Stages of Fatty Liver Disease
Fatty liver disease progresses through distinct histological stages: simple steatosis (NAFL), nonalcoholic steatohepatitis (NASH), advanced fibrosis (stages 3-4), and cirrhosis, with fibrosis stage being the strongest predictor of liver-related outcomes including mortality. 1
Primary Disease Categories
The spectrum of fatty liver disease is divided into two main histological categories based on the presence or absence of hepatocellular injury 1:
Nonalcoholic Fatty Liver (NAFL): Defined as ≥5% hepatic steatosis without evidence of hepatocellular injury (no hepatocyte ballooning) or fibrosis. The risk of progression to cirrhosis and liver failure is considered minimal. 1, 2
Nonalcoholic Steatohepatitis (NASH): Defined as ≥5% hepatic steatosis with inflammation and hepatocyte injury (ballooning), with or without fibrosis. This stage can progress to cirrhosis, liver failure, and hepatocellular carcinoma. 1, 2
Fibrosis Staging System
Fibrosis stage represents the most critical prognostic factor and is scored separately from inflammatory activity 1:
Stage 0: No fibrosis 1
Stage 1: Zone 3 (perivenular) perisinusoidal or periportal fibrosis 1
Stage 2: Both zone 3 and periportal fibrosis 1
Stage 3: Bridging fibrosis with nodularity (advanced fibrosis) 1, 2
Advanced Disease Stages
Advanced fibrosis specifically refers to stages 3 or 4 (bridging fibrosis or cirrhosis), which represents the threshold for significantly increased liver-related mortality 1, 2:
NASH Cirrhosis: Presence of cirrhosis with current or previous histological evidence of steatosis or steatohepatitis 1, 2
Cryptogenic Cirrhosis: Cirrhosis with no obvious etiology, but patients are heavily enriched with metabolic risk factors such as obesity and metabolic syndrome, suggesting burned-out NASH 1
Clinical Significance of Staging
The distinction between stages has profound implications for prognosis and management 1, 2:
Early Stage (F0-1): Minimal risk of progression to cirrhosis, primarily managed with lifestyle modifications 2
Significant Fibrosis (F≥2): Increased risk of progression requiring closer monitoring 2
Advanced Fibrosis (F3-4): Independent risk factor for both liver-related and non-liver-related mortality, requiring surveillance for hepatocellular carcinoma and varices 1, 2
Histological Scoring Systems
Two validated semiquantitative systems assess disease activity separately from fibrosis 1:
NAFLD Activity Score (NAS): Unweighted composite of steatosis, lobular inflammation, and ballooning scores, developed for clinical trials to measure histological changes. Fibrosis is scored separately. 1
SAF Score (Steatosis Activity Fibrosis): Semiquantitative score consisting of steatosis amount, activity (lobular inflammation plus ballooning), and fibrosis, used for both diagnosis and clinical trials 1
Diagnostic Categories Used in Research
The NASH Clinical Research Network utilizes specific diagnostic categories for standardization 1:
- Not NAFLD: <5% steatosis by definition 1
- NAFL, not NASH: ≥5% steatosis with or without lobular and portal inflammation 1
- Borderline steatohepatitis: Most but not all criteria for steatohepatitis present, with accentuation in zone 3 or zone 1 1
- Definite steatohepatitis: All criteria present including steatosis, inflammation, and ballooning 1
Critical Pitfalls to Avoid
Do not assume normal liver enzymes exclude advanced disease—clinically significant fibrosis frequently occurs with aminotransferases below 40 units/L 3. Patients with type 2 diabetes have over 70% prevalence of NAFLD and 12-20% already have clinically significant fibrosis at diagnosis, requiring FIB-4 screening regardless of enzyme levels 3.
Sampling error remains a significant concern in liver biopsy—use large needle size (16 gauge, 2-3 cm length) and recognize that regional variability can affect diagnosis 1. A diagnosis of definite NASH is more common with two cores and biopsies ≥25 mm 1.