Poor Performance of Non-invasive Tests for Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: A Multicentric Asian Study.

BACKGROUND: Non-invasive tests (NITs) are useful to assess advanced fibrosis (AF) in nonalcoholic fatty liver disease (NAFLD). Data from Asian countries suggest that these tests have poor performance. We aimed to assess diagnostic accuracy of established thresholds of biomarker-based NITs and Transient Elastography (TE) in identifying AF and evaluated the utility of a two-step test approach. METHODS: Biopsy-proven 641 NAFLD patients (55.2% males, median age 42 years) were included from three different centers of Asia. AF (≥ F3) was identified as per histological staging (24.8%). RESULTS: TE had the highest area under the receiver operating characteristic curve (AUROC) 0.82 (0.79-0.86), and all other biomarker-based NITs had low AUROC (< 0.7). NITs performed poorly at established thresholds. The combination of NITs utilizing liver stiffness measurement (LSM) and biomarkers, Agile 3+ and FAST, demonstrated acceptable diagnostic accuracy (AUROC 0.82 and 0.78, respectively), but none were superior to LSM alone. LSM measured using appropriate M and XL probes remained accurate regardless of body mass index (BMI); NFS and APRI scores were less accurate at higher BMI ranges. A two-step approach using NFS rule-out criteria (< - 2.97 to rule out) followed by LSM (< 7.3 kPa to rule out and ≥ 12.7 kPa to rule in) correctly classified 62.4% of patients, with only 10.2% of patients incorrectly classified. CONCLUSION: NITs have not been validated to identify AF in the Asian NAFLD population, and internationally accepted thresholds yield high false-negative rates. LSM and LSM-based combination tests remain the most accurate.

Gender survival differences in hepatocellular carcinoma: Is it all due to adherence to surveillance? A study of 1716 patients over three decades.

Background and Aims: Hepatocellular carcinoma (HCC) is one of the commonest causes of cancer-related death worldwide. Whether gender is an independent factor for HCC survival is debatable. We studied the influence of gender on the clinical characteristics of HCC and on survival. Methods: The study cohort comprised patients with HCC seen in our department from 1988 to 2021. Clinical data were prospectively collected. We studied and compared demography, HCC characteristics, and survival between females and males. Survival analysis was censored on October 31, 2015. Results: There were 1716 HCC patients. 343 (20.0%) were females. Females were significantly older at diagnosis (median 69 vs 62 years, P < 0.001). More females were diagnosed via regular HCC surveillance (37.9% vs 29.6%, P = 0.003). Hence, as expected, females had less-advanced HCC at diagnosis with smaller median tumor diameter (30 vs 39.5 mm, P = 0.038), lower frequency of portal vein tumor thrombus (19.4% vs 33.4%, P < 0.001), less distant metastases (7.7% vs 11%, P = 0.043), and earlier Barcelona Clinic Liver Cancer (BCLC) stages (0/A, 39.7% vs 28.4%, P < 0.001). On multivariable analysis, HCC diagnosis via surveillance but not female gender was an independent predictor of improved HCC survival. Conclusions: In this large cohort of multi-ethnic Asian patients, females with HCC were significantly more adherent to surveillance and hence presented with less advanced HCC with correspondingly better overall survival than males. The gender difference in survival is likely due to females having better adherence to HCC surveillance. Surveillance to diagnose early-stage HCC remains crucial in improving outcomes.

The utility of non-invasive tests to assess advanced fibrosis in Asian subjects with chronic hepatitis B and concomitant hepatic steatosis.

BACKGROUND: Chronic hepatitis B (CHB) is endemic to Asia and is a leading cause of liver-related morbidity. The prevalence of concomitant CHB and hepatic steatosis (HS) is increasing in Asia. Non-invasive tests (NITs) including FIB-4, NFS and APRI assess fibrosis in populations with a single aetiology, but not in subjects with concomitant CHB and HS. AIM: To explore the accuracy of NITs in predicting advanced fibrosis in patients with concomitant CHB and HS. METHODOLOGY: This multicentre study of CHB patients who underwent liver biopsy explored clinical characteristics of these subjects, stratified by presence of HS. Fibrosis scores from NITs were compared against histological fibrosis stage in CHB subjects with and without HS. RESULTS: 2262 subjects were enrolled, 74.5% were males, and the mean age was 39.5 years ±11.8 SD. 984 (44.4%) had HS, 824 (36.4%) had advanced fibrosis. In the CHB group, the AUROC for advanced fibrosis were 0.65 (95% CI 0.62-0.69) for FIB-4 and 0.63 (95% CI 0.60-0.66) for APRI. The specificities were 0.94 for FIB-4 greater than 3.25 and 0.81 for APRI greater than 1.5. In the CHBHS group, the AUROC for advanced fibrosis were 0.67 (95% CI 0.63-0.71) for FIB-4, 0.60 (95% CI 0.56-0.64) for APRI and 0.65 (95% CI 0.61-0.69) for NFS. The specificities were 0.95 for FIB-4 greater than 3.25, 0.88 for APRI greater than 1.5 and 0.99 for NFS greater than 0.675. CONCLUSION: The performance of NITs to exclude advanced fibrosis did not differ greatly regardless of HS. FIB-4 and NFS have the best negative predictive values of 0.80 and 0.78, respectively, to exclude advanced fibrosis in CHBHS subjects.

A study of 3013 cases of hepatocellular carcinoma: Etiology and therapy before and during the current decade.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is a significant global problem. With advances in HCC diagnosis and therapy, our hypothesis is that there are significant differences in the clinical characteristics and treatment of HCC over the years. METHODS: Patients with HCC between 1980 and 2018 from three major tertiary hospitals in Singapore were enrolled into a Research Electronic Data Capture database. Clinical characteristics and treatment of HCC were compared between those diagnosed before 2008 (cohort A) and during the current decade (ie from 2008 onwards) (cohort B). RESULTS: There were 3013 patients. Mean age of HCC diagnosis was significantly older in cohort B (68.6 vs 61.2 years, P < 0.001). The most common etiology remained as chronic hepatitis B infection but the proportion due to hepatitis B was significantly lower in cohort B (46.6% vs 57.2%, P < 0.0001). The prevalence of cryptogenic/non-alcoholic steatohepatitis was significantly higher in cohort B than cohort A (27.1% vs 18.6%, P < 0.0001). More patients received curative therapy in cohort B (43.7% vs 27.1%, P < 0.0001. CONCLUSION: In this largest collection of HCC patients in Singapore, patients are diagnosed with HCC at an older age and cryptogenic/non-alcoholic steatohepatitis is becoming more important as an etiology of HCC in the current decade. More patients also received curative therapy in the current decade.

Liver Resection for Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is on the rise worldwide, but data on long-term outcomes after curative operations are limited. The primary aim of this study was to characterize the perioperative and long-term outcomes after liver resection. The secondary aim was to investigate the influence of the histologic severity of nonalcoholic steatohepatitis and its impact on perioperative outcomes and long-term survival. METHODS: A total of 996 patients who underwent liver resection for HCC in our institution were analyzed. Patients were categorized into subgroups of NAFLD vs non-NAFLD HCC based on histologic evidence of hepatic steatosis. Comparisons of patients' demographic, clinical, and surgical characteristics; postoperative complications; and survival outcomes were performed. RESULTS: Eight hundred and forty-four patients had non-NAFLD HCC and 152 patients had NAFLD HCC. Comorbidities were significantly more common in the NAFLD group (p < 0.0001). In the non-NAFLD group, larger median tumor size, higher liver cirrhosis, and lower median neutrophil to lymphocyte ratio were observed (p < 0.0001). The NAFLD group had a greater amount of intraoperative blood loss, more postoperative complications, and longer length of stay. Five-year overall survival was significantly better in the NAFLD group (p = 0.0355). Significant factors that contribute to poorer survival outcomes include age, congestive cardiac failure, Child-Pugh's class B, cirrhosis, tumor size, multinodularity, and R1 resection. For NAFLD group, patients with abnormal parenchyma showed poorer survival and 5-year overall survival rates (64.8% vs 75.6%; p = 0.2291). CONCLUSIONS: Nonalcoholic fatty liver disease-related HCC is associated with greater surgical morbidity and post-hepatectomy liver failure. Despite this, long-term survival outcomes are favorable compared with non-NAFLD etiologies.

Circulating microRNAs as Potential Diagnostic and Prognostic Biomarkers in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer with high mortality, due to late diagnosis and limited treatment options. Blood miRNAs, which circulate in a highly stable, cell-free form, show promise as novel potential biomarkers for early detection of HCC. Whole miRNome profiling was performed to identify deregulated miRNAs between HCC and normal healthy (NH) volunteers. These deregulated miRNAs were validated in an independent cohort of HCC, NH and chronic Hepatitis B (CHB) volunteers and finally in a 3rd cohort comprising NH, CHB, cirrhotic and HCC volunteers to evaluate miRNA changes during disease progression. The associations between circulating miRNAs and liver-damage markers, clinicopathological characteristics and survival outcomes were analysed to identify prognostic markers. Twelve miRNAs are differentially expressed between HCC and NH individuals in all three cohorts. Five upregulated miRNAs (miR-122-5p, miR-125b-5p, miR-885-5p, miR-100-5p and miR-148a-3p) in CHB, cirrhosis and HCC patients are potential biomarkers for CHB infection, while miR-34a-5p can be a biomarker for cirrhosis. Notably, four miRNAs (miR-1972, miR-193a-5p, miR-214-3p and miR-365a-3p) can distinguish HCC from other non-HCC individuals. Six miRNAs are potential prognostic markers for overall survival.