Search for a command to run...
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 will the projected of the of hepatic decompensation, and to NASH are to to by Although to is the leading for liver in women and those of and is on with alcohol as the leading of disease progression from and that fibrosis and the presence of are the of disease The NASH and the fibrosis it it challenging to the of NASH to fibrosis and in Although fibrosis is the of increased and and are in patients with NAFLD in the absence of fibrosis on patients with NASH and at stage 2 fibrosis to as “at-risk” NASH, a higher risk of and progression is by many as the presence and of comorbid disease, and A of patients in NASH that or or may earlier of with a NAFLD fibrosis progression of stage in those with NASH for those with The diagnosis of cirrhosis, by or is important it clinical management. Those with for as as for and for or of patients with cirrhosis, progression to clinical from to Association disease stage and The most of in patients with NAFLD are disease and by liver The of liver fibrosis identified in patients with NAFLD has been linked to the of and fibrosis and are associated with an risk of and than earlier stages of a prospective study of in those with fibrosis stages was with in those with bridging fibrosis and in those with for hepatic was associated with has been associated with a in in clinical with NASH and fibrosis are at higher risk for and and are to “at-risk” The of fibrosis progression and hepatic vary on disease severity, and comorbid disease and are the most of in patients with NAFLD without advanced from liver disease in patients with advanced AND The presence and of and NASH are by that the and of fatty and and to and metabolic metabolic and in the of (eg, and the formation and of from There is in the role of patients with the of a role in the of NASH, with a higher risk associated with of NAFLD as of the that to the of NASH and its many of which can be are the many where may a role and where important as of fatty the and may also these A disease may be an of to that to without is which and the of NASH the of for patients with of that or NASH that (eg, (eg, (eg, A and fatty hepatic and and inflammation, and metabolic the with on the liver (eg, of growth growth and as that and is in patients with NAFLD and is in the and is characterized by increased of fatty from in the and with the progression of NAFLD to that the and of the of to an and that in response to in The and to in can be by and decisions, all of which in the of The of to the of NASH patients has the of tests and Although in some the and progression of NASH are by and resistance, in disease progression is by been associated with more advanced liver disease and the of in The of of in and in that a role in also been linked to the prevalence and of NAFLD, including 2 which may a role in and which in a that an that also to in been linked to NASH, fibrosis, and in a for of also been to be A of the of which is the of this to in disease and as to from the and hepatic may also to the NASH of of patients is to understanding of this disease and its The response of the liver to injury includes and of which to injury and as of a hepatic Although of been a in NASH, its role in the of NASH in remains of NASH an to the liver and and with in and disease inflammation, from to disease to the of NAFLD and disease NAFLD NAFLD is linked to and often the of metabolic (insulin resistance, dyslipidemia, central obesity, and metabolic an risk of progression of NASH and The NAFLD and metabolic may also the liver and (eg, the of that fatty and and The presence and of obesity are associated with NAFLD and disease is an important of the role of obesity in NAFLD characterized by increased and a higher risk of resistance, and hepatic fibrosis, of characterized by increased in the or to be which is more and than the of this more and is the of fatty leading to and of a with NAFLD recent and of NAFLD, or for alcohol including of and (eg, features of (eg, features of advanced liver disease (eg, tests with and and or to not as of liver or 2 diabetes 2 diabetes is the most risk for the of NAFLD, fibrosis and Given the central role that in the of and NAFLD, it is not that patients with a higher prevalence of NAFLD from to and a higher risk of NASH with Furthermore, the probability of advanced fibrosis increases with the of Although is for time and time these the and The NAFLD and is in in its NAFLD is associated with a in in the absence of The presence of NAFLD is associated with a to risk of and patients with NAFLD should be for the presence of Furthermore, as liver disease and diabetes more challenging to The role of in the progression of remains with 2 an and injury and liver not this Although NAFLD has also been in patients with its prevalence is than in and it is to metabolic risk (eg, higher is associated with There is a higher of in those with NAFLD the disease with of in disease to in those with The presence of is to metabolic with to the risk of and has been associated with fibrosis the of or the or are of underlying metabolic disease has not been with NAFLD are as to as those without and the are more in patients with NASH can to and and impact it is to this is by the of the patients to cirrhosis, to remain at high risk for the of and to hepatic of in NAFLD should the of to as on risk and risk of with as fatty or should be when with a not are in patients with NAFLD the disease including advanced liver disease, and to a in and in clinical are often patients with are also in the context of compensated and may on and are Although been used in patients with cirrhosis, the risk of be higher in this and more is patients with and high risk undergoing for liver can be with patients with NAFLD and (eg, or a of with fatty or should be used to the risk of may also when are and are is as an to to can be for of to its on should be when are used in with to a higher risk of is associated with and is also associated with more advanced a of has been linked to of and and increased hepatic Given the NAFLD and patients with NAFLD who are or should be for and or should be for those at high is an important cause of in patients with however, the to which NAFLD is A NAFLD and disease, and increased presence and of and the NAFLD and Furthermore, in a studied the of was the all fibrosis however, the of was the management of risk with the of and is to in patients with comorbid as dyslipidemia, and and is to in those at disease A of 20 that NAFLD was associated with a increased prevalence of NAFLD and NASH are also associated with from the NASH a higher prevalence of in patients with advanced fibrosis with fibrosis The to which the liver to the of of associated metabolic disease remains to be are and for risk in patients with NAFLD the disease including compensated on the and of in patients with cirrhosis, with be in patients with high can be and with fatty or with diabetes are at higher risk for NASH and advanced fibrosis and should be for advanced with NAFLD should be for the presence of Key and of is higher patients with NASH and advanced from is a cause of in patients with NAFLD, and to cancer has the to A NAFLD with NAFLD are most with hepatic steatosis on or liver is important to that provided by most are higher than should be in NAFLD, in which a from to in and from to in of patients should for metabolic of alcohol and of of liver disease as as to identify of and advanced liver disease the clinical is (eg, not associated with metabolic or accompanied by or of steatosis or should be of steatosis or can in or an NASH and should be in clinical can also to hepatic steatosis or or disease in those with underlying NAFLD and should be identified Although risk stratification is not in clinical of and NAFLD in the risk for NAFLD, NASH, and advanced 2 to for of hepatic steatosis and Clinical and advanced fibrosis in steatosis on liver (eg, disease on liver disease with to macrovesicular steatosis or of of steatosis and of hepatic to steatosis of of or may not be of metabolic risk and injury injury to of of metabolic of of hepatic of alcohol can be an important to fatty liver disease progression and should be in all can be as mild to 20 and and or and alcohol increases the probability of advanced in patients with obesity or of and alcohol on liver disease and alcohol the risk of liver cirrhosis, and from liver alcohol liver injury and fibrosis progression and should be in patients with a of mild alcohol on the of but in a alcohol (defined as was associated with in steatosis and and of NASH with patients who not alcohol may the risk for and is in to liver with an of on the to impact disease at an The impact of alcohol and on the of patients with NAFLD, alcohol can be a for liver disease and should be on a with clinically significant hepatic fibrosis should from alcohol Key for those patients with alcohol may the of fibrosis progression and hepatic and in patients with to its with obesity and metabolic risk higher of NAFLD been in patients with growth and the role of in the of hepatic the NAFLD and in remains significant NAFLD and or was in a however, a study of patients for a of was associated with a higher of and the of its metabolic growth are important of and and cellular is associated with and increased and can in resistance, and a growth in patients with NAFLD and associated with obesity and cause of is associated with resistance, and dyslipidemia, with a an increased risk for NASH and of in with and NAFLD been and a study of adults with with and liver in NASH with and hepatic steatosis by patients with and NAFLD, a which and increases growth without liver the a in the and NAFLD is linked to in and resistance, but is not for all A of and and A that NAFLD was associated with in but higher in a by The and NAFLD is often by the presence of obesity and resistance, of which are to be associated with can also resistance, and to the of hepatic study in that a level was associated with NAFLD, and the was for and in study including with by and liver histology, the and steatosis when for and obesity, with no to the of liver or in resistance, and a more role of on metabolic risk for NAFLD in but it should be for as it may The role of and in NAFLD is associated with increased liver as as a higher prevalence of NAFLD and advanced The prevalence of NAFLD is higher in with that higher in women are associated with an increased risk of NAFLD Furthermore, is a likelihood of NAFLD in higher of as as an and the of on NAFLD, hepatic in study that to from and are in The associated increased to the and progression of NAFLD, has not been of in and population a to in the prevalence of NAFLD and an increased risk of women with that is the of disease in a study of women with NAFLD was associated with the of and advanced fibrosis for and this study not for resistance, which may the NAFLD is more in with but not of is as by clinical or this should be Key Although and may be associated with hepatic role on the and progression of and fibrosis remains to be can in women with which with obesity and can NAFLD and more disease in this NAFLD Although NAFLD is associated with obesity, it can also in or in are with or and the prevalence of NAFLD in individuals varies from in the to as high as in with with NAFLD increased metabolic and and in the may also to NAFLD in a significant role in this but the to NAFLD individuals with NAFLD are more of or which is in by a higher prevalence of the in the which to NASH and fibrosis but is more in individuals with NAFLD with patients who or had but is not as it not can also a role and should be in patients of NAFLD in patients without obesity can be clinically may not be for patients with NAFLD, but and in this may be of populations at increased risk for advanced liver disease is to identify and those with clinically significant fibrosis (stage in as those with obesity with metabolic a of or significant alcohol also separate discussion on the role of may identify those with asymptomatic but clinically significant of patients for that may hepatic of is important of with NASH a higher risk of advanced Furthermore, the risk of NAFLD and advanced fibrosis may be of risk and recommendations are in for advanced fibrosis in populations of advanced fibrosis, obesity NAFLD in context of alcohol of a with to 2 diabetes of advanced fibrosis in population should NAFLD be in and practice most NAFLD is asymptomatic or associated with often patients The prevalence of advanced disease is in than in and the to is context to NAFLD on the of metabolic risk or identified as fatty liver by in the absence of of hepatic steatosis disease, disease, alcohol should risk The of this risk is to identify patients who are not to advanced fibrosis to the negative of in in advanced fibrosis, patients in can be in patients with metabolic risk those with or should more risk with patients with and advanced hepatic fibrosis a from available clinical and may be and allow for the of as progression to or decompensation, the of may be robust in patients with more are available, it is that the for in patients with will for the of patients at risk for or with NAFLD practice with steatosis on or for is a clinical of NAFLD, as those with metabolic risk or in liver should with a prevalence of advanced fibrosis, as in the setting, the is on advanced fibrosis a with a high negative the is patients can be in the and without 2 diabetes and metabolic risk can be with or 2 or more metabolic risk are at higher risk for disease and more (eg, should be patients than a of should be has in those should be in those with increased metabolic risk or liver should not be used in patients with a should be or Liver or the for risk stratification in a to should be in those with to exclude of liver disease or when to the increased risk of clinically significant higher prevalence as risk with may be when noninvasive tests (NITs) are or is clinical of more advanced of should for and or may identify patients with “at-risk” NASH with NAFLD and fibrosis stage who may from a as is on clinical or management may be without a liver biopsy. Liver should be when significant fibrosis the presence of “at-risk” NASH (eg, or NIT is are or are that in patients with or advanced fibrosis, an is a of and is for this of in risk is on expert at all stages of disease should be on and those with fibrosis for as of are supported by evidence and are meant to clinical management to rather than be interpreted in isolation. who may a or high risk of advanced disease on should risk the setting, or as are over as to The Liver is for when advanced fibrosis is it can be for risk the of may be in some risk is with an or high risk of fibrosis, patients should be to for and those patients with advanced hepatic fibrosis or cirrhosis, or of of or may the of are often used clinically to identify patients with liver disease but can be in patients with NASH, and advanced hepatic Although are for the of with advanced fibrosis, and or or a of may the presence of liver are the provided by most clinical which is to the of of patients with for NAFLD from risk stratification in the and practice The in the is the of patients with “at-risk” NASH or advanced patients and may from tools as or can be used to risk patients in been or not of clinical Liver should be when is as may with or and or features a diagnosis of advanced or (eg, or when is in liver for NAFLD is not patients with hepatic steatosis or clinically NAFLD on the presence of obesity and metabolic risk should risk with as those with obesity, of cirrhosis, or more than mild alcohol should be for advanced patients with or 2 or more metabolic risk evidence of hepatic risk with should be with NASH are at the highest risk for and for and for with advanced NASH or should be to a for are in patients with advanced liver disease to NASH and should not be used in to exclude the presence of NASH with clinically significant of patients with NASH should be increased risk and for advanced hepatic Key with “at-risk” NASH with at stage 2 fibrosis) are at increased risk of and AND NAFLD Although liver remains the for the and staging of NASH, it has important to and liver for and staging of NASH are not in clinical practice and should be for clinical biomarkers are as tools for more an important of liver of noninvasive biomarkers in with the and of will the diagnosis of patients with clinically disease and response to without the for liver and of hepatic steatosis Although used in clinical for of in those with and a of steatosis The absence of steatosis on not exclude the presence of NASH or the presence of fibrosis, can be when cirrhotic liver is identified or it evidence of (eg, the of hepatic the in with a of hepatic steatosis but not or in liver is an and for liver that is used in clinical role in clinical practice is it is used in Although is to in the diagnosis as as the of liver this is by and the of not a of liver fibrosis in patients with or NAFLD Clinical and fibrosis biomarkers from clinical can of the presence of advanced fibrosis been (eg, NAFLD however, is the most is a and and in its to identify patients with a probability of advanced of and also been associated with and in a change in from risk to risk to high risk may be used to assess clinical Although is to fibrosis as the and to advanced fibrosis, is as a for general and on its and The is a of in of and of patients with NAFLD at increased risk of progression to and clinical The is for clinical as a in the and fibrosis tests may be as risk when is not available for the noninvasive of NAFLD to clinical context of of hepatic steatosis with steatosis can as advanced fibrosis for ≥5% spectrum of to assess of “at-risk” NASH in the of and patients with at stage 2 fibrosis with of advanced fibrosis not in and individuals who high probability not in with obesity 2 to a to a of points not points not with advanced fibrosis, of of or for and for cirrhosis, is associated with increased risk of hepatic patients with by is associated with cirrhosis, but for is by has a for diagnosis of and is also associated with increased risk of hepatic “at-risk” NASH is defined as NASH with stage area the clinical Liver liver in and liver from and NAFLD Liver is a of the liver that increases with fibrosis as as as inflammation, and (eg, is the most used to assess liver and can be used to exclude significant hepatic A recent that a liver can be used to advanced fibrosis, used by and may be associated with NASH, and is associated with a high likelihood of advanced fibrosis, the is in liver may also be in disease that an in liver of on either or may be associated with disease progression and clinical patients with cirrhosis, a with a and by had a of an will some patients with to of these of points to exclude advanced fibrosis and high points to identify advanced fibrosis may be used more points for and are but not been with the more on is more than in the of fibrosis stage and is to be the most of fibrosis in Although is not a to risk stratification in a with NAFLD, it can be an important clinical is a for or when are patients with cirrhosis, by risk of hepatic and The of that with the stage of fibrosis is by is of the Liver by may also be to assess the risk of of and associated with risk of hepatic or that the for by and are but the are provided of these with a of and that associated with and risk of over of a in liver is associated with a higher risk of as as Although more are NIT in patients with may be as for in response to study for the of “at-risk” NASH and biomarkers are study for the of NASH, but these not the level of clinical evidence for in clinical practice. of biomarkers including and and and and biomarkers are in for “at-risk” as may also be for the of “at-risk” an of the this in not been and over remains to be that clinical with liver that may be of are The is a from liver and by and for the of “at-risk” with study on and a with has been to be to A with has been linked to increased risk of hepatic decompensation, and a negative with has a negative for a risk of hepatic A from and is also to identify “at-risk” as a on and may be but of over the over to be and the of in on the context of Although can hepatic it is not as a to identify hepatic steatosis to the NAFLD as a may be used to identify can additionally is or may be used to exclude advanced Key liver and can predict an increased risk of hepatic and AND of NAFLD should of of and staging of fibrosis assess these with a should be at in but in and are also the spectrum of