What is the approach for working up a patient with fatty liver disease?

Workup Approach for Fatty Liver Disease

Step 1: Identify At-Risk Patients Requiring Evaluation

Screen patients with type 2 diabetes, those with 2 or more metabolic risk factors (central obesity, hypertriglyceridemia, low HDL, hypertension, prediabetes), or those with incidental hepatic steatosis on imaging—especially if aminotransferases are elevated. 1

• Patients with only 1 or no metabolic trait have low risk of progression to cirrhosis or HCC, but risk increases stepwise with each additional metabolic condition 1
• Incidentally discovered hepatic steatosis warrants evaluation, particularly when accompanied by elevated ALT, as these patients have significantly higher risk of progression to cirrhosis or HCC 1

Step 2: Initial History and Laboratory Assessment

Alcohol and Substance Use History

• Document detailed alcohol intake using AUDIT-C questionnaire to identify unsuspected alcohol-related liver disease and binge drinking patterns 1
• Half of heavy drinkers with normal BMI and over 90% of obese heavy drinkers have hepatic steatosis; even non-heavy drinkers who binge drink have increased steatosis risk 1
• Complete smoking and illicit drug history is mandatory 1

Medication Review

• Identify drugs that cause steatosis: amiodarone, carbamazepine, sodium valproate, NSAIDs, glucocorticoids, 5-Fluorouracil, methotrexate, tamoxifen, and antiretrovirals (efavirenz) 1
• Approximately 2% of NAFLD cases are attributable to prescribed medications 1

Initial Laboratory Tests

• Order comprehensive metabolic panel (includes liver enzymes, albumin), complete blood count (for platelet count), and lipid panel 1
• These baseline labs allow calculation of simple fibrosis scores (FIB-4, NAFLD Fibrosis Score) 1

Exclude Other Liver Diseases

• Test for hepatitis C antibody with reflex HCV RNA, hepatitis B surface antigen (HBsAg), and consider ANA, AMA, anti-smooth muscle antibodies, immunoglobulins, ferritin, and alpha-1 antitrypsin 1
• This blood aetiology screen should be completed if not already done in primary care 1

Step 3: Risk Stratify Using Non-Invasive Fibrosis Testing

Calculate FIB-4 Score First

• FIB-4 < 1.3 = LOW RISK; FIB-4 1.3-2.67 = INDETERMINATE RISK; FIB-4 > 2.67 = HIGH RISK 1, 2
• For patients age 65+, use FIB-4 < 1.0 as the lower cutoff (upper cutoff remains 2.67) 1
• In patients with high pretest probability (the at-risk groups identified in Step 1), move directly to risk stratification without requiring ultrasound to diagnose steatosis 1

Confirm with Liver Stiffness Measurement (LSM)

• Perform vibration-controlled transient elastography (VCTE/FibroScan): LSM < 8 kPa = LOW RISK; LSM 8-12 kPa = INDETERMINATE RISK; LSM > 12 kPa = HIGH RISK 1, 2
• If VCTE unavailable, ultrasound is acceptable or consider referral to hepatologist for patients with indeterminate/high-risk FIB-4 1
• Other elastography techniques (bidimensional shear wave elastography, point shear wave elastography) can substitute for VCTE 1

Step 4: Management Based on Risk Stratification

LOW RISK (FIB-4 < 1.3 or LSM < 8 kPa)

• Manage in primary care with focus on lifestyle modification and cardiovascular risk reduction 1
• Target 5-10% weight loss through hypocaloric diet (500-1000 kcal deficit daily) and 150-300 minutes of moderate-intensity exercise weekly 3, 2
• Prescribe statins for dyslipidemia—they are safe in fatty liver disease and reduce HCC risk by 37% 2
• Reassess fibrosis using non-invasive tests after 3 years (extend to 5 years if metabolic factors well-controlled and weight loss goals achieved) 1, 3

INDETERMINATE RISK (FIB-4 1.3-2.67 or LSM 8-12 kPa)

• Refer to hepatology for consideration of liver biopsy to confirm NASH and stage fibrosis 3, 2
• Intensive lifestyle intervention targeting 7-10% weight loss is required 3
• For diabetes, prioritize GLP-1 receptor agonists (semaglutide, liraglutide) or pioglitazone—medications with proven liver histological benefit 1, 3
• For non-diabetic patients, consider vitamin E (800 IU daily), GLP-1 receptor agonists, or pioglitazone through shared decision-making 3
• Repeat non-invasive fibrosis testing every 1-3 years 3

HIGH RISK (FIB-4 > 2.67 or LSM > 12 kPa)

• Mandatory hepatology referral for multidisciplinary management 1, 3
• F2 fibrosis (clinically significant fibrosis) represents a critical intervention threshold—this is NOT "early" disease and requires intensive intervention comparable to higher-risk patients 3
• Strong need for structured weight loss programs, anti-obesity medications, or bariatric surgery 1, 3
• Complete alcohol abstinence is mandatory—there is no safe threshold for alcohol intake at this stage 3
• Prefer diabetes medications with NASH efficacy: GLP-1 receptor agonists first-line, pioglitazone second-line 1, 3

CIRRHOSIS (LSM > 20 kPa or clinical/imaging evidence of F4)

• Initiate HCC surveillance with ultrasound every 6 months 1, 2
• Screen for gastroesophageal varices if LSM > 20 kPa or platelet count < 150,000/mm³ 1, 2
• Pharmacotherapy for NASH cirrhosis is very limited and should be avoided until more data become available 1

Critical Pitfalls to Avoid

• Do not assume normal ALT means no disease progression—14-24% of patients with persistently normal ALT have more-than-portal fibrosis and may progress despite normal enzymes 4
• Do not neglect cardiovascular risk assessment—cardiovascular disease is the main driver of mortality in NAFLD patients before cirrhosis develops 2
• Do not fail to address all components of metabolic syndrome simultaneously—combination therapy addressing lifestyle, metabolic factors, and liver-directed pharmacotherapy yields superior outcomes compared to single interventions 3
• Ultrasound has suboptimal sensitivity for mild steatosis, so in high-risk patients, proceed directly to fibrosis risk stratification rather than waiting for imaging confirmation 1