Lean Fatty Liver Disease Poses Serious Health Risks Beyond Body Size

A review of global clinical and mechanistic evidence suggests that metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) in lean people are an overlooked but high-risk form of disease. The analysis, published in Discover Medicine, argues that relying too heavily on body mass index can hide fatty liver and worsening metabolic problems in people with normal weight. Observational studies show that lean MAFLD patients can still have clear signs of liver injury, including higher serum alanine transaminase levels, hepatocyte ballooning, and advancing steatosis, challenging the assumption that metabolic liver disease is mainly confined to people with overweight or obesity.

The perspective was written by Mohammad Abu Faisal and Syeda Humaida Hasan, who searched PubMed, EMBASE, and Google Scholar for studies published from January 2000 through May 2025. Their search included terms such as lean MAFLD, lean MASLD, non-obese NAFLD, normal BMI fatty liver disease, and steatotic liver disease, drawing on original research, systematic reviews, meta-analyses, and expert commentaries. The authors note that the selection of studies was not systematic and depended on clinical judgment rather than a reproducible protocol, which means citation bias may be present. They also distinguish carefully between evidence from cell studies, animal models, cross-sectional human studies, prospective cohorts, and meta-analyses.

The terminology and diagnostic rules for fatty liver disease have changed significantly in recent years. In 2020, MAFLD was introduced as a positive diagnosis that requires hepatic steatosis together with type 2 diabetes, overweight or obesity, or metabolic dysfunction. For lean people, the MAFLD definition requires hepatic steatosis plus at least two of seven metabolic risk markers: increased waist circumference, hypertension, high triglycerides, low high-density lipoprotein cholesterol, prediabetes, insulin resistance, or elevated high-sensitivity C-reactive protein. In 2023, the MASLD term was introduced under the broader category of steatotic liver disease, defining the condition as hepatic steatosis with at least one cardiometabolic risk factor, while unexplained steatosis was labeled cryptogenic steatotic liver disease.

This difference in definitions creates a practical challenge for identifying lean patients. MASLD requires only one cardiometabolic feature, while MAFLD requires at least two metabolic abnormalities in lean individuals, so the two systems overlap only partly. As a result, someone with just one cardiometabolic risk factor may be diagnosed with MASLD but not MAFLD, increasing the chance that the older framework misses cases. Some researchers believe MASLD is better at identifying lean people with metabolically driven steatosis, while others argue that MAFLD is more specific and more sensitive for finding people at higher overall metabolic risk.

The epidemiological data presented in the review point to a sizeable global burden with clear geographic differences. Although non-alcoholic fatty liver disease has historically affected about one-third of the world’s population, the estimated worldwide prevalence of MAFLD has reached 38.77 percent (95% CI 32.94–44.95%). Across global and Asian populations combined, MAFLD affects 5.37 percent of lean people and 29.78 percent of non-obese people. Ethnic variation is also marked: prevalence is highest among Hispanic individuals, followed by white individuals, and lowest in Black populations. In Asian populations, lean NAFLD accounts for 14.55 percent (95% CI 11.32–18.51%), higher than the global lean NAFLD estimate of 13.11 percent (95% CI 10.26–16.62%), and Asian individuals tend to develop steatosis at lower body mass index values than other groups.

At the biological level, lean MAFLD shares the same major disease drivers seen in obese MAFLD, including insulin resistance, lipotoxicity from harmful lipid buildup, inflammatory immune-cell infiltration, and activation of hepatic stellate cells that lead to fibrosis, but it does so without excess adiposity. Genetics appears to play a major role, especially variants in Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and Transmembrane 6 superfamily member 2 (TM6SF2). PNPLA3 variants disrupt liver lipid metabolism, interfere with ketogenesis, and change mitochondrial redox balance, directly contributing to organelle dysfunction. TM6SF2 variants reduce very-low-density lipoprotein secretion, promote fat accumulation in the liver, and raise aspartate aminotransferase levels, with observational studies linking these variants to a 1.6-fold higher risk of MAFLD, although causality has not been proven.

Other pathways involved in liver damage in lean individuals include gut microbiome imbalance, persistent endotoxaemia, and abnormal bile acid signaling. Microbiome studies show reduced levels of Faecalibacterium, Ruminococcus, Lactobacillus, Lachnospira, and Subdoligranulum, along with expansion of Escherichia-Shigella, which weakens the intestinal barrier and promotes systemic endotoxaemia. Endotoxin exposure activates Toll-like receptor pathways in macrophages and causes epigenetic changes that suppress Farnesoid X Receptor signaling, gradually shifting bile acids toward a more inflammatory pattern. At the cellular level, enlarged mitochondria with disturbed dynamics produce excessive reactive oxygen species and energy shortages, eventually leading to apoptotic, pyroptotic, and ferroptotic death of hepatocytes. Higher circulating growth differentiation factor 15 (GDF15) levels have also been linked observationally to increased all-cause and cause-specific mortality.

The clinical picture of lean MAFLD includes serious liver, cardiovascular, and cancer-related risks that do not fit the idea of a harmless condition. Histological studies show that people with lean MAFLD can still have advanced disease and fibrosis even when their body mass index is below 23 kg/m². A cohort study in China found that lean MAFLD ranked second only to diabetes-associated MAFLD in cases of liver failure and cardiac-cerebrovascular events, with a heavier burden than that seen in obese MAFLD groups. An observational meta-analysis of 56,745 people also associated lean MAFLD with higher relative risks of liver cancer (RR 1.77, 95% CI 1.15–2.73), pancreatic cancer (RR 1.97, 95% CI 1.01–3.86), and colorectal cancer (RR 1.53, 95% CI 1.12–2.09) compared with obese MAFLD, though confounding from diabetes and dyslipidaemia may remain.

In light of these patterns, the authors propose a practical, risk-based screening approach for settings with limited resources, while noting that no formal screening protocol for lean MAFLD is currently recommended by professional guidelines. They suggest including waist circumference in routine physical exams along with height and weight to better detect central obesity. They recommend further evaluation in lean people who have risk factors such as type 2 diabetes, prediabetes, dyslipidaemia, hypertension, increased waist circumference, family history of metabolic disease, Asian ethnicity, sarcopenia, or unexplained liver enzyme elevation. Suggested first-line tests include fasting glucose or HbA1c, lipid profiles, liver function tests, hepatic ultrasound, and Fibrosis-4 scoring, with elastography used for those at intermediate or high risk.

The authors also caution that several important limits prevent broad prognostic conclusions at this stage. Much of the evidence comes from cross-sectional studies and observational cohorts, especially in Asia, where referral bias and confounding by age, diabetes, sarcopenia, ethnicity, and lifestyle may affect results. Many of the key molecular findings come from in vitro or animal research and still need confirmation in humans. In addition, changing definitions across NAFLD, MAFLD, and MASLD, along with different BMI thresholds for leanness, make comparisons across studies difficult. The authors conclude that prospective longitudinal studies, research in more diverse populations outside Asia, and randomized controlled trials are needed before risk-based screening can be formally added to clinical guidelines.

Subject of Research: Clinical features, mechanisms, and screening approaches for lean metabolic dysfunction-associated fatty liver disease

Article Title: Lean MAFLD and MASLD represent an underrecognized high risk phenotype beyond body mass index

Article References: Faisal, M. A., & Hasan, S. H. (2026). Lean MAFLD and MASLD represent an underrecognized high risk phenotype beyond body mass index. Discover Medicine, 3(1), Article 134. https://doi.org/10.1007/s44337-026-00654-0

Image Credits: AI Generated

Keywords: MAFLD, MASLD, hepatic steatosis, body mass index, cardiometabolic risk, PNPLA3, liver fibrosis, hepatology, lean, underrecognized, high risk

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Ophelia Keating. Scienmag.

Ophelia Keating. Scienmag.