Noise annoyance and cardiovascular disease risk: results from a 10-year follow-up study.

The relationship between noise annoyance and risk of cardiovascular disease (CVD) still needs to be fully elucidated. Thus, we examined the relationship between noise annoyance and CVD risk in a large population-based cohort study. Cross-sectional (N = 15,010, aged 35-74 years, baseline investigation period 2007-2012) and prospective data (5- and 10-year follow-up from 2012 to 2022) from the Gutenberg Health Study were used to examine the relationship between noise annoyance due to different sources and risk of prevalent and incident CVD comprising atrial fibrillation, coronary artery disease, myocardial infarction, stroke, chronic heart failure, peripheral artery disease, and venous thromboembolism. In cross-sectional analyses, noise annoyance was an independent risk factor for prevalent CVD, with the strongest associations seen for noise annoyance during sleep (e.g., neighborhood noise annoyance: odds ratio 1.20, 95% confidence interval 1.13-1.27, p < 0.0001). While in the 10-year follow-up, mostly positive associations (although not significant) between noise annoyance and incident CVD were observed, no indication of increased CVD risk was observed after 5 years of follow-up. Noise annoyance due to different sources was associated with prevalent CVD, whereas only weak associations with incident CVD were found. Further large-scale studies are needed to establish the relationship between noise annoyance and risk of CVD.

Short-term reduction of dietary gluten improves metabolic-dysfunction associated steatotic liver disease: A randomised, controlled proof-of-concept study.

BACKGROUND: The current management of metabolic dysfunction-associated steatotic liver disease (MASLD) relies on lifestyle intervention. Prior studies have shown that nutritional wheat amylase trypsin inhibitors (ATI) activate toll-like receptor 4 on intestinal myeloid cells to enhance intestinal and extra-intestinal inflammation, including the promotion of murine MASLD, insulin resistance and liver fibrosis. AIMS: We aimed to assess the impact of ATI (gluten)-free diet in liver as well as metabolic parameters of biopsy-proven MASLD patients. METHODS: We performed a 6-week, proof-of-concept 1:1 randomised controlled trial of an ATI-free diet. The controls followed a balanced diet recommended by the German Nutrition Society. We assessed changes in controlled attenuation parameter (CAP), body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR). Patient-reported outcomes were assessed by the CLDQ-NASH questionnaire. Forty-five patients were consecutively enrolled (21 in the intervention arm and 24 in the control arm). RESULTS: Three patients from each arm discontinued the study. In the ATI-free diet group, a significant decrease in BMI (p = 0.018), CAP (p = 0.018) and HOMA-IR (p = 0.042) was observed at 6 weeks. The mean difference in CAP between the two arms at week 6 was 30.5 dB/m (p = 0.039), with a delta significantly higher in the ATI-free diet group (p = 0.043). Only an ATI-free diet could achieve a significant improvement in CLDQ-NASH domains (p value for total scoring: 0.013). CONCLUSIONS: A short-term ATI-free diet leads to significant improvements in liver and metabolic parameters, as well as patient-reported outcomes with good tolerability. A larger follow-up study is justified to corroborate these findings. CLINICAL TRIAL NUMBER: NCT04066400.

Spleen Stiffness-Based Algorithms Are Superior to Baveno VI Criteria to Rule Out Varices Needing Treatment in Patients With Advanced Chronic Liver Disease.

INTRODUCTION: The Baveno VI criteria have set the stage for noninvasive assessment of compensated advanced chronic liver disease (ACLD). The algorithm combining liver stiffness measurement (LSM, <20 kPa) and platelet count (>150,000/µL) safely avoids screening endoscopy for varices needing treatment (VNT) but identifies only a relatively low number of patients. We aimed to evaluate the value of spleen stiffness measurement (SSM) using spleen-dedicated elastography in ruling out VNT. METHODS: In this real-life multicenter retrospective derivation-validation cohort, all consecutive patients with ACLD (defined by LSM ≥10 kPa) with available upper endoscopy, laboratory results, spleen diameter, LSM, and SSM measured with spleen-dedicated transient elastography were included. VNT were defined as medium-to-large varices or small varices with red spots. RESULTS: In the derivation cohort (n = 201, 11.9% VNT), SSM demonstrated excellent capability at identifying VNT (area under the receiver operating characteristic curve [AUROC] 0.88), outperforming LSM (AUROC 0.77, P = 0.03) and platelets (AUROC 0.73, P = 0.002). In comparison with Baveno VI criteria (33.8% spared endoscopies), the sequential Baveno VI plus SSM and a novel spleen size and stiffness model were able to increase the number of patients avoiding endoscopy (66.2% and 71.1%, respectively) without missing more than 5% of VNT. These findings were confirmed in an external validation cohort of patients with more advanced liver disease (n = 176, 34.7% VNT) in which the number of spared endoscopies tripled (27.3% and 31.3% for SSM-based algorithms) compared with Baveno VI criteria (8.5%). DISCUSSION: Spleen stiffness-based algorithms are superior to Baveno VI criteria in ruling out VNT in patients with ACLD and double the number of patients avoiding screening endoscopy.

Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information.

AIMS: Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints. METHODS: Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable. RESULTS: Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance. CONCLUSIONS: This study developed a series of ML models of accuracy ranging from 71.9-99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means.

A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Serum ferritin levels can predict long-term outcomes in patients with metabolic dysfunction-associated steatotic liver disease.

OBJECTIVE: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death. DESIGN: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate. RESULTS: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65). CONCLUSIONS: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD.

Obesity and harmful alcohol consumption are predictors for advanced liver disease in the disease management program for type 2 diabetes.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major risk factor for advanced liver disease. The aim of this prospective cohort study was to assess the prevalence and associated risk factors of liver fibrosis and cirrhosis in primary care centers participating in the diabetes disease management program (DMP) in Germany. METHODS: A total of 175 participants with the diagnosis of T2DM were enrolled in two primary care centers. Steatotic liver disease (SLD; hepatic steatosis, ≥275 dB/m), fibrosis (≥8 kPa), and cirrhosis (≥15 kPa) were assessed non-invasively using vibration-controlled transient elastography. Multivariable logistic regression analysis was performed to identify clinical predictors of fibrosis and cirrhosis. The AUDIT questionnaire was used to screen for alcohol consumption, and a score ≥8 was considered harmful alcohol consumption. RESULTS: The majority of participants were male (62%), and the median age was 66 years (interquartile range 59; 71). The median body mass index was 31.1 kg/m2 , with 58.9% of the participants being obese. Harmful alcohol consumption was prevalent in 8.0% and 20.0% of the entire cohort and in those with cirrhosis, respectively. The prevalence of SLD, fibrosis, and cirrhosis was 77.1%, 42.3%, and 12.0%, respectively. In multivariable logistic regression analysis, obesity, and harmful alcohol consumption were associated with the highest odds of fibrosis (odds ratio [OR] 5.198, 95% confidence interval [CI] 2.269-11.908) and cirrhosis (OR 5.615, 95% CI 1.274-24.756), respectively. CONCLUSION: The prevalence of fibrosis and cirrhosis in patients seen in the diabetes DMP in Germany is high. Obesity and harmful alcohol consumption increase the risk of fibrosis and cirrhosis in people with T2DM. Screening for advanced liver disease and associated risk factors within the DMP program may reduce the liver disease burden in this high-risk population.

Inequities in primary liver cancer in Europe: The state of play.

Given the increasing burden of liver cancer in Europe, it is crucial to investigate how social determinants of health (SDoH) affect liver cancer risk factors and access to care in order to improve health outcomes equitably. This paper summarises the available evidence on the differential distribution of liver cancer risk factors, incidence, and health outcomes in the European Economic Area and the United Kingdom from an SDoH perspective. Vulnerable and marginalised populations have low socio-economic and educational levels and are the most affected by liver cancer risk factors. Reasons for this include varied access to hepatitis B virus vaccination and limited access to viral hepatitis B and C screening, harm reduction, and treatment. Additionally, alcohol-related liver disease remains highly prevalent among individuals with low education, insecure employment, economic instability, migrants, and deprived populations. Moreover, significant variation exists across Europe in the proportion of adults with steatotic liver disease, overweight/obesity, and diabetes, based on geographical area, gender, socio-economic and educational background, and density of ultra-processed food outlets. Inequities in cirrhosis mortality rates have been reported, with the highest death rates among individuals living in socio-economically disadvantaged areas and those with lower educational levels. Furthermore, insufficient healthcare access for key populations with primary liver cancer is influenced by complex healthcare systems, stigmatisation, discrimination, low education, language barriers, and fear of disclosure. These challenges contribute to inequities in liver cancer care pathways. Future studies are needed to explore the different SDoH-interlinked effects on liver cancer incidence and outcomes in European countries. The ultimate goal is to develop evidence-based multilevel public health interventions that reduce the SDoH impact in precipitating and perpetuating the disproportionate burden of liver cancer in specific populations.

Change of Intraocular Pressure Over 5 Years and its Relationship to Cardiovascular Parameters: Results From the Gutenberg Health Study.

Purpose: To investigate the longitudinal change in intraocular pressure (IOP) over 5 years and its relationship with cardiovascular parameters in a population-based sample in Germany. Methods: The Gutenberg Health Study is a prospective, observational, single-center cohort study. The sample was equally stratified for sex, residence, and age decade. IOP was measured with noncontact tonometry at baseline and at 5-year follow-up. Cardiovascular parameters, including body mass index (BMI), systolic blood pressure, and diabetes status, were assessed. Participants without IOP measurement at one time point, who were taking IOP-lowering medications, or who had ophthalmic surgery during the 5-year follow-up interval were excluded, as well as those with glaucoma diagnosis. Univariable and multivariable linear regression analyses were conducted. Results: This analysis included 9633 participants (48.9% female). The mean IOP increased from 14.04 ± 2.78 mmHg at baseline to 14.77 ± 2.92 mmHg at 5-year follow-up (P < 0.001). In multivariable linear regression analyses, an increase in BMI was associated with an increase in IOP over time (P < 0.001), whereas a higher baseline BMI was associated with a lower IOP change (P < 0.001). Higher age and male sex were associated with higher IOP change (P < 0.001). A change in systolic blood pressure was associated with IOP change, whereas baseline systolic blood pressure and diabetes status were not associated. Conclusions: This population-based study found a relationship between IOP change over 5 years and BMI and systolic blood pressure change, respectively. These findings suggest the importance of monitoring cardiovascular risk factors in IOP management.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Global survey of stigma among physicians and patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Patients with fatty liver disease may experience stigma from the disease or comorbidities. In this cross-sectional study, we aimed to understand stigma among patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) and healthcare providers. METHODS: Members of the Global NASH Council created two surveys about experiences/attitudes toward NAFLD and related diagnostic terms: a 68-item patient and a 41-item provider survey. RESULTS: Surveys were completed by 1,976 patients with NAFLD across 23 countries (51% Middle East/North Africa [MENA], 19% Europe, 17% USA, 8% Southeast Asia, 5% South Asia) and 825 healthcare providers (67% gastroenterologists/hepatologists) across 25 countries (39% MENA, 28% Southeast Asia, 22% USA, 6% South Asia, 3% Europe). Of all patients, 48% ever disclosed having NAFLD/NASH to family/friends; the most commonly used term was "fatty liver" (88% at least sometimes); "metabolic disease" or "MAFLD" were rarely used (never by >84%). Regarding various perceptions of diagnostic terms by patients, there were no substantial differences between "NAFLD", "fatty liver disease (FLD)", "NASH", or "MAFLD". The most popular response was being neither comfortable nor uncomfortable with either term (56%-71%), with slightly greater discomfort with "FLD" among the US and South Asian patients (47-52% uncomfortable). Although 26% of patients reported stigma related to overweight/obesity, only 8% reported a history of stigmatization or discrimination due to NAFLD. Among providers, 38% believed that the term "fatty" was stigmatizing, while 34% believed that "nonalcoholic" was stigmatizing, more commonly in MENA (43%); 42% providers (gastroenterologists/hepatologists 45% vs. 37% other specialties, p = 0.03) believed that the name change to metabolic dysfunction-associated steatotic liver disease (or MASLD) might reduce stigma. Regarding the new nomenclature, the percentage of providers reporting "steatotic liver disease" as stigmatizing was low (14%). CONCLUSIONS: The perception of NAFLD stigma varies among patients, providers, geographic locations and sub-specialties. IMPACT AND IMPLICATIONS: Over the past decades, efforts have been made to change the nomenclature of nonalcoholic fatty liver disease (NAFLD) to better align with its underlying pathogenetic pathways and remove any potential stigma associated with the name. Given the paucity of data related to stigma in NAFLD, we undertook this global comprehensive survey to assess stigma in NAFLD among patients and providers from around the world. We found there is a disconnect between physicians and patients related to stigma and related nomenclature. With this knowledge, educational programs can be developed to better target stigma in NAFLD among all stakeholders and to provide a better opportunity for the new nomenclature to address the issues of stigma.

Development and validation of a multivariable risk prediction model for hepatic steatosis in patients with HIV infection.

OBJECTIVE: Early detection of hepatic steatosis in people with HIV (PWH) could prevent progression and inflammation. The aim was to develop and validate a multivariable risk prediction model for hepatic steatosis in German PWH. DESIGN: In this cohort study, 282 PWH were prospectively enrolled, and hepatic steatosis was defined via controlled attenuation parameter (CAP; ≥275 dB/m) using vibration-controlled transient elastography. METHODS: Three multivariable logistic regression models were conducted. Missing values were imputed with multiple imputation. Cut-offs were derived based on Youden-Indices. Performance was assessed via discriminatory and calibrative ability and accuracy via Brier Skill Score. Sensitivity, specificity, and predictive values were calculated. Internal validation was performed via bootstrapping. RESULTS: The prevalence of hepatic steatosis was 35.3% (100/282). Univariate analyses revealed associations with age, waist circumference, BMI, hypertension, hyperlipidemia and gamma-gt. In multivariable analyses, male sex [odds ratio (OR) 2.07, 95% confidence interval (CI) 1.42-3.00, P  = 0.001] and BMI (OR 1.27, 95% CI 1.18-1.36, P  < 0.001) were identified as independent predictors of hepatic steatosis. The naive and optimism-corrected c -statistic of 79% showed a good discriminatory ability, the calibration was well with a slight tendency for overestimation for predicted probabilities above 70%. At the cutoff of 1.95, the specificity was 71% and the negative-predictive value 82.3%. Twenty-seven percent of the 282 patients would be misclassified, 17% as false positives and 10% as false negatives. CONCLUSION: The developed prediction model contributes to the lack of validated noninvasive tools to predict hepatic steatosis in people with HIV. Future studies should include more candidate predictors and externally validate the model.

A global action agenda for turning the tide on fatty liver disease.

BACKGROUND AND AIMS: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. APPROACH AND RESULTS: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. CONCLUSIONS: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

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.

Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver-targeted thyroid hormone receptor-ß selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo. AIMS: To present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO-NAFLD-1 [NCT04197479], MAESTRO-NAFLD-OLE [NCT04951219], MAESTRO-NASH [NCT03900429], MAESTRO-NASH-OUTCOMES [NCT05500222]). METHODS: MAESTRO-NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy-confirmed at-risk NASH. Patients are randomised to a once-daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO-NAFLD-1 is a 52-week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non-invasive testing); ~700 patients from MAESTRO-NAFLD-1 are enrolled in MAESTRO-NAFLD-OLE, a 52-week active treatment extension to further evaluate safety. MAESTRO-NASH-OUTCOMES is enrolling 700 adults with well-compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non-invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient-reported outcomes. CONCLUSION: The MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long-term clinical liver-related outcomes in MAESTRO-NASH (month 54) and MAESTRO-NASH-OUTCOMES (time to event).

Implementation of a liver health check in people with type 2 diabetes.

As morbidity and mortality related to potentially preventable liver diseases are on the rise globally, early detection of liver fibrosis offers a window of opportunity to prevent disease progression. Early detection of non-alcoholic fatty liver disease allows for initiation and reinforcement of guidance on bodyweight management, risk stratification for advanced liver fibrosis, and treatment optimisation of diabetes and other metabolic complications. Identification of alcohol-related liver disease provides the opportunity to support patients with detoxification and abstinence programmes. In all patient groups, identification of cirrhosis ensures that patients are enrolled in surveillance programmes for hepatocellular carcinoma and portal hypertension. When considering early detection strategies, success can be achieved from applying ad-hoc screening for liver fibrosis in established frameworks of care. Patients with type 2 diabetes are an important group to consider case findings of advanced liver fibrosis and cirrhosis, as up to 19% have advanced fibrosis (which is ten times higher than the general population) and almost 70% have non-alcoholic fatty liver disease. Additionally, patients with type 2 diabetes with alcohol use disorders have the highest proportion of liver-related morbidity of people with type 2 diabetes generally. Patients with type 2 diabetes receive an annual diabetes review as part of their routine clinical care, in which the health of many organs are considered. Yet, liver health is seldom included in this review. This Viewpoint argues that augmenting the existing risk stratification strategy with an additional liver health check provides the opportunity to detect advanced liver fibrosis, thereby opening a window for early interventions to prevent end-stage liver disease and its complications, including hepatocellular carcinoma.

Comparison of Inflammatory Cytokine Levels in Hepatic and Jugular Veins of Patients with Cirrhosis.

Background: Systemic inflammation with elevated inflammatory cytokines is a hallmark in patients with cirrhosis and the main driver of decompensation. There is insufficient data on whether inflammatory cytokine levels differ between hepatic and jugular veins, which may have implications for further immunological studies. Methods: Blood from the hepatic and jugular veins of 40 patients with cirrhosis was collected during hepatic venous pressure gradient (HVPG) measurements. Serum levels of 13 inflammatory cytokines (IL-1ß, Int-α2, Int-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-18, IL-23, and IL-33) were quantified by cytometric bead array. Results: Cytokine levels of IFN-α2, IFN-γ, TNF-α, IL-6, IL-8, IL-10, IL-17A, IL-18, IL-23, and IL-33 were significantly elevated in patients with decompensated cirrhosis compared to patients with compensated cirrhosis. When comparing patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mmHg) to patients without CSPH, there were significantly enhanced serum levels of IL-6 and IL-18 in the former group. There was no significant difference between cytokine serum levels between blood obtained from the jugular versus hepatic veins. Even in subgroup analyses stratified for an early cirrhosis stage (Child-Pugh (CP) A) or more decompensated stages (CP B/C), cytokine levels were similar. Conclusion: Cytokine levels increase with decompensation and increasing portal hypertension in patients with cirrhosis. There is no relevant difference in cytokine levels between hepatic and jugular blood in patients with cirrhosis.

Variability of transient elastography-based spleen stiffness performed at 100 Hz.

BACKGROUND: Spleen stiffness measurement (SSM) performed by transient elastography at 100 Hz is a novel technology for the evaluation of portal hypertension in advanced chronic liver disease, but technical aspects are lacking. We aimed to evaluate the intraexamination variability of SSM and to determine the best transient elastography protocol for obtaining robust measurements to be used in clinical practice. METHODS: We analyzed 253 SSM exams with up to 20 scans for each examination, performed between April 2021 and June 2022. All SSM results were evaluated according to different protocols by dividing data into groups of n measurements (from 2 to 19). Considering as reference the median SSM values across all the 20 measurements, we calculated the distribution of the absolute deviations of each protocol from the reference median. This analysis was repeated 1,000 times by resampling the data. Distributions were also stratified by etiology (chronic liver disease versus clinically significant portal hypertension) and different SSM ranges: < 25 kPa, 25-75, and > 75 kPa. RESULTS: Overall, we observed that the spleen stiffness exam had less variability if it exceeded 12 measurements, i.e., absolute deviations ≤ 5 kPa at 95% confidence. For exams with higher SSM values (> 75 kPa), as seen in clinically significant portal hypertension, at least 15 measurements are highly recommendable. CONCLUSIONS: Fifteen scans per examination should be considered for each SSM exam performed at 100 Hz to achieve a low intraexamination variability within a reasonable time in clinical practice. RELEVANCE STATEMENT: Performing at least 15 scans per examination is recommended for 100 Hz SSM in order to achieve a low intraexamination variability, in particular for values > 75 kPa compatible with clinically significant portal hypertension. KEY POINTS: • Spleen stiffness measurement by transient elastography is used for stratification in patients with portal hypertension. • At 100 Hz, this method may have intraexamination variability. • A minimum of 15 scans per examination achieves a low intraexamination variability.