Abstract
PREAMBLE The study of NAFLD has intensified significantly, with more than 1400 publications since 2018, when the last American Association for the Study of Liver Diseases (AASLD) Guidance document was published.1 This new AASLD Guidance document reflects many advances in the field pertinent to any practitioner caring for patients with NAFLD and emphasizes advances in noninvasive risk stratification and therapeutics. A separate guideline focused on the management of patients with NAFLD in the context of diabetes has been written jointly by the American Association of Clinical Endocrinology and AASLD.2 Given the significant growth in pediatric NAFLD, it will not be covered here to allow for a more robust discussion of the diagnosis and management of pediatric NAFLD in the upcoming AASLD Pediatric NAFLD Guidance. A "Guidance" differs from a "Guideline" in that it is not bound by the Grading of Recommendations, Assessment Development and Evaluation system. Thus, actionable statements rather than formal recommendations are provided herein. The highest available level of evidence was used to develop these statements, and, where high-level evidence was not available, expert opinion was used to develop guidance statements to inform clinical practice. Key points highlight important concepts relevant to understanding the disease and its management. The most profound advances in NAFLD relevant to clinical practice are in biomarkers and therapeutics. Biomarkers and noninvasive tests (NITs) can be used clinically to either exclude advanced diseases or identify those with a high probability of cirrhosis.3,4 NIT "cut points" vary with the populations studied, underlying disease severity, and clinical setting. Those proposed in this guidance are meant to aid decision-making in the clinic and are not meant to be interpreted in isolation. Identifying patients with "at-risk" NASH (biopsy-proven NASH with stage 2 or higher fibrosis) is a more recent area of interest. Although the definitive diagnosis and staging of NASH remain linked to histology, noninvasive tools can now be used to assess the likelihood of significant fibrosis, predict risk of disease progression and decompensation, make management decisions, and, to some degree, assess response to treatment. There is an ongoing debate over the nomenclature of fatty liver disease, which had not been finalized at the time this guidance was published. At the culmination of a rigorous consensus process, it is intended that any formal change in nomenclature will advance the field without a negative impact on disease awareness, clinical trial endpoints, or the drug development/approval process. Furthermore, it should allow for the emergence of newly recognized disease subtypes to address the impact of disease heterogeneity, including the role of alcohol, on disease progression and response to therapy. Input from patients has been central to all stages of the consensus process to ensure the minimization of nomenclature-related stigma. DEFINITIONS NAFLD is an overarching term that includes all disease grades and stages and refers to a population in which ≥5% of hepatocytes display macrovesicular steatosis in the absence of a readily identified alternative cause of steatosis (eg, medications, starvation, monogenic disorders) in individuals who drink little or no alcohol (defined as < 20 g/d for women and <30 g/d for men). The spectrum of disease includes NAFL, characterized by macrovesicular hepatic steatosis that may be accompanied by mild inflammation, and NASH, which is additionally characterized by the presence of inflammation and cellular injury (ballooning), with or without fibrosis, and finally cirrhosis, which is characterized by bands of fibrous septa leading to the formation of cirrhotic nodules, in which the earlier features of NASH may no longer be fully appreciated on a liver biopsy. UPDATE ON EPIDEMIOLOGY AND NATURAL HISTORY The prevalence of NAFLD and NASH is rising worldwide in parallel with increases in the prevalence of obesity and metabolic comorbid disease (insulin resistance, dyslipidemia, central obesity, and hypertension).5,6 The prevalence of NAFLD in adults is estimated to be 25%–30% in the general population7–9 and varies with the clinical setting, race/ethnicity, and geographic region studied but often remains undiagnosed.10–14 The associated economic burden attributable to NASH is substantial.15–17 The prevalence of NASH in the general population is challenging to determine with certainty; however, NASH was identified in 14% of asymptomatic patients undergoing colon cancer screening.14 This study also highlights that since the publication of a prior prospective prevalence study,18 the prevalence of clinically significant fibrosis (stage 2 or higher fibrosis) has increased >2-fold. This is supported by the projected rise in NAFLD prevalence by 2030, when patients with advanced hepatic fibrosis, defined as bridging fibrosis (F3) or compensated cirrhosis (F4), will increase disproportionately, mirroring the projected doubling of NASH.5,19 As such, the incidence of hepatic decompensation, HCC, and death related to NASH cirrhosis are likewise expected to increase 2- to 3-fold by 2030.5 Although expected to increase further, NASH-related cirrhosis is already the leading indication for liver transplantation in women and those >65 years of age and is on par with alcohol as the leading indication overall.20–22 Natural history of disease progression Data from meta-analyses and pooled studies demonstrate that fibrosis and the presence of steatohepatitis are the primary predictors of disease progression.23–25 The collinearity between NASH and the fibrosis it induces makes it challenging to demonstrate the independent contribution of NASH to fibrosis and adverse outcomes in multivariable analyses.26,27 Although fibrosis is the primary determinant of adverse outcomes, increased liver-related morbidity and mortality and nonhepatic malignancy are observed in patients with NAFLD even in the absence of fibrosis on initial biopsy.25 Nevertheless, patients with NASH and at least stage 2 fibrosis (F2), referred to as "at-risk" NASH, have a demonstrably higher risk of liver-related morbidity and mortality.24,28 Fibrosis progression is influenced by many factors such as the presence and severity of comorbid disease, genomic profile, and environmental factors. A meta-analysis of placebo-treated patients in 35 NASH trials found minimal progression, suggesting that nonpharmacologic factors (frequent visits/monitoring, dietary or lifestyle counseling, or changes) may reduce progression.29 An earlier meta-analysis of cohorts with longitudinal paired biopsies30 demonstrated a NAFLD fibrosis progression rate of one stage per 7 years in those with NASH versus 14 years for those with NAFL.30 The diagnosis of cirrhosis, determined by biopsy or noninvasively, is important because it changes clinical management. Those with cirrhosis require biannual screening for HCC as well as screening for varices and monitoring for signs or symptoms of decompensation.31,32 Among patients with cirrhosis, progression to clinical decompensation ranges from 3% to 20% per year.12,33–35 Association between disease stage and adverse outcomes The most common causes of death in patients with NAFLD overall are cardiovascular disease (CVD) and nonhepatic malignancy, followed by liver disease. The amount of liver fibrosis identified histologically in patients with NAFLD has been strongly linked to the development of liver-related outcomes and death.24,26,36,37 Bridging fibrosis and cirrhosis are associated with an exponentially greater risk of liver-related morbidity and mortality than earlier stages of fibrosis.23,24,35 In a prospective study of 1773 patients, all-cause mortality in those with fibrosis stages 0–2 was 0.32 per 100 person-years, compared with 0.89 per 100 person-years in those with bridging fibrosis and 1.76 per 100 person-years in those with cirrhosis. After correcting for multiple factors, hepatic decompensation was associated with all-cause mortality (HR, 6.8; 95% CI, 2.2–21.3).35 Cirrhosis regression has been associated with a 6-fold reduction in liver-related events in clinical trials.38Key points: Patients with NASH and F2–4 fibrosis are at higher risk for liver-related events and mortality and are considered to have "at-risk" NASH. The rates of fibrosis progression and hepatic decompensation vary depending on baseline disease severity, genetic, individual environmental, and comorbid disease determinants. CVD and nonhepatic malignancies are the most common causes of mortality in patients with NAFLD without advanced fibrosis; death from liver disease predominates in patients with advanced fibrosis. MOLECULAR AND CELLULAR PATHOGENESIS The presence and severity of NAFL and NASH are substantially determined by factors that govern the supply and disposition of fatty acids, diacylglycerols, ceramides, cholesterol, phospholipids, and other intrahepatic lipids. Energy oversupply and limited adipose tissue expansion contribute to insulin resistance and metabolic disease.39 When energy intake exceeds metabolic needs and disposal capacity, carbohydrates, in the form of dietary sugars (eg, fructose, sucrose, and glucose), drive the formation and accumulation of intrahepatic fat from de novo lipogenesis (DNL).40,41 There is substantial interindividual heterogeneity in the role of DNL among patients with NAFLD.42,43 In addition, the type of fat consumed plays a role in the development of NASH, with a higher risk associated with saturated versus unsaturated fat consumption (Figure 1).44–46FIGURE 1: Pathogenic drivers of NAFLD as therapeutic targets. Overview of the major mechanisms that lead to the phenotype of NASH and its consequences, many of which can be leveraged therapeutically. Not shown are the many areas where genetic polymorphisms may play a role and where important modifying factors such as choleste