis.

Peg-IFNα-2a Contributed to HBs Antigen Seroclearance in a Patient with Chronic Hepatitis B Administered Nucleic Acid Analogs: A Three-year Follow-up.

We treated a 51-year-old Japanese man with chronic hepatitis B (viral load 7.6 LC/mL, genotype C). Hepatitis B virus DNA and HBe antigen were undetectable during the administration of the nucleic acid analogs (NUCs) lamivudine and adefovir, although the concentration of HBs antigen (HBsAg) was 851.2 IU/mL. The HBsAg levels were reduced 150-fold when pegylated-interferon (Peg-IFN) α-2a was administered weekly for 48 weeks and did not increase during the rest period. Therefore, Peg-IFNα-2a was administered twice each week. During this time, HBsAg reached undetectable concentrations, and HBs antibody was detected and continued to be detectable during the three-year follow-up. These unprecedented findings suggest that IFN may contribute to the seroclearance of HBsAg in patients treated with NUCs.

Identification of microRNA associated with the elimination of hepatitis C virus genotype 1b by direct-acting antiviral therapies.

BACKGROUND AND AIM: Direct-acting antiviral (DAA) therapies have been proven to be highly effective for the eradication of hepatitis C virus (HCV) without resistance-associated substitutions (RASs). However, even in cases with no detected RASs, treatment sometimes fails, suggestive of the existence of some host-related factors involved in HCV eradication by DAAs. To explore such factors, we analyzed the serum microRNAs (miRNAs) of patients who received DAA treatment. METHODS: The serum miRNA expression levels of 39 patients with chronic HCV infection without any detectable RASs, who achieved sustained virological response with asunaprevir/daclatasvir or grazoprevir/elbasvir therapy, were investigated cyclopedically, using oligonucleotide microarrays. The effects of specific miRNAs on the replication of HCV were measured in the HCV genomic replicon containing Huh-7 hepatoma cells. RESULTS: Along with the disappearance of HCV, the expression quantiles of 16 miRNAs in the asunaprevir/daclatasvir group and 18 miRNAs in the grazoprevir/elbasvir group showed a tendency to increase or decrease. Among these molecules, adjustments for multiple testing yielded a significant differential expression at a false discovery rate of less than 5% for only one molecule, hsa-miR-762. Its expression quantile increased after HCV exclusion in all patients who had achieved sustained virological response. Quantitative polymerase chain reaction analysis validated a significant increase in the serum hsa-miR-762 after disappearance of HCV. On the contrary, hsa-miR-762 was decreased in the relapse and breakthrough of HCV in DAA failures. Transfection of hsa-miR-762 into cultured HCV-infected hepatocytes significantly decreased HCV-RNA replication. CONCLUSION: These data suggest that hsa-miR-762 is one of the host factors participating in HCV exclusion by DAA therapy.

A case report of granulocyte colony-stimulating factor-producing hepatocellular carcinoma that recurred after long-term complete response.

The granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates cell proliferation and differentiation of precursor cells in the bone marrow. Several cases of G-CSF-producing malignant tumors in various organs have been reported, but there are only nine cases of G-CSF-producing hepatocellular carcinoma (HCC) reported in the English literature. G-CSF-producing tumors grow rapidly and have a high probability of distant metastases; thus, they generally have a poor prognosis. Given that the mechanism of the carcinogenesis of G-CSF-producing HCC remains unclear, an efficient treatment strategy also remains to be elucidated. We report herein a case of G-CSF-producing HCC accompanied by leukocytosis and high serum G-CSF concentrations in the disease progression stage after long-term complete response. We also reviewed previous reports to investigate the clinical behaviors of G-CSF-producing HCC, including our case. Clinicians should consider G-CSF-producing HCC in patients with a hepatic mass and drastic leukocytosis, without any evidence of infection and blood disorders. Early diagnosis and prompt therapy, including radical resection, may provide a more favorable prognosis.

L-carnitine reduces hospital admissions in patients with hepatic encephalopathy.

AIM: The aim of this study was to determine whether oral L-carnitine administration reduces the blood ammonia concentration and number of hospital admissions for hepatic encephalopathy in patients with advanced cirrhosis. METHODS: Of 68 patients with hepatic encephalopathy treated with oral L-carnitine supplementation from April 2013 to March 2016, we enrolled 19 patients who had received full standard treatment. We analyzed blood ammonia concentration, number of hospital admissions, and prognosis to determine how effective L-carnitine was in achieving mid-term to long-term suppression of recurrent hepatic encephalopathy. RESULTS: Median blood ammonia concentrations at the start, 1 week, 12 weeks, 24 weeks, and 48 weeks were 159, 79, 75, and 82 µg/dL, respectively. Blood ammonia concentrations 12 week, 24 weeks, and 48 weeks after L-carnitine administration were significantly lower than those at the start (P < 0.0001, respectively). During the 3 years prior to oral L-carnitine administration, the enrolled patients were hospitalized a total of 29 times for hepatic encephalopathy. However, during the 3 years following oral L-carnitine administration, they were admitted a total of six times for hepatic encephalopathy (P < 0.001). Median survival time was 40.9 months. Child-Pugh scores before and after oral L-carnitine administration differed significantly, whereas liver reserve function, nutritional status, and muscle index did not change significantly. CONCLUSIONS: Oral L-carnitine administration is effective and free of adverse effects in patients with hyperammonemia and reduces the number of hospital admissions for hepatic encephalopathy.

Antihypertensive drug telmisartan inhibits cell proliferation of gastrointestinal stromal tumor cells in vitro.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. The angiotensin II type 1 receptor blockers, telmisartan and candesartan, are widely used antihypertensive drugs that inhibits cancer cell proliferation; however, its underlying mechanisms in mesenchymal tumors, including GIST, remains unknown. The present study aimed to investigate the effect of telmisartan on GIST­T1 cells and its underlying mechanism. Telmisartan and candesartan inhibited the proliferation of these cells by blocking the G0 to G1 cell cycle transition, which was accompanied by a decrease in cell cycle­related proteins such as cyclin D1. Furthermore, telmisartan exposure significantly altered microRNA expression in vitro. In conclusion, telmisartan suppressed human GIST cell proliferation by inducing cell cycle arrest in vitro.

Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis.

Aspirin, a nonsteroidal anti­inflammatory drug (NSAID), is known to inhibit cell proliferation in a variety of cancers. However, the underlying mechanism of this inhibition remains unknown. We investigated the effects of aspirin on hepatocellular carcinoma (HCC) cells using in vitro and in vivo models. Six HCC cell lines and a liver cancer cell line including Huh­7 were used in assays that evaluated cell proliferation, cell cycle, and apoptosis. Flow cytometry, enzyme­linked immunosorbent assay (ELISA), western blot analysis, and phosphorylated receptor tyrosine kinase array were used to evaluate the effects of aspirin on the cells, and microRNAs (miRNAs) were analyzed by a miRNA array chip. The results were validated in vivo using a nude mouse model of Huh­7­xenografted tumors. Our results showed that aspirin exhibited an antiproliferative effect on all cell lines. Moreover, aspirin induced G0/G1 cell cycle arrest and modulated the levels of cell cycle­related molecules such as cyclin E, cyclin D1, and cyclin­dependent kinase 2 (Cdk2). In addition, aspirin upregulated the levels of caspase­cleaved cytokeratin 18, increased the proportion of early apoptotic cells, decreased the levels of clusterin and heat shock protein 70 (HSP 70), upregulated the levels of miRNA­137 and inhibited epidermal growth factor receptor (EGFR) activation. In addition, we observed that aspirin suppressed cell proliferation partially through the miRNA­137/EGFR pathway. Our in vivo results showed that aspirin reduced the growth of xenograft tumors in nude mice. In conclusion, aspirin was able to inhibit the growth of HCC cells by cell cycle arrest, apoptosis, and alteration of miRNA levels in in vitro and in vivo models.

Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Clinical management has improved the prognosis of early HCC, but that of advanced HCC remains poor. Sorafenib, an oral multikinase inhibitor, provided a treatment option for advanced-stage HCC, and prolonged the survival and inhibited tumor progression as first-line therapy in patients with advanced HCC. In this study, we investigated if specific microRNAs could act as predictive biomarkers of sorafenib effectiveness and indicate the best time to switch to second-line therapies. Sorafenib inhibited the proliferation of the Li-7, Hep3B, HepG2 and Huh7 liver cancer cell lines (effective group), but not that of the HLE, HLF and ALEX cancer cell lines (non-effective group). A microRNA (miRNA/miR) analysis was performed comparing sorafenib-effective and non-effective cells lines as well as serum samples from patients with HCC from sorafenib-effective (complete response/partial response) and -non-effective (progressive disease) groups before sorafenib administration and detected three differentially-expressed miRNAs that were common among the in vivo and in vitro samples. The increase rate (effective/non-effective) of hsa-miR-30d in the medium was higher than that in the cancer cells. hsa-miR-30d was highly expressed in the serum and exosomes of patients with HCC in the effective group when compared to those of the non-effective group. Additionally, the hsa-miR-30d expression in the medium of cancer cell lines was highly upregulated in the effective group compared with the non-effective group. These results suggested that hsa-miR-30d might be secreted by the cancer cells to the serum through the exosomes. We identified a specific circulating miRNA that is related to refractory HCC under sorafenib therapy. Therefore, hsa-miR-30d might serve as a predictive biomarker for the efficacy of sorafenib therapy in HCC.

Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study.

Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0-2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.

Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

Clinical outcomes of hepatitis C virus elimination using glecaprevir and pibrentasvir in hemodialysis patients: A multicenter study.

AIM: The incidence of hepatitis C virus (HCV) infection is much higher in hemodialysis patients than that in healthy individuals. The prognosis of hemodialysis patients with HCV infection is poorer than that without HCV infection. Therefore, antiviral intervention is pivotal for HCV infection in hemodialysis patients. Recent evaluations of the pangenotypic regimen of glecaprevir/pibrentasvir show that it is highly effective and safe for HCV-infected hemodialysis patients. However, a few reports showed that the effect of HCV elimination by glecaprevir/pibrentasvir improved liver dysfunction or anemia. The aim of the present study was to determine clinical outcomes after HCV elimination using the glecaprevir/pibrentasvir regimen in HCV-infected hemodialysis patients. METHODS: This study was a retrospective, six-center study conducted in Japan, in which 24 hemodialysis patients with HCV genotype 1-2 treated with glecaprevir/pibrentasvir were recruited. Blood examinations were performed at end of treatment (EOT), and at 3, 6, and 12 months post-treatment during the 12-month follow-up period. RESULTS: The overall sustained virologic response rate was 100% (24/24). During the DAA treatment period, adverse events were observed in 20.8% of patients (5/24), and pruritus was the most frequently observed in 12.5% (3/24). Interestingly, we observed an improved control of anemia after EOT with a significant increase in hemoglobin levels. In addition, total bilirubin was diminished, and platelet counts and albumin, total cholesterol, and alpha-fetoprotein levels remained unchanged after EOT in hemodialysis patients. Furthermore, erythropoietin concentration was not increased after EOT. CONCLUSIONS: HCV elimination using glecaprevir/pibrentasvir treatment might be a major breakthrough for the control of anemia in hemodialysis patients.

Efficacy of combined modality therapy with sorafenib following hepatic arterial injection chemotherapy and three-dimensional conformal radiotherapy for advanced hepatocellular carcinoma with major vascular invasion.

The prognosis of hepatocellular carcinoma (HCC) patients exhibiting macroscopic vascular invasion (MVI) is poor, and the most appropriate treatment approach remains unclear. The current study aimed to investigate the efficacy and safety of sorafenib treatment following chemoradiotherapy for advanced HCC exhibiting MVI. A newly reported regimen, including 5-fluorouracil and cisplatin therapy (NewFP), plus three-dimensional conformal radiotherapy (3D-CRT) for MVI was used as the initial treatment. Additionally, sorafenib, as a secondary treatment, was administered after NewFP plus 3D-CRT for MVI. The present retrospective study enrolled patients with unresectable advanced HCC that was treated with NewFP plus 3D-CRT for MVI between January 2009 and December 2017. In total, 32 HCC patients with MVI were registered. Of these 32 patients, 18 were treated with NewFP plus 3D-CRT for MVI (NewFP + 3D-CRT group) and 14 were treated with sorafenib following NewFP plus 3D-CRT for MVI (sorafenib after NewFP + 3D-CRT group). The study endpoints were overall survival, overall response rate and disease control rate. Clinical factors influencing overall survival were identified using univariate and multivariate analyses. The median survival time in the NewFP + 3D-CRT group and sorafenib following NewFP + 3D-CRT group was 6.7 and 49.2 months, respectively (P=0.0003). For patients with advanced HCC exhibiting MVI, the initial treatment with NewFP plus 3D-CRT for MVI was well tolerated. The administration of sorafenib as the secondary treatment following NewFP plus 3D-CRT for MVI was associated with a significantly higher overall response rate, disease control rate and increased overall survival as compared with the NewFP plus 3D-CRT treatment.

Serum microRNA-125a-5p as a potential biomarker of HCV-associated hepatocellular carcinoma.

During diagnosis of early stage hepatocellular carcinoma (HCC), single or small lesions are difficult to identify using screening ultrasonography, and conventional tumor markers are frequently negative. MicroRNAs (miRNAs) are small non-coding RNAs that suppress the translation of target mRNAs and exert significance as biomarkers. The aim of the present study was to use samples of patients with HCC and those with other liver diseases caused by hepatitis C virus (HCV) infection to investigate the expression profile of serum miRNAs, and identify a miRNA that can serve as a HCC biomarker. Initially, changes in 2,555 miRNAs between pre- and post-curative treatment serum from 12 patients with early stage HCC were examined using microarray analysis. The serum levels of miR-125a-5p in 40 individuals with HCV-associated chronic hepatitis (CH), liver cirrhosis (LC) or HCC were measured using reverse transcription-quantitative polymerase chain reaction, and 5 miRNAs, including miR-125a-5p, miR-423-5p, miR-1247, miR-1304 and miR-3648, were identified to be downregulated following curative treatment in patients with HCC. Among these, miR-125a-5p was identified to be similarly decreased following treatment in all patients. Additionally, the expression levels of miR-125a-5p were significantly upregulated in patients with HCC in the early and advanced stages of disease, compared with patients with CH or LC (P<0.05). Serum miR-125a-5p fluctuates depending on the presence of HCC, and may serve as a noninvasive biomarker to aid in diagnosing early carcinogenesis in HCV-associated chronic liver diseases.

Albumin-Bilirubin Score Differentiates Liver Fibrosis Stage and Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Virus Infection: A Retrospective Cohort Study.

The albumin-bilirubin (ALBI) score was originally established to stratify prognosis in patients with cirrhosis. The diagnostic accuracy of ALBI score in liver fibrosis staging in patients with chronic hepatitis B remains to be investigated. The present retrospective study, therefore, aimed to evaluate the ability of this score to stage liver fibrosis in these patients. Briefly, consecutive patients with hepatitis B virus (HBV) infection who underwent liver biopsy examinations in Kagawa University Hospital were enrolled. Liver fibrosis stage was assessed using a modified Meta-Analysis of Histological Data in Viral Hepatitis score. Albumin-bilirubin scores were calculated according to the following equation: (log10 total bilirubin [T-Bil] × 0.66) + (albumin [Alb] × -0.085). A total of 91 patients were enrolled in this study. Albumin-bilirubin score was able to differentiate stage 4 from stage 3 fibrosis (P < 0.05). When an ALBI score of -2.190 was adopted as the cutoff value for differentiating stage 4 from stages 1-3, the sensitivity, specificity, and positive likelihood ratio were 85.7%, 74.0%, and 3.300, respectively. Kaplan-Meier analysis showed that baseline ALBI scores < -2.190 correlated with better hepatocellular carcinoma (HCC)-free survival (P < 0.05). In conclusion, ALBI score can be used for liver fibrosis staging in Japanese chronic hepatitis B patients and can help distinguish cirrhotic from non-cirrhotic status. Furthermore, ALBI score was useful as a prognosis biomarker in our patients, with smaller ALBI scores predicting better HCC-free survival. Because calculating ALBI score is easy using serum T-Bil and Alb alone, ALBI score will help clinicians with decision-making in management of HBV-infected patients.

Albumin-bilirubin score indicates liver fibrosis staging and prognosis in patients with chronic hepatitis C.

AIM: Albumin-bilirubin (ALBI) grade was investigated to predict prognosis of patients with cirrhosis. It was defined using the ALBI score calculated based on serum total bilirubin and albumin, which represent liver function. The diagnostic accuracy for liver fibrosis staging in patients with chronic hepatitis using the ALBI score has not been investigated well. This study aimed to evaluate the diagnostic abilities of the ALBI score for liver fibrosis staging in chronic hepatitis and cirrhosis in Japanese patients with hepatitis C virus (HCV) infection. METHODS: Japanese patients with HCV infection who underwent liver biopsy examinations were enrolled in a retrospective study. Fibrosis staging and activity grading were assessed using the modified METAVIR score. The ALBI score was calculated according to the following equation: Log10 total bilirubin (µmol/L) × 0.66 + albumin (g/L) × (-0.085). RESULTS: A total of 382 patients were enrolled in this study. The ALBI score differentiated fibrosis stage 4 from 3 and stage 3 from 2 (P < 0.05). When an ALBI score of -2.125 was adopted as a cut-off value, the sensitivity and specificity were 73.2% and 87.1%, respectively, with a positive likelihood ratio of 5.67 to differentiate stage 4 from stages 1-3. Kaplan-Meier analysis showed that smaller ALBI scores at baseline correlated with better hepatocellular carcinoma (HCC)-free and overall survival (P < 0.05). CONCLUSIONS: The ALBI score indicates liver fibrosis staging in Japanese patients with HCV infection. Furthermore, smaller ALBI scores predict better HCC-free survival and overall survival. The ALBI score has the potential to expand its application from cirrhosis to chronic hepatitis.

Complement Component 3 as a Surrogate Hallmark for Metabolic Abnormalities in Patients with Chronic Hepatitis C.

OBJECTIVE: We investigated the correlation between serum complement component 3 (C3) levels and metabolic and histological abnormalities in patients with chronic hepatitis C (CH-C). METHODS: Obesity and insulin resistance were estimated by calculating body mass index (BMI) and the values of the homeostasis model for assessment of insulin resistance (HOMA-IR), respectively. Severity of hepatic steatosis and fibrosis were evaluated by New Inuyama Classification and the classification proposed by Brunt and colleagues, respectively. The degree of hepatic C3 expression was examined, using an immunohistochemical procedure. RESULTS: Serum C3 levels were significantly correlated with BMI, HOMA-IR value, and serum triglyceride levels in CH-C patients. Histological analysis revealed that serum C3 levels were significantly elevated in proportion to the severity of hepatic steatosis in such patients. The serum C3 level tended to increase as the severity of hepatic fibrosis progressed. However, the degree of C3 expression in hepatocytes was not associated with serum C3 level among those patients. CONCLUSIONS: These results suggest that the elevation of serum C3 levels may reflect obesity, insulin resistance, and/or hepatic steatosis in patients with CH-C, and that the increase in the synthesis of C3 may derive from the activation of cells other than hepatocytes in those patients.