BACKGROUND: Cleavage products from collagen formation and degradation hold potential as first-line biomarkers for the risk of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we evaluated the performance of PRO-C3, PRO-C6, C4M, PRO-C18L, and the clinical score ADAPT (age, diabetes, PRO-C3, and platelet count) to detect patients with an LSM >8 kPa or >12 kPa in comparison to the Fibrosis-4 Index (FIB-4).
METHODS: Serum from patients with MASLD (n = 269) from six Swedish University Hospitals was analyzed using enzyme-linked immunosorbent assay-based methods. Liver stiffness measurement (LSM) by vibration-controlled transient elastography was performed. The area under the curve (AUC), calibration curves, and net benefit analysis were used.
RESULTS: An LSM >8 kPa was found in 108 (40.1%) patients. PRO-C3, PRO-C6, C4M, and PRO-C18L had AUCs ranging from 0.48 to 0.62. ADAPT had the highest AUC (0.73, 95% confidence interval [CI] = 0.67-0.79) to detect patients >8 kPa, compared to FIB-4 (0.71, (95%CI = 0.64-0.77, p = 0.35), and had a higher net benefit compared to FIB-4 from a probability threshold of 15%. FIB-4 and ADAPT performed equally well to detect patients with an LSM >12 kPa, AUC 0.76 versus 0.76, p = 0.93.
CONCLUSIONS: ADAPT seems to be marginally better than FIB-4 in identifying patients with an LSM >8 kPa. However, the clinical utility of ADAPT as a first line test is uncertain, especially in low-risk populations. The overall performance of FIB-4 was similar to that of ADAPT in detecting patients with an LSM of >12 kPa. Altogether, the results suggest that ADAPT might be useful to detect earlier stages of fibrosis in MASLD, but that FIB-4 remains a first-line test for advanced fibrosis.

The progressive use of noninvasive tests (NITs) has changed the way hepatologists diagnose and manage patients with chronic liver disease, mainly because of their easiness to use and the ability to be repeated during follow-up. Liver stiffness measurement is the NIT with more scientific evidence. NITs have demonstrated to be useful to detect not only liver fibrosis but also the presence of clinically significant portal hypertension. Moreover, current evidence supports they can also be useful to evaluate the prognosis of patients with chronic liver disease.

OBJECTIVE: Noninvasive 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 increased alcohol intake (MetALD) is essential.
METHODS: 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 (FIB-4) and NAFLD fibrosis score (NFS) were assessed. Advanced hepatic fibrosis (F3) was defined as MRE ≥ 3.6 kPa.
RESULTS: 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 ≥ 3.6 kPa 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.
CONCLUSIONS: The newly defined MetALD exhibited a high FIB-4 performance, demonstrating reasonable sensitivity and negative predictive value for the initial screening of advanced hepatic fibrosis in MetALD.
UNASSIGNED: 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 nonalcoholic fatty liver disease fibrosis scores in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with increased alcohol intake (MetALD). We found that the newly identified MetALD group had high diagnostic accuracy with FIB-4, similar to 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.

The screening of colorectal cancer (CRC) is pivotal for both the prevention and treatment of this disease, significantly improving early-stage tumor detection rates. This advancement not only boosts survival rates and quality of life for patients but also reduces the costs associated with treatment. However, the adoption of CRC screening methods faces numerous challenges, including the technical limitations of both noninvasive and invasive methods in terms of sensitivity and specificity. Moreover, socioeconomic factors such as regional disparities, economic conditions, and varying levels of awareness affect screening uptake. The coronavirus disease 2019 pandemic further intensified these cha-llenges, leading to reduced screening participation and increased waiting periods. Additionally, the growing prevalence of early-onset CRC necessitates innovative screening approaches. In response, research into new methodologies, including artificial intelligence-based systems, aims to improve the precision and accessibility of screening. Proactive measures by governments and health organizations to enhance CRC screening efforts are underway, including increased advocacy, improved service delivery, and international cooperation. The role of technological innovation and global health collaboration in advancing CRC screening is undeniable. Technologies such as artificial intelligence and gene sequencing are set to revolutionize CRC screening, making a significant impact on the fight against this disease. Given the rise in early-onset CRC, it is crucial for screening strategies to continually evolve, ensuring their effectiveness and applicability.

BACKGROUND: People with compensated cirrhosis receive the greatest benefit from risk factor modification and prevention programs to reduce liver decompensation and improve early liver cancer detection. Blood-based liver fibrosis algorithms such as the Aspartate Transaminase-to-Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) index are calculated using routinely ordered blood tests and are effective screening tests to exclude cirrhosis in people with chronic liver disease, triaging the need for further investigations to confirm cirrhosis and linkage to specialist care.
OBJECTIVE: This pilot study aims to evaluate the impact of a population screening program for liver cirrhosis (CAPRISE [Cirrhosis Automated APRI and FIB-4 Screening Evaluation]), which uses automated APRI and FIB-4 calculation and reporting on routinely ordered blood tests, on monthly rates of referral for transient elastography, cirrhosis diagnosis, and linkage to specialist care.
METHODS: We have partnered with a large pathology service in Victoria, Australia, to pilot a population-level liver cirrhosis screening package, which comprises (1) automated calculation and reporting of APRI and FIB-4 on routinely ordered blood tests; (2) provision of brief information about liver cirrhosis; and (3) a web link for transient elastography referral. APRI and FIB-4 will be prospectively calculated on all community-ordered pathology results in adults attending a single pathology service. This single-center, prospective, single-arm, pre-post study will compare the monthly rates of transient elastography (FibroScan) referral, liver cirrhosis diagnosis, and the proportion linked to specialist care in the 6 months after intervention to the 6 months prior to the intervention.
RESULTS: As of January 2024, in the preintervention phase of this study, a total of 120,972 tests were performed by the laboratory. Of these tests, 78,947 (65.3%) tests were excluded, with the remaining 42,025 (34.7%) tests on 37,872 individuals meeting inclusion criteria with APRI and FIB-4 being able to be calculated. Of these 42,025 tests, 1.3% (n=531) had elevated APRI>1 occurring in 446 individuals, and 2.3% (n=985) had elevated FIB-4>2.67 occurring in 816 individuals. Linking these data with FibroScan referral and appointment attendance is ongoing and will continue during the intervention phase, which is expected to commence on February 1, 2024.
CONCLUSIONS: We will determine the feasibility and effectiveness of automated APRI and FIB-4 reporting on the monthly rate of transient elastography referrals, liver cirrhosis diagnosis, and linkage to specialist care.
BACKGROUND: Australian New Zealand Clinical Trials Registry ACTRN12623000295640; https://tinyurl.com/58dv9ypp.
UNASSIGNED: DERR1-10.2196/56607.

Accurate diagnosis and staging of liver fibrosis is crucial to the individualized management of patients with chronic liver disease. Liver biopsy remains the reference standard for the assessment of steatosis, necroinflammation, and fibrosis. However, over the past decade, there has been an exponential growth in noninvasive tests (NITs) designed to assess liver fibrosis and steatosis. These NITs range from serum biomarkers to imaging assessments of liver tissue stiffness. Current noninvasive methods overcome the limitations of non-specific laboratory markers, conventional imaging, and invasive procedures, and are now starting to be adopted. The Fibrosis-4 index, Enhanced Liver Fibrosis test, and elastography have gained the strongest clinical footholds for the diagnosis of advanced fibrosis. There remains significant interest in demonstrating superiority of any specific test or, alternatively, optimizing a sequential algorithm to provide the most accurate diagnosis of fibrosis staging. This article reviews currently available noninvasive methods for assessing liver fibrosis and steatosis.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is believed to be the most common chronic liver disease worldwide. Therapies are under development for nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, such that the prevalence of NASH with liver fibrosis, which is likely to require treatment, may be of interest to healthcare decision makers. Noninvasive tests are used in initial screening for NASH, as well as in observational studies of NASH prevalence. However, existing evidence does not address how estimated prevalence varies with different noninvasive tests. This analysis estimated the prevalence of NASH among US adults and assessed variation with different noninvasive tests. Methods: A cross-sectional analysis was conducted using the 2017-March 2020 National Health and Nutrition Examination Survey cycle. Participants with presumed NAFLD (steatosis and without alternative causes of liver disease) were identified, among whom NASH was predicted based on FAST score, Fibrosis-4 (FIB-4), and AST-to-Platelet Ratio Index (APRI) cutoffs across 11 scenarios. Among NASH participants, fibrosis stages were explored based on distribution across the spectrum of liver-stiffness measurements. Results: Among participants with complete data for the analysis (N=6969), prevalence of presumed NAFLD was 25.6%. Within presumed NAFLD, prediction of NASH using imaging-based NIT cutoffs yielded estimated prevalence of 1.3%-4.8% (3.3 million-12.2 million) based on FAST score cutoffs from 0.35-0.67. Using biomarker-based NIT cutoffs yielded estimated prevalence of 0.4%-12.3% (1.0 million-14.5 million) based on FIB-4 cutoffs from 0.90-2.67, and 0.1%-1.9% (0.2-5.0 million) based on APRI cutoffs from 0.50-1.50. Conclusion: Prevalence of NASH among US adults was estimated to range from 1.3% to 4.8% when predicted using imaging-based noninvasive test values for participants with presumed NAFLD, generally aligning with estimates in the literature of prevalence of biopsy-confirmed NASH. Use of biomarker-based noninvasive test values for prediction of NASH yielded a wider range of estimates with FIB-4, and a considerably lower range of estimates with APRI.

OBJECTIVE: Clinical guidelines have expanded the indications for nonalcoholic fatty liver disease (NAFLD) screening to type 2 diabetes mellitus and obesity, which are conditions common in populations who receive care in urban safety-net settings. This study aimed to evaluate safety-net primary care and endocrinology clinicians\' knowledge of NAFLD, determine barriers and facilitators to screening, and examine perspectives on the use of electronic health record tools for risk assessment.
METHODS: Sequential explanatory mixed methods using survey and qualitative interviews with primary care, primary care subspecialty, and endocrinology clinicians in an urban safety-net health care system.
RESULTS: A total of 109 participants completed the survey (36.5% response rate), and 13 participated in interviews. Most respondents underestimated or did not know the prevalence of NAFLD (68%), did not use the recommended noninvasive tests for risk stratification (65%), and few were comfortable with screening for (27%) or managing (17%) NAFLD. Endocrinologists had greater knowledge of risk factors but lower rates of comfort and more often felt that screening was not their responsibility. The qualitative themes included the following: (1) lack of knowledge about screening, (2) concern for underdiagnosing NAFLD, (3) perception of severity impacts beliefs about screening, (4) screening should occur in primary care but is not normative practice, (5) concerns exist about benefit, (6) competing demands with a complex population hinder screening, and (7) a need for easier ways to integrate screening into practice.
CONCLUSIONS: Knowledge gaps may hamper uptake of new guidelines for NAFLD screening in primary care and endocrinology clinics in an urban safety-net health care system. Implementation strategies focused on training and educating clinicians and informed by behavioral economics may increase screening.

OBJECTIVE: The diagnostic performance of the Fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is poor in patients with type 2 diabetes mellitus (T2DM). We determined the usefulness of the Enhanced Liver Fibrosis (ELF) test in patients with T2DM.
METHODS: A total of 1228 patients with biopsy-proven NAFLD were enrolled. The diagnostic performance of the ELF test for predicting advanced fibrosis in participants with or without T2DM was evaluated in comparison with the FIB-4 index and NFS.
RESULTS: Overall, the area under the curve of the ELF test for predicting advanced fibrosis was greater (0.828) than that of the FIB-4 index (0.727) and NFS (0.733). The diagnostic performance of the ELF test (area under the curve, 0.820) was also superior to that of the FIB-4 index (0.698) and NFS (0.700) in patients with T2DM. With the low cutoff values for each noninvasive test, the ELF test provided an acceptable false negative rate (cutoff value 9.8, 6.7%) in this population, unlike the FIB-4 index (1.30, 14.5%) and NFS (-1.455, 12.4%). After propensity score matching to avoid selection bias including age, sex, body mass index, and the prevalence of advanced fibrosis, the ELF test with a low cutoff value showed a high sensitivity (≥91.4%) and a high negative predictive value (≥96.8%), irrespective of the presence or absence of T2DM.
CONCLUSIONS: The high diagnostic performance of the ELF test for predicting advanced fibrosis in individuals with or without T2DM could address an unmet medical need for accurate assessment of liver fibrosis in patients with diabetes and NAFLD.

Metabolic-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), has emerged as a prominent global cause of chronic liver disease and is increasingly recognized as associated with atherosclerotic vascular illness, consolidating its position along traditional cardiovascular risk factors. Individuals with MASLD exhibit a combination of metabolic syndrome risk factors, carotid atherosclerosis, and increased arterial stiffness, hinting at shared pathogenesis. In this study, we aim to explore liver involvement and arterial stiffness within metabolic syndrome. We enrolled 75 patients (30 male and 45 female) with either liver steatosis on conventional ultrasound, altered liver function tests, or the presence of cardiometabolic risk factors after excluding liver pathology other than MASLD. Clinical evaluation, laboratory measurements, abdominal and carotid ultrasounds, vibration-controlled transient elastography (VCTE, Fibroscan), and assessment with the Arteriograph (Tensiomed) were performed. The 26 patients diagnosed with MetS had significantly higher liver involvement as quantified via the hepatic steatosis index (HSI), Fibrosis-4 (FIB4), aspartate aminotransferase to platelet ratio index (APRI) category, and VCTE measurements, as well as Agile 3+ and Agile 4 scores which use a combination of clinical and laboratory parameters together with results obtained from VCTE to reflect the probability of advanced liver fibrosis or cirrhosis. Patients with MetS also exhibited more pronounced vascular involvement as quantified via arterial stiffness measurements and CIMT (carotid intima-media thickness). We applied a two-step clustering algorithm to enhance our analysis, which gave us pertinent insight into the interplay between metabolic syndrome elements and typologies of hepatic steatosis and arterial stiffness degrees. Notably, of the three obtained clusters, the cluster showing increased levels of hepatic steatosis and arterial stiffness also exhibited the highest prevalence of metabolic syndrome and its constituting components. The results have significant clinical implications, advocating for a comprehensive diagnostic approach when MetS or MASLD is suspected.