Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol consumption are major causes of hepatocellular carcinoma (HCC) worldwide. We performed a systematic review of epidemiologic studies carried out on HCC aetiology in Southern Europe, an area with an intermediate– high prevalence of these agents as well as of putative risk factors such as tobacco smoking, diabetes and obesity. To retrieve the articles, we performed a Medline search for titles and abstracts of articles. After the Medline search, we reviewed the papers and reference lists to identify additional articles. A synergism between HCV infection and HBV infection, overt (hepatitis B virus antigen (HbsAg) positivity) or occult (HBsAg negativity with presence of HBV DNA in liver or serum), is suggested by the results of some studies. The pattern of the risk for HCC due to alcohol intake shows a continuous dose–effect curve without a definite threshold, although most studies found that HCC risk increased only for alcohol consumption above 40–60 g of ethanol per day. Some evidence supports a positive interaction of alcohol intake probably with HCV infection and possibly with HBV infection. A few studies found that coffee has a protective effect on HCC risk due to various risk factors. Some data also support a role of tobacco smoking, diabetes and obesity as single agents or preferably cofactors in causing HCC. In countries with a relatively high alcohol consumption and intermediate levels of HCV and HBV infections (1–3% of population infected by each virus), such as Mediterranean countries, the three main risk factors together account for about 85% of the total HCC cases, leaving little space to other known risk factors, such as haemochromatosis, and to new, still unrecognised, factors as independent causes of HCC. Oncogene (2006) 25, 3756–3770. doi:10.1038/sj.onc.120955

Evolving Role for Pharmacotherapy in NAFLD/NASH

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P \u3c 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy

European 'NAFLD Preparedness Index' - Is Europe ready to meet the challenge of fatty liver disease?

Background & Aims: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent emerging condition that can be optimally managed through a multidisciplinary patient centred approach. National preparedness to address NAFLD is essential to ensure that health systems can deliver effective care. We present a NAFLD Preparedness Index for Europe. Methods: In June 2019, data were extracted by expert groups from 29 countries to complete a 41-item questionnaire about NAFLD. Questions were classified into 4 categories: policies/civil society (9 questions), guidelines (16 questions), epidemiology (4 questions), and care management (12 questions). Based on the responses, national preparedness for each indicator was classified into low, middle, or high-levels. We then applied a multiple correspondence analysis to obtain a standardised preparedness score for each country ranging from 0 to 100. Results: The analysis estimated a summary factor that explained 71.3% of the variation in the dataset. No countries were found to have yet attained a high-level of preparedness. Currently, the UK (75.5) scored best, although falling within the mid level preparedness band, followed by Spain (56.2), and Denmark (43.4), whereas Luxembourg and Ireland were the lowest scoring countries with a score of 4.9. Only Spain scored highly in the epidemiology indicator category, whereas the UK was the only country that scored highly for care management. Conclusions: The NAFLD Preparedness Index indicates substantial variation between countries’ readiness to address NAFLD. Notably, even those countries that score relatively highly exhibit deficiencies in key domains, suggesting that structural changes are needed to optimise NAFLD management and ensure effective public health approaches are in place. Lay summary: Non-alcoholic fatty liver disease (NAFLD), which is closely associated with obesity, metabolic syndrome, and diabetes, is a highly prevalent condition that can be optimally managed through a multidisciplinary patient-centred approach. National preparedness to address NAFLD is essential to allow for effective public health measures aimed at preventing disease while also ensuring that health systems can deliver effective care to affected populations. This study defined preparedness as having adequate policies and civil society engagement, guidelines, epidemiology, and care management. NAFLD preparedness was found to be deficient in all 29 countries studied, with great variation among the countries and the 4 categories studied

FibroScan-aspartate aminotransferase (FAST) score for monitoring histological improvement in non-alcoholic steatohepatitis activity during semaglutide treatment: post-hoc analysis of a randomised, double-blind, placebo-controlled, phase 2b trial

\ua9 2023Background: Currently, assessment of candidate pharmacotherapies in patients with non-alcoholic steatohepatitis (NASH) involves invasive liver biopsy. Non-invasive scores, such as the FibroScan-aspartate aminotransferase (FAST) score, are used to identify candidates for therapy, but their ability to assess disease progression or treatment effect is unknown. We aimed to assess the association between FAST score and histological endpoints. Methods: We conducted a post-hoc analysis using data from a prior randomised, double-blind, placebo-controlled, phase 2b trial at 143 sites across 16 countries. Patients (aged 18–75 years) with biopsy-confirmed NASH, fibrosis stage 1–3, and a Non-alcoholic fatty liver disease Activity Score (NAS) ≥4 were enrolled between January 2017 and September 2018, and randomly assigned to receive once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg or placebo for 72 weeks. A subgroup analysis of patients with FAST score and histological data in the pooled semaglutide treatment and placebo arms at baseline and week 72 was performed. The original trial is registered at ClinicalTrials.gov, NCT02970942. Findings: A total of 122 patients were included in this post-hoc analysis (93 received semaglutide and 29 received placebo). FAST score reduction was associated with achieving the primary endpoint of NASH resolution without worsening of fibrosis in the pooled semaglutide group (area under the receiver operating curve 0.69; 95% confidence interval [CI] 0.58, 0.81). Mean FAST score reduction from baseline to week 72 was greatest in patients who met the primary endpoint vs those who did not in both the semaglutide (−0.40 [95% CI –0.84, 0.04] vs −0.22 [95% CI –0.74, 0.30] points; p = 0.002) and placebo groups (−0.25 [95% CI –0.72, 0.23] vs 0.00 [95% CI –0.50, 0.50] points; p = 0.047). Similarly, mean reductions in FAST score at week 72 were greater in those with NAS improvement vs those without in the semaglutide and placebo groups (≥1 point, −0.36 [95% CI –0.82, 0.11] vs −0.08 [95% CI –0.53, 0.38] points [p < 0.001] and −0.25 [95% CI –0.64, 0.14] vs −0.06 [95% CI –0.40, 0.53] points [p = 0.001]; ≥2 points, −0.40 [95% CI –0.86, 0.06] vs −0.14 [95% CI –0.56, 0.28] points [p < 0.001] and −0.29 [95% CI –0.67, 0.09] vs −0.05 [95% CI –0.40, 0.50] points; [p < 0.001]). A FAST score reduction of more than 0.22 points after semaglutide treatment was associated with meeting the primary endpoint (sensitivity 78%; specificity 60%; positive likelihood ratio 1.26; negative likelihood ratio 0.25; odds ratio 4.93). Interpretation: The potential of the FAST score as a non-invasive monitoring tool to identify histological changes following treatment requires further evaluation and validation. Funding: Novo Nordisk A/S

Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease

BACKGROUND: Liver biopsy is considered the gold standard for assessing histologic lesions of non-alcoholic fatty liver disease (NAFLD). The aim was to develop and validate a new biomarker of non alcoholic steato hepatitis (NASH) the NashTest (NT) in patients with NAFLD. METHODS: 160 patients with NAFLD were prospectively included in a training group, 97 were included in a multicenter validation group and 383 controls. Histological diagnoses used Kleiner et al's scoring system, with 3 classes for NASH: "Not NASH", "Borderline", "NASH"). The area under the ROC curves (AUROC), sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV, NPV) were assessed. RESULTS: NT was developed using patented algorithms combining 13 parameters: age, sex, height, weight, and serum levels of triglycerides, cholesterol, alpha2macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl-transpeptidase, transaminases ALT, AST, and total bilirubin. AUROCs of NT for the diagnosis of NASH in the training and validation groups were, respectively, 0.79 (95%CI 0.69–0.86) and 0.79 (95%CI 0.67–0.87; P = 0.94); for the diagnosis of borderline NASH they were: 0.69 (95%CI 0.60–0.77) and 0.69 (95%CI 0.57–0.78; P = 0.98) and for the diagnosis of no NASH, 0.77 (95%CI 0.68–0.84) and 0.83 (95%CI 0.67–0.90; P = 0.34). When the two groups were pooled together the NashTest Sp for NASH = 94% (PPV = 66%), and Se = 33% (NPV = 81%); for borderline NASH or NASH Sp = 50% (PPV = 74%) and Se = 88% (NPV = 72%). CONCLUSION: In patients with non-alcoholic fatty liver disease, NashTest, a simple and non-invasive biomarker reliably predicts the presence or absence of NASH

A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH). Methods: In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively. Results: None of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD. Conclusions: We found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries. Lay summary: We conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries

Identification of Patients with Advanced Fibrosis Due to Nonalcoholic Fatty Liver Disease: Considerations for Best Practice

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) prevalence has increased in the past two decades, resulting in a significant but under-recognised public health burden. This impacts the prevalence of advanced fibrosis, end-stage liver disease and associated extrahepatic manifestations. To understand the challenges in recognising patients with advanced fibrosis due to NASH and develop a standardised approach to screen these patients, the authors of this document provided their opinions and expertise from practice and published evidence to identify key challenges and current approaches for diagnosing NASH. The severity of liver fibrosis due to NASH is the main indicator of associated morbidity and mortality outcomes. Therefore, identifying patients with, or at risk of, advanced fibrosis due to NASH and linking them to appropriate care is critical. This can be challenging due to a lack of awareness of NASH among healthcare professionals and a lack of standardised protocols for identifying patients. Simple noninvasive tests may provide an opportunity to facilitate early identification of these patients. This article proposes a simple, universally applicable diagnostic algorithm for use in clinical practice, that includes sequential use of noninvasive tests, ideally a biological marker and an imaging technique, which may help to facilitate early diagnosis of these patients. In the opinion of the authors, early detection of advanced fibrosis is fundamental in the efforts to halt the progression of NASH and diagnostic algorithms may facilitate pre-emptive interventions to curtail the disease

Utility of pathologist panels for achieving consensus in NASH histologic scoring in clinical trials: Data from a phase 3 study

Copyright \ua9 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.Background: Liver histopathologic assessment is the accepted surrogate endpoint in NASH trials; however, the scoring of NASH Clinical Research Network (CRN) histologic parameters is limited by intraobserver and interobserver variability. We designed a consensus panel approach to minimize variability when using this scoring system. We assessed agreement between readers, estimated linear weighted kappas between 2 panels, compared them with published pairwise kappa estimates, and addressed how agreement or disagreement might impact the precision and validity of the surrogate efficacy endpoint in NASH trials. Methods: Two panels, each comprising 3 liver fellowship-trained pathologists who underwent NASH histology training, independently evaluated scanned whole slide images, scoring fibrosis, inflammation, hepatocyte ballooning, and steatosis from baseline and month 18 biopsies for 100 patients from the precirrhotic NASH study REGENERATE. The consensus score for each parameter was defined as agreement by ≥2 pathologists. If consensus was not reached, all 3 pathologists read the slide jointly to achieve a consensus score. Results: Between the 2 panels, the consensus was 97%-99% for steatosis, 91%-93% for fibrosis, 88%-92% for hepatocyte ballooning, and 84%-91% for inflammation. Linear weighted kappa scores between panels were similar to published NASH CRN values. Conclusions: A panel of 3 trained pathologists independently scoring 4 NASH CRN histology parameters produced high consensus rates. Interpanel kappa values were comparable to NASH CRN metrics, supporting the accuracy and reproducibility of this method. The high concordance for fibrosis scoring was reassuring, as fibrosis is predictive of liver-specific outcomes and all-cause mortality