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. 2023 May 1;77(5):1797-1835.
doi: 10.1097/HEP.0000000000000323. Epub 2023 Mar 17.

AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

Mary E Rinella  1 , Brent A Neuschwander-Tetri  2 , Mohammad Shadab Siddiqui  3 , Manal F Abdelmalek  4 , Stephen Caldwell  5 , Diana Barb  6 , David E Kleiner  7 , Rohit Loomba  8
Affiliations

AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

Mary E Rinella et al. Hepatology. .
No abstract available

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Conflict of interest statement

CONFLICTS OF INTEREST

Brent A. Neuschwander-Tetri consults/advises Akero, Arrowhead, BMS, Clinical Care Options, GSK, Glympse, Hepion, High Tide, HistoIndex, Labcorp, LG Chem, Madrigal, Merck, Sagimet, Senseion, Target RWE, 89Bio, has stock options with HepGene, HeptaBio and receives research grants paid to his institution from BMS, HighTide, Intercept, Inventiva, Madrigal. Mohammad S. Siddiqui consults/advises Sagimet and AMRA. Manal F. Abdelmalek consults/advises 89 Bio, Bristol-Myers Squibb, Hanmi, Intercept, Inventiva, Madrigal, Merck, NGM Bio, Novo Nordisk, SonicIncytes, Theratechnologies, Fishawack Inc., Terra Firma Inc. and receives research grants paid to her institution from Allergan, Boeringher- Ingelheim, Bristol Myers Squibb, Celgene, Durect, Enanta, Enyo, Galmed, Genentech, Gilead, Hanmi, Intercept, Inventiva, Madrigal, Novo Nordisk, Poxel, Target NASH, Viking. Stephen Caldwell receives research support from Gilead, Galectin, Madrigal, Prometheus, Exact, GenFit, Inventiva, Zydus, Durect, Royalty, Avanos. David E. Kleiner is an unpaid consultant/collaborator with HistoIndex and HighTide. Rohit Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, AstraZeneca, Eli Lilly, Inipharma, Intercept, Ionis, Madrigal, Novo Nordisk, Pfizer, Sagimet, Theratechnologies, 89 bio, Takeda, Terns Pharmaceuticals and Viking Therapeutics. Co-founder of LipoNexus Inc. The remaining authors have no conflicts to report.

Figures

FIGURE 1
FIGURE 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 cholesterol, types of dietary fats consumed [saturated vs. polyunsaturated fatty acid (PUFA)], the gut microbiome, uric acid, and periodic hypoxia (sleep apnea) may also influence these pathways. A primary disease driver may be an oversupply of fat to adipocytes such that their ability to store triglyceride without inducing cell stress is exceeded, which activates inflammatory pathways and causes insulin resistance. Understanding the major drivers of NASH facilitates the rational development of therapies for patients with NASH. Specific sites of intervention that might prevent or resolve NASH include interventions that modulate food intake (eg, portion sizes, bariatric surgery, satiety regulators), increase energy disposal (eg, exercise, thermogenesis), improve adipocyte insulin sensitivity [eg, peroxisome proliferator-activated receptor (PPAR)γ ligands], impair de novo lipogenesis (eg, acetyl-coenzyme A carboxylase and fatty acid synthase inhibitors), increase hepatic oxidative metabolism (PPARα ligands and thyroid hormone receptor beta agonists), and attenuate inflammation, cell death, and fibrogenesis. Therapeutic agents affecting multiple metabolic pathways throughout the body with potential beneficial effects on the liver include peptide hormone analogs (eg, analogs of fibroblast growth factor-19, fibroblast growth factor-21, glucagon-like peptide-1, gastric inhibitory peptide, glucagon) and nuclear receptor ligands such as drugs that target PPARα, PPARδ, PPARγ, thyroid hormone receptor β, and farnesoid X receptor. Abbreviations: ER, endoplasmic reticulum; CVD, cardiovascular disease.
FIGURE 2
FIGURE 2
Algorithm for the evaluation of patients at risk for or with established NAFLD across practice settings. Patients with steatosis noted on imaging or for whom there is a clinical suspicion of NAFLD, such as those with metabolic risk factors or unexplained elevation in liver chemistries, should undergo further evaluation. In settings with a low prevalence of advanced fibrosis, such as in the primary care setting, the emphasis is on excluding advanced fibrosis using a test with a high negative predictive value. When the fibrosis-4 index (FIB-4) is <1.3, patients can be followed in the primary care setting and reassessed periodically. Patients without prediabetes/type 2 diabetes mellitus (T2DM) and 1–2 metabolic risk factors can be reassessed every 2–3 years. Patients with prediabetes/T2DM or 2 or more metabolic risk factors are at higher risk for disease progression, and more frequent FIB-4 monitoring (eg, every 1–2 y) should be considered. In patients older than age 65, a FIB-4 cutoff of > 2.0 should be used. FIB-4 has low accuracy in those under age 35; thus, secondary assessment should be considered in those <35 with increased metabolic risk or elevated liver chemistries. FIB-4 should not be used in acutely ill patients. In patients with FIB4 ≥ 1.3, a secondary assessment should be done [preferentially vibration-controlled elastography (VCTE) or Enhanced Liver Fibrosis (ELF) initially] or the patient referred for further risk stratification (if being seen in a nongastroenterology/hepatology setting). Direct referral to gastroenterology/hepatology should be considered in those with aminotransferases persistently (> 6 mo) above normal to exclude other causes of liver disease or when FIB4 > 2.67 due to the increased risk of clinically significant fibrosis. In higher prevalence settings, such as gastroenterology/hepatology clinics, additional risk assessment with magnetic resonance elastography (MRE) may be appropriate when noninvasive tests (NITs) are indeterminate or there is clinical suspicion of more advanced disease. Identification of cirrhosis should prompt screening for HCC and esophageal varices. In addition, MRE or corrected T1 (cT1) may help identify patients with “at-risk” NASH (NASH with NAFLD activity score ≥ 4 and fibrosis stage ≥ 2) who may benefit from a therapeutic intervention as they become available. If cirrhosis is suspected based on NITs, clinical data, or imaging findings, then cirrhosis-based management may be initiated without a liver biopsy. Liver biopsy should be considered when NITs suggest significant fibrosis (≥ F2), especially if additional evaluation suggests the presence of “at-risk” NASH (eg, using FAST, MEFIB, MAST, or cT1), NIT assessment is indeterminate, aminotransferases are persistently elevated (> 6 mo), or additional/alternate diagnoses are suspected. Note that in patients with confirmed or suspected advanced fibrosis, an ELF ≥ 11.3 is a predictor of future liver-related events and is approved for this purpose; use of other ELF cutoffs in secondary risk assessment is based on expert option. Patients at all stages of disease should be counseled on lifestyle modifications, and those with ≥ F2 fibrosis targeted for pharmacological interventions as they become available. Specific threshold values of NITs are approximations supported by current evidence and are meant to guide clinical management through primary care to gastroenterology/hepatology practices rather than be interpreted in isolation. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; PCP, primary care provider.
FIGURE 3
FIGURE 3
Histology of NAFLD. Liver biopsy shows characteristic features of the spectrum of NAFLD. (A) Hepatic steatosis (typically zone 3) without ballooned hepatocytes or fibrosis [hematoxylin and eosin (H&E), ×200]. (B) Multiple ballooned hepatocytes with Mallory-Denk bodies (arrows) and mild lobular inflammation (circles) (H&E, ×400). (C) Ballooned hepatocytes (arrows) with moderate lobular inflammation (circle) (H&E, ×200). (D) Some cases of steatohepatitis may show significant portal inflammation and interface hepatitis (arrows) (H&E, ×200). (E) Dense perisinusoidal and periportal fibrosis (blue stain), with a thin connecting fibrotic bridge (Masson trichrome, ×200). (F) Cirrhosis (nodule formation) due to steatohepatitis (Masson trichrome, ×100).
FIGURE 4
FIGURE 4
A multidisciplinary approach to the management of NAFLD. Optimal care of the patient with NAFLD requires a multidisciplinary approach. The majority of patients are in the primary care/endocrine setting, in which management of medical comorbidities should be optimized, with preference given to treatments for type 2 diabetes mellitus, hypertension, or obesity that likely also have beneficial effects on NAFLD. In this setting, at-risk patients should be identified and initial risk stratification performed [ie, fibrosis-4 index (FIB-4) ± vibration controlled elastography or Enhanced Liver Fibrosis]. The role of the gastroenterologist/hepatologist includes more comprehensive liver risk stratification, exclusion of other liver diseases, and a focus on liver-directed therapy. Close communication between gastroenterology/hepatology and primary care or endocrinology facilitates multidisciplinary management of metabolic comorbidities as well as the prioritization of medications or interventions that may also offer liver benefits (see the Treatment section). All patients should undergo dietary/nutritional assessment and a plan established for regular follow-up independent of gastroenterology/hepatology visits. The need for more specialized obesity management, including bariatric surgery referral, health psychology, and additional cardiology or lipid metabolic support, should be assessed on an individual basis (dotted arrows).
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