Factors associated with high costs of patients with metabolic dysfunction-associated steatotic liver disease: an observational study using the French CONSTANCES cohort.

BACKGROUND & AIMS: Despite its high prevalence in the western world metabolic dysfunction-associated steatotic liver disease (MASLD) does not benefit from targeted pharmacological therapy. We measured healthcare utilisation and identified factors associated with high-cost MASLD patients in France. METHODS: The prevalent population with MASLD (including non-alcoholic steatohepatitis) in the CONSTANCES cohort, a nationally representative sample of 200,000 adults aged between 18 and 69, was linked to the French centralised national claims database (SNDS). Study participants were identified by the fatty liver index (FLI) over the period 2015-2019. MASLD individuals were classified according as "high-cost" (above 90th percentile) or "non-high cost" (below 90th percentile). Factors significantly associated with high costs were identified using a multivariate logistic regression model. RESULTS: A total of 14,437 predominantly male (69%) participants with an average age of 53 ± SD 12 years were included. They mainly belonged to socially deprived population groups with co-morbidities such as diabetes, high blood pressure, mental health disorders and cardiovascular complications. The average expenditure was €1860 ± SD 4634 per year. High-cost MASLD cost €10,863 ± SD 10,859 per year. Conditions associated with high-cost were mental health disorders OR 1.79 (1.44-2.22), cardiovascular diseases OR 1.54 (1.21-1.95), metabolic comorbidities OR 1.50 (1.25-1.81), and respiratory disease OR 1.50 (1.11-2.00). The 10% high-cost participants accounted for 58% of the total national health care expenditures for MASLD. CONCLUSION: Our results emphasize the need for comprehensive management of the comorbid conditions which were the major cost drivers of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in European countries, affecting 4­50% of the European population. Confirmation of diagnosis requires liver biopsy which is an invasive procedure. We studied the healthcare costs of patients with MASLD in order to identify cost predictors and cost drivers. We found that patients cost on average €1860 per year. Conditions associated with high-cost were mental health disorders, cardiovascular diseases, metabolic comorbidities, and respiratory disease.

WFUMB Guidelines/Guidance on Liver Multiparametric Ultrasound. Part 2: Guidance on Liver Fat Quantification.

The World Federation for Ultrasound in Medicine and Biology (WFUMB) has promoted the development of this document on multiparametric ultrasound. Part 2 is a guidance on the use of the available tools for the quantification of liver fat content with ultrasound. These are attenuation coefficient, backscatter coefficient, and speed of sound. All of them use the raw data of the ultrasound beam to estimate liver fat content. This guidance has the aim of helping the reader in understanding how they work and interpret the results. Confounding factors are discussed and a standardized protocol for measurement acquisition is suggested to mitigate them. The recommendations were based on published studies and experts' opinion but were not formally graded because the body of evidence remained low at the time of drafting this document.

Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

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

BACKGROUND: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in type 2 diabetes (T2DM) patients are lacking. The aim of this multicenter prospective study was to compare head-to-head FAST (FibroScan-aspartate aminotransferase [AST]), MAST (magnetic resonance imaging [MRI]-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in T2DM patients. METHODS: 330 T2DM outpatients with biopsy-proven metabolic dysfunction associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-PDFF and MRE at the time of liver biopsy (LB) were studied. The main outcome was fibrotic MASH, defined as NAS ≥ 4 (with at least one point each) and fibrosis stage ≥ 2 (centrally reviewed). RESULTS: 245 patients (median age 59 years, male 65%, BMI 31 kg/m2; fibrotic MASH 39%) had all data available for scores comparison. FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p = 0.41) but outperformed FNI (0.74; p = 0.01) and MEFIB (0.68; p < 0.0001). When using original cutoffs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom LB would be avoided (69% vs. 48%, 46%, 39%, respectively; p < 0.001). When using cutoffs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p < 0.001). CONCLUSION: Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify T2DM patients with fibrotic MASH in secondary/tertiary diabetes clinics. Cutoffs adapted to T2DM population should be considered. TRIAL REGISTRATION NUMBER: NCT03634098.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

Test characteristics for combining non-invasive liver fibrosis staging modalities in individuals with Hepatitis C virus.

Non-invasive methods have largely replaced biopsy to identify advanced fibrosis in hepatitis C virus (HCV). Guidelines vary regarding testing strategy to balance accuracy, costs and loss to follow-up. Although individual test characteristics are well-described, data comparing the accuracy of using two tests together are limited. We calculated combined test characteristics to determine the utility of combined strategies. This study synthesizes empirical data from fibrosis staging trials and the literature to estimate test characteristics for Fibrosis-4 (FIB4), APRI or a commercial serum panel (FibroSure®), followed by transient elastography (TE) or FibroSure®. We simulated two testing strategies: (1) second test only for those with intermediate first test results (staged approach), and (2) second test for all. We summarized empiric data with multinomial distributions and used this to estimate test characteristics of each strategy on a simulated population of 10,000 individuals with 4.2% cirrhosis prevalence. Negative predictive value (NPV) for cirrhosis from a single test ranged from 98.2% (95% CB 97.6-98.8%) for FIB-4 to 99.4% (95% CB 99.0-99.8%) for TE. Using a staged approach with TE second, sensitivity for cirrhosis rose to 93.3-96.9%, NPV to 99.7-99.8%, while PPV dropped to <32%. Using TE as a second test for all minimally changed estimated test characteristics compared with the staged approach. Combining two non-invasive fibrosis tests barely improves NPV and decreases or does not change PPV compared with a single test, challenging the utility of serial testing modalities. These calculated combined test characteristics can inform best methods to identify advanced fibrosis in various populations.

Algorithms for Early Detection of Silent Liver Fibrosis in the Primary Care Setting.

More than one-third of the adult world population has steatotic liver disease (SLD), with a few percent of individuals developing cirrhosis after decades of silent liver fibrosis accumulation. Lack of systematic early detection causes most patients to be diagnosed late, after decompensation, when treatment has limited effect and survival is poor. Unfortunately, no isolated screening test in primary care can sufficiently predict advanced fibrosis from SLD. Recent efforts, therefore, combine several parameters into screening algorithms, to increase diagnostic accuracy. Besides patient selection, for example, by specific characteristics, algorithms include nonpatented or patented blood tests and liver stiffness measurements using elastography-based techniques. Algorithms can be composed as a set of sequential tests, as recommended by most guidelines on primary care pathways. Future use of algorithms that are easy to interpret, cheap, and semiautomatic will improve the management of patients with SLD, to the benefit of global health care systems.

Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. METHODS: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. RESULTS: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). CONCLUSIONS: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. IMPACT AND IMPLICATIONS: Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

Implementation of a liver health check in people with type 2 diabetes.

As morbidity and mortality related to potentially preventable liver diseases are on the rise globally, early detection of liver fibrosis offers a window of opportunity to prevent disease progression. Early detection of non-alcoholic fatty liver disease allows for initiation and reinforcement of guidance on bodyweight management, risk stratification for advanced liver fibrosis, and treatment optimisation of diabetes and other metabolic complications. Identification of alcohol-related liver disease provides the opportunity to support patients with detoxification and abstinence programmes. In all patient groups, identification of cirrhosis ensures that patients are enrolled in surveillance programmes for hepatocellular carcinoma and portal hypertension. When considering early detection strategies, success can be achieved from applying ad-hoc screening for liver fibrosis in established frameworks of care. Patients with type 2 diabetes are an important group to consider case findings of advanced liver fibrosis and cirrhosis, as up to 19% have advanced fibrosis (which is ten times higher than the general population) and almost 70% have non-alcoholic fatty liver disease. Additionally, patients with type 2 diabetes with alcohol use disorders have the highest proportion of liver-related morbidity of people with type 2 diabetes generally. Patients with type 2 diabetes receive an annual diabetes review as part of their routine clinical care, in which the health of many organs are considered. Yet, liver health is seldom included in this review. This Viewpoint argues that augmenting the existing risk stratification strategy with an additional liver health check provides the opportunity to detect advanced liver fibrosis, thereby opening a window for early interventions to prevent end-stage liver disease and its complications, including hepatocellular carcinoma.

Prospective Comparison of Attenuation Imaging and Controlled Attenuation Parameter for Liver Steatosis Diagnosis in Patients With Nonalcoholic Fatty Liver Disease and Type 2 Diabetes.

BACKGROUND & AIMS: Similarly to the controlled attenuation parameter (CAP), the ultrasound-based attenuation imaging (ATI) can quantify hepatic steatosis. We prospectively compared the performance of ATI and CAP for the diagnosis of hepatic steatosis in patients with type 2 diabetes and nonalcoholic fatty liver disease using histology and magnetic resonance imaging-proton density fat fraction (MRI-PDFF) as references. METHODS: Patients underwent ATI and CAP measurement, MRI, and biopsy on the same day. Steatosis was classified as S0, S1, S2, and S3 on histology (<5%, 5%-33%, 33%-66%, and >66%, respectively) while the thresholds of 6.4%, 17.4%, and 22.1%, respectively, were used for MRI-PDFF. The area under the curve (AUC) of ATI and CAP was compared using a DeLong test. RESULTS: Steatosis could be evaluated in 191 and 187 patients with MRI-PDFF and liver biopsy, respectively. For MRI-PDFF steatosis, the AUC of ATI and CAP were 0.86 (95% confidence interval [CI], 0.81-0.91) vs 0.69 (95% CI, 0.62-0.75) for S0 vs S1-S3 (P = .02) and 0.71 (95% CI, 0.64-0.77) vs 0.69 (95% CI, 0.61-0.75) for S0-S1 vs S2-S3 (P = .60), respectively. For histological steatosis, the AUC of ATI and CAP were 0.92 (95% CI, 0.87-0.95) vs 0.95 (95% CI, 0.91-0.98) for S0 vs S1-S3 (P = .64) and 0.79 (95% CI, 0.72-0.84) vs 0.76 (95% CI, 0.69-0.82) for S0-S1 vs S2-S3 (P = .61), respectively. CONCLUSION: ATI may be used as an alternative to CAP for the diagnosis and quantification of steatosis, in patients with type 2 diabetes and nonalcoholic fatty liver disease.

Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer.

PURPOSE: The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making. EXPERIMENTAL DESIGN: Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC). RESULTS: GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33-0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31-0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74-1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07-0.72). CONCLUSIONS: GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.

Prospective direct comparison of non-invasive liver tests in outpatients with type 2 diabetes using intention-to-diagnose analysis.

BACKGROUND: No prospective diagnostic studies have directly compared widespread non-invasive liver tests in patients with type 2 diabetes (T2D) using the intention-to-diagnose method for each of the three main histological features of metabolic dysfunction associated steatotic liver disease - namely fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), and steatosis. AIMS: To compare the performance of nine tests using the intention-to-diagnose rather than the standard method, which would exclude non-evaluable participants METHODS: Biopsy was used as the reference with predetermined cut-offs, advanced fibrosis being the main endpoint. The Nash-FibroTest panel including FibroTest-T2D, SteatoTest-T2D and MashTest-T2D was optimised for type 2 diabetes. FibroTest-T2D was compared to vibration-controlled transient elastography stiffness (VCTE), two-dimensional shear-wave elastography stiffness (TD-SWE), and Fibrosis-4 blood test. NashTest-T2D was compared to aspartate aminotransferase. SteatoTest-T2D was compared to the controlled attenuation parameter and the hepatorenal gradient. RESULTS: Among 402 cases, non-evaluable tests were 6.7% for VCTE, 4.0% for hepatorenal gradient, 3.2% for controlled attenuation parameter, 1.5% for TD-SWE, 1.2% for NashTest-T2D, and 0.02% for Fibrosis-4, aspartate aminotransferase and SteatoTest-T2D. The VCTE AUROC for advanced fibrosis was over-estimated by 6% (0.83 [95% CI: 0.78-0.87]) by standard analysis compared to intention-to-diagnose (0.77 [0.72-0.81] p = 0.008). The AUROCs for advanced fibrosis did not differ significantly in intention-to-diagnose between FibroTest-T2D (0.77; 95% CI: 0.73-0.82), VCTE (0.77; 95% CI: 0.72-0.81) and TD-SWE(0.78; 0.74-0.83) but were all higher than the Fibrosis-4 score (0.70; 95% CI all differences ≥7%; p ≤ 0.03). For MASH, MashTest-T2D had a higher AUROC (0.76; 95% CI: 0.70-0.80) than aspartate aminotransferase (0.72; 95% CI: 0.66-0.77; p = 0.035). For steatosis, AUROCs did not differ significantly between SteatoTest-T2D, controlled attenuation parameter and hepatorenal gradient. CONCLUSIONS: In intention-to-diagnose analysis, FibroTest-T2D, TD-SWE and VCTE performed similarly for staging fibrosis, and out-performed Fibrosis-4 in outpatients with type 2 diabetes. The standard analysis over-estimated VCTE performance. CLINICALTRIAL: gov: NCT03634098.

Roles of Radiological Tests in Clinical Trials and the Clinical Management of Nonalcoholic Fatty Liver Disease.

Radiological testing is now routinely used for clinical trial prescreening, diagnosis, and treatment and referral. The CAP performs well in detecting fatty liver but is unable to grade and track longitudinal changes. MRI-PDFF is a better technique for evaluating longitudinal changes and is used as a primary endpoint in trials of antisteatotic agents. The probability of detecting liver fibrosis using radiological testing techniques is high when performed at referral centers, and reasonable imaging strategies include the combination of FIB-4 and VCTE, the FAST Score, MAST, and MEFIB. The strategy currently recommended is the sequential application of FIB-4 and VCTE.

High Prevalence of NASH and Advanced Fibrosis in Type 2 Diabetes: A Prospective Study of 330 Outpatients Undergoing Liver Biopsies for Elevated ALT, Using a Low Threshold.

OBJECTIVE: Most people with type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH) or advanced fibrosis (AF) remain undiagnosed, resulting in missed opportunities for early intervention. This multicenter, prospective study assessed the yield of using routinely available data to identify these patients. RESEARCH DESIGN AND METHODS: A total of 713 outpatients with T2DM, screened in four diabetology clinics for nonalcoholic fatty liver disease according to American Diabetes Association criteria, were referred to hepatologists for further work-up (Fibrosis-4 and vibration-controlled transient elastography [VCTE]). A liver biopsy was proposed when ALT levels were persistently >20 IU/L in female patients or >30 IU/L in male patients, in the absence of other liver disease. RESULTS: Liver biopsies were performed in 360 patients and considered adequate for reading after central review for 330 specimens (median patient age, 59 years; male patients, 63%; median BMI and HbA1c values, 32 and 7.5%, respectively). Prevalence of NASH, AF, and cirrhosis were 58%, 38%, and 10%, respectively. Liver lesions were independently associated with the components of metabolic syndrome but not with the micro- and macrovascular complications of T2DM. Models based on routinely available data with or without VCTE had good accuracy to predict AF (respectively: area under the receiver operating characteristic curve [AUROC], 0.84 and 0.77; and correctly classified 59% and 45%) and NASH (respectively: AUROC, 0.82 and 0.81; 44% and 42%). CONCLUSIONS: Despite the use of a low ALT threshold, prevalence of NASH (58%) or AF (38%) was high. Routinely available data had a high yield in identifying patients with T2DM with AF and/or NASH requiring further liver assessment.

Noninvasive Assessment of Liver Fibrosis in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of liver-related morbidity and mortality worldwide, afflicting approximately a billion individuals. NAFLD is a slowly progressive disease that may evolve in a subset of patients toward cirrhosis, hepatocellular carcinoma, and end-stage liver disease. Liver fibrosis severity is the strongest predictor of clinical outcomes. The emergence of effective therapeutics on the horizon highlights the need to identify among patients with NAFLD, those with severe fibrosis or cirrhosis, who are the most at risk of developing complications and target them for therapy. Liver biopsy has been the reference standard for this purpose. However, it is not suitable for large-scale population evaluation, given its well-known limitations (invasiveness, rare but severe complications, and sampling variability). Thus, there have been major efforts to develop simple noninvasive tools that can be used in routine clinical settings and in drug development. Noninvasive approaches are based on the quantification of biomarkers in serum samples or on the measurement of liver stiffness, using either ultrasound- or magnetic resonance-based elastography techniques. This review provides a roadmap for future development and integration of noninvasive tools in clinical practice and in drug development in NAFLD. We discuss herein the principles for their development and validation, their use in clinical practice, including for diagnosis of NAFLD, risk stratification in primary care and hepatology settings, prediction of long-term liver-related and non-liver-related outcomes, monitoring of fibrosis progression and regression, and response to future treatment.

Validation of a screening algorithm for hepatic fibrosis by Doppler ultrasound and elastography in a general population.

BACKGROUND: Early detection can prevent the initial stages of fibrosis from progressing to cirrhosis. PURPOSE: To evaluate an algorithm combining three echographic indicators and elastographic measurements to screen for hepatic fibrosis in an unselected population. MATERIAL AND METHODS: From May 2017 to June 2018, all patients with no history and no known chronic liver disease who were referred for an ultrasound (US) were prospectively included in eight hospitals. The indicators being sought were liver surface irregularity, demodulation of hepatic veins, and spleen length >110 mm. Patients presenting at least one of these underwent elastography measurements with virtual touch quantification (VTQ) or supersonic shear imaging (SSI). If elastography was positive, patients were referred to hepatologist for fibrosis evaluation. Reference standard was obtained by FibroMeterVCTE or biopsy. A FibroMeterVCTE result >0.384 indicated a "necessary referral" to a hepatologist. RESULTS: Of the 1501 patients included, 504 (33.6%) were positive for at least one US indicator. All of them underwent US elastography, with 85 being positive. Of the patients, 58 (3.6%) had a consultation with a liver specialist: 21 had positive FibroMeterVCTE and nine had an indication of biopsy for suspicion of fibrosis. This screening algorithm made it possible to diagnose 1.6% of patients in our population with unknown fibrosis. Of the patients, 50% referred to the liver specialist were "necessary referrals." CONCLUSION: Our study suggests that three simple US indicators with no systematic elastographic measurement could be applied in day-to-day practice to look for hepatic fibrosis in an unsuspected population allowing relevant referrals to a hepatologist.