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Lean MASLD

TL;DR — About 19.2% (95% CI 15.9–23.0) of the NAFLD population is lean and 40.8% (36.6–45.1) is non-obese; in the general population 5.1% (3.7–7.0) have lean NAFLD and 12.1% (9.3–15.6) non-obese NAFLD (Ye 2020, PMID 32413340). This alone falsifies BMI as a screening gate. The phenotype is not benign: among lean or non-obese NAFLD, 39.0% (24.1–56.3) have steatohepatitis, 29.2% (21.9–37.9) significant fibrosis and 3.2% (1.5–5.7) cirrhosis (PMID 32413340). Outcomes split by organ. Liver-related mortality is higher in lean than overweight/obese disease (1.33 vs 0.76 per 1,000 patient-years; OR 3.56, 95% CI 3.45–3.67, p<0.01), while all-cause, cardiovascular and cancer mortality are similar (Cheah 2025, PMID 40087205). A 2.9-million-patient Japanese cohort concurs and sharpens it: liver-event risk in lean MASLD was comparable to non-lean (aHR 1.35, 0.87–2.08) and far above normal liver (aHR 5.94, 3.95–8.92), while cardiovascular-event risk was lower than non-lean (aHR 0.73, 0.64–0.84) and indistinguishable from normal liver (aHR 0.99, 0.88–1.12) (Wakabayashi 2024, PMID 38570344). Mechanistically the phenotype differs — altered bile-acid handling, higher FGF19, distinct gut microbiota (Chen 2020, PMID 31442319) — and the AGA has issued specific best-practice advice including that lean individuals in the general population should not be routinely screened, but that screening should be considered above age 40 with type 2 diabetes (Long 2022, PMID 35842345).

Definitions and prevalence

"Lean" means BMI <25 kg/m² (non-Asian) or <23 kg/m² (Asian); "non-obese" is the wider band below the obesity threshold (Long 2022, PMID 35842345).

Metric Estimate (95% CI) Source
Lean fraction within the NAFLD population 19.2% (15.9–23.0) Ye 2020, PMID 32413340 (93 studies, n=10,576,383, 24 countries)
Non-obese fraction within NAFLD 40.8% (36.6–45.1) PMID 32413340
Lean NAFLD in the general population 5.1% (3.7–7.0) PMID 32413340
Non-obese NAFLD in the general population 12.1% (9.3–15.6) PMID 32413340
Lean-MAFLD in the general population 1.94% (1.10–3.39), I²=98.7% Cheah 2025, PMID 40087205 (n=10,013,382)
Lean body habitus among individuals with NAFLD (AGA estimate) 7–20% Long 2022, PMID 35842345
Lean MASLD share of global population 13%, especially in Asia Danpanichkul 2025, PMID 39439408
Incidence of NAFLD in the non-obese population 24.6 per 1,000 person-years (13.4–39.2) PMID 32413340

Prevalence of non-obese NAFLD in the general population varies from ≤25% in Malaysia and Pakistan to >50% in Austria, Mexico and Sweden (PMID 32413340) — a range wide enough that the lean-MAFLD pooled figure of 1.94% (which uses a stricter international-consensus definition) and the lean-NAFLD figure of 5.1% should not be read as measuring the same thing.

Histological severity

Feature among lean/non-obese NAFLD Prevalence (95% CI)
Non-alcoholic steatohepatitis 39.0% (24.1–56.3)
Significant fibrosis (stage ≥2) 29.2% (21.9–37.9)
Cirrhosis 3.2% (1.5–5.7)

Source: Ye 2020, PMID 32413340. Against this, a biopsy-proven Caucasian cohort of 538 found that lean NAFLD patients had a more favourable metabolic and histological profile than non-lean (p<0.05 for all) (Chen 2020, PMID 31442319) — the two are reconcilable only if lean disease is less severe on average at any given moment but progresses to comparable endpoints, which is what the outcome data suggest.

Outcomes: a liver-heavy, heart-light phenotype

Outcome Lean vs non-lean Source
Liver-related mortality 1.33 vs 0.76 per 1,000 patient-years; OR 3.56 (3.45–3.67), p<0.01 Cheah 2025, PMID 40087205
All-cause mortality 10.08 vs 8.94 per 1,000 PY; OR 1.92 (0.01–220.57), p=0.33 PMID 40087205
Cardiovascular mortality 2.53 vs 2.07 per 1,000 PY; OR 1.91 (0.02–142.76), p=0.58 PMID 40087205
Cancer mortality 3.42 vs 3.15 per 1,000 PY; OR 1.99 (0.29–13.52), p=0.13 PMID 40087205
Liver events, 5-year cumulative incidence lean 0.065%, non-lean 0.039%, normal liver 0.006%; lean vs normal aHR 5.94 (3.95–8.92); lean vs non-lean aHR 1.35 (0.87–2.08) Wakabayashi 2024, PMID 38570344 (n=2.9 million, median 4.2 years)
Cardiovascular events, 5-year cumulative incidence non-lean 0.779%, lean 0.600%, normal liver 0.254%; lean vs non-lean aHR 0.73 (0.64–0.84); lean vs normal aHR 0.99 (0.88–1.12) PMID 38570344

Note how wide the odds-ratio intervals are in the Cheah meta-analysis for every endpoint except liver-related mortality — those comparisons are effectively uninformative, and the paper's conclusion rests on the liver-mortality contrast plus the observation that metabolic characteristics (blood pressure, LDL, triglycerides, glucose, HbA1c) were similar between lean and overweight/obese MAFLD. A narrative synthesis states that lean MASLD carries equal or higher overall mortality, with an increased risk of HCC, while non-lean disease is more prone to cardiovascular outcomes and T2D, and that liver-related events and extrahepatic cancer risk are similar; it also flags under-reporting of alcohol consumption and limited regional representation as constraints on this literature (Danpanichkul 2025, PMID 39439408).

The liver half of that picture is not in dispute. The cardiovascular half is one of the sharper unresolved contradictions in this literature, and it should not be smoothed over.

The lean-MASLD cardiovascular contradiction

Study Population CVD events CVD mortality All-cause mortality
Wakabayashi 2024, PMID 38570344 2.9M Japanese, median 4.2 y lean vs non-lean aHR 0.73 (0.64–0.84) not reported not reported
Huo 2026, PMID 41093635 UK Biobank 153,192 + Kailuan 29,700 + China Kadoorie 3,329; 5,030 lean; median 14.2 y lean vs non-lean HR 0.89 (0.83–0.95) HR 1.22 (1.05–1.41) HR 1.26 (1.14–1.39)
Souza 2024, PMID 39117942 22 cohorts, >1M NAFLD patients, 13.0% lean unadjusted RR 0.82 (0.70–0.95); adjusted HR 0.89 (0.77–1.02), ns RR 1.09 (0.71–1.66); HR 1.26 (0.89–1.78), ns not pooled
Nso 2024, PMID 38599554 21 studies; 7,153 lean vs 23,514 non-lean MASLD MACE OR 0.9 (0.7–1.2), p=0.7; CVD odds 40% lower, p=0.01 OR 1.5 (1.2–1.8), p<0.0001 OR 1.4, p=0.06
Wongtrakul 2024, PMID 38278181 14 studies, 94,181 NAFLD, 11.3% lean, 7,443 deaths, median 8.4 y — — HR 1.61 (1.37–1.89), I²=77%, robust to stratification by fibrosis adjustment
Ghani 2025, PMID 40406910 75,921 MASLD (Banner + Michigan, 2012–2023), 4.99% lean higher incidence of CVD after adjustment — higher
Al Ta'ani 2026, PMID 41614694 TriNetX, 67,519 lean vs 67,519 propensity-matched non-lean, 7 y composite CV HR 1.21 (1.13–1.30); heart failure HR 1.23 (1.16–1.31); cerebrovascular HR 1.33 (1.24–1.43) — HR 1.48 (1.38–1.59)

Three positions are held simultaneously in the current literature, and the disagreement is not merely a matter of precision:

  1. Fewer cardiovascular events, more cardiovascular deaths. This is Huo's finding within a pooled analysis of three cohorts — CVD incidence HR 0.89 alongside CVD-mortality HR 1.22 (PMID 41093635) — and Nso's meta-analytic result independently (CVD odds 40% lower, cardiovascular mortality OR 1.5; PMID 38599554). If the event and mortality estimates are comparable, higher case fatality is one possible explanation, not a demonstrated finding. It is also not what the lower prevalence of hypertension and dyslipidaemia reported in the same synthesis would predict.
  2. No cardiovascular difference at all once confounders are handled. Souza's adjusted pooled estimates cross unity for both CVD (HR 0.89, 0.77–1.02) and cardiovascular mortality (HR 1.26, 0.89–1.78), with I² of 78% and 46% (PMID 39117942). On this reading the apparent protection is an artefact of unadjusted analysis.
  3. Higher cardiovascular events too. Two large EHR-based cohorts using contemporary MASLD criteria — 75,921 patients at Banner/Michigan (PMID 40406910) and 135,038 propensity-matched patients in TriNetX (PMID 41614694) — find lean individuals have more cardiovascular disease, more heart failure, more cerebrovascular events and higher mortality.

The methodological split maps onto the data source: cohorts reporting lower CV risk are population-based (Japanese health checkups, UK Biobank, Kailuan, China Kadoorie), while those reporting higher CV risk are health-system EHR cohorts (TriNetX, Banner/Michigan). Differential ascertainment is a plausible explanation for the split, but none of these studies tested it. Ethnic composition also differs, so the data-source explanation cannot be isolated from population differences.

What survives all designs: liver-related mortality is roughly 2–3.5 fold higher in lean MASLD (OR 3.56, 3.45–3.67, PMID 40087205; RR 2.22, 1.57–3.15 and HR 2.26, 1.14–4.51, PMID 39117942; HR 2.31, 1.54–3.46, PMID 41093635), and all-cause mortality is 1.26–1.61 fold higher (PMIDs: 41093635, 38278181), with Wongtrakul's estimate unchanged after stratifying on fibrosis-stage adjustment — meaning the excess is not simply more advanced fibrosis at diagnosis. The clinically actionable conclusion is unchanged and does not depend on resolving the cardiovascular question: lean MASLD is not the benign phenotype BMI-anchored screening implicitly assumes.

Distinct mechanism

In 538 Caucasian patients with biopsy-proven NAFLD, 30 lean healthy controls and parallel murine models (Chen 2020, PMID 31442319):

  • Bile-acid levels were significantly higher in NAFLD with advanced than earlier fibrosis.
  • Lean NAFLD patients had higher serum secondary bile acids and FGF19 (a surrogate for intestinal FXR activity) and reduced C4 (7α-hydroxy-4-cholesten-3-one), all p<0.05, with the differences more pronounced at early than advanced fibrosis (p<0.05).
  • Lean patients showed an altered gut microbiota profile; similar findings appeared in lean and non-lean murine models.
  • Treating lean-model mice with an apical sodium-dependent bile acid transporter inhibitor (SC-435) markedly increased fgf15, shifted bile-acid and microbiota profiles, and improved steatohepatitis.

Genetics contribute proportionally more. In 177 lean non-alcoholic SLD cases (47 cryptogenic, 130 MASLD) versus 677 matched lean controls and 3,090 overweight/obese SLD cases in the Mayo Clinic Biobank, lean cases had metabolic and genetic profiles intermediate between lean controls and overweight/obese cases, including intermediate rates of diabetes, hypertension, hyperlipidaemia and of PNPLA3 risk-allele homozygosity. Diabetes was an independent predictor of SLD among lean individuals; lean MASLD versus lean cryptogenic SLD was more likely to be homozygous for GCKR risk alleles; and FIB-4 accurately predicted advanced fibrosis in lean individuals (Sato-Espinoza 2025, PMID 40944478). Against a strong genetic contribution, a review notes that PNPLA3 and TM6SF2 variants did not significantly modify mortality differences between lean and non-lean populations (PMID 39439408). See genetics.

AGA best-practice advice

The AGA Clinical Practice Update on lean NAFLD gives eleven best-practice advice statements. The operative ones (Long 2022, PMID 35842345):

# Advice
1 Diagnose lean NAFLD at BMI <25 kg/m² (non-Asian) or <23 kg/m² (Asian)
2 Evaluate routinely for T2D, dyslipidaemia and hypertension
3 Risk-stratify for hepatic fibrosis to identify advanced fibrosis or cirrhosis
4 Do not routinely screen lean individuals in the general population; consider screening those >40 years with type 2 diabetes
5 Consider NAFLD in lean individuals with metabolic disease, elevated liver biochemistry, or incidental steatosis
6 Query alcohol consumption patterns routinely in all patients with lean NAFLD
7 Rule out other causes: HIV, lipodystrophy, lysosomal acid lipase deficiency, familial hypobetalipoproteinaemia, and medication-induced steatosis (methotrexate, amiodarone, tamoxifen, steroids)
8 Current evidence is inadequate to support routine genetic-variant testing
9 Consider biopsy where the contributing cause or fibrosis stage is uncertain
10 Serum indices (NFS, FIB-4) and imaging (TE, MRE) may substitute for biopsy, repeated at 6-month to 2-year intervals depending on stage and response

Advice 7 is the distinctive one. In a lean patient, steatosis is more likely than in an obese patient to signal something other than metabolic dysfunction, and the differential is specific: inherited and genetic disorders, lipodystrophy, drug-induced steatosis and inflammatory disorders (PMID 35842345). See red flags and safety concerns.

Advice 6 also earns its place because the MASLD definition tolerates alcohol intake up to the MetALD threshold, and misclassification is likelier in a lean patient whose steatosis is otherwise unexplained (nomenclature and definitions).

Open questions

  • Should lean MASLD be treated differently? Trials of resmetirom, semaglutide and lifestyle intervention were conducted in predominantly overweight and obese populations, and the meta-analysis of weight change found response not modified by baseline BMI (lifestyle and weight loss) — but weight loss as a therapeutic lever is inherently constrained in a lean patient. Ye's authors argue explicitly that clinical trials "should include participants across all body-mass index ranges" (PMID 32413340). No trial has been enriched for lean disease.
  • Is the bile-acid axis a lean-specific target? ASBT inhibition improved steatohepatitis in the lean murine model (PMID 31442319); no human trial of a bile-acid-transport-targeted therapy stratified by BMI has been retrieved. Query run 2026-09-02: (NASH OR MASH OR NAFLD OR MASLD) AND (lean OR "non-obese" OR "normal weight" OR "normal BMI") — 2,043 records; no BMI-stratified interventional trial identified.
  • Why does liver-related mortality diverge while cardiovascular risk does not? The organ split is reproducible across a meta-analysis and a 2.9-million cohort (PMIDs: 40087205, 38570344), and no mechanism has been proposed that predicts both directions.
  • Is cardiovascular risk in lean MASLD lower, equal, or higher? Population-based cohorts say lower (HR 0.73–0.89; PMIDs: 38570344, 41093635), pooled adjusted analysis says no difference (HR 0.89, 0.77–1.02; PMID 39117942), and two US health-system cohorts say higher (HR 1.21–1.33; PMIDs: 41614694, 40406910). No study has compared the designs within one population, and the discrepancy is currently indistinguishable from an ascertainment artefact.
  • Why would lean MASLD have fewer cardiovascular events but more cardiovascular deaths? Two independent syntheses report this combination (PMIDs: 41093635, 38599554). Higher case fatality would be the arithmetic explanation; no candidate mechanism — sarcopenia, cardiac reserve, delayed presentation — has been tested against it.
  • Are lean MASLD patients metabolically lean at all? The Mayo Biobank data show an intermediate metabolic and genetic profile (PMID 40944478), consistent with lean MASLD being partly invisible to BMI-based classification. Outcome analyses using direct visceral-fat measures rather than BMI remain a useful next step.
  • How much lean MASLD is misclassified alcohol or a monogenic disorder? Objective biomarker studies now quantify alcohol misclassification in broader SLD populations: 15.9% of 391 overweight/obese patients underreported alcohol, with PEth increasing MetALD diagnoses fourfold and ALD diagnoses threefold (PMID 40517819); among 46,406 PEth-tested patients initially classified as MASLD, 20% had PEth in the MetALD range and 13% in the ALD range (PMID 40228582). Neither study was lean-specific. As of 2026-09-02, the fraction of lean MASLD reclassified by PEth and systematic genetic testing remains unquantified.
  • Should genotype guide management here, given the intermediate PNPLA3 burden? AGA says current evidence is inadequate for routine genetic testing (PMID 35842345), while lean disease is where the genetic contribution is proportionally largest and GCKR discriminates MASLD from cryptogenic SLD (PMID 40944478).

References

  1. Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020;5(8):739-752. PMID 32413340
  2. Cheah MCC, Crane H, George J. Global prevalence, metabolic characteristics, and outcomes of lean-MAFLD: a systematic review and meta-analysis. Hepatol Int. 2025;19(3):607-618. PMID 40087205
  3. Wakabayashi SI, Tamaki N, Kimura T, et al. Natural history of lean and non-lean metabolic dysfunction-associated steatotic liver disease. J Gastroenterol. 2024;59(6):494-503. PMID 38570344
  4. Chen F, Esmaili S, Rogers GB, et al. Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation. Hepatology. 2020;71(4):1213-1227. PMID 31442319
  5. Long MT, Noureddin M, Lim JK. AGA Clinical Practice Update: Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals: Expert Review. Gastroenterology. 2022;163(3):764-774.e1. PMID 35842345
  6. Danpanichkul P, Suparan K, Prasitsumrit V, et al. Long-term outcomes and risk modifiers of metabolic dysfunction-associated steatotic liver disease between lean and non-lean populations. Clin Mol Hepatol. 2025;31(1):74-89. PMID 39439408
  7. Sato-Espinoza K, Vierkant RA, Chotiprasidhi P, et al. Clinical and Genetic Predictors of Non-Alcoholic Steatotic Liver Disease and Fibrosis in Lean Individuals. Liver Int. 2025;45(10):e70300. PMID 40944478
  8. Tavaglione F, et al. Clinical utility of phosphatidylethanol to detect underreported alcohol use and enhance steatotic liver disease subclassification. J Hepatol. 2025;83(5):1023-1034. PMID 40517819
  9. Vaz J, et al. Phosphatidylethanol levels distinguish steatotic liver disease subgroups and are associated with risk of major liver outcomes. J Hepatol. 2025;83(5):1011-1022. PMID 40228582
  10. Huo Z, Chen Y, Huang Y, et al. Long-term prognosis of lean MASLD: evidence from three population-based prospective cohorts. Gut. 2026;75(4):772-785. PMID 41093635
  11. Souza M, Diaz I, Al-Sharif L. Liver and cardiovascular outcomes in lean non-alcoholic fatty liver disease: an updated systematic review and meta-analysis of about 1 million individuals. Hepatol Int. 2024;18(5):1396-1415. PMID 39117942
  12. Al Ta'ani O, Alhalalmeh Y, Alabdallat M, et al. Increased Cardiovascular and Cerebrovascular Events in Patients With Lean vs Non-lean MASLD: A Multicenter Analysis. Clin Transl Gastroenterol. 2026;17(4):e00974. PMID 41614694
  13. Nso N, Mergen D, Ikram M, et al. Cardiovascular morbidity and mortality in lean vs. non-lean MASLD: A comprehensive meta-analysis. Curr Probl Cardiol. 2024;49(6):102569. PMID 38599554
  14. Wongtrakul W, Charatcharoenwitthaya N, Charatcharoenwitthaya P. Lean non-alcoholic fatty liver disease and the risk of all-cause mortality: An updated meta-analysis. Ann Hepatol. 2024;29(3):101288. PMID 38278181
  15. Ghani L, Aboona MB, Faulkner CS, et al. Increased Mortality Among Lean Versus Non-Lean Adults With MASLD: A Multicenter Study. J Gastroenterol Hepatol. 2025;40(8):1919-1925. PMID 40406910