NASH vs MASLD: Understanding the Nomenclature and Clinical Approach
Terminology Clarification
NASH (Non-Alcoholic Steatohepatitis) and MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease, formerly MAFLD) represent overlapping but not identical diagnostic frameworks for metabolic fatty liver disease. The key distinction is that NASH is a histologic diagnosis requiring liver biopsy, while MASLD is a clinical diagnosis based on the presence of hepatic steatosis plus metabolic dysfunction 1, 2.
The Nomenclature Evolution
- NAFLD (Non-Alcoholic Fatty Liver Disease) was the traditional umbrella term encompassing both simple steatosis (NAFL) and steatohepatitis (NASH), defined by excluding significant alcohol consumption (≥30 g/day for men, ≥20 g/day for women) 1
- MAFLD/MASLD represents a newer diagnostic framework emphasizing the metabolic drivers of disease rather than alcohol exclusion 2, 3
- Studies show 97.2% of biopsy-proven NAFLD patients meet MAFLD criteria, with excellent concordance (kappa coefficient 0.83-0.94) 4, 5
The practical reality: these terms describe essentially the same patient population with nearly identical long-term outcomes, including all-cause and liver-related mortality 4.
Diagnostic Approach in High-Risk Adults
Step 1: Identify High-Risk Patients Requiring Evaluation
Screen the following populations 6, 7:
- All adults with type 2 diabetes or prediabetes, particularly those with obesity or cardiovascular disease 7
- Overweight/obese patients (BMI >25 kg/m² for non-Asian, >23 kg/m² for Asian populations) 6
- Patients with metabolic syndrome components: waist circumference ≥94/80 cm (men/women), blood pressure ≥130/85 mmHg, fasting glucose ≥100 mg/dL, triglycerides >150 mg/dL, HDL <40/50 mg/dL 1
- Any patient with incidental hepatic steatosis on imaging 6, 7
- Patients over age 40 with type 2 diabetes, even if lean 7
Step 2: Initial Laboratory and Clinical Assessment
Obtain the following baseline tests 6:
- Comprehensive metabolic panel including ALT, AST, alkaline phosphatase, GGT, albumin, bilirubin 6
- Complete blood count with platelets 6
- Fasting glucose or hemoglobin A1c 6
- Fasting lipid profile 6
- INR 6
Critical pitfall: Do not exclude fatty liver disease based on normal ALT alone—50% of NAFLD patients have normal transaminases 6. Similarly, AST:ALT ratio >1 does not exclude the diagnosis, as this ratio reverses in advanced disease 6.
Step 3: Exclude Competing Liver Diseases
Rule out 1:
- Viral hepatitis (hepatitis B and C serology)
- Hemochromatosis (iron saturation, ferritin, HFE mutation testing if indicated) 1
- Autoimmune hepatitis (if very high aminotransferases, high globulin, or high autoantibody titers) 1
- Medication-induced steatosis (tamoxifen, amiodarone, methotrexate, corticosteroids) 2
- Wilson disease (in younger patients)
- Alpha-1 antitrypsin deficiency
Risk Stratification for Advanced Fibrosis
Primary Screening Tool: FIB-4 Index
Calculate FIB-4 at diagnosis for every patient using age, ALT, AST, and platelet count 6, 7:
FIB-4 = (Age × AST) / (Platelet count × √ALT)
- FIB-4 <1.3 (or <2.0 if age >65): Low risk for advanced fibrosis—repeat testing in 2-3 years, as only 12% show significant progression over 3 years 6
- FIB-4 1.3-2.67: Indeterminate risk—proceed to second-tier testing 6, 7
- FIB-4 >2.67: High risk for advanced fibrosis—proceed to second-tier testing and consider hepatology referral 6, 7
Second-Tier Testing for Indeterminate or High FIB-4
For patients with FIB-4 1.3-2.67 or >2.67, proceed with one of the following 6:
Enhanced Liver Fibrosis (ELF) Panel 6:
Vibration-Controlled Transient Elastography (FibroScan) 6:
MR Elastography: Most accurate noninvasive method but expensive; primarily used in clinical trials 6
When to Perform Liver Biopsy
Consider liver biopsy in the following scenarios 1, 6:
- Suspected NASH with advanced fibrosis based on noninvasive testing 6
- Indeterminate noninvasive test results that are discordant with clinical suspicion 6
- When concurrent chronic liver disease cannot be excluded without histology 1, 6
- Patients with metabolic syndrome and persistently abnormal liver biochemistries who would benefit diagnostically and prognostically 1
Histologic Definitions
NAFL (simple steatosis): Bland steatosis with minimal or no inflammation 1
NASH: Macrovesicular steatosis + hepatocyte ballooning + mixed lobular inflammation ± zone-3 perisinusoidal fibrosis 1
Important nuance: Both NAFL and NASH exist on a disease continuum rather than as separate entities, with fibrosis progression rates of 14 years (stage 0→1) for NAFL versus 7 years for NASH 1. Even patients with bland steatosis can progress to NASH, especially with metabolic risk factors 1.
Treatment Approach
Lifestyle Modification (First-Line for All Patients)
Target 7-10% weight loss through diet and exercise for improving histologic outcomes including fibrosis 7:
- Weight loss improves steatosis, inflammation, and fibrosis 7
- Avoid fructose and sugar-sweetened beverages 7
- Regular physical activity provides benefit independent of weight loss 7
Aggressive Metabolic Comorbidity Management
NAFLD/MASLD patients have increased mortality from cardiovascular disease, extrahepatic cancer, and liver-related complications—manage all metabolic risk factors aggressively 7:
- Optimize glycemic control in diabetes 7
- Treat dyslipidemia per cardiovascular risk guidelines 7
- Manage hypertension—hypertension doubles the rate of fibrosis progression 7
- Address cardiovascular disease risk comprehensively 7
Pharmacologic Therapy
Currently, no FDA-approved medications specifically for NAFLD/NASH exist, though several candidates are in clinical trials 2. Treatment should focus on:
- Insulin sensitizers for patients with insulin resistance 3
- Antioxidants (vitamin E, ursodeoxycholic acid) have shown improvement in liver histology and enzymes 3
Key Clinical Pearls
The shift from NAFLD to MAFLD/MASLD nomenclature emphasizes metabolic dysfunction as the primary driver rather than alcohol exclusion 2, 3. However, this represents a conceptual reframing rather than a change in clinical management, as the patient populations overlap by >97% 4, 5.
Insulin resistance (HOMA-IR ≥2.5) is the most significant factor for both NASH development (OR 4.1) and liver fibrosis (OR 2.9) 5. This underscores why metabolic optimization is central to treatment.
The presence of three or more metabolic components significantly increases the proportion of NASH, while increasing metabolic components parallels increasing liver fibrosis 5.