Performance of novel collagen turnover biomarkers to detect increased liver stiffness in MASLD.

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.

Diagnostic Performance of Noninvasive Tests in Patients with MetALD in a Health Check-up Cohort.

BACKGROUND AND AIMS: 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. CONCLUSION: 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. IMPACT AND IMPLICATIONS: 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.

Noninvasive Assessment of Portal Hypertension.

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.

Colorectal cancer screening: The value of early detection and modern challenges.

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.

Impact of an Automated Population-Level Cirrhosis Screening Program Using Common Pathology Tests on Rates of Cirrhosis Diagnosis and Linkage to Specialist Care (CAPRISE): Protocol for a Pilot Prospective Single-Arm Intervention Study.

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. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12623000295640; https://tinyurl.com/58dv9ypp. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56607.

Noninvasive Methods for Assessing Liver Fibrosis and Steatosis.

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.

Prevalence of Nonalcoholic Steatohepatitis and Associated Fibrosis Stages Among US Adults Using Imaging-Based vs Biomarker-Based Noninvasive Tests.

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.

Safety-Net Primary Care and Endocrinology Clinicians' Knowledge and Perspectives on Screening for Nonalcoholic Fatty Liver Disease: A Mixed-Methods Evaluation.

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. CONCLUSION: 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.

Accuracy of the Enhanced Liver Fibrosis Test in Patients With Type 2 Diabetes Mellitus and Its Clinical Implications.

BACKGROUND AND AIMS: 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.

Interactions between Metabolic Syndrome, MASLD, and Arterial Stiffening: A Single-Center Cross-Sectional Study.

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.

A Cross-sectional Real-life Study of the Prevalence, Severity, and Determinants of Metabolic Dysfunction-associated Fatty Liver Disease in Type 2 Diabetes Patients.

Background and Aims: Most data on liver assessment in type 2 diabetes mellitus (T2DM) patients are from retrospective cohorts with selection bias. We aimed at appraising the feasibility, results, and benefits of an outpatient systematic noninvasive screening for metabolic dysfunction-associated fatty liver disease (MAFLD) severity and determinants in T2DM patients. Methods: We conducted a 50-week cross-sectional study enrolling adult T2DM outpatients from a diabetes clinic. An algorithm based on guidelines was applied using simple bioclinical scores and, if applicable, ultrasound and/or elastometry. Results: Two hundred and thirteen patients were included. Mean age and body mass index were 62 years and 31 kg/m2 and 29% of patients had abnormal transaminase levels. The acceptance rate of additional liver examinations was 92%. The prevalence of MAFLD, advanced fibrosis and cirrhosis was 87%, 11%, and 4%, respectively. More than half of the cases of advanced fibrosis had not been suspected and were detected by this screening. MAFLD was associated with poor glycemic control, elevated transaminases, low HDL-C and the absence of peripheral arterial disease. Advanced fibrosis was linked to high waist circumference and excessive alcohol consumption, which should be interpreted with caution owing to the small number of patients reporting excessive consumption. Conclusions: Simple bioclinical tools allowed routine triage of T2DM patients for MAFLD severity, with high adherence of high-risk patients to subsequent noninvasive exams.

Identification of High-Risk Patients With Nonalcoholic Fatty Liver Disease in Endocrinology Clinics.

The twin epidemics of obesity and type 2 diabetes continue to increase worldwide, so does the associated chronic liver disease, nonalcoholic fatty liver disease (NAFLD). Although NAFLD has been thought of as a benign liver disease, current evidence suggests that it is a complex liver disease that, for approximately 20% of patients, can progress to fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant, and death. It is important to note that, given NAFLD's association with metabolic syndrome, the number one cause of death among those with NAFLD is related to cardiovascular diseases. In addition, NAFLD is associated with impaired patient-reported outcomes and a significant economic burden. As such, efforts are now aimed at using noninvasive tests (NITs) to identify patients with NAFLD and those who are at risk of liver disease progression and adverse outcomes in endocrinology practices whereby appropriate risk stratification and referrals can be undertaken. In this review, we discuss the most common NITs used and provide a simple clinically relevant algorithm using these NITs to identify patients with NAFLD who are at risk of adverse outcomes and subsequent clinical management and referral.

Canagliflozin and Metabolic Associated Fatty Liver Disease in Patients With Diabetes Mellitus: New Insights From CANVAS.

CONTEXT: Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent among patients with type 2 diabetes mellitus (T2DM); however, there is still no approved pharmacological treatment. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been suggested to beneficially modify liver-related outcomes in patients with diabetes. OBJECTIVE: We aimed to investigate the effects of the SGLT-2 inhibitor canagliflozin on liver-related outcomes in patients with advanced T2DM and high cardiovascular risk. METHODS: We performed a secondary post hoc analysis of 2 large double-blind randomized controlled trials, CANVAS (NCT01032629) and CANVAS-R (NCT01989754), which included patients with T2DM and high cardiovascular risk who were randomized to receive either canagliflozin or placebo once daily. The primary endpoint was a composite of improvement of alanine aminotransferase (ALT) levels >30% or normalization of ALT levels. Secondary endpoints included change in noninvasive tests of fibrosis and weight reduction of >10%. RESULTS: In total, 10 131 patients were included, with a median follow-up of 2.4 years (mean age 62 years; mean duration of diabetes 13.5 years; 64.2% male). Of those patients, 8967 (88.5%) had MAFLD according to hepatic steatosis index and 2599 (25.7%) exhibited elevated liver biochemistry at baseline. The primary composite endpoint occurred in 35.2% of patients receiving canagliflozin and in 26.4% with placebo (adjusted odds ratio [aOR] 1.51; 95% CI, 1.38-1.64; P < .001). Canagliflozin led to improvements in some noninvasive tests of fibrosis (NFS, APRI, FNI). Significant weight reduction of >10% (within 6 years) was achieved in 12.7% with canagliflozin compared to 4.1% with placebo (aOR 3.45; 95% CI, 2.91-4.10; P < .001). CONCLUSION: In patients with T2DM, treatment with canagliflozin vs placebo resulted in improvements in liver biochemistry and metabolism and might beneficially affect liver fibrosis.

Investigation of liver fibrosis with serum biochemical parameters before treatment with direct-acting antivirals, at the end of treatment, and in the first and third year after treatment in patients with chronic hepatitis C.

Aim of the study: In the treatment of chronic hepatitis C, the need for non-invasive methods, other than invasive methods, is increasing for the detection of fibrosis before and after treatment. In our study, we aimed to determine the changes in histological response with post-treatment biochemical scoring in patients treated with direct-acting antivirals. Material and methods: Between June 1, 2016, and January 1, 2020, 125 patients followed up with a diagnosis of chronic hepatitis C, who presented to Haseki Training and Research Hospital, were enrolled in the study. Scores of APRI, Fibro Q, Fibrosis-4 (FIB-4) index, Doha score, Fibro alpha, and fibrosis-cirrhosis index were used to evaluate the liver fibrosis of the patients with examinations before treatment, at the end of treatment and at the 12th week, first year, and third year after treatment. The study was conducted as a retrospective observational case series. Results: One hundred twenty-five patients were enrolled in the study. The mean age was 55.5 ±15.9 years. Patients were divided into two groups according to their baseline FIB-4 values: cirrhotic/noncirrhotic. Seven (5.6%) patients had compensated cirrhosis; there were no decompensated cirrhotic patients. There was a statistically significant decrease in scores of APRI, FIB-4, Fibro Q, and Doha score calculated during the end-of-treatment three-year follow-up period. Conclusions: It was shown that serum fibrosis scores, such as APRI, FIB-4, Fibro Q, and Doha score, could be used to detect fibrosis before treatment and to follow histological improvement after treatment with direct-acting antivirals (DAA) in chronic hepatitis C patients.

FibroScan Predicts Liver Fibrosis Progression in Chronic HBV Infection Patients with No Clear Indication for Antiviral Therapy: A Retrospective Cohort Study.

Background and Aims: Chronic hepatitis B virus (HBV) infection patients who do not fulfill the typical treatment indications should be followed up. This study aimed to evaluate the risk of liver fibrosis progression (LFP) and assess the role of noninvasive tests (NITs) of liver fibrosis in monitoring LFP in these patients. Methods: A total of 116 patients with active HBV replication, persistently normal or minimally elevated alanine aminotransferase (ALT) levels, and no or mild hepatic necroinflammation or fibrosis based on liver biopsy tests at baseline and followed by a repeated liver biopsy assessment during follow-up. LFP was defined as increase in METAVIR fibrosis score by 1 score or more. Results: Among 116 patients, 40 (34.5%) progressed by at least one fibrosis stage, 16 (13.8%) progressed by at least two fibrosis stages at a median follow-up interval of 27 months (IQR: 12-36). Multivariate analysis confirmed the significant association of an increase in liver stiffness measurement (LSM) value with LFP on histology (p =0.005). The AUROC of LSM value increase rate is significantly higher than that of serum-based NITs of liver fibrosis for the prediction of LFP (p < 0.05). An increase in LSM by 20% is the optimal cutoff for the prediction of LFP. Conclusion: LFP is non-negligible in patients with active HBV replication, persistently normal or minimally elevated ALT, and initially no or minimal hepatic necroinflammation or fibrosis. Serial LSM tests would be more reliable in identifying LFP than serum-based NITs, and easier to obtain than serial liver biopsy tests.

Evaluation of fibrosis with noninvasive biochemical tests in chronic viral hepatitis B.

Background and Aim: Early diagnosis and treatment of chronic hepatitis B (CHB) disease are important for the prevention of complications such as cirrhosis and hepatocellular cancer. Liver biopsy is an invasive, complicated, and expensive diagnostic method, which is the gold standard for detecting fibrosis. The aim of this study was to investigate the role of these tests in predicting liver fibrosis and treatment decision. Materials and Methods: A total of 1051 patients diagnosed with CHB between 2010 and 2020 in the Gaziantep University Gastroenterology Department were retrospectively evaluated. AAR, API, APRI, FIB-4, KING score, and FIBROQ score were calculated at the time of onset diagnosis. In addition, the Zeugma score, a new formula that is thought to be more sensitive and specific, was determined. Noninvasive fibrosis scores were compared according to the biopsy results of the patients. Results: In this study, the area values under the curve were 0.648 for the API score, 0.711 for the APRI score, 0.716 for the FIB-4 score, 0.723 for the KING score, 0.595 for the FIBROQ score, and 0.701 for the Zeugma score (p<0.05). No statistically significant difference was obtained for the AAR score. The KING, FIB-4, APRI, and Zeugma scores were the best indicators for detecting advanced fibrosis. For KING, FIB-4, APRI, and Zeugma scores, the cutoff value for the prediction of advanced fibrosis were ≥8.67, ≥0.94, ≥16.24, and ≥9.63 with a sensitivity of 50.52%, 56.77%, 59.64%, and 52.34%, specificity of 87.26%, 74.96%, 73.61%, and 78.11%, respectively (p<0.05). In our study, we compared the globulin and GGT parameters with fibrosis, which we used in the Zeugma score formula. Globulin and GGT mean values were significantly higher in the fibrosis group (p<0.05). There was a statistically significant correlation between fibrosis and globulin and GGT values (p<0.05, r=0.230 and p<0.05, r=0.305, respectively). Conclusion: The KING score was found to be the most reliable method for the noninvasive detection of hepatic fibrosis in patients with chronic HBV. The FIB-4, APRI, and Zeugma scores were also shown to be effective in determining liver fibrosis. It was shown that the AAR score was not sufficient for detecting hepatic fibrosis. The Zeugma score, a novel noninvasive test, is a useful and easy tool to evaluate liver fibrosis in patients with chronic HBV and has better accuracy than AAR, API, and FIBROQ.

Impact of Type 2 Diabetes on the Accuracy of Noninvasive Tests of Liver Fibrosis With Resulting Clinical Implications.

BACKGROUND & AIMS: Noninvasive tests (NITs) of liver fibrosis have been suggested to be less accurate in type 2 diabetes mellitus (T2DM). We aimed to compare the accuracy of 6 NITs between patients with or without T2DM, explain any differences, and adapt diagnostic algorithms for clinical practice accordingly. METHODS: We included 1051 patients with nonalcoholic fatty liver disease with liver biopsy, blood fibrosis tests (Nonalcoholic Fatty Liver Disease Fibrosis Score, FIB4, Fibrotest, FibroMeter), vibration-controlled transient elastography (VCTE), and the combinatory elasto-blood test FibroMeterVCTE. The study endpoint was advanced fibrosis on liver biopsy. RESULTS: NIT areas under the receiver operating characteristic curve were significantly lower in patients with T2DM, mostly because of a decrease in specificity. For FIB4, this decrease in specificity was only related to the higher age of patients with T2DM enrolled. For Fibrotest, FibroMeter, and FibroMeterVCTE, the decrease in specificity was related to age but also to higher alpha2-macroglobulin level, which is known to increase in T2DM. Sensitivity was unaffected by T2DM, but it masked a doubled raw number of false negatives because of the 2-fold higher prevalence of advanced fibrosis in that setting. The sequential algorithm FIB4-vibration-controlled transient elastography had 90.3% accuracy in patients without T2DM vs 79.0% in those with (P < .001). Algorithms using first-line specialized tests maintained a low rate of false negatives and false positives in T2DM. CONCLUSIONS: The decrease in NIT accuracy observed in T2DM is partly biased by the different characteristics of the groups studied, but also linked to T2DM itself through modification of the levels of some NIT biomarkers. Specialized tests should be used first-line to diagnose advanced liver fibrosis in T2DM.

Development and Validation of a Score for Fibrotic Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Noninvasive assessment of histological features of nonalcoholic fatty liver disease (NAFLD) has been an intensive research area over the last decade. Herein, we aimed to develop a simple noninvasive score using routine laboratory tests to identify, among individuals at high risk for NAFLD, those with fibrotic nonalcoholic steatohepatitis (NASH) defined as NASH, NAFLD activity score ≥4, and fibrosis stage ≥2. METHODS: The derivation cohort included 264 morbidly obese individuals undergoing intraoperative liver biopsy in Rome, Italy. The best predictive model was developed and internally validated using a bootstrapping stepwise logistic regression analysis (2000 bootstrap samples). Performance was estimated by the area under the receiver operating characteristic curve (AUROC). External validation was assessed in 3 independent European cohorts (Finland, n = 370; Italy, n = 947; England, n = 5368) of individuals at high risk for NAFLD. RESULTS: The final predictive model, designated as Fibrotic NASH Index (FNI), combined aspartate aminotransferase, high-density lipoprotein cholesterol, and hemoglobin A1c. The performance of FNI for fibrotic NASH was satisfactory in both derivation and external validation cohorts (AUROC = 0.78 and AUROC = 0.80-0.95, respectively). In the derivation cohort, rule-out and rule-in cutoffs were 0.10 for sensitivity ≥0.89 (negative predictive value, 0.93) and 0.33 for specificity ≥0.90 (positive predictive value, 0.57), respectively. In the external validation cohorts, sensitivity ranged from 0.87 to 1 (negative predictive value, 0.99-1) and specificity from 0.73 to 0.94 (positive predictive value, 0.12-0.49) for rule-out and rule-in cutoff, respectively. CONCLUSION: FNI is an accurate, simple, and affordable noninvasive score which can be used to screen for fibrotic NASH in individuals with dysmetabolism in primary health care.

The Potential Role of Fatigue in Identifying Patients With NASH and Advanced Fibrosis Who Experience Disease Progression.

BACKGROUND AND AIMS: Fatigue is common in patients with advanced liver disease. We investigated fatigue and clinical outcomes among patients with advanced nonalcoholic steatohepatitis (NASH). METHODS: In this study, patients with biopsy confirmed NASH and bridging fibrosis (F3) or compensated cirrhosis (F4) were followed for up to 2 years. The Chronic Liver Disease Questionnaire for Nonalcoholic Steatohepatitis (CLDQ-NASH) fatigue domain at baseline (range, 1-7; lower score indicating worse fatigue) quantified fatigue. The Cox proportional hazards model was used to study time to liver-related clinical events (progression to histologic cirrhosis or hepatic decompensation in F3, hepatic decompensation in F4). RESULTS: Of the 1679 NASH patients with fibrosis, 802 had F3 and 877 had F4 (58 ± 9 years of age, 40% male, 74% type 2 diabetes). During median follow-up of 16 months (interquartile range, 14-18), 15% (n = 123) of NASH F3 patients experienced liver-related events and 3.5% (n = 31) of NASH F4 patients experienced hepatic decompensation. Mean baseline CLDQ-NASH fatigue score in F3 patients was 4.77 ± 1.36; NASH F3 patients who experienced liver-related events had lower baseline scores: 4.47 ± 1.36 vs 4.83 ± 1.35 (P = .0091). The mean fatigue score in F4 was 4.56 ± 1.44; these scores were lower in patients who decompensated in follow-up: 3.74 ± 1.31 vs 4.59 ± 1.43 (P = .0011). The association of lower fatigue scores and risk of liver-related or decompensation events was significant after adjustment for confounders (adjusted hazard ratio per 1 point in fatigue score in F3, 0.85; 95% confidence interval, 0.74-0.97; P = .02; adjusted hazard ratio in F4, 0.62; 95% confidence interval, 0.48-0.81; P = .0004). CONCLUSION: Worse fatigue at baseline is associated with a higher risk of adverse clinical events in patients with NASH-related advanced fibrosis and cirrhosis.

Real-world assessment of SmartExam, a novel FibroScan computational method: A retrospective single-center cohort study.

BACKGROUND AND AIM: SmartExam is a novel computational method compatible with FibroScan that uses a software called SmartDepth and continuous controlled attenuation parameter measurements to evaluate liver fibrosis and steatosis. This retrospective study compared the diagnostic accuracy of conventional and SmartExam-equipped FibroScan for liver stiffness measurement (LSM). METHODS: The liver stiffness and the associated controlled attenuation parameters of 167 patients were measured using conventional and SmartExam-Equipped FibroScan as well as reference methods like magnetic resonance elastography (MRE) and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) measurements to assess its diagnostic performance. M or XL probes were selected based on the probe-to-liver capsule distance for all FibroScan examinations. RESULTS: The liver stiffness and controlled attenuation parameter (CAP) correlation coefficients calculated from conventional and SmartExam-equipped FibroScan were 0.97 and 0.82, respectively. Using MRE/MRI-PDFF as a reference and the DeLong test for analysis, LSM and the area under the receiver operating characteristic curve for CAP measured by conventional and SmartExam-equipped FibroScan showed no significant difference. However, the SmartExam-equipped FibroScan measurement (33.6 s) took 1.4 times longer than conventional FibroScan (23.2 s). CONCLUSIONS: SmartExam has a high diagnostic performance comparable with that of conventional FibroScan. Because the results of the conventional and SmartExam-equipped FibroScan were strongly correlated, it can be considered useful for assessing the fibrosis stage and steatosis grade of the liver in clinical practice, with less variability but little longer measurement time compared with the conventional FibroScan.