Updates in nonalcoholic fatty liver disease

Abstract

In parallel with the obesity epidemic and rising metabolic comorbidities, the prevalence of NAFLD has reached 25% worldwide.¹ NAFLD encompasses a spectrum of conditions defined by hepatic steatosis without significant contributions from secondary causes, such as alcohol, medications, or inborn errors of metabolism.¹ A subtype of NAFLD is NASH characterized by inflammation, ballooned hepatocytes with and without fibrosis, which increases the risk for progression to cirrhosis and end-stage liver disease.² While NAFLD is most commonly associated with obesity, nonoverweight or obese individuals (body mass index < 25 kg/m² and < 23 kg/m² in Asian individuals) can also develop NAFLD, termed “lean NAFLD,” which is likely related to genetic factors.³ Patients with NAFLD experience both increased liver-related mortality and overall mortality, with the most common cause of death being cardiovascular disease, followed closely by cancer.^1,4 Hepatic fibrosis predicts liver-related and all-cause mortality, which increases exponentially with each fibrosis stage.⁵ Given the pace of the NAFLD epidemic, increased study within the field, and rapidly changing evaluation and management recommendations, several new guidance documents have been published since 2021. The following review will summarize key clinical updates on identifying and managing patients with NAFLD with fibrosis from the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterology Association (AGA), and the American Association of Clinical Endocrinology (AACE) to assist providers in managing this complex disease.

EVALUATION OF PATIENTS AT RISK FOR NAFLD WITH ADVANCED FIBROSIS

The 2023 AASLD Practice Guidance on the Clinical Assessment and Management of NAFLD recommends screening for advanced fibrosis in patients with type 2 diabetes mellitus (T2DM), obesity with metabolic complications, individuals with NAFLD in the context of moderate alcohol use (up to 21–39 g/d in women and up to 31–59 g/d in men), and in first degree relatives with cirrhosis due to NAFLD/NASH.³ The association between T2DM and NAFLD has been well demonstrated, with the probability of advanced fibrosis increasing with the duration of T2DM.³ With this strong association, the AACE also recommends that all patients with NAFLD be tested for T2DM, and individuals with prediabetes, T2DM, type 1 diabetes mellitus, and obesity-based/adiposity-based chronic disease should be assessed for the presence and severity of NAFLD.⁶

In 2021, the AGA created a clinical care pathway to provide an algorithmic approach to NAFLD screening, diagnosis, and risk stratification. This pathway aims to assist primary care providers in identifying those patients with NAFLD who would most benefit from specialty care referral due to increased risk for liver-related complications. The initial step identifies patients with NAFLD at greatest risk for clinically significant fibrosis including those with (1) T2DM, (2) 2 or more metabolic risk factors (central obesity, dyslipidemia, hypertension, and prediabetes), or (3) incidental findings of hepatic steatosis or elevated aminotransferases.² Once recognized, these patients should be screened for excessive alcohol use, evaluated for alternative etiologies of chronic liver disease, and assessed using standard laboratory tests, the results of which can be used to calculate the Fibrosis-4 (FIB-4) score.² The FIB-4 score is an easy-to-calculate, noninvasive measure of liver fibrosis based on age, alanine aminotransferase, aspartate aminotransferase, and platelet count. The score has a high negative predictive value for advanced fibrosis if the result is low, has good diagnostic accuracy for advanced fibrosis if elevated, and correlates well with clinical outcomes.^7,8

Within the AGA clinical care pathway, the FIB-4 score guides the need for further noninvasive fibrosis assessment with liver stiffness measurement (LSM) using vibration-controlled transient elastography. Patients with an FIB-4 score of <1.3 are at very low risk for advanced hepatic fibrosis and, thus, do not require referral to hepatology. The pathway recommends these individuals undergo repeat noninvasive testing with laboratory testing in 2–3 years. An indeterminate FIB-4 score of 1.3–2.67 necessitates further risk assessment with LSM. Patients with an FIB-4 score >2.67 are at increased risk for advanced fibrosis and should be referred to hepatology for management, ideally by a multidisciplinary team. Among patients with an indeterminate FIB-4 score of 1.3–2.67, those with an LSM <8 kPa are at low risk for advanced fibrosis, and repeat noninvasive testing is recommended in 2–3 years. Patients with an LSM >8 kPa should be referred to hepatology with management by a multidisciplinary team.²

Notably, the accuracy of the FIB-4 score varies with extremes of age. Thus, caution should be used in its interpretation for patients 65 years of age or above and those below 35 years of age given the risk of false-positive and false-negative results, respectively.⁹ Additionally, patients with thrombocytopenia due to nonliver-related etiologies may have falsely elevated FIB-4 scores. Alternative means for noninvasive fibrosis assessments or liver biopsy need to be considered if indicated.

In addition to the FIB-4 score, other noninvasive tests can be used to assess fibrosis in patients with NAFLD. Per the European Association for the Study of the Liver (EASL), in patients with NAFLD, noninvasive testing may be used to rule out advanced fibrosis.¹⁰ EASL suggests using LSM by transient elastography, the enhanced liver fibrosis test, FibroMeter, FibroTest, FIB-4 score, and the NAFLD fibrosis score with test specific cut off values to rule out advanced fibrosis.¹⁰

MEDICAL MANAGEMENT OF NAFLD

Once patients with NAFLD and advanced fibrosis are identified, a multidisciplinary approach can best address and prevent complications particularly given the high prevalence of nonhepatic metabolic comorbidities.² A key goal of NAFLD treatment efficacy is decreased fibrosis stage as this has been well documented as a surrogate marker for improved liver-related and all-cause mortality.⁵ A multidisciplinary management plan may include lifestyle modifications, pharmacologic treatments, and endobariatric interventions. Pilot studies of multidisciplinary clinics for NAFLD have resulted in weight loss and improvement in liver chemistries.^11,12 However, further studies are needed to demonstrate improvement in liver histology, fibrosis, and patient outcomes.

Engaging patients in multidisciplinary care may be challenging as patients often feel clinically well. Patient education is vital in these instances, including a discussion regarding hepatic fibrosis, and the morbidity and mortality associated with NAFLD, in addition to the beneficial effects of lifestyle modifications. Counseling that the most common cause of mortality in patients with NAFLD without advanced fibrosis is cardiovascular disease and nonhepatic malignancy can help to underscore the importance of NAFLD management.³ For patients without access to multidisciplinary NAFLD care, several online resources regarding nutrition, exercise, behavioral health, and clinical trials are available (Table 1).¹³

TABLE 1.

NAFLD resources for patients¹³

American Liver Foundation	liverfoundation.org	Education materials, wellness webinars, and nutritional guides for patients with liver disease, including NAFLD
OLDWAYS	oldwayspt.org	Mediterranean diet recipes and educational programs
US Department of Veterans Affairs MOVE! Weight Management Program	www.move.va.gov	Weight management and health promotion program for US Veterans
National Institute of Health	www.niddk.nih.gov/health-information/liver-disease/nafld-nash/eating-diet-nutrition	Treatment, lifestyle modifications, and clinical trials for NAFLD
American Heart Association	https://www.heart.org/en/healthy-living/healthy-eating/eat-smart/nutrition-basics/mediterranean-diet	Nutritional information including the Mediterranean diet
Center for Disease Control and Prevention	www.cdc.gov/physicalactivity/basics/adults/index.htm	Physical activity recommendations and guidelines

Lifestyle modifications

Lifestyle interventions to achieve weight loss and improve cardiovascular risk factors remain the mainstay of treatment for NAFLD.² Histologic improvement has been shown to be proportional to the amount of weight lost, with the greatest histologic improvement and fibrosis regression seen in patients with ≥10% of body weight lost.¹⁴ The Mediterranean diet is recommended in NAFLD patients for weight loss and improvement in cardiovascular risk factors. This diet has been demonstrated to decrease hepatic steatosis even in the absence of weight loss.¹⁵ NAFLD patients should be instructed to restrict alcohol consumption; even low-level alcohol use has been associated with increased liver-related adverse events, as alcohol can be a cofactor in the progression of liver disease^3,16 Abstinence from alcohol in patients with NAFLD may decrease the risk of fibrosis progression and decrease the risk of hepatic and extrahepatic malignancies. Thus, the AASLD recommends that patients with clinically significant fibrosis (≥F2 fibrosis) should completely abstain from alcohol use.³

The AGA Clinical Practice Update also recommends 150–300 minutes of moderate-intensity exercise or 75–150 minutes of vigorous-intensity aerobic exercise per week in addition to dietary modifications to achieve weight loss goals and improve cardiometabolic health.¹⁶ Though statins have not been shown to improve NASH histologically, statins are safe and recommended for cardiovascular risk reduction in patients with NAFLD, including those with compensated cirrhosis.³

A major challenge in the management of NAFLD is helping patients to achieve and sustain weight loss. Though there are no FDA-approved drugs for the treatment of NAFLD, pharmacologic, bariatric, and endobariatric interventions are ways to help achieve weight loss. A challenge in managing lean NAFLD is that recommending weight loss in these patients may not be appropriate. The AGA recommends lifestyle interventions with diet, exercise, avoidance of fructose, and a modest weight loss of 3%–5% of body weight in patients with lean NAFLD.¹⁷

Pharmacologic therapies

Although there are currently no FDA-approved medications for the treatment of NAFLD, several promising agents are being studied with a broad range of mechanisms of action. Resmetirom, a thyroid hormone receptor agonist, increases hepatic fat metabolism, decreases lipotoxicity, and decreases hepatic fat content.¹⁸ Obeticholic acid, a farsenoid X receptor agonist, has been associated with significant improvement in hepatic fibrosis.¹⁹ Several diabetes medications are also currently being investigated for the treatment of NAFLD. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin, work by decreasing renal glucose reabsorption and have been shown to reduce hepatic lipid content.²⁰ Glucagon-like peptide 1 (GLP1) receptor agonists used for the treatment of diabetes increase satiety, decrease post-prandial glucagon secretion, and increase post-prandial insulin secretion.²¹ Both semaglutide and liraglutide have been associated with resolution in NASH.^22,23 Dipeptidyl peptidase IV (DPP4) inhibitors, including sitagliptin and vidagliptin, enhance GLP1 activity and initially showed promise.²¹ However, treatment with sitaliptin was not associated with a reduction in hepatic fat, and ongoing studies with vidagliptin are underway.^24,25 Lanifibranor is a pan peroxisome proliferator–activated receptor agonist that improves insulin sensitivity and has been associated with improvement in liver histology based on the Steatosis, Activity, and Fibrosis score.²⁶ Thiazolidinediones including pioglitazone are peroxisome proliferator–activated receptor γ agonists that have been demonstrated to improve insulin sensitivity in diabetes. In NASH, pioglitazone in patients with the CYP2C8*3 allele was associated with a change in fibrosis, highlighting the potential of utilizing pharmacogenetics in the treatment of NAFLD.^24,27

Bariatric and endobariatric and metabolic therapies

Beyond pharmacologic treatments and pharmacogenetics, emerging treatments for NAFLD include bariatric surgery and endobariatric and metabolic therapies (EBMTs). Bariatric surgery can improve NASH, hepatic fibrosis, and cardiovascular risk factors but is not an established treatment recommendation for NAFLD.^1,28,29 FDA-approved EBMTs include the intragastric balloon and endoscopic sleeve gastrectomy.³⁰ EBMTs have been associated with improvement in liver fibrosis, hepatic steatosis, and insulin resistance.³⁰ While these therapies show promise in the treatment of NAFLD, they do carry risks. Complications of bariatric surgery include anastomotic leak and strictures, dumping syndrome, malabsorption, wound infection, gastroesophageal reflux disease, and vitamin deficiencies.³¹ Side effects and complications of EBMTs include weight regain, pancreatitis, intraprocedural bleeding, and symptomatic gastroesophageal reflux disease.³²

Given the rising prevalence of NAFLD and the associated increased mortality risk, a systematic and efficient approach is needed to identify patients at the highest risk for disease progression.^2,3 Research in NAFLD is rapidly evolving; thus, it will be imperative for providers who care for patients with metabolic diseases including obesity, T2DM, and NAFLD to remain informed. This review provides a brief update regarding the diagnosis, screening, and management of at-risk patients. The mainstay remains a multidisciplinary approach to improved overall metabolic health with diet, restricted alcohol consumption, exercise, consideration of pharmacologic therapies for obesity and NASH, and regular fibrosis assessments. With the multiple advances in the field and novel use of biomarkers, and pharmacologic and endobariatric therapies, the future of NAFLD care is promising (Figures 1 and 2, Table 2).

FIGURE 1.

Management of NAFLD.¹⁶ Abbreviations: DPP4, dipeptidyl peptidase IV; FXR, farsenoid X receptor; GLP1, glucagon-like peptide 1; SGLT2, sodium-glucose cotransporter-2.

FIGURE 2.

Populations at risk for NAFLD with clinically significant fibrosis.³ Abbreviation: DM, diabetes mellitus.

TABLE 2.

Suggested pharmacologic agents for weight loss³³

Agent	Adverse effects	When to avoid
Semaglutide	Delayed gastric emptying, nausea, and vomiting Increased risk of pancreatitis and gallbladder disease	Personal or family history of medullary thyroid carcinoma History of multiple endocrine neoplasia type 2 Pregnancy
Liraglutide	Delayed gastric emptying, nausea, and vomiting Increased risk of pancreatitis and gallbladder disease	Personal or family history of medullary thyroid carcinoma History of multiple endocrine neoplasia type 2 Pregnancy
Phentermine/Topiramate ER	Tachycardia Constipation Dry mouth	History of cardiovascular disease Uncontrolled hypertension Pregnancy (topiramate is teratogenic)
Naltrexone-Buproprion ER	Headache Sleep disturbance Nausea Constipation Vomiting	Avoid in patients with seizure disorders or at risk for seizures Do not use with concomitant opiates
Phentermine	Cardiac effects including tachycardia and hypertension	History of cardiovascular disease

CONFLICTS OF INTEREST

Janice Jou receives grants from Gilead. Cynthia Moylan advises Boehringer Inghelheim. She receives institutional grants from Exact Sciences and GSK. The remaining authors have no conflicts to report.

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