Paediatric steatotic liver disease has unique characteristics: A multisociety statement endorsing the new nomenclature.

Nonalcoholic fatty liver disease (NAFLD) has been a commonly used term and diagnosis in paediatric hepatology, gastroenterology, and endocrinology clinics for over 30 years. A multisociety Delphi process has determined a new name "Steatotic Liver Disease" (SLD) as the overarching term for disorders associated with hepatic lipid accumulation. Our Societies give our support to steatotic liver disease as the best overarching term for use in our communities. Metabolic dysfunction-associated steatotic liver disease (MASLD) overcomes many of the shortcomings of the name NAFLD. Here, we highlight several points of the new nomenclature that are of particular importance for our community and their consequences for implementation including: diagnostic criteria, considering alternate diagnoses, practical implementation, research, advocacy, and education for paediatricians. As with all nomenclature changes, it will take a concerted effort from our paediatric societies to help integrate the optimal use of this into practice.

MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease.

Fatty liver associated with metabolic dysfunction is common, affects a quarter of the population, and has no approved drug therapy. Although pharmacotherapies are in development, response rates appear modest. The heterogeneous pathogenesis of metabolic fatty liver diseases and inaccuracies in terminology and definitions necessitate a reappraisal of nomenclature to inform clinical trial design and drug development. A group of experts sought to integrate current understanding of patient heterogeneity captured under the acronym nonalcoholic fatty liver disease (NAFLD) and provide suggestions on terminology that more accurately reflects pathogenesis and can help in patient stratification for management. Experts reached consensus that NAFLD does not reflect current knowledge, and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term. This opens the door for efforts from the research community to update the nomenclature and subphenotype the disease to accelerate the translational path to new treatments.

Performance of non-invasive fibrosis scores in non-alcoholic fatty liver disease with and without morbid obesity.

BACKGROUND: Non-invasive scores, such as the non-alcoholic fatty liver disease (NAFLD) Fibrosis Score (NFS), are increasingly used for liver fibrosis assessment in patients with NAFLD. The aim of this study was to assess the applicability and reliability of non-invasive fibrosis scores in NAFLD patients with and without morbid obesity. METHODS: Three hundred sixty-eight patients with biopsy-proven NAFLD identified between January 2012 and December 2015 were studied; 225 with morbid obesity (biopsy obtained during bariatric surgery) and 143 patients without (termed as "conventional"). RESULTS: Median age was 47 years, 57% were female. Median body mass index (BMI) was 42.9 kg/m2 with significant differences between our conventional and morbidly obese patients (BMI 29.0 vs. 50.8 kg/m2, p < 0.001). Overall, 42% displayed mild/moderate and 16% advanced liver fibrosis (stage III/IV). All tested scores were significantly linked to fibrosis stage (p < 0.001 for all). FIB-4 (AUROC 0.904), APRI (AUROC 0.848), and NFS (AUROC 0.750) were identified as potent predictors of advanced fibrosis, although NFS overestimated fibrosis stage in morbid obesity. Limiting BMI to a maximum of 40 kg/m2 improved NFS' overall performance (AUROC 0.838). FIB-4 > 1.0 indicated high probability of advanced fibrosis (OR = 29.1). FIB-4 predicted advanced fibrosis independently from age, sex, BMI, and presence of morbid obesity. CONCLUSIONS: Our data suggest that FIB-4 score is an accurate predictor of advanced fibrosis in NAFLD throughout all BMI stages. Without adjustment, NFS tends to overestimate fibrosis in morbidly obese NAFLD patients. This problem may be solved by implementation of an upper BMI limit (for NFS) or adjustment of diagnostic thresholds.

Clinical and Molecular Biomarkers for Diagnosis and Staging of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard for NAFLD diagnosis. Due to the risks associated with liver biopsy and the impossibility to apply it on a large scale, it is now necessary to identify non-invasive biomarkers, which may reliably identify patients at higher risk of progression. Therefore, several lines of research have tried to address this issue by identifying novel biomarkers using omics approaches, including lipidomics, metabolomics and RNA molecules' profiling. Thus, in this review, we firstly report the conventional biomarkers used in clinical practice for NAFL and NASH diagnosis as well as fibrosis staging, and secondly, we pay attention to novel biomarkers discovered through omics approaches with a particular focus on RNA biomarkers (microRNAs, long-noncoding RNAs), showing promising diagnostic performance for NAFL/NASH diagnosis and fibrosis staging.

Clinical validation of the FLIP algorithm and the SAF score in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Histological classifications used to diagnose/stage non-alcoholic fatty liver disease (NAFLD) are based on morphology, with undetermined clinical correlates and relevance. We assessed the clinical relevance of the fatty liver inhibition of progression (FLIP) algorithm and the steatosis, activity, and fibrosis (SAF) scoring system. METHODS: One hundred and forty consecutive patients with suspected NAFLD and a separate validation cohort of 78 patients enrolled in a therapeutic trial, all with central reading of liver biopsy, were included. FLIP and SAF were used to categorize patients with non-alcoholic steatohepatitis (NASH), non-NASH NAFLD (NAFL), or non-NAFLD. The SAF activity score assessed hepatocyte ballooning and lobular inflammation; a histologically severe disease was defined as a SAF activity score of ≥3 and/or bridging fibrosis or cirrhosis. Clinical, biochemical, and metabolic data were analyzed in relation to histology. RESULTS: Patients with NASH according to the FLIP algorithm had a clinical profile distinct from those with NAFL, with a higher prevalence of metabolic risk factors (increased body mass index [BMI], central obesity, serum glucose, and glycated hemoglobin), more severe insulin resistance (fasting insulin and homeostasis model assessment for insulin resistance [HOMA-IR] values), and higher levels of aminotransferases. Similar findings were documented for patients with severe disease vs. those without. Positive linear trends existed between NASH or severe disease and increasing BMI and HOMA-IR. There was a strong association between liver fibrosis and NASH or SAF-defined scores of activity. Patients with either significant or bridging fibrosis overwhelmingly had NASH, and bridging fibrosis most often coexisted with severe activity. CONCLUSIONS: The FLIP algorithm/SAF score, although based on purely morphological grounds, are clinically relevant, as they identify patients with distinct clinical and biological profiles of disease severity. Disease activity in NAFLD is associated with fibrosis severity. LAY SUMMARY: The examination of liver tissue under the microscope (histology) serves to define the type and severity of non-alcoholic fatty liver disease morphologically, and is also used to determine improvement in therapeutic or natural history clinical trials. The FLIP algorithm/SAF classification is a new histological classification well validated on morphological but not clinical grounds. Here, we demonstrate that different disease categories defined by the FLIP/SAF classification correspond to entities of different clinical and biological severity. We also show a strong association between the activity of steatohepatitis (defined histologically) and the amount of fibrotic scar.

[NASH: new terminology and what else is new in 2020]. / NASH†: nouvelle terminologie et nouveautés en 2020.

Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of hepatic pathology ranging from non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH) occasionally complicated with hepatic fibrosis or even cirrhosis. In order to propose a diagnosis with positive criteria, a panel of experts recently proposed the use of an alternative nomenclature, metabolic-dysfunction-associated fatty liver disease (MAFLD) whose use remains debated. In addition, in Switzerland and elsewhere, there is strong epidemiological growth of NAFLD. The next years will probably see the approval of new therapies for NAFLD/NASH but, at present, management remains focused on lifestyle interventions and joint monitoring by the primary care physician and, when necessary, the specialist.

La stéatopathie non alcoolique (NAFLD) comprend un spectre de pathologies allant de la stéatose hépatique non alcoolique à la stéatohépatite non alcoolique (NASH) parfois compliquée d'une fibrose hépatique, voire d'une cirrhose. Afin de proposer un diagnostic avec des critères positifs, un panel d'experts a récemment proposé l'utilisation d'une nomenclature alternative, la stéatopathie associée à la dysfonction métabolique (Metabolic-Dysfunction-Associated Fatty Liver Disease, MAFLD) dont l'utilisation reste discutée. D'autre part, la NAFLD est en pleine croissance épidémiologique en Suisse comme ailleurs. Les prochaines années vont probablement voir l'approbation de nouvelles thérapeutiques pour la NAFLD/NASH mais, à l'heure actuelle, la prise en charge reste centrée sur les mesures hygiéno-diététiques et le suivi conjoint par le médecin de premier recours et, si nécessaire, par le spécialiste.

Mapping the triglyceride distribution in NAFLD human liver by MALDI imaging mass spectrometry reveals molecular differences in micro and macro steatosis.

Hepatic lipid accumulation, mainly in the form of triglycerides (TGs), is the hallmark of non-alcoholic fatty liver disease (NAFLD). To date, the spatial distribution of individual lipids in NAFLD-affected livers is not well characterized. This study aims to map the triglyceride distribution in normal human liver samples and livers with NAFLD and cirrhosis with imaging mass spectrometry (MALDI IMS). Specifically, whether individual triglyceride species differing by fatty acid chain length and degree of saturation correlate with the histopathological features of NAFLD as identified with classical H&E. Using a recently reported sodium-doped gold-assisted laser desorption/ionization IMS sample preparation, 20 human liver samples (five normal livers, five samples with simple steatosis, five samples with steatohepatitis, and five samples with cirrhosis) were analyzed at 10-µm lateral resolution. A total of 24 individual lipid species, primarily neutral lipids, were identified (22 TGs and two phospholipids). In samples with a low level of steatosis, TGs accumulated around the pericentral zone. In all samples, TGs with different degrees of side-chain saturation and side-chain length demonstrated differential distribution. Furthermore, hepatocytes containing macro lipid droplets were highly enriched in fully saturated triglycerides. This enrichment was also observed in areas of hepatocyte ballooning in samples with steatohepatitis and cirrhosis. In conclusion, macro lipid droplets in NAFLD are enriched in fully saturated triglycerides, indicating a possible increase in de novo lipogenesis that leads to steatohepatitis and cirrhosis.

Metabolomic Identification of Subtypes of Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a consequence of defects in diverse metabolic pathways that involve hepatic accumulation of triglycerides. Features of these aberrations might determine whether NAFLD progresses to nonalcoholic steatohepatitis (NASH). We investigated whether the diverse defects observed in patients with NAFLD are caused by different NAFLD subtypes with specific serum metabolomic profiles, and whether these can distinguish patients with NASH from patients with simple steatosis. METHODS: We collected liver and serum from methionine adenosyltransferase 1a knockout (MAT1A-KO) mice, which have chronically low levels of hepatic S-adenosylmethionine (SAMe) and spontaneously develop steatohepatitis, as well as C57Bl/6 mice (controls); the metabolomes of all samples were determined. We also analyzed serum metabolomes of 535 patients with biopsy-proven NAFLD (353 with simple steatosis and 182 with NASH) and compared them with serum metabolomes of mice. MAT1A-KO mice were also given SAMe (30 mg/kg/day for 8 weeks); liver samples were collected and analyzed histologically for steatohepatitis. RESULTS: Livers of MAT1A-KO mice were characterized by high levels of triglycerides, diglycerides, fatty acids, ceramides, and oxidized fatty acids, as well as low levels of SAMe and downstream metabolites. There was a correlation between liver and serum metabolomes. We identified a serum metabolomic signature associated with MAT1A-KO mice that also was present in 49% of the patients; based on this signature, we identified 2 NAFLD subtypes. We identified specific panels of markers that could distinguish patients with NASH from patients with simple steatosis for each subtype of NAFLD. Administration of SAMe reduced features of steatohepatitis in MAT1A-KO mice. CONCLUSIONS: In an analysis of serum metabolomes of patients with NAFLD and MAT1A-KO mice with steatohepatitis, we identified 2 major subtypes of NAFLD and markers that differentiate steatosis from NASH in each subtype. These might be used to monitor disease progression and identify therapeutic targets for patients.

Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5% of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a "three-hit" process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 has been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may result in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 is more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 is up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major DMEs and transporters. We also discuss the potential mechanisms underlying these alterations.

Diagnosis and Assessment of NAFLD: Definitions and Histopathological Classification.

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of clinical and histopathological changes including "simple" steatosis, steatosis with inflammation, steatohepatitis, cirrhosis, and hepatocellular carcinoma. It was initially described in the context of drug-induced liver injury and acute liver disease following jejunoileal bypass surgery, but since the early 1980s it has been widely acknowledged as the hepatic manifestation of metabolic syndrome. It now represents a burgeoning public health crisis and is fast becoming the main indication for liver transplantation in some parts of the world. Its true incidence and prevalence are unknown, although estimates have been made from large imaging studies. Liver biopsy interpretation is still regarded as the gold standard for making accurate diagnoses in NAFLD, but sampling limitations are recognized. Furthermore, clear definitions for key histopathological components have been lacking, resulting in significant interobserver variations in making a diagnosis of steatohepatitis. In this review the authors consider some aspects of classification and variant forms of NAFLD such as that occurring in children. They provide an update on grading and staging systems and histopathological prognostic factors, and address the role of liver biopsy in contemporary clinical care of patients with NAFLD.

Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease.

PURPOSE: To evaluate the diagnostic performance of previously proposed high-specificity magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) thresholds for diagnosis of steatosis grade 1 or higher (PDFF threshold of 6.4%), grade 2 or higher (PDFF threshold of 17.4%), and grade 3 (PDFF threshold of 22.1%) by using histologic findings as a reference in an independent cohort of adults known to have or suspected of having nonalcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This prospective, cross-sectional, institutional review board-approved, HIPAA-compliant single-center study was conducted in an independent cohort of 89 adults known to have or suspected of having NAFLD who underwent contemporaneous liver biopsy. MR imaging PDFF was estimated at 3 T by using magnitude-based low-flip-angle multiecho gradient-recalled-echo imaging with T2* correction and multipeak modeling. Steatosis was graded histologically (grades 0, 1, 2, and 3, according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system). Sensitivity, specificity, and binomial confidence intervals were calculated for the proposed MR imaging PDFF thresholds. RESULTS: The proposed MR imaging PDFF threshold of 6.4% to diagnose grade 1 or higher steatosis had 86% sensitivity (71 of 83 patients; 95% confidence interval [CI]: 76, 92) and 83% specificity (five of six patients; 95% CI: 36, 100). The threshold of 17.4% to diagnose grade 2 or higher steatosis had 64% sensitivity (28 of 44 patients; 95% CI: 48, 78) and 96% specificity (43 of 45 patients; 95% CI: 85, 100). The threshold of 22.1% to diagnose grade 3 steatosis had 71% sensitivity (10 of 14 patients; 95% CI: 42, 92) and 92% specificity (69 of 75 patients; 95% CI: 83, 97). CONCLUSION: In an independent cohort of adults known to have or suspected of having NAFLD, the previously proposed MR imaging PDFF thresholds provided moderate to high sensitivity and high specificity for diagnosis of grade 1 or higher, grade 2 or higher, and grade 3 steatosis. Prospective multicenter studies are now needed to further validate these high-specificity thresholds.

[Variants of the course of non-alcoholic fatty liver disease in patients with ischemic heart disease and possibility of hypolipidemic therapy].

In developed countries cardiovascular pathology is the leading cause of death among the population in more than 50% cases. In 30% of patients the ischemic heart disease is related to obesity, which accompanies steatosis and steatohepatitis. Disturbance of lipid metabolism plays one of the key roles in combination of ischemic heart disease and non-alcoholic fatty liver disease. Possibilities of safe administration of hypolipidemic therapy in patients with disturbance of lipid metabolism have not been studied completely. The aim of the research was to evaluate variants of the course of non-alcoholic fatty liver disease in patients with ischemic heart disease and possibilities of safe hypolipidemic therapy. 60 patients with chronic heart disease in combination with non-alcoholic fatty liver disease have been examined. On investigation three variants of non-alcoholic fatty liver disease course in patients with ischemic heart disease have been differentiated on the basis of portal vein size, levels of liver transaminase and index of 13C-methaticine respiratory test. Important differences of steatohepatitis from steatosis are increased level of aspartate aminotransferase, lowered liver metabolism by 30% and decreased cumulative dose by 42%. Patients with ischemic heart disease and steatosis are recommended hypolipidemic therapy according to standards of treatment. At the same time hypolipidemic agents should be administered with caution to the patients with ischemic heart disease and steatohepatitis.

Progress is impossible without change: understanding the evolving nomenclature of steatotic liver disease and its effect on hepatology practice.

The American, European, and Latin American liver societies have proposed a change in the nomenclature we use to describe alcohol-related liver disease and non-alcoholic fatty liver disease. Additionally, a term encompassing both is now advocated: steatotic liver disease, which includes metabolic dysfunction associated steatotic liver disease (MASLD) and MASLD with greater alcohol consumption (MetALD). These classifications offer increased relevance for clinicians, researchers, and patients alike. In this Viewpoint, we discuss the basis for this nomenclature shift and how it was developed. We also explore the challenges that will be faced in the adoption of such change. The proposed change seeks to banish stigma associated with phrasing such as alcoholic and fatty. However stigma, particularly related to the term fatty, is culturally nuanced, and reflects different entities depending on location. If such a change is internationally accepted, there will be wide-reaching effects on practitioners in primary care and metabolic medicine, and on patients. We discuss those effects and the opportunities the nomenclature change could offer, particularly for patients with alcohol and metabolic risk factors who represent a group previously ignored by clinical trials.

A global survey on the use of the international classification of diseases codes for metabolic dysfunction-associated fatty liver disease.

BACKGROUND: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11. METHODS: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members. RESULTS: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%). CONCLUSIONS: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision.

New nomenclature for fatty liver disease.

This review investigates that, in 2023, fatty liver disease underwent a name change to "steatotic liver disease" (SLD). SLD now includes metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and metabolic and alcohol-related liver disease (MetALD). The renaming aims to better incorporate alcohol intake and metabolic risk factors into disease classification and to diminish the stigma associated with the previous nomenclature. Early identification of the patient's aetiology is important for the prognosis which can be improved by interventions against the causative risk factors.