Validation of the new 2021 EASL algorithm for the noninvasive diagnosis of advanced fibrosis in NAFLD.

BACKGROUND AND AIMS: The European Association for the Study of the Liver (EASL) has recently proposed an algorithm for the diagnosis of advanced liver fibrosis. We aimed to evaluate the diagnostic accuracy of this algorithm in nonalcoholic fatty liver disease (NAFLD). APPROACH AND RESULTS: One thousand fifty-one patients with NAFLD, liver biopsy, and four noninvasive tests (NITs; Fibrosis-4 [FIB4], vibration controlled transient elastography [VCTE], FibroMeter, Fibrotest) were included. The enhanced liver fibrosis (ELF) score was available in 396 patients. A cohort of 230 patients from primary care/diabetes clinics had FIB4, VCTE, and ELF. Compared with the performance of single NITs, agreement between two NITs (FIB4 and VCTE, VCTE and patented serum tests) increased specificity and positive predictive value by 20%, thus justifying the sequential use proposed in the EASL algorithm. The FIB4/VCTE/FibroMeter and FIB4/VCTE/Fibrotest algorithms performed similarly, providing 85% diagnostic accuracy and a liver biopsy requirement rate of only 10%. The FIB4/VCTE/ELF algorithm performed similarly in the subgroup where ELF was available. Simulations of algorithm accuracies at different prevalence showed that positive predictive values rapidly increased, reaching a plateau above 75% starting at 15% prevalence. Negative predictive values remained higher than 90% up to 25% prevalence. The rate of liver biopsy requirement remained stable, increasing by only 5% between low and high prevalence settings. When the EASL algorithm was applied in the primary care/diabetes clinic cohort, liver biopsy requirement was only 3%, and the agreement among the three steps provided 75% positive predictive value. CONCLUSIONS: Our study validates the algorithm proposed by the EASL in its latest 2021 guidelines for the diagnosis of advanced fibrosis in the setting of NAFLD.

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.

Inter-platform Variability of Liver Elastography: Pairwise Comparisons of Four Devices.

This study was aimed at determining whether liver stiffness measurements by 2-D shear wave elastography using GE's (2D-SWE-GE) and Canon's (2D-SWE-Canon) newest apparatus and vibration-controlled transient elastography (VCTE) share the same distribution of values compared with Hologic Supersonic Imagine (2D-SWE-SSI). In participants with chronic liver disease recruited in two university centers from August 2020 to February 2021, liver stiffness was measured the same day by the same operator with 2D-SWE-SSI plus one of the following devices: 2D-SWE-GE (n = 314), 2D-SWE-Canon (n = 311), and VCTE-M probe (n = 812). VCTE-M and 2D-SWE-SSI values shared the highest correlation and concordance coefficients (0.933 and 0.920, respectively) and a coefficient of variation below 20%, whatever the range of values. 2D-SWE-GE had the lowest variations, with 2D-SWE-SSI values below 13 kPa. However, both 2D-SWE-GE and 2D-SWE-Canon exhibited a frank underestimation of the high percentiles' 2D-SWE-SSI values with coefficients of variation of -21.7% and -25.8% from 13- to 17-kPa values, and -44.3% and -32.4% from 17-kPa values, respectively. In conclusion, knowledge of the vendor-specific distribution of values is mandatory for interpreting results obtained with different machines. If all four techniques behave closely in low values allowing excluding advanced chronic liver diseases in larger populations, discrepancies are observed in high percentile values.

Long-term prognosis of patients with metabolic (dysfunction)-associated fatty liver disease by non-invasive methods.

BACKGROUND: Non-invasive assessment of fibrosis is predictive of the prognosis of non-alcoholic and alcoholic fatty liver disease but this has not been demonstrated in metabolic (dysfunction)-associated fatty liver disease (MAFLD). AIMS: We assessed the prognosis of non-invasive methods in patients with MAFLD. METHODS: All consecutive patients with MAFLD, with liver stiffness measurements, FIB-4 (Fibrosis-4), and LIVERFASt were included in this cohort study. The primary endpoint was analysed by the Kaplan-Meier method and secondary endpoints were estimated by Gray test or logistic regression. Factors independently associated with overall mortality and morbidity were identified by a multivariate Cox model. The prognostic performance of non-invasive methods for prediction of mortality was evaluated by Harrell's C-index and for morbidity by area under the receiver operating characteristics curve (AUC). RESULTS: A total of 1239 patients with MAFLD were analysed (median age 56 years, male 56.5%, median body mass index 31 kg/m2 and obesity 59%). The median follow-up was 62 months [42-91 months] and 73 (5.8%) subjects died. Baseline results of non-invasive methods were correlated with overall and liver-related mortalities (P < 0.001), and with all-cause and liver-related outcomes (P < 0.001). A predictive model (composed of clinical parameters and liver stiffness measurement, FIB-4 or LIVERFASt) was an excellent predictor of overall and liver-related mortalities (C-index 0.8-0.9), and a good predictor of overall and liver-related morbidities (AUC 0.72-0.74). CONCLUSION: Baseline liver stiffness measurement, FIB-4 and LIVERFASt can predict global and liver-related mortality and morbidity in patients with MAFLD and could be prognosis endpoints in clinical trials.

Long-term prognosis of patients with alcohol-related liver disease or non-alcoholic fatty liver disease according to metabolic syndrome or alcohol use.

BACKGROUND & AIMS: The boundary between non-alcoholic (NAFLD) and alcohol-related liver disease (ALD) is based on alcohol consumption. However, metabolic syndrome and alcohol use frequently co-exist. The aim of this study was to determine prognostic factors of long-term morbidity and mortality in patients with NAFLD or ALD. METHODS: From 2003 to 2016, all consecutive NAFLD or ALD patients were prospectively included in this cohort study. We evaluated overall survival, specific cause of mortality and occurrence of any complication. The primary endpoint was analysed by the Kaplan Meier method, secondary endpoints were estimated by Gray test method or logistic regressions. Factors independently associated with overall mortality and morbidity were identified by a multivariate Cox model. RESULTS: A total of 3365 patients (1667 with ALD and 1698 with NAFLD) were included. Median follow-up was 54 months (range: 30-86) and 563 subjects died. In the overall population, overall mortality was higher in patients with ALD (HR: 10.1 [7.57-13.3]), and with weekly alcohol consumption >7 units (HR:1.66 [1.41-1.96]). Liver-related mortality was higher in patients with ALD (HR: 11 [7.27-16.5]). In the NAFLD group, weekly alcohol consumption >1 unit was associated with higher overall mortality (HR: 1.9 [1.1-3.4]), and weekly alcohol consumption >7 units was associated with higher overall morbidity (OR: 1.89 [1.61-2.21]). In the ALD group, the presence of metabolic syndrome was associated with higher overall (HR:1.27 [1.02-1.57]), and liver (HR: 1.47 [1.1-1.96]) mortalities, and overall (OR: 1.46 [1.14-1.88]), liver (OR: 1.46 [1.14-1.88]) morbidities. CONCLUSION: In fatty liver diseases, light alcohol consumption and metabolic syndrome are prognosis cofactors.

Reliability Criteria of Two-Dimensional Shear Wave Elastography: Analysis of 4277 Measurements in 788 Patients.

BACKGROUND & AIMS: Two-dimensional shear wave elastography (2D-SWE) is an accurate method for the non-invasive evaluation of liver fibrosis. We aimed to determine the reliability criteria and the number of necessary reliable measurements for 2D-SWE. METHODS: 788 patients with chronic liver disease underwent liver biopsy and 2D-SWE examination in three centers. The 4277 2D-SWE measurements performed were 2:1 randomly divided into derivation (n = 2851) and validation (n = 1426) sets. Reliability criteria for a 2D-SWE measurement were defined in the derivation set from the intrinsic characteristics given by the device (mean liver stiffness, standard deviation, diameter of the region of interest), with further evaluation in the validation set. RESULTS: In the whole population of 4277 measurements, AUROC for bridging fibrosis was 0.825 ± 0.006 and AUROC for cirrhosis was 0.880 ± 0.006. Mean stiffness and coefficient of variation (CV) were independent predictors of bridging fibrosis or cirrhosis. From these two parameters, new criteria were derived to define a reliable 2D-SWE measurement: stiffness <8.8 kPa, or stiffness between 8.8-11.9 kPa with CV <0.25, or stiffness ≥12.0 kPa with CV <0.10. In the validation set, AUROC for bridging fibrosis was 0.830 ± 0.013 in reliable measurements vs 0.667 ± 0.031 in unreliable measurements (P < .001). AUROC for cirrhosis was 0.918±0.014 vs 0.714 ± 0.027, respectively (P < .001). The best diagnostic accuracy for a 2D-SWE examination was achieved from three reliable measurements. CONCLUSIONS: Reliability of a 2D-SWE measurement relies on the coefficient of variation and the liver stiffness level. A 2D-SWE examination should include three reliable measurements according to our new criteria.

Assessment of hepatic steatosis by controlled attenuation parameter using the M and XL probes: an individual patient data meta-analysis.

BACKGROUND: Diagnostic tools for liver disease can now include estimation of the grade of hepatic steatosis (S0 to S3). Controlled attenuation parameter (CAP) is a non-invasive method for assessing hepatic steatosis that has become available for patients who are obese (FibroScan XL probe), but a consensus has not yet been reached regarding cutoffs and its diagnostic performance. We aimed to assess diagnostic properties and identify relevant covariates with use of an individual patient data meta-analysis. METHODS: We did an individual patient data meta-analysis, in which we searched PubMed and Web of Science for studies published from database inception until April 30, 2019. Studies reporting original biopsy-controlled data of CAP for non-invasive grading of steatosis were eligible. Probe recommendation was based on automated selection, manual assessment of skin-to-liver-capsule distance, and a body-mass index (BMI) criterion. Receiver operating characteristic methods and mixed models were used to assess diagnostic properties and covariates. Patients with non-alcoholic fatty liver disease (NAFLD) were analysed separately because they are the predominant patient group when using the XL probe. This study is registered with PROSPERO, CRD42018099284. FINDINGS: 16 studies reported histology-controlled CAP including the XL probe, and individual data from 13 papers and 2346 patients were included. Patients with a mean age of 46·5 years (SD 14·5) were recruited from 20 centres in nine countries. 2283 patients had data for BMI; 673 (29%) were normal weight (BMI <25 kg/m2), 530 (23%) were overweight (BMI ≥25 to <30 kg/m2), and 1080 (47%) were obese (BMI ≥30 kg/m2). 1277 (54%) patients had NAFLD, 474 (20%) had viral hepatitis, 285 (12%) had alcohol-associated liver disease, and 310 (13%) had other liver disease aetiologies. The XL probe was recommended in 1050 patients, 930 (89%) of whom had NAFLD; among the patients with NAFLD, the areas under the curve were 0·819 (95% CI 0·769-0·869) for S0 versus S1 to S3 and 0·754 (0·720-0·787) for S0 to S1 versus S2 to S3. CAP values were independently affected by aetiology, diabetes, BMI, aspartate aminotransferase, and sex. Optimal cutoffs differed substantially across aetiologies. Risk of bias according to QUADAS-2 was low. INTERPRETATION: CAP cutoffs varied according to cause, and can effectively recognise significant steatosis in patients with viral hepatitis. CAP cannot grade steatosis in patients with NAFLD adequately, but its value in a NAFLD screening setting needs to be studied, ideally with methods beyond the traditional histological reference standard. FUNDING: The German Federal Ministry of Education and Research and Echosens.

Rates of Postoperative Recurrence of Crohn's Disease and Effects of Immunosuppressive and Biologic Therapies.

BACKGROUND & AIMS: The Rutgeerts' scoring system is used to evaluate patients with Crohn's disease (CD) following ileocolic resection, based on endoscopic findings at the anastomosis and in the neoterminal ileum. We investigated rates of clinical and surgical recurrence of CD after surgery and effect of therapy modification based on post-operative endoscopic findings. METHODS: We collected data from 365 adults with CD (20% with Rutgeerts' score i0, 10% with score i1, 49% with score i2, 12% with score i3, 9% with score i4) who underwent ileocolonoscopy within 12 months of ileocolic resection with anastomosis from 2000 through 2013 at 2 centers in Belgium and France. Patients were followed for 3 y or more after the ileocolonoscopy. Clinical post-operative recurrence (POR) was defined as occurrence of CD symptoms along with biologic, radiologic, and/or endoscopic features of disease activity; modified surgical POR was defined as either an endoscopic or surgical intervention. RESULTS: After a median follow-up time of 88 months, 48% of patients had clinical POR and 26% had modified surgical POR. Rates of survival without clinical POR or a modified surgical POR were lower in patients with Rutgeerts' scores of i2, i3, or i4 compared to patients with scores of i0 or i1 (P < .001 and P = .02). New immunosuppressant or biological therapy was initiated following endoscopy in 129/254 patients (51%) with Rutgeerts' score of i2, i3, or i4 vs 7/111 patients (6%) with scores of i0 or i1 (odds ratio for new therapy, 14.9; 95% CI, 7.1-36.8; P < .001). A modest decrease in risk of clinical POR was observed for patients with Rutgeerts scores of i3 or i4 after initiation of immunosuppressive or biological therapy based on endoscopic findings (Breslow P = .03), but this was not observed for patients with scores of i2 (Breslow P = .46). CONCLUSIONS: Use of immunosuppressants and tumor necrosis factor antagonists to treat patients with an asymptomatic endoscopic post-operative recurrence of CD did not reduce long-term risk of clinical recurrence in patients with Rutgeerts' scores of i2, but it had a small effect in patients with scores of i3 or i4.

Transient Versus Two-Dimensional Shear-Wave Elastography in a Multistep Strategy to Detect Advanced Fibrosis in NAFLD.

BACKGROUND AND AIMS: The combination of laboratory and elastography tests allows the accurate diagnosis of advanced liver fibrosis in patients with NAFLD. In this study, we compared the diagnostic performances of a two-step strategy (laboratory tests and vibration-controlled transient elastography [VCTE] or two-dimensional shear-wave elastography with SuperSonic Imagine [2D-SWE-SSI]) and the added value of a three-step strategy (laboratory tests and two elastography methods). APPROACH AND RESULTS: From a prospective registry, we retrospectively selected 577 consecutive patients with suspicion of NAFLD who underwent laboratory tests to calculate the Fibrosis-4 (FIB-4) score, liver stiffness evaluation by VCTE (M and XL probes) and 2D-SWE-SSI, and liver biopsy. The diagnostic performances and need for liver biopsy in unclassified patients for the diagnosis of advanced fibrosis (F ≥ 3) in multistep strategies were compared. The area under the curve of FIB-4, VCTE, and 2D-SWE-SSI was 0.74, 0.82, and 0.88, respectively. Using the same thresholds, the FIB-4/2D-SWE-SSI and FIB-4/VCTE diagnostic performances were comparable (sensitivity, 71.4% and 66%; specificity, 91.4% and 91.5%; and accuracy, 83.7% and 81.4%; all P = not significant). Conversely, more patients required liver biopsy after 2D-SWE-SSI (24.6% versus 15.3%, P < 0.001). Performing a second elastography technique in patients with unreliable or gray zone (between 8 and 10 kPa) results greatly decreased the need for liver biopsy (42/577, 7.3%). The diagnostic performances (accuracy, sensitivity, and specificity) of FIB-4/2D-SWE-SSI/VCTE and FIB-4/VCTE/2D-SWE-SSI were comparable (81.1%, 71.5%, and 87.9% versus 81.3%, 69.7%, and 89.5%, respectively; all P = not significant). CONCLUSIONS: Using the same cutoff values, 2D-SWE-SSI is as accurate as VCTE for advanced liver fibrosis diagnosis in NAFLD. The three-step strategy in selected patients strongly decreased the need for liver biopsy while maintaining excellent accuracy.

Impact of Preexisting Inflammatory Bowel Disease on the Outcome of Liver Transplantation for Primary Sclerosing Cholangitis.

Approximately 80% of patients with primary sclerosing cholangitis (PSC) also have inflammatory bowel disease (IBD), and its effect on the outcomes of liver transplantation (LT) for PSC is unclear. We retrospectively collected data from adults who underwent LT for PSC from 1989 to January 2018 in 4 French LT centers. We compared the rates of patient and graft survivals and of complications after LT. Among 87 patients, 52 (60%) had preexisting IBD. Excluding those who died within the first 3 months, the 10-year patient survival and graft survival rates were 92.6% (95% confidence interval [CI], 84.3%-100%) and 77.1% (53.8%-85.3%), respectively, in the PSC with IBD (PSC-IBD) group and 97.1% (91.4%-100%; P = 0.44) and 83.2% (69.6%-96.9%; P = 0.43) in the isolated PSC group, respectively. Exposure to azathioprine after LT was significantly associated with mortality (odds ratio [OR], 15.55; 1.31-184.0; P = 0.03), whereas exposure to mycophenolate mofetil was associated with improved survival (OR, 0.17; 95% CI, 0.04-0.82; P = 0.03), possibly an era effect. The rate of recurrent PSC was 21% in the PSC-IBD group and 11% in the isolated PSC group (P = 0.24). Severe infections occurred in 125 per 1000 person-years in both groups. Exposure to mycophenolate mofetil was associated with a lower risk of infection (OR, 0.26; 95% CI, 0.08-0.85; P = 0.03). The presence of IBD was associated with cytomegalovirus (CMV) infection (OR, 3.24; 95% CI, 1.05-9.98; P = 0.04). IBD prior to LT for PSC may not affect patient or transplant survival but may increase the risk of CMV infection.

Agreement Between 2-Dimensional Shear Wave and Transient Elastography Values for Diagnosis of Advanced Chronic Liver Disease.

BACKGROUND & AIMS: Inter-platform variation in liver stiffness evaluation (LSE) could hinder dissemination and clinical implementation of new ultrasound methods. We aimed to determine whether measurements of liver stiffness by bi-dimensional shear wave elastography (2D-SWE) with a Supersonic Imagine apparatus are comparable to those made by vibration-controlled transient elastography (VCTE). METHODS: We collected data from 1219 consecutive patients with chronic liver disease who underwent LSE by VCTE and 2D-SWE (performed by blinded operators), on the same day, at a single center in France from September 2011 through June 2019. We assessed the ability of liver stiffness value distributions and 2D-SWE performances to identify patients with compensated advanced chronic liver disease (cACLD) according to the Baveno VI criteria, based on VCTE cut-off values. RESULTS: VCTE and 2D-SWE values correlated (Pearson's correlation coefficient, 0.882; P < .0001; Lin concordance coefficient, 0.846; P < .0001). The median stiffness values were 6.7 kPa with VCTE (interquartile range, 4.8-11.6 kPa) and 7.1 kPa with 2D-SWE (interquartile range, 5.4-11.1 kPa) (P = .736). 2D-SWE values were slightly higher in the low percentiles and lower in the high percentiles; the best match with VCTE values were at approximately 7-9 kPa. The area under the curve of 2D-SWE for identifying of VCTE values below 10 was 0.964 (95% CI, 0.952-0.976) and for VCTE values above 15 kPa was 0.976 (95% CI, 0.963-0.988), with Youden index-associated cut-off values of 9.5 and 13kPa and best accuracy cut-off values of 10 kPa and 14 kPa, respectively. A 2D-SWE cut-off value of 10 kPa detected VCTE values below 10k Pa with 92% sensitivity, 87% specificity, and 91% accuracy. CONCLUSIONS: Measurement of liver stiffness by VCTE or 2D-SWE produces comparable results. 2D-SWE accurately identifies patients with cACLD according to the Baveno VI criteria based on VCTE cut-off values. A 10 kPa 2D-SWE cut-off value can be used to rule out cACLD.

No Change in Determining Crohn's Disease Recurrence or Need for Endoscopic or Surgical Intervention With Modification of the Rutgeerts' Scoring System.

The postoperative endoscopic recurrence score, commonly referred to as the Rutgeerts score, was designed to predict clinical recurrence risk in Crohn's disease (CD) patients undergoing ileocolonic resection based on early endoscopic findings at the anastomosis and in the neoterminal ileum.1 In the pivotal publication, the i2 category, including aphthous lesions in the terminal ileum as well as ileocolonic anastomosis lesions, had a heterogeneous recurrence risk. Because anastomotic ulcers were suspected to be postsurgical ischemic lesions and less predictive of progressive disease,2 a modified Rutgeerts score (mRS) was proposed: i2a, lesions confined to the anastomosis ±<5 isolated aphthous ulcers in the ileum; i2b, more than 5 aphthous ulcers in the ileum with normal mucosa in between, ± anastomotic lesions.3,4.