What does a diagnosis of fatty liver disease in a patient with a normal Body Mass Index (BMI) imply and where should they be referred for further evaluation and management?

Fatty Liver in Normal BMI: What It Means and Where to Refer

A fatty liver in a patient with normal BMI represents "lean NAFLD," a distinct entity affecting 7-20% of NAFLD patients that requires the same systematic risk stratification as obese NAFLD, with referral decisions based primarily on fibrosis risk scores rather than BMI status. 1

Definition and Diagnostic Criteria

Lean NAFLD is diagnosed when hepatic steatosis occurs in patients with BMI <25 kg/m² (non-Asian) or <23 kg/m² (Asian). 1 This condition affects approximately 10.8% of lean individuals and represents a clinically important subset that differs from typical NAFLD in several ways. 1

Key Clinical Characteristics

Lean NAFLD patients typically present with:

• Older age and more frequently male gender compared to the general lean population 1
• Fewer metabolic syndrome components than obese NAFLD patients, but similar risk for advanced fibrosis 1
• Higher transaminase levels (ALT/AST) compared to overweight/obese NAFLD patients 2
• Possible genetic variants (such as TM6SF2 rs58542926) that protect against obesity but not hepatic fat accumulation 1

Initial Evaluation and Risk Stratification

Mandatory First Step: Calculate FIB-4 Score

Every patient with fatty liver and normal BMI must have a FIB-4 score calculated immediately, even if liver enzymes are normal. 3, 4 The FIB-4 formula is: (Age × AST) / (Platelet count × √ALT). 5

This is the critical decision point that determines referral versus primary care management. 3

Metabolic and Cardiovascular Assessment

All lean NAFLD patients require systematic evaluation for type 2 diabetes, dyslipidemia, and hypertension. 1 Despite having fewer metabolic risk factors than obese NAFLD patients, lean individuals with NAFLD still demonstrate:

• Similar or higher cardiovascular event rates compared to overweight/obese NAFLD patients 1
• Alterations in bile salt and cholesterol metabolism 1
• Increased prevalence of cardiometabolic risk factors compared to lean individuals without NAFLD 1

Referral Decision Algorithm

LOW RISK: Manage in Primary Care

Patients with FIB-4 <1.3 (age <65) or <2.0 (age ≥65) can be managed in primary care without specialist referral. 3, 4, 5

These patients have:

• Very low incidence of liver-related events (2.6 per 1000 patient-years) 3, 4
• Focus on lifestyle modifications and cardiovascular risk reduction 3, 4
• Repeat FIB-4 surveillance every 2-3 years 3, 5

INDETERMINATE RISK: Consider Referral for Second-Tier Testing

Patients with FIB-4 between 1.3-2.67 require additional non-invasive testing, which may necessitate hepatology referral. 5

Second-line options include:

• Enhanced Liver Fibrosis (ELF) score (refer if >9.5) 3, 4
• Liver stiffness measurement by elastography (refer if ≥12.0 kPa) 3, 4, 5
• Magnetic resonance elastography if available 4

HIGH RISK: Immediate Hepatology/Gastroenterology Referral

Refer immediately to a gastroenterologist or hepatologist if any of the following are present: 3, 4, 5

• FIB-4 score >2.67 5
• Liver stiffness ≥12.0 kPa on elastography 3, 4
• ELF score >9.5 3, 4
• Thrombocytopenia, AST > ALT ratio, or hypoalbuminemia 5
• Clinical features suggesting cirrhosis 1, 5
• Persistently elevated liver enzymes >6 months without clear NAFLD risk factors 3, 4

Critical Clinical Implications

Prognosis and Disease Progression

Lean NAFLD patients may have lower prevalence of advanced fibrosis at baseline compared to obese NAFLD, but those who develop advanced fibrosis face similar or potentially higher liver-related mortality risk. 1 The data shows:

• Advanced fibrosis increases liver-related mortality 16.7-fold for F3 and 42.3-fold for F4/cirrhosis 3
• In one longitudinal study, lean NAFLD patients had higher risk of liver-related death than obese NAFLD patients, though baseline fibrosis was more advanced 1
• Overall mortality may be higher in lean NAFLD compared to obese NAFLD (HR 1.96), possibly due to unrecognized comorbidities 6

Hepatocellular Carcinoma Surveillance

Patients with lean NAFLD and clinical markers of cirrhosis require HCC surveillance with abdominal ultrasound ± AFP every 6 months. 1

Common Pitfalls to Avoid

Do Not Rely on Normal Liver Enzymes

Normal transaminases do not exclude advanced fibrosis or cirrhosis in lean NAFLD. 4 Many clinicians incorrectly over-rely on liver enzymes rather than metabolic risk factors and fibrosis scores. 4

Do Not Assume Lean Equals Low Risk

Approximately 12% of NAFLD patients presenting to tertiary centers have normal BMI, and they retain similar risk for advanced fibrosis as obese patients. 1, 2 The absence of obesity does not eliminate the need for systematic risk stratification. 1

Exclude Significant Alcohol Consumption

Before diagnosing lean NAFLD, confirm alcohol intake is <14 drinks/week for women or <21 drinks/week for men. 4

Age Limitations of FIB-4

FIB-4 and similar non-invasive scores have not been validated in patients under 35 years and should be interpreted with caution in young patients. 3, 4

Primary Care Management for Low-Risk Patients

When managing lean NAFLD patients who do not require referral:

• Implement lifestyle modifications including Mediterranean diet and regular exercise 5
• Treat cardiovascular risk factors aggressively (diabetes, dyslipidemia, hypertension) 1, 5
• Repeat FIB-4 and liver panel every 2-3 years 3, 5
• Perform annual cardiovascular risk assessment 5
• Consider modest weight loss even in normal BMI patients, as weight maintenance throughout adulthood is critical for NAFLD prevention 7