What are the risk factors for fatty liver disease?

Risk Factors for Fatty Liver Disease

The major risk factors for nonalcoholic fatty liver disease (NAFLD) include obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome, with obesity being the strongest predictor—prevalence exceeds 90% in patients undergoing bariatric surgery. 1

Metabolic Risk Factors

Obesity and Body Composition

• Excessive BMI and visceral obesity are the most well-documented risk factors for NAFLD, with prevalence rates exceeding 90% in severely obese patients undergoing bariatric surgery 1
• Up to 5% of bariatric surgery patients may have unsuspected cirrhosis at the time of surgery 1
• Sarcopenia increases NAFLD risk approximately four-fold, independent of obesity or metabolic syndrome, and when combined with NAFLD, increases advanced fibrosis risk by 1.8 times 1

Diabetes and Insulin Resistance

• Type 2 diabetes mellitus carries a 60-75% prevalence of NAFLD 1, 2
• In one ultrasonographic study, 69% of diabetic patients had NAFLD, and among those with fatty infiltration who underwent biopsy, 87% had histologic confirmation 1
• Insulin resistance syndromes, including lipoatrophic diabetes, significantly increase NAFLD risk 1

Dyslipidemia

• High serum triglycerides and low HDL cholesterol are very common in NAFLD patients 1
• The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics is approximately 50% 1, 2

Metabolic Syndrome

• Metabolic syndrome confers a 50% prevalence of NAFLD 1, 2
• The presence of two or more metabolic risk factors (central obesity, hypertriglyceridemia, low HDL, hypertension, prediabetes) substantially increases risk 1

Demographic Risk Factors

Age

• NAFLD prevalence increases progressively with age 1
• Older patients with NAFLD have increased likelihood of disease progression to advanced fibrosis and higher mortality rates 1

Sex

• Male gender is an independent risk factor for fatty liver disease 1
• In a study of 26,527 subjects, NAFLD prevalence was 31% in men versus 16% in women 1

Ethnicity

• Hispanic individuals have significantly higher prevalence of NAFLD compared to non-Hispanic whites 1
• Non-Hispanic blacks have significantly lower prevalence compared to non-Hispanic whites 1
• American-Indian and Alaskan-Native populations show lower prevalence (0.6-2.2%), though this may be underestimated due to lack of histologic definition 1

Endocrine and Metabolic Disorders

Several endocrine conditions independently increase NAFLD risk beyond their association with obesity: 1

• Hypothyroidism increases NAFLD prevalence by 1.6 times 1
• Polycystic ovary syndrome increases incidence approximately 2.2 times 1
• Hypogonadism is an independent risk factor 1
• Hypopituitarism increases NAFLD risk 1
• Obstructive sleep apnea is associated with increased NAFLD prevalence 1

Lifestyle and Behavioral Factors

Physical Activity

• Decreased physical activity increases both prevalence and incidence of NAFLD 1
• Sedentary lifestyle contributes to disease development independent of other metabolic factors 1

Alcohol Consumption

• While NAFLD is defined by absence of harmful alcohol consumption, even low alcohol intake can double the risk for adverse liver-related outcomes in patients with existing NAFLD 3
• Alcohol synergistically worsens liver damage when combined with other metabolic risk factors 4, 5

Weight Loss History

• Severe rapid weight loss, especially in initially obese individuals, can precipitate NAFLD 1

Genetic Factors

Genetic polymorphisms play a major role in NAFLD susceptibility and progression: 1

• PNPLA3 (patatin-like phospholipase domain-containing 3) single nucleotide polymorphisms significantly affect disease development and progression 1
• TM6SF2 (transmembrane 6 superfamily member 2) variants influence disease severity 1
• In Korean populations, SAMM50 (sorting and assembly machinery component 50) is associated with NAFLD prevalence and severity 1

Medication-Induced Risk

Certain medications are associated with secondary hepatic steatosis and should be avoided when possible: 1, 3

• Corticosteroids 1, 3
• Amiodarone 1, 3
• Methotrexate 1, 3
• Tamoxifen 1, 3
• Valproate (causes microvesicular steatosis) 1

Other Associated Conditions

Additional conditions that increase NAFLD prevalence include: 1

• Pancreatoduodenal resection 1
• Psoriasis 1

Clinical Implications

When evaluating patients for NAFLD risk, prioritize screening in those with: 1

• Type 2 diabetes (regardless of other risk factors) 1
• Two or more metabolic risk factors 1
• Steatosis on any imaging modality or elevated aminotransferases 1
• Persistent unexplained elevation of serum alanine aminotransferase 1

Common pitfall: Failing to recognize that cardiovascular disease, not liver disease, is the leading cause of death in NAFLD patients before cirrhosis develops, making comprehensive cardiovascular risk assessment essential 3, 2