What is non‑alcoholic steatohepatitis (NASH)?

What is NASH (Nonalcoholic Steatohepatitis)?

NASH is the presence of ≥5% hepatic steatosis with inflammation and hepatocyte injury (ballooning), with or without fibrosis, occurring in the absence of significant alcohol consumption. 1

Core Diagnostic Criteria

NASH represents the inflammatory and progressive form of nonalcoholic fatty liver disease (NAFLD) and is distinguished from simple fatty liver by three key histological features 1:

• Hepatic steatosis affecting ≥5% of hepatocytes 1
• Hepatocyte injury manifested as ballooning degeneration 1
• Lobular inflammation with mixed inflammatory infiltrate 1
• Fibrosis may be present at any stage but is not required for diagnosis 1

Critical Distinction from Simple Fatty Liver

The distinction between NASH and nonalcoholic fatty liver (NAFL) is clinically crucial because their prognoses differ dramatically 1:

• NAFL shows ≥5% steatosis WITHOUT hepatocellular injury or ballooning, carries minimal risk of progression to cirrhosis 1
• NASH includes inflammation and hepatocyte injury, can progress to cirrhosis (20% of cases), liver failure, and hepatocellular carcinoma 1, 2

Epidemiology and Population Impact

NASH affects 3-6% of the US population, with prevalence increasing substantially over the past decade 2, 3:

• Annual prevalence increased from 1.51% in 2010 to 2.79% in 2020 3
• NASH has become the third most common cause of hepatocellular carcinoma in the United States 4
• NASH is now the second most common indication for liver transplantation 4, 2

Metabolic Associations

NASH is strongly associated with metabolic dysfunction 1, 2:

• Obesity is present in 70-90% of NASH patients and represents the strongest risk factor 5, 2
• Type 2 diabetes occurs in 60-75% of NAFLD patients, with diabetes conferring an OR of 18.61 for NASH 4, 3
• Dyslipidemia is present in approximately 50% of patients 4
• Metabolic syndrome is present in approximately 50% of NAFLD patients 4

Mortality and Clinical Outcomes

Cardiovascular disease remains the most common cause of death in NASH patients, but liver-related mortality is substantially elevated compared to simple steatosis 1, 4:

• All-cause mortality rate: 25.56 per 1,000 person-years 2
• Liver-specific mortality rate: 11.77 per 1,000 person-years 2
• Approximately 20% of NASH patients develop cirrhosis 2
• The degree of liver fibrosis is the strongest predictor of mortality 4

Diagnostic Approach

Liver biopsy remains the only accepted method for definitive NASH diagnosis, as noninvasive tests cannot reliably distinguish NASH from simple steatosis 2, 6:

• Imaging (ultrasound, CT, MRI) can detect steatosis but cannot diagnose inflammation or ballooning 5, 6
• Aminotransferases are typically elevated 2-4 fold, with AST:ALT ratio typically <1 (distinguishing from alcoholic liver disease) 5, 7
• Critical pitfall: Aminotransferases can be normal in NASH, and clinically significant fibrosis frequently occurs with aminotransferases below 40 units/L 8

Histological Scoring

The NAFLD Activity Score (NAS) is used in clinical trials to measure histological changes 1, 8:

• NAS is an unweighted composite of steatosis, lobular inflammation, and ballooning scores 1, 8
• Fibrosis is scored separately from 0 (no fibrosis) to 4 (cirrhosis) 8
• "At-risk NASH" is defined as NAS ≥4 with fibrosis stage ≥2 6

Essential Exclusion Criteria

To diagnose NASH, secondary causes of hepatic steatosis must be excluded 1:

• No significant alcohol consumption (by definition) 1
• Exclude steatogenic medications (amiodarone, methotrexate, tamoxifen, corticosteroids) 5
• Exclude viral hepatitis (particularly HCV genotype 3) 5
• Exclude hereditary disorders (Wilson disease, hemochromatosis, alpha-1 antitrypsin deficiency) 5