Optimizing Early Detection of Nonalcoholic Steatohepatitis: A Patient-Centered Initiative

Statement of Need/Program Overview

Delays in screening and diagnosis contribute to poor outcomes for patients with nonalcoholic steatohepatitis (NASH). Noninvasive screening techniques and biomarkers are important diagnostic tools, but they are unfamiliar to some clinicians. The major risk factors for the development of NASH, including obesity, type 2 diabetes mellitus, and cardiovascular disease, are prevalent in the United States. Symptoms of NASH may go unrecognized rather than treated, especially early symptoms. Primary care providers need guidance on how to work efficiently in a multidisciplinary team responsible for screening and risk stratification of patients with NASH. Pervasive health inequities negatively affect certain populations at risk for or living with NASH. Many patients—and even some clinicians—are not familiar with the disease. Clinicians must be ready to provide comprehensive education and wellness platforms to mitigate the effects of NASH in their patients.

Target Audience

This activity is designed for general practitioners and other non-liver specialist clinicians involved in the early identification and diagnosis of NASH in at-risk populations.

Educational Objectives

After completing this activity, the participant should be better able to:

1. Describe key risks for the development of NASH.
2. Select appropriate noninvasive diagnostic tests to stratify risk in patients with NASH.
3. Identify current guidance-recommended strategies for screening, evaluation, and referral of patients with NASH.
4. Discuss health disparities that continue to affect underserved populations living with NASH.
5. Review individualized care plans involving education, support, and empowerment for patients with NASH.

Faculty

Physician Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Clinical and Patient Educators Association (CPEA) and Applied Clinical Education (ACE). CPEA is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation

CPEA designates this enduring activity for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CPEA Contact Information

For information about the accreditation of this program, please contact CPEA at inquire@cpea-assn.org.

Instructions for Obtaining Credit

To receive credit, participants must participate in the activity, pass the post-test with a score of at least 75%, and complete the evaluation. CME certificates will be sent via email to those successfully completing the activity.

Computer System Requirements

• Operating system: Windows or Macintosh
• Media viewing requirements: Adobe Reader
• Supported browsers: Microsoft Edge, Firefox, Google Chrome, Safari, and Opera
• A good internet connection

Fee Information & Refund/Cancellation Policy

There is no fee for this educational activity.

Disclosures of Relevant Financial Relationships

CPEA adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the ACCME and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of an accredited continuing education program provided by CPEA are required to disclose all financial relationships with any ineligible company within the past 24 months to CPEA. All financial relationships reported are identified as relevant and mitigated by CPEA in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. CPEA vetted the content of this activity to assure objectivity and that the activity is free of commercial bias.

All relevant financial relationships have been mitigated.

The faculty have the following relevant financial relationships with ineligible companies:

Meena Bansal, MD:

• Consulting fees (eg, advisory boards): Fibronostics, GlaxoSmithKline, Intercept, Madrigal, Novo Nordisk
• Contracted research (principal investigators must provide information, even if received by the institution): Histoindex, Pfizer
• Honoraria: The Kinetix Group

The planners and managers have the following relevant financial relationships with ineligible companies:

• The planners and managers at CPEA have no relevant financial relationships to disclose.
• The planners and managers at ACE have no relevant financial relationships to disclose.

Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. CPEA and ACE do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Jointly provided by the Clinical and Patient Educators Association and Fatty Liver Foundation

This activity is distributed by Applied Clinical Education and CMEZONE.COM.

Nonalcoholic fatty liver disease (NAFLD) describes a range of hepatic conditions characterized by excess lipid accumulation in the liver (steatosis) in the absence of a secondary cause for hepatic fat accumulation.^1,2 NAFLD includes nonalcoholic fatty liver, which typically involves steatosis without inflammation and is generally benign, and nonalcoholic steatohepatitis (NASH), which can be severe and progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), liver transplantation, and death.^1-3 NAFLD is a leading cause of chronic liver disease worldwide.¹

Recently, updates to NAFLD nomenclature have been proposed by the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) in collaboration with the Latin American Association for the Study of the Liver.⁴ Using a modified Delphi process, the expert panel proposed the terms “steatotic liver disease” to describe the various etiologies of steatosis and “metabolic dysfunction–associated steatotic liver disease” (MASLD) to replace NAFLD.⁴ Subcategories of MASLD are defined based on the presence of cardiometabolic risk factors and the amount of alcohol consumed per week.⁴

Although most patients with NAFLD will not progress to advanced fibrosis or cirrhosis, it is critical to identify and treat those who will.^5,6 Currently, the AASLD does not recommend routine NAFLD screening for the general population but does recommend it for patients who have diabetes, obesity with metabolic complications, or a first-degree relative with cirrhosis⁷; and clinical practice guidelines from the EASL and Asian Pacific Association for the Study of the Liver suggest screening for patients with key risk factors (obesity, cardiovascular disease [CVD], and type 2 diabetes mellitus [T2DM]).^8,9 However, less than 20% of patients with NAFLD receive a diagnosis, leaving many individuals unidentified and thus untreated, including those at risk for progression and severe disease.¹⁰ Several methods are available to aid in the detection of NAFLD and NASH, including many noninvasive tools and biomarkers, but clinicians may not be aware of these resources or how to use them effectively.^11,12 This activity provides a review of key considerations for the early screening, evaluation, and referral of patients with NASH.

The estimated global prevalence of NAFLD has increased to more than 30%, making NAFLD the most common form of chronic liver disease (Figure 1).^13,14 In the United States, more than one-third of adults have NAFLD, with recent estimates approaching 50%.¹⁴ The prevalence of NASH is also increasing rapidly, although it is difficult to directly measure NASH prevalence because a diagnosis can only be made via a liver biopsy.^5,15 Recent estimates suggest that the global prevalence of NASH is roughly 5%, and among patients with NAFLD, approximately 20% have histology indicative of NASH.^15,16

Figure 1. Estimated global prevalence of nonalcoholic fatty liver disease.¹⁴

The pathophysiology of NASH is complex and involves multiple body systems.⁵ In the “multiple hit” theory, several parallel factors—such as inflammation, insulin resistance, altered lipogenesis, or metabolic conditions—stress the liver and culminate in liver disease.¹⁷ These stressors contribute to an accumulation of fatty, apoptotic hepatocytes that trigger inflammatory and wound-healing responses that lead to fibrosis and liver damage (Figure 2).^5,18 Indeed, NAFLD and NASH are strongly associated with obesity and lipid and metabolic disorders.¹⁵

Figure 2. The pathophysiology of nonalcoholic steatohepatitis.¹⁸

FFA, free fatty acid; TG, triglyceride.

The pathophysiology of NASH can be influenced by genetics and environmental factors, such as diet and exercise.⁵ Key risk factors for NASH include obesity, CVD, T2DM, and metabolic syndrome (Table 1).^9,18,19 Aberrations in genes, including PNPLA3, GCKR, TM6SF2, and MBOAT7, have been linked to the development of NAFLD.²⁰ However, a polymorphism in HSD17B13 confers protection.²¹ Risk factors for disease progression in NAFLD and NASH include age, body mass index (BMI), fibrosis stage, and the presence of comorbidities including T2DM, hypertension, and psoriasis.¹⁹ Several biomarkers are also under investigation for their ability to predict NASH progression.⁷

NASH can have severe consequences for liver function; it is a leading cause of liver transplantation (number one cause in women; second overall after alcohol consumption) and significantly increases the risk for liver-specific mortality.^22,23 NASH may or may not occur with hepatic fibrosis, although the degree of fibrosis is related to NASH and liver-specific disease outcomes.¹⁵ Approximately 20% of patients with NASH will develop cirrhosis, which can progress to HCC.²⁴ The rate of progression to HCC is 12 times higher in patients with NASH than in those with NAFLD.²³ NASH remains a leading cause of liver transplantation for patients with HCC.²²

The effects of NASH are not limited to the liver. Extrahepatic manifestations of NASH can affect the function of multiple body systems, including the arteries, heart, pancreas, and kidneys. Cardiovascular complications are the most important concern for patients with NASH; despite its liver-centric effects, the primary cause of death for these patients is CVD.¹⁵ Atherosclerosis and hypertension also are common among patients with NASH and may be related to the degree of liver fibrosis.^25,26 The vast majority of patients with NASH (>80%) are classified as overweight or obese. Dyslipidemia and T2DM have been reported in 72% and 44% of patients with NASH, respectively.²³ T2DM exhibits a close relationship with NASH stemming from the overlap in components of metabolic syndrome; as many as 56% of obese patients with T2DM have NASH.²⁵ Other comorbidities associated with NASH include obstructive sleep apnea, chronic kidney disease, polycystic ovarian syndrome, HIV, hypothyroidism, psoriasis, colorectal cancer, endocrinopathies, and osteoporosis (Figure 3).⁹

Figure 3. Common comorbidities in NAFLD.²⁷
NAFLD, nonalcoholic fatty liver disease

Most patients with NASH are asymptomatic or present with nonspecific symptoms, such as fatigue, and NASH is typically detected during evaluation for unrelated conditions.¹⁵ The “gold standard” for NASH diagnosis and staging is a liver biopsy, which can identify the hallmarks of NASH: steatosis with lobular inflammation and hepatocyte ballooning.²⁸ However, a biopsy can be expensive, invasive, is vulnerable to sampling error and intra- and interobserver variability, and may put patients at risk for complications and morbidity.^19,29,30 Several less invasive diagnostic approaches, including serum biomarkers and liver stiffness measurements, can provide valuable insight into a patient’s risk for NASH and disease progression.²⁸ The primary care provider (PCP) sits at the front line of identifying and managing patients with NAFLD and NASH and plays an important role in the timely recognition and referral of patients with severe disease.¹² As fibrosis is the single most important determinant of poor liver outcomes in NASH, early risk stratification for significant fibrosis is critical. The following sections detail noninvasive diagnostic tools that general practitioners can use to diagnose and stage patients with NASH (Table 2).

Fibrosis-4 Index

The fibrosis-4 index (FIB-4) is one of the most rigorously validated tests for NAFLD and among the highest-performing diagnostic tests for advanced fibrosis.³¹ The FIB-4 score is calculated using a formula that considers the patient’s age, plasma alanine and aspartate aminotransferases (ALT/AST), and platelet count (PLT).³² The formula for the FIB-4 score is age (years)×AST (U/L)/[PLT (10⁹/L)×ALT ½ (U/L)].³² The FIB-4 has particularly high diagnostic accuracy for ruling out advanced fibrosis, with a sensitivity of 78%, specificity of 71%, positive predictive value of 40%, and negative predictive value of 93%.³¹

The FIB-4 is inexpensive to perform and heavily validated but has some limitations to its use. It is not accurate in younger patients (aged <35 years) and may require a higher cutoff in older patients (aged >65 years). In addition, more than 30% of patients have FIB-4 or other predictive model scores that fall into the indeterminant range and require subsequent assessment.^7,31 High-risk patients are the most likely to be assessed with the FIB-4 and have a lower rule-out threshold than low-risk patients.⁷ Finally, the FIB-4 is not as accurate at ruling in as it is ruling out advanced fibrosis and requires confirmatory biopsy for subsequent confirmation of a NASH diagnosis.³¹

Enhanced Liver Fibrosis Test

The Enhanced Liver Fibrosis test (ELF; Siemens) is a patented, specialized blood test that analyzes multiple biomarkers that have been linked to liver fibrosis, including tissue inhibitor of metalloproteinase-1, amino-terminal propeptide of type III procollagen, and hyaluronic acid.²⁸ Via these biomarkers, the ELF test uses the rate of liver extracellular matrix metabolism to approximate the severity of liver fibrosis.³² Although less heavily validated than the FIB-4, the ELF test accurately diagnoses liver fibrosis.²⁸ The calculations underlying the ELF score have changed over time; for diagnosing advanced fibrosis using the Siemens-recommended diagnostic thresholds, the ELF test has an AUROC (area under the receiver operating characteristic curve) of 0.83 (95% CI, 0.71-0.90), with a specificity of 86% and sensitivity of 65%.³¹ ELF results can be sent to the company for analysis, and is now also available through Labcorp (insurance coverage varies). The ELF test is more expensive than the FIB-4. Of note, the FIB-4, ELF test, and other serum-based screens for advanced fibrosis are unable to match the diagnostic accuracy of a biopsy, but still have clinical value as less invasive screens to assess risk.³³

Vibration-Controlled Transient Elastography

Vibration-controlled transient elastography (VCTE) uses ultrasound to measure the controlled attenuation parameter, an acoustic metric that shows good sensitivity and specificity for diagnosing fat in the liver.²⁹ Commercially available VCTE devices include the FibroScan (Echosens), Virtual Touch Quantification (Siemens), and Aixplorer (SuperSonic Imagine).²⁸ Although data are limited, the devices demonstrate similar performance.²⁸ Two different handheld probe sizes are available (M and XL), each with its own performance metrics.²⁹ VCTE shows good diagnostic accuracy for advanced fibrosis, with an AUROC of 0.87 for the M probe and 0.86 for the XL probe.³⁵ On its own, VCTE is more accurate for ruling out advanced fibrosis than ruling it in.³¹ When used with other serum biomarkers, VCTE can identify patients with high-risk NASH.³⁶

Some limitations hinder the uptake of VCTE. The results can be affected by patient fasting status and BMI, and obese patients can be more difficult to measure.³¹ VCTE is also subject to operator error.³¹ Measurement quality increases with operator experience, but failed or unreliable measurements can occur in nearly 30% of patients.³¹ Other confounding factors, including necroinflammation, hepatic congestion, and extrahepatic cholestasis, can increase liver stiffness and thus bias the measurements toward fibrosis.³¹

Magnetic Resonance Elastography

Magnetic resonance elastography (MRE) uses magnetic resonance imaging (MRI) technology to measure the elasticity of tissue and can generate cross-sectional maps of liver stiffness (elastograms) that indicate fibrosis.²⁹ MRE images can be 2-dimensional (2D) or 3-dimensional (3D).²⁹ 2D MRE is the most common, but 3D MRE measures a greater proportion of the liver and may be more accurate. However, 3D MRE requires specialized expertise to implement.²⁹ MRE is the most accurate of the elastography assessments, with an AUROC of 0.93, and shows good performance for discriminating among different stages of fibrosis.^35,37 In head-to-head comparisons, MRE shows better diagnostic accuracy for earlier stages of fibrosis than VCTE.²⁹

Several limitations hinder the use of MRE. Access to elastography may be limited in certain settings.⁷ Some patients may find the MRI scanner difficult to tolerate due to discomfort or obesity, and others may have metal implants that prevent them from using the equipment safely.²⁹ In general, MRE and VCTE are effective for detecting fibrosis, but they are unable to detect early-stage NASH features that would be identified via histology (eg, hepatocyte ballooning).³⁸ MRE also may be more expensive than VCTE, but more studies are needed to understand cost-efficacy comparisons for these imaging technologies.²⁹

Iron-Corrected T1

Iron-corrected T1 mapping (cT1) is an MRI-based biomarker that correlates with key NASH features, including ballooning and fibrosis.^39,40 The MRI T1 relaxation time provides information on the water content of tissue, but the presence of iron can affect T1 signals.⁴⁰ Correcting for the influence of iron yields the cT1 value, which can provide useful insight into a patient’s risk for NASH and may predict clinical outcomes.^39,40 The cT1 is a proprietary biomarker developed by Perspectum.

In clinical studies, higher cT1 values are associated with liver inflammation and fibrosis, andcT1 has shown high accuracy at diagnosing and staging NASH.³⁸ In a meta-analysis, higher cT1 values correlated with increasing NAFLD severity and showed high accuracy for distinguishing patients with NASH from those without (AUROC, 0.78; 95% CI, 0.74-0.82).³⁸ A combination of MRI liver fat measurement along with cT1 outperforms other imaging-based methods for identifying advanced NASH.³⁶ As cT1 is an emerging biomarker, further validation is required.⁷

Clinical practice guidelines are available to help PCPs assess and manage patients with NAFLD and NASH (Figure 4).^7,32 Following standardized pathways in primary care has been shown to improve the diagnosis and management of patients with advanced fibrosis and chronic liver disease.⁴¹ Sequential use of noninvasive testing is a strategy that has been shown to improve the identification of patients with advanced forms of NAFLD.²⁸

Figure 4. Algorithm for the evaluation of patients at risk for or with established NAFLD across practice settings.⁷

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELF, Enhanced Liver Fibrosis; FIB-4, fibrosis-4 index; GI, gastrointestinal; MRE, magnetic resonance elastography; NAFLD, nonalcoholic fatty liver disease; NIT, noninvasive testing; PCP, primary care provider; T2DM, type 2 diabetes mellitus; VCTE, vibration-controlled transient elastography.

Copyright © 2023 American Association for the Study of Liver Diseases. Reused with permission from Rinella ME, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835

PCPs should consider patients with obesity, T2DM, metabolic syndrome, imaging results indicative of steatosis, or consistently elevated plasma aminotransferases to be at high risk for NAFLD.^27,32 For patients with suspected NAFLD based on metabolic risk factors or an incident finding of fatty liver on imaging, the AASLD recommends primary risk assessment using the FIB-4 to identify those who are unlikely to have advanced fibrosis.⁷

Low FIB-4 Score

Patients with a FIB-4 score of less than 1.3 are considered to have low risk for progression to fibrosis at the time of measurement and are not recommended for specialist referral. This group represents most patients (70%) in primary care.⁴¹ Those with 1 or 2 metabolic risk factors and/or T2DM and a FIB-4 score of less than 1.3 are recommended for rescreening every 1 to 3 years; repeated testing can help identify patients at risk for future severe liver disease.^7,42 For individuals with non-severe NAFLD, important preventive interventions can be implemented in the primary care setting without referral to a specialist.⁴¹ PCPs can help these patients manage lifestyle factors to decrease the risk for progression to severe liver disease.²⁷

Indeterminate FIB-4 Score

FIB-4 scores between 1.3 and 2.67 are considered indeterminate results that require secondary testing. PCPs can order and interpret secondary testing to rule out advanced fibrosis or refer the patient to a specialist.⁷ VCTE is preferred for secondary testing, but the ELF test and MRE, as well as combinations of screening approaches, are also informative if VCTE is unavailable.^7,27,32 Diagnostic thresholds for advanced liver fibrosis in the indeterminate population are shown in Table 3.

In one study, secondary testing of patients with indeterminant FIB-4 results via the ELF test ruled out advanced liver disease in 40% of participants and led to specialist referral for 19%.⁴¹ Those with discordant test results or other suspicions of advanced NASH should be referred for specialist evaluation.⁷

For “at-risk” NASH, which is defined as a NAFLD Activity Score of 4 or greater and stage 2 or higher fibrosis, helpful screening tools include the FibroScan-AST, MRE+FIB-4 (MEFIB), and MRI-AST.^43,44 Patients with significant fibrosis as indicated by noninvasive testing should be referred to a specialist for further assessment, and the PCP should continue to manage the patient.²⁷

High FIB-4 Score

Patients with a FIB-4 score of more than 2.67 have elevated risk for advancing to fibrosis and are recommended for referral to specialty care (hepatologist or gastroenterologist).⁷ The AASLD recommends that patients with FIB-4 scores indicative of moderate or high risk for advanced disease undergo secondary risk assessment via VCTE or ultrasound measurements.⁷

Multidisciplinary management is a key component of treating patients with NASH, and PCPs play an important role in optimizing care for these individuals.⁷ Patients with NASH may require care from hepatologists, obesity management professionals, endocrinologists, or gastroenterologists to keep liver disease and related comorbidities in check.¹² According to Mayo Clinic, all patients with NAFLD—as is feasible—should be encouraged to maintain regular visits with their PCPs for monitoring, help managing their condition, and support in complying with lifestyle and other interventions.²⁷ PCPs can help patients manage other aspects of their general health, for example, by keeping them up-to-date with vaccines.³³ Alignment across the multidisciplinary care team is critical to optimize treatment and encourage patient compliance and cooperation with a healthy lifestyle.⁹

Unfortunately, disparities exist among patients with NASH. The prevalence of NAFLD and NASH varies by race, sex, and ethnicity, with higher prevalence among men and Hispanic individuals and lower prevalence among Black patients.^45,46 Prognosis also seems worse for Black and Hispanic patients compared with white patients, although these data are more variable.⁴⁵ Underserved populations experience worse morbidity and mortality due to NASH; in one study of patients hospitalized for cirrhosis, Black patients had less cirrhosis and liver-related complications but were more likely to die and had longer hospital stays and higher costs than white patients.⁴⁷

Multiple complex factors contribute to disparities in health care. In addition, genetic factors, environmental and cultural influences, socioeconomics, and access to health care all affect the diagnosis and management of chronic diseases.^45,48 Uneven distribution of NAFLD risk factors, including T2DM and hyperlipidemia, may contribute to the variation in disease burden across demographics, but the relationship between risk factors and NASH prevalence also varies by demographics and does not explain disparities in outcomes.⁴⁸ Certain social determinants of health (SDOH) have been linked to disparities in NASH, including food insecurity, low income level, exposure to environmental toxins, and government health insurance status.⁴⁶

Clinicians must recognize and work against these disparities to improve outcomes for all patients. Embracing an approach that incorporates SDOH can promote more equitable health outcomes. A key aspect of equitable patient care is combating implicit bias or negative attitudes unconsciously projected toward specific groups or individuals. Implicit biases and structural racism against marginalized groups are well documented in the health care setting and can have direct effects on patient outcomes.⁴⁹ Of note, these biases may not be solely racial but can be toward any marginalized group including obese/overweight patients, non-English speakers, or those with mental health issues.⁴⁹ Clinicians must recognize and actively mitigate implicit biases within their practices to ensure equitable outcomes for patients with NASH.

PCPs play a central role in encouraging their patients with NASH to participate in treatment decisions and engage with their treatment journey.⁵⁰ There are no FDA-approved treatments for NASH, but the condition is treatable.^7,27,30,32 Disease management is centered on lifestyle modification to prevent disease progression and control of comorbidities.^7,27,33 Weight loss is a critical component of NASH management (Table 4) and can lead to improvement in fibrosis and other markers of liver disease, but improvements are only seen with weight loss exceeding 10% of body weight.^12,27,32 It can be incredibly difficult for patients to achieve and sustain the weight loss levels required to improve fibrosis, but a PCP can play a key role in supporting patients through their weight loss journey.^7,27

Table 4. Weight Management in NAFLD3
FIB-4	<1.3	1.3-2.67	>2.67
LSM, kPa	<8	8-12	>12
ELF	<7.7	7.7-9.8	>9.8
General lifestyle changes	Decrease sedentary time, increase daily movement; reduce stress through exercise and other methods
Dietary recommen- dations	Creating an energy deficit is the priority; reduce saturated fat, starch, and added sugars Persons with cirrhosis require individualized nutritional assessment and treatment planning
Exercise	To improve cardiometabolic health, support weight loss, and mitigate sarcopenia: aerobic exercise for 30-60 min 3-5 d/wk + resistance training 20-20 min 2-3 times per wk)
Alcohol intake	Minimize	Minimize	Avoid if F3 or cirrhosis (F4)
Weight loss goal (if overweigh/or obese)	Greater weight loss associated with greater liver and cardiometabolic benefit
Weight loss tools	Behavioral modification counseling, in person or via remote programs	Greater intensity of weight loss to reverse steatohepatitis and fibrosis	Specialized/structured obesity management program, anti-obesity medications, bariatric surgery
Medical therapy to treat obesity	Phentermine, phentermine-topiramate ER, naltrexone/ bupropion, orlistat, liraglutide 3 mg/d, semaglutide 2.4 mg/wk	GLP1-RA preferred for NASH	GLP1-RA preferred for NASH
Bariatric surgery	Consider to treat obesity and comorbidities	Strong consideration to treat steatohepatitis and fibrosis	Stronger consideration to treat steatohepatitis and fibrosis; avoid in decompensated cirrhosis
ELF, Enhanced Liver Fibrosis; ER, extended-release; FIB-4, fibrosis-4 index; GLP-1RA, glucagon-like peptide-1 receptor agonist; LSM, liver stiffness measurement; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. Reprinted from Endocrine Practice 28(5). Cusi K, 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), 528-562. Copyright © 2022, with permission from Elsevier.

Behavior-based interventions can promote success with weight loss.⁷ Interventions that incorporate exercise, physical activity, and dietary optimization can help patients lose weight and improve NASH outcomes.¹² PCPs can tailor exercise programs to a patient’s preferences and capabilities and provide education and support for dietary interventions that support weight loss.⁷ Patients should reduce their caloric intake and curb consumption of saturated fats and refined carbohydrates, such as high-fructose corn syrup and sugary drinks, to lose weight and improve insulin sensitivity.¹² Macronutrients aligned with the Mediterranean diet can improve liver and cardiovascular health, and coffee consumption also may be beneficial.^7,33 FDA-approved weight loss medications or bariatric surgery also may complement these efforts.¹²

Patients with a BMI greater than 30 kg/m2 and comorbidities, including NASH, may be candidates for bariatric surgery. Histologic improvement has been observed in this cohort, but clinicians must carefully weigh the risks and benefits when considering bariatric surgery, especially in individuals with NASH cirrhosis.^27,32,51 Patients with a BMI of 35 kg/m2 or more who have been unsuccessful with other weight management approaches, especially those with T2DM, may be good candidates for surgical intervention.²⁷

Patient education is a critical component of diagnosing and managing NASH, as many patients remain unaware of the disease and how it could affect their lives. In a publication from a panel of experts in metabolic diseases, the authors indicated that up to 95% of patients with high risk for fatty liver disease may be unaware of their condition.⁵⁰ PCPs play a vital role in public access to reliable medical education.

A variety of patient-focused resources can empower those with NASH to take the initiative in managing their disease, personalizing their treatment, and optimizing their health. Organizations providing educational resources for patients with NASH include the Fatty Liver Foundation, National Library of Medicine, National Institute of Diabetes and Digestive and Kidney Diseases, AASLD, and American Liver Foundation (Table 5). PCPs can direct their patients to these resources for up-to-date information about NAFLD and NASH.

The Fatty Liver Foundation also provides patients access to The Wellness League, a resource designed to support individuals with NALFD and NASH. The Wellness League is a comprehensive educational resource that empowers patients through information on managing their disease, including treatment, diagnostic information, and social support. Patients also have access to coaching and peer-driven navigation programs designed to support a healthy lifestyle. A search tool provided by The Wellness League is also valuable for patients to find local resources and services, including health care, food resources, and job training.

NASH is a severe form of NAFLD that causes fibrosis, cirrhosis, cancer, and mortality. PCPs play an important role in recognizing the signs of, screening for, and managing patients with NAFLD and NASH. A variety of noninvasive tools are available to assess a patient’s risk for NASH and assist the PCP in making referral and management decisions within the primary care setting. Patients with NASH face a challenging treatment journey and are subject to significant disparities in health care, but PCPs are in a unique position to assist them. PCPs can support patients through NASH identification and treatment and empower them to optimize their lifestyle to minimize the effects and progression of their disease. Through these efforts, PCPs can improve outcomes for the growing population of patients with NASH.