Association of liver fibrosis with extrahepatic cancer in steatotic liver disease patients with PNPLA3 I148M GG genotype.

The impacts of patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M-rs738409, methylenetetrahydrofolate reductase (MTHFR) Ala222Val-rs1801133, and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys-rs671 on the outcomes of Taiwanese patients with steatotic liver disease (SLD) have remained elusive. An 8-year prospective cohort study of patients with (n = 546) and without (n = 580) SLD (controls) was undertaken in a Taiwanese tertiary care center. The 546 SLD patients comprised 306 (56.0%) men and 240 (44.0%) women with mean ages of 53.3 and 56.4 years, respectively. Compared with the controls, SLD patients had an increased frequency of the PNPLA3 I148M-rs738409 GG genotype (25.5 vs. 5.9%, p = 0.001). Among the SLD patients, 236 (43.1%) suffered cardiovascular events, 52 (9.5%) showed extrahepatic cancers, 13 (2.38%) experienced hepatic events, including hepatocellular carcinoma (n = 3, 0.5%) and liver cirrhosis (n = 8, 1.47%), and none died. The Fibrosis-4 (FIB-4) scores were associated with extrahepatic cancer (hazard ratio [HR] 1.325; 95% confidence interval [CI], 1.038-1.691) and cirrhosis development (HR 1.532; 95% CI, 1.055-2.224), and the PNPLA3 I148M-rs738409 G allele (ß = 0.158, 95% CI, 0.054-0.325) was associated with the FIB-4 score. Stratified analyses showed that the impact of the FIB-4 score on extrahepatic cancer development was evident only in SLD patients with the PNPLA3 I148M-rs738409 GG genotype (HR 1.543; 95% CI, 1.195-1.993) and not in patients with the GC or CC genotype. Moreover, the ALDH2 Glu504Lys-rs671 G allele had a dose-dependent effect on alcoholism, and the MTHFR and ALDH2 genotypes were not significantly associated with SLD patient outcomes. In conclusion, special vigilance should be exercised for emerging extrahepatic cancer in SLD patients with the PNPLA3 I148M-rs738409 GG genotype and high FIB-4 scores.

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction-associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in patients with type 2 diabetes (T2DM) are lacking. The aim of this multicenter prospective study was to perform a head-to-head comparison of FAST (FibroScan-aspartate aminotransferase [AST]), MAST (MRI-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in patients with T2DM. METHODS: A total of 330 outpatients with T2DM and biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-proton density fat fraction and MRE at the time of liver biopsy were studied. The main outcome was fibrotic MASH, defined as NAS ≥4 (with at least one point for each parameter) and fibrosis stage ≥2 (centrally reviewed). RESULTS: All data for score comparisons were available for 245 patients (median age 59 years, 65% male, median BMI 31 kg/m2; fibrotic MASH in 39%). FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p = 0.41) but outperformed FNI (0.74; p = 0.01) and MEFIB (0.68; p <0.0001). When using original cut-offs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom liver biopsy would be avoided (69% vs. 48%, 46%, 39%, respectively; p <0.001). When using cut-offs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p <0.001). CONCLUSION: Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. IMPACT AND IMPLICATIONS: Among patients with type 2 diabetes (T2DM), identifying those with metabolic dysfunction-associated steatohepatitis and significant fibrosis, who are the most at risk of developing clinical liver-related outcomes and who may benefit from pharmacologic treatments, is an unmet need. In this prospective multicenter study, we compared four non-invasive scores, three based on imaging (MRI or ultrasound technologies) and one on laboratory blood tests, for this purpose, using original and study-specific cut-offs. Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. TRIAL REGISTRATION NUMBER: NCT03634098.

Liver Stiffness Measurement and Risk Prediction of Hepatocellular Carcinoma After HCV Eradication in Veterans With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis secondary to chronic hepatitis C virus (HCV) are at risk for hepatocellular carcinoma (HCC) despite a sustained virological response (SVR). We examined whether post-SVR liver stiffness measurement (LSM) could be used to stratify HCC risk. METHODS: This was a retrospective cohort study of 1850 participants identified from the Veterans Health Administration, with HCV cirrhosis and SVR, followed up over 5099 person-years, from the time of post-SVR elastography until death, HCC, or the end of the study. RESULTS: The risk of HCC increased by 3% with every 1-kPa increase in LSM (adjusted hazard ratio [aHR], 1.03, 95% confidence interval [CI], 1.01-1.04; P < .001) and decreased with the number of years from SVR (aHR, 0.79; 95% CI, 0.70-0.90; P = .0003). The adjusted annual risk of HCC was 2.03% among participants with post-SVR LSM <10 kPa, 2.48% in LSM 10-14.9 kPa (aHR, 1.71; 95% CI, 1.01-2.88; P = .046), 3.22% for LSM 15-19.9 kPa (aHR, 1.59; 95% CI, 0.78-3.20; P = .20), 5.07% among LSM 20-24.9 kPa (aHR, 2.55; 95% CI, 1.30-5.01; P = .01), and 5.44% in LSM ≥25 kPa (aHR, 3.03; 95% CI, 1.74-5.26; P < .0001). The adjusted annual risk of HCC was < 0.4% in participants with LSM <5 kPa and without diabetes mellitus. CONCLUSIONS: LSM predicts rates of HCC in patients with HCV cirrhosis after SVR at multiple cutoff levels and offers a single test to predict portal hypertension-related complications and HCC. Patients with LSM <5 kPa in the absence of diabetes mellitus had a low risk of HCC in which surveillance could be discontinued.

Prediction of hepatocellular carcinoma and liver-related events in anti-HDV positive individuals.

BACKGROUND AND AIMS: Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis, with a high risk of developing hepatocellular carcinoma (HCC) and liver-related mortality. Risk stratification is needed to guide HCC surveillance strategies and to prioritize treatment with antiviral agents. METHODS: We conducted a multicenter retrospective cohort of anti-HDV positive individuals managed at sites in the Netherlands and the United Kingdom. We studied the 5-year cumulative incidences of HCC and liver-related events (first of HCC, liver transplantation and liver-related mortality), in the overall cohort and among relevant subgroups. RESULTS: We analyzed 269 anti-HDV positive individuals with a median follow-up of 4.3 years in which 47 first events occurred. The 5-year cumulative incidences of HCC and liver-related events were 3.8% and 15.6% in the overall cohort. The 5-year cumulative incidence of HCC and liver-related events for individuals without cirrhosis was 0% and 0.9% compared to 12% and 41.3% for individuals with cirrhosis (p<0.001). The 5-year cumulative incidence of HCC and liver-related events was 0% and 2.1% among individuals with low PAGE-B scores, compared to 3.2% and 21.1% with intermediate and 25.4% and 45.5% with high risk scores (p<0.001). We found comparable results for the FIB-4 score. Findings were consistent regardless of cirrhosis or detectable HDV RNA (p<0.001). CONCLUSION: Anti-HDV positive individuals are at high risk of adverse liver-related outcomes. The incidences of HCC was negligible among individuals without cirrhosis and among individuals with low baseline PAGE-B and/or FIB-4 scores. Therefore, these score can be used to guide HCC surveillance strategies and potentially also for treatment prioritization.

Serum dithiothreitol-oxidizing capacity (DOC) is a promising biomarker for excluding significant liver fibrosis: a proof-of-concept study.

BACKGROUND: APRI and FIB-4 scores are used to exclude clinically significant fibrosis (defined as stage ≥ F2) in patients with chronic viral hepatitis. However, the cut-offs for these scores (generated by Youden indices) vary between different patient cohorts. This study aimed to evaluate whether serum dithiothreitol-oxidizing capacity (DOC), i.e., a surrogate test of quiescin sulfhydryl oxidase-1, which is a matrix remodeling enzyme, could be used to non-invasively identify significant fibrosis in patients with various chronic liver diseases (CLDs). METHODS: Diagnostic performance of DOC was compared with APRI and FIB-4 for identifying significant fibrosis. ROC curve analyses were undertaken in: a) two chronic hepatitis B (CHB) cohorts, independently established from hospitals in Wenzhou (n = 208) and Hefei (n = 120); b) a MASLD cohort from Wenzhou hospital (n = 122); and c) a cohort with multiple CLD etiologies (except CHB and MASLD; n = 102), which was identified from patients in both hospitals. Cut-offs were calculated using the Youden index. All CLD patients (n = 552) were then stratified by age for ROC curve analyses and cut-off calculations. RESULTS: Stratified by CLD etiology or age, ROC curve analyses consistently showed that the DOC test was superior to APRI and FIB-4 for discriminating between clinically significant fibrosis and no fibrosis, when APRI and FIB-4 showed poor/modest diagnostic performance (P < 0.05, P < 0.01 and P < 0.001 in 3, 1 and 3 cohort comparisons, respectively). Conversely, the DOC test was equivalent to APRI and FIB-4 when all tests showed moderate/adequate diagnostic performances (P > 0.05 in 11 cohort comparisons). DOC had a significant advantage over APRI or FIB-4 scores for establishing a uniform cut-off independently of age and CLD etiology (coefficients of variation of DOC, APRI and FIB-4 cut-offs were 1.7%, 22.9% and 47.6% in cohorts stratified by CLD etiology, 2.0%, 26.7% and 29.5% in cohorts stratified by age, respectively). The uniform cut-off was 2.13, yielded from all patients examined. Surprisingly, the uniform cut-off was the same as the DOC upper limit of normal with a specificity of 99%, estimated from 275 healthy control individuals. Hence, the uniform cut-off should possess a high negative predictive value for excluding significant fibrosis in primary care settings. A high DOC cut-off with 97.5% specificity could be used for detecting significant fibrosis (≥ F2) with an acceptable positive predictive value (87.1%). CONCLUSIONS: This proof-of-concept study suggests that the DOC test may efficiently rule out and rule in significant liver fibrosis, thereby reducing the numbers of unnecessary liver biopsies. Moreover, the DOC test may be helpful for clinicians to exclude significant liver fibrosis in the general population.

Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

OBJECTIVE: Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. DESIGN: Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. PATIENTS AND MEASUREMENTS: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. RESULTS: Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. CONCLUSIONS: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.

Penetrance, cancer incidence and survival in HFE haemochromatosis-A population-based cohort study.

BACKGROUND AND AIMS: Haemochromatosis is characterized by progressive iron overload affecting the liver and can cause cirrhosis and hepatocellular carcinoma. Most haemochromatosis patients are homozygous for p.C282Y in HFE, but only a minority of individuals with this genotype will develop the disease. The aim was to assess the penetrance of iron overload, fibrosis, hepatocellular carcinoma and life expectancy. METHODS: A total of 8839 individuals from the Austrian region of Tyrol were genotyped for the p.C282Y variant between 1997 and 2021. Demographic, laboratory parameters and causes of death were assessed from health records. Penetrance, survival, and cancer incidence were ascertained from diagnosed cases, insurance- and cancer registry data. Outcomes were compared with a propensity score-matched control population. RESULTS: Median age at diagnosis in 542 p.C282Y homozygous individuals was 47.8 years (64% male). At genotyping, the prevalence of iron overload was 55%. The cumulative penetrance of haemochromatosis defined as the presence of provisional iron overload was 24.2% in males and 10.5% in females aged 60 years or younger. Among p.C282Y homozygotes of the same ages, the cumulative proportion of individuals without fibrosis (FIB-4 score < 1.3) was 92.8% in males and 96.7% in females. Median life expectancy was reduced by 6.8 years in individuals homozygous for p.C282Y when compared with population-matched controls (p = .001). Hepatocellular carcinoma incidence was not significantly higher in p.C282Y homozygotes than in controls matched for age and sex. CONCLUSION: Reduced survival and the observed age-dependent increase in penetrance among p.C282Y homozygotes call for earlier diagnosis of haemochromatosis to prevent complications.

Serum-free light chains as a dependable biomarker for stratifying patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Adaptive immunity is gaining a significant role in progression of metabolic dysfunction-associated steatotic liver disease (MASLD). B-cell activity can be assessed by serum-free light chains (sFLCs) k and λ levels. The objective of the present investigation is to examine the utility of sFLCs as non-invasive biomarkers for the stratification of MASLD. METHODS: We enrolled a consecutive cohort from an outpatient liver unit. Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) was made with liver biopsy according to current guidelines. Compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) were defined according to Baveno VII criteria. sFLCs were measured by turbidimetry using an immunoassay. RESULTS: We evaluated 254 patients, 162/254 (63.8%) were male. Median age was 54 years old, and the median body mass index was 28.4 kg/m2. A total of 157/254 (61.8%) subjects underwent liver biopsy: 88 had histological diagnosis of MASH, 89 were considered as simple metabolic dysfunction-associated steatotic liver (MASL) and 77/254 (30.3%) patients with compensated metabolic dysfunction-associated cirrhosis. By using Baveno VII criteria, 101/254 (39.7%) patients had cACLD; among them, 45/101 (44.5%) had CSPH. Patients with cACLD showed higher sFLC levels compared with patients without cACLD (p < .01), and patients with CSPH showed higher sFLC levels than patients without CSPH (p < .01). At multivariable analysis, sFLCs were associated with cACLD (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. κFLC was associated with CSPH (p < .05) independently from γ-globulins and other known dysmetabolic risk factors. CONCLUSION: sFLCs could be a simple biomarker for stratification of cACLD in MASLD patients.

Pharmaco-Economic Assessment of Screening Strategies for High-Risk MASLD in Primary Care.

BACKGROUND AND AIMS: Several scientific associations recommend a sequential combination of non-invasive tests (NITs) to identify high-risk MASLD patients but their cost-effectiveness is unknown. METHODS: A cost-utility model was developed to assess the incremental cost-effectiveness ratio (ICER) of recommended screening strategies for patients with clinically suspected MASLD, specifically those with type 2 diabetes (T2D) and obesity with multiple cardiometabolic risk factors which will be initiated in primary care. Six screening strategies were assessed, using either vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test as a second-line test following an initial Fibrosis-4 (FIB-4) assessment as the first line NIT. The model included treatment effects of resmetirom for metabolic dysfunction-associated steatohepatitis (MASH) patients with F2 or F3 fibrosis. RESULTS: All screening strategies for high-risk MASLD in US incurred additional costs compared to no screening, ranging from $13 587 to $14 730 per patient with T2D and $14 274 to $15 661 per patient with obesity. However, screening reduced long-term costs, ranging from $22 150 to $22 279 per patient with T2D and $13 704 to $13 705 per patient with obesity, compared to $24 221 and $14 956 for no screening, respectively. ICERs ranged from $26 913 to $27 884 per QALY for T2D patients and $23 265 to $24 992 per QALY for patients with obesity. While ICERs were influenced by VCTE availability, they remained cost-effective when using ELF as the second-line test. Our findings remain robust across a range of key parameters. CONCLUSIONS: Screening for high-risk MASLD is cost-effective according to recent guidelines. Implementing these screening strategies in primary care should be considered.

Clinical Utility of Genetic Variants in PNPLA3 and TM6SF2 to Predict Liver-Related Events in Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND AND AIMS: Fibrosis-4 (FIB-4) index and genetic polymorphisms have been used in assessing the risk of liver-related events (LRE) in metabolic dysfunction-associated steatotic liver disease (MASLD). To establish a more efficient prediction strategy for LRE, we investigated a combined approach that uses the FIB-4 index and genetic polymorphisms. METHODS: We enrolled 1304 Japanese patients with biopsy-proven MASLD in this longitudinal multicenter cohort study. PNPLA3, TM6SF2, GCKR and MBOAT7 genotypes were genotyped, and polygenic risk score high fat content (PRS-HFC) were calculated. RESULTS: During the follow-up period of 8.1 year, 96 LRE occurred and 53 patients died. PNPLA3, TM6SF2 and GCKR genotypes were associated with LRE development. We divided patients into three groups based on the FIB-4 index and PNPLA3 and TM6SF2 genotype. The cumulative LRE development rate in each group was 2.1%/28.9%/53.5%, respectively, at 10 years. Multivariate analysis revealed hazard ratios (HRs) for LRE of 10.72 in the high-risk group and 4.80 in the intermediate-risk group. Overall survival in each group was 98.8%/85.2%/72.4%, respectively, at 10 years. HRs for prognosis were 8.74 in the high-risk group and 5.62 in the intermediate-risk group. Patients with FIB-4 index > 2.67 and high PRS-HFC had HR of 6.70 for LRE development and HR of 6.07 for prognosis compared to patients with FIB-4 ≤ 2.67. CONCLUSIONS: The approach of measuring the FIB-4 index first followed by assessment of genetic polymorphisms efficiently detected patients at high risk of developing LRE. Therefore, this two-step strategy could be used as a screening method in large populations of patients with MASLD.

Diagnostic accuracy of non-invasive tests to screen for at-risk MASH-An individual participant data meta-analysis.

BACKGROUND & AIMS: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions. METHODS: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported. RESULTS: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%. CONCLUSIONS: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations.

Integrating PNPLA3 into clinical risk prediction.

The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.

Use of non-invasive diagnostic tools for metabolic dysfunction-associated steatohepatitis: A qualitative exploration of challenges and barriers.

BACKGROUND AND AIMS: Non-invasive tests (NITs) are underutilized for diagnosis and risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD), despite good accuracy. This study aimed to identify challenges and barriers to the use of NITs in clinical practice. METHODS: We conducted a qualitative exploratory study in Germany, Italy, United Kingdom and United States. Phase 1 participants (primary care physicians, hepatologists, diabetologists, researchers, healthcare administrators, payers and patient advocates; n = 29) were interviewed. Phase 2 participants (experts in MASLD; n = 8) took part in a group discussion to validate and expand on Phase 1 findings. Finally, we triangulated perspectives in a hybrid deductive/inductive thematic analysis. RESULTS: Four themes hindering the use of NITs emerged: (1) limited knowledge and awareness; (2) unclear referral pathways for patients affected by liver conditions; (3) uncertainty over the value of NITs in monitoring and managing liver diseases; and (4) challenges justifying system-level reimbursement. Through these themes, participants perceived a stigma associated with liver diseases, and primary care physicians generally lacked awareness, adequate knowledge and skills to use recommended NITs. We identified uncertainties over the results of NITs, specifically to guide lifestyle intervention or to identify patients that should be referred to a specialist. Participants indicated an ongoing need for research and development to improve the prognostic value of NITs and communicating their cost-effectiveness to payers. CONCLUSIONS: This qualitative study suggests that use of NITs for MASLD is limited due to several individual and system-level barriers. Multi-level interventions are likely required to address these barriers.

Evaluation of soluble suppression of tumorigenicity 2 (sST2) as serum marker for liver fibrosis.

BACKGROUND & AIMS: With the increase in patients at risk of advanced liver disease due to the obesity epidemic, there will be a need for simple screening tools for advanced liver fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a serum biomarker for fibrotic processes. The aim of this study was to evaluate sST2 as marker for liver fibrosis in patients successfully treated for chronic hepatitis C. METHODS: 424 patients from the Swiss Hepatitis C Cohort Study were screened for inclusion in this post-hoc cohort study. Inclusion criteria were sustained virological response (SVR), available elastography (VCTE) and serum samples for biomarker analysis before and after treatment. For the validation of sST2, values were compared to VCTE, FIB-4 and APRI using Spearman's correlation and AUROC analyses. RESULTS: Data of 164 subjects were finally analyzed. Median sST2 values slightly increased with VCTE-derived fibrosis stages and remained stable after reaching SVR within the respective fibrosis stage, suggesting that sST2 is not influenced by liver inflammation. However, correlation of sST2 pre- and post-treatment with VCTE was fair (Spearman's rho = 0.39 and rho = 0.36). The area under the curve (AUROC) for sST2 in detecting VCTE-defined F4 fibrosis (vs. F0-F3) before therapy was 0.74 (95%CI 0.65-0.83), and 0.67(95%CI 0.56-0.78) for the discrimination of F3/F4 fibrosis vs. F0-F2. Adding sST2 to either APRI or FIB-4, respectively, increased diagnostic performance of both tests. CONCLUSIONS: sST2 can potentially identify patients with advanced fibrosis as a single serum marker and in combination with APRI and FIB-4.

Prognostic Value of the Pretransplant Fibrosis-4 Index on Non-Relapse and Overall Mortality following Unrelated Single-Unit Cord Blood Transplantation in Adults.

INTRODUCTION: The fibrosis-4 (FIB-4) index is a noninvasive marker of liver fibrosis. The FIB-4 index predicts poor outcomes in patients with hepatic and non-hepatic diseases. However, the association of the FIB-4 index with mortality and liver-related clinical outcomes following cord blood transplantation (CBT) is unclear. METHODS: We retrospectively evaluated the impact of the pretransplant FIB-4 index on outcomes in 336 adults following single-unit unrelated CBT at our institution. RESULTS: In multivariate analyses, when the FIB-4 index <1.3 group was used as the reference, non-relapse mortality was significantly higher in the FIB-4 index 1.3-2.67 (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.19-5.30) and FIB-4 index >2.67 (HR, 2.34; 95% CI, 1.12-4.90) groups. Overall mortality was significantly higher in the FIB-4 index >2.67 group (HR, 1.66; 95% CI, 1.00-2.73), but with only marginal significance in the FIB-4 index 1.3-2.67 group (HR, 1.59; 95% CI, 0.96-2.64). Hematopoietic recovery, acute and chronic graft-versus-host disease of the liver, and veno-occlusive disease/sinusoidal obstruction syndrome were not associated with the pretransplant FIB-4 index. CONCLUSION: The pretransplant FIB-4 index is accurate and useful in predicting mortality in adult patients undergoing single-unit unrelated CBT.

Prognostic performance of a two-step method using the Fibro-Scope system for metabolic dysfunction-associated steatotic liver disease.

AIM: Fibro-Scope is an artificial intelligence/neural network system for the noninvasive diagnosis of hepatic fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. We aimed to examine the diagnostic performance of a two-step method that used the Fibrosis-4 (FIB-4) index and Fibro-Scope system for the assessment of Japanese patients with metabolic dysfunction-associated steatotic liver disease. METHODS: We analyzed a longitudinal study cohort of 796 Japanese patients with biopsy-proven metabolic dysfunction-associated steatotic liver disease during a follow-up period of 6.4 years. The predictive performance of the two-step method of FIB-4 index and Fibro-Scope for liver-related events and prognostic performance of that were assessed in the patients. RESULTS: In the 796 patients, by classifying the intermediate zone, defined by FIB-4 index 1.30-2.67, using the Fibro-Scope, the final classification was 69.6% low risk, 28.3% high risk, and 2.1% in the middle-risk group. The sensitivity and specificity for predicting advanced fibrosis (≥F3) was 84.0% and 84.0%. During the follow-up period, 52 (6.5%) patients developed liver-related events and 35 died. Multivariate analysis revealed that high-risk patients derived from the two-step method had hazard ratios of 30.1 or the development of liver-related events and 7.8 for outcome. CONCLUSIONS: The two-step method using the FIB-4 index and Fibro-Scope contributed to improving the diagnostic performance by picking up high-risk patients from those classified as intermediate risk with the FIB-4 index. This noninvasive method, which uses a blood sample is a cost-effective screening method, is suitable for clinical practice in Japan.

Validation study of age-independent fibrosis score (Fibrosis-3 index) in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

The change in Fibrosis-4 index in Japanese patients with type 2 diabetes treated by a fixed-ratio combination therapy of insulin degludec and liraglutide: A retrospective observational study.

AIM: The efficacy of titratable fixed-ratio combination therapy by a combination preparation of insulin degludec and liraglutide (IDegLira) in Japanese patients with type 2 diabetes, focusing particularly on the change in Fibrosis-4 index (FIB-4), a noninvasive method for the evaluation of liver fibrosis, was investigated. METHODS: As the full analysis set, 113 patients were treated with IDegLira. The patients were categorized into two groups according to the absence (GLP-1RA-naïve group, n = 72) or presence (GLP-1RA-treated group, n = 41) of glucagon-like peptide-1 receptor agonist (GLP-1RA) use before starting IDegLira. The clinical parameters were retrospectively determined over 6 months. RESULTS: The glycated hemoglobin value was significantly reduced in both groups. The bodyweight significantly decreased from 67.4 ± 11.0 kg at baseline to 66.4 ± 11.6 kg at 6 months in the GLP-1RA-naïve group, although it slightly increased in the GLP-1RA-treated group. FIB-4 significantly decreased from 1.60 ± 0.84 at baseline to 1.49 ± 0.74 at 6 months in the GLP-1RA-naïve group. Although FIB-4 significantly increased in the GLP-1RA-treated group, it remained within the low-risk level for liver fibrosis. CONCLUSION: Fixed-ratio combination therapy using IDegLira for the treatment of type 2 diabetes is useful for glycemic control and weight management. In particular, IDegLira may be more effective for lowering FIB-4 than adding unused oral antidiabetic agents or increasing the dose of insulin in GLP-1RA-naïve patients.

Interleukin-33 and liver natural killer cells: A novel perspective on antitumor activity in liver fibrosis.

AIM: Liver fibrosis, heralding the potential progression to cirrhosis and hepatocellular carcinoma (HCC), compromises patient survival and augments post-hepatectomy recurrence. This study examined the detrimental effects of liver fibrosis on the antitumor functions of liver natural killer (NK) cells and the interleukin-33 (IL-33) signaling pathway. METHODS: Our investigation, anchored in both human physiologies using living and deceased donor livers and the carbon tetrachloride (CCl4)-induced mouse fibrosis model, aimed to show a troubling interface between liver fibrosis and weakened hepatic immunity. RESULTS: The Fibrosis-4 (FIB-4) index emerged as a salient, non-invasive prognostic marker, and its elevation correlated with reduced survival and heightened recurrence after HCC surgery even after propensity matching (n = 385). We established a strong correlation between liver fibrosis and liver NK cell dysfunction by developing a method for extracting liver NK cells from the liver graft perfusate. Furthermore, liver fibrosis ostensibly disrupted chemokines and promoted IL-33 expression, impeding liver NK cell antitumor activities, as evidenced in mouse models. Intriguingly, our results implicated IL-33 in diminishing the antitumor responses of NK cells. This interrelation, consistent across both mouse and human studies, coincides with clinical data suggesting that liver fibrosis predisposes patients to an increased risk of HCC recurrence. CONCLUSION: Our study revealed a critical relationship between liver fibrosis and compromised tumor immunity, emphasizing the potential interference of IL-33 with NK cell function. These insights advocate for advanced immunostimulatory therapies targeting cytokines, such as IL-33, aiming to bolster the hepatic immune response against HCC in the context of liver fibrosis.

Fibrosis-4 score for screening of metabolic dysfunction-associated steatotic liver disease (MASLD): Data from a population-based sample in Tuscany.

BACKGROUND AND AIM: To verify the prevalence of positive Fibrosis-4 (FIB-4) score, a screening test for metabolic-associated liver disease, in a large population-based sample in the Tuscany Italian Region, and to identify sub-populations at higher risk which could be targeted by specific screening programs. METHODS AND RESULTS: Population-based survey performed in the Italian region of Tuscany, with Tuscany health informative system's administrative data. We included 594,923 subjects, of which 32% had available data for the FIB-4 calculation. The overall proportion of subjects with an FIB-4 value > 1.3, was 41.6% of those with available exams, and 12,8% of the whole population, whereas 5.4% and 1.7% had FIB-4 >2.67. In those younger than 80 years, FIB >1.3 had a 33.1% and 9.4%. People with diabetes mellitus had higher figures (52.8.% and 28.9% for FIB>1.3). Among subjects aged 70 years or over, 74.9% of those with available data and 38.4% of the general population had a FIB-4>1.3, whereas 32% and 16% had a FIB-4 > 2. CONCLUSIONS: The relevant proportion of FIB-4 positivity in the general population poses a significant burden for further screening with liver elastography. Targeting people with diabetes, excluding people older than 80 years and/or adopting a FIB-4 threshold of 2 in those aged more than 70 years could increase the cost-effectiveness of the screening procedures.