Metabolic Mayhem: The Overlooked Crisis of Fatty Liver Disease

In recent years, the term fatty liver disease has entered the medical world, often overshadowed by other lifestyle diseases like obesity and metabolic conditions such as diabetes. The surge is closely linked to rising obesity, sedentary behavior, and unhealthy dietary habits.

Fatty liver disease refers to excessive fat accumulation in more than 5% of liver cells without heavy alcohol use ^[1]. Non-alcoholic fatty liver disease (NAFLD), the most common type, is becoming a silent pandemic affecting millions worldwide. Even with its severity, NAFLD is underdiagnosed and often ignored by the public and medical community.

To clarify the evolving terminology:

• NAFLD (Non-Alcoholic Fatty Liver Disease)

• NASH (Non-Alcoholic Steatohepatitis)

• MASLD (Metabolic dysfunction-associated steatotic liver disease, new term for NAFLD)

• MASH (Metabolic dysfunction-associated steatohepatitis, new term for NASH)

Since NAFLD progresses slowly, most people are unaware of their condition until it reaches an advanced stage, such as MASH (formerly NASH), cirrhosis, or even liver cancer.

According to studies, NAFLD has been renamed as Metabolic dysfunction-associated steatotic liver disease (MASLD). It is the most common liver disorder globally, with an estimated prevalence of over 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis ^[5].

“Lipotoxic spillover” – MASH not only affects the liver but also impacts the heart, muscles, and kidneys through circulation.

Epidemiology

Global prevalence: ~25% in the general population ^[1]
Higher in patients with type 2 diabetes (up to 55.5%) ^[1]
Geographic variations: Lower in Africa (13.48%), higher in the Middle East (31.79%) and South America (30.45%) ^[1]
The prevalence of MASH is estimated to be 3–5% in the general population ^[1]
Pediatric NAFLD is emerging as a growing concern, with rates increasing due to rising childhood obesity and sedentary behaviors. Early onset may lead to more aggressive disease progression in adulthood ^[1].

Comparison with Alcoholic Fatty Liver Disease (AFLD)

Unlike AFLD, which is caused by excessive alcohol intake, NAFLD and MASLD develop in individuals with little to no alcohol consumption. However, both conditions can lead to similar liver damage, including cirrhosis and liver failure ^[1].

Pathogenesis of NAFLD

NAFLD and its progression to MASH have been explained by the “2-hit” hypothesis, initially proposed by Day and James ^[2].

First hit: Accumulation of free fatty acids, rather than triglycerides, causes liver damage through toxic effects.
Second hit: Oxidative stress, inflammation, and mitochondrial dysfunction worsen the condition.

Metabolic Factors
Obesity: Strongest risk factor, with >95% of severely obese patients developing NAFLD ^[1]
Metabolic Syndrome: Bidirectional relationship with NAFLD
Type 2 Diabetes: Present in >50% of NAFLD patients ^[1]
Insulin Resistance: Central to disease pathogenesis

Gut Microbiome
Altered bacterial composition, increased intestinal permeability, and changes in short-chain fatty acid production can impact the liver.

Genetic Factors
Genes like PNPLA3, TM6SF2, GCKR, MBOAT7, and HSD17B13 play distinct roles in genetic susceptibility.

Epigenetic Factors
DNA methylation changes (mostly hypomethylation), histone modifications, and microRNA dysregulation (miR-122, miR-33, miR-34)

Environmental Factors
Diet and Lifestyle: High-fat and high-carbohydrate diets and sedentary lifestyle
Smoking and air pollution (especially PM2.5) accelerate disease progression ^[1]

Demographics
Prevalence increases with age (2.6% in children to 34% in adults) ^[1]
Gender: Mixed findings, but males may have more severe disease progression

Diagnostic Definition
NAFLD: Presence of ≥5% macro vesicular steatosis in liver tissue ^[3]
MASH: Requires three components – macro vesicular steatosis, inflammation, and hepatocyte ballooning
Disease severity: Measured using the NAFLD Activity Score (NAS)

Barriers to Diagnosis
Lack of early symptoms, insufficient public awareness, and limited screening protocols lead to underdiagnosis, particularly in primary care settings.

Treatment
Despite medical advances, lifestyle modifications remain the most effective approach.

Approximately 130 clinical trials are ongoing for MASH treatment, with only five drugs in phase III trials:

• Obeticholic acid

• Elafibranor

• Cenicriviroc

• Selonsertib

Weight Loss and NAFLD
≥10% weight loss leads to MASH resolution in 90% and fibrosis regression in 45% of cases.
Moderate, sustained weight loss is more beneficial than crash diets.
Non-obese individuals may benefit from 3–5% reduction; obese individuals need 7–10%.

Dietary Intervention

• Low-carb diets reduce liver fat by 43% in 2 weeks ^[4]

• High-protein diets reduce hepatic fat by 36–48% in 6 weeks ^[4]

• Cutting sugary drinks to ≤1% of daily calories lower hepatic triglycerides ^[4]

• Low-level alcohol intake (≤20g/day) may reduce fibrosis risk

Physical Activity and Exercise

• Aerobic exercise: 20–30% reduction in hepatic steatosis ^[4]

• Resistance training: 13% reduction in liver fat, improved metabolic health ^[4]

• Sedentary time is an independent risk factor, even light activity interruptions improve outcomes

Policy Implications and Screening

Routine screening for MASLD should be considered in high-risk groups (e.g., diabetics, obese patients). Healthcare systems should prioritize early detection and personalized interventions to prevent progression.

Clinical Implications

Given the lack of response to conventional therapies, MASLD demands innovative and fast-acting solutions. While drug therapy is still under clinical evaluation, lifestyle intervention remains the cornerstone of care. A multidisciplinary approach is crucial, as cardiovascular disease is the leading cause of death in MASLD patients (38% vs. 9% liver-related deaths^[4].

Conclusion

Fatty liver disease is not a trivial lifestyle ailment, it is a silent epidemic tied to modern living. As obesity, sedentary habits, and processed diets become more common, so does the risk for MASLD and MASH. Early detection, public awareness, and consistent lifestyle interventions can reverse its course. Recognizing and acting on this crisis now could prevent a global wave of preventable liver and cardiovascular complications.

References

1. Juanola, Oriol, Sebastián Martínez‑López, Rubén Francés, and Isabel Gómez‑Hurtado. “Non‑Alcoholic Fatty Liver Disease: Metabolic, Genetic, Epigenetic and Environmental Risk Factors.” International Journal of Environmental Research and Public Health 18, no. 10 (2021): 5227. https://www.mdpi.com/1660-4601/18/10/5227
   
   

2. Ezzat, Wafaa Mohamed. “Impact of Lifestyle Interventions on Pathogenesis of Nonalcoholic Fatty Liver Disease.” World Journal of Gastroenterology 30, no. 20 (2024): 2633–2637. https://pmc.ncbi.nlm.nih.gov/articles/PMC11154675/
   
   

3. Yoo, Jeong‑Ju, et al. “Recent Research Trends and Updates on Nonalcoholic Fatty Liver Disease.” Clinical and Molecular Hepatology 25, no. 1 (2019): 1–11. https://pmc.ncbi.nlm.nih.gov/articles/PMC6435971/
   
   

4. Zelber‑Sagi, Shira, and Jeremy B. Moore. “Lifestyle Modification in NAFLD/NASH: Facts and Figures.” Journal of Hepatology Reports 1, no. 6 (2019): 468–479. https://pmc.ncbi.nlm.nih.gov/articles/PMC7005657/
   
   

5. Sandireddy, Reddemma, S. Sakthivel, P. Gupta, J. Behari, M. Tripathi, and B.K. Singh. “Systemic Impacts of Metabolic Dysfunction‑Associated Steatotic Liver Disease (MASLD) and Metabolic Dysfunction‑Associated Steatohepatitis (MASH) on Heart, Muscle, and Kidney Related Diseases.” Frontiers in Cell and Developmental Biology 12 (July 16, 2024): Article 1433857.https://pubmed.ncbi.nlm.nih.gov/39086662/

_MSM/SE