What is NASH (Non-Alcoholic Steatohepatitis)?
NASH is a progressive form of fatty liver disease defined by the presence of ≥5% hepatic steatosis plus inflammation with hepatocyte injury (ballooning), with or without fibrosis, occurring in the absence of significant alcohol consumption. 1
Defining Characteristics
NASH represents the more severe end of the non-alcoholic fatty liver disease (NAFLD) spectrum and is distinguished from simple fatty liver (NAFL) by three key histologic features that can only be definitively diagnosed by liver biopsy 1:
- Macrovesicular steatosis (≥5% of hepatocytes affected) 1
- Hepatocyte ballooning (cellular injury and swelling) 1
- Mixed lobular inflammation (inflammatory cell infiltration) 1
- Zone-3 perisinusoidal fibrosis may or may not be present 1
The American Association for the Study of Liver Diseases emphasizes that hepatocyte ballooning is the critical distinguishing feature separating NASH from simple steatosis. 1
Clinical Significance and Natural History
NASH is clinically important because it can progress to cirrhosis, liver failure, and hepatocellular carcinoma, whereas simple fatty liver (NAFL) typically remains non-progressive. 1
Disease Progression Rates:
- Approximately 30-40% of NASH patients will develop fibrosis 1
- Fibrosis progression occurs faster in NASH (7 years from stage 0 to stage 1) compared to NAFL (14 years) 1
- Approximately 20% of NASH patients will progress to cirrhosis 2
- Patients with NASH cirrhosis develop hepatocellular carcinoma at a rate of 2-3% per year 1
A critical caveat: Recent paired biopsy studies challenge the traditional view that NAFL and NASH are separate entities, showing they exist on a continuum where even bland steatosis can progress to NASH, particularly with metabolic risk factors. 1
Epidemiology
NASH affects an estimated 3-12% of the US population, representing approximately 20% of all NAFLD patients. 1, 2
The global prevalence of NAFLD (the broader category) is approximately 25%, with the highest rates in the Middle East (31.79%) and South America (30.45%). 1
Associated Conditions and Risk Factors
NASH is strongly associated with metabolic dysfunction 1, 2:
- Obesity 1, 2
- Type 2 diabetes mellitus 1, 2
- Metabolic syndrome 1, 2
- Dyslipidemia 1, 2
- Hispanic ethnicity (associated with PNPLA3 I148M variant) 1
- Advanced age 1
Mortality and Morbidity Impact
NASH is associated with significantly increased mortality compared to the general population, with an annual all-cause mortality rate of 25.56 per 1,000 person-years and liver-specific mortality of 11.77 per 1,000 person-years. 2
Beyond liver-related complications, NASH patients face increased cardiovascular mortality, which is actually the leading cause of death in this population. 3 A histologic diagnosis of NASH is independently associated with cardiovascular disease. 1
NASH is currently the third leading cause of cirrhosis and the third most common indication for liver transplantation in the United States, and is predicted to become the leading indication. 1, 2
Diagnostic Requirements
The only accepted method for definitively diagnosing NASH is liver biopsy. 1, 2 While noninvasive tests and scoring systems exist to characterize NAFLD, they cannot reliably distinguish NASH from simple steatosis. 2
The diagnosis requires excluding secondary causes of hepatic fat accumulation 1:
- Significant alcohol consumption (>21 drinks/week in men, >14 drinks/week in women) 1
- Long-term steatogenic medications 1
- Monogenic hereditary disorders 1
Current Treatment Landscape
No FDA-approved pharmacologic therapies currently exist specifically for NASH. 4, 2 Lifestyle modification with weight loss remains the most effective treatment, with substantial histologic improvement (including fibrosis regression) directly correlated with degree of weight loss. 1, 3, 2
Vitamin E and pioglitazone have shown benefit in select patients with biopsy-proven NASH, though neither is FDA-approved for this indication. 1