Development and Validation of the Nonalcoholic Fatty Liver Disease Familial Risk Score to Detect Advanced Fibrosis: A Prospective, Multicenter Study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD)-related fibrosis is heritable, but it is unclear how family history may be used to identify first-degree relatives with advanced fibrosis. We aimed to develop and validate a simple risk score to identify first-degree relatives of probands who have undergone assessment of liver fibrosis who are at higher risk of NAFLD with advanced fibrosis. METHODS: This prospective, cross-sectional, familial study consisted of a derivation cohort from San Diego, California, and a validation cohort from Helsinki, Finland. This study included consecutive adult probands (n = 242) with NAFLD and advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 of their first-degree relatives. All included probands and first-degree relatives underwent evaluation of liver fibrosis, the majority by magnetic resonance elastography. RESULTS: A total of 396 first-degree relatives (64% male) were included. The median age and body mass index were 47 years (interquartile range, 32-62 y) and 27.6 kg/m2 (interquartile range, 24.1-32.5 kg/m2), respectively. Age (1 point), type 2 diabetes (1 point), obesity (2 points), and proband with NAFLD and advanced fibrosis (2 points) were predictors of advanced fibrosis among first-degree relatives in the derivation cohort (n = 220) and formed the NAFLD Familial Risk Score. The area under the receiver operator characteristic curve of the NAFLD Familial Risk Score for detecting advanced fibrosis was 0.94 in the validation cohort (n = 176). The NAFLD Familial Risk Score outperformed the Fibrosis-4 index in the validation cohort (area under the receiver operator characteristic curve, 0.94 vs 0.70; P = .02). CONCLUSIONS: The NAFLD Familial Risk Score is a simple and accurate clinical tool to identify advanced fibrosis in first-degree relatives. These data may have implications for surveillance in NAFLD.

Validation of AGA clinical care pathway and AASLD practice guidance for nonalcoholic fatty liver disease in a prospective cohort of patients with type 2 diabetes.

BACKGROUND AND AIMS: Recently, the American Gastroenterological Association and the American Association for the Study of Liver Diseases developed clinical pathways to evaluate populations at high risk for NAFLD. We assessed the diagnostic performance of the new guidance in a well-phenotyped cohort of patients with Type 2 diabetes mellitus (T2DM). APPROACH AND RESULTS: This prospective study enrolled patients age ≥50 years with T2DM. Participants underwent a standardized clinical research visit with MRI and ultrasound-based assessment of liver fat and stiffness and Enhanced Liver Fibrosis (ELF) testing. Of 417 participants (36% men) with T2DM with FIB-4 and MRE data, the prevalence of NAFLD was 64% and 12% had advanced fibrosis (MRE≥3.63 kPa). Applying the American Gastroenterological Association pathway of FIB-4 and vibration-controlled transient elastography, the false negative rate was 3.3% and 18% would qualify for specialty referral. Applying the FIB-4 + ELF American Association for the Study of Liver Diseases pathway, the false negative rate was 4.5%, but 50% would qualify for specialty referral. Applying higher ELF cut points improved the pathway, yielding a similar false negative rate of 4.9% but decreased specialty referral to 27%. CONCLUSION: Validation of the American Gastroenterological Association clinical pathway in a prospectively recruited cohort with T2DM revealed a low false negative rate and avoided specialty referral in a large percentage of patients. The American Association for the Study of Liver Diseases pathway with FIB-4 + ELF resulted in a high rate of specialty referral, which improved with the utilization of higher ELF cut points and may serve as an alternative for primary care and endocrinology clinics without access to vibration-controlled transient elastography.

Clinical utility of liver fat quantification for determining cardiovascular disease risk among patients with type 2 diabetes.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are independent risk factors for cardiovascular disease (CVD). AIMS: To examine the clinical utility of liver fat quantification for determining CVD risk among a well-phenotyped cohort of patients with T2DM. METHODS: This was a cross-sectional analysis of a prospective cohort of adults aged ≥50 with T2DM. Liver fat was quantified with magnetic resonance imaging proton-density-fat-fraction (MRI-PDFF), an advanced imaging-based biomarker. Patients were stratified into a higher liver fat group (MRI-PDFF ≥ 14.6%), and a lower liver fat group (MRI-PDFF < 14.6%). The co-primary outcomes were CVD risk determined by Framingham and Atherosclerotic Cardiovascular Disease (ASCVD) risk scores. High CVD risk was defined by risk scores ≥20%. RESULTS: Of the 391 adults (66% female) in this study, the mean (±SD) age was 64 (±8) years and BMI 30.8 (±5.2) kg/m2 , respectively. In multivariable analysis, adjusted for age, gender, race, and BMI, patients in the higher liver fat group had higher CVD risk [OR = 4.04 (95% CI: 2.07-7.88, p < 0.0001)] and ASCVD risk score [OR = 2.85 (95% CI: 1.19-6.83, p = 0.018)], respectively. CONCLUSION: Higher liver fat content increases CVD risk independently of age, gender, ethnicity and BMI. These findings raise the question whether liver fat quantification should be incorporated into risk calculators to further stratify those with higher CVD risk.

A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes.

BACKGROUND & AIMS: There are limited prospective data on patients with type 2 diabetes mellitus (T2DM) specifically enrolled and systematically assessed for advanced fibrosis or cirrhosis due to non-alcoholic fatty liver disease (NAFLD). Therefore, we aimed to evaluate the prevalence of advanced fibrosis and cirrhosis in a prospectively recruited cohort of adults with T2DM. METHODS: This prospective study enrolled adults aged ≥50 years with T2DM, recruited from primary care or endocrinology clinics. Participants underwent a standardized clinical research visit with MRI-proton density fat fraction (MRI-PDFF), magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE) and controlled-attenuation parameter. NAFLD was defined as MRI-PDFF ≥5% after exclusion of other liver diseases. Advanced fibrosis and cirrhosis were defined by established liver stiffness cut-off points on MRE or VCTE if MRE was not available. RESULTS: Of 524 patients screened, 501 adults (63% female) with T2DM met eligibility. The mean age and BMI were 64.6 (±8.1) years and 31.4 (±5.9) kg/m2, respectively. The prevalence of NAFLD, advanced fibrosis and cirrhosis was 65%, 14% and 6%, respectively. In multivariable adjusted models, adjusted for age and sex, obesity and insulin use were associated with increased odds of advanced fibrosis (odds ratio 2.50; 95% CI 1.38-4.54; p = 0.003 and odds ratio 2.71; 95% CI 1.33-5.50; p = 0.006, respectively). Among 29 patients with cirrhosis, two were found to have hepatocellular carcinoma and one patient had gallbladder adenocarcinoma. CONCLUSION: Utilizing a uniquely well-phenotyped prospective cohort of patients aged ≥50 years with T2DM, we found that the prevalence of advanced fibrosis was 14% and that of cirrhosis was 6%. These data underscore the high risk of advanced fibrosis/cirrhosis in adults aged ≥50 years with T2DM. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is common in patients with type 2 diabetes (T2DM), however, there are limited prospective data characterizing the prevalence of advanced fibrosis and cirrhosis using the most accurate non-invasive biomarkers of liver fat and fibrosis. We show that 14% of older adults with T2DM have advanced fibrosis and 6% have cirrhosis, which places them at risk for liver failure and liver cancer. Accurate prevalence rates and comparative analysis regarding the diagnostic accuracy of non-invasive tests in this population will guide the optimal screening strategy and future cost-effectiveness analyses. These results will inform future Hepatology and Endocrinology practice guidelines regarding NAFLD screening programs in older adults with T2DM.

Risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease.

BACKGROUNDA pilot, single-center study showed that first-degree relatives of probands with nonalcoholic fatty liver disease (NAFLD) cirrhosis have a high risk of advanced fibrosis. We aimed to validate these findings using 2 independent cohorts from the US and Europe.METHODSThis prospective study included probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD, with at least 1 first-degree relative. A total of 396 first-degree relatives - 220 in a derivation cohort and 176 in a validation cohort - were enrolled in the study, and liver fibrosis was evaluated using magnetic resonance elastography and other noninvasive imaging modalities. The primary outcome was prevalence of advanced fibrosis in first-degree relatives.RESULTSPrevalence of advanced fibrosis in first-degree relatives of probands with NAFLD with advanced fibrosis, NAFLD without advanced fibrosis, and non-NAFLD was 15.6%, 5.9%, and 1.3%, respectively (P = 0.002), in the derivation cohort, and 14.0%, 2.6%, and 1.3%, respectively (P = 0.004), in the validation cohort. In multivariable-adjusted logistic regression models, age of ≥50 years (adjusted OR [aOR]: 2.63, 95% CI 1.0-6.7), male sex (aOR: 3.79, 95% CI 1.6-9.2), diabetes mellitus (aOR: 3.37, 95% CI 1.3-9), and a first-degree relative with NAFLD with advanced fibrosis (aOR: 11.8, 95% CI 2.5-57) were significant predictors of presence of advanced fibrosis (all P < 0.05).CONCLUSIONFirst-degree relatives of probands with NAFLD with advanced fibrosis have significantly increased risk of advanced fibrosis. Routine screening should be done in the first-degree relatives of patients with advanced fibrosis.FUNDINGSupported by NCATS (5UL1TR001442), NIDDK (U01DK061734, U01DK130190, R01DK106419, R01DK121378, R01DK124318, P30DK120515, K23DK119460), NHLBI (P01HL147835), and NIAAA (U01AA029019); Academy of Finland grant 309263; the Novo Nordisk, EVO, and Sigrid Jusélius Foundations; and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 777377. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and the EFPIA.

Comparative efficacy of an optimal exam between ultrasound versus abbreviated MRI for HCC screening in NAFLD cirrhosis: A prospective study.

BACKGROUND: Retrospective studies report that visualisation of the liver may be severely limited using ultrasound (US), potentially contributing to diminished sensitivity for detection of hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, but there are limited prospective data. AIMS: To compare liver visualisation scores prospectively for US and abbreviated hepatobiliary phase (HBP) magnetic resonance imaging (AMRI) in a cohort of participants with NAFLD cirrhosis and a clinical indication for HCC surveillance. METHODS: This prospective multicenter study included 54 consecutive participants (67% women) with NAFLD cirrhosis who underwent contemporaneous US as well as HBP-AMRI with gadoxetic acid. Primary outcome was the proportion of imaging examinations with severe limitations in liver visualisation (visualisation score C) compared head-to-head between US and AMRI. RESULTS: The mean (± standard deviation) age was 63.3 years (±8.4) and body mass index was 32.0 kg/m2 (±6.0). Nineteen participants (35%) had severe visualisation limitations on US, compared with 10 (19%) with AMRI, p < 0.0001. Nine (17%) participants had <90% of the liver visualised on US, compared with only 1 (2%) participant with AMRI, p < 0.0001. Obesity was a strong and independent predictor for severe visualisation limitation on US (OR 5.1, CI 1.1-23.1, p = 0.03), after adjustment for age, sex and ethnicity. CONCLUSION: More than one-third of participants with NAFLD cirrhosis had severe visualisation limitations on US for HCC screening, compared with one-sixth on AMRI. US adequacy should be reported in all clinical studies and when suboptimal then AMRI may be considered for HCC screening.

Liver stiffness by magnetic resonance elastography is associated with increased risk of cardiovascular disease in patients with non-alcoholic fatty liver disease.

BACKGROUND: Magnetic resonance elastography (MRE) is a reliable non-invasive alternative to liver biopsy for assessing liver fibrosis. There are limited data regarding an association between liver fibrosis by MRE and risk of cardiovascular disease (CVD). AIM: To investigate the association of high-risk CVD phenotype determined by coronary artery calcification (CAC) with liver fibrosis by MRE in patients with non-alcoholic fatty liver disease (NAFLD). METHOD: This was a cross-sectional analysis of well-characterised, prospective cohorts including 105 patients with NAFLD (MR imaging-derived proton density fat fraction ≥ 5%) with contemporaneous cardiac computed tomography (CT) and MRE. Patients were assessed using MRE for liver stiffness, and cardiac CT for the presence of CAC (defined as coronary artery calcium score > 0). Odds of presence of CAC were analysed using logistic regression analysis. RESULTS: The average age and body mass index were 54.9 years and 32.9 kg/m2 respectively. In this cohort, 49.5% of patients had CAC and 35.2% had significant liver fibrosis (defined as MRE ≥2.97 kPa). Compared to patients without CAC, those with CAC were older (50.0 [39.0-59.0] vs 63.0 [55.5-67.5], P < 0.001) and had higher Framingham risk score (FRS, 1.0 [0.5-3.5] vs 6.0 [2.0-12.0], P < 0.001). In multivariable-adjusted analysis, liver stiffness as a continuous trait on MRE was independently associated with the presence of CAC in a sex and age-adjusted model (adjusted odd ratios [aOR] = 2.23, 95% confidence interval [CI] = 1.31-4.34, P = 0.007) as well as in a FRS-adjusted model (aOR = 2.16, 95% CI = 1.29-4.09, P = 0.008). When analysed as a dichotomous trait, significant fibrosis (MRE-stiffness ≥2.97 kPa) remained independently associated with the presence of CAC in both FRS-adjusted model and sex and age-adjusted model (aOR = 3.21-3.53, P = 0.013-0.017). In addition, CAC was more prevalent in patients with significant fibrosis than those without as determined by MRE (67.6% vs 39.7%, P = 0.012). CONCLUSION: Liver stiffness determined by MRE is an independent predictor for the presence of CAC in patients with NAFLD. Patients with NAFLD and significant fibrosis by MRE should be considered for further cardiovascular risk assessment, regardless of their FRS.

Clinical Utility of an Increase in Magnetic Resonance Elastography in Predicting Fibrosis Progression in Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: Cross-sectional studies have shown that magnetic resonance elastography (MRE) is accurate in the noninvasive detection of advanced fibrosis in nonalcoholic fatty liver disease (NAFLD). However, there are limited data on the longitudinal association between an increase in liver stiffness on MRE and fibrosis progression in NAFLD. Therefore, using a well-characterized prospective cohort of patients with biopsy-proven NAFLD, we aimed to examine the longitudinal association between a 15% increase in liver stiffness on MRE and fibrosis progression in NAFLD. APPROACH AND RESULTS: This prospective cohort study included 102 patients (62.7% women) with biopsy-proven NAFLD who underwent contemporaneous MRE and liver biopsy at baseline followed by a repeat paired liver biopsy and MRE assessment. The primary outcome was odds of fibrosis progression by one or more stage as assessed by the Nonalcoholic Steatohepatitis Clinical Research Network histologic scoring system. The mean (±SD) of age and body mass index (BMI) were 52 (±14) years and 32.6 (±5.3) kg/m2 , respectively. The median time interval between the two paired assessments was 1.4 years (interquartile range 2.15 years). The number of patients with fibrosis stages 0, 1, 2, 3, and 4 was 27, 36, 12, 17, and 10, respectively. In unadjusted analysis, a 15% increase in MRE was associated with increased odds of histologic fibrosis progression (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.17-10.76; P = 0.0248). These findings remained clinically and statistically significant even after multivariable adjustment for age, sex, and BMI (adjusted OR, 3.36; 95% CI, 1.10-10.31; P = 0.0339). A 15% increase in MRE was the strongest predictor of progression to advanced fibrosis (OR, 4.90; 95% CI, 1.35-17.84; P = 0.0159). CONCLUSIONS: A 15% increase in liver stiffness on MRE may be associated with histologic fibrosis progression and progression from early fibrosis to advanced fibrosis.