NAFLD vs. MAFLD: The Good, the Bad and the Ugly

NAFLD vs. MAFLD: The Good, the Bad, and the Ugly

Comprehensive Summary of Lecture by Prof. S.P. Singh

1. Main Clinical Topics Discussed

• The ongoing nomenclature debate between NAFLD (Non-Alcoholic Fatty Liver Disease) and MAFLD (Metabolic-Associated Fatty Liver Disease)
• The heterogeneous pathogenesis of fatty liver disease beyond insulin resistance and metabolic syndrome
• Patient perspectives on nomenclature, with a focus on South Asian populations
• Implications of disease renaming for research, clinical practice, and public health policy

2. Key Learning Points, Guidelines, and Recommendations

Origins of the Controversy

• The proposed shift to MAFLD originated from a **2020 consensus publication in *Gastroenterology*** advocating for the term "Metabolic-Associated Fatty Liver Disease"
• A significant cohort of original co-authors subsequently publicly dissented, including globally recognized NAFLD researchers (Younossi, Rinella, Harrison, Brunt, Goodman, Cohen, and Loomba), describing the change as premature

Pathogenesis: Beyond Insulin Resistance

• NAFLD is a heterogeneous, multifactorial condition; reducing it to a hepatic manifestation of dysmetabolism oversimplifies its pathogenesis
• Multiple non-metabolic pathways implicated include:

- Genetic polymorphisms (e.g., *PNPLA3* SNP rs738409) — associated with steatosis independent of insulin resistance and serum lipids

- Gut dysbiosis — NAFLD associated with reduced abundance of specific bacterial taxa, independent of BMI, and distinct intestinal microbiome metabolite profiles

- Environmental stressors — pesticide exposure and particulate air pollution independently linked to NAFLD development

- Bile acid dysregulation — elevated serum bile acid levels independently associated with NASH, particularly in non-diabetic patients, independent of obesity and insulin resistance

- Circadian rhythm disruption — implicated in fibrosis-related pathways in NAFLD

South Asian-Specific Considerations

• A substantial proportion of South Asian NAFLD patients do not exhibit insulin resistance or obesity, challenging the MAFLD framing:

- Prof. Singh's 2015 study (submitted 2004): ~50% of NAFLD patients were not overweight or obese

- Bangladesh study: Two-thirds of NAFLD patients had normal insulin resistance

3. Specific Clinical Data, Statistics, and Study Results Cited

4. Practical Takeaways for Clinicians

• Do not uncritically adopt MAFLD solely on the basis of expert advocacy; demand robust pathogenic and perceptive evidence before accepting a nomenclature change
• Assess insulin resistance and metabolic syndrome cautiously in South Asian and other lean/non-obese NAFLD patients — a significant proportion will not meet MAFLD metabolic criteria and may be misclassified or missed entirely
• Evaluate multiple pathogenic contributors beyond dysmetabolism: genetics (*PNPLA3*), gut microbiome, bile acid levels