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There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression. Understanding of pathogenic mechanisms and clinical features of NAFLD is driving progress in therapeutic strategies now in clinical trials.

Our understanding of nonalcoholic fatty liver disease pathophysiology continues to advance rapidly. Accordingly, the field has moved from describing the clinical phenotype through the presence of nonalcoholic steatohepatitis (NASH) and degree of fibrosis to deep phenotyping with a description of associated comorbidities, genetic polymorphisms and environmental influences that could be associated with disease progression. These insights have fuelled a robust therapeutic pipeline across a variety of new targets to resolve steatohepatitis or reverse fibrosis, or both. Additionally, some of these therapies have beneficial effects that extend beyond the liver, such as effects on glycaemic control, lipid profile and weight loss. In addition, emerging therapies for NASH cirrhosis would have to demonstrate either reversal of fibrosis with associated reduction in portal hypertension or at least delay the progression with eventual decrease in liver-related outcomes. For non-cirrhotic NASH, it is the expectation that reversal of fibrosis by one stage or resolution of NASH with no worsening in fibrosis will need to be accompanied by overall survival benefits. In this Review, we summarize NASH therapies that have progressed to phase II and beyond. We also discuss some of the potential clinical challenges with the use of these new therapies when approved.The therapeutic pipeline for nonalcoholic steatohepatitis (NASH) is expanding as insights into disease pathophysiology are gained. This Review summarizes progress in the development of NASH therapies, current and ongoing clinical trials, and potential challenges with emerging therapies.

The clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma. In this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios. Of 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9–18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p<0·0001), had higher BMI (p<0·0001), and were more likely to present with metabolic comorbidities (diabetes [p<0·0001], hypertension [p<0·0001], and hyperlipidaemia [p<0·0001]) or cardiovascular disease at presentation (p=0·0055) than patients with hepatocellular carcinoma due to other causes. They were also more likely to be non-cirrhotic (38·5%, 27·9–50·2 vs 14·6%, 8·7–23·4 for hepatocellular carcinoma due to other causes; p<0·0001). Patients with NAFLD-related hepatocellular carcinoma had larger tumour diameters (p=0·0087), were more likely to have uninodular lesions (p=0·0003), and had similar odds of Barcelona Clinic Liver Cancer stages, TNM stages, alpha fetoprotein concentration, and Eastern Cooperative Oncology Group (ECOG) performance status to patients with non-NAFLD-related hepatocellular carcinoma. A lower proportion of patients with NAFLD-related hepatocellular carcinoma underwent surveillance (32·8%, 12·0–63·7) than did patients with hepatocellular carcinoma due to other causes (55·7%, 24·0–83·3; p<0·0001). There were no significant differences in treatment allocation (curative therapy, palliative therapy, and best supportive care) between patients with NAFLD-related hepatocellular carcinoma and those with hepatocellular carcinoma due to other causes. Overall survival did not differ between the two groups (hazard ratio 1·05, 95% CI 0·92–1·20, p=0·43), but disease-free survival was longer for patients with NAFLD-related hepatocellular carcinoma (0·79, 0·63–0·99; p=0·044). There was substantial heterogeneity in most analyses (I2>75%), and all articles had low-to-moderate risk of bias. NAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma. None.

In this phase 2 trial involving adults with metabolic dysfunction–associated steatohepatitis and liver fibrosis, survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis.

Nonalcoholic fatty liver disease (NAFLD) was first described as a distinct clinical entity four decades ago. However, the condition has become the centre of attention within hepatology owing to its high prevalence and growing contribution to the burden of end-stage liver disease in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD with a focus on landmark findings that have influenced current paradigms and key knowledge gaps that need to be filled to make progress. Specifically, a timeline of scientific discovery of both basic disease mechanisms (with a focus on human data) and the evolution of knowledge about the clinical course of the disease is provided and related to current approaches to treat and eventually prevent NAFLD.Nonalcoholic fatty liver disease (NAFLD) was first described four decades ago, but it is increasingly important owing to its high prevalence in the general population. This Perspective provides an overview on the development of knowledge related to NAFLD, focusing on landmark findings.

In a phase 3 randomized trial, 199 patients with type 1 hepatorenal syndrome were assigned to receive the vasoconstrictor terlipressin plus albumin and 101 to receive placebo plus albumin. Renal function was better with terlipressin than with placebo; however, mortality was not lower, and terlipressin was associated with adverse events, including respiratory failure.

Non-alcoholic fatty liver disease (NAFLD) has emerged as a common cause of liver-related morbidity and mortality. Tackling this condition at a societal level will require a clear understanding of the burden of disease in the general population. However, a major limitation of such an assessment, particularly in a real-world setting, is the low rate of diagnosis of the condition, as recently identified by Alexander et al. (BMC Med 16:130, 2018). Therein, the likelihood that the condition is indeed underdiagnosed and the potential causes for such underdiagnosis are discussed. The authors underscore the need for physician education and for development of simple evaluation tools that are both robust and implementable in a primary care setting, along with effective therapeutics to overcome this apathy towards NAFLD. Importantly, there remains a need for additional data on the prevalence of non-alcoholic steatohepatitis, the more aggressive form of NAFLD, especially with progressive fibrosis, along with patient outcomes to inform health policy decisions related to screening, surveillance, and access to therapeutics.

Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA methyltransferase Dnmt3a decreased, the global DNA methylation was unaltered. Among individual genes, only HMG-CoA reductase (Hmgcr) was hypermethylated, and no methylation changes were observed in fatty acid synthase (Fasn), nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (Nfκb1), c-Jun, B-cell lymphoma 2 (Bcl-2) and Caspase 3. NAFLD was associated with hepatic methionine deficiency and homocysteine elevation, resulting mainly from impaired homocysteine remethylation, and aberrancy in methyltransferase reactions. Despite increased PRMT1 expression, hepatic ADMA was depleted while circulating ADMA was increased, suggesting increased export to circulation.

The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 2·2, 95% CI 1·4 to 3·3; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosis and management have evolved rapidly alongside the increasing prevalence of obesity and related complications. Hepatology has expanded its focus beyond late-stage cirrhosis and portal hypertension to earlier, complex MASLD cases in younger patients, necessitating closer collaboration with endocrinology. The renaming of nonalcoholic fatty liver disease (NAFLD) to MASLD reflects its pathophysiology, reduces stigma, and has prompted new research directions. Noninvasive tests such as liver stiffness measurement now play a crucial role in diagnosis, reducing reliance on invasive liver biopsies. However, advanced omics technologies, despite their potential to enhance diagnostic precision and patient stratification, remain underutilized in routine clinical practice. Behavioral factors, including posttraumatic stress disorder (PTSD) and lifestyle choices, influence disease outcomes and must be integrated into patient management strategies. Primary care settings are critical for early screening to prevent progression to advanced disease, yet sizable challenges remain in implementing effective screening protocols. This Review explores these evolving aspects of MASLD diagnosis and management, emphasizing the need for improved diagnostic tools, multidisciplinary collaboration, and holistic care approaches to address existing gaps and ensure comprehensive patient care across all healthcare levels.