How does lean NAFLD/NASH differ prognostically from non-lean NAFLD/NASH?

Prognostic Differences Between Lean and Non-Lean MASLD/MASH

Lean MASLD/MASH patients face paradoxically higher all-cause mortality (64% increased risk) and cardiovascular mortality (40% increased risk) compared to non-lean patients, despite having lower baseline fibrosis stages and fewer metabolic comorbidities. 1

Mortality Outcomes

Overall Survival:

• Lean MASLD patients demonstrate equal or higher overall mortality rates compared to non-lean counterparts, despite appearing metabolically healthier at baseline 2
• In compensated cirrhosis specifically, lean patients have a 64% increased risk of all-cause mortality (aHR = 1.64) 1
• This mortality paradox persists even though lean patients have lower prevalence of diabetes (46.7% vs 73.9%) at baseline 1

Cardiovascular Mortality:

• Lean MASLD patients experience 40% higher cardiovascular-related mortality (aHR = 1.40) despite similar rates of major adverse cardiovascular events (MACE) 1
• This represents a critical clinical paradox: lean patients have better baseline cardiometabolic profiles but worse cardiovascular death outcomes 1

Liver-Related Outcomes

Hepatic Decompensation:

• Lean MASLD patients have 33% lower risk of hepatic decompensation (aSHR = 0.67) compared to non-lean patients 1
• Cross-sectional studies consistently show lean patients have lower prevalence of advanced fibrosis and cirrhosis at baseline 3
• Despite lower baseline fibrosis, nearly 5% of lean NAFLD patients experienced liver-related events over 7.5 years of follow-up 3

Disease Progression:

• A Swedish registry study with nearly 20 years of follow-up showed lean NAFLD patients had lower fibrosis stages at baseline but higher risk for developing severe liver disease compared to non-lean patients 3
• In a small longitudinal study (median 8.4 years), lean participants had higher risk of liver-related death, though this cohort had higher baseline advanced fibrosis 3

Hepatocellular Carcinoma:

• Lean MASLD populations demonstrate increased risk of HCC development 2
• HCC surveillance with abdominal ultrasound ± AFP twice yearly is recommended for lean NAFLD patients with clinical markers of cirrhosis 3

Cardiometabolic Profile Differences

Baseline Metabolic Risk Factors:

• Lean MASLD patients have lower proportion of cardiometabolic risk factors including hypertension, type 2 diabetes, metabolic syndrome, and less atherosclerotic disease 3
• However, when compared to lean subjects without NAFLD, lean MASLD patients have similar or higher prevalence of multiple cardiometabolic risk factors 3
• Lean patients are more likely to be older, more frequently male, and more often Asian 3

Cardiovascular Events:

• Despite better baseline profiles, lean MASLD patients have similar or higher cardiovascular event rates as overweight/obese persons with NAFLD 3
• Non-lean MASLD patients are more prone to incident cardiovascular outcomes and type 2 diabetes development 2

Key Risk Modifiers

Critical Prognostic Factors:

• Advanced age increases mortality risk in lean MASLD 2
• Presence of hepatic fibrosis (even at lower stages) significantly impacts outcomes 2
• Type 2 diabetes mellitus presence modifies risk 2
• Baseline advanced fibrosis at diagnosis predicts worse liver-related outcomes 3

Genetic Variants:

• MASLD-related genetic variants (PNPLA3, TM6SF2) do not significantly affect mortality differences between lean and non-lean populations 2
• The TM6SF2 rs58542926 (T) allele may protect against diet-associated obesity in lean NAFLD 3

Clinical Implications for Risk Stratification

Mandatory Fibrosis Assessment:

• All lean MASLD patients require risk stratification for hepatic fibrosis to identify advanced fibrosis or cirrhosis 3
• Use FIB-4 and NAFLD Fibrosis Score as initial screening (FIB-4 outperforms NFS in lean patients) 3, 4
• If noninvasive tests are indeterminate, perform second-line testing with transient elastography or MR elastography 3
• Repeat testing at 6-month to 2-year intervals depending on fibrosis stage 3

Cardiovascular Risk Management:

• Aggressively evaluate and treat modifiable cardiovascular risk factors (diabetes, dyslipidemia, hypertension) in all lean MASLD patients 3
• This is critical given the paradoxically higher cardiovascular mortality despite better baseline profiles 1

Screening Recommendations:

• Do not perform routine screening for NAFLD in lean individuals in the general population 3
• Screen lean individuals over age 40 with type 2 diabetes 3
• Consider screening lean individuals with metabolic diseases 3

Common Pitfalls to Avoid

Do not assume lean MASLD is benign: The lower BMI creates false reassurance, but these patients face equal or worse mortality outcomes 1, 2

Do not underestimate cardiovascular risk: Despite fewer baseline metabolic comorbidities, lean patients have higher cardiovascular mortality requiring aggressive risk factor modification 1

Do not delay fibrosis assessment: Even though baseline fibrosis is typically lower, progression risk remains significant and requires systematic monitoring 3

Do not apply obesity-focused treatment paradigms: Lean patients achieve NAFLD remission with only 3-5% weight loss versus 7-10% needed in obese patients 3