From the Guidelines
NASH develops through a complex pathophysiological process involving insulin resistance, lipotoxicity, oxidative stress, and inflammation, ultimately leading to liver damage and potentially cirrhosis or liver failure. The primary driver of this process is insulin resistance, which increases lipolysis in adipose tissue and leads to elevated free fatty acid delivery to the liver, promoting de novo lipogenesis and impairing fatty acid oxidation, causing lipid accumulation within hepatocytes 1. The accumulated fat becomes toxic through lipotoxicity, triggering oxidative stress when mitochondria produce reactive oxygen species while processing excess fatty acids, activating inflammatory pathways with Kupffer cells releasing pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β 1.
Key factors contributing to the development and progression of NASH include:
- Insulin resistance and metabolic syndrome
- Genetic factors, such as the PNPLA3 gene variant
- Gut dysbiosis and increased intestinal permeability
- Activation of hepatic stellate cells leading to fibrosis
- Presence of comorbidities like type 2 diabetes, which is a major risk factor for developing NASH and disease progression 1.
Recent studies have estimated that NAFLD is prevalent in over 70% of people with type 2 diabetes, with steatohepatitis affecting more than half of these individuals, and a significant proportion having clinically significant fibrosis 1. The lipotoxicity model of NASH identifies free fatty acid metabolites as the primary driver of cellular injury and death, leading to hepatocyte apoptosis, necrosis, and inflammation 1. Understanding the complex interplay between these factors is crucial for the diagnosis, management, and prevention of NASH, particularly in high-risk populations like those with type 2 diabetes.
From the Research
Pathophysiology of NASH
The pathophysiology of Non-Alcoholic Steatohepatitis (NASH) is a complex process involving multiple factors, including:
- Hepatic steatosis, which is the initial presentation of NASH, caused by dysfunction of lipid metabolism within hepatocytes due to genetic factors, diet, and insulin resistance 2
- Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, which contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver 2, 3
- The gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS), which may be dysregulated and impaired during the development of NASH and liver fibrosis 2
- Translocation of bacteria or its end-products entering the liver, which can activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis 2
Key Factors Contributing to NASH
Some key factors that contribute to the development of NASH include:
- Insulin resistance and type 2 diabetes, which can lead to liver injury via insulin resistance and an excess of free fatty acids in hepatocytes 4
- Sedentary lifestyle and modern Western nutrition, which can lead to liver injury via insulin resistance and an excess of free fatty acids in hepatocytes 4
- Genetic predispositions, which can affect lipid metabolism and contribute to the development of NASH 2, 3
- Adipokines and cytokines, which can play a role in inflammation and fibrogenesis in NASH 4
Disease Progression
NASH can progress to fibrosis, which can lead to cirrhosis and liver failure, and even hepatocellular carcinoma 5, 6. The disease progression is influenced by various factors, including the degree of hepatic steatosis, inflammation, and fibrosis, as well as the presence of other metabolic disorders such as obesity and diabetes.