Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol.

Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721.

Which preoperative assessment modalities best identify patients who are suitable for enhanced recovery after liver transplantation? A systematic review of the literature and expert panel recommendations.

BACKGROUND: To implement Enhanced Recovery After Surgery (ERAS) protocols for liver transplant (LT) candidates, it is essential to identify tools that can help risk stratify patients by their risk of early adverse post-LT outcomes. OBJECTIVE: We aimed to identify pre-LT tools that assess functional capacity, frailty, and muscle mass that can best risk stratify patients by their risk of adverse post-LT outcomes. METHODS: We first conducted a systematic review following PRISMA guidelines, expert panel review and recommendations using the GRADE approach (PROSPERO ID CRD42021237434). After confirming there are no studies evaluating assessment modalities for ERAS protocols for LT recipients specifically, the approach of the review focused on pre-LT modalities that identify LT recipients at higher risk of worse early post-LT outcomes (≤90 days), considering that this is particularly pertinent when evaluating candidates for ERAS. RESULTS: Twenty-two studies were included in the review, encompassing three different types of pre-LT modalities: evaluation of physical function (including frailty and general physical scores like the Karnofsky Performance Status (KPS), assessment of cardiopulmonary capacity, and estimation of muscle mass and composition. The majority of studies evaluated frailty assessment and muscle mass. Most studies, except for liver frailty index (LFI), were retrospective and single-center. All assessment modalities could identify, in different grade, LT recipients with higher risk of early post-LT mortality, length of stay or postoperative complications. CONCLUSIONS: We identified four pre-LT assessment tools that could be used to identify patients who are suitable for ERAS protocols: (1) KPS (quality of evidence moderate, grade of recommendation strong); (2) LFI (quality of evidence moderate, grade of recommendation strong); (3) abdominal muscle mass by CT (quality of evidence moderate, grade of recommendation strong); and (4) cardiopulmonary exercise testing (CPET) (quality of evidence moderate, grade of recommendation weak). We recommend that selection of the appropriate tool depends on the specific clinical setting and available resources to administer the tool, and that use of a tool be incorporated into the routine preoperative assessment when considering implementation of ERAS protocols for LT.

Noninvasive assessment of clinically significant portal hypertension using ΔT1 of the liver and spleen and ECV of the spleen on routine Gd-EOB-DTPA liver MRI.

PURPOSE: To analyze the predictive value of ΔT1 of the liver and spleen as well as the extracellular volume fraction (ECV) of the spleen as noninvasive biomarkers for the determination of clinically significant portal hypertension (CSPH) on routine Gd-EOB-DTPA liver MRI. METHOD: 195 consecutive patients with known or suspected chronic liver disease from 9/2018 to 7/2019 with Gd-EOB-DTPA liver MRI and abdominal T1 mapping were retrospectively included. Based on the presence of splenomegaly with thrombocytopenia, ascites and portosystemic collaterals, the patients were divided into noCSPH (n = 113), compensated CSPH (cCSPH, ≥1 finding without ascites; n = 55) and decompensated CSPH (dCSPH, ascites ± other findings; n = 27). T1 times were measured in the liver, spleen and abdominal aorta in the unenhanced and contrast-enhanced T1 maps. Native T1 times and ΔT1 of the liver and spleen as well as ECV of the spleen were compared between groups using the Kruskal-Wallis test with Dunn's post hoc test. Furthermore, cutoff values for group differentiation were calculated using ROC analysis with Youden's index. RESULTS: ΔT1 of the liver was significantly lower in patients with cCSPH and dCSPH (p < 0.001) compared to patients with noCSPH. In the ROC analyses for differentiation between noCSPH and CSPH (cCSPH + dCSPH), a cutoff of < 0.67 for ΔT1 of the liver (AUC = 0.79) performed better than ΔT1 (AUC = 0.69) and ECV (AUC = 0.63) of the spleen with cutoffs of > 0.29 and > 41.9, respectively. CONCLUSION: ΔT1 of the liver and spleen in addition to ECV of the spleen allow for determination of CSPH on routine Gd-EOB-DTPA liver MRI.

Noninvasive Assessment of Schistosoma-Related Periportal Fibrosis.

Schistosomiasis affects nearly 250 million individuals in the world. Hepatosplenic schistosomiasis (HSS) results in periportal fibrosis (PPF) and portal hypertension (pHTN). Ultrasound has been extensively used for the diagnosis of Schistosoma-related PPF and a number of staging methods have been validated for this purpose such as Strickland classification and Niamey protocol. Nevertheless, the application of noninvasive techniques, particularly elastography modalities, has not been well explored. In this review, we describe the various noninvasive diagnostic tools for assessment of Schistosoma-related PPF including US parameters, serum biomarkers, and US-based elastography techniques. While elastography techniques have demonstrated value in the evaluation of HSS, the evidence remains limited with most studies recruiting a small number of patients. Longitudinal studies with larger sample size are required in order to devise robust criteria to accurately assess the performance of noninvasive techniques in the prediction of both regression and progression of the degree of PPF and identify their cost-effectiveness in community screening.

Muscle psoas indices measured by ultrasound in cirrhosis - Preliminary evaluation of sarcopenia assessment and prediction of liver decompensation and mortality.

BACKGROUND: No data on the European population exists regarding the use of an ultrasoundbased measurement of psoas diameter for sarcopenia assessment in cirrhosis. AIMS: To determine the applicability of an ultrasound measurement of the psoas muscle diameter in patients with decompensated liver cirrhosis and to assess whether this surrogate is associated with hospitalization due to decompensation and mortality. METHODS: In 75 consecutive patients with decompensated liver cirrhosis and in 20 control subjects (January 2016 to November 2017), psoas muscle diameter was prospectively measured. The reliable measurements were used for the further analysis. Relevant clinical and laboratory data was collected. RESULTS: Ultrasound measurement was applicable in 100% of control and in 72% of study subjects. Psoas to height ratio was significantly related to hospitalization and mortality (p < 0.0001, HR 0.717, 95% CI: 0.622-0.828 and p = 0.022; HR = 0.825, 95% CI: 0.701-0.973) as was psoas muscle index (p < 0.0001, HR = 0.881, 95% CI: 0.836-0.929 and p = 0.017; HR = 0.930, 95% CI: 0.876-0.987). CONCLUSIONS: Ultrasound measurement of psoas muscle diameter and its derived indices is applicable and associated with hospitalization and mortality in patients with decompensated liver cirrhosis.

Assessment of Hepatic Vascular Network Connectivity with Automated Graph Analysis of Dynamic Contrast-enhanced US to Evaluate Portal Hypertension in Patients with Cirrhosis: A Pilot Study.

PURPOSE: To test whether graph analysis of vascular images obtained with hepatic dynamic contrast material-enhanced (DCE) ultrasonography (US) allows calculation of the degree of organization of the liver circulation and whether graph properties are correlated to the severity of portal hypertension. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Fifteen patients with liver cirrhosis (nine men; mean age ± standard deviation, 55 years ± 8) who underwent DCE US and hepatic venous pressure gradient (HVPG) measurement and four healthy subjects (two men and two women; mean age, 34 years ± 4) were included between January 2007 and December 2008. Individual graph models ("vascular connectomes") were computed on the basis of time series analysis of video sequences of DCE US examinations (conducted with the disruption-reperfusion technique). Graph analysis was performed, and the clustering coefficient C was calculated. Correlations between clustering coefficient and HVPG were assessed. RESULTS: Healthy subjects had a high clustering coefficient of vascular connectome (C = 0.4447; interquartile range [IQR], 0.3864-0.4679), suggesting a highly organized hepatic vascular network. Conversely, patients with cirrhosis showed a low clustering coefficient, indicating disruption of normal anatomy (C = 0.0288; IQR, 0.0157-0.0861; P = .001 vs healthy subjects). The clustering coefficient decreased as HVPG increased, with a clustering coefficient of 0.0237 (IQR, 0.0066-0.0378) in patients with HVPG of at least 10 mm Hg versus 0.1180 (IQR, 0.0987-0.1414) in those with HVPG of less than 10 mm Hg (P = .006). The correlation between the best model derived from the distribution of the clustering coefficient (10 bins) of vascular connectome and HVPG had a Pearson correlation of 0.977 (root mean squared error, 1.57 mm Hg; P < .0001). CONCLUSION: This pilot study demonstrates that graph modeling of vascular connectivity based on video processing of liver DCE US examinations and subsequent graph analysis enable calculation of personalized parameters that reflect the degree of organization of the hepatic microvascular network and are correlated to the severity of portal hypertension in cirrhosis.

Non-invasive assessment of non-alcoholic fatty liver disease: ultrasound and transient elastography.

Non-alcoholic fatty liver disease (NAFLD) is extremely prevalent in the Western world. Non-invasive diagnostic methods should be able to reflect the presence and severity of liver fatty changes and the presence and severity of hepatic inflammation and fibrosis (features of non-alcoholic steato-hepatitis), since these are related to the risk of progression and clinical complications. This article will: a) review the rational basis for the use of ultrasound and transient elastography in patients with NAFLD; b) summarize available data regarding the diagnostic performance of these two widely used non-invasive imaging methods in patients with NAFLD; and c) give an overview of newer sonographic applications that might be used in clinical practice in the near future in this field.

A MELD-based model to determine risk of mortality among patients with acute variceal bleeding.

BACKGROUND & AIMS: Patients with cirrhosis with acute variceal bleeding (AVB) have high mortality rates (15%-20%). Previously described models are seldom used to determine prognoses of these patients, partially because they have not been validated externally and because they include subjective variables, such as bleeding during endoscopy and Child-Pugh score, which are evaluated inconsistently. We aimed to improve determination of risk for patients with AVB. METHODS: We analyzed data collected from 178 patients with cirrhosis (Child-Pugh scores of A, B, and C: 15%, 57%, and 28%, respectively) and esophageal AVB who received standard therapy from 2007 through 2010. We tested the performance (discrimination and calibration) of previously described models, including the model for end-stage liver disease (MELD), and developed a new MELD calibration to predict the mortality of patients within 6 weeks of presentation with AVB. MELD-based predictions were validated in cohorts of patients from Canada (n = 240) and Spain (n = 221). RESULTS: Among study subjects, the 6-week mortality rate was 16%. MELD was the best model in terms of discrimination; it was recalibrated to predict the 6-week mortality rate with logistic regression (logit, -5.312 + 0.207 • MELD; bootstrapped R(2), 0.3295). MELD values of 19 or greater predicted 20% or greater mortality, whereas MELD scores less than 11 predicted less than 5% mortality. The model performed well for patients from Canada at all risk levels. In the Spanish validation set, in which all patients were treated with banding ligation, MELD predictions were accurate up to the 20% risk threshold. CONCLUSIONS: We developed a MELD-based model that accurately predicts mortality among patients with AVB, based on objective variables available at admission. This model could be useful to evaluate the efficacy of new therapies and stratify patients in randomized trials.

Assessment of portal hypertension by transient elastography in patients with compensated cirrhosis and potentially resectable liver tumors.

BACKGROUND & AIMS: Patients with cirrhosis and small hepatocellular carcinoma with normal bilirubin and hepatic venous pressure gradient (HVPG) <10 mm Hg have >70% 5-year survival after hepatic resection. On the contrary, patients with HVPG ≥10 mm Hg (clinically significant portal hypertension, CSPH) frequently develop decompensation following surgery, with around 50% 5-year survival. Liver stiffness (LS) evaluation by transient elastography might non-invasively identify CSPH. We investigated the usefulness of LS predicting CSPH in patients with compensated cirrhosis and potentially resectable liver tumors. METHODS: Ninety-seven consecutive Child-Pugh A patients with potentially resectable liver tumors referred for HVPG measurement were prospectively evaluated. In fasting conditions LS was measured before the hemodynamic study. RESULTS: HVPG could be measured in all patients, whereas LS could not be measured in 18 (18.5%) obese patients. In the 79 patients with valid LS, 32 (40.5%) had CSPH; mean HVPG was 8.8±4.7 mm Hg. Mean LS was 18.4±12.3 kPa. LS showed a moderate correlation with HVPG (r=0.552; p<0.001). LS<13.6 kPa had high sensitivity (91%) but low specificity (57%) excluding CSPH. Conversely, LS>21 kPa had low sensitivity (53%) and high specificity (91%) predicting CSPH. 35% of patients had LS between 13.6 and 21 kPa ("grey zone"). CONCLUSIONS: These data suggest that in real-life scenarios half of patients with potentially resectable liver nodules can be non-invasively classified as having or not CSPH by LS. However, in the remaining half, LS is either not applicable or inaccurate. In this last population HVPG is still a non replaceable method to detect CSPH.