Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives
Abstract
:1. Introduction
History, Prevalence, Nomenclature Controversies
2. Body
2.1. The Pathogenesis of NAFLD and NASH
2.2. Hepatic Fatty Acid Metabolism
2.3. Genetics and Heritability
2.4. Dietary Intake
2.5. Physical Activity
2.6. Metabolic Dysfunction and Insulin Resistance
2.7. Gut-Liver Axis
2.7.1. Case Identification for NAFLD and NASH
Surrogate Test for NAFLD Case-ID | Test Components | Sensitivity | Specificity |
---|---|---|---|
Radiology | |||
Liver Ultrasound [128,129] | 84.8% | 93.6% | |
Nb. More sensitive with increasing degrees of steatosis | – | ||
Liver Computed Tomography [130,141] | 72.7–82% | 91.3–100% | |
Nb. More sensitive with increasing degrees of steatosis | – | ||
MRI-PDFF [142] | – | 93% | 94% |
FibroScan CAP [131,132] | |||
M Probe | 79% | 74% | |
Nb. Cut-off of 294 dB/m can be used to differentiate no steatosis from any degree of steatosis [132] | – | ||
XL Probe | |||
Nb. Cut-off of 297 dB/m can be used to differentiate no steatosis from any degree of steatosis [132] | 79.8% | 73.5% | |
Composite Scores | |||
Fatty Liver Index [134,143] | BMI, waist circumference, triglycerides, γ-glutamyltransferase | ||
FLI < 30 (used to rule out NAFLD) | 81–87% | 64–65% | |
FLI ≥ 60 (used to rule in NAFLD) | 44–61% | 86–90% | |
Framingham Steatosis Index [136,144] | Age, sex, BMI, triglycerides, hypertension, diabetes mellitus, alanine aminotransferase (ALT), aspartate aminotransferase (AST) | ||
FSI ≥ 23 (used to rule in/out NAFLD) | 52–79% | 71–80% | |
Dallas Steatosis Index [137] | Age, sex, BMI, triglycerides, hypertension, diabetes mellitus, ALT, ethnicity, glucose | ||
<−1.4 risk (low risk of NAFLD) | 86% | 59% | |
≥0% risk (high risk of NAFLD) | 51% | 90% | |
Hepatic Steatosis Index [135,144] | Sex, BMI, diabetes mellitus, ALT, AST | ||
HSI < 30 (used to rule out NAFLD) | 87.8–93.1% | 25–40% | |
HSI ≥ 36 (used to rule in NAFLD) | 25–46% | 79–93.1% | |
NAFLD Liver Fat Score [144,145] | Diabetes mellitus, metabolic syndrome, ALT, AST, fasting insulin | ||
NAFLD-LFS < −0.640 (used to rule in/out NAFLD) | 48.1–86% | 71–83.4% |
2.7.2. Differential Diagnoses for Hepatic Steatosis
2.7.3. Cirrhosis and Cardiovascular Risk Assessment
Risk Assessment in NAFLD | Test Components | Sensitivity | Specificity |
---|---|---|---|
Radiology—Advanced Fibrosis | |||
Magnetic Resonance Elastography [176] | – | 83% | 89% |
LSM-VCTE [133] | |||
Nb. Different literature uses different cut-offs | |||
Cut-offs: | |||
LSM < 7.4 kPa (used to rule out advanced fibrosis) | – | 90% | 60% |
LSM ≥ 12.1 kPa (used to rule in advanced fibrosis) | 55% | 90% | |
Composite Scores—Advanced Fibrosis | |||
FIB-4 [133,166] | ALT, AST, platelets, age | ||
Nb. Different literature uses different cut-offs | |||
Cut-offs: | |||
FIB-4 < 0.88 (used to rule out advanced fibrosis) | 90% | 39% | |
FIB-4 < 1.3 (used to rule out advanced fibrosis) | 74% | 64% | |
FIB-4 > 2.31 (used to rule in advanced fibrosis) | 38% | 90% | |
FIB-4 > 2.67 (used to rule in advanced fibrosis) | 30% | 94% | |
FIB-4 (for those ≥ 65 years of age) [177] | ALT, AST, platelets, age | ||
Nb. Different literature uses different cut-offs | |||
Cut-offs: | |||
FIB-4 < 1.3 (used to rule out advanced fibrosis) | 93% | 35% | |
FIB-4 > 2.0 (used to rule in advanced fibrosis) | 77% | 70% | |
NAFLD Fibrosis Score (NFS) [133] | Age, BMI, impaired fasting glucose, T2DM, ALT, AST, platelets, albumin | ||
Nb. Different literature uses different cut-offs | |||
Cut-offs: | |||
NFS < −2.55 (used to rule out advanced fibrosis) | 90% | 36% | |
NFS > 0.28 (used to rule in advanced fibrosis) | 29% | 90% | |
Enhanced Liver Fibrosis Test [163,172] | Type III procollagen peptide, hyaluronic acid, tissue inhibitor of metalloproteinase-1 | ||
Cut-offs: | |||
ELF < 9.8 (used to rule out advanced fibrosis) | 57.5–65% | 86–88.9% | |
ELF > 11.3 (used to rule in advanced fibrosis) | 19.5–36% | 96–99.1% | |
FibroTest [178] | α2 -macroglobulin, apolipoprotein A1, haptoglobin, total bilirubin, γ-glutamyltranspeptidase (GGT) | ||
Cut-offs: | |||
FibroTest < 0.30 (used to rule out advanced fibrosis) | 92% | 71% | |
FibroTest > 0.70 (used to rule in advanced fibrosis) | 25% | 97% | |
BARD Score [162,179] | BMI, ALT, AST, T2DM | ||
Cut-off: | |||
Score ≥ 2 (used to rule in/out advanced fibrosis) | 75.2% | 61.6% | |
FORNS Index [180,181] | Age, platelets, cholesterol, GGT | ||
Nb. Data are limited for NAFLD | |||
Cut-offs: | |||
Score ≤ 4.2 (used to rule out advanced fibrosis) | 100% | 54.8% | |
Score > 6.9 (can be used to rule in fibrosis) | 42.9% | 95.7% | |
FibroScan-AST (FAST) Score [182] | VCTE-LSM, CAP, AST | ||
Nb. Composite of LSM-VCTE and biochemistry | |||
Cut-offs: | |||
FAST ≤ 0.35 (used to rule out advanced fibrosis) | 89% | 64% | |
FAST ≥ 0.65 (used to rule in advanced fibrosis) | 49% | 92% |
3. Outcomes of NAFLD and NASH
3.1. NAFLD—Liver Outcomes
3.2. NAFLD—Cardiovascular Outcomes
3.3. NAFLD—Diabetes Mellitus and Chronic Kidney Disease
3.4. NAFLD—Obstructive Sleep Apnoea
3.5. Impact of Steatosis on Other Liver Diseases
4. Treatment Options
4.1. Lifestyle Modification—Diet
4.2. Lifestyle Modification—Exercise
4.3. Lifestyle Modification—Tobacco and Alcohol
4.4. Supplementation and Pharmacotherapy
4.5. Future Directions in NAFLD
5. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Dietary Factor | Epidemiological Association | Proposed Mechanism | Micronutrient Effect on NAFLD Progression |
---|---|---|---|
Vitamins | |||
Vitamin E | Poorly defined [66] | Regulates oxidative stress, inflammation, cellular apoptosis [67] | ↓ (Sometimes used for treatment) |
Vitamin A | Low serum levels in NAFLD/NASH [68] | Regulates de novo lipogenesis and hepatic lipid metabolism [67] | ?↓ (Complex interplay [69]) |
Vitamin C | Low intake in NAFLD/NASH [70] | Regulates oxidative stress, adiponectin | ?↓ (Possibly contributes [70]) |
Vitamin D | (Probably) low in NAFLD/NASH [71,72] | Oxidative stress [72], insulin resistance [67], autophagy [67] | ↓ |
Minerals | |||
Zinc | Mixed data [73,74] | Deficiency may worsen oxidative stress [64] and insulin resistance [75] | ?↓ (Animal model [64] and preliminary human [76] data) |
Selenium | Mixed data [77] | Antioxidant, apoptosis regulation [77] | ?↓ (Reduced fibrosis [78]) |
Copper | Low hepatic and serum copper in NAFLD/NASH [79] | Oxidative stress, upregulate triglyceride synthesis [64] | ↓ |
Iron | Elevated ferritin associated with NAFLD/NASH severity [80,81] | Hepatic lipid peroxidation [82], impairment of hepatic lipid homeostasis [64] | ↑ |
Trial Name | Trial Therapies | Recruiting | ClinicalTrials.gov ID |
---|---|---|---|
An Investigator Initiated Prospective, Four Arms Randomized Comparative Study of Efficacy and Safety of Saroglitazar, Vitamin E and Life Style Modification in Patients With Nonalcoholic Fatty Liver Disease (NAFLD)/Non-alcoholic Steatohepatitis (NASH) |
| Yes | NCT04193982 |
Lanifibranor in Patients With Type 2 Diabetes & Nonalcoholic Fatty Liver Disease |
| Yes | NCT03459079 |
A Phase 3 Study to Evaluate the Safety and Biomarkers of Resmetirom (MGL-3196) in Non Alcoholic Fatty Liver Disease (NAFLD) Patients (MAESTRO-NAFLD1) |
| No | NCT04197479 |
A Phase 3 Study to Evaluate Safety and Biomarkers of Resmetirom (MGL-3196) in Patients With Non-alcoholic Fatty Liver Disease (NAFLD), MAESTRO-NAFLD-Open-Label-Extension (MAESTRO-NAFLD-OLE) |
| Yes | NCT04951219 |
Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment (REGENERATE) |
| No | NCT02548351 |
Study Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (REVERSE) |
| No | NCT03439254 |
Comparative Study Between Obeticholic Acid Versus Vitamin E in Patients With Non-alcoholic Steatohepatitis |
| No | NCT05573204 |
Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH) (ESSENCE) |
| Yes | NCT04822181 |
Study of Semaglutide for Non-Alcoholic Fatty Liver Disease (NAFLD), a Metabolic Syndrome With Insulin Resistance, Increased Hepatic Lipids, and Increased Cardiovascular Disease Risk (The SLIM LIVER Study) |
| Yes | NCT04216589 |
Researching an Effect of GLP-1 Agonist on Liver STeatosis (REALIST) (REALIST) |
| No | NCT03648554 |
A Study of Tirzepatide (LY3298176) in Participants With Nonalcoholic Steatohepatitis (NASH) (SYNERGY-NASH) |
| Yes | NCT04166773 |
Dapagliflozin Efficacy and Action in NASH (DEAN) |
| Yes | NCT03723252 |
Dapagliflozin in Type 2 Diabetes Mellitus Patients (T2DM) With Nonalcoholic Fatty Liver Disease (NAFLD) |
| Yes | NCT05459701 |
A Single Center, Randomized, Open Label, Parallel Group, Phase 3 Study to Evaluate the Efficacy of Dapagliflozin in Subjects With Nonalcoholic Fatty Liver Disease |
| Yes | NCT05308160 |
Effect of Empagliflozin on Liver Fat in Non-diabetic Patients |
| No | NCT04642261 |
Efficacy and Safety of Dapagliflozin in Patients With Non-alcoholic Steatohepatitis |
| Yes | NCT05254626 |
Canagliflozin on Liver Inflammation Damage in Type 2 Diabetes Patients With Nonalcoholic Fatty Liver Disease |
| No | NCT05422092 |
Effect of Oral Anti-diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non-alcoholic Fatty Liver |
| Yes | NCT04976283 |
Low-Dose Pioglitazone in Patients With NASH (AIM 2) |
| Yes | NCT04501406 |
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Clayton-Chubb, D.; Kemp, W.; Majeed, A.; Lubel, J.S.; Hodge, A.; Roberts, S.K. Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives. Nutrients 2023, 15, 687. https://doi.org/10.3390/nu15030687
Clayton-Chubb D, Kemp W, Majeed A, Lubel JS, Hodge A, Roberts SK. Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives. Nutrients. 2023; 15(3):687. https://doi.org/10.3390/nu15030687
Chicago/Turabian StyleClayton-Chubb, Daniel, William Kemp, Ammar Majeed, John S. Lubel, Alex Hodge, and Stuart K. Roberts. 2023. "Understanding NAFLD: From Case Identification to Interventions, Outcomes, and Future Perspectives" Nutrients 15, no. 3: 687. https://doi.org/10.3390/nu15030687