NAFLD Fibrosis Score

NAFLD (Non-Alcoholic Fatty Liver Disease) is an umbrella term for fat accumulation in the liver not explained by alcohol use or secondary causes. NASH (Non-Alcoholic Steatohepatitis) is the progressive subtype characterised by hepatic steatosis plus inflammation and ballooning injury, often with fibrosis. In 2020, an international expert panel proposed renaming NAFLD to MAFLD (Metabolic-Associated Fatty Liver Disease) to better reflect its metabolic origins. In 2023, Delphi consensus renamed it again to MASLD (Metabolic Dysfunction-Associated Steatotic Liver Disease) with MASH for its inflammatory subtype. These name changes have not yet been universally adopted; NAFLD and NASH remain in widespread clinical and research use.

In early NAFLD and NASH, ALT is typically higher than AST, reflecting active hepatocellular inflammation predominantly involving ALT-rich liver cells. As fibrosis advances and liver cell mass decreases, ALT production falls disproportionately relative to AST. Additionally, ALT is produced exclusively in hepatocytes, while AST is also produced in muscle, heart, and red blood cells. In advanced cirrhosis, the falling ALT (fewer functioning hepatocytes) and rising AST (often combined with mitochondrial injury) causes the ratio to exceed 1.0. An AST/ALT ratio >2 strongly suggests alcoholic hepatitis or advanced cirrhosis.

Non-invasive fibrosis assessment tools include: FibroScan (transient elastography) — the most validated, measures liver stiffness in kPa; >8 kPa = significant fibrosis, >12 kPa = likely cirrhosis. ELF (Enhanced Liver Fibrosis) panel — measures hyaluronic acid, PIIINP, and TIMP-1; FIB-4 Index — age × AST / (platelets × √ALT), cut-offs <1.3 (low risk) and >2.67 (high risk); APRI score — AST / (platelet count); MRI elastography — gold standard for non-invasive assessment but expensive and limited availability.

FIB-4 = Age(years) × AST(U/L) / (Platelet count(×10^9/L) × √ALT(U/L)). Cut-offs: <1.3 = low risk (F0–F1); 1.3–2.67 = indeterminate; >2.67 = high risk (F3–F4). FIB-4 is simpler than NFS (4 variables vs 6) and has similar discriminatory performance. Current NICE and EASL guidelines recommend FIB-4 as the initial screening tool for liver fibrosis in primary care and diabetes clinics due to its simplicity. NFS provides slightly more information in the intermediate range. Both tools should be followed by FibroScan in the indeterminate zone.

EASL, NICE, and AASLD guidelines recommend screening for NAFLD/MAFLD fibrosis in patients with: type 2 diabetes, metabolic syndrome (obesity + dyslipidaemia + hypertension ± insulin resistance), incidentally detected elevated liver enzymes, unexplained thrombocytopaenia, incidental hepatic steatosis on imaging, and obesity (BMI >30). In diabetic patients, a FIB-4 <1.3 reliably excludes advanced fibrosis; those with FIB-4 ≥1.3 should proceed to FibroScan. Universal NAFLD screening in diabetes clinics with FIB-4 is cost-effective and recommended by the 2023 EASL-EASD-EASO Clinical Practice Guidelines.

Lifestyle modification (10% body weight loss significantly reduces fibrosis, and >15% can lead to complete NASH resolution in a proportion of patients) remains the cornerstone treatment. FDA-approved pharmacological therapies: resmetirom (Rezdiffra, a thyroid hormone receptor-β agonist) was approved by the FDA in March 2024 for MASH with liver fibrosis (F2–F3) — the first drug specifically approved for NASH/MASH. GLP-1 receptor agonists (semaglutide) have shown significant fibrosis improvement in trials. FXR agonists (obeticholic acid) and PPAR agonists (lanifibranor) are in late-stage trials. Bariatric surgery achieves the most profound and sustained liver histological improvement.

Patients with NAFLD-related cirrhosis have an annual HCC incidence of 2–4%, comparable to other causes of cirrhosis. Notably, a significant proportion of NAFLD-related HCC (up to 20–30%) develops in non-cirrhotic livers with advanced fibrosis (F3) — a pattern less common in viral hepatitis. Risk factors for NAFLD-HCC include: cirrhosis (strongest), male sex, age >60, diabetes, obesity, alcohol use (even moderate), and genetic factors (PNPLA3 I148M variant). Six-monthly liver ultrasound + AFP surveillance is recommended for all NAFLD cirrhosis patients.

Yes — the NFS can be serially calculated to track fibrosis progression or regression over time. A decrease in NFS associated with weight loss, diabetes remission, or pharmacological treatment reflects improved fibrosis status. However, NFS has significant variability and the indeterminate zone limits its precision for detecting small changes. FibroScan (liver stiffness measurement) is more sensitive for detecting short-term changes and is the preferred tool for treatment response monitoring in clinical trials.