DESCRIPTION:The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review is to provide clinicians with guidance on the use of noninvasive tests (NITs) in the evaluation and management of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD affects nearly 30% of the global population and is a growing cause of end-stage liver disease and liver-related health care resource utilization. However, only a minority of all patients with NAFLD experience a liver-related outcome. It is therefore critically important for clinicians to assess prognosis and identify those with increased risk of disease progression and negative clinical outcomes at the time of initial assessment. It is equally important to assess disease trajectory over time, particularly in response to currently available therapeutic approaches. The reference standard for assessment of prognosis and disease monitoring is histologic examination of liver biopsy specimens. There are, however, many limitations of liver biopsies and their reading that have limited their use in routine practice. The utilization of NITs facilitates risk stratification of patients and longitudinal assessment of disease progression for patients with NAFLD. This clinical update provides best practice advice based on a review of the literature on the utilization of NITs in the management of NAFLD for clinicians. Accordingly, a combination of available evidence and consensus-based expert opinion, without formal rating of the strength and quality of the evidence, was used to develop these best practice advice statements. METHODS:This Expert Review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: NITs can be used for risk stratification in the diagnostic evaluation of patients with NAFLD. BEST PRACTICE ADVICE 2: A Fibrosis 4 Index score <1.3 is associated with strong negative predictive value for advanced hepatic fibrosis and may be useful for exclusion of advanced hepatic fibrosis in patients with NAFLD. BEST PRACTICE ADVICE 3: A combination of 2 or more NITs combining serum biomarkers and/or imaging-based biomarkers is preferred for staging and risk stratification of patients with NAFLD whose Fibrosis 4 Index score is >1.3. BEST PRACTICE ADVICE 4: Use of NITs in accordance with manufacturer's specifications (eg, not in patients with ascites or pacemakers) can minimize risk of discordant results and adverse events. BEST PRACTICE ADVICE 5: NITs should be interpreted with context and consideration of pertinent clinical data (eg, physical examination, biochemical, radiographic, and endoscopic) to optimize positive predictive value in the identification of patients with advanced fibrosis. BEST PRACTICE ADVICE 6: Liver biopsy should be considered for patients with NIT results that are indeterminate or discordant; conflict with other clinical, laboratory, or radiologic findings; or when alternative etiologies for liver disease are suspected. BEST PRACTICE ADVICE 7: Serial longitudinal monitoring using NITs for assessment of disease progression or regression may inform clinical management (ie, response to lifestyle modification or therapeutic intervention). BEST PRACTICE ADVICE 8: Patients with NAFLD and NITs results suggestive of advanced fibrosis (F3) or cirrhosis (F4) should be considered for surveillance of liver complications (eg, hepatocellular carcinoma screening and variceal screening per Baveno criteria). Patients with NAFLD and NITs suggestive of advanced hepatic fibrosis (F3) or (F4), should be monitored with serial liver stiffness measurement; vibration controlled transient elastography; or magnetic resonance elastography, given its correlation with clinically significant portal hypertension and clinical decompensation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

Bile acids (BAs) serve as signalling molecules, efficiently regulating their own metabolism and transport, as well as key aspects of lipid and glucose homeostasis. BAs shape the gut microbial flora and conversely are metabolised by microbiota. Disruption of BA transport, metabolism and physiological signalling functions contribute to the pathogenesis and progression of a wide range of liver diseases including cholestatic disorders and MASLD (metabolic dysfunction-associated steatotic liver disease), as well as hepatocellular and cholangiocellular carcinoma. Additionally, impaired BA signalling may also affect the intestine and kidney, thereby contributing to failure of gut integrity and driving the progression and complications of portal hypertension, cholemic nephropathy and the development of extrahepatic malignancies such as colorectal cancer. In this review, we will summarise recent advances in the understanding of BA signalling, metabolism and transport, focusing on transcriptional regulation and novel BA-focused therapeutic strategies for cholestatic and metabolic liver diseases.