Cryptogenic Steatotic Liver Disease: A Lean Phenotype Linked to Increased Liver-Related Mortality

Introduction

Steatotic liver disease (SLD), commonly known as fatty liver disease, typically develops in individuals with obesity or metabolic risk factors such as diabetes, hypertension, and hyperlipidemia. However, a subset of patients with fatty liver remain lean without the typical cardiovascular or metabolic risk profile, a condition referred to as cryptogenic SLD. This entity has remained poorly defined, leading to challenges in diagnosis, management, and prognostication. Recent research has aimed to elucidate the clinical characteristics and outcomes of cryptogenic SLD, highlighting its significance as a distinct phenotype with a substantial impact on liver-related morbidity and mortality.

Background and Objectives

The term “cryptogenic” denotes unknown origin. In the context of SLD, cryptogenic SLD describes fatty liver disease occurring in individuals who do not have recorded cardiometabolic risk factors (CMRFs) such as obesity, diabetes, hypertension, or dyslipidemia. This study operationalized cryptogenic SLD as lean SLD (body mass index <25 kg/m²) without documented CMRFs, differentiating it from lean metabolic dysfunction-associated SLD.

The primary objective was to investigate the clinical features and long-term outcomes of cryptogenic SLD to better understand its pathophysiology and risk implications.

Study Design and Methodology

The investigation involved analysis of several cohorts, primarily leveraging data from the UK Biobank (UKB) magnetic resonance proton density fat fraction (MR-PDFF) cohort. Participants with a PDFF (proton density fat fraction) of 5% or greater were classified as having SLD.

Key cohorts included:

• UKB MR-PDFF cohort: 30,847 participants with liver fat quantification via MRI.
• UKB hepatic steatosis index-based cohort for validation.
• Three external cross-sectional cohorts including the National Health and Nutrition Examination Survey (NHANES) and the Korean National Health Insurance Service (KNHIS).
• Two longitudinal cohorts (UKB hepatic steatosis index and KNHIS) for outcome assessment.

Participants were grouped into cryptogenic SLD and lean metabolic dysfunction-associated SLD based on presence or absence of CMRFs. Genetic risk variants (PNPLA3 and TM6SF2), liver fibrosis markers, and liver imaging characteristics were also analyzed.

Key Findings

In the MR-PDFF cohort, 3.4% of participants had non-obese SLD. Of these, 13.7% met criteria for cryptogenic SLD and 86.3% were classified as lean metabolic dysfunction-associated SLD.

Metabolic and Liver Profiles: Cryptogenic SLD individuals displayed less favorable metabolic and liver function markers compared with those without SLD or CMRFs. This suggests underlying liver injury despite the absence of conventional metabolic risk.

Genetic Associations: The prevalence of risk alleles in the PNPLA3 and TM6SF2 genes was notably higher in the cryptogenic SLD group. These genetic variants are known to influence fat accumulation and fibrosis progression in liver disease, indicating a potential genetic susceptibility in cryptogenic SLD.

Imaging and Fibrosis: Patients with cryptogenic SLD exhibited higher contrast-enhanced liver MRI T1-weighted signals, consistent with inflammation or fibrosis. Magnetic resonance elastography cohorts showed increased fibrosis rates, underscoring a higher risk of liver scarring in this population.

Mortality Outcomes: Longitudinal analyses revealed that cryptogenic SLD was associated with a 2.5-fold increased risk of liver-related death in the KNHIS cohort, and a similarly elevated but less precise risk in the UKB hepatic steatosis index cohort. Crucially, this association persisted even after excluding individuals with strict alcohol consumption criteria, supporting the distinct pathogenic role of cryptogenic SLD separate from alcohol-related liver disease.

Discussion

This research identifies cryptogenic SLD as a significant clinical entity within non-obese individuals with fatty liver. Although lacking classic metabolic risk factors, these patients harbor liver injury markers and have an elevated risk of advanced liver disease and mortality.

The study highlights the need for increased awareness and diagnostic consideration of fatty liver disease even in lean patients without metabolic syndrome features. Genetic predisposition, as evidenced by PNPLA3 and TM6SF2 variants, likely contributes to disease pathogenesis in this subgroup.

The higher fibrosis prevalence suggests that cryptogenic SLD patients may progress silently to advanced liver fibrosis or cirrhosis without typical clinical warning signs, emphasizing the importance of tailored screening strategies in this population.

Clinical Implications

Clinicians should consider non-obese individuals presenting with fatty liver on imaging for further evaluation, even in absence of metabolic risk factors. Advanced liver fibrosis assessment tools, including elastography or MRI-based methods, might be warranted.

While lifestyle interventions remain foundational—including balanced nutrition and regular physical activity—specific treatment strategies for cryptogenic SLD are not yet established. Considering genetic susceptibility and fibrosis risk, closer clinical monitoring and potentially novel therapeutics targeting fibrogenesis may be an area of future research.

Conclusion

Cryptogenic steatotic liver disease represents a distinct and clinically meaningful phenotype predominantly affecting lean individuals without traditional cardiometabolic risk factors. This condition is associated with liver injury markers and significantly increased liver-related mortality risk. Enhanced clinical recognition, appropriate liver fibrosis assessments, and further studies into pathogenesis and therapeutic options are essential to improve outcomes in this underserved population.

References

Yoon EL, Lee HY, Lee J, et al. Cryptogenic steatotic liver disease: a lean phenotype associated with increased liver-related mortality. Gut. 2026 Aug 14. PMID: 42463421. Available from: https://pubmed.ncbi.nlm.nih.gov/42463421/