Diagnosis and Management of Non-Alcoholic Fatty Liver Disease
Publication Date: September 1, 2017
Last Updated: March 14, 2022
Guidance Statements
Evaluation
1. Ongoing or recent alcohol consumption >21 standard drinks on average per week in men and >14 standard drinks on average per week in women is a reasonable threshold for significant alcohol consumption when evaluating patients with suspected NAFLD.
2. Patients with unsuspected HS detected on imaging who have symptoms or signs attributable to liver disease or have abnormal liver chemistries should be evaluated as though they have suspected NAFLD and worked up accordingly.
3. Patients with incidental HS detected on imaging who lack any liver-related symptoms or signs and have normal liver biochemistries should be assessed for metabolic risk factors (e.g., obesity, diabetes mellitus, or dyslipidemia) and alternate causes for HS such as significant alcohol consumption or medications.
4. Routine Screening for NAFLD in high-risk groups attending primary care, diabetes, or obesity clinics is not advised at this time because of uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to long-term benefits and cost-effectiveness of screening.
5. There should be a high index of suspicion for NAFLD and NASH in patients with type 2 diabetes. Clinical decision aids such as NFS or fibrosis-4 index (FIB-4) or vibration controlled transient elastography (VCTE) can be used to identify those at low or high risk for advanced fibrosis (bridging fibrosis or cirrhosis).
6. Systematic screening of family members for NAFLD is not recommended currently.
7. When evaluating a patient with suspected NAFLD, it is essential to exclude competing etiologies for steatosis and coexisting common CLD.
8. In patients with suspected NAFLD, persistently high serum ferritin, and increased iron saturation, especially in the context of homozygote or heterozygote C282Y HFE mutation, a liver biopsy should be considered.
9. High serum titers of autoantibodies in association with other features suggestive of autoimmune liver disease (>5 ULN aminotransferases, high globulins, or high total protein to albumin ratio) should prompt a work-up for autoimmune liver disease.
10. Initial evaluation of patients with suspected NAFLD should carefully consider the presence of commonly associated comorbidities such as obesity, dyslipidemia, IR or diabetes, hypothyroidism, polycystic ovary syndrome, and sleep apnea.
11. In patients with NAFLD, MetS predicts the presence of SH, and its presence can be used to target patients for a liver biopsy.
12. NFS or FIB-4 index are clinically useful tools for identifying NAFLD patients with higher likelihood of having bridging fibrosis (stage 3) or cirrhosis (stage 4).
13. VCTE or MRE are clinically useful tools for identifying advanced fibrosis in patients with NAFLD.
2. Patients with unsuspected HS detected on imaging who have symptoms or signs attributable to liver disease or have abnormal liver chemistries should be evaluated as though they have suspected NAFLD and worked up accordingly.
3. Patients with incidental HS detected on imaging who lack any liver-related symptoms or signs and have normal liver biochemistries should be assessed for metabolic risk factors (e.g., obesity, diabetes mellitus, or dyslipidemia) and alternate causes for HS such as significant alcohol consumption or medications.
4. Routine Screening for NAFLD in high-risk groups attending primary care, diabetes, or obesity clinics is not advised at this time because of uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to long-term benefits and cost-effectiveness of screening.
5. There should be a high index of suspicion for NAFLD and NASH in patients with type 2 diabetes. Clinical decision aids such as NFS or fibrosis-4 index (FIB-4) or vibration controlled transient elastography (VCTE) can be used to identify those at low or high risk for advanced fibrosis (bridging fibrosis or cirrhosis).
6. Systematic screening of family members for NAFLD is not recommended currently.
7. When evaluating a patient with suspected NAFLD, it is essential to exclude competing etiologies for steatosis and coexisting common CLD.
8. In patients with suspected NAFLD, persistently high serum ferritin, and increased iron saturation, especially in the context of homozygote or heterozygote C282Y HFE mutation, a liver biopsy should be considered.
9. High serum titers of autoantibodies in association with other features suggestive of autoimmune liver disease (>5 ULN aminotransferases, high globulins, or high total protein to albumin ratio) should prompt a work-up for autoimmune liver disease.
10. Initial evaluation of patients with suspected NAFLD should carefully consider the presence of commonly associated comorbidities such as obesity, dyslipidemia, IR or diabetes, hypothyroidism, polycystic ovary syndrome, and sleep apnea.
11. In patients with NAFLD, MetS predicts the presence of SH, and its presence can be used to target patients for a liver biopsy.
12. NFS or FIB-4 index are clinically useful tools for identifying NAFLD patients with higher likelihood of having bridging fibrosis (stage 3) or cirrhosis (stage 4).
13. VCTE or MRE are clinically useful tools for identifying advanced fibrosis in patients with NAFLD.
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Biopsy
14. Liver biopsy should be considered in patients with NAFLD who are at increased risk of having SH and/or advanced fibrosis.
15. The presence of MetS, NFS or FIB-4, or liver stiffness measured by VCTE or MRE may be used for identifying patients who are at risk for SH and/or advanced fibrosis.
16. Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies for HS and the presence and/or severity of coexisting CLDs cannot be excluded without a liver biopsy.
15. The presence of MetS, NFS or FIB-4, or liver stiffness measured by VCTE or MRE may be used for identifying patients who are at risk for SH and/or advanced fibrosis.
16. Liver biopsy should be considered in patients with suspected NAFLD in whom competing etiologies for HS and the presence and/or severity of coexisting CLDs cannot be excluded without a liver biopsy.
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Histopathology
17. Clinically useful pathology reporting should include a distinction between NAFL (steatosis), NAFL with inflammation, and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning). A comment on severity (mild, moderate, or severe) may be useful. Specific scoring systems such as NAS(128) and/or SAF(128,129) may be used as deemed appropriate.
18. The presence or absence of fibrosis should be described. If present, a further statement related to location, amount, and parenchymal remodeling is warranted.
18. The presence or absence of fibrosis should be described. If present, a further statement related to location, amount, and parenchymal remodeling is warranted.
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Management
19. Pharmacological treatments aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis.
20. Weight loss generally reduces HS, achieved either by hypocaloric diet alone or in conjunction with increased physical activity. A combination of a hypocaloric diet (daily reduction by 500-1,000 kcal) and moderate-intensity exercise is likely to provide the best likelihood of sustaining weight loss over time.
21. Weight loss of at least 3%-5% of body weight appears necessary to improve steatosis, but a greater weight loss (7%-10%) is needed to improve the majority of the histopathological features of NASH, including fibrosis.
22. Exercise alone in adults with NAFLD may prevent or reduce HS, but its ability to improve other aspects of liver histology remains unknown.
23. Metformin is not recommended for treating NASH in adult patients.
24. Pioglitazone improves liver histology in patients with and without T2DM with biopsy-proven NASH. Therefore, it may be used to treat these patients. Risks and benefits should be discussed with each patient before starting therapy.
25. Until further data support its safety and efficacy, pioglitazone should not be used to treat NAFLD without biopsy-proven NASH.
26. It is premature to consider GLP-1 agonists to specifically treat liver disease in patients with NAFLD or NASH.
27. Vitamin E (rrr a-tocopherol) administered at a daily dose of 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH and therefore may be considered for this patient population. Risks and benefits should be discussed with each patient before starting therapy.
28. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
29. Foregut bariatric surgery can be considered in otherwise eligible obese individuals with NAFLD or NASH. 30. It is premature to consider foregut bariatric surgery as an established option to specifically treat NASH.
31. The type, safety, and efficacy of foregut bariatric surgery in otherwise eligible obese individuals with established cirrhosis attributed to NAFLD are not established. In otherwise eligible patients with compensated NASH or cryptogenic cirrhosis, foregut bariatric surgery may be considered on a case-by-case basis by an experienced bariatric surgery program.
32. UCDA is not recommended for the treatment of NAFLD or NASH.
33. Omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia in patients with NAFLD.
34. Patients with NAFLD should not consume heavy amounts of alcohol. 35. There are insufficient data to make recommendations with regard to nonheavy consumption of alcohol by individuals with NAFLD.
34. Patients with NAFLD should not consume heavy amounts of alcohol.
35. There are insufficient data to make recommendations with regard to nonheavy consumption of alcohol by individuals with NAFLD.
36. Patients with NAFLD are at high risk for cardiovascular morbidity and mortality. Thus, aggressive modification of CVD risk factors should be considered in all patients with NAFLD.
37. Patients with NAFLD or NASH are not at higher risk for serious liver injury from statins. Thus, statins can be used to treat dyslipidemia in patients with NAFLD and NASH. While statins may be used in patients with NASH cirrhosis, they should be avoided in patients with decompensated cirrhosis.
38. Until further safety and efficacy data become available in patients with NASH, we recommend that OCA should not be used off-label to treat NASH.
39. Patients with NASH cirrhosis have high prevalence of CVD. Thus, careful attention should be paid to identifying CVD, whether clinically apparent or occult, during the transplant evaluation process.
40. Patients with NASH cirrhosis should be screened for gastroesophageal varices according to the AASLD and ACG practice guidelines.
41. Patients with cirrhosis suspected because of NAFLD should be considered for HCC screening according to the AASLD practice guidelines.
42. Current evidence does not support routine screening and surveillance for HCC in patients with noncirrhotic NASH.
43. Current evidence does not support routinely repeating a liver biopsy in patients with NAFL or NASH, but this may be considered on a case-by-case basis
20. Weight loss generally reduces HS, achieved either by hypocaloric diet alone or in conjunction with increased physical activity. A combination of a hypocaloric diet (daily reduction by 500-1,000 kcal) and moderate-intensity exercise is likely to provide the best likelihood of sustaining weight loss over time.
21. Weight loss of at least 3%-5% of body weight appears necessary to improve steatosis, but a greater weight loss (7%-10%) is needed to improve the majority of the histopathological features of NASH, including fibrosis.
22. Exercise alone in adults with NAFLD may prevent or reduce HS, but its ability to improve other aspects of liver histology remains unknown.
23. Metformin is not recommended for treating NASH in adult patients.
24. Pioglitazone improves liver histology in patients with and without T2DM with biopsy-proven NASH. Therefore, it may be used to treat these patients. Risks and benefits should be discussed with each patient before starting therapy.
25. Until further data support its safety and efficacy, pioglitazone should not be used to treat NAFLD without biopsy-proven NASH.
26. It is premature to consider GLP-1 agonists to specifically treat liver disease in patients with NAFLD or NASH.
27. Vitamin E (rrr a-tocopherol) administered at a daily dose of 800 IU/day improves liver histology in nondiabetic adults with biopsy-proven NASH and therefore may be considered for this patient population. Risks and benefits should be discussed with each patient before starting therapy.
28. Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.
29. Foregut bariatric surgery can be considered in otherwise eligible obese individuals with NAFLD or NASH. 30. It is premature to consider foregut bariatric surgery as an established option to specifically treat NASH.
31. The type, safety, and efficacy of foregut bariatric surgery in otherwise eligible obese individuals with established cirrhosis attributed to NAFLD are not established. In otherwise eligible patients with compensated NASH or cryptogenic cirrhosis, foregut bariatric surgery may be considered on a case-by-case basis by an experienced bariatric surgery program.
32. UCDA is not recommended for the treatment of NAFLD or NASH.
33. Omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia in patients with NAFLD.
34. Patients with NAFLD should not consume heavy amounts of alcohol. 35. There are insufficient data to make recommendations with regard to nonheavy consumption of alcohol by individuals with NAFLD.
34. Patients with NAFLD should not consume heavy amounts of alcohol.
35. There are insufficient data to make recommendations with regard to nonheavy consumption of alcohol by individuals with NAFLD.
36. Patients with NAFLD are at high risk for cardiovascular morbidity and mortality. Thus, aggressive modification of CVD risk factors should be considered in all patients with NAFLD.
37. Patients with NAFLD or NASH are not at higher risk for serious liver injury from statins. Thus, statins can be used to treat dyslipidemia in patients with NAFLD and NASH. While statins may be used in patients with NASH cirrhosis, they should be avoided in patients with decompensated cirrhosis.
38. Until further safety and efficacy data become available in patients with NASH, we recommend that OCA should not be used off-label to treat NASH.
39. Patients with NASH cirrhosis have high prevalence of CVD. Thus, careful attention should be paid to identifying CVD, whether clinically apparent or occult, during the transplant evaluation process.
40. Patients with NASH cirrhosis should be screened for gastroesophageal varices according to the AASLD and ACG practice guidelines.
41. Patients with cirrhosis suspected because of NAFLD should be considered for HCC screening according to the AASLD practice guidelines.
42. Current evidence does not support routine screening and surveillance for HCC in patients with noncirrhotic NASH.
43. Current evidence does not support routinely repeating a liver biopsy in patients with NAFL or NASH, but this may be considered on a case-by-case basis
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Children and Adolescents
44. Children with fatty liver who are very young or not overweight should be tested for monogenic causes of CLD such as fatty acid oxidation defects, lysosomal storage diseases, and peroxisomal disorders, in addition to those causes considered for adults.
45. Low serum titers of autoantibodies are often present in children with NAFLD, but higher titers, particularly in association with higher serum aminotransferases, high globulins, or high total protein to albumin ratio, should prompt a liver biopsy to exclude AIH and related autoimmune disorders.
46. Because of a paucity of evidence, a formal recommendation cannot be made with regard to screening for NAFLD in children with overweight and obesity.
47. Liver biopsy in children with suspected NAFLD should be performed in those in whom the diagnosis is unclear or in whom there is possibility of multiple diagnoses, or before initiating potentially hepatotoxic medical therapy.
48. A liver biopsy to establish a diagnosis of NASH should be obtained before starting children on pharmacological therapy for NASH.
49. Pathologists interpreting pediatric liver biopsies should recognize the unique pattern frequently found in children with NAFLD to appropriately characterize pediatric NAFLD.
50. Intensive lifestyle modification improves aminotransferases and liver histology in children with NAFLD and thus should be the first line of treatment.
51. Metformin at 500 mg twice-daily offers no benefit to children with NAFLD and thus should not be prescribed to specifically treat NAFLD or NASH. The effect of metformin administered at a higher dose is not known.
52. Vitamin E (RRR a-tocopherol) 800 IU/day offers histological benefits to some children with biopsyproven NASH. Long-term safety of high-dose vitamin E in children is unknown. Vitamin E may be used to treat NASH in children, but risks and benefits should be discussed with each patient.
45. Low serum titers of autoantibodies are often present in children with NAFLD, but higher titers, particularly in association with higher serum aminotransferases, high globulins, or high total protein to albumin ratio, should prompt a liver biopsy to exclude AIH and related autoimmune disorders.
46. Because of a paucity of evidence, a formal recommendation cannot be made with regard to screening for NAFLD in children with overweight and obesity.
47. Liver biopsy in children with suspected NAFLD should be performed in those in whom the diagnosis is unclear or in whom there is possibility of multiple diagnoses, or before initiating potentially hepatotoxic medical therapy.
48. A liver biopsy to establish a diagnosis of NASH should be obtained before starting children on pharmacological therapy for NASH.
49. Pathologists interpreting pediatric liver biopsies should recognize the unique pattern frequently found in children with NAFLD to appropriately characterize pediatric NAFLD.
50. Intensive lifestyle modification improves aminotransferases and liver histology in children with NAFLD and thus should be the first line of treatment.
51. Metformin at 500 mg twice-daily offers no benefit to children with NAFLD and thus should not be prescribed to specifically treat NAFLD or NASH. The effect of metformin administered at a higher dose is not known.
52. Vitamin E (RRR a-tocopherol) 800 IU/day offers histological benefits to some children with biopsyproven NASH. Long-term safety of high-dose vitamin E in children is unknown. Vitamin E may be used to treat NASH in children, but risks and benefits should be discussed with each patient.
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Abbreviations: AASLD, American Association for the Study of Liver Diseases; ACG, American College of Gastroenterology; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; APRI, AST to platelet ratio index; AST, aspartate aminotransferase; AUROC, area under the receiver operating curve; BMI, body mass index; CI, confidence interval; CLD, chronic liver disease; CT, computed tomography; CVD, cardiovascular disease; ELF, Enhanced Liver Fibrosis; FDA, U.S. Food and Drug Administration; FIB-4, fibrosis-4 index; FLD, fatty liver disease; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDL, high-density lipoprotein; HF, hepatic fibrosis; HS, hepatic steatosis; ICD-10, International Classification of Diseases, Tenth Revision; IR, insulin resistance; LDL, low-density lipoprotein; LT, liver transplantation; METs, metabolic equivalents; MetS, metabolic syndrome; MR, magnetic resonance; MRE, MR elastography; MRI, magnetic resonance imaging; NAFL, nonalcoholic fatty liver; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic fatty liver disease; NASH CRN, NASH Clinical Research Network; NFS, NAFLD fibrosis score; NIAAA, National Institute on Alcohol Abuse and Alcoholism; OCA, obeticholic acid; PNPLA-3, patatin-like phospholipase domain-containing protein 3; PPAR, peroxisome proliferator-activated receptor gamma; RCT, randomized controlled trial; SAF, Steatosis Activity Fibrosis; SH, steatohepatitis; T2DM, type 2 diabetes mellitus; TE, transient elastography; TG, triglyceride; TONIC, treatment of nonalcoholic fatty liver disease in children; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; VCTE, vibration controlled transient elastography; WD, Wilson’s disease.
Recommendation Grading
Overview
Title
Diagnosis and Management of Non-Alcoholic Fatty Liver Disease
Authoring Organization
American Association for the Study of Liver Diseases
Publication Month/Year
September 1, 2017
Last Updated Month/Year
January 17, 2024
Supplemental Implementation Tools
Document Type
Guideline
External Publication Status
Published
Country of Publication
US
Document Objectives
This guidance provides a data-supported approach to the diagnostic, therapeutic, and preventive aspects of nonalcoholic fatty liver disease (NAFLD) care.
Target Patient Population
Patients with nonalcoholic fatty liver disease
Inclusion Criteria
Female, Male, Adolescent, Adult, Child, Older adult
Health Care Settings
Ambulatory, Childcare center, Hospital, Outpatient
Intended Users
Nurse, nurse practitioner, physician, physician assistant
Scope
Assessment and screening, Diagnosis, Prevention, Management, Treatment
Diseases/Conditions (MeSH)
D008107 - Liver Diseases, D010372 - Pediatrics, D063766 - Pediatric Obesity, D065626 - Non-alcoholic Fatty Liver Disease, D005234 - Fatty Liver
Keywords
pediatric, pediatric obesity, liver disease, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease (NAFLD)
Source Citation
HEPATOLOGY, VOL. 67, NO. 1, 2018
Supplemental Methodology Resources
Methodology
Number of Source Documents
385
Literature Search Start Date
January 1, 2010
Literature Search End Date
November 15, 2021