Higher Fibrosis Research Articles

Improving Recurrence Prediction in Intrahepatic Cholangiocarcinoma: The Synergistic Impact of the FIB-4 Index and Tumor Burden Score on Post-hepatectomy Outcomes.

The prognostic role of the fibrosis-4 (FIB-4) index relative to intrahepatic cholangiocarcinoma (ICC) after hepatectomy remains unclear. This study sought to characterize the impact of the FIB-4 index and tumor burden score (TBS) on recurrence and overall survival (OS). ICC patients undergoing hepatectomy (2000-2020) were identifiedusing a multi-institutional database. Patients were categorized as low (low TBS/low FIB-4 index), intermediate (low TBS/high FIB-4 index or high TBS/low FIB-4 index), and high (high TBS/high FIB-4 index). Among 1168 patients in different TBS and FIB-4 index cohorts, 3-year recurrence varied considerably. For instance, among the patients with low TBS, individuals with a high FIB-4 index had a greater risk of recurrence than patients with a low FIB-4 index (59.9 vs. 47.7%; P=0.01). Among patients with a high TBS, individuals with a high versus a low FIB-4 index had a higher incidence of recurrence (76.8 vs. 69.0%; P=0.04). A similar pattern was observed among patients with both a low FIB-4 index (low [47.7%] vs. high [69.0%] TBS) and a high FIB-4 index (low [59.9%] vs. high [76.8%] TBS; both P<0.001). Patients with a high [27.5%] versus a low [48.8%] TBS; P<0.001) and patients with a high [34.2%] versus a low [43.5%] FIB-4 index; P=0.01) had a worse OS. The multivariable analysis demonstrated an increasing risk of recurrence in the intermediate-index (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.20-2.16; P=0.001) and high-index (HR, 2.13; 95% CI 1.45-3.13; P<0.001) groups versus the low-index group. Both tumor-related and non-tumorous characteristics should be used to predict risk of recurrence and survival more accurately among patients with ICCfollowing hepatic resection.

Both fibrosis-4 index and fibrosis-5 index can predict the prognosis of patients after percutaneous coronary intervention

Abstract Backgrounds: The Fibrosis-4 (FIB-4) index and Fibrosis-5 (FIB-5) index are non-invasive indicators reflecting liver fibrosis. Previous studies show their association with acute heart failure and myocardial infarction prognosis. However, there are few reports on the relationship between the two indices and the prognosis of patients after percutaneous coronary intervention (PCI). Purpose This study aims to explore and compare the predictive value of both indices for PCI patient prognosis. Method Data for this study were obtained from a retrospective cohort comprising patients admitted to and discharge d from 72 secondary and tertiary hospitals between 2010 and 2023. Inclusion criteria comprised patients undergoing PCI during hospitalization. The initial test results of these patients after admission were collected, and the FIB-4 (FIB-4 = age (years) × aspartate aminotransferase (AST [U/L]) / (platelets [10^9/L] × alanine aminotransferase [ALT {U/L}]½) and FIB-5 (FIB-5 = [albumin (g/L) × 0.3 + platelet count (10^9/L) × 0.05] - [alkaline phosphatase (U/L) × 0.014 + AST/ALT ratio × 6 + 14]) indices were calculated. Patients were divided into low (N = 83082), medium (N = 16618), and high (N = 7932) FIB-4 groups, as well as low (N = 18642), medium (N = 12106), and high (N = 76884) FIB-5 groups based on predefined cutoff values. The primary endpoint was one-year cardiovascular mortality, with secondary endpoints including one-year all-cause mortality and one-year recurrent myocardial infarction. Results The study included 107,632 patients after PCI whose FIB-4 index and FIB-5 index could be simultaneously calculated during hospitalization. Multivariable Cox regression analysis revealed that compared to the low FIB-4 group, both the high FIB-4 group (aHR 1.935; 95%CI 1.592-2.353) and the medium FIB-4 group (aHR 1.487; 95%CI 1.251-1.768) had an increased risk of one-year cardiovascular death (P0.05). Conclusions The present study indicated that both FIB-4 and FIB-5 could be used to predict the prognosis of patients after PCI. High FIB-4 index and low FIB-5 index were predictive factors for 1-year cardiovascular death, 1-year all-cause death, and 1-year recurrent myocardial infarction in patients after PCI, with no statistical difference in predictive value between the two.

Utility of Quantitative Assessment of Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl Human Serum Albumin SPECT/CT in the Identification of Severe Liver Fibrosis: Its Complementary Diagnostic Value with Other Liver Function Indices.

To evaluate the value of Tc-99m-diethylenetriamine-penta-acetic acid-galactosyl human serum albumin (99mTc-GSA) single photon emission computed tomography (SPECT) for assessing liver fibrosis, and to assess its complementary value to other liver function indices such as fibrosis-4 (FIB-4) index and indocyanine green (ICG) clearance test parameters (ICG-R15 and ICG-K). Seventy-eight patients with chronic liver disease and hepatocellular carcinoma who underwent 99mTc-GSA scintigraphy and other liver function tests including ICG test and FIB-4 index prior to hepatectomy were studied. 99mTc-GSA imaging was performed with SPECT/CT scanner (Discovery NM/CT 670). Immediately after injection of 99mTc-GSA, dynamic imaging was performed for 20min, followed by SPECT data acquisition for 6min. LHL15 which is a conventional index by 99mTc-GSA planar images, and liver uptake ration (LUR) was measured from 99mTc-GSA SPECT images. From the liver resection specimens, the degree of liver fibrosis was graded according to the Ludwig scale (F0-4). Significant differences in LUR, LHL15, ICG-R15, ICG-K, platelet count and FIB-4 index were found between the F0-3 and F4 liver fibrosis patient groups (P < 0.05). Multivariate logistic regression analysis revealed that LUR and ICG-K were independent factors for identifying severe liver fibrosis (F4). Area under the curve of receiver operating curve analysis for the logistic regression model using LUR and ICG-K was 0.83. In the patient group with higher FIB-4 (≥ 3.16), the diagnostic performance of LUR for detecting severe liver fibrosis was significantly better than LHL15 (AUC: 0.83 vs. 0.75, P = 0.048). In the high FIB-4 index group, the sensitivity and specificity for identifying F4 was 88% and 85%, respectively, with LUR cutoff value of 41.2%. LUR, measured by 99mTc-GSA SPECT, is a useful indicator for identifying sever liver fibrosis. Particularly in patients with high FIB-4 index (≥ 3.16), LUR can be a valuable indicator to identify severe liver fibrosis with high diagnostic accuracy.

Associated Factors for Liver Fibrosis and Histological Activity Index in Treatment-Naïve HBeAg-Positive Chronic Hepatitis B Infection: Insights from a Retrospective Analysis.

The study aimed to identify predictors of advanced fibrosis score and histological activity index (HAI) in HBeAg-positive patients to facilitate early disease detection and reduce the need for invasive biopsies. The single-center retrospective study included treatment-naïve HBeAg-positive chronic hepatitis B (CHB) patients. Patients with HAI ≥6 and/or fibrosis ≥2 were considered to have significant liver damage. Independent determinants were identified by univariate and multivariate logistic regression analysis. Cut-off values for variables were determined by receiver operating characteristics (ROCs) curve analysis. The study enrolled a cohort of 66 patients, with 51.5% male and a median age of 26 (22.7-34.2) years. In assessing necroinflammation, no significant differences were observed in age and gender between patients with HAI <6 and HAI ≥6. However, patients with HAI ≥6 exhibited higher aspartate aminotransferase (AST) levels compared to those with HAI <6. Furthermore, lower albumin levels and platelet (PLT) counts, along with higher fibrosis-4 (FIB-4) scores, were associated with HAI ≥6. In the evaluation of fibrosis, while gender distribution did not differ significantly, patients with fibrosis grade ≥2 were older and had higher HAI scores, HAI ≥6 ratios, and FIB-4 scores compared to those with fibrosis grade <2. Multivariate analysis identified albumin as a significant predictor for both HAI ≥6 and fibrosis grade ≥2. The area under ROC (AUROC) values of albumin for predicting HAI ≥6 and fibrosis ≥2 were 0.696 and 0.698, respectively, indicating moderate predictive ability. Albumin was found to be an independent predictor of liver damage in HBeAg-positive CHB patients. The fact that the optimal threshold values detected for both HAI ≥6 and fibrosis ≥2 in this patient group were close to normal values suggests that clinicians should be more cautious in monitoring albumin levels and other pre-defined parameters to avoid delays in diagnosis.

Referral to hepatology is lower in patients with excessive alcohol use who have mental health disorders despite a high fibrosis-4 index.

Alcohol use disorder (AUD) is a multifaceted disease, and integration of AUD treatment between mental health and hepatology is necessary to improve outcomes. We aimed to ascertain whether patients with excessive alcohol use (EAU) and high FIB-4, which is a non-invasive method to identify advanced liver disease, are appropriately referred to hepatology and detect which clinical barriers, if any, might pertain. Records of patients with excessive alcohol use between 2013 and 2023 were extracted from a large public system. Demographics, alcohol-related hospitalizations, mental health conditions, Charlson comorbidity index (CCI) and referral patterns were evaluated. Comparisons were made between those referred to hepatology versus not. 1131 subjects showed evidence of EAU but on further review, 189 were in alcohol-remission. The remaining 942 (636 men, age 55.7 ± 14.5 years, 548 white, 363 black, 19 Hispanic) subjects with CCI 2.61 ± 2.23 were further analyzed for FIB-4 score and referral patterns. 316 patients had active EAU and a high FIB-4, of whom only 116 (37%) were referred to hepatology. Patients with alcohol-related mental health concerns and admitted for trauma were less likely to be referred. Logistic regression showed referral was higher with alcohol-related liver hospitalizations (OR: 9.25, 95% CI: 4.90-17.47, p < 0.001), higher CCI (OR: 6.23, 95% CI: 3.00-12.94, p < 0.0001) and lower with mental health admissions (OR: 0.36, 95% CI: 0.15-0.48, p < 0.001) or mental health diagnoses (OR: 0.36, 95% CI: 0.15-0.82, p = 0.02) and increasing age (OR: 0.95, 95% CI: 0.92-0.97, p < 0.001). In a large public health system, almost 63% of patients with EAU and FIB-4 >2.67 are not referred to hepatology for evaluation. Patients not referred were more likely to have alcohol-related mental-health hospitalizations and mental health diagnoses, while those with liver-related hospitalizations and comorbidities were more likely to be referred. Greater education of mental health providers and for teams taking care of inpatients admitted with alcohol-related mental health concerns would better integrate care and improve outcomes for patients with higher risk for advanced liver disease.

Fibrosis-4 Score Is Associated with Mortality in Hemodialysis Patients with Chronic Viral Hepatitis: A Retrospective Study.

Chronic hepatitis B and C infections are major causes of morbidity and mortality in end-stage kidney disease (ESKD) patients on hemodialysis (HD). The Fibrosis-4 (FIB-4) score is a non-invasive method to evaluate chronic liver disease. However, it is unclear whether there is a connection between the FIB-4 score and major adverse cardiovascular events (MACEs) and mortality in patients on HD. This study investigates the relationship between FIB-4 scores, MACEs, and mortality in HD patients. A 5-year retrospective study included 198 HD patients with chronic hepatitis B and C from Chang Gung Memorial Hospital. FIB-4 scores were categorized into high (>2.071), middle (1.030~2.071), and low (<1.030) tertiles for cross-sectional analyses. MACEs and mortality were tracked longitudinally. Patients with high FIB-4 scores had lower hemoglobin and albumin levels. Cox multivariate analysis showed that high FIB-4 scores (aHR: 1.589) and diabetes mellitus (aHR: 5.688) were significant factors for all-cause mortality. The optimal FIB-4 score for 5-year mortality was 2.942. FIB-4 scores were not significant for predicting 5-year MACEs. High FIB-4 scores are associated with increased 5-year all-cause mortality risk in HD patients with chronic hepatitis virus infection.

Characterizing outcomes in a large cohort of latinx patients with autoimmune hepatitis

Introduction and ObjectivesThis study aimed to characterize a large cohort of Latinx patients with autoimmune hepatitis (AIH) and analyze clinical outcomes, including biochemical remission, duration of steroid treatment, fibrosis regression, and incidence of clinical endpoints (hepatic decompensation, need for liver transplant, and death). Materials and MethodsThis was a retrospective descriptive study of patients with biopsy proven AIH (2009–2019) at a single urban center. Demographics, medical comorbidities, histology, treatment course, biochemical markers, fibrosis using dynamic non-invasive testing (NIT), and clinical outcomes at three months and at one, two, and three years were analyzed. Results121 adult patients with biopsy-proven AIH were included: 43 Latinx (35.5%) and 78 non-Latinx (65.5%). Latinx patients were more likely to have metabolic dysfunction-associated steatotic liver disease (MASLD) (p = 0.004), and had higher Fibrosis-4 (FIB-4) (p = 0.0279) and AST-to-Platelet-Ratio-Index (APRI) (p = 0.005) at one year. Latinx patients took longer to reach biochemical remission than non-Hispanic Whites (p = 0.031) and longer to stop steroids than non-Hispanic Blacks (p = 0.016). There were no significant differences based on ethnicity in histological fibrosis stage at presentation or incidence of clinical endpoints. ConclusionsMASLD overlap is highly prevalent in Latinx AIH patients. Longer time to biochemical remission and worse NITs support that this population may have slower fibrosis regression with standard of care AIH treatment. This may indicate differing response rates due to genetic polymorphisms affecting drug metabolism and immune response among Latinx individuals and is less likely related to AIH/MASLD overlap based on the findings of this study.

Reproducibility and Repeatability of US Shear-Wave and Transient Elastography in Nonalcoholic Fatty Liver Disease.

Background US shear-wave elastography (SWE) and vibration-controlled transient elastography (VCTE) enable assessment of liver stiffness, an indicator of fibrosis severity. However, limited reproducibility data restrict their use in clinical trials. Purpose To estimate SWE and VCTE measurement variability in nonalcoholic fatty liver disease (NAFLD) within and across systems to support clinical trial diagnostic enrichment and clinical interpretation of longitudinal liver stiffness. Materials and Methods This prospective, observational, cross-sectional study (March 2021 to November 2021) enrolled adults with NAFLD, stratified according to the Fibrosis-4 (FIB-4) index (≤1.3, >1.3 and <2.67, ≥2.67), at two sites to assess SWE with five US systems and VCTE with one system. Each participant underwent 12 elastography examinations over two separate days within 1 week, with each day's examinations conducted by a different operator. VCTE and SWE measurements were reported in units of meters per second. The primary end point was the different-day, different-operator reproducibility coefficient (RDCDDDO) pooled across systems for SWE and individually for VCTE. Secondary end points included system-specific RDCDDDO, same-day, same-operator repeatability coefficient (RCSDSO), and between-system same-day, same-operator reproducibility coefficient. The planned sample provided 80% power to detect a pooled RDCDDDO of less than 35%, the prespecified performance threshold. Results A total of 40 participants (mean age, 60 years ± 10 [SD]; 24 women) with low (n = 17), intermediate (n = 15), and high (n = 8) FIB-4 scores were enrolled. RDCDDDO was 30.7% (95% upper bound, 34.4%) for SWE and 35.6% (95% upper bound, 43.9%) for VCTE. SWE system-specific RDCDDDO varied from 24.2% to 34.3%. The RCSDSO was 21.0% for SWE (range, 13.9%-35.0%) and 19.6% for VCTE. The SWE between-system same-day, same-operator reproducibility coefficient was 52.7%. Conclusion SWE met the prespecified threshold, RDCDDDO less than 35%, with VCTE having a higher RDCDDDO. SWE variability was higher between different systems. These estimates advance liver US-based noninvasive test qualification by (a) defining expected variability, (b) establishing that serial examination variability is lower when performed with the same system, and (c) informing clinical trial design. ClinicalTrials.gov Identifier NCT04828551 © RSNA, 2024 Supplemental material is available for this article.

Is There a Link between Chronic Obstructive Pulmonary Disease and Lung Adenocarcinoma? A Clinico-Pathological and Molecular Study.

Chronic Obstructive Pulmonary Disease (COPD) and lung cancer are strictly related. To date, it is unknown if COPD-associated cancers are different from the tumors of non-COPD patients. The main goal of the study was to compare the morphological/molecular profiles of lung adenocarcinoma (LUAD) samples of COPD, non-COPD/smokers and non-COPD/non-smokers, and to investigate if a genetic instability also characterized non-pathological areas. This study included 110 patients undergoing surgery for a LUAD, divided into three groups: COPD/smoker LUAD (38), non-COPD/smoker LUAD (54) and non-COPD/non-smoker LUAD (18). The tissue samples were systemically evaluated by pathologists and analyzed using a 30-gene Next Generation Sequencing (NGS) panel. In a subset of patients, tissues taken far from the neoplasia were also included. The non-COPD/smoker LUAD were characterized by a higher proliferative index (p = 0.001), while the non-COPD/non-smoker LUAD showed higher percentages of lepidic pattern (p = 0.008), lower necrosis, higher fibrosis, and a significantly lower mutation rate in the KRAS and PIK3CA genes. Interestingly, the same gene mutations were found in pathological and normal areas exclusively in the COPD/smokers and non-COPD/smokers. COPD/smoker LUAD seem to be similar to non-COPD/smoker LUAD, particularly for the genetic background. A less aggressive cancer phenotype was confirmed in non-COPD/non-smokers. The genetic alterations detected in normal lungs from smokers with and without COPD reinforce the importance of screening to detect early neoplastic lesions.

Clinical Characteristics of Steatotic Liver Disease Categories in a Large Cohort of Japanese Health Checkup Participants

Background and AimsThe clinical characteristics and risk factors involved in the development of liver fibrosis in the subtypes of steatotic liver disease (SLD) remain unknown. We examined the clinical characteristics of SLD subtypes using a large Japanese cohort. MethodsWe performed a cross-sectional analysis (total n=108,446). In this cohort, SLD was diagnosed by ultrasonography. Individuals with none of the cardiometabolic risk factors were excluded. ResultsAccording to their NAFLD and metabolic dysfunction-associated SLD (MASLD) status based on the database, participants with cardiometabolic criteria were allocated to the MASLD, MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) with metabolic dysfunction groups. Of 30,857 subjects with SLD, 21,488 (69.6%) had nonalcoholic fatty liver disease (NAFLD), and 20,922 (67.8%) had MASLD. There were few differences in the clinical characteristics between NAFLD and MASLD. After adjustment for clinical variables, we found that male patients with MetALD [odds ratio (OR) 2.26; 95% confidence interval (CI) 1.87–2.84] and ALD with metabolic dysfunction (OR 3.92; 95% CI 2.85–5.39) had a significantly higher risk for advanced liver fibrosis (diagnosed by Fibrosis-4 (FIB-4) index >2.67) compared to those with MASLD. In female patients with ALD, metabolic dysfunction (OR 5.80; 95% CI 2.51–13.4) and systemic blood pressure of ≥130 mmHg were significant risk factors for high FIB-4 (males: OR 3.38, 95% CI 2.51–4.55; females: OR 4.34, 95% CI 2.66–7.07, P<0.001). ConclusionsAlcohol intake and systolic blood pressure are independent contributors to liver fibrosis progression assessed by FIB-4 in SLD.

Value of CT quantification in progressive fibrosing interstitial lung disease: a deep learning approach.

To evaluate the relationship of changes in the deep learning-based CT quantification of interstitial lung disease (ILD) with changes in forced vital capacity (FVC) and visual assessments of ILD progression, and to investigate their prognostic implications. This study included ILD patients with CT scans at intervals of over 2 years between January 2015 and June 2021. Deep learning-based texture analysis software was used to segment ILD findings on CT images (fibrosis: reticular opacity + honeycombing cysts; total ILD extent: ground-glass opacity + fibrosis). Patients were grouped according to the absolute decline of predicted FVC (< 5%, 5-10%, and ≥ 10%) and ILD progression assessed by thoracic radiologists, and their quantification results were compared among these groups. The associations between quantification results and survival were evaluated using multivariable Cox regression analysis. In total, 468 patients (239 men; 64 ± 9.5 years) were included. Fibrosis and total ILD extents more increased in patients with larger FVC decline (p < .001 in both). Patients with ILD progression had higher fibrosis and total ILD extent increases than those without ILD progression (p < .001 in both). Increases in fibrosis and total ILD extent were significant prognostic factors when adjusted for absolute FVC declines of ≥ 5% (hazard ratio [HR] 1.844, p = .01 for fibrosis; HR 2.484, p < .001 for total ILD extent) and ≥ 10% (HR 2.918, p < .001 for fibrosis; HR 3.125, p < .001 for total ILD extent). Changes in ILD CT quantification correlated with changes in FVC and visual assessment of ILD progression, and they were independent prognostic factors in ILD patients. Quantifying the CT features of interstitial lung disease using deep learning techniques could play a key role in defining and predicting the prognosis of progressive fibrosing interstitial lung disease. • Radiologic findings on high-resolution CT are important in diagnosing progressive fibrosing interstitial lung disease. • Deep learning-based quantification results for fibrosis and total interstitial lung disease extents correlated with the decline in forced vital capacity and visual assessments of interstitial lung disease progression, and emerged as independent prognostic factors. • Deep learning-based interstitial lung disease CT quantification can play a key role in diagnosing and prognosticating progressive fibrosing interstitial lung disease.

Diagnostic performance of non-invasive tests in patients with MetALD in a health check-up cohort

Non-invasive tests (NITs) for liver fibrosis have been recognized for their clinical utility in metabolic dysfunction-associated steatotic liver disease (MASLD). However, their diagnostic efficacy in detecting liver fibrosis is notably reduced in patients with alcohol-related liver disease. Therefore, ascertaining the reliability of NITs in patients with MASLD with moderate alcohol intake (MetALD) is essential. In this cross-sectional study, we reviewed data from 7,918 health check-up participants who underwent both magnetic resonance elastography (MRE) and ultrasound for the diagnosis of hepatic steatosis. The participants were categorized into MASLD and MetALD groups, and the performance of fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were assessed. Advanced hepatic fibrosis (F3) was defined as MRE ≥3.6kPa. The prevalence of MetALD was 5.8% in this health check-up cohort, and 1.5% of these patients exhibited advanced hepatic fibrosis. Both MetALD and MASLD displayed similar metabolic profiles and hepatic fibrosis burdens. The diagnostic performance of FIB-4 and NFS for MRE ≥3.6kPa showed no noticeable differences in the area under the receiver-operating characteristic values between the two groups (0.85 vs. 0.80 in FIB-4). Moreover, the sensitivity (71.4%), specificity (77.3%), and both positive (4.6%) and negative (99.4%) predictive values of NITs for MetALD closely mirrored those observed for MASLD. FIB-4 performed well for the initial screening of advanced hepatic fibrosis in MetALD, demonstrating reasonable sensitivity and negative predictive values. In this cross-sectional study, data from 7,918 participants who underwent MRE were analyzed to assess the performance of fibrosis-4 (FIB-4) and non-alcoholic fatty liver disease fibrosis scores in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with moderate alcohol intake (MetALD). We found that FIB-4 had high diagnostic accuracy in the newly identified MetALD group, similar to that in the MASLD population. These results highlight the potential of FIB-4 as a reliable screening tool for MetALD, even when specific subgroups are considered. Therefore, FIB-4 is a valuable screening tool for identifying advanced fibrosis in the MetALD population.

A Possible Reversible Cause of Cognitive Impairment: Undiagnosed Cirrhosis and Potential Hepatic Encephalopathy in Patients with Dementia

BackgroundDementia and hepatic encephalopathy (HE) have symptom overlap and are challenging to differentiate. The presence of undiagnosed cirrhosis may lead to missed opportunities to treat HE, which was found in a veterans database. This needs validation in a non-veteran cohort. MethodsA retrospective cohort study was conducted between 2009 and 2019 using national non-Veteran patient data from the multi-center TriNetX database. Participants included 68,807 patients with a dementia diagnosis at ≥2 visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) index, which indicates liver disease. Prevalences of high FIB-4 scores (>2.67 and >3.25) were measured within the cohort, and associations between high FIB-4 and comorbidities/demographics were examined. ResultsWithin the cohort (44.7% male, 78.0% White, mean age 72.73 years (±11.09), 7.6% (n = 5815) had a FIB-4 index > 3.25 and 12.8% (n = 8683) had FIB-4 > 2.67. In multivariable logistic regression models, FIB-4 > 3.25 was associated with male gender (OR: 1.42 [1.33-1.51]), congestive heart failure (OR: 1.73 [1.59-1.87]), viral hepatitis (OR: 2.23 [1.84-2.68]), alcohol use disorder (OR: 1.39 [1.22-1.58]), and chronic kidney disease (OR: 1.38 [1.28-1.48]), and inversely associated with White race (OR: 0.76 [0.71-0.82]) and diabetes (OR: 0.82 [0.77-0.88]). Similar findings were associated with the FIB-4 > 2.67 threshold. ConclusionThe findings of this national cohort suggest that the FIB-4 index could be utilized to screen for potential undiagnosed cirrhosis in patients with dementia, and that hepatic encephalopathy might be misdiagnosed as dementia or cause worsening of cognitive function in patients with dementia.

Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD.

There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events. We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy. Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events. Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.

A High Fibrosis-4 Index is Associated with a Reduction in the Estimated Glomerular Filtration Rate in Non-obese Japanese Patients with Type 2 Diabetes Mellitus.

Liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD), and one of the most important risk factors for NAFLD is type 2 diabetes (T2DM). The Fibrosis-4 (FIB-4) index, a noninvasive liver fibrosis score, has been found to be useful for estimating liver fibrosis. Because individuals with non-obese NAFLD were recently reported to be metabolically unhealthy and have a higher risk of T2DM than individuals with obese NAFLD, we hypothesized that the clinical factors related to a high FIB-4 index would differ between non-obese and obese Japanese T2DM patients. Accordingly, we examined the relationship between clinical factors and the FIB-4 index in non-obese and obese Japanese patients with T2DM. We divided 265 patients into two groups by BMI level - a non-obese group (n = 149) and an obese group (n = 116) - and examined the correlation between the FIB-4 index and clinical parameters. Single regression analysis revealed that a high FIB-4 index was correlated with a reduction in the estimated glomerular filtration rate and hypertension in the non-obese group. Importantly, multiple regression analysis showed that only a reduction in the estimated glomerular filtration rate was significantly associated with a high FIB-4 index in the non-obese group. These results demonstrated that non-obese T2DM patients with a high FIB-4 index might be at risk of kidney dysfunction. Our findings may enable the more appropriate treatment of T2DM patients based on BMI level.

Advanced liver fibrosis is associated with decreased gait speed in older patients with chronic liver disease

This study investigated whether the progression of liver fibrosis affects the prevalence of sarcopenia and incidence of decreased gait speed in older patients with chronic liver disease (CLD). Patients with CLD aged ≥ 60 years were classified into low, intermediate, and high fibrosis 4 (FIB-4) index groups according to the degree of liver fibrosis. The prevalence of sarcopenia and incidence of decreased gait speed (< 1.0 m/s) were compared among the three groups. Logistic regression analysis was performed to investigate factors affecting the risk of decreased gait speed. No significant difference was observed in the prevalence of sarcopenia among the three groups, but the incidence of decreased gait speed significantly differed (p = 0.029). When analyzed individually, a significant difference in decreased gait speed incidence was observed between the high and low FIB-4 index groups (p = 0.014). In logistic regression analysis, the progression of liver fibrosis (odds ratio: 1.32, 95% confidence interval: 1.13–1.55) and lower extremity muscle strength (LEMS) (odds ratio: 0.92, 95% confidence interval: 0.88–0.97) were significantly associated with decreased gait speed. As liver fibrosis progresses in older patients with CLD, it becomes important to focus on not only skeletal muscle mass and grip strength, but also gait speed and LEMS.

Undiagnosed Cirrhosis and Hepatic Encephalopathy in a National Cohort of Veterans With Dementia

Dementia and hepatic encephalopathy (HE) are challenging to distinguish clinically. Undiagnosed cirrhosis in a patient with dementia can lead to missed opportunities to treat HE. To examine the prevalence and risk factors of undiagnosed cirrhosis and therefore possible HE in veterans with dementia. A retrospective cohort study was conducted between 2009 and 2019 using data from the Veterans Health Administration (VHA) and 2 separate validation cohorts from the Richmond Veterans Affairs Medical Center. Data analysis was conducted from May 20 to October 15, 2023. Participants included 177 422 US veterans with a diagnosis of dementia at 2 or more clinic visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the Fibrosis-4 (FIB-4) score. Demographic and clinical characteristics. An FIB-4 score (>2.67 suggestive of advanced fibrosis and >3.25 suggestive of cirrhosis), capped at age 65 years even for those above this cutoff who were included in the analysis. Among 177 422 veterans (97.1% men; 80.7% White; mean (SD) age, 78.35 [10.97] years) 5.3% (n = 9373) had an FIB-4 score greater than 3.25 and 10.3% (n = 18 390) had an FIB-4 score greater than 2.67. In multivariable logistic regression models, FIB-4 greater than 3.25 was associated with older age (odds ratio [OR], 1.07; 95% CI, 1.06-1.09), male gender (OR, 1.43; 95% CI, 1.26-1.61), congestive heart failure (OR, 1.48; 95% CI, 1.43-1.54), viral hepatitis (OR, 1.79; 95% CI, 1.66-1.91), Alcohol Use Disorders Identification Test score (OR, 1.56; 95% CI, 1.44-1.68), and chronic kidney disease (OR, 1.11; 95% CI, 1.04-1.17), and inversely associated with White race (OR, 0.79; 95% CI, 0.73-0.85), diabetes (OR, 0.78; 95% CI, 0.73-0.84), hyperlipidemia (OR, 0.84; 95% CI, 0.79-0.89), stroke (OR, 0.85; 95% CI, 0.79-0.91), tobacco use disorder (OR, 0.78; 95% CI, 0.70-0.87), and rural residence (OR, 0.92; 95% CI, 0.87-0.97). Similar findings were associated with the FIB-4 greater than 2.67 threshold. These codes were associated with cirrhosis on local validation. A local validation cohort of patients with dementia showed a similar percentage of high FIB-4 scores (4.4%-11.2%). The findings of this cohort study suggest that clinicians encountering patients with dementia should be encouraged to screen for cirrhosis using the FIB-4 score to uncover reversible factors associated with cognitive impairment, such as HE, to enhance outcomes.

Comparison of all-cause mortality associated with non-alcoholic fatty liver disease and metabolic dysfunction-associated fatty liver disease in Taiwan MJ cohort.

The global burden of non-alcoholic fatty liver disease (NAFLD) is rising. An alternative term, metabolic dysfunction-associated fatty liver disease (MAFLD), instead highlights the associated metabolic risks. This cohort study examined patient classifications under NAFLD and MAFLD criteria and their associations with all-cause mortality. Participants who attended a paid health check-up (2012-2015) were included. Hepatic steatosis (HS) was diagnosed ultrasonographically. NAFLD was defined as HS without secondary causes, while MAFLD involved HS with overweight/obesity, type 2 diabetes mellitus, or ≥2 metabolic dysfunctions. Mortality was tracked via the Taiwan Death Registry until November 30, 2022. Of 118,915 participants, 36.9% had NAFLD, 40.2% had MAFLD, and 32.9% met both definitions. Participants with NAFLD alone had lower mortality, and those with MAFLD alone had higher mortality, than individuals with both conditions. After adjustment for potential confounders, the hazard ratios (HRs) for all-cause mortality were 1.08 (95% confidence interval [CI], 0.78 to 1.48) for NAFLD alone and 1.26 (95% CI, 1.09 to 1.47) for MAFLD alone, relative to both conditions. Advanced fibrosis conferred greater mortality risk, with HRs of 1.93 (95% CI, 1.44 to 2.58) and 2.08 (95% CI, 1.61 to 2.70) for advanced fibrotic NAFLD and MAFLD, respectively. Key mortality risk factors for NAFLD and MAFLD included older age, unmarried status, higher body mass index, smoking, diabetes mellitus, chronic kidney disease, and advanced fibrosis. All-cause mortality in NAFLD and/or MAFLD was linked to cardiometabolic covariates, with risk attenuated after multivariable adjustment. A high fibrosis-4 index score, indicating fibrosis, could identify fatty liver disease cases involving elevated mortality risk.

Biomarkers of fibrosis and portal hypertension in Fontan-associated liver disease in children and adults

BackgroundFontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD. AimInvestigate biomarkers correlating with severity of liver biopsy fibrosis in FALD. MethodsA retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores. ResultsSixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa. ConclusionsAPRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients.

Potential role of Fibrosis-4 score in hepatocellular carcinoma screening: The Kangbuk Samsung Health Study.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death, with low survival rates worldwide. Fatty liver disease (FLD) significantly contributes to HCC. We studied the screening performance of different methods for identifying HCC in patients with FLD or with metabolic risk factors for FLD. Korean adults (n=340825) without a prior HCC diagnosis were categorized into four groups: normal (G1), ≥2 metabolic risk factors (G2), FLD (G3), and viral liver disease or liver cirrhosis (G4). The National Cancer Registry data were used to identify HCC cases within 12months. We assessed the area under the receiver operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of individual or combined screening methods. In 93 HCC cases, 71 were identified in G4, whereas 20 cases (21.5%) in G2 and G3 combined where ultrasound and Fibrosis-4 performed similarly to alpha-fetoprotein and ultrasound. In G2, Fibrosis-4 and ultrasound had the highest area under the receiver operating characteristic curve (0.93 [0.87-0.99]), whereas in G3, the combined screening methods had the highest area under the receiver operating characteristic curve (0.98 [0.95-1.00]). The positive predictive value was lower in G2 and G3 than in G4, but was >5% when restricted to a high Fibrosis-4 score. More than 21% of HCC cases were observed in patients with diagnosed FLD or at risk of FLD with metabolic risk factors. Nevertheless, screening for HCC in individuals without cirrhosis or viral hepatitis yielded very low results, despite the potential value of the Fibrosis-4 score in identifying individuals at high risk of HCC.