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Background & Aims: The SALVE Histopathology Group (SHG) developed and validated a grading and staging system for the clinical and full histological spectrum of alcohol-related liver disease (ALD) and evaluated its prognostic utility in a multinational cohort of 445 patients., Methods: SALVE grade was described by semiquantitative scores for steatosis, activity (hepatocellular injury and lobular neutrophils) and cholestasis. The histological diagnosis of steatohepatitis due to ALD (histological ASH, hASH) was based on the presence of hepatocellular ballooning and lobular neutrophils. Fibrosis staging was adapted from the Clinical Research Network staging system for non-alcoholic fatty liver disease and the Laennec staging system and reflects the pattern and extent of ALD fibrosis. There are 7 SALVE fibrosis stages (SFS) ranging from no fibrosis to severe cirrhosis., Results: Interobserver κ-value for each grading and staging parameter was >0.6. In the whole study cohort, long-term outcome was associated with activity grade and cholestasis, as well as cirrhosis with very broad septa (severe cirrhosis) (p <0.001 for all parameters). In decompensated ALD, adverse short-term outcome was associated with activity grade, hASH and cholestasis (p = 0.038, 0.012 and 0.001, respectively), whereas in compensated ALD, hASH and severe fibrosis/cirrhosis were associated with decompensation-free survival (p = 0.011 and 0.001, respectively). On multivariable analysis, severe cirrhosis emerged as an independent histological predictor of long-term survival in the whole study cohort. Severe cirrhosis and hASH were identified as independent predictors of short-term survival in decompensated ALD, and also as independent predictors of decompensation-free survival in compensated ALD., Conclusion: The SALVE grading and staging system is a reproducible and prognostically relevant method for the histological assessment of disease activity and fibrosis in ALD., Lay Summary: Patients with alcohol-related liver disease (ALD) may undergo liver biopsy to assess disease severity. We developed a system to classify ALD under the microscope by grading ALD activity and staging the extent of liver scarring. We validated the prognostic performance of this system in 445 patients from 4 European centers., Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice., Methods: This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH., Results: A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences of portal hypertension in patients with NASH were maintained across different strata of LSM values. LSM ≥25 kPa was the best cutoff to rule in CSPH in alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, and nonobese patients with NASH, whereas in obese NASH patients, the positive predictive value was only 62.8%. A new model for patients with NASH (ANTICIPATE-NASH model) to predict CSPH considering body mass index, LSM, and platelet count was developed, and a nomogram was constructed. LSM ≤15 kPa plus platelets ≥150 × 10/L ruled out CSPH in most etiologies., Discussion: Patients with cACLD of NASH etiology, especially obese patients with NASH, present lower prevalences of portal hypertension compared with other cACLD etiologies. LSM ≥25 kPa is sufficient to rule in CSPH in most etiologies, including nonobese patients with NASH, but not in obese patients with NASH.

Purpose:  Clinically significant portal hypertension (CSPH) is responsible for most of the complications in patients with cirrhosis. Liver stiffness (LS) measurement by vibration-controlled transient elastography (VCTE) is currently used to evaluate CSPH. Bi-dimensional shear wave elastography from General Electric (2D-SWE.GE) has not yet been validated for the diagnosis of PHT. Our aims were to test whether 2D-SWE.GE-LS is able to evaluate CSPH, to determine the reliability criteria of the method and to compare its accuracy with that of VCTE-LS in this clinical setting., Materials and Methods:  Patients with chronic liver disease referred to hepatic catheterization (HVPG) were consecutively enrolled. HVPG and LS by both VCTE and 2D-SWE.GE were performed on the same day. The diagnostic performance of each LS method was compared against HVPG and between each other., Results:  2D-SWE.GE-LS was possible in 123/127 (96.90 %) patients. The ability to record at least 5 LS measurements by 2D-SWE.GE and IQR < 30 % were the only features associated with reliable results. 2D-SWE.GE-LS was highly correlated with HVPG (r = 0.704; p < 0.0001), especially if HVPG < 10 mmHg and was significantly higher in patients with CSPH (15.52 vs. 8.14 kPa; p < 0.0001). For a cut-off value of 11.3 kPa, the AUROC of 2D-SWE.GE-LS to detect CSPH was 0.91, which was not inferior to VCTE-LS (0.92; p = 0.79). The diagnostic accuracy of LS by 2D-SWE.GE-LS to detect CSPH was similar with the one of VCTE-LS (83.74 % vs. 85.37 %; p = 0.238). The diagnostic accuracy was not enhanced by using different cut-off values which enhanced the sensitivity or the specificity. However, in the subgroup of compensated patients with alcoholic liver disease, 2D-SWE.GE-LS classified CSPH better than VCTE-LS (93.33 % vs. 85.71 %, p = 0.039)., Conclusion:  2D-SWE.GE-LS has good accuracy, not inferior to VCTE-LS, for the diagnosis of CSPH., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: The assessment of liver fibrosis is essential in the management of patients with chronic liver diseases. Liver biopsy is considered the gold standard procedure for this purpose, though the recent development of new elastosonographic techniques to measure liver stiffness (LS) noninvasively is promising. Point quantification elastography (PQE) showed good results but less is known about the level of skill needed to obtain reliable results. The aim of the study was to evaluate the reproducibility of PQE in assessing LS in healthy subjects comparing three operators with different expertise., Methods: Between December 2012 and April 2013, 50 consecutive healthy volunteers (18 males, 32 females), median age 30 years (range 25-66) and BMI 22.4 (range 16.7-33.6) were submitted to PQE (iU22 Philips, Bothell, WA, USA) by three operators: two US and elastography providers (one expert and one with intermediate skill) and a skilled transient elastography (Fibroscan) operator with no expertise in US. Intra- and inter-observer agreements were assessed by intraclass correlation coefficient (ICC)., Results: PQE measurement was obtained in all subjects by all evaluators. No significant differences of mean liver stiffness were found among operators (P = 0.980). Intra-observer agreement was excellent 0.918 (0.941 for expert, 0.917 for intermediate and 0.888 for novice). The ICC of the inter-observer agreement among the three ratters was excellent (0.882) and was higher in normal than overweight patients (0.923 vs. 0.603; P = 0.011)., Conclusion: PQE is a reliable and reproducible non-invasive method for the assessment of LE, and can be performed also by a non-experienced operator.

Background: The diagnostic performance of biochemical scores and artificial neural network models for portal hypertension and cirrhosis is not well established., Aims: To assess diagnostic accuracy of six serum scores, artificial neural networks and liver stiffness measured by transient elastography, for diagnosing cirrhosis, clinically significant portal hypertension and oesophageal varices., Methods: 202 consecutive compensated patients requiring liver biopsy and hepatic venous pressure gradient measurement were included. Several serum tests (alone and combined into scores) and liver stiffness were measured. Artificial neural networks containing or not liver stiffness as input variable were also created., Results: The best non-invasive method for diagnosing cirrhosis, portal hypertension and oesophageal varices was liver stiffness (C-statistics=0.93, 0.94, and 0.90, respectively). Among serum tests/scores the best for diagnosing cirrhosis and portal hypertension and oesophageal varices were, respectively, Fibrosis-4, and Lok score. Artificial neural networks including liver stiffness had high diagnostic performance for cirrhosis, portal hypertension and oesophageal varices (accuracy>80%), but were not statistically superior to liver stiffness alone., Conclusions: Liver stiffness was the best non-invasive method to assess the presence of cirrhosis, portal hypertension and oesophageal varices. The use of artificial neural networks integrating different non-invasive tests did not increase the diagnostic accuracy of liver stiffness alone., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Liver stiffness (LS), spleen stiffness (SS) and serum markers have been proposed to non-invasively assess portal hypertension or oesophageal varices (EV) in cirrhotic patients. We aimed to evaluate the performance of a stepwise algorithm that combines Lok score with LS and SS for diagnosing high-risk EV (HREV) and to compare it with other already-validated non-invasive methods., Methods: We performed a cross-sectional study including 136 consecutive compensated cirrhotic patients with various aetiologies, divided into training (90) and validation (46) set. Endoscopy was performed within 6 months from inclusion for EV screening. Spleen diameter was assessed by ultrasonography. LS and SS were measured using Fibroscan. Lok score, platelet count/spleen diameter ratio, LSM-spleen diameter to platelet ratio score and oesophageal varices risk score (EVRS) were calculated and their diagnostic accuracy for HREV was assessed. The algorithm classified patients as having/not-having HREV. Its performance was tested and compared in both groups., Results: In the training set, all variables could select patients with HREV with moderate accuracy, the best being LSPS (AUROC = 0.818; 0.93 sensitivity; 0.63 specificity). EVRS, however, was the only independent predictor of HREV (OR = 1.521; P = 0.032). The algorithm correctly classified 69 (76.66%) patients in the training set (P < 0.0001) and 36 (78.26%) in the validation one. In the validation group, the algorithm performed slightly better than LSPS and EVRS, showing 100% sensitivity and negative predicted value., Conclusion: The stepwise algorithm combining Lok score, LS and SS could be used to select patients at low risk of having HREV and who may benefit from more distanced endoscopic evaluation., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Liver stiffness measurement (LSM) is a good, but still limited tool to noninvasively assess complications and prognosis in patients with advanced liver disease. This review aims to consider the role of LSM for the diagnosis of portal hypertension-related complications and for assessment of prognosis in cirrhotic patients, and to highlight the drawbacks as well as some alternatives for improving the performance. Hence, this field is far from being closed, and deserves more attention. There is still a place for more carefully designed studies to find new, innovative and reliable approaches.

Background & Aims: Liver stiffness (LS) is increased in liver cirrhosis, higher values being associated with complications, among them the development of hepatocellular carcinoma (HCC). However, LS values alone cannot accurately differentiate patients with HCC. Therefore, our aim was to study the performance of LS measurement data and common biomarkers for the detection of HCC in HCV related liver cirrhosis., Methods: We performed a case matching study comparing HCV cirrhotic patients with and without HCC (72 in each group) that were identical in terms of sex, age, BMI and duration of HCV infection. All patients underwent LS measurement, endoscopy, liver imaging and liver function tests. A multiple regression analysis was performed and a HCC detection model was calculated, which was further validated in another group of 40 HCV infected cirrhotics, of whom 52% had HCC., Results: In the HCC group, LS was significantly higher (42 vs 27 kPa, p<0.0001). In the multivariate analysis higher values of LS, alanine-aminotransferase (ALAT), alpha-fetoprotein (AFP) and interquartile range (IQR) of LS measurements were independently associated with the presence of HCC (p<0.0001 for all parameters; Odds Ratios of 8.27, 1.01, 1.04 and 1.16, respectively). The detection model combining the four variables showed a good diagnostic performance in both training and validation groups, with AUROCs of 0.86 and 0.8, respectively. All variables were also positively correlated with tumor size., Conclusion: In HCV related cirrhosis, HCC is associated with increased LS and IQR values and high ALAT and AFP levels. By combining these four parameters into a regression model, liver cancer may be noninvasively predicted with good accuracy.

Background & Aims: The current study aimed to establish the liver stiffness (LS) cut-off values and their performance in the prediction of the fibrosis stage in chronic hepatitis C (CHC) patients, to find the anthropometric and biochemical factors leading to overestimation of the fibrosis stage and to analyze the factors leading to the technique failure., Methods: 1,202 consecutive CHC patients were prospectively included in the study. All of them underwent percutaneous liver biopsy for grading and staging the disease (METAVIR) and were referred to LS measurement 1 day prior to biopsy., Results: LS values varied between 2.8-75 kPa. Transient elastography success rate (SR) ranged between 0-100% (84.82 +/- 24.46%). In 27 patients (2.2%), no valid measurement was obtained; high BMI influenced independently the measurement failure. In 11.2% of cases, the SR was <60%, but 10 valid measurements were nevertheless recorded; the female sex and high BMI were the only factors independently leading to a SR<60%. AUROCs for the diagnosis of fibrosis F≥1, F≥2, F≥3, and F=4 were 0.879, 0.889, 0.941 and 0.970, for the cut-off values of 5.3 kPa, 7.4 kPa, 9.1 kPa and 13.2 kPa respectively, and they did not significantly differ from the adjusted AUROC values. The patients with false positive results were younger and had significantly higher serum aminotransferase (ALT, AST) and gamma glutamyl-transpeptidase levels than the patients with concordant results. The multivariate analysis showed that only high ALT levels influenced independently the occurrence of false positive results., Conclusion: Transient elastography is a useful non-invasive method for the assessment of fibrosis in CHC patients. However, it must be interpreted in the clinical and biochemical context, in order to insure high-quality results.

Objective: Hepatic fibrosis, the principal pointer to the development of a liver disease within chronic hepatitis C, can be measured through several stages. The correct evaluation of its degree, based on recent different non-invasive procedures, is of current major concern. The latest methodology for assessing it is the Fibroscan and the effect of its employment is impressive. However, the complex interaction between its stiffness indicator and the other biochemical and clinical examinations towards a respective degree of liver fibrosis is hard to be manually discovered. In this respect, the novel, well-performing evolutionary-powered support vector machines are proposed towards an automated learning of the relationship between medical attributes and fibrosis levels. The traditional support vector machines have been an often choice for addressing hepatic fibrosis, while the evolutionary option has been validated on many real-world tasks and proven flexibility and good performance., Methods and Materials: The evolutionary approach is simple and direct, resulting from the hybridization of the learning component within support vector machines and the optimization engine of evolutionary algorithms. It discovers the optimal coefficients of surfaces that separate instances of distinct classes. Apart from a detached manner of establishing the fibrosis degree for new cases, a resulting formula also offers insight upon the correspondence between the medical factors and the respective outcome. What is more, a feature selection genetic algorithm can be further embedded into the method structure, in order to dynamically concentrate search only on the most relevant attributes. The data set refers 722 patients with chronic hepatitis C infection and 24 indicators. The five possible degrees of fibrosis range from F0 (no fibrosis) to F4 (cirrhosis)., Results: Since the standard support vector machines are among the most frequently used methods in recent artificial intelligence studies for hepatic fibrosis staging, the evolutionary method is viewed in comparison to the traditional one. The multifaceted discrimination into all five degrees of fibrosis and the slightly less difficult common separation into solely three related stages are both investigated. The resulting performance proves the superiority over the standard support vector classification and the attained formula is helpful in providing an immediate calculation of the liver stage for new cases, while establishing the presence/absence and comprehending the weight of each medical factor with respect to a certain fibrosis level., Conclusion: The use of the evolutionary technique for fibrosis degree prediction triggers simplicity and offers a direct expression of the influence of dynamically selected indicators on the corresponding stage. Perhaps most importantly, it significantly surpasses the classical support vector machines, which are both widely used and technically sound. All these therefore confirm the promise of the new methodology towards a dependable support within the medical decision-making., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background/aims: Transient elastography (TE) is a noninvasive method for predicting liver fibrosis, mainly validated in patients with viral hepatitis. Information is still limited concerning its performance in non-alcoholic steatohepatitis (NASH) patients. We aimed to assess the value of TE in the prediction of fibrosis stage in NASH as well as the factors determining the discordance between the TE-predicted and the biopsy-proven fibrosis stage in these patients., Methods: Liver biopsy and TE were performed on 72 consecutive NASH patients. Fibrosis, lobular inflammation, ballooning and steatosis were evaluated (Brunt system)., Results: Liver stiffness (LS) values ranged from 2.80 to 16.90 kPa. In the univariate analysis, LS was correlated with fibrosis (r=0.661; p<0.0001), steatosis (r=0.435, p<0.0001), ballooning (r=0.385; p=0.001) and lobular inflammation (r=0.364; p=0.002). In multivariate analysis, only fibrosis significantly correlated with LS (p<0.0001). The median (and range) LS values (kPa) according to the fibrosis stages were: 4.90 (2.80-7.30) for F0; 6.15 (4.80-12.50) for F1; 6.90 (3.30-16.90) for F2 and 14.00 (10.70-14.10) for F3, with significant difference between stages, except for F1-F2 (p=0.249). Cut off values were calculated for predicting each fibrosis stage: 5.3 kPa (AUROC=0.879) for F1; 6.8 kPa (AUROC=0.789) for F2; and 10.4 kPa (AUROC=0.978) for F3. Patients with false-positive results had a significantly higher ALT level than those with concordant results (p=0.039)., Conclusion: In NASH patients, TE allows a reliable assessment and prediction of liver fibrosis, especially in advanced stages. Steatosis, ballooning and inflammation do not influence liver stiffness.

Background and Aims: The current study aims to evaluate the performance of a new elastographic method (ARFI) in noninvasive fibrosis assessment and to compare it to another validated technology (transient elastography, TE)., Method: 112 consecutive chronic hepatitis C patients (histologically proven according to the Metavir scoring system: 12.5% F0, 26.6% F1, 16.1% F2, 7.1% F3, 37.5% F4) were prospectively included in this study. They were examined on the same day, using both ARFI (with shear wave velocity--SWV-quantification) and TE (with liver stiffness quantification)., Results: SWV is correlated only with fibrosis (r=0.717, p less than 0.0001) and necroinflammatory activity (r=0.328, p=0.014), but not with steatosis (r=0.122, p=0.321). There is a significant increase of SWV in parallel with the increase in the fibrosis stage: 1.079+/-0.150 (F0-F1), 1.504+/-0.895 (F2), 1.520+/-0.575 (F3), 2.552+/-0.782 (F4), p<0.0001, but there is a certain degree of overlap between the consecutive stages F1-F2 (p=0.072), F2-F3 (p=0.965). SWV cut-off values (m/s) that were predictive for each fibrosis stage were: 1.19 (F more or equal to 1), 1.34 (F>or=2), 1.61 (F more or equal to 3) and 2.00 (F4). AUROC for ARFI vs TE were: 0.709 vs 0.902, p=0.006 (F>or=1), 0.851 vs 0.941, p=0.022 (F>or=2), 0.869 vs 0.926, p=0.153 (F>or=3) and 0.911 vs 0.945, p=0.331 (F4)., Conclusions: ARFI allows SWV quantification, in strong correlation with the fibrosis stage. Steatosis does not influence SWV. The maximal performance of the method consists of the prediction in severe fibrosis and cirrhosis. The diagnostic accuracy is strongly comparable to TE only for the prediction of severe fibrosis and cirrhosis, whereas for earlier stages, TE performs better.

Purpose: In chronic liver diseases, liver stiffness (LS) is increased, primarily because of liver fibrosis, but other factors, such as intrahepatic deposits, may also be involved. We hypothesized that intrahepatic copper accumulation occurring in Wilson's disease (WD) also leads to an increase in LS. The aim of this study was thus to investigate the changes in LS during treatment in pediatric patients with WD.Methods: Consecutive patients younger than 18 years old, whose WD was diagnosed between 2008 and 2013, were enrolled. All patients underwent testing for liver function and urinary copper excretion, and LS was measured on transient elastography at baseline and at 6- to 12-month intervals during specific therapy.Results: Nine patients were included in the analysis; only two were diagnosed with cirrhosis. The median LS decreased during treatment from 15.1 kPa (range, 5.1-66 kPa) at baseline to 10 kPa (4-16.1 kPa) at follow-up interval 1, and to 6.1 kPa (3.9-11.6 kPa) at follow-up interval 2 (p < 0.0001). In parallel, the differences in urinary copper excretion over the follow-up period were not statistically significant, although the decrease in LS correlated with the increase in urinary copper excretion (r = 0.6).Conclusions: In pediatric patients with WD, LS is high at the time of diagnosis and decreases during specific treatment, in parallel with an increase in the urinary copper concentration. [ABSTRACT FROM AUTHOR]