Guideline sources The following summarized guidelines for the evaluation and management of non-alcoholic fatty liver disease (NAFLD) are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2023; 2018), the American Diabetes Association (ADA 2023), the American Gastroenterological Association (AGA 2022; 2021), the American Association of Clinical Endocrinologists (AACE/AASLD 2022), the Expert Committee on NAFLD (ECON/NASPGHAN 2017), the European Association for the Study of Obesity (EASO/EASD/EASL 2016), and the American College of Endocrinology (ACE/AACE 2016). 1 2 3 5 6 7 8 9 10 Guidelines 1. Screening and diagnosis Indications for screening, adult patients: https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 1/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway p As per AASLD 2023 guidelines: g, Do not obtain general population-based screening for nonalcoholic fatty liver disease. D Screen for advanced fibrosis in patients at high-risk, such as patients with T2DM, medically complicated obesity, family history of cirrhosis, or more than mild alcohol consumption. E As per AASLD/AACE 2022 guidelines, obtain screening for nonalcoholic fatty liver disease and advanced fibrosis in patients with any of the following: obesity and/or features of metabolic syndrome prediabetes or T2DM mellitus hepatic steatosis on any imaging study persistently elevated plasma aminotransferase levels (over 6 months). B Show 3 more As per AASLD 2018 guidelines: Avoid obtaining routine screening for nonalcoholic fatty liver disease in high-risk adult patients attending primary care, diabetes, or obesity clinics because of uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to long-term benefits and cost-effectiveness of screening. D Maintain a high index of suspicion for nonalcoholic fatty liver disease and NASH in patients with T2DM. Consider using clinical decision aids (such as the nonalcoholic fatty liver disease fibrosis score, FIB-4 index, or vibration-controlled transient elastography) to identify patients at high risk for advanced fibrosis. E As per EASO/EASD/EASL 2016 guidelines, screen for nonalcoholic fatty liver disease relying on the demonstration of excessive liver fat in patients with insulin resistance and/or metabolic risk factors (obesity or metabolic syndrome). A Show 3 more Indications for screening, pediatric patients: As per ADA 2023 guidelines: Screen for nonalcoholic fatty liver disease by measuring AST and ALT at diagnosis and annually thereafter in pediatric patients with T1DM. B Consider referring to gastroenterology for persistently elevated or worsening transaminases. C As per AASLD/AACE 2022 guidelines, screen pediatric patients of any age and adolescent patients with obesity or T2DM (but not T1DM) for nonalcoholic fatty liver disease using serum ALT. B Show 2 more As per AASLD 2018 guidelines, insufficient evidence to recommend screening for nonalcoholic fatty liver disease in pedatric patients with overweight and obesity. I Indications for screening, family relatives: As per AASLD 2023 guidelines, counsel first-degree relatives of patients with NASH cirrhosis regarding their increased individual risk and offer screening for advanced hepatic fibrosis. E https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 2/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway As per AASLD 2018 guidelines, do not obtain systematic screening of family members for nonalcoholic fatty liver disease. D 2. Classification and risk stratification Assessment of fibrosis risk: As per AASLD 2023 guidelines: Obtain primary risk assessment with FIB-4 index in all patients with hepatic steatosis or clinically suspected nonalcoholic fatty liver disease based on the presence of obesity and metabolic risk factors. E Repeat primary risk assessment with FIB-4 index every 1-2 years in patients with prediabetes, T2DM, or 2 metabolic risk factors (or imaging evidence of hepatic steatosis). E As per AACE 2022 guidelines, use liver fibrosis prediction calculations to assess the risk of nonalcoholic fatty liver disease with liver fibrosis. Use the FIB-4 index as the initial noninvasive test. B As per AASLD 2018 guidelines: Consider using the presence of metabolic syndrome, assessing nonalcoholic fatty liver disease fibrosis score or FIB-4, or obtaining liver stiffness measurement by vibration-controlled transient elastography or magnetic resonance elastography to identify patients at risk for steatohepatitis and/or advanced fibrosis. E Assess nonalcoholic fatty liver disease fibrosis score or FIB-4 index for identifying patients with nonalcoholic fatty liver disease at higher risk of having bridging fibrosis (stage 3) or cirrhosis (stage 4). E As per EASL 2016 guidelines, obtain biomarkers, scores of fibrosis, and transient elastography as acceptable noninvasive procedures for the identification of patients at low risk of advanced fibrosis/cirrhosis. B Show 4 more 3. Diagnostic investigations Initial evaluation: As per AASLD 2023 guidelines, do not obtain an ultrasound to identify hepatic steatosis due to low sensitivity across the nonalcoholic fatty liver disease spectrum, although standard ultrasound can detect hepatic steatosis. Consider using a controlled attenuation parameter as a point-of-care technique to identify steatosis. D Show 3 more As per AASLD 2018 guidelines, assess patients with hepatic steatosis on imaging for nonalcoholic fatty liver disease if there are symptoms or signs of liver disease or abnormal liver chemistries. E Show 3 more https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 3/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway As per EASL 2016 guidelines: Screen patients with steatosis for secondary causes of nonalcoholic fatty liver disease, including alcohol intake. A Obtain ultrasound as first-line imaging for nonalcoholic fatty liver disease to provide additional diagnostic information. A Transient elastography: As per AACE 2022 guidelines: Consider obtaining further workup with a liver stiffness measurement (transient elastography) or enhanced liver fibrosis test, as available, in high-risk patients with an indeterminate or high FIB-4 index score. C Obtain vibration-controlled transient elastography to identify advanced disease and predict liver-related outcomes to stage the risk of fibrosis in patients with nonalcoholic fatty liver disease. Consider obtaining alternative imaging including shear wave elastography and/or magnetic resonance elastography. B As per AASLD 2018 guidelines, obtain vibration-controlled transient elastography or magnetic resonance elastography as noninvasive means to identify advanced fibrosis in patients with nonalcoholic fatty liver disease. E Magnetic resonance spectroscopy: do not obtain proton magnetic resonance spectroscopy for quantitative estimation of liver fat in clinical settings. D Serum biomarkers: As per AASLD 2023 guidelines, do not assess serum aminotransferase levels in isolation to exclude the presence of NASH with clinically significant fibrosis. D As per EASL 2016 guidelines, obtain serum biomarkers and scores as an acceptable alternative for the diagnosis of steatosis whenever imaging tools are not available or feasible (such as in large epidemiological studies). B Genetic testing: recognize that carriers of the PNPLA3 I148M and TM6SF2 E167K variants have a higher liver fat content and increased risk of NASH. Consider obtaining genotyping in selected patients and clinical trials. B Evaluation for autoimmune liver disease: obtain a workup for autoimmune liver disease in patients with high serum titers of autoantibodies in association with other features suggestive of autoimmune liver disease (highly elevated aminotransferases, high serum globulins, or high total protein to albumin ratio). E Screening for comorbidities: As per AASLD 2023 guidelines: Screen for T2DM in patients with nonalcoholic fatty liver disease. E Do not obtain routine measurement of testosterone levels in male patients with nonalcoholic fatty liver disease. Treat hypogonadism if present as suggested by clinical signs or symptoms. D https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 4/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway As per AGA 2021 guidelines, screen patients with nonalcoholic fatty liver disease for coexisting metabolic conditions, such as obesity, diabetes mellitus, hypertension, dyslipidemia, and CVD. Initiate aggressive management for these comorbidities. E As per AASLD 2018 guidelines, screen for commonly associated comorbiditiesm such as obesity, dyslipidemia, insulin resistance, diabetes, hypothyroidism, PCOS, and sleep apnea, as part of the initial evaluation of patients with suspected nonalcoholic fatty liver disease. E As per EASL 2016 guidelines, screen all patients with steatosis for features of metabolic syndrome, independent of liver enzymes. A Show 6 more Screening for gastroesophageal varices: screen patients with cirrhosis due to NASH for gastroesophageal varices, as outlined in evidence-based guidelines for cirrhosis. E 4. Diagnostic procedures Liver biopsy: As per AACE 2022 guidelines, evaluate patients undergoing bariatric surgery for the presence and severity of NASH and consider performing a liver biopsy at the time of bariatric surgery. Perform liver biopsy if presurgical stratification suggests indeterminate or high risk of liver fibrosis. B As per AASLD 2018 guidelines, consider performing a liver biopsy in patients with suspected nonalcoholic fatty liver disease, persistently high serum ferritin, and increased iron saturation, especially in the context of homozygote or heterozygote C282Y HFE mutation. E Show 4 more As per EASL 2016 guidelines, diagnose NASH by a liver biopsy showing steatosis, hepatocyte ballooning and lobular inflammation. A Pathological scoring: ensure that pathology reports for liver biopsy include a distinction between nonalcoholic fatty liver (steatosis), nonalcoholic fatty liver with inflammation, and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning). Consider including a comment on severity (mild, moderate, or severe). E Show 2 more 5. Medical management General principles: As per AASLD 2023 guidelines, recognize that there are currently no FDA-approved medications for the treatment of nonalcoholic fatty liver disease. Consider initiating drugs approved to treat associated comorbidities with potential benefit in nonalcoholic fatty liver disease in the appropriate clinical setting. E As per AASLD 2018 guidelines, initiate specific pharmacological treatments for improving liver disease only in patients with biopsy-proven NASH and fibrosis. E https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 5/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway As per EASL 2016 guidelines, reserve pharmacotherapy for patients with NASH, particularly with significant fibrosis (stage F2). Consider initiating pharmacotherapy to prevent disease progression in patients with less severe disease, but at high risk of disease progression (with diabetes, metabolic syndrome, persistently increased alanine transaminase, high necroinflammation). B Glucose-lowering agents: As per AASLD 2023 guidelines, consider initiating semaglutide for its approved indications (T2DM/obesity) in patients with NASH, as it confers a cardiovascular benefit and improves NASH. E Show 3 more As per AACE 2022 guidelines, initiate pioglitazone and GLP-1 receptor agonists in patients with T2DM and biopsy-proven NASH. A Show 3 more As per AASLD 2018 guidelines, consider initiating pioglitazone in patients with biopsy-proven NASH with or without diabetes. Discuss the risks and benefits with each patient before starting therapy. E Show 2 more As per EASL 2016 guidelines: Consider initiating pioglitazone, with or without vitamin E, in patients with NASH. C Insufficient evidence to recommend an optimal duration of therapy. Discontinue treatment in patients with increased alanine transaminase at baseline if there is no reduction in aminotransferases after 6 months of therapy. I Bile acids: As per AASLD 2023 guidelines, do not use UDCA for the treatment of patients with NASH. D As per AASLD 2018 guidelines: Do not use UDCA for the treatment of patients with nonalcoholic fatty liver disease or NASH. D Do not use obeticholic acid (off-label) for the treatment of patients with NASH. D Other agents: As per AASLD 2023 guidelines, do not use silymarin for the treatment of patients with NASH. D As per AACE 2022 guidelines, insufficient evidence to recommend other pharmacotherapies in patients with NASH. I Management of comorbidities: As per AASLD 2023 guidelines: Initiate statins for CVD risk reduction in patients with nonalcoholic fatty liver, including compensated cirrhosis. Consider initiating statins with careful monitoring in patients with decompensated cirrhosis and high CVD risk. E Offer lifestyle changes and supplementation with omega-3 fatty acids, icosapent ethyl, or fibrates for the management of hypertriglyceridemia. E https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 6/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway As per AACE 2022 guidelines, manage obesity, metabolic syndrome, prediabetes, diabetes mellitus, dyslipidemia, hypertension, and CVD in patients with nonalcoholic fatty liver disease based on the current standards of care. A Show 3 more As per AASLD 2018 guidelines, consider offering aggressive modification of CVD risk factors in all patients with nonalcoholic fatty liver disease. E Show 2 more As per AACE 2016 guidelines, consider offering orlistat, C liraglutide, B and bariatric surgery C in addition to lifestyle changes for weight loss as high as 10-40% of body weight to decrease hepatic inflammation, hepatocellular injury, and fibrosis. B As per EASL 2016 guidelines, consider initiating statins to reduce LDL cholesterol and prevent cardiovascular risk with no benefits or harm on liver disease. Insufficient evidence to recommend n-3 PUFAs in patients with NASH although they reduce both plasma and liver lipids. B 6. Nonpharmacologic interventions Weight loss: As per AASLD 2023 guidelines, offer a diet leading to a caloric deficit in patients with nonalcoholic fatty liver disease with overweight or obesity. Encourage diets with limited carbohydrates and saturated fat and enriched with high fiber and unsaturated fats (such as the Mediterranean diet) when possible due to their additional cardiovascular benefits. E As per AACE 2022 guidelines: Advise lifestyle changes in patients with excess adiposity and nonalcoholic fatty liver disease with a goal of at least 5% (preferably 10%) weight loss for liver histologic and cardiometabolic benefit. Advise participating in a structured weight loss program, when possible, tailored to the patient's lifestyle and personal preferences. B Advise dietary modifications in patients with nonalcoholic fatty liver disease, including reduction of macronutrient content to induce energy deficit (with restriction of saturated fat, starch, and added sugar) and adopting healthier eating patterns, such as the Mediterranean diet. A As per AGA 2021 guidelines, offer lifestyle modifications, including diet and exercise, to achieve weight loss in all patients with nonalcoholic fatty liver disease. Recognize that weight loss 5% of total body weight can decrease hepatic steatosis, weight loss 7% of total body weight can lead to NASH resolution, and weight loss 10% of total body weight can result in fibrosis regression or stability. E Show 5 more As per AASLD 2018 guidelines: Advise weight loss to reduce hepatic steatosis, achieved either by a hypocaloric diet alone or in conjunction with increased physical activity. E https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 7/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway Advise a 7-10% weight loss to improve the majority of the histopathological features of NASH, including fibrosis. E As per AACE 2016 guidelines: Offer lifestyle interventions involving calorie restriction and moderate-to-vigorous physical activity targeting 4-10% weight loss in patients with overweight or obesity and nonalcoholic fatty liver disease. A Consider advising a Mediterranean dietary pattern or meal plan for improving hepatic steatosis, independent of weight loss. B As per EASL 2016 guidelines: Set a 7-10% weight loss as the target of most lifestyle interventions in patients with overweight/obesity to improve liver enzymes and histology. B Consider offering energy restriction and excluding nonalcoholic fatty liver disease-promoting components (processed food, and food and beverages high in added fructose). Adjust the macronutrient composition according to the Mediterranean diet. B Physical activity: As per AASLD 2023 guidelines, encourage increasing physical activity to the extent possible in patients with nonalcoholic fatty liver disease. Consider providing individualized prescriptive exercise recommendations to increase sustainability and benefits independent of weight loss. E As per AACE 2022 guidelines, advise exercising to improve body composition and cardiometabolic health. Advise participating in structured exercise programs, when possible, tailored to the patient's lifestyle and personal preferences. A As per AGA 2021 guidelines: Consider offering regular physical activity in patients with nonalcoholic fatty liver disease, with a target of 150-300 minutes of moderate-intensity or 75-150 minutes of vigorous-intensity aerobic exercise per week. Consider offering resistance training complementary to aerobic exercise. Recognize that the impact of exercise on nonalcoholic fatty liver disease can enhance the positive effect of the hypocaloric diet. E Consider offering specialized physical activity programs in patients with sarcopenia. E As per AASLD 2018 guidelines, advise exercising to prevent or reduce hepatic steatosis in adult patients with nonalcoholic fatty liver disease. E As per EASL 2016 guidelines, recognize that unhealthy lifestyles play a role in the development and progression of nonalcoholic fatty liver disease. Assess dietary and physical activity habits as part of comprehensive nonalcoholic fatty liver disease screening. A Show 2 more Alcohol restriction: As per AASLD 2023 guidelines, advise abstaining from alcohol use completely in patients with clinically significant hepatic fibrosis ( F2). E As per AGA 2021 guidelines, advise alcohol restriction or elimination from the diet in adult patients with nonalcoholic fatty liver disease. E https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 8/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway As per AASLD 2018 guidelines: Advise avoiding the consumption of heavy amounts of alcohol in patients with nonalcoholic fatty liver disease. E Insufficient evidence regarding non-heavy consumption of alcohol in patients with nonalcoholic fatty liver disease. I Omega-3 fatty acids: as per AASLD 2018 guidelines, do not use omega-3 fatty acids as a specific treatment of nonalcoholic fatty liver disease or NASH, but consider offering them for the treatment of hypertriglyceridemia in patients with nonalcoholic fatty liver disease. D Vitamin E: As per AASLD 2023 guidelines, consider offering vitamin E to improve NASH in selected patients without diabetes. Insufficient evidence regarding the use of vitamin E in patients with cirrhosis. E As per AACE 2022 guidelines, consider offering vitamin E supplements for the treatment of NASH in patients without T2DM mellitus. Do not use vitamin E in patients with T2DM mellitus or advanced fibrosis. B As per AASLD 2018 guidelines: Consider offering vitamin E 800 IU/day to improve liver histology in non-diabetic adult patients with biopsy-proven NASH. Discuss the risks and benefits with each patient before starting therapy. E Do not offer vitamin E in patients with NASH and diabetes mellitus, nonalcoholic fatty liver disease without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis. D As per EASL 2016 guidelines, consider offering vitamin E in patients with NASH. C 7. Surgical interventions Bariatric surgery: As per AASLD 2023 guidelines, consider performing bariatric surgery as a therapeutic option in patients meeting the criteria for metabolic weight loss surgery, as it effectively resolves nonalcoholic fatty liver disease or NASH in most patients without cirrhosis and reduces mortality from CVD and malignancy. E As per AACE 2022 guidelines, consider performing bariatric surgery as an option to treat nonalcoholic fatty liver disease C and improve cardiometabolic health B in patients with nonalcoholic fatty liver disease and a BMI of 35 kg/m , or 32.5 kg/m in Asian populations, particularly if T2DM mellitus is present. Consider performing bariatric surgery as an option in patients with a BMI of 30-34.9 kg/m , or 27.5-32.4 kg/m in Asian populations. C Show 3 more As per AASLD 2018 guidelines: Consider performing foregut bariatric surgery in otherwise eligible patients with obesity and nonalcoholic fatty liver disease or NASH. E https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 9/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway Insufficient evidence to recommend foregut bariatric surgery as a specific treatment option for NASH. I As per EASL 2016 guidelines, recognize that bariatric surgery reduces liver fat by improving obesity and diabetes, reduces NASH progression, and improves histological lesions of NASH, including fibrosis. B Liver transplantation (indications): offer liver transplantation in patients with NASH with end- stage liver disease, liver failure and/or HCC. A Liver transplantation (pre-transplant evaluation): obtain careful evaluation to identify CVDs, whether clinically apparent or occult, during the transplant evaluation process in patients with cirrhosis due to NASH. E 8. Specific circumstances Lean patients (screening): Do not obtain routine screening for nonalcoholic fatty liver disease in lean persons in the general population. D Consider obtaining screening for nonalcoholic fatty liver disease in > 40 years old patients with T2DM. C Lean patients (diagnosis): Suspect nonalcoholic fatty liver disease in lean patients with metabolic diseases (such as T2DM, dyslipidemia, and hypertension), elevated liver biochemical tests, or incidentally noted hepatic steatosis. B Diagnose lean nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease and BMI < 25 kg/m (non-Asian race) or BMI < 23 kg/m (Asian race). B Lean patients (differential diagnosis): exclude other causes of liver disease, including other causes of fatty liver, such as human immunodeficiency virus, lipodystrophy, lysosomal acid lipase deficiency, familial hypobetalipoproteinemia, and medication-induced hepatic steatosis (methotrexate, amiodarone, tamoxifen, and steroids), in patients with lean nonalcoholic fatty liver disease. B Show 2 more Lean patients (risk stratification): stratify lean patients with nonalcoholic fatty liver disease for hepatic fibrosis to identify patients with advanced fibrosis or cirrhosis. B Lean patients (noninvasive assessment of fibrosis): consider using serum indices (nonalcoholic fatty liver disease fibrosis score and Fibrosis-4 score) and imaging techniques (transient elastography and magnetic resonance elastography) as alternatives to liver biopsy for fibrosis staging and patient follow-up. Consider obtaining these tests at the time of diagnosis and repeat at intervals of 6 months to 2 years, depending on the fibrosis stage and the patient's response to intervention. C Lean patients (imaging): obtain a second noninvasive test (such as transient elastography or magnetic resonance elastography) to confirm the stage and prognosis of nonalcoholic fatty liver https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 10/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway disease if noninvasive tests (such as Fibrosis-4 and nonalcoholic fatty liver disease fibrosis score) are indeterminate. B Lean patients (liver biopsy): consider performing liver biopsy as the reference standard if there is uncertainty regarding contributing causes of liver injury and/or the stage of liver fibrosis. C Lean patients (genetic testing): insufficient evidence to recommend routine testing for genetic variants in patients with lean nonalcoholic fatty liver disease. I Lean patients, lifestyle modifications: As per AGA 2022 guidelines, offer lifestyle intervention, including exercise, diet modification, and avoidance of fructose- and sugar-sweetened drinks, to target a modest weight loss of 3-5% in lean patients with nonalcoholic fatty liver disease. B As per AGA 2021 guidelines, offer a hypocaloric diet in lean patients (BMI 26 kg/m non-Asian or BMI 24 kg/m Asian) with a lower target weight-loss threshold of 3-5%, as they experience similar histologic benefits for steatosis and NASH as patients with overweight or obesity. E Lean patients (vitamin E): consider offering vitamin E in lean patients with biopsy-confirmed NASH, but without T2DM or cirrhosis. C Lean patients (glucose-lowering agents): Consider initiating oral pioglitazone 30 mg daily in lean patients with biopsy-confirmed NASH without cirrhosis. C Insufficient evidence regarding the role of GLP-1 agonists and SGLT-2 inhibitors in the management of lean patients with nonalcoholic fatty liver disease. I Lean patients (serial clinical assessment): follow-up lean patients with nonalcoholic fatty liver disease with insulin resistance and altered body fat distribution, even though they have less severe metabolic disturbance than overweight patients with nonalcoholic fatty liver disease. B Lean patients (surveillance for hepatocellular carcinoma): consider obtaining HCC surveillance with abdominal ultrasound with or without serum AFP twice per year in lean patients with nonalcoholic fatty liver disease and clinical markers compatible with liver cirrhosis. C Pediatric patients, screening: As per AASLD/AACE 2022 guidelines, screen pediatric patients of any age and adolescent patients with obesity or T2DM (but not T1DM) for nonalcoholic fatty liver disease using serum ALT. B Show 2 more As per AASLD 2018 guidelines, insufficient evidence to recommend screening for nonalcoholic fatty liver disease in pedatric patients with overweight and obesity. I As per ECON/NASPGHAN 2017 guidelines, consider obtaining screening beginning between ages 9 and 11 years in all pediatric patients with obesity (BMI 95th percentile) and in pediatric patients with overweight (BMI 85th and < 94th percentile) with additional risk factors (central adiposity, insulin resistance, prediabetes or diabetes, dyslipidemia, sleep apnea, or family history of nonalcoholic fatty liver disease/NASH). B Show 9 more https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 11/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway Pediatric patients, diagnosis: As per AASLD/AACE 2022 guidelines, consider diagnosing pediatric nonalcoholic fatty liver disease with imaging (ultrasound or MRI-proton density fat fraction) or liver biopsy, in combination with exclusion of non-nonalcoholic fatty liver disease causes of hepatic steatosis, such as Wilson's disease, mitochondrial disease and medications. C Show 2 more As per AASLD 2018 guidelines, test for monogenic causes of chronic liver disease (such as fatty acid oxidation defects, lysosomal storage diseases, and peroxisomal disorders), in pediatric patients with hepatic steatosis who are very young or not overweight, in addition to evaluating for the causes considered for adult patients. E Show 4 more As per ECON/NASPGHAN 2017 guidelines, exclude alternative etiologies for elevated ALT and/or hepatic steatosis and investigate the presence of coexisting chronic liver diseases in the evaluation of pediatric patients with suspected nonalcoholic fatty liver disease. A Show 5 more As per EASO/EASD/EASL 2016 guidelines, consider using predictors of fibrosis, including elastometry, acoustic radiation force impulse imaging and serum biomarkers, to help reduce the number of biopsies in pediatric patients. C Pediatric patients, management: As per AASLD/AACE 2022 guidelines: Advise lifestyle modifications in pediatric patients with nonalcoholic fatty liver disease, promoting the adoption of dietary changes to create an energy deficit, with reduction in sugar consumption as first-line lifestyle modification and increased physical activity aiming for BMI optimization. B Consider initiating GLP-1 receptor agonists for the treatment of pediatric obesity and T2DM. C As per AASLD 2018 guidelines, advise intensive lifestyle modifications as first-line therapy to improve aminotransferases and liver histology in pediatric patients with nonalcoholic fatty liver disease. E Show 2 more As per ECON/NASPGHAN 2017 guidelines, advise lifestyle modifications to improve diet and increase physical activity as first-line therapy in all pediatric patients with nonalcoholic fatty liver disease. B Show 11 more As per EASO/EASD/EASL 2016 guidelines: Offer a healthy diet and physical activity to improve steatosis and hepatic inflammation in pediatric patients with nonalcoholic fatty liver disease. B Insufficient evidence to recommend safe and effective drug treatment for fibrosis in pediatric patients with nonalcoholic fatty liver disease. I https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 12/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway Pediatric patients (follow-up): screen pediatric patients with nonalcoholic fatty liver disease for dyslipidemia at diagnosis and periodically as indicated by current lipid guidelines for children. B Show 6 more 9. Follow-up and surveillance Indications for referral: As per AASLD 2023 guidelines, refer patients with suspected advanced NASH or discordant noninvasive tests to a specialist for evaluation, management, and/or further diagnostic evaluation. E As per AACE 2022 guidelines: Refer patients with persistently elevated ALT or AST levels and/or with hepatic steatosis on imaging and indeterminate risk (FIB-4 index 1.3-2.67, liver stiffness measurement 8-12 kPa or enhanced liver fibrosis test 7.7-9.8) or high risk (FIB-4 index > 2.67, liver stiffness measurement > 12 or enhanced liver fibrosis > 9.8) based on blood tests and/or imaging to a gastroenterologist or hepatologist for further assessment (considering including a liver biopsy). B Refer patients with clinical evidence of advanced liver disease (ascites, hepatic encephalopathy, esophageal varices, or evidence of hepatic synthetic dysfunction) to a gastroenterologist/hepatologist for further care. B Serial clinical assessment: follow-up patients with obesity as it is the major phenotype and risk condition for nonalcoholic fatty liver disease driven by insulin resistance and also increases the risk of advanced disease. A Show 2 more Serial laboratory and imaging assessment: as per AASLD 2023 guidelines, consider using improvement in ALT or reduction in liver fat content by imaging in response to an intervention as a surrogate for histological improvement in disease activity. E Surveillance for hepatocellular carcinoma: As per AASLD 2023 guidelines, obtain routine surveillance for HCC, esophageal varices, and monitoring for decompensation in patients with NASH cirrhosis. E As per AASLD 2018 guidelines: Consider obtaining screening for HCC in patients with cirrhosis due to suspected nonalcoholic fatty liver disease. E Do not obtain routine screening and surveillance for HCC in patients with NASH without cirrhosis. D As per EASL 2016 guidelines, insufficient evidence regarding the timing and cost-effectiveness of surveillance for HCC, although nonalcoholic fatty liver disease is a risk factor for HCC which may also develop in the pre-cirrhotic stage, and the risk is further increased by the presence of the PNPLA3 rs738409 C>G polymorphism. I https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 13/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway Clinical findings Symptoms Past medical history Fatigue Diabetes mellitus Muscle weakness Dyslipidemia RUQ pain Hypopituitarism Hypothyroidism Abdominal exam Liver cirrhosis Metabolic syndrome Ascites Obesity Hepatomegaly PCOS Splenomegaly Prediabetes Lab findings Sleep apnea Insulin resistance Integument exam serum ALP Jaundice serum ALT Palmar erythema serum AST Spider angiomata serum ferritin serum total cholesterol Histological findings serum triglycerides Hepatic steatosis Liver fibrosis Steatohepatitis References 1. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018 Jan;67 1 328 357. Open 2. European Association for the Study of the Liver EASL , European Association for the Study of Diabetes EASD , European Association for the Study of Obesity EASO . EASL EASD EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64 6 1388 402. Open 3. Zobair M Younossi, Kathleen E Corey, Joseph K Lim. AGA Clinical Practice Update on Lifestyle Modification Using Diet and Exercise to Achieve Weight Loss in the Management of Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology. 2021 Feb;160 3 912 918. Open 4. Stephan C Bischoff, Johann Ockenga, Ahad Eshraghian et al. Practical guideline on obesity care in patients with gastrointestinal and liver diseases Joint ESPEN/UEG guideline. Clin Nutr. 2023 Apr 10;42 6 987 1024. Open https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 14/15 6/30/23, 1:17 AM Non-alcoholic fatty liver disease Pathway 5. Mary E Rinella, Brent A Neuschwander-Tetri, Mohammad Shadab Siddiqui et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023 Feb 3. Open 6. Michelle T Long, Mazen Noureddin, Joseph K Lim. AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review. Gastroenterology. 2022 Jul 13;S0016 5085 22 00628 X. Open 7. Kenneth Cusi, Scott Isaacs, Diana Barb 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 May;28 5 528 562. Open 8. Miriam B Vos, Stephanie H Abrams, Sarah E Barlow et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD ECON and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition NASPGHAN . J Pediatr Gastroenterol Nutr. 2017 Feb;64 2 319 334. Open 9. W Timothy Garvey, Jeffrey I Mechanick, Elise M Brett et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016 Jul;22 Suppl 3 1 203. Open 10. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 11. Lim JK, Flamm SL, Singh S et al. American Gastroenterological Association Institute Guideline on the Role of Elastography in the Evaluation of Liver Fibrosis. Gastroenterology. 2017 May;152 6 1536 1543. Open 12. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 13. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open https://web.pathway.md/diseases/recpOIw1RVWHM7Bev 15/15