What is the appropriate workup and management for a patient with suspected fatty liver disease?

Fatty Liver Disease Workup

All patients with suspected fatty liver disease require immediate FIB-4 score calculation to stratify fibrosis risk, comprehensive metabolic and serological screening to exclude alternative diagnoses, and mandatory alcohol assessment with complete abstinence if any advanced fibrosis is present. 1, 2, 3

Initial Risk Identification

Identify high-risk patients requiring workup:

• Type 2 diabetes (70% have NAFLD, 12-20% have significant fibrosis) 4, 3
• Two or more metabolic risk factors (central obesity, hypertriglyceridemia, low HDL, hypertension, prediabetes) 1, 3
• Incidental hepatic steatosis on any imaging modality 1, 3
• Elevated aminotransferases 1, 3

Alcohol Assessment (Critical First Step)

Complete and permanent alcohol abstinence is mandatory - even low-level consumption (9-20 g daily) in patients with metabolic risk factors doubles the risk of adverse liver outcomes. 2

• Document alcohol intake quantitatively using AUDIT-C questionnaire 1, 2
• AUDIT-C scores >19 indicate alcohol dependency requiring addiction services referral 2
• Screen for binge drinking patterns, which increase steatosis risk even in non-heavy drinkers 1
• All alcohol must stop completely if advanced fibrosis or cirrhosis is present 2

Laboratory and Serological Workup

Initial comprehensive panel:

• Complete blood count (assess platelets for FIB-4 calculation) 1
• Liver function tests: AST, ALT, GGT, alkaline phosphatase, bilirubin, albumin 1
• Fasting glucose, HbA1c, and 75g oral glucose tolerance test (OGTT) in high-risk groups 1
• Lipid panel: total cholesterol, HDL, triglycerides 1
• Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody with reflex RNA testing 1

Extended serological screen to exclude alternative diagnoses:

• Autoimmune markers: ANA, anti-smooth muscle antibody, anti-mitochondrial antibody, immunoglobulins 1
• Iron studies: ferritin and transferrin saturation (if elevated with C282Y HFE mutation, consider liver biopsy) 1
• Alpha-1 antitrypsin level 1
• Ceruloplasmin (Wilson disease screening if age <40) 1
• TSH (thyroid disease) 1

Pitfall: High serum titers of autoantibodies (ANA >1:160 or anti-smooth muscle >1:40) occur in 21% of NAFLD patients but are generally benign epiphenomena; however, if ALT >5× ULN with high globulins, workup for autoimmune hepatitis is required. 1

Medication and Drug History

Document all medications that may cause or worsen steatosis:

• Antiarrhythmics (amiodarone) 1
• Anticonvulsants (carbamazepine, valproate) 1
• Glucocorticoids 1
• Methotrexate (document cumulative dose - accelerates fibrosis progression) 1
• Tamoxifen 1
• Antiretrovirals (efavirenz) 1
• Consider discontinuation of hepatotoxic medications after risk assessment 1

Fibrosis Risk Stratification (Most Critical Step)

Calculate FIB-4 score immediately using: (Age × AST) / (Platelet count × √ALT) 1, 2, 4, 3

FIB-4 <1.3 (age <65) or <2.0 (age ≥65): LOW RISK

• Manage in primary care with lifestyle interventions 1, 2, 4
• Only 2.6 liver-related events per 1,000 patient-years 4
• Repeat FIB-4 and liver panel every 2-3 years 1, 4
• Focus on cardiovascular risk reduction 4, 3

FIB-4 1.3-2.67: INDETERMINATE RISK

• Requires second-tier testing with vibration-controlled transient elastography (VCTE/FibroScan) or Enhanced Liver Fibrosis (ELF) score 1, 2, 4
• If VCTE unavailable, ultrasound acceptable with consideration for hepatology referral 1

Liver stiffness measurement interpretation (VCTE):

• LSM <8 kPa: Low risk - manage in primary care, repeat in 2-3 years 1
• LSM 8-12 kPa: Indeterminate - hepatology referral for monitoring, re-evaluate in 2-3 years 1
• LSM >12 kPa: High risk - hepatology referral for MR elastography or liver biopsy 1
• LSM ≥20 kPa: Highly suggestive of cirrhosis - requires variceal screening 4

FIB-4 >2.67: HIGH RISK

• Mandatory hepatology referral for further evaluation including possible liver biopsy 1, 2, 4

Additional high-risk features requiring immediate hepatology referral regardless of FIB-4:

• Thrombocytopenia (platelets <150,000/mm³) 4
• AST > ALT ratio 4
• Hypoalbuminemia 4
• ALT persistently >2× ULN after 3 months despite addressing modifiable factors 2
• ALT >8× ULN (urgent referral) 2
• Evidence of synthetic dysfunction or hepatic decompensation 2
• Clinical signs of cirrhosis or portal hypertension 2

Metabolic Comorbidity Assessment

Screen for associated conditions:

• Type 2 diabetes screening mandatory in all NAFLD patients using fasting glucose or HbA1c 1
• 75g OGTT in high-risk groups (HbA1c 5.7-6.4%, impaired fasting glucose) 1
• Assess for polycystic ovary syndrome 1
• Screen for obstructive sleep apnea 1
• Evaluate for hypothyroidism 1
• Comprehensive cardiovascular disease risk assessment 1

Critical point: In patients with type 2 diabetes, look for NAFLD irrespective of liver enzyme levels, as T2DM patients are at high risk of disease progression even with normal transaminases. 1

Imaging

Abdominal ultrasonography:

• First-line imaging technique to diagnose hepatic steatosis 1, 3
• If steatosis present on ultrasound with indeterminate or high-risk FIB-4, consider hepatology referral 1

Advanced imaging (typically in specialist setting):

• MR elastography for fibrosis assessment in indeterminate cases 1
• MR spectroscopy or proton density fat fraction for quantifying hepatic fat (primarily for clinical trials) 1

Diabetes-Specific Management Considerations

For patients with type 2 diabetes and suspected NAFLD:

• Preferentially use GLP-1 receptor agonists (improve liver histology, promote weight loss, cardiovascular and kidney benefits) 2
• Consider pioglitazone (improves steatohepatitis and fibrosis in biopsy-proven NASH, but monitor for weight gain, edema, bone fracture risk in women) 2
• Insulin treatment does not worsen NAFLD despite increasing body fat 1

Follow-Up Surveillance

Low-risk patients (FIB-4 <1.3):

• Repeat non-invasive fibrosis testing every 2-3 years 1, 4, 3
• Annual cardiovascular risk assessment 4
• Annual diabetes screening with HbA1c 4

Indeterminate-risk patients:

• Re-evaluate fibrosis risk every 1-3 years 3

Cirrhosis patients:

• HCC surveillance with ultrasound every 6 months 3
• Variceal screening if LSM >20 kPa or platelets <150,000/mm³ 3