What is NASH (Nonalcoholic Steatohepatitis)?
NASH is a progressive form of fatty liver disease defined by the presence of ≥5% hepatic steatosis combined with inflammation and hepatocyte injury (ballooning), with or without fibrosis, occurring in individuals without significant alcohol consumption. 1
Histologic Definition and Diagnostic Criteria
NASH requires liver biopsy for definitive diagnosis and is characterized by three key histologic features 1:
- Macrovesicular steatosis (≥5% of hepatocytes containing fat)
- Hepatocyte ballooning (cellular injury with swelling)
- Lobular inflammation (mixed inflammatory infiltrate including neutrophils)
- Zone 3 perisinusoidal fibrosis may be present but is not required for diagnosis 1
Additional histologic features frequently seen but not required include Mallory-Denk bodies (damaged intermediate filament inclusions) and acidophil bodies (apoptotic hepatocytes) 1.
Distinction from Simple Fatty Liver
NASH differs critically from nonalcoholic fatty liver (NAFL) in both histology and prognosis 1:
- NAFL: ≥5% steatosis without hepatocyte ballooning or significant inflammation; minimal progression risk
- NASH: ≥5% steatosis WITH inflammation and ballooning; can progress to cirrhosis, liver failure, and hepatocellular carcinoma 1
The presence of hepatocyte ballooning is the key distinguishing feature that separates NASH from NAFL 1.
Clinical Significance and Natural History
NASH carries substantial morbidity and mortality risk 2:
- Affects 3-6% of the US population (approximately 20% of patients with NAFLD have NASH) 1, 2
- 20% of NASH patients will develop cirrhosis 2
- All-cause mortality rate: 25.56 per 1,000 person-years 2
- Liver-specific mortality rate: 11.77 per 1,000 person-years 2
- NASH is the third leading cause for liver transplant in the United States and predicted to become the leading indication 1, 2
Fibrosis Progression
Approximately 30-40% of NASH patients develop progressive fibrosis 1:
- Fibrosis progression rate from stage 0 to stage 1: 7 years for NASH versus 14 years for NAFL 1
- Advanced fibrosis (bridging fibrosis or cirrhosis) significantly increases risk of hepatic decompensation and hepatocellular carcinoma 1
- 2-3% of patients with NASH cirrhosis develop hepatocellular carcinoma annually 1
Associated Metabolic Conditions
NASH is strongly associated with metabolic dysfunction 1, 2:
- Obesity (most common association)
- Type 2 diabetes mellitus
- Dyslipidemia
- Metabolic syndrome
- Insulin resistance
These metabolic comorbidities are not merely associations but active drivers of disease progression 1.
Pathophysiologic Mechanisms
NASH develops through multiple parallel mechanisms 3, 4:
- Lipotoxicity: Accumulation of toxic lipid species beyond simple triglycerides
- Oxidative stress and ER stress: Drive hepatocellular injury 3, 5
- Hepatocyte apoptosis: Key contributor to liver injury 3
- Kupffer cell activation: Initiates and perpetuates inflammatory response 3
- Extrahepatic factors: Adipose tissue dysfunction, gut microbiome alterations, and gastrointestinal hormones contribute to disease progression 3, 4
Important Clinical Caveats
Alcohol consumption thresholds must be excluded for NASH diagnosis: <30 g/day for men and <20 g/day for women 6. Secondary causes of hepatic steatosis (steatogenic medications, hereditary disorders) must also be ruled out 1.
NASH can progress even from bland steatosis, particularly in the presence of metabolic risk factors, challenging the traditional view of NAFL and NASH as separate entities rather than a disease continuum 1.
Hepatocellular carcinoma can develop in NASH patients without cirrhosis, though the risk appears low and routine surveillance in non-cirrhotic NASH is not currently recommended 1.