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Background and Aim: We conducted a study using the Fibrosis-3 (FIB-3) index, which is the established age-independent index of fibrosis in nonviral liver disease and addresses the limitations of the FIB-4 index in older age group, to assess the liver fibrosis risk among diverse demographic groups in the general population. Methods: We analyzed 31 327 individuals who underwent health examinations between 2013 and 2020 and investigated the distribution of the FIB-3 index by age group. In addition, we examined the age distribution of the FIB-3 index stratified by background factors, such as sex, body mass index (BMI), alcohol consumption habits, and the presence or absence of fatty liver. Results: In terms of age-specific distribution, the FIB-3 index remained below 1.5 in >90% of cases until the age of 50 years but exceeded 1.5 beyond the age of 50 years, in approximately 30% among those aged 70 years. Notably, the FIB-3 index above 31 years old was significantly higher in men than in women. Among the different BMI categories, individuals with BMI < 18.5 exhibited the highest prevalence of fibrosis. Habitual drinkers had a higher proportion with FIB-3. index ≥1.5, and some had FIB-3 index ≥2.5, raising the suspicion of advanced hepatic fibrosis. No distinct association was identified between the FIB-3 index and the presence of fatty liver. Conclusions: The FIB-3 index was useful for identifying cases of advancing hepatic fibrosis in a health checkup population. Liver fibrosis progresses with age in the general population, especially among men, those with low BMI, and habitual drinkers.
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BACKGROUND/AIM: The aim of this study was to compare the therapeutic efficacy of ablation and surgery in solitary hepatocellular carcinoma (HCC) measuring ≤5 cm with a large HCC cohort database. METHODS: The study included consecutive 2,067 patients with solitary HCC who were treated with either ablation (n=1,248) or surgery (n=819). Th e patients were divided into three groups based on the tumor size and compared the outcomes of the two therapies using propensity score matching. RESULTS: No significant difference in recurrence-free survival (RFS) or overall survival (OS) was found between surgery and ablation groups for tumors measuring ≤2 cm or >2 cm but ≤3 cm. For tumors measuring >3 cm but ≤5 cm, RFS was significantly better with surgery than with ablation (3.6 and 2.0 years, respectively, P=0.0297). However, no significant difference in OS was found between surgery and ablation in this group (6.7 and 6.0 years, respectively, P=0.668). CONCLUSION: The study suggests that surgery and ablation can be equally used as a treatment for solitary HCC no more than 3 cm in diameter. For HCCs measuring 3-5 cm, the OS was not different between therapies; thus, ablation and less invasive therapy can be considered a treatment option; however, special caution should be taken to prevent recurrence.
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Improving grain quality is a primary objective in contemporary rice breeding. Japanese modern rice breeding has developed two different types of rice, eating and sake-brewing rice, with different grain characteristics, indicating the selection of variant gene alleles during the breeding process. Given the critical importance of promptly and efficiently identifying genes selected in past breeding for future molecular breeding, we conducted genome scans for divergence, genome-wide association studies, and map-based cloning. Consequently, we successfully identified two genes, OsMnS and OsWOX9D, both contributing to rice grain traits. OsMnS encodes a mannan synthase that increases the white core frequency in the endosperm, a desirable trait for sake brewing but decreases the grain appearance quality. OsWOX9D encodes a grass-specific homeobox-containing transcription factor, which enhances grain width for better sake brewing. Furthermore, haplotype analysis revealed that their defective alleles were selected in East Asia, but not Europe, during modern improvement. In addition, our analyses indicate that a reduction in grain mannan content during African rice domestication may also be caused a defective OsMnS allele due to breeding selection. This study not only reveals the delicate balance between grain appearance quality and nutrition in rice but also provides a new strategy for isolating causal genes underlying complex traits, based on the concept of "breeding-assisted genomics" in plants.
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Oryza , Protéines de Saccharomyces cerevisiae , Oryza/génétique , Boissons alcooliques , Étude d'association pangénomique , Mannanes , Fermentation , Saccharomyces cerevisiae , Amélioration des plantes , Grains comestibles/génétiqueRÉSUMÉ
AIM: Multiple studies have revealed the correlation between gut microbiome and the response to checkpoint inhibitors (CPIs) in patients with cancer, and oral administration of butyrate-producing enterobacteria has been reported to enhance the efficacy of CPIs. However, the effects of enterobacteria on patients with hepatocellular carcinoma (HCC) are not well understood. METHODS: In this retrospective multicenter study, we enrolled 747 patients with advanced HCC, treated with atezolizumab and bevacizumab combination therapy. Tumor response, survival, and adverse effects were compared between 99 patients who ingested drugs containing butyric acid-producing enterobacteria (butyric acid group) and the remaining patients (control group). RESULTS: Objective response and disease control rates in butyric acid group (29.7% and 77.8%, respectively) were higher than those in the control group (26.4% and 72.7%, respectively). However, the differences were not statistically significant (p = 0.543 and p = 0.222, respectively). No difference in median survival time was observed between the two groups (20.0 months and 21.4 months, respectively; p = 0.789), even after matching the backgrounds of the patients with propensity scores (p = 0.714). No adverse effects occurred upon the administration of butyrate-producing bacteria. However, proteinuria (41.4% vs. 30.9%; p = 0.041), fever (17.2% vs. 10.2%, p = 0.036), and diarrhea (15.2% vs. 6.2%; p = 0.001) occurred more frequently in the butyric acid group. CONCLUSION: Butyrate-producing bacteria does not enhance the efficacy of atezolizumab-bevacizumab combination therapy in patients with HCC.
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Carcinome hépatocellulaire , Effets secondaires indésirables des médicaments , Tumeurs du foie , Humains , Bévacizumab/effets indésirables , Carcinome hépatocellulaire/traitement médicamenteux , Acide butyrique , Enterobacteriaceae , Tumeurs du foie/traitement médicamenteuxRÉSUMÉ
BACKGROUND: The albumin-bilirubin (ALBI) score and the modified ALBI (mALBI) grade are known useful prognostic factors for patients with hepatocellular carcinoma (HCC) treated with lenvatinib (LEN-HCC). However, the ALBI score requires complicated logarithmic calculations. Therefore, we attempted to create a simplified score. METHODS: We developed the albumin simplified (ALBS) grade that corresponded to mALBI using the data of 5985 newly developed HCC and examined the usefulness of this grading system for the prediction of the prognosis of 678 patients with LEN-HCC. RESULTS: The analysis using Cox proportional hazard models revealed that the overall survival of patients with LEN-HCC was not correlated with the total bilirubin but albumin (Alb), which means that the prediction with Alb alone was logical. The ALBS grade cutoffs that corresponded to mALBI grade 1, 2a, 2b, and 3 were Alb ⧠4.0 g/dL, 4.0 g/dL > Alb â§3.5 g/dL, 3.5 g/dL > Albâ§2.8 g/dL, and Alb < 2.8 g/dL, respectively. The stratification ability of the ALBS grade for LEN-HCC was good. The Akaike information criterion (AIC) and c-index were comparable with those of mALBI (AIC 4096.3 vs. 4090.7, c-index 0.765 vs. 0.778). The prognosis of LEN-HCC was stratified by the ALBS grade at 1 month after starting LEN, and patients with ALBS grade 1/2a demonstrated better survival than patients with ALBS grade 2b/3 regardless of the ALBS grade before treatment. CONCLUSION: The ALBS grade is easy to calculate and is useful for the prediction of the prognosis of LEN-HCC.
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Carcinome hépatocellulaire , Tumeurs du foie , Bilirubine , Humains , Phénylurées , Pronostic , Quinoléines , Études rétrospectives , SérumalbumineRÉSUMÉ
OBJECTIVE: Patients with chronic hepatitis C virus (HCV) infection who achieve sustained virologic response (SVR) to anti-HCV therapy, that is the eradication of HCV, are recommended to continue regular hospital visits for the surveillance of hepatocellular carcinoma (HCC) that can develop after SVR. However, it is unclear how well patients with SVR adhere to post-SVR follow-up over the long term. We investigated this adherence and the factors associated with it. METHODS: Medical record data on regular hospital visits were reviewed in 1329 patients with no history of HCC who achieved SVR by anti-HCV therapy. At the time of SVR confirmation, all patients were advised to continue regular visits, and the risk of post-SVR HCC was explained. The adherence rate of post-SVR follow-up and associated factors were analyzed. RESULTS: Adherence rates decreased continuously over time, as follows: 76.6% at 5 years, 62.4% at 10 years, 48.8% at 15 years, and 35.3% at 20 years after SVR. Adherence rates did not differ based on the degree of baseline liver fibrosis and were significantly lower in patients who achieved SVR by interferon (IFN)-free therapy and those with HCV genotype 2b. CONCLUSION: Adherence to post-SVR follow-up decreased over the long term, and rates differed by patient background. Adherence was especially poor in patients who achieved SVR by IFN-free therapy, and therefore, strategies are necessary to encourage these patients to maintain their regular schedule of hospital visits.
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Carcinome hépatocellulaire , Hépatite C chronique , Tumeurs du foie , Antiviraux/usage thérapeutique , Carcinome hépatocellulaire/diagnostic , Carcinome hépatocellulaire/épidémiologie , Carcinome hépatocellulaire/étiologie , Hepacivirus/génétique , Hépatite C chronique/complications , Hépatite C chronique/diagnostic , Hépatite C chronique/traitement médicamenteux , Humains , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/épidémiologie , Tumeurs du foie/étiologie , Réponse virologique soutenueRÉSUMÉ
OBJECTIVES: Non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of progressing to hepatocellular carcinoma (HCC). The presence of NHHNs is a strong risk factor for HCC development in patients with chronic hepatitis C virus (HCV) infection after the achievement of sustained virologic response (SVR). However, it is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection. We therefore explored serum markers that potentially indicate the presence of NHHNs. METHODS: Three serum markers, alpha-fetoprotein (AFP), FIB-4 index, and Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi), were measured in 481 patients with HCV infection and no history of HCC who underwent EOB-MRI. The associations between these serum marker levels and the presence of NHHNs were investigated. RESULTS: All three markers were associated with the presence of NHHNs. M2BPGi predicted the presence of NHHNs more accurately than AFP and FBB-4 index; M2BPGi had the highest area under the receiver operating characteristic curve. Multivariate analysis identified male gender and high M2BPGi as factors associated with the presence of NHHNs. When patients were stratified by the degree of liver fibrosis, M2BPGi increased with the progression of fibrosis. In addition, NHHNs were more prevalently detected in patients with higher M2BPGi (COI > 3.46) in patients with similar fibrosis degree. CONCLUSIONS: M2BPGi is a serum marker that potentially identifies HCV patients with high risk of the presence of NHHNs, for whom EOB-MRI should be considered. KEY POINTS: ⢠Non-hypervascular hypointense nodule on EOB-DTPA-enhanced MRI is pre-HCC nodule with high likelihood of progressing to HCC, which is a strong predictor for HCC that develops after the eradication of HCV in patients with HCV infection. ⢠It is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection due to limited access, limited availability of MRI equipment, and high costs. ⢠Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi) levels effectively indicate the presence of NHHNs and can be used to identify patients with high risk of their presence, for whom EOB-DTPA-enhanced MRI should be considered.
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Carcinome hépatocellulaire , Hépatite C chronique , Hépatite C , Tumeurs du foie , Carcinome hépatocellulaire/anatomopathologie , Produits de contraste/pharmacologie , Acide gadopentétique , Hepacivirus , Hépatite C/complications , Hépatite C chronique/complications , Hépatite C chronique/imagerie diagnostique , Humains , Cirrhose du foie/complications , Tumeurs du foie/anatomopathologie , Imagerie par résonance magnétique/méthodes , Mâle , AlphafoetoprotéinesRÉSUMÉ
Non-hypervascular hypointense nodules (NHHNs) on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of hypervascularization progressing to typical hypervascular hepatocellular carcinoma (HCC). NHHNs that were present before the start of anti-hepatitis C virus (HCV) therapy is a risk marker for HCC development after achieving sustained virologic response (SVR). In this report, we show a patient without a previous history of HCC in whom HCC developed by hypervascularization of NHHN after SVR. This patient achieved SVR more than 8 years before NHHN developed into HCC, and during this time NHHN had been present but had remained unchanged in size and imaging features as shown by repeated EOB-MRI. Hepatocarcinogenic potential of NHHNs persist for a long time after SVR, despite the eradication of HCV.
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Background and Aims: The Fibrosis-4 (FIB-4) index has been used to predict liver fibrosis in various liver diseases, including nonalcoholic fatty liver disease (NAFLD). Because the FIB-4 formula uses age, different cutoff values may be required for different age groups, making the interpretation difficult. To avoid the influence of age, we attempted to create a new score, the Fibrosis-3 (FIB-3) index. Methods: The FIB-3 index was created using a training cohort of 735 NAFLD cases using aspartate aminotransferase, alanine amino transferase, and platelet for predicting fibrosis. The abilities of the FIB-3 and FIB-4 indices were compared among different age groups in the training cohort and validation cohort with 324 patients. The FIB-3 index was also compared with other liver fibrosis indices. Results: The area under the receiver operating characteristic curve (AUROC) values of the FIB-3 and FIB-4 indices for predicting F3-F4 fibrosis were 0.764 and 0.762, respectively, in the training cohort. No difference in the AUROC values was observed between the 2 indices in the validation cohort. The differences in the accuracies of FIB-3 between elderly and nonelderly patients were 0.140 and 0.178, respectively, in each cohort and were smaller than those of FIB-4 index (0.199 and 0.336, respectively). Analysis using a joined cohort revealed that the AUROC of FIB-3 for predicting F3-F4 fibrosis (0.774) was the highest among the 5 fibrosis scores examined and was comparable to that of FIB-4. Conclusion: The FIB-3 index is an improved version of the FIB-4 index and can effectively predict liver fibrosis in patients with NAFLD.
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BACKGROUND AND AIM: Hepatic angiography procedures such as transarterial chemoembolization (TACE) are essential procedures for managing patients with hepatocellular carcinoma (HCC), and are usually performed with femoral access. However, femoral access causes patient discomfort and may be associated with the risk of hematoma or pseudoaneurysm at puncture site. We evaluated the safety, feasibility, and patient comfort of hepatic angiography procedures performed with radial access. METHODS: In this single-institution, retrospective, time-frame study, a total of 206 patients who underwent hepatic angiography procedures with radial access, which were first used on October 2017 at our institution, were compared with 240 patients who underwent the same procedures with femoral access before this period. Several measures were assessed, including procedure time and safety. In addition, a questionnaire was used to compare the access types regarding procedure-associated discomfort. RESULTS: Hepatic angiography procedures performed with radial access, including TACE, were completed in all patients without complications. The procedure time was comparable between radial access and femoral access. Most patients preferred radial to femoral access. Patients taking anticoagulants were able to complete the procedures without discontinuing these drugs. CONCLUSIONS: Hepatic angiography procedures with radial access resulted in less discomfort than those with femoral access, and the two approaches showed similar feasibility and safety. Radial access can be introduced as a routine technique for hepatic angiography procedures.
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INTRODUCTION: Achieving sustained virologic response (SVR) to antiviral therapy for hepatitis C virus (HCV) infection is an important step for eliminating HCV infection worldwide. However, recurrence of HCV viremia may occur due to HCV reinfection and confirmation of the long-term absence of HCV viremia, i.e., the absence of HCV reinfection, is necessary in post-SVR patients. In this report, we studied the long-term results of serum HCV RNA measurements in patients with SVR in whom serum HCV RNA was monitored over decades. METHODS: Serum HCV RNA was measured at every visit in a total of 1,392 SVR patients who underwent regular visits to the hospital after SVR, of whom 434 patients (31.2%) had continued regular visits for more than 10 years. RESULTS: No patients demonstrated positive serum HCV RNA during follow-up after SVR with a total of 23,187 HCV RNA tests. CONCLUSIONS: This study confirmed the absence of reinfection with HCV in Japanese general population with SVR for decades. Once HCV had been eradicated by anti-HCV therapy, HCV infection rarely recurs even in a lifetime in Japan, unless patients are in high risk group of HCV infection and drop out for follow-up.
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Hépatite C chronique , Hépatite C , Antiviraux/usage thérapeutique , Hepacivirus/génétique , Hépatite C/traitement médicamenteux , Hépatite C/épidémiologie , Hépatite C chronique/traitement médicamenteux , Hépatite C chronique/épidémiologie , Humains , Japon/épidémiologie , ARN viral , Récidive , RéinfectionRÉSUMÉ
BACKGROUND: Identification of risk factors for the development of hepatocellular carcinoma (HCC) after a sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) infection is urgently needed for HCC surveillance. AIMS: To evaluate whether the presence of non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) before direct-acting antivirals (DAAs) therapy is a risk factor for de novo HCC development after SVR. METHODS: The presence of NHHNs was examined with EOB-MRI before the start of DAA therapy in 383 patients with HCV infection who achieved SVR. The incidence of de novo HCC after SVR was compared between patients with versus without NHHNs. RESULTS: NHHNs were detected before DAA therapy in 32 patients (8.4%). The incidence of de novo HCC after SVR was significantly higher in patients with NHHNs than in those without (1-, 3-, 5-year incidence, 9.8%, 24.2% and 41.6% vs. 0%, 1.2% and 4.4%, P < 0.0001). The presence of NHHNs before DAA therapy (adjusted HR, 10.86; 95% CI, 4.03-31.64) and cirrhosis (adjusted HR, 7.23; 95% CI, 1.88-35.85) were independently associated with a higher incidence of HCC after SVR. A higher incidence of de novo HCC after SVR remained after adjustment for age, gender, regular alcohol intake, diabetes, cirrhosis, FIB-4 index and serum alpha-foetoprotein with inverse probability of treatment weighting. CONCLUSIONS: This study confirmed that the presence of NHHNs before DAA therapy is a strong risk factor for the development of de novo HCC after SVR.
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Carcinome hépatocellulaire , Hépatite C chronique , Hépatite C , Tumeurs du foie , Antiviraux/usage thérapeutique , Carcinome hépatocellulaire/imagerie diagnostique , Carcinome hépatocellulaire/épidémiologie , Carcinome hépatocellulaire/étiologie , Produits de contraste/usage thérapeutique , Acide gadopentétique , Hépatite C/traitement médicamenteux , Hépatite C chronique/complications , Hépatite C chronique/traitement médicamenteux , Humains , Tumeurs du foie/imagerie diagnostique , Tumeurs du foie/épidémiologie , Tumeurs du foie/étiologie , Imagerie par résonance magnétique , Réponse virologique soutenueRÉSUMÉ
AIM: Nonalcoholic steatohepatitis (NASH) is a risk factor for nonvirus-related hepatocellular carcinoma, which is increasing in prevalence. The aim of this study was to clarify the clinical application of fucosylated alpha-fetoprotein (AFP-L3) in the process of nonalcoholic fatty liver (NAFL) disease development. METHODS: Serum samples from 115 diabetes mellitus (DM), 36 NAFL, and 119 NASH patients were analyzed for AFP-L3 expression using raw data of a micro total analysis system. These data were then compared with the clinical characteristics of the patients. A validation study was also undertaken with 55 samples (17 NAFL and 38 NASH). RESULTS: Trace amounts of AFP-L3 were detected in 3.5%, 16.7%, and 58.0% of patients with DM, NAFL, and NASH, respectively. The odds ratio of AFP-L3 positivity for the diagnosis of NASH in multivariate analysis was 9.81 (95% confidence interval, 3.77-25.5). The rates in patients without fibrosis or with stage 1, stage 2, stage 3, and stage 4 fibrosis were 14.7%, 31.3%, 63.0%, 86.2%, and 100%, respectively. The rates were significantly increased according to the advancement of liver fibrosis (p < 0.001); however, no difference in the positive rate of AFP-L3 was observed between patients with and without fatty livers and between patients with normal and abnormal transaminase. The same relationship was also observed in the validation cohort. CONCLUSION: Abnormal fucosylation of AFP occurred in patients with NASH, so it could be useful for the screening of NASH in patients with DM, as well as for the differential diagnosis of NASH and the evaluation of fibrosis.
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Background: The current coronavirus disease 2019 (COVID-19) pandemic has strongly influenced many aspects of the medical care, including cancer surveillance. Aims: We investigated how the COVID-19 pandemic influenced surveillance for hepatocellular carcinoma (HCC), focusing on patients with hepatitis C virus infection who were receiving surveillance for HCC after sustained virologic response (SVR) in Japan. Methods: Patients who achieved SVR between 1995 and 2017 and continued receiving surveillance were compared by month in terms of the rate at which they kept their scheduled visits for HCC surveillance from July 2019 to May 2020. Results: The percentage of kept scheduled visits was above 97% before February 2020. By contrast, it declined sharply after March 2020 when COVID-19 became pandemic; the percentages were 75.5% in March, 63.0% in April and 49.1% in May 2020 (July 2019-February 2020 vs March-May 2020, P < 0.0001). Similar declines were observed in patients with cirrhosis or advanced fibrosis and in those with a history of HCC. Whereas most patients who cancelled a scheduled visit before February 2020 did not reschedule it, the majority of patients with cancellations after March 2020 did want to reschedule. Conclusions: The percentages of scheduled visits that were kept declined rapidly after COVID-19 became pandemic in Japan, although the spread of COVID-19 is relatively mild and the legal restriction of people's behaviour and movement is absent. Instituting measures to follow-up with cancelled patients and resume surveillance will be necessary in the future.
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OBJECTIVES: Diabetes mellitus is a risk factor for non-B, non-C hepatocellular carcinoma (NBNC-HCC); however, the number of diabetes mellitus patients is too large to examine tumor occurrence with periodic imaging modalities. Thus, the aim of this study was to develop a novel strategy for early detection of NBNC-HCC in diabetes mellitus patients. PATIENTS AND METHODS: Ninety-three diabetes mellitus patients who had a single NBNC-HCC tumor less than 2 cm in diameter were selected from 6789 HCC patients. As controls, 172 tumor-free diabetes mellitus patients were enrolled. Characteristics were compared between groups. Furthermore, the efficacy of FIB4A, a new integrated score with FIB4 and alpha-fetoprotein, was analyzed as a marker for the early diagnosis of NBNC-HCC. RESULTS: Age, percentage of males, alcohol consumption, total bilirubin, transaminases, γ-glutamyl transpeptidase, FIB4 index, alpha-fetoprotein, and des-gamma-carboxy-prothrombin were higher in NBNC-HCC patients, whereas albumin and platelet counts were higher in the diabetes mellitus control group. Among these factors, the FIB4 index showed the highest odds ratio [OR: 20.0, 95% confidence interval (CI): 9.60-41.7] followed by alpha-fetoprotein (OR: 12.8, 95% CI: 6.53-25.4). A newly developed score, FIB4A, showed the highest area under the receiver operating characteristic curve (0.959) among the factors examined. The sensitivity was 86.2% at a Youden index cutoff (3.5) and it increased to 95.4%, while keeping high specificity (70.9%) when a cutoff of 2.5 was used. CONCLUSION: FIB4A is a potential marker for early detection of NBNC-HCC in patients with diabetes mellitus. However, further studies are needed to confirm these findings.