343 Non-alcoholic Fatty Liver Diseases and Non-alcoholic

Steatohepatitis

 NAFLD Overview:

 Most common cause of chronic liver disease globally.

 Estimated global prevalence: 1 billion; US prevalence: 80-100 million.
 Strongly linked to insulin resistance, obesity, and metabolic syndrome.
 Can occur in lean individuals, especially those with lipodystrophy.
 Ethnic/racial differences in prevalence: lowest in African Americans, highest in
Hispanics.

 Disease Spectrum:

 Ranges from benign hepatic steatosis to cirrhosis and liver cancer.

 Risk of cirrhosis increases with progression to nonalcoholic steatohepatitis (NASH).
 NASH can lead to stable disease, fibrosis, or cirrhosis.

 Diagnostic Challenges:

 Imaging cannot distinguish NASH from simple steatosis.

 Serum ALT elevations may indicate liver injury, but not specific to NASH.
 Population-based studies estimate ~6-8% of US adults have cryptogenic ALT
elevations, likely due to NASH.

 Risk Factors and Genetics:

 Advanced fibrosis risk highest in NASH patients >45-50 years old, overweight/obese,
or with type 2 diabetes.
 Genetic variants (e.g., PNPLA3) strongly influence NAFLD severity and progression.
 Hereditary and epigenetic factors also impact susceptibility.

 Heritable Factors and Genetics:

 Genetic variants near TM6SF2, MBOAT7, and PNPLA3 increase NAFLD risk.
 PNPLA3 strongly influences hepatic fat accumulation, NASH severity, and fibrosis.
 Twin studies suggest inheritance contributes to about half of cirrhosis risk.
 Epigenetic factors, influenced by intrauterine exposures, also impact NAFLD
progression.
 Epigenetic alterations in obesity-related metabolic pathways may affect NASH
susceptibility.

 Clinical Implications:

 NAFLD is the leading cause of liver transplantation in the US.

 NAFLD-related cirrhosis elevates primary liver cancer risk, including hepatocellular
carcinoma and intrahepatic cholangiocarcinoma (ICC).
  NAFLD, NASH, and related cirrhosis affect both adults and children.
 Childhood obesity and insulin resistance contribute to rising pediatric NAFLD rates,
indicating future disease burden.

 Pathogenesis of NAFLD:
o Hepatic steatosis results from an imbalance between triglyceride synthesis and
disposal.
o Obesity exacerbates triglyceride accumulation through altered intestinal
microbiota, increased energy harvest, and insulin resistance.
o Insulin resistance leads to hyperinsulinemia, promoting lipid uptake and
synthesis.
o Triglyceride accumulation alone is not hepatotoxic, but its metabolic by-
products can damage hepatocytes (lipotoxicity).
o Lipotoxicity triggers inflammation and deregulates repair mechanisms, leading
to NASH.
o NASH severity varies based on the intensity and duration of lipotoxic liver
injury.
 Progression to Cirrhosis and Liver Cancer:
o Cirrhosis results from inefficient liver repair, leading to fibrous scarring.
o Liver cancer arises when transformed cells evade normal growth control
mechanisms.
o Mechanisms of cirrhosis and carcinogenesis are poorly understood due to the
complexity of liver regeneration.
 Clinical Implications:
o Heterogeneity in liver repair mechanisms complicates diagnosis and treatment.
o Current strategies focus on preventing and reducing lipotoxic liver injury to
mitigate disease progression.

DIAGNOSIS
 Diagnosis of NAFLD:

 Requires evidence of increased liver fat without hazardous alcohol consumption.

 Alcohol thresholds: >1 drink/day for women, >2 drinks/day for men (1 drink = 10g
ethanol).
 Exclusion of other causes of liver fat accumulation and injury (e.g., certain drugs,
viral hepatitis).

 Diagnostic Approach:

 Non-invasive methods include history, physical exam, liver imaging (ultrasound

preferred, CT or MRI for enhanced sensitivity), and blood tests.
 Liver may not be enlarged, and liver function tests can be normal in NAFLD.
 Diagnosis confidence increases with identification of NAFLD risk factors: obesity,
insulin resistance/type 2 diabetes, metabolic syndrome indicators,
pituitary/hypothalamic neoplasms, polycystic ovary syndrome, hypothyroidism,
obstructive sleep apnea.