Metabolic-associated fatty liver voxel-based quantification on CT images using a contrast adapted automatic tool.

BACKGROUND & AIMS: Metabolic-dysfunction associated fatty liver disease (MAFLD) is highly prevalent and can lead to liver complications and comorbidities, with non-invasive tests such as vibration-controlled transient elastography (VCTE) and invasive liver biopsies being used for diagnosis The aim of the present study was to develop a new fully automatized method for quantifying the percentage of fat in the liver based on a voxel analysis on computed tomography (CT) images to solve previously unconcluded diagnostic deficiencies either in contrast (CE) or non-contrast enhanced (NCE) assessments. METHODS: Liver and spleen were segmented using nn-UNet on CE- and NCE-CT images. Radiodensity values were obtained for both organs for defining the key benchmarks for fatty liver assessment: liver mean, liver-to-spleen ratio, liver-spleen difference, and their average. VCTE was used for validation. A classification task method was developed for detection of suitable patients to fulfill maximum reproducibility across cohorts and highlight subjects with other potential radiodensity-related diseases. RESULTS: Best accuracy was attained using the average of all proposed benchmarks being the liver-to-spleen ratio highly useful for CE and the liver-to-spleen difference for NCE. The proposed whole-organ automatic segmentation displayed superior potential when compared to the typically used manual region-of-interest drawing as it allows to accurately obtain the percent of fat in liver, among other improvements. Atypical patients were successfully stratified through a function based on biochemical data. CONCLUSIONS: The developed method tackles the current drawbacks including biopsy invasiveness, and CT-related weaknesses such as lack of automaticity, dependency on contrast agent, no quantification of the percentage of fat in liver, and limited information on region-to-organ affectation. We propose this tool as an alternative for individualized MAFLD evaluation by an early detection of abnormal CT patterns based in radiodensity whilst abording detection of non-suitable patients to avoid unnecessary exposure to CT radiation. Furthermore, this work presents a surrogate aid for assessing fatty liver at a primary assessment of MAFLD using elastography data.

Phenotypes of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) typically develops as a consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis, has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) also can develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not elucidated completely, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardiometabolic risk factors and the molecular targets that could be tackled effectively. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and health care burden, the mechanistic data promoting MASLD, metabolic dysfunction-associated steatohepatitis, and MASLD-HCC. Its natural history, prognosis, and treatment are addressed specifically, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies also are discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.

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.).

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.

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.

Platform trials to overcome major shortcomings of traditional clinical trials in non-alcoholic steatohepatitis? Pros and cons.

Non-alcoholic fatty liver disease is a condition that affects 25% of the population. Non-alcoholic steatohepatitis (NASH) is a progressive form of the disease that can lead to severe complications such as cirrhosis and hepatocellular carcinoma. Despite its high prevalence, no drugs are currently approved for the treatment of NASH. The drug development pipeline in NASH is very active, yet most assets do not progress to phase III trials and those that do reach phase III often fail to achieve the endpoints necessary for approval by regulatory agencies. Amongst other reasons, the methodological and operational features of traditional clinical trials in NASH might impede optimal drug development. In this regard, platform trials might be an attractive complement or alternative to conventional clinical trials. Platform trials use a master protocol which enables evaluation of multiple investigational medicinal products concurrently or sequentially with a single, shared control arm. Through Bayesian interim analyses, these trials allow for early exit of drugs from the trial based on success or futility, while providing participants better chances of receiving active compounds through adaptive randomisation. Overall, platform trials represent an alternative for patients, pharmaceutical companies, and clinicians in the quest to accelerate the approval of pharmacologic treatments for NASH.

Outcomes of Patients with Severe Obesity and Cirrhosis with Portal Hypertension Undergoing Bariatric Surgery: a Systematic Review.

PURPOSE: Thus far, little attention has been paid to bariatric surgery (BS) in patients with severe obesity (SO) and cirrhosis with portal hypertension (PH). To address this knowledge gap, we systematically reviewed the available literature and evidence about BS in patients with SO and cirrhosis with PH. We inform on the perioperative and long-term outcomes of this intervention. MATERIALS AND METHODS: Articles were identified in MEDLINE, SCOPUS, LILACS, and SCIELO, and included if they analyzed SO patients with clinically significant PH and reported the characteristics and outcomes of BS. RESULTS: Six articles, including 32 patients, were included. The most frequent type of BS was sleeve gastrectomy performed in 27 patients. Perioperative transfusions were often not required, with only one case report describing the use of 1 unit of packed red blood cells post-operatively. Neither intraoperative nor post-op deaths were reported. All patients reported significant weight loss with improvements in comorbidities during the follow-up periods. Overall, 27 out of 29 patients had T2DM resolution, and 13 out of 23 had arterial hypertension resolution. One study reported improvements in the parameters of fibroscan. CONCLUSION: This systematic review described the outcomes of BS among patients with SO with cirrhosis and PH. Performing this kind of surgery among these patients appears safe and associated with acceptable perioperative and long-term outcomes. However, further studies are required to provide evidence-based, strong recommendations.

NAFLD as the metabolic hallmark of obesity.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, associated with a high risk of progression to NASH, liver cirrhosis and hepatocarcinoma. Its prevalence is closely related to obesity (understood as adipose-based disease and insulin resistance), which makes that at present NAFLD can be considered a metabolic dysfunction hallmark, regardless of the body mass index. Despite being such a prevalent condition, with such severe consequences, at present there are no reliable biomarkers for its diagnosis or specific treatment. Significant and sustained weight loss, as well as some antidiabetic treatments, has shown promising results for NAFLD but data needs confirmation in larger clinical trials and longer follow-up. Efforts should be made for a better and more accurate baseline diagnosis (including large-scale genetics), identification of patients at higher risk for progression to NASH as well as adequate treatment, to allow us to offer a personalized approach in NAFLD in the context of precision medicine.

Forty-Year Trends in Cardiac Implantable Electronic Device Infective Endocarditis.

Background: Studies investigating cardiac implantable electronic device infective endocarditis (CIED-IE) epidemiological changes and prognosis over long periods of time are lacking. Methods: Retrospective single cardiovascular surgery center cohort study of definite CIED-IE episodes between 1981-2020. A comparative analysis of two periods (1981-2000 vs 2001-2020) was conducted to analyze changes in epidemiology and outcome over time. Results: One-hundred and thirty-eight CIED-IE episodes were diagnosed: 25 (18%) first period and 113 (82%) second. CIED-IE was 4.5 times more frequent in the second period, especially in implantable cardiac defibrillators. Age (63 [53-70] vs 71 [63-76] years, P < .01), comorbidities (CCI 3.0 [2-4] vs 4.5 [3-6], P > .01), nosocomial infections (4% vs 15.9%, P = .02) and transfers from other centers (8% vs 41.6%, P < .01) were significantly more frequent in the second period, as were methicillin-resistant coagulase-negative staphylococcal (MR-CoNS) (0% vs 13.3%, P < .01) and Enterococcus spp. (0% vs 5.3%, P = .01) infections, pulmonary embolism (0% vs 10.6%, P < .01) and heart failure (12% vs 28.3%, p < .01). Second period surgery rates were lower (96% vs 87.6%, P = .09), and there were no differences in in-hospital (20% vs 11.5%, P = .11) and one-year mortalities (24% vs 15%, P = .33), or relapses (8% vs 5.3%, P = 0.65). Multivariate analysis showed Charlson index (hazard ratios [95% confidence intervals]; 1.5 [1.16-1.94]) and septic shock (23.09 [4.57-116.67]) were associated with a worse prognosis, whereas device removal (0.11 [.02-.57]), transfers (0.13 [.02-0.95]), and second-period diagnosis (0.13 [.02-.71]) were associated with better one-year outcomes. Conclusions: CIED-IE episodes increased more than four-fold during last 40 years. Despite CIED-IE involved an older population with more comorbidities, antibiotic-resistant MR-CoNS, and complex devices, one-year survival improved.

Outpatient Parenteral Antibiotic Treatment vs Hospitalization for Infective Endocarditis: Validation of the OPAT-GAMES Criteria.

Background: Outpatient parenteral antibiotic treatment (OPAT) programs are increasingly used to manage infective endocarditis (IE), but current criteria for indicating OPAT are markedly conservative. We aimed to investigate whether more liberal criteria for indicating OPAT in IE can be safely used. Methods: This was a prospective multicenter nationwide cohort study (2008-2018). Rates of readmission, recurrences, and 1-year mortality were compared between hospital-based antibiotic treatment (HBAT) and OPAT. Risk factors for readmission and mortality in OPAT patients were investigated by logistic regression. Patients did not fulfill OPAT-GAMES (Grupos de Apoyo al Manejo de la Endocarditis en ESpaña) criteria if they had any of the following: cirrhosis, severe central nervous system emboli, undrained abscesses, severe conditions requiring cardiac surgery in nonoperable patients, severe postsurgical complications, highly difficult-to-treat microorganisms, or intravenous drug use. Results: A total of 2279 HBAT patients and 1268 OPAT patients were included. Among OPAT patients, 307 (24.2%) did not fulfill OPAT-GAMES criteria. Overall, OPAT patients presented higher rates of readmission than HBAT patients (18.2% vs 14.4%; P = .004), but no significant differences were found in the propensity analysis. Patients not fulfilling OPAT-GAMES criteria presented significantly higher rates of readmission than HBAT and OPAT-GAMES (23.8%, 14.4%, 16.4%; P < .001), whereas no significant differences were found in mortality (5.9%, 8%, 7.4%; P = .103) or recurrences (3.9%, 3.1%, 2.5%; P = .546). Not fulfilling OPAT-GAMES criteria was associated with higher risk of readmission (odds ratio [OR], 1.43; 95% CI, 1.03-1.97; P = .03), whereas cardiac surgery was associated with lower risk (OR, 0.72; 95% CI, 0.53-0.98; P = .03). Conclusions: OPAT-GAMES criteria allow identification of IE patients at higher risk of long-term complications to whom OPAT cannot be safely administered.

Impact of the COVID-19 pandemic on the care and outcomes of people with NAFLD-related cirrhosis.

Background & Aims: The COVID-19 pandemic has had a major negative impact on health systems and many chronic diseases globally. We aimed to evaluate the impact of the first year of the pandemic on the outcomes of people with NAFLD cirrhosis. Methods: We conducted a before-after study in four University hospitals in Catalonia, Spain. Study subperiods were divided into Pre-pandemic (March/2019-February/2020) vs. Pandemic (March/2020-February/2021). The primary outcome was the rate of first liver-related event (LRE). Overall clinical outcomes (LREs plus cardiovascular plus all-cause mortality) were also assessed. Results: A total of 354 patients were included, all of whom were compensated at the beginning of the study period; 83 individuals (23.5%) had a history of prior hepatic decompensation. Mean age was 67.3 years and 48.3% were female. Median BMI was 31.2 kg/m2 and type 2 diabetes was present in 72.8% of patients. The rates of first LRE in the Pre-pandemic and Pandemic periods were 7.4% and 11.3% (p = 0.12), respectively. Whilst the rate of overall events was significantly higher in the Pandemic period (9.9% vs. 17.8%; p = 0.009), this was strongly associated with COVID-19-related deaths. The rate of worsened metabolic status was significantly higher in the Pandemic period (38.4% vs. 46.1%; p = 0.041), yet this was not associated with the risk of first LRE during the Pandemic period, whereas type 2 diabetes (odds ratio [OR] 3.77; 95% CI 1.15-12.32; p = 0.028), albumin <4 g/L (OR 4.43; 95% CI 1.76-11.17; p = 0.002) and Fibrosis-4 score >2.67 (OR 15.74; 95% CI 2.01-123.22; p = 0.009) were identified as risk factors in the multivariable analysis. Conclusion: Overall, people with NAFLD cirrhosis did not present poorer liver-related outcomes during the first year of the pandemic. Health system preparedness seems key to ensure that people with NAFLD cirrhosis receive appropriate care during health crises. Lay summary: Mobility restrictions and social stress induced by the COVID-19 pandemic have led to increased alcohol drinking and worsened metabolic control (e.g., weight gain, poor control of diabetes) in a large proportion of the population in many countries. We aimed to analyze whether people with cirrhosis due to non-alcoholic fatty liver disease, who are particularly vulnerable to such lifestyle modifications, were significantly impacted during the first year of the pandemic. We compared the clinical situation of 354 patients one year before the pandemic and one year after. We found that although metabolic control was indeed worse after the first year of the pandemic and patients presented worse clinical outcomes, the latter was mostly due to non-liver causes, namely COVID-19 itself. Moreover, the care provided to these patients did not worsen during the first year of the pandemic.

High frequency of acute decompensation and cancer in patients with compensated cirrhosis due to nonalcoholic fatty liver disease: A retrospective cohort study.

The natural history of compensated cirrhosis due to nonalcoholic fatty liver disease (NAFLD) has not been completely characterized. The aim of the present study was to assess the incidence and risk factors of acute decompensation of cirrhosis, hepatocellular carcinoma, and extrahepatic cancers. This was a multicenter, retrospective, cohort study including 449 patients with compensated cirrhosis due to NAFLD. We calculated cumulative incidences and used competitive risk analysis to determine the risk factors associated with decompensation and cancer development. Over a median of 39 months of follow-up, 124 patients (28%) presented acute decompensation. The most frequent decompensation was ascites (21%) followed by hepatic encephalopathy (15%), variceal bleeding (9%), and spontaneous bacterial peritonitis (3%). Acute-on-chronic liver failure was diagnosed in 6% of patients during follow-up. Liver function parameters and specifically an albumin level below 40 g/L were independently associated with an increased risk of decompensation. The presence of ischemic heart disease was independently associated with acute decompensation. Seventy-eight patients (18%) developed hepatocellular carcinoma or extrahepatic cancers during follow-up (51 and 27, respectively). Conclusion: Patients with compensated cirrhosis due to NAFLD are at high risk of severe liver complications, such as the development of acute decompensation, in a relative short follow-up time. This population is at high risk of hepatic and extrahepatic cancers.

Enterohepatic Shunt-Driven Cholemia Predisposes to Liver Cancer.

BACKGROUND & AIMS: Pathogenesis of hepatocellular carcinoma (HCC), which kills millions annually, is poorly understood. Identification of risk factors and modifiable determinants and mechanistic understanding of how they impact HCC are urgently needed. METHODS: We sought early prognostic indicators of HCC in C57BL/6 mice, which we found were prone to developing this disease when fed a fermentable fiber-enriched diet. Such markers were used to phenotype and interrogate stages of HCC development. Their human relevance was tested using serum collected prospectively from an HCC/case-control cohort. RESULTS: HCC proneness in mice was dictated by the presence of congenitally present portosystemic shunt (PSS), which resulted in markedly elevated serum bile acids (BAs). Approximately 10% of mice from various sources exhibited PSS/cholemia, but lacked an overt phenotype when fed standard chow. However, PSS/cholemic mice fed compositionally defined diets, developed BA- and cyclooxygenase-dependent liver injury, which was exacerbated and uniformly progressed to HCC when diets were enriched with the fermentable fiber inulin. Such progression to cholestatic HCC associated with exacerbated cholemia and an immunosuppressive milieu, both of which were required in that HCC was prevented by impeding BA biosynthesis or neutralizing interleukin-10 or programmed death protein 1. Analysis of human sera revealed that elevated BA was associated with future development of HCC. CONCLUSIONS: PSS is relatively common in C57BL/6 mice and causes silent cholemia, which predisposes to liver injury and HCC, particularly when fed a fermentable fiber-enriched diet. Incidence of silent PSS/cholemia in humans awaits investigation. Regardless, measuring serum BA may aid HCC risk assessment, potentially alerting select individuals to consider dietary or BA interventions.

LiverScreen project: study protocol for screening for liver fibrosis in the general population in European countries.

BACKGROUND: The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. METHODS: This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. DISCUSSION: This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country. TRIAL REGISTRATION: This study is registered on Clinicaltrials.gov ( NCT03789825 ).

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.

Influence of Type 2 Diabetes in the Association of PNPLA3 rs738409 and TM6SF2 rs58542926 Polymorphisms in NASH Advanced Liver Fibrosis.

Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d'Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13−10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63−9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03−77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16−41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR ≥ 5.2, OR = 14.33; 95%CI 2.14−18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71−650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively.

Risk factors for persistent enterococcal bacteraemia: a multicentre retrospective study.

OBJECTIVES: Conditions favouring persistent enterococcal bacteraemia (p-EB) have not been fully investigated yet. The aim of our study is to analyse risk factors for p-EB and its impact on mortality. METHODS: International two-centre retrospective study of all hospitalised adults with enterococcal bacteraemia managed with follow-up blood cultures (BCs) during the period 2011-2019. Exclusion criteria were: (1) death within 72 hours from index BCs and (2) polymicrobial bacteraemia. Primary endpoint was p-EB, defined as further isolation of the same species of Enterococcus spp. from BCs after at least 72 hours of appropriate antibiotic therapy. Multivariable logistic regression model was performed to assess risk factors for p-EB. The impact of p-EB on 30-day mortality was assessed by Kaplan-Meier survival curve and Cox regression multivariable model. RESULTS: During the study period, 244 enterococcal bacteraemia were diagnosed. P-EB were 13.5% (33/244). At multivariable analysis, factors independently associated with p-EB were hematologic malignancy (OR 4.60 [95% CI 1.32-16.00], P = 0.01), infective endocarditis (OR 7.99 [95% CI 2.20-28.9], P = 0.002), and use of daptomycin as initial treatment (OR 4.50 [95% CI 1.29-15.61], P = 0.018). Mortality rate was higher in the p-EB group (32% vs. 18%). Kaplan-Meier survival curve showed that patients with p-EB were less likely to survive at 30 days from index BCs (log-rank P = 0.002). Using a Cox regression model, independent predictors of 30-day mortality were hematologic malignancy (HR 2.30 [95% CI 1.02-4.11], P = 0.043), p-EB (HR 1.93 [95% CI 0.92-4.04], P = 0.08), and septic shock (HR 5.92 [95% CI 2.17-16.30], P = 0.001). CONCLUSION: P-EB was diagnosed mainly in very fragile patients and in those receiving daptomycin as frontline therapy. P-EB may have an impact on mortality.

Non-Invasive Tests of Liver Fibrosis Help in Predicting the Development of Hepatocellular Carcinoma among Patients with NAFLD.

Background: The potential role of non-invasive tests (NITs) for liver fibrosis for hepatocellular carcinoma (HCC) prediction remains poorly known. Methods: Retrospective analysis of a NAFLD cohort from a single university hospital in Barcelona, Spain. Incidence rates and cumulative incidence for the overall cohort, as well as cirrhotic and non-cirrhotic patients were calculated. Logistic regression analyses were carried out to investigate risk factors of HCC. Results: From the entire cohort of 1040 patients, 996 patients (95.8%) were analyzed, in whom 35 cases of HCC were detected, of which 26 (72.4%) HCC incident cases were newly diagnosed during a median follow-up of 2.5 (1.9−3.6) years. Two-hundred and thirty-one (23.2%) were cirrhotic at baseline. With the exception of 2 (7.7%) cases of HCC, the rest were diagnosed in cirrhotic patients. Overall HCC cumulative incidence was 9.49 (95% CI 6.4−13.9) per 1000 person-years. The incidence rate for cirrhotic patients was 41.2 (95% CI 27.6−61.6) per 1000 person-years and 0.93 (95% CI 0.23−3.7) per 1000 person-years for patients without cirrhosis. Overall mortality was significantly higher amongst patients with HCC (4.4% vs. 30.8%, p < 0.001). In patients with available liver biopsy (n = 249, 25%), advanced fibrosis (F3−F4) was significantly associated with higher HCC incidence, but not steatosis, lobular inflammation, nor ballooning. In the overall cohort, FIB-4 ≥1.3 (HR 8.46, 95% CI 1.06−67.4, p = 0.044) and older age (HR 1.06, 95% CI 1.01−1.11, p = 0.025) were associated with increasing risk of HCC over time, whereas in cirrhotic patients predictors of HCC included decreasing values of albumin (HR 0.34, 95% CI 0.13−0.87, p = 0.024), platelets (HR 0.98, 95% CI 0.98−0.99, p = 0.001), and increasing values of liver stiffness (HR 1.03, 95% CI 1.00−1.06, p = 0.016). Conclusions: In a Spanish cohort of NAFLD patients, HCC was rare in non-cirrhotic patients. NITs might play a relevant role at predicting HCC.