The proliferation of atypical hepatocytes and CDT1 expression in noncancerous tissue are associated with the postoperative recurrence of hepatocellular carcinoma.

Recently, we reported that extent of proliferation of atypical hepatocytes (atypical hepatocytes) was most important histological risk factor for development of hepatocellular carcinoma (HCC) from chronic hepatitis C or liver cirrhosis. Here, we aimed to clarify whether the atypical hepatocytes in noncancerous sections is also involved in postoperative recurrence. Furthermore, we investigated significant genes involved in the atypical hepatocytes. Association between the extent of atypical hepatocytes in noncancerous tissue and postoperative recurrence was validated in 356 patients with HCC. Next, we identified putative signature genes involved in extent of atypical hepatocytes. First, atypical hepatocytes or hepatocytes other than the atypical hepatocyte in noncancerous sections of 4 HCC patients were selectively collected by laser capture microdissection (LCM). Second, the gene expression profiles of the selected hepatocyte populations were compared using Ion AmpliSeq Transcriptome Human Gene Expression Kit (Thermo Fisher SCIENTIFIC, Waltham, MA, USA) analysis. Finally, we validated the mRNA expression of the extracted genes in noncancerous frozen liver tissue from 62 patients with HCC by RT-qPCR to identify the signature genes involved in both the extent of atypical hepatocytes and postoperative recurrence. Furthermore, the extent of atypical hepatocytes and CDT1 expression in noncancerous sections from 8 patients with HCC were also validated by selectively collecting samples using LCM. The extent of atypical hepatocytes was associated with postoperative recurrence. Of the genes that showed significant differences in expression levels between two populations, the expression of the chromatin licensing and DNA replication factor 1 (CDT1) gene was most strongly associated with the extent of atypical hepatocytes and was also associated with postoperative recurrence. Furthermore, CDT1-positive cells that exhibited stronger expression resembled those morphologically considered to be atypical hepatocytes. CDT1 and Ki-67 were colocalized in the nuclei of both hepatocytes and cancer cells. The hepatocytes in noncancerous livers were not uniform in each hepatocyte population, suggesting that the accumulation of genetic abnormalities was variable. We found that the strong degree of atypical hepatocytes and high CDT1 mRNA expression represent a high carcinogenic state of the liver. Thus, we consider the evaluation of degree of these could support the personalized medicine.

Left Gastric Vein Width Is an Important Risk Factor for Exacerbation of Esophageal Varices Post Balloon-Occluded Retrograde Transvenous Obliteration for Gastric Varices in Cirrhotic Patients.

Background and Objectives: Balloon-occluded retrograde transvenous obliteration (BRTO) could be currently one of the best therapies for patients with gastric varices. This study examined the exacerbation rates for esophageal varices following BRTO for gastric varices in patients with hepatic cirrhosis. Materials and Methods: We enrolled 91 cirrhotic patients who underwent BRTO for gastric varices. In total, 50 patients were examined for exacerbation rates of esophageal varices following BRTO. Esophageal varices and their associated exacerbation were evaluated by upper gastrointestinal endoscopy. Patients were allocated into two groups according to the main inflow tract for gastric varices: (1) 37 patients in the left gastric vein (LGV) group with an LGV width of more than 3.55 mm, and (2) 13 patients in the non-LGV group who had short gastric vein or posterior gastric vein. Moreover, treatment outcomes were retrospectively analyzed. Results: LGV width (p < 0.01) was the major risk factor for the deterioration of esophageal varices post BRTO. In addition, LGV was the most common inflow tract, and the LGV group contained 74% (37/50) of patients. The exacerbation rates of esophageal varices at 1, 2, 3, and 4 years post BRTO were 40%, 62%, 65%, and 68%, respectively. The comparison of the exacerbation rates for esophageal varices following BRTO according to inflow tract showed that the exacerbation rates were significantly higher in the LGV group than those of the non-LGV group (p = 0.03). In more than half of the subjects, LGV was the main inflow tract for gastric varices, and this group experienced more frequent exacerbations of esophageal varices following BRTO compared to patients with different inflow tract sources. Conclusion: Careful attention should be paid to the LGV width when BRTO is performed for gastric varices.

Large-volume cell-free and concentrated ascites reinfusion therapy improves venous flow in patients with liver cirrhosis.

PURPOSE: Hemodynamic change after total paracentesis was investigated because it might lead to various complications. Although cell-free and concentrated ascites reinfusion therapy (CART) is safer and more effective than total paracentesis in theory, hemodynamic change after CART has been never reported. And previous studies did not mention hemodynamics of the venous system. METHODS: We investigated the hemodynamic change, including that of the venous system, before and after CART using color Doppler ultrasonography and fast Fourier transform analysis. Twenty-eight patients with tensive cirrhotic ascites underwent ultrasonography the day before and after total volume CART. The diameter and velocity of the main, right, and left portal vein; inferior vena cava (IVC); and right renal vein were measured using ultrasonography. RESULTS: A total of 11.8 ± 4.4 L of ascites (range 3.6-20.9 L) was filtered and concentrated to 0.85 ± 0.40 L (range 0.36-1.50 L). The diameter of the IVC increased from median 13.5 ± 5.4 mm (range 4-25 mm) to 18.5 ± 4.1 mm (range 7-29 mm) (p = 0.007). The diameter of the right segmental renal vein significantly increased after KM-CART [from 5.0 ± 1.0 (4-8) mm to 7.0 ± 2.0 (3-10) mm] (p = 0.011). Hemodynamic change of the portal venous system was not significant. The time to the next CART in patients with an IVC diameter ≥ 20 mm and < 20 mm was 86 days and 20.5 days (p = 0.035), respectively. CONCLUSION: Tensive ascites results in venous congestion in patients with cirrhotic ascites. CART improved venous flow, but it did not change the hemodynamics of the portal venous system.

Japanese Man with HCV Genotype 4 Infection and Cirrhosis Who Was Successfully Treated by the Combination of Glecaprevir and Pibrentasvir.

A 74-year-old man with a history of transfusion at 35 years old in Egypt was referred to our hospital. He was infected with hepatitis C virus (HCV) genotype 4 (GT4), which is a rare HCV GT in Japan, and was also diagnosed with hepatic compensated cirrhosis. We safely treated the patient for 12 weeks with the combination of glecaprevir and pibrentasvir, and a sustained virologic response (SVR) was achieved. This is the first report of HCV GT4 infection in a treatment-naïve Japanese patient with cirrhosis in whom SVR was achieved with the combination treatment of glecaprevir and pibrentasvir.

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.

Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines.

Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.

Superinfection of hepatitis A virus in hepatocytes infected with hepatitis B virus.

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis including acute liver failure. Hepatitis B infection (HBV) occurs worldwide, with the highest rates in Asian and African countries, and there are several reports that HAV infection may have a more severe clinical course in patients with chronic HBV infection. We previously demonstrated that Japanese miso extracts have inhibitory effects on HAV replication. In the present study, we examined the replication of HAV and HBV in a hepatocyte superinfection model and the inhibitory effects of Japanese miso extracts on both viruses. According to the results, HAV infection inhibited HBV replication in superinfected hepatocytes, and Japanese rice-koji miso extracts had inhibitory effects on HAV replication. Our findings provide useful information for clinicians in managing HAV infection in patients with chronic HBV infection.

Prior hepatitis B virus infection as a co-factor of chronic hepatitis C patient survival after resection of hepatocellular carcinoma.

BACKGROUND: Prior hepatitis B virus infection (PBI) may increase the risk of developing hepatocellular carcinoma (HCC), but the impact of PBI on clinical outcomes following treatment for HCC remains unknown. The aim of this study was to clarify whether PBI affects clinical outcomes after liver resection for hepatitis C virus (HCV)-related HCC by retrospective cohort study. METHODS: PBI patients were defined as those negative for hepatitis B surface antigen and positive for anti-hepatitis B core antibody. Surgical outcomes of HCV-related HCC patients with PBI were compared to those without PBI. Survival of patients with non-B non-C HCC with and without PBI were also compared. RESULTS: In the HCV group, the median overall survival of 165 patients with PBI was 4.7 years (95% confidence interval [CI], 3.9-5.9), and was significantly shorter compared with 263 patients without PBI (6.6 years [5.3-9.8]; p = 0.015). Conversely, there was no significant difference in recurrence-free survival between the two groups (1.8 years [95% CI, 1.4-2.0] vs 2.0 years [1.7-2.3]; p = 0.205). On Cox proportional hazards regression model, independent factors for overall survival were PBI (hazard ratio 1.38 [95% CI, 1.02-1.87]; p = 0.033), multiple tumors (p = 0.007), tumor size (p = 0.002), and liver cirrhosis (p <  0.001). On the other hand, in the non-B non-C HCC group, both the median overall survival (6.5 years [95% CI, 4.8-7.1]) and recurrence-free survival (2.4 years, [95% CI, 1.5-3.3]) in 104 patients with PBI were not significantly different from those (7.5 years [5.5 - NA; p = 0.932]; and 2.2 years [1.7-2.7; p = 0.983]) in 213 patients without PBI. CONCLUSIONS: PBI and HCV in conjunction with each other affect the survival of patients that have undergone resection for HCC.

Follow-up Results of HCV GT2 Patients After Sofosbuvir/Ribavirin Therapy: Careful Attention to Occurrence of HCC.

BACKGROUND: We examined treatment the efficacy and data on long-term outcomes in real-world Japanese patients infected with hepatitis C virus (HCV) genotype 2 treated with 12-week sofosbuvir/ribavirin combination therapy. PATIENTS AND METHODS: In a total of 86 patients who were treated with sofosbuvir/ribavirin, sustained virological response (SVR) rates and long-term-outcomes were retrospectively analyzed. RESULTS: The adherence to this combination therapy was 98.8%. The rates of SVR at week 24 (SVR24) achieved with this treatment according to the 'intention-to-treat' and 'per-protocol' analyses were 89.5% and 96.2%, respectively. Two patients who experienced relapse did not have any previously reported resistance-associated substitutions in the HCV non-structural protein 5B (NS5B) polymerase region. We did not observe any patients who experienced late relapse but did observe that 50% and 1.3% of patients with and without a previous history of hepatocellular carcinoma (HCC), respectively, developed HCC after achieving SVR24 (with a mean follow-up period of 2.7±0.8 years). CONCLUSION: Patients with SVR should be carefully followed-up to screen for the occurrence of HCC, although it is infrequent.

Possible association of arrestin domain-containing protein 3 and progression of non-alcoholic fatty liver disease.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing worldwide. Several effective drugs for these diseases are now in development and under clinical trials. It is important to reveal the mechanism of the development of NAFLD and NASH. We investigated the role of arrestin domain-containing protein 3 (ARRDC3), which is linked to obesity in men and regulates body mass, adiposity and energy expenditure, in the progression of NAFLD and NASH. We performed knockdown of endogenous ARRDC3 in human hepatocytes and examined the inflammasome-associated gene expression by real-time PCR-based array. We also examined the effect of conditioned medium from endogenous ARRDC3-knockdown-hepatocytes on the apoptosis of hepatic stellate cells. We observed that free acids enhanced the expression of ARRDC3 in hepatocytes. Knockdown of ARRDC3 could lead to the inhibition of inflammasome-associated gene expression in hepatocytes. We also observed that conditioned medium from endogenous ARRDC3-knockdown-hepatocytes enhances the apoptosis of hepatic stellate cells. ARRDC3 has a role in the progression of NAFLD and NASH and is one of the targets for the development of the effective treatment of NAFLD and NASH.

Exosomes and Hepatocellular Carcinoma: From Bench to Bedside.

As hepatocellular carcinoma (HCC) usually occurs in the background of cirrhosis, which is an end-stage form of liver diseases, treatment options for advanced HCC are limited, due to poor liver function. The exosome is a nanometer-sized membrane vesicle structure that originates from the endosome. Exosome-mediated transfer of proteins, DNAs and various forms of RNA, such as microRNA (miRNA), long noncoding RNA (lncRNA) and messenger RNA (mRNA), contributes to the development of HCC. Exosomes mediate communication between both HCC and non-HCC cells involved in tumor-associated cells, and several molecules are implicated in exosome biogenesis. Exosomes may be potential diagnostic biomarkers for early-stage HCC. Exosomal proteins, miRNAs and lncRNAs could provide new biomarker information for HCC. Exosomes are also potential targets for the treatment of HCC. Notably, further efforts are required in this field. We reviewed recent literature and demonstrated how useful exosomes are for diagnosing patients with HCC, treating patients with HCC and predicting the prognosis of HCC patients.

Apoptosis and non-alcoholic fatty liver diseases.

The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice.

Association of mRNA expression of iron metabolism-associated genes and progression of non-alcoholic steatohepatitis in rats.

BACKGROUND: Excess iron is associated with non-alcoholic steatohepatitis (NASH). RESULTS: mRNA expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, hepcidin, hephaestin and transferrin receptor 1 in liver were higher in high fat, high cholesterol-containing diet (HFCD) group than in normal diet (ND) group. mRNA levels of divalent metal transporter 1 and transferrin receptor 1, which stimulate iron absorption and excretion, were enhanced in small intestine. Epithelial mucosa of small intestine in HFCD group was characterized by plasma cell and eosinophil infiltration and increased vacuoles. Iron absorption was enhanced in this NASH model in the context of chronic inflammation of small intestinal epithelial cells, consequences of intestinal epithelial cell impairment caused by HFCD. Iron is transported to hepatocytes via portal blood, and abnormalities in iron absorption and excretion occur in small intestine from changes in iron transporter expression, which also occurs in NASH liver. Knockdown of hepcidin antimicrobial peptide led to enhanced heavy chain of ferritin expression in human hepatocytes, indicating association between hepcidin production and iron storage in hepatocytes. CONCLUSIONS: Iron-related transporters in liver and lower/upper portions of small intestine play critical roles in NASH development. METHODS: Expression of iron metabolism-related genes in liver and small intestine was analyzed in stroke-prone spontaneously hypertensive rats (SHR-SP), which develop NASH. Five-week-old SHR-SP fed ND or HFCD were examined. mRNA and protein levels of iron metabolism-related genes in liver and small intestine from 12- and 19-week-old rats were evaluated by real-time RT-PCR and immunohistochemistry or Western blot.

Persistent Hepatic Inflammation Plays a Role in Hepatocellular Carcinoma After Sustained Virological Response in Patients with HCV Infection.

Objective: Hepatitis C virus (HCV) infection has long been treated with interferon therapy (IFN). Currently, more than 90% of IFN-treated patients show a sustained virological response (SVR) when also treated with ribavirin and/or a protease inhibitor. Histological inflammation and fibrosis improve in IFN-treated patients, which indicates HCV clearance. IFN also reduces the incidence of hepatocellular carcinoma (HCC). However, a small proportion of patients with SVR develop HCC. To investigate the causes of hepatic carcinogenesis after SVR, we compared the liver histological findings before IFN to those after the development of HCC. Patients and methods: In total, 602 patients infected with type C chronic hepatitis or with liver cirrhosis who received IFN therapy during the period from 1992 through 2015 were included in this study. We assessed 14 of the 287 patients who achieved an SVR. Results: HCC was diagnosed by computed tomography, angiography or liver biopsy. The longest time from the SVR until HCC detection was 16.5 years, and the mean was 7.2±4.6 years. Nine of the 14 patients underwent surgery and one radiofrequency ablation. The histological findings of 10 patients were available for comparison. The comparison of the histological findings before treatment with those after the HCC diagnosis revealed an amelioration of liver fibrosis and other inflammatory changes. All ten patients showed improvements in fibrosis and steatosis. However, we observed that mild inflammatory change persisted from 1.8 years to 16.5 years after the confirmation of SVR in all cases. Conclusion: We suspect that persistent histological inflammation is one of the factors contributing to hepatocarcinogenesis (i.e., HCC development) even after successful treatment.

Portal-systemic Encephalopathy due to Complicated Spleno-renal Shunt Successfully Treated with Balloon-occluded Retrograde Transvenous Obliteration Using a Double Coaxial Balloon Catheter System and Shape-memory Coils.

A 70-year-old woman with hepatitis C cirrhosis underwent balloon-occluded retrograde transvenous obliteration for hepatic encephalopathy due to spleno-renal shunt. Because the shunt was thick, long, and winding, we used a coaxial and double interruption system, which enables the effective occlusion of the drainage route, and shape-memory coils, which are more physically stable than conventional metallic coils because they form three-dimensional loops. The patient was successfully treated with the combined usage of these devices, resulting in a normal serum ammonia level. Thereafter, the patient was treated with direct-acting antivirals, and a sustained virological response was achieved.

Diabetes mellitus not an unfavorable factor on the prognosis of hepatitis C virus-related hepatocellular carcinoma.

AIM: Diabetes mellitus (DM) is a potential risk factor for hepatocarcinogenesis, especially in patients with hepatitis C virus (HCV) infection. We aimed to elucidate whether DM influences the surgical outcomes of patients with hepatocellular carcinoma (HCC). METHODS: Our patients were routinely controlled to keep urinary glucose excretion to less than 3.0 g/day before surgery, and the serum glucose level under 200 mg/dL after surgery. The surgical outcomes and postoperative complications of 112 patients with HCV-related HCC with DM (DM group) were compared to those of 112 propensity-matched patients without DM (non-DM group). RESULTS: After a median follow-up of 3.2 years (range, 0.2-11.3 years), the median overall (5.2 years; 95% confidence interval, 3.8-6.5 years) and recurrence-free survival (2.2 years; 1.7-2.9 years) in the DM group were not significantly different from those (6.3 years; 5.4-7.1 years, P = 0.337; and 2.2 years; 1.7-3.6 years, P = 0.613) in the non-DM group. The independent factors related to overall survival were the background liver (hazard ratio, 2.06; 95% confidence interval, 1.27-3.39, P = 0.014) and tumor differentiation grade (2.07; 1.14-4.05, P = 0.015). Thirty-two patients (28.5%) in the DM group and 32 patients (28.5%) in the non-DM group had morbidities after operation, with no significant difference between the groups (P = 1.000). Furthermore, postoperative control status of DM did not affect the prognostic outcome. CONCLUSION: Diabetes mellitus does not affect the surgical outcomes of patients with HCV-related HCC, and it is not an unfavorable factor when selecting candidates for liver resection of HCC.

Renal vein dilation predicts poor outcome in patients with refractory cirrhotic ascites.

AIM: Renal venous hypertension is known to be associated with worsening of renal function in patients with decompensated heart failure. Intra-abdominal hypertension including cirrhotic ascites also leads to renal venous hypertension. We aimed to clarify the effect of renal venous hypertension on cirrhotic ascites. METHODS: Two hepatologists measured the left renal vein diameter in 142 consecutive patients with refractory cirrhotic ascites using non-contrast computed tomography. The renal vein diameter was measured at the renal vein main trunk and upstream of the confluence of collateral veins. RESULTS: The inter-observer agreements were high for the measurements of the left renal vein (r = 0.918, P < 0.001). The median overall survival for patients with renal vein diameter ≥11 mm was less than that for patients with renal vein diameter <11 mm (P < 0.001; 2.5 vs. 32.0 months). One-year survival rates were 15.3% versus 66.4%. Multivariate analysis revealed renal vein diameter ≥11 mm (hazard ratio, 2.94; P < 0.001; 95% confidence interval, 1.67-5.20) and a high Model for End-stage Liver Disease score combined with serum sodium level (MELD-Na) (hazard ratio, 3.39; P < 0.001; 95% confidence interval, 2.00-5.74) were significant independent predictors of mortality. CONCLUSIONS: Renal vein dilation is a risk factor of mortality in patients with refractory cirrhotic ascites, independent of the MELD-Na score.

Involvement of Ornithine Carbamoyltransferase in the Progression of Chronic Hepatitis C and Liver Cirrhosis.

Background: The involvement of serum ornithine carbamoyltransferase (OCT) in the progression of chronic hepatitis and liver cirrhosis is unclear. Methods: A total 256 patients with chronic hepatitis C and 5 healthy controls were examined. Serum OCT concentrations were measured by enzyme-linked immunosorbent assay. Serum OCT concentrations were compared with serum cytokine and chemokine levels, and with disease severity and development of hepatocellular carcinoma (HCC). Results: The median OCT concentrations were 21.8 ng/ml for healthy controls, 36.7 ng/ml for F0 stage disease, 48.7 ng/ml for F1 stage, 77.9 ng/ml for F2 stage, 104.8 ng/ml for F3 stage, and 121.4 ng/ml for F4 stage. OCT concentrations were correlated with aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet counts, indocyanine green retention rate at 15 min, prothrombin times, the molar ratio of branched chain amino acids to tyrosine, and tyrosine. Furthermore, there were significant correlations among OCT concentrations and IP10 and IL18 levels. There were weak correlations between serum OCT concentrations and liver histology. The cumulative incidence of HCC in the high-OCT concentration group (≥75.3 ng/ml) was higher than that in the low-OCT concentration group. Conclusion: The measurement of serum OCT concentration may provide a useful marker of disease severity, and thus could be a useful marker for a high risk of HCC occurrence.