Diagnosis and Assessment of Fatty Liver Disease

Initial Laboratory Evaluation

The American Association for the Study of Liver Diseases recommends initial screening with liver transaminases (ALT and AST), followed by a comprehensive metabolic panel, complete blood count, and exclusion of other liver diseases through specific serologic testing 1, 2
ALT and AST are the most readily available and commonly used tests, with non-alcoholic fatty liver disease (NAFLD) typically showing mildly elevated levels (AST and/or ALT) with an AST:ALT ratio <1 in early disease 1, 2
The AST:ALT ratio may reverse to >1 in advanced fibrosis or cirrhosis, but this does not exclude NAFLD 1, 2
Critical caveat: 50% of patients with NAFLD have completely normal liver chemistries, and up to 80% of non-alcoholic steatohepatitis (NASH) patients may still be identified through elevated transaminases alone 1, 2
Normal ALT does not exclude NASH - this is a common pitfall that leads to missed diagnoses 1, 2
Alkaline phosphatase and gamma-glutamyltransferase (GGT) may be mildly elevated, but bilirubin typically remains normal unless advanced disease is present 1, 2
Complete blood count to assess for thrombocytopenia (suggests portal hypertension) 1, 2
International normalized ratio (INR) and albumin - abnormalities indicate cirrhosis or advanced disease 1, 2
Fasting glucose or hemoglobin A1c to assess for diabetes 1, 2
Fasting lipid profile including triglycerides and HDL 1, 2
Creatinine for baseline renal function 1, 2

Hepatitis B surface antigen and hepatitis C antibody to exclude viral hepatitis 1, 2, 3
Serum iron, total iron-binding capacity, and ferritin to exclude hemochromatosis 1, 3
Autoimmune markers (antinuclear antibody, smooth muscle antibody) if high aminotransferases (>5x upper limit normal) or elevated globulins suggest autoimmune hepatitis 3, 4
Alpha-1 antitrypsin level for suspected deficiency 1, 3
Ceruloplasmin if Wilson disease is suspected (particularly in younger patients) 1, 3
TSH to exclude thyroid disorders as an extrahepatic cause 3, 4

FIB-4 index (calculated from age, platelet count, AST, ALT) is the most validated initial test with a cutoff <1.3 offering 77.8% sensitivity and 71.2% specificity to exclude advanced fibrosis 5
NAFLD Fibrosis Score (NFS) uses 6 parameters (age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio) with a cutoff of -1.455 showing 72.9% sensitivity and 73.8% specificity 3, 4, 5
Enhanced Liver Fibrosis (ELF) panel (hyaluronic acid, tissue inhibitor of metalloproteinase 1, N-terminal procollagen III-peptide) has AUROC 0.90 with 80% sensitivity and 90% specificity for advanced fibrosis 3, 4
Transient elastography (FibroScan) measures liver stiffness and is FDA-approved for clinical use 3, 4

Initial screening in high-risk patients (metabolic syndrome, diabetes): Obtain ALT and AST 1, 2
If transaminases elevated or high clinical suspicion: Order comprehensive panel including full liver chemistry panel, CBC with platelets, INR, albumin, creatinine, metabolic assessment, and viral hepatitis serologies 1, 2, 3
Calculate FIB-4 as first-line fibrosis assessment 5
Consider liver biopsy if indeterminate noninvasive test results, suspicion of competing liver disease, risk factors for NASH with advanced fibrosis, or findings suggesting cirrhosis 1, 3, 4, 6

Do not rely on normal ALT to exclude NAFLD or NASH - half of NAFLD patients have normal transaminases 1, 2
Do not assume AST:ALT >1 excludes NAFLD - this ratio reverses in advanced disease 1, 2
Do not skip fibrosis assessment - fibrosis stage, not steatosis or inflammation, determines mortality risk 3, 5
Do not forget to exclude alcohol use - obtain detailed alcohol history as AST:ALT >2 suggests alcoholic liver disease rather than NAFLD 7, 8