Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD, formerly NAFLD)

Educational Objectives

The goal of this program is to improve the diagnosis and management of metabolic dysfunction-associated steatotic liver disease. After hearing and assimilating this program, the clinician will be better able to:

1. Optimize use of vibration-controlled transient elastography in assessment of liver stiffness.
2. Use the Fibrosis-4 Index for Liver Fibrosis in liver disease.

Summary

Introduction: the new nomenclature for nonalcoholic fatty liver disease (NAFLD) was introduced to better categorize patients, especially those with moderate alcohol consumption; the diagnostic criteria include features of the metabolic syndrome agreed upon in 2009 (ie, cardiometabolic risk factors)

Epidemiology: ≈30% of adults in the United States have metabolic dysfunction-associated steatotic liver disease (MASLD); patients with elevated markers (NAFLD activity score >4, fibrosis score ≥2) are at high risk for disease progression; ≈95% of individuals with steatohepatitis and advanced fibrosis are undiagnosed; predictive modeling by Mellinger et al (2018) suggests an increase in NAFLD cases, especially in advanced stages; cardiometabolic factors (eg, obesity, insulin) are significant risk factors for disease progression; as genetic factors are less actionable on an individual basis, they were not included in the revised guidelines

Updated guidelines: owing to significant advancements, pediatric NAFLD is now addressed in a separate document; active screening is recommended for high-risk individuals; a risk stratification algorithm was provided to help clinicians assess patient risk; an optimal care model for patients with NAFLD was outlined

Pearls: liver enzymes — the likelihood of having normal liver enzymes increases with advanced liver disease; alanine transaminase ≥30 U/L should be considered abnormal; ultrasonography — not recommended because patients with <30% or 20% steatosis may be missed; steatosis decreases in advanced disease; fibrosis may appear identical to steatosis; controlled attenuation parameter — may be used to detect steatosis but cannot quantify the degree of steatosis; magnetic resonance imaging proton density fat fraction (MRI-PDFF) is the gold standard for such quantification but is not necessary for clinical practice; treatment of comorbidities is recommended for stages 1 and 2 disease; stage 3 (precirrhosis) is characterized by advanced fibrosis; patients with stage 4 disease (cirrhosis) are at the highest risk for outcomes

Risk factors: recent prospective evidence confirms a correlation between diabetes and liver disease, showing a markedly increased risk for fibrosis progression in patients with diabetes (6%-20%) compared with the general population (0.9%-2%); screening for advanced fibrosis is recommended for high-risk populations, including those with medically complicated obesity; even moderate alcohol use can significantly accelerate progression; a first-degree relative with cirrhosis increases the risk by ≈18%; population-based screening is not recommended; the American Association of Clinical Endocrinology guidelines on the treatment of steatotic liver disease in the diabetic setting align with guidelines provided by the American Association for the Study of Liver Diseases (AASLD)

Diagnosis and prognostication: the enhanced liver fibrosis (ELF) score is a US Food and Drug Administration (FDA)-approved method for predicting the progression to advanced fibrosis, calculated using 3 biomarkers; patients with an ELF score <9.8 are at low risk for an imminent clinically significant event, so less aggressive monitoring is needed; patients with a high ELF score (11.5 or 12) have a significantly increased risk for decompensation and may benefit from referral to a transplant center; vibration-controlled transient elastography (VCTE, eg, FibroScan) measures the stiffness of the liver; it is used as a surrogate marker for fibrosis; while a normal VCTE result is generally reliable, high results need corroboration; shear-wave elastography is used to evaluate liver stiffness; while less widely available than VCTE, magnetic resonance elastography (MRE) offers more accurate readings, especially in obese patients; the cost of MRE has decreased significantly, making it more accessible

Diagnostic algorithm: the Fibrosis-4 (FIB-4) Index for Liver Fibrosis, based on 4 factors, is useful for risk assessment in primary care settings; a FIB-4 score <1.3 indicates a low risk for advanced liver disease, allowing patients to be followed in primary care; a study found low utilization of the score, leading to unnecessary referrals; secondary testing options for patients with intermediate or high-risk liver disease include VCTE, Acoustic Radiation Force Impulse (ARFI) test, and ELF; although not approved for this indication, ELF is useful in settings where advanced imaging techniques are not available; refer patients who are at high risk based on these results; hepatologists then consider whether tertiary testing, eg, MRE, corrected T1 MRI, or liver biopsy, is necessary

Management: all patients must receive treatment for their cardiometabolic risks; the FIB-4 score can predict death; patients with high-risk FIB-4 scores have higher rates of liver-related events, major adverse cardiac events, and hepatocellular carcinoma; primary risk assessment with FIB-4 is recommended for patients with steatosis or suspected MASLD (based on the presence of obesity or other cardiometabolic risk factors); patients with ≥2 cardiometabolic risk factors may benefit from more frequent screening and secondary testing; noninvasive testing — the FibroScan-aspartate aminotransferase (FAST) score combines components of the FIB-4 score and liver stiffness to identify patients with stage 2 disease or higher and active hepatitis; a significant difference between the current guideline and the previous one is the inclusion of specific thresholds for detecting advanced fibrosis; these thresholds may help identify patients with active steatohepatitis and avoid unnecessary liver biopsies; patients with advanced fibrosis should abstain from alcohol consumption; histology and liver fat content may improve after interventions to reduce weight

Evidence on pharmacotherapy: the PIVENS trial by Chalasani et al (2009) compared placebo with vitamin E and pioglitazone; vitamin E met the primary endpoint of specific histologic changes, while pioglitazone did not; however, this may be attributed to a design flaw in the trial; the FDA approval endpoints for liver disease are resolution of steatohepatitis and fibrosis; semaglutide met the first endpoint but not the second; the weight loss caused by semaglutide, a glucagon-like peptide (GLP)-1 agonist, drives its benefits in the liver; Frias et al (2021; SURPASS-2 trial) showed significant weight loss and reduction in steatosis in nondiabetic patients treated with semaglutide; GLP-1 agonists have shown a reduction in cardiovascular mortality and cardiorenal benefits; ongoing phase 2 trials suggest that sodium glucose cotransporter-2 inhibitors may be beneficial in patients with cirrhosis and may reduce ascites

Lifestyle recommendations: must be tailored to the individual; caloric restriction through various dietary approaches, eg, the Mediterranean diet, intermittent fasting, low-carbohydrate diets, is crucial for weight loss and improvement in liver function; even modest weight loss of 5% can improve liver chemistries, while 7% to 10% weight loss may improve fibrosis; exercise is recommended, but individual approaches should be considered based on the patient’s capabilities; alcohol consumption should be minimized; coffee, ≤4 cups a day, may have beneficial effects on fibrosis progression; multidisciplinary care is important

Readings

Ajmera V, Cepin S, Tesfai K, et al. A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes. J Hepatol. 2023;78(3):471-478. doi:10.1016/j.jhep.2022.11.010; Chalasani NP, Sanyal AJ, Kowdley KV, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009;30(1):88-96. doi:10.1016/j.cct.2008.09.003; Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022;28(5):528-562. doi:10.1016/j.eprac.2022.03.010; Estes C, Razavi H, Loomba R, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123-133. doi:10.1002/hep.29466; European Association for the Study of the Liver (EASL). Electronic address: [email protected]; European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO); European Association for the Study of the Liver (EASL). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024;81(3):492-542. doi:10.1016/j.jhep.2024.04.031; Jia S, Zhao Y, Liu J, et al. Magnetic resonance imaging-proton density fat fraction vs. transient elastography-controlled attenuation parameter in diagnosing non-alcoholic fatty liver disease in children and adolescents: a meta-analysis of diagnostic accuracy. Front Pediatr. 2022;9:784221. doi:10.3389/fped.2021.784221; Ko E, Yoon EL, Jun DW. Risk factors in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(Suppl):S79-S85. doi:10.3350/cmh.2022.0398.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Rinella is a consultant for Boehringer Ingelheim USA Corporation, Cytodyn Inc., GSK, Intercept, PLC, Madrigal Pharmaceuticals Inc., NGM Biopharmaceuticals Inc., and Sonic Incytes Medical Corp. Members of the planning committee reported nothing relevant to disclose. Dr. Rinella's lecture contains information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Rinella was recorded at the 8th Annual Updates in Digestive Diseases, held on September 9, 2023, in Chicago, IL, and presented by University of Chicago Medicine. For more information about the upcoming CME activities from this presenter, please visit cme.uchicago.edu. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

GE382201

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.