What best describes the pathophysiology of NAFLD progression to NASH and fibrosis?

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Multiple Choice

What best describes the pathophysiology of NAFLD progression to NASH and fibrosis?

Insulin resistance is the trigger that leads to fat accumulation in the liver. When tissues don’t respond well to insulin, fat is released from adipose tissue in greater amounts and delivered to the liver, while insulin resistance also boosts new fat production in hepatocytes and impairs export of fat as VLDL. This creates hepatic steatosis. The presence of excess fatty acids and lipid intermediates causes lipotoxic stress—oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress—that activates inflammatory pathways. Kupffer cells and other immune cells release cytokines like TNF-α and IL-6, fueling inflammation and converting simple steatosis into steatohepatitis (NASH). The inflammatory environment then activates hepatic stellate cells, driving fibrogenesis and fibrosis. Over time, this fibrotic process can progress toward cirrhosis, but not all patients progress, and progression is a gradual process rather than immediate. Alcohol use and viral infections can cause liver inflammation, but they are not the primary drivers of NAFLD progression, and cirrhosis is not an inevitability for every patient.

Insulin resistance is the trigger that leads to fat accumulation in the liver. When tissues don’t respond well to insulin, fat is released from adipose tissue in greater amounts and delivered to the liver, while insulin resistance also boosts new fat production in hepatocytes and impairs export of fat as VLDL. This creates hepatic steatosis. The presence of excess fatty acids and lipid intermediates causes lipotoxic stress—oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress—that activates inflammatory pathways. Kupffer cells and other immune cells release cytokines like TNF-α and IL-6, fueling inflammation and converting simple steatosis into steatohepatitis (NASH). The inflammatory environment then activates hepatic stellate cells, driving fibrogenesis and fibrosis. Over time, this fibrotic process can progress toward cirrhosis, but not all patients progress, and progression is a gradual process rather than immediate. Alcohol use and viral infections can cause liver inflammation, but they are not the primary drivers of NAFLD progression, and cirrhosis is not an inevitability for every patient.

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