Liver stiffness as a cornerstone in heart disease risk assessment.

Metabolic dysfunction-associated steatotic liver disease (MASLD) typically presents with hepatic fibrosis in advanced disease, resulting in increased liver stiffness. A subset of patients further develops liver cirrhosis and hepatocellular carcinoma. Cardiovascular disease is a common comorbidity in patients with MASLD and its prevalence is increasing in parallel. Recent evidence suggests that especially liver stiffness, whether or not existing against a background of MASLD, is associated with heart diseases. We conducted a narrative review on the role of liver stiffness in the prediction of highly prevalent heart diseases including heart failure, cardiac arrhythmias (in particular atrial fibrillation), coronary heart disease, and aortic valve sclerosis. Research papers were retrieved from major scientific databases (PubMed, Web of Science) until September 2023 using 'liver stiffness' and 'liver fibrosis' as keywords along with the latter cardiac conditions. Increased liver stiffness, determined by vibration-controlled transient elastography or hepatic fibrosis as predicted by biomarker panels, are associated with a variety of cardiovascular diseases, including heart failure, atrial fibrillation, and coronary heart disease. Elevated liver stiffness in patients with metabolic liver disease should lead to considerations of cardiac workup including N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide determination, electrocardiography, and coronary computed tomography angiography. In addition, patients with MASLD would benefit from heart disease case-finding strategies in which liver stiffness measurements can play a key role. In conclusion, increased liver stiffness should be a trigger to consider a cardiac workup in metabolically compromised patients.

Enhanced diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based Agile scores.

BACKGROUND & AIMS: Currently available non-invasive tests, including fibrosis-4 index (FIB-4) and liver stiffness measurement (LSM by VCTE), are highly effective at excluding advanced fibrosis (AF) (F ≥3) or cirrhosis in people with non-alcoholic fatty liver disease (NAFLD), but only have moderate ability to rule-in these conditions. Our objective was to develop and validate two new scores (Agile 4 and Agile 3+) to identify cirrhosis or AF, respectively, with optimized positive predictive value and fewer indeterminate results, in individuals with NAFLD attending liver clinics. METHODS: This international study included seven adult cohorts with suspected NAFLD who underwent liver biopsy, LSM and blood sampling during routine clinical practice or screening for trials. The population was randomly divided into a training set and an internal validation set, on which the best-fitting logistic regression model was built, and performance and goodness of fit were assessed, respectively. Furthermore, both scores were externally validated on two large cohorts. Cut-offs for high sensitivity and specificity were derived in the training set to rule-out and rule-in cirrhosis or AF and then tested in the validation set and compared to FIB-4 and LSM. RESULTS: Each score combined LSM, AST/ALT ratio, platelets, sex and diabetes status, as well as age for Agile 3+. Calibration plots for Agile 4 and Agile 3+ indicated satisfactory to excellent goodness of fit. Agile 4 and Agile 3+ outperformed FIB-4 and LSM in terms of AUROC, percentage of patients with indeterminate results and positive predictive value to rule-in cirrhosis or AF. CONCLUSIONS: The two novel non-invasive scores improve identification of cirrhosis or AF among individuals with NAFLD attending liver clinics and reduce the need for liver biopsy in this population. IMPACT AND IMPLICATIONS: Non-invasive tests currently used to identify patients with advanced fibrosis or cirrhosis, such as fibrosis-4 index and liver stiffness measurement by vibration-controlled transient elastography, have high negative predictive values but high false positive rates, while results are indeterminate for a large number of cases. This study provides scores that will help the clinician diagnose advanced fibrosis or cirrhosis. These new easy-to-implement scores will help liver specialists to better identify (1) patients who need more intensive follow-up, (2) patients who should be referred for inclusion in therapeutic trials, and (3) which patients should be treated with pharmacological agents when effective therapies are approved.

Vibration-controlled transient elastography for noninvasive evaluation of liver steatosis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) refers to a large spectrum of liver disorders and is the most common cause of metabolic liver disease. The current gold standard for diagnosing NAFLD is liver biopsy, which can lead to severe complications. PURPOSE: Among the noninvasive diagnostic options, we chose to use a FibroScan and developed an algorithm applying the Voigt rheological model to assess the viscoelastic properties of the liver and evaluate its performance for the diagnosis of steatosis. METHODS: Twenty-two healthy volunteers and 20 patients with steatosis were included. For each subject, we used a modified FibroScan, whose data had been processed by our algorithm to separate the two viscoelastic components, stiffness µ, and viscosity η. The liver elasticity µFibroscan measured by the FibroScan was also recorded. Mann-Whitney tests and receiver operating characteristics (ROCs) curve analyses were performed to compare the parameters between the two groups, and Pearson's correlation coefficients were used to assess the correlations between the parameters. RESULTS: We found a good correlation between η and µFibroscan (r = 0.75), and poor correlations between µ and both η and µFibroscan (r = 0.33 and r = 0.03, respectively). We also showed that η and µFibroscan were higher in patients with steatosis compared to healthy volunteers, with area under the ROCs (AUROC) curve at 0.814 and 0.891, respectively. Conversely, µ was not different between the two groups (AUROC = 0.557). CONCLUSIONS: Our novel method successfully separated the two viscoelastic properties of the liver, of which the parameter η is a sensitive indicator for steatosis.

FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.

BACKGROUND: The burden of non-alcoholic fatty liver disease (NAFLD) is increasing globally, and a major priority is to identify patients with non-alcoholic steatohepatitis (NASH) who are at greater risk of progression to cirrhosis, and who will be candidates for clinical trials and emerging new pharmacotherapies. We aimed to develop a score to identify patients with NASH, elevated NAFLD activity score (NAS≥4), and advanced fibrosis (stage 2 or higher [F≥2]). METHODS: This prospective study included a derivation cohort before validation in multiple international cohorts. The derivation cohort was a cross-sectional, multicentre study of patients aged 18 years or older, scheduled to have a liver biopsy for suspicion of NAFLD at seven tertiary care liver centres in England. This was a prespecified secondary outcome of a study for which the primary endpoints have already been reported. Liver stiffness measurement (LSM) by vibration-controlled transient elastography and controlled attenuation parameter (CAP) measured by FibroScan device were combined with aspartate aminotransferase (AST), alanine aminotransferase (ALT), or AST:ALT ratio. To identify those patients with NASH, an elevated NAS, and significant fibrosis, the best fitting multivariable logistic regression model was identified and internally validated using boot-strapping. Score calibration and discrimination performance were determined in both the derivation dataset in England, and seven independent international (France, USA, China, Malaysia, Turkey) histologically confirmed cohorts of patients with NAFLD (external validation cohorts). This study is registered with ClinicalTrials.gov, number NCT01985009. FINDINGS: Between March 20, 2014, and Jan 17, 2017, 350 patients with suspected NAFLD attending liver clinics in England were prospectively enrolled in the derivation cohort. The most predictive model combined LSM, CAP, and AST, and was designated FAST (FibroScan-AST). Performance was satisfactory in the derivation dataset (C-statistic 0·80, 95% CI 0·76-0·85) and was well calibrated. In external validation cohorts, calibration of the score was satisfactory and discrimination was good across the full range of validation cohorts (C-statistic range 0·74-0·95, 0·85; 95% CI 0·83-0·87 in the pooled external validation patients' cohort; n=1026). Cutoff was 0·35 for sensitivity of 0·90 or greater and 0·67 for specificity of 0·90 or greater in the derivation cohort, leading to a positive predictive value (PPV) of 0·83 (84/101) and a negative predictive value (NPV) of 0·85 (93/110). In the external validation cohorts, PPV ranged from 0·33 to 0·81 and NPV from 0·73 to 1·0. INTERPRETATION: The FAST score provides an efficient way to non-invasively identify patients at risk of progressive NASH for clinical trials or treatments when they become available, and thereby reduce unnecessary liver biopsy in patients unlikely to have significant disease. FUNDING: Echosens and UK National Institute for Health Research.

Diagnostic Performance of MR Elastography and Vibration-controlled Transient Elastography in the Detection of Hepatic Fibrosis in Patients with Severe to Morbid Obesity.

Purpose To evaluate the diagnostic performance and examination success rate of magnetic resonance (MR) elastography and vibration-controlled transient elastography (VCTE) in the detection of hepatic fibrosis in patients with severe to morbid obesity. Materials and Methods This prospective and HIPAA-compliant study was approved by the institutional review board. A total of 111 patients (71 women, 40 men) participated. Written informed consent was obtained from all patients. Patients underwent MR elastography with two readers and VCTE with three observers to acquire liver stiffness measurements for liver fibrosis assessment. The results were compared with those from liver biopsy. Each pathology specimen was evaluated by two hepatopathologists according to the METAVIR scoring system or Brunt classification when appropriate. All imaging observers were blinded to the biopsy results, and all hepatopathologists were blinded to the imaging results. Examination success rate, interobserver agreement, and diagnostic accuracy for fibrosis detection were assessed. Results In this obese patient population (mean body mass index = 40.3 kg/m2; 95% confidence interval [CI]: 38.7 kg/m2, 41.8 kg/m2]), the examination success rate was 95.8% (92 of 96 patients) for MR elastography and 81.3% (78 of 96 patients) or 88.5% (85 of 96 patients) for VCTE. Interobserver agreement was higher with MR elastography than with biopsy (intraclass correlation coefficient, 0.95 vs 0.89). In patients with successful MR elastography and VCTE examinations (excluding unreliable VCTE examinations), both MR elastography and VCTE had excellent diagnostic accuracy in the detection of clinically significant hepatic fibrosis (stage F2-F4) (mean area under the curve: 0.93 [95% CI: 0.85, 0.97] vs 0.91 [95% CI: 0.83, 0.96]; P = .551). Conclusion In this obese patient population, both MR elastography and VCTE had excellent diagnostic performance for assessing hepatic fibrosis; MR elastography was more technically reliable than VCTE and had a higher interobserver agreement than liver biopsy. © RSNA, 2016 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on January 25, 2017.

AdipoScan: A Novel Transient Elastography-Based Tool Used to Non-Invasively Assess Subcutaneous Adipose Tissue Shear Wave Speed in Obesity.

We describe a novel device called the AdipoScan that was adapted from the FibroScan to specifically assess shear wave speed (SWS) in human abdominal subcutaneous adipose tissue (scAT). Measurement reproducibility was assessed on tissue-mimicking phantoms with and without repositioning, with resultant coefficients of variation of 1% and 0%, respectively, as well as in vivo (14% and 7%, respectively). The applicability of the AdipoScan was tested on 19 non-obese volunteers, and a scAT thickness >2 cm was found to be mandatory to perform a valid measurement. Abdominal scAT SWS was assessed in 73 severely obese subjects, all candidates for bariatric surgery. Subcutaneous AT SWS was positively associated with scAT fibrosis and obesity-related co-morbidities such as hypertension, glycemic status, dyslipidemia and liver dysfunction. These results suggest that the AdipoScan could be a useful non-invasive tool to evaluate scAT fibrosis and metabolic complications in obesity. Further investigation is required to evaluate the relevance of using the AdipoScan to predict patient weight trajectories and metabolic outcomes after bariatric surgery.

Transient elastography with the XL probe rapidly identifies patients with nonhepatic ascites.

BACKGROUND: In contrast with other elastographic techniques, ascites is considered an exclusion criterion for assessment of fibrosis stage by transient elastography. However, a normal liver stiffness could rule out hepatic causes of ascites at an early stage. The aim of the present study was to determine whether liver stiffness can be generally determined by transient elastography through an ascites layer, to determine whether the ascites-mediated increase in intra-abdominal pressure affects liver stiffness, and to provide initial data from a pilot cohort of patients with various causes of ascites. METHODS AND RESULTS: Using the XL probe in an artificial ascites model, we demonstrated (copolymer phantoms surrounded by water) that a transient elastography-generated shear wave allows accurate determination of phantom stiffness up to a water lamella of 20 mm. We next showed in an animal ascites model that increased intra-abdominal pressure does not affect liver stiffness. Liver stiffness was then determined in 24 consecutive patients with ascites due to hepatic (n = 18) or nonhepatic (n = 6) causes. The cause of ascites was eventually clarified using routine clinical, imaging, laboratory, and other tools. Valid (75%) or acceptable (25%) liver stiffness data could be obtained in 23 patients (95.8%) with ascites up to an ascites lamella of 39 mm. The six patients (25%) with nonhepatic causes of ascites (eg, pancreatitis, peritoneal carcinomatosis) had a significantly lower liver stiffness (<8 kPa) as compared with the remaining patients with hepatic ascites (>30 kPa). Mean liver stiffness was 5.4 kPa ± 1.3 versus 66.2 ± 13.3 kPa. CONCLUSION: In conclusion, the presence of ascites and increased intra-abdominal pressure does not alter underlying liver stiffness as determined by transient elastography. We suggest that, using the XL probe, transient elastography can be used first-line to identify patients with nonhepatic ascites at an early stage.

Transient micro-elastography: A novel non-invasive approach to measure liver stiffness in mice.

AIM: To develop and validate a transient micro-elastography device to measure liver stiffness (LS) in mice. METHODS: A novel transient micro-elastography (TME) device, dedicated to LS measurements in mice with a range of measurement from 1-170 kPa, was developed using an optimized vibration frequency of 300 Hz and a 2 mm piston. The novel probe was validated in a classical fibrosis model (CCl(4)) and in a transgenic murine model of systemic amyloidosis. RESULTS: TME could be successfully performed in control mice below the xiphoid cartilage, with a mean LS of 4.4 ± 1.3 kPa, a mean success rate of 88%, and an excellent intra-observer agreement (0.98). Treatment with CCl(4) over seven weeks drastically increased LS as compared to controls (18.2 ± 3.7 kPa vs 3.6 ± 1.2 kPa). Moreover, fibrosis stage was highly correlated with LS (Spearman coefficient = 0.88, P < 0.01). In the amyloidosis model, much higher LS values were obtained, reaching maximum values of > 150 kPa. LS significantly correlated with the amyloidosis index (0.93, P < 0.0001) and the plasma concentration of mutant hapoA-II (0.62, P < 0.005). CONCLUSION: Here, we have established the first non-invasive approach to measure LS in mice, and have successfully validated it in two murine models of high LS.

Liver stiffness: a novel parameter for the diagnosis of liver disease.

The noninvasive quantitation of liver stiffness (LS) by ultrasound based transient elastography using FibroScan® has revolutionized the diagnosis of liver diseases, namely liver cirrhosis. Alternative techniques such as acoustic radiation impulse frequency imaging or magnetic resonance elastography are currently under investigation. LS is an excellent surrogate marker of advanced fibrosis (F3) and cirrhosis (F4) outscoring all previous noninvasive approaches to detect cirrhosis. LS values below 6 kPa are considered as normal and exclude ongoing liver disease. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. LS highly correlates with portal pressure, and esophageal varices are likely at values >20 kPa. Many other factors may also increase LS such as hepatic infiltration with tumor cells, mast cells (mastocytosis), inflammatory cells (all forms of hepatitis) or amyloidosis. In addition, LS is directly correlated with the venous pressure (eg, during liver congestion) and is increased during mechanic cholestasis. Thus, LS should always be interpreted in the context of clinical, imaging and laboratory findings. Finally, LS has helped to better understand the molecular mechanisms underlying liver fibrosis. The novel pressure-stiffness-fibrosis sequence hypothesis is introduced.

Cross-validation of magnetic resonance elastography and ultrasound-based transient elastography: a preliminary phantom study.

PURPOSE: To cross-validate two recent noninvasive elastographic techniques, ultrasound-based transient elastography (UTE) and magnetic resonance elastography (MRE). As potential alternatives to liver biopsy, UTE and MRE are undergoing clinical investigations for liver fibrosis diagnosis and liver disease management around the world. These two techniques use tissue stiffness as a marker for disease state and it is important to do a cross-validation study of both elastographic techniques to determine the consistency with which the two techniques can measure the mechanical properties of materials. MATERIALS AND METHODS: In this study, 19 well-characterized phantoms with a range of stiffness values were measured by two clinical devices (a Fibroscan and an MRE system based respectively on the UTE and MRE techniques) successively with the operators double-blinded. RESULTS: Statistical analysis showed that the correlation coefficient was r(2) = 0.93 between MRE and UTE, and there was no evidence of a systematic difference between them within the range of stiffnesses examined. CONCLUSION: These two noninvasive methods, MRE and UTE, provide clinicians with important new options for improving patient care regarding liver diseases in terms of the diagnosis, prognosis, and monitoring of fibrosis progression, as well for evaluating the efficacy of treatment.

Liver stiffness measurement in children using FibroScan: feasibility study and comparison with Fibrotest, aspartate transaminase to platelets ratio index, and liver biopsy.

OBJECTIVE: Transient elastography (FibroScan) is a novel, noninvasive, rapid bedside method to assess liver fibrosis by measuring liver stiffness in adult patients. The usefulness of FibroScan in children with chronic liver diseases is unknown. The aim of this prospective study was to evaluate the feasibility of liver stiffness measurement and to compare FibroScan, Fibrotest, and aspartate transaminase to platelets ratio index (APRI) with liver biopsy for the diagnosis of cirrhosis in children with chronic liver diseases. PATIENTS AND METHODS: Between February 2004 and October 2005, 116 consecutive children with chronic liver diseases were prospectively included. All except 1 child (58 boys, mean age 10.7 years) could have noninvasive tests for fibrosis: FibroScan, Fibrotest, and APRI, and, when necessary, a liver biopsy (n = 33). RESULTS: FibroScan, Fibrotest, and APRI were correlated with clinical or biological parameters of chronic liver diseases, but the FibroScan marker correlated most with all parameters. By histology, the METAVIR fibrosis category score was F1 in 7 cases, F2 in 8 cases, F3 in 6 cases, and F4 in 12 cases. FibroScan, Fibrotest, and APRI were significantly correlated with the METAVIR fibrosis score. For the diagnosis of cirrhosis, the area under the receiver operating characteristic curve was 0.88, 0.73, and 0.73 for FibroScan, Fibrotest, and APRI, respectively. CONCLUSIONS: These results indicate that liver stiffness measurement is feasible in children and is related to liver fibrosis. A specific probe dedicated to children and slender patients has thus been developed and is currently under evaluation. The FibroScan equipped with this specific probe could become a useful tool for the management of chronic liver diseases in children.

Transient elastography: a new noninvasive method for assessment of hepatic fibrosis.

Chronic hepatitis is accompanied by progressive deposit of hepatic fibrosis, which may lead to cirrhosis. Evaluation of liver fibrosis is, thus, of great clinical interest and, up to now, has been assessed with liver biopsy. This work aims to evaluate a new noninvasive device to quantify liver fibrosis: the shear elasticity probe or fibroscan. This device is based on one-dimensional (1-D) transient elastography, a technique that uses both ultrasound (US) (5 MHz) and low-frequency (50 Hz) elastic waves, whose propagation velocity is directly related to elasticity. The intra- and interoperator reproducibility of the technique, as well as its ability to quantify liver fibrosis, were evaluated in 106 patients with chronic hepatitis C. Liver elasticity measurements were reproducible (standardized coefficient of variation: 3%), operator-independent and well correlated (partial correlation coefficient = 0.71, p < < 0.0001) to fibrosis grade (METAVIR). The areas under the receiver operating characteristic (ROC) curves were 0.88 and 0.99 for the diagnosis of patients with significant fibrosis (>/= F2) and with cirrhosis ( = F4), respectively. The Fibroscan is a noninvasive, painless, rapid and objective method to quantify liver fibrosis.